Prem Puri: Editor

Prem Puri
Editor
Pediatric
Surgery
General Principles and
Newborn Surgery
Pediatric Surgery
Prem Puri
Editor
Pediatric Surgery
General Principles and Newborn
Surgery
With 487 Figures and 114 Tables

Editor
Prem Puri
Department of Pediatric Surgery
Beacon Hospital
Dublin, Ireland
School of Medicine and Medical Science and
Conway Institute of Biomedical Research
University College Dublin
Dublin, Ireland
ISBN 978-3-662-43587-8 ISBN 978-3-662-43588-5 (eBook)

ISBN 978-3-662-43589-2 (print and electronic bundle)
https://doi.org/10.1007/978-3-662-43588-5
© Springer-Verlag GmbH Germany, part of Springer Nature 2020
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or
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The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt
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The publisher, the authors, and the editors are safe to assume that the advice and information in this
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authors or the editors give a warranty, expressed or implied, with respect to the material contained
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regard to jurisdictional claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer-Verlag GmbH, DE, part of
Springer Nature.
The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany
To my brother, Kailash, for his love, support, and inspiration
throughout my life and career.
Preface
During the past two decades, major advances in prenatal diagnosis, imaging,
anesthesia, and intensive care, as well as the introduction of new surgical
techniques including minimally invasive surgery and robotic technology, have
radically altered the management of newborns, infants, and children with
surgical conditions. In recent years, important basic science advances in the
fields of regenerative medicine and tissue engineering, pharmacotherapy,
genetics, immunology, embryology, and developmental biology offer hope
of the translation of basic science discoveries to new clinical therapies for
children in the future.
Pediatric Surgery provides an authoritative, comprehensive, and up-to-date
international reference on the surgical management of both common and rare
diseases in infants and children, written by the world’s foremost experts. The
vast amount of information included in Pediatric Surgery is divided into three
volumes, to be published separately: General Principles and Newborn Sur-
gery; General Pediatric Surgery, Tumors, Trauma and Transplantation; and
Pediatric Urology. There are three different publication formats of the refer-
ence works: (1) printed book, (2) a static e-version on SpringerLink that
mirrors the printed book, and (3) a living reference also on SpringerLink that
is constantly updateable, allowing the reader to rapidly find up-to-date infor-
mation on a specific topic. Each chapter is organized in the form of a well-
defined and structured review of the topic that allows readers to search and find
information easily.
General Principles and Newborn Surgery has 85 chapters focusing on
general principles and newborn surgery. The first 38 chapters are devoted to
general principles including important topics such as fetal counseling for
congenital malformations, surgical safety in children, innovations in mini-
mally invasive surgery, fast-track pediatric surgery, ethical considerations in
pediatric surgery, childhood obesity, surgical problems of children with phys-
ical disabilities, clinical research and evidence-based pediatric surgery, tissue
engineering and stem cell research, patient- and family-oriented pediatric
surgical care, and surgical implications of human immunodeficiency virus
infection in children. The remaining 47 chapters in General Principles and
Newborn Surgery are devoted to the management of congenital malformations
in the newborn, each chapter providing a step-by-step detailed practical guide
on the operative approach including high-quality color illustrations to clarify
and simplify various operative techniques.
vii
viii Preface
My hope is that Pediatric Surgery will act as a reference book for the
management of childhood surgical disorders, providing information and guid-
ance to pediatric surgeons, pediatric urologists, neonatologists, pediatricians,
and all those seeking more detailed information on surgical conditions in
infants and children.
I wish to thank most sincerely all the contributors from around the world for
their outstanding work in the preparation of this innovative international
reference book on the management of surgical conditions in infants and
children. I also wish to express my gratitude to Dr. Julia Zimmer, Dr. Hiroki
Nakamura, and Dr. Anne Marie O’Donnell for their help in the preparation of
this book. I wish to thank the editorial staff of Springer, particularly
Ms. Audrey Wong-Hillmann and Ms. Nivedita Baroi, for all their help during
the preparation, production, and publication of this important reference book.
Dublin, Ireland Prem Puri

January 2020
Contents
Volume 1
Part I General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1 Embryology of Congenital Malformations .............. 3

Dietrich Kluth and Roman Metzger
2 The Epidemiology of Birth Defects . . . . . . . . . . . . . . . . . . . . . 35
Edwin C. Jesudason
3 Prenatal Diagnosis of Congenital Malformations . . . . . . . . . 49
Tippi C. MacKenzie and N. Scott Adzick
4 Fetal Counseling for Congenital Malformations . . . . . . . . . . 65
Kokila Lakhoo
5 Anatomy of the Infant and Child . . . . . . . . . . . . . . . . . . . . . . 83
Mark D. Stringer
6 Perinatal Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Carlos E. Blanco and Eduardo Villamor
7 Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Aliza M. Olive, Aimee G. Kim, and Alan W. Flake
8 Specific Risks for the Preterm Infant . . . . . . . . . . . . . . . . . . . 137
Emily A. Kieran and Colm P. F. O’Donnell
9 Pediatric Clinical Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Andrew J. Green and James J. O’Byrne
10 Transport of Sick Infants and Children . . . . . . . . . . . . . . . . . 167
Julia Zimmer and Prem Puri
11 Pediatric Respiratory Physiology . . . . . . . . . . . . . . . . . . . . . . 181
Bettina Bohnhorst and Corinna Peter
12 Pediatric Cardiovascular Physiology . . . . . . . . . . . . . . . . . . . 201
Albert P. Rocchini and Aaron G. DeWitt
13 Pediatric Hepatic Physiology . . . . . . . . . . . . . . . . . . . . . . . . . 219
Mark Davenport and Nedim Hadzic
ix
x Contents
14 Metabolism of Infants and Children . . . . . . . . . . . . . . . . . . . 231

Faraz A. Khan, Jeremy G. Fisher, Eric A. Sparks, and
Tom Jaksic
15 Fluid and Electrolyte Balance in Infants and Children . . . . . 245
Joseph Chukwu and Eleanor J. Molloy
16 Vascular Access in Infants and Children . . . . . . . . . . . . . . . . 263
Hiroki Nakamura, Rieko Nakamura, and
Thambipillai Sri Paran
17 Nutrition in Infants and Children . . . . . . . . . . . . . . . . . . . . . . 273
Agostino Pierro and Simon Eaton
18 Access for Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Julia Zimmer and Michael W. L. Gauderer
19 Tracheostomy in Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
Martin Lacher, Jan-Hendrik Gosemann, and
Oliver J. Muensterer
20 Pediatric Airway Assessment . . . . . . . . . . . . . . . . . . . . . . . . . 329
Eimear Phelan and John Russell
21 Stomas of Small and Large Intestine . . . . . . . . . . . . . . . . . . . 339
Andrea Bischoff and Alberto Peña
22 Preoperative Assessments in Pediatric Surgery . . . . . . . . . . . 351
Linda Stephens and John Gillick
23 Principles of Pediatric Surgical Imaging . . . . . . . . . . . . . . . . 375
David Rea, Clare Brenner, and Terence Montague
24 Hematological Problems in Pediatric Surgery . . . . . . . . . . . . 387
Ciara O’Rafferty and Owen Patrick Smith
25 Surgical Safety in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
George G. Youngson and Craig McIlhenny
26 Anesthesia and Pain Management . . . . . . . . . . . . . . . . . . . . . 427
Aidan Magee and Suzanne Crowe
27 Immunology and Immunodeficiencies in Children . . . . . . . . 443
Saima Aslam, Fiona O’Hare, Hassan Eliwan, and
Eleanor J. Molloy
28 Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Scott S. Short, Stephanie C. Papillon, and Henri R. Ford
29 Principles of Minimally Invasive Surgery in Children . . . . . 477
Steven Rothenberg and Samiksha Bansal
30 Innovations in Minimally Invasive Surgery in Children . . . . 487
Todd A. Ponsky and Gavin A. Falk
Contents xi
31 Fast-Track Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . 505

M. Reismann and Benno Ure
32 Ethical Considerations in Pediatric Surgery . . . . . . . . . . . . . 513
Jacqueline J. Glover and Benedict C. Nwomeh
33 Childhood Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 529
Regien Biesma and Mark Hanson
34 Surgical Problems of Children with Physical Disabilities . . . 541
Casey M. Calkins and Keith T. Oldham
35 Clinical Research and Evidence-Based Pediatric
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Dennis K. M. Ip, Kenneth K. Y. Wong, and
Paul Kwong Hang Tam
36 Tissue Engineering and Stem Cell Research . . . . . . . . . . . . . 577
Paolo De Coppi
37 Patient- and Family-Oriented Pediatric Surgical Care . . . . . 593
Katelynn C. Bachman, Ronald C. Oliver, and Mary E. Fallat
38 Surgical Implications of Human Immunodeficiency
Virus Infection in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . 603
Alastair J. W. Millar, Jonathan Karpelowsky, and Sharon Cox
Part II Newborn Surgery: Head and Neck . . . . . . . . . . . . . . . . . . . 615
39 Choanal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

40 Macroglossia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Abdulrahman Alshafei and Thambipillai Sri Paran
41 Pierre Robin Sequence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631
Udo Rolle, Aranka Ifert, and Robert Sader
42 Lymphatic Malformations in Children . . . . . . . . . . . . . . . . . 641
James Wall, Karl Sylvester, and Craig Albanese
43 Stridor in the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
Sam J. Daniel
Volume 2
Part III Newborn Surgery: Esophagus . . . . . . . . . . . . . . . . . . . . . . . 659
44 Esophageal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

Michael E. Höllwarth and Holger Till
45 Congenital Esophageal Stenosis . . . . . . . . . . . . . . . . . . . . . . . 681
Masaki Nio, Shintaro Amae, and Motoshi Wada
xii Contents
46 Esophageal Duplication Cyst . . . . . . . . . . . . . . . . . . . . . . . . . 691

Dakshesh Parikh and Melissa Short
47 Esophageal Perforation in the Newborn . . . . . . . . . . . . . . . . 705
David S. Foley
Part IV Newborn Surgery: Chest . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
48 Congenital Airway Malformations . . . . . . . . . . . . . . . . . . . . . 715

Richard G. Azizkhan
49 Vascular Rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
Benjamin O. Bierbach and John Mark Redmond
50 Pulmonary Air Leaks of the Neonate . . . . . . . . . . . . . . . . . . . 751
Prem Puri and Jens Dingemann
51 Chylothorax and Other Pleural Effusions in Neonates . . . . . 761
Richard G. Azizkhan
52 Congenital Malformations of the Lung . . . . . . . . . . . . . . . . . 775
Keith T. Oldham and Kathleen M. Dominguez
53 Congenital Diaphragmatic Hernia . . . . . . . . . . . . . . . . . . . . . 797
54 Extracorporeal Membrane Oxygenation for Neonatal
Respiratory Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 817
Jason S. Frischer, Charles J. H. Stolar, and Ronald B. Hirschl
Part V Newborn Surgery: Gastrointestinal . . . . . . . . . . . . . . . . . . 827
55 Pyloric Atresia and Prepyloric Antral Diaphragm . . . . . . . . 829

Girolamo Mattioli and Sara Costanzo
56 Infantile Hypertrophic Pyloric Stenosis . . . . . . . . . . . . . . . . . 841
Takao Fujimoto
57 Gastric Volvulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
Alan E. Mortell and David Coyle
58 Gastric Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
Adam C. Alder and Robert K. Minkes
59 Duodenal Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
Yechiel Sweed and Alon Yulevich
60 Malrotation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 897
Augusto Zani and Agostino Pierro
61 Congenital Hyperinsulinism . . . . . . . . . . . . . . . . . . . . . . . . . . 905
Contents xiii
62 Jejunoileal Atresia and Stenosis . . . . . . . . . . . . . . . . . . . . . . . 913

Alastair J. W. Millar, Alp Numanoglu, and Sharon Cox
63 Colonic and Rectal Atresias . . . . . . . . . . . . . . . . . . . . . . . . . . 925
Tomas Wester
64 Duplications of the Alimentary Tract . . . . . . . . . . . . . . . . . . . 935
Mark D. Stringer
65 Mesenteric and Omental Cysts . . . . . . . . . . . . . . . . . . . . . . . . 955
Suzanne Victoria McMahon, Dermot Thomas McDowell, and
Brian Sweeney
66 Necrotizing Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 963
Stephanie C. Papillon, Scott S. Short, and Henri R. Ford
67 Meconium Ileus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
Pietro Bagolan, Francesco Morini, and Andrea Conforti
68 Meconium Peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
Jose L. Peiró and Emrah Aydin
69 Neonatal Ascites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Elke Zani-Ruttenstock and Augusto Zani
70 Hirschsprung’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
Prem Puri, Christian Tomuschat, and Hiroki Nakamura
71 Hirschsprung-Associated Enterocolitis . . . . . . . . . . . . . . . . . 1031
Farokh R. Demehri, Ihab F. Halaweish, Arnold G. Coran, and
Daniel H. Teitelbaum
72 Variants of Hirschsprung Disease . . . . . . . . . . . . . . . . . . . . . . 1045
Prem Puri, Jan-Hendrik Gosemann, and Hiroki Nakamura
73 Anorectal Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1059
Andrea Bischoff, Belinda Hsi Dickie, Marc A. Levitt, and
Alberto Peña
74 Congenital Pouch Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Amulya K. Saxena and Praveen Mathur
75 Congenital Segmental Dilatation of the Intestine . . . . . . . . . 1099
Yoshiaki Takahashi, Yoshinori Hamada, and Tomoaki Taguchi
76 Short Bowel Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1107
Michael E. Höllwarth
Part VI Newborn Surgery: Liver and Biliary Tract . . . . . . . . . . . . 1125
77 Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127

Mark Davenport and Amy Hughes-Thomas
xiv Contents
78 Congenital Biliary Dilatation . . . . . . . . . . . . . . . . . . . . . . . . . 1145

Atsuyuki Yamataka, Geoffrey J. Lane, and Joel Cazares
Part VII Newborn Surgery: Anterior Abdominal Wall Defects . . . 1165
79 Omphalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1167
Jacob C. Langer
80 Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1177
Marshall Z. Schwartz and Shaheen J. Timmapuri
81 Omphalomesenteric Duct Remnants . . . . . . . . . . . . . . . . . . . 1189
Kenneth K. Y. Wong and Paul Kwong Hang Tam
82 Conjoined Twins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1197
Juan A. Tovar
Part VIII Newborn Surgery: Spina Bifida and Hydrocephalus . . . 1211
83 Spina Bifida and Encephalocele . . . . . . . . . . . . . . . . . . . . . . . 1213

Jonathan R. Ellenbogen, Michael D. Jenkinson, and
Conor L. Mallucci
84 Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1237
Jonathan R. Ellenbogen, J. Kandasamy, and Conor L. Mallucci
Part IX Newborn Surgery: Long-Term Outcomes in Newborn

Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1257
85 Long-Term Outcomes in Newborn Surgery . . . . . . . . . . . . . . 1259

Risto J. Rintala, Mikko P. Pakarinen, and Antti Koivusalo
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1291
About the Editor
Prem Puri is the Newman Clinical Research

Professor at the University College Dublin School
of Medicine and Medical Science and Consultant
Paediatric Surgeon and Director of Surgical
Research at the Beacon Hospital. He is currently
the President of the World Federation of Associa-
tions of Pediatric Surgeons (WOFAPS) Founda-
tion and Secretary of the International Board of
Pediatric Surgical Research. He is Past President
of the World Federation of Associations of Pedi-
atric Surgeons (WOFAPS) and of the European
Paediatric Surgeons’ Association (EUPSA). He is
Editor-in-Chief of Paediatric Surgery Interna-
tional and also on the Editorial Board of several
other journals. He was the Director of Research
(1989–2009) and President (2009–2016) of the
National Children’s Research Centre, Our Lady’s
Children’s Hospital, Dublin.
He has been awarded many Honorary Fellow-
ships, including the American Surgical Associa-
tion (ASA), American Academy of Pediatrics,
American Pediatric Surgical Association, Cana-
dian Association of Paediatric Surgeons, Japanese
Society of Pediatric Surgeons, and also Argentin-
ean, Austrian, Canadian, Czech, Croatian, Cuban,
Indian, South African, and Ukrainian pediatric
surgical associations.
xv
xvi About the Editor
Professor Puri is known internationally for his

research into underlying mechanisms causing
birth defects, and innovative treatments, which
have benefited children all over the world. He is
a multi-award-winning researcher whose previous
awards include People of the Year Award
(Highest Irish National Award), the prestigious
Denis Browne Gold Medal by the British Associ-
ation of Paediatric Surgeons, and Rehbein Medal
by the European Paediatric Surgeons’ Association
for outstanding contribution to pediatric surgery.
He has been a Visiting Professor to many leading
universities all over the world and invited speaker
at over 250 international scientific meetings. He
has published 10 books, 147 chapters in text-
books, and over 700 articles in peer-reviewed
journals. He is the Editor of Newborn Surgery,
regarded as the authoritative book in the field,
and the fourth edition is now published, and also
of the widely acclaimed Pediatric Surgery (Atlas
Series), which is in its second edition. His
research has been cited over 20,000 times in
peer-reviewed articles.
Contributors
Craig Albanese New York Presbyterian Hospital, New York, NY, USA
Adam C. Alder Division of Pediatric Surgery, Children’s Medical Center -
Plano, Center for Pectus and Chest Wall Anomalies, Division of Pediatric
Surgery, Children’s Health, Department of Surgery, UTSW, Dallas, TX, USA
Abdulrahman Alshafei Paediatric Surgery, Our Lady’s Children’s Hospital,
Crumlin, Dublin, Ireland
Shintaro Amae Department of Surgery, Miyagi Children’s Hospital, Sendai,
Japan
Saima Aslam Discipline of Paediatrics, Trinity College, The University of
Dublin, Dublin, Ireland
Tallaght Hospital and Coombe Women’s and Infants University Hospital,
Dublin, Ireland
Emrah Aydin The Center for Fetal, Cellular and Molecular Therapy, Pedi-
atric General and Thoracic Surgery Division, Cincinnati Children’s Hospital
Medical Center (CCHMC), Cincinnati, OH, USA
Richard G. Azizkhan Children’s Hospital and Medical Center, University of
Nebraska College of Medicine, Omaha, NE, USA
Katelynn C. Bachman University of Louisville School of Medicine, Louis-
ville, KY, USA
Pietro Bagolan Neonatal Surgery Unit, Department of Medical and Surgical
Neonatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Samiksha Bansal Department of Pediatric Surgery, Rocky Mountain Hospi-
tal for Children at Presbyterian/St. Luke’s, Denver, CO, USA
Benjamin O. Bierbach Department of Paediatric Cardiac Surgery, German
Paediatric Heart Center Sankt Augustin, Sankt Augustin, Germany
Regien Biesma Department of Epidemiology and Public Health Medicine,
Royal College of Surgeons in Ireland, Dublin, Ireland
Andrea Bischoff Division of Pediatric Surgery, International Center for
Colorectal and Urogenital Care, Children’s Hospital Colorado, Aurora, CO,
USA
xvii
xviii Contributors
Carlos E. Blanco Department of Neonatology, National Maternity Hospital,

Dublin, Ireland
Bettina Bohnhorst Department of Pediatric Pulmonology, Allergology and
Neonatology, Hannover Medical School, Hannover, Germany
Clare Brenner Department of Radiology, Our Lady’s Children’s Hospital,
Dublin, Ireland
Casey M. Calkins Division of Pediatric Surgery, Medical College of Wis-
consin, The Children’s Hospital of Wisconsin, Milwaukee, WI, USA
Joel Cazares Department of Pediatric General and Urogenital Surgery,
Juntendo University School of Medicine, Tokyo, Japan
Department of Pediatric Surgery, Hospital Regional de Alta Especialidad
Materno Infantil, Monterrey, Mexico
Joseph Chukwu Clinical Research Unit, National Children’s Research Cen-
tre, Our Lady’s Children’s Hospital, Dublin, Ireland
Andrea Conforti Neonatal Surgery Unit, Department of Medical and Surgi-
cal Neonatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Arnold G. Coran Section of Pediatric Surgery, C.S. Mott Children’s Hospi-
tal and the University of Michigan School of Medicine, Ann Arbor, MI, USA
Sara Costanzo Department of Paediatric Surgery, University of Genoa,
Genoa, Italy
Paediatric Surgery Unit, “V. Buzzi” Children’s Hospital, Milan, Italy
Sharon Cox Division of Paediatric Surgery, Faculty of Health Sciences,
University of Cape Town, Red Cross War Memorial Children’s Hospital,
Cape Town, South Africa
David Coyle Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
Suzanne Crowe Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
Sam J. Daniel Department of Pediatric Surgery, Montreal Children’s Hospi-
tal, McGill University, Montreal, QC, Canada
Mark Davenport Department of Paediatric Surgery, Kings College Hospital
NHS Foundation Trust, London, UK
Paolo De Coppi Great Ormond Street Hospital and UCL Institute of Child
Health, London, UK
Farokh R. Demehri Section of Pediatric Surgery, C.S. Mott Children’s
Hospital and the University of Michigan School of Medicine, Ann Arbor,
MI, USA
Aaron G. DeWitt Department of Pediatric and Communicable Diseases,
C.S. Mott Children’s Hospital, Congenital Heart Center, University of
Michigan, Ann Arbor, MI, USA
Contributors xix
Belinda Hsi Dickie Colorectal and Complex Pelvic Malformation Center,

Department of Surgery, Boston Children’s Hospital, Boston, MA, USA
Jens Dingemann Centre of Pediatric Surgery Hannover, Hannover Medical
School and Bult Children’s Hospital, Hannover, Germany
Kathleen M. Dominguez Pediatric Surgery, Marshfield Clinic, Marshfield,
WI, USA
Simon Eaton Department of Paediatric Surgery, UCL Institute of Child
Health and Great Ormond Street Hospital for Children NHS Trust, London,
UK
Hassan Eliwan Discipline of Paediatrics, Trinity College, The University of
Dublin, Ireland
Jonathan R. Ellenbogen Department of Neurosurgery, Alder Hey Chil-
dren’s NHS Foundation Trust, Liverpool, UK
Department of Neurosurgery, The Walton Centre NHS Foundation Trust,
Liverpool, UK
Gavin A. Falk Division of Pediatric Surgery, Miami Children’s Hospital,
Miami, FL, USA
Mary E. Fallat University of Louisville School of Medicine, Louisville, KY,
USA
Hiram C. Polk, Jr. Department of Surgery, Division of Pediatric Surgery,
University of Louisville School of Medicine, Louisville, KY, USA
Norton Healthcare, Norton Children’s Hospital, Louisville, KY, USA
Jeremy G. Fisher Center for Advanced Intestinal Rehabilitation, Depart-
ment of Surgery, Boston Children’s Hospital and Harvard Medical School,
Boston, MA, USA
Alan W. Flake Center for Fetal Diagnosis and Therapy, Children’s Hospital
of Philadelphia, Philadelphia, PA, USA
David S. Foley Department of Surgery, University of Louisville School of
Medicine, Louisville, KY, USA
Henri R. Ford Division of Pediatric Surgery, Children’s Hospital Los
Angeles, Los Angeles, CA, USA
Jason S. Frischer Colorectal Center, ECMO Program, Division of Pediatric
General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH, USA
Takao Fujimoto Department of Paediatric Surgery, Imperial Gift Founda-
tion, Aiiku Maternal and Children’s Medical Center, Tokyo, Japan
Michael W. L. Gauderer University of South Carolina School of Medicine
Greenville, Greenville, SC, USA
xx Contributors
John Gillick Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland

Children’s University Hospital, Dublin, Ireland
Jacqueline J. Glover Department of Pediatrics and Center for Bioethics and
Humanities, University of Colorado Anschutz Medical Campus and The
Children’s Hospital Colorado, Aurora, CO, USA
Jan-Hendrik Gosemann Department of Pediatric Surgery, University of
Leipzig, Leipzig, Germany
Andrew J. Green Department of Clinical Genetics, Our Lady’s Hospital,
School of Medicine and Medical Science, University College Dublin, Belfield,
Dublin, Ireland
Nedim Hadzic Paediatric Liver Centre, Kings College Hospital, London, UK
Ihab F. Halaweish Section of Pediatric Surgery, C.S. Mott Children’s Hos-
pital and the University of Michigan School of Medicine, Ann Arbor, MI,
USA
Yoshinori Hamada Department of Surgery, Kansai Medical University,
Osaka, Japan
Mark Hanson Institute of Developmental Sciences, Faculty of Medicine,
University of Southampton, Southampton, UK
Ronald B. Hirschl Section of Pediatric Surgery, C.S. Mott Children’s Hos-
pital, University of Michigan, Ann Arbor, MI, USA
Michael E. Höllwarth Department of Paediatric and Adolescent Surgery,
Medical University of Graz, Graz, Austria
Amy Hughes-Thomas Department of Paediatric Surgery, Kings College
Hospital, London, UK
Aranka Ifert Carolinum, Institute of Dentistry, Frankfurt, Germany
Dennis K. M. Ip School of Public Health, The University of Hong Kong,
Hong Kong, China
Tom Jaksic Center for Advanced Intestinal Rehabilitation, Department of
Surgery, Boston Children’s Hospital and Harvard Medical School, Boston,
MA, USA
Michael D. Jenkinson Department of Neurosurgery, The Walton Centre
NHS Foundation Trust, Liverpool, UK
Edwin C. Jesudason NHS Lothian, Edinburgh, UK
J. Kandasamy Department of Neurosurgery, Western General Hospital,
Edinburgh, UK
Jonathan Karpelowsky Paediatric Oncology and Thoracic Surgery, Chil-
dren’s Hospital at Westmead Children’s cancer research Unit, University of
Sydney, Sydney, Australia
Contributors xxi
Faraz A. Khan Center for Advanced Intestinal Rehabilitation, Department

of Surgery, Boston Children’s Hospital and Harvard Medical School, Boston,
MA, USA
Emily A. Kieran Department of Neonatology, The National Maternity Hos-
pital, Dublin, Ireland
National Children’s Research Centre, Dublin, Ireland
School of Medicine and Medical Science, University College Dublin, Dublin,
Ireland
Aimee G. Kim Center for Fetal Diagnosis and Therapy, Children’s Hospital
Dietrich Kluth Department of Pediatric Surgery, University Hospital, Uni-
versity of Leipzig, Leipzig, Germany
Antti Koivusalo Department of Pediatric Surgery, Children’s Hospital, Hel-
sinki University Central Hospital, University of Helsinki, Helsinki, Finland
Martin Lacher Department of Pediatric Surgery, University of Leipzig,
Leipzig, Germany
Kokila Lakhoo Paediatric Surgery, Children’s Hospital Oxford, Oxford Uni-
versity Hospitals, University of Oxford, Oxford, UK
Geoffrey J. Lane Department of Pediatric General and Urogenital Surgery,
Jacob C. Langer Division of General and Thoracic Surgery, Hospital for
Sick Children, University of Toronto, Toronto, ON, Canada
Marc A. Levitt Center for Colorectal and Pelvic Reconstruction, Nationwide
Children’s Hospital, Columbus, OH, USA
Tippi C. MacKenzie Eli and Edythe Broad Center for Regeneration Medi-
cine, Fetal Treatment Center, University of California, San Francisco, CA,
USA
Aidan Magee Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
Conor L. Mallucci Department of Neurosurgery, Alder Hey Children’s NHS
Foundation Trust, Liverpool, UK
Praveen Mathur Department of Pediatric Surgery, SMS Medical College,
Jaipur, Rajasthan, India
Girolamo Mattioli Department of Paediatric Surgery, Giannina Gaslini
Research Institute and University of Genoa, Genoa, Italy
Dermot Thomas McDowell Department of Paediatric Surgery, Our Lady’s
Children’s Hospital, Crumlin, Dublin, Ireland
Craig McIlhenny Forth Valley Royal Hospital, Larbert, Scotland, UK
Suzanne Victoria McMahon Department of Paediatric Surgery, Our Lady’s
xxii Contributors
Roman Metzger Department of Paediatric and Adolescent Surgery, Paracel-

sus Medical University Salzburg, Salzburg, Austria
Alastair J. W. Millar Emeritus Professor of Paediatric Surgery, Faculty of
Health Sciences, Department of Paediatric Surgery, University of Cape Town,
Red Cross War Memorial Children’s Hospital, Cape Town, Rondebosch,
South Africa
Robert K. Minkes Division of Pediatric Surgery, Golisano Children’s Hos-
pital Lee Health, Fort Myers, FL, USA
Eleanor J. Molloy Department of Neonatology, Paediatrics, National Mater-
nity Hospital, Dublin, Ireland
UCD School of Medicine and Medical Sciences, University College Dublin,
Dublin, Ireland
Neonatology, Our Lady’s Children’s Hospital, Dublin, Ireland
Paediatrics, Royal College of Surgeons in Ireland, Dublin, Ireland
Discipline of Paediatrics, Trinity College, The University of Dublin, Dublin,
Ireland
Dublin, Ireland
Terence Montague Department of Anesthesia, Our Lady’s Children’s Hos-
pital, Dublin, Ireland
Francesco Morini Neonatal Surgery Unit, Department of Medical and Sur-
gical Neonatology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Alan E. Mortell Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
Oliver J. Muensterer Department of Pediatric Surgery, University Medicine
Mainz, Johannes Gutenberg University, Mainz, Germany
Hiroki Nakamura National Children’s Research Centre, Our Lady’s Chil-
dren’s Hospital, Dublin, Ireland
Department Pediatric General and Urogenital Surgery, Juntendo University
School of Medicine, Tokyo, Japan
Rieko Nakamura Department of Anesthesiology, Nihon University School
of Medicine, Tokyo, Japan
Masaki Nio Department of Pediatric Surgery, Tohoku University Graduate
School of Medicine, Sendai, Japan
Alp Numanoglu Division of Paediatric Surgery, Faculty of Health Sciences,
University of Cape Town, Red Cross War Memorial Children’s Hospital, Cape
Town, South Africa
Benedict C. Nwomeh Department of Surgery, Ohio State University College
of Medicine, Columbus, OH, USA
Nationwide Children’s Hospital, Columbus, OH, USA
Contributors xxiii
James J. O’Byrne Department of Clinical Genetics, Our Lady’s Hospital,

Colm P. F. O’Donnell National Maternity Hospital, Dublin, Ireland
School of Medicine, University College Dublin, Dublin, Ireland
National Children’s Research Centre, Crumlin, Dublin, Ireland
Fiona O’Hare Discipline of Paediatrics, Trinity College, The University of
Dublin, Ireland
Ciara O’Rafferty Department of Haematology, Our Lady’s Children’s Hos-
pital, Crumlin, Dublin, Ireland
Keith T. Oldham Division of Pediatric Surgery, Medical College of Wiscon-
sin, Children’s Hospital of Wisconsin, Children’s Corporate Center, Milwau-
kee, WI, USA
Aliza M. Olive Center for Fetal Diagnosis and Therapy, Children’s Hospital
Ronald C. Oliver Norton Healthcare, Norton Children’s Hospital, Louis-
ville, KY, USA
Mikko P. Pakarinen Department of Pediatric Surgery, Children’s Hospital,
Helsinki University Central Hospital, University of Helsinki, Helsinki,
Finland
Stephanie C. Papillon Division of Pediatric Surgery, Children’s Hospital
Los Angeles, Los Angeles, CA, USA
Thambipillai Sri Paran Paediatric Surgery, Our Lady’s Children’s Hospital,
Trinity College, Dublin, Ireland
Dakshesh Parikh Birmingham Children’s Hospital NHS FT, Birmingham,
UK
Alberto Peña Division of Pediatric Surgery, International Center for Colorectal
and Urogenital Care, Children’s Hospital Colorado, Aurora, CO, USA
Colorectal Center for Children, Division of Pediatric Surgery, Cincinnati
Children’s Hospital Medical Center, Cincinnati, OH, USA
Jose L. Peiró University of Cincinnati, Cincinnati, OH, USA
Pediatric General and Thoracic Surgery Division, Cincinnati Fetal Center,
Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, OH,
USA
Corinna Peter Department of Pediatric Pulmonology, Allergology and Neo-
natology, Hannover Medical School, Hannover, Germany
Eimear Phelan Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
xxiv Contributors
Agostino Pierro Division of General and Thoracic Surgery, The Hospital for
Sick Children, University of Toronto, Toronto, ON, Canada
Department of Surgery, University of Toronto, Toronto, Canada
Todd A. Ponsky Division of Pediatric Surgery, Akron Children’s Hospital,
Akron, OH, USA
Prem Puri Department of Pediatric Surgery, Beacon Hospital, Dublin,
Ireland
School of Medicine and Medical Science and Conway Institute of Biomedical
Research, University College Dublin, Dublin, Ireland
David Rea Department of Radiology, Our Lady’s Children’s Hospital,
Dublin, Ireland
John Mark Redmond Our Lady’s Children’s’ Hospital, Dublin, Ireland
Mater Misericordiae University Hospital, Dublin, Ireland
M. Reismann Department of Pediatric Surgery and Urology, Astrid Lindgren
Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden
Risto J. Rintala Department of Pediatric Surgery, Children’s Hospital, Hel-
sinki University Central Hospital, University of Helsinki, Helsinki, Finland
Albert P. Rocchini Department of Pediatric and Communicable Diseases,
C.S. Mott Children’s Hospital, Congenital Heart Center, University of
Michigan, Ann Arbor, MI, USA
Udo Rolle Department of Pediatric Surgery and Pediatric Urology, Goethe
University Frankfurt, Frankfurt, Germany
Steven Rothenberg Department of Pediatric Surgery, Rocky Mountain Hos-
pital for Children at Presbyterian/St. Luke’s, Denver, CO, USA
John Russell Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
Robert Sader Department of Oral, Maxillofacial, and Plastic Facial Surgery,
Goethe University Frankfurt, Frankfurt, Germany
Amulya K. Saxena Department of Pediatric Surgery, Chelsea and Westmin-
ster Hospital NHS Foundation Trust, Imperial College London, London, UK
Marshall Z. Schwartz Drexel University College of Medicine,
St. Christopher’s Hospital for Children, Philadelphia, PA, USA
N. Scott Adzick The Division of Pediatric General and Thoracic Surgery,
The Center for Fetal Diagnosis and Treatment, Children’s Hospital of Phila-
delphia, Philadelphia, PA, USA
Melissa Short Department of Paediatric Surgery, Birmingham Children’s
Hospital, Newcastle upon Tyne, UK
Scott S. Short Division of Pediatric Surgery, Children’s Hospital Los
Angeles, Los Angeles, CA, USA
Contributors xxv
Owen Patrick Smith Department of Haematology, Our Lady’s Children’s

Hospital, Crumlin, Dublin, Ireland
University College Dublin, Dublin, Ireland
Eric A. Sparks Center for Advanced Intestinal Rehabilitation, Department of
Surgery, Boston Children’s Hospital and Harvard Medical School, Boston,
MA, USA
Linda Stephens Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
Charles J. H. Stolar Emeritus Professor of Surgery and Pediatrics, Columbia
University, College of Physicians and Surgeons, New York, NY, USA
California Pediatric Surgery Group, Goleta, CA, USA
Morgan Stanley Children’s Hospital, Division of Pediatric Surgery, New York,
NY, USA
Mark D. Stringer Department of Paediatric Surgery, Wellington Hospital,
Wellington, New Zealand
Department of Paediatrics and Child Health, University of Otago, Wellington,
New Zealand
Yechiel Sweed Department of Pediatric Surgery, Galilee Medical Center,
Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel
Brian Sweeney Department of Paediatric Surgery, Our Lady’s Children’s
Karl Sylvester Lucile Packard Children’s Hospital at Stanford University,
Stanford, CA, USA
Tomoaki Taguchi Department of Pediatric Surgery, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan
Yoshiaki Takahashi Department of Pediatric Surgery, Graduate School of
Medical Sciences, Kyushu University, Fukuoka, Japan
Paul Kwong Hang Tam Department of Surgery, Li Ka Shing Faculty of
Medicine, The University of Hong Kong, Hong Kong, China
Daniel H. Teitelbaum Section of Pediatric Surgery, C.S. Mott Children’s
Hospital and the University of Michigan School of Medicine, Ann Arbor, MI,
USA
Holger Till Department of Paediatric and Adolescent Surgery, Medical Uni-
versity of Graz, Graz, Austria
Shaheen J. Timmapuri Rutgers/Robert Wood Johnson Medical School,
Bristol–Myers Squibb Children’s Hospital, New Brunswick, NJ, USA
Christian Tomuschat National Children’s Research Centre, Our Lady’s
Children’s Hospital, Dublin, Ireland
Juan A. Tovar Department of Pediatric Surgery, Hospital Universitario La
Paz, Universidad Autonoma de Madrid, Madrid, Spain
xxvi Contributors
Benno Ure Center of Pediatric Surgery Hannover, Hannover Medical School

and Children’s Hospital Bult, Hannover, Germany
Eduardo Villamor Department of Pediatrics, School for Oncology and
Developmental Biology (GROW), Maastricht University Medical Center
(MUMC+), Maastricht, The Netherlands
Motoshi Wada Department of Pediatric Surgery, Tohoku University Gradu-
ate School of Medicine, Sendai, Japan
James Wall Pediatric General Surgery, Stanford University, Stanford, CA,
USA
Tomas Wester Department of Pediatric Surgery, Karolinska University Hos-
pital, Karolinska Institutet, Stockholm, Sweden
Kenneth K. Y. Wong Department of Surgery, Li Ka Shing Faculty of
Medicine, The University of Hong Kong, Hong Kong, China
Atsuyuki Yamataka Department of Pediatric General and Urogenital Sur-
gery, Juntendo University School of Medicine, Tokyo, Japan
George G. Youngson Department of Paediatric Surgery, University of Aber-
deen, Royal Aberdeen Children’s Hospital, Aberdeen, Scotland, UK
Alon Yulevich Department of Pediatric Surgery, Galilee Medical Center,
Bar-Ilan University, Safed, Israel
Augusto Zani Division of General and Thoracic Surgery, The Hospital for
Sick Children, Toronto, Canada
Department of Surgery, University of Toronto, Toronto, Canada
Elke Zani-Ruttenstock Division of General and Thoracic Surgery, The
Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
Julia Zimmer National Children’s Research Centre, Our Lady’s Children’s
Department of Pediatric Surgery, Hannover Medical School, Hannover,
Germany
Part I
General
Embryology of Congenital Malformations
1
Dietrich Kluth and Roman Metzger
Contents
Misconceptions and/or Outdated Theories
Concerning Normal and Abnormal
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
A Shortage of Study Material (Both Normal and
Abnormal Embryos) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
A Shortage of Explanatory Images of Embryos and Developing
Embryonic Organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Difficulties in the Interpretation of Serial Sections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Animal Models Used for Applied Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Embryos of Different Species for the Study of
Normal Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Surgical Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Chemical Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Genetic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Spontaneous Malformations Without Genetic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Scanning Electron Microscopic Atlas of
Normal and Abnormal Development in Embryos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Foregut Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Development of the Diaphragm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Development of the Hindgut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Development of the External Genitalia
and the Urethra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
D. Kluth (*)
Department of Pediatric Surgery, University Hospital,
University of Leipzig, Leipzig, Germany
e-mail: dirkkluth@web.de;
dietrich.kluth@medizin.uni-leipzig.de
R. Metzger
Department of Paediatric and Adolescent Surgery,
Paracelsus Medical University Salzburg, Salzburg, Austria
e-mail: romanpatrick.metzger@medizin.uni-leipzig.de;
roman.metzger@medizin.uni-leipzig.de
© Springer-Verlag GmbH Germany, part of Springer Nature 2020 3

P. Puri (ed.), Pediatric Surgery,
https://doi.org/10.1007/978-3-662-43588-5_1
4 D. Kluth and R. Metzger
The Development of the Midgut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Testicular Descent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Abstract According to Haeckel’s “biogenetic law,” a

Today, the embryology of numerous congeni- human embryo recapitulates in its individual
tal anomalies in humans is still a matter of development (ontogeny) the morphology
speculation. This is due to a number of reasons observed in all lifeforms (phylogeny). This
which include: means that during its development, an advanced
species (a human embryo) seems to pass through
• Misconceptions and/or outdated theories stages represented by adult organisms of more
concerning normal and abnormal primitive species (Gilbert 2003). This theory has
embryology been used to “bridge” gaps in the understanding of
• A shortage of study material (both normal normal embryonic development and still has an
and abnormal embryos) impact on the nomenclature of embryonic organs.
• A shortage of explanatory images of This explains why human embryos have
embryos and developing embryonic organs “cloacas” like adult birds and “branchial” clefts
• Difficulties in the interpretation of serial like adult fish.
sections The term “Hemmungsmißbildung” stands for
the theory that malformations actually represent
In recent years, a number of animal models “frozen” stages of normal embryonic develop-
had been established which helped to over- ment. This theory too has been used to “bridge”
come the shortage of both normal and abnor- gaps in the understanding of normal embryonic
mal embryos. However, a general agreement development in a manner which could best
on when, why, and how abnormal develop- describe as “reversed embryology.” As a result,
ment takes place still does not exist. As a result, our knowledge of normal embryology stems
many typical malformations are still not more from pathological-anatomic interpretations
explained satisfactorily and pediatric surgeons of observed malformations than from proper
of all specialties are still confused when they embryological studies. The theory of the “rota-
are confronted with the background of normal tion of the gut” as a step in normal development is
and abnormal embryologic development. a perfect example for this misconception
(Fig. 1a). Others are “failed fusion of the urethral
folds” (hypospadia, Fig. 1b), “failed closure of
Keywords
the pleuroperitoneal canals” (congenital dia-
Human birth defects · Animal models ·
phragmatic hernia, Fig. 1c), or “persistent cloaca”
Teratology · Human embryology
(Fig. 1d).
Misconceptions and/or Outdated A Shortage of Study Material (Both

Theories Concerning Normal Normal and Abnormal Embryos)
and Abnormal Embryology
Today, a growing number of animal models exist
Our understanding of the normal and abnormal which allow embryological studies in various
development of embryos is still influenced by two embryological fields. This includes studies in nor-
theories: mal as well as in abnormal embryos. Especially
(a) The “biogenetic law” after Haeckel (1975) for the studies of esophageal and anorectal
(b) The theory of “Hemmungsmißbildungen” malformations, a number of animal models had
(Schwalbe 1906) been established.
1 Embryology of Congenital Malformations 5
Fig. 1 Theory of “Hemmungsmißbildungen”: typical development (Modified after Bromann 1902): impaired
examples. (a) Schematic drawing of the “rotation of the closure of diaphragmatic membranes causes diaphragmatic
gut” (After McVay et al. 2007, with permission from hernia. AO aorta, E esophagus, L diaphragm derived from
Elsevier). Impaired rotation causes “malrotation.” (b) lateral body wall, PN phrenic nerve, P pericardium, PPM
Schematic drawing of urethral development (Modified pleuroperitoneal membrane, VC vena cava, PPC
after Hamilton et al. 1962). Hypospadia as a result of pleuroperitoneal canal, M diaphragm derived from dorsal
impaired fusion of urethral folds (UG). AP anal pit, GP mesenterium. (d) Schematic drawing of cloacal develop-
glans penis, UO urethral opening, US urethral sulcus, SS ment (Stephens 1963). Impaired formation of the urorectal
scrotal swelling. (c) Schematic drawing of diaphragmatic septum causes anorectal malformations
A Shortage of Explanatory Images (a) Serial sectioning of embryos and time-

of Embryos and Developing Embryonic consuming three-dimensional reconstructions
Organs are not necessary.
(b) The embryo can be studied in all three dimen-
Advanced technology in a number of fields gives sions “online.”
much better insights into human development. (c) The images and photographs are of superior
This includes ultrasonography of fetuses as well quality (Fig. 2).
as magnetic resonance imaging (MRI). For
detailed embryological studies, scanning electron
microscopy is still a very useful tool. Recently, Difficulties in the Interpretation
STEDING published a scanning electron micro- of Serial Sections
scopic atlas of human embryos which provides
detailed insights into normal human embryology Although a number of specific tasks demand the
(Steding 2009). Scanning electron microscopy is serial section of embryos, the difficulties in the
the perfect tool to document embryonic structures: interpretation must not be underestimated. Three-
Fig. 2 Scanning electron microscopy (SEM) electron female rat, ED 20. The highest magnification shows
microscopy enables a wide range of magnification and a detailed structures on the cell surface (SEM Pictures © D.
superior quality of photographs: perineal region of a Kluth)
dimensional (3D) reconstructions, although feasi- animal models, the detailed study of normal
ble, are tainted with a loss of information, not only embryos of the same species is mandatory.
caused by the sectioning itself but also by the use of We used scanning electron microscopy (SEM) in
3D image software. chicken, rat, and murine embryos in order to study
certain embryological processes of the normal
embryology of the foregut, the hindgut, the midgut,
Animal Models Used for Applied
the testicular descent, and the development of the
Embryology
external genitalia. The advantage of chicken embryos
is the high availability at low costs. They are easily
Over the last two decades. a number of animal
accessible in the eggshell, and further breeding is
models have been developed with the potential to
possible when the eggs are treated accordingly.
gain a better understanding of the morphology of
Embryos of rats and mice can be obtained in compa-
not only malformed but also normal embryos. These
rable large numbers; however, local regulations may
animal models can be grouped in five subgroups:
limit the usage of mammalian embryos.
1. Embryos of different species for the study of
(a) The chicken embryo was used to study foregut
normal embryology
development. The aim was to clarify whether
2. Surgical models
lateral ridges occur in the developing foregut or
3. Chemical models
not and, when present, if they fuse to form the
4. Genetic models
tracheoesophageal septum (Kluth et al. 1987;
5. “Spontaneous” malformations of unclear cause
Metzger et al. 2011a) (Fig. 3).
(b) Rat embryos were used to study, i.e., devel-
Embryos of Different Species opmental processes during testicular descent,
for the Study of Normal Embryology to clarify if “rotation” takes place during gut
development (Fig. 4a), to assess the question
Human embryos are rare. Human embryos if “cloacas” actually exist in rat embryos, and
displaying typical anomalies are extremely rare. how the differentiation of the developing
Therefore it makes sense to study specific devel- hindgut takes place (Fiegel et al. 2011;
opmental processes in embryos of animals with Metzger et al. 2011a; Kluth et al. 2011a)
humanlike abnormalities. However, in all cases of (Fig. 4b).
Fig. 3 Animal models: chicken model is used to study the lateral ridges (insert) which are thought to appear in the
normal development of the foregut. (a) Schematic drawing foregut and which form the epithelial tracheoesophageal
of the developing foregut (Modified after Gray and septum. (b) Schematic picture of the “water tap theory.”
Skandalakis 1972c). Dotted arrows indicate the growth The lung anlage forms as a diverticulum which grows
directions of the esophagus (gray) and trachea (white). caudal and thus forms the trachea (Drawing modified
The small arrow in between indicates the growth direction after Merei and Hutson 2002)
of the assumed septum. The thick arrows point to the
Fig. 4 Animal models: rat embryos were used to study midgut development (a) and hindgut development (b) (SEM
Pictures © D. Kluth)
(c) Mouse embryos were studied in the widely used by embryologist especially in the
SD-mouse model (Fig. 5). Here, normal and field of epithelial/mesenchymal interactions
abnormal hindgut development was studied (Goldin and Opperman 1980; Steding 1967;
(Kluth et al. 1995a). Jacob 1971). Pediatric surgeons have used this
model to study morphological processes involved
Surgical Models in intestinal atresia formation (Molenaar and
Tibboel 1982; Schoenberg and Kluth 2002),
In the past, the chicken was an important surgical gastroschisis (Aktug et al. 1997), and
model to study embryological processes. As men- Hirschsprung’s disease (Meijers et al. 1992). The
tioned above, the easy access to the embryo, its Czech embryologist Lemez (1980) used chicken
broad availability, and its cheapness make it an embryos in order to induce tracheal agenesis with
ideal model for experimental studies. It has been tracheoesophageal fistula (Fig. 6).
Fig. 5 Animal models: SD-mice were used to study of an anorectal malformation with rectourethral fistula (F)
anorectal malformations. (a) Notice the short tail in a and a blind ending rectal pouch (RP) are detectable.
heterocygotic SD mouse. (b) Histology of the pelvic U urethra. (c) The spectrum of malformations seen in
organs in a newborn heterozygous SD-mouse. The features SD-mice
Apart from these purely embryonic models, a (e) Nitrofen (Ambrose et al. 1971; Tenbrinck
large number of fetal models had been developed et al. 1990; Kluth et al. 1990; Costlow and
in the last 30 years. Although they were mainly Manson 1981; Irtani 1984)
created to study the feasibility of fetal interven- (f) Suramin and trypan (Männer and Kluth 2003,
tions (Harrison et al. 1980), they also contributed 2005)
to our current knowledge of normal and abnormal
fetal development and fetal organ systems.
Models (a–d) have been used to study atresia
formation in the esophagus, the midgut, and the
anorectum. Model (e) was developed to study
Chemical Models malformations of the diaphragm, the lungs, the
heart, and kidneys (hydronephrosis). Model
It is well known that a number of chemicals (drugs, (f) was used in chicken embryos to study the
chemical fertilizers) can alter normal development formation of cloacal exstrophy.
of humans and animals alike. Some of these had We used the nitrofen model to study the mor-
been used to induce malformations similar to those phology of diaphragmatic hernia formation in rat
found in humans. Most important today are: embryos (Fig. 7).
(a) The adriamycin model (Thompson et al. 1978;
Diez-Pardo et al. 1996; Beasley et al. 2000)
(b) Etretinate (Kubota et al. 1998; Liu et al. 2003) Genetic Models
(c) All-trans-retinoic acid (ATRA) (Bitoh et al.
2002; Hashimoto et al. 2002; Sasaki et al. Many aspects make genetic models the ideal
2004) model for the studies of abnormal development.
(d) Ethylenethiourea (Arana et al. 2001; Qi et al. In the past, a number of genetic models have
2002) been used for embryological studies of
Fig. 6 Animal models: experimental embryology in technique, (b) arrows indicate the area where the clips
chicken embryos. Metal clips were used to induce tracheal were positioned (SEM picture of a chicken embryo).
atresia (Lemez 1980). (a) Schematic drawing of the (SEM Picture and schematic drawing © Dietrich Kluth)
Fig. 7 Animal models: the nitrofen model of diaphrag- exposure on days 9.5, 10.5, 11.5, 12.5, and 13.5. Most
matic hernia. (a) Newborn rat with diaphragmatic hernia hernias were seen after nitrofen exposure on day 11.5
after nitrofen exposure at day 11.5. (b) Results of nitrofen
malformations. While older models were mostly (a) Models of spontaneous origin: The
the product of spontaneous mutations, newer SD-mouse model (Dunn et al. 1940; Kluth
models are, in most instances, the result of et al. 1991). In the SD-mouse model,
genetic manipulations mainly in mice (trans- anorectal malformations are combined with
genic mice). The following models have been anomalies of the kidneys, the spine, and the
used by pediatric surgeons: external genitalia (Fig. 5).
(b) Inheritance models: the pig model of anal Recently, Botham et al. studied developmental
atresia (van der Putte and Neeteson 1984; disorders of the duodenum in mutations of the
Lambrecht and Lierse 1987) (Fig. 9). In fibroblast growth factor receptor 2 gene
pigs, anorectal malformations are seen quite (Fgfr2IIIb) (Botham et al. 2012). They noted an
frequently. One out of 300 newborn piglets increased apoptotic activity in the duodenal epi-
present with anorectal malformations without thelium of Fgfr2IIIb -/- embryos at day 10.5,
evidence of genetical alterations. followed by a disappearance of the endoderm at
(c) “Knockout” models. day 11.5. Interestingly, the duodenal mesoderm
(d) Viral models. also disappeared within 2 days, and an atresia was
formed. Similar processes had been observed in
The number of transgenic animal models is newborn piglets whose esophageal epithelium
currently growing fast. For pediatric surgeons was removed via endoscopy (Booß and Okmian
those models are of major importance, which 1974; Komfält and Okmian 1973). This procedure
result in abnormalities of the fore- and hindgut. resulted in esophageal atresias in these piglets.
Here, interference with the Sonic hedgehog (Shh) In humans, viral infections are known to cause
pathway has proven to be very effective malformations. Animal models that use viral
(Litingtung et al. 1998; Kim et al. 2001; Mo infections important for pediatric surgeons are
et al. 2001). There are two ways to interfere with very rare. One exception is the murine model of
that pathway: extrahepatic biliary atresia (EHBA) (Petersen
et al. 1997). In this model, newborn Balb/c mice
I. Targeted deletion of Sonic hedgehog are infected with rhesus rotavirus group A45. As a
(Litingtung et al. 1998; Kim et al. 2001) result, the full spectrum of EHBA develops as it is
II. Deletion of one of the three transcription fac- seen in newborn with this disease. However, this
tors Glil, Gli2, and Gli3 (Kim et al. 2001; Mo model is not a model to mimic failed embryology.
et al. 2001) But it highlights the possibility that malformations
are not caused by embryonic disorders but caused
It has been demonstrated, that targeted dele- by fetal or even postnatal catastrophes.
tion of Sonic hedgehog resulted in homozygous
Shh null mutant mice in the formation of foregut
malformations like esophageal atresia/stenosis, Spontaneous Malformations Without
tracheoesophageal fistulas, and tracheal/lung Genetic Background
anomalies (Litingtung et al. 1998). In the hind-
gut, the deletion of Sonic hedgehog caused the In chicken embryos, a number of spontaneous
formation of “cloacas” (Kim et al. 2001), while malformations can be observed. It is not quite
Gli2 mutant mice presented with the “classic” clear which processes cause them. One reason
form of anorectal malformations and Gli3 may be a prolonged storage (more than 3 days)
mutants showed minor forms like anal stenosis in fridges below 8 C before breeding is started
(Kim et al. 2001; Mo et al. 2001). Interestingly, (Sydow H, Göttingen, Germany, “personal
the morphology of Gli2 mutant mice embryos communication”). Spontaneous malformations
resembles that of heterozygous SD-mice of the head anlage (i.e., double anlage of the
embryos, while Shh null mutant mice embryos head, Fig. 8), the anlage of the heart, as well as
had morphological similarities with homozy- abnormalities of the embryonic position
gous SD-mice embryos. It is interesting to note (heterotaxia) are frequently seen (Sydow H,
that after administration of adriamycin, abnor- Göttingen, Germany, “personal communica-
mal pattern of Shh distribution could be demon- tion”) (Fig. 9).
strated in the developing foregut (Arsic et al. This part on embryology and animal models
2004). highlights not only the importance to study
Scanning Electron Microscopic Atlas

of Normal and Abnormal Development
in Embryos
In this section we want to present examples of

normal and abnormal development as we have
seen them in our studies in our labs over the past
30 years using scanning electron microscopy
(SEM). We use the form of an embryological
atlas following the old motto “A picture says
more than a thousand words.” We focus on the
following developmental processes:
1. Normal and abnormal foregut development
(chicken embryos)
2. Normal and abnormal development of the dia-
phragm (rat embryos)
Fig. 8 Spontaneous malformation seen in a chicken
embryo: double anlage of the head fold (Picture courtesy
3. Development of the midgut (rat embryos)
of H. Sydow, Göttingen, Germany) 4. Normal and abnormal development of the
hindgut (mice and rats)
5. The development of the external genitalia and
the urethra (rat embryos)
6. Testicular descent (rat embryos)
Foregut Development
Normal Foregut Development

Traditionally, foregut malformations like esopha-
geal atresias and tracheoesophageal fistulas are
explained by a faulty formation of the so-called
“tracheoesophageal septum.” It is believed that
normal septation takes place in two steps:
Fig. 9 Animal models: a newborn piglet with anorectal
malformation (Picture courtesy of W. Lambrecht, Ham- I. Lateral endodermal ridges appear in the prim-
burg, Germany) itive foregut which fuse and form the tracheoe-
sophageal septum.
embryos with experimental malformations but II. This solid endodermal septum is partly
also the study of normal animal embryos. Today, removed by apoptosis and substituted by mes-
much information in current textbooks on human enchymal cells (Fig. 3).
embryology stems actually from studies done in
animals of varies species. Many of these are out- This theory had been described in detail by
dated. The wide use of transgenic mice in order to Rosenthal (1931) and Smith (1957). However,
mimic congenital malformations makes morpho- neither Zaw Tun (1982) nor O’Rahilly and Müller
logical studies of the organ systems in normal (1984) were able to confirm these sequences of
mice mandatory. Otherwise the interpretation of embryological events. According to them, the
the effects by deletion of genetic information can term “separation” is a misnomer as the formation
be very difficult or even misleading. of the trachea is simply the result of the
Fig. 10 Embryology of the esophagus: SEM studies in magnification in (d). ES esophagus, TR trachea. (e) Process
chicken embryos. (a) The foregut of a chicken embryo of of fusion in the outflow tract of an embryonic heart
stage 20/21, 3.5 days old. (b) The foregut is opened from (chicken embryo). Cushions in the outflow tract of the
lateral. The inner surface of the foregut is seen. Notice the heart (c) fuse to form a septum. (f) Notice the fusion line
absence of lateral folds (arrows). ES esophagus, TR tra- which can be seen in an older embryo (arrows) (Pictures 10
chea, * = tip of the tracheoesophageal fold. (c) View into e, f courtesy of G. Steding, Göttingen, Germany). SEM
the foregut from cranial. The tip of the tracheoesophageal Pictures 10a–d © Dietrich Kluth
fold can be seen. Notice the absence of fusion (higher
downgrowth of the respiratory diverticulum studies we were unable to identify ridges in the
(Fig. 3) (Merei and Hutson 2002). lateral foregut wall. Furthermore, signs of fusions
Using SEM, we studied the normal develop- of lateral foregut components were also not seen.
ment of the foregut in chicken embryos (Kluth As a reference, we added SEM pictures of the
et al. 1987; Metzger et al. 2011a; Kluth and outflow tract in chicken hearts (pictures 10e, f
Habenicht 1987). courtesy of G. STEDING, Göttingen, Germany).
The first goal of these studies was to see if Here, ridges appear which fuse and form the septa
lateral endodermal ridges appear inside the fore- of the conus and the truncus. Note that a line of
gut and if they fuse (Fig. 10). However, in our fusion can be seen as an indicator that fusion
Fig. 11 Embryology of the esophagus: formation of the still part of the common foregut. LaF larynx anlage, ES
respiratory tract. (a) Lung buds are the forerunners of the esophagus, L Br bronchi, St stomach, ** = fold which
bronchi (LB). CF common space of the foregut. (b) The marks the border between the pharynx and esophagus.
bronchi start to develop (L Br). A trachea is not visible yet. (SEM Pictures © Dietrich Kluth)
CF common space of the foregut. (c) The trachea (Tr) is
actually took place. As no signs of fusion can be the area of the common foregut is reduced in size
demonstrated in the foregut, theories dealing with and later forms the pharyngo-tracheal canal
improper formations of the tracheoesophageal (Kluth et al. 1987).
septum are obsolete (Zaw Tun 1982). The formation of esophageal atresia (Fig. 13)
The second goal was to visualize the early Although a number of models for abnormal
formation of the lung bud (Fig. 11). In our series foregut development exist, a clear morphological
of embryos, we could demonstrate that after the description of the embryological events that
formation of the early lung anlage, two lung buds finally lead to esophageal atresias is still missing.
appear, which are the forerunners of the bronchi. Based on our observations, the development of
The anlage of the trachea itself is seen later as the the malformation can be explained by disorders
floor of a “common foregut” chamber (Metzger either of the formation of the folds or of their
et al. 2011a). Thus, not the trachea but the bronchi developmental movements (Kluth et al. 1987;
are the first organs of the respiratory tree that Metzger et al. 2011a; Kluth and Habenicht 1987):
develop. This speaks against the idea of a simple (a) Atresia of the esophagus with fistula
downgrowth of the tracheal anlage as assumed by (Fig. 13C1):
Zaw Tun and O’Rahilly and Müller (Zaw Tun The dorsal fold of the foregut bends too far
1982; O’Rahilly and Muller 1984). ventrally. As a result the descent of the larynx
The third goal was to identify possible mecha- is blocked. Therefore the common tracheoe-
nisms of differentiation of the foregut into the sophageal space remains partly undivided and
larynx, pharynx, trachea, and esophagus. In our lies in a ventral position. Due to this ventral
embryos, we could identify typical markers in the position, the common space differentiates
foregut (Fig. 12). In the dorsal aspect of the fore- into trachea.
gut, a fold appears which marks the borderline (b) Atresia of the trachea with fistula (Fig. 13C2):
between the pharynx and esophagus. Cranially The foregut is deformed on its ventral side.
the larynx develops, and caudally, a fold appears The developmental movements of the folds
between the developing trachea and the esopha- are disturbed, and the tracheoesophageal
gus. In the next developmental steps, these folds space is dislocated in a dorsal direction,
approach each other but do not fuse. As a result, where it differentiates into esophagus.
Fig. 12 Embryology of the esophagus: the common space larynx fold (LaF) from cranial, the tracheoesophageal fold
of the foregut is reduced in size by a system of folds. (a) (*) from caudal, and the fold between the pharynx and
The trachea is still part of the common space (CF). LaF esophagus (**) from dorsal. (SEM Picture and schematic
Larynx anlage. (b) The size of the CF common foregut is drawing © Dietrich Kluth)
reduced by the growth of folds, which are formed by the
(c) Laryngo-tracheo-esophageal clefts the diaphragmatic development. For practical rea-

(Fig. 13C3): Faulty growth of the folds results sons it is essential to note that the early diaphragm
in the persistence of the primitive tracheoe- consists of two parts:
sophageal space. (a) The septum transversum which, in young
embryos, is identical to the floor of the
In our collection of chicken embryos, we came pericardium
across an embryo with abnormal foregut features (b) The structures that surround the pleural cav-
(Fig. 13b). When compared to normal embryos of ity. They are:
the same age group (Fig. 13a), the following I. The posthepatic mesenchymal plate
statements can be made: (I) Obviously, the phar- (PHMP) (Irtani 1984), which covers the
ynx ends blindly. (II) The dorsal part of the com- dorsal aspect of the liver and is in conti-
mon foregut space is missing. (III) The ventral nuity to the septum transversum ventrally
part of the common space has the size of a trachea. and cranially.
(IV) This foregut looks like the hypothetical form II. The pleuroperitoneal fold (PPF) which
C1 in Fig. 13. separated the pleura from the peritoneal
cavity. This fold connects ventrally to the
septum transversum and the PHMP and
Development of the Diaphragm dorsally to the mesonephric ridge (Mayer
et al. 2011). This PPF is a structure that is
Normal Development identical to the pleuroperitoneal membrane
The traditional theories of diaphragmatic devel- of the old literature (Kluth et al. 1989).
opment have been summarized by Kluth et al. III. The dorsal mediastinum which contains
(1989). Using SEM, we have recently restudied the esophagus, the trachea, and the aorta.
Fig. 13 Embryology of the esophagus: hypothetical for- common foregut space. Consequently, the rest of the com-
mation of foregut malformations. (a) Normal foregut of a mon space develops into trachea, and an esophageal atresia
chicken embryo, view from lateral into the foregut. Notice with lower fistula develops. (C2) The common foregut
the reduced size of the common foregut space (***) due to space is reduced in size from ventral (*). Consequently
the development of the folds. La Larynx. (b) Chicken the rest of the common space develops into esophagus, and
embryo with a spontaneous foregut malformation. The a tracheal atresia with fistula occurs (very rare).
pharynx ends blindly. Part of the trachea is in normal (C3) Impaired development of the dorsal fold and the
position and of tracheal size. The dorsal part of the com- tracheoesophageal fold leads to an undivided common
mon foregut space is missing (*). (c) Hypothetical expla- foregut space and a laryngo-tracheo-esophageal cleft.
nation of foregut maldevelopment. (C1) The dorsal fold (SEM Picture and schematic drawing © Dietrich Kluth)
(*) between the pharynx and larynx grows too deep into the
According to our SEM studies, the PHMP process of the pleuroperitoneal openings (PPO) is
plays the most important role in normal diaphrag- depicted. At embryonic day (ED) 13, the forma-
matic development. In Figs. 14 and 15, the closure tion of the PHMP and its lower border can be seen
Fig. 14 Normal development of the diaphragm: caudal indicate the direction of future PHMP growth. Note the
growth of the posthepatic mesenchymal plate (PHMP) large area of the liver still uncovered by the PHMP. (b) Rat
(Irtani 1984). (a) Rat embryo, ED 13. View at the dorsal embryo 13.5 days. Note the caudal growth of the PHMP
part of the diaphragm. The dorsal diaphragm is short. The within 12 h (second dark line). The uncovered liver is
black line marks the caudal border of the PHMP. Arrows markedly smaller. (SEM Pictures © Dietrich Kluth)
(Fig. 14a). The PHMP then expands (b) Failure of muscularization of the lumbocostal
dorsolaterally at embryonic day 13.5 (Fig. 14b), trigone and pleuroperitoneal canal, resulting in
establishing a new lower border. a “weak” part of the diaphragm (Gray and
In Fig. 15, the final closure of the PPO is Skandalakis 1972a; Holder and Ashcraft 1979)
shown. In this process the PHMP starts to cover (c) Pushing of the intestine through posterolat-
the last free areas of the liver (Fig. 15a). In this eral part (foramen of Bochdalek) of the dia-
process, the pleuroperitoneal fold (PPF) plays phragm (Bremer 1943)
only a minor role. (d) Premature return of the intestines into the
In the literature, the nomenclature of the vari- abdominal cavity with the canal still open
ous parts of the diaphragm is confusing. We use (Gray and Skandalakis 1972a; Holder and
the term PPF for a structure which was formally Ashcraft 1979)
known as pleuroperitoneal membrane (Kluth et al. (e) Abnormal persistence of the lung in the
1989; Mayer et al. 2011). The term PPF is used pleuroperitoneal canal, preventing proper clo-
differently by Greer and coworkers (Clugston sure of the canal (Gattone and Morse 1982)
et al. 2010). Their PPF is very similar to the (f) Abnormal development of the early lung and
PHMP as described by IRITANI and us but posthepatic mesenchyme, causing non-closure
seems to include the ventral part of our PPF. of pleuroperitoneal canals (Irtani 1984)
Abnormal Development Of these theories, failure of the pleuroperitoneal

In the past, several theories were proposed to membrane to meet the transverse septum is the
explain the appearance of posterolateral diaphrag- most popular hypothesis to explain diaphragmatic
matic defects: herniation. However, using SEM techniques (Kluth
(a) Defects caused by improper development of et al. 1989; Mayer et al. 2011), we could not dem-
the pleuroperitoneal membrane (Grosser and onstrate the importance of the pleuroperitoneal
Ortmann 1970; Gray and Skandalakis 1972a; membrane for the closure of the so-called
Holder and Ashcraft 1979) pleuroperitoneal canals (Fig. 15).
of congenital diaphragmatic hernia (CDH) devel-

opment lacks any embryological evidence. Fur-
thermore the proposed timing of this process is
highly questionable (Kluth 1993).
Animal Model
An animal model for diaphragmatic hernia has
been developed (Ambrose et al. 1971; Tenbrinck
et al. 1990; Kluth et al. 1990; Costlow and Man-
son 1981; Irtani 1984) using nitrofen as noxious
substance. In these experiments CDHs were pro-
duced in a reasonably high percentage of new-
borns (Kluth et al. 1990). We collected a number
of affected embryos of different age groups and
studied these using SEM (Kluth and Tander 1995;
Kluth 1993). Our results (Figs. 16 and 17) are as
follows:
(a) Timing of diaphragmatic defect appearance.

Iritani (Irtani 1984) was the first to notice that
nitrofen-induced diaphragmatic hernias in
mice are not caused by an improper closure
of the pleuroperitoneal openings but rather
the result of a defective development of the
Fig. 15 Normal development of the diaphragm: closure of posthepatic mesenchymal plate (PHMP). In
the pleuroperitoneal openings (PPO). Rat ED 15 (a) and
ED 16 (b). Most of the liver (Li) is covered by the post- our study in rats, clear evidence of disturbed
hepatic mesenchymal plate (PHMP). At ED 16 the only development of the diaphragmatic anlage was
intra-abdominal organ seen is the tip of the gonads (Go). seen on ED 13 on the left and ED 14 on the
(SEM Pictures © Dietrich Kluth) right diaphragm anlage (Fig. 14) (Kluth and
Tander 1995; Kluth et al. 1996). In all
It is still speculated that delayed or inhibited embryos affected, the PHMP was too short.
closure of the diaphragm will result in a diaphrag- This age group is equivalent to 4–5 week-old
matic defect that would allow herniation of the gut human embryos (Kluth and Tander 1995).
into the fetal thoracic cavity. In a series of normal (b) Location of diaphragmatic defect. In our SEM
staged embryos, we measured the width of the study, the observed defects were localized in
pleuroperitoneal openings and the transverse the area of the PHMP (Fig. 14). We identified
diameter of gut loops (Kluth et al. 1995a). On two distinct types of defects (Haeckel 1975):
the basis of these measurements, we estimated large “dorsal” defects and (Schwalbe 1906)
that a single embryonic gut loop requires at least small “central” defects (Kluth and Tander
an opening of 450 μm size to herniate into the fetal 1995). Large defects extended into the region
pleural cavity. However, in none of our embryos, of the pleuroperitoneal openings. In these
the observed pleuroperitoneal openings were of cases, the closure of the pleuroperitoneal
appropriate dimensions. This means that delayed openings was usually impaired by the mas-
or inhibited closure of the pleuroperitoneal canal sive ingrowth of the liver (Figs. 14 and 15). If
cannot result in a diaphragmatic defect of suffi- the defects were small, they were consistently
cient size. Herniation of the gut through these isolated from the pleuroperitoneal openings
openings is therefore impossible. Thus the pro- which closed normally at the 16th or 17th
posed theory about the pathogenetic mechanisms day of gestation. Thus, in our embryos with
Fig. 16 Dorsal diaphragms after nitrofen exposure at rat arrow points to the closed pleuroperitoneal openings
ED 11.5. (a, b) Rat embryo at ED 14. The abnormal anlage (PPO). (d) Rat ED 18. The hernia is big. Two lobes of the
of the right diaphragm is easy to see. Dotted arrows mark the liver project into the thorax. The big arrow points to the vena
diameter of the uncovered liver (Li). On the left, the devel- cava. Small arrows mark the border of the PPO, which is
opment of the posthepatic mesenchymal plate (PHMP) is open due to the ingrowth of the liver. Note that the size of the
normal. On the right, the PHMP stopped to grow to caudal. diaphragmatic defect is much larger than the PPO itself.
(c) Rat ED 17. A small hernia (liver) can be seen. Note the (SEM Pictures © Dietrich Kluth)
position close to the vena cava (large arrow). The small
CDH, the region of the diaphragmatic defect further lung growth is hampered. In the fol-
was a distinct entity and was separated from lowing stages, up to two- thirds of the thoracic
that part of the diaphragm where the cavity can be occupied by the liver (Figs. 16
pleuroperitoneal “canals” are localized. We and 17). Herniated gut was found in our
conclude therefore that the pleuroperitoneal embryos and fetuses only in late stages of
openings are not the precursors of the dia- development (21 days and newborns)
phragmatic defect. (Fig. 17). In all of these, the lungs were
(c) Why lungs are hypoplastic. Soon after the already hypoplastic, when the bowel entered
onset of the defect in the 14-day-old embryo, the thoracic cavity (Kluth and Tander 1995).
the liver grows through the diaphragmatic
defect into the thoracic cavity (Fig. 14). This
indicates that from this time on, the available Based on these observations, we conclude that
thoracic space is reduced for the lung, and the early ingrowth of the liver through the
Fig. 17 Huge hernias after nitrofen exposure. (a) Rat ED animals, the gut can be found inside the thoracic cavity.
20. In none of our embryos, the gut could be found in this (SEM Pictures © Dietrich Kluth)
age group. (b) Rat ED 21. In this age group and older
diaphragmatic defect is the crucial step in the thus form the septum. Van de Putte (vd Putte 1986)
pathogenesis of lung hypoplasia in CDH. This denied the existence of any process of septation.
indicates that growth impairment is not the result In the recent years we studied the cloacal
of lung compression in the fetus but rather the development in rats and SD-mice embryos using
result of growth competition in the embryo: the SEM techniques (Kluth et al. 1995a, 2011a; Kluth
liver that grows faster than the lung reduces the and Lambrecht 1997).
available thoracic space. If the remaining space is The first goal of these studies was to see if lateral
too small, pulmonary hypoplasia will result. ridges appear inside the “cloaca” and if these actu-
ally fuse to form an endodermal septum (Fig. 18).
As in the foregut of chick embryos, we were unable
Development of the Hindgut to see lateral ridges (Fig. 18c) projecting into the
cloacal lumen. Signs of median fusion of lateral
Normal Development cloacal parts were also lacking (Fig. 18a, b). How-
As in the foregut, a process of septation has been ever, in contrast to Van de Putte (vd Putte 1986), our
postulated for the proper subdivision of the “clo- SEM studies indicate that downgrowth of the tip of
aca” into the dorsal anorectum and the ventral the urorectal fold takes place (Fig. 19a, b), although
sinus urogenitalis. Disorders in this process of it is probably not responsible for the formation of
differentiation are thought to be the cause of clo- cloacal malformations.
acal anomalies such as persistent cloaca and Our findings on normal embryology of the
anorectal malformations (Stephens 1963). hindgut were:
However, for many years, this process of
septation has been under dispute. Some authors (a) The “cloaca” is not subdivided into two equal
(Toumeux 1888; DeVries and Friedland 1974) parts (Fig. 19a, b). The much larger ventral
believe that the descent of a single fold separates part gives rise to the future distal urethra.
the urogenital part from the rectal part by ingrowth (b) The dorsal “cloaca” contains the future
of mesenchyme. Others (Retterer 1890) think that anorectal region. The future anal opening is
lateral ridges appear in the lumen of the cloaca, situated in the dorsal part of the “cloacal’
which progressively fuse along the midline and membrane,” close to the tail fold (Fig. 19b).
Fig. 18 Normal
development of the hindgut.
Rat ED 14. (a) The ventral
part of the cloaca is
removed. As in the foregut,
signs of fusion are lacking.
(b) Schematic drawing of
the situation in (a). (c) After
removal of the lateral wall
of the cloaca, internal ridges
which could form an
urorectal septum are not
detectable. (SEM Pictures
and schematic drawing ©
Dietrich Kluth)
Fig. 19 Normal development of the hindgut. a, b The that the “cloaca” is not equally divided by the line. The
“cloaca” (c) in a rat embryo ED 14.5 has the following gray area in the schematic drawing marks the area of the
features: proximal urethra (PU), distal urethra (DU), rec- future anus. It lies in the dorsal part of the cloacal mem-
tum (HG), tail gut (TG), cloacal membrane. The line marks brane close to the tail fold. (SEM Pictures and schematic
the border between the rectum and urethra. The schematic drawing © Dietrich Kluth)
drawing shows the situation in a rat embryo ED 14. Note
Fig. 20 Normal (a) and abnormal hindgut (c) in hetero- fistula). The cloacal membrane (CM) is too short. In
zygous SD-mouse embryos. Note that in the abnormal (b, d) the findings are summarized in schematic drawings.
hindgut, the dorsal cloaca, which contains the area of the A future bladder, U ureter, W WOLFF duct, HG rectum
future anus, is completely missing. As a result, the rectum (hindgut), C “cloaca,” TG tail gut. (SEM Pictures and
keeps in contact with the urethra too high (so-called schematic drawing © Dietrich Kluth)
Abnormal Development In all affected embryos, we made the following

As already mentioned, a number of animal models observations (Fig. 20a–d):
exist which allow embryological studies of abnor-
mal hindgut development. In our studies we used (a) Compared to normal embryos (Fig. 20a, b),
embryos obtained from SD-mice. The SD-mouse is we found abnormally shaped cloacas. The
a spontaneous mutation of the house mouse, char- dorsal part was always missing (Fig. 20c, d).
acterized by a short tail (Fig. 5). Homozygous or (b) The cloacal membrane was always too short
heterozygous offspring of these mice shows skele- (Fig. 20c, d). In all cases the dorsal part of the
tal, urogenital, and anorectal malformations (Kluth cloacal membrane was absent.
et al. 1991). Therefore, these animals are ideal for (c) The proximal hindgut joined the cloaca at an
detailed studies of anorectal malformations. abnormal position (Fig. 20c, d).
Figure 21 summarizes the developmental pro- Impairment of this process of fusion is thought
cesses in a sketch. to result in the different forms of hypospadias
(Gray and Skandalakis 1972b). In order to get
more information about this process, we studied
Development of the External Genitalia the formation of the external genitalia in staged rat
and the Urethra embryos and fetuses (Kluth et al. 1988, 2011a).
Many investigators (Felix 1911; Spaulding 1921; Normal Development of the External
Glenister 1958) believe that the urethra develops Genitalia
by fusion of the paired urethral folds (Fig. 22) This study was carried out in normal rat embryos
which takes place following the disintegration and fetuses between embryonic day 17.5 (Fig. 22)
(rupture) of the ventral part of the cloacal mem- and embryonic day 20 (Fig. 24).
brane, the so-called “urogenital membrane.”
Fig. 21 Hypothetical line of events in anorectal “cloaca” is missing, which normally contains the area of
malformations. (a) In young embryos, the cloacal mem- the future anal canal. (c) The rectum remains attached to
brane is too short. (b) As a result, the dorsal part of the the future urethra. (Schematic drawing © Dietrich Kluth)
Fig. 22 Normal genital development. It is a common urethral sulcus, SS scrotal swelling. In (b) the phallus of
assumption that the “cloacal membrane” ruptures not a normal rat embryo is shown. In this age group
only in the dorsal (anal) part but also in the ventral (ure- (ED 17,5), the sex of the embryo cannot be estimated by
thral) part. This would lead to a situation as depicted in (a). the appearance of the outer genitals. (SEM Picture ©
AP anal pit, GP glans penis, UO urethral opening, US Dietrich Kluth)
Fig. 23 Rupture of the

dorsal cloacal membrane in
a rat embryo (ED 17.5).
(a, b) The rupture of the
membrane is clearly seen.
(c) In high magnification
the situation is visible in
detail. Half of the genitals is
removed by micro
preparations. The tip of the
urorectal fold can be seen
(URF). Ventrally the
opening of the urethra is
seen (UO). The rectum (Re)
opens dorsally (AO). Fusion
of the URF with the cloacal
membrane, as assumed by
some researchers, does not
take place. EC ectoderm,
CP cloacal plate, d Ur distal
urethra, p Ur proximal
urethra. (SEM Pictures ©
Dietrich Kluth)
(a) Rupture of the cloacal membrane (Fig. 23). A rupture of the ventral part of the cloacal
At embryonic day 17.5, the dorsal disinte- membrane cannot be seen in older embryos
gration of the cloacal membrane can be seen and fetuses. In males, the transient urethral
(Fig. 23a, b). The ventral (urethral) part of the opening disappears. Later a “raphe” is seen
cloacal membrane remains intact. In Fig. 23c, in this position (Fig. 24a). In females, this
this process of disintegration is seen in more “raphe” is missing (Fig. 24b).
detail. The ectodermal part of the cloacal (c) Special dissections of a rat embryo at
membrane shows clear signs of disintegra- embryonic day 18.5 allow the following
tion. The tip of the urorectal fold is seen statements (Fig. 25a–c): The urethra is com-
which later forms the perineum. Ventral to posed of two parts, the proximal and the
the tip of the urorectal fold, an opening is distal part. The epithelium of the distal part
seen which is in connection to the distal ure- reaches to the tip of the phallus. It is inter-
thra. Dorsally the anal opening is seen. At this esting to see that the urethra is connected to
time point, the external genitals allow no dif- the perineal region by a short canal, the
ferentiation between the sexes. so-called “cloacal canal.” In our opinion
(b) Further development of the external genitalia. this is the future female urethra.
Fig. 24 Rat fetuses ED 20, (a) male rat, (b) female rat. male phallus. This raphe is not the result of fusion, as
The sex is discernable by external inspection of the geni- generally believed. In female rats this “raphe” is missing.
tals. Note the “raphe” (*) in (a), which is typical for the (SEM Pictures © Dietrich Kluth)
Summarizing our results we found: with a female-type urethra. Origin of this malfor-
mation complex is an undifferentiated stage as
(a) In rats, the urethra is always present as a may be seen in the 18.5-day-old rat embryo.
hollow organ during urethral embryogenesis
and that it is always in contact with the tip of
the genitals. The Development of the Midgut
(b) Initially a double urethral anlage exists. The
differentiation in female and male urethra Traditional Theories
happens in rats more than 18.5 days old. Traditionally, the midgut development is
(c) We had no evidence for the disintegration of described as a process of “rotation.” In this pro-
the urogenital cloacal membrane and a fusion cess the following parts are involved: the distal
of lateral portions within the perineum. part of the duodenum, the small bowel, and most
parts of the big bowel. The process of rotation
Abnormal Development of the External takes place in two phases (Mall 1898; Frazer and
Genitalia (Hypospadia Formation) Robbins 1915):
In our opinion, more than one embryological
mechanism is at play in the formation of the (a) In the first phase, the midgut loop develops
hypospadia complex (Kluth et al. 1988, 2011a). inside the umbilicus (so-called “physiological
The moderate degrees, such as the penile and herniation of the midgut”). Here, a 90-anti-
glandular forms, represent a developmental arrest clockwise rotation around the axis of the mes-
of the genitalia. They take their origin from a entery is thought to take place.
situation comparable to the 20-day-old embryo. (b) After the “return” of the midgut into the
Consequently the penis, not the urethra, is the abdominal cavity, another anti-clockwise
primary organ of the malformation. Perineal and “rotation” of 180 is thought to take place
scrotal hypospadias are different from the type inside the abdominal cavity (second phase).
discussed previously. Pronounced signs of femi- As a result, the region of the cecum moves to
nization in these forms suggest that we are dealing the right, thus overcrossing the mesenteric
Fig. 25 Phallus of a rat ED

18.5. (a) The sex is not
discernable by external
inspection. The lateral
portion of the phallus and
the lateral wall of the
urethra are removed. p Ur
proximal urethra, d UR
distal urethra, Re rectum.
(b) The sketch describes the
situation in (a): p Ur
proximal urethra, d UR
distal urethra, CC urethral
opening in females. Note
that the urethra in this stage
is not sexually determined.
The female urethra is short
and ends at the CC opening.
(c) The male urethra is
formed by the distal urethra,
which extends to the tip of
the phallus. Sy symphysis,
Ur urethra, C cloacal
membrane, Re rectum.
(SEM Pictures and
schematic drawings ©
Dietrich Kluth)
root, while the flexura duodeno-jejunalis is (a) A central part with the duodenum and the
pushed to the left beneath the root of the distal colon close to the root of the mesentery.
mesentery (see schematic drawing in (b) A ventral part inside the extra embryonic coe-
Fig. 1b) (Mall 1898; Frazer and Robbins lom of the umbilicus (so-called “physiologi-
1915). These two phases sum up 270 . In cal herniation”). Here the cecum and the distal
contrast to this description, Grob (1953) sub- small bowel can be identified.
divides this intra-abdominal process of rota- (c) A middle part which connects the central part
tion into two steps of 90 each. with the ventral part inside the umbilicus. Here
the umbilical vessel, the small bowel on the
Own Observations right, and the proximal part of the colon on the
We studied midgut development in rat embryos left can be seen (Figs. 26b and 27d).
using SEM (Figs. 26, 27, and 28) (Metzger 2011a;
Kluth et al. 1995b, 2003). Starting at embryonic In the further development (ED 14–16),
day 13, the following parts of the midgut loop can growth activities are seen in the area of the duo-
be seen (Fig. 26a): denum and inside the extraembryonic coelom.
Fig. 26 Normal development of the midgut. (a) Rat development of the central part, the duodenal loop (du), is
embryo ED 13. The early midgut consists of three parts: seen. Note that the duodenojejunal junction is pushed
a central part with the primitive duodenal loop (du), an beneath the root of the mesentery (arrows in c). This is
extraembryonal part in the extraembryonic sac of the umbi- caused by longitudinal growth of the duodenum. sb mall
licus (ce), and a straight part in between (sb). (b, c) The bowel loops, li liver. (SEM Pictures © Dietrich Kluth)
Figure 26 shows the steps important for the to the formation of bowel loops inside the umbi-
duodenal developmental. In Fig. 26b (rat embry- licus and, later, inside the abdominal cavity. The
onic day 15) the duodenojejunal loop has been growth activity of the large bowel is minimal,
formed due to longitudinal growth of the duode- compared to that of the small bowel. Neither in
num. Further growth pushes this loop beneath the the phase of loop formation inside the extraem-
root of the mesentery (Fig. 26c). bryonic coelom of the umbilicus nor in the phase
Figure 27 shows the development of the intra- following the “return” of the gut into the abdom-
umbilical loops. These loops are the result of inal cavity rotation of the gut around the axis of
longitudinal lengthening of the small gut. Note the mesentery can be observed. All processes in
the absence of any signs of rotation around the midgut development are the result of longitudinal
axis of the mesentery in Fig. 27d in a phase of lengthening of gut.
active loop development inside the extra embry-
onic coelom.
Figure 28 shows the “return” of the midgut into Testicular Descent
the abdominal cavity. The cecum is seen inside the
abdominal cavity in a ventral position close to the Since John Hunter in 1762, many researchers
abdominal wall (embryonic day 17). The colon is studied the embryology of testicular descent. In
entirely to the left in this phase of development. It is many of these studies, the importance of the
a small bowel loop which is still extraembryonic gubernaculum during this process has been
inside the umbilicus. In this phase of small bowel highlighted. However, a clear illustration of this
“return,” the bowel loops have already developed rather simple process is still lacking (Heyns and
locally inside the abdominal cavity (Fig. 26c). Hutson 1995).
We conclude from our observations that the Today, most researchers in the field (Heyns
midgut can be subdivided in three parts, of 1987; Hullinger and Wensing 1985; Wensing
whom the central and the ventral parts are of 1988; Hutson et al. 2015) see two developmental
major importance. Localized longitudinal growth phases during testicular descent:
in the area of the duodenum leads to the formation
of the duodenojejunal loop and its final position (a) The intra-abdominal descent: In this phase,
beneath the root of the mesentery. At the same the testis, which initially lies in close contact
time, localized growth of the small bowel has led to the kidney, moves into the inguinal area.
Fig. 27 Normal development of the midgut. (a) Rat ED inside the extraembryonic sac of the umbilicus. Arrows
13. The cecum and the most distal part of the small gut indicate the direction of growth. (d) Note that during
are seen in the extraembryonic sac of the umbilicus. this process, rotation around the axis of the mesentery
Dotted arrows indicate the border between extraembry- does not take place. ce cecum, sb small bowel, co colon,
onic and intraembryonic coelom. (b, c) Rapid lengthen- mV mesenteric vessel. (SEM Pictures © Dietrich Kluth)
ing of the small bowel leads to the formation of loops
(b) The inguinal descent: In this phase the testis both gonads are initially in close approximation
moves into the area of the scrotum. to the kidneys.
Starting at embryonic day 16.5, the testis
We (Fiegel et al. 2010, 2011) studied the mor- moves away from the lower pole of the kidney.
phology of testicular descent in rat embryos On ED 19 the testis is located between the lower
between embryonic day 15 and 20 using SEM in kidney pole and the roof of the bladder
order to illustrate in detail the various steps of the (Fig. 30a) and moves toward the bladder neck
testicular development. While in rat embryos at at ED 21 (Fig. 30b). This brings the intra-
embryonic day 15 male and female gonads look abdominal descent to an end and the inguinal
still identical (Fig. 29a), they become clearly dis- descent starts.
tinguishable in rats of embryonic day At the end of the intra-abdominal descent
16 (Fig. 29b). The male gonad is getting thicker (ED 22), the bulb of the gubernaculum is still
and slightly shorter than the female gonad, but visible. (Fig. 31a). A little later, around birth
Fig. 28 Normal development of the midgut. Rat ED 17. (arrow). Co colon, du duodenum. (b) Higher magnification
(a) The cecum (ce) is found in the abdominal cavity. A of the area of the ventral body wall. Ce cecum, co colon.
small bowel loop is still outside in the umbilical sac (SEM Pictures © Dietrich Kluth)
(embryonic day 22), the bulb disappears partially

and the processus vaginalis peritonei (PVP)
develops (compare with Fig. 31b). Notice the
rest of the bulb at the lower pole of the PVP. In
this phase, the corda of the gubernaculum is still
visible and attached to the caudal part of the
epididymis, which has entered the PVP. At birth
and later, the testis finally enters the PVP
(Fig. 31c).
The Role of the Gubernaculum

In our series, we studied the formation and the
fate of the gubernaculum (Fig. 32). In rat
embryos at embryonic day 16, the gubernaculum
consists of two parts, the gubernacular bulb and
the corda of the gubernaculum (Fig. 32a). The
corda is rather attached to the lower anlage of the
epididymis (Fig. 32a–c) than to the testis, as it is
often described in the literature. Furthermore, it
is often assumed that the testis is pulled down-
ward by corda and bulbus. While this – in initial
stages – seems to be morphologically possible,
we identified later stages, where the testis and
Fig. 29 Descensus of the testis. Rat ED 15, female rat in (a),
male rat in (b). Notice the difference in the size of the male
gubernaculum were positioned in such a way
and female gonads (go). Both gonads lie in close approxima- that pulling of the testis by the gubernaculum
tion to the kidneys (ki). (SEM Pictures © Dietrich Kluth) seems to be impossible (Fig. 32c, e).
Fig. 30 Testicular descent: intra-abdominal descent close to the bladder in the inguinal area. This movement
(first phase). (a) Male rat, ED 19. The gonads relative to the urinary bladder cannot be attributed to the
(go) have lost contact to the lower pole of the kidneys relatively ascent of the kidneys. (SEM Pictures © Die-
(ki) and lie in the middle portion between the kidney and trich Kluth)
bladder (bl). (b) Male rat, ED 21. The gonads are now
Fig. 31 Testicular descent: inguinal descent (second by arrows. The epididymis has entered the PVP. The
phase). (a) Male rat ED 21. The testis (T ) has reached corda of the gubernaculum is still visible. (c) Male
a position close to the inguinal region. The bulbic newborn D 1–5. Not only the epididymis but also half
gubernaculum (GB) is still present. BL bladder, AE of the gonads (T ) has entered the PVP. The
epididymis. (b) Male newborn rat, D 0. The bulbic gubernaculum has completely disappeared. Arrows
part of the gubernaculum (GB) disappeared, and the mark the border between the peritoneal cavity and
processus vaginalis peritonei is formed (PVP). The the PVP. AE epididymis. (SEM Pictures © Dietrich
border between peritoneal cavity and PVP is marked Kluth)
Thus in our findings, we cannot support the We believe that intra-abdominal pressure
opinions about the role of the gubernaculum probably plays an active role at least in the
during the testicular descent. Its main role phase of the inguinal phase of testicular
seems to be its transformation into the PVP. descent.
Fig. 32 Testicular descent: in this series of SEM pictures, researchers believe that tension caused by the corda is at
the morphology of the gubernaculum is shown (rat ED 19). play during testicular descent. However, the morphology
(a, b) Here the gubernaculum consists of two parts, the of the insertion zone of the corda into the anlage of the
corda of the gubernaculum (arrows in a, b) and the bulbus epididymis shown in (a, b) speaks against this assumption.
of the gubernaculum (GB). The corda inserts rather into the Sketch on the left shows expected morphology (traction!)
caudal anlage of the epididymis (AE)/mesonephric ridge versus observed morphology on the right. AE epididymis,
than into the testis (T ), as often assumed. BL bladder. (c) T testis, GB bulbus of the gubernaculum. (e) The sketch
While in (a, b) tension caused by the gubernaculum seems summarizes our morphological data on the developmental
to be theoretically possible, (c) demonstrates that the testis sequence of the testicular descent. (SEM Pictures and
(T ) is rather blocked by the bulb of the gubernaculum (GB) schematic drawings © Dietrich Kluth)
than pulled. Rat ED 21, AE epididymis. (d) Many
abnormalities and their embryogenesis. Pediatr Surg

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The Epidemiology of Birth Defects
2
Edwin C. Jesudason
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Birth Prevalences Are the Cornerstone of Birth Defects Epidemiology . . . . . . . . . . . . . . . . 36
Why Is It Important to Collect Birth Defects Data? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
The Practical Challenges of Birth Defects Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Ethical and Scientific Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
On the “Causation” of Birth Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Birth Defects Epidemiology and the Pediatric Surgeon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
Abstract genetic investigations. Instead, it may be more

Birth defects are emerging as the leading cause helpful to see birth defects as complex systems
of infant death worldwide. Their epidemiologi- problems, akin to surgical errors. As such, better
cal investigation was prompted by the recogni- understanding of birth defects may require sur-
tion of congenital rubella syndrome and of geons equipped with “engineer style” training in
thalidomide-related phocomelia. Pediatric sur- statistics, modelling, and complex dynamic sys-
geons require good data on birth defects as a tems, rather than the current vogue for molecular
baseline for reporting their own outcomes. biology approaches. Finally, birth defects are
Hence, birth defects data are the foundation to sensitive to widely different influences ranging
quality control and improvement in neonatal from assisted reproduction to depleted uranium
surgery. However, good epidemiological study weapons. So for a broad swathe of population
of birth defects is challenged practically by lim- health issues, birth defects may provide an early
ited resources and dispersed populations and warning signal – that can be heeded only with
scientifically by prioritization of reductionist proper epidemiological measurement.
Keywords
E. C. Jesudason (*) Birth defects · Epidemiology · Epigenomics ·
NHS Lothian, Edinburgh, UK Complex systems · Teratology · Fetal
e-mail: ejesudason@caltech.edu;
diagnosis and therapy
edwin.jesudason@nhslothian.scot.nhs.uk

https://doi.org/10.1007/978-3-662-43588-5_2
36 E. C. Jesudason
Introduction large and unknowable numbers of defects that

will be missed over a given census period due to
Through human history, the most feared outcomes unrecorded miscarriage and the like.
of pregnancy have included maternal death and That said, birth prevalences are not straightfor-
birth defects. As affluence has increased, mothers ward either. Databases differ in whether they will
now die far less often. However, affluence also include terminations for defects and also the cir-
affords technologies for assisted reproduction and cumstances in which they will include fetal deaths
more lethal warfare that both appear to swell the as stillbirths or exclude them as miscarriages. The
ranks of children born with birth defects (Davies latter choice is commonly made according to ges-
et al. 2012; Hindin et al. 2005). With the decline in tational age, but unhelpfully some registries use a
deaths from infectious disease, birth defects will weight cutoff instead. Given that many of these
soon be the leading cause of infant mortality (Car- defects are rare, methodological choices like these
mona 2005). can produce large artifacts in overall birth preva-
For many pediatric surgeons, birth defects rep- lences (Duke et al. 2009).
resent a small but important sample of their over- Fortunately, concerted investment in multina-
all work – either because rates are relatively low – tional registries like EUROCAT has smoothed
or afflicted children do not live to reach them. some of these differences, allowing clinicians a
However, if neonatal surgeons are properly to readier comparison between countries and over
judge their outcomes and to advise expectant par- time. Inevitably, however, human choices over
ents, they need to have regard for the epidemiol- measurement are associated with their
ogy of particular birth defects in their catchment – corresponding problems.
and to have a feel for which of the above best One such is the issue of “terathanasia,” which
explains their local rates. has been suggested as a mechanism by which
Modern birth defects epidemiology arose from folate reduces the birth prevalence of neural tube
two hazards that became apparent during the defects (Stockley and Lund 2008; Wald 1991).
course of the last century. The first was the recog- The argument goes that folate may in fact
nition of congenital rubella as a distinct malfor- enhance fetal loss in cases of neural tube defect
mation syndrome – and the later insight that this (Hook and Czeizel 1997). If this loss occurs
problem could be subdued through vaccination earlier and gets classified as miscarriages, the
programs (Monif et al. 1965; Condon and Bower apparent birth prevalence of the particular defect
1993). The second were the children with missing falls, even though the drug is increasing the
limb segments – whose mothers, badly sickened losses overall.
by pregnancy, had tried thalidomide as a refuge
from nausea and vomiting (Taussig 1962). These
children with phocomelia warned clinicians of the Why Is It Important to Collect Birth
need for greater watchfulness, not just for ancient Defects Data?
infections but also modern drugs (Khoury 1989).
Given these problems, one might ask why regis-
tries strive to collect such data? The first reason is
Birth Prevalences Are the Cornerstone that pediatric surgeons need to judge their results
of Birth Defects Epidemiology in light of true prevalences and with proper appre-
ciation of any hidden mortality, in order to
Birth defects epidemiology rests on the counting improve care (Dindo et al. 2010). Neonatal sur-
of a particular birth anomaly within an overall geons have a particular need to contend with the
cohort of births. This generates a birth prevalence problem of “hidden mortality” as described by
rather than, as is often quoted, a birth incidence. Harrison et al. for congenital diaphragmatic her-
Birth incidences are impractical because of the nia (CDH) (Harrison et al. 1978). Jaffray et al.
2 The Epidemiology of Birth Defects 37
showed that neglecting the presurgical deaths in is worthwhile to try and understand these prob-
CDH led to over optimistic estimates of CDH lems and to underpin the planning and provision
survival (Stege et al. 2003). Therefore, birth of services.
defects epidemiology sets a kind of baseline Fourth, the developing human is constantly
under later audits in neonatal surgery. threatened by the evolution of infectious disease,
Second, the advent of antenatal ultrasound to by new drugs, and by other chemicals. Birth
screen for birth defects has made it important to defects monitoring is essential to ensure that new
collect data so that worried parents can be prop- agents do not repeat the disasters seen with rubella
erly informed. This is a responsibility that the and with thalidomide. For example, certain strains
profession must bear for the parents, having over- of influenza pose a greater risk to pregnant
seen the introduction of such diagnostic tech- women, prompting advice that they be vaccinated.
niques. However, even though parental However, the safety profile of such vaccination
counselling and ultrasound screening rely on epi- can only sensibly be judged by epidemiological
demiological information, the screening itself examination of their birth cohort relative to
may confound good data collection: parents may unvaccinated cohorts (Pasternak et al. 2012).
seek to terminate, meaning that cases can be mis- Influenza is only one example where evolving
sed from any census without the knowledge of the infectious diseases will continue to pose new
researchers; alternatively, new awareness of the threats. So continual surveillance is needed both
defect may add to the count of such birth defects to check for effects of the agent itself and for the
(where previously none would have presented); impact of any countermeasures we may
screening may change a host of treatment choices recommend.
that impact on final outcome. Congenital lung Fifth, there is emerging evidence that certain
malformations fall into this category, where types of childhood cancer are more common in
some lesions would likely not have presented those children who have had birth defects
were it not for prenatal diagnosis. Congenital dia- (Carozza et al. 2012; Botto et al. 2013). This risk
phragmatic hernia is another example where birth is not shared by all defects and does not seem to
prevalences and outcomes are important for the apply to all pediatric cancers. However, the asso-
advisement of parents when considering the value ciation is an important and instructive one. In
of fetal interventions (Harrison et al. 2003). In the adults the strongest population risk factor for can-
CDH field, surgeons have spent the last decade cer is age. In children, this does not apply straight-
trying to establish whether tracheal occlusion is forwardly. Instead, childhood cancer could be
better than best postnatal management. All the seen as more of a developmental defect, where
while, investigators have struggled with epidemi- even largely normal cells persist abnormally or get
ological questions. For example, is the antenatally stuck at abnormal locations where their onward
treated group representative of all comers or are fate then becomes cancerous (Carter et al. 2012).
some CDH cases being terminated beyond the In this paradigm, it is important to pick up the
notice of fetal surgeons? Regarding prognosis, children with birth defects and to be able to follow
do measures of fetal lung size prospectively dis- them over time in order to understand the different
tinguish those CDH fetuses who will survive possible links between the original lesion and the
without prenatal intervention, from those who subsequent tumor.
will not? (Ba’ath et al. 2007). Finally, good birth registries can help fight
The third reason to audit birth defects is that, as the crime of selective female feticide, by
well as becoming the leading cause of infant mor- pinpointing where and how these children dis-
tality, they are also associated with preterm birth appear from the record (Abrejo et al. 2009). This
and with long-term disability (Lumley 2003). is a vast problem that can be highlighted, by
Both are hugely costly both emotionally and thoughtful epidemiological study of births and
financially, so study of birth defects epidemiology birth defects.
38 E. C. Jesudason
The Practical Challenges of Birth follow them closely ab initio. In this approach,
Defects Epidemiology birth defects epidemiology can become the cor-
nerstone for improved surgical audit from the
Ascertainment problems reverberate throughout neonatal period onward (Horton 1996, 2010).
the practice of neonatal surgery to affect issues
ranging from birth defects data to postnatal prob-
lems like necrotizing enterocolitis (NEC) (Duke Ethical and Scientific Considerations
et al. 2009; Stege et al. 2003; Boyd et al. 2005;
Forrester and Merz 2001). In the UK, NEC is now There is an argument that epidemiological study
the leading cause of postsurgical death in children of birth defects is a moral good because improved
(NCEPOD 2011). As a problem of the preterm, it understanding helps to remove the fear and blame
is more common in those with birth defects and historically associated with congenital anomalies.
early hospitalization. Yet our data collection in By showing how birth defects are common and
this population leaves much to be desired. In a how they feature in every population, clinicians
recent UK audit of deaths after surgery in chil- can help parents struggling with unwarranted feel-
dren, major units simply failed to submit case ings of personal guilt. The importance of this for
notes in more than 60% of deaths. The auditors the parents, their affected child, and indeed other
were unable to do more than ask again but to no siblings should never be disregarded (Horan
avail (NCEPOD 2011). This illustrates that col- 1982). Similarly, good birth defects surveillance
lection of data for surgical outcomes in neonatal can assuage public panic when novel threats are
surgery leaves substantial room for improvement perceived, whether from new medicines, infec-
in the twenty-first century. tions, or technologies. The public is often keen
In well-resourced countries, it is hard to under- to learn if new agents pose a risk to them or to their
stand why such data collection remains so prob- unborn children. Without proper registries, clini-
lematic. One may conclude simply that surgeons cians are condemned to tackle such questions
do not accord such data reporting the priority it from a position of ignorance, which only exacer-
deserves. Failures to collect birth defects data are bates population fears (Yu et al. 2005).
more comprehensible in settings where mothers Then there is the case that epidemiological
live in remote regions, undergo seasonal migra- study can help not only with the practical man-
tion, or are nomadic. In such circumstances, birth agement of birth defects but also in the longer-
defects epidemiology may appear to be a low term scientific understanding of such lesions.
priority relative to the daily challenges of subsis- Day-to-day, surgeons treat individual patients
tence. However, this would be to overlook an providing an invaluable perspective. However
important opportunity to understand population from this vantage, clinicians may struggle to see
health and even the scientific basis of birth or explain broader changes in disease patterns. For
defects. For example, Africa features the greatest example, in recent years, epidemiological study
human genetic diversity in the world, so studies has confirmed surgeons’ hunches that, for reasons
there are well placed to pinpoint any roles for that are unclear, the prevalence of gastroschisis
genetic variation in the origins of human malfor- has risen (Kilby 2006; Fig. 1). The identification
mation, or other diseases too (Campbell and of new factors to explain this trend will most
Tishkoff 2010). likely require prior and ongoing surveillance of
Investment in good birth defects registries is birth defects.
one strategy to try and embed comprehensive data Specifically, gastroschisis has been linked with
collection at the earliest stage in the life course. young maternal age, vasoactive drugs, and subtle
The aim is then to recapture these children, first clotting defects – the latter two supporting the
identified at birth, as they progress and develop. thesis that the defect results from a late vascular
Children with birth defects remain at higher risk insult that leads to involution of part of the
of needing further surgery, so it makes sense to abdominal wall (Feldkamp et al. 2007). However,
metabolic syndrome, but there is reason to believe

that it applies to other organ systems too. In this
model, population health depends on maternofetal
health, so birth defects monitoring becomes a
barometer for societal well-being.
The scientific enquiry into birth defects can of
course dig deeper than epidemiological pattern
recognition. But even for more sophisticated
genomic study of birth defects, index cases need
collecting and tracking to minimize bias from
missing cases. So even if unmoved by the clinical
and practical reasons for birth defects monitoring,
it is clear that registries are a vital stepping stone
for large genomic investigations looking for fun-
damental causes. This type of scientific investiga-
tion is important not only for the individual birth
defects but also for what it tells us about such
defects in general and also what it can tell the
parents about causation. Here, there is an unfortu-
nate tendency to elide congenital with genetic,
i.e., to take what was present at birth, as genetic.
This manifests as a tendency to pretend each con-
genital anomaly has a gene defect that is respon-
sible and lends itself to popular narratives
characterized as “the race to find the gene for
Fig. 1 “Liver-out” gastroschisis in a newborn (Image used
courtesy of the author) X.” As far as possible, this unhelpful thinking
needs to be addressed empirically (Lippman
1992; Gilbert and Sarkar 2000; Ahn et al. 2006).
epidemiological surveillance has continued to add Rational genomic investigation of birth defects
valuable information to this mix. Injuries to should really focus resources on African
mothers during pregnancy are not uncommon. In populations due to their greater genetic diversity
fact intentional abusive injuries are well recog- (Campbell and Tishkoff 2010). Surgeons are often
nized. Associated with this are certain birth a little surprised and skeptical about this, imagin-
defects including gastroschisis (Tinker et al. ing instead that the greatest genetic diversity lies
2011). In this model, the abdominal wall defect in the mixed populations of the new world. How-
may still arise from clotting, but the latter may ever, the greater genetic diversity in Africa is
occur as a result of a maternal injury response. straightforwardly explicable. Imagine each
Without birth defects epidemiology, we have little human genome represented by a particular choice
way to explore such potential causes in our search of playing cards from the deck of 52. For the
for mechanism and prevention. This exploration larger part of human history, this “deck of cards”
becomes more important when it is appreciated was under development in Africa. When almost
that many adult diseases, often lifelong and all the deck had been “finalized,” groups of
expensive, appear to be set up by prenatal life humans left Africa with their card subsets, to
(Barker 2007). So birth registries can measure colonize distant lands. Hence, the diversity of
fetal health to help understand the coming burden populations derived from this diaspora is limited
of adult disease and the preparations necessary to more or less to the genomes with which their
meet it. This thesis is most fully expanded for ancestors migrated away. Therefore, genetic
cardiovascular health, hypertension, and the diversity in Africa exceeds that in other
40 E. C. Jesudason
continents. This has major but still unaddressed correct. For example, isolated duodenal atresia,
implications for medical research in general and often but not inevitably, is associated with
genomic research in particular. Current genome- Downs, and it often has a good prognosis – sub-
wide association studies are often performed in very ject to any cardiac lesion (Grosfeld and Rescorla
selected groups within the human species. This has 1993).
every potential to omit key discoveries with great The second set of defects that confront sur-
potential. So even if there is some significant and geons are the late ones, and here the example is
knowable genetic basis to common non-syndromic gastroschisis, an abdominal wall defect of uncer-
birth defects, it is important not to neglect the most tain origin. The contested argument made with
diverse populations from the search (de Vries et al. gastroschisis and its associated small bowel atre-
2011). And a key way to engage them is through sias is that they result from relatively late vascular
perinatal care and birth defects monitoring. accidents (Feldkamp et al. 2007; Curry et al.
So far, it appears that few of the common birth 2000). This is contrasted with omphalocele – an
defects arise from a single gene defect. When such early lesion that is sometimes multisystem and
genetic causes fail to materialize, it is tempting to genetically based. Again, however, none of these
race off toward the next big thing – epigenetics or stories is straightforward. For example, intestinal
similar (Bernal and Jirtle 2010). Imprinting can atresias can be induced in genetic knockout mice
help understand syndromes like Beckwith- where they would seem to be early events (Nichol
Wiedemann and Angelman (Piedrahita 2011). et al. 2011; Fairbanks et al. 2005). Similar uncer-
However, it is also unlikely that all birth defects tainties are present for a host of other defects too.
will have a simply defined and modifiable epige- In CDH, it is unclear how the diaphragmatic
netic cause. Though initially, unsettling these defect relates to the lung one and whether the
observations are also liberating: they mean that Bochdalek lesion is a failure of closure of the
in few cases do parents have to worry about pleuroperitoneal canals or a separate hole (Keijzer
repeated transmission of a problem to the next et al. 2000; Jesudason et al. 2000).
child. And for this reason, they may experience It would seem therefore that the distinction
less guilt. While all this is helpful, it may be between early and late lesions has utility mainly
unsettling for the pediatric surgeon who is being in reminding clinicians when they need to look
asked to provide an answer to why this happened. most diligently for associated anomalies. Its
For this reason, it is necessary to say something explanatory power in terms of mechanism is per-
here about types of birth defects and their possible haps not as strong as once believed. The famous
causes. experiments to induce small bowel atresia in pups
by ligating the mesentery in utero, show only one
way to arrive at the lesion, not necessarily the way
On the “Causation” of Birth Defects (Nichol et al. 2011); the same point is more obvi-
ous in the field of CDH with its various surgical
Conventionally, it has been helpful to teach that and nonsurgical models, each of which can pro-
birth defects fall into two groups, early and late. duce a type of lung hypoplasia (Jesudason 2002;
The early ones are genuine problems in morpho- Mortell et al. 2006).
genesis, and as early events, often associate with Perhaps because genomics for birth defects
other anomalies. In this context, one can include, has failed to yield target after target, there has
e.g., duodenal atresia or esophageal atresia, with been a swing back toward interest in the
their major structural lesion and common associ- mechanics of development, i.e., toward a theory,
ation with other malformations (Pedersen et al. for at least some defects, where physical forces
2012; Spitz et al. 1994). It has been tempting to contribute significantly to the observed pheno-
assume that these earlier lesions have a poorer type (Nelson et al. 2005; Nelson and Gleghorn
prognosis and are more likely to harbor a genetic 2012). Here, however, might be a good point to
cause. However this is not straightforwardly call a truce and to consider an alternative and
more practical way to see birth defects and their down the landscape to emerge between any num-
epidemiology. ber of potential valleys, the final choice reflecting
In this view, birth defects are complex phe- the phenotype (Waddington 1942). In this model,
nomena with multiple inputs, ranging from the development is about “canalizing” the organism,
genome to physical forces (Gilbert and Sarkar reducing its potential forms into an actual one.
2000; Goldberger et al. 2002). In that regard, Again, if Waddington is right, it may be somewhat
they are similar to surgical errors in as much as nonsensical to expect every birth defect to yield an
the majority are systemic failures that arise when ultimate cause. Instead much of what presents as
several circumstances align (McCulloch and birth defects to pediatric surgeons may represent
Catchpole 2011; Reason 1995, 2000). In compar- just the stochastic error inherent in any program
ison, surgeons do not seek the genomic reasons for normal development. Added to this, perturba-
for the surgical error. Moreover, there is an accep- tions at vulnerable phases may then change the
tance that some error is inevitable in any human final phenotype by tipping Waddington’s ball
system – not that this excuses efforts to reduce from one valley to the next. Fortunately, most of
it. By analogy, birth defects are propensities development is robust to challenges like this, but
waiting to be realized when various circumstances it can be seen that a short infection (rubella), a
align (Reason 1995, 2000). In other words, human drug exposure, or even a physical trauma at a
development is a program that has evolved to critical time may suffice to tilt the system. There-
yield mostly normal newborns but which has a after, the program will still work but now leads on
finite and inherent error rate. Therefore, it is con- to produce what we call a birth defect.
ceivable that many birth defects arise simply from Here, the difference between congenital and
variation in the normal program, without needing genetic becomes very sharp. Antenatal events
to posit a trigger lesion as a cause (Elowitz et al. may have little or nothing to do with genetics,
2002). but be manifest as congenital defects (Tinker
In this model, there are multiple ways to et al. 2011). So the effort to find every case and
arrange the trachea and esophagus, the most com- to sequence every nucleic acid needs to be viewed
mon of which is the normal anatomy. However, if with some circumspection. Not only is there the
for any reason this lowest free energy route is not present cost and distraction of pursuing such
claimed, then the organism defaults, not to ran- research enterprises, there is the longer-term ques-
domness (any type of connection or lack thereof), tion about whether children’s genetic privacy is
but to an ordered constellation of anomalies that being given up before they are old enough to
arise with predictable frequency. So the Type C decide on this for themselves (de Vries et al.
atresia is the next commonest variant – itself 2011; Grosse et al. 2010). We have already seen
echoing aspects of older evolutionary anatomy. that anonymity can readily be breached by careful
Similarly with imperforate anus, if normality comparison of “anonymized” genomic studies
does not develop there is a default to older ver- and publicly available named data (Homer et al.
sions like the cloaca. 2008; Wjst 2010; Hayden 2013). If genomic
If most birth defects represent error rates inher- screening is not going to yield what we need,
ent within a normal program then it makes less why subject children to it at the beginning of
sense striving to extract every piece of genetic life? (Slaughter 2007).
data on them. It may be more helpful to look at By comparison, birth defects epidemiology
the distribution of lesions between populations to can provide information for parents, surgeons,
test if the same alternative forms arise with the and service providers at a fraction of the current
same frequencies when the normal path of devel- costs of genomic studies. Investing in these regis-
opment is not achieved (Pedersen et al. 2012). tries may also help determine to what extent com-
This view of development accords with mon birth defects represent the inherent error rate
Waddington’s famous epigenetic landscape in of the human development program. This is a
which the organism is represented as a ball rolling serious question given the tendency to cut
42 E. C. Jesudason
resources for such databases, even as genetic stud- these trainees may be better off studying complex
ies are advanced. In many countries, the resources dynamic systems so they can apply this to both
do not yet exist for large genetic studies, and it birth defects and to surgical safety (Lippman
would be a pity if they were distracted from the 1992; Gilbert and Sarkar 2000; Goldberger et al.
simpler task of collecting good data on birth 2002). In this context, a systems approach to birth
defects first (Boyd et al. 2005; Grosse et al. 2010). defects represents a generic education for dealing
with complex dynamics in healthcare (McCulloch
and Catchpole 2011; Reason 1995, 2000).
Birth Defects Epidemiology Similarly, a fuller training in statistics may be
and the Pediatric Surgeon very helpful for surgeons to inform their patients.
A recent study suggested that birth defect rates
At the end of the discussion above, a pediatric were doubled in babies of first cousin marriages in
surgeon could be forgiven for feeling over- the Born in Bradford study (Sheridan et al. 2013).
whelmed by the uncertainty and complexity of However, as the astute accompanying commenta-
the situation, and rather put off by the inability tor noticed, this represented a rise from about
to give simple concrete answers as to why certain 3–6%, which was the same uplift in risk associ-
birth defects arise. Reflection will however ated a maternal age of 34 years or more. Similarly,
emphasize that this discomfort is useful. First, it the expert commentator unearthed some paradox-
simulates in small measure the confusion and lack ical relationships with smoking, showing that a
of control experienced by parents when keen sense of statistics and an appreciation of
confronted by a birth defect (Horan 1982). Sec- research are each helpful to interpreting papers
ond, it helps reinforce that whatever the relatives (Bittles 2013). Together, this shows that surgeons
may opine, the cause of birth defects is rarely also need to be alive to the power and pitfalls of
straightforward and almost never reducible to an research data in this evocative field.
act or acts during pregnancy or periconceptual life. Having established that birth defects epidemi-
It is easy to forget how much human society ology is important and that surgeons need to know
craves explanation and – next to that – blame about it, where do surgeons go for this type of
(Wright 2010). With each new birth defect, the information? Unfortunately, many surgical
focus of attention can rapidly become the parents, reports on birth defects have been small institu-
even at the time they are most vulnerable. Sur- tional series with inadequate power to explain.
geons can act as protectors and advocates for the Therefore calls for greater registration of
parents, by emphasizing what is not known as patients in trials and databases are well founded.
well as what is; by standing by the idea that such Such registries can help surgeons use better data.
defects are usually manifestations of complex Both EUROCAT (http://www.eurocat-network.
systems that are inherently unpredictable. How- eu/accessprevalencedata/prevalencetables) and
ever, some surgeons may insist on reductionist the International Clearing House for Birth Defects
explanations, or argue it is a “cop out” not to (http://www.icbdsr.org) are good starting
discuss cause. It is ironic therefore that when resources for surgeons wishing to know more
they err in theatre, the same surgeons adhere to about this topic (Pedersen et al. 2012). Books
complex system explanations that tend not to like this provide useful pointers as do colleagues
apportion individual responsibility (Cuschieri in clinical genetics who, despite their name, will
2003). often catalogue unusual anomalies without obvi-
The systems approach also has consequences ous cause.
for the training of pediatric surgeons. It will be Applied scientists can also be a useful resource –
appreciated that time spent peering into the genet- because complex systems are frequent in engi-
ics of birth defects using highly atypical murine neering and safety (Davidz and Nightingale
models may not be the best investment for the 2008; Park and Park 2004). Their insights can
surgical trainee or their future patients. Indeed, help surgeons to move beyond linear models
reliant on the central dogma of molecular biology. Table 1 Birth prevalence of malformations 2007–2011
Not only is DNA insufficient to explain all birth grouped by EUROCAT category. Note rates for each cate-
gory are inclusive of cases with chromosomal lesions and
defects, but the information that it carries is derived from registries with EUROCAT membership
dwarfed by that carried, e.g., in posttranslational
Live birth + fetal death +
modifications like glycosylation (Turnbull and termination/10,000 births
Field 2007). This point – perhaps nonobvious at Organ system (to 2 s.f.)
first – is that glycosylation and other posttransla- All 210
tional processing vastly diversify the tertiary Congenital heart 65
structures determined strictly by the genome. disease
This reinforces how genomic information may Limb 35
be fundamentally insufficient to explain birth Chromosomal 29
defects: e.g., intrauterine influences from the envi- Urinary 27
ronment could instead be transduced via altered Nervous system 20
Genital 19
posttranslational protein modifications (Thomp-
Digestive system 14
son et al. 2007, 2009, 2010, 2011).
Orofacial clefts 13
Therefore, pediatric surgeons need access to
Other malformations 10
wide expertise to best advise families with birth Respiratory 5.4
defects – at times of great need, misunderstanding Abdominal wall 5.3
and fear. A humbling uncertainty surrounds much defects
of what is taught and told academically about such Genetic syndromes + 3.8
defects. Frank sharing of this can help the parents microdeletions
understand that they are not alone in their struggle Eye 3.5
to understand their new reality. For the time being, Ear, face, neck 2.8
surgeons have to begin with the data currently Teratogenic 1.0
syndromes with
available. The tables included here show the malformations
commonest birth defects by organ system
(Table 1) and then list those that are likely to
present to pediatric surgeons (Table 2). The data track the impacts of adverse weather, earthquakes,
is drawn from the EUROCAT databases and is or even impeding flu epidemics (Hattori and Ieee
therefore subject to the important caveats listed on 2012). Store purchases may also give an early hint
their website. of such events. Given what store chains can divine
about individual lifestyles, it remains to be seen
whether their techniques, such as collaborative
Conclusion and Future Directions filtering, can be used to identify obscure risk fac-
tors for birth defects (Cho et al. 2002). Certainly,
It has been argued here that birth defects are best the present generation of children are perhaps the
interrogated with a systems approach rather than first in which a store card records most purchases
via molecular biology. A similar shift away from to which they have ever been exposed. At present,
linear drug-receptor paradigms in non- this seems like an area ripe for exploration.
communicable adult diseases may alleviate the Another advance that one may see is the intro-
current stagnation within the blockbuster drug duction of near patient interfaces that allow the
pipeline (DiMasi et al. 2004). parent to enter more of their information and that
Computing is more powerful than ever and of their child in cases of birth defects. Shifting
data storage becoming relatively cheap (Stein data ownership may be an effective way to
2010). Therefore tantalizing possibilities exist to increase participation, particularly when
use bigger data to delve into birth defects epide- resources for dedicated data gatherers are scarce.
miology. For example, scientists have been able to The question then arises whether nations, rich
use social media like Facebook and Twitter to and poor, are building healthcare teams equipped
44 E. C. Jesudason
Table 2 Birth prevalence of malformations of relevance future. By this standard, birth defects monitoring
to pediatric surgery (2007–2011) grouped by diagnosis provides an early warning system for humanity as
from registries with EUROCAT membership. Note rates
for each category are inclusive of cases with chromosomal a whole. Therefore, if climate change exerts subtle
lesions; (b) these are birth prevalences (including fetal effects, it may be that these will be detected first in
death/terminations) and not necessarily the prevalences at the birth prevalences of key defects (Rylander
pediatric surgical units et al. 2011; Van Zutphen et al. 2012; Auger et al.
Live birth + fetal death + 2017). Similarly, increased use of genetically
termination/10,000 births modified crops seems likely to fuel public demand
Anomaly (to 2 s.f.)
for good data on birth defects – to ensure that risk
Downs 18
to humans is minimal (Islam and Miah 2006).
Hypospadias 14
Finally, areas of Iraq exposed to depleted uranium
Congenital 7.8
hydronephrosis shells report increased birth defect rates (Hindin
Spina bifida 4.3 et al. 2005; Marshall 2008; Busby et al. 2010).
Edward’s 3.9 Disturbingly, the World Health Organization is
Anorectal 2.7 alleged to have been complicit in efforts to sup-
malformations press this “bad news” (Ahmed 2013). Birth
Diaphragmatic hernia 2.3 defects epidemiology is often difficult in peace-
Exomphalos 2.5 time, so it is understandable there would be con-
Gastroschisis 2.4 troversy about conflict-related birth defects.
OA/TOF 2.2
However, healthcare professionals have a respon-
Duodenal atresia/ 1.1
stenosis
sibility to speak truth to power even on these
Bilateral renal 0.90
uncomfortable matters. Otherwise, Katz high-
agenesis lights how technical language, and rhetoric can
Hirschsprung disease 0.90 be used all too expediently to ignore the true depth
Intestinal atresia/ 0.70 of even major problems (Katz 1992).
stenosis
CCAM 0.70
Posterior urethral 0.68
valves/prune belly Cross-References
Indeterminate sex 0.59
Bladder exstrophy/ 0.55 ▶ Clinical Research and Evidence-Based Pediat-
epispadias ric Surgery
Situs inversus 0.55 ▶ Embryology of Congenital Malformations
Amniotic band 0.41
▶ Fetal Counseling for Congenital Malformations
Biliary atresia 0.21
▶ Fetal Surgery
Conjoined twins 0.14
▶ Long-Term Outcomes in Newborn Surgery
▶ Pediatric Clinical Genetics
to do such work. Medicine is still taught around

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Prenatal Diagnosis of Congenital
Malformations 3
Tippi C. MacKenzie and N. Scott Adzick
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Amniocentesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Chorionic Villus Sampling (CVS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Biochemical Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Percutaneous Umbilical Blood Sampling (PUBS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Fetal Cells in the Maternal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Prenatal Diagnosis of Specific Surgical Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Neck Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Sacrococcygeal Teratoma (SCT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Congenital Chest Lesions: Congenital Pulmonary Adenomatoid Malformation and
Bronchopulmonary Sequestration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Congenital Diaphragmatic Hernia (CDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Gastrointestinal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Esophageal and Bowel Atresias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Abdominal Wall Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Prenatal Diagnosis of Renal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Upper Urinary Tract Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Lower Urinary Tract Obstruction (LUTO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
T. C. MacKenzie (*)
Eli and Edythe Broad Center for Regeneration Medicine,
Fetal Treatment Center, University of California, San
Francisco, CA, USA
e-mail: Tippi.Mackenzie@ucsfmedctr.org
N. Scott Adzick
The Division of Pediatric General and Thoracic Surgery,
The Center for Fetal Diagnosis and Treatment, Children’s
Hospital of Philadelphia, Philadelphia, PA, USA
e-mail: Adzick@email.chop.edu
# Springer-Verlag GmbH Germany, part of Springer Nature 2020 49

https://doi.org/10.1007/978-3-662-43588-5_3
50 T. C. MacKenzie and N. Scott Adzick
Myelomeningocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Abstract mode of delivery and, in some cases, may lead to

The convergence of progress in genetic and elective termination of the pregnancy. In rare
radiographic methods for prenatal diagnosis cases, various forms of in utero therapy may be
now makes it possible to diagnose most con- possible (Table 1).
genital anomalies early in gestation. Thus, it is Multidisciplinary care and nondirective
now possible to accurately counsel affected counseling are the crux of appropriate prenatal
families about their prognosis and to plan for management of most congenital anomalies. The
appropriate perinatal care using a multi- perinatal care of the patients involves many dif-
disciplinary team approach. In rare cases of ferent medical disciplines, including obstetri-
severe or fatal anatomic abnormalities, fetal cians, sonographers, neonatologists, geneticists,
intervention may be offered by experienced pediatric surgeons, and pediatricians. It is essen-
centers. In this chapter, we discuss common tial that the affected family be treated using a team
prenatal diagnostic tools as well as the man- approach and that information and experience be
agement strategies for patients with surgical exchanged freely.
diseases such as neck masses, congenital dia- Prenatal diagnosis has defined a “hidden mor-
phragmatic hernias (CDH), lung masses, tality” for some lesions such as congenital
sacrococcygeal teratomas (SCTs), and diaphragmatic hernia (CDH), bilateral hydro-
myelomeningocele. There are strategies that nephrosis, sacrococcygeal teratoma (SCT), and
have been developed through decades of expe- cystic hygroma. These lesions, when first
rience with animal models and collaborative
analysis of clinical outcomes worldwide. Our
understanding of the underlying disease pro- Table 1 Diseases amenable to fetal surgical intervention
cesses that contribute to prognosis is rapidly in selected cases
evolving and will continue to refine the current Effect on
recommendations for these patients. Malformation development In utero treatment
Congenital Pulmonary Tracheal
diaphragmatic hypoplasia, occlusion and
Keywords hernia respiratory release
Prenatal diagnosis · Fetal surgery · Congenital failure
anomalies CPAM or BPS Pulmonary Maternal steroids,
hypoplasia, thoracoamniotic
hydrops shunting,
lobectomy
Introduction Sacrococcygeal Massive Excision
teratoma arteriovenous
Advances in prenatal diagnosis now allow accu- shunting,
placentamegaly,
rate identification of many congenital anatomic
hydrops
defects so that affected families may be counseled Urethral Hydronephrosis, Vesicoamniotic
appropriately. For most congenital malformations obstruction lung hypoplasia shunting, laser
diagnosed in utero, planned delivery at term can ablation of PUV
allow appropriate medical and surgical therapy Myelomeningocele Damage to the Closure of defect
after birth. The benefit of prenatal diagnosis is spinal cord,
paralysis
that the process can influence the timing or the
3 Prenatal Diagnosis of Congenital Malformations 51
evaluated and treated postnatally, demonstrate a nervous system, the ability to obtain cross-
favorable selection bias. The most severely sectional imaging has made this tool a crucial
affected fetuses often die in utero or immediately adjunct to ultrasound for many pediatric surgical
after birth, before an accurate diagnosis has been diseases, including measurement of lung sizes in
made. Consequently, such a condition detected CDH and evaluation of airway anatomy in neck
prenatally may have a worse prognosis than the masses. Although the modality is sometimes lim-
same condition diagnosed after delivery. ited by patient comfort at later gestational ages,
In this chapter, we will present a brief summary improvements in scanning techniques continue to
of commonly used diagnostic methods and then bring MRI to the forefront of prenatal diagnosis.
review the prenatal diagnosis of several pediatric
surgical diseases.
Amniocentesis
Ultrasound Amniocentesis has become the gold standard for

detecting fetal chromosomal abnormalities.
It is now routine to perform a prenatal evaluation Amniocentesis is usually performed at
of fetal anatomy by ultrasound for almost all 15–16 weeks’ gestation and involves a very low
pregnancies. It is especially important to per- risk of fetal injury or loss. However, amniocente-
form ultrasound screening for pregnancies with sis earlier in gestation (11–12 weeks) can entail a
maternal risk factors (e.g., age over 35 years, higher rate of pregnancy loss, increased risk of
diabetes, previous child with anatomic or chro- iatrogenic fetal deformities, and increased post-
mosomal abnormality) and if there is an eleva- amniocentesis leakage rate. For this reason, the
tion in maternal serum alpha-fetoprotein most reliable method for first trimester diagnosis
(MSAFP). Most defects can be reliably diag- remains chorionic villus sampling. In addition to
nosed in the late first or early second trimester screening for the most common chromosomal
by a skilled sonographer. Early in gestation, abnormalities using karyotyping, modern
nuchal translucency measurements can often sequence analysis and microarrays have revolu-
detect chromosomal abnormalities. Since these tionized our ability to detect small deletions or
measurements can be made by transvaginal duplications that are not apparent with
ultrasound at 10–15 weeks’ gestation, ultra- karyotyping. A recent study comparing the effi-
sound can be a critical early test for high-risk cacy of karyotyping to microarray determined that
pregnancies. Nuchal cord thickening may also the latter is more sensitive in identifying small
be a marker for congenital heart disease and may deletions and duplications in 6% of samples with
be a valuable initial screen to detect high-risk a normal karyotype but less sensitive in identify-
fetuses for referral for fetal echocardiography. It ing balanced translocations or fetal triploidy
is important to remember that sonography is (Wapner et al. 2012). Given the expense of micro-
operator-dependent; the scope and reliability of array analysis and the realization that it sometimes
the information obtained is directly proportional reveals copy number variations of uncertain clin-
to the skill and experience of the sonographer. ical significance, it is currently reserved for
patients in whom there is a high pretest suspicion
for genetic abnormalities.
MRI
Fetal MRI has greatly enhanced our ability to Chorionic Villus Sampling (CVS)
diagnose and treat fetal malformations. The use
of ultrafast scanning techniques has eliminated the CVS involves sampling the chorion frondosum,
artifacts caused by fetal motion. While MRI is the precursor for the placenta, using either a trans-
most commonly used to evaluate the fetal central cervical or transabdominal approach under
ultrasound guidance. Since CVS may be Fetal Cells in the Maternal Circulation
performed at 10–14 weeks’ gestation, it can be a
useful test for patients with advanced maternal age Maternal-fetal cellular trafficking is the bidirec-
and other risk factors for chromosomal anomalies. tional passage of cells between the fetus and the
Similar to amniocentesis, the cells obtained may mother during gestation, which has clinical impli-
be subjected to a variety of tests including karyo- cations for multiple diseases. Since fetal cells cross
type, microarray analysis, and enzymatic activity. into maternal blood, the detection of fetal cells and
However, CVS can lead to diagnostic errors due to cell-free DNA in the maternal circulation could
maternal decidual contamination or genetic mosa- form the basis for a noninvasive method of prenatal
icism of the trophoblastic layer of the placenta. genetic diagnosis. While the number of intact cells
When performed by experienced operators, the in the circulation is limited, amplification of fetal
pregnancy loss rate is equivalent to second trimes- cell-free nucleic acids using real-time polymerase
ter amniocentesis. chain reaction (PCR) has growing utility in early
prenatal diagnosis (Maron and Bianchi 2007).
Fetal DNA can be detected reliably by 9 weeks
Biochemical Markers and increases with gestational age. This method
can be used for gender determination in the first
Fetal anomalies such as Down’s syndrome and trimester (if Y chromosome sequences are found,
neural tube defects are associated with elevations the fetus is male and, if not, assumed to be female)
of particular enzymes in maternal blood, which and can thus be helpful in counseling for X-linked
forms the basis for biochemical screening. One of disorders. Rhesus factor determinations are also
the most common prenatal diagnostic tests is the accurate and can avoid unnecessary treatment of
so-called triple test, which includes measuring Rh-negative mother if the fetus is also negative. In
serum alpha-fetoprotein with human chorionic the future, it may be expanded to detecting pater-
gonadotropin and unconjugated estriol. This nally inherited single gene mutations. Non-invasive
screening is performed in the early second trimes- prenatal testing is becoming the routine screening
ter, and the detection rate for Down’s is 69%, with test for prenatal diagnosis of aneuploides.
a 5% false-positive test (Wald et al. 1997). A
positive result on the serum screening test indi-
cates a need for chromosome analysis by Prenatal Diagnosis of Specific Surgical
amniocentesis. Lesions
Neck Masses
Percutaneous Umbilical Blood
Sampling (PUBS) Prenatal diagnosis and appropriate management
can be lifesaving for fetuses with airway obstruc-
Although more invasive, obtaining fetal blood tion. The fetal airway can be compromised either
directly from the umbilical cord allows the ability due to extrinsic compression from a solid tumor
to diagnose various metabolic and hematological such as a cervical teratoma or due to intrinsic
disorders. For diseases such as Rh disease, the defects in the airway such as congenital high
technique can also allow transfusion of the fetus. airway obstruction syndrome (CHAOS).
The procedure is performed at around 18 weeks’ Although large congenital neck masses causing
gestation under ultrasound guidance. In various airway obstruction previously carried an enor-
large series, the mortality from the procedure has mous perinatal mortality, the advent of the ex
been reported to be 1–2%, with increasing mor- utero intrapartum treatment (EXIT) procedure
tality with long procedure times and multiple (Mychaliska et al. 1997) has improved their out-
punctures. come by providing a means of controlling the
airway during delivery and converting an airway

emergency into an elective procedure.
Cystic hygroma is a severe diffuse lymphatic
malformation which is frequently associated with
hydrops, polyhydramnios, and other abnormali-
ties. Chromosomal abnormalities are very com-
mon. There are two groups of prenatally
diagnosed cervical lymphangiomas: those diag-
nosed in the second trimester are usually in the
posterior triangle of the neck, have a high inci-
dence of associated abnormalities, and carry a
very poor prognosis (Gallagher et al. 1999).
Those diagnosed later in gestation are most often
isolated lesions and generally do not lead to
hydrops. Hydrops is an ominous finding in fetuses
with cystic hygroma, and it is important to mon-
itor the fetus for development of hydrops by serial Fig. 1 EXIT procedure for giant neck mass (Adapted
from Mackenzie and Adzick 2011, reprinted with
evaluations.
permission)
Cervical teratomas are asymmetrical lesions
that are frequently unilateral, with well-defined
margins. They may also be multiloculated, irreg- intubation are performed (Fig. 1). If the airway
ular masses with solid and cystic components. cannot be secured in this way, a rigid broncho-
Most teratomas contain calcifications. Fetal MRI scope is inserted to determine the anatomy. If
is a very useful adjunct to ultrasound in evaluating necessary, a tracheostomy can be performed.
giant neck masses in defining the position of the After securing the airway, surfactant is adminis-
airway with respect to the mass and the presence tered for premature fetuses, the cord is clamped,
of tracheal deviation and esophageal compres- and the infant is taken to an adjacent operating
sion. T1-weighted images may help differentiate room for resuscitation. In a recent review of 87
teratomas from lymphangiomas. Careful mapping EXIT procedures, we found that the EXIT proce-
of the airway allows adequate preparation for the dure is a safe mode of delivery for patients with
various strategies to secure the airway during the giant neck masses and potential airway obstruc-
EXIT procedure. tion at birth. We had a 100% success rate in
The EXIT procedure, originally designed for accessing the airway under placental support,
removal of tracheal clips in patients with CDH and the procedure-related mortality rate was
(Mychaliska et al. 1997), has proven lifesaving for zero. The success of an EXIT procedure depends
many fetuses with giant neck masses or large oral on a thorough evaluation of the prenatal images
lesions. This procedure involves performing a for surgical planning and a highly skilled multi-
maternal hysterotomy and obtaining control of disciplinary team approach (Laje et al. 2012).
the fetal airway while the fetus remains on pla- The EXIT procedure has also been useful in the
cental support. In order to prevent uterine contrac- perinatal resuscitation of fetuses with a range of
tions during the procedure, the mother is given anomalies expected to cause hemodynamic com-
inhalational anesthetic and tocolytics, warm promise at birth, such as giant lung masses (EXIT
saline is infused through a level I device, and to resection), CHAOS, severe congenital heart
only head and shoulders of the fetus are delivered. disease with CDH (EXIT to extracorporeal mem-
After attaching a pulse oximeter to the fetal hand brane oxygenation, ECMO), and even
to monitor heart rate and oxygen saturation, direct thoracopagus conjoined twins with a single
laryngoscopy and, if possible, endotracheal heart. The most critical component of the EXIT
procedure is deep inhalational anesthesia, which

maximizes uteroplacental blood flow to avoid
fetal hypoxia. It is therefore critically different
from a Cesarean section and carries the risk of
significant maternal blood loss if there is not care-
ful coordination between the surgical and anes-
thetic teams.
Sacrococcygeal Teratoma (SCT)
Sacrococcygeal teratoma is the most common

newborn tumor and may arise due to misdirected
migration of primordial germ cells during devel-
opment. The Altman classification defines four
types with differing prognoses: type 1 tumors are
external, with at most a small presacral compo-
nent and carry the best prognosis. Type 2 tumors
are predominantly external with a large
intrapelvic portion. Type 3 lesions are predomi- Fig. 2 MRI of large sacrococcygeal teratoma (Adapted
nantly intrapelvic with abdominal extension with from Mackenzie and Adzick 2011, reprinted with
only a minor external component and type permission)
4 lesions are entirely intrapelvic and abdominal.
The latter have the worst prognosis since they are by the release of vasoactive compounds from the
difficult to diagnose, sometimes less amenable to edematous placenta. As with other fetal masses,
surgical resection, and frequently malignant at the the development of hydrops is a grave sign.
time of diagnosis because of the delay in diagno- The prediction of which fetuses with SCT are
sis. Overall, prenatally diagnosed SCT has a at highest risk for developing hydrops is the crit-
worse prognosis than those diagnosed at time of ical issue in prenatal management. A thorough
birth. prenatal evaluation with US, MRI, and fetal echo-
On prenatal ultrasound, SCT appears as a cardiography is important in defining such a
mixed solid and cystic lesion arising from the group. Factors such as rapid tumor growth and
sacrum. The tumor frequently contains calcifica- large solid component have been associated with a
tions. Since there is acoustic shadowing by the higher risk of developing hydrops. Since hydrops
fetal pelvic bones, it is not always possible to is likely an indicator of hemodynamic compro-
determine the most cephalad portion of the mise, echocardiographic measurements are supe-
tumor by ultrasound. Fetal MRI (Fig. 2) may rior to anatomic ones in defining the worst cases.
determine the intrapelvic dimensions of the For example, in a recent evaluation of numerous
tumor as well as the presence of hemorrhage. echocardiographic measurements in fetuses with
Those fetuses with mainly solid and highly vas- SCT and twin reversed arterial perfusion syn-
cular SCT have a higher risk of developing drome (TRAP), measurements indicating high
hydrops. High-output cardiac failure may occur output were correlated with worse outcome
as a result of the hemodynamic effects of the large (Byrne et al. 2011). These include a high cardio-
blood flow to the tumor, and anemia from hemor- thoracic ratio, combined cardiac output (CCO)
rhage into the tumor may compound this problem. >550 ml/kg/min, aortic valve regurgitation, and
In severe cases, the mother with placentamegaly aortic or mitral Z score >2. In another series
develops “mirror syndrome,” a severe preeclamp- (Wilson et al. 2009), rapid tumor growth
tic state with vomiting, hypertension, proteinuria, (>150 cm3/week) and a high CCO identified a
and edema. This phenomenon may be mediated group of fetuses with a higher risk of prenatal
mortality. The solid component of the mass is an can be microcystic, macrocytic, or both. Prenatal
important prognostic indicator: a recent report ultrasound can generally distinguish individual
showed that when the solid tumor volume is nor- cysts in macrocystic disease, while microcystic
malized to the head volume, fetuses with a ratio lesions usually have the appearance of an
<1 all survive, whereas those with a volume >1 echogenic, solid lung mass. Bronchopulmonary
have 61% mortality (Sy et al. 2009). Recently the sequestration (BPS) is an aberrant lung mass that
Cincinnati Fetal Center reported that the overall is nonfunctional and usually has a systemic blood
survival rate to discharge was 25% in patients supply. It may be difficult to distinguish micro-
with hydropsfetalis, 67% in patients with high cystic CPAM from BPS on ultrasound. Indeed,
cardiac output status in utero, and 100% in there is growing evidence that the two lesions
patients with normal fetal cardiac output (Peiro may be related embryologically, with several
et al. 2016). reported cases of hybrid lesions which have
Prenatal interventions for SCT include cyst CPAM-like architecture and a systemic blood sup-
aspiration (for those with a dominant cystic comply. Some of these lesions may decrease in size
ponent), amnioreduction (for those with severe, during prenatal period, but postnatal evaluation is
symptomatic polyhydramnios), amnioinfusion still warranted to detect residual disease for resec-
(for those with bladder outlet obstruction, to facil- tion because of the risk of pulmonary infections
itate placement of a vesicoamniotic shunt), or and the development of tumors such as
open fetal surgery for resection of the mass. The pleuropulmonary blastoma.
latter option should only be considered for fetuses The critical information needed for accurate
with impending high-output failure, rapid growth, prenatal diagnosis and counseling is the size of
type I lesion amenable to resection, and gesta- the lesion, the presence of large cysts that may be
tional age between 20 and 32 weeks. For fetuses amenable for drainage for large lesions, the pres-
older than 32 weeks and impending hydrops, ence of hydrops, and the presence of a systemic
emergent delivery with postnatal resection should feeding vessel. A combined approach with US
be considered. and MRI can answer these questions. MRI is
Fetal resection of SCT has led to some survi- useful in delineating the normal lung from abnor-
vors, but remains plagued by a high perinatal mal and in distinguishing BPS from the surround-
mortality, likely because a fetus that is already ing lung due to its high signal intensity and
moribund secondary to hydrops does not tolerate homogeneous appearance. However, ultrasound
the operation. It is important to note that the pur- is more accurate in demonstrating systemic feed-
pose of fetal resection is debulking, and a coming vessels.
plete oncologic resection is usually performed Fetuses with large chest masses can develop
postnatally. Given a high rate of preterm labor hydrops, which is the primary prognostic factor
after open fetal surgical resection, some groups for survival. While the exact cause of hydrops in
have attempted minimally invasive treatments these patients is not known, is it believed to be
such as radiofrequency ablation (RFA), but the secondary to obstruction of the vena cava or car-
difficulty in controlling heat from the RFA device diac compression from extreme mediastinal shift.
precludes widespread use of this approach. Historically, the development of hydrops has indi-
cated a grave prognosis with 100% mortality, and
it is important to predict which fetuses are at high
Congenital Chest Lesions: Congenital risk for this complication. The volume of the
Pulmonary Adenomatoid CPAM compared to the head circumference
Malformation and Bronchopulmonary (CPAM volume ratio, CVR) is an important prog-
Sequestration nostic indicator: fetuses with a CVR greater than
1.6 are more likely to develop hydrops
Congenital pulmonary adenomatoid malforma- (Crombleholme et al. 2002). It is also important
tion (CPAM) represents a spectrum of diseases to recognize that there is an expected period of
characterized by cystic lesions of the lung which growth during the second trimester, after which
steroids may be offered. In addition, the strategy

is only effective for microcystic CPAMs and is
less likely to be effective for macrocystic or mixed
lesions (Morris et al. 2009). The mechanism by
which steroids reverse hydrops remains unknown:
their beneficial effects cannot simply be ascribed
to reductions in the size or rate of growth of the
CPAM as there was variable growth in these
patients, and a natural growth plateau is well-
described. Further studies into the basic biology
of CPAM to understand how steroids may influ-
ence alveolar maturation or hydrops are areas of
active research interests in many laboratories.
Fig. 3 Ultrasound image of large CCAM following the
placement of a thoracoamniotic shunt. L lung (Adapted
permission Congenital Diaphragmatic Hernia
(CDH)
the mass usually gets smaller with respect to the
fetus. Therefore, CVR should be measured at The prenatal diagnosis and management of CDH
multiple consecutive visits. Fetuses with BPS continues to evolve. This disease is usually diag-
can also develop pleural effusions. nosed on a screening ultrasound evaluation,
For fetuses with a large macrocystic CPAM which can show herniated abdominal viscera,
containing a dominant cyst, or a large pleural abnormal upper abdominal anatomy, mediastinal
effusion causing pulmonary hypoplasia, shift away from the side of herniation, and, in
thoracoamniotic shunting (Fig. 3) may be lifesav- severe cases, polyhydramnios. The presence of
ing: in one series of 19 high-risk fetuses who abdominal contents seen in the chest on a trans-
underwent prenatal shunt placement (Wilson verse sonographic scan at the level of a four-
et al. 2004), survival was 67% (6/9) in the pleural chamber view of the heart is required for diagno-
effusion group and 70% (7/10) for the CPAM sis. The extent of pulmonary hypoplasia, which is
group, with an average age of delivery at 33+ a major contributor to postnatal morbidity, is pro-
weeks. portional to the timing of herniation, the size of
Fetuses with large microcystic CPAMs (thus the diaphragmatic defect, and the amount of vis-
not amenable for shunting) and signs of hydrops cera herniated. Right-sided CDH is less common
require a different approach. Although open fetal than on the left but is a more severe disease with a
surgery was initially performed, the recognition particularly high rate of prenatal complications
that maternal administration of steroids can such as polyhydramnios, premature rupture of
reverse hydrops has been an exciting new devel- membranes, and preterm labor (Hedrick et al.
opment in the antenatal management of this dis- 2004).
ease. Multiple centers have reported on the The best predictor of outcome in CDH has
experience with maternal steroids in large CPAM been the right lung-to-head circumference ratio
with CVR >1.6 and impending hydrops (Curran (LHR), defined as right lung area (measured at
et al. 2010; Morris et al. 2009; Peranteau et al. the level of the transverse four-chamber cardiac
2007). Overall, there are 31 reported patients with view) divided by head circumference (Fig. 4). The
microcystic CPAM with CVR >1.6 and/or utility of LHR in predicting survival has been
hydrops who were treated with steroids (reviewed validated in a recent multicenter trial (Jani et al.
in Curran et al. 2010), with resolution of hydrops 2006), with LHR <1 portending a very poor
in 80% and survival to discharge in 87%. If prognosis. The position of the liver is an indepen-
hydrops does not resolve, a second course of dent prognostic indicator. For example, fetuses
Fig. 4 Ultrasound of CDH at the level of the transverse

four-chamber view of the heart (H) showing measurements
used for LHR calculation on the right lung (L) (Adapted
permission)
Fig. 5 MRI of a CDH showing the liver (L) and stomach

who have an intrathoracic liver (“liver up”) need (S) in the chest (Adapted from Mackenzie and Adzick
ECMO more frequently than those with the liver 2011, reprinted with permission)
down (80% vs. 25%) and have a higher mortality
(45% vs. 93%) (Hedrick et al. 2007). Since the between normal and CDH lungs (Cannie et al.
growth rate of the lung during gestation is differ- 2009). Finally, MRI may better define the extent
ent from that of the head, the LHR is only prog- of liver herniation (Fig. 5), which carries impor-
nostic between 22 and 28 weeks’ gestation. To tant prognostic significance.
account for gestational age-related differences in The current approach to in utero treatment of
the LHR, the observed-to-expected (O/E) ratio CDH is tracheal occlusion with reversal, based on
has been developed, which normalizes the decades of refinement in both the lamb model and
observed LHR in a CDH fetus to that of a normal clinical experience. The basis for this approach is
gestational age-matched fetus. The prognostic the recognition that fetal tracheal occlusion leads
value of the O/E ratio has also been validated by to compensatory lung growth due to decrease in
a multicenter analysis, which determined a signif- lung liquid egress, as confirmed in lamb models of
icant correlation between the O/E and survival CDH. Although a subsequent randomized clinical
(Deprest et al. 2009a; Jani et al. 2007), such that trial comparing prenatal tracheal occlusion (using
fetuses with O/E <15% rarely survive, whereas a clip or balloon, but without reversal) did not
those with O/E >45% have excellent survival. show a treatment benefit (Harrison et al. 2003),
Given the challenges in accurately measuring this may have been secondary to a generous inclu-
LHR, many investigators have focused on devel- sion criteria (LHR <1.4) as well as preterm labor,
oping MRI measurements of lung volume in CDH which remains the Achilles’ heel of fetal surgery.
(reviewed in Victoria et al. (2013)). MRI has been It is now recognized that reversal of tracheal
used to calculate a fetal lung volume (FLV), which occlusion may confer more benefit. Thus, the
can be predictive of survival. MRI also has the current approach involves tracheal occlusion
potential to give information on lung function, using a percutaneous, fetoscopically placed bal-
which has not been possible by ultrasound. For loon (FETO) and subsequent reversal of occlusion
example, diffusion-weighted imaging (DWI) may prior to delivery (reviewed in Deprest et al. 2009b;
give insights into developmental differences Jelin and Lee 2009).
The European experience with fetal tracheal tracheoesophageal fistula, renal agenesis, and
occlusion and reversal has been quite favorable. limb defects).
In a multicenter trial of 210 patients with severe Duodenal atresia has a characteristic “double-
CDH (LHR <1 and liver up), FETO resulted in an bubble” appearance on prenatal ultrasound,
improved survival compared to historic controls resulting from dilatation of the stomach and prox-
(left CDH, 24.1–49.1%; right CDH, 0–35.3% imal duodenum. The incidence of associated
(P < 0.001)) (Jani et al. 2009). However, there malformations is high (57% in one recent series
was a high (47%) rate of PPROM and ten patients (Choudhry et al. 2009) (classically with Down’s
died due to difficulties with balloon retrieval. A syndrome and endocardial cushion defects)) and
similar approach is also currently offered at UCSF those who are prenatally diagnosed are more
for fetuses with LHR 1.0 with liver up, involv- likely to have associated anomalies (Choudhry
ing fetoscopic tracheal occlusion with a balloon et al. 2009). In a review of all small intestinal
catheter followed by fetoscopic retrieval. atresias, Hemming et al. (Hemming and Rankin
The realization that infants with severe CDH 2007) reported that 25% have chromosomal
succumb to pulmonary hypertension (more so anomalies and 25% have other structural
than pulmonary hypoplasia) has fueled interest anomalies.
in measuring prenatal surrogates of pulmonary
hypertension to guide counseling and manage-
ment. Fetal echocardiography may be used to Abdominal Wall Defects
measure surrogates of pulmonary hypertension
such as the pulmonary artery diameter as well as Omphalocele is a midline abdominal wall defect,
pulmonary artery reactivity to maternal hyper- usually near the insertion point of the umbilical
oxygenation (Broth et al. 2002). In addition, cord. This defect is usually characterized by her-
there is fetal production of inflammatory media- niated abdominal viscera covered by a sac, but in
tors that predicts the onset of neonatal pulmo- utero rupture can also be seen. Prenatal diagnosis
nary hypertension (Fleck et al. 2013), of omphaloceles should always prompt genetic
underlining the need to understand and treat the testing to rule out chromosomal abnormalities
physiologic pathways that lead to vascular such as Beckwith-Wiedemann syndrome, as well
remodeling. as echocardiography to rule out cardiac anomalies
such as pentalogy of Cantrell. Omphalocele may
also be seen as part of the OEIS sequence
Gastrointestinal Lesions (omphalocele, exstrophy of the bladder, imperfo-
rate anus, and spinal anomalies), requiring multi-
Esophageal and Bowel Atresias ple operations with considerable morbidity.
Patients with giant omphaloceles (containing pre-
Esophageal atresia (EA) is typically diagnosed on dominantly liver, with a defect >5 cm) can have a
prenatal ultrasound by the presence of a small or prolonged course with high long-term morbidity,
absent stomach bubble and polyhydramnios, but especially with respiratory and feeding difficulties
no ultrasound finding is sensitive or specific for (Biard et al. 2004).
esophageal atresia. While patients with pure EA Gastroschisis is a right-sided paraumbilical
are sometimes diagnosed prenatally, those with defect in which the intestine is exposed to the
the more common C-type EA with tracheoe- amniotic fluid. Ultrasound findings include free-
sophageal atresia are not usually diagnosed pre- floating bowel outside the abdominal cavity,
natally, since there is often a stomach bubble seen which may appear thickened due to peel forma-
prenatally. Esophageal atresia is associated with tion from exposure to amniotic fluid. Dilated
anatomic and chromosomal abnormalities, most loops of bowel may be seen from obstruction
notably trisomy 18 and VACTERL (vertebral secondary to protrusion from a small defect or
anomalies, anal atresia, cardiac anomalies, from the presence of an atresia, seen in 8–10%
in most series. The pathophysiology of bowel prevent in utero bowel damage must be tempered
damage is likely due to amniotic fluid exposure with the risks of prematurity in these infants,
and bowel constriction, the latter leading to ische- many of whom are small for gestational age. Bio-
mia and venous obstruction. In addition to bowel chemical characteristics of the amniotic fluid to
damage, which results in delayed ability to toler- quantify markers of fetal distress may carry prog-
ate feeds postnatally, many infants also have intra- nostic significance but are not currently used in
uterine growth retardation for unclear reasons: clinical practice. Regarding the mode of delivery,
70% are below the 50th percentile at birth (this it has been established that Cesarean delivery
number is overestimated on prenatal measure- (originally proposed to protect the exposed
ments, since the abdominal cavity is small bowel from further damage during birth) does
because of the defect) (Wilson and Johnson 2004). not appear to confer any outcome benefit (How
Patients with gastroschisis are usually catego- et al. 2000; Segel et al. 2001). Thus, the mode of
rized as simple (isolated gastroschisis, very low delivery for abdominal wall defects can be vaginal
mortality) vs. complex (those who also have except in cases of giant omphalocele, in whom the
bowel atresias, perforation, volvulus, or bowel risk of liver rupture and dystocia mandate a Cae-
necrosis and a higher mortality (28% in Molik sarian section. The issue of whether transport
et al. 2001; 8.7% in Abdullah et al. 2007)). The prior to delivery impacts outcome (secondary to
goal of prenatal ultrasound in gastroschisis is to ongoing ischemia and damage to the exposed
predict outcomes, usually measured as the time to intestines during transport) has also been studied
achieve full feeds after birth. Ultrasound charac- and, interestingly, does not appear to make a dif-
teristics such as bowel dilatation, bowel wall ference in one series (Murphy et al. 2007). The
thickening, and mesenteric flow have been stud- current strategy for management is serial ultra-
ied by many groups as possible prognostic indi- sounds to monitor for signs of fetal distress, with
cators. A recent review of 64 cases of planned delivery near term. Interestingly, there is
gastroschisis reported three in utero mortalities a higher rate of spontaneous preterm premature
(two fetal demises and one termination) with an rupture of membranes in patients with
overall postnatal mortality of 9%. Interestingly, gastroschisis (Barseghyan et al. 2012), which
prenatal ultrasound findings were not predictive should prompt appropriate counseling.
of the postnatal course for any of the parameters
examined (simple vs. complex, primary vs. silo,
hospital length, time to enteral feedings, etc.). In Prenatal Diagnosis of Renal Anomalies
addition, prenatal ultrasound can identify the rare
group of patients who develop strangulation of the Prenatally diagnosed hydronephrosis (HN),
exteriorized bowel, also known as “vanishing which includes dilated renal pelvis and calyces
bowel syndrome,” which can lead to short bowel with or without dilatation of the bladder and ure-
syndrome (Vogler et al. 2008). ter, represents a broad spectrum of diseases with
Careful prenatal analysis of the umbilical cord widely disparate prognoses (reviewed in Yiee and
insertion and all other anatomical features by Wilcox 2008). The Society for Fetal Urology
means of US and MRI is the key to determining defines four grades with increasing severity, with
the correct diagnosis. Accurate diagnosis is grade 1 being split pelvis only and grade 4 being
imperative for appropriate prenatal counseling, dilated pelvis with distended calyces and thinned
delivery planning and postnatal treatment of the parenchyma. In addition, an anterior-posterior
fetus carrying an abdominal wall defect (Victoria diameter >10 mm has been suggested as being
et al. 2018). predictive of fetuses who will need some postnatal
Prenatal diagnosis of gastroschisis has pro- intervention (Wollenberg et al. 2005). The differ-
mpted the question of whether the timing or ential diagnosis of prenatal hydronephrosis
mode of delivery should be altered in these includes ureteropelvic junction (UPJ) obstruction,
patients. With regard to timing, the urgency to multicystic kidney, primary obstructive
megaureter, ureterocele, ectopic ureter, and poste- of fetuses. Drainage of the bladder three times at
rior urethral valves. Severe, bilateral 48–72 h intervals with measurement of sodium,
hydronephrosis leads to oligohydramnios with a chloride, osmolality, calcium, β-2 microglobulin,
fetus small for gestational age. Prenatal and total protein should be performed to deter-
oligohydramnios carries significant pulmonary mine renal function. In this strategy, the later taps
morbidity. In addition, the lack of amniotic fluid indicate the characteristics of recently produced
hinders accurate ultrasound diagnosis of concur- urine, and a decrease in the electrolytes, proteins,
rent anomalies so that MRI is a useful adjunct to and tonicity correlates with a favorable outcome
help define the cause of hydronephrosis. (Wu and Johnson 2009).
The rationale for prenatal intervention origi-
nates from sheep models of the disease, in which
Upper Urinary Tract Obstruction bladder outlet obstruction in fetal lambs
reproduced the pulmonary hypoplasia and renal
The most common cause of prenatal HN is dysplasia seen in patients with bilateral obstruc-
ureteropelvic junction (UPJ) obstruction. The tive uropathy. Fetal intervention in prenatal
prognosis of prenatally diagnosed HN is excel- obstructive uropathy is only warranted in male
lent, especially if there is unilateral disease with- fetuses with oligohydramnios, bladder distention,
out significant dilatation of the renal pelvises. In and bilateral hydronephrosis (with no other abnor-
one large series, 80% were normal at 3 years and malities), who have improving urine profiles with
17% were normal at birth, suggesting spontane- serial bladder drainage. In female fetuses, LUTO
ous resolution of the problem (Kitagawa et al. is generally part of a complex cloacal anomaly,
1998). Only 17% needed surgical intervention. and fetal intervention has not been beneficial.
Prenatally diagnosed HN requires follow-up Male fetuses may be considered for
with ultrasound at birth and at 1 month. If there vesicoamniotic shunting or fetal cystoscopy with
is any evidence of abnormality, a voiding cystoscopic ablation of posterior urethral valves
cystourethrogram and diuretic renal scintigram (Smith-Harrison et al. 2015). More recently, fetal
should be performed (Johnson and Freedman microcystoscopy and mechanical disruption of
1999). PUV have been reported. This method is promis-
ing in that it provides a more physiologic method
for bladder drainage.
Lower Urinary Tract Obstruction Although vesico-amniotic shunting in a fetus
(LUTO) with oligohydramnios can be technically chal-
lenging, the survival benefit of prenatal shunting
The most common cause of lower urinary tract in carefully selected populations of fetuses has
obstruction is posterior urethral valves (PUV); it is been reported. In a recent series of 18 patients
also seen in prune belly syndrome and urethral who had VA shunts for PUV (Bouchard et al.
atresia (Wu and Johnson 2009). In addition to 2002), prune belly syndrome (Bouchard et al.
attendant renal dysplasia, the most important fac- 2002), and urethral atresia (Mychaliska et al.
tor in the morbidity and mortality from fetal ure- 1997; Biard et al. 2005), the outcomes were that
thral obstruction is pulmonary hypoplasia eight patients have good renal function, four have
secondary to oligohydramnios (Nakayama et al. mild renal insufficiency, and six required hemodi-
1986). For patients with posterior urethral valves, alysis with subsequent transplantation. Respira-
prenatal diagnosis defines a subgroup of patients tory problems and frequent urinary tract
with very poor prognosis, with 64% incidence of infections were seen in eight and nine patients,
renal failure and transient pulmonary failure, com- respectively. While short-term outcomes are vari-
pared to 33% in the postnatally diagnosed group able in different reports, a recent prospective reg-
(Reinberg et al. 1992). Serial fetal urine analysis istry of pregnant women with male fetuses with
may provide prognostic information in this group LUTO, who were given the option of either
conservative management or vesicoamniotic

shunting showed that the majority of fetuses
with LUTO received conservative management,
which was associated with better short- and long-
term outcomes. A significant proportion of these
pregnancies had normal amniotic fluid volume
and a gestational age at diagnosis of 24
weeks, characteristics shown to be associated
with improved survival (Morris et al. 2015).
Myelomeningocele
Myelomeningocele (MMC) is the most common

form of spina bifida, affecting 1 in 2,000 births per
year. It is a neural tube defect characterized by the
protrusion of the spinal cord and meninges Fig. 6 Ultrasound of fetus with MMC showing the sac
(crossmarks) over the spinal defect (arrow) (Adapted from
through open vertebral arches. Prenatal diagnosis Mackenzie and Adzick 2011, reprinted with permission)
is usually secondary to maternal serum testing
with elevated serum AFP, which can be followed
by testing of the amniotic fluid to confirm the of ventriculoperitoneal shunting, as well as motor
diagnosis. The ultrasound characteristics include function in the prenatal surgery group (Adzick
the “lemon” and “banana” signs which are et al. 2011). As expected, there was a higher rate
scalloping of the frontal bone and abnormal ante- of preterm delivery after fetal intervention. If fetal
rior curvature of the cerebellar hemispheres, repair is not performed, fetuses with MMC should
respectively. Most fetuses have an associated be delivered by planned Caesarian section to
Arnold-Chiari malformation, characterized by avoid trauma to the cord during the birth process.
the caudal displacement of the vermis and cere-
bellum with midbrain herniation through the fora-
men magnum. Ultrasound confirmation can be Conclusion and Future Directions
made as early as 18 weeks, which allows locali-
zation of the defect (Fig. 6) as well as assessment Prenatal diagnosis of fetuses with anatomic and
of limb function and the presence of clubbing or genetic abnormalities has made it possible to
of the Arnold-Chiari malformation. define the natural history of these abnormalities,
Analysis of the potential benefits of fetal repair determine the pathophysiologic causes that affect
of MMC has been accomplished in sheep models outcome, and formulate management based on
of the defect, thus providing a compelling reason prognosis. Since many congenital anomalies are
for in utero repair, the first nonlethal disease to be associated with others, it is important to perform a
considered for this treatment. The goals of fetal careful ultrasound evaluation and genetic analysis
repair are to prevent the chemical and mechanical when one abnormality is discovered. Although
trauma to the exposed spinal cord, to resolve the most prenatally diagnosed conditions do not
hindbrain herniation frequently seen with this require fetal intervention, the process allows
defect, to decrease the need for postnatal ventricu- appropriate counseling and perinatal management
loperitoneal shunting, and to allow time for pos- of the affected family. In select cases, open or
sible neural regeneration after repair. The results fetoscopic interventions can be lifesaving. Accu-
of a multicenter randomized controlled trial com- racy in prenatal diagnosis will continue to grow in
paring prenatal to postnatal repair were recently the era of genomics and personalized medicine.
reported, which demonstrated a benefit in the rate The challenge for pediatric and fetal surgeons is to
continue to develop safer and less invasive thera- Clifton MS, Harrison MR, Ball R, Lee H. Fetoscopic trans-
pies based on a more refined understanding of uterine release of posterior urethral valves: a new tech-
nique. Fetal Diagn Ther. 2008;23:89–94.
fetal and maternal pathophysiology. Crombleholme TM, Coleman B, Hedrick H, et al. Cystic
adenomatoid malformation volume ratio predicts out-
come in prenatally diagnosed cystic adenomatoid mal-
formation of the lung. J Pediatr Surg. 2002;37:331–8.
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Fetal Counseling for Congenital
Malformations 4
Kokila Lakhoo
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Congenital Malformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Fetal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Minimally Invasive Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Invasive Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Future Developments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Specific Surgical Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Congenital Diaphragmatic Hernia (CDH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Cystic Lung Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Abdominal Wall Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Tracheoesophageal Fistula (TOF) and Esophageal Atresia (OA) . . . . . . . . . . . . . . . . . . . . . . . 74
Gastrointestinal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Abdominal Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Sacrococcygeal Teratomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Renal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Abstract to prospective parents. Prenatal diagnosis has

Fetal counseling is best achieved by a multi- remarkably improved our understanding of
disciplinary team that can favorably influence surgically correctable congenital malfor-
the perinatal management of prenatally diag- mations. It has allowed us to influence the
nosed anomalies and provide this information delivery of the baby, offer prenatal surgical
management, and discuss the options of termi-
nation of pregnancy for seriously handicap-
K. Lakhoo (*)
Paediatric Surgery, Children’s Hospital Oxford, Oxford
ping or lethal conditions. Antenatal diagnosis
University Hospitals, University of Oxford, Oxford, UK has also defined an in utero mortality for some
e-mail: kokila.lakhoo@paediatrics.ox.ac.uk

https://doi.org/10.1007/978-3-662-43588-5_4
66 K. Lakhoo
lesions such as diaphragmatic hernia and fetus. Pediatric surgeons are often called to
sacrococcygeal teratoma so that true outcomes counsel parents once a surgical abnormality is
can be measured. The limitation of in utero suspected on a prenatal scan. The referral base
diagnosis cannot be ignored. The aim of pre- for a pediatric surgeon now includes the perina-
natal counseling is to provide information to tal period. Expertise in surgical correction of
prospective parents on fetal outcomes, possible congenital malformations may favorably influ-
interventions, appropriate setting, time and ence the perinatal management of prenatally
route of delivery, and expected postnatal out- diagnosed anomalies, by changing the site of
comes, immediate and long term. delivery for immediate postnatal treatment or
altering the mode of delivery to prevent
Keywords obstructed labor or hemorrhage: early delivery
Fetal counseling · Congenital surgical to prevent ongoing fetal organ damage or treat-
malformations ment in utero to prevent, minimize, or reverse
fetal organ injury as a result of a structural
defect. Recent literature has confirmed the
Introduction favorable impact of prenatal surgical consulta-
tion in influencing the site of delivery in approx-
Congenital malformations affect 3% of babies imately 45%, changing the mode of delivery by
born in the United States and account for 20% of 10%, reversing the decision to terminate a preg-
all infant death (Matthews et al. 2015; Sharma nancy by 4.6%, and changing the diagnosis in
et al. 2017). The evolution of high-resolution 7% of pregnancies (Patel et al. 2008).
imaging studies and perinatal testing techniques Counseling parents about prenatally
have revolutionized the prenatal diagnosis of suspected surgically correctable anomalies
structural abnormalities (Moaddab et al. 2017). should not be solely performed by obstetricians
As a consequence, congenital malformations are or pediatricians. Similarly, the pediatric surgeon
now diagnosed earlier and in a greater number of performing these prenatal consultations must be
patients than even before. Prenatal diagnosis of a aware of differences between the prenatal and
congenital anomaly may result in significant postnatal natural history of the anomaly. There is
psychological distress for parents of affected often a lack of understanding of the natural his-
babies. Counseling may assist parents to cope tory and prognosis of a condition presenting in
during this difficult time. The primary aim of the newborn and the same condition diagnosed
prenatal counseling is to educate parents about prenatally.
their child’s anomaly. Marokakis et al. (2016) The diagnosis and management of complex
performed a systematic review of prenatal fetal anomalies require a multidisciplinary team
counseling for congenital malformation and encompassing obstetricians, neonatologists,
recommended that (1) prenatal counseling geneticists, pediatricians, pediatric surgeons, and
should be offered as soon as possible after par- occasionally other specialists with expertise to
ents receive their baby’s diagnosis; (2) the health deal with all the maternal and fetal complexities
professionals involved in counseling should be of a diagnosis of a structural defect. This team
knowledgeable, emphatic, and ideally those who should be able to provide information to prospec-
will be involved in the future care of the baby; tive parents on fetal outcomes, possible interven-
and (3) counseling should comprehensively tions, appropriate setting, time and route of
cover all aspects of the condition diagnosed delivery, and expected postnatal outcomes. The
such as natural history of the anomaly, treatment role of the surgical consultant, in this team, is to
options, prognosis, etc. present information regarding the prenatal and
Advances in prenatal diagnosis and manage- postnatal natural history of an anomaly, its surgi-
ment often demand the need for pediatric sur- cal management, and the long-term outcome
geons to be involved in the prenatal care of the (Lakhoo et al. 2012).
4 Fetal Counseling for Congenital Malformations 67
Congenital Malformation
Congenital malformations account for one of the

major causes of perinatal mortality and morbidity.
Single major birth defects affect 3% of newborns,
and 0.7% of babies have multiple defects. The
prenatal hidden mortality is higher since many
will miscarry spontaneously. Despite improve-
ments in perinatal care, serious birth defects still
account for 20% of all deaths in the newborn
period and an even greater percentage of serious
morbidity later in infancy and childhood
(CEMACH 2005). The major causes of congeni-
Fig. 1 Nuchal thickening
tal malformation are chromosomal abnormalities,
mutant genes, multifactorial disorders, and terato-
genic agents. gestation). Pregnancies identified as being high
risk maybe offered further invasive diagnostic
investigations such as amniocentesis or chorionic
Prenatal Diagnosis villus sampling. Structural abnormalities difficult
to define on ultrasound such as hindbrain lesions
Prenatal diagnosis has remarkably improved our or in the presence of oligohydramnios or raised
understanding of surgically correctable congenital maternal BMI (body mass index) may be better
malformations. It has allowed the fetal medicine imaged on ultrafast magnetic resonance imaging.
professionals to influence the delivery of the baby, With the increasing range of options and sophis-
offer prenatal surgical management, and discuss tication of diagnostic methods, parents today are
the options of termination of pregnancy for seri- faced with more information, choice, and deci-
ously handicapping or lethal conditions. Antena- sions than ever before, which can create as well
tal diagnosis has also defined an in utero mortality as help to solve dilemmas. The different tests and
for some lesions such as diaphragmatic hernia, screening procedures commonly in use are
omphalocele, and sacrococcygeal teratomas so outlined below.
that true outcomes can be measured. Prenatal
ultrasound scanning has improved since its first
use 30 years ago, thus providing better screening Fetal Imaging
programs and more accurate assessment of fetal
anomalies. Screening for Down’s syndrome may Ultrasound Examination
now be offered in the first trimester (e.g., nuchal Gray-scale ultrasound remains the main method
scan combined test) (Fig. 1) or second trimester of prenatal screening for fetal structural
(e.g., quadruple blood test) (Malone et al. 2005). anomalies.
Better resolution and increased experience with Most women are offered a first-trimester scan.
ultrasound scans have led to the recognition of The most accurate time to date a pregnancy is
ultrasound soft markers which have increased between 11 and 13 weeks. At this time, measure-
the detection rate of fetal anomalies but at the ment of the nuchal translucency can also be
expense of higher false-positive rates. performed. This involves measuring an area at
Routine ultrasound screening can identify the back of the baby’s neck (Fig. 1). All fetuses
structural anomalies at the time of the routine have this, but there is an association between an
anomaly scan (at around 20 weeks) or increas- increased nuchal thickness and the risk of a chro-
ingly commonly at the time of the dating or nuchal mosomal abnormality. When combined with bio-
translucency scan (at around 11–13 weeks’ chemical markers, this can give an estimation of
68 K. Lakhoo
the risk of chromosomal disorders, the most com- hydronephrosis, and nuchal thickening. Their
mon of which is T21, which is significantly more presence creates anxiety among sonographers
accurate than that based on maternal age alone. since the finding may be transient with no patho-
The combined test of nuchal translucency (NT), logical relevance or may be an indicator of
pregnancy-associated plasma protein-A (PAPP- significant anomalies such as chromosomal
A), and free β-human chorionic gonadotropin abnormalities (Bricker et al. 2000), cystic
(free β-hCG) gives a detection rate of 85% for fibrosis (echogenic bowel), Down’s syndrome
trisomy 21 with a false-positive rate of 3% (Eng- (nuchal thickening), or renal abnormalities
els et al. 2013). (hydronephrosis). Once soft markers are detected
An increased nuchal translucency with a nor- should they be reported or further invasive tests
mal karyotype can be associated with an increased offered is a dilemma faced by obstetricians.
risk of a range of structural anomalies and syn- Reporting these markers has increased detection
dromes (Fig. 1). rates at the expense of high false-positive rates.
The mechanisms by which some abnormalities The UK National Screening Committee now has a
give rise to this transient anatomical change of policy of which markers should and should not be
nuchal translucency are poorly understood (Col- reported (http://fetalanomaly.screening.nhs.uk/
lins and Impey 2012). Although some abnormal- standardsandpolicies).
ities can be seen at the time of the nuchal scan Three-dimensional images from new ultra-
(11–14 weeks), most are detected at the 20-week sound machines are becoming increasingly com-
anomaly scan. Some abnormalities such as monplace. As well as delighting parents, these
gastroschisis have a higher detection rate on a images can be useful for diagnosis and planning
scan than others, e.g., cardiac abnormalities. postnatal care, for example, with facial deformi-
If the nuchal translucency measurement is ties. They are also leading to improved imaging
increased and the karyotype is normal, there is a and better diagnostic accuracy.
higher risk for a cardiac anomaly, and these high-
risk fetuses may be referred for fetal echocardiog- Fetal Echocardiography
raphy, which provides better prenatal cardiac The field of fetal echocardiography has seen a
assessment than the routine screening scan (Pajkrt rapid expansion in the last decade to the extent
et al. 2004). Ultrasound surveillance is essential that most structural cardiac anomalies can now be
during the performance of invasive techniques detected prenatally (Taketazu et al. 2006). Condi-
such as amniocentesis, chorionic villus sampling tions such as diaphragmatic hernia, omphalocele,
(CVS), and shunting procedures. It is also useful and duodenal atresia have a high association with
for assessing fetal viability before and after such cardiac anomalies. Identifying these cardiac
procedures. Some abnormalities such as tracheoe- anomalies prenatally has assisted in prenatal
sophageal fistula, bowel atresia, diaphragmatic counseling and planning for postnatal manage-
hernia, and hydrocephaly may present later in ment. Other conditions such as twin-to-twin trans-
pregnancy and thereby not detected on the routine fusion, large cystic lung lesions, and
18-week scan. sacrococcygeal teratomas may cause cardiac dys-
Overall, around 60% of structural birth defects function which can be easily diagnosed or con-
are detected prenatally, but the detection rate firmed on echocardiography and help with
varies from 0% (isolated cleft palate) to close to predicting outcomes (Rogers et al. 2013).
100% (gastroschisis) depending on the defect.
True wrong diagnoses are rare, but false-positive Magnetic Resonance Imaging
diagnoses do occur; some are due to natural pre- The advantage of magnetic resonance imaging
natal regression, but most are due to ultrasound (MRI) over ultrasound for imaging intracranial
“soft markers.” abnormalities is well recognized especially for
Ultrasound “soft markers” are changes noted brainstem, posterior fossa, and neural tube anom-
on prenatal scan that are difficult to define. Exam- alies (Pugash et al. 2008). Magnetic resonance
ples are echogenic bowel (Patel et al. 2004), imaging may assist in better defining some lesions
difficult to view on conventional prenatal scan- has also given rise to many legal and ethical
ning such as the presacral teratomas, posterior challenges such as its use to produce an unaf-
urethral valves in the presence of fected, human leucocyte antigen (HLA) compat-
oligohydramnios, chest lesions, etc. MRI is also ible “savior sibling.”
useful in the obese patient. Other advantages of
MRI include the fact that the images can be exam-
ined offline by several readers, whereas 2D ultra- Invasive Diagnostic Tests
sound images usually require real-time
interpretation by the operator. At present MRI is Amniocentesis and chorionic villus sampling
complementary to ultrasound and is unlikely to (CVS) are the two most commonly performed
replace conventional ultrasound scans (Garcia- invasive diagnostic tests.
Flores et al. 2013).
Amniocentesis
Amniocentesis is commonly used for detecting
Minimally Invasive Diagnostic Tests chromosomal abnormalities and less often for
molecular studies, metabolic studies, and fetal
Prenatal Maternal Serum Screening infection. It is performed after 15-week gestation
Interest in detecting circulating fetal cells and carries a low risk of fetal injury or loss
(cffDNA = cell-free fetal DNA) in maternal (0.5–1%). Full karyotype analysis takes approxi-
blood for diagnostic purposes has grown since mately 2 weeks but newer.
the advent of fluorescence-activated cell sorting RAPID techniques using FISH (fluorescent in
(FACS) (Herzenberg et al. 1979) and is now situ hybridization) or PCR (polymerase chain
becoming available commercially for the diagno- reaction) can give limited (usually for trisomies
sis of chromosomal anomalies. Fetal Rh-D typing 21, 18, and 13) results within 2–3 days.
for fetal blood group determination and fetal sex
determination using cffDNA are now used rou- Chorionic Villus Sampling (CVS)
tinely in the management of hemolytic diseases. CVS is the most reliable method for first-trimester
Using cffDNA to diagnose single gene disorders diagnosis and can be performed after 10-week
is problematic, and further research is in need. gestation. The test involves ultrasound-guided
biopsy of the chorionic villi. The added risk for
Genetic Diagnoses fetal loss is approximately 1–2%. The samples
Antenatal detection of genetic abnormalities is obtained may be subjected to a variety of tests
increasing especially in high-risk pregnancies including full karyotype, rapid karyotyping
with the discovery of less invasive testing. Preim- (FISH–PCR), enzyme analysis, or molecular
plantation genetic diagnosis (PGD) has replaced studies. Approximate timing of chromosomal
invasive testing for many genetic conditions by results is 1–2 weeks for karyotyping and
process of sampling in vitro fertilized embryos 2–3 days for FISH and PCR.
and obtaining genetic analysis the same day so
that unaffected embryos may be used for implan- Fetal Blood Sampling (FBS)
tation. The most common indications are chromo- Rapid karyotyping of CVS and amniotic fluid
somal abnormalities, X-linked diseases, and samples FISH and PCR has replaced fetal blood
single gene disorders (Basille et al. 2009). sampling for many conditions. However, FBS is
PGD has been successfully used for autoso- still required for the diagnosis and treatment of
mal recessive disorders such as cystic fibrosis, hematological conditions and some viral infec-
autosomal dominant diseases including tions. When required it is usually performed by
Huntington’s disease, and X-linked disorders ultrasound-guided needle sampling after 18-week
including fragile X syndrome and Duchenne gestation rather than the more invasive fetoscopic
muscular dystrophy. PGD is extremely promis- technique. Mortality from this procedure is
ing for families affected by genetic disorders but reported to be 1–2%.
70 K. Lakhoo
Future Developments Minimally invasive techniques, such as ablation

of vessels in sacrococcygeal teratomas, fetoscopic
The aim of prenatal diagnosis and testing is to ablation of posterior urethral valves, tracheal
have 100% accuracy without fetal loss or injury occlusion for congenital diaphragmatic hernia,
and no maternal risk. A national plan to improve etc., are either established or are currently under
Down’s screening using ultrasound and biochem- trial. However, laser ablation in twin-to-twin
ical combination tests is now in place in the transfusion is now well established.
United Kingdom. Research into new markers for
chromosomal abnormalities is ongoing. The fetal
Specific Surgical Conditions
nasal bone is one such example, which may assist
in detecting babies with chromosomal
Congenital Diaphragmatic Hernia
abnormalities.
(CDH)
The search for fetal components in maternal
blood is now available as the Harmony test.
CDH accounts for 1 in 3000 live birth and chal-
Success in the genome projects for prenatal
lenges the neonatologist and pediatric surgeons in
diagnosis of some genetic conditions has encour-
the management of this high-risk condition
aged and excited scientist to continue research in
(Fig. 2). Mortality remains high (more than
this field.
60%) when the “hidden” mortality of in utero
Rapid detection techniques will soon replace
death and termination of pregnancy are taken
traditional cultures for karyotyping. Microarray
into account. Lung hypoplasia and pulmonary
testing of fetal cells is rapidly being introduced;
hypertension account for most deaths in isolated
some advice microarray testing whenever a fetal
CDH newborns. Associated anomalies (30–40%)
structural anomaly is detected on scan. There are
signify a grave prognosis with a survival rate of
many ethical dilemmas involved with this, in par-
less than 10%.
ticular because of the absence of any phenotype
In the United Kingdom, most CDH are diag-
with fetal testing.
nosed at the 20-week anomaly scan with a detec-
tion rate approaching 60%, although as early as
Fetal Surgery 11-week gestation has been reported. MRI has a
useful role in accurately differentiating CDH from
There is a spectrum of interventions ranging from cystic lung lesions and may be useful in measur-
simple aspiration of cysts to open fetal surgery. ing fetal lung volumes as a predictor of outcome.
Fig. 2 Prenatal and postnatal images of left congenital diaphragmatic hernia

Cardiac anomalies (20%), chromosomal anoma- Surgery for CDH is no longer an emergency
lies of trisomies 13 and 18 (20%), and urinary, procedure. Delayed repair following stabilization
gastrointestinal, and neurological (33%) can is employed in most pediatric surgical centers.
coexist with CDH and should be ruled out by Primary repair using the transabdominal route is
offering the patient fetal echocardiogram, amnio- achieved in 60–70% of patients with the rest
centesis, and detailed anomaly scan. These asso- requiring a prosthetic patch.
ciated anomalies and, in isolated lesions, early
detection, liver in the chest, polyhydramnios,
and fetal lung-head ratio (LHR) of less than Cystic Lung Lesions
1 are implicated as poor predictors of outcome
(Deprest and De Coppi 2012). In these patients Congenital cystic adenomatoid malformations
with poor prognostic signs, fetal surgery for CDH (CCAMs), bronchopulmonary sequestrations
over the last two decades has been disappointing; (BPS), or “hybrid” lesions containing features of
however, benefit from fetal intervention with tem- both are common cystic lung lesions noted on
porary tracheal occlusion (FETO) has been prenatal scan. Less common lung anomalies
reported in early European trials but awaits further include bronchogenic cysts, congenital lobar
randomized studies from Europe and United emphysema, and bronchial atresia. Congenital
States (Dekoninck et al. 2011). Favorable out- cystic lung lesions are rare anomalies with an
comes in CDH with the use of antenatal steroids incidence of 1 in 10,000 to 1 in 35,000.
have not been resolved in the clinical settings. Prenatal detection rate of lung cysts at the
Elective delivery at a specialized center is routine 18–20-week scan is almost 100% and
recommended with no benefit from caesarean may be the commonest mode of actual presenta-
section. tion (Fig. 3). Most of these lesions are easily
Postnatal management (Haroon and Chamber- distinguished from congenital diaphragmatic her-
lain 2013) is aimed at reducing barotrauma to the nia; however, ultrasound features of CCAM or
hypoplastic lung by introducing high-frequency BPS are not sufficiently accurate and correlate
oscillatory ventilation (HFOV) or permissive poorly with histology. MRI though not routinely
hypercapnia and treating the severe pulmonary used may provide better definition for this
hypertension with nitric oxide. No clear benefits condition.
for CDH with ECMO (extracorporeal membrane Bilateral disease and hydrops fetalis are indi-
oxygenation) have been concluded in a 2002 cators of poor outcome, whereas mediastinal shift,
Cochrane ECMO study (Elbourne et al. 2002). polyhydramnios, and early detection are not poor
Fig. 3 Prenatal and postnatal images of CCAM

72 K. Lakhoo
Fig. 4 Chest radiograph and CT scan showing left lower lobe CCAM
prognostic signs. Recently, CCAM volume ratio appropriate; however, smaller lesions are less
(CVR), ratio of the volume of CCAM/fetal head likely to be symptomatic at birth and could be
circumference, is shown to be an important deter- delivered at the referring institution with follow-
minant of outcome with a high CVR ratio indica- up in a pediatric surgery clinic.
tive of poor outcome (Cass et al. 2013). In the Postnatal management (Lakhoo 2010) is dic-
absence of termination, the natural fetal demise of tated by clinical status at birth. Symptomatic
antenatally diagnosed cystic lung disease is 28%. lesions require urgent radiological evaluation
Spontaneous involution of cystic lung lesions can with chest radiograph and ideally CT scan
occur, but complete postnatal resolution is rare, (Figs. 3 and 4) followed by surgical excision. In
and apparent spontaneous “disappearance” of asymptomatic cases, postnatal investigation con-
antenatally diagnosed lesions should be sists of chest CT scan within 1 month of birth,
interpreted with care, as nearly half of these even if regression or resolution is noted on prena-
cases subsequently require surgery. tal scanning. Plain radiography should not be
In only 10% of cases, the need for fetal inter- relied upon since it will miss and underestimate
vention arises. The spectrum of intervention many lesions.
includes simple centesis of amniotic fluid, Surgical excision of postnatal asymptomatic
thoracoamniotic shunt placement, percutaneous lesions remains controversial, with some centers
laser ablation, and open fetal surgical resection opting for conservative management. The
(Adzick 2009). Use of maternal steroids has approach to treating this asymptomatic group
been reported to reverse hydrops in microscopic has evolved in some centers, whereby a CT scan
CCAM but not in macroscopic CCAM, and the is performed within 1 month post birth, followed
mechanism of this response to maternal steroids is by surgery before 6 months of age due to the
unclear (Curran et al. 2010). A large cystic mass inherent risk of infection and malignant
(macroscopic CCAM) and hydrops in isolated transformation.
cystic lung lesions are the only real indication
for fetal intervention.
Normal vaginal delivery is recommended Abdominal Wall Defects
unless maternal conditions indicate otherwise.
Large lesion is predicted to become symptomatic Omphalocele (exomphalos) and gastroschisis are
shortly after birth (as high as 45% in some series); both common but distinct abdominal wall defects
thus delivery at a specialized center would be with an unclear etiology and a controversial
prognosis. Attention may be drawn to their pres- allowed to slowly granulate and epithelialize by
ence during the second trimester because of raised application of antiseptic solution (Morgan et al.
maternal serum alpha-fetoprotein level or abnor- 2012).
mal ultrasounds scan.
Gastroschisis
Exomphalos Gastroschisis is an isolated lesion that usually
Exomphalos is characteristically a midline defect, occurs on the right side of the umbilical defect
at the insertion point of the umbilical cord, with a with evisceration of the abdominal contents
viable sac composed of amnion and peritoneum directly into the amniotic cavity. The incidence
containing herniated abdominal contents (Fig. 5). is increasing from 1.66 per 10,000 births to 4.6 per
Incidence is known to be 1 in 4000 live births. 10,000 births affecting mainly young mothers
Associated major abnormalities which include tri- typically less than 20 years old. Associated anom-
somies 13, 18, and 21, Beckwith-Wiedemann alies are noted in only 5–24% of cases with bowel
syndrome (macroglossia, gigantism, exo- atresia, the most common coexisting abnormality.
mphalos), Pentalogy of Cantrell (sternal, pericar- On prenatal scan with a detection rate of 100%,
dial, cardiac, abdominal wall, and diaphragmatic the bowel appears to be free floating or the loops
defect), and cardiac, gastrointestinal, and renal may appear to be thickened due to damage by
abnormalities are noted in 60–70% of cases; thus amniotic fluid exposure causing an inflammatory
karyotyping in addition to detailed sonographic response and a “peel” formation or damage due to
review and fetal echocardiogram is essential for constriction of the mesentery causing delay in
complete prenatal screening (Patel et al. 2009). venous and lymphatic drainage. Dilated loops of
Fetal intervention is unlikely in this condition. bowel (Fig. 6) may be seen from obstruction sec-
If termination is not considered, normal vaginal ondary to protrusion from a defect or atresia due to
delivery at a center with neonatal surgical exper- intestinal ischemia.
tise is recommended and delivery by caesarean Predicting outcome in fetuses with
section only reserved for large exomphalos with gastroschisis based on prenatal ultrasound finding
exteriorized liver to prevent damage. Surgical remains a challenge. There is no consensus on
repair includes primary closure or a staged bowel dilatation as a predictor of outcome
repair with a silo for giant defects (Islam 2012). (Mears et al. 2010; Huh et al. 2010). Also thick-
Occasionally in vulnerable infants with severe ened matted bowel and Doppler measurements of
pulmonary hypoplasia or complex cardiac abnor- the superior mesenteric artery are not accurate
malities, the exomphalos may be left intact and predictors of outcome. To reduce the rate of
Fig. 5 Prenatal and postnatal images of exomphalos

74 K. Lakhoo
Fig. 6 Prenatal and postnatal images of gastroschisis
third-trimester fetal loss, serial ultrasounds are independent surgeon (Fig. 7). The incidence is
performed to monitor the development of bowel estimated at 1 in 3000 births. Prenatally, the con-
obstruction and delivery around 37 weeks dition may be suspected from maternal poly-
recommended at a center with neonatal surgical hydramnios and absence of a fetal stomach
expertise. bubble at the 20-week anomaly scan. Prenatal
Delivery by caesarean section has no advan- scan diagnosis of TOF/OA is estimated to be
tage to normal vaginal route. Despite efforts to less than 42% sensitive with a positive predicted
plan elective delivery, 50% of cases will require value of 56% (Choudhry et al. 2007). Additional
emergency caesarean section due to development diagnostic clues are provided by associated anom-
of fetal distress. alies such as trisomy (13, 18, 21), VACTERL
Various methods of postnatal surgical repair sequence (vertebral, anorectal, cardiac, tracheoe-
(Islam 2012) include the traditional primary clo- sophageal, renal, limbs), and CHARGE associa-
sure, reduction of bowel without anesthesia, tion (coloboma, heart defects, atresia choanae,
reduction by preformed silo, or by means of a retarded development, genital hypoplasia, ear
traditional silo. Coexisting intestinal atresia abnormality). These associated anomalies are pre-
could be repaired by primary anastomosis or sent in more than 50% of cases and worsen the
staged with stoma formation. Variation in achiev- prognosis; thus prenatal karyotyping is essential
ing full enteral feeding due to prolonged gut (Morgan et al. 2012). Duodenal atresia may coex-
dysmotility is expected in all cases. ist with TOF/OA. The risk of recurrence in sub-
The long-term outcome in gastroschisis is sequent pregnancies for isolated TOF/OA is less
dependent on the condition of the bowel. In than 1%. Delivery is advised to be at specialized
uncomplicated cases, the outcome is excellent in center with neonatal surgical input.
more than 90% of cases. Postnatal surgical management is dependent
on the size and condition of the baby, length of
esophageal gap, and associated anomalies
Tracheoesophageal Fistula (TOF) (Kunisaki and Foker 2012). Primary repair of the
and Esophageal Atresia (OA) esophagus is the treatment of choice; however, if
not achieved, staged repair with upper esophageal
Repair of TOF/OA is a condition, which measures pouch care and gastrostomy or organ replacement
the skill of pediatric surgeons from trainee to with the stomach or large bowel are other options
Fig. 7 (a) Prenatal imaging of suspected TOF with poly- tracheoesophageal fistula with esophageal atresia. (c)
hydramnios and small stomach. (b) Plain radiograph show- Plain radiograph showing esophageal pouch tube and no
ing esophageal pouch tube and distal gas confirming abdominal gas confirming isolated esophageal atresia
(Friedmacher and Puri 2012). Associated anoma- Duodenal atresia has a characteristic “double
lies require evaluation and treatment. Minimally bubble” appearance on prenatal scan, resulting
invasive thoracoscopic approach to the repair of from the simultaneous dilatation of the stomach
TOF may be offered by advanced pediatric endo- and proximal duodenum. Detection rate on
surgical centers. second-trimester anomaly scan is almost 100%
Early outcome of a high leak rate and esopha- in the presence of polyhydramnios and the “dou-
geal stricture requiring dilatation in 50% of cases ble bubble” sign. Associated anomalies are pre-
are expected where the anastomosis of the esoph- sent in approximately 50% of cases with most
agus is created under tension (Burge et al. 2013). notably trisomy 21 in 30% and cardiac anomalies
Long-term outcomes are indicated by in 20% and the presence of the VACTERL (17%)
improved perinatal management and inherent association (vertebral, anorectal, cardiac,
structural and functional defects in the trachea tracheoesophageal, renal, and limbs) (Choudhry
and esophagus. In early life, growth of the child et al. 2009; Morgan et al. 2012, 2013).
is reported to be below the 25 centile in 50% of The incidence of duodenal atresia is 1 in 5000
cases, respiratory symptoms in two thirds of live birth. The postnatal survival rate is >95%
TOF/OA, and gastroesophageal reflux recorded with associated anomalies, low birth weight, and
in 50% of patients. Quality of life is better in prematurity contributing to the <5% mortality.
the isolated group with successful primary repair Temporary delay in enteral feeding occurs due to
as compared to those with associated anomalies the dysmotility in the dilated stomach and
and delayed repair (Koivusalo et al. 2005; Fallon duodenum.
et al. 2014). There are many bowel abnormalities which
may be noted on prenatal scanning such as dilated
bowel, ascites, cystic masses, hyperperistalsis,
Gastrointestinal Lesions polyhydramnios, and echogenic bowel (Ruiz
et al. 2009); however, none is absolutely predic-
The presence of dilated loops of bowel (>15 mm tive of postnatal outcome. Patients with obstruc-
in length and > 17 mm in diameter) on prenatal tion frequently have findings (especially in the
ultrasound scan is indicative of bowel third trimester) of bowel dilatation (Fig. 8), poly-
obstruction. hydramnios, and hyperperistalsis. Ultrasound is
76 K. Lakhoo
Fig. 8 Prenatal and postnatal imaging of intestinal atresia
much less sensitive in diagnosing large bowel diagnoses include extralobar pulmonary seques-
anomalies than those with small bowel anomalies tration and pancreatic, splenic, urachal, and adre-
(Patel et al. 2004). Since the large bowel is mostly nal cysts. Almost all cysts are benign and many
a reservoir, with no physiologic function in utero, are self-limiting; however, these cysts create a
defects in this region such as anorectal high level of anxiety for the prospective parents,
malformations or Hirschsprung’s disease are especially suspected adrenal cyst. Regular antena-
very difficult to detect. Bowel dilatation and tal consultation and fetal counseling by the appro-
echogenic bowel may be associated cystic fibro- priate team may reduce parental anxiety levels.
sis; therefore, all such fetuses should undergo There is a very small role for fetal intervention.
postnatal evaluation for this disease (Al-Kouatly Resolution of these cysts was reported in 25% of
et al. 2001). Prenatally diagnosed small bowel cases, and 30% came to surgical intervention
atresia does not select for a group with a worse (Sherwood et al. 2008). Postnatal imaging is
prognosis, and survival rates are 95–100%. essential.
Abdominal Cysts Sacrococcygeal Teratomas
Abdominal cystic lesions are not uncommonly Sacrococcygeal teratoma (SCT) is the comm-
diagnosed at antenatal ultrasound (US) exami- onest neonatal tumor accounting for 1 in 35,000
nation (Fig. 9). A cystic mass identified in this to 40,000 births (Fig. 10; Pauniaho et al. 2013).
way may represent a normal structural variant or a Four types have been defined, namely (Altman
pathological entity requiring surgical intervention et al. 1974), type 1 external tumor with a small
postnatally. Despite increasingly sophisticated presacral component, type 2 external tumors with
equipment, some congenital anomalies have sig- a large presacral component, type 3 predominantly
nificant false-positive rates on US, and fetal cystic presacral with a small external component, and
abdominal masses in particular can be difficult to type 4 entirely presacral. Type 4 carries the worst
diagnose accurately (Sherwood et al. 2008). prognosis (Koivusalo et al. 2005) due to delay in
Excluding cysts of renal origin, the differential diagnosis and malignant presentation. Doppler
diagnosis includes ovarian cysts, enteric duplica- ultrasound is the diagnostic tool; however, fetal
tion cysts, meconium pseudocyst, mesenteric MRI provides better definition of the intrapelvic
cysts, and choledochal cysts. Less common component. SCT is a highly vascular tumor, and
Fig. 9 (a) Prenatal abdominal cyst; (b) prenatal ovarian cyst
Fig. 10 Prenatal MRI and postnatal image of sacrococcygeal teratoma
the fetus may develop high cardiac output failure, ultrasounds is mandatory to exclude recurrence of
anemia, and ultimately hydrops with a mortality the disease (Usui et al. 2012).
of almost 100%. Fetal treatment of tumor resec-
tion or ablation of feeding vessel has been
attempted in hydropic patients with minimal suc- Renal Anomalies
cess. Caesarean section may be offered to patients
with large tumors to avoid the risk of bleeding Urogenital abnormalities are among the
during delivery. Postnatal outcomes following commonest disorders seen in the perinatal
surgery in type 1 and 2 lesions are favorable; period and account for almost 20% of all prena-
however, type 3 and 4 tumors may present with tally diagnosed anomalies (Brand et al. 1994).
urological and bowel problems with less favor- Many structural anomalies of the kidney and
able outcomes (Tailor et al. 2009). Long-term urinary tract can be detected by antenatal ultra-
follow-up with alpha-fetoprotein and serial pelvic sound, allowing early diagnosis and opportunity
78 K. Lakhoo
to counsel parents and plan further investiga- monitored over a 17-year period, and from an anal-
tions and management (Marokakis et al. 2016). ysis of six patient series, the conclusion is that this
The routine use of antenatal ultrasound scans has approach is safe (Joseph 2006).
resulted not only in the early detection of these
conditions but in selected cases has led to the Lower Urinary Tract Obstruction
development of management strategies, includ- Posterior urethral valves (PUV) are the most
ing fetal intervention aimed at preservation of common cause for lower urinary tract obstruc-
renal function. Two major issues are the indication in boys with an incidence of 1 in 2000–4000
tions for intervention in bladder outlet obstruc- live male births. The diagnosis of PUV is
tion and early pyeloplasty in infancy in cases suspected on the prenatal ultrasound finding of
with hydronephrosis (Chevalier 2004). bilateral hydronephrosis associated with a thick-
Prenatal evaluation of a dilated urinary tract is ened bladder and decreased amniotic fluid vol-
based on serial ultrasound scans as well as mea- ume (Fig. 11). Serial fetal urine analysis may
surement of urinary electrolytes. Ultrasonography provide prognostic information on renal func-
provides measurements of the renal pelvis, assess- tion. Prenatal diagnosis for patients with PUV
ment of the renal parenchyma, as well as the detec- is a poor prognostic sign with 64% incidence of
tion of cysts in the cortex. In severe disease, lack of renal failure and transient pulmonary failure,
amniotic fluid may make ultrasound assessment of compared to 33% in the postnatally diagnosed
the renal tract difficult, and MRI may be helpful. patients (Walsh and Johnson 1999). Pulmonary
Oligohydramnios is indicative of poor renal func- hypoplasia secondary to oligohydramnios
tion and poor prognosis owing to the associated largely contributes to the morbidity and mortal-
pulmonary hypoplasia. Urogenital anomalies coex- ity from fetal urethral obstruction (Ruano et al.
ist with many other congenital abnormalities, and 2016). Outcomes of fetal intervention with
amniocentesis should be offered in appropriate vesico-amniotic shunting or fetal cystoscopic
cases. It is estimated that 3% of infants will have ablation of urethral valve have not been very
an abnormality of the urogenital system, and half of successful. Almost 90% of fetuses with urinary
these will require some form of surgical interven- tract dilatation will not require fetal interven-
tion (Steinhart et al. 1988). tion. Fetal intervention may play a role in severe
cases with progressive renal dilatation and
Upper Urinary Tract Obstruction development of oligohydramnios.
Antenatal hydronephrosis accounts for 0.6–0.65% Postnatal management includes ultrasound con-
pregnancies (Davenport et al. 2013). The most firmation of the diagnosis, bladder drainage via a
common cause of prenatal hydronephrosis is suprapubic or urethral route, and contrast imaging
pelvi-ureteric junction (PUJ) obstruction, others of the urethra. Primary PUV ablation, vesicostomy,
being transient hydronephrosis, physiological and ureterostomy are postnatal surgical options.
hydronephrosis, multicystic kidney, posterior ure- The overall outcome from this disease is unfavor-
thral valves, ureterocele, ectopic ureter, etc. The able (Joseph 2006; Matsell et al. 2016).
prognosis is excellent in antenatally diagnosed uni-
lateral hydronephrosis and in renal pelvic diameter
of <10 mm. Spontaneous resolutions are noted in Conclusion and Future Directions
20% of patients at birth and 80% at 3 years of age.
Only 17% of prenatally diagnosed hydronephrosis The boundaries of pediatric surgical practice have
need surgical intervention. Postnatal management been extended by prenatal diagnosis. The care of
of hydronephrosis requires ultrasound at birth and patients with surgically correctable defects can
at 1 month of age and further evaluation with now be planned prenatally with the collaborative
imaging and scintigraphy if an abnormality is effort of obstetricians, geneticists, neonatologists,
suspected. The nonoperative treatment of antena- and pediatric surgeons. Essential to prenatal
tally detected hydronephrosis has been carefully counseling is the understanding of the specific
Fig. 11 Prenatal and postnatal imaging of posterior urethral valves
surgical condition’s prenatal natural history, the Altman RP, Randolph JG, Lilly JR. Sacrococcygeal tera-
limitations of prenatal diagnosis, the detection of toma: American Academy of Pediatrics surgical section
Survey-1973. J Pediatr Surg. 1974;9:389–98.
associated anomalies, the risks and indications of Basille C, Frydman R, El Aly A, Hesters L, Fanchin R,
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nent of pediatric surgical practice and should be 2009;145(1):9–13.
Brand IR, Kaminopetros P, Cave M, Irving HC,
ensured in the training programs for future pedi- Lilford RJ. Specificity of antenatal ultrasound in the
atric surgeons. Yorkshire region: a prospective study of 2261 ultra-
sound detected anomalies. Br J Obstet Gynaecol.
1994;101:392–7.
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Anatomy of the Infant and Child
5
Mark D. Stringer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Growth and Proportions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
The Fetal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Circulatory Changes After Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
The Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Central Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Umbilical Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Upper Airway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Trachea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Bronchial Tree . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Thorax and Mechanics of Breathing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Abdominal Wall and Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Abdominal and Pelvic Cavities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Liver, Gallbladder, and Spleen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Genitourinary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Kidneys and Suprarenal Glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Bladder and Ureter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Genitalia and Reproductive Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Musculoskeletal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Skull and Face . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Vertebral Column, Pelvis, and Limbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
M. D. Stringer (*)
Department of Paediatric Surgery, Wellington Hospital,
Department of Paediatrics and Child Health, University of
Otago, Wellington, New Zealand
e-mail: mark.stringer@ccdhb.org.nz

https://doi.org/10.1007/978-3-662-43588-5_5
84 M. D. Stringer
Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Skin and Subcutaneous Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Abstract differentiation, and apoptosis (Sinclair and

There are key differences between the anatomy Dangerfield 1998). Growth is often proportional.
of the child and adult, most marked in newborn Thus, the pelvis and lower limbs in a neonate are
infants. These differences affect the accuracy of proportionately small (Diméglio 2006). However,
surface anatomical landmarks, surgical growth may be differential. For example, the head
approaches and procedures, physiological and of a full-term newborn infant accounts for about
cardiorespiratory parameters and responses, 25% of body length and 20% of body surface area,
and the ability to compensate for congenital but corresponding figures in an adult are about
malformations and/or the effects of surgical 13% and 9%, respectively (Fig. 2). The ratio of
treatment. Anatomical differences in children body surface area to weight decreases with age:
that are particularly relevant to pediatric sur- the surface area of a neonate is about 0.25m2
geons are discussed using a systems approach, compared to the average adult value of 1.73 m2.
focusing on growth and proportions, cardiovas- Consequently, neonates are more vulnerable to
cular and respiratory systems, the abdominal heat loss.
wall and gastrointestinal tract, and the genito- The mean length of a full-term newborn mea-
urinary, musculoskeletal, and nervous systems. sured from crown to heel is around 48–50 cm and
birth weight 3.4 kg (normal range 2.7–4.6 kg), but
Keywords there are variations between ethnic groups. The
Anatomy · Neonatal anatomy · Infant mean birth weight of a baby born in the United
anatomy · Clinical anatomy Kingdom to parents from the Indian subcontinent
is about 400 g less (Kelly et al. 2009). Growth
weight and height velocity are maximal in early
Introduction infancy and peak again at puberty. Mean body
weight at 3 years is around 13–15 kg and at
A newborn infant more than triples in length, and its
10 years is about 30–35 kg.
weight increases some 20-fold in the process of
About 75–80% of a newborn’s weight is water
reaching maturity. During development, a few
and 15–28% is fat (Standring 2008); by 1 year of
structures involute, while most change in size
age, total body water has decreased to adult values
and/or position. Consequently, the anatomy of the
of around 60% of body weight.
child, and especially the infant, differs from adults
(Table 1 and Fig. 1). This chapter summarizes the
key differences between the anatomy of the child
and adult that are most relevant in pediatric surgery. Cardiovascular System
The Fetal Circulation

Growth and Proportions
In the fetus, the lungs and airways are fluid filled,
The growth of an individual from its earliest stage and the placenta regulates oxygen supply and
to maturity results in an increase in size and mass carbon dioxide removal (▶ Chap. 12, “Pediatric
and includes cellular processes such as division, Cardiovascular Physiology”). The fetus is
5 Anatomy of the Infant and Child 85
Table 1 Key anatomical differences between infants and adults

Cardiovascular system Recent transition from fetal circulation
Relatively large heart
Potential for congenital heart defects
Prominent thymic shadow on chest X-ray
Respiratory system Obligate nose breathing
Short neck with high larynx
Ability to breathe whilst suckling
Subglottis is the narrowest part of the airway
Highly compliant chest wall
Greater reliance on diaphragm for breathing
Abdomen Relatively wide abdomen
Short inguinal canal
Propensity to inguinal hernias and undescended testes
Small amount of intra-abdominal fat
Proportionately large liver
Poor radiological distinction between small and large bowel
Small pelvic cavity
Intra-abdominal bladder and body of uterus
Proportionately large suprarenal glands
Musculoskeletal system Proportionately large head, small pelvis, and lower limbs
Open fontanelles
Relatively underdeveloped face and mandible
Horizontal auditory tube
No spinal curvatures (other than shallow sacral curve)
Absence of most secondary ossification centers
Shallow and relatively larger acetabulum
Relatively small gluteal muscles
Nervous system Relatively large brain with full complement of neurons but
incomplete myelination of axons
Proportionately large cerebral ventricles
Spinal cord terminates at lower level
Skin Variable subcutaneous fat (with some brown fat)
Thin skin, immature sweating
Greater body surface area to weight ratio
Head accounts for 20% of body surface area
relatively hypoxemic; the partial pressure of oxy- aspect of the left branch of the portal vein directly
gen in the umbilical vein is around 4.7 kPa opposite the opening of the umbilical vein and
(35 mmHg) and SaO2 80–90% (Murphy 2005). passes superiorly and laterally between the left
Oxygen delivery is maintained by a high concen- lobe and the caudate lobe of the liver to terminate
tration of fetal hemoglobin (which binds oxygen in the left hepatic vein near its entry into the
with greater affinity than adult hemoglobin) along inferior vena cava (IVC). About 50–60% of
with a relatively high cardiac output. Fetal blood umbilical venous blood flow passes directly
is transported from the placenta via the umbilical through the ductus venosus, bypassing the hepatic
vein to the left branch of the portal vein lying circulation (Murphy 2005). A valve around the
within the umbilical recess of the liver (Fig. 3). margin of the opening of the IVC into the right
The ductus venosus arises from the posterior atrium directs this relatively well-oxygenated
86 M. D. Stringer
Desaturated systemic blood returning from the

fetal superior vena cava and coronary sinus is
directed preferentially to the right ventricle. How-
ever, a high pulmonary vascular resistance and the
presence of a patent ductus arteriosus result in less
than 15% of the fetal combined ventricular output
reaching the lungs (Archer 2005). The ductus
arteriosus shunts blood from the bifurcation of
the pulmonary trunk into the aortic arch, just distal
to the origin of the left subclavian artery. At term,
the ductus arteriosus is about 8–12 mm long and
4–5 mm wide at its origin from the pulmonary
trunk; the thoracic aorta by comparison measures
about 5–6 mm in diameter (Standring 2008). The
walls of the ductus arteriosus are rich in smooth
muscle. Ductal patency is maintained by locally
produced prostaglandins, which inhibit muscle
contraction in response to oxygen.
Fig. 1 Diagram illustrating the relative proportions of

viscera in the newborn (Adapted from Crelin 1973, p. 75) Circulatory Changes After Birth
At birth, clamping of the umbilical cord increases

peripheral vascular resistance and left-sided car-
diac pressures and decreases right-sided cardiac
pressures. The lungs inflate, and, as a result of this
along with oxygen-induced pulmonary vasodila-
tation (mediated via nitric oxide), pulmonary vas-
cular resistance falls dramatically. The ductus
arteriosus also begins to close. Blood is therefore
diverted from the pulmonary trunk into the pul-
monary circulation. Increased venous return to the
left atrium causes a rise in left atrial pressure.
Right atrial pressure falls as a result of reduced
venous return secondary to occlusion of the
umbilical vein. These changes in atrial pressure
force the free margin of the primary atrial septum
to flatten against and subsequently adhere to the
upper margin of the fossa ovalis, resulting in
functional closure of the foramen ovale. A perma-
Fig. 2 The relative proportions of the head, trunk, and nent seal usually develops during the first year
lower limbs in a neonate and adult (Adapted from of life.
Diméglio 2006, p. 40) Cardiovascular adaptation to neonatal life
therefore requires the functional closure of three
blood from the placenta through the foramen fetal conduits:
ovale into the left atrium. Better oxygenated
blood is therefore ejected from the left ventricle • Foramen ovale. Functional closure of the fora-
to supply the fetal coronary circulation and brain. men ovale occurs immediately after birth
Fig. 3 The fetal circulation

88 M. D. Stringer
consequent on differential atrial pressures; per- respiratory distress syndrome (Evans and
manent anatomical closure usually follows in Archer 1990).
early infancy. Incomplete fusion of the primary • Ductus venosus. Spontaneous closure of the
atrial septum with the limbus of the fossa ductus venosus begins immediately after birth
ovalis occurs in up to 25% of individuals (Meyer and Lind 1966) and is usually complete
(Hagen et al. 1984), resulting in a small poten- by about 17 days of age (Loberant et al. 1992;
tial atrial communication, a patent foramen Fugelseth et al. 1997). Closure may be tempo-
ovale (PFO). Typically this has no conse- rarily delayed in the presence of congenital
quences because of the flap-like arrangement heart disease, presumably as a result of ele-
of the opening and differential atrial pressures. vated venous pressure. In the adult, a fibrous
However, a PFO may rarely be associated with remnant, the ligamentum venosum, runs
paradoxical embolism (passage of an embolus within the fissure separating the left lobe of
from the venous system through an abnormal the liver and the caudate lobe. Persistent
communication between the chambers of the patency of the ductus venosus is rare, but
heart causing a systemic arterial embolus, e.g., more common in boys, and may cause long-
an embolic stroke) and an increased risk of term problems such as hepatic encephalopathy
decompression sickness in divers (Holmes (Stringer 2008).
et al. 2009). After closure of the foramen
ovale, the valve of the IVC that was prominent
in the fetus becomes flimsy or disappears. The Heart
• Ductus arteriosus. In the full-term neonate
with no congenital heart disease, the ductus In the full-term neonate, mean systolic blood pres-
arteriosus starts to close immediately after sure in the first week of life is 70–80 mmHg
birth. Smooth muscle contraction within the (lower in preterm infants), heart rate is 120–140
ductus is probably mediated by several mech- beats/min, and cardiac output measured by Dopp-
anisms: an increased arterial oxygen concen- ler ultrasound is about 250 mL/kg/min. As the
tration, suppression of endogenous pulmonary circulation is established, the work of
prostaglandin E2 synthesis, plasma catechol- the right side of the heart decreases and the left
amines, and neural signaling. In addition, duc- increases, resulting in changes in ventricular mus-
tal blood flow is reversed as a result of cle thickness. At birth, the mean wall thickness of
increased systemic vascular resistance (due to both ventricles is about 5 mm, whereas in adults
the absence of the placental circulation) and the left ventricle is about three times as thick as the
decreased pulmonary vascular resistance. right (Standring 2008). The neonatal heart is rel-
Functional closure of the ductus is complete atively large in relation to the thorax, and it
within 3 days in more than 90% of term infants occupies a larger proportion of the lung fields on
(Evans and Archer 1990). Structural closure a chest radiograph compared to an adult (Fig. 4).
occurs more gradually, leaving the fibrous Congenital cardiac malformations (8 per 1000
ligamentum arteriosum connecting the bifurca- live births (Archer 2005)) account for up to a
tion of the pulmonary trunk (near the origin of quarter of all developmental anomalies. They
the left pulmonary artery) to the underside of include dextrocardia (isolated or part of situs
the aortic arch. The prevalence of a patent inversus), isomerism, and structural defects (sep-
ductus arteriosus persisting beyond 72 h of tal defects, abnormal atrioventricular or ventricu-
age is inversely related to gestational age and loarterial connections, and valvular anomalies).
weight. It is relatively rare in term neonates but Ventriculoseptal defects are the most frequent,
occurs in 80% of infants weighing less than more often affecting the membranous part of the
1200 g at birth (Dice and Bhatia 2007). Persis- interventricular septum than the muscular part. A
tent ductal shunting is particularly common in true atrial septal defect occurs when there is a
preterm infants, especially those with failure of normal development of the septum
Fig. 4 Supine anteroposterior neonatal chest radiograph. Fig. 5 A peripheral long line lying within a left-sided
Note the prominent superior mediastinal thymic shadow superior vena cava (arrows) in a neonate
which is asymmetric on this rotated film (white arrows).
Compared to an adult, the hemidiaphragms are relatively
flat, the ribs are more horizontal, and the heart size is catheter tip should not be positioned in the
relatively large (although the transverse cardiothoracic proximal SVC because it may migrate into the
ratio should still be less than 60% (Arthur 2001))
ostium of the azygos vein and cause venous
thrombosis.
primum and/or atrioventricular endocardial cush- A persistent left-sided SVC is present in
ions. Coarctation of the aorta is often included 0.3–0.5% of individuals; it usually drains into
within the spectrum of congenital heart disease the right atrium either directly or via the coronary
even though it affects the aorta. Typically, there sinus (Iovino et al. 2012) (Fig. 5). This anatomical
is narrowing or occlusion of the juxta-ductal seg- variant is usually asymptomatic, but its existence
ment of aorta just distal to the origin of the left is important to recognize when inserting a central
subclavian artery although preductal (involving venous line from the left internal jugular or left
the aortic arch and its major branches) and even subclavian vein since cardiac arrhythmias and
postductal coarctation can occur. coronary sinus thrombosis have been reported as
complications.
The left brachiocephalic vein lies at a relatively
Central Veins higher level in the thorax and is potentially at risk
of injury during tracheostomy.
Central venous catheters in children are gener-
ally positioned such that the catheter tip lies just
outside the cardiac silhouette on a chest radio- Umbilical Vessels
graph, typically at the junction between the
superior vena cava (SVC) and right atrium. The normal umbilical cord contains two relatively
This is in order to reduce the small but serious thick-walled umbilical arteries and, near the
risk of atrial perforation and cardiac tamponade 12 o’clock position, one larger but thin-walled
from migration of the catheter tip. The upper umbilical vein. The presence of a single umbilical
right atrium may be an acceptable position for artery may be associated with other congenital
the catheter tip in some cases, especially if it is anomalies, particularly renal, vertebral, anorectal,
envisaged that the catheter will be in place long and cardiovascular malformations (Martínez-
enough for the child to grow substantially or if Frías et al. 2008; Rittler et al. 2010), and an
the catheter is to be used for hemodialysis. The increased risk of perinatal mortality (Mu et al.
90 M. D. Stringer
2008). However, routine karyotyping and renal higher vertebral level in the neonate (T12-L1)
sonography in an infant with an isolated single (Standring 2008) compared to the adult
umbilical artery is not indicated (Mu et al. 2008; (L1) (Mirjalili et al. 2012a), and the aortic bifur-
Deshpande et al. 2009). cation is similarly slightly more cranial (at the
At birth, the umbilical vessels constrict rapidly upper border of L4).
in response to a fall in umbilical cord temperature
and hemodynamic changes. Occlusion of the
umbilical artery is facilitated by the “folds of Respiratory System
Hoboken,” constriction rings along the length of
the umbilical artery produced by oblique or trans- Upper Airway
verse bundles of myofibroblasts (Röckelein et al.
1990). Numerous mediators of umbilical vessel Relative to an adult, the newborn infant has a large
vasoconstriction have been proposed, including head, short neck, small face and mandible, and
bradykinin and endothelin-1, some of which are large tongue (Crelin 1973). The entire surface of
produced locally within the umbilical cord. Post- the tongue lies within the oral cavity, unlike in the
natally, the obliterated umbilical arteries become older child and adult where its posterior third is in
the paired medial umbilical folds or ligaments that the oropharynx. Neonates are obligate nose
are visible under the peritoneum of the anterior breathers and do not begin to breathe orally until
abdominal wall below the umbilicus; the proximal about 4 months of age. These features make
segment of each umbilical artery remains patent as infants more at risk of airway obstruction.
the superior vesical artery. The intra-abdominal The neonatal nasopharynx curves smoothly
portion of the umbilical vein becomes the backward and downward to join the oropharynx,
ligamentum teres. The urachus has normally invo- rather than forming a right angle as in adults
luted before birth leaving the median umbilical (Fig. 6). The hyoid bone and larynx are positioned
fold or ligament. higher in the neck. Consequently, the upper mar-
The umbilical vessels can be catheterized gin of the neonate’s epiglottis (which is more
within 24–48 h of birth to provide vascular access
for resuscitation, intravascular monitoring, fluid
administration, blood transfusion, and/or paren-
teral nutrition (Anderson et al. 2008). The tip of
an umbilical artery catheter is usually positioned
above the diaphragm but below the ductus
arteriosus (“high” position equivalent to T6–T9
vertebral level). Sometimes, the catheter tip is
sited below the origin of the renal and inferior
mesenteric arteries but above the aortic bifurca-
tion (“low” position at L3–L4 vertebral level).
Arteries
The femoral artery is palpable midway between

the anterior superior iliac spine and pubic tubercle
in the neonate (Van Schoor et al. 2009); this is
slightly more lateral than in an adult where its
surface marking is midway between the anterior
Fig. 6 Sagittal magnetic resonance image of the upper
superior iliac spine and symphysis pubis (Hale airway in a newborn. T tongue, SP soft palate,
et al. 2010). The renal arteries are at a slightly E epiglottis (Courtesy of Professor Terry Doyle)
horizontal than an adult’s) extends to the level of endotracheal tube critical. The tip of the tube is
the soft palate, and the posterior nares are in direct usually best sited between the clavicles, 1–2 cm
continuity with the larynx. This allows the infant above the carina, which corresponds to the ver-
to breathe while suckling. Ingested liquids pass tebral body of T1. As in adults, the trachea starts
lateral to the epiglottis via the piriform fossae. at the level of the sixth cervical vertebra but
Despite immature coordination of swallowing bifurcates at a relatively higher level (approxi-
and breathing, the risk of pulmonary aspiration mately T4) than in adults (approximately T5/T6
is reduced by the high position of the larynx. vertebral level (Mirjalili et al. 2012b)). The tra-
The higher more anterior position of the larynx chea is abnormally short in DiGeorge syndrome
also means that it is easier to intubate the trachea (Wells et al. 1989). The trachea is rich in elastic
with a straight-bladed laryngoscope. As the infant tissue (Kamel et al. 2009) and readily deform-
grows, the larynx descends, and the epiglottis able, especially in neonates where the cartilage
loses contact with the soft palate. rings are soft. The right main bronchus is wider
The narrowest part of the infant’s upper airway and steeper than the left, and the carina is
(about 3.5 mm in a term neonate) is the subglottis at more likely to lie slightly to the left of the middle
the level of the cricoid cartilage, rather than the of the trachea. An inhaled foreign body is there-
vocal cords as in adults (Fayoux et al. 2008). Muco- fore more likely to enter the right lung (Tahir
sal edema in this region is more likely to compro- et al. 2009).
mise the airway (▶ Chap. 43, “Stridor in the
Newborn”). As endotracheal tube cuffs tend to lie
at this level, uncuffed tubes are preferred in neonates Bronchial Tree
and young children. The internal diameter (mm) of
an appropriate uncuffed endotracheal tube from The bronchial tree is largely developed by the
about 1 year of age can be estimated from the 16th week of intrauterine life; thereafter,
formula (age/4) + 4 (O’Meara and Watton 2012). conducting airways (down to the level of the
The thyroid cartilage is shorter, lies nearer the terminal bronchioles) mostly increase in size
hyoid bone, and has a less well-developed laryn- rather than number (Jeffery 1998). Respiratory
geal prominence in children. Although the thyroid bronchioles develop and form alveoli as gestation
cartilage is slightly smaller in girls from birth progresses; type 2 pneumocytes begin surfactant
(Fayoux et al. 2008), gender differences in laryn- production at about 26 weeks’ gestation. At birth,
geal shape and size only begin to become apparent 85% of alveoli have formed. Lung growth is espe-
at about 3 years of age (Crelin 1973) and do not cially rapid during infancy and is largely due to
become well established until puberty. Adult men continuing alveolar development. It is generally
have a much more noticeable laryngeal prominence agreed that most alveoli are formed by 2 years of
than women because the thyroid laminae are larger age and simply increase in size thereafter
and meet at a more acute angle (mean 75 in men (Thurlbeck 1982; Hislop 2002), but there is evi-
compared to 90 in women) (Jotz et al. 2014). dence to indicate that some alveoli continue to be
In 3–8-year-olds, upper airway lymphoid tis- formed in early childhood (Burri 2006).
sue is particularly prominent. At this age, Intermittent cyclical fetal “breathing” move-
adenotonsillar hypertrophy may cause airway ments are detectable from about 11 weeks’ gesta-
obstruction, particularly when sleeping at night tion. Fluid produced by the fetal lungs is essential
(obstructive sleep apnea). for normal growth and development of the lungs;
there is a net egress of fluid from the lungs, which
is either swallowed or mixes with the amniotic
Trachea fluid. Fetal lung fluid production decreases a few
days before term delivery switching to net
The trachea is short, measuring as little as 3 cm reabsorption during labor. Before the infant takes
in premature neonates, making positioning of an his/her first breath, the terminal bronchioles and
92 M. D. Stringer
alveoli are still filled with fluid. At birth, a new- much smaller proportion of fatigue resistant type I
born infant delivered by caesarean section has muscle fibers in their diaphragmatic and intercos-
more lung fluid than an infant delivered vaginally. tal muscles as compared to older infants (Keens
For the alveoli to expand adequately, surface ten- et al. 1978).
sion must be reduced; this is achieved by the The neonatal thymus is variable in size at birth
release of surfactant from type II pneumocytes but typically large (up to 5 cm wide and 1 cm
lining the alveoli. Surfactant also prevents alveo- thick). It is a prominent feature on a chest X-ray
lar collapse on expiration, which explains why (Fig. 4). The thymus overlies the trachea, great
very premature infants with inadequate surfactant vessels (especially the left brachiocephalic vein),
production develop respiratory distress. and upper anterior surface of the heart. After the
Remodeling of the pulmonary vessels begins first year of life, it becomes progressively smaller
immediately after birth leading to reduced pulmo- and less vascular, and the lymphoid tissue is
nary vascular resistance. increasingly replaced by fat.
The small size of both the upper and lower
airways in infants and children makes them more
susceptible to obstruction than their adult Abdominal Wall and Gastrointestinal
counterparts. Tract
Abdominal and Pelvic Cavities

Thorax and Mechanics of Breathing
The infant’s abdomen is relatively wide and pro-
The neonatal thorax has the shape of a truncated tuberant because the diaphragm is flatter and the
cone and is more rounded in circumference than pelvic cavity smaller. The distance between the
an adult’s. In an adult, the compliance of the chest costal margin and iliac crest is proportionately
wall and lung are similar, but a neonate’s chest greater. For these reasons, transverse supra-
wall is up to five times more compliant than its umbilical incisions provide good surgical access
lungs (Standring 2008). Consequently, it is easily in young children. The rectus abdominis muscles
deformable, as is readily apparent in an infant with may be relatively wide apart in an infant creating
chest wall recession associated with respiratory divarication, which resolves with growth.
distress. The greater compliance of the chest The infant’s peritoneal cavity is relatively shal-
wall in children means that serious visceral inju- low anteroposteriorly because there is no lumbar
ries can occur following blunt trauma without lordosis and the paravertebral gutters are poorly
radiologic evidence of rib fractures. developed. There are numerous anatomical differ-
The respiratory rate of a full-term newborn is ences between the child and adult that are relevant
about 40–44 breaths/min. The ribs are more hor- to pediatric laparoscopy: working spaces are
izontal and contribute less to chest expansion. smaller; the position and size of some organs
Infants rely mainly on diaphragmatic breathing. such as the bladder and liver are different; the
The diaphragm is relatively flat at birth (Fig. 4) relatively shallow peritoneal cavity means that
and becomes more dome shaped with continuing the great vessels may be more at risk of injury
growth. Diaphragmatic contraction tends to pull when inserting a trocar; the abdominal wall is
the ribs inward; concomitant outward movement more compliant and the peritoneum more elastic;
of the abdomen (thoracoabdominal paradox) is a and the inferior epigastric vessels are relatively
normal finding in newborns. larger. The greater omentum is delicate and mem-
The work of breathing is greater in an infant branous, rarely extending much below the level of
than an adult and greater still in a preterm infant. the umbilicus. The neonate has less fat in the gut
This is due to numerous factors including greater mesenteries and around the viscera.
chest wall compliance. Furthermore, neonates, The inguinal canal in the newborn is short and
and particularly those that are premature, have a more vertically orientated because the superficial
Fig. 7 Midline sagittal section of a plastinated neonatal sacral promontory and pubic bone [P]). V vagina, R rectum
(a) and adult (b) female pelvis. Note the relative positions (Courtesy of the W.D. Trotter Anatomy Museum, Univer-
of the bladder (B) and uterus (U ), the curvature of the sity of Otago)
sacrum (S), and the angle of the pelvis (dotted line between
inguinal ring lies just medial to the deep ring. 1 cm (Gupta and Jadcherla 2006). Lower esopha-
Despite its length, the canal can still be opened geal sphincter pressure is particularly low during
via a short incision in its anterior wall (the external the first month or two of life. The narrowest part of
oblique aponeurosis) when repairing an inguinal the upper digestive tract is where the
hernia, even in premature infants. The canal cricopharyngeus muscle blends with the upper
lengthens with growth. esophagus, a potential site of esophageal perfora-
Compared to an adult, the true pelvis (the part tion during the passage of a nasogastric tube
below the pelvic brim) in the neonate is small, (Gander et al. 2009).
both relatively and absolutely. It is also more The anterior surface of the stomach is over-
circular in cross section, orientated more verti- lapped by the left lobe of the liver, which extends
cally, and has a less pronounced sacral curve. close to the spleen. The capacity of the neonatal
The urinary bladder, ovaries, and uterus are all stomach is approximately 30–35 mL at term but
partly intra-abdominal, and the rectum occupies reaches 100 mL by the fourth week. The newborn
most of the true pelvis (Fig. 7). stomach is typically very small in infants with
isolated esophageal atresia. Gastric emptying is
relatively slow and poorly coordinated in the
Gastrointestinal Tract first few weeks of life, even though the gastric
muscle layers are developed. Gastric acid is pre-
At term, the newborn esophagus is about 8–10 cm sent on the first day of life in most premature
long from the level of the cricoid cartilage to the infants of at least 27 weeks’ gestation, although
diaphragm (Crelin 1973); the upper and lower basal acid output is low during the first 24 h
esophageal sphincters each extend over about (Marciano and Wershil 2007).
94 M. D. Stringer
The small bowel of the infant is distributed Liver, Gallbladder, and Spleen
more horizontally because of the shape of the
abdominal cavity and position of the bladder. The neonatal liver weighs about 120 g at term
The mean length of the small intestine from the and comprises about 4% of body weight
duodenojejunal flexure to the ileocaecal junction (as compared to 2% in the adult); it more than
is around 160 cm when measured along its anti- doubles in weight during the first year. The rela-
mesenteric border in vivo in the full-term neonate tively large liver fills much of the upper abdo-
(Struijs et al. 2009) but is considerably longer men. Its inferior border extends 1–2 cm below
when measured at autopsy (Weaver et al. 1991). the costal margin, and the left lobe overlaps the
Mean length is nearer 100 cm at about 30 weeks’ stomach and extends more laterally. The prema-
gestation (Struijs et al. 2009). The mesentery con- ture baby’s liver is particularly fragile and vul-
tains relatively little fat, making identification of nerable to injury (e.g., from an abdominal
mesenteric blood vessels much easier. In older retractor). The neonatal gallbladder is more
children, lymph nodes are readily identifiable in intrahepatic, and its fundus may not extend
the small bowel mesentery and may be prominent below the inferior border of the liver; a more
in the absence of disease. adult type configuration is evident after 2 years
The mean length of the colon from the of age.
ileocaecal junction to the upper rectum in the The tip of the newborn’s spleen is often pal-
term infant in vivo is about 55 cm (Struijs et al. pable just below the left costal margin. Normal
2009; Mirjalili et al. 2017). Compared to adults, values for spleen lengths at different ages in
the caecum and ascending and descending colon childhood have been established using ultra-
are relatively short and the transverse colon, sig- sound (Megremis et al. 2004). The tail of the
moid colon, and rectum relatively long. The cae- pancreas is in contact with the splenic hilum in
cum tapers to a proportionately wider appendix more than 90% of cases, a much greater propor-
with a relatively wider orifice. The mean length of tion than in adults (Üngör et al. 2007). Accessory
the large bowel increases to about 73cm at 4–6 spleens are found at autopsy in about 14% of
years and 95cm at 9–11 years (Mirjalili et al. fetuses and neonates as compared to 10% of
2017). In children, the transverse colon is the adults (Cahalane and Kiesselbach 1970), but it
longest segment and contributes approximately is uncertain whether this is a true difference in
30% of the total length of the large bowel. The prevalence.
cecum is located in the right upper quadrant in a
substantial minority of infants but is in the right
lower quadrant in almost all school age children. Genitourinary System
In infants, the anal canal has well-defined anal
columns and prominent anal sinuses (Shafik Genitourinary anomalies are among the
1980); stasis within these sinuses may be a cause commonest congenital malformations, and so it
of perianal sepsis, particularly in male infants, is especially important to understand the normal
although other factors are probably also involved anatomy of the newborn.
(Nix and Stringer 1997).
Neonatal small bowel has few circular folds
(valvulae conniventes), and the neonatal colon Kidneys and Suprarenal Glands
has no haustra. It is therefore difficult to distin-
guish the small and large bowel on plain abdom- By 8 weeks of gestation, the urethra is patent, and
inal radiographs of the newborn. Their relative the fetal kidneys are beginning to make urine.
position (central small bowel vs. peripheral large Fetal urine output increases steadily during preg-
bowel) and caliber are a rough guide, but a con- nancy and accounts for the majority of amniotic
trast study may be required to accurately differen- fluid in the second half of pregnancy (Maged et al.
tiate small from large bowel. 2014). At birth the kidneys are about 4–5 cm in
length compared to a mean length of 11 cm in resolve spontaneously with growth (Godley and
adults. The renal pelvis measures less than 5 mm Ransley 2010).
anteroposteriorly, and fetal lobulation of the kid-
neys is still present. Individual nephrons are com-
posed of (i) a renal corpuscle consisting of a Genitalia and Reproductive Tract
central glomerulus surrounded by a capsule and
concerned with plasma filtration and (ii) a renal During development the testis “descends” from
tubule that produces urine by selective the urogenital ridge, and by about the sixth
reabsorption of the filtrate. At birth there are month of gestation, the testis lies adjacent to
about one million renal corpuscles in the cortex the deep inguinal ring; it is connected to the
of each kidney. Postnatally, nephron mass developing scrotum by the gubernaculum.
increases, but no new nephrons are made. The About 1 month later, the testis begins its
glomerular filtration rate (GFR) is low in new- inguinoscrotal descent accompanied by a tongue
borns, particularly in the premature infant, but of peritoneum, the processus vaginalis. About
doubles by 2 weeks of age in the full-term infant 4% of boys born at term have an undescended
and reaches adult values (120 mL/min per testis(es); this figure is higher in premature
1.73m2) by 1–2 years (Lissauer and Clayden infants. By 3 months of age, the prevalence of
2007). cryptorchidism has fallen to 1.5%. Further spon-
The suprarenal glands are relatively large at taneous testicular descent does not occur after
birth with a proportionately thick cortex. Their 6 months of age. The precise timing and process
average combined weight is 9 g compared with of closure of the processus vaginalis are uncer-
7–12 g in the adult. Both glands become smaller tain (Godbole and Stringer 2010). Surgical stud-
in absolute and relative terms in the neonatal ies have shown that a patent processus vaginalis
period due to shrinkage of the suprarenal cortex is present in around 60% of contralateral groin
(Kangarloo et al. 1986). explorations in infants with a unilateral inguinal
hernia in the first 2 months, falling to around
40% after 2 years of age. Autopsy studies have
Bladder and Ureter indicated that the processus is patent in about
80% of newborns, decreasing to about 15–20%
The bladder is mostly intra-abdominal at birth in adults. Boys with cryptorchidism have higher
(Fig. 7) with its apex midway between the pubis patency rates.
and the umbilicus in the unfilled state. Manual The prostate and seminal vesicles are well
expression of urine (Credé’s maneuver) and developed at birth. The penis and scrotum are
suprapubic aspiration are therefore relatively relatively large, and the scrotum has a broad
easy. The bladder does not achieve its adult base and relatively thick walls. The inner surface
pelvic position until about the sixth year of the prepuce (foreskin) begins to separate from
(Standring 2008). The apex of the bladder is the glans penis in the fetus, but only 4% of new-
continuous with the median umbilical fold or borns have a fully retractile foreskin. By 6–7 years
ligament which represents the obliterated of age, about 8% of uncircumcised boys will still
urachus. A urachal remnant (sinus, cyst, patent have a nonretractile foreskin, but this figure
urachus, etc.) is a consequence of incomplete decreases to about 1% by 17 years of age (Oster
involution. The intravesical segment of the ure- 1968), emphasizing that the natural history of the
ter (intramural and submucosal portions) foreskin is one of spontaneous separation.
lengthens from about 0.5 cm in neonates to In female infants, the ovary lies in the lower
1.3 cm (the adult value) by 10–12 years of age. part of the iliac fossa and only descends into the
An abnormally short submucosal tunnel is one ovarian fossa within the true pelvis during early
of the causes of vesicoureteric reflux (VUR) in childhood as the pelvis deepens. At birth the ova-
preschool children; this type of VUR tends to ries are relatively large and contain the full
96 M. D. Stringer
complement of primary oocytes, each surrounded secondary to postnatal molding as a conse-

by a single layer of follicular cells forming the quence of head positioning.
primordial follicles. Of the seven million oocytes Serial measurements of head circumference
estimated to be present in the female fetus, only give an indication of brain growth; 80% of adult
one million remain at birth, and this number head size is achieved by 5 years of age. Abnormal
decreases further to approximately 40,000 by head enlargement may be familial or indicate
puberty. hydrocephalus, while poor head growth may
In the term infant, the uterus is about 3–5 cm reflect neurological impairment from a variety of
long, and the cervix forms two-thirds or more of causes or malnutrition.
its length (Fig. 7). Female newborns have a rela- Fontanelles are formed where several skull
tively prominent clitoris (mean length of 4 mm vault bones meet. The two most prominent are
(Oberfield et al. 1989)) and labia. The vagina is the anterior fontanelle overlying the superior sag-
about 3 cm long and is relatively thick walled with ittal venous sinus at the junction of the metopic
a fleshy hymen. After withdrawal of maternal and sagittal sutures (the bregma) and the posterior
hormones, the uterus and vagina diminish in size. fontanelle at the junction of the sagittal and
lambdoid sutures (the lambda) (Sundaresan et al.
1990). The size of the anterior fontanelle at birth is
Musculoskeletal System very variable; if unduly large, it may be an indi-
cation of congenital hypothyroidism or a skeletal
Skull and Face disorder (Davies et al. 1975). The timing of clo-
sure of the fontanelles is also variable, but the
The skull vault is formed by intramembranous anterior fontanelle is obliterated by 2 years of
ossification, the facial skeleton is derived from age in 95% of children (Acheson and Jefferson
neural crest membrane bones, and the skull base 1954) and the posterior by 2 months of age
and some bony pharyngeal arch derivatives (Bickley and Szilagyi 2009).
(e.g., hyoid bone and ossicles) by endochondral Postnatal growth of the skull is associated with
ossification (Standring 2008). During birth, the disproportionate growth of the facial skeleton and
margins of the frontal and parietal bones are able mandible, both of which are small in comparison
to slide over each other. In the first 2 days of life, to the skull vault at birth (Fig. 8). The bony exter-
palpable overriding of the bones of the vault is nal ear canal is not developed, and the mastoid
common. Persistent ridging of suture lines may process is absent at birth. Consequently, the facial
indicate craniosynostosis. Growth at the coronal nerve is potentially at risk of injury (e.g., from
suture is mostly responsible for fronto-occipital obstetric forceps) where it emerges from the
expansion of the skull; premature fusion causes stylomastoid foramen. At birth, the two halves of
brachycephaly if bilateral and plagiocephaly if the mandible are united by a fibrous symphysis
unilateral. The latter must be distinguished from that fuses in early childhood. The mandibular rami
asymmetric flattening of the back of the skull are at a more obtuse angle to the body of the
(deformational plagiocephaly) in premature mandible. The mandible changes shape as the
babies secondary to postnatal gravitational teeth erupt and the muscles of mastication and
molding. Growth at the metopic and sagittal chin develop.
sutures increases skull breadth, the metopic The maxillary and ethmoid sinuses are
suture fusing at around 18 months of age, and present at birth, but the sphenoid sinus is poorly
the sagittal suture at puberty. Premature fusion developed, and the frontal sinuses are absent
of the sagittal suture (sagittal craniosynostosis) (Crelin 1973). The auditory tube is almost
is the most common form of craniosynostosis horizontal, increasing the risk of middle ear
and produces an elongated skull. This must be disease; it becomes more vertical during child-
distinguished from the long thin head (dolicho- hood. The hard palate is short, only slightly
cephaly) sometimes seen in premature babies arched, and ridged by transverse folds which
Fig. 8 Comparison of a neonatal (a) and adult male (b) fontanelle. The mastoid process has not developed at birth
skull. Note the relatively small size of the face and mandi- (Courtesy of the W.D. Trotter Anatomy Museum, Univer-
ble in the neonate, the cranial vault sutures, and the anterior sity of Otago)
assist with suckling. The nasolacrimal duct discs and ligaments of the upper cervical spine
which drains tear secretions from the conjuncti- (occiput-C2), whereas older children tend to
val sac to the inferior meatus of the nasal cavity injure the subaxial region of the cervical spine
is relatively short and wide at birth but may be (C3-C7), a pattern more similar to adults
obstructed due to incomplete canalization, lead- (O’Meara and Watton 2012; Leonard et al. 2014;
ing to excessive tearing, discharge, and Ribeiro da Silva et al. 2016). Moreover, children
infection. are more likely to have a subluxation without
fracture of the cervical spine or a spinal cord
injury without radiographic abnormality. Conse-
Vertebral Column, Pelvis, and Limbs quently, clinical assessment of the injured child
with a potential cervical spine injury is essential,
Apart from a mild sacral curve, the vertebral col- even in the presence of normal cervical spine
umn in the neonate lacks the fixed spinal curva- radiographs.
tures present in adults. After birth, the thoracic The anatomy of the sacral hiatus and caudal
curvature develops first, and then, as the infant canal varies between individuals but also varies
learns to control its head, sit, stand, and walk, with age. When performing a caudal anesthetic
curvatures in the cervical and lumbar spines block, neonates are more at risk of inadvertent
develop which help to maintain the center of dural puncture than older children and adults
gravity of the trunk when walking. The sacral because the termination of the dural sac is nearer
promontory “descends” and becomes more the sacral hiatus and the sacrum is more cartilag-
prominent. inous providing less rigid bony definition (Lees
The pattern of cervical spine injuries is differ- et al. 2014).
ent in children, reflecting anatomical differences, In the fetus, hemopoiesis occurs in the liver,
namely, a relatively large head, more flexible spleen, and bone marrow, but after birth it is
neck, and less well-developed cervical muscles largely restricted to the bone marrow of the verte-
(Knox 2016). Most cervical spine injuries in chil- brae, ribs, sternum, proximal long bones, and
dren under 8 years of age affect the intervertebral diploe of the skull.
98 M. D. Stringer
Fig. 9 The bony skeleton

of a newborn baby. There
are no carpal bones at birth,
there are separate
ossification centers for the
hip, and secondary centers
of ossification in the long
bones are absent except for
the lower end of the femur
and upper end of tibia
(Specimen prepared by
Professor J.H. Scott in
1895. Courtesy of the
W.D. Trotter Anatomy
Museum, University of
Otago)
Of the 800 or so ossification centers in the the only secondary centers of ossification in the
human skeleton, just over half appear after birth; long bones are in the femoral and tibial condyles
these include most secondary ossification centers and humeral head (Crelin 1973). The iliac crest,
(Fig. 9). Cartilage is abundant at birth. None of the acetabular floor, and ischial tuberosity are all
carpal bones have ossification centers at birth and cartilaginous.
The acetabulum is relatively large and shallow the first 3 months of life. The supracristal plane
at birth and has a characteristic Y-shaped triradiate between the upper limits of the iliac crests is
cartilaginous epiphyseal plate at the site of union slightly higher (L3/4 rather than L4); a lumbar
between the ilium, ischium, and pubis. Nearly puncture in the newborn should not be performed
one-third of the neonatal femoral head lies outside above this level to avoid the risk of injuring the
the acetabulum, making the hip joint easier to spinal cord.
dislocate. Developmental dysplasia of the hip
affects about 1 in 100 live births and is more
common in girls. The neonatal femoral neck is Skin and Subcutaneous Tissue
short, and the femoral shaft is straight. The prox-
imal femoral growth plate in early infancy is intra- Body fat is laid down in the fetus from about
articular so that infection in the proximal femoral 34 weeks’ gestation and, with appropriate intra-
metaphysis may cause a septic arthritis. The lower uterine nutrition, increases until term. Plantar fat
limb muscles in the newborn are relatively under- pads give the neonate a flat-footed appearance.
developed, and the gluteal muscle mass is small. Brown fat is a modified form of adipose tissue in
The thighs tend to be abducted and flexed, the the newborn concentrated at the back of the neck,
knees flexed and the foot dorsiflexed and inverted. in the interscapular region, and in pararenal areas.
In congenital talipes equinovarus (club foot), It is composed of adipocytes with mitochondria
maldevelopment of the talus causes inversion that have large and numerous cristae adapted to
and supination of the foot and adduction of the heat production. Despite this specialized fat, the
forefoot. neonate’s ability to regulate temperature is poorly
developed.
At birth, breast tissue is similarly developed in
Nervous System girls and boys. It may appear prominent due to
the influence of maternal hormones, even leading
At term, the neonatal brain weighs between to the secretion of a small amount of fluid
300 and 400 g and accounts for about 10% of (witch’s milk). Supernumerary nipple(s) may be
body weight (compared to 2% in the adult) (Crelin found along the mammary ridges (milk lines)
1973). Brain growth is especially rapid during the which extend on each side from the axilla to the
first year of life, when the brain reaches 75% of its groin.
adult volume. In the term infant, the number of Neonatal skin is relatively thin. The ability to
neurons is already established at birth; brain see peripheral veins is very dependent on the
growth is due to an increase in size of nerve cell thickness of the subcutaneous tissues. Common
bodies, development of additional neuronal con- sites for peripheral venous cannulation include:
nections, proliferation of neuroglia and blood ves- the dorsal arch veins of the hands and feet, the
sels, and myelination of axons. Myelination is at cephalic vein at the wrist, the volar aspect of the
its peak in the first 6 months of life but continues wrist (where the veins are small and fragile), the
until maturity (Standring 2008). The arrangement cubital fossa, the saphenous vein immediately
of sulci and gyri at birth is similar to the adult, anterior to the medial malleolus or behind the
although the central sulcus is slightly further for- medial aspect of the knee, and the superficial
ward and the cerebral ventricles are proportion- temporal vein anterior to the ear.
ately larger. Mean head circumference at term is
34 cm.
The termination of the spinal cord, the conus Conclusion
medullaris, may extend as low as the level of the
L3 vertebra in the neonate, whereas in the adult, it There are key differences between the anatomy of
is usually around the lower border of L1. The the child and adult that affect the utility of tradi-
conus is readily visualized by ultrasound scan in tional surface anatomical landmarks, surgical
100 M. D. Stringer
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of normal physiological and cardiorespiratory geal perforation in children. Pediatr Surg Int.
2009;25:395–401.
parameters and responses. Pediatric surgeons Godbole PP, Stringer MD. Patent processus vaginalis. In:
need to be aware of these differences. Gearhart JP, Rink RC, Mouriquand PDE, editors. Pedi-
atric urology. 2nd ed. Philadelphia: Saunders, Elsevier;
2010. p. 577–84.
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Perinatal Physiology
6
Carlos E. Blanco and Eduardo Villamor
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
The Fetal Circulation and Its Transition at Birth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Closure of the Ductus Venosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Closure of the Foramen Ovale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Fall in Pulmonary Vascular Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Closure of the Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
The Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Abstract Keywords
This chapter will discuss the mechanisms pre- Fetus · Fetal breathing · Lung development ·
paring the fetus to be born, the transition at Birth · Pulmonary circulation · Ductus
birth, and the successful adaptation to the arteriosus · Control of breathing
air-breathing world. This chapter will review
the respiratory system including lung develop-
ment, maturation, and role of surfactant system Introduction
and the respiratory drive and chemoreceptor
role and the circulatory system including fetal In order to succeed in this transition, the respira-
circulation and its changes at birth. tory system must be developed enough to assure a
sufficient alveolar exchange area, it must have a
drive to offer a continuous breathing activity, and
the circulatory system should start perfusing the
C. E. Blanco (*) lungs instead of the placenta.
Department of Neonatology, National Maternity Hospital,
Dublin, Ireland
e-mail: carlosblancogroningen@gmail.com
E. Villamor
Department of Pediatrics, School for Oncology and
Developmental Biology (GROW), Maastricht University
Medical Center (MUMC+), Maastricht, The Netherlands
e-mail: e.villamor@mumc.nl

https://doi.org/10.1007/978-3-662-43588-5_6
104 C. E. Blanco and E. Villamor
The Fetal Circulation and Its Transition et al. 1997). Accordingly, constriction and relax-
at Birth ation of fetoplacental arteries and veins have been
demonstrated in response to a number of agonists
The development of an adequate placental circu- and physical stimuli. Moreover, various authors
lation providing a low-resistance vascular bed for have suggested that the fetoplacental vasculature
efficient gas and nutrient exchange between shows some form of flow matching similar to
maternal and fetal blood is vital to the develop- hypoxic pulmonary vasoconstriction. This mech-
ment of the fetus and to the formation of a func- anism, termed hypoxic fetoplacental vasocon-
tional cardiovascular system (Finnemore and striction (Cooper et al. 2006; Hampl et al. 2002;
Groves 2015). The fetal circulation is character- Weir et al. 2005), would divert blood flow to the
ized by high pulmonary vascular resistance placental areas with better maternal perfusion as
(PVR), low systemic vascular resistance (SVR), hypoxic pulmonary vasoconstriction diverts pul-
the presence of an additional low-resistance vas- monary blood flow to the better ventilated areas of
cular bed (i.e., the placental bed), and right-to-left the lung (Weir et al. 2005; Aaronson et al. 2006;
shunting via the foramen ovale and ductus Russell et al. 2008).
arteriosus (DA) (Dzialowski et al. 2011). Distri- Clamping of the umbilical cord at birth elimi-
bution of blood flow to the lungs, systemic organs, nates the placental circulation producing a con-
and placenta is determined by local vascular resis- spicuous increase in SVR. Simultaneously, as the
tance. The placental vascular bed receives about lung assumes the respiratory function, the pulmo-
40–50% of the combined ventricular output, nary circulation undergoes a striking transition
whereas the lungs receive less than 10%. In characterized by an immediate eight- to tenfold
response to fetal hypoxemia, distribution of car- rise in pulmonary blood flow and a sustained
diac output and venous return is altered in an decrease in PVR (Abman 1999; Abman and Ste-
effort to maintain perfusion and O2 delivery to vens 1996; Kinsella and Abman 1995; Ziegler
the vital organs such as the heart, brain, and adrenal et al. 1995). The postnatal fall in PVR and rise in
glands (Reuss and Rudolph 1980; Noori et al. SVR result in a reversal of the relationships pre-
2004). Thus, during maternofetal hypoxia, the per- sent in the fetus. Increasing blood return to the
centage of systemic venous blood not sent to the heart via the pulmonary veins raises the pressure
placenta for oxygenation is decreased, whereas the of the left atrium above that of the right, causing a
proportion of umbilical venous blood contributing functional closure of the foramen ovale. While the
to fetal cardiac output is increased (Reuss and DA is still patent, the flow of blood through it will
Rudolph 1980; Noori et al. 2004). change to a left-to-right shunt, but the DA nor-
The human placenta was widely thought of as a mally achieves functional closure within 48 h
passive organ in which blood flow depends only after birth. Because the foramen ovale and ductus
on the pressure difference between the umbilical arteriosus are only functionally closed and the
arteries and vein connecting it to the fetus (Talbert pulmonary circulation is very sensitive to vaso-
and Sebire 2004; Sebire and Talbert 2002). How- constrictive stimuli, the neonatal circulatory pat-
ever, more recent evidences indicate that the reg- tern can readily revert to the fetal pattern. In the
ulation of vasomotor tone in the vessels of the following paragraphs, the different circulatory
fetoplacental circulation is important to maintain events that take place during the transition
an adequate blood supply that makes possible between fetal and postnatal life will be analyzed
maternofetal gas and solute exchange (Talbert in more detail.
and Sebire 2004; Sebire and Talbert 2002; Cooper
et al. 2006). As fetoplacental blood vessels lack
autonomic innervation, control of vascular tone is Closure of the Ductus Venosus
mainly influenced by circulating and/or locally
released vasoactive agents as well as by physical The ductus venosus has a central role in the dis-
factors, such as flow or oxygen tension (Khong tribution of highly oxygenated umbilical venous
6 Perinatal Physiology 105
blood to the heart. The ductus venosus is a shunt Closure of the Foramen Ovale
between the umbilical vein and the inferior vena
cava which allows highly oxygenated and Anatomically, the foramen ovale comprises over-
nutrient-rich umbilical venous blood to bypass lapping portions of the septum primum and sep-
the liver and reach the central circulation rapidly tum secundum, acting as a one-way flap valve
(Dzialowski et al. 2011). A large proportion of allowing continuous right-to-left flow during
inferior vena cava blood return crosses the fora- fetal life (Sommer et al. 2008). Immediately after
men ovale into the left atrium to the left ventricle birth, with the acute increase in pulmonary blood
and is thus distributed to the coronary and cerebral flow, left atrial pressure rises to exceed right
circulations. The PO2 of blood supplying the atrial pressure, pushing the septum primum right-
heart, brain, head, and neck is higher by ward, against the septum secundum, and shutting
4–5 mmHg than that of blood in the descending the flap of the foramen ovale. Afterward, the sep-
aorta. Although the ductus venosus has received tum primum fuses to the septum secundum, com-
less attention than the DA, it is now well accepted pleting septation of the atria. However, in
that it plays a major role in the regulation of 20–25%, incomplete fusion leads to the persis-
fetal circulation (Seravalli 2016). Inlet of the ves- tence of the flap valve, leaving a patent foramen
sel is under active control, and a compensatory ovale (Sommer et al. 2008). In general, individ-
mechanism, supported by transient dilatation, is uals with patent foramen ovale are never identi-
supposed to increase oxygenated blood flow fied because they have no symptoms. However,
through the ductus venosus during hypoxia or there is increasing interest in the evaluation and
reduced umbilical flow (Kiserud et al. 2000). treatment of patent foramen ovale, which has been
The absence of the ductus venosus is associated associated with various pathologic conditions,
with a high incidence of fetal anomalies such as cryptogenic stroke, decompression sick-
and adverse outcomes, including associated ness, platypnea-orthodeoxia syndrome, and
malformations, chromosomal aberrations, in migraine (Cruz-Gonzalez et al. 2009).
utero heart failure, and the absence of the portal
vein (Contratti et al. 2001). Functional closure of
the ductus venosus, which is followed by ana- Fall in Pulmonary Vascular Resistance
tomic closure, is virtually complete within a few
weeks of birth. However, the ductus venosus of Although the regulation of the pulmonary circu-
almost all neonates remains open for a certain lation in the fetus and newborn is under many
period after birth with important variations in the interacting and redundant signaling pathways,
volume of blood flow (Murayama et al. 2006). the ability to adapt to changes in the availability
The closure of the ductus venosus is more delayed of O2 is probably the most relevant (Ward 2008).
in preterm neonates, and patent ductus venosus The fetal lung is continuously exposed to a low O2
appears to be related to alterations in ammonia tension which induces a vigorous hypoxic pulmo-
detoxification, blood coagulation, and regulation nary vasoconstriction (Abman and Stevens 1996;
of serum total bile acid concentration (Murayama Abman et al. 1987; Blanco et al. 1988a). This
et al. 2006). Rarely, there is congenital absence of physiological level of hypoxia maintains the
ductus venosus, and the blood returning from the fetal type of circulation and also promotes normal
placenta takes an alternative route (Garcia- vascular growth. However, an increase in the
Delgado et al. 2017). Congenital absence of ductus degree of hypoxia results in abnormal signaling
venosus is often associated with fetal cardiac and and vascular remodeling (Abman and Stevens
extracardial anomalies and associated with adverse 1996; Abman et al. 1987; Blanco et al. 1988a).
perinatal outcome. The prognosis depends on the At birth, with the onset of breathing, PVR
patterns of abnormal venous circulation, on the dramatically decreases, and pulmonary blood
associated malformations, and on chromosomal flow increases such that the entire right ventricular
abnormalities (Maruotti et al. 2018). output goes to the lung, as they assume the
function of gas exchange. The hemodynamic and Abman 1995): (1) maladaptation, in which
changes in the pulmonary circulation after birth vessels are presumably of normal structure
are regulated by various mechanical factors and but have abnormal vasoreactivity; (2) excessive
vasoactive agents in a complicated but coordi- muscularization, in which smooth muscle cell
nated manner. These mechanisms are not only thickness is increased and the muscle extends
involved in the immediate postnatal fall in PVR distally to vessels that usually are nonmuscular;
but also help maintain the low PVR in the new- and (3) underdevelopment, in which lung hypo-
born and the adult. Besides the increase in O2 plasia is associated with decreased number of
tension, several other mechanisms contribute to pulmonary arteries. Either as a primary condition
the normal fall in PVR at birth, including the or secondary to other pulmonary or extra-
establishment of a gas-liquid interface in the pulmonary diseases, PPHN is an important cause
lung, rhythmic distension of the lung, and shear of cardiorespiratory failure and responsible for a
stress (Abman 1999; Abman and Stevens 1996; relevant percentage of morbidity in the neonatal
Abman et al. 1991). These physical stimuli act, at intensive care units (Abman 1999; Kinsella and
least partially, through the production of vasoac- Abman 1995). The progress made in our under-
tive products. An increased release of vasodila- standing of the regulation of the perinatal pulmo-
tors, in particular nitric oxide (NO) and nary circulation has helped in the development of
prostaglandin (PG)I 2, and a decreased release of new treatments for PPHN, such as NO inhalation,
vasoconstrictors such as platelet-activating factor PGI2 inhalation, inhibition of cGMP degradation
(PAF) or endothelin (ET)-1, as well as changes in by type 5 phosphodiesterase with sildenafil, inhi-
their signaling pathways, contribute significantly bition of cAMP degradation with milrinone, and
to the fall in PVR (Abman 1999; Ziegler et al. inhibition of ET-1 with bosentan (Gao and Raj
1995; Shaul 1999; Gao and Raj 2010). Normally, 2010).
pulmonary arterial pressure falls to the half of the
systemic pressure by 24 h and then progressively
decreases to adult levels within 2–6 weeks (Haw- Closure of the Ductus Arteriosus
orth and Hislop 2003). Therefore, the process of
pulmonary circulatory transition is not limited to The DA is distinguished from the surrounding
the first moments of extrauterine life, but it vasculature by its embryologic derivation from
extends during the following weeks (Haworth the left sixth aortic arch, the contribution of migra-
and Hislop 2003). tory neural crest cells, and exquisite sensitivity to
Failure of the pulmonary circulation to oxygen tension (Reese 2006). Low O2 tension,
undergo a normal transition results in persistent high levels of circulating PGE2, and locally pro-
pulmonary hypertension of the newborn (PPHN), duced PGE2 and PGI2 are the main factors
a clinical syndrome of various neonatal cardiopul- maintaining patency of the DA in utero (Clyman
monary disorders which are characterized by 2006; Bouayad et al. 2002; Smith 1998).
sustained elevation of PVR after birth, leading to Classically, the process of DA is divided into
right-to-left shunting of blood across the DA or two sequential steps: functional and structural.
foramen ovale and severe hypoxemia (Abman and However, it should be noted that these steps over-
Stevens 1996; Ziegler et al. 1995). PPHN is a lap, and the causative agents may be shared
pathophysiological phenomenon occurring in a (Coceani and Baragatti 2012). Several events pro-
heterogeneous group of diseases with a wide mote the constriction of the DA in the full-term
diversity of etiologies. These range from transient newborn: (1) the increase in arterial PO2, (2) the
reversible pulmonary hypertension attributable to decrease in blood pressure within the ductus
perinatal insults to irreversible fixed structural lumen (due to the postnatal decrease in PVR),
malformations of the lung. Diseases associated and (3) the decrease in circulating PGE2 (due to
with the syndrome of PPHN can be classified the loss of placental PG production and the
in three categories (Abman 1999; Kinsella increase in PG removal by the lung), as well as
the decrease in the number of PGE2 receptors in development (Greer and Martin-Caraballo 2017).
the ductus wall (Clyman 2006; Bouayad et al. Periodic non-air intrauterine breathing pattern
2002; Clyman 2004). Intertwined with functional must change at birth to a continuous
closure, structural closure may encompass up to air-breathing pattern. This change happens after
four distinct mechanisms of varying impact clamping the umbilical cord, full perfusion of the
depending on the species (Coceani and Baragatti lungs, changes in temperature, changes in behav-
2012): (1) development of intimal cushions ioral state, increase in metabolism, increase in
(Clyman 2006; Coceani and Baragatti 2012), afferent input to the central nervous system,
(2) mechanical solicitation from turbulent blood changes in levels of prostaglandins, and many
flow along the narrowing lumen (Coceani and other changes associated with the moment of
Baragatti 2012), (3) intramural hypoxia which birth.
inhibits local production of PGE2 and NO and Breathing-like activity in utero is present from
induces production of growth factors (Clyman very early in gestation and is the consequence of
2006; Coceani and Baragatti 2012), and (4) inter- rhythmic activation of respiratory neurons in the
action of platelets with the vessel wall which brainstem (Bystrzycka et al. 1975; Bahoric and
adopts a prothrombotic phenotype (Echtler et al. Chernick 1975); however, these breathing move-
2010). ments play no part in fetal gas exchange. The
A patent DA (PDA) in the first 3 days of life is efferent activity of these respiratory neurons acti-
a physiologic shunt in healthy term and preterm vates the respiratory motoneurons and hence the
newborn infants. In contrast, failure of DA closure muscles, mainly the diaphragm, which generate a
after birth is a common complication of premature negative intrathoracic pressure. In fetal lamb
delivery that is still presenting challenges in terms spasm of the diaphragm at the 38th day of gesta-
of diagnosis, assessment, and treatment options tion (term 147 days) and rhythmic movements of
(Smith 1998). Even when it does constrict, the the diaphragm at the 40th day of gestation have
premature DA frequently fails to develop pro- been described (Barcroft 1946). Chronic record-
found hypoxia and anatomic remodeling and is, ings from fetal lambs in utero performed at
therefore, susceptible to reopening (Clyman approximately 50 days of gestation showed two
2004). PDA in preterm infants is associated with types of diaphragmatic activity: (1) unpatterned
significant morbidities including intraventricular discharge and (2) patterned, bursting discharge
hemorrhage, necrotizing enterocolitis, and (Cooke and Berger 1990). In the human fetus,
bronchopulmonary dysplasia. However, there is thoracic movements were observed from the
intense controversy regarding whether PDA is 10th–12th week of gestation (Vries de et al.
truly causative (Stoller et al. 2012). Furthermore, 1982). At this time in gestation, there is still not
it is unknown if prophylactic and/or symptomatic a clear pattern, and FBM appear to be more
PDA therapy will cause substantive improve- “freewheeling.”
ments in outcome (Hamrick and Hansmann Later in gestation in the fetal lamb
2010). Therefore, over recent years, the clinical (75–110 days), movements of the diaphragm
approach to patency of the DA in the premature start to become periodic. At this age they are
neonate has been the subject of intensive often associated with nuchal muscle activity and
reevaluation (Stoller et al. 2012). rapid eye movements (Clewlow et al. 1983; Ioffe
et al. 1987). A more definitive pattern starts to
appear at 108–120 days of gestation when breath-
The Respiratory System ing movements become organized into a more
complex state, now associated with the presence
Fetal Breathing Movements (FBM) of rapid eye movements and nuchal muscle activ-
Breathing movements have been demonstrated in ity (Clewlow et al. 1983; Ioffe et al. 1987; Bowes
the fetus of every mammalian species investigated et al. 1981; Szeto et al. 1992). At this time in
and are a critical component of normal fetal gestation, the electroencephalographic activity,
commonly known as electrocortical activity small bilateral lesions are made in the lateral pons
(ECoG), still not does show any signs of differen- (Johnston and Gluckman 1989). The mecha-
tiation. However, by 120–125 days of gestation, nisms, origin, and location for this inhibition are
the ECoG shows a clear differentiation into not clear, but it is known that it is of central origin
low-voltage, high-frequency activity (range and that it can be overridden in utero and at the
13–30 Hz, LVECoG) and high-voltage, time of birth when breathing becomes continuous.
low-frequency activity (3–9 Hz, HVECoG)
(Clewlow et al. 1983; Dawes et al. 1972; Szeto Peripheral Chemoreceptor Function In
et al. 1985; Szeto 1990). At this gestational age, Utero
breathing movements are rapid and irregular, with The concept that peripheral chemoreceptors could
a frequency of 0.1–4 Hz and amplitude of produce effects on breathing can be traced to
3–5 mmHg, and they produce small movements experiments conducted over 50 years ago in
of tracheal fluid (<1 mL) (Harding et al. 1985). which breathing was shown to be stimulated in
There are now two clearly defined fetal behavioral exteriorized mid-gestation animal fetuses by hyp-
states in the fetal lamb: there is no nuchal muscle oxia or cyanide (Hanson 1986). In late gestation,
activity during LVECoG, but rapid eye move- the descending inhibitory effects on breathing
ments and FBM are present. Polysynaptic spinal arising from the fetal brainstem in hypoxia and
reflexes are also relatively inhibited during the with HVECoG (see above) dominate. It was per-
LVECoG state (Blanco et al. 1983a). During haps the increasing interest in these processes that
HVECoG, there are no eye movements or FBM, caused the scientific community to lose sight of
but nuchal muscle activity is present, and poly- the implications of the earlier observations. The
synaptic reflexes are stronger (Blanco et al. idea became prevalent that the carotid chemore-
1983a). The link between ECoG state and FBM ceptors were quiescent in utero and were activated
implies either that breathing activity is facilitated at birth, perhaps by the increase in sympathetic
(or even stimulated) during LVECoG or that it is nervous activity. In addition, when it became clear
inhibited during HVECoG. During LVECoG that normal fetal arterial PO2 in late gestation,
there is more neural activity in cortical and sub- both in the sheep and the human fetus, was
cortical structures, including the brainstem reticu- ca. 3 Kpa (25 mmHg), it was thought that if the
lar formation. This facilitatory state could increase chemoreceptors were functional, they would be so
the sensitivity for tonic stimuli, such as the level intensely stimulated that powerful reflex effects
of arterial CO2, and generate respiratory output. would be induced continuously. This was clearly
This hypothesis is supported by the observation not the case, although it had been shown that
that there are no breathing movements during fetal brainstem transection removed inhibitory effects
hypocapnia even during the LVECoG state on breathing (Barcroft 1938; Dawes 1984) and
(Kuipers et al. 1994). Extending this idea, the permitted stimulation of breathing activity during
absence of FBM during HVECoG could be due hypoxia. It was therefore essential to readdress the
to a disfacilitation, as reported during quiet sleep question of arterial chemoreceptor function in
in the adult when slow waves appear in the EEG utero. It was found that both carotid (Blanco
(Steriade et al. 1994; Phillipson et al. 1981). Other et al. 1984) and aortic (Blanco et al. 1982) che-
evidence also leads us to believe that during moreceptors were spontaneously active at the nor-
HVECoG there is an active inhibition of breathing mal arterial PO2 in fetal sheep and that they
activity, because in fetal sheep FBM and ECoG responded with an increase in discharge if PO2
were dissociated after the brainstem was trans- fell or PCO2 rose. There were several very impor-
ected at the level of the colliculi (Dawes et al. tant implications of these findings. Firstly, it was
1983). Furthermore, FBM response to hypercap- clear that the peripheral chemoreceptors would be
nia is limited to LVECoG activity in the intact able to stimulate fetal breathing under some cir-
fetus, but hypercapnia can produce continuous cumstances but that it was the balance between
breathing in both LVECoG and HVECoG after this stimulatory input and the normally dominant,
inhibitory input from higher centers which deter- of FBM (Smith et al. 1990a) are not mediated by
mined the characteristics of fetal breathing (see prostaglandin (Smith et al. 1990b) but by adeno-
above). Secondly, it redirected attention to the role sine (Watson et al. 1999).
the carotid chemoreceptors play in initiating car- Bennet et al. (1990) showed that large doses of
diovascular reflex responses to hypoxia (Bartelds thyrotropin-releasing hormone (TRH) can induce
et al. 1993; Giussani et al. 1993). Lastly, the stimulation of FBM. This effect may be at the
observation that the fetal peripheral chemorecep- level of the respiratory neurons where TRH can
tors discharge spontaneously (at ca. 5 Hz) at the be localized, but its physiological significance is
normal fetal arterial PO2 made it clear that the rise not known. This may also be true of the effects of
in PO2 at birth would silence them. Their sensi- the cholinergic agonist, pilocarpine, and serotonin
tivity to PO2 would then have to reset to the adult (5-HT) precursor L-5-hydroxytryptophan (L-5-
range postnatal, and this has generated research HTP) (Hanson et al. 1988; Fletcher et al. 1988).
into the mechanisms of this resetting (Blanco et al. Both of these agents stimulate FBM, but pilocar-
1988b; Kumar and Hanson 1989). pine induces LVECoG and L-5-HTP induces
Recently, it was reported that prenatal smoking HVECoG. This stresses again the coincidental
exposure disrupts peripheral chemoreceptor func- rather than causal relationship between FBM and
tion and, as a result, has a deleterious effect on LVECoG. 5-HT has been implicated in neural
apnea patterns in preterm babies (Stephan- mechanisms controlling adult sheep, but the site
Blanchard 2010). Prenatal smoking has negative of action in the fetus is not known. A range of
effects on the chemosensory control of breathing opiates has effects on FBM (Hasan et al. 1988),
and enhances the duration of apneic episodes with but the physiological localization of their effects
desaturation and may increase an infant’s risk of has not been established.
an insufficient response to respiratory challenges The high rate of progesterone synthesis by the
during sleep. placenta in late gestation exposes the fetus to high
concentrations of progesterone and its metabo-
Pharmacological Control lites. Progesterone can influence fetal behavior,
Prostaglandins exert a powerful influence on and normal progesterone production tonically
FBM and postnatal breathing. Prostaglandin E2 suppresses arousal or wakefulness in the fetus
(PGE2) decreases the incidence of FBM (Crossley et al. 1997; Nicol et al. 1997).
(Kitterman et al. 1983), whereas meclofenamate Lastly, one of the striking aspects of FBM is
and indomethacin, inhibitors of PG synthesis, that FBM cease 24–48 h before parturition. The
increase FBM (Kitterman et al. 1979; Wallen mechanism involved is not known. Kitterman
et al. 1986; Patrick et al. 1987). The effect of et al. (1979) excluded a rise in plasma PGE2,
prostaglandins appears to be central, as it is inde- and Parkes et al. (1988) showed that it did not
pendent of the peripheral chemoreceptors (Murai occur if the fall in plasma progesterone was
et al. 1987) and because central administration of prevented.
meclofenamate stimulates FBM (Koos 1982,
1985). The same effects can be produced postna- Lung Growth Associated with FBM
tally, with PGE2 decreasing, and meclofenamate Fetal breathing movements have an important role
and indomethacin increasing, ventilation in lambs in lung growth and in development of respiratory
(Guerra et al. 1989; Long 1988). However, the muscles and neural regulation. By opposing lung
change in the concentration of PGE2 that occurs recoil, FBM help to maintain the lung expansion
around birth cannot be solely responsible for that is now known to be essential for normal
either the decrease in FBM seen immediately growth and structural maturation of the fetal
before birth (Patrick et al. 1987; Wallen et al. lungs. FBM induce complex and variable changes
1988) or the onset of continuous breathing post- in thoracic dimensions; these induce small alter-
natally (Lee et al. 1989). The well-established ations in the shape of the lungs that may act as a
effects of ethyl alcohol to reduce the incidence stimulus to lung growth. The prolonged absence
or impairment of FBM is likely to result in a experiments show that FBM can become contin-
reduced mean level of lung expansion, which uous through the operation of various mecha-
can lead to hypoplasia of the lungs (Inanlou nisms including disinhibition during HVECoG,
et al. 2005). Moreover, static distension decreases changes in the balance between stimulatory and
steady-state SP-A and SP-B mRNA levels in the inhibitory neuromodulators, increased arousability,
whole lung, whereas cyclic stretching increases and changes in chemoreceptor sensitivity
SP-B and SP-A expression two- to fourfold and (Lagercrantz et al. 1994). Some, but not all, of
enhances 3H-choline incorporation into saturated these mechanisms are likely to play an important
phosphatidylcholine (Sanchez-Esteban et al. role at birth.
1998). Experiments designed to observe changes in
breathing activity after cord occlusion have led to
Changes at Birth two main hypotheses: (1) The exclusion of fetal-
At birth breathing activity must become continu- placental circulation leads to the disappearance of
ous in order to fulfill its gas exchange function. hormones or neuromodulators which exert contin-
After occlusion of the umbilical cord, the neonatal uous tonic inhibition (through the CNS) during
ECoG still cycles between low- and high-voltage fetal life and that this allows continuous breathing
states, which seem to have identical spectral char- postnatally (Adamson et al. 1987, 1991; Boddy
acteristics to the fetal states. LVECoG activity is et al. 1974; Sawa et al. 1991). There are reports
associated with the absence of nuchal muscle indicating that prostaglandins originating from
activity, rapid eye movements, and inhibition of placental tissue can inhibit fetal breathing activity
polysynaptic reflexes, and HVECoG is associated (Alvaro et al. 2004). Although this is a possible
with the presence of nuchal muscle activity, lack explanation, it is not yet demonstrated that such a
of rapid eye movements, and enhanced polysyn- substance is responsible for the modulation by
aptic reflexes (Blanco et al. 1983b). However, ECoG of FBM. It was shown that breathing move-
despite the fact that after birth the HVECoG ments of goat fetuses maintained in an extrauter-
state seems to be similar to the equivalent fetal ine incubation system for more than 24 h were
state, breathing activity is present. episodic, suggesting that intermittent breathing
Studies of the mechanisms involved in the movements are intrinsic to the fetus, independent
establishment of continuous breathing at birth of placenta-derived factors (Kozuma et al. 1999).
have followed two lines: (a) attempts to induce (2) Breathing activity is dependent on the level of
continuous breathing in utero and (b) observation PaCO2 in utero and at birth (Kuipers et al. 1994).
of establishment of continuous breathing during It is known that during hypocapnia, fetal and
situations aimed at mimicking birth. neonatal breathing is reduced (Kuipers et al.
It is well established that the inhibition of FBM 1994, 1997; Adamson et al. 1987). Hypercapnia
during HVECoG can be overridden as demon- stimulates breathing activity, but in utero this is
strated by the presence of continuous breathing inhibited during quiet sleep. However, this inhi-
during metabolic acidosis (Molteni et al. 1980; bition can be overridden after lesions in the lateral
Hohimer and Bissonnette 1981) and administra- pons (Johnston and Gluckman 1989) or when
tion of prostaglandin synthetase inhibitors hypercapnia is combined with cooling (Kuipers
(Kitterman et al. 1979; Wallen et al. 1986; Koos et al. 1997). This might be explained by changes
1985), 5-hydroxytryptophan (Fletcher et al. 1988; in the CO2 sensitivity of central and/or peripheral
Quilligan et al. 1981), catecholamines (Jansen chemoreceptors or due to changes in the balance
et al. 1986), pilocarpine (Hanson et al. 1988), between central inhibitory and excitatory mecha-
thyrotropin-releasing hormone (Bennet et al. nisms caused by an increase in afferent input at
1988), corticotropin-releasing factor (Bennet birth. In this hypothesis, both changes in afferent
et al. 1990), and central or peripheral fetal cooling input from chemo- and thermoreceptors to the
(Gluckman et al. 1983; Kuipers et al. 1997) and by CNS and changes in CNS sensitivity to these
lesions within the CNS (see above). These inputs are important in the transition from fetal
to neonatal breathing. Changes in the plasma level Copyright © 2011 From Newborn Surgery, Third Edition,
of a placental neuromodulator at birth may then by Prem Puri. Reproduced by permission of Taylor and
Francis Group, LLC, a division of Informa plc.
serve to maintain postnatal breathing after its ini-
tiation. More insight into these mechanisms may
offer an explanation for the occurrence of apneic
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Fetal Surgery
7
Aliza M. Olive, Aimee G. Kim, and Alan W. Flake
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Imaging and Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Principles of Maternal-Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Indications and Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Positioning and Draping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Incision and Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Fetoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
Ex Utero Intrapartum Therapy (EXIT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Anatomic Anomalies Currently Managed by Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . 121
Congenital Bronchopulmonary Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Congenital Diaphragmatic Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Myelomeningocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Sacrococcygeal Teratoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Twin-to-Twin Transfusion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
Abstract by Harrison was published three decades ago

The first description of open maternal-fetal (Adzick 2003). At that time, the diagnostic and
surgery for correction of anatomic anomalies surgical tools for prenatal treatment of the fetus
were just being developed, and the concept of
the fetus as a patient was the subject of philo-
sophical and ethical debate. Since then, great
A. M. Olive (*) · A. G. Kim · A. W. Flake
Center for Fetal Diagnosis and Therapy, Children’s progress has been made in the ability to diag-
Hospital of Philadelphia, Philadelphia, PA, USA nose fetal abnormalities, predict their outcome,
e-mail: OliveA@email.chop.edu; KimA@email.chop.edu; and perform surgical interventions when
flake@email.chop.edu

https://doi.org/10.1007/978-3-662-43588-5_7
116 A. M. Olive et al.
appropriate. The concept of the fetus as a intraperitoneal transfusion of a hydropic fetus for
patient has become a standard of care, and the Rh disease by Sir Liley in 1963, and this repre-
ethical framework for maternal-fetal interven- sents the first acknowledgment of the fetus as a
tion is well developed (Adzick, Semin Fetal patient (Jancelewicz and Harrison 2009). The
Neonatal Med 15(1):1–8, 2010). While appli- modern era of fetal surgery was conceived and
cation of open fetal surgery has remained lim- developed by Michael R. Harrison and colleagues
ited to a relatively small number of highly at the University of California, San Francisco
selected fetuses and is practiced in only a few (UCSF), during the late 1970s and 1980s. The
centers, the development of this field has accel- same group performed the first open fetal surgery
erated technological progress in prenatal diag- for an anatomic anomaly creating bilateral
nosis and intervention, led to improved ureterostomies in a fetus with congenital bilateral
understanding of the pathophysiology and nat- hydronephrosis due to urinary tract obstruction
ural history of candidate disorders, allowed (Harrison et al. 1982).
comprehensive counseling of parents in cen- In the last four decades, the field of fetal sur-
ters with focused expertise in fetal anomalies, gery and therapy has slowly evolved, with con-
and driven the evolution of less invasive ther- comitant advancement of imaging modalities,
apeutic approaches. The purpose of this chap- diagnostic tools, and operative techniques critical
ter is to describe the current status of fetal to clinical application of prenatal diagnosis and
surgical intervention and to speculate regard- treatment. Currently fetal surgery and therapy
ing future developments in this rapidly evolv- include a spectrum of procedures ranging from
ing field. ultrasound-guided shunt placement and image-
guided fetoscopic procedures to the more invasive
Keywords open fetal surgery and ex utero intrapartum treat-
Fetal surgery · Fetoscopy · Ex utero ment (EXIT) procedures (Bouchard et al. 2002).
intrapartum therapy · Congenital cystic This chapter aims to review key diagnostic tools
adenomatous malformation · Congenital utilized in current maternal-fetal surgery, discuss
diaphragmatic hernia · Myelomeningocele · the underlying principles of this field, and
Sacrococcygeal teratoma · Twin-to-twin summarize the pathophysiology, diagnosis, and
transfusion syndrome treatment of specific congenital disorders relevant
to fetal surgery. These conditions include
bronchopulmonary airway malformations, con-
Introduction genital diaphragmatic hernia (CDH), myelo-
meningocele (MMC), sacrococcygeal teratoma
Fetal surgery is a specialty born of clinical neces- (SCT), and twin-to-twin transfusion syndrome
sity. Observations of fetuses with congenital (TTTS) (Table 1).
anomalies and neonates with irreversible end-
organ damage led to the compelling rationale
that correction in utero might arrest progression Imaging and Diagnostics
of disease or even reverse the pathophysiology
and restore normal development. First, research Current progress in fetal diagnosis, intervention,
in animal models was needed to study the devel- and treatment would not have been possible with-
opment and progression of specific fetal defects. out the prerequisite advances in laboratory diag-
Those early endeavors not only validated the nostic and imaging technologies. Fetal ultrasound
initial hypothesis but also lead to innovative was first described in the late 1960s and remains
techniques and technologies to further clinical the primary imaging modality for prenatal screen-
application. ing and diagnosis with its proven utility, relatively
The earliest report of successful therapeutic low cost, and widespread availability (Hopkins
intervention on the fetal patient was and Feldstein 2009). Further, ultrasonography is
7 Fetal Surgery 117
Table 1 Anatomic anomalies currently treated by fetal therapy

Anomaly Rationale for in utero therapy Fetal interventions
Extrinsic or intrinsic Stabilization of airway and circulatory support before Ex utero intrapartum therapy
airway compression interruption of uteroplacental gas exchange (EXIT)
Congenital lung Reversal of pulmonary hypoplasia and cardiac failure Open surgery: lobectomy;
lesion fetoscopic shunting of
macrocystic lesions
Congenital Reversal of pulmonary hypoplasia and pulmonary Fetoscopic tracheal balloon
diaphragmatic hernia hypertension occlusion (FTO)
(CDH)
Myelomeningocele Protection of exposed spinal cord and cessation of Open surgery: closure of
(MMC) cerebrospinal fluid leakage; prevention or reversal of defect
hindbrain herniation and hydrocephalus
Sacrococcygeal Reversal of steal phenomenon and high-output cardiac Open surgery: tumor
teratoma (SCT) failure; prevention of polyhydramnios debulking
Twin-to-twin Normalization of inter-twin transfusion; reversal of cardiac Fetoscopic laser
transfusion syndrome failure photocoagulation
(TTTS)
advantageous due to its multiplanar capability, limited to amniocentesis, chorionic villus sam-
Doppler flow depictions, high spatial resolution, pling (CVS), cordocentesis, and maternal blood
and real-time assessment. Limitations of ultraso- sampling for fetal products.
nography include a relatively small field of view,
beam attenuation by maternal adipose tissue, poor
image quality in oligohydramnios, poor acoustic Principles of Maternal-Fetal Surgery
access to the fetal head when it lies deeper in the
pelvis, and limited visualization of the posterior Indications and Contraindications
fossa due to calvarial calcification later in gesta-
tion. When fetal intervention is a consideration, The prerequisites for consideration of open fetal
diagnostic certainty supported by accurate and surgery include (1) an accurate prenatal diagnosis
specific details is paramount to the plan of care, and exclusion of associated anomalies; (2) pres-
and magnetic resonance imaging (MRI) is a useful ence of a correctable lesion that, if left untreated,
adjunct and may be required for specific anoma- will lead to fetal demise or severe irreversible
lies (Bulas 2007). The advantages of MRI include organ damage before birth; (3) well-defined natu-
a larger field of view, superior soft-tissue contrast, ral history of the disorder allowing selection of
more precise volumetric measurements, and fetuses that will benefit from prenatal interven-
greater accuracy in demonstrating intracranial tion; and (4) technical feasibility of fetal surgery
abnormalities. However, long-term safety after with an acceptable risk-to-benefit ratio for both
exposure to high-field MRI has not been demon- mother and fetus (Chervenak and McCollough
strated, and there are concerns for effects on 2007). Contraindications to fetal surgery include
embryogenesis, chromosomal structure, and fetal complex chromosomal or associated anatomic
development. As a precaution, MRI is not abnormalities in the fetus, maternal risk factors
recommended during the first trimester. Gadolin- including incompetent cervix, placentomegaly,
ium contrast crosses the placenta and has been maternal mirror syndrome, morbid obesity, any
found in animal studies to be associated with serious comorbid conditions, including prohibi-
growth retardation. Therefore, gadolinium con- tive psychiatric or psychosocial disorders, drug
trast is not recommended in pregnant patients. or alcohol abuse, and heavy smoking.
As for prenatal laboratory diagnostics, Any patient carrying a fetus diagnosed with an
Geaghan provided a thorough review of current anomaly that may require fetal intervention
techniques (Geaghan 2012) including but not should be referred to a fetal treatment center for
a multidisciplinary evaluation, including detailed continuous electrocardiographic monitoring, and

ultrasonography, fetal MRI, and fetal echocardi- pulse oximetry. Multiple large-bore intravenous
ography. In addition, fetal karyotype, rapid fluo- catheters are inserted for access. Sequential com-
rescent in situ hybridization analysis for common pression devices are used to prevent deep venous
aneuploidies, and hybridization arrays should be thrombosis, and fluid management is aimed at
performed to rule out major chromosomal abnor- euvolemia to prevent maternal postoperative non-
malities and common genetic defects. Thorough cardiac pulmonary edema.
counseling for patients based on this extensive
workup is crucial and includes a detailed nondi-
rective discussion of all available options for the Positioning and Draping
pregnancy and the risks and benefits of each,
including nonoperative management, termination, The patient is positioned supine with left lateral
and palliative care. If open fetal surgery is an tilt obtained by placing a roll under the right side
option, the mother should be counseled on the to minimize aortocaval compression from the
risks and consequences, including the future risk gravid uterus and to increase venous return. The
of uterine rupture and the need for preemptive skin is prepped from the mid-thorax to the mid-
cesarean delivery in the current and all future thigh, and the operative field is squared off with
pregnancies (Wilson et al. 2004). sterile towels and covered with a fenestrated and
pocketed drape.
Anesthesia
Incision and Exposure
Anesthesia for maternal-fetal surgery is uniquely
challenging because two patients are being cared The initial incision is generally a low transverse
for at once. Patients should be admitted before any abdominal incision. Precise mapping of the pla-
planned open fetal procedure for monitoring and centa is paramount because placental position
initiation of tocolysis. Because of the risk for determines the type of fascial opening, as well as
chorioamnionitis, intravenous antibiotics are hysterotomy placement. If the placenta is poste-
given before incision. A type and screen are suf- rior, subcutaneous flaps are raised and the fascia
ficient for most minimally invasive procedures, divided in the midline from the umbilicus to the
but open procedures require available cross symphysis pubis, but if it is anterior, the muscle
matched blood for the mother and warm type O- and fascia must be divided transversely to allow
negative blood for the fetus which can be cross for anterior rotation of the uterus and a posterior
matched with the maternal sample to avoid reac- hysterotomy. Once the uterus is exposed, a ring
tion with maternal antibodies that cross the retractor is positioned for exposure.
placenta. Before the hysterotomy is created, the uterus is
Anesthesia for open fetal cases is a combina- palpated to evaluate for sufficient relaxation. Fetal
tion of epidural anesthesia and deep inhalational and placental position are then confirmed with
general anesthesia. Anesthesia is initiated with ultrasound. Electrocautery is used under ultra-
placement of an epidural catheter to provide both sound guidance to map placental margins on the
intraoperative and postoperative pain manage- uterine surface, and a safe site is identified that
ment. General anesthesia is then induced with avoids the placenta and uterine vasculature. The
inhalational agents, with a goal of minimum alve- lower segment of the uterus is avoided due to an
olar concentration of 2–2.5 to provide adequate increased postoperative risk of preterm labor,
uterine relaxation. Maternal monitoring includes amniotic fluid leak, and chorioamnionitis.
blood pressure monitoring via radial artery cathe- After the appropriate hysterotomy site has been
ter and blood pressure cuff, a Foley catheter, identified, traction sutures are placed through the
7 Fetal Surgery 119
Fig. 1 (a) Demonstration of traction suture placement. (c) Continuing the hysterotomy using a specialized surgi-
Ultrasound imaging delineates the position of the fetus cal stapler. A surgical stapler with absorbable staples is
and the margins of the placenta so that the hysterotomy inserted through a window in the uterus created by elec-
can be performed safely in a region that will provide the trocautery. This is used to compress the myometrium and
optimal exposure of the fetus. In this illustration, the ultra- control the membranes. (d) Demonstration of uterine clo-
sound probe is placed against the exposed uterus and is sure. The hysterotomy here is approximated with two
seen guiding the safe placement of the first traction suture layers of absorbable suture. Amniotic fluid volume is
in the center of the planned hysterotomy. (b) Demonstra- restored before completion of the closure with warmed
tion of division of the myometrium and membranes Ringer’s lactate and antibiotics infused through a catheter
between traction sutures using the electrocautery.
uterine wall and fetal membranes under ultra- hysterotomy, while keeping the membranes intact
sound guidance (Fig. 1a, b). A 2 cm incision is for closure. The staples are absorbable, which aid
then made in the myometrium between the sutures in preserving future fertility. A pressurized infuser
using electrocautery, and the membranes are visu- is used to instill warm lactated Ringer’s into the
alized and incised. A specialized uterine stapler is amniotic space, which maintains fetal temperature
passed through the opening in the fetal mem- and amniotic fluid volume, thereby preventing
branes, and the stapler is fired once in both direc- uterine contraction and cord compression. Finally,
tions away from the initial incision (Fig. 1c). This a fetal peripheral intravenous line is placed for
stapler compresses the myometrium and controls infusion of fluids, blood, and medications, and a
the membranes to minimize blood loss during pulse oximeter is applied to the fetal hand.
Closure present. Patients should return for ultrasounds

twice per week until delivery. At 36 weeks gesta-
Closure of the gravid uterus requires adequate tion, an amniocentesis is performed to assess fetal
strength to prevent rupture and amniotic fluid lung maturity, and the fetus is delivered via cesar-
leak, but must do not contribute to infertility in ean section once the lungs are mature.
the future. After return of the fetus to the amniotic
space, the closure is performed in two layers. Full-
thickness double-armed absorbable stay sutures Outcomes
placed approximately 2 cm apart and 2 cm away
from the staple line are placed first and held on While no maternal deaths have been reported
traction, while a running second suture line is following maternal-fetal surgery to date, these
placed just outside the staple line through the procedures are associated with significant short-
myometrium and membranes (Fig. 1d). Warmed term morbidity. In a retrospective study of 178
lactated Ringer’s solution is infused to restore women who underwent open, fetoscopic, or per-
amniotic fluid volume to baseline, and intra-amni- cutaneous ultrasound-guided procedures, the
otic antibiotic is administered before tying the most commonly observed complications included
running layer of suture. The interrupted stay preterm premature rupture of membranes, preterm
sutures are then tied, and the uterine closure is labor, and preterm delivery. Additional complica-
buttressed with an omental flap. The maternal tions that have been observed include chorion
laparotomy is closed in multiple layers. Skin is amnion membrane separation, chorioamnionitis,
closed using a subcuticular running absorbable placental abruption, pulmonary edema, and bleed-
suture, and a transparent dressing is applied in ing requiring transfusion. The overall complica-
order to allow for continued fetal ultrasound mon- tion rate is significantly lower for percutaneous
itoring postoperatively. procedures. Subsequent pregnancies after open
maternal-fetal surgery are at risk for uterine dehis-
cence and rupture if labor is allowed to occur, but
Postoperative Care fertility is not affected.
Because preterm labor is a relatively common

complication, tocolysis is continued postopera- Fetoscopy
tively. Pain management is continued using the
epidural catheter placed preoperatively, which When first developed in the 1970s, fetoscopy
prevents uterine irritability once the inhaled anes- functioned as a diagnostic tool but has since
thetic has worn off. Daily fetal echocardiography become a tool for minimally invasive fetal inter-
is performed to evaluate for evidence of indo- ventions with the development of more advanced
methacin toxicity, which may manifest as ductal camera equipment and endoscopic devices. Fetos-
constriction, tricuspid regurgitation, or copy has similar complications to open fetal sur-
oligohydramnios. A tocodynamometer is used to gery, including bleeding, preterm premature
monitor uterine activity, and the fetal heart rate is rupture of membranes, preterm labor with deliv-
followed for signs of distress. Ultrasounds are ery <32 weeks, chorioamniotic separation, pre-
performed daily while the patient is in the hospital term delivery, and chorioamnionitis. The risk of
to assess amniotic fluid and membrane status, fetoscopic complications correlates with the size
anatomic status, and fetal movement. of the fetoscope, the number of trocar sites, and
Most maternal-fetal surgery patients are the length of the procedure. For simple proce-
discharged by postoperative day 4 but should dures, the risk of preterm labor is lower than
remain on modified bed rest for 2 weeks following open fetal surgery. Most of these procedures can
discharge. Patients can return to moderate activity be performed with only local anesthesia. How-
after that if no signs of uterine irritability are ever, any procedure that would potentially cause
7 Fetal Surgery 121
fetal pain should include intramuscular injection via a limited neck dissection, keeping in mind that
of an opioid and a paralytic agent for fetal tracheal anatomy may be significantly distorted in
anesthesia. cases of giant fetal neck masses, and the carina
may be superiorly displaced. Rigid bronchoscopy
and/or tracheostomy may be used in some cases,
Ex Utero Intrapartum Therapy (EXIT) and decompression or debulking may be required
in order to obtain an airway (Moldenhauer 2013).
The EXIT procedure was developed to allow A successful EXIT procedure relies on ade-
removal of tracheal clips and establishment of an quate uterine relaxation to maintain uteroplacental
airway at the time of delivery after prenatal tra- blood flow and prevent placental separation.
cheal occlusion had been performed in severe However, this relaxation can lead to maternal
cases of CDH. However, the indications for postoperative bleeding. Additional maternal risks
EXIT have expanded to include any case in of EXIT include uterine rupture or scar dehiscence
which difficulty in obtaining an airway is antici- in a subsequent pregnancy and wound infection.
pated, including congenital high airway obstruc- The goal is to have the fetus off placental support
tion syndrome (CHAOS), giant anterior neck within 60 min, although procedures up to 2.5 h
masses including cervical teratomas, pharyngeal have been reported. Risks to the fetus during
tumors, mediastinal tumors, and hypoplastic cra- EXIT include hypoxic brain injury, bradycardia,
niofacial syndrome, or cases in which a thoracic hemorrhage, and death secondary to cord com-
mass will require resection in order to ventilate the pression, loss of myometrial relaxation, and pla-
patient as in giant thoracic masses with dramatic cental abruption, all of which cause inadequate
mediastinal shift (large solid CPAMs) (Bouchard uteroplacental gas exchange.
et al. 2002).
Similar to open maternal-fetal surgery, the
patient is positioned supine, with left lateral tilt Anatomic Anomalies Currently
to maximize blood flow to the uterus and placenta Managed by Fetal Surgery
as well as venous return. Inhalational anesthesia is
utilized to achieve maximal uterine relaxation, Congenital Bronchopulmonary
and intramuscular narcotic and paralytic agents Malformations
are given to prevent fetal discomfort and move-
ment. As with open maternal-fetal surgery, ultra- Congenital bronchopulmonary malformations
sound is used to map the placental edges, and the represent a continuum of abnormalities of the
uterus is opened with the same absorbable stapler bronchopulmonary unit for which classification
used in open fetal surgery to prevent blood loss remains in evolution. They include a spectrum
and control the membranes. In cases with severe of disease entities ranging from congenital pul-
polyhydramnios or large cystic masses, monary airway malformation (CPAM – formerly
amnioreduction or cyst aspiration may be required congenital cystic adenomatoid malformation or
before hysterotomy is performed. A peripheral CCAM) to bronchopulmonary sequestration
intravenous line is obtained on the fetus, a pulse (BPS), with an intermediate subset of “hybrid”
oximeter is applied to the exposed fetal hand, and lesions which exhibit characteristics of both.
continuous fetal transthoracic echocardiography While they differ considerably in their pathologic
is utilized to assess fetal cardiac function and features, from a fetal perspective, these lesions are
volume status. Warmed lactated Ringer’s solution usually diagnosed by ultrasound as space-occu-
is infused to maintain uterine volume and fetal pying cystic and/or solid lesions. There are
temperature. The placental circulation is kept no known associated anomalies with CPAM,
intact while an airway is established. Intubation whereas approximately 10% of fetuses with
may be performed either ante- or retrograde; the intralobar and 50% with extralobar BPS
later accomplished using the Seldinger technique have associated anomalies, including
tracheoesophageal fistula, congenital heart BPS is a mass of nonfunctioning lung tissue of

defects, CDH, aneuploidy, or foregut duplication. which the defining developmental feature is the
absence of a communicating bronchus. These
Pathophysiology lesions have systemic arterial supply, which
CPAMs are benign multicystic lung masses that most often arises from the thoracic aorta but can
most often involve a single lobe of the lung and arise from any systemic source. An extralobar
derive their blood supply from the pulmonary BPS has its own investing pleura, no communica-
circulation. This heterogeneous group of congen- tion with the native bronchial tree, and usually
ital cystic and non-cystic lung masses is charac- systemic venous drainage although pulmonary
terized by an extensive overgrowth of immature venous drainage is occasionally observed. On
primary bronchioles localized to one segment of the other hand, an intralobar BPS shares visceral
the bronchial tree. The current classification sys- pleural investment with the normal lung and gen-
tem defined by Stocker classifies CPAM into five erally has pulmonary venous drainage. The
types that differ by location, cystic structure, size, lesions may be aerated after birth due to tracking
and epithelial lining. However, from a practical of air through the pores of Kohn and, thus, in
perspective, prenatal classification of CPAM is contrast to extralobar BPS, are subject to
divided into two categories based on prenatal US mucostasis and infection.
findings (Fig. 2): (Adzick and Kitano 2003) Fetal BPS and CCAM lesions range in severity
macrocystic lesions containing a single or multi- from small with minimal clinical significance to
ple cysts that are 5.0 mm in diameter or greater rapidly growing masses that cause mediastinal
and (Adzick 2010) microcystic lesions presenting shift and cardiac failure related to tamponade
as a solid echogenic mass on prenatal US. The physiology with secondary fetal hydrops. Fetal
tissue contained in a CCAM does not participate hydrops and placentomegaly from these lesions
in normal gas exchange, but bronchial connec- can lead to placental vasoreactivity, causing
tions do exist to the cyst and which can lead to development of the maternal mirror syndrome, a
air trapping. condition where the mother develops progressive
Fig. 2 Practical prenatal classification of CPAM. (a) Microcystic lesions present as a solid echogenic mass on prenatal
US. (b) Macrocystic lesions with a single or multiple cysts 5.0 mm in diameter or greater
7 Fetal Surgery 123
preeclamptic symptoms, which “mirror” fetal Based on the type of CPAM, the prenatal CVR,
pathophysiology. and gestational age, a management strategy can be
formulated to optimize outcome. In recent years
Diagnosis the prenatal treatment of large microcystic
Diagnosis of cystic lung lesions is based on iden- CPAMS with a CVR of >1.6 and/or the presence
tification of an echogenic mass in the fetal chest of hydrops at less than 32 weeks gestation has
(Fig. 2) that may be solid, cystic, or mixed. Dopp- changed. Whereas open fetal surgery and lobec-
ler ultrasound will show either systemic (BPS), tomy were once the primary option for fetal treat-
pulmonary (CCAM), or both (hybrid lesions) arte- ment centers, the majority of these patients
rial blood supply. The differential diagnosis of respond to steroid treatment, with inhibition of
these lesions includes peripheral bronchial atresia, further CPAM growth and/or regression of
bronchogenic or neurenteric cysts, congenital hydrops. The mechanism of steroid effect in this
lobar emphysema, and CDH. Ultrasound of circumstance is speculative, but the phenomenon
CCAMs may show mediastinal shift away from has been documented by multiple fetal treatment
large lesions or polyhydramnios secondary to centers with very few open resections performed
esophageal compression. Hydrops may be evident since this strategy was implemented. In a recent
in severely affected fetuses. Lymphatic and study, 100% survival was achieved in fetuses with
venous congestion may lead to pleural effusion, hydrops (5/5) or a CPAM volume ratio (CVR)
which could cause tension hydrothorax and sec- >1.6 at the time of steroid administration. This
ondary hydrops. compares to a mortality of 100% in fetuses with
hydrops and a 56% mortality in fetuses with a
Treatment CVR >1.6 among historical controls. In contrast
Experience with serial imaging of large numbers to microcystic CPAMs, macrocystic CPAMs do
of fetuses with CPAM has clarified the pre- and not consistently respond to steroid treatment and
perinatal natural history of this anomaly. There is should be treated by thoracoamniotic shunting if
a typical pattern in CPAM growth consisting of a hydrops are evolving. A current algorithm for
period of growth relative to the size of the fetus management of fetuses with CPAM is shown in
until approximately 26 weeks gestation when Fig. 3.
growth plateaus. After 28 weeks the CPAM typi- When maternal-fetal surgery is required, the
cally gets smaller relative to the size of the fetus as arm and hand on the affected side are exposed,
measured by the CPAM volume ratio or CVR. and the fetus is rotated to expose the chest wall,
The CVR is calculated by dividing CPAM volume leaving the head and remainder of the body within
(length height width 0.52) by the head the amniotic sac. Once intravenous access is
circumference. In addition, the CVR has proven obtained and a pulse oximeter is attached, the
on retrospective and prospective assessment to be fetus is treated with atropine and volume loaded
the most useful predictor of the evolution of to counter reflexive bradycardia and cardiovascu-
hydrops. Presentation with a CVR of 1.6 in a lar collapse, which are often seen with acute
CPAM without a dominant cyst predicts a less decompression of the chest when the tumor is
than 3% risk of developing hydrops. If the CVR exposed. Electrocautery is used to create a large
is >1.6, the risk of hydrops is around 75%. CVR posterolateral thoracotomy at the sixth intercostal
has proved very useful in counseling patients, space. The lobe containing the CPAM is exterior-
determining the intensity of serial follow-up, and ized (Fig. 4a). The attachments to surrounding
choosing which patients to preemptively treat lung tissue are divided, and the lobar pulmonary
with steroids. Other parameters such a mass-tho- artery is ligated prior to ligation of the vein and
rax ratio, cystic predominance of the lesion, and bronchus in order to avoid lobar congestion. The
eventration of the diaphragm, while associated bronchus is ligated next, followed by the pulmo-
with large lesions, do not add independent predic- nary vein (Fig. 4b). The thoracotomy is then
tive value to the CVR. closed followed by uterine closure as described
Detailed Sonography
Ultrafast MRI Isolated CPAM
Associated without fetal
Anomalies Fetal Echocardiogram
(Amniocentesis) hydrops
Low Risk
CVR < 1.6
Follow up
Counsel Isolated CPAM with Serial
US
High Risk No mediastinal

Microcystic or CVR > 1.6 Shift
Macrocystic
no large cysts
Mild/moderate
Trial of mediastinal
shift
Steroids
Extreme
mediastinal
No Hydrops shift
Hydrops
<32 weeks
>32 weeks
Delivery at
Open Fetal Surgery (Microcystic) or Delivery at term
tertiary
Thoracoamniotic Shunt EXIT-to-CPAM resection Elective
center - Neonatal
(Macrocystic) Resection resection
Fig. 3 Algorithm for management of congenital pulmonary airway malformation (CPAM)
Fig. 4 (a) Resection of a fetal CCAM. The picture illus- the tumor can be seen bulging from the incision. (b) A hilar
trates the fetal position with the arm and chest wall dissection has been performed, and the pulmonary artery
exposed, with the head inside the uterus. Continuous echo- and bronchus have been divided. The pulmonary vein is
cardiographic monitoring is performed during the proce- being ligated prior to removal of the tumor
dure. In this image, a thoracotomy has been performed, and
above. Delivery following maternal-fetal surgery Outcomes

should be planned as late as possible to avoid Open fetal surgical resections for microcystic
complications associated with prematurity. CCAM are associated with 60% survival with
7 Fetal Surgery 125
most patients enjoying a good quality of life. through the ductus arteriosus or foramen ovale,
Thoracoamniotic shunt placements for macro- which then causes acidosis and hypoxemia.
cystic CCAM have been reported to decrease The severity of CDH is related to the timing of
CCAM mass volumes by an average of 50% and herniation as well as the volume occupied by the
up to 80% and are associated with approximately herniated abdominal viscera in the thoracic cavity.
75% survival. If herniation occurs after lung development is
nearly complete, the manifestations of the disease
are much less severe, and a better outcome is seen.
Congenital Diaphragmatic Hernia If, however, herniation occurs earlier in develop-
ment, severe lung hypoplasia occurs, leading to a
Congenital diaphragmatic hernia (CDH) is a poorer prognosis. CDH therefore can be thought
developmental defect in the diaphragm, which of as a spectrum of disease, ranging from mildly
leads to herniation of abdominal viscera into the affected infants with relatively normal lungs to
chest. CDH affects 1 in 3000 live births and is those with such severe hypoplasia that survival
most often sporadic, although familial cases have is unlikely.
been reported. CDH is often syndromic; 25–57%
of live born cases and 95% of stillborn fetal cases Diagnosis
occur with associated abnormalities. These asso- CDH is most often diagnosed prenatally on
ciated anomalies include hydronephrosis, congen- screening anatomic ultrasound, with the differen-
ital heart defects, renal agenesis, extralobar tial diagnosis including diaphragmatic
sequestrations, and neurologic defects including eventration, bronchogenic cysts, bronchial atre-
hydrocephalus, spina bifida, and anencephaly. Of sia, enteric cysts, congenital cystic adenomatoid
prenatally diagnosed cases, 10–20% of CDH malformation, bronchopulmonary sequestration,
cases are associated with chromosomal abnormal- and teratoma. Diagnosis of CDH on ultrasound
ities including trisomies 13, 18, and 21. depends on visualization of abdominal organs in
the chest. The pathognomonic finding is a fluid-
Pathophysiology filled stomach on a transverse view posterior to
The diaphragmatic defect seen in CDH is the the left heart in the lower thorax. Other features
result of failure of the foramen of Bochdalek to that are often seen on ultrasound include small
close between 8 and 10 weeks of gestation. The abdominal circumference, right mediastinal shift,
pathophysiology of CDH consists of fixed pulmo- and no evidence of the stomach below the dia-
nary and vascular hypoplasia and reversible pul- phragm. When CDH is present on the right, the
monary vascular reactivity. The herniation of right lobe of the liver is usually herniated, which
abdominal contents occurs at a critical phase of often leads to misdiagnosis because the liver has
lung development when branching morphogene- similar echogenicity to the lung. In this case the
sis generates the normal bronchial and arterial diagnosis is often missed altogether or confused
tree. The resultant pulmonary hypoplasia includes with a solid chest mass. However, hepatic vascu-
varying degrees of reduced airway branching, lature can be identified by ultrasound and MRI
alveolar structures, and vascular components. techniques (Fig. 5a) to allow excellent
This leads to decreased lung surface area for gas discrimination.
exchange as well as a fixed increase in pulmonary Because CDH has a wide range in severity and
vascular resistance. The pulmonary vasculature is a high frequency of associated anomalies, a com-
also morphologically abnormal, with hyper- plete prognostic assessment is critical (Hedrick
muscular peripheral pulmonary arteries that have 2013). This includes high-resolution ultrasound,
a thickened media. This causes increased pulmo- fetal MRI, echocardiography, and genetic testing,
nary vasoreactivity and pulmonary hypertension. all between 20 and 24 weeks gestation. This time
This resulting pulmonary hypertension leads to frame allows for complete counseling for families,
persistence of the fetal circulation, with shunting with the option for elective termination. The
Liv S
b Fetal CDH Detailed sonography

Associated Ultrafast MRI Isolated
Anomalies Fetal echocardiogram Anomaly
Amniocentesis
Counsel Prognostic evaluation

Gestational age
Degree of herniation
Polyhydramnios
O/E LHR < 25%
Liver up
Fetoscopic balloon Planned delivery with

tracheal occlusion if within postnatal therapy
the context of a clinical
trial
Fig. 5 (a) Sagittal section of fetal MRI demonstrating liver (Liv) herniated above the diaphragm. The stomach (S) is also
seen in the thorax posterior to the liver. (b) Algorithm for the management of fetal CDH
extreme importance of accurate counseling has only reports of CDH survivors with congenital
led to investigation of factors predictive of poor heart disease (CHD) have a combination of rela-
outcome in CDH fetuses. CDH with associated tively mild CDH and cardiac biventricular anat-
major anomalies has a very poor prognosis. The omy. Mortality associated with severe CDH and
7 Fetal Surgery 127
univentricular CHD nears 100%, and comfort care pre- and postnatal events that accompany it. The
should be offered. Poor outcomes are also associ- potential for poor outcome in a severe case of
ated with familial CDH, bilateral CDH, CDH CDH, including death and severe pulmonary, gas-
associated with specific genetic abnormalities, trointestinal, and neurologic morbidity, should be
and syndromic CHD. discussed. The standard prenatal management for
Liver herniation has historically been the most CDH is expectant, with ultrasound screening for
important poor prognostic indicator in CDH and prenatal complications. The majority of pregnan-
can be assessed by ultrasound or MRI. In left- cies with isolated CDH deliver at term, with a
sided CDH, the presence of liver in the chest is 3–8% stillbirth rate. CDH infants with poly-
associated with a very large defect, indicative of hydramnios due to kinking of the gastroesopha-
early herniation of viscera, causing severe pulmo- geal junction are at increased risk of preterm labor.
nary hypoplasia. A recent study showed mortality Prematurity and its associated pulmonary insuffi-
of 65% when the liver is up versus 7% when the ciency are often lethal when combined with the
liver is below the diaphragm. In addition, liver pulmonary hypoplasia seen in severe CDH. Ultra-
position proved to be predictive of the need for sound is recommended once a month up to
postnatal extracorporeal membrane oxygenation 32 weeks gestation and then weekly to screen for
(ECMO), with 80% of liver up patients requiring polyhydramnios. The current algorithm for man-
ECMO, versus 25% of liver down patients. agement of fetuses with CDH is shown (Fig. 5b).
In addition to herniation of the liver, various The first attempted fetal intervention for CDH
indirect measurements of lung volume have been involved a patch repair of the defect. However,
developed with prognostic relevance to CDH. The fetuses with liver up did not tolerate this interven-
ratio between right lung area (measured at the tion due to kinking of the umbilical vein, which
level of the four-chamber heart view) and head led to intrauterine demise. In addition, there was
circumference (LHR) can be measured by ultra- no significant difference in survival for liver
sound and has been validated as a prognostic down-treated CDH fetuses repaired in utero
indicator when measured between 22 and when compared with postnatal repairs. Because
24 weeks gestation. The clinical utility of LHR of these limitations, open fetal repair was aban-
is controversial, as the measurements are subjec- doned (Harrison et al. 1997).
tive and widely dependent on the skill and expe- Tracheal occlusion (TO) (Deprest et al. 2010)
rience of the sonographer. The most widely used is a more recent fetal intervention of interest for
lung measurement to predict morbidity and mor- CDH and treatment of pulmonary hypertension.
tality is the observed to expected lung area to head The theory behind TO for CDH is that fetal lungs
circumference ratio (O/E LHR), which is mea- are net producers of lung fluid and that lung
sured by ultrasound or MRI. However, many growth is related to airway fluid pressure, nor-
CDH patients who have what appears to be an mally regulated by laryngeal mechanisms. It has
adequate lung volume for survival have signifi- been shown in animal models that shunting fluid
cant morbidity and mortality from the disease due from the lungs to the amniotic space can induce
to pulmonary hypertension. Therefore, it is pulmonary hypoplasia but that fetal lungs undergo
unlikely that prenatal lung volume estimations hyperplastic growth when the trachea is occluded.
will ever provide complete prognostic accuracy Accelerated lung growth and improved pulmo-
due to the poor correlation between lung volume nary function have been shown in the rat nitrofen
and pulmonary vascular bed reactivity. and fetal lamb models of TO in CDH. However,
clinical trials for TO using open and fetoscopic
Treatment of CDH approaches have shown mixed results, including a
Prenatal management of CDH begins with thor- prospective trial performed at Children’s Hospital
ough counseling, which relies heavily on an accu- of Philadelphia (Flake et al. 2000) showing that
rate diagnosis. It is paramount that the family neonates with CDH treated with TO had severe
understands the severity of CDH and the possible respiratory compromise, even when lung growth
had occurred. A randomized, controlled trial of of morbidity combined with the increasing sur-
fetoscopic TO from UCSF failed to show benefit. vival of CDH patients to discharge creates the
More recently, Jan Deprest et al. (2011) along with prerogative for ongoing coordinated care for
the Eurofetus study group have applied a mini- these patients.
mally invasive method for TO using a deployable
balloon inserted through a single small trocar. The
initial reported results are promising, and a multi- Myelomeningocele
center randomized controlled trial in North Amer-
ica and Europe known as the Tracheal Occlusion Myelomeningocele (MMC) occurs in approxi-
to Accelerate Lung Growth trial has recently mately 1 in every 3000 live births and remains
begun and will evaluate the efficacy of this tech- one of the most common congenital defects
nique. At the present time the efficacy of TO despite widespread appreciation of the preventa-
for CDH is unproven, and there is potential for tive effects of folic acid supplementation. This
harm using this technique. It should only be condition is characterized by a defect in the ver-
done in the context of a well-designed clinical tebral arches allowing protrusion of the meninges
trial to establish efficacy prior to further clinical and neural elements with devastating neurologic
dissemination. consequences including paralysis of the lower
extremities, developmental delay, and inconti-
Outcomes in CDH nence of bowel and bladder. MMC represents
Currently, survival for infants born with CDH at the first application of fetal surgery to a nonlethal
a tertiary center is 70–92%, which represents an disorder, culminating in the recent publication of
improvement in survival relative to several the Management of Myelomeningocele Study
decades ago. However, it is important to note (MOMS), which demonstrated a clear advantage
with any discussion of CDH survival that com- of prenatal closure of MMC compared to standard
parisons can only be made between patients that postnatal treatment (Adzick et al. 2011; Adzick
are accurately stratified for severity. Improved 2013).
survival is credited to a shift from early surgical
intervention and aggressive ventilatory manage- Pathophysiology and Natural History
ment to delayed surgery and parenchymal spar- The conceptualization and validation of the
ring strategies such as permissive hypercapnia “two-hit” hypothesis were a critical step in the
and early ECMO if ventilatory criteria are consideration of MMC as a compelling target
exceeded. These numbers do not take into disorder for fetal therapy, despite its nonlethal
account cases of CDH that die outside a tertiary nature. The first “hit” is the primary failure of
center or fetal loss due to abortion or stillbirth. neural tube closure, allowing for the resultant
Transport of infants with CDH is associated with second “hit,” which is exposure of the neural
worse survival than infants who are born at a elements to amniotic fluid and mechanical
tertiary center. trauma within the intrauterine environment.
Morbidity for CDH survivors includes respira- There is a body of clinical and experimental
tory, musculoskeletal, nutritional, gastrointestinal, evidence supporting the concept that the major-
and neurological complications. The CHOP Pul- ity of the neural damage is related to the second
monary Hypoplasia Program has prospectively hit, creating the compelling rationale for fetal
evaluated over 300 CDH survivors. Of the 41 surgical closure. The fetal lamb MMC model
CDH survivors initially studied, 90% were found was most influential in supporting a clinical
to have abnormal muscle tone at 6 months and trial of prenatal MMC closure by confirming
51% at 24 months. Many CDH survivors suffer that amniotic fluid exposure of the exposed neu-
from diminished neurocognitive and language ral elements resulted in severe neural damage
skills, and the risk of autism significantly which could be prevented by prenatal closure
increased (Danzer et al. 2016).The high incidence of the defect (Meuli et al. 1995). In addition to
7 Fetal Surgery 129
the open neural defect, almost all fetuses with Treatment

MMC display a constellation of neuroanatomic The algorithm for treatment of MMC is shown
abnormalities referred to as the Arnold-Chiari II (Fig. 6c). Fetal MMC repair is offered to patients
malformation, characterized by descent of the based on the inclusion criteria established in the
posterior fossa contents through the foramen MOMS trial, including singleton pregnancy with
magnum, with resultant hindbrain herniation, an MMC at level T1 through S1, Arnold-Chiari II
inferior displacement of the cerebellar vermis, malformation, gestational age 19 to 25 weeks, and
and elongation and kinking of the medulla. The normal karyotype without coexisting severe
hindbrain herniation impairs normal circulation anomalies.
of cerebral spinal fluid and results in develop- The operative procedure begins with a low
ment of hydrocephalus requiring shunt place- transverse laparotomy, followed by creation of a
ment in 80–90% of cases. Almost half of these hysterotomy as described above. The fetus is posi-
patients experience shunt complications, includ- tioned to expose the MMC lesion. Continuous
ing failure secondary to obstruction or infection intraoperative fetal echocardiographic monitoring
within the first year. This contributes signifi- is critical. Fetal anesthesia is provided by the
cantly to the morbidity and mortality of MMC maternal inhalational anesthetic, and a narcotic
as well as the cognitive deficit. Although 70% of dose is delivered intramuscularly to the fetus.
postnatally repaired MMC patients have an IQ The cystic membrane of the MMC is excised
higher than 80, only half are able to live inde- and the spinal cord untethered. The dura is
pendently as adults, even with adapted reflected over the defect and closed with a running
accommodations. suture, followed by the paraspinal myofascial
flaps, and then the skin. If the skin cannot be
Diagnosis closed primarily, an acellular dermal graft is
Expectant mothers may be referred to a fetal sur- used to assist with the closure. Cesarean delivery
gery center with abnormal screening blood work, is mandated for this and all subsequent
such as an elevated maternal serum AFP level, pregnancies.
which is suggestive of a neural tube defect
(NTD) and a concerning screening ultrasound. Outcomes
These patients will likely require further workup The MOMs trial was powered to recruit 200
including a dedicated ultrasound and MRI to char- participants but was halted after randomization
acterize the spinal cord defect as well as any of 183 patients when a planned interim
associated brain abnormalities. An amniocentesis analysis demonstrated clear benefit for prenatal
should also be performed to detect potential asso- surgery (Adzick et al. 2011). The fetal surgery
ciated syndromes. MMC lies on one end of a group showed significant reduction in rates of
spectrum of spinal dysraphism that includes shunt placement at 1 year (40% versus 82%)
myelocele, meningocele, and lipomyelome- and improvement in neuromotor function
ningocele, among others, and counseling a family by 30 months of age, including the ability to
with regard to options and outcomes necessitates walk without orthotics (42% vs. 21%).
clarity of the diagnosis. Ultrasonography is still The degree and presence of hindbrain herniation
the mainstay of MMC imaging and is used to were also improved, with no hindbrain
assess for lower extremity function, clubfoot herniation in 36% of fetal surgery patients and
anomalies, and spinal level of the defect and to 4% of postnatal surgery patients and severe
rule out other associated gross structural hindbrain herniation in 6% of fetal surgery
malformations. Ultrafast sequencing techniques patients and 22% of postnatal surgery patients.
for fetal MRI are a particularly useful adjunct to The benefits of fetal repair outweighed the
better elucidate the defect and associated CNS complications related to prematurity and the
abnormalities, including hindbrain herniation maternal morbidity seen in the study
and hydrocephalus (Fig. 6a, b). (Golombeck et al. 2006).
a b
HB HB
c Fetal MMC
Detailed sonography Isolated
Associated Ultrafast MRI Fetal anomaly/No
Anomalies echocardiogram maternal
Amniocentesis exclusions
GA < 26
Hindbrain weeks GA >26
Herniation and weeks
T1 –S1
No Hindbrain
Counsel Herniation Term cesarean
Prenatal Repair and/or S2 and delivery with
below postnatal surgery
Fig. 6 (a) MRI appearance of hindbrain (HB) herniation spaces in the cisterna magna are uniformly restored after
in Arnold-Chiari II malformation. (b) Reversal of hind- fetal repair. (c) Algorithm for management of fetal MMC
brain herniation 3 weeks after fetal repair of MMC. Fluid
Sacrococcygeal Teratoma and a small external component, and type IV

tumors are entirely presacral without external or
Sacrococcygeal teratoma (SCT) is the most com- intrapelvic extensions.
mon solid tumor in the neonate with an incidence
of 1 in 40,000 births and a female-to-male ratio of Pathophysiology and Natural History
4:1. These tumors arise from the primitive streak SCTs are predominantly benign, though they have
and are composed of elements from all three germ malignant potential. The majority of patients diag-
layers. The American Academy of Pediatrics Sur- nosed late in gestation or postnatally do well after
gical Section classifies SCTs according to their complete resection, which includes complete
relation to the pelvis: type I tumors are external, removal of the coccyx to prevent recurrence. The
with a small presacral component, type II tumors mortality rate for a prenatally diagnosed SCT
are predominantly external with intrapelvic exten- ranges from 30% to 50%. This high mortality is
sion, type III tumors are predominantly internal attributed to a variety of factors. These prenatally
with intrapelvic and intra-abdominal extension diagnosed tumors are often large, and mass effect
7 Fetal Surgery 131
can lead to maternal-obstetric complications and compression against the rim of the hysterotomy in
preterm labor with associated fetal demise. More this position, and the fetus should be continuously
acutely, SCTs can hemorrhage internally causing monitored for signs of cord compression. Care must
rapid enlargement of the tumor, leading to fetal be taken to keep the remainder of the fetus within the
anemia. SCTs can also rupture into the amniotic amniotic sac; inadvertent delivery of the whole fetus
cavity, resulting in sudden death. Arteriovenous can lead to uterine contraction, inability to place the
shunting and the associated vascular steal phe- fetus back in the amniotic sac, and preterm labor.
nomenon can lead to high-output cardiac failure, Once the tumor is exteriorized, a Hegar dilator
placentomegaly, and fetal hydrops. Fetal mortality should be placed in the rectum to delineate anat-
approaches 100% once these latter processes omy, and the skin around the anorectal sphincter is
develop. Prenatal indicators of poor prognosis incised. Fetal skin around the base of the tumor is
include tumor size, rate of growth, predominantly then incised, controlling the large subcutaneous
solid composition, high vascularity, signs of high- veins. A tourniquet is applied around the base of
output cardiac failure, placentomegaly, hydrops, the tumor where the skin has been incised to
and the occurrence of maternal complications. restrict blood flow to the tumor. A handheld har-
monic scalpel is then used to divide the tumor at
Diagnosis its base, using suture ligation for larger vessels.
Ultrasound can be used to confirm the diagnosis Any intrapelvic component of the tumor should
and characterize the mass in terms of size, com- be left as well as the coccyx, to be excised at the
position (cystic versus solid), and vascularity. Fre- time of definitive resection postnatally. Once the
quent surveillance is key in following high-risk tumor bed is hemostatic, the fetus can be returned
tumors, defined as large, rapidly growing, pre- to the amniotic cavity and the hysterotomy closed,
dominantly solid tumors that exhibit high blood as described in previous sections.
flow. Surveillance includes frequent echocardiog- Postoperatively, because of the risk of maternal
raphy and Doppler blood flow measurements to mirror syndrome, maternal fluid balance should
assess the evolution of high-output physiology. be closely monitored, and fetal echocardiography
MRI aids in providing anatomic definition and should also be performed frequently to follow
assessing intrapelvic extension (Fig. 7a). resolution of the hydrops and placentomegaly.
Treatment Outcomes
The evolution of high-output physiology and sec- Fetal SCT represents the most challenging of the
ondary hydrops in a fetus with SCT is nearly always anomalies treated by open fetal surgery. The
associated with fetal demise and supports the ratio- derangement of fetal and maternal physiology
nale for performing open fetal surgery. Fetuses with results in a high rate of preterm labor with rela-
large type I tumors exhibiting clear evidence of tively short intervals between fetal intervention
early hydrops related to tumor flow prior to and delivery. For appropriately selected fetuses,
28 weeks gestation are candidates for open fetal survival rates of 50–70% can be expected; how-
surgery with debulking of the tumor. Fetal interven- ever, quality of life is variable with a high poten-
tion aims to prevent progression of vascular steal tial for severe morbidity. Parents should be fully
phenomenon and high-output physiology. If informed of both the negative and positive out-
hydrops or placentomegaly should develop after comes after fetal intervention, and fetal surgery
28 weeks, early delivery with debulking is should only be undertaken when the specific indi-
recommended. This allows stabilization of the crit- cation of high-output cardiac failure is present
ically ill newborn in the neonatal intensive care unit with evidence of impending cardiac decompensa-
(NICU) prior to definitive resection. tion and early hydrops. After 27–28 weeks, pre-
The hysterotomy site is chosen to allow exterior- emptive cesarean delivery at the first sign of fetal
ization of the tumor and the caudal end of the fetus. or maternal decompensation is preferable to fetal
However, the umbilical cord is at risk for surgery with immediate debulking of the tumor
b Fetal SCT US, fetal echocardiogram,

MRI, amniocentesis
High Risk SCT Low Risk SCT
Serial US,
echocardiography
AAPSS Type 1 Type II, III, IV
Progressive Progressive Precipitous Tumor Hemorrhage, Impending

Evolution of Evolution of development of Abnl Dopplers, Abnl Preterm labor
High output cardiac High output cardiac high output cardiac biophysical profile, due to
failure < 30 weeks failure > 30 weeks failure > 27 weeks fetal heart tracings polyhydramnios/
>27 weeks tumor, > 27 weeks
Early
Delivery
Active
Preterm labor, No maternal or
Maternal placental
Mirror, compromise
Placentomegaly
Fetal EXIT Elective CS

Emergency CS
Surgery Procedure after 36 weeks
Fig. 7 (a) Coronal section on MRI of fetus with large SCT. (b) Algorithm for management of fetal SCT
and transfer to the NICU (Roybal et al. 2011). An prevalence of TTTS is approximately 1 in 2000
algorithm for management of the fetus with SCT pregnancies and usually occurs during the second
is shown in Fig. 7b. trimester. TTTS has a variable and unpredictable
course. If untreated, it is associated with a nearly
90% mortality rate for both fetuses.
Twin-to-Twin Transfusion Syndrome
Pathophysiology of TTTS
Twin-to-twin transfusion syndrome (TTTS) is a TTTS is caused by chorionic plate anastomoses
fetal malformation that affects 10–15% of mono- between the two fetal circulations that cause
chorionic diamniotic pregnancies. The overall unbalanced circulation exchange. Studies using a
7 Fetal Surgery 133
radiologic tracer have shown that inter-twin trans- Table 2 Quintero staging for TTTS
fusion is nearly universal in TTTS. True connec- Stage Findings
tions between pairs of arteries (AA) or veins (VV) I Oligohydramnios in donor (DVP < 2 cm) and
from the two fetal circulations are located on the polyhydramnios in recipient (DVP > 8 cm)
chorionic plate. These anastomoses are bidirec- II Stage I plus no visible bladder in donor fetus
tional, and the net flow direction is determined III Stage II plus Doppler abnormality of reverse
flow in the ductus venosus, absent or reverse
by pressure differences between the circulations.
end diastolic flow in the umbilical artery, or
Anastomoses between a chorionic vein and the pulsatile flow in the umbilical vein
twin’s chorionic artery lead to transfusion of IV Stage II or III and hydrops fetalis in either fetus
blood from one twin to the other in a single direc- V Demise of one or both fetuses
tion and are referred to as arteriovenous (AV)
anastomoses. These AV anastomoses are often
multiple and balanced by other AV anastomoses polyhydramnios with a deepest vertical pocket
in the opposite direction. TTTS is most often seen of >8 cm. In addition, a severely abnormal Dopp-
when AV anastomoses are present without AA ler waveform will be seen in the donor umbilical
anastomoses. artery. As the disease progresses, evidence of an
In TTTS, the donor twin becomes hypo- abnormal ductus venosus waveform, cardiomyop-
volemic and oliguric, while the recipient twin athy, and hydrops may be seen. The presence or
becomes hypervolemic and polyuric. Because of absence of a visible bladder provides important
these changes, the donor twin has activation of the staging information and should be assessed.
renin-angiotensin system in an effort to preserve TTTS is staged clinically based on guidelines
intravascular volume. This leads to hypertension, proposed by Quintero in 1999 (Table 2) (Quintero
reduced placental perfusion, and growth retarda- et al. 1999). The Quintero staging system is useful
tion. On the other hand, the recipient twin has to compare treatment results as well as to decide
increased renal perfusion and urine output to which management strategy to employ. The
counter the volume overload and also may be Quintero system does not, however, include cardio-
exposed to renin-angiotensin upregulation vascular factors that are important for prognosis.
through placental shunts. The recipient commonly The CHOP cardiovascular scoring system described
has cardiac abnormalities, including myocardial by Rychik and colleagues (Rychik et al. 2007) is
hypertrophy, increased velocities of pulmonic and more useful for assessing disease severity and
aortic outflow, AV valve regurgitation, as well as selecting appropriate fetal intervention candidates.
right ventricular outflow obstruction and pul- It should be noted that TTTS does not progress from
monic stenosis, which may be from increased one stage to the other in an orderly fashion. A full
cardiac afterload caused by systemic anatomic scan should be performed to rule out other
hypertension. defects, ascites, hydrops, or preexisting brain dam-
age, as well as assessment of maternal cervical
Diagnosis of TTTS length to determine if cerclage is necessary. Fetal
Diagnosis of TTTS begins with a monochorionic echocardiography should also be performed to eval-
twin gestation with a single placental mass, a thin uate cardiac function.
inter-twin membrane often less than 2 mm thick,
concordant fetal gender, and the absence of a Treatment of TTTS
“twin peak” sign. All monochorionic diamniotic The current mainstay for treatment of TTTS is
twin gestations should be screened frequently, fetoscopic selective laser photocoagulation
starting in the second trimester. The first sign of (SLPC) targeting the anastomoses that contribute
TTTS on ultrasound is unequal amniotic fluid to the imbalance of flow, performed between 18
volumes between the two amniotic sacs. To and 26 weeks gestation (Senat et al. 2004). His-
make the diagnosis, the donor fetus must have torically, amnioreduction was the primary treat-
oligohydramnios with a deepest vertical pocket ment modality for TTTS but is now rarely applied
of <2 cm, and the recipient fetus must have as primary therapy unless TTTS develops outside
the gestational age where SLPC is safe. The treat- including cerebral palsy, blindness, hemiparesis,
ment for Stage I TTTS is a controversial subject and spastic quadriplegia.
because most Stage I patients do not progress to a
later stage, but a trial of SLPC for Stage I disease
is currently underway in Europe. Conclusion and Future Directions
SLPC is performed percutaneously, most often
under local anesthesia. A 2–3 mm fetoscope is Fetal surgery has seen dramatic progress in the last
inserted, with or without a trocar, under ultra- three decades, especially in the ability to diag-
sound guidance. The placental vasculature is nose, appropriately select, and treat fetuses with
mapped using direct visualization as well as structural malformations that, if left untreated,
Doppler ultrasound to identify anastomoses and would result in fetal demise or severely affect
to define the placental equator. All anastomoses quality of life. In some cases, fetal surgery has
between the two placental circulations are clearly altered the natural history of the disease
targeted for ablation with a 30–50 W diode laser. and improved outcomes, namely, CCAM, TTTS,
Amnioreduction may also be performed at the end and MMC.
of the procedure if necessary to reduce intrauter- In order for the field to continue to grow,
ine pressure. Because of the incidence of both several areas require continued study. First,
early and late complications of SLPC, close fol- maternal and fetal risk remain high, and renewed
low-up is important for all patients. efforts to reduce morbidity and mortality associ-
ated with maternal-fetal intervention are para-
Outcomes of TTTS mount, including improvement in maternal
The Eurofetus trial was a multicenter randomized tocolysis to control frequent preterm delivery.
controlled trial that compared serial In addition, further innovations in endoscopic
amnioreduction to SLPC for TTTS. The laser instrumentation and imaging modalities will
therapy group had higher survival of at least one contribute to more advanced minimally invasive
fetus to at least 28 days of age, 76% vs. 56% in the approaches to replace open procedures. Further-
amniocentesis group. In addition, the laser group ing capabilities for image-guided interventions
had a higher mean gestational age at delivery, with to safely permit diagnosis and treatment at even
an average of 33 vs. 29 weeks in the amniocente- earlier gestational time points will decrease the
sis group. Most importantly, at 6-month follow- risk of preterm labor and premature delivery.
up, the laser group had improved neurologic out- Randomized controlled trials when appropriate
comes, with a decreased risk of periventricular are essential to establish a clear benefit of
leukomalacia. maternal-fetal surgery for patients, allowing
While SLPC is much less invasive than it once experimental therapies to move into clinical
was, there are still significant complications that application.
accompany the procedure. Aside from the com-
plications associated with fetoscopy itself, SLPC
can be complicated by pseudoamniotic band Cross-References
sequence, TTTS recurrence, iatrogenic mono-
amnionicity, and twin anemia polycythemia ▶ Congenital Airway Malformations
sequence, which is defined as anemia in one ▶ Congenital Diaphragmatic Hernia
fetus and polycythemia in the co-twin with normal ▶ Congenital Malformations of the Lung
AFV in both fetal sacs. A major long-term con- ▶ Extracorporeal Membrane Oxygenation for
cern for TTTS survivors is neurodevelopmental Neonatal Respiratory Failure
abnormalities, affecting 6–25% of patients treated ▶ Fetal Counseling for Congenital Malformations
with SLPC (van Klink et al. 2016). These range ▶ Prenatal Diagnosis of Congenital Malformations
from minor defects to major abnormalities ▶ Spina Bifida and Encephalocele
7 Fetal Surgery 135
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Specific Risks for the Preterm Infant
8
Emily A. Kieran and Colm P. F. O’Donnell
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
General . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Respiratory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Pulmonary Hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Bronchopulmonary Dysplasia (BPD) and Chronic Lung Disease (CLD) . . . . . . . . . . . . . 140
Apnea of Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Cardiovascular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Patent Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Central Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Retinopathy of Prematurity (ROP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Gastrointestinal Tract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Feeding and Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Necrotizing Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Spontaneous Bowel Perforation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
E. A. Kieran
Department of Neonatology, The National Maternity
Hospital, Dublin, Ireland
National Children’s Research Centre, Dublin, Ireland
School of Medicine and Medical Science, University
College Dublin, Dublin, Ireland
C. P. F. O’Donnell (*)
National Maternity Hospital, Dublin, Ireland
School of Medicine, University College Dublin, Dublin,
Ireland
National Children’s Research Centre, Crumlin, Dublin,
Ireland
e-mail: codonnell@nmh.ie

https://doi.org/10.1007/978-3-662-43588-5_9
138 E. A. Kieran and C. P. F. O’Donnell
Inguinal Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144

Umbilical Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Abstract nization; Preterm birth. Fact sheet N 363, 2015;

Preterm birth – birth before 37 completed weeks Lissauer and Fanaroff 2011). In the United King-
of gestation – occurs in approximately 5–18% of dom, an estimated 10% of infants are delivered
births worldwide. Babies born preterm have prematurely and 12% in the United States (Lissauer
increased mortality and are at a greater risk of and Fanaroff 2011). The World Health Organiza-
morbidity and long-term adverse outcomes than tion defines preterm birth into three sub-categories
infants born at term. Though the rate of preterm based on gestational age: extremely preterm infants
birth is relatively lower in developed countries born <28 weeks, very preterm infants born 28–31
than in developing countries, prematurity is the +6 weeks, and moderate-to-late preterm infants
leading cause of neonatal mortality in both born 32–37 weeks (World Health Organization;
developing and developed countries. Infants Preterm birth. Fact sheet N 363, 2015). In the
born prematurely have less time to develop in developed world, prematurity is the leading cause
utero, and their organs and body systems are still of neonatal mortality, and babies born preterm are
undergoing physiological development process at a greater overall risk of morbidity and long-term
at the time of birth. This immaturity of body adverse outcomes than infants born at term (Bhutta
organs combined with low birth weight puts et al. 2002; Marlow et al. 2005). Extremely preterm
preterm infants at risk of developing various infants are at highest risk of death and suffering
short- and long-term complications. Babies adverse events; and the chances of survival and
born extremely preterm (<28 weeks of gesta- survival without long-term sequelae increase with
tion) are at highest risk of developing medical increasing gestation at birth (Horbar et al. 2012).
problems that are specific and unique to the Advances in the care of extremely preterm infants
preterm population, and they should be managed over the last decades have increased rates of sur-
differently to term infants during hospitalization vival, and published data shows improved out-
in the neonatal period. comes for these infants. However, with medical
advances, infants are surviving from much earlier
Keywords gestations, and therefore we still see poor outcomes
Infant, newborn · Premature · Respiratory with a high rate of long-term neurodevelopmental
distress syndrome · Apnoea · Retinopathy · problems (Horbar et al. 2012; Costeloe et al. 2012;
Necrotizing enterocolitis Moore et al. 2012).
Preterm infants differ greatly from term infants in
size and appearance as the major period of in utero
Introduction growth is in the third trimester of pregnancy (weeks
28–37). Birth weight is the most commonly used
Approximately 5–18% of babies are born preterm variable to express the size of an infant and to record
(i.e., before 37 weeks of completed gestation) growth over time. It is also frequently used to
worldwide. Prematurity affects about 7–12% of describe categories of infants born prematurely
births in developed countries (World Health Orga- (low birth weight (LBW) < 2500 g; very low birth
8 Specific Risks for the Preterm Infant 139
weight (VLBW) < 1500 g; extremely low birth preterm infants are most at risk of water loss and
weight (ELBW) < 1000 g) (Rennie et al. 2012). should be cared for in humidified incubators to
When infants are born prematurely, their vari- minimize water loss by evaporation.
ous organs and body systems have had less time to Preterm infants, in particular ELBW infants
develop in utero. After the preterm infant is born, with intrauterine growth restriction (IUGR), are
it has to adapt to extrauterine life while also ensur- at an increased risk of developing hypoglycemia
ing the ongoing development and maturation of than term infants. They should have their blood
the organs that should have continued in utero sugar level (BSL) checked on admission to the
during the third trimester of pregnancy up to the NICU and should be commenced on a dextrose
time of birth. These relative immaturities of body containing intravenous solution as soon as possi-
organs combined with low birth weights contrib- ble to maintain BSL in an acceptable range,
ute to the various short- and long-term complica- ideally>2.6 mmol. Prolonged symptomatic hypo-
tions that preterm infants are at risk of developing. glycemia can lead to long-term neurodeve-
Preterm infants can experience difficulties lopmental consequences.
affecting all body systems at various stages during
their admission to the neonatal intensive care unit
(NICU). The diagnosis, treatment, and manage- Respiratory
ment options for the specific conditions can best
be explained by system. Respiratory Distress Syndrome
The commonest respiratory disorder that preterm

General infants can experience is respiratory distress syn-
drome (RDS) also known as hyaline membrane
Preterm infants frequently need support and mon- disease (HMD). RDS significantly contributes to
itoring immediately post-delivery. A pediatric team the risk of death and morbidity in preterm infants.
should be present in the delivery room for every RDS is caused by the combination of lung imma-
anticipated preterm delivery. The number of staff turity and a deficiency in the production and func-
and experience level depends on the expected gestion of surfactant in the preterm infant lungs.
tation age, estimated birth weight, and number of Alveolar development and native surfactant pro-
infants (more staff needed for multiple births). duction in the lungs occur from 23 weeks of
Due to a combination of their low birth weight, gestation and continue into early childhood. The
large body surface area-to-mass ratio, thin fragile more premature an infant is born, the higher their
skin, and relatively low percentage of insulating risk of developing RDS and the more severe the
brown fat, preterm infants are at risk of heat loss course may be.
and hypothermia. On admission to the NICU, they Clinical symptoms and signs of RDS develop
should be cared for in a neutral thermal environ- within the first few hours of birth, worsen over the
ment, ideally in a prewarmed, closed incubator first 48–72 h of life, and then gradually improve.
until they are mature enough to maintain their The typical clinical features of RDS are tachypnea
own temperature in an open cot. Preterm infants (>60 breaths per minute); expiratory grunting;
should only be cared for on an open exposed intercostal, subcostal, and sternal recessions;
surface under radiant heat if easy access is nasal flaring; cyanosis; and low oxygen satura-
required, e.g., for procedures such as central vas- tions and may be further complicated by apnea
cular catheter (CVC) insertion. and bradycardia.
Newborn infant total body water content is Significant advances in the prevention and
much higher to that of older children and adults. management of RDS have occurred over the last
Preterm infants, with their thin fragile skin, lose 40 years. Administration of intramuscular corti-
water by evaporation through the skin. Extremely costeroids to women who are at risk of delivering
preterm reduces the risk of death from and sever- Stoll et al. 2010). It is characterized by fresh
ity of respiratory disease in preterm infants blood seen coming up the trachea and into the
(Liggins and Howie 1972; Papageorglou et al. mouth or out the endotracheal tube if the infant is
1979; Gamsu et al. 1989). Exogenous surfactant receiving mechanical ventilation. The causes of
therapy reduced mortality and respiratory morbid- pulmonary hemorrhage are poorly understood. It
ity in preterm infants with RDS (Fujiwara et al. is thought to be associated with abnormal and rap-
1980; Hallman et al. 1985; Enhorring et al. 1985; idly changing blood flow in the vessels in the lungs
Shapiro et al. 1985; Jobe 1993; Wiswell 2001). over the first few days of life (Wiswell 2001;
Improvements in knowledge and methods of inva- Papworth and Cartlidge 2001). Associated factors
sive and noninvasive ventilation in preterm include RDS, invasive mechanical ventilation, pat-
infants have also improved their outcome ent ductus arteriosus (PDA), and coagulopathy.
(Chernick 1973; Cox et al. 1974; Kattwinkel There is a statistically significant increased incidence
et al. 1973; Rhodes and Hall 1973; Morley et al. in preterm infants who receive prophylactic surfac-
2008; SUPPORT Study Group 2010). tant, but not in infants who receive surfactant as a
rescue therapy for RDS (Aziz and Ohlsson 2012;
Soll and Ozek 2009). There are few proven treat-
Pneumothorax ments for pulmonary hemorrhage. Strategies com-
monly used include measures to increase the mean
Pneumothoraces in preterm infants are associated airway pressure during mechanical ventilation (e.g.,
with increased mortality and severity of lung dis- relatively higher positive end-expiratory pressure,
ease along with other long-term morbidities. The high-frequency oscillation) and to close a PDA.
main precipitator of pneumothoraces is RDS, and,
similar to RDS, the risk of pneumothorax is larg-
est in the more preterm infants with approximately Bronchopulmonary Dysplasia (BPD)
7% of infants born <29 weeks of gestation and Chronic Lung Disease (CLD)
affected (Morley et al. 2008; SUPPORT Study
Group 2010; Stoll et al. 2010). Chronic respiratory insufficiency is a leading
Clinical signs of pneumothorax are a rapid cause of death in preterm infants and is associated
deterioration in respiratory status with increased with poor neurodevelopmental outcome in survi-
oxygen requirements, hypoxia, hypercapnia, and vors. The term “bronchopulmonary dysplasia”
respiratory acidosis. Breath sounds may be (BPD) was originally used to describe the findings
decreased on the affected side, and there may be on histological examination of samples of lung
asymmetry of chest wall movement on examina- tissue taken from preterm infants who had died
tion. Diagnosis is confirmed in chest X-ray or in from respiratory failure. As more preterm infants
emergency chest transillumination with a cold survived, the term BPD was applied to infants
light source. Small pneumothoraces in a stable who had characteristic changes on chest X-ray
infant may resolve spontaneously; however the and were oxygen dependent at 28 days of life.
majority of large pneumothoraces, especially As greater numbers of infants born at earlier ges-
those under tension with midline shift, are treated tations survived, it became apparent that 28 days
with chest drain insertion or needle aspiration of life was quite a different stage of development
with or without chest drain insertion. for infants born at 24 weeks compared to infants
born at 34 weeks of gestation. Chronic lung dis-
ease (CLD) of prematurity was thus diagnosed in
Pulmonary Hemorrhage infants who still had an oxygen requirement at
36 weeks of corrected gestational age (CGA).
Pulmonary hemorrhage – bleeding directly into The risk of BPD is highest in infants born
the lung parenchyma – is reported in 3–7% of extremely preterm and very low birth weight
preterm infants with RDS and is associated with with 25–30% of VLBW infants requiring supple-
significant mortality and morbidity (Jobe 1993; mental oxygen at 36 weeks of CGA (Jobe 1993).
Along with extreme prematurity, BPD is caused pressure generally spontaneously increases over
by a combination of factors and is most frequently the first 24 h of life. A commonly used definition
seen, but not specific to, infants who had severe for “normal” blood pressure in preterm newborns
RDS requiring prolonged mechanical ventilation is that the mean arterial pressure reading, taking
and high oxygen requirements. Consequences of from an invasive arterial catheter, should be equal
BPD include long-term oxygen requirement and to or above the gestational age in weeks. One
potential need for home oxygen therapy, oral feed- important factor clinicians looking after preterm
ing aversion caused by long-term ventilatory sup- infants should take into account in relation to
port preventing oral feeding and necessitating systemic blood pressure is combining the reading
long-term nasogastric/gastrostomy feeding, with other clinical signs of organ and tissue per-
increased energy expenditure due to increased fusion such as capillary refill time, urine output,
respiratory effort and subsequent poor growth and laboratory markers such as blood lactate.
and nutritional deficiencies, and an increased sus- Much research is ongoing and proposed in the
ceptibility to respiratory infections in particular area of blood pressure management and treatment
bronchiolitis caused by respiratory syncytial in preterm infants.
virus (RSV).
Patent Ductus Arteriosus

Apnea of Prematurity
The ductus arteriosus provides a connection
Apnea of prematurity is characterized by an between the pulmonary artery and descending
absence of breathing for more than 10 s and can aorta of the fetus; after birth, this ductus closes as
precipitate episode of bradycardia and decrease in the infant adapts to life outside the uterus. Failure
oxygen saturation. It typically affects infants born of closure, patient ductus arteriosus (PDA), leads to
<32 weeks of gestation. Most episodes of apnea a persistence in the connection between the pulmo-
are brief; however prolonged episodes that are nary artery and aorta. Extremely preterm infants are
associated with bradycardia and low oxygen sat- at greatest risk of developing a PDA. The clinical
urations should be prevented as both factors have significance depends on the amount and direction
been associated with an increased risk of long- of blood flow across the open duct. Over the first
term neurodevelopmental problems. Treatment few days of life, when the pulmonary blood pres-
options include gentle tactile stimulation, nasal sures decrease and systemic blood pressure
continuous positive airway pressure (CPAP) with increases, blood flows in a left-to-right side direc-
or without supplemental inflating pressure, and tion across the duct. Concerns arise when the left-
the use of methylxanthines, caffeine, or theophyl- to-right side flow of blood causes hemodynamic
line, both of which are proven therapies for apnea compromise with increased pulmonary blood flow
of prematurity. Caffeine has been proven to lower that can result in pulmonary overload and pulmo-
the incidence of bronchopulmonary dysplasia nary hypertension and decreased systemic blood
(BPD) (Schmidt et al. 2006). flow leading to hypoperfusion of other organs
including the brain. The majority of PDAs close
spontaneously over time; however there are treat-
Cardiovascular ment options available if the duct is thought to be
causing significant compromise. The prostaglandin
Blood Pressure synthase inhibitors, indomethacin and ibuprofen,
can be used prophylactically for the prevention of
There is little consensus on either the normal PDA or as treatment for known PDA (Ohlsson
range of systemic blood pressure in preterm et al. 2013; Van Overmeire et al. 1997; Ment
infants or in the optimal method of treatment for et al. 1994; Schmidt et al. 2001). Surgical ligation
infants with low blood pressure (Dempsey and of PDA, via left lateral thoracotomy, can be carried
Barrington 2006, 2007). ELBW infant’s blood out in some preterm infants in which the PDA is
thought to be causing significant problems such as seen in grade III–IV bleeds and includes post-
dependence on mechanical ventilation. hemorrhagic ventricular dilatation (PHVD) with
subsequent hydrocephalus, which may necessitate
ventricular access device or ventricular-peritoneal
Congenital Heart Disease shunt insertion, and porencephalic cyst formation.
The presence of these complications is associated
Similar to infants born at term, preterm infants are with a poorer prognosis with a high risk of mor-
at risk of congenital structural cardiac defects such tality and cerebral palsy and significant learning
as septal defect. Preterm infants who are born with difficulties in survivors (Costeloe et al. 2012;
such defects have a significantly poorer prognosis Moore et al. 2012; Adams-Chapman et al. 2008).
than term infants with similar lesions due to their
smaller size, and therefore it is technically more Periventricular Leucomalacia
difficult to carry out surgical repair. Frequently Periventricular leucomalacia (PVL) is the typical
these infants have to grow to a certain weight white matter injury that is seen on cranial ultra-
before surgical correction can be offered, and of sound of infants born prematurely with VLBW
those preterm infants who do reach surgery, the infants most at risk. It is characterized by loss in
mortality and morbidity are much higher than volume of the white matter around the ventricles.
term infants undergoing similar operations. The cause of PVL is thought to be a combination of
factors including in utero stress; decreased cerebral
blood flow, for example, due to cardiovascular
Central Nervous System instability; hypoxia; acidosis; and infection. The
infants most at risk are the smallest and sickest of
Intraventricular Hemorrhage infants in the NICU. Unlike IVH, PVL typically
Intraventricular hemorrhage (IVH) is the most only appears on ultrasound 3 or more weeks after
common neurological complication of preterm the causative event. Over time single or multiple
delivery and is associated with an increased risk cystic areas can develop in the periventricular
of adverse long-term neurological outcome. They lesions, cystic PVL. Similar to IVH, infants with
are diagnosed and monitored on cranial ultra- PVL are at a significant risk of morbidity and long-
sound carried out sequentially over the first few term neurodevelopmental complications (Costeloe
days of life and throughout admission to the et al. 2012; Moore et al. 2012; Dyet et al. 2006).
NICU. IVH are caused by bleeding from the ger-
minal matrix, the small network of capillaries
around the caudate nucleus of the immature Retinopathy of Prematurity (ROP)
brain, into the surrounding ventricular system.
Typically IVH develop within the first 72 h of Blood vessels start to proliferate in the retina of
birth. IVH are traditionally graded from I to IV the fetus after 30–32 weeks of gestation. Infants,
according to the extent of the brain involvement particularly those born before 30 weeks of gesta-
with grade IV being the most severe (Papile et al. tion, are at increased risk of disorganized prolif-
1978). The germinal matrix disappears by eration of blood vessels after 32 weeks
32 weeks of gestation (Lissauer and Fanaroff postmenstrual age. Unchecked, this can lead to
2011), and therefore the infants most at risk of retinal scarring, sight loss, and eventual retinal
developing an IVH and in particular severe IVH detachment and was responsible for an epidemic
are the most premature infants with 10–20% of of blindness in preterm survivors in the 1950s and
infants born before 30 weeks of gestation being 1960s. Extreme preterm birth and prolonged
affected (Adams-Chapman et al. 2008) and in exposure to high concentrations of supplemental
babies born at 501–1500 g a rate of severe IVH oxygen increase the risk of ROP. However, blind-
(grade III and IV35) of 6.4% (Horbar et al. 2012). ness is now an unusual outcome among preterm
The most severe complication of IVH is typically survivors, thanks largely to effective treatments
(laser photocoagulation and intravitreal injection risk factors can be affected; these include perinatal
of anti-vascular endothelial growth factors) that asphyxia, congenital cardiac disease requiring
are given to infants identified following the regu- surgery, and structural gastrointestinal conditions
lar and routine ophthalmological screening. such as Hirschsprung’s disease (Rennie et al.
2012). Reported rates from large neonatal net-
works range from 5% to 11% of VLBW infants,
Gastrointestinal Tract and, similar to other complications of prematurity,
the more immature the infant, the greater risk with
Feeding and Nutrition 14% of infants born <26 weeks being affected
decreasing to 1% of infants born at >32 weeks
Like all newborn infants, preterm infants all lose (Lissauer and Fanaroff 2011; Horbar et al. 2012;
weight over the first few days of life. In the third Rennie et al. 2012; Stoll et al. 2010; Rees et al.
trimester, the fetus gains approximately 2010; Yee et al. 2012).
100–150 g per week in utero. Preterm infants The disease process starts as inflammation in
have a much higher rate of energy expenditure the bowel wall which progresses to tissue necrosis
than if they remained in the uterus; for this reason, and eventually bowel perforation. It may be local-
they in general take longer than term infants to ized to one area of the bowel wall but in more
regain their birth weight. As their bodies are grow- severe cases is generalized and extensive. Any
ing rapidly and they have high energy require- part of the gastrointestinal tract (GIT) can be
ments, it is important to try and give preterm affected; however the terminal ileum, cecum,
infants as much energy and nutrients as possible and ascending colon are the common sites. The
to meet their needs. The optimum way to feed a exact cause of NEC remains unknown; however
newborn infant is enterally. However preterm along with prematurity, multiple risk factors are
infants may only able to tolerate small volumes taught to play a contributing role, e.g., infants who
of feed in the first few days of life, and this volume have decreased blood supply to the GIT either in
has to be increased gradually over the first week or utero or postnatally, for example, due to IUGR or
two of life. To ensure the infants receive adequate a large PDA. The risk of NEC is known to be
fluid and nutrients, extremely preterm infants increased in preterm infants who receive formula
often receive parenteral nutrition (PN), while feed with maternal breast milk known to be of
enteral feeding is established. Due to an inability benefit at preventing the development of NEC.
to coordinate the combination of the suck and Typically NEC develops in the second to third
swallow reflexes, extremely preterm infants are week of life; however it is not uncommon for
not able to feed orally until approximately extremely preterm infants to develop NEC after
33–35 weeks of corrected gestation; prior to this, the first month of life after a period of relative
infants are fed enterally through a naso-/ stability when they present with an acute deterio-
orogastric tube. ration. Signs and symptoms associated with the
onset of NEC include bilious vomits or aspirates
up naso-/orogastric tube, feed intolerance, abdom-
Necrotizing Enterocolitis inal distension and tenderness with or without
discoloration, and fresh blood in the stool. Other
Necrotizing enterocolitis (NEC) is the most com- clinical signs include those associated with sepsis
mon severe gastrointestinal problem that can such as apnea and bradycardia, tachycardia, hypo-
affect preterm infants, and it significantly tension, temperature instability, poor perfusion,
increases their rates of mortality and morbidity and shock. If the disease process progresses,
(Lissauer and Fanaroff 2011; Neu and Walker bowel perforation can occur. Diagnosis is made
2011; Fitzgibbons et al. 2009; Rees et al. 2007; from clinical signs and symptoms and radiologi-
Hintz et al. 2005). NEC is primarily a disease of cal characteristic findings on plain film abdomen
prematurity; however, term infants with specific (PFA). Abnormalities on PFA include dilated
bowel loops, thickening of bowel wall, and intra- Inguinal hernias should be monitored closely for
mural air (pneumatosis). Late findings are air in signs of strangulation, and parents should be
the portal venous system, and if perforation educated on the signs and symptoms of hernia
occurs, free air is seen in the abdomen on PFA strangulation and be aware of the need for urgent
and lateral decubitus abdominal X-ray. presentation to a pediatric surgical center if
Initial management of NEC is to withhold strangulation occurs.
enteral feeds and commence broad-spectrum anti-
biotics which provide cover against both Gram-
positive and Gram-negative organisms. If bowel Umbilical Hernia
perforation occurs, one of various surgical inter-
ventions should be considered (Neu and Walker Preterm infants are more at risk than term infants
2011; Rees et al. 2005; Moss et al. 2006). Long- for developing umbilical hernias. Similar to ingui-
term complications of NEC include poor growth nal hernia, they are more common in extremely
and weight gain and poorer neurodevelopmental preterm and infants with bronchopulmonary dys-
outcome (Rees et al. 2007; Hintz et al. 2005). plasia. Incarceration of an umbilical hernia is rare,
Stricture formation and the possibility of associ- and in general, they resolve over time during the
ated intestinal obstruction are risks in infants who first year of life.
have recovered from NEC.
Spontaneous Bowel Perforation Infection
Spontaneous bowel perforation affects extremely As a result of their immature immune system,
preterm infants. Typically it has an earlier onset compared to term infants, preterm infants are at
than bowel perforation associated with NEC and an increased risk of sepsis. Those who develop
occurs in the first week of life before the infant is early-onset sepsis (EOS), sepsis acquired before
established on enteral feeds. The management is or during birth, or late-onset sepsis (LOS), sepsis
similar to that of perforated NEC. onset at >72 h of age has overall higher rates of
mortality and morbidity (Bulkowstein et al. 2016;
Pammi and Weisman 2015). Group B streptococ-
Inguinal Hernia cus and coliforms such as E. coli, colonized in the
mother, are the most common organisms to cause
Inguinal hernias are commonly seen in preterm EOS, while LOS is mainly due to nosocomial
infants with a reported incidence of 9% in all infection with the most common organisms
infants 32 weeks, 11% in infants born being coagulase-negative staphylococcus. The
<1500 g, and 17% of infants born <1000 g presence of indwelling devices such as central
(Rennie et al. 2012; Kumar et al. 2002). They venous catheters, peripheral venous or arterial
are seen in boys much more frequently than girls lines, endotracheal tubes, and chest drains
and can be unilateral or bilateral. The high inci- increases the risk of infection by acting as a
dence in convalescing preterm infants is thought focus for infection source and therefore should
to be due to a combination of weak abdominal only be inserted if absolutely necessary and
muscles and long period of relatively high should be removed as soon as possible. Strict
intra-abdominal pressure associated with antiseptic techniques should be followed when
bronchopulmonary dysplasia and respiratory carrying out any invasive procedure in a preterm
support. There is a high risk of strangulation, infant, and their skin should be monitored closely
and therefore they should be repaired as soon for signs of breakdown, which can act as an infec-
as the infant is stable and suitable for anesthetic. tion source for infection.
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Pediatric Clinical Genetics
9
Andrew J. Green and James J. O’Byrne
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Diagnosis of Malformation Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Definitions Used with Congenital Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
A Clinical Genetic Approach to Diagnosis of Malformation Syndromes . . . . . . . . . . . . . . 151
Genetic Etiology of Congenital Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Chromosome Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Single-Gene Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Polygenic/Multifactorial Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Chromosomal G-Banding Analysis (Standard Karyotyping) . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Fluorescent In Situ Hybridization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Array Comparative Genomic Hybridization/
Chromosomal Microarray Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Specific Testing for Common Known Single-Gene Mutations . . . . . . . . . . . . . . . . . . . . . . . . . 163
Next-Generation Sequencing and Gene Panels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Abstract
The primary aim of this chapter is to introduce
A. J. Green (*)
the pediatric surgeon to the fundamental con-
Department of Clinical Genetics, Our Lady’s Hospital,
Crumlin, Dublin, Ireland cepts of clinical genetics and equip him/her
with the basic genetic terminology and tools
School of Medicine and Medical Science, University
College Dublin, Belfield, Dublin, Ireland to manage some of the malformation syn-
e-mail: andrew.green@olchc.ie; andrew.green@ucd.ie dromes commonly encountered in surgical
J. J. O’Byrne practice, particularly during the newborn
Department of Clinical Genetics, Our Lady’s Hospital,
e-mail: James.O'Byrne@olchc.ie; obyrnej@tcd.ie

https://doi.org/10.1007/978-3-662-43588-5_10
150 A. J. Green and J. J. O’Byrne
period. A clinical genetic approach to diagno- Diagnosis of Malformation Syndromes

sis, etiology, and inheritance patterns of mal-
formation syndromes is outlined. Genetic Introduction
investigations, often employed to help unearth
a diagnosis including chromosomal G-banding One child in 40 (2.5%) is born with a significant
analysis/standard karyotyping, fluorescent in major congenital anomaly which accounts for
situ hybridization, and array comparative 20–25% of perinatal and childhood mortality.
genomic hybridization analysis/chromosomal Most affected children have a single isolated
microarray, are described and discussed in major congenital anomaly, in the absence of any
detail along with single-gene tests and the underlying syndrome. However, where a child has
development of next-generation sequencing more than one congenital anomaly, with or without
and gene panels. dysmorphic features, the possibility of an underly-
ing genetic syndrome or association should be con-
sidered. Awareness of this possibility is very
Keywords
important for management of the patient and for
Chromosome disorders · Single-gene
advising the whole family. Examples of the com-
disorders · Karyotype · Microarray · Next-
moner congenital anomalies, grouped by the organ
generation sequencing
system affected, and the approximate birth inci-
dence are shown in Table 1. It is also important to
note that approximately 10% of the normal
Introduction
Genetic disorders are common in pediatric prac- Table 1 Examples of major congenital anomalies
tice and contribute to between 30% and 70% of Examples of major Birth incidence (per
childhood hospital admissions. Genetic condi- congenital anomalies 1,000 births)
tions cause a range of clinical problems including Cardiovascular 10
malformations, metabolic disorders, learning dis- Ventricular septal defect 2.5
Atrial septal defect 1
ability, or neurological disease. With over 5,000
Patent ductus arteriosus 1
different genetic conditions, almost every aspect
Fallot’s tetralogy 1
of pediatrics will involve managing children with
Central nervous system 10
genetic disorders. Clinical geneticists can offer
Anencephaly 1
expertise both in diagnosing rare and ultra-rare Hydrocephalus 1
genetic disorders and advising families with Microcephaly 1
known genetic disorders. This chapter will focus Lumbosacral spina bifida 2
on the approach a clinical geneticist takes when Gastrointestinal 4
reviewing infants and children with congenital Cleft lip/palate 1.5
anomalies and diagnosing malformation syn- Diaphragmatic hernia 0.5
dromes, the different forms of genetic diseases Esophageal atresia 0.3
which can cause congenital anomalies, and the Imperforate anus 0.2
up-to-date genetic investigations that are avail- Limb 2
able to aid the clinician to arrive at these diagno- Transverse amputation 0.2
ses. It is hoped the chapter will equip the pediatric Urogenital 4
and neonatal surgeon with the baseline genetic Bilateral renal agenesis 2
knowledge required to manage those cases of Polycystic kidneys 0.02
(infantile)
children with malformations who have (or may
Bladder extrophy 0.03
have) an underlying genetic diagnosis.
9 Pediatric Clinical Genetics 151
population will have a minor congenital anomaly, genetic and nongenetic origins. Pierre Robin
such as fifth finger clinodactyly or a single palmar sequence is the grouping of cleft palate, micro-
crease, which, in the absence of any other problems, gnathia, and glossoptosis, which can have at
is of no major significance. least 30 different causes. A sequence therefore
does not have a specific cause or inheritance
pattern.
Definitions Used with Congenital An association can be defined as a clustering
Anomalies of anomalies, which is not a sequence, which
occur more frequently than by chance, but has
Distinctions can be drawn between several differ- no prior assumption about causation. An example
ent forms of congenital anomaly. is the association of VATER, whose acronym is
A disruption can be defined as an anomaly made up from the grouping of vertebral anoma-
which is caused by an interference in the structure lies, anal abnormalities, tracheooesophageal fis-
of a normally developing organ. A good example tula, and radial or renal anomalies. There is no
would be the digital constrictions and amputations clear cause for VATER, although it can rarely
caused by amniotic bands. Amniotic bands are occur in people with chromosome 22q11 micro-
strands of tissue which cross from one wall of deletions and can also rarely be mimicked by
the amniotic sac to the other and can constrict Fanconi’s anemia.
parts of the developing fetus. A syndrome is a description of a group of
A deformation can be defined as an anomaly symptoms and signs and a pattern of anomalies,
which is caused by an external interference in the where there is often a known cause, or an
structure of a normally developing organ. An assumption about causation. The looser defini-
example would be talipes equinovarus caused by tion of “syndrome” to describe any anomaly
chronic oligohydramnios, perhaps from an should be avoided. The term can include chro-
amniotic leak. mosomal disorders such as Down’s syndrome or
A malformation can be defined as an anomaly single-gene disorders such as van der Woude
which is caused by an intrinsic failure in the syndrome which can cause cleft lip and palate
normal development of an organ. Common exam- with lower lip pits.
ples would be congenital heart disease, cleft lip
and palate, and neural tube defects.
A dysplasia is an abnormal organization of A Clinical Genetic Approach
cells in a tissue, often specific to a particular to Diagnosis of Malformation
tissue. For example, achondroplasia is a skeletal Syndromes
dysplasia caused by a mutation in the FGFR3
gene. Most dysplasias are single-gene disorders. History: When reviewing a child with a congeni-
A sequence can be defined as a primary mal- tal anomaly, a comprehensive medical history and
formation which results in secondary deforma- examination is an essential starting point toward a
tions. An example is Potter’s sequence which is diagnosis. Several important aspects of the history
the group of anomalies consisting of pulmonary need to be explored including a detailed three-
hypoplasia, oligohydramnios, talipes, cleft pal- generation family history, with reference not
ate, and hypertelorism (see Fig. 1). All of these only to a history of the same anomaly, but other
anomalies arise as a result of the failure of urine anomalies as well. The history should include
production in the fetus. The cause of Potter’s documentation of consanguinity, ethnicity, preg-
sequence and failure of urine production could nancy losses, stillbirths, and neonatal deaths and
be posterior urethral valves, dysplastic or cystic any history of potential teratogens in the preg-
kidneys, or renal agenesis, all of which can have nancy, considering the likely embryological
Fig. 1 Potter’s sequence
timing of the anomaly. Teratogens can include should be sought. If the anomalies do not fit into
prescribed medications that the mother has taken a sequence, then a syndrome or association diag-
during pregnancy, recreational drugs, maternal nosis should be attempted. If a malformation
diabetes mellitus, and prolonged maternal syndrome diagnosis is achieved, it is important
hyperthermia. to remember that syndromes can be caused by
Examination and Investigations: In the pres- chromosomal, single-gene (monogenic),
ence of one congenital anomaly, a very careful multiple-gene (polygenic) disorders or by envi-
examination should be carried out to check for ronmental agents. If cause is unknown and there
any other subtle abnormalities or for dysmorphic is more than one malformation or significant
facial features, e.g., to check for hydrocephalus dysmorphology, chromosomal analysis should
in an infant with a spinal meningomyelocele. A be requested. A clinical genetic opinion should
diagnostic approach to congenital anomalies is also be sought, as a clinical geneticist can often
outlined in Fig. 2. Deformations and disruptions help greatly in achieving a diagnosis, as well as
need to be excluded first. If the pattern of in counseling parents about the likelihood of
malformations fits into a well-described malfor- recurrence of similar problems in other family
mation sequence, then a cause for that sequence members.
Fig. 2 A diagnostic approach to congenital anomalies
Table 2 Causes of congenital anomalies

Genetic Etiology of Congenital Causes of congenital anomalies Relative frequency
Anomalies Genetic
Chromosomal 6%
Introduction Single gene 7.5%
Multifactorial/polygenic 20–30%
The genetic causes of congenital abnormalities, Environmental
outlined in Table 2, include chromosomal, mono- Drugs, infections, maternal 5–10%
genic, or polygenic/multifactorial disorders with illness
the latter being the most frequent genetic cause. Unknown 50%
Other causes are classified under environmental Total 100%
agents and include teratogens, maternal illness
(e.g., diabetes), and infections. It is important to is therefore worthwhile to pursue a diagnosis
note that about 50% do not have any clear cause wherever possible. Also accurate etiological
and most are isolated or non-syndromal. Nonethe- determination can have specific implications for
less, parents and families often want an explana- treatment, prognosis, and assessment of recur-
tion as to the origin of their child’s anomaly, and it rence risk and counseling of families.
Chromosome Disorders child, with a separate extra chromosome 21.

Under these circumstances, it is not necessary to
Disorders of either chromosome number or struc- check parental chromosomes. Clinicians should
ture affect about 6/10,000 births and about 6% of be aware of a rare translocation form of Down’s
all congenital anomalies are caused by a chromo- syndrome which can be readily distinguished on
some disorder (see Table 2). A finite number of the child’s chromosomal G-banding analysis, and
disorders of chromosome number exist, and those the unaffected parents of affected children should
most commonly observed are Down’s syndrome, be offered chromosomal G-banding analysis as
Edward’s syndrome, and Patau’s syndrome, they may carry a balanced form of a chromosome
which will be discussed below. There are poten- translocation.
tially thousands of disorders of chromosome
structure, many of which are extremely rare or Patau’s Syndrome
unique to a particular family. Usually chromo- Patau’s syndrome is caused by the presence of an
some disorders are new genetic events in the extra chromosome 13 and is a condition that is
affected child; however, a small subset of chro- usually lethal in the newborn period. It is a rare
mosome disorders can be inherited. In these cases, condition and occurs in about 1 in 5,000 births.
a balanced chromosome rearrangement called a Affected children have congenital heart disease,
translocation may present in one or other healthy polydactyly, cleft lip and palate, microcephaly,
parent. Chromosome disorders are detected by and often a single frontal lobe in their brain
cytogenetic analysis, and the three most com- (holoprosencephaly). Like Down’s syndrome,
monly used analyses are chromosomal 95% are new genetic events. There are rare trans-
G-banding analysis which is often referred to as location forms which can run in families, and
“karyotyping,” fluorescent in situ hybridization again the distinction between the common and
(FISH), and high-resolution array comparative rare forms can be identified on the baby’s chro-
genomic hybridization (aCGH) more commonly mosomal G-banding analysis.
referred to as “microarray” (for more details on
these techniques, see section “Genetic Testing”). Edward’s Syndrome
Edward’s syndrome is caused by the presence of
Down’s Syndrome an extra chromosome 18 and is a condition that is
Down’s syndrome is the commonest chromosome usually lethal in the newborn period. It occurs in
disorder, with an average incidence estimated at about 1 in 3,000 births. Affected children are
1 in 700 births and is characterized by the pres- usually extremely small and have congenital
ence of an extra (third) chromosome 21. The most heart disease, exomphalos, renal anomalies,
frequent congenital anomaly in children with clenched hands, and rocker bottom feet. Over
Down’s syndrome is congenital heart disease, 95% are new genetic events in the affected infant.
usually an atrioventricular defect. However, chil-
dren with Down’s syndrome are also more prone Other Chromosome Disorders
to duodenal and jejunal atresias and Klinefelter’s syndrome is a condition character-
Hirschsprung’s disease. Children with Down’s ized by the presence of an extra X chromosome
syndrome will also have varying degrees of learn- in a male, i.e., 47,XXY. Boys with Klinefelter’s
ing difficulty, and it is associated with deafness syndrome rarely present surgically in childhood.
and hypothyroidism. There is predominance of However, a significant number can have delayed
leukemia among patients with Down’s syndrome puberty, teenage gynecomastia, or fertility issues
including both acute myeloid leukemia and acute in later life.
lymphoblastic leukemia. Children with Down’s Turner’s syndrome is the presence of a single X
syndrome are at a 20-fold increased risk of acute chromosome in a female, i.e., 45,X. Girls with Tur-
lymphoblastic leukemia. Over 90% of Down’s ner’s syndrome are more prone to congenital heart
syndrome arises as a new genetic event in the disease, classically coarctation of the aorta, and also
have renal anomalies. They may present in the new- recessive. Other rare patterns of inheritance
born period with these anomalies in the presence or include X-linked dominant, mitochondrial inheri-
absence of “puffy hands and feet” caused by lymph- tance, triplet repeat disorders, and genetic imprint-
edema. Short stature is a feature and spontaneous ing. The various single-gene disorders are
puberty is unlikely, due to ovarian dysgenesis. discussed under these headings below.
Di George or velocardiofacial syndrome is usu-
ally caused by a very small deletion of one of Autosomal Dominant Inheritance
chromosomes 22 which is detectable by FISH. Autosomal dominant disorders are caused by a
A wide range of congenital anomalies may be mutation in one of the two copies of a specific
present, most commonly congenital heart disease. gene. Families will often have several generations
Cleft palate and laryngeal and renal anomalies may affected, and usually the number of males and
also be present in association with hypocalcemia, females affected is approximately equal. The hall-
learning difficulties, and immunodeficiency. mark of autosomal dominant inheritance is father
to son transmission. Each child born to a person
with an autosomal dominant disorder has a 50:50
Single-Gene Disorders chance of inheriting the gene mutation responsi-
ble for the condition and is thereby predisposed to
Single-gene or monogenic disorders are caused by developing the condition (see. Fig. 3). However,
an alteration in one or both copies of one specific not all people with an autosomal dominant disor-
gene. Over 4,000 single-gene disorders have been der have a family history of the condition; some
described, and about 7.5% of all congenital anom- people can represent a new mutation in the specific
alies are caused by a single-gene disorder (see gene for their condition. For some autosomal dom-
Table 2). Single-gene disorders can be divided inant conditions such as Marfan’s syndrome or
into groups via their inheritance pattern of which neurofibromatosis type 1 (NF1), the new mutation
there are three principal modes: autosomal domi- rate can be 20–30%. Autosomal dominant disor-
nant, autosomal recessive, and X-linked ders also often display variability in both
Fig. 3 Autosomal
dominant inheritance
penetrance (whether a person develops any sign of affected by an autosomal recessive disorder will
the condition) and expression (how the condition automatically carry the condition (see Fig. 4b).
manifests). For example, NF1 will almost always The risk to a child, born to a couple, one of
manifest in someone who has an altered NF1 gene, whom is a confirmed carrier of the condition and
but different people with NF1 can manifest the one of whom is not, depends on the population
condition in different ways, with some people risk that the second parent is a carrier for an
showing mild expression with a few skin lesions alteration in the same gene.
and others with severe intracerebral complications. Autosomal recessive disorders are com-
This means that NF1 is almost completely pene- monly observed in pediatric practice, and
trant but the expression of the condition is very some may require surgery in the neonatal
variable. In contrast, only 80% of people who have period. The frequency of the autosomal reces-
a single altered gene for the rare hereditary form of sive disorders encountered depends on the
retinoblastoma will actually develop an eye tumor. patient population. Each regional population
The penetrance in this situation is 80%, but the has its own recessive disorders, where the fre-
expression of the altered gene is consistent, as quency of carriers for those disorders is highest.
manifested by a retinoblastoma. For instance, cystic fibrosis (CF) is a very com-
Autosomal dominant disorders are not common autosomal recessive disorder in Western
monly seen in neonatal surgical practice; how- Europe, whereas sickle cell anemia is the
ever, examples that may be observed in families commonest autosomal recessive disorder in
with reduced penetrance include Hirschsprung’s West Africa. Some other examples of autoso-
disease, Beckwith-Wiedemann syndrome, and mal recessive conditions are beta-thalassemia,
pyloric stenosis. Some forms of craniosynostosis spinal muscular atrophy, several of the
and orofacial clefting can also be a result of an mucopolysaccharidoses, and congenital adre-
autosomal dominant disorder. Rare childhood nal hyperplasia. Direct genetic diagnosis is
cancer predisposition syndromes such as poly- available for many of these conditions.
posis coli, retinoblastoma, and Li-Fraumeni syn- Many countries have a newborn screening pro-
drome are inherited in an autosomal dominant gram which includes testing for a number of auto-
manner. somal recessive disorders including galactosemia,
homocystinuria, sickle cell disease, and CF. Also,
among some populations, carrier testing for cer-
Single-Gene Disorders and Autosomal tain autosomal recessive diseases is available to
Recessive Inheritance couples planning a pregnancy or to women in the
Autosomal recessive disorders are caused when early stages of pregnancy.
both copies of a particular gene responsible for the
condition are altered. Both parents would carry
the condition and be unaffected as each parent Single-Gene Disorders and X-Linked
would have one normal and one altered gene. In Recessive Inheritance
most cases, carrying an autosomal recessive con- X-linked conditions are caused by alterations in
dition has no effect on the person. Two of the a gene on the X chromosome. Classic examples
child’s four grandparents are likely to carry the of such conditions include hemophilia A and B,
condition, and it is probable that many of the Duchenne and Becker muscular dystrophy, and
patient’s relatives would unknowingly carry the Hunter’s syndrome. Males have only one X
condition. chromosome, and therefore those with an altered
When both parents carry an alteration in the gene manifest the disease, as there is no normal
same autosomal recessive gene, there is a 25% or copy of the gene to compensate. Females have
one in four chance to each of their children of two X chromosomes, and therefore, even if a
inheriting both altered copies and probably the female has an altered gene, the normal gene
condition (see Fig. 4a). A child born to a person usually offsets the effect of the altered gene.
Fig. 4 Autosomal
recessive inheritance
Females can therefore carry an X-linked condi- sons of a man with an X-linked condition are all
tion, while only some females will manifest the normal, as they inherit his Y chromosome and
disorder. The daughters of a man with an not his X chromosome (see Fig. 5a). When a
X-linked recessive condition are all obligate car- woman is a carrier of an X-linked condition,
riers, as they all inherit his X chromosome. The each of her sons has a 50:50 chance of being
Fig. 5 X linked recessive

inheritance
affected, and each of her daughters has a 50:50 boys may not have any family history of the
chance of being a carrier (see Fig. 5b). There can condition. Approximately one-third of boys
be a relatively high mutation rate for some with the X-linked condition Duchenne muscular
X-linked recessive conditions, and affected dystrophy occur as a result of new mutations.
Single-Gene Disorders and Atypical but the expression appears to have an X-linked
Forms of Inheritance recessive influence.
X-linked dominant inheritance is a much rarer Triplet repeat expansions can cause single-
inheritance pattern of single-gene disorders than gene disorders in conditions such as fragile X
those discussed above. It can be difficult to dis- syndrome, Huntington’s disease, Friedreich’s
tinguish from autosomal dominant inheritance ataxia, and several forms of spinocerebellar
when observing of the family tree with the excep- ataxia. With these conditions, a gene is considered
tions that females will be more mildly affected and normal when it has a small stable number of three
male-to-male transmission does not occur. An DNA (triplet) repeat copies (e.g., 20 C-A-G
example of an X-linked dominant condition is repeats). The person is unaffected as the gene
hypophosphatemic rickets. functions normally and the children of that person
Mitochondrial inheritance is a very unusual inherit the same number of repeats in their gene
pattern of inheritance and observed in inherited and so are unaffected too. If the gene has a larger
diseases caused by single-gene disorders of the number of repeats than normal, then the function
mitochondrial genome. Most of the proteins nec- of the gene and encoded protein may be
essary for the mitochondrial function and struc- compromised and person may become affected.
ture are encoded for by the nuclear genome and This instability of the repetitive element may
so follow the standard Mendelian inheritance result in even further expansion in the next gener-
patterns. Mitochondria however also contain ation and the affected children of that person may
their own small genome of 18 kilobases, with have more serious disease. This phenomenon,
many copies per cell as each cell contains many where a condition appears to worsen from gener-
mitochondria. The mitochondrial genome does ation to generation, is known as anticipation. One
not follow the Mendelian patterns of inheritance of the most extreme examples of this molecular
and replicates independently and far more fre- mechanism is observed with congenital myotonic
quently than the nuclear genome. Several impor- dystrophy, where a minimally affected mother can
tant mitochondrial proteins are encoded by the have a profoundly affected infant as a small unsta-
mitochondrial genome, but mitochondria are ble repeat expansion in the mother increases to
only inherited via oocytes and not sperm. There- many hundreds of repeats in her affected infant.
fore, where a gene alteration is in the mitochon- Genetic Imprinting is demonstrated by condi-
drial genome, it will pass exclusively down the tions such as Prader-Willi syndrome, Angelman’s
female line, but both males and females can be syndrome, Russell-Silver syndrome, Beckwith-
affected. The children of an affected male will Wiedemann syndrome, and the rare condition of
not inherit his mitochondrial gene alteration. transient neonatal diabetes mellitus. Surgical
Children with mitochondrial disorders usually input may be required in the neonatal period for
display multisystemic involvement and can pre- some of these conditions (e.g., exomphalos repair
sent with varied symptoms at any age, including in Beckwith-Wiedemann syndrome).
myoclonic seizures, acute acidosis, muscle In genetic imprinting, an imprinted gene
weakness, deafness, or diabetes. A number of becomes marked during meiosis to indicate the
point mutations and deletions in the mitochon- parent from which it is inherited. For some genes,
drial genome have been described in patients it appears to be important not only to inherit two
with a wide variety of conditions, including copies of that gene but to inherit one from each
MELAS (mitochondrial encephalopathy with parent. Some genes may be silenced, depending
lactic acidosis and stroke-like episodes) or upon which parent has passed on that gene. An
MERRF (myoclonic epilepsy with ragged red example of imprinting is demonstrated when a
fibers on muscle biopsy). To complicate matters small deletion of chromosome 15q occurs.
further, Leber’s hereditary ophthalmopathy is a Depending upon whether the deletion occurs on
mitochondrially inherited condition, with a char- the maternally or paternally derived chromosome
acteristic mutation in the mitochondrial genome, 15, a different effect is observed. If the deletion
occurs on the chromosome inherited from a Genetic Testing

child’s normal father, the child will develop
Prader-Willi syndrome (PWS). If the same dele- Chromosomal G-Banding Analysis
tion occurs on the chromosome inherited from a (Standard Karyotyping)
child’s normal mother, the child will develop a
clinically distinct condition, Angelman’s syn- Chromosomal G-banding analysis is now often
drome (AS). In addition, if a child inherits two referred to a “karyotyping.”
copies of chromosome 15 from the one parent, Indications for carrying out a standard chromo-
uniparental disomy (UPD), the child will develop somal G-banding analysis in a neonate with con-
Prader-Willi or Angelman’s syndrome (maternal genital anomalies are if signs suggestive of a
UPD results in PWS, while paternal UPD results known chromosome disorder such as Down’s or
in AS). The genes in this area of chromosome Patau’s syndrome are observed, or if the baby has a
15 are therefore said to be “imprinted.” suspected disorder of sexual development, where
the chromosomal gender is important to identify.
Previously, this would have been considered the
Polygenic/Multifactorial Disorders first-line test of a child with multiple mal-
formations, but now the recommended first-line
Polygenic/multifactorial gene disorders are dis-
test in an infant or older child with multiple
orders that do not have a clear mode of inheri-
malformations is high-resolution array CGH (see
tance, where a disease may arise as a result of
section “Array Comparative Genomic Hybridiza-
the effects of several genes and/or be influenced
tion/Chromosomal Microarray Analysis”).
by several environmental factors. It is estimated
To examine chromosomes using chromosomal
that these polygenic disorder conditions cause
G-banding analysis, dividing cells (usually lym-
up to 30% of congenital anomalies (see
phocytes, amniotic fluid cells, or fibroblasts) in
Table 2). Examples of a congenital anomaly
culture must be examined. Cells are arrested in
that is thought to follow polygenic inheritance
the metaphase stage of mitosis where the chromo-
are neural tube defects such as spina bifida or
somes are condensed and easily visualized. Using
anencephaly. A threshold effect is thought to
“Giemsa” stain, a characteristic positive and nega-
exist where hypothesized genetic factors,
tive “G”-banding pattern is observed on each chro-
known environmental factors (e.g., inadequate
mosome. Each chromosome has a constriction,
maternal folic acid levels in the first trimester),
called a centromere, dividing the chromosome
sand other chance factors combine to result in a
into a short (p) arm and a long (q) arm. Each arm
neural tube defect. Another example is cleft lip
has a number of prominent bands, which can then
and palate, which usually occurs in the absence
be subdivided into smaller bands. For example, the
of a family history. However, monozygotic
gene for the ABO blood group is localized to
(identical) twins have a high concordance for
chromosome 9q34. The gene thus lies in the fourth
cleft palate, and the recurrence risk in another
sub-band from the centromere (q34) of the third
child is known to be higher than the population
risk suggesting a genetic influence. However, band from the centromere (q34) on the long arm
the genetic influence does not follow a typical (q34) of chromosome 9 (9q34).
Mendelian or single-gene pattern of inheritance Chromosome abnormalities can broadly be
suggesting that other factors are often neces- classified into abnormalities of chromosome num-
sary for the condition to manifest. Other exam- ber or structure. The critical issue in most cases for
ples of polygenic disorders include congenital determining the significance of a chromosome
heart disease, non-syndromic Hirschsprung’s abnormality is whether the abnormality gives
disease, vesico-ureteric reflux, and coeliac rise to an excess or deficiency of the normal dip-
disease. loid state (aneuploidy).
Abnormalities of chromosome number are rel- coding material on a very small short (p) arm. These
atively common, but many are not recognized, as translocations can run in families, and those who
they may result in the early loss of a pregnancy. carry a Robertsonian translocation involving chro-
Triploidy (69 chromosomes) and tetraploidy mosomes 21 or 13 may be at significantly higher
(92 chromosomes) are relatively common causes risk of having a child with Down’s or Patau’s syn-
of early pregnancy loss. Trisomy, the presence of a drome as an unbalanced product of the transloca-
single extra chromosome (47 chromosomes), is tion. The distinction between the rare translocation
also a common cause of miscarriage. Specific form of these conditions and the more common
trisomies can give rise to children with many non-disjunction form can be identified on the child’s
congenital anomalies, the commonest being tri- chromosome G-banding analysis.
somy 21 (Down’s syndrome), trisomy 13 (Patau’s
syndrome), and trisomy 18 (Edwards’ syndrome)
which are discussed in more detail in sections Fluorescent In Situ Hybridization
“Down’s Syndrome,” “Patau’s Syndrome,” and
“Edward’s Syndrome.” All these trisomies usu- Fluorescent in situ hybridization (FISH) uses spe-
ally occur as a result of autosomal non-disjunction cific fluorescently labelled small DNA fragments
in meiotic division of the oocyte. In or probes corresponding to 40–50 kb of DNA from
non-disjunction, the specific chromatids fail to specific regions of chromosomes which allows for
separate, resulting in an extra chromosome in targeted higher resolution analysis of specific chro-
one oocyte, and it tends to occur more frequently mosomes. An example where this technology
with increasing maternal age. would be commonly used is testing for the submi-
Abnormalities of chromosome structure can croscopic deletion of chromosome 22q11 which
occur in many ways including inversions, inser- occurs in most cases of Di George syndrome.
tions, duplications, deletions, isochromosomes, FISH can also be carried out to get a rapid
ring chromosomes, and translocations. Inversions, analysis for numerical chromosome anomalies
both pericentric and paracentric, are usually bal- such as Down’s syndrome, without the need for
anced and inherited without any phenotypic effect. culturing blood cells, by analyzing interphase
For a person who carries a balanced paracentric nuclei with a FISH probe containing chromosome
inversions, there is usually a low risk of producing 21 material. FISH testing can also be used to give
a live-born baby with an unbalanced chromosome a rapid determination of the chromosomal gender
rearrangement, but pericentric inversions may using X and Y probes in interphase nuclei.
carry a higher risk. Insertions, duplications, dele-
tions, isochromosomes, and ring chromosomes are
all usually aneuploid and often associated with Array Comparative Genomic
significant clinical abnormalities. Hybridization/Chromosomal
Two types of translocations occur, reciprocal and Microarray Analysis
Robertsonian. Reciprocal translocations occur
where there is exchange of genetic material from Array comparative genomic hybridization (array
one arm of a chromosome in return for genetic CGH) is a relatively new technology employed in
material from a different chromosome. These are clinical practice and a form of molecular
usually balanced, without any clinical effect, but karyotyping that can detect losses (deletions) or
may again carry a risk of having a child with con- gains (duplications) of chromosomal segments or
genital anomalies due to an unbalanced karyotype. variations in the expected number of copies of
Robertsonian translocations occurs between the DNA in certain segments of the genome known as
acrocentric chromosomes (i.e., chromosomes copy number variations (CNVs) at a resolution of at
13–15, 21, and 22), where there is no appreciable least 100 times greater than conventional G-banding
Fig. 6 Array CGH analysis
Patient DNA Control DNA
This should really be

single stranded and
fragmented…
Array containing
oligonucleotides
Red = Deletion
Green = Duplication
Yellow= No change/Normal
chromosome analysis. This technology is often a red fluorescent dot. When there is more patient
referred to a “microarray,” but it is important to be than control DNA (duplication), the patient label
aware that many different types of “microarray” is over replicated and is indicated by a green dot.
exist such as single-nucleotide polymorphism When there are no copy number changes, there
(SNP) array as well as mRNA, protein, and tissue should be equal amounts of control-labelled and
microarrays. Array CGH and SNP array are the most patient-labelled DNA (yellow dots).
commonly used array types in the clinical setting, Array CGH analysis should be considered in
while the others are used mainly in the research infants born with multiple malformations or signif-
world to look for variants of individual genes, icant dysmorphology. Genomic array technology
protein-protein interactions, and the molecular biol- will identify pathogenic chromosomal anomalies
ogy or immunohistochemistry of the samples. in up to 30% of infants with multiple malformations,
Array CGH compares the patient’s DNA to and it is reported the likelihood of an abnormal array
control DNA using two different fluorescent CGH increases with the number of clinical abnor-
labels (see Fig. 6). Labelled control (red) and malities, i.e., patients with 4 clinical variables
patient (green) DNA arrangements are hybridized have demonstrated a 30% incidence of abnormal
to an array (chip) containing oligonucleotide pro- chromosomal microarray findings compared with
bes (DNA sequences from genes throughout the ~9% of patients with 3 clinical variables.
human genome). A digital imaging system is used Array CGH has advantages over chromosomal
to capture and quantify the fluorescence ratio G-banding analysis and FISH. Array CGH may
which indicates any differences in the patient’s detect DNA imbalances much more precisely than
genome compared to the control genome. When chromosomal G-banding analysis and can reveal
only the control DNA is present in a region, the which specific genes are included in the deletion
absence of patient DNA (deletion) is indicated by or gain. Array CGH can detect chromosome
imbalances when there are no clues to what the DNA-based tests are being used in diagnosis and
chromosome anomaly might be and so would not prediction of single-gene disorders.
be detected by performing specific FISH. It can The two major techniques used in specific
further define breakpoints and the size of the molecular genetic analysis are the polymerase
imbalances in certain cases. chain reaction (PCR) and the less frequently
Although array CGH is more detailed than used southern blotting.
standard chromosomal G-banding analysis, it PCR is a technique which allows amplification
has not replaced G-banding in all situations. of a specific genetic region in large quantities from
Array CGH will not identify balanced chromo- a small amount of DNA template. Using oligonu-
some rearrangements such as balanced transloca- cleotide primers, DNA generated by PCR can be
tions and inversions as these do not result in any used to detect known pathogenic DNA mutations
loss or gain of chromosome material. Array CGH and give a diagnosis, even without any knowledge
will also not detect some types of polyploidy such of the patient’s clinical status, e.g., the PCR detec-
as triploidy or low-level mosaicism (<20%). A tion of the Phe508del deletion in both copies of a
chromosomal G-banding analysis would be nec- person’s cystic fibrosis transmembrane regulator
essary to detect these balanced anomalies and (CFTR) gene immediately gives a diagnosis of
aneuploidies and in situations where mosaicism CF. Similarly a PCR test detects a deletion of
is suspected would be the preferred primary test. exons seven and eight in both alleles of a gene
Array CGH will also not detect point mutations or called SMN on chromosome 5q in almost all
epigenetic abnormalities. children with spinal muscular atrophy. If the
The results of microarray testing are often search is for an unknown DNA mutation, such
complex and require confirmation and careful as those seen in hereditary breast and ovarian
interpretation, often with the assistance of a clin- cancer, then many pieces of DNA generated by
ical geneticist. PCR can be sequenced and analyzed using an
Three possible results may be attained from array automated DNA analyzer.
CGH: (a) a normal result with no clinically signifi- Southern blot analysis of DNA from infants
cant variation, (b) a definitely abnormal result with a with congenital myotonic dystrophy shows a very
known pathological variation, and (c) a variation of large expansion in a triplet repeat DNA sequence
unknown significance (VUS). VUS are often CNVs. in the myotonin kinase gene on chromosome 19.
Every person has approximately 100 CNVs which
can affect numerous genes but are only sometimes
pathogenic. It may be difficult to establish the sig- Next-Generation Sequencing and Gene
nificance of some CNVs, and targeted parental array Panels
CGHs are usually recommended in the first instance
to help with the interpretation. With the advent of massive parallel sequencing, or
next-generation sequencing, it is now possible to
sequence large sections of genomes in a short time
Specific Testing for Common Known frame. These rapid technological advances along
Single-Gene Mutations with the continued identification of pathogenic
causing genes mutations and the improvement in
Laboratory tests for single-gene disorders have genotype-phenotype correlations have led to the
been available for a considerable amount of development of “gene panels” for hundreds of con-
time. Tests such as hemoglobin electrophoresis ditions. Gene panels are now available to investigate
for sickle cell anemia and thalassemia or enzyme children with specific malformations. Examples of
assays for Tay-Sachs’ disease are examples of conditions that gene panel testing is now available
tests that predate the genetic testing era and for include arthrogryposis, anophthalmia, cranio-
remain very effective in resolving clinical issues synostosis, non-syndromic Hirschsprung’s disease,
in individual families. Increasingly specific holoprosencephaly, lissencephaly, overgrowth,
skeletal dysplasias, vascular malformations, and to translate a specific mutation into an absolute
polycystic kidney disease. condition risk.
Although these panels are currently expensive, In time to come, we would expect that panel
prices are expected to fall, and in the long run, gene testing will become standard for children of
targeted gene panel testing, led by an experienced all ages presenting with malformations.
clinical geneticist, can be a low-cost, time-effective
test particularly if the suspected disorder has a
phenotype that could be caused by a number of Conclusions and Future Directions
genes. One such example of a very useful gene
panel is one that is applicable to disorders of the As the capacity for diagnosis of genetic conditions
Noonan syndrome spectrum which contain condi- continues to develop at a rapid pace, medical sub-
tions such as Noonans, lentigines, electrocardio- specialties, traditionally rarely aligned with clini-
graphic conduction defects, ocular hypertelorism, cal genetics, are encountering on a far more
pulmonary stenosis, abnormalities of the genitals, frequent basis patients with genetic diagnoses.
retarded growth and deafness (LEOPARD), This requires the clinicians working in specialities
cardiofaciocutaneous, and Costello syndromes. like pediatric surgery to keep abreast of develop-
These are a genetically heterogeneous group of ments in the area of clinical genetics, a challenge
autosomal dominant disorders that often have not easily surmountable in this era of such rapid
over lapping clinical features and can be difficult technological advance. Array CGH was added to
to differentiate. The gene panel now contains up to mainstream clinical practice in the last decade,
11 genes (BRAF, KRAS, HRAS, NRAS, while gene panels are currently available for hun-
MAP2K1, MAP2K2, PTPN11, RAF1, CBL, dreds of different conditions and the list in
SOS1, SHOC2) which can help distinguish which expanding on an almost daily basis. Soon the
condition is present. Another example of a gene ability to examine the coding regions of all
panel with a high clinical utility is available is that 23,000 genes with exomic sequencing will be
for Meckel Gruber syndrome which is the most standard in clinic practice and will eventually be
common syndromic form of neural tube defect. It followed by whole genomic sequencing.
presents with a classic triad of clinical features of Although this exciting new technology will
occipital encephalocele, cystic kidneys, and increase the diagnostic rate of genetic disorders,
fibrotic change of the liver, but the phenotype it will bring a new set of challenges such as an
may also include features such as postaxial poly- increased number of VUS and the ethical dilemma
dactyly, skeletal dysplasia, microphthalmia, genital of reporting variations in genes not associated
anomalies, cleft lip and palate, and heart defects, with the phenotype under investigation.
and any one of a number of genes (CC2D2A, Noninvasive prenatal screening is another new
CEP290, MKS1, RPGRIP1L, TCTN2, genetic technology that will influence neonatal
TMEM216, TMEM67) may be causative. surgical practice. It is now widely available for
Gene panel tests are constructed, analyzed, and the investigation of trisomies 21, 18, and 13 and is
reported with an intentional blindness to all, but a being expanded to screen for many other genetic
specifically selected list of genes and clinicians conditions. This will increase the number of pre-
should be cognizant of which genes were not natal diagnoses which will allow for early prepa-
reported when interpreting a test result. Panel test ration of required surgical management in the
are also more likely to identify a VUS than a newborn period or even in utero.
deleterious mutation. In addition not all genes Pediatric and in particular neonatal surgical
included in panel tests are unequivocally linked practice will continue to become more involved
to the disease/phenotype, and for most genes, the with the subspecialty of clinical genetics as the
penetrance is highly variable making it challenging surgeons encounter on a more frequent basis cases
and conditions with a known genetic. The tech- ▶ Esophageal Atresia

nology to investigate the genetics of these condi- ▶ Gastroschisis
tions is becoming available to an increasing breath ▶ Omphalocele
of specialties including pediatric surgery. Close ▶ Macroglossia
liaison between surgeons and clinical geneticists ▶ Pierre Robin Sequence
will be essential in managing these investigations ▶ Tissue Engineering and Stem Cell Research
and diagnoses correctly and overcoming the
associated challenges.
Further Reading
OMIM, Online Mendelian Inheritance in Man – a database
Cross-References of human genes and genetic disorders developed by
staff at Johns Hopkins www.ncbi.nlm.nih.gov/Omim/
▶ Anorectal Malformations Orphanet – a database (in several languages) of genetic
▶ Choanal Atresia disorders, clinical information, clinic listings and
research and diagnostic genetic testing for a wide
▶ Congenital Airway Malformations
range of disorders www.orpha.net
▶ Congenital Biliary Dilatation Contact a Family – a UK charity for families with disabled
▶ Congenital Diaphragmatic Hernia children, which offers information on specific condi-
▶ Congenital Esophageal Stenosis tions and rare disorders. www.cafamily.org.uk
Understanding Gene testing (n.d.) – a website with infor-
▶ Congenital Malformations of the Lung
mation on basic genetic concepts, and the utility and
▶ Duodenal Obstruction limitations of genetic testing http://www.accessex
▶ Embryology of Congenital Malformations cellence.org/AE/AEPC/NIH/
Transport of Sick Infants and Children
10
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Transport Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Airway Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Circulation and Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Documentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Transport Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Vehicles and Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Transport Vehicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Monitoring and Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
Transport Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Receiving Center . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Special Considerations for Neonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Prenatal Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Neonatal Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174
Temperature Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
Transport Incubators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
J. Zimmer
Department of Pediatric Surgery, Hannover Medical
School, Hannover, Germany
e-mail: zimmer.julia@mh-hannover.de
P. Puri (*)
Department of Pediatric Surgery, Beacon Hospital, Dublin,
Ireland
School of Medicine and Medical Science and Conway
Institute of Biomedical Research, University College
e-mail: prem.puri@ncrc.ie

https://doi.org/10.1007/978-3-662-43588-5_11
168 J. Zimmer and P. Puri

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
Abstract a large interdisciplinary team consisting of pediatri-

Due to centralization and resource optimiza- cian/neonatologist, anesthetist, radiologist, patholo-
tion, treatment of severely ill children and gist, biochemist, nurses, and other disciplines
patients with complex diseases can only be necessary dealing with the patient (Puri and
provided in highly specialized tertiary centers. Doodnath 2011). Injured or severely ill children
To ensure optimal care, sick children must may present in hospitals which may not be equipped
therefore be transported safely to these hospi- to manage complex pediatric medical requirements,
tals, sometimes over considerable distances. and thus, an emergency transport to a pediatric
The transport modus should fulfill the special tertiary care facility must be organized (Quinn et
needs of the pediatric and neonatal patients al. 2015). The objective is to transport the critically
with its unique anatomic and physiologic con- ill or severely injured child to a tertiary hospital in
ditions requiring trained and skilled staff and the right condition and in the right time by an
specially equipped vehicles. Field triage is appropriately trained and skilled team of health pro-
needed to discriminate between the more- and fessionals. Prompt access to high quality care offers
less-severely injured and find the optimal mode the best and only chance of a successful outcome.
of transport. Transport team and transport vehicle should be
Transport team and vehicle should be an a natural physical extension of the intensive care
extension of the pediatric or neonatal intensive unit, able to supply advanced critical care man-
care unit, able to supply the technical facilities agement for children of all ages at remote sites and
for advanced critical care management for chil- during transport to a tertiary hospital (Ajizian and
dren of all ages in the area of primary care and Nakagawa 2007). Effective and efficient treat-
during transport to the hospital. ment can only be available by optimizing
During the past two decades, the approach resources, medical and technical equipment, and
of pediatric transport care has changed dramat- skilled staff in a few specialist pediatric centers
ically considering the knowhow, capabilities, which have responsibilities to a particular region
and transportation of neonates, infants, and (Messner 2011). There has been a dramatic devel-
older children. This chapter aims to describe opment in the last three decades regarding to the
current considerations regarding the different knowledge, capabilities, and delivery of neonatal
transportation modalities and age-dependent and pediatric transport (Moss et al. 2005; Ratnavel
requirements. 2009). There is strong evidence that the use of
specialist transport teams results in improved sur-
Keywords vival for critically ill children (Calhoun et al.
Primary care · Transfer management · 2017; Edge et al. 1994; Orr et al. 2009;
Neonatal transport · Pediatric transport · High Ramnarayan et al. 2010).
risk patients · Golden hour
Transport Management
Introduction
Transport teams and clinics should follow bench-
Successful outcome of a medical treatment or an marks of transport consensus groups for best prac-
operation in pediatric surgery depends not only on tices and quality improvement in transport
the skills of the pediatric surgeon but also on that of procedure and clinical care (Schwartz et al. 2015).
10 Transport of Sick Infants and Children 169
The transport staff must cautiously monitor the hospitals which are not otherwise equipped to care
patient’s condition during the travel as well as for injured children (Fenton et al. 2016).
ventilation and oxygenation, cardiovascular, met- Telemedicine delivers information and health-
abolic, and thermal support (Messner 2011). care advice across distances (Patel et al. 2015).
Previously, a swift transfer management Real-time video and phone conferences can be
(“scoop and run”) has been postulated to rush equally good in quality, connectivity, and dura-
the patient to the hospital as quick as possible tion. Especially videos seem to improve the
(Stroud et al. 2008). This idea of the “golden patients’ assessment and disposition as they not
hour,” the time between harm and arrival at spe- only support communication with the referring
cialized center for definitive care, originated in hospital staff but also help to see and interact
1973 (Cowley et al. 1973; Stroud et al. 2008). with patient and parents likewise (e.g., see certain
Because of this management, early implementa- body aspects in advance; see and correct ventila-
tion of goal-directed therapy was often delayed tor settings, etc.) (Patel et al. 2015).
until arrival at the intensive care unit (ICU), but
early goal-driven treatment, e.g., for septic shock
and head trauma has been shown to improve out- Airway Management
come in adults and children likewise (Stroud et al.
2008). After arrival in the primary care area, one should
Factors associated with time to arrival at a ensure that the airway is clear, the child is well
pediatric trauma center are field triage and deci- oxygenated, and ventilation can be maintained
sion-making, which correlate with the injury’s during transport if required. If there is any risk
severity and rapid transport of the most severely for deterioration of spontaneous respiration dur-
injured children to definitive trauma care (Odetola ing transport, the patient needs to be intubated
et al. 2016). before departure, because emergency intubation
To improve transport quality, everyone while travelling may be hazardous or difficult
involved in pediatric transport should be aware (Lloyd 1996). Airway suction of intubated
of physiologic deterioration, laboratory values, patients should be performed regularly.
interventions, equipment failure, process error, Endotracheal intubation is considered the
and safety issues (Gunz et al. 2014). Jones et al. gold standard for airway management (Freeman
identified that these so-called UNSEMs et al. 2016). Because regular training is neces-
(unintended injury, near miss, suboptimal sary to maintain this skill, there is now often
action, error, management complication) are focus on providing sufficient sustained bag
especially more likely when transport originates mask ventilation in pediatric patients instead
from a scene compared to hospital (Jones et al. (Freeman et al. 2016). Mask ventilation, how-
2016). ever, can be difficult over long periods of time,
Despite the urge of ensuring specialized pedi- especially in a moving vehicle (Bosch et al.
atric trauma treatment, a significant number of 2014; Freeman et al. 2016). Laryngeal airways
pediatric trauma transfers are preventable (Fenton are also frequently chosen alternatives because
et al. 2016). Fenton et al. recently showed that in they require minimal training, can be quickly
their trauma transportation cohort, 87% of the placed, do not require direct visualization, and
children were discharged within 24 h, demonstrat- may be easier to sustain than mask ventilation
ing that beside high transportation costs, often (Freeman et al. 2016).
little medical treatment is required for a consider-
able amount of patients, and the current triage
system needs to be optimized. Tools such as Circulation and Homeostasis
image-sharing networks and telemedicine pro-
grams may help to limit unnecessary transfers by Secure routes of intravenous (i.v.) access should
providing contact to pediatric trauma specialists at be in place as severely injured children or
neonates with congenital malformations may broad-spectrum antibiotics should be started if

experience abnormal loss of water, electrolytes, there is a risk of infection.
proteins, or blood, which must be replaced to
prevent hypovolemia and shock (Puri and
Doodnath 2011). Intravenous fluids (IVF) should Documentation
be started immediately and, if necessary, inotropic
catecholamines to maintain organ perfusion Following essential documents should be trans-
(Lloyd 1996; McHugh and Stringer 1998). ferred with the pediatric or neonatal patient: a
Trauma-induced hemorrhage is considered the copy of the children’s chart including the com-
main cause of preventable death in the first 24 h plete medical data and notes, all X-rays/ultra-
after admission (Garwe et al. 2016; Holcomb et al. sound/MRI/CT scans, laboratory reports, and
2011). Its management usually includes early nursing documentation (urine output, passage of
rapid intravenous fluid replacement at the site of stools, vaccination status, blood type, other med-
the accident and during transport to the trauma ication administration) (Puri and Doodnath 2011).
center (Garwe et al. 2016). However, a propen- In case that operative treatment is already
sity-adjusted survival analysis by Garwe et al. foreseeable, the parental consent for operation
showed neither a beneficial nor an adverse effect (signed by the mother if the parents are not
from prehospital IVF, and the authors concluded married) should be sent in case the parents can-
that time-consuming venous access and IVF not accompany their child. Also, contactable
maintenance should not be the reason for delay phone number of parents and hospital/ward
as their IVF patients had significant prolonged should be exchanged in case of urgent
scene, transport, and total prehospital times consultations.
(Garwe et al. 2016). A meticulous documentation of vital param-
Besides IVF, goal-directed resuscitative eters during transport is important as in certain
interventions such as early peripheral adminis- conditions (e.g., shock and traumatic head
tration of inotropic agents and correction of injury) unrecognized hypotension and/or hyp-
electrolyte abnormalities (including abnormal oxia are associated with increased morbidity
glucose and calcium levels) influence the out- and mortality (Hewes et al. 2016; Larsen et al.
come of critically ill children (Stroud et al. 2011; Zebrack et al. 2009). Heart rate; blood
2015). Additionally, maintenance of pulse oxim- pressure; pulse oximetry and, if required, Glas-
etry >95%, continuous measurement of vital gow Coma Scale; respiratory rate; and blood
signs, oscillometric blood pressure readings glucose should be assessed and documented in
every 3–5 min, and threshold age-adjusted pediatric transport. However, vital signs are far
heart rates maintenance are recommended too often documented infrequently (Drayna et al.
(Stroud et al. 2015). 2015; Hewes et al. 2016). Likewise, any kind of
In case of excessive fluid losses or IVF, a intervention during the transport procedure
urinary catheter helps to closely monitor the uri- needs to be documented (cardiopulmonary
nary output. Depending on the trauma in the pedi- resuscitation, medication, ventilation, i.v. place-
atric patient, but crucial for almost every neonate, ment, intravenous fluids, etc.).
an adequately sized and securely taped nasogas-
tric tube should be placed to prevent vomiting and
aspiration. It should be kept on open drainage, Transport Team
attached to a low-pressure suction pump aspirated
or suctioned frequently to prevent occlusion Although it is widely accepted that specific trans-
(Lloyd 1996). Glucose blood levels need to be port training is required for staff transferring neo-
monitored on a regular base and corrected if nec- natal and pediatric patients (Fenton and Leslie
essary (Puri and Doodnath 2011). Prophylactic 2009; Orr et al. 2009; Stroud et al. 2013), the
benefit of specialist transport teams remains con- associated with specific lesions (Puri and
troversial (Meyer et al. 2016b). Doodnath 2011). The staff should be familiar
Several studies found that transport morbidity with equipment on board and should be experi-
during high-risk transfers is reduced by having enced in stabilizing an infant or child in sub-
pediatric transport teams (PTT) on board due to optimal conditions.
fewer adverse events (e.g., improper endotracheal
intubation or loss of vascular access) (Calhoun
et al. 2017; Edge et al. 1994; Orr et al. 2009; Vehicles and Equipment
Ramnarayan et al. 2010). In contrast, Meyer
et al. found no significant difference in adjusted Transport Vehicles
48-h pediatric ICU mortality for children trans-
ported by pediatric transport teams (Meyer et al. The transport staff is constantly facing complex
2016b). Furthermore, a recent Cochrane analysis decisions from the time of the initial referral call
has shown that there is no credible evidence from as well as throughout transport and clinical care
literature-based randomized trials to support or for the child, with one of these decisions being the
confute the benefits of specialist neonatal trans- choice of the optimal transportation mode for each
port staff for neonatal outcome on morbidity and patient (Quinn et al. 2015).
mortality as there are currently no eligible trials to The mode of transport dependents on travel
compare (Chang et al. 2015). However, general distance, geography, weather conditions, ground
emergency medical services (EMS) often feel traffic, vehicle availability, size of the transport
uncomfortable treating children due to lack of team, the nature of the children’s problem, and the
skills/ knowledge/training which leads to stress need for speed (Messner 2011). One should be
and anxiety and, as a consequence, errors in med- aware that deterioration of the patient’s medical
ical treatment (Cushman et al. 2010). Moreover, it condition may be influenced by transport-related
has been stated that frequently adverse events and factors such as response and stabilization time or
near misses in the pediatric EMS environment, the transport vehicle (Borrows et al. 2010; Puri
mostly due to omission, are not reported (Cush- and Doodnath 2011; Ramnarayan et al. 2010).
man et al. 2010). Specific problems are related to Ground ambulances, rotary-wing aircraft (heli-
pediatrics, medication/calculation errors, proce- copters), and fixed-wing aircraft are currently
dural skill performance, unsuitable equipment popular conveyances. The level of clinical con-
size, parental interference, and omission of treat- cern in coherence with the perceived travel dis-
ment related to providers’ discomfort with the tance and potential respiratory or neurovascular
patient’s age (Cushman et al. 2010). problems have been found to significantly influ-
Children transported by pediatric transport ence the decision to mobilize a helicopter (Quinn
teams are usually younger and sicker (Calhoun et al. 2015). Interestingly, other clinical concerns
et al. 2017). Despite longer transport times, chil- such as heart rate, blood pressure, or perfusion
dren transported by PTT do not have an increased have not been found to be statistically significant
hospital length of stay or more adverse events factors in choosing a helicopter for interfacility
during transport (Calhoun et al. 2017). transfer (Quinn et al. 2015). If the concern is
Individual and local factors will determine lower, ground transport ambulances are chosen
whether the referring or receiving center sends more frequent, even if that means that the out of
the transport team. The composition of the team hospital time is prolonged. This circumstance is
members may also vary institutionally. Preferably, not necessarily a disadvantage as critical care
the transport team consists of a neonatologist/ transport teams are highly trained to deliver a
pediatrician/physician with pediatric experience wide range of life support measures and aggres-
and a trained neonatal/pediatric nurse familiar sive medical management on transport, even on
with and able to anticipate potential problems the road (Quinn et al. 2015).
Advances in aircraft design and technical tube cuff pressure (ETTCP) regularly exceeds
equipment allow now even mobile extracorporeal recommended pressure limits even at relatively
membrane oxygenation (ECMO) for critically ill low altitudes (but no additional pressure increase
children on board of modern rotator and fixed- related to cuffed endotracheal tubes size, Long et
wing aircrafts (Broman et al. 2015; Bryner et al. al. 2016; Orsborn et al. 2016), which potentially
2014; Holt et al. 2016). However, a major disad- has the risk of decreasing mucosal blood flow and
vantage of air transport is that additionally sepa- cause tracheal stenosis or rupture (Orsborn et al.
rate ground transport is necessary at both 2016). The ETTCP should be kept below
receiving and referring institution to move the 30 cm H2O as there is evidence that tracheal
child between airport and hospital. Exceptions mucosal perfusion is endangered when ETTCP
are those in which helicopter landing sites are exceeds 30 cm H2O and that the blood flow over
available at both centers. Vibration is not usually the tracheal rings and posterior tracheal walls is
detrimental to the patient but can dislodge lines absent when ETTCP exceeds 50 cm H2O
and tubes and adversely affect monitoring equip- (Orsborn et al. 2016; Seegobin and van Hasselt
ment (Gajendragadkar et al. 2000). Noise and 1984). Regular ETTCP checks before and during
vibration may cause distress and discomfort to transport are advisable as well as the use of saline
the patient, resulting in deterioration of the clini- instead of air for cuff blockage (Orsborn et al.
cal condition and may also complicate the moni- 2016).
toring of vital signs (Gajendragadkar et al. 2000; The benefit of air transport is controversial.
Puri and Doodnath 2011). Transport stretcher and Brown et al. postulated that helicopter EMS is
child should be securely strapped in case of tur- associated to improved survival compared to
bulence of the plane. Altitude effects on the chil- ground transport in pediatric trauma population
dren’s body can be detrimental (Jackson and (Brown et al. 2016). Other authors, however,
Skeoch 2009). With increasing altitude, the partial state that helicopter/air service is often overused
pressure of oxygen decreases; therefore, diffusion (Meyer et al. 2016a; Michailidou et al. 2014).
of oxygen across the alveolar membranes Stewart et al. found that ground versus helicopter
becomes more difficult, arising in decreasing oxy- transport type is not significantly associated with
gen saturation in the infant. To maintain the same survival, length of stay in the ICU, or discharge
level of oxygenation, a higher percentage of oxy- management (Stewart et al. 2015). In their study,
gen may be required. Moreover, the barometric helicopter EMS did not result independently in
pressure will also decrease with increasing altitude, better outcomes for pediatric trauma patients,
the volume of gas will increase, and any air trapped and moreover, they found that 22.3% of their
in a body cavity will expand, which could have children transported by helicopter EMS were not
a dramatic effect on pulmonary function, and small even significantly injured (Stewart et al. 2015).
insignificant air leaks can become dangerous (Puri
and Doodnath 2011). This is particularly vital in
the setting of pneumothoraces, pneumoperitoneum, Monitoring and Equipment
or intramural gas (Gajendragadkar et al. 2000). It is
therefore important to ensure that all air leaks are Due to impaired lighting, noise, vibration, and
drained, if possible (Puri and Doodnath 2011). space limitation, clinical evaluation of the
Medial staff operating in air travel should patient can be limited, and proper functioning
receive special training regarding the aircraft envi- monitor equipment is essential. Pulse oximetry,
ronment and also specific problems that they may hemodynameter (for invasive and noninvasive
encounter in safety, logistics (landing sites), or measures of arterial pressure), electrocardio-
airborne environment (Fenton and Leslie 2009). graph (ECG), thermometer, and pressure trans-
Personnel serving air transport need to consider ducers for central venous and intracranial
the influence of altitude on cuff pressure. Two pressure must be on board. There is often no
recent studies found that the cuffed endotracheal electrical connection available while travelling,
Table 1 Transfer equipment for neonatal and pediatric An increasing importance has the so-called
transports family-centered care during the transport proce-
Adequate-sized transport stretcher or transport incubator dure (Joyce et al. 2015; Mullaney et al. 2014).
Monitors – ECG, blood pressure, pulse oximeter, Parental accompaniment has been found to be
respiratory frequency, temperature emotionally beneficial to the child, reduce separa-
Infusion pumps
tion anxiety and parental anxiety, and improve
Resuscitation drugs and equipment
parental satisfaction and child cooperation during
Supply for respiratory support: bags and masks, portable
oxygen supply, ventilator, oropharyngeal airways, cuffed procedures (Joyce et al. 2015; Macdonald et al.
and uncuffed endotracheal tubes 2012; Piira et al. 2005). Physicians involved in
Portable nitric oxide supply transport of sick children should be educated in
Thorax drainage sets family-centered care.
Urinary catheters Schwartz et al. recently evaluated quality met-
Broad-spectrum antibiotics rics for pediatric and neonatal critical care trans-
Blood glucose monitoring device port (Schwartz et al. 2015). Identified as very
Document folder with all relevant information of patient important were “unplanned dislodgement of ther-
and parents
apeutic devices, verification of tracheal tube
Maps/navigation system
placement, average mobilization time of the trans-
Mobile telephone
port team, first-attempt tracheal tube placement
(Adopted from Puri and Doodnath (2011)
success, rate of transport-related patient injuries,
rate of medication administration errors, rate of
and monitors and syringe pumps must be able to patient medical equipment failure during trans-
run on battery (McHugh and Stringer 1998). An port, rate of cardiopulmonary resuscitation
appropriate stock of airway and ventilatory performed during transport, rate of serious report-
equipment (self-inflating resuscitation bags, able events, unintended neonatal hypothermia
masks, airways, laryngoscopes, cuffed and upon arrival to destination, rate of transport-
uncuffed endotracheal tubes of various size, related crew injury, and the use of a standardized
humidifiers, portable suction apparatus, oxygen patient care hand-off” (Schwartz et al. 2015).
supplies, etc.) as well as i.v. supplies, Everyone involved in the transport procedure
intraosseous needles, chest tubes, umbilical should bear these cachets in mind whenever trans-
catheter kits, and emergency drugs should be ferring patients to assure good transfer
present at any time (Puri and Doodnath 2011). management.
Table 1 lists necessary transfer equipment for Any incident during transfer must be reported
neonatal and pediatric transports. Figure 1 shows and critically reviewed as this can reduce the
an emergency kit containing drugs and medical number of adverse events during transport of
aids for pediatric and neonatal transport. sick children by providing staff training and
implementation of guidelines for maintenance
readiness of equipment (Moss et al. 2005).
Transport Procedure
A good transfer requires early and effective com- Receiving Center

munication between the referring and specialist
center, stabilization of the patient before the trans- On arrival at the receiving center, a brief report for
fer, and preparation of special needs and care the reason of transport (accident, operation, con-
during transport (Lloyd 1996) to avoid prevent- genital malformation, clinical deterioration of pre-
able adverse events such as vomiting with aspira- existent disease, etc.), transport problems, or
tion, airway obstruction, hypovolemia, or adverse events while travelling as well as the
hypothermia (Puri and Doodnath 2011). Prefera- current status of vital sign parameters should be
bly, transfer is arranged at a senior level. given by the transport team to the receiving care
Fig. 1 Emergency kit

containing emergency
drugs, intravenous fluids,
tubes, needles, cannulas,
and catheters. The shown
equipment is property of the
National Neonatal
Transport Programme
Ireland (NNTP) (Picture
taken with permission of
NNTP)
unit staff. For neonatal transport, also data of

prenatal reports, labor, delivery, and details of Special Considerations for Neonates
the newborn’s resuscitation need to be added
(Puri and Doodnath 2011). The accompanying Prenatal Transfer
transport physician should evaluate the patient
and all documents together with the accepting The best and safest way to care for both mother
surgeon and neonatologist/pediatrician or anes- and the newborn is the transfer of the pregnant
thetist, if necessary. Foronda et al. reviewed the woman to a high-risk perinatal center before
importance of an accurate handover after transport delivery (Messner 2011). This involves especially
of severely ill children as communication failure high-risk fetus such extremely preterm and very
and human factors (professional hierarchies, lack low birth weight fetuses and those with life-threat-
of teamwork, role ambiguity, differences in ening neonatal surgical problems (Puri and
values) are serious factors for detrimental health Doodnath 2011). Another special problem of
outcomes. The authors highlighted that during these high-risk babies is hypothermia as it
handover and also during transfer, specialized adversely affects the neonatal outcome and
teams using standardized communication (includ- seems to be an independent predictor of mortality
ing handover tools and mnemonics) can improve (Goldsmit et al. 2012; McCall et al. 2008; Puri and
the patients’ outcomes, transport costs, and pro- Doodnath 2011).
vider satisfaction likewise (Foronda et al. 2016).
The parents should be introduced to all staff
who will be involved in the care of their child. Neonatal Transfer
Every procedure should be explained in a clear
and comprehensive language to avoid confusion Transport of a surgical newborn to a tertiary center
and parental fear. If necessary, the consent form for specialized pediatric surgical care may
should be updated. Further examinations (blood become necessary if a prenatal transfer is not
tests, imaging procedures) can be ordered feasible, the child’s surgical condition is prena-
subsequently. tally unknown, or the neonate develops the
surgical emergency postnatally. Table 2 lists neo- neonates suffer deterioration during transport
natal conditions requiring transport to a tertiary regardless their clinical status, resulting in a
center for surgical care. Figure 2 shows higher risk of early neonatal mortality
gastroschisis in conjoined twins. (Goldsmit et al. 2012). Therefore, precaution
Transferring a newborn without proper sta- and careful attention to pre-transfer manage-
bilization is associated with increased morbidity ment will provide a higher safety margin during
and mortality, and therefore no neonate should the transport, especially as the vehicle environ-
be transported without sufficient resuscitation to ment is usually noisy, and the access to the
survive the journey (Puri and Doodnath 2011). patient is restricted, leading to potential diffi-
Nevertheless, a high percentage of referred culties in providing adequate treatment should
problems arise (Lloyd 1996). For neonates, the
usage of inhaled nitric oxide on the road as well
Table 2 Neonatal surgical conditions requiring transport
as high-frequency oscillation ventilation has
to a tertiary center for operative care
been shown to be feasible and safe (Chassery
Congenital diaphragmatic hernia
et al. 2015; Lowe and Trautwein 2007; Mainali
Choanal atresia
et al. 2007). To assure an optimal neonatal
Esophageal atresia with tracheoesophageal fistula
transport by guiding accompanying doctors
Airway and pulmonary malformations
Cardiac defects
and operating the equipment, some institutions
Gastroschisis
use advanced neonatal nurse practitioners
Omphalocele (ANNPs) or have formed a special nursing
Gastrointestinal obstruction and perforation transport team (Fenton and Leslie 2009; Leslie
Necrotizing enterocolitis and Stephenson 1997).
Hirschsprung’s disease For good documentation and referral practice
Anorectal malformation in newborns, it should be clearly stated whether
Bladder exstrophy and how much vitamin K was administered. A
Cloacal exstrophy sample of maternal blood should be sent along
Spina bifida for cross-matching as well as a cord blood speci-
Cervical and sacrococcygeal teratomas men and a copy of maternal records (including
Birth trauma complete maternal history, labor, and delivery
Conjoined twins records) (Puri and Doodnath 2011).
Fig. 2 Conjoined twins

with gastroschisis
Temperature Regulation temperature of 15 C/59 F (Koch 1999). Cardio-

respiratory monitor, pulse oximeter, oxygen ana-
Neonatal thermoregulation requires critical atten- lyzer, oxygen and air cylinders, infusion pump,
tion. Hypothermia causes an increase in the neo- double plexiglass walls, and shock-absorbing
nate’s metabolic rate with a subsequent increase in wheels must be commercially provided (Puri and
glucose and oxygen use ensuing acidosis, and if Doodnath 2011). In the case of transporting very
not reversed, persistent pulmonary hypertension sick neonates and preterm babies, ventilation may
of the neonate develops (Puri and Doodnath be required. In these cases, the incubator should
2011). Unlike older children and adults, neonates be equipped with a mechanical ventilator which is
are unable to maintain thermogenesis through time-cycled, pressure-limited, and capable of
shivering. Their heat-producing mechanism is delivering conventional ventilations and constant
limited to metabolism of brown fat and peripheral positive airway pressure (Koch 1999). When
vasoconstriction (Gillick and Puri 2009; McCall securing the neonate in the incubator, one must
et al. 2008). Hypothermia with a core body tem- keep in mind the infant’s size, the extreme sensi-
perature below 36.4 C (97.5 F) is associated to tivity of preterm skin, the reduced muscle tone,
increased neonatal mortality, which can be low body profile, and body weight distribution.
avoided by warming the baby to a core tempera- Figure 3 shows a modern transport incubator
ture of at least 36.5 C and using a pre-warmed system including equipment for ventilation, deliv-
transport incubator in a pre-warmed ambulance ery of nitric oxide, cooling, suction, and infusion.
(McCall et al. 2008). Hypothermia may also Special ambulances have space for one or two of
occur as a sign of infection and must implicate these transport systems, providing optimal trans-
diagnostic evaluation and antibiotic treatment if port for sick neonates (Fig. 4),
required (Gillick and Puri 2009). On the other
hand, one should also avoid hyperthermia above
37 C (98.6 F) as it correlates with perinatal Conclusion and Future Directions
depression and hypoxic brain injury (Gillick and
Puri 2009). The main challenge for health-care providers
dealing with the pediatric population is its unique
subset consisting of neonates, infants, toddler,
Transport Incubators school-aged children, and adolescents, and there-
fore “age-appropriate” skills and equipment is
Standard requirements for transport incubators are mandatory. The care management of injured chil-
established in an international standard (Interna- dren and high-risk newborn has changed consid-
tional Electrotechnical Commission 2009; Koch erably in the last decades. Improvements in
1999). An incubator is a central piece of equip- therapeutic interventions and transport vehicles
ment that has to provide warmth, visibility, and as well as equipment and education have contrib-
access. Every incubator must be able to maintain a uted to the opportunity to deliver critical care in
specific temperature under a variety of different the field (Stroud et al. 2015). Every child with a
ambient conditions (e.g., 15 C/5 F to 28 C/ serious condition requiring transport to a special-
82 F) (Koch 1999). The patient compartment of ized hospital must be assessed and stabilized by
the transport incubator is usually equipped with a experienced staff prior to and during transport as
front flap for loading for good access to the neo- adequate stabilization before transport is associ-
nate in the event of an emergency (Koch 1999). ated with reduced morbidity and mortality. Bring-
Incubators should be able to run on batteries and ing the facilities of the intensive care unit
must be equipped with a recharger. Guidelines management to the patient’s bedside during trans-
state that the energy of the battery should be port should be the overall aim of every transport.
sufficient for a minimum of 90 min in an ambient Ongoing assessment and improvement in
Fig. 3 Transportable
incubator system with
monitor, ventilator, nitric
oxide delivery system,
humidification, suction,
cooling, and infusion
pumps. The shown
equipment is property of the
National Neonatal
Transport Programme
Ireland (NNTP) (Picture
taken with permission of
NNTP)
Cross-References
▶ Anatomy of the Infant and Child

▶ Fluid and Electrolyte Balance in Infants and
Children
▶ Pediatric Airway Assessment
▶ Pediatric Cardiovascular Physiology
▶ Perinatal Physiology
▶ Pediatric Respiratory Physiology
▶ Specific Risks for the Preterm Infant
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Pediatric Respiratory Physiology
11
Bettina Bohnhorst and Corinna Peter
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Embryonic Phase (Until Eighth Week
of Gestation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Pseudoglandular Phase (5th–17th
Week of Gestation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Canalicular Phase (16th–26th Week of Gestation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Saccular Phase (24th Week of Gestation
Until Birth) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Alveolar Phase (36th Week of Gestation to
18 month–4 years Postnatal) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Prenatal Development of the Pulmonary Surfactant System . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
The Role of Lung Fluid and Fetal Breathing
Movements in Lung Organogenesis
and Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Physiology of Transition from Intra- to Extrauterine Life . . . . . . . . . . . . . . . . . . . . . . . . . 187
Respiratory Physiology of the Neonatal Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Pulmonary Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Pulmonary Gas Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Lung Volumes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Airway Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Lung Compliance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Respiratory Distress Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
Clinical Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
X-Ray Findings in RDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Prevention/Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
B. Bohnhorst (*) · C. Peter

Department of Pediatric Pulmonology, Allergology and
Neonatology, Hannover Medical School, Hannover,
Germany
e-mail: bohnhorst.bettina@mh-hannover.de;
peter.corinna@mh-hannover.de

https://doi.org/10.1007/978-3-662-43588-5_12
182 B. Bohnhorst and C. Peter
Persistent Pulmonary Hypertension of the Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196

Etiology of PPHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
Diagnosing PPHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
General Management of PPHN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Specific Medical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
Abstract Introduction
This chapter provides information about
structural and biochemical lung develop- Lung architecture consists of two multiple-
ment, which starts as early as the fifth week branched, treelike systems, the airways, and the
of gestational age but can last up to 4 years vasculature, which develop in a well-coordinated
postnatally. During the intrauterine period, way from the primary lung bud to the final gener-
fetal breathing movements and lung fluid are ation of millions of alveolar gas exchange units. In
essential factors for regular lung maturation contrast to other organs like the brain or heart,
and growth. Transition from intrauterine to which develop and begin their functions early in
extrauterine life is a critical phase, during fetal life, the lung starts its process of differentia-
which clearance of lung fluid and lung expan- tion and function during the second half of preg-
sion due to air filling on the one hand and nancy. Whereas histological changes during lung
establishment of pulmonary blood flow due development are well described, genetic and cel-
to a marked reduction of pulmonary vascular lular mechanisms controlling lung development
resistance on the other hand are the key fea- are complex and yet partially understood
tures of this process. In contrast to older (Morrisey and Hogan 2010). Five phases of lung
infants and adults, respiratory physiology of development are distinguished. The boundaries of
neonates is characterized by a relatively small these phases are not precise: at any time, there
airway diameter enhancing airway resistance, may be a substantial difference of development
a higher chest wall compliance, and weakness between distinct areas of the lung and, moreover,
of respiratory muscles, making the newborn a significant variability between individuals. The
much more vulnerable to respiratory failure. subsequent description of lung development is
Dysfunctional transition may result in respi- illustrated in Fig. 1.
ratory distress and persistent pulmonary
hypertension, both of them still being impor-
tant causes of morbidity and mortality. Their Embryonic Phase (Until Eighth Week
present-day management includes prenatal of Gestation)
steroid treatment, intratracheal surfactant
application, mechanical ventilation, and a The respiratory system emerges from the ventral
differentiated medical therapy. wall of the anterior foregut. Approximately on day
28, the two primary lung buds appear. At the same
time the single foregut tube separates into a dorsal
Keywords esophagus and a ventral trachea. The two primary
Lung development · Surfactant system · lung buds extend into the surrounding mesenchyme
Transition to extrauterine life · Neonatal and then start division. On day 32 five lobar buds
respiratory physiology · Respiratory distress · (three on the right, two on the left side) exist which
Pulmonary hypertension further develop into the mature lung lobes. The
11 Pediatric Respiratory Physiology 183
Fig. 1 The five phases of lung development
branching process proceeds, and by the seventh widening of existing airways, further branching
week of gestation, the subsegmental branches of does not happen. As the name suggests, the lung
the airways have already been established. At that looks like a gland during the pseudoglandular
time, the development of the vascular components phase. The tubules are coated with a single-layered
of the lungs is initiated as well. The pulmonary epithelium. At the tenth week of gestation carti-
arteries originate from the ventral part of the sixth lages, smooth muscles and small glands appear in
aortic arch, and the pulmonary veins grow out of a the walls of the bronchial tubes. The respiratory
dorsal bud of the commune atrium of the developing epithelium begins to differentiate, and cilia emerge
heart. During the further development, the pulmo- in the proximal airways. In general, the airways
nary arteries always follow the airways, whereas the differentiate in a centrifugal direction.
pulmonary veins will grow in the septa of the con-
nective tissue.
Canalicular Phase (16th–26th Week
of Gestation)
Pseudoglandular Phase (5th–17th
Week of Gestation) The characteristic feature of the canalicular phase
is the approach of epithelial tubuli and pulmonary
Due to repeated dichotomous branching, conduc- capillaries. By vigorous growth of capillaries, the
tive airways and the associated pulmonary arteries mesenchyme is penetrated by a network of canals,
are formed, resulting in 16–25 generations of prim- originally giving this phase its name. Today, the
itive airways at the end of this phase. Thereafter, term is deduced from the widening of the tubuli
additional growth occurs only by elongation and into canaliculi. This process congests the
surrounding mesenchyme resulting in a close con- At the time of birth, the lung does not consist of
tact between canaliculi and capillaries. Simulta- mature alveoli but of approximately 200 million
neously, differentiation of the primitive epithelial terminal sacculi. These differentiate into the
cells into flat type I (representing the blood-air 300–600 million alveoli finally completing lung
barrier and being ultimately responsible for gas development.
exchange) and cuboid type II pneumocytes (sur-
factant synthesis) starts. This phase of lung devel-
opment is particularly important, because at the Prenatal Development
end of this period, the lungs are enabled to per- of the Pulmonary Surfactant System
form gas exchange to a limited extent giving the
fetus the chance of viability. Pulmonary surfactant is a lipoprotein mixture,
uniquely located at the air-liquid interface of the
lung. Its functions include both reduction of inter-
Saccular Phase (24th Week of Gestation facial surface tension depending on the lung vol-
Until Birth) ume to prevent lung collapse and to reduce work
of breathing, as well as inhibiting and inactivating
During this phase a substantial increase of lung environmental pathogens.
parenchyma and a remarkable change in the Surfactant consists of 90% lipid components,
appearance of the lungs occur. Connective tissue mainly phospholipids (80–85%) and cholesterol,
becomes less prominent, the airspace increases and 10% protein components (Haagsman and van
considerably, and the airspace walls undergo a Golde 1991). Phosphatidylcholine (PC) with its
significant thinning. The distal airspaces divide disaturated molecular species dipalmitoylphos-
into saccules which by and large are the last gen- phatidylcholine (DPPC) is the predominant phos-
eration of the airway branch. The walls of the pholipid. The protein component contains four
airspaces correspond to the primary septa. At the surfactant proteins: surfactant protein-A (SP-A),
end of this phase, the first alveoli emerge. Usually, SP-B, SP-C, and SP-D. Surfactant is produced
preterm infants born during the early saccular and secreted by type II alveolar cells. SP-A regu-
phase can be sufficiently oxygenated with some lates the uptake of phospholipids into type II cells
kind of ventilatory support. After 34 weeks of and surfactant secretion. Both SP-A and SP-B are
gestation, in most cases the infant is able to sustain responsible for the formation and the structural
itself with oxygen. integrity of surfactant components. The hydro-
phobic proteins SP-B and SP-C interact inten-
sively with the lipids and promote the formation
Alveolar Phase (36th Week of Gestation of surfactant layers and their adsorption to the
to 18 month–4 years Postnatal) air-liquid interface. The hydrophilic proteins
SP-A and SP-D are mainly responsible for the
The development of alveoli starts – a process that innate host defense system of the lung by both
will continue for months to years after birth. The directly killing microorganisms or by enhancing
alveoli emerge by further division of the primary the uptake of pathogens by phagocytes (Orgeig
septa into secondary septa, which form the barrier et al. 2010).
for gas exchange and are only a few nanometers The phospholipids and the proteins are synthe-
thick. This barrier consists of three layers: the thin sized in the endoplasmic reticulum, then modified
process of the type I pneumocytes, both the basal by the Golgi apparatus, and finally stored in the
membrane of the pneumocytes and the endothelial lamellar bodies (see Fig. 2). The lamellar bodies
cells of the capillaries, and the thin extensions of are released into the liquid lining the alveoli by
the endothelial cells. With ongoing maturation, exocytosis across the cell plasma membrane.
each capillary is simultaneously attached to at Thereafter they morph into a grid structure called
least two alveoli. tubular myelin, which provides the lipids for the
Fig. 2 Surfactant synthesis
surface film. Due to the amphipathic nature of the Maturation of the surfactant system is mainly
phospholipid molecules (one hydrophilic and one controlled by mechanical forces and neurohor-
hydrophobic end each), they adsorb to the monal factors. Mechanical forces include lung
air-liquid interface forming a surface layer that distension by lung liquid and fetal breathing
lowers the surface tension. Compression of that movements (see below), the most important neu-
film results in further reduction of the surface rohormonal factors are cortisol, thyroid hor-
tension, because the phospholipid molecules are mones, and adrenergic agonists (Mendelson and
insoluble and thus packed more densely, therefore Boggaram 1991).
facilitating an adequate regulation of surface ten- In general, cortisol is the major regulatory hor-
sion. Approximately 90% of the secreted phos- mone for terminal maturation of the fetus and
pholipids are reabsorbed by the type II prenatal preparation for birth. During the first
pneumocytes and reutilized for further surfactant and second trimester of pregnancy, the main
synthesis. source of fetal cortisol is the mother; while in the
The pulmonary surfactant system is one of the last trimester, the fetus is able to synthesize and
last systems to develop before birth (Orgeig et al. release cortisol under fetal hypothalamic control
2011). Both SP-B and SP-C proproteins and their which results in a considerable increase of cortisol
mRNA are detectable in human lung tissue in the levels.
25th week of gestation, SP-D and its mRNA even With respect to surfactant maturation, cortisol
as early as the 16th week. In fetal lung tissue, specifically induces phospholipid synthesis. Fur-
lamellar bodies are sporadically found after the thermore, cortisol directly stimulates the type II
20th week of gestation and regularly after the 24th pneumocyte to release surfactant, which drasti-
week. DPPC appears at low levels in amniotic cally elevates the surfactant concentration in the
fluid between 24 and 28 weeks of gestation. The alveolar compartment. This effect is utilized in
surfactant proteins SP-A and SP-B appear after case of imminent preterm birth.
30–31 weeks for the first time. Although the sur- As with cortisol, the levels of thyroid hor-
factant system undergoes a maturation process mones and adrenergic agonists increase as term
until term at 40 weeks, preterm infants often approaches. Regarding surfactant maturation, T3
have sufficient amounts of surfactant to warrant and T4 act synergistically with glucocorticoids by
gas exchange as from the 24th week of gestation. particularly enhancing the lipid components of
surfactant and stimulating surfactant secretion of Human fetal breathing movements (FBMs)
type II pneumocytes. Adrenergic agonists contrib- were first observed over 120 years ago once rhyth-
ute to surfactant maturation by increasing the syn- mical fetal movements transmitted through the
thesis of SP-A, -B, and -C and enhancing choline maternal abdominal wall were described and pre-
incorporation into phospholipids resulting in sumed to correspond to FBMs (Boddy and
increased surfactant phospholipid synthesis. Mantell 1972). It was, however, only after
At term birth, the type II pneumocytes of the decades that this phenomenon was proven when
fetus contain much more surfactant than the adult the technique of ultrasound became available.
lung, and this surfactant is provided for release at FBMs are characterized by rhythmic contrac-
delivery. The initiation of breathing after birth tions of the diaphragm, intercostal, and laryngeal
causes mechanical stretch, thus deforming the muscles. FBMs intermittently reduce intratho-
type II cells, and this triggers surfactant release. racic pressure hence expanding the fetal lung.
They usually occur during the second half of
pregnancy but have been detected as early as
The Role of Lung Fluid and Fetal tenth week of gestation (de Vries et al. 1986).
Breathing Movements in Lung First, FBMs occur as single isolated movements
Organogenesis and Growth and escalate to episodes of more clustered events
later on. During gestation, intensity of FBMs
At the end of the nineteenth century, it became increases. Normally, in the third trimester of preg-
evident that the fetal lungs are filled with a fluid nancy, FBMs are present within 50–70% of the
in utero. It was erroneously believed far into the time with a pronounced diurnal variation reaching
twentieth century that the liquid was inhaled a peak in the evening and a minimum in the early
amniotic fluid. However, the following three hours of the morning (Dawes 1974). With accel-
findings led to the conclusion that fetal lung erating gestational age, both inspiratory and expi-
liquid is created by an active secretion of the ratory displacement of the fetal abdominal wall
lung itself (Olver et al. 2004): (1) the presence increases just as the inspiratory and expiratory
of lung fluid despite of congenital airway atre- velocities do. Despite of the age-dependent
sias, (2) the fact that the introduction of a radi- change of fetal breathing patterns, the frequency
opaque contrast medium into the amniotic cavity of FBMs does not vary over time and ranges
was not associated with its subsequent appear- between 40 and 70/min (Florido et al. 2005).
ance in the fetal airways, and (3) the difference The changing pattern of FBMs with ongoing
in the composition of lung fluid in comparison to pregnancy is believed to result from maturation of
amniotic fluid. Meanwhile, it is taken for sure the respiratory neural control. Since the possibil-
that the production of lung fluid is induced by an ity to study the human fetus is limited, most
active chloride transport into the lung lumen by knowledge about prenatal respiratory control is
alveolar type II cells. Sodium follows passively derived from animal experiments. A restricted
and fluid flows to balance the osmotic gradient. area of the medulla containing the pre-Bötzinger
Lung liquid is more viscous than amniotic fluid, complex is necessary for generating respiratory
thus keeping the lungs free of the later. Lung rhythm in utero as well as later in life (Greer
fluid is present as early as the sixth week of et al. 2006). Besides, fetal breathing is responsive
gestation, and secretion reaches its peak in the to chemical stimuli and agents affecting postnatal
third trimester (McCray et al. 1992). During the breathing. Fetal breathing can be stimulated by
last weeks of gestation, the lung liquid volume high levels of carbon dioxide (CO2) especially in
reaches a level which is considerably greater a behavioral state which corresponds to REM
than the analogous level of the functional resid- sleep in children and adults. With ongoing preg-
ual capacity of the lung after birth. Shortly nancy the threshold of CO2 which stimulates
before birth a decline in lung liquid volume breathing declines, thus preparing the fetus for
already occurs. breathing after birth. Another potent stimulus of
fetal breathing is external cooling. Therefore, the in case of CDH results in an accumulation of lung
triggers for breathing after birth already work fluid and subsequently lung expansion (Ruano
during fetal life (Darnall 2010). et al. 2012). However, the effect is limited if
In contrast to postnatal breathing, decreasing further lung expansion is impossible because the
PO2 inhibits rather than stimulates fetal breathing, available intrathoracic space is already occupied
a phenomenon which is called fetal hypoxic by herniated viscera.
depression. In preterm infants the fetal response In general, it is not completely clarified
to hypoxia might persist leading to the well- whether hypoplastic lungs will attain a normal
known apnea of prematurity. It is presumed that structure during postnatal life, but there is quite
the activation of adenosine receptors contribute to some evidence that these lungs will be perma-
the hypoxic inhibition of fetal breathing. There- nently impaired.
fore, the administration of adenosine receptor Besides the impact described above, FBMs
antagonists such as caffeine stimulates FMBs – a affect pulmonary development by influencing
major treatment used in apnea of prematurity as lung epithelial cell differentiation. In fact, it is
well (Mathew 2011). Finally, fetal breathing is well known that mechanical stress generated by
abolished or reduced by maternal anesthesia or the fetus plays a role in how differentiating tis-
sedation. sues respond to gene instructions. The expres-
For adequate lung development and structural sion of growth factors, as, e.g., platelet-derived
maturation, a high level of lung distension in the growth factors (PDGFs), insulin-like growth
fetus is apparently necessary which is achieved by factors (IGFs), and thyroid transcription factor
both the presence of lung fluid and FBMs. 1 (TTF-1), which are relevant mediators of lung
Lung liquid is secreted against a resistance organogenesis, is upregulated by rhythmic
provided by the upper respiratory tract (URT), mechanical stretch. In contrast, insufficient
therefore generating a pressure which is FBMs lead to reduced expression of these
2–3 mmHg above amniotic fluid pressure and growth factors resulting in disturbed lung cell
acting as an expanding force to stretch the lung cycle kinetics, i.e., decreased cell proliferation
and stimulate growth (Olver et al. 2004). There is and increased cell death. Besides, in the absence
evidence that change in volume is a more influen- of FBMs, the type I pneumocyte is unable to
tial prerequisite for optimal lung growth than flatten, thus hampering sufficient gas exchange,
change in pressure. Changes in the resistance of and type II pneumocytes are not able to compile,
the URT associated with FBMs play a major role store, and release surfactant (Inanlou et al.
in controlling the amount of lung fluid. The rela- 2005).
tively high level of lung liquid volume is
maintained because the pulmonary recoil pressure
is opposed by the resistive effect of the URT Physiology of Transition from Intra- to
during apnea and by rhythmic contractions of Extrauterine Life
the diaphragm during FBMs, respectively
(Harding and Hooper 1996). Reductions of lung Since the fetal lung is not at all concerned with gas
expansion lead to lung hypoplasia, composed of exchange, only 10% of the right ventricular output
reduced lung volume and structural impairment. pass through the lungs, the remainder being
Lung hypoplasia is based on a lack of FBMs, shunted to the left ventricle and the aorta via the
reduced intrathoracic space, or a combination of foramen ovale and the ductus arteriosus,
both of them. The reasons for diminished lung respectively.
expansion include neuromuscular disorders, Accordingly, the pulmonary vascular resis-
which cause respiratory muscle fatigue, pleural tance (PVR) is high in utero. Therefore, establish-
effusions, skeletal dysplasia, oligohydramnios, ment of functional residual capacity (FRC) and
and congenital diaphragmatic hernia (CDH). The pulmonary blood flow are crucial for normal
surgical procedure of fetal tracheal occlusion used transition.
To establish FRC, the newborn has to accom- during inspiration and a marked positive pressure
plish three procedures: clearance of lung fluid, (mean about 70 cmH2O, range 18–115 cmH2O)
expansion of the lungs with air, and prevention during expiration by exhaling against a closed
of lung collapse. glottis (Vyas et al. 1986). This facilitates the estab-
The precise mechanisms of lung fluid clear- lishment of the FRC. In healthy infants, the mean
ance are yet incompletely understood, although volume of the first breath is about 40 ml, and a
fundamental factors seem to be clarified. With considerable FRC with a mean of 10–15 ml is
onset of labor, the clearance of lung liquid is generated in this way, reaching the normal value
induced by mechanical forces. The limited intra- of 30 ml/kg body weight within 2–3 h. Addition-
uterine space will cause a high pressure on the ally, there is a post-inspiratory activity of the
chest wall and increase transpulmonary pressure respiratory muscles, which counteracts the pas-
leading to a loss of lung fluid of approximately sive recoil of the lungs and the chest and therefore
50%. Furthermore, labor increases the release of helps to maintain FRC. Simultaneously, recruit-
cortisol, thyroid hormones, and fetal adrenaline, ment of surfactant to the air-liquid interface
which cause a stop of the chloride depending fluid reduces the surface tension, sustaining FRC and
secretion by the alveolar type II cells and stimu- preventing lung collapse. The residual amount of
lates them to reabsorb fluid by activating Na + lung liquid which still fills the airways after birth
channels (Te Pas et al. 2008). is cleared by the transpulmonary pressure gener-
After delivery, an amount of 25–33% of lung ated by the first breath, which causes a shift of
fluid will be ejected through mouth and nose. The lung liquid from the airways into the interstitium
mechanism is presumably the high compression and subsequent removal by the pulmonary circu-
of the fetal chest during progression through the lation and lymphatic vessels. Moreover, the rise in
distal part of the birth canal, the so-called vaginal alveolar PO2 stimulates the activation of Na +
squeeze. When delivery occurs before onset of channels resulting in further absorption of lung
labor, i.e., in case of cesarean section, these mech- fluid.
anisms are virtually absent, resulting in greater The average respiratory rate immediately after
liquid retention within the lungs and being the birth is 60/min (range 24–106), remains constant
explanation for the increased respiratory morbid- for a few hours, and gradually declines to values
ity seen in those infants. of 40/min (range 32–48) after 1 day.
Breathing undergoes a transition at birth from During fetal life, oxygen saturation (SpO2) is
an intermittent process in the fetus to a continuous about 60–70% and can drop to values as low as
one in the newborn. Animal studies suggest that 30% during birth process without developing aci-
the initiation and maintenance of continuous dosis. Within the first minute after birth, SpO2 is
breathing after birth is mainly due to a drop in about 60% with a lower range of 30% even in
body temperature and an elevation of PCO2 after healthy, term infants and increases steadily to
cord clamping (Kuipers et al. 1997). The first values above 90% within 8 min (range
breath after birth usually appears within 10–18 s 5–10 min) (Dawson et al. 2010). In infants born
(range 0.5–72 s). by cesarean section, saturations are 2–3% lower
Because there is no elastic recoil of the chest compared with infants born vaginally, and there is
wall after birth, only little passive inflation of the an almost 2 min delay in reaching a SpO2 above
lungs appears, and the first breath requires an 90%. This knowledge is important to avoid
active effort of the infant, which mainly consists unnecessary administration of oxygen after birth.
of a contraction of the diaphragm (Saunders and In the healthy newborn, the normal SpO2 value,
Milner 1978). Accordingly, the pressure gradient i.e., 97–100%, is reached within a few hours after
between oral cavity and alveoli provides the gas birth.
entry into the lungs. During first breath, the baby Establishment of pulmonary blood flow is
produces a large negative intrathoracic pressure accompanied by dramatic changes in the circula-
(mean about 50 cmH2O, range 28–105 cmH2O) tory system. Compared with small pulmonary
arteries in postnatal life, comparable arteries dur- phosphorylation and release of ATP. NO itself
ing fetal life have a more cuboidal endothelium initiates rapid vasodilation by stimulating the sol-
and a pronounced medial smooth muscle coat in uble guanylate cyclase in the smooth vascular cell
relation to the external diameter. This structural and thus converting GTP into cGMP. The increase
pattern is assumed to be responsible for the of intracellular cGMP induces a decrease of Ca++
increased vasoreactivity and the high PVR of the influx and therefore a relaxation of the smooth
fetus (Lakshminrusimha and Steinhorn 1999). vascular cell (see Fig. 3, right).
The mediator of this high pulmonary vascular Prostacyclin (PGI2) is the most potent of the
tone is mainly a low oxygen tension (approximate prostaglandins and is generated by the enzyme
30–50 Torr, depending on gestational age and cyclooxygenase (COX) from arachidonic acid.
whether the oxygen tension is measured in the PGI2 activates the enzyme adenylate cyclase,
umbilical vein or umbilical artery (Nicolaides which converts ATP to cAMP. The increase of
et al. 1989)) promoting synthesis of platelet- cAMP also results in a relaxation of the smooth
activating factor (PAF) and endothelial-released muscle cells by decreasing the Ca++ influx (Gao
vasoconstrictors, the most important one being and Raj 2010).
endothelin-1 (ET-1), a potent vasoactive peptide, Pulmonary vasodilation leads to rapid struc-
which bonds with the ETA receptor of the vascular tural changes of the pulmonary microvasculature
smooth muscle cells. Anyway, vasoconstriction is with significant thinning of the vessel walls, a
achieved by elevating intracellular Ca++ concen- flattening of the endothelial cells, and a widening
tration and sensitizing myofilaments to Ca++ (Gao of the lumen. Later on, the dilation is followed by
and Raj 2010). Vasoconstriction is further a reduction of the musculature, a process which
maintained by low basal secretion of vasodilators continues over several weeks (Hall and Haworth
like nitric oxide (NO) and prostacyclin (PGI2) (see 1987).
Fig. 3, left). Pulmonary vasodilation results in a nearly ten-
By clamping the cord, the infant is cut off from fold increase of pulmonary perfusion within a few
the low-resistance placental vascular bed. Accord- minutes. The enhanced pulmonary venous return
ingly, the systemic vascular resistance suddenly with a rise of the left atrial pressure above the right
rises, hence facilitating closure of the foramen atrial pressure further promotes closure of the
ovale. Cessation of the blood flow through the foramen ovale. Increase of pressure in the sys-
umbilical vein causes a collapse of the ductus temic circulation on one hand and decrease of
venosus. The onset of air breathing is accompa- pressure in the pulmonary circulation on the
nied by a marked increase of oxygen tension other hand reverse the blood flow through the
leading to vasodilation of the pulmonary vessels ductus arteriosus from right to left to left to right.
on one hand and to a closure of the ductus The smooth muscle cells of the ductus arteriosus
arteriosus on the other. react to the increase of oxygen tension with con-
Dilation of pulmonary vessels is achieved both striction, leading to functional closure within
by the NO-mediated system and the prostaglandin 24–48 h after delivery with the result that the
system in a complementary fashion. Endothelial adult circulatory pattern is established. Later on,
nitric oxide synthase (eNOS) plays a decisive role the anatomical closure of the ductus arteriosus
in the transition of pulmonary circulation will be achieved within the next weeks of life,
(Lakshminrusimha and Steinhorn 1999). In the being completed in more than half of the cases
presence of oxygen, eNOS converts l-arginine after 4 weeks of age and in 90% of the cases after
into l-citrulline and NO. At term gestation a mat- 8 weeks. The high PVR declines continuously
urational increase of the eNOS protein level postpartum to about half of the systemic arterial
occurs being crucial for a sufficient synthesis of pressure within 3 days. At the age of 2–3 months,
NO, because NO is not stored in the cell. The pulmonary arterial pressure has further decreased
release of NO is stimulated by oxygen both to the normal level of about 15% of the systemic
directly and indirectly by an increase of oxidative arterial pressure (Kliegmann et al. 2007).
190
Fig. 3 Mediators of pulmonary vasculature tone regulation PVR pulmonary vascular GTP guanosine triphosphate, sGC soluble guanylate cyclase, cGMP cyclic guanosine
resistance, PAF platelet-activating factor, PAFr PAF receptor, ET-1 endothelin 1, ETA monophosphate, ATP adenosine triphosphate, AC adenylyl cyclase, cAMP cyclic aden-
endothelin-1 receptor a, NO nitric oxide, eNOS endothelial nitric oxide synthetase, AA osine monophosphate, PDE5 phosphodiesterase 5 which hydrolises and inactivates
arachidonic acid, COX cyclooxygenase, PGI2 prostacyclin, IP prostacyclin receptor, cGMP, PDE3 phosphodiesterase 3 which hydrolises and inactivates cAMP
B. Bohnhorst and C. Peter
Fig. 4 Bronchial tree and bronchopulmonary segments
the right lung and the lingula in the left lung,

Respiratory Physiology
respectively; and numbers 6–10 the two lower
of the Neonatal Period
lobes (see Fig. 4).
The segmental bronchi further subdivide into
The primary postnatal function of the respiratory
bronchioles and terminal bronchioles, which con-
system is to provide sufficient oxygenation and to
stitute the furthest parts of the air conducting
eliminate CO2. Oxygenation and CO2 elimination
system. Bronchi and bronchioles differ not only
are influenced by a variety of factors such as lung
in size but also in extension of cartilage, type of
anatomy, pulmonary circulation, lung volume,
epithelium, and blood supply. The amount of car-
compliance, and resistance of the respiratory sys-
tilage corresponds to the size of the respective
tem. Abnormalities in any of these factors may
bronchial tube, leaving no cartilage at the level
lead to respiratory failure. Typical symptoms of
of the bronchioles (Koeppen and Stanton 2008).
such failure during the neonatal period are
Attached to the terminal bronchioles is a large
tachypnea; dyspnea with signs of increased work
number of small respiratory bronchioles, resulting
of breathing including nasal flaring; jugular,
in a substantial rise of total surface area. The
inter-, and subcostal recessions, and cyanosis.
respiratory bronchioles already contain alveoli,
therefore presenting the beginning of the gas
exchange region. They extend into the ductus
Anatomy alveolares and finally into the sacculi alveolares,
which are saclike airspaces composed of closely
The trachea branches into right and left main adjacent alveoli.
bronchus. The right main bronchus divides into Even though the airway anatomy in newborns
upper, middle, and lower, the left one into upper is the same as in older infants and adults, it differs
and lower lobar bronchi. The lobar bronchi split in some crucial aspects such as airway diameter,
further into segmental bronchi. The region aerated chest wall compliance, and strength of respiratory
by a segmental bronchus constitutes the func- muscles (Kliegmann et al. 2007).
tional anatomic unit of the lung. Each lung con- As airway resistance is inversely proportional to
tains ten segments: numbers 1–3 form the two the fourth power of the radius of the airways
upper lobes; numbers 4 and 5 the middle lobe in (Hagen-Poiseuille’s law, V = π r4 : 8 n l ,
ΔP), halving of the airway lumen will increase the blood returns to the right atrium through the
the resistance 16-fold. Due to their inherently lower bronchial veins, whereas the residual blood drains
airway diameter, neonates are therefore eminently into the left atrium through pulmonary veins.
vulnerable to further reduction of airway lumen,
e.g., caused by inflammation or secretion. A reduc-
tion in airway diameter leads to turbulent flow,
Pulmonary Gas Exchange
which additionally enhances airway resistance. Fur-
thermore, as neonates and young infants are pre-
Pulmonary gas exchange takes place in the alve-
dominantly nose breathers, even a minimal amount
oli through a tight alveolar-capillary network.
of nasal obstruction is already harmful.
Therefore, O2 and CO2 exchange is limited by
The chest wall of a neonate is highly compli-
perfusion. The alveoli are coated with an epithe-
ant, allowing a smooth passage through the birth
lium consisting of type I and type II cells, the
canal on one hand and further lung growth on the
former being the primary site for gas exchange
other hand. By way of contrast, the high chest wall
as their thin cytoplasm, and their proximity to
compliance promotes collapse of the lungs, which
the capillary endothelium is ideal for optimal gas
is particularly disadvantageous in case of an
diffusion. O2 and CO2 passively diffuse across
already restricted lung function, for example, in
this barrier into plasma and red blood cells. The
children with respiratory distress syndrome
extent of diffusion is influenced by differences
(RDS).
in solubility, with CO2 being far more soluble
Another factor contributing to the sensitivity of
than O2, and also by differences in partial pres-
the respiratory situation in the neonatal period is
sures of the two gases. Gas exchange is best at
the inferior strength of the respiratory muscles
the initial capillaries since the differences in
leading to a limited ability to maintain adequate
partial pressures of O2 and CO2, respectively,
ventilation, a fortiori during the course of a lung
between the capillaries and the alveoli are
disease (Abu-Shaweesh 2004).
highest in this area. When the alveolar-capillary
membrane is thickened, diffusion may become
impaired.
Pulmonary Circulation
Due to anatomic dead space, not the entire gas
volume gets exchanged. Furthermore there are
Two separate blood systems, namely, the pulmo-
alveoli which are ventilated but unperfused
nary and the bronchial circulation, run through the
(ventilation-perfusion mismatch). Under healthy
lungs. The pulmonary circulation is a
conditions this ventilation-perfusion mismatch is
low-pressure, low-resistance system. It takes
minimal but it may increase considerably in spe-
deoxygenated blood to the gas exchanging units
cial diseases such as atelectasis.
for oxygenation and removal of CO2.
The pulmonary arteries are the only arteries of
the body carrying deoxygenated blood. Pulmo-
nary vessels with a diameter larger than 50 μm Lung Volumes
contain smooth muscle and can actively regulate
their diameter, thereby altering the resistance of The total volume of air that can be contained in the
the blood flow (Koeppen and Stanton 2008). Pul- lungs is the so-called total lung capacity (TLC).
monary vasculature constricts in response to hyp- All other lung volumes (LV) are parts of the TLC
oxemia, hypercapnia, and acidosis. In contrast, it (see Fig. 5):
dilates as a result of hyperoxemia, hypocapnia,
and alkalosis. The bronchial arteries branch from – Tidal volume (VT) is the volume which is
the aorta, follow the bronchial tree including their moved during breathing at rest.
divisions, and supply oxygenated blood to the – FRC is the volume of air remaining in the lungs
lung parenchyma. Approximately one third of at the end of expiration during breathing.
Fig. 5 Lung volumes and capacities

Fig. 6 Pressure-volume-curve with high, low, and ideal
functional residual capacities (FRCs)
– Inspiratory capacity (IC) is the volume which and even more importantly, the generations of
can be inspired with a forced inspiration fol- smaller airways are built parallel rather than in
lowing a normal expiration. series. Since the resistance of airways arranged
– Inspiratory (IRV) and expiratory reserve vol- in parallel is reciprocal to the sum of the individ-
ume (ERV) are the volumes which can addi- ual resistances, the overall resistance of the small
tionally be in- or expired after a normal breath. airways is negligible. Thus, as the airway diame-
– Vital capacity (VC) is the total volume of ter decreases, the resistance of each individual
exhaled air from a maximal inspiration to a airway increases, but the enlargement in the num-
maximal expiration. ber of parallel pathways reduces the resistance at
– Residual volume (RV) is the air remaining in each generation of branches. This is in marked
the lungs after a complete expiration. All contrast to the pulmonary blood vessels, in which
except FRC and RV can be measured directly most of the resistance is attributable to small
by spirometry. vessels.
The product of VT and respiratory rate is the

minute ventilation, which is defined as the total
Lung Compliance
volume of air inspired each minute.
Lung compliance (CL) is a measure of the elastic
properties of the lung and an index on how easily
Airway Resistance the lung can be distended. It is defined as the
quotient of a change of LV and required pressure
Resistance is the major factor influencing airway (CL = ΔV : Δp). The ideal situation is given
flow rates. According to Hagen-Poiseuille’s law when small changes in pressure induce large
stated above, one might expect that the dominat- changes in volume. At the extremes, high or low
ing site of airway resistance consists of the volume, even large changes in pressure result in
smallest airways. However, resistance is predom- only minimal changes in volume, which is unde-
inantly affected by the large bronchi. The smallest sirable (see Fig. 6). CL is affected by several
airways contribute only little to the overall total respiratory disorders such as RDS.
resistance for two reasons: firstly, as the total The product of compliance and resistance is
cross-sectional area increases due to further the time constant, which is a value that describes
branching, airflow velocity decreases substan- how quickly expiration can be done. One time
tially because the flow becomes laminar. Secondly constant is defined as the time necessary to
complete 63% of VT exhalation. After four time Fetal growth restriction and fetal exposure to
constants, 99% of VT is expired. With increasing inflammation may cause early lung maturation
compliance or resistance, the time constant is by structural stimulation and surfactant matura-
prolonged. This has to be considered in mechan- tion as shown in an animal model (Jobe 2012).
ical ventilation. State of lung maturation at birth is a major out-
come variable. Due to persistent structural
immaturity of the lung, bronchopulmonary dys-
plasia (BPD) develops in many of the smallest
Respiratory Distress Syndrome infants.
Pathophysiology
Incidence
RDS is characterized by surfactant deficiency and
a structurally immature lung. The major variable The incidence of RDS is inversely related to ges-
is the level of both structural and biochemical lung tational age and birth weight. The more premature
maturation at birth. the infant is born, the higher is the risk for RDS.
The crucial biochemical event is the synthesis Therefore, incidence of RDS is 90% in infants
and storage of sufficient surfactant (Jobe 2012). born <28, 15–30% in infants born between 32%
Surfactant stabilizes the inflation of alveoli by and 36%, and 5% in infants born with >37 weeks
lowering surface tension. It is of importance to of gestation (Stoll et al. 2010). Even infants born
remember that the effect of surfactant is markedly at term can rarely suffer from RDS. In those cases
increased in smaller alveoli compared to larger genetic conditions such as surfactant protein-B or
ones. The result is an equalization of the pressure ABCA3 (ATP-binding cassette subfamily A
in the smaller and larger alveoli leading to a sta- member 3) deficiency have to be considered as a
bilization of the alveoli itself. In the absence of differential diagnosis.
surfactant, small alveoli would drain into large The risk for RDS increases in case of cesarean
alveoli due to their high pressure enhancing the section delivery, multiple birth, male gender,
imbalance even more. The absence of pulmonary white infants, and maternal diabetes. Therefore,
surfactant leads to failure to attain adequate FRC elective cesarean section in low-risk pregnancies
and subsequently to atelectasis. should not be performed before 39 weeks of ges-
Synthesis of surfactant does not solely tation. A reduced risk for RDS is found in preg-
depend on gestational age but is additionally nancies with chronic or pregnancy-related
influenced by factors such as pH, temperature, hypertension, maternal infection, intrauterine
and perfusion. Asphyxia, hypoxemia, and pul- stress, and especially antenatal corticosteroid pro-
monary ischemia especially in combination with phylaxis (Sweet et al. 2013).
hypovolemia, hypotension, and cold stress may
suppress surfactant synthesis. Furthermore, lung
injury caused by high oxygen concentrations Clinical Symptoms
and mechanical ventilation may result in further
surfactant reduction. The typical clinical presentation of RDS is respi-
Surfactant deficiency leads to a physiologically ratory distress characterized by cyanosis,
high pulmonary opening and ventilation pressure, tachypnea, and increased work of breathing
causing epithelial lesion at the terminal airways including nasal flaring, jugular, inter-, and sub-
and alveoli. This injury allows plasma transfer costal recessions. Apart from these typical clin-
from vascular compartment into regions of gas ical signs, diagnosis of RDS is verified on the
exchange, leading to the typical histological pic- basis of characteristic chest x-ray findings
ture of hyaline membrane syndrome (Hallman such as ground glass appearance and air
2013). bronchograms.
X-Ray Findings in RDS CPAP

In preterm infants the use of mechanical ventila-
A fine reticular granularity of the parenchyma and tion should be minimized where possible. Appli-
positive air bronchograms are the typical findings cation of CPAP with a positive end-expiratory
in x-ray. These signs are often more prominent in pressure (PEEP) is beneficial for stabilization of
the left lower lobe due to superimposition of the the chest wall, assistance of respiratory muscles,
cardiac shadow. Depending on the extent of radio- and restoration of FRC.
logical signs, RDS is classified as grade I–IV. Early use of CPAP has shown a decrease in the
X-ray findings are influenced by various factors need for mechanical ventilation (SUPPORT
such as phase of respiration, use of continuous Study Group of the Eunice Kennedy Shriver
positive airway pressure (CPAP) or mechanical NICHD Neonatal Research Network 2010a).
ventilation, lung expansion, and administration Recent large clinical trials have demonstrated
of surfactant, the latter possibly normalizing the that infants of 26–29 weeks of gestation managed
image instantaneously. Therefore, in some with early CPAP can get along without intubation
patients x-ray findings and clinical course are or surfactant in about 50% of cases (Dunn et al.
poorly correlated. As x-ray findings are not patho- 2011). Additionally, caffeine therapy should be
gnomonic, differential diagnoses such as early- applied at least in very low birth weight infants
onset sepsis must be taken into account. to minimize need for and duration of mechanical
ventilation (Schmidt et al. 2012).
Prevention/Therapy Surfactant
The clinical surfactant treatment era started with
Interventions to prevent RDS should start before the report by Fujiwara et al. in 1980 and has
birth and involve both obstetricians and pediatri- revolutionized neonatal respiratory care (Fujiwara
cians as a team. Crucial goals of this cooperation et al. 1980). Since that time many strategies and
should be an in utero transfer to a perinatal center therapies for surfactant application have been
in case of high risk for preterm birth, prolongation investigated. Studies focused on optimal surfac-
of pregnancy, and application of antenatal tant preparation, dose, time, and method of
corticosteroids. administration.
Current recommendations are to apply natural
Antenatal Corticosteroids surfactant preparations, to utilize a policy of early
Studies carried out in preterm infants have con- rescue surfactant therapy, and to consider the
firmed strong evidence for the role of antenatal INSURE technique (INtubation, SURfactant,
steroids in reducing the incidence of RDS and, Extubation to CPAP). Extremely preterm infants
additionally, the risk of neonatal death, intraven- who require intubation for stabilization in the
tricular hemorrhage, and necrotizing enterocolitis. delivery room should be given surfactant even
Therefore, antenatal corticosteroid therapy – pref- before RDS is confirmed radiologically (Sweet
erably by betamethasone – is recommended for all et al. 2013).
women at risk of preterm delivery before 34 com- A second and sometimes third intratracheal
pleted weeks of gestation. The optimal point of surfactant dose 6–8 h after the previous one
time for corticosteroid therapy is more than 24 h should be given in case of ongoing oxygen
and less than 7 days before delivery. Beyond requirement and need for mechanical ventilation.
14 days after antenatal corticosteroid treatment, Immediately after surfactant application, a hyper-
the benefits begin to decrease (Roberts and oxic peak should be avoided by reducing oxygen
Dalzell 2006). Studies have yet to confirm supply. Although it has been shown that surfactant
whether the benefits on the outcome outweigh treatment significantly decreases mortality and air
the risks of side effects in short and long term if leak, one has to keep in mind that surfactant
repeated courses of corticosteroids are being used. application itself bares a risk for air leak for a
brief period by reducing surface tension and manifestation, the right-to-left atrial and ductal
improving compliance. Therefore, not only oxy- shunting continue, leading to a circulatory pattern
gen but also inspiratory pressure should be called “persistent fetal circulation” (PFC) with its
reduced after surfactant application when possi- typical pre-postductal difference of oxygen satu-
ble. Saturation target should be aimed between ration, i.e., a much lower saturation postductal
90% and 95%, as lower oxygen saturations of compared to the one preductal. PPHN appears as
85–89% were shown to result in an increase of either idiopathic or as a contributing factor in
mortality in extremely preterm infants (SUP- various diseases like RDS, asphyxia, MAS, con-
PORT Study Group of the Eunice Kennedy genital heart defects, and lung hypoplasia espe-
Shriver NICHD Neonatal Research Network cially in the cause of CDH (Lakshminrusimha and
2010b). Surfactant or surfactant lavages can also Steinhorn 1999). In spite of recent advances in
be applied in other situations such as severe meco- therapy, PPHN still is a devastating disorder with
nium aspiration syndrome (MAS), as meconium a mortality exceeding 10% of all cases (Konduri
inhibits surfactant function and surfactant treat- and Kim 2009).
ment may decrease the need for extracorporeal
membrane oxygenation (ECMO).
Etiology of PPHN
Perspective Hypoxia, an abnormal pulmonary vasculature and

an elevated vascular reactivity, constitutes the
Consistent use of antenatal corticosteroids, characteristic features of PPHN. Vascular re-
decreased exposure to mechanical ventilation, modeling includes proliferation of the smooth
improvement of ventilation techniques, and new muscles into the intra-acinar arteries (normally
techniques of surfactant application have resulted not muscular), an increased medial-wall thickness,
in lower rates of RDS in neonates in the last years where the smallest – normally muscle-free – arter-
(Hallman 2013). However, many preterm infants ies are most severely affected, and a substantial
still develop BPD despite the benefits of surfactant. narrowing of the arterial lumen leading to a
Recent techniques delivering surfactant reduction of the total cross-sectional area of the
intratracheally by using a fine catheter during pulmonary vascular bed. Besides, the adventitial
spontaneous breathing on CPAP may be promis- connective tissue is markedly proliferated, which
ing although data on long-term outcomes have yet seems to be equally important in the development
to be evaluated. of PPHN (Murphy et al. 1981). Based on animal
An old idea of surfactant application without studies, one assumes that these structural changes
necessity of ventilation, which is currently are accompanied by defects in the NO and pros-
reevaluated, is surfactant nebulization. If techni- taglandin synthesis. In case of an inflammatory
cally feasible, this form of surfactant treatment process, e.g., pneumonia, RDS, MAS, high levels
would be the most sophisticated and less invasive of leukotrienes, thromboxane, and platelet-
technique (Kribs 2011). Pilot trials on this issue activating factor contribute to the missing reduc-
are encouraging and randomized trials are pres- tion in PVR. Moreover, circulating levels of ET-1
ently ongoing. are increased in case of PPHN (Gao and Raj
2010).
Persistent Pulmonary Hypertension

of the Newborn Diagnosing PPHN
Persistent pulmonary hypertension (PPHN) Cyanosis is the striking clinical symptom of

emerges from a failure to achieve the normal PPHN commonly in combination with respiratory
postnatal decline in PVR. In case of maximal distress. The suspected diagnosis is usually
confirmed by echocardiography, which allows for to prevent further lung damage. Analgesia and
describing the hemodynamic profile of the infants, sedation by use of morphine, fentanyl, or mid-
including estimation of pulmonary artery pressure azolam should be consistently applied to avoid
by Doppler velocity measurement of tricuspid stress reaction, which contributes to
regurgitation jet, assessment of right ventricular elevated PVR.
function, and depiction of right-to-left atrial and Acidosis must be eliminated as it can act as a
ductal shunting. During treatment of PPHN, echo- pulmonary vasoconstrictor, whereas the use of
cardiography is the determining diagnostic tool to alkalosis is still under controversy because long-
decide about the choice of therapeutic interven- term benefits have not yet been proven and its
tions and evaluate the effects of therapy (Dhillon constricting effect on cerebral vessels, leading to
2012). Right and/or left ventricular dysfunction reduced cerebral perfusion, is associated with
with low output, leading to decreased oxygen worse neurodevelopmental outcome in survivors
transport to the periphery and acidosis, appears of PPHN (Konduri and Kim 2009). To stabilize
to be the major risk factor for poor outcome in right and left ventricular function and systemic
infants with PPHN. hemodynamics, the application of volume, pref-
erably balanced electrolyte solution, and inotropic
and vasopressor agents often are necessary. Com-
General Management of PPHN monly, dobutamine, epinephrine, and noradrena-
line are utilized.
General management mainly consists of mechan- ECMO is the treatment of ultima ratio being
ical ventilation, support of cardiac function, cor- generally indicated if the oxygenation index
rection of systemic arterial hypotension, and ((mean airway pressure FiO2 100)/PaO2) is
maintenance of regular acid-base and electrolyte above 40. While ECMO can be lifesaving in
balance. severe cases, its use is associated with potential
The goal of mechanical ventilation is establish- side effects like intracranial hemorrhage and dam-
ment of an adequate lung expansion to ensure age of the carotid artery.
proper ventilation and to avoid the adverse effects
of high or low lung volumes on PVR. In cases
where appropriate lung recruitment is not Specific Medical Treatment
achieved with conventional ventilation, the use
of high-frequency oscillatory ventilation (HFO) Pulmonary vasodilation can be achieved either by
is recommended. Hypoxia (enhancing pulmonary supporting the endogenous vasodilator capacity,
vasoconstriction) as well as hyperoxia (causing i.e., increasing the levels of NO and PGI2 or by
oxidative stress) should be avoided, and oxygen antagonizing the effects of vasoconstricting
tension should be kept at a low normal range, i.e., agents, i.e., application of phosphodiesterase
60–80 torr, to ensure adequate pulmonary blood inhibitors like sildenafil and milrinone or the
flow (Konduri and Kim 2009). Gentle ventilation ET-1 receptor antagonist bosentan (see Table 1).
with moderate hypercapnia is worth considering Due to the complexity of the signaling pathways
Table 1 Mediators of pulmonary hypertension and medical approach

Support of endogenous vasodilator capacity Antagonism of the effect of vasoconstricting agents
Substance Mode of action Substance Mode of action
NO Increase of smooth Sildenafil inhibition of PDE 5 with subsequent increase of
muscle cGMP level (C22H30N6O4S) intracellular cGMP
Prostacyclin Increase of smooth Milrinone Inhibition of PDE 3 with subsequent increase of
(C20H32O5) muscle cAMP level (C12H9N3O) intracellular cAMP
Bosentan ET-1 receptor antagonism with attenuation of the
(C27H29N5O6S) vasoconstricting effect of ET-1
in PPHN, using combinations of therapies seems twice a day. Data regarding the application in
to be particularly promising. newborns are limited, and its benefit in improve-
Inhaled NO (iNO) is the mainstay of PPHN ment of oxygenation in case of PPHN is contro-
medication, since it causes immediate selective versial (Mohamed and Ismail 2012; Steinhorn
pulmonary vasodilation by increasing the intracel- et al. 2016; More et al. 2016).
lular cGMP levels in the smooth muscle. iNO
improves the oxygenation within a few minutes
after starting its application. Several randomized
controlled trials revealed that iNO significantly Conclusion and Future Directions
reduces mortality and the need of ECMO in new-
borns with PPHN (Konduri and Kim 2009). iNO During fetal life a high level of lung distension,
should be initiated with a dose of 20 ppm, which is attained by both FBMs and the presence
although once established, lower doses of of lung fluid, is crucial for regular lung growth and
6–10 ppm may suffice. During treatment, a close structural maturation. Premature birth or a lack of
monitoring of methemoglobin, a toxic by-product FBMs and/or lung fluid causes infants to have
of NO, is badly needed. structurally immature or abnormal lungs resulting
In cases of poor response to iNO, pulmonary in respiratory distress in combination with more
dilation can be achieved by inhalative administra- or less pronounced pulmonary hypertension.
tion of PGI2 (iloprost), which causes vasodilation Despite considerable advances in neonatal care,
by enhancing the cAMP levels in the smooth i.e., antenatal corticosteroids, surfactant applica-
muscle cells therefore acting complementary tion, and improvement of ventilation techniques,
to iNO. there is quite some evidence that those lungs will
As phosphodiesterases (PDE) are responsible be persistently impaired during postnatal life. In
for hydrolyzing cGMP to GMP (PDE 5) and many cases neonatal care comes too late to
cAMP to AMP (PDE 3), therefore inactivating achieve further regular lung development. There-
these substrates and limiting the vasodilating fore, major attempts should be made to prevent
effect of NO and PGI2, the application of PDE preterm birth on the one hand and to develop and
inhibitors offers an additional benefit in the treat- improve intrauterine treatment strategies on the
ment of PPHN. Sildenafil is a selective inhibitor of other.
PDE 5 and operates synergistically with NO by
preserving the increased cGMP produced by
NO. Sildenafil has to be administered orally with Cross-References
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mum of 2 mg/kg/dose. Due to its short half-life, ▶ Congenital Diaphragmatic Hernia
sildenafil should be delivered every 4 h (Porta and ▶ Extracorporeal Membrane Oxygenation for
Steinhorn 2012). Neonatal Respiratory Failure
Recent data indicate that milrinone, a selective ▶ Perinatal Physiology
PDE 3 inhibitor and therefore increasing the bio- ▶ Pediatric Respiratory Physiology
availability of cAMP, has a special benefit in the ▶ Specific Risks for the Preterm Infant
treatment of PPHN, as it improves oxygenation
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Pediatric Cardiovascular Physiology
12
Albert P. Rocchini and Aaron G. DeWitt
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Determinants of Cardiac Output . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Preload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Afterload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Contractility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
Regulation of Whole-Body Oxygen Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
The Fetal Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212
How Selected Types of Congenital Heart Disease
Affect Cardiovascular Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
Abstract rate. As in adults, these four factors interact

Knowledge of cardiovascular physiology is with each other in a complex fashion. How-
critical for the perioperative management of ever, there are specific age-related differences
all pediatric surgical patients. The purpose of in how changes in these variables affect the
the cardiovascular system is to deliver oxygen performance of the heart of a fetus, neonate,
to the tissues. Adequate oxygen delivery is or older child. Perturbations in normal
determined by oxygen content of the blood age-related cardiovascular physiology, as is
and cardiac output. The latter is determined seen patients with unrepaired, repaired, and
by preload, afterload, contractility, and heart palliated congenital heart disease, is common
in pediatric surgical patients.
A. P. Rocchini (*) · A. G. DeWitt
Keywords
Department of Pediatric and Communicable Diseases,
C.S. Mott Children’s Hospital, Congenital Heart Center, Preload · Contractility · Afterload · Oxygen
University of Michigan, Ann Arbor, MI, USA transport · Heart rate · Cardiac output ·
e-mail: rocchini@med.umich.edu; rocchini@umich.edu;
dewitta@med.umich.edu

https://doi.org/10.1007/978-3-662-43588-5_13
202 A. P. Rocchini and A. G. DeWitt
Congenital heart disease · Heart failure · CO ¼ HR SV (2)

Cyanosis
Third, stroke volume is the difference between
end-diastolic volume (EDV) and end-systolic vol-
Introduction ume (ESV).
Understanding the age-related differences in nor- SV ¼ EDV ESV (3)

mal cardiovascular physiology is critical to ade-
quately manage the pediatric patient’s pre- and
postoperative cardiovascular needs. The current
chapter summarizes cardiovascular physiology Determinants of Cardiac Output
in the child, neonate, and fetus. The chapter will
also describe how understanding the principles of Regardless of age, the major determinants of car-
normal cardiovascular physiology is invaluable in diac output are preload, afterload, contractility,
managing common cardiovascular problems in and heart rate (Anderson et al. 1982; Thornburg
children and neonates. and Morton 1986). At all ages, increasing the
The primary role of the cardiovascular system inotropic state of the heart has a positive effect
is to deliver sufficient oxygen to meet the meta- on cardiac function, whereas increasing afterload
bolic needs of the body’s tissues (see section has a negative effect. However when dealing with
“Regulation of Whole Body Oxygen Delivery”). the response of the whole body, it is almost impos-
Oxygen delivery is proportional to tissue blood sible to only change one of these variables without
flow, and there are three basic equations that also affecting another variable in kind. Thus the
determine tissue blood flow. First, based on net physiologic response is the combined effect of
Ohm’s law for fluids (Hall 2012), it states that the intervention on several variables. For exam-
blood flow through any tissue is equal to the ple, in the isolated papillary muscle, increasing
pressure gradient across the tissue divided by the rate of muscle stimulation (i.e., increasing the
vascular resistance of that tissue. For the cardio- “heart rate” variable) always results in an increase
vascular system, Ohm’s law for fluids would state in the force of contraction (Anderson et al. 1982).
that whole-body blood flow (cardiac output (CO)) However, in children, pacing the heart at incre-
is equal to driving pressure (mean arterial blood mentally faster rates causes a decrease in stroke
pressure (MAP)) minus mean venous pressure volume and no change or even a slight decrease in
divided by vascular resistance of the whole body cardiac output. The opposite effects, seen in vivo,
(the systemic vascular resistance (SVR)). How- are the result of a complex interaction of venous
ever, since mean venous pressure is relatively return, ventricular end-diastolic volume, inotropic
small, it is usually omitted (see section “How state, heart rate, and afterload.
Selected Types of Congenital Heart Disease Patient age also can affect cardiovascular func-
Affect Cardiovascular Physiology” for exceptions tion. For example, in the fetus, an increase in
to this practice). systemic afterload has a much greater deleterious
effect on fetal right ventricular function than left
Ohm’s Law for the Cardiovascular System: ventricular function, whereas in the child or
infant, an increase in systemic afterload has a
MAP much greater deleterious effect on left ventricular
CO ¼ (1)
SVR function than on right ventricular function (Reller
et al. 1987). The following sections describe how
The second equation states that cardiac output preload, afterload, contractility, and heart rate
is equal to the product of heart rate (HR) and affect cardiac output and cardiovascular physiol-
stroke volume (SV). ogy. When applicable, the aim of this chapter is to
12 Pediatric Cardiovascular Physiology 203
Fig. 1 (a) Graphical analysis of the cardiac function curve function and venous return curves. Because the neonatal
and venous return curve in the child (solid lines) and myocardium stiff preload reserve occurs at a lower pres-
neonate (dashed lines) at steady-state conditions. The sure than the child. Low precapillary tone in the neonate
graph consists of simultaneous plots of indexed cardiac results in a shift in plasma volume form the intravascular
output and venous return as a function of atrial pressure or compartment to the interstitium which in turn results in
indexed end-diastolic pressure. The solid dots represent the both a lower MCFR and a steeper slope to the venous
steady state where the two curves intersect (i.e., the point return curve. (b) Graphically represents the effect of a
where cardiac output is equal to venous return). Preload fluid bolus on the cardiac function curve and venous return
reserve is the point on the cardiac function curve where curve in the child (solid lines) and neonate (dashed lines).
further increases in end-diastolic volume result little In the child with a fluid bolus, blood volume increases, and
change in cardiac output. Mean circulatory filling pressure the venous return curve shifts to the right, resulting in both
(MCFP) represents the degree of filing of the whole circu- an increase in cardiac output and atrial pressure. Whereas,
lation (the theoretical atrial pressure when cardiac output is in the neonate, because of the low precapillary tone and
zero) and relates to blood volume to vascular capacity. reduced preload reserve, cardiac output changes little
Although steady-state indexed cardiac output is similar despite atrial pressure increasing to near the same level as
between the neonate and the child, there are a number of the child
differences between the neonate’s and the child’s cardiac
describe age-related differences that are seen in only small increments in end-diastolic volume
the child, neonate, and fetus. and stroke volume follow from a further increase
in filling pressure. The end-diastolic pressure at
which further increases result in little to no change
Preload in cardiac output is termed the preload reserve
(Fig. 1a). Although the Frank-Starling relation-
General Principles ship exists in both the newborn and older child,
From a clinical standpoint, preload is defined as the magnitude of the relationship is frequently
ventricular end-diastolic volume/pressure or atrial diminished in the newborn. In the fetus and new-
filling pressure. The Frank-Starling relationship born, since the myocardium is immature and has
(Starling 1915) describes the ability of the heart reduced compliance (greater stiffness), the pre-
to increase its cardiac output as end-diastolic vol- load reserve occurs at a lower pressure than in
ume increases (Fig. 1a). The physiological basis the child. (Friedman 1972).
of the Frank-Starling relationship is that as Two of the major determinants of preload are
end-diastolic volume increases, myocyte sarco- circulating blood volume and venous tone. In the
mere length is increased as well. This causes an fetus and early neonatal period, there are signifi-
increase in contractile forces and a resultant cant changes in the way plasma volume and
increase in cardiac output. However, as left ven- venous tone are regulated (Assali et al. 1970).
tricular end-diastolic pressure becomes elevated, During the days before delivery, there is an
increased capillary pressure with a resultant number of clinical trials in adults that suggest that
plasma volume shift to the interstitium. During chronic blockade of mineralocorticoid receptors
labor the increased release of vasoactive hor- results in improved cardiac remodeling (Gonzalez
mones (vasopressin, cortisol, and norepinephrine) et al. 2004). It is important when considering the
results in a further shift of plasma volume to the use of diuretics to avoid too much diuresis. If the
interstitium. These perinatal fluid shifts persist for child’s preload is reduced below their preload
the first week or two of life and are an adaptive reserve, cardiac output will decrease (Fig. 1a). Con-
advantage for the neonate in that they enable the sultation with a pediatric cardiologist or another
neonate to rapidly recover from acute blood loss. provider experienced with pediatric heart failure
In fact, the fetus can restore blood volume in one management is recommended.
tenth the time it takes an adolescent to restore their
blood volume. However, it is critical to remember
that when doing fetal interventions or surgery, the Afterload
fetus will tolerate moderate blood loss without
significant changes to heart rate, ventricular func-
General Principles
tion, or pressure. In this way, standard monitoring The second determinant of cardiac output is after-
load, defined as the tension or stress developed in
can fail because with enough blood loss, both
the wall of the ventricle. The major components of
blood pressure and ventricular function can pre-
cipitously decrease, and without immediate trans- afterload are the pressure in the ventricle and the
volume of the ventricle. More, precisely, afterload
fusion, fetal demise will occur.
is related to ventricular wall stress (σ) where:
The neonate is in a transition state for blood
pressure regulation with both low blood pressure
P:r
and low precapillary tone. Because of low pre- σ/ ðP, systolic ventricular pressure; r,
capillary tone and increased ventricular stiffness, h
administered intravenous fluids are rapidly radius of the ventricle; h, wall thicknessÞ:
redistributed to the interstitium. This interstitial
fluid is retained for several reasons: the neonate Unless aortic stenosis is present, the pressure
experiences little change in vasopressin and renin that the ventricle generates during ejection is aor-
levels, atrial natriuretic factor only transiently tic pressure (or systolic blood pressure).Afterload
increases, and because of the reduced glomerular is increased when aortic systolic pressure and/or
filtration rate, urine flow only very transiently systemic vascular resistance are increased and
increases. As a result of all of these factors the when the ventricle is dilated. Afterload is
neonate is especially prone to edema formation decreased with increased wall thickness.
(Fig. 1b). When afterload increases there is an increase in
end-systolic volume and a decrease in stroke vol-
Therapeutic Implications ume and cardiac output. The physiological basis
Preload control is a mainstay of symptomatic for this increase in end-systolic volume is that an
therapy for heart failure. This is accomplished increase in afterload decreases the velocity of fiber
with the use of diuretics. Table 1 lists many of shortening, which reduces the rate of ventricular
the commonly used diuretics and current dose ejection, resulting in more blood left in the ven-
recommendations. The most common diuretic tricle at the end of systole. Therefore, although
used to symptomatically treat heart failure in the afterload per se does not alter preload, the resul-
child is furosemide (Lasix). One diuretic that may tant increase in end-systolic volume results in a
have more benefit than just symptomatic therapy is secondary increase in preload. This interaction
spironolactone (Aldactone) which is a mineralocor- between preload and afterload is why vasodilators
ticoid receptor blocker (Chatterjee 2002). In addi- are effectively used in the treatment of heart fail-
tion to causing fluid retention, aldosterone is known ure. Since vasodilators decrease arterial pressure
to cause myocardial fibrosis. There are now a (afterload), the ventricle can then eject blood
Table 1 Medications used to treat congestive heart failure

Dosing
Class Drug Dose interval Comments
Diuretic Hydrochlorothiazide 2.0–3.0 mg/kg up to 50 mg/ bid-qid Will increase uric acid level
day
Furosemide 0.5–2.0 mg/kg up to 6 mg/ qd-qid
kg/day
Spironolactone 1.0–3.3 mg/kg bid Potassium sparing used with causing
with CEI
Metolazone 0.2–0.4 mg/kg qd
ACE Benazepril 0.2 mg/kg up to 10 mg/day qd Contraindicated in pregnancy; check
Captopril 0.3–0.5 mg/kg/day up to tid serum potassium, creatinine. Cough
6 mg/kg and angioedema are side effects
Enalapril 0.08 mg/kg up to 5 mg/day qd-bid
Lisinopril 0.07 mg/kg up to 40 mg/ qd
day
ARB Irbesartan 6–12 years:75–150 mg/day qd Contraindicated in pregnancy; check
Losartan 0.7 mg/kg/day up to 50 mg/ qd serum potassium, creatinine
day
Β-blocker Metoprolol 1.0–2.0 mg/day up to qd
6.0 mg/kg/day
Vasodilator Hydralazine 0.75 mg/kg up to 7.5 mg/kg qid Tachycardia, fluid retention, lupus-
like synd.
Prazosin 0.05–0.1 mg/kg up to tid
0.5 mg/kg
Inotrope Digoxin Digitalizing dose; bid
20–40 ug/kg depending on
age Maintenance dose
5–10 ug/kg
Dobutamine 2.0–20 μg/kg/min IV
Dopamine 2.0–20 μg/kg/min IV
Milrinone Loading dose 0.05–1 mg/
kg then 0.5–0.75 μg/kg/
min
Epinephrine 0.05–2 μg/kg/min IV
Lexi-Comp Online™, Pediatric Lexi-Comp Online™, Pediatric & Neonatal Lexi-Drugs Online™, Hudson, Ohio: Lexi-
Comp, Inc.; 2013
Allen et al. (2013)
ACE angiotensin converting enzyme inhibitor, ARB angiotensin receptor blocker, synd. syndrome
faster, which results in an increase in cardiac Afterload also has a quantitatively different
output and a resultant decrease in end-systolic effect on right and left ventricular function.
volume. Since less blood remains in the ventricle Because of differences in ventricular geometry,
after systole, the ventricle will fill to a smaller systolic wall stress of the right ventricle is greater
end-diastolic volume (preload) than before the than that of the left ventricle in the face of similar
reduction in afterload. This is an example of the arterial pressures. This increase in right ventricu-
complex interaction between the variables deter- lar systolic wall stress causes the right ventricular
mining cardiac output. Long-term cardiac output ejection fraction to be more negatively affected by
remains increased despite the decreased preload an increase in arterial pressure. This explains why
because stroke volume is ultimately increased (the patients with pulmonary hypertension often pre-
reduction in end-diastolic volume is less than the sent with systemic hypotension – afterload
reduction in end-systolic volume). decreases right ventricular systolic function,
pulmonary blood flow falls, left ventricular pre- Low-dose beta-blockade has been used success-
load falls, and systemic cardiac output (and blood fully in the treatment of congestive cardiomyopa-
pressure) falls. thy. This agent works by interfering with the
The cardiovascular function of both the neona- deleterious effects of increased sympathetic activ-
tal and adolescent heart is negatively affected by ity (Eichhorn 1992; Bruns et al. 2001; Rusconi
an increase in afterload (Thornburg and Morton et al. 2004). As with diuretic management, heart
1986; Pinson et al. 1987). However, there is a failure management should be undertaken with
maturational difference in the effect of afterload expert consultation.
on myocardial function. The neonatal ventricle With gram-negative septic shock or anaphylac-
cannot eject against arterial pressures as well as tic shock, it may be necessary to increase systemic
the adolescent heart. Even when corrected for afterload in order to maintain an adequate cardiac
muscle cross-sectional area, the neonatal myocar- output. In this situation, although systemic blood
dium is weaker, and ventricular wall is thinner flow is high, because of severe vasodilation, the
than the adolescent heart causing this quantitative cardiac output is not high enough to maintain
difference in response to afterload. Furthermore, arterial pressure. The pharmacologic agents that
in the neonate and fetus, increases in arterial pres- are used in this situation are epinephrine, norepi-
sure have a much greater negative effect on stroke nephrine, and vasopressin (Efrati et al. 2004;
volume of the right ventricle than that of the left, Morelli et al. 2009).
whereas in the child or adolescent increases in
arterial pressure have a much greater negative
effect on left ventricular stroke volume than on Contractility
right ventricular stroke volume. In the fetus and
neonate, this difference is a consequence of a General Principles
widely patent ductus arteriosus and the relatively The third determinant of cardiac output is contrac-
larger right ventricular stroke volume, tility, the intrinsic ability of the heart to contract
end-diastolic volume, and free wall curvature in independent of the influences of either preload or
the presence of similar right and left ventricular afterload. The ability to produce force during con-
free wall thicknesses (Pinson et al. 1987). traction depends on the incremental degrees of
binding between myosin and actin filaments
Therapeutic Implications (Hall 2012). The degree of binding that occurs is
The pharmacologic agents that are most useful in directly related to myocardial intracellular cal-
altering afterload are vasodilators (Table 1). These cium concentration. The heart normally changes
agents are important therapeutic agents in the its contractile state through modulation of the
treatment of neonates, children, and adolescents sympathetic nervous system. Increased sympa-
with heart failure secondary to a large left-to-right thetic tone results in the release of catecholamines
shunt, severe atrioventricular and semilunar valve (norepinephrine and epinephrine) from sympa-
regurgitation, dilated cardiomyopathy, chronic thetic nerve terminal and the adrenal gland, acti-
hypertension, and postoperative low-output states vating the beta-adrenergic receptors, which
(Beekman et al. 1984; Artman and Graham 1987; ultimately increase cytosolic calcium concentra-
Bengur et al. 1991). Angiotensin converting tion and thereby increasing contractile force. At
enzyme inhibitors are the most commonly used any given preload and afterload, an increase in
class of afterload-reducing agents (Stern et al. contractility will cause an increase in cardiac out-
1990; Lewis and Chabot 1993). In addition to put and a resultant increase in blood pressure.
reducing ventricular afterload, they have been The immature heart responds to positive ino-
shown in adults with congestive cardiomyopathy tropic agents with an increase in left ventricular
to also improve cardiovascular remodeling output; however in comparison to the older child’s
(Gonzalez et al. 2004). Another means of afterl- heart, this response is reduced. In mature cardiac
oad control is low-dose beta-receptor blockade. muscle, the movement of calcium through the
dihydropyridine-sensitive calcium channel and its dopamine exerts its inotropic effects by stimulat-
interaction with the ryanodine receptors on the ing the beta-adrenergic receptors in the heart. But,
sarcoplasmic reticulum (SR) are essential for it can also cause alpha-receptor stimulation,
calcium-induced calcium release from the SR which is important in vascular smooth muscle,
(Fabiato 1989; Valdivia et al. 1995). Calcium- causing some degree of vasoconstriction and
induced calcium release amplifies the effect of increased blood pressure (Bhatt-Mehta and
the calcium current on cytosolic calcium concen- Nahata 1989). Alternatively, dobutamine tends
tration (Valdivia et al. 1995). In the absence of to have more pure beta-adrenergic effect with
calcium-induced calcium release, trans- reflex systemic vasodilatation producing no net
sarcolemmal calcium flow results in a strength of effect on systemic pressure (Ferguson et al.
contraction that is only a fraction of that achieved 1989). Milrinone is another intravenous inotrope
in the presence of the amplification system. This is that is frequently used in the infant. Milrinone is
the case for the neonatal or fetal heart which has a phosphodiesterase inhibitor and increases con-
greater dependence on extracellular calcium than tractility by inhibiting the breakdown of cyclic
the heart of the child or adolescent. This is due to adenosine monophosphate (AMP). Besides
(1) reduced calcium-induced calcium release being a positive inotropic agent, it also reduces
(dihydropyridine-sensitive calcium channels and afterload. Thus milrinone is likely to lower blood
ryanodine receptors increase with age) and pressure slightly. It is also useful in producing
(2) smaller volume SR (absolute and relative SR some degree of pulmonary artery vasodilation
volume increases with age). These are two expla- and is therefore an ideal agent for the infant with
nations for why calcium channel blockers, such as severe congestive heart failure and pulmonary
verapamil, are poorly tolerated in the newborn and artery hypertension (Meyer et al. 2011).
can lead to cardiovascular collapse. If pharmacologic therapy alone is not enough
to increase contractility enough to maintain an
Therapeutic Implications adequate cardiac output, mechanical devices can
Contractility may be iatrogenically altered by the be used to support the circulation. The most com-
administration of inotropic agents (Table 1). The monly used mechanical support device is extra-
oldest agent in this class is digitalis. Digoxin is corporeal membrane oxygenation. More recently
still the most commonly used chronic inotropic ventricular assist devices have been used in
agent. It increases contractility by inhibiting the infants with end-stage cardiomyopathy as a bridge
sodium-potassium-ATPase pump resulting in an to cardiac transplantation (Gajarski et al. 2003;
increase in intracellular sodium which in turn Almond et al. 2013).
stimulates calcium entry into the cell by the
sodium-calcium exchanger; the increased intra-
cellular calcium leads to increased contractility. Heart Rate
Studies have suggested that digitalis also helps
heart failure by inhibiting sympathetic nerve traf- General Principles
fic and thus decreases cardiac metabolic demands Changes in heart rate have the same effect on
(Ferguson et al. 1989). In addition to digoxin, ventricular output in both the neonatal and the
there are other intravenous inotropic agents, the child heart (Anderson et al. 1986). Increases in
majority of which stimulate the beta-adrenergic heart rate induced by atrial pacing result in a
receptor in the heart, which in turn increases pro- decrease of ventricular performance. Stroke vol-
duction of adenylate cyclase activity and ulti- ume falls with an increase in heart rate, a conse-
mately contractility. These agents are especially quence of decreasing end-diastolic filling time
useful in managing severe acute congestive heart and end-diastolic volume; however, because the
failure and cardiogenic shock. Depending on the decrease in stroke volume is usually proportional
individual agent, blood pressure can be either to the increase in heart rate, the net effect is either
increased or slightly decreased. For example, no change or a slight fall in cardiac output. In
comparison to the child and adolescent, the fetus having the child place their head in cold water
and neonate have a relatively high resting heart recruits the diving reflex and can stop the tachy-
rate. Because of the high basal heart rate, a neo- cardia. A rapid intravenous infusion of adenosine
nate’s cardiac output can rarely be increased by is also very effective in terminating SVT (Crosson
increasing heart rate. et al. 1994). The usual dose is a 0.1 mg/kg bolus,
Unlike pacing, a spontaneous increase in heart increasing by 0.1 mg increments to a maximum of
rate is usually associated with an increase in car- 0.4 mg/kg. A few serious side effects associated
diac output. A spontaneous heart rate change dif- with adenosine administration included atrial
fers from a similar change in heart rate due to atrial fibrillation, ventricular tachycardia (VT),
pacing because the underlying stimuli that cause asystole, apnea, and bronchospasm. Because of
the spontaneous rate change also will affect these potential side effects, adenosine should be
inotropy, venous return, and/or afterload. For administered in an area where cardioversion and
example, an increase in venous return that main- cardiopulmonary resuscitation can be performed.
tains end-diastolic volume despite a rate-induced If these measures fail, expert consultation with
shortening of diastolic filling can result in an someone familiar with pediatric arrhythmia man-
increase in stroke volume. Similarly, if the stimu- agement is recommended. Children with supra-
lus to increase heart rate is associated with an ventricular tachycardia and mild to moderate
increase in contractility, even though venous congestive heart failure may be initially treated
return may not increase the increase in heart rate, with adenosine; however other pharmacologic
will still result in an increase in cardiac output. agents such as digoxin, amiodarone, and pro-
Exceptions to the positive effect of a spontaneous cainamide may be helpful if adenosine fails to
increase in heart rate on cardiac output can usually convert the tachycardia. Table 2 lists many of the
be explained by an increase in arterial pressure commonly used antiarrhythmic agents and current
(Thornburg and Morton 1986). The negative dose recommendations. In the past digoxin was
effect of afterload on ventricular function results the preferred agent to treat the infant or child with
is a fall in stroke volume and cardiac output. supraventricular tachycardia. However, many car-
diologists now avoid using digoxin, since in the
Therapeutic Implications presence of Wolff-Parkinson-White syndrome
Tachyarrhythmias can occur in the infant and (WPW), digoxin can increase conduction velocity
young child and cause heart failure. The most across the accessory pathway leading to an accel-
common type of tachyarrhythmia is supraventric- eration of the ventricular response and in the pres-
ular tachycardia (SVT). The incidence of parox- ence of atrial flutter result in the development of
ysmal SVT is 1 in 250–1,000 children. Although ventricular fibrillation.
SVT occurs most commonly in males younger When tachycardia is the cause of the heart
than 4 months of age, it also occurs in both male failure, esmolol and propranolol (which may fur-
and female children and adolescents. SVT can ther depress cardiac function) are frequently used
even be present in the fetus. If the SVT is as first-line agents to acutely treat supraventricular
sustained for greater than 24–48 h, heart failure tachycardia. Once the tachycardia has been termi-
will likely occur. The treatment for SVT regard- nated, beta-blockers are effective long-term anti-
less of cause is similar. If the infant or child arrhythmic therapy for infants and children with
becomes acidotic or hypotensive, immediate syn- supraventricular tachycardia.
chronized direct-current cardioversion should be In the postoperative cardiac patient, amiodarone
performed, at a dosage of 1–2 watt-sec/kg (Atkins is being used with increasing frequency for the
and Kerber 1994). If the child is stable and rela- emergency treatment of supraventricular tachycar-
tively asymptomatic, then in most situations, any dia, especially. Intravenous administration of
intervention that increases atrioventricular node amiodarone has been reported to terminate the
refractoriness is likely to work. Application of an tachycardia within 2 h of the initial bolus in over
ice water bag directly to the center of the face or 40% of patients (Figa et al. 1994; Perry et al. 1996).
12
Table 2 Commonly used pharmacologic agents to treat tachyarrhythmias

Onset
of Cardiovascular
Drug Dosage action Potential adverse effects Drug interactions contraindications Comments
Adenosine 100–150 μg/kg given rapid <5 s Dyspnea, bronchospasm, Theophylline – Prolong QT Have defibrillator available
IV; Double dose sequentially headache, chest pains, AV adenosine is less when administering, in the
to max of 300 μg/kg block/asystole, PVCs, atrial effective event of ventricular rate
fibrillation, torsades de Digoxin – increases Second- or third- acceleration, torsades de
pointes, hypotension risk VT degree AV block, pointes, or VF
except in the presence
of pacemaker
Diazepam-potentiated Sick sinus syndrome
Pediatric Cardiovascular Physiology
effects of adenosine
Amiodarone Bolus: 5 mg/kg over 10 min Within Hypotension, sinus arrest or Digoxin – increases Sick sinus syndrome Closely monitor blood
Infusion of 10–15 ug/kg/day 5 min of bradycardia, AV block digoxin levels or AV block – except pressure, heart rate, and
initial if pacemaker present rhythm
bolus Procainamide– causes Cardiogenic shock Hypotension can be treated
increase levels with volume and calcium
Warfarin – increase
INR
Esmolol Load 500 μg/kg over Within Hypotension, dizziness, Digoxin – increases Sinus bradycardia, Use with caution in patients
1–2 min Maintenance: 1–2 min headache, nausea, level second- or third- with decrease renal function,
50–200 μg/kg/min bronchospasm, decreased Morphine – degree heart block, diabetes, or asthma
cardiac output causes, increase cardiogenic shock,
esmolol level overt heart failure
Procainamide Load: infants 7–10 mg/kg Within Hypotension, increased Amiodarone – causes Second- and third- Continuous ECG and BP
over 45 min; older children 30 min ventricular response with increase concentration degree AV block monitoring
12 mg/kg Infusion 40–50 μg/ atrial flutter, bradycardia, of procainamide without pacemaker
kg/min occasionally may asystole, depressed Digoxin – causes Congestive heart Monitor potassium levels – if
need up to 100 μg/kg/min ventricular function, fever increase in digoxin failure potassium decreases
myalgia, AV block, levels Prolonged QT interval arrhythmias may increase
confusion, dizziness, and
headache
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Allen et al. (2013)
AV atrioventricular, VF ventricular fibrillation, INR international normalization ratio, VT ventricular tachycardia, PVCs premature ventricular contractions, BP blood pressure
209
The major side effects of amiodarone include chronotropic incompetence (Brubaker and
hypotension, decreased ventricular function, and Kitzman 2011) (this can occur in children with
bradycardia. chronic heart failure, s/p Fontan procedure, or on
Intravenous procainamide can be very effec- chronic beta-adrenergic blockade).
tive in patients with refractory supraventricular There is a strong association with maternal
tachycardia. The combination of procainamide connective tissue disease and congenital complete
and a beta-blocker is especially effective in heart block. A mother with systemic lupus
treating refractory atrial flutter in the neonate. erythematosus has a 1 in 20 risk of having a
Although verapamil is an effective agent to child with complete heart block if she is anti-Ro
treat supraventricular tachycardia in the child, it positive. Anti-SSA and anti-SSB antibodies (pre-
is contraindicated in the infant with congestive viously termed anti-Ro and anti-La, respectively)
heart failure. The use of verapamil in infants has can cross the placenta and inflame the myocar-
resulted in cardiovascular collapse and death dium and destroy the atrioventricular node (Litsey
(Epstein et al. 1985). et al. 1985; Ramsey-Goldman et al. 1986). How-
In the postoperative child or children in an ever, complete heart block in the neonate may or
intensive care setting, esophageal overdrive pac- may not need treatment. The decision on whether
ing can be used to convert supraventricular tachy- to place a pacemaker in an infant with heart block
cardia. If a temporary atrial wire is placed at the depends on the presence of in utero heart failure
time of cardiothoracic surgery, atrial overdrive (hydrops fetalis) or the development of postnatal
pacing can be used as well. The advantages of congestive heart failure. Heart rate alone is usu-
these modalities are not only treating the arrhyth- ally not an indication for pacemaker placement;
mia but also helping to make a definitive diagnosis however, if the infant’s heart rate remains at below
of the tachycardia. Overdrive pacing involves 50 beats per min, a pacemaker is frequently
pacing the atrium at a rate slightly higher than the required. In the asymptomatic child with congen-
rate of the tachycardia, and with cessation of pac- ital complete heart block, a temporary pacemaker
ing, sinus rhythm will usually return. Pacing is may need to be placed prior to performing most
effective in most forms of supraventricular tachy- surgical procedures requiring general anesthesia.
cardia including atrial flutter (Dick et al. 1988).
VT is unusual in the pediatric patient. It is most
commonly seen in infants with intracardiac Regulation of Whole-Body Oxygen
tumors, such as rhabdomyomas, in infants and Delivery
children with long QT syndrome, and in children
after trauma to the chest. As with SVT, if the child Since the primary role of the cardiovascular sys-
is hemodynamically unstable (hypotensive and tem is to provide sufficient oxygen to meet the
acidotic), immediate direct-current cardioversion metabolic needs of the body, the relationship
should be performed (synchronized if there is a between oxygen consumption and oxygen deliv-
pulse; nonsynchronized if pulseless). In hemody- ery is critical. Whole-body oxygen consumption
namically stable child, VT is usually treated with a is defined as amount of oxygen used by all of the
lidocaine drip; however beta-blockers and even tissues. The amount of oxygen carried from the
amiodarone are used. Intravenous magnesium sul- lungs to the tissues (systemic oxygen delivery
fate is also helpful in children with ventricular DO2) is given by the following equation:
tachycardia (especially if the tachycardia is tor-
sades de pointes).
DO2 ¼ COðcardiac outputÞ
The only situations in which increasing heart
rate may be beneficial to the child with heart CaO2 ðarterial oxygen contentÞ (4)
failure are when the rate is markedly slow due to
either heart block (this can be especially a prob- Arterial oxygen content comprises oxygen
lem with neonates with congenital heart block) or bound to hemoglobin and oxygen dissolved in
plasma. The amount of oxygen bound to hemo- temperature, decreases in pH, and increases in
globin is a function of hemoglobin concentration 2,3-DPG; whereas fetal hemoglobin shifts the
(Hb (gm/100 ml)), the arterial oxygen saturation curve to the left. A shift in the curve to the left, as
of hemoglobin (SaO2), and the oxygen-carrying is seen with fetal hemoglobin, causes a lower (PO2)
capacity of hemoglobin (1.36 ml O2 per gram of to achieve a given saturation (a higher affinity of
hemoglobin). Dissolved oxygen is linearly related hemoglobin for oxygen and thus giving the fetus the
to the arterial partial pressure of oxygen (PO2) and help that it needs with oxygen transport in a
is equal to [0.003 vol % /mmHg low-oxygen environment with a relatively fixed
PO2(mmHg)]. Therefore the follow equation cardiac output). Likewise, a shift to the right causes
defines arterial oxygen content: a higher (PO2) to achieve a given saturation (a lower
affinity of hemoglobin for oxygen, which facilitates
unloading oxygen to the tissues).
CaO2 ¼ ðHb SaO2 1:36Þ
At rest systemic oxygen delivery should
þ ð0:003 vol%=mmHg PO2 ðmmHgÞÞ (5) always greatly exceed resting oxygen consump-
tion (VO2), and the oxygen extraction ratio (EO2)
When calculating arterial oxygen content, (ratio of oxygen consumption to oxygen delivery)
dissolved oxygen can usually be neglected unless is around 25%. This leaves a substantial reserve
the individual is extremely anemic and/or is for increasing the extraction rate. At normal levels
receiving a high inspired oxygen concentration of oxygen delivery, oxygen consumption is con-
that result in a high arterial PO2. Therefore Eq. 4 stant and independent of oxygen delivery. As
becomes: oxygen delivery is gradually reduced, an increase
in oxygen extraction ratio maintains the oxygen
consumption level constant. Eventually a point is
DO2 ¼ COðcardiac outputÞ
reached at which oxygen extraction cannot
ðHb SaO2 1:36Þ (6) increase enough (around an extraction ratio of
55%) to maintain oxygen consumption constant.
Arterial oxygen saturation of hemoglobin Below this level of oxygen delivery, the critical
(SaO2) is a function of (PO2) and the oxyhemo- oxygen delivery level, oxygen consumption is
globin dissociation curve. The oxyhemoglobin limited by supply (Schumacker and Cain 1987).
dissociation curve is sigmoid in shape. This The goal of managing the critically ill child or
results in a curve that is steep up to a (PO2) of neonate is to keep oxygen delivery well above the
60 mmHg and then becomes shallower, critical oxygen delivery level, otherwise tissue
approaching 100% saturation asymptotically hypoxemia and acidosis will develop. A decrease
(e.g., at a (PO2) of 100 mmHg, the (SaO2) is in oxygen delivery can occur if there is a large
approximately 97%, and at 40 mmHg, a typical decrease in any one of its major determinants (Hb,
mixed venous value, the (SaO2) is approximately SaO2, or CO) or a small reduction in more than
75%). The shape of the oxyhemoglobin dissocia- one of these factors, such as would occur with a
tion curves has important implications (West critical illness. Of these three determinants of
1974). The steep portion of the curve between oxygen delivery, the only one that the body by
20 and 60 mmHg permits unloading of oxygen itself can regulate on a minute-to-minute basis is
form hemoglobin at relatively high (PO2) values, cardiac output. We have already discussed in the
thus enabling delivery of large amounts of oxygen previous section how acute changes in preload,
into the tissue. The oxyhemoglobin dissociation afterload, contractility, and heart rate can affect
curve is influenced by a number of factors such as cardiac output. The normal range of cardiac out-
pH, temperature, amount of 2,3-diphosphoglycerate put for infants and children is between 3.5 and
(2,3-DPG), and type of hemoglobin (e.g., fetal 5.0 L/min/m2. When cardiac output decreases
hemoglobin). Factors that shift the oxyhemoglobin below 2 l/min/m2, mortality rate significantly
dissociation curve to the right are increases in increases (Parr et al. 1975; Pollack et al. 1985).
The major determinants of systemic arterial oxy- connect to the inferior vena cava through the
gen saturation are pulmonary function (i.e., lung ductus venous (Dawes et al. 1954; Rudolph and
disease) and the presence of right-to-left intracar- Heymann 1967). The oxygenated umbilical blood
diac shunt (i.e., cyanotic congenital heart disease). flow mixes with the poorly oxygenated portal
Increasing the inspired oxygen concentration will blood from the gastrointestinal tract. Because of
improve systemic arterial oxygen saturation in the Eustachian valve in the right atrium, the higher
children and infants with lung disease but has little saturated umbilical venous blood preferentially
effect in a child with cyanotic congenital heart streams across the foramen ovale into the left
disease. In the absence of lung disease and cya- atrium (Kiserud et al. 1992), whereas the lower
notic heart disease, the infant or child will tolerate saturated blood from both the distal inferior vena
a decrease in hemoglobin level to as low as 7 gm/ cava and from the superior vena cava enter the
100 ml, whereas if the arterial saturation decreases tricuspid valve and are directed to the right ven-
to below 80% (either due to lung dysfunction tricle. Although there are preferential patterns of
and/or cyanotic heart disease), the infant or child flow, some of the blood from the placenta does
may only tolerate their hemoglobin decreasing to enter the tricuspid valve, and some of the blood
14 gm/100 ml. from the distal inferior vena cava and superior
Of course, while optimizing oxygen delivery is vena cava enters the foramen ovale. Both right
one way to avoid tissue hypoxia, one can lower and left ventricles pump to the systemic circula-
the critical threshold by decreasing oxygen tion. The right ventricular output is directed
demand. Sedation, intubation, mechanical venti- through the ductus arteriosus to the descending
lation, neuromuscular blockade, aggressive fever thoracic aorta, and the left ventricular output is
control, treating infections, and halting feeds are directed although the aortic valve to the ascending
all techniques that can be utilized to decrease aorta. Because of the preferential streaming of
oxygen demand. umbilical venous return, the most oxygenated
blood goes to the left ventricle and is distributed
to the heart and cerebral circulations, whereas the
The Fetal Circulation lower oxygenated blood goes to the right ventricle
and is distributed to the pulmonary arteries,
When taking care of the fetus or neonate, in addi- abdominal organs, and placental arteries
tion to understanding preload, afterload, contrac- (Rudolph and Heymann 1967; Rudolph 2000).
tility, and heart rate, it is also critical to also Because of this unique fetal circulation, many
understand how birth affects the cardiovascular types of congenital heart disease that are not com-
system. The fetal circulation differs from the patible with life after birth are well tolerated in
child or adolescent circulation in a number of utero. For example, infants with hypoplastic or
ways. The child or adolescent circulation is char- atretic left or right ventricular outflow tracts
acterized as blood flow in series. That is, blood develop normally in utero, whereas after birth
returns to the heart from the venous system to the these lesions are fatal unless surgery is performed.
right atrium, and ventricle and is then injected into With birth there is a rapid transformation from the
the lungs for oxygenation. Oxygenated blood then fetal circulation to the child or adolescent circula-
returns through the pulmonary veins to the left tion. This transformation involves elimination of
atrium, and ventricle and is then ejected into the the umbilical-placental circulation, establishment
arterial system. The right ventricle works against of an adequate pulmonary circulation, and sepa-
the low afterload of the pulmonary circulation, ration of the left and right sides of the heart by
whereas the left ventricle works against the high closure of the ductus arteriosus and foramen ovale
afterload of the systemic circulation. In the fetus, (Rudolph 2000). Persistence of the fetal circula-
oxygenation and carbon dioxide elimination takes tion after birth means that adequate pulmonary
place in the placenta. Oxygenated blood flows to circulation is not achieved and fetal channels
the fetus through the umbilical veins which have not been closed. For example, infants with
congenital diaphragmatic hernia may have persis- of congenital heart disease are frequently associ-
tence of the fetal circulation because of high pul- ated with other congenital lesions that require
monary resistance due to poor oxygenation and general surgical procedures to be performed in
persistent patency of the foramen ovale and the newborn period. For example, tetralogy of
ductus arteriosus. Fallot and ventricular septal defects are common
There are some cardiac and noncardiac lesions in infants with tracheoesophageal fistulas, anal
that are not tolerated in utero. As mentioned atresia, and other lesions common to VACTERL
above, the fetus is prone to edema formation association. Interrupted aortic arch, truncus
with volume overload. Fetal anemia, atrioventric- arteriosus, and tetralogy of Fallot are frequently
ular valve regurgitation, tachycardia, bradycardia, present in infants with the DiGeorge syndrome.
and arteriovenous malformations all can lead to Hypoplastic left heart syndrome has been reported
increased end-diastolic volume and pressure in to occur in infants with congenital diaphragmatic
the right ventricle (which is responsible for the hernia. More than 60% of infants with Down
majority of the combined cardiac output in the syndrome have congenital heart disease (patent
fetus) (Rudolph 2000). This increase in ductus arteriosus, ventricular septal defects, atrio-
end-diastolic pressure and volume causes elevated ventricular septal defects, and tetralogy of Fallot).
systemic venous pressure which can lead to Because of the strong association of congenital
edema formation, ascites, and pleural effusions. heart disease with other congenital anomalies that
This phenomenon is termed hydrops fetalis. require general surgery in the newborn period, a
Hydrops fetalis is important for the pediatric sur- cardiology consultation and echocardiogram are
geon to consider for two reasons. One, one may be frequently necessary prior to the surgical proce-
called upon to place abdominal or pleural drains in dure. The exact management of the infant depends
symptomatic newborns. Two, when managing on the type of congenital heart disease.
these patients, birth does not necessarily fix the In infants with restricted pulmonary blood
above problems, and definitive diagnosis and flow, such as seen with tetralogy of Fallot and/or
timely treatment is necessary. pulmonary atresia, ductal patency is necessary in
order to maintain adequate oxygenation. If a
ductus was present in fetal life, it can usually be
How Selected Types of Congenital maintained patent with the administration of pros-
Heart Disease Affect Cardiovascular taglandin E1. If the ductus is patent, low-dose
Physiology prostaglandin (0.02–0.03 μg/kg/min) is usually
sufficient to maintain its patency, but if the ductus
Congenital heart disease and congenital heart dis- is virtually closed, higher doses (0.1 μg/kg/min)
ease surgery can cause drastic alterations in typi- of prostaglandin may be initially necessary. Side
cal cardiovascular physiology. A complete effects associated with prostaglandin administra-
understanding of this is beyond the scope of this tion include apnea, seizures, fevers, hypotension,
chapter, and expert consultation is required to and flushing. Once the infant has been stabilized,
manage these patients. However, there are certain then more definitive therapy can be contemplated
pathophysiologic themes in patients with congen- (complete repair or systemic to pulmonary artery
ital heart disease about which pediatric surgeons shunt).
should be aware. In infants with hypoplastic left heart syndrome,
Heart defects are the most common form of initial management requires that an atrial septal
congenital defects. The exact incidence is unclear defect be present and that ductal patency be
based on what is defined as “congenital heart maintained. In these infants, systemic blood flow
disease,” but around 6 in 1,000 of babies born is directly related to both pulmonary vascular
will have moderate or severe congenital heart resistance and oxygen saturation, while systemic
disease, while many more will have less severe blood flow is inversely related to systemic vascu-
lesions (Hoffman and Kaplan 2002). Certain types lar resistance (i.e., as pulmonary resistance
decreases, pulmonary blood flow increases to the systemic arterial system) cause few symp-
resulting in a higher oxygen saturation and a toms for neonates. However, they may appear
lower systemic blood flow). The ideal systemic cyanotic, and their oxygen saturation, as mea-
oxygen saturation in an infant with hypoplastic sured by pulse oximetry or arterial blood gas
left heart syndrome is around 80%. When oxygen sampling, will be lower than normal. Understand-
saturations are in the high 80s to low 90s, the ratio ing the lesions that can cause a right-to-left shunt
of pulmonary to systemic blood flow can exceed is beyond the scope of this chapter. However
4:1 resulting in systemic hypoperfusion; when when managing these patients, whether their
oxygen saturation is in the high 70s to low 80s, right-to-left shunt is secondary to unrepaired or
the pulmonary to systemic flow ratio is nearly palliated cardiac disease, it is important to remem-
balanced. Ideally these infants respire spontane- ber that the etiology of worsened arterial
ously without supplemental oxygen. In some desaturation is more complex than a patient with-
cases, in order to augment systemic blood flow, out cardiac disease. For instance, if a patient with
it may be necessary to cause pulmonary vasocon- a right-to-left shunt has a drop in pulse oximetry
striction which can be accomplished by placing from 80% to 70%, the etiology may be secondary
the infant in a mixture of room air and nitrogen to pulmonary venous desaturation (i.e., lung dis-
lowering the FiO2. Once the infant has been sta- ease) as is the case the majority of time for patients
bilized, surgical or hybrid palliation is performed. with normal hearts. However, systemic arterial
In some selected cases, cardiac transplantation saturation in patients with right-to-left shunt may
may be the best surgical option for the infant. also be lower secondary to systemic venous
Infants with ventricular or atrioventricular sep- desaturation or decreased pulmonary blood flow.
tal defects usually have no symptoms from their The former is seen with increased oxygen extrac-
heart disease during the first month of life. Con- tion at the tissues which may be due to decreased
gestive heart failure from a ventricular septal oxygen supply (low cardiac output, low hemoglo-
defect is usually the result of excess pulmonary bin concentration, etc.) or increased oxygen
blood flow from a “left-to-right shunt.” The two demand (fever, seizures, infection, etc.). The latter
major determinants of left-to-right shunt flow is seen with anatomic obstruction (worsened pul-
across a ventricular septal defect are the size of monary valvar stenosis, narrowed shunt,
the defect and the ratio of pulmonary arteriolar to narrowed aortopulmonary collaterals, etc.) and
systemic arteriolar resistance. Since in a full-term physiologic obstruction (elevated downstream
infant it usually takes from 4 to 6 weeks for the (left atrial or pulmonary venous) pressure,
pulmonary resistance to drop to normal levels, increased pulmonary vascular resistance, etc.).
infants with large ventricular level defects do not Thus, these patients should be managed with the
usually develop heart failure until the second aid of consultative services experienced with
month of life. Causes of early heart failure in an complex congenital heart disease.
infant with a ventricular septal defect include The majority of children who have had suc-
(1) prematurity, (2) inappropriate use of pulmo- cessful repair of congenital heart disease have
nary vasodilators (like supplemental oxygen), and normal or near normal cardiovascular physiology
(3) associated cardiac lesions. The two lesions after successful surgical correction. The one major
most often associated with the early development exception is the child who has had a total
of congestive heart failure are the presence of a pulmonary-cavo anastomosis or Fontan opera-
coarctation of the aorta and, especially in the case tion. The introduction in 1971 of the Fontan pro-
of atrioventricular septal defect, the presence of cedure (which directly diverts all systemic venous
significant atrioventricular valvular regurgitation. blood into the pulmonary arteries) revolutionized
Similar left-to-right shunting lesions, most the treatment of complex congenital heart disease
“right-to-left” shunting lesions (when the sys- (Fontan and Baudet 1971). Fundamental to the
temic venous blood bypasses the pulmonary vas- physiology of the Fontan circulation is that pul-
cular bed and the deoxygenated blood is pumped monary blood flow is no longer determined by the
pumping of the right ventricle. Instead pulmonary and/or intensivists familiar with Fontan physiol-
blood flow relies upon an energy gradient between ogy is recommended.
the systemic veins and the pulmonary arteries Lastly, in the introduction, when describing
without a pressure gradient. Any postoperative Ohm’s law, it was mentioned that when determin-
conditions that significantly increase pulmonary ing driving pressure, venous pressure was omitted
resistance (pneumonia, atelectasis, pneumotho- because it is negligible compared to arterial pres-
rax, etc.) will not be well tolerated since the sys- sure. This is not always the case in patients with
temic venous pressure may be unable to overcome cardiac disease. Elevated venous pressures are
the resistance and provide forward blood flow. seen in Fontan patients, in patients with diastolic
The fluid status of these children must be closely dysfunction, and in iatrogenic caval obstruction.
monitored to ensure an adequate central venous In patients with elevated venous pressures, it is
pressure since this is the driving force for pulmo- important to remember that adequate cardiac out-
nary blood flow. This is why abdominal insuffla- put may require supranormal arterial blood pres-
tion (frequently used in laparoscopic surgery) can sure. This phenomenon of downstream pressure
have such a deleterious effect on this population. in determining blood flow applies to individual
Venous return and pulmonary blood flow are organs as well. Knowledge of this concept is vital
maintained through (1) adequate intravascular to the pediatric general and subspecialty surgical
volume repletion and (2) patient positioning. management. For example, cerebral perfusion
Blood return from the superior vena cava is pressure (the difference of the mean arterial
aided by gravity. Simple interventions such as blood pressure and the intracranial pressure) is a
having the child sit up or elevating the head of vital concept in neurosurgery when determining
the bed will improve venous return. Similarly, blood flow (and thus oxygen delivery) to the
elevating the legs may also augment blood return brain. Another example is compartment syn-
from the inferior vena cava. drome, whether abdominal or musculoskeletal,
Since pulmonary blood flow relies on passive when the downstream interstitial pressure rises
venous return, any increase in intrathoracic pres- disproportionately compared to the mean arterial
sure can have a deleterious effect on cardiac out- blood pressure. In all of these examples, if the
put. Elevated intrathoracic pressures from positive mean arterial blood pressure does not rise to com-
pressure ventilation will negatively affect venous pensate for elevated downstream venous/intersti-
return in the child with Fontan physiology. tial pressures, oxygen delivery is impaired, and
Although in Fontan patients, excessive positive tissue necrosis can occur.
end expiratory pressure (PEEP) can increase pul-
monary vascular resistance (Williams et al. 1984),
it can be of benefit in the child with Fontan phys- Conclusions and Future Directions
iology; PEEP at appropriate levels both maintains
functional residual capacity (leading to a decrease The future of surgery for congenital and acquired
in pulmonary vascular resistance by avoidance of heart disease is exciting. New preservation tech-
atelectasis and hypoxic vasoconstriction) and niques, including mechanical circulatory support,
increases arterial oxygen concentration. However, for the heart and other organs can lessen the
spontaneous respiration creates a negative intra- effects of ischemic time for explanted organs.
thoracic pressure with inspiration, which Tissue engineers are attempting to “grow” new
increases systemic venous return and ultimately cardiac valve and muscle tissue (Hasan et al.
pulmonary blood flow (Lofland 2001). Therefore, 2016; Parvin Nejad et al. 2016). With the proper
if at all possible, it is important to extubate the extracellular scaffolding, the hope is that someday
child with Fontan physiology as early as possible. and whole organ could be regenerated. If these
When perioperative invasive and non-invasive tissues are engineered without major histocompat-
positive pressure ventilation is necessary, expert ibility antigens or with patients’ own tissue, then
consultation by anesthesiologists, cardiologists, these novel tissues could be transplanted into a
recipient with less or no need for immunosuppres- Artman M, Graham Jr TP. Guidelines for vasodilator ther-
sion. Finally, the age of single-center surgical tri- apy of congestive heart failure in infants and children.
Am Heart J. 1987;113(4):994–1005.
als will be replaced by multiinstitutional Assali NS, Johnson GH, Brinkman 3rd CR, Kirschbaum
collaborations to overcome the limited number TH. Control of pulmonary and systemic vasomotor
of pediatric patients with rare diseases. tone in the fetus and neonate. Am J Obstet Gynecol.
Surgical advances are inevitable. New tech- 1970;108(5):761–72.
Atkins DL, Kerber RE. Pediatric defibrillation: current
niques and technology will push the boundaries flow is improved by using “adult” electrode paddles.
of which lesions get repaired, when then get Pediatrics. 1994;94(1):90–3.
repaired (including fetal interventions), and how Beekman RH, Rocchini AP, Dick 2nd M, Crowley DC,
they are repaired. What will not change is that Rosenthal A. Vasodilator therapy in children: acute and
chronic effects in children with left ventricular dysfunc-
good surgical results are in part determined by tion or mitral regurgitation. Pediatrics. 1984;73
the avoidance of tissue hypoxia. Limiting oxygen (1):43–51.
demand and optimizing oxygen delivery are the Bengur AR, Beekman RH, Rocchini AP, Crowley DC,
two avenues to achieve this. In particular, knowl- Schork MA, Rosenthal A. Acute hemodynamic effects
of captopril in children with a congestive or restrictive
edge of the age-related differences in the determi- cardiomyopathy. Circulation. 1991;83(2):523–7.
nants of oxygen delivery, namely, oxygen content Bhatt-Mehta V, Nahata MC. Dopamine and dobutamine
and cardiac output, is essential when caring for in pediatric therapy. Pharmacotherapy. 1989;9
perioperative surgical patients. Preload, afterload, (5):303–14.
Brubaker PH, Kitzman DW. Chronotropic incompetence:
contractility, and heart rate interact in predictable causes, consequences, and management. Circulation.
ways to affect cardiac output, but the effect and 2011;123(9):1010–20.
magnitude of intervention is dependent on the Bruns LA, Chrisant MK, Lamour JM, Shaddy RE, Pahl E,
maturity of the cardiovascular system. Blume ED, et al. Carvedilol as therapy in pediatric heart
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Pediatric Hepatic Physiology
13
Mark Davenport and Nedim Hadzic
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Liver Blood Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Fetal Life and Transitional Circulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Postnatal Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Metabolic Functions of Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Bile Formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Bilirubin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Bile Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Hepatic (or Canalicular) Bile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Hormonal Control of Bile Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Carbohydrate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Protein Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Albumin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Nitrogen Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
The Role of the Liver in Hemostasis and Clotting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Abstract
The liver is a complex organ with a central role
M. Davenport (*) in processing the effects of phasic enteral nutri-
Department of Paediatric Surgery, Kings College Hospital
NHS Foundation Trust, London, UK tion, while ensuring metabolic homeostasis. It
e-mail: markdav2@ntlworld.com; therefore successfully combines various com-
mark.davenport@kingsch.nhs.uk plementary biochemical processes involving
N. Hadzic proteins, carbohydrates, and lipids. It contrib-
Paediatric Liver Centre, Kings College Hospital, utes to the breakdown and hence absorption of
London, UK ingested lipids and is an integral part of
e-mail: nedim.hadzic@kcl.ac.uk

https://doi.org/10.1007/978-3-662-43588-5_14
220 M. Davenport and N. Hadzic
cholesterol metabolism and excretion. It supply derived from the hepatic arteries is rela-
remains the only site of excretion of the prod- tively trivial.
ucts of heme degradation via absorption, con- At the time of birth, major transitional hemo-
jugation, and excretion of bilirubin. dynamic changes occur including functional clo-
The liver also plays a central role in synthe- sure of ductus arteriosus and foramenovale,
sis of key protein components of the coagula- reduction in right pulmonary arterial pressures,
tion cascade. and the cessation of umbilical blood flow. This
leads to functional closure of the ductus venosus
Keywords and separation of the portomesenteric venous sys-
Liver physiology · Protein metabolism · Lipid tems and a marked increase in well-oxygenated
metabolism · Bile excretion · Carbohydrate blood flow via the hepatic artery. Commencement
metabolism of enteral nutrition and consequent increases in
intestinal perfusion also lead to increased sinusoi-
dal liver perfusion and bile flow.
Introduction
The liver is a complex organ with a central role in Postnatal Life

processing the effects of phasic enteral nutrition,
while ensuring metabolic homeostasis. It there- The liver is the most vascular organ in the body
fore successfully combines various complemen- with about 25–30% of its mass consisting entirely
tary biochemical processes involving proteins, of blood. Similarly, the blood flow through it is
carbohydrates, and lipids. It contributes to the considerable being about 100 mL/min/100 g liver
breakdown and hence absorption of ingested weight (or 30 ml/min/kg body weight) and there-
lipids and remains the only site of excretion of fore about 25% of the cardiac output at rest.
the products of heme degradation. Hepatic blood flow is derived from two sources
that are structurally and functionally distinct.
Approximately two-thirds is provided through
Liver Blood Flow the portal vein draining the splanchnic organs at
low pressure (~7 mmHg). The trans-sinusoidal
Fetal Life and Transitional Circulation pressure gradient, between the portal vein and
the inferior vena cava, is therefore normally only
All blood returning passively from the placenta is a few mmHg. Conversely, the mean hepatic arte-
carried through the umbilical vein which joins the rial pressure in adults is ~100 mmHg and is pha-
left portal vein in the liver. Most of the flow then sic, dependent on the cardiac cycle. Actual mixing
bypasses the sinusoidal network via the ductus of these two streams occurs in the sinusoids with
venosus to return to the inferior vena cava (IVC) common hepatic venous outflow. At sinusoidal
and right side of the heart. An oxygen saturation level, blood flow can also be seen to vary from
of ~80% is observable in the umbilical vein very rapid to stagnant and even at times is
(Lautt 2009). reversed.
There is a degree of functional asymmetry Circulating sinusoidal blood only flows past
during fetal life not seen after birth with the right about 16 hepatocytes prior to exiting the microvas-
side perfused with less well-oxygenated blood cular unit of the liver (the acinus) into the hepatic
derived from portal blood flow, and therefore it venule with the average hepatocyte exposed to a
has a proportionally greater role in hematopoiesis. sinusoid on at least two sides. The other important
The left side, by contrast, receives blood mainly sinusoidal characteristic is the large endothelial
from the umbilical vein and has a higher content fenestrations that permit large molecules, such as
of oxygen-dependent enzymes and is more active albumin and lipoproteins, to pass from blood into
in drug binding and metabolism. The blood the underlying space of Disse.
13 Pediatric Hepatic Physiology 221
The liver cannot control portal blood flow, One mechanism for this may be its autonomic
which is simply the splanchnic outflow. Thus if nerve supply; certainly the hepatic artery, if not
the hepatic vascular resistance is increased, for the portal vein, has a rich sympathetic nerve sup-
example, by the stimulation of the hepatic sympa- ply with α-adrenergic receptors mediating a vaso-
thetic nerves, the portal pressure rises, but portal constrictor response.
blood flow does not fall. Vascular resistance to
portal flow occurs both at pre-sinusoidal sites
within the portal venules and at post-sinusoidal Metabolic Functions of Liver
sites within the hepatic venules, and these have
been shown to be passively distensible (Lautt Bile Formation
1996, 2009). There is a clear compensatory
inverse relationship between portal blood flow Bile is a complex solution, produced continuously
and hepatic arterial flow, a phenomenon first by hepatocytes, modified by the cells of the prox-
observed by Betz in 1863 (Betz 1863), which imal biliary tree, stored and concentrated within
therefore tends to maintain constant total hepatic the gallbladder, and, finally, excreted into the duo-
blood flow. This mechanism, however, does not denal postprandial milieu in concert with the
completely compensate but rather buffers the effect ongoing digestive processes of the foregut. It
of portal blood flow changes on total hepatic flow combines various functions such as that of excre-
and has come to be known as the hepatic arterial tion (of bilirubin and cholesterol) and of digestion
buffer response (HABR) (Lautt 1983). (via bile salts). Approximately 500–600 ml of bile
The suggested mechanism of the HABR is as is secreted per day, which is equivalent to ~25 ml/
follows. Adenosine is constantly secreted into the h in an average 70-kg man with a serum osmolal-
space of Mall, a small isolated fluid compartment ity of ~300 mOsm/kg.
at the periphery of the lobule through which Table 1 illustrates the key components.
passes the terminal components of the portal
triad (i.e., fine branches of the hepatic artery,
portal vein, and bile ductule). The concentration Bilirubin
of adenosine, a potent vasodilator, is regulated by
the rate of washout from the space of Mall into the Bilirubin is an open chain tetrapyrrole with eight
blood vessels. When portal blood flow decreases, side chains (Mol. Wt. = 585) (Fig. 1) that in its
less adenosine is washed away, and the elevated pure form has a yellow-reddish color (hence the
adenosine concentration leads to dilation of the name).
hepatic artery. A second form of intrinsic hepatic It is the main by-product (via biliverdin) from
arterial regulation is arterial autoregulation, pre- the oxidation and breakdown of the heme moiety
viously thought to be myogenic in nature. Hence, arising from red cell destruction (80%) and other
if arterial pressure is decreased leading to a reduc- proteins such as myoglobin, catalase, etc. (20%)
tion in arterial blood flow, this washes away less in the reticuloendothelial system tissue of the
adenosine from the space of Mall. Accumulated spleen, bone marrow, etc. The rate-limiting step
adenosine then causes arterial dilation and an in this sequence is microsomal heme oxygenase,
increase in flow. Both the HABR and auto- and about 250–400 mg/day of bilirubin can be
regulation work through the same mechanism produced in an adult (Figs. 1 and 2).
and operate simultaneously, thus leading to poten- Bilirubin is a fat-soluble compound which has
tially complex interactions. Additionally, extrin- to be transported attached to albumin on a high-
sic factors such as circulating hormones (e.g., affinity binding site (1:1) within the circulation to
gastrin, glucagons) and various portal venous the sinusoids of the liver. There, albumin-bound
nutrients interact to affect the hepatic circulation bilirubin is able to pass through the fenestrations
in a number of complex ways, not the least to and via an active transport process in the hepato-
allow increase in total blood flow after a meal. cyte membrane (binding to glutathione
Table 1 Solute concentration in bile

Solute Main component Percentagea
Bile acids Primary bile acids (cholic and chenodeoxycholic acid) 60
Fatty acids 10
Cholesterol 10
Proteins Albumin, immunoglobulins, liver-specific proteins, e.g., 50 nucleotidase 7
Inorganic salts/metals Na, K, HCO3, Cl, Cu 5
Bilirubin Mono/diglucuronide 3
Phospholipids Phosphatidylcholine 3
a
Percentages represent ratio to solute concentration (mg/ml)
CH2 CH2
CH3
H CH3
C CO
H3C H 3C COOH COO− COO−
N N CH2 NH H2C H2C
N
HC Fe CH O H3C H3C H3C H3C
N N Haem O Biliverdin
H3C CH3 oxygenase N HN reductase O N N N N O
C
H 2+
COOH H H H H
Fe
H2C CH3
H 3C
HOOC COOH
Haem Biliverdin Bilirubin
Fig. 1 Breakdown of heme moiety via biliverdin to bili- (Figure reproduced with permission from: Motterlini and
rubin with liberation of carbon monoxide. Key enzymes Otterbein 2010)
are heme oxygenase and biliverdin reductase
Hemoglobin Bilirubin ligandin Bilirubin 2

7
(unconjugated) (Conjugated with 3
Haem oxygenase
glucuronic acid)
Biliverdin
bound to albumin
6 UDPGT
Globin + Heme
urobilinogen
Bacterial enzymes
urobilin
Stercobilinogen
(excreted in urine)
Stercobilin
(by bacterial action)
Fig. 2 Overview of excretion of bilirubin and its metabolism

S-transferase, aka ligandin) moves to the endo- physiological jaundice, and in these it is always
plasmic reticulum where it undergoes conjuga- unconjugated, appearing from 24 h of life and
tion. The aim is to alter its physiochemical usually fading in the second week. Its origin is
properties into a polar, water-soluble molecule multifactorial and appears related to immature
ready for excretion. The main carbohydrate con- liver enzymes (such as glucuronyltransferase), a
jugate is glucuronic acid, but glucose and xylose higher turnover of red cells (incorporating the
are also possible; the main enzyme involved is transition from fetal to adult hemoglobin) and,
therefore uridine diphosphate glucuronosyl- occasionally, to the effects of breastfeeding.
transferase (UDPGT). Gilbert syndrome is
caused by functional defects in this enzyme and
leads to an essentially benign, recurrent Bile Acids
unconjugated jaundice, particularly at times of
stress or fasting. Bile acids are synthesized in the hepatocyte by a
Conjugated bilirubin (mostly as the complex multienzyme process (with at least
diglucuronide form) is then secreted into the bili- 17 steps) from cholesterol. They have four main
ary canaliculus via a complex carrier-mediated functions: providing the main pathway for deg-
mechanism. There are a number of inborn errors radation and excretion of excess cholesterol,
of metabolism that are characterized by a failure maintaining solubility of that cholesterol while
of this conjugation process, but the classical in the biliary tree, aiding intestinal dietary lipid
example is that of the Crigler-Najjar syndrome absorption in the formation of intestinal mixed
(Crigler and Najjar 1952 ) where there are high micelles, and, finally, facilitation of fat-soluble
serum levels of unconjugated bilirubin due to vitamin absorption. Cholesterol itself is an
defects in the UDPGT gene. almost completely insoluble, hydrophobic com-
Bilirubin is further metabolized within the dis- pound but with bile acids and phospholipids is
tal small intestine by bacterial β-glucuronidase able to exist in a clear, single-phase solution in
action to urobilinogen compounds, and a propor- the bile.
tion is reabsorbed in the distal ileum and There are two primary bile acids, cholic
recirculated enterohepatically. Further conversion (~30% of total bile acids) and chenodeoxycholic
in the colon occurs to stercobilin and acid (~45%), and two secondary bile acids,
stercobilinogen, both of which give feces its deoxycholic and lithocholic acid. These latter
characteristic color. Acquisition of such organ- compounds are the product of anaerobic colonic
isms is age dependent and not really complete bacterial action and later portal venous
until the second year of life (Norin et al. 1985). reabsorption (Aries et al. 1969). All bile acids
The classical method of measuring bilirubin in are conjugated in the hepatocyte with the amino
blood uses the diazo reaction and is known as the acids taurine and glycine and secreted into the
van den Bergh test with two forms being identi- biliary canaliculus by a series of membrane-
fied. The direct reaction estimates the conjugated bound enzymes (e.g., bile salt export pump), ren-
bilirubin fraction, and, with the addition of a pro- dering them impermeable to reabsorption across
moter (alcohol), the indirect reaction measures the cell membranes (Fig. 3).
unconjugated fraction. Normal values for total Intestinal deconjugation (again by bacterial
bilirubin range from 5 to 20 μmol/L action) occurs to allow distal ileal reabsorption
(0.3–1.2 mg/dL) with >95% in the and recirculation.
unconjugated form. The enterohepatic circulation is a complex
uptake mechanism in both the ileal enterocyte
Physiology of Newborn Jaundice and the hepatocyte sinusoidal membrane that
Jaundice is clinically detectable in white skin and efficiently recycles bile acids (Redinger 2003).
sclera when it is >50 μmol/L (3 mg/dL). Up to Both the ileal Na+ bile acid transporter and the
60% of newborn infants will exhibit the so-called hepatocyte Na+-dependent bile acid transporter
Hepatocyte Biliary
r Canaliculus
ABCB4
Phospholipid
Mixed
ABCB11 micelle
Bile Acid
Simple
micelle
ABCG5
Cholesterol
Fig. 3 Excretion and formation of mixed micelles (Figure reproduced by permission of author, Ms. E Makin)
are homologous but different proteins. Sinusoidal to osmotically active glutathione and related
uptake from portal venous blood ensures a very low thiol secretion into the canaliculus. There is
circulating level of total bile acids (<5 μmol/L). also then an active process moderated by the
The actual bile acid loss in feces is <5% of the bile cholangiocytes of the biliary canaliculi which
acid pool, but even this may have pathological tends to dilute and alkalinize by secreting bicar-
consequences as highly hydrophobic molecules bonate and chloride and reabsorbing glucose.
such as deoxycholic acid are cytotoxic and may About one-half of the hepatic bile output enters
act a colon tumor promoter. the gallbladder where it is then concentrated by
a factor of four to six by the removal of water
and electrolytes.
Hepatic (or Canalicular) Bile
Hepatic bile is the fluid secreted directly into Hormonal Control of Bile Flow
the biliary canaliculus and is classically divided
into two components, named because of the There are a variety of foregut hormones which
predominant organic solute, the bile acid- have an action on the flow of bile and produce a
dependent (BADF) and the bile acid-indepen- phasic response to the oral ingestion of food.
dent (BAIF) fractions. The former comprises Cholecystokinin (CCK) is a family of hor-
about one-half of canalicular bile output and mones, with the most active being an octapeptide
is an active transport process with osmotic (CCK-8). It has structural similarities to gastrin
movement of water and electrolytes via para- and shares some of the same receptors. It is
cellular junctions. The latter is probably related secreted by I-cells in the duodenal and small
bowel mucosa in response to protein and fat with stimulate the sphincter of Oddi, impairing bile
its main effects on the liver, gallbladder, pancreas, flow (Nyberg et al. 1992).
and interestingly the central nervous system
(CNS). CCK causes gallbladder and, to a lesser
extent, common hepatic duct contraction and
relaxes the sphincter of Oddi by a direct effect Carbohydrate Metabolism
on smooth muscle which is independent of auto-
nomic innervation. The liver plays a central and primary role in the
In the pancreas it stimulates increased enzyme control of blood glucose levels (Fig. 4). This is a
output. CCK receptors are widely distributed in crucial homeostatic mechanism because of the
the central nervous system (CNS), and it can central nervous system’s absolute requirement
therefore act as a neurotransmitter causing nausea, for glucose as a metabolic substrate, at least in
anxiety, and perhaps inhibition of hunger the early part of the fasting period. Control is
(anorexigenic). achieved by a complex interplay between two
Secretin was the original “hormone” to be main metabolic pathways. These are the creation
recognized by Bayliss and Starling in 1902. It and later breakdown of a storage carbohydrate
is a polypeptide of 27 amino acids that is polymer from glucose (glycogenesis and glyco-
secreted by the S-cells of the duodenal mucosa genolysis) and secondly the ability to create glu-
with stimulatory effects on canalicular bile flow cose from other molecules such as amino acids
by increasing bicarbonate secretion. One other (gluconeogenesis), in the absence or exhaustion
mechanism involved is via its effect on of glycogen.
aquaporin-1 water channels, present in the api- Glycogen is found principally in the liver
cal and basolateral membrane of cholangiocytes (making up ~10% of its mass) and muscle. How-
(Cantor et al. 1992). It also regulates the output ever, because there is a greater overall muscle
of pancreatic juice again by increasing bicarbon- mass, most of the body’s glycogen is found in
ate secretion and inhibits gastric acid production the latter. Glycogenesis is controlled by the action
from the parietal cells leading to an alkaline of the enzyme complex, glycogen synthase, and
duodenal environment. Similarly to CCK, secre- regulated by c-AMP-dependent protein kinase,
tin is also believed to be a neuropeptide, promoted by the action of insulin. Glycogenolysis
although its physiological role remains to be is controlled by the enzyme glycogen phosphory-
defined. There is also evidence of it playing a lase which produces glucose-1-phosphate, isom-
role in osmoregulation by its action on various erizing to glucose-6-phosphate for glycolysis and
extravisceral sites. energy release in muscle and for circulating glu-
The physiological role of other gastrointesti- cose by the action of glucose-6-phosphatase in
nal hormones is still unclear, but a number liver. The main hormonal control exerted in this
appear to have stimulatory hepatobiliary actions. process is by the action of glucagon, epinephrine
For instance, gastrin has a weak secretin-like (adrenaline), and cortisol.
effect, glucagons can also induce BSIF About 40% of an oral glucose load is stored
choleresis; bombesin stimulates biliary bicar- by glycogen synthesis, principally in the liver
bonate and fluid output (Marinelli et al. 1999) (~65%), although there is also significant stor-
as does vasoactive intestinal polypeptide age by the muscle (~25%) and kidney (~10%).
(Thimister et al. 1998). The range of inhibitory About 60% of this liver glycogen arises as a
hormones is less but includes somatostatin, result of the direct pathway described already
substance P, and the distal gut hormone pan- with the remainder indirectly via conversion
creatic peptide YY. Somatostatin, in particular, from three-carbon compounds such as lactate,
has been shown to reduce total hepatic bile out- pyruvate, and alanine (Woerle et al. 2003;
put, to reduce bile acid secretion, and to Petersen et al. 2001).
Iactate
pyruvate glycogen
alanine
glycogen
glucagon 8 2
insulin insulin 7
gluconeogenesis 3
(via GLUT-4)
5 4
insulin glucagon
Vagal stimuli catecholamines
cortisol
glucose growth hormone
glycogen
glycogen synthase Sympathetic stimuli
glycogen
phosphoryluse
glutamine
Na+ and glucose co-transport

via GLUT-5 receptor
Fig. 4 Central role of the liver in carbohydrate metabolism
The CNS requirement for circulating glu- muscle and renal cortical tissue. Ketogenesis
cose means that other mechanisms must exist occurs in the hepatocyte mitochondrial matrix
following the extinction of glycogen storage, where free fatty acids (FFA) are first broken
i.e., gluconeogenesis. The process of gluconeo- down to acetyl CoA via β-oxidation. The acetyl
genesis is exclusive to the liver and the kidney CoA is then used in ketogenesis. The primary
although there are substrate differences; for regulator of ketone body synthesis is fatty acid
instance, alanine gluconeogenesis only occurs availability; hence increases in plasma FFA
in the liver, while glutamine gluconeogenesis concentration (by high glucagon, low insulin
primarily occurs in the kidney (Magnusson levels) cause increased β-oxidation and high
et al. 1994; Stumvoll et al. 1998). The most concentrations of acetyl CoA, resulting in
important substrates are pyruvate, lactate, glyc- ketone body synthesis.
erol, and glucogenic amino acids (especially Lactate is a product of anaerobic glycolysis,
alanine). principally in muscle, which can be taken up and
Ketone bodies (i.e., acetoacetate, metabolized in various tissues (e.g., myocardium)
β-hydroxybutyrate, and acetone) circulate nor- to provide energy. However, only in the liver and
mally in low concentrations (<0.3 mM) and are the kidney can lactate be a substrate for gluconeo-
perfectly capable of crossing the blood-brain genesis. This glucose-lactate-glucose cycling
barrier to be used as CNS fuel if given the between the tissues is known as the Cori cycle.
chance (e.g., in the fasted state). They are also The total amount of lactate involved is large (up to
the preferential glucose-sparing fuel in the heart 1,500 mmols/day in adults), and if liver
mitochondrial metabolism is not adequate, then increases, at least in normal subjects, with exoge-
the condition of lactic acidosis results. nous administration (Barle et al. 2001). Stress or
inflammation tends to cause an initial fall in syn-
thesis due to a rise in production of acute phase
proteins, but later there is an actual increase in
Protein Synthesis albumin synthesis. Low plasma albumin levels are
often associated with fluid shifts rather than any
About 25% of all protein synthesis occurs in the
diminution in synthesis.
liver, with the major products being albumin, α1-
The main circulating protein in fetal life is
globulins [e.g., high-density lipoproteins (HDLs)
α-fetoprotein (AFP) and is the direct equivalent
and very high-density lipoproteins (VHDLs), gly-
to albumin produced by the liver.
coproteins, haptoglobulins], α2-globulins (e.g.,
ceruloplasmin, plasminogen, prothrombin),
β-globulins [e.g., low-density lipoproteins
Nitrogen Metabolism
(LDLs) and very low-density lipoproteins
(VLDs), transferrin], and coagulation factors.
The liver is the major site of nitrogen metabolism
in the body. This arises either endogenously from
amino acid breakdown or exogenously as
Albumin ingested dietary protein and from the action of
colonic bacteria. Nitrogen, derived from excess
This is the main circulating plasma protein amino acids, can be eliminated via transamina-
(35–40 g/dl) in postnatal life and was first tion, deamination, and urea formation; the
sequenced in 1975. It consists of 584 amino residual carbon skeleton being conserved as car-
acids with a molecular weight of ~66,500 and is bohydrate (gluconeogenesis), or synthesized to
synthesized in the rough endoplasmic reticulum fatty acids. Amino acids can therefore be catego-
of the hepatocyte and secreted via a series of rized as either glucogenic or ketogenic
intermediates (preproalbumin, prealbumin) into depending on their products. Thus glucogenic
the circulation either directly via the space of amino acids are those that produce pyruvate or
Disse or via hepatic lymphatics. There is a con- TCA cycle intermediates (e.g., α-ketoglutarate or
tinual flow of albumin into the extravascular space oxaloacetate) and hence are precursors to glucose.
(about 4%/h – the so-called transcapillary escape All amino acids are at least partly glucogenic
rate). Nevertheless, it is the main source of intra- except lysine and leucine, which because they
vascular oncotic pressure (up to 80%) and has an give rise to acetyl CoA or acetoacetyl CoA only
overall half-life of ~20 days. Its other roles are therefore ketogenic. A smaller number of
include binding (e.g., drugs) and transport (e.g., amino acids (isoleucine, phenylalanine, threo-
bilirubin), scavenging of free radicals, and possi- nine, tryptophan, and tyrosine) have both
bly a role in anticoagulation. The site of degrada- glucogenic and ketogenic potential.
tion is not known with precision but may be the The urea cycle, which involves arginine,
hepatic sinusoidal endothelial network. There is ornithine, and citrulline, utilizes two molecules
no storage form of albumin, and therefore changes of ammonia and produces one molecule of water-
in its level depend on its synthesis or its loss from soluble urea for excretion in the kidney. Hyper-
the body. ammonemia (>40 mmol/l) occurs in a number of
Impaired albumin synthesis is seen in protein liver disorders, rarely in relation to primary urea
malnutrition and cirrhosis (either by a reduced cycle enzyme defects and more commonly in
liver cell mass per se or by nutrient diminution acute liver failure, cirrhosis, portosystemic shunts,
consequent on disordered vascularity). It is also etc. Elevated serum ammonia is related to the
under a degree of hormonal control and dimin- development of hepatic encephalopathy,
ishes with low growth hormone levels and although the actual mechanism is multifactorial
and still debated. It includes changes in cerebral cytosol, a process promoted by insulin. Triglycer-
hemodynamics, production of false neurotrans- ide synthesis also occurs from glycerol and fatty
mitters, and activation of central γ-aminobutyric acids. β-oxidation of fatty acids occurs in mito-
acid-benzodiazepine receptors by endogenous chondria and appears to be the hepatocyte’s main
ligands, zinc deficiency, and alterations in cerebral source of ATP and NADH for energy supply.
metabolism (Riordan and Williams 1997; Strauss
et al. 2001).
The Role of the Liver in Hemostasis
and Clotting
Lipid Metabolism
There are two distinct phases in the coagulation of
The three main classes of circulating lipids are blood.
cholesterol, triglycerides and phospholipids. As
might be expected they are all insoluble in water 1. Primary hemostasis occurs when platelets
and are all carried in solution by complexing with adhere to exposed collagen in injured vascular
lipoproteins. These were first described in the endothelium, becoming activated and liberat-
1920s and subsequently named according to ing factors which contribute to the subsequent
their “buoyant density” into chylomicrons, very coagulation cascade (e.g., thromboxane A2,
low-density lipoproteins (VLDLs), low-density Factor V) and attracting further platelet aggre-
lipoproteins (LDLs), and high-density lipopro- gates and leucocytes.
teins (HDLs). A fifth class of very high-density 2. Secondary hemostasis involves activation of
lipoproteins (VHDLs) was more recently recog- the two pathways of the coagulation cascade,
nized. Chylomicrons are the largest, produced by the contact activation pathway (formally
enterocytes and contain large amounts of triglyc- known as the intrinsic pathway) and the tissue
eride (>80%), while HDLs are small molecules factor pathway (formally known as the extrin-
partly synthesized by hepatocytes and contains sic pathway) that leads to the formation of
virtually no triglyceride. The half-life of chylomi- fibrin from fibrinogen. Both coagulation path-
crons is short (~30 min) as their function is to ways consist of a series of reactions, in which a
transport dietary lipid to the lipid storage area in serine protease (usually) and its glycoprotein
adipose tissue. The main lipoproteins secreted by cofactor are activated to components which
the liver are VLDLs, often in response to an then catalyze the next reaction in the cascade.
increase in circulating fatty acids, and controlled The penultimate stage is the conversion of
by estrogens, insulin, and possibly thyroid hor- prothrombin to thrombin, now known as the
mones. LDLs probably arise as a result of degra- “thrombin burst,” and then conversion of
dation of VLDLs. HDLs are secreted from fibrinogen to the cross-linked fibrin polymer,
hepatocytes as biconcave discs but change mor- the actual fabric of the hemostatic clot. Coag-
phology by the action of an hepatic enzyme, lec- ulation factors are generally indicated by
ithin-cholesterol acyltransfersase (LCAT), into Roman numerals, with a lowercase
a more spherical object capable of transporting a appended to indicate an active form.
cholesterol within its core. Clinically such HDL
levels have an inverse relationship with athero- Thrombolysis and fibrinolysis are important
sclerosis, and to some extent, presumably because counterweights to the coagulation process and are
of the liver origin of LCAT, cirrhotics share the largely dependent on the effects of protein C
same tendency. VHDLs contain mostly albumin (which degrades the cofactors Factor Va and Fac-
and carry mostly free fatty acids. tor VIIIa), its cofactor protein S and antithrombin
There are other key functions of the hepatocyte III (which degrades thrombin and Factor Xa).
in lipid metabolism. Fatty acids are synthesized Additionally, tissue plasminogen activator (t-PA)
from acetyl CoA (via malonyl CoA) in the and urokinase-type plasminogen activator (u-PA)
are also important and again are synthesized in the Conclusions and Future Directions
liver.
Fat-soluble vitamin K is an essential factor to There has been a recent increase in understanding
hepatic γ-glutamyl decarboxylase that adds a of liver physiology prompted not so much by
second carboxyl group to glutamic residues on experimentation in the laboratory but by the
Factors II, VII, IX, and X, as well as protein S, growth in molecular biology. Bile secretion is
protein C, and protein Z. Vitamin K deficiency multilayered and more complex than realized
either pathologically (e.g., cholestasis and malab- with implications on congenital conditions such
sorption) or therapeutically (e.g., warfarin) as the family of progressive familial intrahepatic
impairs the function of the enzyme and leads to cholestasis. Our understanding of vascular liver
the formation of proteins induced in vitamin K physiology has direct implications during the
absences (PIVKAs) which cause partial or operation of liver transplantation making this pro-
non-gamma carboxylation affecting the coagula- cedure safer with perhaps reduced complications
tion factors’ ability to bind. related to poor reperfusion and primary non-
All coagulation factors are produced in the function.
liver except for von Willebrand factor (vWF),
which is produced in endothelial cells, and possi-
bly Factor VIII. Von Willebrand’s factor is also a
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▶ Biliary Atresia
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Nyberg B, Angelin B, Einarsson K. Somatostatin does not eases: from pathobiology to pharmacological targets.
block the effect of vasoactive intestinal peptide on bile World J Gastroenterol. 2006;12:4445–51.
secretion in man. Eur J Clin Investig. 1992;22:60–6.
Metabolism of Infants and Children
14
Faraz A. Khan, Jeremy G. Fisher, Eric A. Sparks, and Tom Jaksic
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
The Metabolic Response to Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
Nutritional Assessment/Estimation of Energy Expenditure During Illness . . . . . . . 233
Nutrient Reserves and Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Macronutrient Intake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Review of Protein Metabolism and Requirement During Illness . . . . . . . . . . . . . . . . . . . . . . 236
Protein Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Modulating Protein Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Carbohydrate Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Glucose Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Abstract protracted illness. Appropriate nutritional

Despite advances in the field of nutrition, prev- intervention following any metabolic stress is
alence of malnutrition remains strikingly high predicated upon an understanding of the pro-
in hospitalized patients particularly those with found, yet predictable, alteration in metabo-
lism. The primary aim of these interventions
is to augment the short-term benefits of the
F. A. Khan (*) · J. G. Fisher · E. A. Sparks · T. Jaksic pediatric metabolic response to insult or injury
Center for Advanced Intestinal Rehabilitation, Department
of Surgery, Boston Children’s Hospital and Harvard
while minimizing any long-term conse-
Medical School, Boston, MA, USA quences. The metabolic state following insult
e-mail: fkhan@med.wayne.edu; or injury progresses through two predictable
jeremy.fisher@childrens.harvard.edu; eric. stages: an initial hypometabolic “ebb phase,”
sparks@childrens.harvard.edu;
tom.jaksic@childrens.harvard.edu

https://doi.org/10.1007/978-3-662-43588-5_15
232 F. A. Khan et al.
followed quickly by a prolonged increase in requirements, increased substrate turnover, and

overall metabolic rate called the “flow phase.” relatively reduced lean body stores. These factors
Quantification of energy requirements is an render the prompt institution of nutritional therapy
important first step in the design of appropriate particularly important in ill children.
nutritional strategies, as dietary regimens that
both underestimate and overestimate energy
needs are associated with injurious conse- The Metabolic Response to Stress
quences. Pediatric patients additionally have
several key differences as compared to adults The metabolic response to illness due to stressors
in terms of available metabolic reserves, base- such as inflammation, trauma or surgery has been
line energy, and substrate requirements. The well described. Cuthbertson was the first investi-
metabolic stress response leads to enhanced gator to describe the primary role that whole-body
protein, glucose, and lipid turn over to provide protein catabolism plays in the systemic response
energy and substrate needed for healing and to injury (Cuthbertson 1970). He established that
recovery. This enhanced substrate turnover is the metabolic state following injury progresses
beneficial in the short-term, but the conse- through two stages: an initial hypometabolic
quences of sustained catabolism may be quite “ebb phase,” followed quickly by a prolonged
rapidly deleterious in children. While this sub- increase in overall metabolic rate, called the
strate breakdown cannot be completely “flow phase” (Cuthbertson 1942). The initial
reversed, knowledge of the key differences in brief ebb phase is characterized by decreased
the pediatric metabolic stress response can help enzymatic activity, reduced oxygen consumption,
design nutritional regimens, which can miti- low cardiac output, and a core temperature that
gate the deleterious effects associated with may be subnormal. This is quickly superseded by
sustained catabolism to a large extent by appro- the hypermetabolic flow phase, characterized by
priate provision of energy and nutritional increased cardiac output, oxygen consumption,
substrates. and glucose production. During this period, fat
and protein mobilization is manifested by
Keywords increased urinary nitrogen excretion and weight
Catabolism · Metabolic response · loss. This catabolic flow phase is mediated by a
Macronutrient · Energy expenditure surge in cytokines accompanied by a stereotypic
endocrine response to injury. Ultimately this
results in an increased availability of macronutri-
Introduction ents (glucose, amino acids and fatty acids) that are
essential for healing.
Despite advances in the nutritional therapy, the The metabolic stress response is beneficial in
prevalence of malnutrition among hospitalized the short-term, but the consequences of sustained
patients, especially those with protracted illness, catabolism may be quite rapidly deleterious in
remains high (Delgado et al. 2008). Appropriate children, as they have limited tissue stores and
nutritional intervention is predicated upon an substantial nutrient requirements for growth.
understanding of the profound, yet predictable, Thus, the prompt institution of nutritional support
alteration in metabolism associated with inflamma- is a priority in sick neonates and children. The
tion, trauma, and surgery. These changes are goal of nutrition in this setting is to augment the
chiefly catabolic in nature and involve the dramatic short-term benefits of the pediatric metabolic
mobilization of the host substrates to facilitate response to injury while minimizing any long-
recovery. Although children and adults share qual- term consequences. Overall, the macronutrient
itative responses to metabolic stress, the quantita- needs of the critically ill or injured child are
tive aspects are markedly different. Pediatric governed by the severity and persistence of the
patients have higher baseline protein and energy underlying illness. In general the metabolic stress
14 Metabolism of Infants and Children 233
response is characterized by enhanced protein, reliably detected on the basis of weight-to-height

glucose and lipid turn over and although these ratio, triceps skin fold, mid- to upper arm circum-
changes might be expected to increase the energy ference, hand strength, albumin concentration,
requirement available data suggests that such an total protein level, or creatinine-to-height ratio
increase is variable and typically modest (Mehta (Baker et al. 1982).
and Jaksic 2010). Therefore accurate assessment In general, REE ), rates per kilogram decline
of energy requirements in individual patients with age from infancy to young adulthood, at
allows optimal caloric supplementation and which time the rate becomes stable. REE can be
avoids the untoward effects of both underfeeding measured using direct or indirect methods. The
and overfeeding. Children with established criti- direct calorimetric method measures the heat
cal illness demonstrate a unique hormonal and released by a subject at rest and is based on the
cytokine profile characterized by an elevation in principle that all energy is eventually converted to
serum levels of insulin, the catabolic hormones heat. In practice, the patient is placed in a ther-
(glucagon, cortisol, catecholamines), as well as mally isolated chamber and the heat dissipated is
IGF-1 (Insulin like growth factor-1) and IGFBP- measured for a given period of time (Seale and
3 (Insulin like growth factor binding protein). Rumpler 1997). This method is the true gold
Cytokines such as (IL-1, IL-6) are also elevated standard for measured energy expenditure. Direct
and are produced by the host’s own macrophages. calorimetry is not practical for most hospitalized
This may explain the stereotypic nature of the children, and REE is often estimated using stan-
metabolic stress response irrespective of the incit- dard equations. This method has several limita-
ing injury. tions owing to the high individual variability in
energy expenditure, particularly in the most criti-
cally ill patients, the actual measurement of rest-
Nutritional Assessment/Estimation ing energy expenditure REE is therefore
of Energy Expenditure During Illness recommended as standard equations available
are unreliable.
Quantification of energy requirements is impor- The measured REE), not only shows variations
tant for the design of appropriate nutritional strat- among individuals; rather it is also variable during
egies. Dietary regimens that both underestimate the various phases of clinical illness in the same
and overestimate energy needs are associated with patient and to an extent is dependent on severity of
injurious consequences. Total energy expenditure injury. For instance, an infant with respiratory
(TEE) for all patients includes resting energy distress on pressure support is likely to have a
expenditure (REE), energy allotted to physical higher energy requirement due to increased work
activity, and diet-induced thermogenesis. By def- of breathing. The same patient, when started on
inition, resting energy expenditure encompasses mechanical ventilation with muscle relaxants, is
body’s energy requirement for growth and main- unlikely to have the same energy requirements.
tenance. Physical activity, which is low in the Infants with congenital diaphragmatic hernia on
postoperative period or during severe illness, and extracorporeal membrane oxygenation (ECMO)
diet-induced thermogenesis are of reduced signif- support have been shown to have energy expendi-
icance in the surgical patient. tures of approximately 90 kcal/kg/day. When off
A gross estimate with several limitation of ECMO and extubated the same patients may have
calorie expenditure can be obtained by using the energy requirements as high as 140 kcal/kg/day.
Dietary Reference Intakes for energy require- Indirect calorimetry measures VO2 (the vol-
ments, based on a child’s age, weight, height, ume of oxygen consumed) and VCO2 (the volume
and physical activity. Although careful clinical of CO2 produced) and uses a correlation factor
examination is helpful in making a determination based on urinary nitrogen excretion to calculate
of a child’s nutritional status, previous research the overall rate of energy production (Ferrannini
demonstrates that the depleted state could not be 1988). The measurement of energy needs is
“indirect” because it does not use direct tempera- calorimetry. Its use is limited in infants on
ture changes to determine energy needs. Indirect ECMO because a large proportion of the patient’s
calorimetry, usually with the aid of a “metabolic oxygenation and ventilation is performed through
cart,” provides a measurement of the overall respi- the membrane oxygenator. Therefore the use of
ratory quotient (RQ), defined as the ratio of CO2 indirect calorimetry for assessment and monitor-
produced to O2 consumed (VCO2/VO2), for a ing of nutrition intake requires attention to its
given patient. Oxidation of carbohydrates yields limitations as well as expertise in the interpreta-
an RQ of 1.0, whereas fatty acid oxidation gives tion. Nonetheless, its application in children at
an RQ of 0.7. However, the role of the RQ as a high risk for underfeeding and overfeeding
marker of substrate use and as an indicator of appears warranted.
underfeeding or overfeeding is limited. Numerous Nonradioactive stable isotope based tech-
factors, related and unrelated to feeding, can alter niques are another adjunct available to measure
the value of a measured RQ in critically ill patients REE in the pediatric patient. Stable isotope tech-
making assumptions of RQ values and substrate nology has been available for many years and was
oxidation invalid (Joosten et al. 1999; Chwals first applied for energy expenditure measurement
1994; McClave and Snider 1992; McClave et al. in humans in 1982 (Schoenheimer and Rittenberg
2003). Some of these factors include hyperventi- 1935). Both 13C-labeled bicarbonate and doubly
lation, acidosis, effects of inotropic agents and labeled water (2H218O) have been used to measure
neuromuscular blocking agents, and an individ- TEE in pediatric surgical patients (Mehta et al.
ual’s response to a given substrate load and injury. 2008) and have been shown to correlate well with
Measurements at the extremes however are clini- indirect calorimetry. The 13C-labeled bicarbonate
cally relevant and helpful in guiding changes to method allows the calculation of REE solely on
the nutritional regimen. An RQ higher than 0.85 the basis of infusion rate and the ratio of labeled to
relatively reliably indicates the absence of under- unlabeled CO2 in expired breath samples at steady
feeding, and an RQ higher than 1.0 reliably indi- state. Orally administered stable isotopes of water
cates the presence of overfeeding (Hulst et al. (2H2O and H218O) mix with the body water, and
2005). the 18O is lost from the body as both water and
Furthermore, in the setting of wide diurnal and CO2, while the 2H is lost from the body only as
day-to-day variability of REE in critically ill indi- water. The difference in the rates of loss of the
viduals, the extrapolation of short-term calorimet- isotopes 18O and 2H from the body reflects the rate
ric REE measurements to 24-h REE may of CO2 production, which can be used to calculate
introduce errors. The use of steady state measure- the TEE (Schoeller and Hnilicka 1996). Of note
ments may decrease these errors. Steady state is doubly labeled water method has limitations in
defined by changes in VO2 and VCO2 of less than children who have increased capillary permeabil-
10% over a period of five consecutive minutes. ity, decreased urine output, fluid overload, or are
The values for the mean REE from this steady receiving diuretics.
state period may be used as an accurate represen- In general, any increase in energy expenditure
tation of the 24-h TEE inpatients with low levels during illness or after surgery is variable. Avail-
of physical activity (Long et al. 1971). In a patient able evidence suggests that the increase is far less
who fails to achieve steady state and is metaboli- than originally hypothesized. In children with
cally unstable, more prolonged testing may be severe burns, the initial REE during the flow
required (minimum of 60 min), and possibly phase of injury is increased by 50% but then
24-h indirect calorimetry should be considered. returns to normal during convalescence. A retro-
Indirect calorimetry is not accurate in the set- spective stratification of surgical infants into low-
ting of air leaks (around the endotracheal tube, in and high-stress cohorts based on the severity of
the ventilator circuit, or through a chest tube) or in underlying illness found that high-stress infants
patients on ECMO support. High inspired oxygen undergo moderate short-term elevations in energy
fraction (FiO2> 0.6) will also affect indirect expenditure after surgical interventions (Chwals
et al. 1995). Low-stress infants do not manifest Table 1 Macronutrient reserves stratified by age
any increase in energy expenditure during the Protein Carbohydrate Fat
course of illness. Hence, critically ill neonates Age group (%) (%) (%)
have only a small and usually short-termin crease Neonate 11 14 0.4
in energy expenditure. Although children have Children (age 15 17 0.4
increased energy requirements from increased 10 years)
Adults 18 19 0.4
metabolic turnover during illness, their caloric
needs in the setting of surgical stress or critical
illness may be lower than previously considered
likely as a result of halted or slowed growth and secondary to their increased brain-to-body mass
the use of sedation and muscle paralysis. There- ratio. Neonatal glycogen stores are even more
fore as discussed, energy requirement estimates in limited in the early postpartum period, especially
this group of patients remain variable and possibly in the preterm infant. Short periods of fasting can
is incorrectly estimated, mandating an accurate predispose the newborn to hypoglycemia. Thus,
measurement of energy expenditure when possi- when infants are burdened with illness or injury,
ble. The use of arbitrary stress multipliers in con- the process of gluconeogenesis (the production of
junction with energy expenditure formulae is to be glucose from proteins) is quickly activated. Older
discouraged. patients retain fat that can be mobilized to produce
As there is a direct relation between cumulative large amounts of energy, whereas neonates only
caloric imbalance and mortality rate in critically ill have a small reserve of lipids.
patients, (Bartlett et al. 1982) delaying nutritional The most striking difference between the adult
support for such measurements is not ideal. Prac- and pediatric patient is the quantity of stored pro-
tically, the recommended dietary caloric intake for tein. The protein reserve per kilogram of the
healthy children is a reasonable starting point for non-obese adult is nearly twice that of the neo-
the upper limit of caloric allotment in the hospi- nate, leaving no buffer for the neonate to lose any
talized child and subsequent adjustments should significant amount of protein over the course of
be made when REE can be quantified more accu- protracted illness or injury. An important feature
rately. In case REE values cannot be measured of the metabolic stress response, unlike in starva-
than demonstration of appropriate catch growth tion, is that provision of dietary glucose does not
in convalescence is a helpful marker of adequate halt gluconeogenesis. Consequently, the catabo-
caloric provision. lism of muscle protein to produce glucose con-
tinues unabated in this situation (Long et al.
1976).
Nutrient Reserves and Requirements Along with lower metabolic reserves, neonates
and children share much higher baseline energy
The neonate and child differ significantly from the requirements. Studies have consistently demon-
adult patient in the proportion of available meta- strated that the resting energy expenditure for
bolic reserve. Table 1 outlines the macronutrient neonates is two to three times that of adults
stores of the neonate, child, and adult in percent- when standardized for body weight (Reichman
age of total body weight (Forbes and Bruining et al. 1983). Clearly, the child’s rapid growth and
1976). Stored carbohydrates are limited in all cellular differentiation heavily influences the
age groups and afford only acute provisions magnitude of the corresponding energy metabo-
when necessary. Additionally, compared with lism. This may be related to the increased body
adults, neonates have a high demand for glucose surface area and possibly a higher brain-to-body
and have higher rates of glucose turnover (Long mass ratio.
et al. 1971). Since glucose is the primary energy Basic macronutrient, total energy and
source for the central nervous system, its more recommended distribution of energy derived via
rapid turnover in neonates is thought to be each macronutrient for the infant, child, and adult
Table 2 Recommended dietary allowance of water and macronutrients

Water Protein CHO Fat Linoleic α-Linoleic
Age group (L/day) (g/day) (g/day) (g/day) (g/day) (g/day)
0–6 months 0.7 9.1 60 31 4.4 0.5
6–12 months 0.8 11.0 95 30 4.6 0.5
1–3 years 1.3 13 130 ND 7 0.7
4–8 years 1.7 19 130 ND 10 0.9
Males 2.4 34 130 ND 12 1.2
9–13 years
14–18 years 3.3 52 130 ND 16 1.6
Females 2.1 34 130 ND 10 1.0
9–13 years
14–18 years 2.3 46 130 ND 11 1.1
remainder reside in the free amino acid pool.

Table 3 Acceptable macronutrient energy distribution
ranges Proteins are continually degraded into their con-
stituent amino acids and resynthesized in the
Child Child Adult
(1–3 years) (4–18 years) percent process of protein turnover. The reutilization of
percent of percent of of amino acids released by protein breakdown is
Macronutrient energy energy energy extensive. Synthesis of proteins from the
Fat 30–40 25–35 20–35 recycling of amino acids is more than two times
Carbohydrate 45–65 45–65 45–65 greater than that from dietary protein intake. An
Protein 5–20 10–30 10–35 advantage of high protein turnover is that it
allows the body flexibility in meeting changing
Table 4 Total recommended intake values for energy by physiologic needs.
life stage The high protein turnover does require the
Age group Male (kcal/day) Female (kcal/day) input of energy to power both protein degradation
0–6 months 570 520 and synthesis. At baseline, infants are known to
7–12 months 743 679 have higher rates of protein turnover than adults
1–2 years 1,046 992 (up to 12 g/kg/day for healthy newborns com-
3–8 years 1,742 1,642 pared with 3.5 g/kg/day in adults) (Beaufrere
9–13 years 2,279 2,071 1994). Even higher rates of protein degradation
14–18 years 3,152 2,368 have been measured in premature and low birth
weight infants (Denne et al. 1996). For example, it
has been demonstrated that extremely low birth
based on recommendations by the National Acad- weight infants receiving no dietary protein can
emy of Sciences are listed in Tables 2, 3, and 4 lose in excess of 1.2 g/kg/day of endogenous
(Institute of Medicine (US) 2005). protein. It is noteworthy that this early protein
loss can be minimized with institution of amino
acid supplementation at 1–1.5 g/kg/day, even in
Macronutrient Intake the face of overall modest energy intake. Infants
must maintain a positive protein balance to attain
Review of Protein Metabolism normal growth and development, thus any net loss
and Requirement During Illness may be problematic.
The ratio between protein synthesis and degra-
Amino acids are the key building blocks required dation is significantly enhanced in the metaboli-
for growth and tissue repair. The vast majority cally stressed patient such as children with severe
(98%) are found in existing proteins, and the burn injuries or patients with cardiorespiratory
failure requiring ECMO (Felig 1973). A study of detoxified to urea through the urea cycle. The
critically ill infants and children found an 80% amino acid carbon skeleton can then enter the
increase in protein turnover, which correlated with gluconeogenesis pathway. Alternatively the
the duration of the critical illness. This process amino groups can be transferred to pyruvate,
serves to redistribute amino acids from skeletal thereby forming the amino acid alanine via the
muscle to the liver, wound site, and tissues taking glucose-alanine cycle in skeletal muscle. When
part in the inflammatory response. The well- alanine is transported to the liver and detoxified,
established increase in hepatically derived acute pyruvate is re-formed and can be converted to
phase proteins (including C-reactive protein, glucose through gluconeogenesis (Felig 1973).
fibrinogen, transferrin, and α 1-acid glycopro- Though a helpful short-term adaptation, the
tein), along with the concomitant decrease in extent of protein catabolism correlates with the
transport proteins (albumin and retinol-binding ultimate morbidity and mortality of the surgical
protein) is evidence of this protein redistribution. patient. Increased protein metabolism over the
Although rates of both protein synthesis and long periods of critical illness can result in pro-
breakdown increase, overall protein breakdown gressive breakdown of skeletal, diaphragmatic,
predominates. This inequity eventually leads to a and cardiac muscle. Therefore the process can
whole-body hypercatabolic state with ensuing net lead to loss of lean body mass, respiratory com-
negative protein and nitrogen balance. Protein promise, or fatal arrhythmia. Healthy,
loss is evident in elevated levels of excreted uri- non-stressed neonates require a positive protein
nary nitrogen during critical illness, the degree of balance of nearly 2 g/kg/day for appropriate
which correlates with the severity of critical ill- growth and development (Wiener et al. 2008).
ness. In addition to the reprioritization of protein Therefore even a mild negative protein balance
for tissue repair, healing and inflammation, the when prolonged significantly impacts a child’s
body appears to have an increased need for glu- growth and development.
cose production during times of metabolic stress, Fortunately, amino acid supplementation tends
which leads to an accelerated rate of gluconeo- to promote positive protein balance in critically ill
genesis during illness and injury. This is seen in patients. This is thought to be secondary to an
both children and adults, however appears to be increase in protein synthesis while the rate of
accentuated in infants with low body weight. The protein degradation is dependent on the severity
increased production of glucose during illness is of illness.
necessary, because glucose represents a versatile Table 5 lists recommended quantities of dietary
energy source for tissues taking part in the inflam- protein provision for hospitalized children.
matory response. Unfortunately, the provision of It should be noted that toxicity from excessive
additional dietary glucose does not suppress the protein administration has been reported, particu-
body’s need for increased glucose production. larly in children with impaired renal and hepatic
Therefore, net protein breakdown continues even function. In most instances, institution of protein
in the face of glucose supplementation (Van Aerde allotments greater than 3 g/kg/day is not indicated.
et al. 1994). In premature neonates even higher protein allot-
Specific amino acids are transported from mus- ments i.e. 3.5 g/kg/day may be necessary to opti-
cle to the liver to facilitate hepatic glucose pro- mize growths. Studies using higher protein
duction. The initial step of amino acid catabolism
involves removal of the toxic amino group (NH3).
Table 5 Estimated protein requirement for critically ill
Through transamination, the amino group is trans-
children
ferred to α-ketoglutarate, thereby producing glu-
Age (years) Protein (gm/kg/day)
tamate. The addition of another amino group
0–2 2.0–3.0
converts glutamate to glutamine, which is subse-
2–13 1.5–2.0
quently transported to the liver. Here, the amino
13–18 1.5
groups are removed from glutamine and
provisions in the range of 6 g/kg/day in children on rates of organ failure and infectious complica-
have demonstrated significant morbidity, includ- tions and even identified a trend toward increased
ing azotemia, pyrexia, strabismus, and lower IQ mortality in the group receiving supplemental
scores. glutamine (Heyland et al. 2013). Based on the
available data children with burns, trauma, and
critical illness are therefore unlikely to benefit
Protein Quality from glutamine supplementation.
Arginine plays an important role in modulation
In addition to the quantity, the specific amino acid of immune function, protein synthesis, and tissue
formulation may be important in optimizing repair. This amino acid also helps maintain intes-
accretion of whole-body protein (Mehta and tinal mucosal integrity. Low plasma levels of argi-
Compher 1997). Infants have an increased nine and glutamine have been found in very low
requirement per kilogram for the essential amino birth weight infants with NEC. Arginine supple-
acids compared with adults. In particular, neo- mentation in this group not only improves plasma
nates have immature biosynthetic pathways that levels but also decreases the incidence of this
may temporarily alter their ability to synthesize devastating disease. In spite of these reports
specific amino acids. One example is the amino based on the strength of available evidence case
acid histidine, which has been shown to be a for arginine supplementation cannot be made.
conditionally essential amino acid in infants up
to 6 months of age.
The restricted availability of the amino acid Modulating Protein Metabolism
cysteine also may have clinical relevance in the
critically ill child. Cysteine is a required substrate Dietary supplementation of amino acids does
for the production of glutathione, the body’s increase protein synthesis but appears to have
major antioxidant. In critically ill children, cyste- little or no effect on protein-breakdown rates.
ine catabolism is increased significantly. At the The dramatic increase in protein breakdown dur-
same time, rates of glutathione synthesis are ing critical illness, coupled with the known asso-
decreased by 60%. In this way, cysteine may ciation between protein loss and patient mortality
become a conditionally essential amino acid in and morbidity, has stimulated a wide array of
the sick child. Essentiality of cysteine however is research efforts in search of therapy aimed at
still under investigation. modulating protein metabolism in critical illness.
Glutamine has been studied extensively in both Such efforts have been largely unrevealing. A
pediatric and adult patients in the ICU. It is an number of putative anabolic agents have been
important amino acid source for gluconeogenesis, tested including high doses of growth hormone,
intestinal energy production, and ammonia detox- instituting tight glycemic control, insulin-derived
ification. In healthy subjects, glutamine is a non- growth factor I (IGF-I), high-dose insulin (Agus
essential amino acid; although it has been et al. 2006) and testosterone with varying degrees
hypothesized that glutamine may become condi- of success. However none of the above mentioned
tionally essential in critically ill patients. Because therapies have been able to consistently demon-
it is difficult to keep glutamine dissolved in solu- strate meaningful utility in the clinical setting. The
tion, standard PN formulations do not include search for an effective anabolic agent is ongoing.
glutamine. Early studies found improvement in
outcomes for adult patients receiving glutamine
both parenterally and enterally (Griffiths et al. Carbohydrate Metabolism
1997). A well designed randomized controlled
trial since then evaluating enteral and parenteral Glucose production and availability are a priority
supplementation of glutamine in adult critically ill in the pediatric metabolic stress response. Glucose
patients however failed to demonstrate any effect is the primary energy source for the brain,
erythrocyte, renal medulla, as well as being used mixed dietary regimen of glucose and lipid lowers
extensively in the inflammatory response. Injured the effective RQ in neonates. This approach will
and septic adults demonstrate a threefold increase provide the child with full nutritional supplemen-
in glucose turnover, glucose oxidation, and glu- tation while alleviating any increased ventilatory
coneogenesis (Whyte et al. 1983). This increase is burden and difficulties with hyperglycemia.
of particular importance in neonates who have
elevated glucose utilization at baseline (Agus
et al. 2012). Moreover, glycogen stores provide Glucose Control
only a limited endogenous supply of glucose in
both adults and neonates. The key difference Administration of high caloric (glucose load) diets
between adults and neonates is the increased in the early phase of critical illness may exacer-
demand in the former. During illness, the admin- bate hyperglycemia, increase CO2 generation
istration of exogenous glucose does not halt the with an increased load on the respiratory system,
elevated rates of gluconeogenesis. Thus, net pro- promote hyperlipidemia resulting from increased
tein catabolism continues unabated (Van Aerde lipogenesis, and result in a hyperosmolar state.
et al. 1994). However a combination of glucose Early investigations in critically ill adults dem-
and amino acids can improve the overall protein onstrated that aggressive control of hyperglyce-
balance primarily by augmentation of protein mia improved outcomes. A remarkable 43%
synthesis. reduction in mortality was reported in post-
In the past, nutritional support regimens for cardiac surgery patients in an adult ICU by
critically ill patients used large amounts of glu- implementing strict glycemic control (arterial
cose in an attempt to overcome the body’s need blood glucose levels below 110 mg/dL) using
for glucose production. It is now clear that excess insulin infusion in the treatment group as com-
glucose has unwanted consequences including pared with control patients undergoing standard
increased CO2 production and the promotion of therapy (average blood glucose level of
hepatic steatosis (Tappy et al. 1998). Adult 150–160 mg/dL) (Van den Berghe et al. 2006).
patients in the ICU fed with high-glucose PN Subsequent large randomized controlled trials of
demonstrate a 30% increase in oxygen consump- tight glucose control in medical and mixed
tion, a 57% increase in CO2 production, and con- medical-surgical ICU settings however, have
sequently, a 71% elevation in minute ventilation. failed to replicate this mortality benefit (Wiener
This surplus can thus significantly increase the et al. 2008).
ventilatory burden (Covelli et al. 1981). In criti- A large international randomized trial, found
cally ill infants, the conversion of excess glucose that intensive glucose control increased mortality
to fat also correlates with increased CO2 produc- among adults in the ICU: a blood glucose target of
tion and higher respiratory rates. Finally, some 180 mg or less per deciliter resulted in lower
data in critically ill neonates have shown that mortality than did a target of 81–108 mg per
excess caloric allotments of carbohydrate are par- deciliter secondary to increased frequency of
adoxically associated with an increased rate of net hypoglycemic events associated with mainte-
protein breakdown (Shew et al. 1999). nance of tighter glycemic control (NICE-
When designing a nutritional regimen for the SUGAR Study Investigators 2009).
critically ill child, excessive carbohydrate calories Both hyperglycemia and hypoglycemia are
should be avoided. A mixed fuel system, with prevalent in PICU patients and are associated
both glucose and lipid substrates, should be uti- with death and increased length of stay
lized to meet the patient’s caloric requirements. (Wintergerst et al. 2006). Critically ill children
When the postoperative neonate is fed a high- who do not survive have higher peak glucose
glucose diet, the corresponding RQ is approxi- levels and longer duration of hyperglycemia than
mately 1.0, and may be higher than 1.0 in selected survivors (Srinivasan et al. 2004). Similar to the
patients, signifying increased lipogenesis. A adult literature, early studies targeting blood
glucose concentrations to age-adjusted normal with illness and trauma, the provision of dietary
fasting concentrations reported improved short- glucose does not decrease fatty acid turnover in
term outcome of patients in PICU particularly in times of illness. The increased demand for lipid
children with severe burns, where reduced infec- utilization in critical illness coupled with the lim-
tion rates and improved survival were reported ited lipid stores in the neonate puts the metaboli-
(Pham et al. 2005). At the same time these treat- cally stressed infant at high risk for the
ment strategies targeting tighter glycemic con- development of essential fatty acid deficiency
trol tended to report a higher incidence of (Friedman et al. 1976).
hypoglycemic events. A larger study examining Preterm infants have been shown to develop
pediatric cardiac surgical patients assigned to biochemical evidence of essential fatty acid defi-
strict glycemic control or standard control no ciency 2 days after the initiation of a fat-free
difference in the infection rate (8.6 vs. 9.9 per nutritional regimen (Giovannini et al. 1995). In
1,000 patient-days), mortality (5/488 vs. 6/484), humans, the polyunsaturated fatty acids linoleic
length of stay, or measures of organ failure, as and linolenic acid are considered essential fatty
compared with standard care (Agus et al. 2012). acids because the body cannot manufacture them
Although it is prudent to avoid prolonged hyper- by desaturating other fatty acids. Linoleic acid is
glycemia, i.e. blood glucose greater than used by the body to synthesize arachidonic acid,
180 mg/dL in the pediatric ICU patients, more an important intermediary in prostaglandin syn-
aggressive glycemic control is not supported by thesis. If an individual lacks dietary linoleic acid,
the current data. the formation of arachidonic acid (a tetraene, with
four double bonds) cannot occur and
eicosatrienoic acid (atriene, with three double
Lipid Metabolism bonds) accumulates in its place. Clinically, a
fatty acid profile can be performed on human
Along with protein and carbohydrate metabolism, serum and an elevated triene-to-tetraene ratio
the turnover of lipid is generally increased by greater than 0.4 is characteristic of biochemical
critical illness, major surgery, and trauma in the essential fatty acid deficiency. This value is some-
pediatric patient (Nordenström et al. 1982). Dur- what variable and dependent on the specific labo-
ing the early ebb phase, triglyceride levels may ratory assay utilized. Signs of fatty acid
initially increase as the rate of lipid metabolism deficiencies include dermatitis, alopecia, throm-
decreases. However, this process reverses itself in bocytopenia, increased susceptibility to infection,
the predominantly flow phase. During this time, and overall failure to thrive. To avoid essential
critically ill adult patients have demonstrated two- fatty acid deficiency in neonates, the allotment of
fold to fourfold increase in lipid turnover. Criti- linoleic and linolenic acid is recommended at
cally ill children on mechanical ventilation have concentrations of 4.5% and 0.5% of total calories,
increased rates of fatty acid oxidation (Powis et al. respectively. In addition, some evidence exists
1998). The increased lipid metabolism is thought that the long-chain fatty acid docosahexaenoic
to be proportional to the overall degree of illness. acid (DHA), a derivative of linolenic acid, also
Thirty to 40% of free fatty acids are oxidized for may be deficient in preterm and formula-fed
energy. RQ values may decline during illness, infants and DHA supplementation may reduce
reflecting an increased utilization of fat as an the incidence of bronchopulmonary dysplasia in
energy source. This suggests that fatty acids are infants with birthweight less than 1,250 g (Manley
a prime source of energy in metabolically stressed et al. 2011).
pediatric patients. In addition to the rich energy Parenterally delivered lipid solutions also pro-
supply from lipid substrate, the glycerol moiety vide the additional benefit of limiting the need for
released from triglycerides may be converted to excessive glucose provision. These lipid emul-
pyruvate and used to manufacture glucose. As sions provide a higher quantity of energy per
seen with the other catabolic changes associated gram than does glucose (9 kcal/g vs. 4 kcal/g).
This reduces the overall rate of CO2 production, inflammatory process. Derivatives of omega-6
the RQ value, and the incidence of hepatic fatty acids such as leukotriene B4 are predomi-
steatosis (Van Aerde et al. 1994). Some risks nantly pro-inflammatory mediators whereas EPA
must be considered when starting a patient on and DHA derived from omega-3 fats have potent
intravenous lipid administration. These include immune-modulatory effect.
hypertriglyceridemia, a possible increased risk of Substitution of the soy derived lipid compo-
infection, and decreased alveolar oxygen- nent of PN with fish oil has been associated with
diffusion capacity (Freeman et al. 1990). Most an improvement in the hyperbilirubinema and
institutions, therefore, initiate lipid provisions in possibly improved survival in patients with intes-
children at 0.5–1.0 g/kg/day and advance over a tinal failure associated liver disease (IFALD)
period of days to 2–3 g/kg/day. However, recently (Nandivada et al. 2017). The possible reason for
more aggressive nutritional support interventions, this observation includes the less
without additional risk of clinical or metabolic pro-inflammatory nature of omega-3 derived
adverse sequelae and improved growth in the mediators (Anez-Bustillos et al. 2016), coupled
neonatal period, have been reported. Higher initial with a decreased hepatic clearance of the
lipid infusion rates (2 g/kg/day) during the first parenteral lipid and presence of plant sterols
week of life in very low birth weight neonates (phytosterols) in soy based PN solutions (Carter
have also been used without significant adverse et al. 2007). Phytosterols (e.g., stigmasterol,
outcomes. Lipid administration is generally b-sitosterol, and campesterol) present in soy
restricted to 30–40% of total caloric intake in based lipid formulations exert this effect by sup-
critically ill children in an effort to prevent pression of canalicular bile transporter expression
immune dysfunction, although this practice has leading to impairment of biliary secretion (Carter
not been validated in a formal clinical trial. In et al. 2007). The role of fish oil as primary pre-
settings of prolonged fasting or uncontrolled dia- ventive strategy for IFALD is currently under
betes mellitus, the accelerated production of glu- study.
cose depletes the hepatocyte of needed
intermediaries in the citric acid cycle. When this
occurs, the acetyl-coenzyme A (CoA) generated Conclusion and Future Directions
from the breakdown of fatty acids cannot enter the
citric acid cycle. Instead, it forms the ketone bod- Provision of adequate nutrition to critically ill
ies acetoacetate and β-hydroxybutyrate. These pediatric patients necessitates consideration of
ketone bodies are released by the liver and used various aspects of metabolism. Accurate assess-
for energy production in place of glucose in cer- ment of dietary needs can also be challenging
tain tissues such as skeletal muscle and brain. especially in children admitted to critical care
Conversely during surgical illness elevated units with multiple medical problems. Nutritional
serum insulin levels inhibit production of ketone status of these patients has a significant influence
bodies (Birkhahn et al. 1981). on the outcome of their primary critical illness.
In addition to their nutritional role, fatty acids Optimized nutritional therapy should be
may influence inflammatory and immune events established to optimize their nutritional status in
by changing lipid mediators and inflammatory a timely manner.
protein and coagulation protein expression.
After ingestion, omega-6 and omega-3 fats
are metabolized by an alternating series of Cross-References
desaturase and elongase enzymes that transform
them into the membrane-associated lipids ▶ Fluid and Electrolyte Balance in Infants and
arachidonic acid, eicosapentaenoic (EPA), and Children
docosahexaenoic (DHA) acids, respectively, ▶ Pediatric Hepatic Physiology
which are essential signaling mediators in the ▶ Short Bowel Syndrome
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Fluid and Electrolyte Balance in
Infants and Children 15
Joseph Chukwu and Eleanor J. Molloy
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Water Distribution in Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246
Water Homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Insensible Water Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Disorders of Body Fluid Volume: Dehydration and ECF Depletion . . . . . . . . . . . . . . . 249
Volume Depletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
Fluid and Electrolyte Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Electrolytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Sodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Potassium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Calcium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Phosphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
J. Chukwu (*)
Clinical Research Unit, National Children’s Research
Centre, Our Lady’s Children’s Hospital, Dublin, Ireland
e-mail: joe.chukwu@gmail.com; josephchukwu@rcsi.ie
E. J. Molloy
Department of Neonatology, Paediatrics, National
Maternity Hospital, Dublin, Ireland
UCD School of Medicine and Medical Sciences,
Neonatology, Our Lady’s Children’s Hospital, Dublin,
Ireland
Paediatrics, Royal College of Surgeons in Ireland, Dublin,
Ireland
Discipline of Paediatrics, Trinity College, The University
of Dublin, Dublin, Ireland
Tallaght Hospital and Coombe Women’s and Infants
University Hospital, Dublin, Ireland
e-mail: elesean@hotmail.com

https://doi.org/10.1007/978-3-662-43588-5_16
246 J. Chukwu and E. J. Molloy
Acid-Base Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257

Acid-Base Balance Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Perioperative Management in Infants and Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Intraoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Fluid and Electrolyte Balance in Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Total Parenteral Nutrition (TPN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260
Abstract the fluid and electrolyte composition and mainte-

Fluids and electrolyte management in infants nance of homeostasis at the different stages of
and children is continuously evolving as the infancy and childhood are essential to the effective
understanding of fluid and electrolyte require- management of fluid and electrolyte deficit in sur-
ments is progressing. Postnatal transition gical pediatric patients.
marked by predictable changes in body water
including contraction of extracellular volume
and insensible fluid loss, primarily across the Water Distribution in Infants and
skin barrier. Knowledge of the fluid and elec- Children
trolyte composition and maintenance of
homeostasis at different stages of infancy and The body water composition varies throughout
childhood are essential to the effective man- infancy and childhood. While the infants’ total
agement of fluid and electrolyte deficit in body water is around 75%, it falls to 65–70% in
infants and children undergoing surgery. toddlers and falls further to 60% in the adolescents
Fluid therapy in infants in the intensive care as shown in Fig. 1 (Somers 2009). The total body
unit may be guided using three clinical indica- content in males is higher than in females by
tors: change in body weight, serum sodium 2–10% after puberty (Greenbaum 2010b). About
concentration, and urine output. two thirds of the total body water is within the
intracellular compartment; the rest is in the extra-
cellular compartment as shown in Fig. 2.
Keywords
Fluid balance · Electrolyte balance · Acid-base
Table 1 Calculation of daily maintenance fluid require-
balance · Dehydration · Osmolality · ment and intravenous fluid infusion rate
Perioperative management
Intravenous
Total daily fluid
maintenance fluid infusion rate
Introduction Body weight (kg) requirement in 24 h (ml/h)
0–10 100 ml/kg 40
During the time of rapid postnatal transition, for 11–20 1,000 ml þ 50 ml/ 40 þ (2 ml/
kg for each kg kg/h for each
example, term and preterm neonates have different above 10 kg kg weight
fluid requirements and electrolyte changes to the above 20 kg)
older children and adults (Table 1). Age and gender >20 1,500 þ 20 ml/kg 60 þ (1 ml/
are the most important determinants of this wide for each kg weight kg/h for each
variation in fluid and electrolyte requirements above 20 kg kg weight
above 20 kg)
(Bianchetti and Simonetti 2009). Knowledge of
15 Fluid and Electrolyte Balance in Infants and Children 247
hydrostatic pressure, and capillary permeability.

Although albumin mass consists of 50% of total
blood protein, it only accounts for 25% of the total
oncotic pressure. Albumin is anionic and attracts
cations into the intravascular compartment (Gibbs-
Donnan effect). This is due to the high intracellular
concentration of nondiffusible anions (Brandis).
Water enters the cell down to its concentration
gradient. A second Gibbs-Donnan effect is set up
by the Na+/K+ ATPase in the cell membrane by
preventing sodium entry into the cell, sodium being
the impermeable to charged cation (Brandis 2001).
Effective Circulating Volume (ECV)

Fig. 1 Total body water composition in the preterm, The arterial component of the intravascular volume
infant, and the adolescent perfusing the tissues at any particular time is the
effective circulating volume (ECV) (Bullock et al.
2001; Somers 2009). However, the volume of the
arterial blood varies with the ECF volume; hence,
maintenance of both ECV and ECF volumes is
closely related. Since the ECF volume is dependent
on the state of its sodium content, ECF volume is
controlled by urinary sodium excretion (Bullock
et al. 2001). Volume receptors are located in the
carotid sinuses, the aortic arch, and the kidney
(Somers 2009). While the volume receptors in the
carotid sinuses and the aortic arch control the ECV
through the sympathetic nervous and the natriuretic
systems, the kidneys control the ECV via the renin-
angiotensin II-aldosterone system (Skorecki and
Brenner 1981; Patel 2009). The effects of these
Fig. 2 Body water distribution between the intracellular
fluid (ICF) and extracellular fluid (ECF) compartments in
responses result in the adjustment of the glomerular
the preterm neonate, the infant, and the adolescent filtration rate, peritubular Starling forces, and renal
microvascular hemodynamics as well as the tubular
flow rate, fluid composition, and trans-tubular ion
The extracellular fluid (ECF) compartment con- gradients (Skorecki and Brenner 1981).
sists of interstitial fluids which make up two thirds
of the ECF and the intravascular fluid (plasma) Serum Osmolality
accounts for the other third. The rest of the ECF is Serum osmolality is defined as the concentration of
transcellular fluid which includes the peritoneal, solute per weight of water. It is measured in mosm/
synovial, cerebrospinal, and intraocular fluids. kg H20. The true (total) blood osmolality is the sum
The body fluid compartments are determined by of osmolalities of all blood solutes. Sodium pre-
their electrolyte compositions. While the sodium dominantly contributes to the plasma osmolality.
determines the ECF volume, potassium regulates Other solutes that contribute to the true osmolality
the ICF volume. Starling’s forces control the include glucose, urea, and other ions. Serum osmo-
partitioning of fluids into ECF and ICF. The three lality is not directly measured but can be estimated
mechanisms that control fluid distribution across by the following formula: (sodium x2) þ glucose.
capillary membrane are oncotic pressure, This implies multiplying the concentration of
serum sodium (in mmol/l) by two and adding this to diabetes insipidus, and dehydration have to be
the glucose concentration (in mmol/l). taken into account in interpreting the results of this
test (Carter and Marshall 2010).
Water Homeostasis Renal Blood Flow

Nephrons are functional in the fetus by 8 weeks of
Sodium status determines volume status, while gestation, but they continue to develop and mature
water intake and excretion control maintain osmo- up to the 34th week when all the glomeruli are
lality. The two systems that regulate water balance present. The abdominal aorta provides the blood
include the thirst mechanism which is stimulated by supply to the kidneys through the left and right
increased plasma osmolality and the antidiuretic renal arteries. The proportion of cardiac output dis-
hormone (ADH, also called vasopressin) secretion tributed to the kidneys increases from 15% to 18% in
which is stimulated by decreased plasma volume. the first month of life to about 20–25% in adulthood.
ADH regulates urinary water loss by increasing the
renal reabsorption of water. Water balance controls Glomerular Filtration Rate
osmolality. The normal osmolality ranges between The glomerular filtration rate (GFR) is the rate at
285 and 295 mosm/kg. When both volume deple- which water and dissolved solutes in blood are
tion and increased osmolality occur at the same filtered into the kidneys. The GFR provides an
time, maintenance of intravascular volume takes estimate of the renal function as this is determined
precedence over maintenance of osmolality by an intact tubular function and glomerular fil-
(Greenbaum 2010b). The kidney is the principal tration (Mahan 2010). The normal range of GFR
regulator of sodium balance by alteration of the is 80–125 ml/min/1.73m2. The GFR of the full-
proportion of filtered sodium that is reabsorbed term newborn is 40 ml/min/1.73m2, and this
(Greenbaum 2010b). Significant morbidity and increases rapidly within the first 2 years to reach
mortality are associated with volume overload espe- adult values of 100–120 ml/min/1.73 m2 and sta-
cially in critically ill children (Greenbaum 2010b). bilizes at this level (Mahan 2010). Indirect mea-
surement of GFR can be obtained by estimating
the endogenous creatinine clearance using a 24-h
Insensible Water Loss urine collection (Lum 2002). The GFR can be
quickly estimated by measuring child’s length in
Insensible water loss represents about a third of the centimeters and plasma creatinine levels using the
total daily maintenance fluid requirements. This loss formula outlined below (Lum 2002).
occurs by evaporation through the skin and the Ccr(ml/ min /1 . 73m2) = 0.55
lungs. A febrile child loses an additional 10–15% height (cm)/PCr(mg/dl) (Lum 2002)
per one degree centigrade rise in temperature above
38 centigrade through this means (Greenbaum ðCcr ¼ Creatinine clearance; PCr ¼ plasma creatinineÞ
2010b). Insensible water loss through the lungs is
increased in children who are tachypneic and those In infants less than 1 year old, the factor should
with tracheostomy tubes (Greenbaum 2010b). be 0.45 instead of 0.55. However, estimating GFR
using such substituted measurements based on
Sweating serum creatinine or cystatin C clearance is not
Sweating occurs in both infants and children. Fluid good substitutes for a measured GFR (Becker
lost through the sweat is not insensible as it contains and Friedman 2013). The most accurate means
both salt and water. The normal sweat chloride of measuring GFR is by inulin infusion – a sub-
concentration is <40 mmol/l, but in children with stance which is not metabolized, reabsorbed, or
cystic fibrosis, a level >60 mmol/l is diagnostic. secreted by the renal tubules (Mahan 2010). Using
However, causes of false-positive sweat tests such this method, the formula for calculating GFR is as
as adrenal insufficiency, eczema, nephrogenic follows: GFR = [U] V/[P] ; (U = urinary
concentration of inulin; [P] = serum inulin con- compared to older children. Infants and children
centration and V = urine flow rate). with some underlying medical or surgical condi-
tions such as gastroschisis and cyclical vomiting
syndrome are more prone to dehydration than
Disorders of Body Fluid Volume: normal children.
Dehydration and ECF Depletion
Consequences of Dehydration
Volume Depletion Dehydration results in decreased effective circu-
lating volume (#ECV), decreased perfusion, tis-
Volume depletion is any condition leading to sue ischemia, acid-base balance disorders, and
decreased effective circulating volume. In this eventually end-organ failure.
condition salt and water are lost. Examples
include vomiting, diuretics, bleeding, and seques- Symptoms and Signs of Dehydration
tration of fluid in the third space. Third-space There are three groups of signs and symptoms asso-
fluids are fluids that are still within the body but ciated with dehydration (Bianchetti et al. 2009)
are not in equilibrium with the vascular fluids which are those related to the manner of loss (e.g.,
(Filston et al. 1982). This can occur in children vomiting), symptoms related to the disturbance of
with pleural effusion, ascites, edema, and severe acid-base balance, and symptoms related to the
sepsis. Estimation of the volume of third-space effects of volume depletion.
fluid is difficult (Filston et al. 1982).
Degree of Dehydration
Dehydration Most are accurately assessed by the degree of acute
This implies mainly water loss resulting in hyper- weight change from baseline, but this parameter is
natremia, an increased serum osmolality, and intra- not always available at the initial presentation.
cellular water depletion. The fluid balance is altered Since weight in children increases with age, using
due to fluid loss being greater than fluid intake. In a weight taken few weeks apart might not be an
isotonic dehydration (mostly isonatremic), water option especially in younger children. If a recent
and salt are lost in equal proportions. In hypertonic weight is available, the degree of acute weight loss
(mostly hypernatremia), water is predominantly reflects the degree of fluids loss. One kilogram of
lost, while in hypotonic (always hyponatremic), a body weight loss equates one litre of fluid loss. In
higher proportion of salt than water is lost. The three reality however the degree of dehydration is
main sites of fluid loss are gastrointestinal assessed clinically by a combination of history
(vomiting, diarrhea, blood loss), the skin (burns, and physical exam findings. The following signs
fever, CF), urine (diabetes insipidus, diuretics, and symptoms in combination are useful for
osmotic diuresis, diabetes mellitus, alcohol, etc.). assessing the degree of dehydration: dry mucous
Prolonged decreased fluid intake can also lead to membrane, sunken eyes, reduced urine output,
dehydration, but this is rare in infants and children. delayed capillary refill time, tachycardia, and
However, breast-fed babies are more likely to be deep and/or rapid respiration (Table 2). In infants
dehydrated due to reduced fluid intake especially
during the early neonatal period when maternal Table 2 Signs and symptoms of dehydration in infants
and children
breast milk production is still low.
Infants and children
Risk Factors for Dehydration Dry mucous membranes
Infants are more susceptible than older children Sunken eyes
due to higher fluid turnover in the former com- Reduced urine output
Delayed capillary refill
pared to the latter. Infectious diarrhea is more
Tachycardia
common in infants than in older children. Infants
Deep þ/ rapid respiration
are not able to communicate their need for fluids
Table 3 Clinical dehydration scale in children aged assessing the degree of dehydration as it is affected
1 month and 36 months (Bailey et al. 2010; Friedman by intake and increased tissue breakdown.
et al. 2004; Woolley and Burton 2009)
Score
0 if Score 1 if Score 2 if
Characteristic present present present Fluid and Electrolyte Management
General Normal Thirsty, Drowsy,
appearance restless, limp, Infants and older children admitted to the hospital
sleepy, or comatose who are unable to tolerate oral fluids require care-
irritable ful management of fluid and electrolyte balance.
Eyes Normal Slightly Deeply Additional care may be required for those requir-
sunken sunken
ing surgical and medical procedure. Children with
Tongue Moist Sticky Dry
Tears Present Decreased Absent
underlying medical conditions such as diabetes
and heart or renal failure require special consider-
ation. Children in septic shock and trauma and
burn patients also require special attention. There-
Table 4 Eight-point scale for assessing the degree of
fore, in planning the initiation of fluid therapy in
dehydration
infants and children, these variables must be taken
Scores Degree of dehydration
into consideration (Tables 5 and 6). Consideration
0 No dehydration
should also be given to modifying any existing
1–4 Some dehydration
local guidelines to the needs of each child’s fluid
5–8 Moderate to severe dehydration
and electrolyte requirements.
The major component of maintenance water
includes the total urine output in the last 24 h.
whose anterior fontanelles are still open, a sunken This accounts for about 60% of the total mainte-
fontanelle is a useful sign for assessing the degree nance water. Insensible loss through the skin and
of dehydration. Late signs in both infants and chil- the respiratory tract accounts for about 35% of the
dren include decreased skin turgor and arterial maintenance fluid, while about 5% of the mainte-
hypotension. nance fluid is lost through the stool. Maintenance
A four-item eight-point rating scale for fluid should also be adjusted for ongoing losses
assessing the degree of dehydration has been especially from the GI tract. Ongoing GI losses
developed for children less than 4 years old occur through diarrhea, vomiting, gastrointestinal
using a combination of general appearance, drainage tubes, nasogastric tube, gastro-jejunal
eyes, mucous membrane, and the presence or tubes, intestinal mucocutaneous fistulae, etc.
absence of tears (Goldman et al. 2008, Tables 3 Maintenance fluid therapy may need to be
and 4). decreased in the following circumstances: inap-
propriate ADH secretion, congestive heart failure,
Laboratory Testing oliguric renal failure, patent ductus arteriosus,
These tests can confirm whether dehydration is head trauma, and hypothyroidism The following
present or not and can detect associated electrolyte factors should be considered in assessing fluid and
and acid-base balance disturbances but are not electrolyte requirement in infants and older chil-
useful for assessing the degree of dehydration. dren (Tables 7, 8, 9, and 10): recent acute weight
The following laboratory findings might point to change, urine output, specific gravity and osmo-
the presence of dehydration: decreased fractional lality, serum sodium and creatinine, blood urea,
excretion of sodium, decreased urinary spot and osmolality. In the hospitalized patient, the
sodium concentration <30 mmol/l, increased uri- fluid input and output chart should also be
nary concentration >450 mosm/kg water, and assessed in order to estimate the fluid deficit.
decreased serum bicarbonate <17 mmol/l. The Slower fluid resuscitation in African children suf-
serum urea concentration is less useful for fering from hypovolemic shock is more beneficial
Table 5 Composition of commonly used intravenous fluids in infants and children (Melbourne 2012)
Naþ Cl K+ Lactate Ca++ Glucose
Type of fluid Indications for use (mmol/L) (mmol/L) (mmol/L) (mmol/L) (mmol/L) (gram/L)
0.9% NaCl Resuscitation fluid 150 150 – – – –
(normal saline) in shock and trauma
0.9% NaCl Maintenance fluid in 150 150 – – 5
with 5% sick children and in
dextrose children with
hyponatremia
Hartmann’s Intraoperative and 130 110 5 30 2 –
solution postoperative
maintenance fluid
10% dextrose Used for the – – – – – 10
in water treatment of
hypoglycemia
Table 6 Indications for parenteral nutrition in infants and Table 9 Daily lipid requirements in infants and children
children
Initiation 1 g/kg/day
Bowel surgery Advancement 0.5 g/kg/day
Burns Maximum requirement 2–3 g/kg/day
Trauma
Short bowel syndrome
Intestinal pseudo-obstruction Table 10 Daily caloric requirements in infants and chil-
Inflammatory bowel disease dren (Kraus 1998)
Multiple organ failure
Daily caloric requirements
Post-bone marrow transplantation Age group (years) (kcal/kg/day)
Malnutrition – malignancy, cystic fibrosis, anorexia 0–1 90–120
nervosa
1–7 75–90
7–12 60–75
12–18 30–60
Table 7 Daily electrolyte requirements in infants and

children (Kraus 1998)
than rapid fluid resuscitation in these individuals
Electrolyte/element Daily maintenance requirements
as was demonstrated in the Fluid Expansion as
Sodium 2–4 mEq/kg/day
Supportive Therapy (FEAST) trial (Maitland et al.
Potassium 2–3 mEq/kg/day
2011).
Calcium 0.46–2.32 mEq/kg/day
Magnesium 0.25–0.50 mEq/kg/day
Chloride 2–3 mEq/kg/day
Phosphate 1–2 mEq/kg/day Electrolytes
Sodium
Table 8 Daily protein requirements in infants and chil-
Sodium is the main electrolyte of the ECF respon-
dren (Kraus 1998)
sible for the maintenance of intravascular volume
Age group Protein requirement (g/kg/day)
and osmolality. Sodium, chloride and bicarbonate
Infants 2.5–3.0
anions account for 90% of the ECF osmolality.
>1 year 1.5–2.0
Serum sodium concentration is maintained by a
Adolescents 1.0–1.5
combination of water intake, insensible losses,
and urinary dilution. The normal range is hyponatremia include cerebral edema and
135–145 mmol/l. osmotic demyelination.
Dysnatremia Hypernatremia
Hypernatremia is defined as serum sodium
Hyponatremia >150 mmol/l. This is a relatively uncommon con-
Hyponatremia is defined as sodium level dition after the age of 2 weeks occurring in 1 in
<130 mmol/l. In this condition the effective cir- 2,000 children admitted to hospital (Forman et al.
culating level might be increased, normal, or 2012). Relative deficit of water with reduced thirst
decreased. Hypovolemic hyponatremia occurs as sensation and/or reduce intake of water is the main
a result of volume depletion, while normo- or cause of hypernatremia. However hypernatremia
hypervolemic may be due to volume dilution. may result from excessive sodium intake (Vogt et
When the ECV decreases, vasopressin is released al. 2009). This is a rare but potentially fatal cause of
as a result and this is the most common cause of hypernatremia in children and results in much
hyponatremia in children. higher urinary sodium: creatinine ratio and urinary
In dilutional hyponatremia, syndrome of inap- fractional sodium excretion than other causes of
propriate ADH secretion (SIADH) leads to hypernatremia (Forman et al. 2012).
increased vasopressin secretion resulting in water The risk factors for hyponatremia in infants and
retention, volume expansion, and hyponatremia, children include excessive water GI loss as a result
while in hypovolemic hyponatremia, fluid and elec- of gastroenteritis, systemic infection, postoperative
trolyte loss leads to decreased ECV which in turn cardiac surgery, and chronic neurological conditions
triggers vasopressin secretion, water retention, and (Forman et al. 2012). Significant morbidity and
hyponatremia. In cerebral salt wasting syndrome mortality are associated with severe hypernatremia.
(CSWS) on the other hand, increased renal salt loss The main complications associated with hyper-
leads to volume depletion which in turn stimulates natremia include dural sinus thrombosis, intracranial
increased vasopressin leading to volume depletion hemorrhage, osmotic demyelination, and shrinkage
and hyponatremia. The important distinguishing of the brain cell. Treatment of this condition may
feature between SIADH and CSWS is volume result in cerebral edema (Hoorn et al. 2012).
depletion in CSWS compared to the relative vol- The management of hypernatremia includes
ume overload in SIADH. While CSWS is treated addressing the root cause by taking a good history
by volume and salt repletion, SIADH is treated by and performing adequate physical examination
fluid restriction (Peruzzo et al. 2010). and managing fluid volume and electrolyte
SIADH is common in critically ill children. balance. Robertson et al. investigated the
The diagnosis of SIADH is based on the classic “relationship between fluid management, changes
criteria developed by Schwartz and Batter and in serum sodium and outcome in hypernatremia
includes hyponatremia with hypo-osmolality associated with gastroenteritis” in South African
with continuing urinary sodium loss, urine that children and concluded that adverse outcome was
is less maximally dilute, no clinical signs of neither independently associated with intravenous
volume depletion, and the absence of other fluid sodium concentration nor with the rate of fall
possible causes of hyponatremia. The most com- of serum sodium (Robertson et al. 2007). How-
mon causes of postoperative hyponatremia ever, Fang et al. in a retrospective study in Chi-
in children are subclinical volume depletion nese children, investigated the factors in fluid
and the administration of hypotonic fluids management of hypernatremic dehydration
(Peruzzo et al. 2010). Other causes include patients that could prevent the development of
stress, pain, nausea, and narcotics all of which cerebral edema and identified “too rapid a rate of
stimulate ADH release. The symptoms of hypo- rehydration, an initial fluid bolus to rapidly
natremia include nausea, headache, diplopia, expand plasma volume and the severity of the
falls, seizures, and coma. The complications of hypernatremia” as the major risk factors for the
development of this complication (Fang et al. excretion and renal tubular acidosis type IV.
2010). A slow rehydration rate over 48–72 h was Drugs that interfere with the renin-angiotensin-
suggested as the best way to prevent this problem aldosterone system (mineralocorticoid receptor
(Fang et al. 2010). blockers) such as spironolactone, antifungal
drugs, heparin, NSAIDs, succinylcholine, and
beta-blockers can cause hyperkalemia. Potas-
Potassium sium-containing compounds used during
aggressive potassium supplementation, blood
Potassium is the main intracellular fluid. Potas- transfusion, and medicinal herbs may also result
sium homeostasis is maintained by the Na þ K in hyperkalemia.
ATPase which facilitates the transport of potas-
sium back into the cell against its concentration Symptoms and Signs of Hyperkalemia
gradient. The serum potassium concentration The most concerning feature of hyperkalemia is
is therefore maintained with in a very narrow the effect on the cardiac conducting system. The
range of 3.5–5 mmol/l. Disorders of main symptoms and signs of hyperkalemia
potassium metabolism include hypokalemia or include muscle weakness and muscle cramps.
hyperkalemia. ECG changes start with tall peaked T waves,
followed by prolonged PR interval, loss of P
Hyperkalemia waves, widened QRS complex, and finally ven-
Hyperkalemia is defined as serum potassium tricular fibrillation and a sine wave (Greenbaum
levels greater than 5.5 mmol/l. Mild hyperkalemia 2010c). Death might result if hyperkalemia is not
is defined as serum potassium level between 5.5 treated. Muscle paralysis and cardiac arrhythmias
and 6.0 mmol/l; moderate hyperkalemia is are the two main complications of hyperkalemia.
between 6.1 and 6.9, while severe hyperkalemia Treatment of hyperkalemia is aimed at preventing
is greater than 7 mmol/l (Ahee and Crowe 2000). or ameliorating these complications.
Serum potassium level greater than 10 mmol/l is
fatal if not treated (Tran 2005). Diagnostic Tests
Causes of hyperkalemia in children and The diagnostic tests for hyperkalemia include
infants include pseudohyperkalemia due mainly serum electrolytes, urea and creatinine, serum
to sample hemolysis but may also be due bicarbonate, platelets, and white cell counts.
thrombocytosis and leukocytosis. Redistribu- Other tests include urine potassium, urine creati-
tive hyperkalemia results from acidosis (serum nine, plasma renin, and aldosterone.
potassium decreases by 0.4 for each 0.1 point
decrease in serum pH) and rapid cell death in Treatment of Hyperkalemia
tumor lysis syndrome, trauma, diabetes The two basic principles guiding the management
ketoacidosis, intravascular coagulation, and of life-threatening hyperkalemia include mem-
rhabdomyolysis (Greenbaum 2010c; Hoorn et brane stabilization to block the effect of the excess
al. 2012). Primary adrenal insufficiency or potassium on the myocyte transmembrane poten-
unresponsiveness can also cause hyperkalemia. tial and cardiac conduction and reduction of extra-
In congenital adrenal hyperplasia due to 21- cellular potassium levels (Hoorn et al. 2012).
hydroxylase deficiency, the male infants usually The therapeutic approach depends on the serum
present with salt wasting, metabolic acidosis, potassium level, associated ECG changes, and on
hyperkalemia, and hypovolemia. This presenta- whether the condition is likely to worsen or not
tion is less common in affected female infants as (Greenbaum 2010c).
they are diagnosed and treated during the new- Intravenous calcium gluconate or calcium chlo-
born period (Greenbaum 2010c). Hyperkalemia ride helps in stabilizing the cardiac membrane and
can result from both acute and chronic renal in reducing the risk of cardiac arrhythmias associ-
disease due to reduced renal potassium ated with hyperkalemia. It is recommended for
serum K > 7 mmol/l with or without ECG changes potassium are lost through vomits as gastric fluids
(Hoorn et al. 2012). This treatment does not lower contain low concentrations of potassium of about
serum potassium levels. Insulin with glucose helps 10 mEq/l. However, the associated chloride loss in
to move the potassium from the ECF to the ICF. It gastric fluid leads to metabolic acidosis and hypo-
does reduce the plasma potassium but not the total volemia which results in increased urinary loss of
body potassium. Frequent monitoring of serum potassium. Other causes of hypokalemia include
potassium and glucose is required during this treat- redistributive hypokalemia which is due to alkalo-
ment. β-2 adrenergic agonists such as intravenous sis and hypothermia, hypokalemic paralysis, and
salbutamol can also help shift potassium into the the administration of drugs such as insulin and β-
cells (Murdoch et al. 1991, while sodium bicarbon- adrenergics like salbutamol, Risperdal, and chloro-
ate also helps shift potassium intracellularly. How- quine (Greenlee et al. 2009). Administration of
ever, sodium bicarbonate administration is only loop diuretics also leads to hypokalemia. Primary
recommended when acidosis coexists with hyper- or secondary aldosteronism results in increased
kalemia. Loop diuretics remove excess potassium renal potassium loss, metabolic alkalosis, sodium
from the plasma. It is recommended if hyper- retention, and hypertension. Hypomagnesemia,
volemia is present. renal tubular acidosis types I and II, eating disor-
Sodium or calcium polystyrene sulfonate is an ders, laxative abuse, and low-potassium intake are
ion exchange resin that can either be administered other causes of hypokalemia.
by mouth or per rectum. The main drawback is
that it takes approximately 4 hours to work and Symptoms and Signs of Hypokalemia
that oral administration of calcium polystyrene The symptoms of hypokalemia include paresthe-
sulfonate in preterm neonates with suspected or sia, muscle cramps, muscle weakness, and paral-
proven ileus is associated with increased risk of ysis which may occur at serum potassium levels
intestinal obstruction (Ohlsson and Hosking <2.5 mmol/l. Leg muscles are usually affected
1987). In this group of patients, insulin and glu- first followed by the arm muscles (Greenbaum
cose infusion is preferred over oral or rectal resin 2010c). The signs of hypokalemia are hyporeflexia
administration (Vemgal and Ohlsson 2012). and ECG changes which includes flat of T waves,
Fludrocortisone can be given if there is associated short PR interval, and U waves (Ford 2002).
adrenal insufficiency. Patients with hyperkalemia
associated with chronic renal impairment may
require hemodialysis or hemofiltration to remove Complications of Hypokalemia
the excess potassium. This can also be employed Hypokalemia is associated with the following
in intensive care settings. In addition to the above complications: arrhythmias which may occur in
measures, potassium should be avoided in all the a child with coexistent heart disease (Greenbaum
fluids administered to this patient. 2010c). The types of arrhythmia in hypokalemia
include ventricular fibrillation, ventricular and
Hypokalemia atrial tachycardia, and premature ventricular con-
This is defined as serum potassium level tractions. Ileus, respiratory failure (secondary to
<3.5 mmol/l. Severe hypokalemia results when the weakness of the respiratory muscles), glucose
serum potassium level is less than 2.5 mmol/l. intolerance, and rhabdomyolysis are other symp-
toms associated with hypokalemia (Jain et al.
Causes of Hypokalemia 2011). The risk of rhabdomyolysis is increased if
The four mechanisms that lead to hypokalemia in a child with hypokalemia embarks on exercise.
children and infants include low potassium intake,
redistributive or transcellular shift, renal losses, and Investigations of Hypokalemia
non-renal losses. The most common causes of The following investigations should be carried out
hypokalemia in infants and children are diarrhea in a child with hypokalemia: serum electrolytes,
and vomiting. While potassium and bicarbonate are urea and creatinine, magnesium, and phosphate.
lost in diarrheal stools, only minimal amounts of Blood gas should be done to determine the serum
bicarbonate levels as coexistent metabolic acidosis salt. Ongoing losses should be corrected for espe-
points to diarrhea as a possible cause, but other cially in surgical patients and in other critically ill
conditions like proximal and distal renal tubular patients.
acidosis have to be considered. Hypokalemic met-
abolic alkalosis indicates gastric losses, hyper-
aldosteronism, or diuretic administration as Calcium
possible causes. Urinary potassium less than
20 mmol might indicate gastrointestinal cause of Serum calcium is closely regulated by the interplay
hypokalemia, while a urinary level greater than of skeletal, renal, and parathyroid factors which
20 mmol indicates renal losses (Hoorn et al. include calcium-sensing receptors, vitamin D3,
2012). Occasionally, urine potassium-to-creatinine and parathyroid hormone (Lietman et al. 2010).
ratio, plasma renin, and aldosterone and thyroid
function test might be required (Hoorn et al. Hypercalcemia
2012). Blood pressure should be measured as coex- Most hypercalcemia is due to osteoclastic bone
istent high blood pressure is associated with resorption (Lietman et al. 2010). Hypercalcemia is
hyperaldosteronism. also a common complication of solid tumors (Sar-
gent and Smith 2010). Rarely, familial hypo-
Treatment of Hypokalemia calciuric hypercalcemia (also termed familial
History, examination, and investigations should benign hypercalcemia) can be the cause of hyper-
be undertaken to identify the underlying cause. calcemia in children (Lietman et al. 2010). Inves-
The main aim of therapy is to restore serum potas- tigations of hypercalcemia include serum urea and
sium to normal. Treatment of hypokalemia is electrolytes, calcium phosphate and magnesium,
influenced by the following factors: how low the vitamin D, PTH, and albumin. Measurement of
serum potassium level is, the child’s renal func- urinary calcium concentration might provide a
tion, presence or absence of symptoms associated clue as to the etiology of hypercalcemia (Davies
with hypokalemia, whether the low potassium 2009). Asymptomatic hypercalcemia does not
level was due to redistributive causes, whether require treatment. The main aims of treatment of
the potassium loss is ongoing, and whether the symptomatic hypercalcemia are to remove the
child is able to tolerate oral potassium supplemen- source of the excessive PTH secretion if possible
tation (Greenbaum 2010c). Intravenous potas- or to the excess serum calcium if removal of the
sium at a rate not exceeding 0.5 mmol/kg/h primary source is not possible (Davies 2009).
should be administered if the child presents with Hyperhydration and diuretics are the initial treat-
the following complications: profound muscle ment modalities for hypercalcemia (Cheung
weakness, cardiac arrhythmia, or respiratory dif- 2009). Bisphosphonate and calcitonin are used
ficulty or if the serum potassium level is very low to treat specific disorders associated with hyper-
(Ford 2002). Otherwise oral potassium supple- calcemia. Recently new therapies have been
ments are usually sufficient to replenish the deficit developed to treat hypercalcemia. These include
unless the child is vomiting, intolerant to oral cathepsin K inhibitor, sclerostin, cinacalcet, and
supplements, or is not allowed to take oral fluids bone morphogenetic protein 2 (Cheung 2009).
due to other medical or surgical indications. In Treatment of hypercalcemia secondary to hyper-
some cases, potassium supplementation may be parathyroidism is by parathyroidectomy (Lietman
needed for a few weeks in order to correct the et al. 2010).
deficit.
Serum potassium should be monitored regu- Hypocalcemia
larly while on potassium supplementation Hypocalcemia is one of the most common disor-
although this might not be accurate in redistribu- ders of mineral metabolism in children. The four
tive causes of hypokalemia. Coexistent hypo- main causative mechanisms of hypocalcemia are
phosphatemia should be treated with a potassium decreased intake or decreased absorption,
phosphate salt instead of the potassium chloride increased binding and sequestration, decreased
mobilization from the bones, and low serum pro- diuretic and proton pump inhibitor therapy. Symp-
tein (Marini and Wheeler 2010). toms of hypomagnesemia are tremors, tetany, sei-
Mild hypocalcemia is usually asymptomatic as zures, nystagmus, and paresthesia. The ECG
long as the ionized calcium levels remain normal changes associated with the condition include pro-
(Marini and Wheeler 2010). The serum calcium longed QT interval, torsades de pointes, and ven-
levels at which symptoms of hypocalcemia tricular fibrillation (Foglia et al. 2004).
develops are variable. Most of the symptoms are The consequences of hypomagnesemia
due to irritability of the neuromuscular junction. include cardiac arrhythmias, which usually results
Cramps, paresthesia, and tetany are the most com- from unrecognized coexistent hypokalemia, insu-
mon symptoms. Others are seizures, hallucina- lin resistance, and nervous disturbance (Ayuk and
tions, and headaches. Respiratory symptoms Gittoes 2011). Administering anesthetic agents to
such as dyspnea and stridor might develop if the patients with hypomagnesemia may increase the
respiratory muscles are affected. The signs asso- risk of cardiac arrhythmias (Gambling et al.
ciated with hypocalcemia include carpopedal 1988). Investigation of hypomagnesemia includes
spasm, facial muscle hyperreflexia, and urea and electrolytes, blood gas, serum calcium,
papilledema. Laboratory investigations of hypo- phosphate, and magnesium. Intravenous magne-
calcemia include serum calcium, phosphate, and sium is the treatment of choice for symptomatic
magnesium. Serum albumin, urea and electro- hypomagnesemia (Ayuk and Gittoes 2011). Oral
lytes, PTH, and vitamin D levels are other labora- magnesium therapy should be used in asymptom-
tory investigations. atic patients.
Hypermagnesemia
Magnesium Hypermagnesemia is rare due to the closely regu-
lated magnesium metabolism (Samsonov 2009).
Magnesium is an important mineral involved in Renal failure and excessive magnesium ingestion
maintaining bone health. Magnesium, like potas- are the two main causes of hypermagnesemia
sium, is an intracellular cation required for many (Samsonov 2009). Patients with Epsom salt poi-
biological processes. It catalyzes more than 300 soning and laxative abuse and those being treated
enzyme systems and is involved in the generation, with magnesium as a cathartic are at increased risk
storage, and transfer of energy in the body of hypermagnesemia (Samsonov 2009). Other
(Gonzalez et al. 2009). Intracellular magnesium causes of hypermagnesemia include tumor lysis
modulates calcium and potassium channels in the syndrome, milk-alkali syndrome, hypothyroid-
cardiac myocyte (Agus and Agus 2001). ism, and Addison’s disease.
Although mild hypermagnesemia is usually
Hypomagnesemia asymptomatic, severe hypermagnesemia is
This results mainly from the imbalance between associated with the following symptoms: head-
the absorption of magnesium from the GI and its ache, nausea, and vomiting. Drowsiness,
excretion from the kidneys (Gonzalez et al. 2009). decreased tendon reflexes, bradycardia, hypo-
Increased GI or renal loss and redistribution mag- tension, and ECG changes (torsades de pointes,
nesium between the extracellular and intracellular arrhythmias, and prolonged QT) (Troung et al.
compartments are other causes of hypomagnese- 2010) are the signs associated with hyper-
mia (Ayuk and Gittoes 2011). Symptomatic hypomagnesemia. The treatment of hyper-
magnesemia is usually associated with magnesemia depends on the serum magnesium
hypocalcemia, hypokalemia, or metabolic acidosis levels and the severity of symptoms and signs.
(Ayuk and Gittoes 2011). Other electrolyte abnor- Mild asymptomatic hypermagnesemia can be
malities associated with hypomagnesemia include treated by discontinuation of magnesium ther-
hyponatremia and hypophosphatemia. Drug- apy. Severe hypermagnesemia may require such
induced hypomagnesemia is associated with measures as forced diuresis, intravenous
calcium gluconate infusion, dialysis, and respi- and creatinine, calcium, phosphate, and magne-
ratory support (Samsonov 2009). sium. Hyperphosphatemia is treated by treating
the underlying cause, limiting intake, and/or
removal of the excess phosphate using phosphate
Phosphate binders (Covic and Rastogi 2013).
Phosphate is a predominantly intracellular anion

involved in several metabolic processes in the Acid-Base Balance
body such as in the generation of adenosine tri-
phosphate (ATP), nucleic acids, and cyclic aden- The normal values for pH in infants and children
osine monophosphate (cAMP) and in the (7.35–7.45) are similar to those in the neonates and
generation of the coagulation cascade. adults. The pH is closely regulated so that cellular
enzymes could function optimally. While mild
Hypophosphatemia chronic deviations from the normal range can be
The causes of hypophosphatemia are decreased tolerated, extreme, rapid deviations increase mor-
GI absorption, increased renal excretion, and tality. The acid-base balance is maintained by the
redistribution between intracellular and extracel- lungs, kidneys, and intracellular buffers
lular compartments (Troung et al. 2010). Mild (Greenbaum 2010a). The pCO2 is maintained
hypophosphatemia may be asymptomatic, but within the normal range of 35–45 mmHg by the
chronic severe hypophosphatemia may cause rapid response of the lungs to the central mecha-
myalgia and muscle weakness (Troung et al. nism that senses changes in pCO2, while the bicar-
2010). Other symptoms of hypophosphatemia bonate level is maintained within the normal range
include bone pain and decreased levels of by the ability of the kidney to regenerate the bicar-
consciousness. bonate utilized in neutralizing organic acids gener-
The investigation of hypophosphatemia ated by the body (Greenbaum 2010a). Lactate and
involves checking the urea, electrolytes, chloride, acid-base balance can be used as markers of cardiac
creatinine, calcium, phosphate, blood pH and output, tissue oxygenation, and cellular perfusion
bicarbonate, parathyroid hormone, and vitamin in perioperative patients. However, in ill patients
D levels. Determining the urinary phosphate, cre- many other factors can contribute to hyper-
atinine, and calcium levels can help determine the lactatemia and these factors need to be addressed
etiology of the hypophosphatemia. as well. Although persistent hyperlactatemia in
postoperative cardiac patients is associated with
Treatment of Hypophosphatemia increased morbidity and mortality, a single mea-
Oral phosphate at a dose of 1–2 mmol/kg/day, in surement of serum lactate is not a good predictor of
two to four divided doses, is preferred to intrave- survival (Allen 2011).
nous supplementation in patients who can tolerate
oral therapy (Troung et al. 2010).
Acid-Base Balance Disorders
Hyperphosphatemia
Hyperphosphatemia is a rare condition seen Acid-base balance disorders may be in the form of
mostly in children with chronic renal failure. It is acidosis (pH < 7.35) or alkalosis (pH > 7.45).
generally asymptomatic but may be associated Metabolic or respiratory disorders can manifest as
with hypocalcemia due to the formation of cal- acidosis or alkalosis. Mixed acid-base disorder
cium phosphate complexes. These are deposited may result when both respiratory and metabolic
in the skin and arterioles of patients with chronic acid-base disturbance coexist. In this case two
hyperphosphatemia. primary processes are going on at the same time.
Laboratory investigation of hyper- Compensatory mechanisms exist to counter acid-
phosphatemia includes serum urea, electrolytes base disturbance. The body attempts to restore the
pH to normal using the compensatory mecha- intraoperative fluids that is isotonic and contains
nisms of the kidneys, lungs, and the intracellular 1–2.5% glucose and bicarbonate precursors like
buffers. lactate, acetate, or malate (Sumpelmann et al.
2011). For replacement of losses, fluids with simi-
Metabolic Acidosis lar compositions as the lost fluid should be used. In
Metabolic acidosis results from a primary reduc- replacing the ongoing losses in surgical patients,
tion in the serum bicarbonate levels with a resul- consideration should also be given to the surgical
tant decrease in the pH levels below 7.35. pathology, the surgical procedure, and the child’s
Addition of organic acid from external sources, comorbid conditions.
altered body metabolic pathways, or rapid admin- Hydration status should be continuously moni-
istration of normal saline may result in metabolic tored in perioperative children. Weight, blood pres-
acidosis. Hyperchloremic acidosis with normal sure, pulse, capillary refill time, urine output, and
anion gap results from the loss of bicarbonate respiratory rate are some of the clinical parameters
ions from the GI or urinary tract. Diabetes used to assess hydration status. In addition strict
ketoacidosis results from the addition of recording of the fluid input and output might be
unmeasured acid and is therefore associated with necessary. The laboratory parameters include
a widened anion gap (Ford 2002). blood urea, electrolyte and osmolality, urine specific
gravity, osmolality, and electrolytes.
Metabolic Alkalosis
Metabolic alkalosis occurs if the pH is >7.45 and
the HCO3 is >35 mEq/l. Metabolic alkalosis may Intraoperative Management
be chloride responsive or chloride resistant. This
categorization is based on urinary chloride concen- Careful intraoperative fluid management and mon-
trations. While the urinary chloride concentration itoring minimize adverse hemodynamic effects
in the chloride-responsive metabolic alkalosis is during and after surgery. Blood loss should be
<15 mEq/l, the urinary chloride concentration in minimized as much as possible since total blood
the chloride-resistant type is >20 mEq/l. Vomiting volume is relatively low especially in very young
and diuretic therapy are the most common causes of infants. A seemingly small-volume loss in such
chloride-responsive metabolic alkalosis, while infants could cause major hemodynamic instability.
adrenal adenoma and Gitelman syndrome cause Other high-risk children are those with preoperative
chloride-resistant metabolic acidosis with high anemia, those on antithrombotic or antiplatelet ther-
blood pressure and without high blood pressure, apy, and those undergoing complex, emergency, or
respectively (Greenbaum 2010a). re-operative surgeries (Vretzakis et al. 2011). Mea-
sures to reduce blood loss in these high-risk patients
include autologous blood donation and
Perioperative Management in Infants normovolemic hemodilution (Vretzakis et al.
and Children 2011). Intravascular monitoring of blood pressure
and central venous pressure should be undertaken
The Holliday-Segar equation for calculating main- during major surgical procedures. Fluid losses
tenance fluid requirements in the postoperative should be carefully documented.
period in infants and children was revisited because
of the frequent occurrence of hyponatremic dehy-
dration using this method (Steurer and Berger Postoperative Management
2011). Isotonic fluids are recommended in such
situations of volume depletion where it is antici- Good preoperative and intraoperative fluid man-
pated that ADH secretion will be stimulated agement obviates fluid and electrolyte problem
(Steurer and Berger 2011). The European Society postoperatively. Replacement of lost fluid dur-
for Paediatric Anaesthesiology recommends ing the surgery may still be ongoing
postoperatively. Ongoing losses may occur from administered within the first hour, and the infec-
wounds, drainages, fistulae, or postoperative tion source should be removed as soon as possible
hemorrhage. Monitoring of the vital signs and (Carcillo et al. 2009).
the fluid input and output should continue during Surgical conditions predisposing children to
the immediate postoperative period. Oliguria, septic shock include intussusception and
hypotension, and transient renal impairment Hirschsprung’s diseases with enterocolitis and
may occur. Serum urea, electrolytes, creatinine, volvulus. Endotoxins produced by Gram-negative
and glucose as well urine specific gravity should bacteria are responsible for most of the clinical
be monitored. SIADH is one of the complica- manifestations of septic shock.
tions to watch out for. Hyperchloremic metabolic
acidosis may arise from the administration of nor-
mal saline so Ringer’s lactate is preferable (Steurer Clinical Manifestations
and Berger 2011).
Management
Crystalloid boluses of 20 ml/kg are infused rap-
Fluid and Electrolyte Balance in Septic idly. Up to 60 ml/kg of resuscitation fluid may be
Shock required. Normal saline is the preferred resusci-
tation fluid. Appropriate antimicrobials should
Shock is defined as a state of acute cardiovascular be initiated as early as possible. In cold shock
dysfunction in which the delivery of oxygen and peripheral adrenaline may be required, while in
nutrients is insufficient to meet the metabolic warm shock adrenaline should be infused cen-
demands of the tissues. Clinically, in shocked trally, while vasodilators might be needed
patients, the capillary refill time is greater than in children with pulmonary hypertension or
2 s. Hypotension is a late sign which is present high systemic vascular resistance (Aneja and
only in decompensated shock in children. The Carcillo 2011). Although maintaining tight
mortality rate is about 5–7%. Every hour delayed glycemic control might be harmful in adults
in initiating appropriate measures to reverse the with septic shock, this issue has not been
shock state increases the mortality by 40%. Septic resolved in pediatric shock. Hydrocortisone is
shock in infants and older children is character- recommended for children with absolute
ized by severe hypovolemia unlike septic shock in cortisol deficiency. Mortality is about 50% in
adults which exhibits a hyperdynamic state children requiring conventional extracorporeal
(Aneja and Carcillo 2011). Aggressive fluid resus- membrane oxygenation (ECMO) but can be
citation is therefore required in children pre- improved by the use of central ECMO
senting with septic shock. Vasoconstriction is a (MacLaren et al. 2011).
common feature of septic shock in children unlike
adults. This is because of the limited cardiac
reserve in children. If vasoconstriction is pro- Total Parenteral Nutrition (TPN)
longed, cardiac failure may result. Inotropes,
vasodilator, and in some cases ECMO may be Total parenteral nutrition is indicated in cases of
required to support cardiac function (Vretzakis et intestinal failure resulting from congenital enter-
al. 2011). Goal-directed therapy over 72 h – main- opathies, massive intestinal surgical resections,
tenance of normal blood pressure and Central intractable diarrheas, and immune-mediated
Venous (CV) oxygen saturations >70% – congenital diarrheal diseases (Kocoshis 2010,
decreases mortality from 40% to 12%. The basic Askegard-Giesmann and Kenney 2015, Table
principles of therapy in septic shock are resusci- 6). TPN is also indicated in pediatric oncology
tation, administration of antimicrobials, and patients especially those undergoing bone mar-
removal of the nidus of infection (Aneja and row transplant (Copeman 1994). TPN can be
Carcillo 2011). Antibiotics should be given via peripheral or central venous access.
Complications associated with TPN therapy Bianchetti MG, Simonetti GD, Bettinelli A. Body fluids and
include sepsis and thrombosis. Adjunctive ther- salt metabolism – part I. Ital J Pediatr. 2009;35(1):36.
Brandis, K. Regulation of cell volume. Fluid Physiol.
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Vascular Access in Infants
and Children 16
Hiroki Nakamura, Rieko Nakamura, and Thambipillai Sri Paran
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Peripheral Venous Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Central Venous Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Peripherally Inserted Central Catheter (PICC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Umbilical Venous Catheters (UVC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
Tunneled and Cuffed Catheter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
Implantable Vascular Access Devices (Ports) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Intraosseous Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Arterial Vascular Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Umbilical Artery Catheterization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
Radial Artery Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Pedal Arterial Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Axillary and Femoral Arterial Cannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Complications and Their Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
H. Nakamura (*)
Department Pediatric General and Urogenital Surgery,
e-mail: hinakamu@juntendo.ac.jp
R. Nakamura
Department of Anesthesiology, Nihon University School
of Medicine, Tokyo, Japan
e-mail: rieko_0228@hotmail.com
T. S. Paran
Paediatric Surgery, Our Lady’s Children’s Hospital,
e-mail: sriparan80@hotmail.com

https://doi.org/10.1007/978-3-662-43588-5_203
264 H. Nakamura et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Abstract Keywords
There has been a significant increase in the Venous access · Arterial access · Central
survival rates of newborns and infants over catheter · Neonatal critical care · Umbilical
the past decade, which is due in large part to catheter
advances in monitoring, vascular access, and
other supportive measures. The use of new
routes of access coupled with innovations in Introduction
materials and catheter size has led to improve-
ments in invasive monitoring, inotropic sup- Vascular access is frequently required in hospital-
port, and the ability to provide total parental ized infants and children for a number of clinical
nutrition. Arterial cannulation is generally uti- conditions. Short-term vascular access is required
lized for continuous blood pressure monitoring for the delivery of intravenous fluids, medication,
and frequent blood draws for laboratory stud- blood product administration, and for obtaining
ies. Sites of access in the newborn include the blood for laboratory analysis. Long-term vascular
radial and pedal arteries as well as the umbili- access is required for total parenteral nutrition,
cal arteries depending on size and age of the chemotherapy, and pharmacotherapy, e.g., antibi-
patient. Other sites are generally reserved for otics. Establishment of a reliable vascular access
emergent situations. Common complications is potentially a life-saving procedure and a critical
involve vasospasm or thromboembolic events, step in resuscitation during an emergency in
generally treated by simple removal of the infants and children.
catheter, with infection extremely rare. Venous Obtaining vascular access in infants and chil-
cannulation remains the most common access dren can be challenging and very demanding.
method with central catheters placed for vaso- Neonates and infants have excessive subcutane-
active medication infusion and parenteral ous fat which makes visualization and palpation
nutrition. The umbilical vein can be utilized of veins difficult. Children are often less coop-
in the short term. The advent of the peripher- erative and repeated attempts at gaining vascu-
ally inserted central catheter (PICC) now lar access may result in psychological trauma in
allows for bedside catheterization of infants the child (Scott-Warren and Morley 2015). Suc-
as small as 500 g. Percutaneous and cut-down cessful venous puncture in infants and children
techniques are still utilized in neonates where a is heavily dependent on the skills of the
PICC line is unable to be obtained or definitive operator.
long-term central access is required. In emer- The choice of vascular access device depends
gency situations such as trauma, an upon the clinical condition, the likely duration and
intraosseous device can be placed in the prox- frequency of treatment, and the properties of the
imal tibia or humerus to provide quick, short- infusate. Therefore, sound knowledge of indica-
term central venous access. As new materials tions, contraindications, advantages, and disad-
and techniques continue to evolve, reliable vantages of different types of vascular access is
vascular access will allow for the management required to provide the best care for the sick child.
of even the smallest and most critically ill The indication and duration of vascular access
neonates. should be carefully considered before cannulation
16 Vascular Access in Infants and Children 265
is attempted to help minimize the number of It is important to reduce pain and distress asso-
attempts and the psychological trauma to the ciated with cannulation. Children may benefit
child and the family. from the application of local anesthetic agents
(e.g., eutectic mixture of local anesthetics
(EMLA) consisting of a mixture of 2.5% lidocaine
and 2.5% prilocaine in a cream base). It is applied
Peripheral Venous Access to the skin over the target veins then covered with
an occlusive dressing for at least 1 h, providing
Peripheral venous catheters are the most com- localized anesthesia for at least 2 h after removal
monly used catheters. Temporary peripheral (Scott-Warren and Morley 2015). It is useful to
access can be obtained in babies at the bedside use specific devices to aid visualization of veins
with 22–24 gauge cannulae. These cannulae are a for shortening duration time. Transillumination
temporary modality when fluids and electrolytes, and near-infrared light devices are used in many
blood products, and the need for exchange trans- hospitals (Scott-Warren and Morley 2015). Ultra-
fusion and drug therapy are required for a rela- sound can show surrounding structures as well as
tively short duration. Most need to be removed the depth of the vessel. Ultrasound, in combina-
within 3 days due to local extravasation, phlebi- tion with a guide wire to access the great saphe-
tis, and infection (Shenoy and Karunakar 2014). nous vein or the volar veins of the forearm, can
The dorsal veins of the hands are good choices facilitate successful venous access in 100% of
for catheterization as the first choices in the place- patients (Triffterer et al. 2012). These modalities
ment of peripheral venous access. The dorsal improve vein visibility, thereby increasing accu-
veins of foot are good choices for neonates and racy and decreasing the pain associated with
infants; however, they should not be chosen for access (Chiao et al. 2013; Guillon et al. 2015).
older children because these catheters in the dorsal
veins of foot is painful and difficult to maintain
them (Larson and Mancini 2016). Superficial
scalp veins are convenient access points but it is
Central Venous Access
generally limited to infants. Shaving of the sur-
Central venous catheters offer many advantages
rounding hair is required, and the maintenance is
over peripheral lines (Fig. 1). Central venous
difficult (Church and Jarboe 2017; Larson and
access is a reliable method of infusing large vol-
Mancini 2016). Median antecubital, basilic, and
umes of fluid, and they can be maintained over the
median cephalic veins are relatively large and
long-term; they allow the administration of total
easy to cannulate. These sites should be reserved
parenteral nutrition, blovel products, chemother-
as second choices in case percutaneously inserted
apy drugs, antibiotics, and vasoactive mediation
central catheter (PICC) is required. External jug-
(Larson and Mancini 2016).
ular veins can be difficult to cannulate because the
infant must often be restrained and placed in a
dependent position to allow the veins to be visu-
alized (Larson and Mancini 2016). Greater saphe- Peripherally Inserted Central Catheter
nous veins are often good targets, especially (PICC)
anterior to the medial malleolus. These are best
visualized with the foot held in plantar flexion. In PICC is available in single-, double-, and triple-
an emergency when no other peripheral access lumen configurations and in sizes ranging from
can be acquired, the distal saphenous veins also 28-gauge catheters for use in premature neonates
represent good targets for peripheral cut-down to 7 Fr triple-lumen catheters (Scott-Warren and
(Church and Jarboe 2017). Morley 2015) (Fig. 2). PICC has become
Fig. 1 Peripherally inserted Pediatric Multi-Lumen Central Venous Catheter set
increasingly common in patients who require to The size of the PICC is not only determined by
keep venous access for intermediate- to long-term the age of the patient, but also by the size of the
period. They have become the most common access vein and the therapy required. In general,
venous access in infants in the neonatal intensive smaller catheters with the least number of lumens
care unit. PICC lines share attributes of both are associated with the lowest complications;
peripheral and central venous access. They can however, very small catheters are more likely
be readily inserted at the bedside under strictly to become blocked (Scott-Warren and Morley
sterile conditions (Larson and Mancini 2016). 2015).
Advantages of PICC in children are that they The tip position of PICC should be confirmed
may be inserted and removed without a general with fluoroscopy or postprocedure chest X-ray
anesthetic in some children and have the lowest and should be in the superior vena cava or just in
complication rate of central venous access devices the atrium, as more peripheral tip locations (axil-
(Scott-Warren and Morley 2015). lary, subclavian, and innominate) are more prone
The saphenous vein or the veins of the ante- to thrombosis and are not suited for high concen-
cubital fossa (basilic, brachial, cephalic vein) are tration dextrose solutions (Farrelly et al. 2016;
those most commonly used in clinical practice. Lyon et al. 2008).
The preferred insertion site for PICC is the basilic
vein above the elbow, as the cephalic vein makes
an acute angle at its junction with the subclavian Umbilical Venous Catheters (UVC)
vein and so may not enter the central vasculature,
and is also much more prone to vasospasm Umbilical venous catheters (UVC) are placed
(Donaldson 2006; Larson and Mancini 2016; directly into the umbilical vein of the neonatal
Scott-Warren and Morley 2015). umbilical cord. There is a time limitation until
Fig. 2 Peripherally inserted central catheter (PICC). Nutriline PICC line ® set
about 3 days of life when the ductus venous Tunneled and Cuffed Catheter
closes. Catheterization of the umbilical vein is
rather common-place in most nurseries and neo- Long-term central venous access can be provided
natal units, and it can be achieved by trained by tunneled catheters (Hickman ®, Broviac ®,
hands with a great degree of success. At the Groshong ®, and Neostar ®). These lines are gen-
time of insertion, the depth of the UVC can be erally preferred to PICC lines when the duration
determined by the formula (1.5 body weight in of therapy is likely to exceed 6–8 weeks. These
kilograms) + 5.5 cm. It is preferred to advance catheters are placed in a central vein using either
the tip of the catheter along the umbilical vein an open surgical cut-down technique or percuta-
through the ductus venous into the proximity of neously utilizing the Seldinger technique (Farrelly
the right atrium, which is just above the level of et al. 2016; Sri Paran et al. 2003). The catheter is
the diaphragm on plain X-ray. This will permit then tunneled away from the vein insertion site to
the administration of a concentrated intravenous a skin exit site. The tip of the cannula should
solution and reduce the risk of thrombosis. reside in the right atrial and superior vena cava
Umbilical vein catheterization should not be junction parallel to the vein wall. Mounted on the
attempted in the patient with a necrotizing line within the tunnel is a Dacron ® cuff into which
enterocolitis, abdominal wall defect, or peritoni- subcutaneous tissue grows over a period of weeks.
tis. No topical antibiotic ointment should be This stabilizes the line and may serve as a barrier
applied to the umbilicus as this increases the preventing the ingress of microorganisms along
risk of local fungal infection. To minimize infec- the line (Scott-Warren and Morley 2015).
tious morbidity, UVC should generally be To prevent hemorrhage, preoperatively the
removed by 14 days or earlier if there are signs child should be optimized for line placement.
of local infection (Farrelly et al. 2016; Scott- For tunneled or implantable ports, the Interna-
Warren and Morley 2015). tional Normalized Ratio should be <1.6 and
platelet count should be >50,000/mm3. Anti- importance (Larson and Mancini 2016).
platelet agents such as aspirin should be stopped Intraosseous access can be gained rapidly with a
5 days before insertion if possible (Farrelly et al. high success rate and so it is recommended in
2016). Preoperative antibiotics at the time of critically ill children if intravenous access cannot
insertion do not reduce the incidence of line infec- be gained within 90 s. Any drug or fluid which can
tion (van de Wetering et al. 2013). be given intravenous may be infused intraosseous
but must be delivered under pressure to overcome
Implantable Vascular Access Devices the intrinsic resistance of the marrow cavity. How-
(Ports) ever, it should not be used in nonemergency situ-
ations. Continuous monitoring of the limb for
Ports are most useful for children requiring inter- signs of extravasation is important. In children,
mittent venous access over a long period of time. the most common site for intraosseous access is
Such conditions include chronic diseases with fre- the broad, flat anteromedial aspect of the proximal
quent exacerbations, for example, cystic fibrosis tibia (Scott-Warren and Morley 2015).
and intermittent chemotherapy (Scott-Warren and
Morley 2015) (Fig. 3). Port systems consist of both
a central line and a titanium or plastic reservoir, Arterial Vascular Access
which sits in a subcutaneous pocket. Ports allow
patients to bathe and swim, require less mainte- Critically ill patients will require an arterial line
nance, and have fewer adverse body-image consid- especially at the time of operation, either because of
erations. The reservoir should not be placed along surgery, when it is expected to result in significant
the lateral chest wall to avoid the risk of catheter fluid shift and hemodynamic instability, or in a neo-
migration. It is important that a non-coring nate, because of a significant underlying cardiopul-
“Huber” needle is used to access the silicone mem- monary disease of the newborn. This arterial line is
brane of the port in order to avoid damage (Farrelly for monitoring the hemodynamic and biochemical
et al. 2016; Scott-Warren and Morley 2015). Lower status, especially throughout the operative procedure.
infection rate is the major advantage of ports, com- In the neonate, right radial artery percutaneous cath-
pared with other access devices. One disadvantage eterization is preferred because it allows sampling of
is that ports require surgical insertion and removal preductal blood for measurement of oxygen tension.
when treatment ceases or complications arise Access to the relevant artery is generally obtained by
(Larson and Mancini 2016). a percutaneous technique but also may be
approached via a formal cut-down.
Intraosseous Access
Umbilical Artery Catheterization
The intraosseous catheter still has a major role in
life-threatening emergency situations when other Umbilical artery catheterization is the most com-
access methods fail and when time is of the utmost mon methodology for monitoring in neonate
Fig. 3 Implantable device

for long-term vascular
access (port)
Table 1 Umbilical artery catheter length calculation Smaller catheters re required, with many oper-
Body ators choosing 24–22 gauge catheters for infants
weight and 22–20 gauge for children depending on the
(g) location of the catheter. Very rarely, a surgical
<1500 g UA length (cm) = cut-down will be needed to achieve arterial
(4 birth weight (kg)) + 7
access. The use of real-time ultrasound guidance
1500 g Low catheter UA length (cm) = Birth
position weight (kg) + 7 with Doppler facility may aid a difficult insertion
High UA length (cm) = (Scott-Warren and Morley 2015).
catheter (3 birth weight (kg)) + 9
position
Pedal Arterial Cannulation
intensive care. Umbilical artery catheterization is When the radial arteries are found unsuitable for
performed by the neonatologist and/or the pedia- intra-arterial monitoring, the next most commonly
trician and rarely an opportunity arises for the used sites for arterial cannulation are the posterior
surgeon to perform this task. The umbilical cord tibial and dorsalis pedis arteries. Once again, these
contains three vessels: one umbilical vein and two sites allow for collateral blood flow and easy
arteries. The umbilical vein is usually the largest maintenance. Access can be obtained percutane-
of the three vessels, has a thin wall, and is located ously or by cut-down. The anatomical relation-
at the 12 o’clock position, whereas, the umbilical ship of the posterior tibial artery posterior to the
arteries are usually smaller than the umbilical medial malleolus provides an easy site for surgical
vein, have a thicker wall, and are located inferior access. Insertion techniques are similar to those
of the umbilical vein. The standard catheter size is described for the radial artery.
from 3.5 to 5.0 Fr. Catheter length must be calcu-
lated before initiating the procedure by using for-
mulas (Table 1). Umbilical artery catheters should Axillary and Femoral Arterial
generally be placed in the high lying position to Cannulation
theoretically decrease the rates of thrombosis and
intestinal ischemia (Barrington, 2000). In all The axillary artery is rarely used by the cut-down
cases, an abdominal radiograph is used to check technique and is reserved mostly for
the catheter position prior to the completion of the intraoperative monitoring of extremely ill babies.
procedure. This is done in situations where the peripheral
When the umbilicus is unsuited for direct cath- pulses are weak and the need for immediate
eterization because of dryness or previous manip- intra-arterial access exists.
ulations, one can attempt similar cannulation by The indication for using femoral artery is sim-
tracing the infraumbilical course of one of the ilar to the one of the axillary route, namely,
arteries and bringing it to the surface through a extreme situations when peripheral circulation is
separate small extraperitoneal incision. poor and immediate access is necessary.
Radial Artery Cannulation Complications and Their Management
Radial artery catheterization is a rather common- The physician should have a thorough knowledge
place procedure in the hand of the neonatologist in of the anatomy and of the potential complications
providing access to intra-arterial monitoring. from the procedure to identify and quickly treat
Before the radial artery is cannulated, an Allen any complications that may arise. Complications
test is performed to assess for adequate collateral for vascular access are divided into two broad
flow between arteries. The result should be clearly categories, acute and long-term (Church and
documented in the chart. Jarboe 2017; Larson and Mancini 2016) (Table 2).
Table 2 Complications of central vascular access devices Long-Term Complications

Acute Long-term The risk of long-term complications of vascular
Central venous access devices access is increased by the duration of catheteriza-
Pneumothorax Infection and sepsis tion. The most common long-term complications
Vascular damage Thrombotic complications include infection, thrombosis, catheter occlusion,
Perforation Deep vein thrombosis and, in some cases, catheter migration (Table 2).
Dissection Pulmonary embolus
Air embolism Phlebitis of the cannulated Infection is the most common complication of
Aberrant catheter vessel long-term vascular access. There are three types
placement Superior vena cava of infection associated with central venous cathe-
Damage to the thoracic syndrome ters: exit-site infection, tunnel or pocket infection,
duct Catheter dislodgement and
Cardiac complications migration and a central line-associated bloodstream infec-
Cardiac irritation tion (CLABSI). Approximately, 10% of central
Cardiac perforation lines develop CLABSI (Ullman et al. 2015).
Local tissue trauma or Many clinical factors have also been impli-
damage
Bleeding into cated in catheter-related infections. Rate of infec-
surrounding tissues tion is the highest in the neonatal population and
Nerve injury in patients with short-bowel syndrome, neutrope-
Implantable ports nia, or other chronic illnesses. In critically ill
Local hematoma Damage to the reservoir children, the most prudent advice is to remove
Difficulty accessing the port
Disconnection of the
the catheter and to attempt vascular access at a
catheter to the port point away from the infected area. In most chil-
Port pocket seroma dren, removing the infected catheter eliminates
Skin breakdown at the the source of infection. Empiric antibiotics may
reservoir site
not be warranted unless the child has signs of
sepsis. Commencing broad-spectrum antibiotics
is generally warranted in critically ill children
after appropriate cultures are obtained. Antibiotics
Acute Complications should be continued for at least 48 h or until
Pneumothorax is the most common acute com- cultures’ results are available (Larson and Man-
plication with central venous access, with cini 2016).
reported rates of up to 4%. For this reason, an Tenderness, induration, erythema, and, occa-
upright chest radiograph should be obtained sionally, purulent drainage at the exit site may
after central venous access is attempted. Small represent a subcutaneous tunnel or port-pocket
pneumothorax usually resolves spontaneously at infection. This type of infection usually requires
rate of approximately 1% per day. Failure to removal of the venous access device and treat-
resolve a small pneumothorax, enlarging pneu- ment with intravenous antibiotics as necessary.
mothorax, or ventilator compromise is an indi- Infection rates decrease when specific catheter-
cation for evacuation (Larson and Mancini care protocols are in place and when well-trained
2016). nursing staff handle the catheters (Larson and
Vascular damages are included as the acute Mancini 2016). In patients with long-term cathe-
complications. Because the internal jugular, sub- ters for TPN for intestinal failure, 70% ethanol
clavian, and femoral veins are all accompanied by locks have been shown to reduce line infection
major arteries, arterial injury may result from cen- from 9.9 to 2.1 per 1000 catheter days. Ethanol
tral venous access. The risk of such complications locks appear to have a low risk of causing resistant
can be reduced by using ultrasound guidance and organisms (Church and Jarboe 2017).
a small access needle. Other complications are Venous thrombosis is another common com-
listed in Table 2. plication of long-term venous access. Venous
thrombosis due to central venous catheters can ▶ Fluid and Electrolyte Balance in Infants and
occur, especially in children with cancer. When Children
possible, treatment involves removal of the ▶ Perinatal Physiology
offending line. Venous stenosis is uncommon, ▶ Principles of Pediatric Surgical Imaging
but more likely to occur with subclavian than ▶ Specific Risks for the Preterm Infant
internal jugular access. Line thrombosis occurs
more commonly in children with cancer. Tissue
plasminogen activator may be successful in cases References
of catheter thrombosis. Occlusion due to lipid or
mineral deposits may be cleared with 70% ethanol Barrington KJ. Umbilical artery catheters in the newborn:
and hydrochloric acid, 0.1 N, respectively, with effects of position of the catheter tip. Cochrane Data-
varying success. If medical therapy is ineffective, base Syst Rev. 2000;(2):CD000505.
Brandao LR, Shah N, Shah PS. Low molecular weight
catheter removal and replacement may be neces- heparin for prevention of central venous
sary. Unequivocal proof that low molecular catheterization-related thrombosis in children.
weight heparin or the use of heparin-bonded cath- Cochrane Database Syst Rev. 2014;(3):CD005982.
eters reduces the incidence of catheter-related Chiao FB, Resta-Flarer F, Lesser J, Ng J, Ganz A, Pino-
Luey D, et al. Vein visualization: patient characteristic
thrombosis is still lacking (Brandao et al. 2014; factors and efficacy of a new infrared vein finder tech-
Johr and Berger 2015). nology. Br J Anaesth. 2013;110(6):966–71.
Complications of device removal include air Church JT, Jarboe MD. Vascular access in the pediatric
embolism, dislodgement of thrombus, and an population. Surg Clin North Am. 2017;97(1):113–28.
Donaldson JS. Pediatric vascular access. Pediatr Radiol.
inability to remove the catheter. Air embolism is 2006;36(5):386–97.
a potentially lethal complication of catheter Farrelly C, Lal P, Trerotola SO, Nadolski GJ, Watts MM,
removal. At the time of removal, the patient Gorrian CM, et al. Correlation of peripheral vein
should be placed flat to fill the central veins to tumour marker levels, internal iliac vein tumour marker
levels and radical prostatectomy specimens in patients
prevent air embolism (Farrelly et al. 2016). with prostate cancer and borderline high prostate-
specific antigen: a pilot study. Cardiovasc Intervent
Radiol. 2016;39(5):724–31.
Conclusions and Future Directions Guillon P, Makhloufi M, Baillie S, Roucoulet C,
Dolimier E, Masquelier AM. Prospective evaluation
of venous access difficulty and a near-infrared vein
With smaller, critically ill neonates being man- visualizer at four French haemophilia treatment centres.
aged in our intensive care units, reliable vascular Haemophilia. 2015;21(1):21–6.
access is a necessity. Improvements in tech- Johr M, Berger TM. Venous access in children: state of the
art. Curr Opin Anaesthesiol. 2015;28(3):314–20.
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opment of new materials allow for stable access Vascular Access in Children. New York: WebMD LLC;
and improved care in premature and newborn 2016. Available from: https://emedicine.medscape.
infants. Standard protocols for their placement, com/article/1018395-overview.
Lyon SM, Given M, Marshall NL. Interventional radiology in
care, and maintenance can help to ultimately the provision and maintenance of long-term central venous
decrease complications. As these catheters con- access. J Med Imaging Radiat Oncol. 2008;52(1):10–7.
tinue to evolve, newer and safer techniques will Scott-Warren V, Morley R. Paediatric vascular access. BJA
soon follow. Education. 2015;15:199–206.
Shenoy S, Karunakar BP. Factors influencing the periph-
eral venous catheter survival in critically ill children in
a pediatric intensive care unit. Indian J Pediatr. 2014;81
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Sri Paran T, Corbally M, Fitzgerald RI. New technique for
fixation of Broviac catheters. J Pediatr Surg. 2003;38
▶ Anatomy of the Infant and Child (1):51–2.
▶ Extracorporeal Membrane Oxygenation for Triffterer L, Marhofer P, Willschke H, Machata AM,
Neonatal Respiratory Failure Reichel G, Benkoe T, et al. Ultrasound-guided
cannulation of the great saphenous vein at the ankle in van de Wetering MD, van Woensel JB, Lawrie
infants. Br J Anaesth. 2012;108(2):290–4. TA. Prophylactic antibiotics for preventing Gram
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CM. Complications of central venous access devices: central venous catheters in oncology
a systematic review. Pediatrics. 2015;136(5): patients. Cochrane Database Syst Rev. 2013;11:
e1331–44. CD003295.
Nutrition in Infants and Children
17
Agostino Pierro and Simon Eaton
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Changes in Body Composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Components of Energy Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Energy Requirements of Surgical and Critically Ill Infants . . . . . . . . . . . . . . . . . . . . . . . . 275
Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Components of Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Complications of Parenteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280
Enteral Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Feeding Routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
Selection of Enteral Feeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Administration of Enteral Feeds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
Complications of Enteral Tube Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Abstract reasons: (i) body stores are often smaller and

Nutritional care of surgical infants and children more precarious; (ii) infants and children
is of major importance. This is for several require not only energy for maintenance but
also for growth; and (iii) as in adults, recovery
from surgery is faster in those patients who are
A. Pierro (*)
Division of General and Thoracic Surgery, The Hospital
adequately nourished. Survival of infants with
for Sick Children, University of Toronto, Toronto, ON, congenital anomalies dramatically improved
Canada following the introduction of parenteral nutri-
e-mail: agostino.pierro@sickkids.ca tion. However, infection and cholestasis
S. Eaton remain problematic for parenterally fed infants
Department of Paediatric Surgery, UCL Institute of Child and children.
Health and Great Ormond Street Hospital for Children
NHS Trust, London, UK
e-mail: s.eaton@ucl.ac.uk

https://doi.org/10.1007/978-3-662-43588-5_18
274 A. Pierro and S. Eaton
Keywords
Energy expenditure · Parenteral nutrition ·
Cholestasis · Enteral nutrition
Introduction
Nutrition is especially important to surgical

infants and children, firstly because of smaller
body stores and relatively higher energy expendi-
ture and secondly because of the requirement for
growth and adequate neurodevelopment. New-
born infants are in a “critical epoch” of develop-
Fig. 1 Body composition changes with age. Percentage
ment: a healthy term infant grows at a rate of
body fat is not shown for adults because of the extremely
25–30 g per day over the first 6 months of life, wide range
so that weight has doubled by the age of 5 months.
Thus, a significant period of inadequate nutrition
may not only affect short-term outcomes but may postnatal period due to decreased interstitial fluid,
also be a risk factor for the long-term menace of which largely corresponds to the physiological
stunted mental and physical development. early postnatal weight loss. Because extracellular
fluid is more easily lost from the body than intra-
cellular fluid and infants have a larger surface area
Changes in Body Composition to body mass ratio, they are more at risk of devel-
oping dehydration than older children and adults.
The body composition of the fetus is markedly This decline in body water reflects also an increase
different from that of adults, and most of the in energy content of the body. The ratio between
changes in body composition take place around resting energy expenditure (REE, in kcal/kg/day) to
the time of birth (▶ Chap. 15, “Fluid and Electro- nonprotein energy reserve (in kcal/kg) gives an
lyte Balance in Infants and Children”) During the approximate estimate of the energy reserve of the
first trimester of pregnancy, when only 1% of infants. This is only ~2 days at 24–25 weeks of
body mass is fat, 90% of body mass is water gestation, increases to ~20 days at term as glycogen
with 65% of body mass made up of extracellular and fat stores increase (Denne et al. 2006), and is in
fluid (Denne et al. 2006). As fat percentage excess of 50 days in the adult, hence the urgent
increases, water decreases from 87% of body need for adequate caloric intake in preterm infants
weight at 24–25 weeks of gestation to 75% at after birth (▶ Chap. 8, “Specific Risks for the Pre-
term (Fig. 1) (Denne et al. 2006), eventually fall- term Infant”). Full-term neonates have higher con-
ing to 65–50% in adulthood. These changes in tent of endogenous fat (approximately 600 g) and
total body water (TBW) are accompanied by a therefore can tolerate a few days of undernutrition.
decrease in the extracellular compartment fluid
(ECF) to intracellular compartment fluid (ICF)
ratio. The ECF is 65% of total body mass at Components of Energy Needs
24–25 weeks of gestation, declining to 40% at
term, whereas ICF increases from 22% at Energy needs can be divided into four compo-
24–25 weeks of gestation to 35% of body mass at nents: basal metabolic rate (i.e., the energy con-
term and then to 40% at 1 month of age. Although sumed in whole body homeostasis), diet-induced
there is a gradual decline in the extracellular com- thermogenesis (energy involved in digestion and
partment, there is a more abrupt loss in the early assimilation), physical activity, and growth. Some
17 Nutrition in Infants and Children 275
Fig. 2 Partition of energy

needs in infants and
children
of these components vary with age (e.g., propor- and Harris and Benedict (Blinman and Cook
tionally more of the energy needs are used in 2011). These empirically derived formulae are
growth of a neonate) and with route of feeding based on weight, height, and/or age of orally fed,
(e.g., diet-induced thermogenesis is low in paren- healthy individuals and thus take no account of
terally fed children). As energy is laid down in the abnormal physiology and/or pathology of
body stores (e.g., fat depots, glycogen, muscle, infants requiring artificial nutritional support. In
and brain), some energy is expended during addition, these equations give strange values at
growth (“the energy cost of growth”). This is lower body masses and thus may not be ideal for
between 0.5 and 5 kcal/g laid down and accounts neonates (Blinman and Cook 2011). Other equa-
for about 10 kcal/kg/day. The components of tions have been developed for stable surgical
energy needs are shown in Fig. 2. Newborn infants (Pierro et al. 1994), tube-fed infants
infants have a significantly higher metabolic rate (Blinman and Cook 2011), and ventilated criti-
and energy requirement per unit body weight than cally ill children (Meyer et al. 2012; White et al.
children and adults: the total energy requirement 2000).
for an extremely low birth weight (i.e., <1,000 g)
preterm infant fed enterally is 130–150 kcal/kg/
day, and that of a term infant is 100–120 kcal/kg/ Energy Requirements of Surgical
day, compared to 60–80 kcal/kg/day for a and Critically Ill Infants
10-year-old and 30–40 kcal/kg/day for a
20-year-old individual (Koletzko et al. 2005a). Although adults show large increases in REE
Of the 100–120 kcal/kg/day required by the term following trauma, surgery, and burns or during
infant, approximately 40–70 kcal/kg/day is severe infection (Hill and Hill 1998), this does
needed for maintenance metabolism, 50–70 kcal/ not appear to be true for infants and children,
kg/day for growth (tissue synthesis and energy although there are few studies in this area, espe-
stored), and up to 20 kcal/kg/day to cover energy cially in children. Critically ill, postsurgical ven-
losses in excreta (Koletzko et al. 2005a). Newborn tilated premature neonates (Garza et al. 2002),
infants receiving total parenteral nutrition (TPN) neonates with necrotizing enterocolitis (Powis
require fewer calories (110–120 kcal/kg/day for a et al. 1999), and surgical infants (with or without
preterm infant and 90–100 kcal/kg/day for a term ECMO) (Jaksic et al. 2001) were shown to have
infant (Koletzko et al. 2005a)), due to the absence similar REE values to healthy neonates, whereas
of energy losses in excreta. others have suggested that REE is increased dur-
Several equations have been used to estimate ing neonatal sepsis (Bauer et al. 2002; Mrozek
REE, and therefore the energy requirements, of et al. 2000). There is a peak in REE 4 h after
infants and children. The most frequently used are neonatal surgery, which was short-lived, returning
those of the World Health Organization, Schofield to baseline within 12–24 h after surgery (Jones
Fig. 3 Resting energy

expenditure of children
randomized to either open
or laparoscopic Nissen
fundoplication (From
McHoney et al. 2009 with
permission)
et al. 1993). There is no further increase in REE in et al. 1998, 1999; Groner et al. 1989). This is
the first 5–7 days following an operation (Jones supported by data indicating that in surgical
et al. 1993; Shanbhogue and Lloyd 1992). The infants receiving parenteral nutrition (PN), there
timing of these changes corresponds with the is a greater impairment in growth for each episode
postoperative changes in catecholamine levels of clinical sepsis (Fig. 4).
and other biochemical and endocrine parameters
(Anand et al. 1987). Thus, there is no clear indi-
cation that increased energy should be provided to Parenteral Nutrition
septic or surgical neonates (Koletzko et al.
2005a). There is little information of postopera- Indications
tive REE in older children or in children undergo-
ing laparoscopy (reviewed McHoney et al. 2009). PN should be utilized when enteral feeding is
There is no hypermetabolic response in the first impossible, inadequate or hazardous for more
24 h following laparoscopic or open surgery in than 4–5 days. The most frequent indications in
children undergoing Nissen fundoplication pediatric surgery are intestinal obstructions due to
(McHoney et al. 2009) (Fig. 3). REE is directly congenital anomalies, although acquired condi-
proportional to growth rate in healthy infants, and tions may require PN for variable lengths of
growth is retarded during acute metabolic stress. time. Although infants with some neonatal surgi-
Studies in adult surgical patients have shown that cal conditions, such as gastroschisis, will all
operative stress causes marked changes in protein receive PN, there are some other congenital anom-
metabolism characterized by a postoperative alies where the use of PN is more controversial.
increase in protein degradation, negative nitrogen An example of this is duodenal atresia
balance, and a decrease in muscle protein synthe- (▶ Chap. 59, “Duodenal Obstruction”), in which
sis. However, changes in whole body protein flux, many surgeons would routinely initiate PN,
protein synthesis, amino acid oxidation, or protein whereas some surgeons preferentially manage
degradation do not seem to occur in infants and patients without PN by the use of trans-
young children undergoing major operations anastomotic tubes (Hall et al. 2011). In addition
(Powis et al. 1998), suggesting that infants and to congenital bowel obstruction, PN may also be
children divert protein and energy from growth to used in cases of necrotizing enterocolitis, short
tissue repair, thereby avoiding the overall increase bowel syndrome, gastroenterological indications,
in REE and catabolism seen in the adult (Powis and respiratory distress.
Fig. 4 Relationship
between poor growth and
repeated episodes of sepsis
in surgical infants receiving
parenteral nutrition (Ong,
Pierro, and Eaton,
unpublished)
Route of Administration lower metabolic cost. The ideal PN regimen there-

fore should provide enough amino acids for pro-
As phlebitis may develop with the use of periph- tein turnover and tissue growth and sufficient
eral veins with solutions exceeding 600 mOsm, it calories to minimize protein oxidation for energy.
is not possible to administer adequate calories for
growth peripherally, and peripheral veins are only Fluid Requirements
used for short-term, partial, nutritional supple- As described above, the hydration and proportion
mentation. In neonates, the umbilical vessels can of extracellular fluid change rapidly in the neo-
be used for provision of PN centrally, although the nate. In a surgical infant, these changes will also
risk of complications increases. Central venous be occurring simultaneously with surgical inter-
catheters are required for older children, or in vention and in initiation of PN. Fluid overload is a
neonates where prolonged administration is neces- possibility in these infants, and careful consider-
sary. Such catheters can either be placed percuta- ation of all fluids administered (PN and other
neously directly in a deep vein, with subcutaneous prescribed drugs), together with daily monitoring
tunneling of the extravascular part of the line, or of weight and electrolytes, is mandatory, at least
can be a peripherally inserted central catheter until PN has been stabilized. Excessive fluid
(PICC). For consideration of technical aspects of administration can result in pulmonary edema, or
placement and management, the reader is directed failure of closure of patent ductus arteriosus. A
to the ESPGHAN/ESPEN guidelines (Koletzko recent report highlighted the poor fluid manage-
et al. 2005b). ment of many neonates receiving PN (NCEPOD
2010). Fluid restriction, or a requirement to
administer other fluids in significant volume, can
Components of Parenteral Nutrition result in the delivery of macronutrients being less
than current recommendations.
The PN formulation includes carbohydrate, fat,
protein, electrolytes, vitamins, trace elements, Glucose
and water. The caloric needs for PN are provided Glucose is a main energy source for body cells
by carbohydrate and lipid. Protein is not used as a and should be the primary energy substrate in PN,
source of calories, since the catabolism of protein covering 60–70% of nonprotein calories
to produce energy is an uneconomic metabolic (Koletzko et al. 2005c). The amount of glucose
process compared to the oxidation of carbohy- that can be infused safely depends on the clinical
drate and fat which produces more energy at a condition and maturity of the infant, and infants
are at risk from both hypoglycemia and hypergly- concentration but is also more frequent in critically
cemia. Glucose infusion should be at least at a rate ill children receiving insulin.
capable of maintaining blood glucose above
2.6 mmol/L, the current consensus definition of Lipids
neonatal hypoglycemia. As the rate of endoge- Lipids provide an energy-dense (9 kcal/g of fat),
nous glucose metabolism in neonates is of the isotonic alternative to glucose as an energy source
order of 5 mg/kg/min, this should be considered for PN, which also prevent essential fatty acid
the lowest infusion rate likely to avoid hypogly- deficiency and facilitate provision of fat-soluble
cemia in a neonate. As glucose tolerance vitamins. Combined infusion of glucose and
increases, the rate of glucose infusion can be lipids confers metabolic advantages over glucose,
increased. However, carbohydrate conversion to because it lowers the metabolic rate and carbon
fat (lipogenesis) occurs when glucose intake dioxide production and increases the efficiency of
exceeds metabolic needs. The potential risks asso- energy utilization (Van Aerde et al. 1989). There
ciated with this process are twofold: accumulation is a close interdependence of carbohydrate and
of the newly synthesized fat in the liver and aggra- lipid infusion rates on the one hand, and net fat
vation of respiratory acidosis resulting from deposition or oxidation on the other (Fig. 5).
increased CO2 production. In addition, hypergly- When the intake of glucose calories exceeds
cemia in ELBW infants is a risk factor for late- 18 g/kg/day (equivalent to REE), net fat oxidation
onset sepsis, mortality, and the risk of developing is minimal regardless of fat intake, and net fat
advanced NEC. A rapid increase in plasma glu- synthesis takes place (Pierro et al. 1993). At a
cose concentration precedes development of carbohydrate intake of 15 g/kg/day, the proportion
NEC, and infants with established NEC have both of energy metabolism derived from fat oxidation
a high prevalence of hyperglycemia and a worse does not exceed 20% even with a fat intake as high
outcome if hyperglycemic (Hall et al. 2004). as 6 g/kg/day. At a carbohydrate intake of 10 g/kg/
Although there has been interest in the potential day, this proportion can be as high as 50% (Pierro
of insulin therapy to decrease hyperglycemia- et al. 1993). However, lipid utilization is often low
related morbidity and mortality in neonates, the and unpredictable in neonates, and consequently,
evidence base for or against control of glucose lipids are usually introduced slowly, especially in
levels in surgical infants and children is lacking. premature neonates (Koletzko et al. 2005d).
Hypoglycemia usually results from sudden inter- Historically, the first and most commonly
ruption of an infusion containing a high glucose used fat emulsions for PN in pediatrics are
Fig. 5 Relationship
between glucose intake and
fat utilization in surgical
infants. Linear relationship
between glucose intake and
fat utilization (r = 0.9;
p < 0.0001). Lipogenesis is
significant when glucose
intake exceeds 18 g/kg/day
(From Pierro et al. 1993
with permission)
based on soybean oil, in which the lipid is protein per day), so they should start to receive
present as long-chain triglycerides (LCT). at least 1–1.5 g/kg/day amino acids parenterally if
Medium-chain triglycerides (MCT) can increase not receiving EN (Zlotkin et al. 1981). Infants are
net fat oxidation without increasing metabolic rate efficient at retaining nitrogen and can retain up to
when used to partially replace LCT (Donnell et al. 80% of the metabolizable protein intake on both
2002). There have been suggestions that oral and intravenous diets (Zlotkin et al. 1981).
MCT/LCT mixtures may improve essential fatty Protein metabolism, and deposition of body pro-
acid status (by protecting essential fatty acids tein for growth, is dependent upon both protein
from oxidation) (Lehner et al. 2006). In the last and energy intake, so that above an energy intake
10 years, several other lipid emulsions have been of 70 kcal/kg/day, the major determinant of nitro-
introduced, based on varying proportions of gen retention in preterm infants is the amino acid
medium-chain triglycerides, monounsaturated tri- intake (Zlotkin et al. 1981). The PN amino acid
glycerides (i.e., olive oil), or omega-3-polyunsat- requirement of term newborn infants is between
urated triglycerides (i.e., fish oil). These have 2.5 and 3.0 g/kg/day, which allows for accretion
been utilized in several small-scale studies, both of body protein (Zlotkin et al. 1981). Complica-
in premature infants and surgical infants. The tions like azotemia, hyperammonemia, and meta-
potential routine use of these novel lipids is com- bolic acidosis have been described in patients
plicated by differences in licensing between dif- receiving high levels of intravenous amino acids
ferent geographical areas and by the maximal rate (Zlotkin et al. 1981) but rarely seen with amino
of administration within the license. The main aim acid intake of 2–3 g/kg/day (Zlotkin et al. 1981).
of the use of novel lipids, however, is to prevent or In patients with severe malnutrition or with addi-
treat cholestasis; this will be considered below. tional losses (i.e., jejunostomy, ileostomy), pro-
High doses of lipid or an accidental rapid tein requirements are higher (Zlotkin et al. 1985).
infusion of lipid may lead to fat overload syn- The nitrogen source of PN is provided as a mix-
drome, characterized by an acute febrile illness ture of amino acids, and mixtures specifically
with jaundice and abnormal coagulation and formulated for neonates are available. However,
respiratory problems (Koletzko et al. 2005d), the ideal amino acid composition for term and
and so lipids are usually advanced slowly, with preterm infants is uncertain. As well as the
close monitoring of triglyceride levels (Koletzko amino acids usually considered essential for
et al. 2005d). Peroxidation in stored fat emul- adult humans, histidine is considered essential
sions and the generation of free radicals during for infants, and the following amino acids have
intravenous infusion of fat in premature infants all been considered “conditionally essential” for
have been reported (Pitkanen et al. 1991). How- neonates: arginine, cysteine, glutamine, taurine,
ever, the degree of free radical production is and tyrosine.
linked to the rate of lipid oxidation, as it has Glutamine is excluded from PN amino acid
been shown that a reduction in the carbohydrate mixtures because of poor stability, although it
to fat ratio in PN diet will result in increased can now be added as a dipeptide. Glutamine is
oxidation of administered fat and a decrease in important for the immune system and the intes-
free radical–mediated lipid peroxide formation tine, as well as being essential as a nitrogen carrier
(Basu et al. 1999). between organs (Eaton et al. 2010). It has been
hypothesized that glutamine supplementation
Amino Acids to parenterally fed neonates would decrease the
In contrast to healthy adults who exist in a state of incidence of infection and decrease to time to
neutral nitrogen balance, infants and children full enteral feeding. One randomized controlled
need to be in positive nitrogen balance in order trial (Albers et al. 2005) in surgical infants
to achieve satisfactory growth and development. found that parenteral glutamine supplementation
Preterm infants who are receiving glucose alone had no significant effect on intestinal permeability
lose protein quickly (at the rate of 1–2% body or nitrogen balance, although this study was not
powered to detect differences in clinical end- Complications of Parenteral Nutrition

points such as incidence of sepsis or duration of
PN. A large multicenter randomized controlled Although parenteral nutrition is life-saving, it is
trial of glutamine-supplemented PN showed that associated with many complications, some of
although glutamine did not decrease the time to which are transient and others life-threatening,
full enteral feeds, or the incidence of sepsis including parenteral nutrition-associated liver dis-
over the full period of PN, it did significantly ease and central liver-associated blood-stream
decrease the incidence of sepsis during the infections.
period of exclusive parenteral feeding, i.e.,
before any enteral nutrition was introduced Infectious Complications
(Ong et al. 2012). In spite of significant improvement in the man-
agement of PN including the introduction of nutri-
Minerals, Vitamins, and Trace Elements tion support teams, infection is still a major
Minerals, vitamins, and trace elements are impor- problem. More than 50% of surgical infants on
tant structurally, as cofactors, or as components of PN have at least one suspected episode of sepsis,
enzymes, and provision of adequate supplies is and around 30% of surgical neonates have at least
important for the growing neonate. Fe, Ca, P, and one positive blood culture (Ong et al. 2012;
Mg should all be provided in adequate amounts Bishay et al. 2011). Repeated episodes of sepsis
for growth and development but, conversely, can may lead to impaired liver function, critical ill-
cause problems if provided in excess of needs or if ness, and removal of central venous catheters.
their metabolism is impaired. In addition, admin- Although catheter-borne infections, which can be
istration of adequate amounts can be problematic, reduced by rigorous precautions, such chlorhexi-
because of lack of stability in solution or lack of dine antisepsis (Bishay et al. 2011), are important,
compatibility with other components. Conse- microbial translocation from the intestine is also a
quently, iron is often only supplemented in significant source of infection in surgical infants
longer-term PN (Koletzko et al. 2005e), whereas on PN (Pierro et al. 1996). Infection with enteric
calcium and phosphate supply depends on solu- microorganisms occurs significantly later than
bility in PN mixtures (Koletzko et al. 2005e). presumed catheter-related infection (Bishay et al.
Vitamins and trace elements are particularly 2012a), supporting the hypothesis that a progres-
important in maintenance of the body’s antioxi- sive impairment of host defenses (Okada et al.
dant defenses (Eaton 2006): vitamins C and E, 2000) and/or increased intestinal permeability
selenium (for glutathione peroxidase), copper, may allow translocation of enteric organisms
zinc, and manganese (all for superoxide after an extended period of PN.
dismutases), chromium, iodine, and molybdenum
can all added to PN. It is suggested that if the Mechanical Complications
duration of PN is less than 4 weeks, of the trace Mechanical complications related to the intrave-
elements, only zinc needs to be added (Koletzko nous infusion of nutrients are not uncommon.
et al. 2005e; American Academy of Pediatrics Extravasation of PN solution is a common com-
Committee on Nutrition 2004). There is little spe- plication of peripheral PN. Unfortunately, even a
cific evidence for individual vitamin require- low osmolarity solution is detrimental for
ments, and the current recommendations are to peripheral veins leading to inflammation and
continue with the available vitamin mixtures, extravasation of the solution, which can cause
which do not appear to cause toxicity or defi- tissue necrosis and infection. Extravasation
ciency in the majority of children (American injury is treated with occlusive dressings or
Academy of Pediatrics Committee on Nutrition hyaluronidase irrigation, but there is little evi-
2004; Koletzko et al. 2005f). Free radical produc- dence base for the best treatment in neonates
tion and lipid peroxidation will be considered in (Wilkins and Emmerson 2004). Intravenous
more detail below. lines may become clogged from thrombus
formation, calcium precipitates, or lipid deposi- diminishing (Kubota et al. 2000), this is probably
tion. There is disagreement on the ideal position related to the more aggressive transition to enteral
of central venous lines (CVL) for PN in infants. feeding rather than to an improvement in the
Some authors advocate the atrium as the ideal intravenous diet. Various clinical factors are
position because this would give less chance of thought to contribute to the development of
catheter dysfunction, whereas others believe that PN-related cholestasis. These include prematurity,
placement in the superior vena cava would low birth weight, duration of PN, immature
reduce the risk of perforation. The current enterohepatic circulation, intestinal microflora,
ESPGHAN/ESPEN recommendations are that septicemia, failure to implement enteral nutrition,
the catheter tip should lie outside the atrium short bowel syndrome due to resection
(Koletzko et al. 2005b), but because complica- (▶ Chap. 76, “Short Bowel Syndrome”), and
tions of either approach are very rare (albeit number of laparotomies (reviewed Carter and
potentially life threatening), there is a paucity Shulman 2007). In addition to the effects of
of evidence from RCTs. extremely low birth weight, and length of time
on PN, infants receiving PN for either
Hepatic Complications gastroschisis or jejunal atresia seem to be at par-
The hepatobiliary complications related to PN ticular risk. PN-related cholestasis has a higher
remain serious and often life threatening. The incidence in premature infants than in children
commonest hepatobiliary complication of PN in and adults. This may be due to the immaturity of
neonates is cholestasis. The clinical significance the biliary secretory system since bile salt pool
of this cholestasis itself is unknown, but if size, synthesis, and intestinal concentration are
untreated, intestinal failure associated liver dis- low in premature infants in comparison with
ease (IFALD) may occur, which can result in the full-term infants (Carter and Shulman 2007).
need for liver transplantation or can result in The etiology of parenteral nutrition-related
death. IFALD has been defined by the British cholestasis remains unclear (Carter and Shulman
Society of Paediatric Gastroenterology, 2007). Possible causes include the toxicity of
Hepatology and Nutrition as: components of parenteral nutrition, lack of enteral
feeding, continuous nonpulsatile delivery of nutri-
• Type 1 early IFALD – persistent elevation of ents and host factors, infection, and sepsis (Carter
alkaline phosphatase (ALP) and γ-glutamyl and Shulman 2007). In particular, the lipid com-
transferase greater than 1.5 times the upper ponent of PN has been particularly implicated and
limit of reference range for at least 6 weeks many units now use alternative lipid management
• Type 2 established IFALD, elevation of ALP strategies (see below). In addition to lipid man-
γ-GT as above, together with elevation of total agement, careful management of these patients
bilirubin (>50 μmol/L), with a conjugated under a multidisciplinary team seems to be bene-
fraction of at least 50% ficial (Bishay et al. 2012b). Bowel lengthening
• Type 3 late IFALD – elevated ALP, total bili- procedures, such as the STEP procedure or longi-
rubin, and clinical signs of end-stage liver tudinal intestinal lengthening, may help transition
disease to enteral nutrition (Sudan et al. 2007), whereas in
those with advanced liver disease and no prospect
Type 1 is thought to be reversible; type 2 is of enteral autonomy, transplantation may be
potentially reversible if enteral feeding is considered.
increased, PN is reduced, and repeated episodes PNAC and IFALD have been linked to the use
of catheter-related sepsis are prevented. The inci- of soybean oil, although other factors are thought
dence of IFALD depends on the length of time on to be involved. Soybean oil contains mostly Ω-6
PN and occurs in up to 50% of infants receiving fatty acids, which are thought to be
long-term PN (Kubota et al. 2000). Although the pro-inflammatory compared with Ω-3 fatty acids.
frequency of this complication seems to be In addition, the amount of phytosterols delivered
in soybean-based lipid emulsions is relatively good quality RCTs, as units already use a variety
high, and phytosterol accumulation has been pos- of alternate lipid management strategies (Flynn
tulated to cause PNAC/IFALD (Clayton et al. and Gowen 2010). It is also questionable whether
1993). Hence in recent years, there has been maintaining an infant on a high dose of soybean-
great interest in adopting hepatoprotective lipid based lipid emulsion after the onset of PNAC/
management strategies in PN of surgical infants IFALD is ethical, so that it is difficult to decide
and children to either prevent or reverse cholesta- on an appropriate comparison group.
sis. Several different approaches have been
adopted:
Enteral Nutrition
i. Decreasing the amount of lipid administered.
This can also be achieved by limiting the time Enteral nutrition remains the preferred route for
on lipid, by lipid-free hours or days. This nutrient delivery. The energy requirement of chil-
could potentially result in poor growth due to dren fed enterally is greater than the intravenous
inadequate calories. requirement because of the energetic cost of
ii. Use of Omegaven®, a lipid emulsion of 10% absorption from the gastrointestinal tract and
fish oil. Fish oil is high in Ω-3 fatty acids and energy lost in the stools. Enteral feedings should
low in phytosterols, so it has been suggested be used in preference to PN. The transition from
to reverse cholestasis in surgical infants on parenteral to enteral feeding should be a short as
long-term PN (Puder et al. 2009). Use of possible. Neonates undergoing abdominal surgery
®
Omegaven as the only lipid source could, for congenital or acquired intestinal dysfunction
however, potentially result in essential fatty often require a period of PN; however, the authors
acid deficiency, due to lack of Ω-6 fatty recommend to start introducing enteral feeding as
acids, and could also result in poor growth, soon as the gastric aspirate is less than approxi-
®
as the dose of Omegaven is limited to 1.0 g/ mately 24 ml/day even if the aspirate is still bil-
kg/day (compared with 3 g/kg/day for ious. There is evidence that during PN of surgical
soybean-based lipid emulsions). infants, the introduction of minimal enteral feed-
iii. Use of lipid emulsions containing a mixture of ing preserves immune function (Okada et al.
long-chain (LCT) and medium-chain (MCT) 1998).
triglycerides (Socha et al. 2007). This has the
advantage of increasing fat utilization
(Donnell et al. 2002), ability to use at up to Feeding Routes
3 g/kg/day, and decreasing the phytosterols
and Ω-6 fatty acids administered while ensur- Alternative feeding routes where children are
ing adequate delivery of essential fatty acids. unable to feed orally include nasogastric or
iv. Use of mixed lipid emulsions such as orogastric tubes, naso-jejunal tubes, gastrostomy
®
SMOF , which is a mixture of soybean, tubes, or jejunostomy tubes (▶ Chap. 18, “Access
medium-chain triglycerides, olive oil, and for Enteral Nutrition”). Gastric feeding is gener-
fish oil (Goulet et al. 2010). This has the ally preferable to intestinal feeding because it
advantages of lowered amounts of phytos- allows for a more natural digestive process, i.e.,
terols and Ω-6 fatty acids, increased fat utili- allows action of salivary and gastric enzymes and
zation, delivery of Ω-3 fatty acids, and ability the antibacterial action of stomach acid. In addi-
to use at up to 3 g/kg/day. tion gastric feeding is associated with a larger
osmotic and volume tolerance and a lower fre-
Despite these different approaches, the evi- quency of diarrhea and dumping syndrome. Thus,
dence base supporting any lipid management transpyloric feeds are usually restricted to infants
strategy is lacking due to the paucity of RCTs in who (i) are unable to tolerate naso- or orogastric
this area. It is difficult to design and implement feeds; (ii) are at increased risk of aspiration; and
(iii) have anatomical contraindications to gastric disaccharides. For fat malabsorption, a formula
feeds, such as microgastria. Neonates are obliga- containing medium-chain triglycerides (MCT)
tory nose breathers, and therefore orogastric feed- should be used. An elemental (free amino acids)
ing may be preferable over nasogastric feeding in or semi-elemental (protein hydrolysate containing
preterm infants to avoid upper airway obstruction. di- and tripeptides) formula may be indicated
However, nasogastric tubes are easier to secure when there is severe malabsorption due to short
and may involve a lower risk of displacement. In bowel syndrome or severe mucosal damage as in
infants requiring gastric tube feeding for extended NEC. Semi-elemental preparations have the
periods (e.g., more than 6–8 weeks), it is advis- advantage of a lower osmolality, are well
able to insert a gastrostomy, to decrease the neg- absorbed, and have a more palatable taste. Infants
ative oral stimulation of repeated insertion of recovering from NEC pose a particular problem,
nasal or oral tubes. The tube can be inserted as malabsorption may be severe and prolonged.
using an open, endoscopic, or laparoscopic These infants may have had small bowel resected,
approach. In infants with significant gastroesoph- in addition to which the remaining bowel may not
ageal reflux, fundoplication with gastrostomy have healed completely by the time feeds are
tube or enterostomy tube placement is indicated begun. Feeding may provoke a relapse of the
(Chowdhury and Pierro 2004; Barnhart 2016). In necrotizing enterocolitis and feeding should there-
preterm infants with gastroesophageal reflux, fore be introduced cautiously. However, there is
enteral feeding can be established via a naso- no strong evidence for the time to reintroduce
jejunal tube inserted under fluoroscopy. Naso- enteral feeds in infants who have had NEC
jejunal feeding usually minimizes the episodes (Bohnhorst et al. 2003).
of gastroesophageal reflux and their conse-
quences. However, it is common for these tubes
to dislocate back in the stomach. Regular analysis Administration of Enteral Feeds
of the pH in the aspirate is essential to monitor the
correct position of the tube. Feeding jejunostomy Enteral feeds can be administered as boluses, con-
tubes can be inserted through existing tinuous feeds, or combination of the two. Bolus
gastrostomy or directly into the jejunum via lap- feeds are more physiological and are known to
arotomy or laparoscopy. stimulate intestinal motility, enterohepatic circu-
lation of bile acids, and gallbladder contraction
(Jawaheer et al. 1995); continuous enteral feeding
Selection of Enteral Feeds leads to an enlarged, noncontractile gallbladder in
infants. Contraction is observed immediately after
Brest milk is widely recognized as the best source resuming bolus enteral feeds and gallbladder vol-
of nutrition, particularly for preterm infants. ume returns to baseline after 4 days. Therefore the
The advantages of feeding preterm infants mode of feeding has important bearings on the
breast milk include improved immune defenses motility of the extrahepatic biliary tree. Bolus
and gastrointestinal function, a 58% reduction in feeds mimic or supplement meals and are easier
the incidence of NEC and improved long-term to administer than continuous feeds since a feed-
neurodevelopment outcomes (Harding et al. ing pump is not required. Bolus feeds are usually
2017). When breast milk is not available, chemi- given over 15–20 min and usually every 3 h; term
cally defined formulae can be used, which are infants can tolerate a period of 4 h without feeds
designed either for term infants or specifically before hypoglycemia occurs. In preterm neonates
for preterm infants. If malabsorption is present or in neonates soon after surgery, 2 hourly feeds
and persists, an appropriate specific formula are occasionally given. Where bolus feeds are not
should be introduced. A soy-based disaccharide- tolerated, for example, in the presence of gastro-
free feed is used when there is disaccharide intol- esophageal reflux, continuous feeds should be
erance resulting in loose stools containing administered via an infusion pump over 24 h.
This modality of feeding is used in infants with function. Okada et al. (1998) have shown that
gastroesophageal reflux, delayed gastric empty- the introduction of small volumes of enteral feed
ing, or intestinal malabsorption. Infants with jeju- improved the impaired host bactericidal activity
nal tubes should receive continuous feeds and not against coagulase negative staphylococci and the
bolus feeds as the stomach is no longer providing abnormal cytokine response observed during total
a reservoir. PN.
Complications of Enteral Tube Feeding Conclusion and Future Directions
Enteral tube feeding is associated with fewer com- Nutrition of surgical infants and children is com-
plications than parenteral feeding. The complica- plicated by the requirement for growth. Inade-
tions can be mechanical including tube blockage, quate or unbalanced nutrition may lead to future
tube displacement or migration, and intestinal problems for these children, and we are now able
perforation. Although infection is less of a risk to start to improve nutrition delivery in order to
than with PN, the risk of infected enteral feeds optimize outcomes as well as survival. Despite
should not be ignored. Other complications advances in nutritional care, such as the multi-
involve the gastrointestinal tract. These include disciplinary approach, complications such as sep-
gastroesophageal reflux with aspiration pneumo- sis and cholestasis remain relatively frequent.
nia, dumping syndrome, and diarrhea. Future research should be aimed toward the pre-
Jejunostomy tubes inserted at laparotomy can be vention and treatment of these complications of
also associated with intestinal obstruction. The artificial nutritional support.
use of hyperosmolar feeds has been associated
with development of necrotizing enterocolitis,
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Access for Enteral Nutrition
18
Julia Zimmer and Michael W. L. Gauderer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Naso-, Orogastric or Naso-, Oroenteric Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Gastrostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Choice of Procedure/Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Complications and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
Gastrostomy Closure and Persistent Gastrocutaneous Fistula . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Jejunostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Choice of Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Devices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Postoperative Care and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 306
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307
Abstract pediatric conditions. They are employed for feed-

Enterostomies are key interventions in the man- ing, decompression, or a combination of both.
agement of various surgical and nonsurgical A large palette of options is now available, the
choice of procedure depends on the specific indi-
cation, the experience of the management team,
J. Zimmer (*) and the available resources. If the access is pri-
Children’s Hospital, Crumlin, Dublin, Ireland marily for long-term feeding, the optimal kind
must be carefully chosen, taking into account the
School, Hannover, Germany patients’ specific needs, comorbidities, habitus,
e-mail: zimmer.julia@mh-hannover.de and caretakers’ experience. Ideally the choice is a
M. W. L. Gauderer team decision. Regular early and long-term fol-
University of South Carolina School of Medicine low-up are essential to assure optimal function-
Greenville, Greenville, SC, USA ality and minimal morbidity.
e-mail: mgauderer@charter.net

https://doi.org/10.1007/978-3-662-43588-5_19
288 J. Zimmer and M. W. L. Gauderer
Keywords
Enteral nutrition · Enteral access · Nasogastric
tube · Orogastric tube · Gastrostomy ·
Gastrojejunal access · Jejunal access ·
Enterostomy · Percutaneous endoscopic
gastrostomy · Laparoscopic-assisted
techniques · Minimally invasive gastrostomy ·
Minimally invasive jejunostomy
Introduction
Enteral access is used for short-, intermediate-, or

long-term feeding, decompression, or a combina-
tion of both. Direct enteral nutrition is indicated
when the patient’s food intake does not meet the
needs to support adequate growth and develop-
ment and to treat malnutrition (Abdelhadi et al.
2016; Vermilyea and Goh 2016). The advantages
of enteral feeding over parenteral nutrition are
well documented, notably the preservation of
essential gastrointestinal physiology, and the
absence of complications of intravenous access
(Vermilyea and Goh 2016; Pang et al. 2017). Fig. 1 Five-year-old with cystinosis demonstrating feed-
ing on a teaching doll
In the last three to four decades, remarkable
progress has been made in enteral access regarding
indications, formulas, and, notably, the advent of
minimally invasive access techniques (Baker et al.
2015; Ray et al. 2017). Although gastrostomies and
jejunostomies were previously performed in
patients with major congenital anomalies of the
gastrointestinal tract and abdominal wall, contem-
porary indications are more likely to be for non-
surgical conditions. Typically, these are children
with the inability to swallow secondary to central
nervous lesions (Fig. 1), or patients requiring feed-
ing supplementation following trauma or chemo-
therapy, chronic malnutrition secondary to anorexia
and other conditions (Abdelhadi et al. 2016).
Fig. 2 Premature infant with continuous nasoenteric
pump feeding
Naso-, Orogastric or Naso-, Oroenteric
Access weeks to a few months (Abdelhadi et al. 2016;
Ricciuto et al. 2015). In addition to nutrition,
Naso- or orogastric or naso- or oroenteric tubes these access devices allow the administration
are well suited for short and intermediary use. of medication or fluids when needed (Fig. 2)
They are usually employed from a couple of (Abdelhadi et al. 2016; Irving et al. 2014). If
18 Access for Enteral Nutrition 289
properly placed, secured, and regularly flushed, Gastrostomy

naso- or orogastric tubes generally decompress
more effectively than gastrostomy tubes Gastrostomy is the preferred choice for long-term
(Vermilyea and Goh 2016). enteral access because it is physiologic, well tol-
A plain abdominal X-ray is still the most erated, and permit both, continuous and bolus
employed method to verify proper tube position feedings. Oral feedings and physiological activi-
(Vermilyea and Goh 2016). However, there is an ties are not interfered with. Additional advantages
understandable hesitation in its use due to radia- include, among others, the option for gastric
tion exposure (Abdelhadi et al. 2016; Irving et al. venting and the administration of nonpalatable
2014). Other accepted methods are visual obser- diets and medications. Although well tolerated
vation of gastric aspirate or gastric pH testing, and essential in the management of numerous
although these can be unreliable (Irving et al. pediatric conditions, gastrostomies have, never-
2014). Furthermore, the use of proton pump inhib- theless, a long list of potential early and late com-
itors or histamine 2 receptor antagonists may complications (Adams et al. 2014; Baker et al. 2015;
plicate pH testing (Vermilyea and Goh 2016). The Campwala et al. 2015; Friedman et al. 2004;
use of electromagnetic device and capnography is Landisch et al. 2016; Naiditch et al. 2010).
currently controversial (Abdelhadi et al. 2016;
Gilbert and Burns 2012; Powers et al. 2011). Ultra-
sound has been proposed to verify tube placement Historical Perspective
in critically ill children, but this technique is lim-
ited, because intragastric contents, mostly gas, Gastrostomy is one of the oldest abdominal oper-
make interpretation difficult (Abdelhadi et al. ations in continuous use. Few procedures have
2016; Adams et al. 2014). Because of the possi- challenged the creativity of surgeons more than
bility of pitfalls, the traditional, simple air insuffla- this seemingly simple conduit between the gastric
tion and auscultation is no longer recommended as mucosa and the surface of the abdominal wall.
the sole method for verification of placement Figure 3 illustrates the evolution of gastric access
(Vermilyea and Goh 2016). since the mid-nineteenth century (Gauderer and
In nonendotracheal intubated children, the Stellato 1986).
main early complication of nasoenteric tube
placement is accidental catheter introduction into
the trachea. Long-term complications of these Indications
tubes include poor securing with damage to the
nose or lip, naso-oto-pharyngeal irritation and Esophageal Abnormalities
infection, gastroesophageal reflux and aspiration, With contemporary approaches to esophageal
and esophageal and gastric mucosal erosion atresia repair, a gastrostomy is no longer routinely
(Abdelhadi et al. 2016; Idowu et al. 2010; Kim employed. It is indicated in cases of esophageal
et al. 2017; Vermilyea and Goh 2016). Fortu- atresia without fistula, difficult repairs, staging
nately, contemporary enteric tubes are highly bio- procedures, and when the child has associated
compatible, hydrophobic, lubricious, and anomalies that may interfere with feeding.
minimally irritating. For neonates, infants, and Gastrostomies are also needed in cases of severe
small children, feeding tubes of sizes 5 and 8 Fr esophageal stricture, such as those secondary to
are well suited. For decompression, they need to ingestion of caustic substances (Gauderer 2011).
be 8 Fr or larger, and not too long. In general,
nasoenteric tubes are preferred over nasogastric Duodenal Obstruction
tubes. However, in certain instances, such as pre- Duodenal obstruction is usually associated with
mature infants, orogastric tubes are used proximal duodenal dilatation, atony, and gastric
(Gauderer 2009). dilatation. If prolonged gastric decompression is
Fig. 3 Evolution of gastrostomy in chronological order of to stomach (1894). Type 4: formation of a tube from the
development. From Gauderer and Stellato (1986, p. 662). gastric wall, (f) without valve (1901) and (g) with valve
Type 1: (a) gastric fistula secondary to gastrotomy (1635). (1899). Type 5: (h) formation of a tube from small or large
Type 2: formation of a gastric cone, (b) through the inci- bowel (1906). Type 6: (i) gastrostomy without celiotomy
sion (1846, by Sedillot and Fenger), and (c) through a (percutaneous endoscopic) (1980). (j and k) contemporary
counterincision (1890, by Ssabanejev). Type 3: formation gastrostomy with two low-profile devices, the original
of a channel from the anterior gastric wall, (d) catheter button and a balloon-type device
parallel to stomach (1891), and (e) catheter perpendicular
anticipated, a fine silicone rubber catheter can be process can be fairly lengthy, direct gastric access
placed alongside a gastrostomy catheter, across via gastrostomy is desirable (Gauderer 2011).
the anastomosis and into the proximal jejunum
during the initial procedure (Gauderer 2011). Other Surgical Pathologies
Although these tubes are sometimes difficult to In any condition in which a prolonged ileus or
place and maintain, this simple and time-honored partial luminal occlusion (e.g., complicated meco-
technique can decrease or eliminate the need for nium ileus, small bowel Hirschsprung’s disease)
parenteral nutrition. is anticipated or in whom a complex feeding reg-
imen is likely (e.g., those with intestinal
Major Abdominal Wall Defects lymphangiectasia), a gastrostomy can facilitate
Surgical repair of gastroschisis , and occasionally management (Gauderer 2011).
other major abdominal wall defects, is usually
followed by a prolonged ileus. Although “Nonsurgical” Pathologies
decompressive gastrostomies are not routinely This is, by far, the most common indication for
indicated, they can be helpful in patients with placement of a gastrostomy in contemporary prac-
gastroschisis and associated atresia, particularly tice. It often becomes necessary in the care of
those requiring long-term continuous feeding patients with failure to thrive, malignancies, trauma,
(Gauderer 2011). and/or inability to swallow, as well as those needing
feeding supplementation, nonpalatable medications,
Short-Gut Syndrome and chronic malabsorption syndromes. Because the
Infants who have lost over 50% of their small neurologically impaired children frequently have
bowel have profound alteration of gastrointestinal foregut dysmotility and gastroesophageal reflux, in
physiology. Initial gastric hypersecretion may addition to swallowing difficulties, anti-reflux pro-
require prolonged drainage. As the remaining cedures are at times added to gastrostomies
intestine undergoes adaptive changes, continuous (Gauderer 2011). However, this topic continues to
enteral feedings become necessary. As this latter be the subject of significant controversy, given the
morbidity of anti-reflux procedures and the avail- initially developed for high-risk pediatric patients
ability of effective medications (Barnhart 2016; (Gauderer et al. 1980). Eventually, it became
Gantasala et al. 2013; Kakade et al. 2015). In gen- known as the “pull” technique. The procedure
eral, gastrostomy and gastrojejunostomy procedures has been employed in children of all ages, includ-
in neurologically impaired and chronically ventila- ing neonates, usually for the purpose of long-term
tor dependent infants and children have as signifi- enteral feeding (Beres et al. 2009; Lalanne et al.
cant risk of postoperative complications, morbidity 2014; Srinivasan et al. 2009; Wilson and Oliva-
and mortality (Chatwin et al. 2013; Liu et al. 2013). Hemker 2001).
Although there is no need for abdominal wall
relaxation, general endotracheal anesthesia is
Choice of Procedure/Technique employed in this age group so that the airway is
protected from compression during endoscopy. The
A wide variety of gastrostomy techniques are procedure is very short and there is no postoperative
available. There are three basic types (Gauderer ileus, no potential for bleeding or wound disruption
2006, 2011; Gauderer and Stellato 1986): and only minimal interference with subsequent
interventions on the stomach, such as a
(A) Formation of a serosa-lined channel from the fundoplication (Gauderer 2009). The main disad-
anterior gastric wall to the skin surface vantage of this and other pure endoscopic tech-
around a catheter. The catheter is placed in niques is that the virtual space between the
the stomach and exits either parallel or verti- stomach and the abdominal wall cannot be visual-
cally to the gastric serosa. ized. This shortcoming can be overcome by the
(B) Formation of a tube or conduit from a full addition of laparoscopic control (Croaker and
thickness gastric wall flap to the skin surface. Najmaldin 1997; Stringel et al. 1995). Although in
(C) Percutaneous techniques, in which the intro- the typical PEG a long tube is initially employed, a
duced catheter holds the gastric and abdomi- primary insertion of a skin-level device is also pos-
nal walls in apposition, with or without the sible (Ferguson et al. 1993; Novotny et al. 2009).
aid of special fasteners. Several other methods of gastrostomy without
laparotomy have been introduced (Gauderer
With certain modifications, each of these 2009). The percutaneous endoscopic “push” tech-
methods can be performed employing minimally nique is performed with the aid of needle-
invasive approaches. Table 1 demonstrates the deployed gastric anchors or “T” fasteners,
most commonly used gastrostomies and their followed by the Seldinger method of guide wire
characteristics. introduction. Progressive tract dilatations and
The open “Stamm” technique is the most widely insertion of a long tube or skin-level gastrostomy
employed gastrostomy with laparotomy and can be device follow (Robertson et al. 1996). A similar
used for children of all sizes, either as an isolated approach is used by interventional radiologists
intervention, or when employed in conjunction and found to be suitable for even very small
with another intra-abdominal procedure. For the stomachs (Cahill et al. 2001; Aziz et al. 2004).
placement of the standard gastrostomy tube or a In the last two decades, other minimally invasive
skin-level device, general anesthesia is preferred approaches, such as laparoscopically aided tech-
because abdominal wall relaxation is required. niques have been introduced. These are essentially
After the tract is well healed, this stoma is suitable expansions of the above methods, significantly
for the passage of dilators or guide wires in children increasing the choices of gastric access techniques
with esophageal strictures. The construction of a available to surgeons managing infants (Humphrey
gastric wall tube is difficult in young children and is and Najmaldin 1997; Rothenberg et al. 1999).
not appropriate for newborns. Recent comparative studies regarding efficacy,
The first gastrostomy without laparotomy was outcome, and complications of the different
the percutaneous endoscopic gastrostomy (PEG), techniques have been published, favoring
Table 1 Comparison of the most commonly used gastrostomies. From Gauderer (2009, p. 371)
Percutaneous
Serosa- Percutaneous imaging guided Laparoscopic and
lined Gastric endoscopic “radiological” laparoscopically
channels tubes techniques techniques assisted techniques
Catheter/stoma device Yes No Yes Yes Yes
continuously in use
Laparotomy Yes Yes No No No
Laparoscopically Possible Yes Yes N/A Yes
feasible
Need for gastric No No Yes No No
endoscopy
Need for abdominal Yes Yes No No Yes and insufflation
relaxation during
operation
Procedure time Short Moderate Very short Short Short
Postoperative ileus Yes Yes No No Some
Potential for bleeding Yes Yes Remote Remote Small
Potential for wound Yes Yes No No No
dehiscence/hernia
Potential for early Yes No Rare Yes Small
dislodgement of
catheter
Potential for gastric Possible Possible Yes Yes Possible
separation
Potential for infection Yes Yes Yes Yes Yes
Potential for Low No Yes Low Low
gastrocolic fistula
Incidence of external Moderate Significant Low Low Low
leakage
“Permanent” No Yes No No No
Suitable for passage of Yes No No No Possible
dilators for esophageal
stricture
Limited diameter of No N/A No Yes No
catheter
Interferes with gastric No Yes No No No
reoperation (e.g.,
fundoplication)
Suitable for infants Yes No Yes Yes Yes
laparoscopic procedures (Akay et al. 2010; Baker Open Technique

et al. 2015; Franken et al. 2015; Landisch et al. The child is placed on the table with a small roll
2016; Liu et al. 2013; Merli et al. 2016; Petrosyan behind the back. A nasogastric tube is inserted for
et al. 2016). However, in the adult population, the decompression and to help identify the stomach.
original PEG remains, by far, the procedure of A small transverse incision is made over the left
choice. For infants with an abnormal epigastric upper rectus abdominis muscle (Fig. 4). This inci-
anatomy, in whom the above techniques are diffi- sion should be neither too high, because it would
cult or impossible to perform, a hybrid procedure bring the catheter too close to the costal margin,
employing a mini-laparotomy and the PEG prin- nor too low, avoiding the colon and the small
ciple was developed (Gauderer 2008). bowel. A short vertical incision is an alternative.
Fig. 5 Gastrotomy site on the anterior gastric wall. The

traction guy suture and the purse-string suture are depicted.
Introduction of a de Pezzer catheter. From Gauderer (2011,
pp. 458–9)
Fig. 4 Gastrostomy incision and catheter exit site. An

alternative is a short vertical midline incision. From The anterior gastric wall is lifted with two guy
Gauderer (2011, pp. 458–9)
sutures (4-0 silk) at the site of the stoma, ensuring
that the posterior wall is not included. A concen-
However, this approach is less desirable because tric purse-string suture (4-0 synthetic, absorbable
the linea alba is the thinnest area of the abdominal material) is placed (Fig. 5). The gastrotomy, at the
wall. Fascial layers are incised transversely and center of the purse-string, is made sharply through
the rectus muscle retracted or transected. When the serosa and muscular wall of the stomach
identification of the stomach is not immediate, (Gauderer 2011).
downward traction of the flimsy greater omentum A small hemostat is introduced to confirm
readily allows visualization of the transverse access into the gastric lumen. We prefer a
colon and stomach (Gauderer 2011). mushroom-type catheter (de Pezzer), sizes
The site of the gastrotomy placement on the 12–14 Fr. gauge, for neonates. The mushroom
anterior gastric wall is critical in infants. A posi- head of the catheter is stretched with a short stylet
tion midway between the pylorus and the esoph- to allow atraumatic introduction into the stomach
agus is chosen. The site should be neither too (Fig. 5). The purse-string is tied to invert the
high, because this would interfere with a seromuscular gastric wall around the tube
fundoplication, should one be needed in the (Fig. 5). Other suitable catheters are the Malecot
future, nor too low, because stomas at the level or the “T tube,” but both have the disadvantage of
of the antrum are prone to leakage and pyloric becoming more easily dislodged. However, a
obstruction by the catheter. The surgeon must not short “T tube” is useful if the stomach is very
place the catheter too close to the greater curva- small. Long balloon-type catheters, which may
ture, to avoid the so-called gastric pacemaker and rupture, also have a greater propensity for distal
to minimize the potential for gastrocolic fistula migration into the small bowel. Skin-level devices
(Gauderer and Stellato 1986). (buttons or balloon-type) may be inserted during
Fig. 6 The purse-string suture is tied. Partial placement of Fig. 7 The continuous monofilament suture placement is
the continuous monofilament suture, used to anchor the continued anteriorly and then tied, providing a 360 fixa-
stomach to the anterior abdominal wall. The catheter is tion of the stomach to the anterior abdominal wall with a
brought out through the counterincision. From Gauderer watertight seal. From Gauderer (2011, pp. 458–9)
(2011, pp. 458–9)
the operation, instead of the traditional long tubes material. The subcutaneous layer is closed with
(Gauderer et al. 1984, Gauderer 2006). The exit a couple of 5-0 or 6-0 synthetic, absorbable
site for the catheter should be through the sutures. The skin can be approximated with
mid-portion of the rectus muscle about 1–2 cm either interrupted or continuous 5-0 or 6-0 sub-
above or below the laparotomy incision (Figs. 6 cuticular sutures. Adhesive strips cover the inci-
and 7). Although some surgeons bring the catheter sion. The catheter is firmly secured with two
out by way of the primary abdominal incision, sutures of 3-0 or 4-0 synthetic monofilament
wound complications that may occur in this set- thread. These sutures are removed after 1 week
ting tend to be more complex (Gauderer and and a small cross-bar is placed loosely to prevent
Stellato 1986). Once the exit site is chosen, the distal catheter migration. Occlusive dressings
anterior gastric wall is secured to the posterior are not used after the first couple of postopera-
aspect of the anterior abdominal wall with four tive days. Conversion of a long tube to a “but-
equidistant sutures or, as illustrated, with a con- ton” can be performed after a firm adherence
tinuous suture of double-ended 4-0 synthetic between gastric and abdominal wall is
monofilament thread (Wilson and Oliva-Hemker established (Gauderer 2011).
2001) (Fig. 7). The catheter position is tested by
injecting and aspirating saline. Gentle traction on Percutaneous Endoscopic Gastrostomy
the catheter assures that its intragastric position is The PEG technique (“Pull”-PEG), as initially
maintained (Gauderer 2011). described (Gauderer et al. 1980), is applicable in
The posterior rectus sheath is closed with a children of all sizes. The procedure must, how-
running suture of 4-0 absorbable, synthetic ever, be done with great precision and endoscopic
material. The anterior rectus sheath is approxi- skill. PEG incorporates these basic elements
mated with interrupted sutures of the same (Gauderer 2011):
Fig. 8 Percutaneous
endoscopic gastrostomy
(PEG). Insufflation of air
through the endoscope to
approximate the stomach to
the abdominal wall and
displace the colon caudally.
Digital pressure is applied
to the proposed gastrostomy
site, which usually
corresponds to the area
where transillumination is
brightest. Transillumination
and clear visualization of an
anterior gastric wall
indentation are key points.
Drawn of long-lasting local
anesthetic into a syringe and
injection of the proposed
PEG. The needle is
advanced further, and
continuous aspiration
pressure is applied to the
plunger. Air aspiration
should only occur when the
tip of the needle enters the
gastric lumen. From
Gauderer (2011, pp. 460–1)
– Gastroscopic insufflation brings the stomach Although there are multiple variations of the
into apposition to the anterior abdominal wall original PEG technique (Croaker and Najmaldin
(Fig. 8). 1997; Ferguson et al. 1993; Gauderer et al. 1980;
– With the stomach apposed to the abdominal Gauderer and Stellato 1986; Novotny et al. 2009;
wall, a cannula is introduced percutaneously Robertson et al. 1996; Stringel et al. 1995) and
into the gastric lumen under direct endoscopic several types of catheters, one must be cautious,
guidance (Fig. 8). because most of these are not suitable for use
– The cannula serves as access to introduce a in infants. We employ a 16 Fr. Gauge (or smaller)
guide wire, which is then withdrawn out of commercially available silicone rubber
the patient’s mouth with the gastroscope pediatric PEG catheter. Larger, stiffer catheters,
(Figs. 8 and 9). A tract is thus established. or those with a stiff, noncollapsible inner
– A PEG catheter with a tapered end is attached retainer, can easily tear the infant’s esophagus
to the oral end of the guide wire and pulled in a (Gauderer 2011).
retrograde fashion until it assumes its final A single dose of an i.v. broad-spectrum antibi-
position, keeping the stomach firmly, but not otic is administered at the outset. The child
too tightly, apposed to the abdominal wall remains in the supine position throughout the
(Fig. 10). procedure. The abdomen is cleansed and sterilely
the left upper quadrant abdominal wall. With the

gastroscope in place, insufflation distends the
stomach, apposes it against the anterior abdominal
wall, and displaces the colon downward. When
the room lights are dimmed, the gastric contour is
clearly visible, particularly in small children.
The preferred gastrostomy site is over the
mid-portion of the left rectus muscle. Digital pres-
sure is exerted at this site, and this is seen by the
endoscopist as a “polypoid lesion” or “mound” on
the anterior gastric wall (gastric transillumination
and endoscopically visualized digital indentation
of the stomach are the most important factors in
safe PEG placement). The endoscopist then places
an endoscopic polypectomy snare around this
invagination of the anterior gastric wall. Digital
pressure is released and a 0.5–0.7 cm skin incision
is made. A hemostat with slightly opened prongs
is placed in the incision, recreating and
maintaining the intragastric “mound” (Fig. 9).
Fig. 9 A small incision is made and a Kelly-type hemostat
is applied to maintain the intragastric indentation. The
Through this incision and through the prongs of
endoscopist places the polypectomy snare around the the hemostat, a 16-gauge, smoothly tapered,
“mound”; the cannula is introduced between the slightly i.v. cannula and needle are thrust through abdom-
spread prongs of the hemostat and then thrust through the inal and gastric walls under endoscopic visualiza-
abdominal and gastric walls into the open snare. The snare
is partially closed but not tightened around the cannula.
tion. This should be performed quickly to avoid
From Gauderer (2011, pp. 460–1) displacing the stomach from the abdominal wall.
The snare, if properly positioned initially, will be
around the advancing cannula. If not, it can be
maneuvered to encircle the cannula. A long,
monofilament synthetic suture or a plastic-
covered steel guide wire is then advanced through
the cannula and grasped by the snare (Fig. 10). If
there is difficulty with the snare, a biopsy or
alligator-type forceps may be used. As the gastro-
scope and snare are withdrawn, the suture is
brought out of the patient’s mouth (Fig. 10). The
previously selected PEG catheter is then
connected to the suture outside the patient’s
mouth and both suture and catheter are coated
Fig. 10 The needle is removed and the guide wire
with a water-soluble lubricant. Traction on the
inserted. The polypectomy snare (alternatively alligator abdominal portion of the suture or guide wire
or biopsy forceps) grasps the guide and exit it through the pulls the catheter in a retrograde fashion, through
mouth. From Gauderer (2011, pp. 460–1) the mouth, esophagus, and stomach, and across
the abdominal wall (Fig. 11). The gastroscope is
draped. Gastroscopy is performed with the reintroduced to verify the catheter position under
smallest pediatric gastroscope available. The direct vision. While re-endoscopy might theoreti-
scope is inserted and advanced slowly into the cally be unnecessary, we believe it adds safety to
stomach, at which point the light is seen through the procedure (Gauderer 2011).
recent studies showed that early feedings (within

3–6 h) are not associated with a higher complica-
tion rate (Corkins et al. 2010; Jensen et al. 2017).
Minimally Invasive Gastrostomies

The application of laparoscopy to pediatric
patients expanded the number of options and
increased the safety of gastrostomy placement.
In addition to the “open” gastrostomy and the
conventional PEG, the insertion of a gastrostomy
device can be performed either as entirely with
laparoscopic assistance (LAP), or laparoscopic
control can be employed to assist with the PEG
approach (LA-PEG) (Baker et al. 2013, 2015;
Georgeson 1998; Livingston et al. 2015; Patel
et al. 2014; Stringel et al. 1995; Turial et al.
2009; Vasseur and Reinberg 2015). Various stud-
ies have demonstrated that laparoscopic control
significantly lower the risk of major complications
Fig. 11 The appropriate sized PEG catheter is attached to in children (Baker et al. 2015; Merli et al. 2016;
the oral end of the guide wire and pulled in a retrograde Petrosyan et al. 2016). Although radiologically
manner through the infant’s esophagus and stomach, and assisted/guided gastrostomies belong to this
then across the gastric and abdominal walls. The inset group, they will not be described here (Baker
shows the position of the catheter at the end of the proce-
dure. From Gauderer (2011, pp. 460–1) et al. 2015; Merli et al. 2016; Petrosyan et al.
2016).
Traction on the catheter is continued until the Laparoscopically Assisted Gastrosto-

inner catheter retainer or “dome” loosely touches mies Direct intra-abdominal visualization by a
the gastric mucosa (Fig. 11). Markings on the com- laparoscope adds safety to the minimally invasive
mercially available catheters, or markings added to procedures and allows for multiple variations for
tubes without marks, are helpful in indicating the constructing a gastrostomy (Croaker and
final position of the tube. The external cross-bar is Najmaldin 1997; Ferguson et al. 1993; Georgeson
then placed (Fig. 10). Excessive pressure by the 1993; Novotny et al. 2009; Robertson et al. 1996;
external cross-bar on the abdominal wall will pro- Stringel et al. 1995). Several approaches have been
duce pressure necrosis and eventual catheter extru- described. In addition to the videoscopically con-
sion, and should be avoided. The tapered catheter trolled PEG, the two most common methods are
end is cut off and a connector attached. Tape is used adaptations of the Stamm technique and modifica-
for temporary catheter immobilization. The cathe- tions of the “push” PEG (Livingston et al. 2015;
ter may be converted to a skin-level device by using Vasseur and Reinberg 2015). The authors’ prefer-
the external port valve at any time. To replace the ence is for the latter because, in order to place a
PEG catheter with a “button” or balloon-type skin- purse-string suture through the exposed segment of
level device, we find it is prudent to wait until firm the anterior gastric wall, the trocar site must be
adhesions between the stomach and abdominal sufficiently enlarged. This may predispose the site
wall are established. This may take 1–3 months or to leakage. To temporarily anchor the stomach to
longer (Gauderer 2011). the abdominal wall, different approaches may be
The PEG catheter can be used immediately after employed, notably T-fasteners and U-stitches. The
insertion, but some centers wait for 24 h or even most suitable site for the gastrostomy is selected in
longer before staring enteral feedings. However, the left upper quadrant and marked. A nasogastric
Fig. 12 Laparoscopically assisted gastrostomy. After the

establishment of pneumoperitoneum, a trocar is inserted at
the gastrostomy site, a grasper is introduced, and the appro-
priate portion of the anterior gastric wall is lifted. Place-
ment of two sutures in the depicted manner. From Gauderer Fig. 13 Insufflation of the stomach with air through the
(2011, p. 462) nasogastric tube. Insertion of a needle through the trocar
site into the gastric lumen, between the two U-stitches. A
Seldinger-type guide wire is passed through the needle into
tube is inserted. Pneumoperitoneum is established the stomach. The tract is dilated over the guide wire to the
in the child’s size-appropriate manner, a trocar is size required to insert either a Foley-type catheter or a
balloon-type skin-level device or another low-profile
placed at the umbilicus and the laparoscope is
access device. These are placed over the same guide wire.
introduced. A needle is pushed through the previ- From Gauderer (2011, p. 462)
ously marked abdominal wall site and the appro-
priate relation between the anterior gastric wall and
the stoma site established. A small skin incision is wire. Stiffening of the catheter shaft with a thin
made and a 5 mm trocar inserted. A grasper is metallic dilator is helpful. The previously placed
introduced and the gastrostomy site on the anterior U-stitches are tied over the wings of the “button”
gastric wall is lifted toward the parietal peritoneum (Figs. 15 and 16). If a long tube is placed, a pair of
(Fig. 12). A U-stitch is passed through the abdom- bolsters is employed. Care must be taken to avoid
inal wall, through the anterior gastric wall, and excessive tension.
back out through the abdominal wall. A second Numerous variations for constructing a
U-stitch is passed parallel to the first one, 1–2 cm laparoscopically controlled or aided gastrostomy
apart (Figs. 12–14). The sutures are lifted, have been introduced. These include one or two
maintaining the stomach in contact with the trocar techniques or micro-invasive strategies
abdominal wall (Fig. 14). The grasper and the (Akay et al. 2010; Baker et al. 2013; Kawahara
trocar are removed. The stomach is insufflated et al. 2006; Patel et al. 2014; Turial et al. 2009):
with air through the nasogastric tube and a needle Large double U-stitch techniques have been mod-
is inserted through the trocar site into the gastric ified, e.g., replacement of U-stitches with a con-
lumen, between the two U-stitches. A Seldinger- tinuous double U-stitch suture (Backman et al.
type guide wire is passed through the needle into 2010), subcutaneous placement of absorbable
the stomach (Fig. 13). The tract is dilated over the stay-sutures (Antonoff et al. 2009), or
guide wire to the size required to insert either a laparoscopically placed sutures to secure the
Foley-type catheter or a balloon-type skin-level stomach to the abdominal wall (Villalona et al.
device. These are placed over the same guide 2011).
and dilators are removed. An appropriate size

balloon-type button is introduced through the
peel away sheath. The latter is removed and the
balloon is inflated with saline (usually 3–5 ml).
The anchoring sutures are lifted outside and tied
subcutaneously. Inspection with both gastroscope
and laparoscope ensures a proper gastrostomy
device placement (Livingston et al. 2015; Hassan
and Pimpalwar 2011).
As a variation, besides the umbilical port two
transabdominally incisions can be made for laparo-
scopic working instruments and only three sutures
may be placed around a proposed gastrostomy site
(Smitherman and Pimpalwar 2009).
Although multiple variations exist and
undoubtedly others will be described, the princi-
Fig. 14 Laparoscopic gastrostomy procedure, intra- ples are essentially the same: safe approximation
abdominal view. U-sutures are placed. The sutures are of the stomach to the abdominal wall, protection
lifted, maintaining the stomach in contact with the abdom- of adjacent organs, and comfortable, tension-free
inal wall. Removal of grasper and trocar. Insufflation of the gastrostomy device placement.
stomach. Insertion of a needle through the trocar site into
the gastric lumen, between the two U-stitches. A Seldinger-
type guide wire is passed through the needle into the
stomach. The tract is dilated over the guide wire to the Choice of Access Device
size required to insert either a Foley-type catheter or a There are several types of commonly used
balloon-type skin-level device.
gastrostomy tubes. The “traditional” long cathe-
ters are characterized by the mode of retention
Laparoscopic-Assisted Percutaneous Endo- (semi-rigid intragastric portion and inflatable
scopic Approach For optimal visualization of intragastric balloon). The skin-level devices or
the structures, laparoscopy has been added to the “buttons” are modifications in which the
conventional PEG in various techniques (Hassan intragastric retention mechanism is similar to
and Pimpalwar 2011; Idowu et al. 2010; Living- those of the long tubes (Gauderer et al. 1984,
ston et al. 2015; Nixdorff et al. 2010; Smitherman Gauderer 2009). A comparison of the devices is
and Pimpalwar 2009). shown in Table 2. Of the conventional, long tubes,
The gastroscope is placed within the stomach the Foley or balloon catheters are the easiest to
and a laparoscopic port is introduced through the insert, but have the disadvantage of balloon defla-
umbilicus. Pneumoperitoneum is achieved tion leading to dislodgement (Gauderer 2009).
depending on the patient’s age. A camera is intro- Additionally, these catheters are prone to distal
duced into the peritoneal cavity, the ideal migration with possible intestinal obstruction.
gastrostomy site is chosen, and a skin incision is The de Pezzer and PEG-type catheters are less
made for the abdominal wall exit site. Under direct prone to dislodgement but are a little harder to
visualization by both gastroscope and laparoscope, insert. The Malecot-type catheters, with its rela-
T-Fasteners are placed from the gastrostomy site tively soft winged tip, are easier to insert but also
on the abdominal wall into the insufflated stomach. more prone to dislodgement (Gauderer 2009).
A needle is placed between the sutures from the All types of catheters can be used for long-term
abdominal incision into the stomach. A guide wire care, but skin-level devices are best suited for this
is then introduced. Under direct visualization an purpose (Fig. 17). The three most commonly
appropriate size dilator–peel away sheath is passed employed skin-level devices are shown in
over this guide wire into the stomach. Guide wire Fig. 18. The original button has the lowest
Fig. 15 Laparoscopic placement of a balloon-type “button.” The previously placed U-stitches are tied over the “wings”
of the skin-level device. From Gauderer (2011, p. 462)
available. However, judging the appropriate but-

ton length prior to insertion may be difficult and
once the button is deployed, it cannot be changed
(Gauderer 2009).
Contemporary balloon-type skin-level devices
have the advantages of greater ease in the changing
process and a feeding adapter that is more securely
connected. Disadvantages include a shorter life
span because of balloon deflation and a slightly
taller external profile. Additionally, the balloon
occupies more intragastric volume and in some
earlier models the protruding tip produced erosions
on the posterior gastric wall (Gauderer 2009).
Fig. 16 Laparoscopic procedure. Postoperative status. The third type is a device with a changeable
Small incision scars and the gastrostomy tube in place
external port-valve. The greatest advantage of this
concept is that an originally placed long
external profile and tends to last considerably gastrostomy tube can be converted to a skin-
longer than the other devices. However, because level device by simply cutting the tube to the
the mushroom head is difficult to collapse desired length above the skin and placing the
completely, its insertion can be more painful. valve in the shaft. The tract is not disturbed, thus
Although accidental connector dislodgement, eliminating the possibility of gastric separation.
after long-term use, could occur with early The conversion can be done either immediately
models, this is not a problem with newer devices after the gastrostomy catheter insertion or any
(Gauderer 2009). A combination PEG catheter- time thereafter. The main disadvantage in the pre-
button for primary insertion is commercially sent model is late valve failure. However, if this
Table 2 Comparison of most commonly used gastrostomy devices. From Gauderer (2009, p. 374)
PEG-type, de Pezzer, Foley Skin-level (“button”
Malecot, T-tube (balloon type) type)
Suitable for initial insertion Yes Yes Yes
Suitable for decompression Yes Yes Yes
Tendency for accidental dislodgement or Moderate (with special Moderate Very Low (except
external migration adaptor) balloon type)
Tendency for internal (distal) migration Moderate High None
Tendency for peristomal leakage Moderate Moderate Low
(particularly large tubes)
Balloon deflation No Yes Yes, with balloon type
Reinsertion Easy to moderately Easy Easy to moderately
difficult difficult
Long-term (particularly ambulatory Adequate Adequate Best suited
patients)
Overall complication rates Significant Significant Low
Fig. 18 The three main gastrostomy device groups. From

Fig. 17 Child with gastrostomy button Gauderer (2009, p. 374)
occurs, the external port-valve is changed, again patient. An additional advantage is that inventory
without removal of the initially placed catheter is markedly simplified as the need for multiple
(Gauderer et al. 1998). Because the valve can be catheter lengths is eliminated (Gauderer 2009).
applied at any level on the shaft of the tube, this The diameter of the long tubes and the skin-
skin-level device becomes specific for each level devices depends on the size of the child and
the purpose of the gastrostomy. For infants and under fluoroscopy to assure an intragastric posi-
small children, 12–16 F tubes are appropriate. For tion of the tube and absence of intraperitoneal
older children, sizes 18–20 F are well suited leakage. If there is any question about the position
(Gauderer 2009). of the catheter, prompt exploration is necessary
(Gauderer 2009).
Complications and Management Wound Separation, Dehiscence, and Ventral

Hernia They are usually the result of technical
Although frequently considered a “simple” proce- problems after open procedures and carry high
dure, a gastrostomy has a considerable potential for morbidity and mortality rates (Gauderer 2009;
early and late morbidity, particularly among neo- Gauderer and Stellato 1986). Leakage from an
nates (Farrelly and Stitelman 2016; Gauderer enlarged incision can be life threatening
2011). Most of the common problems can be pre- (Gauderer 2009). Such mishaps can be mini-
vented with meticulous attention during placement mized by the use of appropriate, small incisions
and subsequent follow-up (Beres et al. 2009). The and by bringing the tube out through a counter-
use of skin-level devices such as the original incision.
gastrostomy button (Gauderer et al. 1984; Gauderer
and Stellato 1986), the balloon-type versions, or the Hemorrhage Major bleeding is usually related
externally placed port-valve has dramatically to inadequate hemostasis at the time of catheter
decreased the most common problems associated insertion (Gauderer 2009). Gentle traction on the
with older, long tubes. Many techniques, whether catheter can control the bleeding, but (Friedman
“open,” endoscopic, or laparoscopically aided, now et al. 2004) reoperation may become necessary.
permit the initial placement of one of these well-
tolerated skin-level devices (Gauderer et al. 1998; Infection This complication can occur with any
Gauderer 2011). type of gastrostomy (Beres et al. 2009; Friedman
et al. 2004; Gauderer and Stellato 1986; Goldin
Complications Related to Operative et al. 2016). Although usually limited to the skin
Technique and subcutaneous tissue, it can lead to full-
thickness abdominal wall loss. Infections can usu-
Separation of Stomach from Abdominal ally be avoided through the use of prophylactic
Wall This most frequently occurs after early antibiotic administration and a skin incision only
gastrostomy tube reinsertion, before a firm adhe- slightly larger than the diameter of the tube
sion between gastric and abdominal walls has (Gauderer 2011).
occurred, but can also occur at any time thereafter.
During the attempt to replace a dislodged catheter, Injury to the Posterior Stomach Wall
the stomach is pushed away from the abdominal and Other Organs The posterior gastric wall
wall; that displacement leads to a partial or com- can be damaged or perforated not only during
plete separation of the stoma. If not recognized the initial procedure but also later during catheter
soon, severe peritonitis and death may result change (Gauderer and Stellato 1986). Once the
(Friedman et al. 2004; Gauderer 2011; Gauderer tube is introduced, air or saline should be injected
and Stellato 1986). To avoid this problem, the to test the tube’s position and function. During
stomach must be firmly anchored to the anterior open procedures, damage to the liver and spleen
abdominal wall and the catheter well secured to can occur through the improper use of retractors
the skin, particularly with the open techniques. In or other instruments (Gauderer 2011). The
the event of early removal or dislodgement of the distended colon may be mistaken for the stomach,
tube, the tract can be gently probed and a thin particularly in patients with intra-abdominal adhe-
Foley catheter inserted. This must be followed sions in whom mobility of intestinal loops is lim-
by injection of a radio-opaque contrast material ited (Gauderer 2009, 2011).
Gastrocolic Fistula Although it can occur with extension a dislodgment of the jejunal tube back
any gastrostomy, this complication is more likely into the stomach may occur, usually requiring
with the percutaneous endoscopic techniques radiologic (fluoroscopy) or endoscopic guided
(Gauderer 2011; Gauderer and Stellato 1986). repositioning.
Appropriate gastric insufflation with downward Improper catheter reintroduction can lead to
colonic displacement, transillumination, and the damage to the pancreas, liver, or spleen, particu-
indentation on the anterior abdominal wall are larly if long stylets or other traumatic instruments
crucial parts during PEG procedure. On the other are used to elongate a mushroom-type tip. Gentle
hand, overinflation must be avoided because it can insertion and aiming toward the gastric cardia or
distort the local anatomy, including the position of fundus is the method least likely to produce injury
the colon. Additionally, air-filled small bowel (Gauderer 2011).
loops will displace the colon cranially and move
it between the stomach and the abdominal wall
(Gauderer 2011). Complications Related to Catheters
Granulation Tissue This is by far the most fre-

Complications Related to Care of Stoma quent problem associated with gastrostomies. If
mild, usually a few applications of silver nitrate
Skin Irritation and Moniliasis Next to granula- are curative. However, if this condition is neglected,
tion tissue, these are the most frequent problems granulation tissue will predispose to leakage, bleed-
encountered. Usually related to leakage, and ing, and chronic discharge. With excessive growth,
compounded by occlusive dressings, irritation is excision and cauterization become necessary. Gran-
best prevented by avoiding any occlusive devices, ulation tissue formation will cease once epitheliali-
including nipples, tape, or gauze pads (Gauderer and zation of the tract has occurred (Gauderer 2011).
Stellato 1986). The site should be kept open and dry
at all times. Ointments and other solutions, except Leakage Severe continuous leakage is uncommon
for the treatment of moniliasis, should be avoided. if the gastrostomy is properly constructed (Gauderer
Catheters, if kept long, can be immobilized with a and Stellato 1986). The usual cause for leakage is the
small external cross-bar (Gauderer 2011). enlargement of the stoma by pivoting motion of the
gastrostomy tube, which is often too large or too stiff
Tube Plugging Catheters must be flushed with (Gauderer and Stellato 1986). Catheters brought
water after each feeding to prevent blockage. In through the incision or the thinner midline are more
neonates, the amount should be small and added prone to this problem. Severe widening of the stoma
to the fluid intake (Gauderer 2011). can lead to skin excoriation, dislodgment of the tube,
metabolic imbalance, and even death (Gauderer
Administration of Improper Feedings Careful 2011; Gauderer and Stellato 1986). Management of
and slow administration of the appropriate nutri- leakage begins with control of granulation tissue and
ent prevents metabolic abnormalities as well as placement of a smaller, softer catheter to avoid
diarrhea and excessive reflux (Gauderer 2011). pivoting motion (Gauderer 2011). In extreme cases,
reoperation or stoma relocation becomes necessary.
Delay and Trauma in the Reintroduction of a
Dislodged Catheter Accidental dislodgement of Internal (Distal) Migration This may occur
long gastrostomy catheter is quite common. The with any gastric tube, but is particularly common
catheter must be replaced before the tract closes, with long, balloon-type catheters (Gauderer 2011;
which can be in a few hours unless it is well Gauderer and Stellato 1986).
matured and epithelium lined. Careful dilation of
the tract is usually successful (Gauderer 2011). In External Migration Overzealous approxima-
gastrostomy skin-level devices with jejunal tion of external immobilizing devices (bumper)
can lead to embedding of the inner cross-bar of the Depending on their expected length of use,
PEG catheter, mushroom tip, or balloon in the jejunostomies can be divided into short-term
gastric and abdominal wall, resulting in the (e.g., nasojejunal catheters), medium-term (e.g.,
so-called buried bumper syndrome (BBS) transgastric jejunal tubes), and long-term access
(Abdelhadi et al. 2016; Cyrany et al. 2016; (see below) and into indirect and direct jejunal
Gauderer 2009, 2011; Gauderer and Stellato access, depending on how the catheters are placed
1986). It occurs not in only in PEG patients but (Gauderer 2009).
also in patients with low-profile balloon G tubes For direct jejunal access, a nonballoon button
and nonballoon G tubes (Abdelhadi et al. 2016). in older children and a T-tube in infants are
The bumper can end up anywhere between the recommended. The T-tube is then converted to a
stomach mucosa and the skin surface, which is skin-level device with the external port-valve.
typical for rigid or semi-rigid internal immobili- Balloon catheters should not be used as they
zation devices (Cyrany et al. 2016). The usual might occlude the lumen. Any of the gastric
presentations are malfunction with limited flow, access devices will work in the Roux-en-Y setup
leakage, lack of to-and-fro motion of the catheter, (DeCou et al. 1993; Gauderer 2009).
or the formation of an abscess (Abdelhadi et al.
2016). The catheter should be removed and
replaced. This problem can be avoided by giving Indications
the catheter enough “play,” i.e., a little to-and-fro
motion (Gauderer 2011). Since the development In the last two decades, there has been an
of skin-level devices such as buttons, problems increased use of jejunostomies in the pediatric
with BBS decreased markedly. age group as many children with complex medical
problems and unable to use a gastrostomy are in
Perforation of Esophagus and Small need for long-term enteral access. Postpyloric
Bowel Accidental inflation of a balloon-type cath- feedings are used to overcome problems related
eter in the esophagus esophagus or small bowel to aspiration, gastric emptying, gastroesophageal
might lead to wall disruption (Gauderer 2011). reflux disease, gastric paresis, microgastria, or
gastric outlet obstruction (Vermilyea and Goh
Gastrostomy Closure and Persistent 2016). Gastrojejunal tubes may eliminate the
Gastrocutaneous Fistula need for anti-reflux surgery in patients with gas-
troesophageal reflux (Axelrod et al. 2006).
When a stoma is no longer needed, the catheter The usual purpose of jejunostomies is feeding,
can be simply removed. If the gastrostomy has whereas the administration of medication is a less
been in place for less than 6–12 months, the tract common use. Classic procedures combined gas-
usually closes spontaneously. If this does not tric decompression combined with intra-jejunal
occur, operative closure under general anesthesia feeding (Fig. 19).
may become necessary. The stoma tract is dis-
sected down to the deepest possible extra-
peritoneal level. The tract is then closed in layers Choice of Procedure
using absorbable sutures (Gauderer 2009, 2011).
Several techniques for insertion of jejunal feeding
tubes have been suggested, such as fine-needle
Jejunostomy catheter jejunostomy, endoscopically or
laparoscopically controlled or percutaneously
Jejunostomies are not used as frequently as inserted jejunal (Pang et al. 2017) (Fig. 20).
gastrostomies because they are more difficult to
place and maintain, are more complication prone Needle Catheter Jejunostomy
and less physiologic (Abdelhadi et al. 2016; These are for short-term use via direct jejunal
Gauderer 2009). access. This approach can be employed as an
adjunct during other intra-abdominal interven- Catheter Placement Directly into

tions. However, these catheters plug easily, are the Jejunum
nearly impossible to change, and are associated This approach is for long-term usage. The tradi-
with several serious complications (Gauderer tional technique is the formation of a Witzel-type
2009). channel. This method has two disadvantages: if
the tube becomes dislodged or plugged, it is diffi-
cult to change, and in small children the formation
of a channel substantially reduces the diameter of
the lumen (Gauderer 2009).
Catheter Placement in a Partially

Excluded Loop
Another example for long-term use of jejunal
access. The main appeals of the Roux-en-Y feed-
ing jejunostomy are the decreased likelihood of
leakage and the possibility of safe catheter
change. However, this approach is more complex
and increases the possibility of early and late
bowel-related complications (DeCou et al. 1993;
Gauderer 2009; Williams et al. 2007).
Devices
Fig. 19 “Classic” combination of gastric decompression Gastrojejunal (GJ) buttons have the same design
and intra-jejunal feeding. From Gauderer (2011, p. 456) as gastrostomy buttons but have additionally a
Fig. 20 Options of jejunal access for select-feeding and (f) Temporary decompression feeding using catheters
decompressing-feeding. (a) Tunneled catheter. (b) Needle when primary anastomosis is unsafe and intestinal exteri-
catheter. (c) T-tube. (d) Button. (e) Proximal decomp- orization is not possible. (g) Roux-en-Y feeding
ression and distal feeding across an anastomosis. jejunostomy. From Gauderer (2006)
associated diarrhea have been reported to be

specifically jejunostomy-related complications
(Abdelhadi et al. 2016; Farrelly and Stitelman
2016; Gauderer 2009). Persistent reflux, tube dis-
lodgement and intestinal perforation have been
associated to a morbidity after gastrojejunal tube
placement (Campwala et al. 2015; Demehri et al.
2016; Farrelly and Stitelman 2016). A
gastrojejunal button which is too big may cause
pyloric obstruction in smaller children (Vermilyea
and Goh 2016).
Fig. 21 Patient with gastrostomy skin-level device and
jejunostomy button
Conclusion and Future Directions

long distal jejunal tube component (Fig. 21)
(Vermilyea and Goh 2016). They are low Although both gastrostomy and jejunostomy are
profile/skin-level, have a one-way valve to pre- basic surgical procedures, one must carefully con-
vent leakage when not in use, and are kept in sider their advantages and disadvantages in
place by a retention balloon (Abdelhadi et al. respect of the patient’s comorbidities as they
2016; Vermilyea and Goh 2016). The gastric mean major intervention in the children’s life. A
part of the GJ tube comes in different French problematic stoma can complicate the manage-
diameters to match the patient’s gastrostomy ment of even a simple, temporary condition.
stoma length. The jejunal length is determined All children with gastrostomies and
by the patient’s size. The smallest GJ button jejunostomies must be carefully followed to prevent
presently available is a 14 F button (Vermilyea long-term catheter-related complications. These
and Goh 2016). The gastric access is usually children benefit from a team approach, including
used for administration of medications while pediatrician, pediatric surgeon, pediatric gastroen-
the jejunal extension is used for enteral nutrition terologist, primary nurse, and nutritionist. It is also
(Abdelhadi et al. 2016). paramount that the parents or caregivers be an
integral part of the decision-making process at the
different stages of management.
Postoperative Care and Complications An important goal in children with feeding
stomas is that, whenever possible, every effort
The postoperative care is similar to that after a should be made to institute or resume oral
gastrostomy. However, feeding should be feedings.
started at a much slower rate to reduce the risk
for ileus and diarrhea. Feedings should be
administered continuously by a pump. Follow- Cross-References
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Robertson FM, Crombleholme TM, Latchaw LA, Jacir j.jpedsurg.2015.06.010.
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https://doi.org/10.1097/MPG.0b013e31819a4e8c. 10.1055/s-2001-14268.
Tracheostomy in Infants
19
Martin Lacher, Jan-Hendrik Gosemann, and
Oliver J. Muensterer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Indications for Tracheostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Preoperative Work-up and Planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Position of Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Incision and Dissection to Expose the Trachea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
Opening the Trachea and Insertion of the Cannula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
Home Instruction and Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
During Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Immediate Post-Op . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Late Post-Op and Homecare . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
Special Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Ex Utero Intrapartum Therapy (EXIT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Emergency Needle Cricothyroidotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Decannulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Practical Steps of the Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Abstract
M. Lacher (*) · J.-H. Gosemann Tracheostomy is usually performed because of
Department of Pediatric Surgery, University of Leipzig, significant upper airway compromise and a
Leipzig, Germany
e-mail: Martin.Lacher@medizin.uni-leipzig.de; need for better tracheobronchial toilet, for pro-
Jan-Hendrik.Gosemann@medizin.uni-leipzig.de longed positive pressure, or for ventilatory
O. J. Muensterer support. The major indications include airway
Department of Pediatric Surgery, University Medicine obstruction, long-term respiratory support,
Mainz, Johannes Gutenberg University, Mainz, Germany and facilitation of secretion clearance.
e-mail: oliver.muensterer@unimedizin-mainz.de

https://doi.org/10.1007/978-3-662-43588-5_20
312 M. Lacher et al.
Tracheostomy is associated with a significant dioxide and sputum into the surrounding atmo-
impact on the psychosocial development of the sphere. The intention of a tracheostomy is to pro-
child. Therefore, any alternative treatment vide a child with a secure, functional access for
option prior to proceeding with tracheostomy gas exchange. It is usually performed because of
should be evaluated. In contrast to adults, tra- significant upper airway compromise and a need
cheostomy is carried out in an open fashion. for better tracheobronchial toilet, for prolonged
Percutaneous dilatational tracheostomy is not positive pressure, or for ventilatory support. A
as suitable for children because the airway is tracheostomy may be temporary or long term, in
small and often unstable. Complications dur- some cases life-long intervention.
ing the procedure include damage to surround- Technically speaking, the term tracheostomy
ing structures, hemorrhage, or pneumothorax/ refers to the surgical creation of a percutaneous
pneumomediastinum. The most common long- opening into the trachea, whereas the term tracheot-
term complications are partial obstruction of omy describes an incision of the trachea. However,
the cannula and accidental decannulation. many practitioners use these terms interchangeably.
Therefore, extensive education of the care- This chapter discusses the indications for and
givers along with preparation of a safe home technical considerations of tracheostomy in
environment is essential for a successful tran- children.
sition to home care. When the initial indication
for a tracheostomy no longer exists, the child
can be decannulated. This process includes Indications for Tracheostomy
confirmation of airway patency, weaning/cap-
ping, and closure of the tracheocutaneous fis- The three major indications for long-term trache-
tula. The latter usually happens spontaneously; ostomy in children are:
surgical closure is necessary in only <10% of
cases. If congenital high airway obstruction is – Airway obstruction
diagnosed prenatally, tracheostomy during ex • Congenital anomalies (e.g., subglottic ste-
utero intrapartum therapy (EXIT) is a special nosis, laryngeal web)
indication. Rarely, a pediatric surgeon may be • Trauma (e.g., birth trauma, child abuse,
required to emergently obtain an airway at the accidents)
bedside via incisional or needle cricothyr- • Tumors (e.g., hemangiomas, lymphatic
oidotomy in an infant who is too unstable for malformations, papillomatosis, cervical
transport to the operating room. Despite the teratoma)
morbidity of the procedure, tracheostomy • Functional obstruction (e.g., vocal cord
nowadays is a routine surgical procedure palsy)
which can be performed safely in experienced • Laryngomalacia/tracheomalacia
institutions. • External compression of the trachea
• Infectious or allergic processes leading to
Keywords swelling (e.g., epiglottitis, diphtheria)
Tracheostomy · Cricothyroidotomy · Ex utero – Long-term respiratory support
intrapartum therapy (EXIT) · Airway • Pulmonary pathology (e.g., bronchopul-
obstruction · Home care · Complications monary dysplasia)
• Hypoventilation syndromes (e.g., Ondine’s
curse, central hypoventilation)
Introduction – Facilitation of secretion clearance (pulmo-
nary toilet)
The trachea is a conduit between the upper airway • Neurologic injury or disease (e.g., cerebral
and the tracheobronchial tree, which delivers palsy, spinal muscular atrophy)
moist warm air to the lungs and expels carbon • Chronic aspiration
19 Tracheostomy in Infants 313
Over the recent years, the incidence of and the Tracheostomy following cardiac surgery, how-
indications for pediatric tracheostomy have ever, does not seem to be a risk factor for
changed. Several decades ago, tracheostomy mediastinitis by itself (Hoskote et al. 2005).
was performed primarily as a life-saving inter- Most of the children who are scheduled for tra-
vention to secure an airway in children with life- cheostomy already have an endotracheal tube in
threatening airway obstruction due to infectious place. For certain indications (e.g., immature
disorders (Aberdeen and Downes 1974). Since airway), the severity of laryngotracheomalacia
then, vaccination programs and anesthetic skills with dynamic airway collapse may be assessed
have dramatically reduced the number of emer- by direct laryngoscopy and/or bronchoscopy
gency tracheostomies performed for acute upper via facemask. It is important to note that direct
airway obstruction. Today, the indication for tra- laryngoscopy requires removal of the endotra-
cheostomy is generally ruled by the anticipation cheal tube, which should only be performed
of long-term (cardio-)respiratory compromise under controlled conditions and with the poten-
due to persistent ventilatory insufficiency, or by tial of surgical intervention if the airway is lost
the presence of a fixed obstruction of the upper during the maneuver.
airway that is unlikely to resolve in the near Pediatric tracheostomy is usually performed
future (Gallagher and Hartnick 2012). A recently electively with secure airways (e.g., for pro-
published study revealed that among ventilated longed intubation). Therefore, it is reasonable
children in Canada, the prevalence of tracheos- to check the hematocrit, platelet count, and
tomy was less than 1.5% (Principi et al. 2008). coagulation factors preoperatively so that ade-
Compared to the current practice in adults, tra- quate correction can be made. In case of an
cheostomy in children is generally less fre- emergency, the decision to perform an emer-
quently indicated, usually placed late in the gent tracheostomy is not affected by any lab
course of a chronic illness, and performed surgi- values.
cally rather than percutaneously (Wood et al. The selection of the appropriate tube type
2012). and size is one of the key elements of preoperative
planning and depends on the dimension of the
child’s airway and the clinical indication
Preoperative Work-up and Planning (McMurray and Holinger 1997). Most pediatric
tracheostomy tubes are cuffless; however, in large
The majority of children undergo the procedure as children and adolescents, cuffed tracheostomy
very young infants. Apart from its morbidity, tra- tubes are sometimes used either. Low-pressure
cheostomy is associated with a significant impact cuffs should be the preferred devices used in
on the psychosocial development of the child. children.
Therefore, any alternative treatment option A suitable tube should be small enough to
prior to proceeding with tracheostomy should be allow the child to phonate by being able to force
evaluated. air around the tube, yet big enough to prevent a
If the skin of the patient’s neck is infected by significant insufflation leak which may cause
bacteria or fungi, this should be treated before hypoventilation (Make et al. 1998; Sherman
any operation is performed unless emergency et al. 2000). However, if the tube is too large or
tracheostomy is indicated. Children who are a cuffed tracheostomy is overinflated for a pro-
planned to undergo congenital heart surgery, longed period of time, it may injure the tracheal
and in whom tracheostomy placement is antici- mucosa by chronic focal pressure, leading to vas-
pated in the future, may be best managed by cular compromise, ulceration, and, ultimately,
completing the cardiac surgery before tracheos- fibrous stenosis. The correct diameter can be
tomy is performed. Otherwise, the risk of car- estimated on the basis of the patient’s endotra-
diac infection may be increased as the sternal cheal tube size, which corresponds to its inner
incision is close to the tracheostomy site. diameter.
The length of the tracheostomy cannula is secure airway. Tracheostomies should be

another important variable, especially in neo- performed using the conventional dissection
nates and infants to allow adequate air entry, technique. In contrast to adults, percutaneous
easy suctioning, and clearance of secretions. If dilatational tracheostomy is not as suitable for
the tube is too short, it may lead to accidental children because the airway is small and often
decannulation or formation of a false tract. A unstable: The trachea is soft, compressible, and
tube that is too long may erode the carina or very mobile. Anatomic landmarks can be diffi-
ventilate a single main bronchus only, most cult to palpate, and a displaced tube may not be
likely the right. This may lead to left mainstem easily replaced.
bronchial occlusion and atelectasis. As selecting Although several techniques of performing a
the correct length is important, tracheostomy tracheostomy exist, they follow a basic guideline:
tubes are usually available in two lengths, short The trachea’s outer wall is exposed. An incision is
or long. made through two of the tracheal cartilaginous
The following pediatric tracheostomy tube rings and a tracheostomy tube inserted into the
sizes, determined on the basis of patient age and windpipe.
weight, were recommended by Wetmore (2003). Regardless of the surgical technique used, the
anesthetist should decrease the amount of inspired
• Premature neonates or babies who weigh less oxygen in the patient gas mix to the lowest frac-
than 1,000 g – 2.5 mm tion possible to prevent a surgical fire in the oper-
• Babies who weigh 1,000–2,500 g – 3 mm ating field (Smith and Roy 2011).
• Neonates aged 0–6 months – 3–3.5 mm
• Infants aged 6 months to 1 year – 3.5–4 mm
• Infants aged 1–2 years – 4–5 mm Position of Patient
For children older than 2 years, the following Once the patient is anesthetized, the infant is
formula for size estimation has been proposed by positioned supine, sufficiently toward the foot
the American Heart Association (2005): of the operating table so that the surgeon can
easily access the infant’s neck and the anesthetist
• Cuffed endotracheal tube ID (mm) = 3.5 can reach and manipulate the endotracheal tube
+(age/4) when necessary. A roll should be placed under the
• Uncuffed endotracheal tube ID (mm) = 4 shoulders to extend the neck (Fig. 1). The occiput
+(age/4) is stabilized by a head ring, and the table is tilted
into a minimal head-up position. After proper
As the child grows, a progressively larger tra- positioning, the entire neck from the lower lip to
cheostomy tube is required. Early signs of the below the nipples is prepped and draped. Care
need for a bigger tube are nocturnal dips in oxy- must be taken that the superior most surgical
gen saturation or low-pressure ventilator alarms. drape allows easy access to the patient by the
To prevent this, the tube size should be increased anesthetist. Any tape of the endotracheal tube
as a planned procedure at least every 2 years should be loosened beforehand so that the anes-
(Hofer et al. 2002). thetist can easily remove the tube at the appropri-
ate time. Care must be taken not to dislodge the
endotracheal tube prematurely.
Technique
The majorities of tracheostomies are elective Incision and Dissection to Expose

procedures and therefore conducted under gen- the Trachea
eral anesthesia. Most children will have already
been endotracheally intubated and may require Once prepped and draped, the surgeon should
more prolonged and/or more effective form of carefully palpate and mark the anatomic
Fig. 1 Position of an infant

for tracheostomy
placement. The shoulders
are elevated on a roll; the
head is hyperextended on
the neck and supported by a
doughnut-form support.
(De Gruyter Thoracic
Surgery in Children and
Adolescents, Walter De
Gruyter GmbH Berlin
Boston, 2016. Copyright
and all rights reserved)
Fig. 2 An adequate skin incision is made midway tracheostomy tube with a small gap. (De Gruyter Thoracic
between the cricoid and the suprasternal notch and deep- Surgery in Children and Adolescents, Walter De Gruyter
ened through fat and platysma, large enough to facilitate GmbH Berlin Boston, 2016. Copyright and all rights
easy exposure of the trachea and accommodate the reserved)
landmarks for the incision. These include the the endotracheal tube and allow safe dissection of
infant’s hyoid bone, thyroid notch, and cricoid the trachea. Alternatively, the incision may be
cartilage. The cricoid is often difficult to palpate, made in the lower neck crease, about the width
especially in neonates. It may be helpful to ask the of one finger above the jugular notch. However, it
anesthetist to jiggle the endotracheal tube from should not be too low to avoid dissecting in the
above to assist with the location of the trachea. mediastinum.
Once the landmarks are identified, an adequate Next, the anterior cervical fascia is opened
horizontal skin incision is made midway between vertically in the midline. The incision is then
the cricoid and the suprasternal notch and deep- deepened until the deep cervical fascia overlying
ened through fat and platysma (Fig. 2). The skin the sternohyoid and sternothyroid strap muscle is
incision should be large enough to accommodate encountered. Branches of the anterior jugular
Fig. 3 The precervical

fascia is opened, and the
strap muscles are divided
longitudinally. (De Gruyter
Thoracic Surgery in
Children and Adolescents,
Walter De Gruyter GmbH
Berlin Boston, 2016.
Copyright and all rights
reserved)
Fig. 4 Two retractors are

placed deep to the muscle
edges of the strap muscles
and gently retract laterally
to better expose the trachea
below (trachea visible in the
center of white circle). (De
Gruyter Thoracic Surgery in
reserved)
vein are cauterized and divided with the bipolar Opening the Trachea and Insertion
diathermy. Once the strap muscles are separated of the Cannula
by blunt dissection (Fig. 3), two retractors are
placed deep to the muscle edges and gently Before making the incision in the trachea, the
retract laterally to better expose the trachea correctly sized tracheostomy cannula should be
below (Fig. 4). opened and available on the operating table. Its
Rarely, the isthmus of the thyroid gland, which outer diameter is visually compared to the
has a variable size and relationship to the trachea, exposed trachea, and the appropriate size is
must be divided for proper tracheostomy position- reconfirmed.
ing. If this is necessary, the use of bipolar dia- To limit bleeding after accessing the lumen of the
thermy is sufficient in small children. In trachea, the delicate pre-tracheal fascia can be lightly
adolescents with a bulky isthmus, the division scored with electrocautery to coagulate any tiny
over suture ligations is preferable. vessels on the surface of the trachea in the midline.
Fig. 5 Traction sutures of

fine polypropylene are
placed around the third
tracheal ring to stabilize the
trachea before incision
(arrows). (De Gruyter
Thoracic Surgery in
reserved)
Fig. 6 The trachea is opened through a midline vertical deformity and reabsorption of cartilage. (De Gruyter Tho-
incision across two to three tracheal rings (dotted line). The racic Surgery in Children and Adolescents, Walter De
incision must be long enough to avoid excess tube pressure Gruyter GmbH Berlin Boston, 2016. Copyright and all
against the cartilages. A tight tube can result in pressure rights reserved)
Before opening the trachea, two polypropylene prevent blood or secretions interfere with the sur-
stay sutures are placed on either side of the tra- geon’s view or enter the trachea. Using a
chea, each one incorporating one or two tracheal No. 11 scalpel blade, a vertical incision is made
rings (Fig. 5). During the operation, these sutures in the trachea through the third, fourth, and fifth
help to distract the tracheal incision for ease of tracheal rings along the score mark (Fig. 6) pre-
placement of the tracheostomy cannula and also serving the first tracheal ring. In neonates and
secure the airway in case of bleeding, dislodge- infants, where distances are small, it is preferable
ment, or loss of retraction. to leave the second ring intact as well.
The anesthetist prepares the endotracheal tube The surgeon asks the anesthetist to withdraw
for removal. Suction should be available to the endotracheal tube gently to clear the
Fig. 7 Tube insertion into the trachea is accomplished by safer than using the tube obturator, the short tip of which
having the anesthetist pull back the endotracheal tube to sometimes slips out of the stoma and allows the tracheos-
the cephalad margin of the new stoma, inserting a tracheal tomy tube to pass anterior to the trachea and into the
suction catheter downward into the trachea through the mediastinum through a false tract. (De Gruyter Thoracic
newly established opening, and then advancing the trache- Surgery in Children and Adolescents, Walter De Gruyter
ostomy tube over the catheter into the trachea caudally GmbH Berlin Boston, 2016. Copyright and all rights
(direction of the black interrupted arrow). This method is reserved)
tracheotomy incision. A tracheostomy cannula, While the assistant holds the tracheostomy
which should be lubricated with a water-soluble tube in place, the skin edges may be secured
surgical lubricant, is then inserted into the tracheal with sutures on each side of the tube (Fig. 8).
opening perpendicularly to the tracheostomy and Special care has to be taken to leave a gap of the
subsequently directed and rotated caudally toward skin around the tube to avoid postoperative surgi-
the carina. A sterile anesthetic connector is fitted cal emphysema by allowing air to escape. Finally,
to the adapter and its end passed out of the surgical the lateral wings of the cannula body need to be
field to the anesthetist (Fig. 7). secured to the patient. The roll underneath the
Once that is achieved, the anesthetist should patients’ shoulders is then removed and an umbil-
administer several deep breaths to the patient to ical or hook-and-loop tape placed around the
prove that the infant can be ventilated adequately neck. This tape is passed through the holes in the
through the new airway, indicating that the can- end of the wings and then tied tightly with the
nula is in proper place. Equal chest rise should be neck in flexed position, which may prevent tube
observed during this maneuver. In case of unilat- dislodgement.
eral right-sided chest rise, the tracheostomy tube The two polypropylene stay sutures that were
may be too long and should be exchanged for a placed in the anterior tracheal wall are now tied at
shorter one. their ends, left 6–8 cm in length, and taped
Particularly in neonates, even a cannula of the securely to the anterior chest wall. In this location,
correct diameter may ultimately be too long with they can be easily found and pulled apart to iden-
its tip resting on the carina. In such cases, several tify the tracheal incision if needed in an emer-
pieces of gauze may be used to bolster the gap gency to reinsertion of the cannula (Fig. 9).
between the skin level and the tracheostomy col- All infants with a fresh tracheostomy should be
lar, thus pulling the tip of the cannula away from transferred to the intensive care unit (ICU) for
the carina. close observation.
Fig. 8 The wings of the tracheostomy tube are bilaterally cannula change. (De Gruyter Thoracic Surgery in Children
sutured to the lateral cervical skin to prevent acute dis- and Adolescents, Walter De Gruyter GmbH Berlin Boston,
lodgement of the fresh tracheostomy using 2–0 silk sutures 2016. Copyright and all rights reserved)
(circle). These sutures will be cut at the time of the first
Fig. 9 The two polypropylene stay sutures that were found and pulled apart to identify the tracheal incision in
placed laterally at the site of tracheotomy are tied in loose case they are needed in an emergency reinsertion of the
loops and taped securely to the anterior chest wall (white cannula. (De Gruyter Thoracic Surgery in Children and
arrows). The sutures are left in place until the first trache- Adolescents, Walter De Gruyter GmbH Berlin Boston,
ostomy change as a precaution against accidental postop- 2016. Copyright and all rights reserved)
erative decannulation. In this location, they can be easily
Early Postoperative Care the utility of routine postoperative chest radiogra-

Most surgeons order a chest X-ray in the recovery phy in pediatric tracheostomy has recently been
room or ICU to verify that the tip of the cannula is questioned. Some authors suggest to reserve a
sufficiently clear of the carina (Fig. 10). However, postoperative chest radiography for cases with
Fig. 10 A postoperative plain chest radiograph is ordered way between the insertion site and the carina (white
either on the operating table or in the recovery room to arrow). (De Gruyter Thoracic Surgery in Children and
verify good placement of the tracheostomy. Ideally, the tip Adolescents, Walter De Gruyter GmbH Berlin Boston,
of the cannula should be located in the mid-trachea, half 2016. Copyright and all rights reserved)
suspicion of a complication on the basis of replaced with ease, it is safe to remove the
intraoperative findings or clinical parameters sutures at the edges of tracheal incision.
(Genther and Thorne 2010).
A spare tracheostomy cannula of the same
model and size as the one placed primarily in the Home Instruction and Care
patient must be available at the bedside at all
times. The tracheostomy tube should be kept Extensive education of the parents or caregivers
clear of secretions by frequent intermittent along with preparation of a safe home environ-
suctioning, particularly in the immediate postop- ment is essential for a smooth and successful
erative period. Moreover, adequate humidifica- transition to home care. Prior to the child’s dis-
tion of the inspired gas should be provided. charge, all caregivers must undergo a structured
During the first postoperative week, the site and detailed training program to become compe-
of the tracheostomy has to be cleaned at least tent in long-term tracheostomy management. This
once a day. The fresh cannula should be left in training includes the acquisition of skills in tube
place for at least 10 days. Thereafter, with appro- exchange, suctioning, cleaning, dressing, fixation,
priate tract formation, the tracheostomy tube can as well as humidification of inspired air and appli-
be changed safely for the first time. The sutures cation of medications. Parents and all caregivers
to the edges of the tracheal incision should be have to become familiar with equipment for con-
left in place until the first tracheostomy change. tinuous or intermittent positive pressure ventila-
All tracheostomy exchanges are an opportunity tion as well as using a bag valve mask device for
to instruct the parents or caregivers on the pro- manual ventilation in conjunction with
cedure. Ideally, the parents will be able to suctioning. Last but not least, the family or care-
change the tracheostomy with confidence and takers must be instructed and certified in emer-
competence at the time of discharge. Once it is gency management and cardiopulmonary
evident that the tracheostomy tube can be resuscitation (Sherman et al. 2000).They must
know how to troubleshoot the entire system in Hemorrhage may occur at the time of surgery
case of problems, including the technical devices and is generally controlled easily with electrocau-
and the cannula attachments (Joseph 2011; tery or vessel ligation. Rarely, especially in neo-
Oberwaldner and Eber 2006). nates, the thyroid gland is located near the incision
The first cannula change should be performed site on the anterior trachea and is inadvertently
on the surgical ward and the opportunity should divided or lacerated. In such cases, bleeding can
be used to further instruct and reassure the par- usually be controlled with sutures or
ents. Until the family becomes familiar and com- electrocautery.
fortable with the management of the cannula and Under rare circumstances, a false passage may
new devices, home nursing visits should be be created during the introduction of the tube, and
arranged. The presence of a nurse at home is subsequent positive pressure ventilation will
absolutely mandatory for the first scheduled tra- result in a pneumothorax or pneumome-
cheostomy change outside of the hospital after diastinum (Genther and Thorne 2010; Donnelly
discharge. et al. 1996).
Immediate Post-Op
Complications
1. Surgical emphysema
Different series have reported complication rates 2. Bleeding if case of innominate or inferior thy-
ranging from 30% to 86% (Carr et al. 2001; Rocha roid artery laceration
et al. 2000; Donnelly et al. 1996). The incidence 3. Obstruction (e.g., clot, mucus)
of complications is related to the initial indication 4. Dislodgment
for the tracheostomy (Halfpenny and McGurk
2000). Moreover, higher complication rates Surgical Emphysema
occur in preterm infants and are associated with Among the most prominent early complications
gestational age, low birth weight, and medical are air-tracking issues, such as pneumothorax,
condition of the child. pneumomediastinum, and subcutaneous emphy-
sema. However, in a recent study on 421 pediatric
tracheostomies, these complications occurred in
During Procedure only 0.7% of all cases (Genther and Thorne 2010).
In this series no significant relationships were
1. Damage to surrounding structures, e.g., esoph- found between the incidence of air-tracking com-
agus, recurrent laryngeal nerve, plication and surgical specialty, patient age, or
brachiocephalic vein circumstances of the procedure (elective, urgent/
2. Hemorrhage emergent) (Genther and Thorne 2010).
3. Pneumothorax/pneumomediastinum
Bleeding
Accidental injuries to the surrounding struc- Compared to intraoperative bleeding, late hemor-
tures should be rare if the surgeon is familiar with rhage is often more problematic and can be more
the anatomy of the infant’s neck. Correspond- serious. The first step of management is to assess
ingly, damage to the vagus nerves, the recurrent whether the hemorrhage is coming from the tra-
laryngeal nerves, the esophagus, or cheal lumen or from the lateral tissues at the site of
brachiocephalic vessels has not been described the incision. This is accomplished by suctioning
in recent pediatric series (Carr et al. 2001; Rocha the cannula and inspecting the wound carefully. If
et al. 2000; Donnelly et al. 1996). the source of bleeding is a small skin vessel, it
usually can be controlled with simple suture liga- Late Post-Op and Homecare
tion or sometimes even with infiltration of 1%
lidocaine containing 1:100,000 epinephrine. 1. Obstruction and dislodgment of tube
A rare type of hemorrhage during the early 2. Granulation tissue
postoperative course is profuse bleeding from 3. Infection/wound breakdown
one of the great vessels, such as the innominate 4. Erosion of the tracheostomy tube
vein or artery. This can occur from erosion of the 5. Fibrosis, scarring, stenosis of the trachea
vessels when a deep and tight-fitting tracheos-
tomy tube compresses the vessels against the The most common complications of home care
manubrium or clavicle. After surgical tracheos- include partial obstruction of the cannula and
tomy, the frequency of this severe complication accidental decannulation. Therefore, the impor-
is reported to be 0.1–1% with a peak incidence at tance of proper education and training of parents
7–14 days post procedure. It is usually fatal unless and caretakers in tracheostomy management, partic-
immediate treatment is instituted (Schaefer and ularly in suctioning, cleaning, and changing the
Irwin 1995; Allan and Wright 2003). cannula, cannot be emphasized enough (Messineo
et al. 1995; Caussade et al. 2000; Reiter et al. 2011).
Obstruction, for Example, Clot and Mucus In the long term, persistent granulation tissue
The cannula can be blocked by mucus, blood may develop at the tracheostomy site as a result of
clots, or pressure of the airway walls. Blockage chronic irritation of the tip of the tracheostomy
can be prevented by frequent suctioning, air tube against the tracheal wall or from the repeated
humidification, and selecting an appropriately suctioning of the trachea. The incidence is
sized tracheostomy tube. reported around 10%. Granulation tissue can be
exophytic at the level of the skin, or intraluminal.
Dislodgement Exophytic granulation tissue at the skin should be
At all times, and especially in the immediate post- cauterized with silver nitrate. This can be initiated
operative period, the cannula can become during outpatient visits and carried out by the
dislodged. As described earlier, there are different caretakers every month if needed. In case of gran-
techniques for securing the cannula in place in ulation tissue located within the trachea at the
order to avoid this complication. Even so, despite stoma site, it can be left alone in most of the
all best efforts, the neck tie may pull loose, and cases until decannulation. In contrast, the forma-
sutures may tear, allowing the cannula to dis- tion of granulation tissue at the tip of the cannula
lodge. If dislodgement occurs, it must be noticed can create a “ball-valve” effect with air trapping
immediately. Therefore, it is recommended to leading to obstructive symptoms or bleeding. This
transfer all infants to the intensive care unit after can be confirmed by introducing a flexible bron-
the procedure for close observation. Replacing the choscope through the cannula to visualize the
cannula in this situation should be performed by tracheal lumen beyond the tip of the tube. Many
someone familiar with cannula insertion. Ideally, authors suggest to remove intraluminal granula-
a surgeon is available to replace the cannula and tion tissue with laser treatments, which are applied
resecure the device. As explained earlier in the via flexible fiber (Epstein 2005).
chapter, the stay sutures on either side of the Infection is an unusual complication and should
trachea should be taped to facilitate access and be treated with the appropriate antimicrobials
retraction in order to expose the tracheal lumen. according to culture results. A superficial wound
Usually it is not necessary to use instruments to dehiscence is usually treated conservatively.
insert the cannula. However, if no proper expo- The presence of a tracheostomy increases mor-
sure can be achieved, two small right-angled tality as well as morbidity. In a retrospective obser-
retractors are sufficient to complete the job. vational cohort analysis of 228 children enrolled in
a university-affiliated home mechanical ventilation (Moldenhauer 2013). Outcomes for fetuses with
program, Edwards et al. reported that those lesions have dramatically improved due to
tracheostomy-related deaths were responsible for the introduction and the advancement of this tech-
19% of all deaths in this patient population. Com- nique (Dighe et al. 2011). Using EXIT it is possi-
plications included obstruction of the tube, bleed- ble to secure the fetal airway and even safely
ing from tracheal granulomas, and misplacement of perform surgery on the fetus while uteroplacental
the tracheostomy tube into a false track (Edwards blood flow is preserved (Moldenhauer 2013).
et al. 2010). However, other studies report on death In most centers, EXIT is not a routinely
rates directly attributable to tracheostomy compli- performed surgical procedure. An experienced
cations of only 0.7% (Carr et al. 2001). Downes interdisciplinary team (anesthesiology, gyne-
and Pilmer compared the incidence of life- cology, neonatology, and pediatric surgery);
threatening tracheostomy-related accidents in chil- extensive, meticulous planning; and close
dren during home ventilation to those cared for in intraoperative monitoring (fetal pulse oximetry,
the hospital in the early 1980s (Downes and Pilmer echocardiography, i.v. access) are required
1993). In this study, the frequency was found to be (Moldenhauer 2013).
eight times greater among those cared for at home Tracheostomy during EXIT to airway is
(2.3/10,000 patient days) versus the pediatric ICU frequently needed when conventional trans-
(0.3/10,000 patient days). pharyngeal endotracheal intubation failed,
especially in patients with fetal neck masses
or other causes of fetal airway obstruction
Special Considerations such as tracheal atresia or other congenital
high airway obstruction (Dighe et al. 2011).
Ex Utero Intrapartum Therapy (EXIT) In particular, prenatal diagnosis of an under-
developed chin, micrognathia, and possibly
When congenital high airway obstruction is polyhydramnios as present in patients with
diagnosed prenatally, management may include Pierre Robin sequence (triad of micrognathia,
tracheostomy during ex utero intrapartum ther- glossoptosis, and U-shaped palatal cleft)
apy (EXIT). In such cases, the baby is delivered (Robin 1994) should be a red flag for the
via controlled C-section with the placental circu- team that is preparing an EXIT procedure and,
lation and the umbilical cord intact while an possibly, tracheostomy (Figs. 11 and 12). The
airway is secured. If this cannot be achieved tracheostomy itself is performed in the previously
by transpharyngeal endotracheal intubation, tra- described technique.
cheostomy must be considered as a life-saving
procedure.
EXIT procedures have been initially described Emergency Needle Cricothyroidotomy
as an approach to secure the newborn’s airway
after prenatal tracheal occlusion for treatment of Rarely, a pediatric surgeon may be required to
lung hypoplasia in the setting of congenital dia- emergently obtain an airway in an infant who is
phragmatic hernia (Mychaliska et al. 1997). too unstable for transport to the operating room
Within the last two decades, the indications for and in whom the airway is acutely compromised
an EXIT procedure have been expanded to secure in a way that precludes securing it noninva-
the fetal airway before complete delivery sively. In this situation, a bedside needle
whenever severe compromise of the neonatal cricothyroidotomy may at least temporarily
airway is anticipated (e.g., extrinsic or intrinsic allow for adequate gas exchange until a more
obstructive malformations of the lung, large definitive airway can be obtained (Mace and
neck masses, and intrathoracic lesions) Khan 2008).
Needle cricothyroidotomy is technically easier

and quicker to perform on children than surgical,
incisional cricothyroidotomy. It is indicated as a
life-saving rescue procedure when an airway can-
not be obtained and maintained by conventional
means (bag mask, endotracheal intubation, laryn-
geal mask, etc.).
The equipment required includes a 16 or 18 g
intravenous over-the-needle catheter, a 5 ml
syringe, the adapter hub of a 3.0 mm endotracheal
tube, an oxygen tube that can connect the source
(wall outlet or oxygen tank), and a bag-valve
device that will be attached to a standard
endotracheal tube.
Fig. 11 Prenatal ultrasound of a fetus, gestational age 30 The patient is positioned supine on a shoulder
+5 weeks, with micrognathia (Photo: courtesy of
Hasbargen U, MD, PhD. Department of Gynecology and roll and the neck is extended. Sedation or local
Obstetrics, Ludwig-Maximilians-University, Munich, Ger- anesthesia is given as indicated. The anterior
many). (De Gruyter Thoracic Surgery in Children and neck is prepped and draped in a sterile fashion.
Adolescents, Walter De Gruyter GmbH Berlin Boston, Right-hand dominant surgeons should stand on
2016. Copyright and all rights reserved)
the patient’s left. In this case, the left hand pal-
pates the cricothyroid membrane with the index
fingertip and stabilizes the trachea in the midline
between the thumb and middle finger. The dom-
inant right hand is used to insert the over-the-
needle catheter with a connected 5 ml syringe
through the cricothyroid membrane percutane-
ously and advance it in a 45 angle inferiorly.
The plunger of the syringe is slightly withdrawn
to create a vacuum while the catheter needle is
advanced. Once the needle enters the trachea, the
practitioner will notice air entry into the syringe
(filling the syringe with a few ml of saline before
the maneuver can help by demonstrating bubbles
upon entry). Once intratracheal position is veri-
fied, the catheter is advanced over the needle into
the trachea, and the needle is withdrawn. The
catheter is hubbed down to the skin, correct
placement is confirmed by again aspirating air
through the catheter, and it is secured in place
using tape.
Subsequently, the 3.0 mm endotracheal tube
Fig. 12 Intraoperative impression of a tracheotomy pro-
cedure during EXIT. The fetus remains partly in utero and adapter hub is connected to the intravenous
connected to the uteroplacental blood flow until the airway catheter (this particular size hub will fit into the
is secure (Photo: courtesy of Hasbargen U, MD, PhD. luer-lock connector of the catheter). The oxygen
Department of Gynecology and Obstetrics, Ludwig-
tubing is connected via a bag-valve device (Yealy
Maximilians-University, Munich, Germany). (De Gruyter
Thoracic Surgery in Children and Adolescents, Walter De et al. 1991). A continuous flow of 8–15 l/min
Gruyter GmbH Berlin Boston, 2016. Copyright and all of 100% oxygen is titrated to achieve adequate
rights reserved) oxygenation without pulmonary overdistension.
In principle, the needle cricothyroidotomy pro- Practical Steps of the Procedure

vides influx of oxygen into the lungs, while efflux
relies on passive flow through the patient’s There is no single best way of tracheal
incompletely obstructed natural airways. If the decannulation. In each child, the approach should
patient’s chest becomes hyperinflated, the inflow be tailored to the individual’s condition (Gray et al.
should be cycled to allow at least partial expira- 1998).
tion through the catheter. Alternatively, a jet ven- Based on practice rather than evidence, the
tilator may be connected for jet ventilation if process of decannulation consists of the following
personnel with appropriate experience are avail- four steps:
able. Complications of needle cricothyroidotomy
include bleeding, infection, aspiration, mechan- 1. Confirmation of airway patency
ical obstruction of the catheter, barotrauma 2. Weaning and capping
including pneumothorax, and damage to the sur- 3. Removal of tracheostomy tube
rounding structures. 4. Closure of the tracheocutaneous fistula (spon-
taneous or surgically)
Decannulation Weaning
There are various ways for this process. The
When the initial indication for a tracheostomy most common one includes the usage of a
no longer exists, decannulation should be consid- Passy-Muir speaking valve (PMV). The PMV
ered. Although this procedure is usually antici- requires the child to exhale through the nose/
pated well in advance, certain criteria have to be mouth while still allowing inhalation via the
met prior to removal of the tracheostomy tube: tracheostomy tube. By doing this, the child
breathes only partially through the tracheostomy
1. The original upper-airway obstruction is which helps the treating surgeon/pulmonologist
resolved. to determine whether the patient is ready to be
2. Airway secretions are controlled. decannulated. Another technique of weaning
3. Mechanical ventilation is no longer needed. from a tracheostomy tube is downsizing, which
means that the current tracheostomy tube size is
The timing for decannulation depends exchanged to a smaller size. Consequently, the
mostly on the indication for the tracheostomy resistance to breathe through your tracheostomy
in the first place. Children with subglottic ste- is increasing, usually requiring more respiration
nosis may have their tube removed at the time activity through the nose and mouth. Both tech-
of their laryngoplasty, which may be any time niques may be conducted in combination during
between 4 and 6 months and 2 years postoper- the weaning process.
atively, sometimes even later. If the reason for
tracheostomy was severe tracheomalacia, it Capping
would be unusual to attempt decannulation Capping is another important step in the
within the first year of age. Instead, the infant decannulation process. A “cap” is placed over the
should undergo repetitive bronchoscopic exam- external tracheostomy tube opening and closes off
ination to assess whether malacia is still present airflow via the tube, therefore allowing respiration
and free of any potential obstructing lesions exclusively through the natural upper airway. Dur-
such as granulation tissue. For this purpose, ing the first time the cap is trialed, the surgeon is
the patient should not be paralyzed and the present to closely assess the child’s tolerance to
anesthesia should be light. breathing through the nose and mouth. After this
At some point the airway will be mature initial capping, trials may be started using a partic-
enough and the airway remains patent, so ular schedule (e.g., to use when awake) or fulltime
decannulation can be attempted. for a period of a few to several days.
If there are any signs of respiratory distress or if Cross-References

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Moreover, the child’s tracheostomy tube should ▶ Congenital Airway Malformations
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signs of airway distress may be too subtle to be ▶ Macroglossia
recognized by family or home care nurses. An ▶ Pediatric Airway Assessment
overnight capping trial should only be conducted ▶ Stridor in the Newborn
in an ICU setting.
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Pediatric Airway Assessment
20
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
Assessment of the Pediatric Airway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Radiology Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
Rigid Microlaryngoscopy Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 333
Differential Diagnosis of Pediatric Stridor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Abstract Keywords
The airway is a complex structure which Stridor · Larynx · Laryngomalacia · Subglottic
extends from the external nares to the junction stenosis · Microlaryngoscopy · Bronchoscopy
of the larynx with the trachea. The infant lar-
ynx is structurally very different to the adult
larynx, especially in infancy, and becomes less Introduction
so as the child grows. The signs and symptoms
of a child with respiratory distress depend on The airway is a complex structure which extends
the location and severity of the obstruction. It is from the external nares to the junction of the
therefore essential to assess and localize the larynx with the trachea. It includes the nose, the
site and cause of the obstruction. paranasal sinuses, the pharynx, the larynx, and the
trachea. The function of the airway includes olfac-
tion, phonation, swallow, humidification, and
conditioning of inspired air. The infant larynx is
E. Phelan (*) · J. Russell
Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland structurally very different to the adult larynx,
e-mail: eimearphelan@hotmail.com;
jdrussell.russell@gmail.com

https://doi.org/10.1007/978-3-662-43588-5_21
330 E. Phelan and J. Russell
especially in infancy, and becomes less so as the dimensions of the nasal cavity have also been
child grows (Wheeler et al. 2007, 2009). described (Zielnik-Jurkiewicz 2006). During the
first 2–5 months of life, the infant’s tongue
touches all borders of the oral cavity. This makes
Anatomy the infant a preferential nasal breather. In children,
the smaller nasal apertures can become obstructed
The nose is composed of the external nose and the by secretions and edema and may increase the
nasal cavity. The nasal cavity is divided by the work of breathing (Dickison 1987).
nasal septum into two compartments that opens The paranasal sinuses are outpouchings from
externally via the nares and into the nasopharynx the lateral wall of the nasal cavity into which they
posteriorly via the choanae. During development, drain and include the ethmoidal, maxillary, fron-
the nasal cavities extend under the influence of the tal, and sphenoid sinuses. The ethmoid and max-
posteriorly directed fusion of the palatal pro- illary sinuses are present at birth. The frontal
cesses. These changes cause the membrane that sinuses develop later usually 5–6 years of age.
separates the palatal processes from the oral cavity The sphenoid sinuses develop much later and
to become progressively thinner and eventually usually present in adolescence.
rupture to form the choanae (Holzman 1998) – The pharynx forms the common upper path-
failure of this membrane to rupture results in way of the aerodigestive tract. It is in free com-
choanal atresia (Fig. 1). In a child, the nose is munication with the nasal cavity, the mouth, and
soft and distensible, with relatively more mucosa the larynx, forming the nasopharynx, oropharynx,
and lymphoid tissue than in the adult (Dickison and laryngopharynx.
1987). The side of each nasal cavity has a roof, a The larynx is situated between the pharynx and
floor, a medial wall, and a lateral wall. The medial trachea, extending from the base of the tongue to
wall is the nasal septum, and the lateral wall has a the cricoid cartilage. It is located high in the neck
bony framework which includes three fingerlike which brings the tip of the epiglottis behind the
structures called turbinates of which there are soft palate. It is the organ of phonation and pro-
three (superior, middle, inferior) covered with tects the lower airways during swallowing and
mucosa. The major nasal air passage lies beneath coughing. The primitive glottis is formed at
the inferior turbinate. Racial differences in the 10 weeks of gestation when the true vocal cords
split – failure of this process results in a congenital
laryngeal web, or in some cases, congenital atresia
of the larynx. Incomplete division of the embry-
onic foregut into the anteriorly positioned trachea
and the posteriorly positioned esophagus results
in tracheoesophageal fistula (Holzman 1998).
The cricoid cartilage lies inferior to the thyroid
cartilage and is the only complete cartilage ring in
the respiratory system. This area is known as the
subglottis and has a diameter of 5–7 mm which is
the smallest part of the larynx. A subglottic diam-
eter of 4 mm or less indicates the presence of
subglottic stenosis (Henick and Holinger 1997)
(Fig. 2). The subglottis is surrounded by loose
connective tissue in which significant edema
may occur due to inflammation or trauma. A
narrowing by 1 mm will result in a decrease in
Fig. 1 Image of posterior choanae demonstrating bilateral cross-sectional area by 75% and, according to
choanal atresia Poiseuille’s law, a 16-fold increase of airway
20 Pediatric Airway Assessment 331
Table 2 Defined
Inspiratory stridor
High-pitched sound. Obstruction at level or above vocal
cords (supraglottis, pharynx)
Expiratory stridor
Prolonged sonorous sound – often confused with
wheeze. Obstruction distal to tracheobronchial tree
(intrathoracic) usually
Biphasic stridor
Inspiratory and expiratory sound-obstruction localized to
subglottic area usually
which enhances speech production. However,

descent of the larynx creates a common passage-
way for both food, foreign bodies, etc. to enter the
airway.
Fig. 2 Image of subglottis demonstrating subglottic
stenosis
Assessment of the Pediatric Airway
Table 1 Pediatric airway anatomical differences com- History – initially a clinical history should be
pared to the adult airway
obtained and should begin with enquiry of any
Size – infant larynx 1/3 of an adult larynx known medical conditions especially any genetic
Vocal process – makes up 50% of glottis compared to
or cardiac issues, birth history (preterm, special
25% in an adult
Smaller subglottis – narrowest segment in the pediatric
care baby unit at birth, previous intubation/venti-
airway. The glottis is the narrowest part of airway in the lation), any history of previous airway injuries or
adult airway surgery. Details should be asked regarding
Tissue consistency – more soft and pliable any problems during previous general anesthesia.
Larynx – located higher in neck, cricoid at level of C4 Specific questions should be asked regarding
(C7 in adult). Epiglottis behind the soft palate and more noisy breathing, apneic or cyanotic episodes,
horizontally placed
cough, recurrent lower respiratory infections,
hoarseness/abnormal cry, or feeding issues such
resistance. In contrast, an adult larynx dimensions as choking, coughing episodes, and fatigue during
is larger, and 1 mm of edema would result in feeding with failure to thrive.
minimal narrowing. The trachea is 4 cm in length The signs and symptoms of a child with respi-
and has a diameter of 3.6 mm. ratory distress depends on the location and sever-
The epiglottis is a leaf-shaped structure ity of the obstruction. It is therefore essential to
attached to the posterior border of the thyroid assess and localize the site and cause of the
cartilage by the thyroepiglottic ligament. The epi- obstruction. Airway obstruction at the level of
glottis in the infant is narrower, softer, and more the nasopharynx or oropharynx produces stertor
horizontally positioned than in the adult (Table 1). (inspiratory low-pitched sound) or snoring.
The pediatric airway is highly compliant, and Supraglottic and glottic obstructions tend to
the cartilaginous support is less developed than in produce inspiratory stridor (stridor is an audible
the adult airway. This leads to increased suscepti- high-pitched noise produced by turbulent air flow
bility to dynamic airway collapse in the presence through a partially obstructed airway – it can be
of airway obstruction (Wheeler et al. 2007). As a inspiratory, expiratory, or biphasic, Tables 2 and
child grows, the larynx descends, separating it 3) caused by collapse of these structures with
from the pharynx – this enlarges the pharynx negative inspiratory pressure. Since the
Table 3 Differential diagnosis for stridor

Laryngomalacia (inspiratory stridor)
Vocal cord palsy (inspiratory in unilateral, biphasic in
bilateral)
Subglottic stenosis (biphasic stridor)
Vascular compression of trachea (expiratory stridor)
Table 4 Reasons for increased risk of airway compromise

in the child
Minimal swelling – results in significant airway
narrowing
Greater chest compliance – results in easier collapse
Easily fatigable respiratory muscles – less able to
Fig. 3 Image of normal larynx
compensate for any respiratory stress
Lower functional reserve volume – quicker oxygen
desaturations
tonsils. The neck should be palpated and assessed
for any abnormal neck masses.
extrathoracic large airways are smallest in diame- Flexible nasal endoscopy – endoscopy of the
ter during inspiration, stridor is usually inspiratory pediatric airway involves the use of a fiber optic
and becomes biphasic in case of critical endoscope. Flexible per nasal/per oral laryngoscopy
narrowing. Intrathoracic airway lesions cause is possible even in neonates, using a small-caliber
expiratory stridor (diameter smallest during expi- fibroscope (2.2 mm) with or without a recording
ration). Stridor caused by fixed subglottic laryn- attachment. It is usually performed without local
geal and cervical tracheal lesions is usually anesthetic with parents’ consent in the outpatient
biphasic. department. This generally gives an excellent view
of the posterior choana, pharynx, supraglottis, and
larynx (Fig. 3). It may also give an adequate view of
Examination the subglottis (Hawkins and Clark 1987; Berkowitz
1998). It is possible to achieve a dynamic view of
The child’s facial expression or the presence of the larynx which allows the pediatric otolaryngolo-
nasal flaring or tracheal tug may suggest respira- gist to assess for laryngomalacia or vocal cord palsy.
tory distress (Table 4). Mouth-breathing or In addition, during the procedure, the pediatric oto-
drooling often occur in the presence of enlarged laryngologist will be able to assess for stridor or a
tonsils or adenoids. There may be signs of previ- weak cry. If an inadequate view is obtained or the
ous trauma or surgery to the head and neck. It also diagnosis is inconclusive, a microlaryngoscopy
important to identify any head and neck heman- bronchoscopy (MLB) examination under general
gioma especially if in the beard distribution as anesthetic is required. MLB is the gold standard
these can be associated with subglottic hemangi- for assessing the pediatric airway. Wilson et al.
oma. Evidence of neuromuscular disease, congen- conclude that the technique is safe and straightfor-
ital abnormalities, or dysmorphic features should ward and allows a diagnosis to be achieved in a
be noted, together with anatomical variants of significant number of cases. They recommend it as
normal including mandibular hypoplasia, small a first-line investigation, reserving MLB for the
mouth, or limited mouth opening. During the group of patients in whom a diagnosis cannot be
examination, it is important to assess if there is made in the outpatient clinic (Moumoulidis et al.
any audible stertor, stridor, abnormal cry, or 2005). Wilson et al. in their study of 66 neonatal
cough. The patency of the nasal apertures should patients demonstrated that a diagnosis could be
be assessed; the tongue, teeth, pharynx, and palate made in approximately 89% with simple stridor
should be inspected if possible to assess for using flexible endoscopy. They recommended that
macroglossia, abnormal palate, or enlarged an MLB be performed only:
1. If the larynx cannot be visualized by flexible foreign bodies or possibility identify areas of air-
laryngoscopy way stenosis (Silva et al. 1998; Strife 1988; John
2. If a child had a clinical history suspicious for a and Swischuk 1992).
subglottic or tracheal pathology Computed tomography/magnetic resonance
3. If the child has significant respiratory distress angiogram can be particularly useful in a child
4. If the child is failing to thrive (Moumoulidis et with airway symptoms where external airway com-
al. 2005). pression, i.e., congenital cardiac (left atrial enlarge-
ment), aortic arch anomalies (vascular ring), or
Olney et al. suggested a direct laryngoscopy tracheobronchial abnormalities (tracheal stenosis,
and bronchoscopy be performed in the following complete tracheal rings) are suspected. Usually
cases (Olney et al. 1999): these investigations are performed following an
MLB which would have demonstrated tracheal/
1. Infants with laryngomalacia and severe respi- bronchi external compression or significant pulsa-
ratory distress, failure to thrive, apneas, or tion. However, a high index of suspicion of
recurrent pneumonia mechanical airway compression should be
2. Infants with symptoms that do not match the maintained in children with recurrent respiratory
degree of laryngomalacia noted by flexible difficulties, stridor, wheezing, dysphagia, or apnea
nasopharyngoscopy unexplained by other causes (Kussman et al. 2004;
3. Infants with synchronous lesions of the larynx Phelan et al. 2011; Boiselle and Ernst 2002).
4. Infants who are likely to require Contrast swallow – traditionally a contrast
aryepiglottoplasty swallow has been used in the investigation of
pediatric stridor with the aim of identifying
Bluestone et al. demonstrated that 17.5% of pathology such as vascular rings and confirming
infants who underwent diagnostic laryngoscopy the presence of gastroesophageal reflux. How-
and bronchoscopy for airway obstruction had two ever, a recent study would suggest that this should
or more synchronous airway lesions detected. be considered as a potential diagnostic investiga-
Thus, laryngoscopy alone, without further tion after an MLB has been performed. In general,
workup of the entire respiratory tract, may fail to the results of a contrast swallow did not change
detect concurrent disorders in infants with airway management nor was it particularly helpful in
obstruction (Gonzalez et al. 1987). However, a making a diagnosis of the cause of stridor
more recent study has shown this rate to be (Kulendra et al. 2013).
lower especially in children with laryngomalacia,
and where they were present, they were not clin-
ically significant (Yeun et al. 2006). It should be Rigid Microlaryngoscopy
highlighted that an MLB should only be carried Bronchoscopy
out in a tertiary pediatric referral unit with dedi-
cated pediatric airway otolaryngologist, pediatric As mentioned earlier, an MLB is performed in
anesthetists, and a pediatric intensive care unit. children where the diagnosis is inconclusive, or
an inadequate view of the airway has been
obtained. This procedure is performed under gen-
Radiology Investigations eral anesthetic and should only be performed in a
tertiary referral unit with appropriately experi-
Airway protocol – chest and airway radiography enced medical team (Fig. 4). The small caliber of
(Cincinnati over penetration, anterior posterior, the airway, the complexity of the equipment, and
and lateral plain x-ray) can be used to evaluate relative physiological instability of a young child
large airway caliber and lung parenchyma. A lat- means that there is little room for error. Because of
eral plain x-ray can also assess the post nasal the shared airway, good communication between
space (enlarged adenoids) and retro-pharynx. the pediatric otolaryngologist and anesthetist is
Plain x-rays may be helpful in identifying inhaled essential before and during the procedure. It is
essential that all equipment is checked prior to light source. The appropriate size bronchoscope is
starting the procedure. Essential equipment chosen based on the age of the child (Table 6). The
includes a laryngoscope, Hopkins rod-lens tele- use of a camera and video recording attachment is
scope and bronchoscope with Hopkins rod tele- extremely useful for other team members to
scope (including the next size down), suction, and observe findings and teaching, and reviewing
post procedure. Anesthesia is usually adminis-
tered via a mask with sevoflurane. Topical
lignocaine (1% children under 10 kg, 4% for
larger children, dose of 4 mg/kg) is administered.
Once adequate anesthesia has been obtained, a
nasopharyngeal tube is inserted to allow for ven-
tilation. Spontaneous ventilation is maintained as
much as possible to maximize the ability to assess
airway dynamics.
The child is carefully positioned and a laryngo-
scope is inserted to visualize the larynx. Once an
adequate view of the larynx is obtained, the laryn-
goscope is then suspended. A rigid Hopkins rod
telescope can then be inserted to allow assessment
of the airway. In some cases, spontaneous ventila-
tion or insufflation technique may not be tolerated.
In these cases, a Hopkins rod telescope is sheathed
with an age appropriate ventilating bronchoscope
and inserted with the aid of a straight or curved
laryngoscope. Sizing of the airway can be
performed by orotracheal intubation with an endo-
tracheal tube that has a leak between 10 and 25 cm
water (leak can be assessed visually by presence of
air bubbles at level of vocal cords). Cotton and
Meyer described a grading system for subglottic
stenosis using the outside diameters of endotracheal
Fig. 4 Image showing microlaryngoscopy set up tubes (Table 5) (Meyer et al. 1994):
Table 5 Percent of laryngotracheal stenosis by endotracheal tube sizing

ID ID ID ID ID ID
Patient age 2.0 ID 2.5 3.0 ID 3.5 4.0 ID 4.5 5.0 5.5 6.0
Premature 40
58
30
0–3 months 68 48 26
3–9 months No detectable 75 59 41 22
lumen
9 months–2 years 80 67 53 38 20
2 years 84 74 62 50 35 19
4 years 86 78 68 57 45 32 17
6 years 89 81 73 64 54 43 30 16
Grade IV Grade Grade Grade
III II I
Table 6 Guidelines for selection of appropriate size Differential Diagnosis of Pediatric

bronchoscope Stridor
Bronchoscope
Bronchoscope outer diameter In 85% of children under 2.5 years presenting
Age size (Karl Storz) (mm)
with stridor, the cause is congenital. Inflamma-
Premature 2.5 3.7
infant tion, trauma, or foreign bodies most often cause
Term 3 5.0 the remaining cases. The age of onset is variable,
newborn to and onset is usually sudden. Congenital stridor is
3 months often not present at birth but usually presents
3–18 months 3.5 5,7 within the first few months of life. Approximately,
1–3 years 4.0 6.7 50% of stridor cases are caused by laryngeal
2–6 years 4.5 7.3 anomalies.
5–10 years 5 7.8
10–16 years 6 8.2 Laryngomalacia:
– Grade I up to 50% obstruction • Most common cause of stridor in infants

– Grade II from 51% to 70% • Usually presents days to weeks after birth
– Grade III above 70% with any detectable • Usually resolves by 12–18 months of age
lumen • Diagnosis made based on history and con-
– Grade IV- no lumen firmed by nasal flexible endoscopy
• Stridor usually most prominent with exertion –
As the pediatric otolaryngologist performs the crying, feeding
MLB, the following checklist is applied: • Classic finding on endoscopy – collapse of
Supraglottis posterior supraglottic larynx during inspiration
• Gastroesophageal reflux frequently associated
– Presence of supraglottic collapse/ with laryngomalacia – secondary to increased
laryngomalacia? negative intrathoracic pressure generated on
inspiration
Glottis • Majority of patients will resolve with time,
occasionally surgery is required especially if
– Vocal cord palsy? there is failure to thrive, apneic, or desaturation
– Laryngeal web? episode (Ayari et al. 2012; Olney et al. 1999)
– Vocal cord lesion (vocal cord polyp, laryngeal
papillomas)? Laryngeal Stenosis:
Subglottis • Laryngotracheal stenosis characterized by

cause (acquired or congenital), area involved
– Subglottic stenosis? (supraglottic, glottic, subglottic larynx), and
– Subglottic hemangioma? degree of stenosis
• Most subglottic stenosis is acquired – the num-
Trachea ber of patients with secondary acquired
laryngotracheal stenosis increased as very low
– Tracheoesophageal fistula? birth weight infant survival increased
– Complete tracheal ring? • Advances in techniques of endotracheal intu-
– Tracheobronchomalacia (during spontaneous bation have decreased the incidence in surviv-
ventilation)? ing neonates to approximately 1%
– External tracheal compression (secondary • Congenital laryngotracheal stenosis is the sec-
vascular anomaly)? ond most common cause of stridor
• Due to failure or incomplete recanalization of

the laryngeal lumen which normally occurs by
tenth week of gestation
• Subglottic stenosis is present in a full-term
infant when the subglottic airway measures
<4 mm (3 mm in a preterm infant)
• Endotracheal tube sizing is the best and most
sensitive way of assessing the degree of steno-
sis(Holinger 1980; Orlow et al. 1997)
Subglottic Hemangioma:
• Congenital subglottic and tracheal hemangi-

omas are uncommon. Fig. 5 Image demonstrating a larynx with laryngeal
• More common in females. papillomatosis
• Patients usually asymptomatic at birth.
• Most common symptom is development of a disease in the birth canal; other factors
biphasic stridor within first few months of life. involved in transmission.
• Approximately 50% have cutaneous hemangi- • Rarely may undergo malignant transformation
omas – infants with hemangiomas in the lip, (3–5%).
chin, mandibular regions (beard distribution) • Treatment – regular MLB and debulking to
are at greatest risk for airway involvement maintain airway. Possible role for vaccination
(Olney et al. 1999). to prevent RRP in future (Wiatrak et al. 2004;
• The natural history of subglottic hemangiomas Jeyakumar and Mitchell 2011).
is a period of rapid growth that slows by
12 months, followed by slow involution. Vascular Anomalies:
• Management options include – oral proprano-
lol; other surgical options may be considered if • Congenital anomalies of the great vessels
beta blocker therapy fails (Buckmiller et al. account for approximately 5% of cases of
2009; Price et al. 2011; Bajaj et al. 2013). stridor.
• Airway symptoms caused by external com-
Recurrent Respiratory Laryngeal Papillomas pression of trachea or bronchi.
(RRP): • Vascular abnormalities include innominate
artery compression, vascular ring, pulmonary
• Caused by human papillomavirus – HPV 6 and sling, aberrant subclavian artery (Backer et al.
11 usually. 2016; Javia et al. 2016).
• Viral particles widely expressed in mucosa of • Maybe associated with other cardiac or airway
infected individuals but expressed in the form abnormalities – 50% of patients with a pulmo-
of papillomas in certain locations (Fig. 5). nary sling have complete cartilaginous tracheal
• Tend to be extensive and recurrent in children rings (Javia et al. 2016).
(juvenile form) – many cases spontaneously • Patients with significant compression usually
regress in adolescence. present early with stridor, but occasionally
• May occasionally involve trachea, lung – symptoms maybe subtle; high index of suspi-
which can be very difficult to treat and poten- cion required.
tially fatal. • Diagnosis – presence of external compres-
• Half of all children born with RRP were born sion or presence of significant pulsation on
by vaginal delivery to mothers with active MLB.
• MR angiogram or CT angiogram to confirm subglottic haemangioma. J Laryngol Otol. 2013;127

diagnosis and provide detailed anatomy of vas- (3):295–8.
Berkowitz R. Neonatal upper airway assessment by awake
cular anomaly. flexible laryngoscopy. Ann Otol Rhinol Laryngol.
• Treatment depends on degree of stenosis and 1998;107:75–80.
clinical symptoms – but usually surgical Boiselle PM, Ernst A. Recent advances in central airway
(Phelan et al. 2011). imaging. Chest. 2002;121:1651–60.
Buckmiller L, Dymenahalli U, Richter GT. Propanolol for
airway haemangiomas. A case report of novel treat-
ment. Laryngoscope. 2009;119(10):2051–4.
Conclusion Dickison AE. The normal and abnormal pediatric airway.
Recognition and management of obstruction. Clin
Chest Med. 1987;8:583–96.
The pediatric airway is a complex structure Gonzalez C, Reilly JS, Bluestone CD. Synchrous airway
which is structurally very different to the adult lesions in infancy. Ann Otol Rhinol Laryngol.
larynx. The signs and symptoms of a child with 1987;96:77–80.
Hawkins D, Clark R. Flexible laryngoscopy in neonates
respiratory distress depend on the location and
and young children. Ann Otol Rhinol Laryngol.
severity of the obstruction. Flexible nasal endos- 1987;96:81–5.
copy generally gives an excellent view of the Henick DH, Holinger LD. Laryngeal development. In:
pediatric airway. If an inadequate view is Holinger LD, Lusk RP, Green CG, editors. Pediatric
laryngology and bronchoesophagology. Philadelphia:
obtained or the diagnosis is inconclusive, a
Lippincott-Raven; 1997. p. 1–33.
microlaryngoscopy bronchoscopy (MLB) Holinger LD. Etiology of stridor in the infant, neonate and
examination under general anesthetic is child. Ann Otol Rhinol Laryngol. 1980;89:397.
required. MLB is the gold standard for assessing Holzman R. Anatomy and embryology of the paediatric
airway. Anesthesiol Clin North Am. 1998;16
the pediatric airway. When carried out by trained
(4):707–27.
personnel in a specialist center, this procedure is Javia L, Harris MA, Fuller S. Rings, slings, and other
a safe, relatively atraumatic procedure with a tracheal disorders in the neonate. Semin Fetal Neonatal
low rate of complications. Rigid and flexible Med. 2016;21(4):277–84.
Jeyakumar A, Mitchell R. HPV vaccination and recurrent
bronchoscopy should be viewed as complimen-
respiratory papillomatosis. Otolaryngol Head Neck
tary and not competing mutually exclusive Surg. 2011;144:133.
techniques. John SD, Swischuk LE. Stridor and upper airway obstruction
in infants and children. Radiographics. 1992;12:625–43.
Kulendra K, Mullineux J, Mc Dermott AL, Williams H.
Are contrast swallows a relevant investigation in for
Cross-References paediatric stridor. Eur Arch Otorhinolaryngol.
2013;270:969–73.
▶ Congenital Airway Malformations Kussman BD, Geva T, McGowan FX. Cardiovascualr
causes of airway compression. Paediatr Anaesth.
▶ Embryology of Congenital Malformations
2004;14:60–74.
▶ Stridor in the Newborn Meyer CM, O’Connor DM, Cotton RT. Proposed grading
▶ Vascular Rings system for subglottic stenosis based on endotracheal
tube sizes. Ann Otol Rhinol Laryngol.
1994;103:319–23.
Moumoulidis I, Gray RF, Wilson T. Outpatient fibreoptic
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Head Neck Dis. 2012;129:257–63. Orlow SJ, Isakoff MS, Blei F. Increased risk of symptom-
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Stomas of Small and Large Intestine
21
Andrea Bischoff and Alberto Peña
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
Most Common Errors in Colostomies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Stoma Mislocation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Prolapse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Retraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Conclusion and Future Direction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 347
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
Abstract creation of the stoma used as part of the treat-

This chapter includes recommendations to cre- ment of other conditions.
ate stomas in pediatric patients suffering from A list of the most common complications
anorectal malformations and Hirschsprung’s observed is presented, with suggestions on the
disease. However, some of the basic principles way to prevent them and the best possible
presented here are also applicable for the treatment when they occur.
Keywords
Colostomy · Ileostomy · Prolapse · Stenosis ·
A. Bischoff (*) Retraction
Division of Pediatric Surgery, International Center for
Colorectal and Urogenital Care, Children’s Hospital
Colorado, Aurora, CO, USA
e-mail: andrea.bischoff@childrenscolorado.org Introduction
A. Peña
Division of Pediatric Surgery, International Center for Stomas of the small and large intestine are ancient
Colorectal and Urogenital Care, Children’s Hospital operations with demonstrated benefit for many
patients, even in modern times when properly
Colorectal Center for Children, Division of Pediatric indicated. However, in spite of the advances of
Surgery, Cincinnati Children’s Hospital Medical Center,
science of technology, these operations have a
Cincinnati, OH, USA
e-mail: alberto.pena@childrenscolorado.org significant morbidity and mortality. Many of the

https://doi.org/10.1007/978-3-662-43588-5_23
340 A. Bischoff and A. Peña
complications are considered preventable, pro-

vided specific recommendations are observed.
Colostomy is a very old surgical procedure. It
was used first by Duret in 1793 (Schärli 1978).
This procedure has saved many lives through
several centuries and continues being a very use-
ful procedure in modern surgical practice, both in
adults and pediatric patients. Interestingly, colos-
tomies also represent a large source of serious
complications. A colostomy, by definition,
means two operations: the opening and the clos-
ing, both with significant morbidity (Peña et al.
2006; Nour et al. 1996; Demirogullari et al. 2011;
Yajko et al. 1976; Ciğdem et al. 2006;
Chandramouli et al. 2004; Mollitt et al. 1980;
Chirdan et al. 2008; Steinau et al. 2001;
Macmahon et al. 1963). Because of that, many
attempts are constantly made to avoid colosto-
mies. Those attempts sometimes benefit many
patients but also hurt others. Colostomy continues Fig. 1 Descending colostomy, with mucous fistula
being a very important procedure that benefits
many patients.
The creation of an intestinal stoma is an oper- the surgeon can be sure that the proximal stoma
ation frequently performed in pediatric surgery, will not prolapse, since the descending colon is
especially for cases of anorectal malformations, normally fixed, attached to the posterior and lateral
necrotizing enterocolitis, and applicable on occa- wall of the abdomen (left gutter). The proximal
sion for Hirschsprung’s disease. Its purpose is to stoma must be matured and located in the center
divert the fecal stream for different reasons. The of a triangle formed by the last left rib, the umbili-
diversion can be total (separated stomas) or partial cus, and the iliac crest in order to allow a colostomy
(loop colostomies). bag to be adapted to a flat surface of the abdomen.
The opening of a colostomy should not be The distal stoma must be separated enough from
underestimated from the technical point of view the proximal one to be sure that it is possible to
if one wants to avoid serious complications. adapt a stoma bag onto it, without covering the
In the management of anorectal malformations, mucous fistula (distal stoma). In addition, the
the goal of a colostomy is to decompress the mucous fistula should be made very small and flat
gastrointestinal tract, but it must be totally diverting (Figs. 1 and 2), since it will only be used for
to avoid fecal contamination of the urogenital tract, irrigations and injection of contrast material to
since over 85% of the patients with an anorectal define the anatomy of the malformation prior to
malformation have a distal communication with the main repair. This maneuver also helps to avoid
the urogenital tract. In addition, there is evidence prolapse of the distal mobile segment of the sig-
that loop colostomies are more prone to prolapse moid. In order to create a very small mucous fis-
(Peña et al. 2006; van den Hondel et al. 2014; Oda tula, the distal bowel must be tapered (Fig. 2).
et al. 2014). In order to achieve these goals a An important step during the creation of a
colostomy is recommended in the left lower quad- colostomy consists in irrigating, with saline solu-
rant with separated stomas (Fig. 1) (Wilkins and tion, the distal portion of the bowel until it is
Peña 1988). The proximal stoma must be created completely clean of meconium. Leaving meco-
using the first mobile portion of the colon, at the nium distally can result in fecalomas and contam-
transition between the descending (fixed) colon ination of the urinary tract when there is a fistula
and the sigmoid (mobile) colon. By doing that, between the rectum and the urinary tract.
21 Stomas of Small and Large Intestine 341
Fig. 2 Distal stoma made

tiny and flat to help avoid
prolapse
The advantages of this type of colostomy in the than anticipated and (2) to revise the stomas by
management of anorectal malformation include: separating them.
The decision to intervene on this problematic
• Leaving intact the entire sigmoid colon which stoma depends on the specific clinical circum-
guarantees that the patient has enough distal stances. Proceeding with the main repair in a
bowel to perform a successful pull-through patient with this kind of colostomy may produce
• Avoiding prolapse of the proximal stoma due fecal contamination of the reconstructed area,
to its proximity to the descending (fixed) colon which may increase the risk of infection. Alter-
• Avoiding prolapse of the distal stoma that natives include (i) to clean the entire gastroin-
belongs to a mobile portion of the colon (sig- testinal tract preoperatively and then keep the
moid) by making a very small and flat stoma patient fasting for a period of time (about a
• Avoiding urinary tract fecal contamination by week) postoperatively receiving parenteral
separating the stomas nutrition or (ii) using a heavy purse string of
• Facilitates the cleaning of the distal limb, absorbable suture in the distal stoma to occlude
which is irrigated at the time of opening its lumen temporarily and avoid the distal pas-
sage of fecal material postoperatively.
2. Colostomy created too distal in the sigmoid,
Most Common Errors in Colostomies not allowing enough distal length for the rectal
pull-through (Fig. 3). In this case the surgeon
Stoma Mislocation
has several options. The first is to perform the
pull-through, taking down the distal stoma
This type of error can occur in different ways:
(mucous fistula) and closing it as a Hartman
pouch. However, sometimes the piece of bowel
1. Proximal and distal stomas placed too close to is so short that it will make a very difficult
each other. When this happens, the colostomy future colostomy closure since the anastomosis
bag covers both stomas and allows for passage will have to be done deep down in the pelvis,
of stool from the proximal to the distal stoma. behind the bladder or urethra.
As a consequence, some patients suffer from The second option is to close the colostomy at
recurrent urinary tract infections. Also, the the time of the main repair and then pull down
stoma bag may be difficult to adapt to the the rectum, leaving the patient without the benefit
skin. The management of this problem can of a protective colostomy and with a colonic
include (1) to perform the main repair earlier anastomosis in the pelvis. For that, it is
recommended to clean the entire gastrointestinal the natural fecal reservoir of the patient. Its
tract preoperatively and to leave the patient resection will result in provoking a tendency
fasting 7–10 days, receiving parenteral nutrition. to diarrhea which will decrease significantly
The third option is to close the colostomy, the chances of bowel control and in patients
pull the rectum down, and create a new prox- with fecal incontinence will decrease the
imal colostomy to divert the stool and protect chances of success with the bowel
the perineum. management.
It is vital to try to save the distal rectum and 3. Inverted stomas (Fig. 4). The functional (prox-
avoid discarding it and pulling through the imal stoma) is inadvertently placed in the loca-
proximal stoma. The distal rectum represents tion normally designated for the mucous
fistula, making it very difficult to adapt the
stoma bag. In addition, due to the same error,
the surgeon may taper the proximal stoma
which may provoke an obstruction. This com-
plication may require a reoperation.
4. Sigmoid colostomy in the upper abdomen
(Fig. 5). In this case the surgeon planned to
do a transverse colostomy. Consequently,
he/she made an incision in the upper abdomen,
found a piece of colon, and brought it out as a
colostomy, believing it was the transverse
colon. Instead a sigmoidostomy was inadver-
tently opened in the upper abdomen, which
then can interfere with the pull-through.
When opening a transverse colostomy, the sur-
geon must remember that newborns with
anorectal malformations have a very dilated
and mobile sigmoid colon that can reach the
diaphragm. When this error is detected, prior to
Fig. 3 Colostomy placed too distal with not enough distal the pull-through, the colostomy must be
bowel for the pull-through moved to the lower abdomen.
Fig. 4 a, b Inverted stomas

(c) Urine may pass from the urinary tract into

the colon. The urine is absorbed, provoking
hyperchloremic acidosis; this is avoided in
cases of descending colostomies because the
urine comes out through the mucous fistula,
due to the shortness of the distal limb.
(d) Incapacity to perform an adequate distal
colostogram. It is not easy to generate
enough hydrostatic pressure from a trans-
verse stoma, to force the contrast through
the fistula.
The diagnosis of a mislocated colostomyis best

determined by a distal colostogram, which is a
routine study done prior to the main repair of an
anorectal malformation.
Fig. 5 Right upper sigmoidostomy instead of a right Prolapse

transverse colostomy
The second most common complication observed
5. Loop colostomies are very popular operations. by the authors in colostomies is prolapse. In most
It is a very appealing procedure mainly series, this complication has been reported as the
because it is easy and quick to open and also most common one (Nour et al. 1996; Yajko et al.
to close. However, dealing with anorectal 1976; Steinau et al. 2001; Macmahon et al. 1963;
malformations is not a good procedure, mainly van den Hondel et al. 2014; Oda et al. 2014). This
because it allows the passing of stool from the can be a serious complication that may result in
proximal to the distal limb. This represents a intestinal loss due to ischemia. Most prolapses can
high risk of fecal contamination in anorectal be avoided by creating the colostomy adjacent to a
malformations since the overwhelming major- fixed portion of the colon. If the colostomy has to
ity of patients with these defects have a fistula be created in a mobile portion of the bowel, it must
between the rectum and the urogenital tract. In be fixed to the anterior abdominal wall, approxi-
addition, the passing of stool into the distal mately 6–7 cm proximal to the stoma. In Fig. 6
limb may provoke fecal impaction of the one can identify the mobile and fixed portions of a
rectosigmoid, which represents a risk of normally rotated colon and understand the
intraoperative fecal contamination. Also, loop segments that are prone to prolapse and will need
colostomies tend to prolapse more frequently fixation to the abdominal wall. Other ways to pre-
than other types (van den Hondel et al. 2014; vent prolapse have been reported (Ng et al. 1997).
Oda et al. 2014). A patient with significant prolapse will benefit
6. Transverse colostomies are not recommended from a surgical revision. There are several impor-
in patients with anorectal malformations for tant maneuvers recommended. A large amount of
the following reasons: packing gauze soaked in povidone-iodine is
(a) The surgeon cannot clean the distal bowel. inserted in the prolapsed bowel, gently reducing
The meconium or stool will remain there the prolapse. Then the abdomen is palpated, feel-
until the day of the main repair. ing “the sausage-like mass” that corresponds to
(b) Higher chances of fecal contamination of the packing gauze inside the bowel, naturally ori-
the urinary tract. ented inside the abdomen. A transverse incision is
Fig. 6 Right transverse colostomy (distal stoma likely to prolapse), left transverse colostomy (proximal stoma likely to
prolapse), descending colostomy (distal stoma likely to prolapse)
then made on top of the palpated mass, usually early retraction represents a surgical emergency.
about 5 cm away from the stoma, opening the A late retraction may represent a serious difficulty
skin, subcutaneous, muscle, aponeurosis, and in managing the stoma, since it will be hard to
peritoneum. The bowel full of gauze is easily adapt the stoma bag. Reoperation with mobiliza-
identified. The peritoneum and aponeurosis are tion of the stoma higher above the skin surface is
closed with interrupted long-term absorbable required.
stitches including in each stitch a bite of the
bowel wall (without taking the packing gauze),
securing it to the abdominal wall, which will Stomas in Cloacal Exstrophy (Soffer et al.
prevent future prolapse. The matured stoma with 2000)
this technique does not need to be touched. A special comment should be made about stomas
in patients born with cloacal exstrophy. A com-
mon misconception is that these patients have a
Stenosis short and therefore useless colon; this concept is
half true. As a consequence, many surgeons per-
This happens more often than what doctors’ sus- form an ileostomy at birth, leaving the distal colon
pect and patients may suffer from obstructive attached to the urinary tract. This is highly incon-
symptoms. When opening a stoma, the surgeon venient because the distal defunctionalized colon
must create an adequate space to pass the func- will become atrophic; in addition, the urine will be
tional bowel through, without being compressed absorbed producing hyperchloremic acidosis that
by the fascia. In other words, creating stomas may interfere with the growth of the baby. It is
through a simple stab wound should be avoided. very important to incorporate every single piece
A circle of skin, as well as a circle of aponeurosis, of colon into the fecal stream, regardless of how
muscle, and peritoneum, must be resected at the small it is. Over time those small pieces of bowel
stoma location. Most cases of stoma stenosis do grow considerably. Another advantage of incor-
not respond to dilations and need reoperation. porating colon in the fecal stream is that those
patients become easier to manage than a patient
Retraction having an ileostomy. Patients that underwent the
opening of an ileostomy leaving the distal colon
This complication represents a technical mistake defunctionalized and connected to the urinary
and therefore a preventable problem. An acute, tract benefit from an operation (“rescue
operation”) consisting in closing the ileostomy surgeons work in environment with limited
separating the colon from the urinary tract and resources.
incorporating it into the fecal stream, creating a
real end colostomy.
Ileostomies
Another special comment should be made about
ileostomies, a common procedure done for total
Colostomies in Hirschsprung’s Disease
colonic aganglionosis and necrotizing enterocoli-
Colostomies were created in most patients with
tis. Since by definition the ileostomy will always
Hirschsprung’s disease in the early times. Sur-
be made in a mobile portion of the bowel, the risk
geons described the “three stages” approach to
of prolapse is very high; therefore fixing the bowel
treat Hirschsprung’s disease: (a) colostomy open-
to the anterior abdominal wall, approximately
ing, (b) resection and pull-through, and
6–7 cm proximal to the stoma, is recommended.
(c) colostomy closure (Swenson et al. 1949). At
All the other complications described for colos-
that time, the recommended location of the stoma
tomy apply for ileostomies. The other particular
was the right transverse colon since that will have
characteristics about ileostomy include managing
over 85% chances to be located in a
the possible electrolyte disturbances. Patients
normoganglionic colon and in addition it would
need to maintain good hydration, and parents
allow performing the resection of the a ganglionic
need to be keen observers of stoma effluent.
segment and pull-through without touching the
These patients tend to have significant sodium
colostomy, giving the patient the benefit of a pro-
losses and may need oral sodium
tective colostomy after the pull-through. Obvi-
supplementation.
ously the disadvantage was that the patients
underwent three major operations.
Later in time, a two-stage approach was pro- Colostomy Closure
posed and became popular. This approach Colostomy closure in the pediatric population is
consisted in opening what was called a “leveling also associated with a high morbidity rate due to
colostomy,” meaning that the colostomy was potential avoidable complications such as anas-
opened just proximal to the transition zone, in a tomotic dehiscence, stricture, wound infection,
demonstrated normoganglionic bowel, as shown bleeding, and death (Peña et al. 2006; Finch
by frozen sections. At the time of the resection and 1976; Rickwood et al. 1979; Hubens et al.
pull-through the patient was left without the ben- 1987; Kiely and Sparnon 1987; Feng et al.
efit of a protective colostomy, since the stoma 2016).
itself was pulled down and anastomosed to the A perioperative protocol for colostomy closure
anal canal. (Bischoff et al. 2010) is recommended here and
More recently, a single primary repair with or consists in (1) admission on the day before sur-
without laparoscopy becomes popular (Langer gery, (2) clear liquids by mouth, (3) proximal
et al. 1996; Georgeson et al. 1995; Pierro et al. stoma irrigations with saline solution, (4) admin-
1997; Cass 1990). In addition, a trans-anal istration of IV antibiotics during anesthesia induc-
resection and pull-through (De la Torre- tion and continued for 24 h, and (5) meticulous
Mondragón and Ortega-Salgado 1998; Langer surgical technique.
et al. 1999) allow performing the full repair
without laparoscopy or laparotomy in about
80% of the cases. Surgical Technique
In spite of all these advances, the colostomy The proximal stoma is packed with povidone-
continues being a very important resource in soaked gauze, and a plastic drape is used to
patients with Hirschsprung’s disease, to be cover the skin of the abdomen. Multiple silk
used in very ill patients with enterocolitis after sutures are placed at the mucocutaneous junc-
complicated pull-throughs or when the tion of the stomas to provide uniform traction
Fig. 7 Multiple silk

sutures in the
mucocutaneous junction
that allows for a uniform
traction. The dotted line
shows the elliptical
incision. The opening is
performed layer by layer
mesenteric defect is repaired. The peritoneal

cavity is profusely irrigated with saline solu-
tion. The abdominal cavity is closed by layers,
using interrupted long-term absorbable sutures
in the aponeurosis (Fig. 10). Special emphasis
is placed in attention to details; avoid dead
spaces and exaggerated use of cautery. A
nasogastric tube is usually not necessary. The
following day after surgery, if the patient does
not have abdominal distention, he (she) is
allowed to drink clear fluids and advance to
regular diet as indicated. The patients usually
Fig. 8 Cleaning the edges of the stomas, preparing for the stay in the hospital for 2–3 days after the
anastomosis
operation.
When the size discrepancy between proxi-
mal to distal stoma is more than 5 to 1, with a
that allows the surgeon to identify the correct distal stoma diameter being less than 1 cm,
dissection plane. A wedge incision is created the colostomy closure may represent a serious
including both stomas. Applying uniform trac- challenge and for that the same technique that
tion, both stomas are carefully dissected pass- is used for cases of colonic atresia can be
ing through the skin, subcutaneous tissue, applied. The technique consists in performing
aponeurosis muscle, and peritoneum (Fig. 7). an end-to-side anastomosis plus a window-
The procedure is carried out observing metic- type of stoma created about 5–10 cm proximal
ulous hemostasis and avoiding contamination. to the anastomosis (Fig. 11). During the first
After the stomas have been separated from the few postoperative days, one can see a large
abdominal wall, the packing gauze is removed, fecal output through the window; eventually
and both stomas are resected using fine baby the output decreases, and the amount of stool
intestinal clamps, placed in a fresh healthy passing through the downstream bowel
portion of the bowel (Fig. 8). A two-layer increases, until the window closes up, the
anastomosis is performed with interrupted fine anastomosis is efficient, and the microcolon
long-term absorbable sutures (Fig. 9). The grows.
Fig. 9 Two-layer anastomosis: a external layer of posterior wall. b Internal layer of posterior wall. c Internal layer of
anterior wall. d External layer of anterior wall
Conclusion and Future Direction
Colostomies and ileostomies are still very useful

procedures that benefit many children and adults
all over the world, when indicated and
performed properly. The technical aspects of
the opening and closure of stomas should not
be underestimated.
Due to the significant morbidity and mortality
related with these procedures, it is understand-
able to see a trend to avoid them. Yet, the risks of
a colostomy or an ileostomy should always be
compared with their potential benefits, in order
to take the best decision that will benefit a
Fig. 10 Closed wound, covered with Dermabond ® patient.
Fig. 11 End-to-side
anastomosis for size
discrepancy greater than
5:1. Window type of stoma
created about 5–10 cm
proximal to the anastomosis
Finch DR. The results of colostomy closure. Br J Surg.

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Kiely EM, Sparnon AL. Stoma closure in infants and
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Preoperative Assessments in Pediatric
Surgery 22
Linda Stephens and John Gillick
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Preoperative Assessment for Day Case
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Clinic Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Patient Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
History and Clinical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Perinatal History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Medication History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Allergy History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
Immunization History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Anesthetic History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Social History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Clinical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Further Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Fasting Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
General Education Opportunities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Completion of the Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
L. Stephens (*)
Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
e-mail: lrstephens80@gmail.com
J. Gillick
e-mail: john.gillick@cuh.ie; johngillick@excite.com

https://doi.org/10.1007/978-3-662-43588-5_24
352 L. Stephens and J. Gillick
Preoperative Assessment for Inpatient Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Blood Grouping and Crossmatching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Preoperative Mechanical Bowel Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Optimization of Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Specific Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
The Child with an Incidental Murmur . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Endocarditis Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
The Child with an Upper Respiratory Tract
Infection (URTI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
The Obese Child . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
The Child with Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
The Child with Cystic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
Preoperative Assessment of the Neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
History and Clinical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Temperature Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Respiratory Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Cardiovascular Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Metabolic Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Acid–Base Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Hypoglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Hypocalcemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Hypomagnesemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Hyperbilirubinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Coagulation Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Laboratory Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
Fluid and Electrolytes and Metabolic
Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
Abstract who performed 460 surgeries for harelip and

Preoperative assessment has been largely cleft palate in the 1900s. He considered chil-
influenced by the evolution and popularity of dren were more safely nursed at home rather
day case surgery, which has been shown to than in the hospital environment (Nicoll and
have major advantages over inpatient surgery Spina Bifida. Glasgow Med J. 1902;58:12–9).
(Sadler et al. Ann R Coll Surg Engl. 1992;74 Now, the majority of pediatric elective surgery
(2):130–3; Suhonen et al. Int J Nurs Pract. is performed on a day case basis, and therefore
2007;13:121–29). Pioneering work in the pre-assessment is essential for this service to
development of day surgery can be attributed perform efficiently and effectively. Fundamen-
to a Scottish pediatric surgeon, James Nicholl, tal to the success of these initiatives is a clear,
22 Preoperative Assessments in Pediatric Surgery 353
comprehensive system that relies on a thor- • Does the child have any comorbid factors that
ough preoperative evaluation tailored to iden- have implications for the delivery of anesthesia
tifying operative risk with access to or their postoperative recovery?
appropriate investigative modalities and suit- • Can this operation be delivered on a day case
ably trained staff. However, there are some basis or is an inpatient bed, high dependency
unique situations in pediatric surgery that unit (HDU) bed, or intensive care unit (ICU)
require a different approach to preoperative bed required in the postoperative period?
assessment, such as the work-up of a neonate • What is the psychological impact on the child as
requiring surgery. These aspects of preopera- a result of the intervention and hospitalization?
tive assessment, and others, will be discussed • Is there a parent/guardian to care for the child
in detail in this chapter. following discharge?
• Are there sufficient facilities to ensure follow-
Keywords up care is adequate?
Anesthesia · Day case surgery · Medical
history · Clinical examination · Investigations · The majority of these questions will be answered
Elective surgery · Emergency surgery · easily, and no problems will be identified. However,
Neonatal surgery the benefit of this assessment is that any major
problems can be identified early so that a manage-
ment plan can be put into action to ensure that the
Introduction child’s condition is optimized, allowing the proce-
dure to be delivered in the safest manner possible.
In the main, preoperative assessment begins in At this stage of the consultation, informed con-
the outpatient clinic, where a child is referred for sent can be taken following discussion of the risks
assessment of a condition that may require sur- and benefits of the procedure. The chief benefits
gery. Careful consideration of the patient and the are that, due to lessened time pressure in the
entire process by the assessing surgeon is funda- outpatient clinic as compared to the morning of
mental to establishing a good start to the surgery, there is sufficient time for discussion and
patient’s journey and is the initial step in the questions, and patients and parents/guardians
pre-assessment stage of this surgical pathway. have time to consider all aspects of the surgery
Therefore, the surgeon must have experience in before the procedure date. Information in the form
pediatric surgery and an adequate knowledge of of leaflets, brochures, videos, or web-based
the prerequisites for anesthesia. They must ask resources can also be offered if available.
themselves several questions during the The next step in the preparation of the child to
consultation: undergo a surgical procedure is the formal pre-
assessment phase. This phase of the pathway can
• Is there a clear indication for this operation? be delivered in several ways depending on the
• Is this the optimal age for this surgery to be child’s age, current health status, and the type of
performed? surgery being provided. These different situations
• What are the risks and benefits of the are considered below.
operation?
• Who is the most appropriate person to perform
this operation? Preoperative Assessment for Day Case
• Does the institution have adequate resources to Surgery
provide this surgery?
• Can complications be managed in this Firstly, the surgeon must decide if the planned
institution? procedure can be delivered in an ambulatory sur-
• Has the child had any problems with anesthesia gery setting. Suitable cases for day case delivery
in the past? must meet the following requirements:
• Low risk of serious complications requiring efficient service delivery in an economical

immediate medical attention, such as fashion.
hemorrhage.
• Symptoms, such as pain and postoperative
nausea and vomiting (PONV), can be con- Clinic Design
trolled by the use of oral medication in combi-
nation with local anesthetic techniques. Clinic organization requires forward planning and
• Oral intake will resume within a few hours adequate funding to function satisfactorily. Ide-
after surgery. ally, the setting should be in a child-friendly envi-
• Patients should be able to mobilize before ronment such as the pediatric outpatient
discharge. department, where staff is familiar with dealing
with children on a daily basis. Availability of
Examples of suitable day case procedures in pediatric nurses with experience in phlebotomy,
pediatric patients are outlined in Table 1. and an appropriate treatment room for performing
Preoperative assessment in a dedicated pre- these tasks, is essential. Availability of radiologi-
assessment clinic is vital to the efficient running cal investigations and a pediatric radiologist to
of a pediatric day case surgery service (Vowles et interpret studies is also necessary. Electrocardio-
al. 1997). Well-organized clinics have been gram and echocardiogram access should be
shown to identify patients unsuitable for day available.
case procedures. Patients that no longer want Assessment may be physician led, nurse led,
treatment (Clark et al. 1999) and cancellations or based on health questionnaires that are com-
have also been shown to be significantly reduced pleted by the patient and/or parent/guardian.
following introduction of these programs in Physician-led assessment tends to be expensive
adult patients (Knox et al. 2009). Theater pro- and unnecessary as nurse-led services have been
ductivity can therefore be improved, ensuring shown to be effective in the pediatric population
(Varughese et al. 2006), maintaining patient
safety and freeing up junior medical staff for
Table 1 Examples of procedures suitable for day case other duties. Health questionnaires are a cost-
surgery in pediatric patients
effective tool; however, they can be mis-
Pediatric surgical interpreted and may overlook the presence of
specialty Procedure
anesthetic risk factors. Clinics should be staffed
General surgery Inguinal herniotomy
with adequately trained pediatric nurses with
Umbilical hernia repair
experience in preoperative assessment. An anes-
Lymph node biopsy
Muscle biopsy
thetic team led by a senior consultant anesthetist
Urology Circumcision supports the clinic and is available to assess
Orchidopexy patients in whom risk factors for anesthesia are
Cystoscopy identified, in order to ensure that the patient is
ENT Tonsillectomy adequately investigated and optimized, minimiz-
Adenoidectomy ing cancellations on the day of surgery. Surgical
Myringotomy and insertion of teams and subspecialty pediatricians should also
grommets be readily available for consultation.
Plastic surgery Pinnaplasty Following careful preparation, it must be
Cleft lip repair ensured that the patient is scheduled for surgery
Hand surgery in a timely fashion. It has been suggested that
Orthopedic surgery Tendon lengthening cancellations are comparable in patients that
Cast changes
were pre-assessed the day before surgery and
Fracture reductions
between 2 and 30 days before surgery (Pollard
Arthroscopy
and Olson 1999). Therefore, it would be
reasonable to conclude that pre-assessment History and Clinical Examination

should take place within 30 days of surgery,
unless a problem that requires preoperative Perinatal History
investigation is highlighted at the outpatient
consultation. A thorough focused history starts with the child’s
perinatal history, which is most relevant in the
neonate or young infant. A child with a history
Patient Assessment of premature birth (<37 weeks gestation) poses
significant challenges for the anesthetist, as they
The healthcare professional evaluating the are at higher risk of respiratory depression and
patient begins by familiarizing themselves with apnea following anesthesia conducted within the
the planned surgical procedure. Important first months of life (Walther-Larsen and Rasmus-
aspects of the surgery that have an impact on sen 2006). Most tertiary centers will proceed with
the delivery of anesthesia and postoperative care day case surgery for healthy term babies with a
are outlined in Table 2. Consideration of these post-conceptual age (PCA) of more than
points will help to focus evaluation and ensure 44 weeks, and ex-premature babies with a PCA
that the assessment is relevant to the procedure of more than 60 weeks (Short and Malik 2009).
that is being undertaken. Before the patient is An overnight stay for postoperative saturation and
seen, a review of the medical notes, in particular, apnea monitoring is recommended for premature
previous anesthetic records, can identify any infants with a PCA of <60 weeks. Other impor-
previous problems such as patient anxiety tant considerations are the presence of chronic
requiring premedication or a difficult airway. lung disease of prematurity, duration of oxygen
At this stage, the assessor is well equipped with dependency, any neurological impairment, and
knowledge and can meet the child and their anemia of prematurity.
carer.
A careful, structured patient assessment is then
carried out, giving particular attention to the Medical History
following:
All current or past medical conditions must be
• History and clinical examination, including accurately recorded. It is important to establish if
calculation of body mass index (BMI) a condition has an impact on the patient’s day-to-
• Respiratory function day life, such as poor exercise tolerance or hypo-
• Cardiovascular status glycemia, if fasting for long periods. It is useful to
• Optimization and management of comorbid document in which institution these conditions are
conditions treated and the responsible medical professional,
• Anesthetic risk factors as this will assist with the procurement of infor-
• Social circumstances mation from these sources, if required.
Specific enquiry about the presence of certain
conditions that have an impact on anesthetic deliv-
Table 2 Factors that impact on the delivery of anesthesia ery and recovery must be undertaken. Asthma is
and postoperative care one of the most common and serious underlying
Factors that impact on the delivery of anesthesia and medical conditions that can affect children under-
postoperative care
going general anesthesia. The incidence of reactive
Procedure length
airway disease has increased markedly in the gen-
Operative position
eral pediatric population and is now approximately
Site of incision
25% of the pediatric surgical population
Expected blood loss
(Zuckerberg and Maxwell 2013). Intraoperative
Anticipated postoperative pain
bronchospasm can be precipitated by laryngoscopy
Table 3 Classification asthma severity by clinical features, from Yawn BP. Factors accounting for asthma variability:
achieving optimal symptom control for individual patients
Severity Symptom frequency Nighttime symptoms %FEV1 of predicted FEV1 variability
Intermittent 2/week 2/month 80% <20%
Mild persistent >2/week 3–4/month 80% 20–30%
Moderate persistent Daily >1/week 60–80% >30%
Severe persistent Continuously Frequent (7/week) <60% >30%
FEV1 forced expiratory volume in 1 s, PEF peak expiratory flow
Table 4 Factors that suggest poorly controlled asthma volume of fluid does not exceed 30 mL (Short
Factors that suggest poorly controlled asthma and Malik 2009), and it is important that the
Daytime symptoms >/=3 days per week, child and their carer are informed of this. In par-
Nighttime symptoms >1 night per week ticular, antiseizure medications, cardiac medica-
Restricted physical activity tions, and inhalers for asthma should not be
Moderate or severe exacerbations withheld on the day of surgery.
Missed school due to asthma Anticoagulants, such as aspirin, are occasion-
Reliever use >/= 3 doses per week ally used in children with cardiac problems. This
Spirometry and peak expiratory flow (PEF) <90% of may have an impact on the surgery and risk of
personal best
bleeding but also on the use of caudal and epidural
local anesthetic techniques. Therefore, consulta-
and intubation, with life-threatening consequences. tion with the surgical, anesthetic, and medical
If a child has a diagnosis of asthma, it is important to teams regarding balancing the risks and benefits
classify the severity. Chronic asthma can be classi- of their perioperative use is imperative.
fied according to clinical features (Table 3). Any Documentation of current or recent steroid use
child with poorly controlled asthma (Table 4), is vital, as patients will need steroid cover during
recent hospitalization for asthma within the previ- surgery to prevent adrenal crisis.
ous 3 months, an exacerbation in the previous In adolescent girls, current estrogen-containing
month, or a room-air oxygen saturation of 96% or oral contraceptive use must be questioned as this
less, is not suitable for a day case procedure under increases the risk of development of deep vein
general anesthetic and requires optimization before thrombosis (DVT) if taken in the perioperative
elective surgery is performed (Zuckerberg and period. As per National Institute for Health and
Maxwell 2013). Care Excellence (NICE) guidance, the oral con-
Seizure control in patients with epilepsy is traceptive pill (OCP) should be stopped 4 weeks
paramount in the perioperative period. Enquiry prior to surgery (Venous Thromboembolism:
regarding frequency, duration and type of seizure, Reducing the Risk 2013).
and the importance of continuing antiseizure med-
ications in the perioperative period is critical to
maintaining perioperative seizure control. Allergy History
The identification of hematological conditions
that could predispose a patient to increased anesthetic Latex and antibiotic allergies are the two most
risk, such as sickle cell anemia, is also essential. common causes of anaphylaxis in pediatric
patients in the perioperative period. Therefore, a
history of previous allergy to any of these agents
Medication History must be documented with particular attention to
the nature of these reactions. Allergy to kiwi fruit,
All current medications and doses should be avocado, chestnuts, and bananas is associated
recorded accurately. Most medications can be with latex allergy. Children with spina bifida and
given safely on the morning of surgery, if the bladder or cloacal exstrophy are known to be at
higher risk of latex allergy and should be treated in of malignant hyperthermia (MH) or suxa-
a latex-free environment. Propofol should be methonium apnea must be documented clearly.
avoided in patients with a history of anaphylactic
reactions to egg. Social History
Recuperation following ambulatory surgery is in

Immunization History
the home setting, and therefore an assessment of
the patient’s home circumstances must be under-
The routine immunization schedule for children in
taken. Parents may be anxious about monitoring
the United Kingdom is given in Table 5. The
their child at home and may have specific con-
Association of Pediatric Anesthetists of Great
cerns about managing pain and wound care.
Britain and Ireland (Association of Paediatric
Therefore it is important to allay their fears and
Anaesthetists of Great Britain and Ireland Guide-
provide them with verbal and written information
lines 2013) recommend the following with regard
about postoperative care at this stage.
to timing of vaccination with respect to anesthesia
and surgery:
• Surgery following immunization with
Clinical Examination
inactivated vaccines.
• Delay surgery 48 h postvaccination to avoid
Initial appraisal allows the assessor to make an
postvaccination symptoms causing diag-
evaluation of the child’s general condition. For
nostic concern perioperatively.
example, one can observe the child’s general
• Surgery following immunization with live
appearance and color and their baseline work of
attenuated vaccines.
breathing, identify dysmorphic features or defor-
• No reason for delay if the child is well at
mities, estimate their nutritional status, and assess
time of preoperative assessment.
their general demeanor and the manner in which
• Vaccination after surgery.
they interact with their carer and the pre-assess-
• No contraindication if the child is well and
ment team.
has recovered from the procedure.
In all patients, the clinical examination should
• Advice for pre-assessment.
include the measurement of the patient’s weight,
• Continue with normal vaccination schedule.
height, body mass index (BMI), heart rate, blood
• For major surgery, risk assessment should take
pressure, respiratory rate, and oxygen saturations
into account the risk of side effects of vaccina-
at room air. These observations assist with the
tion occurring when a prolonged postoperative
assessment of the patient’s current condition and
recovery period is expected.
also provide the anesthetist with a set of baseline
observations to which they may refer back.
Anesthetic History Accurate and thorough assessment of the car-
diovascular and respiratory systems is vital in
Following a review of the patient’s anesthetic order to identify any underlying abnormalities
records, any problems that the patient or carer per- that may afford the patient increased risk of a
ceived that occurred during any anesthetic should perioperative adverse event. A full examination,
be recorded. In particular, stress caused by cannu- with the patient exposed appropriately, should be
lation or induction of anesthesia may have an performed starting with inspection. The work of
impact on any future anesthetic inductions. The breathing should be evaluated, noting any nasal
patient or carer may express preferred methods of flaring, grunting, intercostal or subcostal reces-
delivery of the child’s anesthetic, and these should sion, tracheal tug, head bobbing, or abdominal
be considered. Any specific problems such as anes- breathing. Scars from previous cardiac or thoracic
thetic drug reactions or a personal or family history surgical procedures may also be evident.
Table 5 Routine UK immunization schedule. The Parliamentary Office of Science and Technology, 7 Millbank, London
SW1P 3JA; www.parliament.uk/post, September 2015
Age Vaccination Comments
2 months Diphtheria, tetanus, pertussis, polio, and This 5-in-1 vaccine protects against five diseases, with
Hemophilus influenza B (DTaP/IPV/ children immunized in three stages in their first 4 months.
Hib) They are diphtheria (D), tetanus (T), pertussis (also
known as whooping cough, {aP}), polio (inactivated
polio vaccine or IPV), and meningitis and pneumonia
caused by Hemophilus influenza type b (Hib)
Pneumococcal infection conjugate Protects against pneumonia, septicemia (blood
vaccine (PCV) poisoning), and meningitis caused by the bacterium
Streptococcus pneumoniae
3 months DTaP/IPV/Hib Second dose
Meningococcal C (Men C) Protects against meningitis and septicemia caused by
meningococcal group C bacteria. It does not protect
against the more common meningococcal B bacterial
infections, so parents should be aware of the symptoms of
meningitis
4 months DTaP/IPV/Hib Third dose
PCV Second dose
Men C Second dose
12–13 months Hib/Men C booster Single jab containing Hib (fourth dose) and Men C (third
dose)
PCV Third dose
MMR A 3-in-1 vaccine to protect against measles, mumps, and
rubella
3 years, MMR Second dose
4 months DTaP/IPV A 4-in-1 preschool booster vaccine for diphtheria, tetanus,
pertussis, and polio
12–13 years Human papilloma virus (HPV) Girls only, three doses within 6 months to protect against
some strains of the virus that cause cervical cancer
13–18 years Td/IPV 3-in-1 booster vaccine against diphtheria, tetanus, and
polio
Identification of chest wall deformities such as in the left fourth intercostal space in the mid-
pectus excavatum or carinatum, Harrison’s sulcus clavicular line. Displacement to the left may sug-
in chronic asthma, anterior bulge of the left chest gest the presence of cardiomegaly, while
suggesting cardiomegaly, or signs of scoliosis is displacement to the right may indicate congenital
important as it can have an impact on cardiorespi- dextrocardia. Presence of displacement necessi-
ratory function and reserve. Such patients are at tates further investigation. Auscultation of the
risk of intraoperative complications and pro- lung fields and the precordium should then be
longed postoperative mechanical ventilation and undertaken. Documentation of any abnormal
therefore may require preoperative pulmonary breathing such as diminished sounds or bronchial
function tests, an electrocardiogram (ECG), an breathing should be documented, taking care to
echocardiogram, or cardiology assessment. state their location along with the presence of any
Next, the pulse should be assessed for rhythm, wheeze or crackles. The heart must be auscultated
rate, volume, and character. Femoral pulses to assess for the presence or absence of abnormal
should be palpated as absence may indicate coarc- heart sounds and murmurs. Murmurs should be
tation of the aorta. The apex beat should be found described by defining their intensity (grade 1–6),
site, radiation, timing, duration, pitch, quality, and of these are given in Table 6. However, these
changes with respiration or posture. tests have not been shown to be valid in children
The head, neck, and airway examination is a (Baudouin et al. 2006). Any abnormalities iden-
particularly important component of the pre- tified that may indicate a potentially difficult
anesthetic evaluation. Adequacy of mouth open- airway should be reported to the anesthetist,
ing and neck mobility, the length of the neck, thereby allowing them to assess the child and
and the size of the tongue and mandible are ensure that the appropriate equipment for intu-
important to evaluate as adequate opening of bation, such as the fiber optic bronchoscope, is
the mouth and full range of movement of the available on the day of surgery.
neck is fundamental to successful intubation. A Assessment of loose teeth is particularly impor-
short neck, large tongue, or small mandible all tant in children of 5 years of age or older, as this is
constitute sources of airway obstruction and the stage at which they begin to loose their decid-
may lead to delay or impossibility in intubating uous teeth. All carers should be informed of the
the trachea due to the difficulty in visualizing the risk of dislodgement of loose teeth and should be
glottic opening (Zuckerberg and Maxwell consented for extraction if necessary.
2013). Congenital syndromes, such as Pierre Neurologic status and the extent of neuromus-
Robin sequence or Down’s syndrome, are asso- cular disease should be evaluated and preexisting
ciated with anatomic abnormalities that may deficits documented.
make intubation difficult. In adults, several val- A summary of the assessment of the patient’s
idated scoring systems have been used to aid in physical condition using the American Society of
the prediction of the difficult airway. Examples Anesthesiologists physical status (ASA PS) clas-
sification (Table 7) may be made following com-
pletion of the clinical history and examination.
Table 6 Airway assessment scoring systems Although this classification cannot be used as a
Class/ sole predictor of operative risk, it can be used to
Test grade Description estimate risk in conjunction with other indicators,
Modified Class Ability to see any part of such as the type of operative procedure and the
Mallampati test 0 the epiglottis on mouth skill and experience of the surgeon and anesthe-
opening and tongue
protrusion tist. Therefore it is a useful summary score for all
Class Soft palate, fauces, uvula, members of the ambulatory surgery team as it
1 pillars seen
Class Soft palate, fauces, uvula
2 seen
Class Soft palate, base of uvula Table 7 American Society of Anesthesiologists (ASA)
3 seen physical status classification system
Class Soft palate not visible at ASA physical A normal healthy patient
4 all status 1
Modified Grade Full view of the glottis ASA physical A patient with mild systemic disease
Cormack and 1 status 2
Lehane scale Grade Partial view of the glottis ASA physical A patient with severe systemic disease
2a status 3
Grade Arytenoids or posterior ASA physical A patient with severe systemic disease
2b part of the vocal cords status 4 that is a constant threat to life
only just visible ASA physical A moribund patient who is not
Grade Only epiglottis visible status 5 expected to survive without the
3 operation
Grade Neither glottis nor ASA physical A declared brain-dead patient whose
4 epiglottis visible status 6 organs are being removed for donor
Adapted from Lee et al. (2006) purposes
conveys an assessment of the child’s general undergoing a neurosurgical or cardiovascular pro-

health and operative risk. cedure. An ECG should be performed on children
who have a heart murmur identified during clini-
cal examination or are on medication that may
Investigations have side effects of a cardiac nature.
Sickle cell disease is prevalent in people of
When considering the investigations that should North African, West African, South/sub-Saharan
be performed on children as part of their preoper- African, or African Caribbean descent. General
ative work-up, the ASA PS status of the child anesthesia in these patients can precipitate vaso-
and the grade of surgery (Table 8) must be occlusive events. Therefore, NICE recommends
considered. NICE recommends that all children that patients from the above areas should undergo
between the ages of 6 months and 6 years, classi- testing for sickle cell anemia preoperatively as
fied as ASA 1, undergoing grade 1 and grade 2, knowledge of the presence of this disease allows
non-neurosurgical, non-cardiovascular surgery, optimal management to prevent crisis. Facilities
do not require any routine preoperative investiga- for counseling and treatment should be made
tions (Preoperative Tests 2003). A full blood available for all patients diagnosed with the
count (FBC) and renal profile (RP) should be condition.
considered in all ASA 1 children undergoing Pregnancy testing can easily be forgotten when
grade 3 or 4 surgery and a coagulation screen for assessing the pediatric population for surgery;
neurosurgical procedures. A chest X-ray, ECG, however, it is important in girls of a reproductive
FBC, and RP should be performed, and a coagu- age. In general, the likelihood of pregnancy in
lation screen should be considered if undergoing girls under 15 years is low, and the risks associ-
cardiovascular surgery. ated with most types of procedure are also small.
However, this guidance does not extend its Despite this, there may be certain procedures that
recommendations beyond children with an ASA would be considered particularly high risk to an
status of 1. Therefore, if the child concerned does undisclosed pregnancy, such as lower abdominal
not meet these criteria, their investigations must surgery or that involving perioperative X-ray
be individually tailored to their physical status and screening to the lower abdomen or pelvis. In
to the procedure that is to be undertaken. Children such cases, consented testing of urine to exclude
less than 1 year old with a history of prematurity pregnancy may be considered appropriate (Pre-
and children with a chronic illness are at risk of procedure Pregnancy Checking in Under 16s:
anemia, and therefore a FBC should be considered Guidance for Clinicians 2012).
during preoperative work-up. Indications for a
group and save or crossmatch will be considered
in the section on assessment for inpatient surgery.
A coagulation screen should only be performed in Further Information
patients with a positive family history, history of
abnormal or excessive bleeding, or with clinical Fasting Guidelines
signs suggestive of a bleeding diathesis unless
An extensive Cochrane review revealed that there
is no evidence that children who are denied oral
Table 8 Grades of surgery
fluids for more than 6 hours preoperatively benefit
Grade Example in terms of intraoperative gastric volume and pH
Grade 1 Excision skin lesion compared with children permitted unlimited fluids
Grade 2 Inguinal herniotomy up to 2 hours preoperatively (Brady et al. 2009).
Grade 3 Cholecystectomy
Children permitted fluids have a more comfort-
Grade 4 Colonic resection
able preoperative experience in terms of thirst and
hunger. Therefore, clear fluids can safely be given Preoperative Assessment for Inpatient
without restriction up to 2 h before a general Surgery
anesthetic. Breast milk can be safely given up to
4 hours before an anesthetic, and formula or cow’s Elective inpatient surgery is largely confined to
milk and food can be given up to 6 hours before patients undergoing grade 3–4 surgeries or patients
(Perioperative fasting in adults and children with comorbidities requiring postoperative moni-
2005). Verbal and written instructions should be toring following any grade of surgery. Pre-assess-
provided. ment in this group is also clinic based with an
emphasis on optimization of medical conditions
and the procurement of appropriate essential inves-
Follow-Up tigations to allow the procedure to be undertaken
with minimal risk. Preparation of both the patient
Planned follow-up should be outlined and and parent/guardian for inpatient stay is key as this
emergency contact numbers provided so that aids in psychological preparation for what is a sig-
the carer can easily access services in the post- nificant life event for them. Pre-assessment for
operative period. Wound care advice can also inpatient surgery may be combined with day case
be given at this stage; however, this should be surgery clinics and should follow a similar format.
reiterated prior to discharge on the day of However, there are extra considerations that must
surgery. be discussed.
Investigations
General Education Opportunities
In addition to the investigations that were outlined
Finally, this is a good opportunity for general
previously, several baseline investigations may be
education of the patient and carer. Health
required for children undergoing some inpatient
promotion is an essential part of any patient
procedures. If blood loss is expected and a transfu-
consultation and is of particular importance
sion may be required, a baseline FBC should be
when a specific problem such as obesity is
taken so as to have a preoperative hemoglobin value
encountered.
to refer to, and blood grouping and crossmatching
should be undertaken. If a prolonged anesthetic is
expected or the child will be fasting for long periods
Completion of the Assessment of time postoperatively, a baseline renal profile
should be obtained. Indications for additional tests
At the end of this exercise, a summary of the are related to the child’s comorbid conditions.
child’s comorbidities and an assessment of their
physical condition are made, allowing an anes-
thetic plan to be formulated for the day of surgery. Blood Grouping and Crossmatching
Premedication, method of induction, regional or
local anesthetic techniques, and postoperative Blood grouping and crossmatching are particularly
analgesia plans should be prepared. Any potential important as long delays in the theater list can occur
or identified problems should be highlighted. This if these bloods need to be drawn on the day of
level of planning ensures that the list should pro- surgery. In most centers there will be a local policy
ceed with minimal delays. Preoperative assess- that defines the procedures that require grouping
ment documentation should be included in any with or without crossmatching; however, other fac-
integrated care pathway that is designed for ambu- tors such as the child’s physical condition and the
latory surgery. preoperative hemoglobin may have an impact on
Table 9 Suggested blood product ordering for surgical preoperative bowel preparation (Wille-Jørgensen
procedures et al. 2005). Mechanical bowel preparation has
Suggested blood product been used in children for several different types of
Procedure ordering surgery: elective colorectal surgery, lower urinary
Laparotomy for Group and save tract surgery that utilizes bowel as an augmenter or
intussusception
a conduit, esophageal replacement surgery using a
Laparoscopic Group and save
cholecystectomy colonic interposition graft, and diagnostic
Laparoscopic Crossmatch 1 unit packed red colonoscopic procedures. However, over the last
splenectomy cells 5 years there has been evidence that mechanical
Laparoscopic Group and save bowel preparation may not be beneficial for
fundoplication patients. A multicenter trial showed that the use
Major oncological Crossmatch 2 units packed red of a mechanical bowel preparation in children
resection cells
before colostomy takedown was associated with a
Resection of Crossmatch 1–2 units packed
abdominal red cells depending on age of greater risk of wound infection, no protection from
malignancy child other complications, and a longer length of stay
Bowel resection Crossmatch 1–2 units of packed (Serrurier et al. 2012). There is also evidence that
red cells depending on age of mechanical bowel preparation can be omitted
child
safely in colonic interposition grafting (Leal et al.
Open esophageal Crossmatch 1–2 units of packed
surgery red cells depending on age of
2013), augmentation cystoplasty (Victor et al.
child 2012), and urinary diversion procedures that utilize
Insertion of Group and save ileum as a conduit (Tabibi et al. 2007). Therefore,
Hickman line bowel preparation may be safely omitted for most
(neonate) procedures; however diagnostic colonoscopy relies
Closure of Group and save
on a clean colonic mucosal surface to facilitate the
gastroschisis
recognition of mucosal abnormalities, and there-
Correction of Group and save
duodenal atresia fore mechanical bowel preparation is indicated for
Ladd’s procedure Group and save this procedure.
the decision. As a general rule, all neonates, exclud- Optimization of Nutrition

ing those undergoing pyloromyotomy and inguinal
herniotomy, should have a group and save taken. A Due to the fact that children are dependent on the
group and crossmatch may be required if significant receipt of adequate nutrition to optimize growth,
hemorrhage is expected. Anemic patients and growth failure may occur if they become nutri-
patients with coagulopathies should have a group tionally deplete. It is vitally important that chil-
and crossmatch sent. Fresh frozen plasma, platelets, dren undergoing elective surgery that have a poor
and albumin may also be ordered preoperatively for nutritional status are identified. The typical
those patients with coagulopathies following dis- patients that we may encounter are those that
cussion with the hematology team. A list of pro- suffer from inflammatory bowel disease, and
cedures and suggested blood product ordering is patients with intestinal failure from any cause, as
found in Table 9. these are the population that are more likely to
require surgical intervention. Preoperative evalu-
ation of nutritional status is essential. Height,
Preoperative Mechanical Bowel weight, and head circumference should be taken
Preparation and plotted on an appropriate growth chart. The
child’s general physical condition should be
This has been an area of contention over the last assessed followed by assessment of body fat
number of years with some large randomized trials stores, muscle wasting, edema, rashes, and thin-
in adult patients that have shown limited benefit of ning of the hair, and an examination of the mouth
and teeth, to identify any evidence of dental car- disease is also significant as is the presence of
ies, gingivitis, and angular stomatitis. Significant cardiac symptoms such as shortness of breath,
concerns regarding a child’s nutritional deficiency fatigue, and poor weight gain. These patients
should be discussed with the child’s pediatrician, should all be investigated with a 12-lead ECG,
and the anesthetist and preoperative nutritional echocardiogram, and cardiology assessment.
support may be considered. If the child requires General anesthesia should be deferred until clar-
optimization of their nutritional status, this can be ification of the nature of the murmur. Children
done in many ways. Simply the addition of high- under the age of 1 year with a murmur of any type
calorie supplements may be sufficient. High-cal- should be referred for a cardiology assessment
orie enteral feeds or elemental feeds may also be and their procedure deferred. It is safe to proceed
required. In some cases where malabsorption is a with surgery in children over the age of one if the
major factor, preoperative parenteral nutrition child has an innocent sounding murmur, a nor-
(PN) may be indicated. However, evidence is mal examination, and is asymptomatic. How-
lacking to conclusively prove that this improves ever, they should be referred for outpatient
patient outcomes. PN delivery also requires cen- cardiology assessment.
tral venous access and puts a child at risk of
complications such as line sepsis and PN-induced
cholestasis. Therefore, each patient should be Endocarditis Prophylaxis
assessed on a case-by-case basis, and the risks
and benefits of administering PN should be con- There has been a recent change to the recommen-
sidered before treatment is initiated. dations for the use of antimicrobial prophylaxis in
patients at risk of developing infective endocardi-
tis during dental and surgical procedures. Patients
Specific Considerations with structural congenital heart disease, acquired
valvular heart disease, valve replacement, and
The Child with an Incidental Murmur previous history of infective endocarditis are con-
sidered at high risk of developing infective endo-
Murmurs are common findings in infants and carditis. Prophylaxis is no longer recommended
children. Most originate through normal flow for surgical or dental procedures. NICE recom-
patterns with no structural or anatomic abnor- mends antibiotic prophylaxis if a person at risk of
malities of the heart or vessels and are referred infective endocarditis is receiving antimicrobial
to as innocent or physiological murmurs. If a therapy because they are undergoing a gastroin-
previously undiagnosed murmur is detected dur- testinal or genitourinary procedure at a site where
ing examination of an otherwise healthy child, there is a suspected infection (Prophylaxis
the clinician must be able to discern if this is an Against Infective Endocarditis 2008).
innocent murmur that is clinically insignificant
or a murmur that requires further assessment
before a general anesthetic is undertaken. Inno- The Child with an Upper Respiratory
cent murmurs are asymptomatic, systolic, short, Tract Infection (URTI)
and soft with no other abnormal sounds. They
often have a musical quality and may be tran- URTIs are common in infants and children and are
sient. Red flags that increase the likelihood of a mostly viral in origin. The natural history is a self-
pathologic murmur include a holosystolic or dia- limiting illness that resolves with supportive ther-
stolic murmur, grade 3 or higher murmur, harsh apy. However, an URTI is far from benign when
quality, an abnormal S2, maximal murmur inten- considering general anesthesia as it may put the
sity at the upper left sternal border, a systolic child at increased risk of laryngospasm, oxygen
click, or increased intensity when the patient desaturation, bronchospasm, severe coughing,
stands (Frank and Jacobe 2011). A family history and breath holding during anesthetic induction
of sudden cardiac death or congenital heart and emergence (Tait and Malviya 2005).
Table 10 Systemic manifestations of URTI desaturation, and overall critical respiratory

Systemic manifestations of URTI events (Tait et al. 2008). Therefore, the anesthe-
Temperature greater than 38.5 C tist must ensure that an obese child is optimized
Purulent nasal discharge preoperatively, anticipate perioperative prob-
Productive cough lems, and deal with them appropriately. Parents
Room-air oxygen saturation of less than 96% should be made aware of this increased risk, and
Crackles or wheeze on chest examination education on healthy eating, exercise, and weight
Positive chest radiograph findings loss should be given at the pre-assessment clinic
along with written material and online resources
The risk of airway complications remains high for to assist them in modifying their lifestyle
up to 6 weeks after a URTI, probably as a result of (▶ Chap. 33, “Childhood Obesity”).
altered airway reactivity (Cohen and Cameron
1991). However, studies have found no significant
increase in respiratory complications among chil- The Child with Diabetes
dren anesthetized during an acute URTI (Skolnick
et al. 1998), which has led some to advocate not All children with diabetes should be seen in the
canceling surgery for these children. Therefore, preoperative assessment clinic. The aim is to
each child should be assessed on a case-by-case assess glycemic control, optimize control, and
basis, and the implications of delaying the surgery arrange adjunctive investigations. Glycemic con-
must be weighed against the risks of perioperative trol is assessed by reviewing the child’s recent
complications. Patients who have systemic mani- blood glucose readings. The majority of premeal
festations (see Table 10) should have the surgical readings should be between 4 and 10 mmol/L, and
procedure delayed for 4–6 weeks after the resolu- hypoglycemia should be avoided. An HbA1c can
tion of symptoms (Folkerts et al. 1998). Surgery be taken as a further assessment of glycemic con-
and anesthesia can usually be performed safely in trol. Following this, the insulin or medication
children who have none of these symptoms, par- regime should be reviewed and documented.
ticularly if they do not require endotracheal intu- Any changes that are made to the child’s thera-
bation (Leal et al. 2013). peutic regime should be documented clearly. Any
other appropriate investigations should be under-
taken, and the patient should be scheduled first on
The Obese Child the list to avoid prolonged periods of fasting lead-
ing to hypoglycemia. In conjunction with the
The prevalence of childhood obesity is increas- child’s pediatrician and anesthetist, a preoperative
ing rapidly worldwide (World Health Organisa- medication plan should be formulated so that
tion 1997). The definition of overweight and there is clarity on the day of surgery.
obesity in childhood has been based on pooled
international data for body mass index and has
been linked to the widely used adult obesity The Child with Cystic Fibrosis
cutoff point of 30 kg/m2 (Cole et al. 2000).
Obesity in children can cause significant prob- Cystic fibrosis (CF) is a progressive pulmonary
lems for the anesthetist due to their body habitus. disease that has multisystem consequences pre-
They can have significant hypoventilation or air- disposing these children to associated problems
way obstruction in the supine position and under that require surgical intervention. Patients with
anesthesia and are at increased risk for aspiration CF have an incidence of postoperative complica-
pneumonitis (Zuckerberg and Maxwell 2013). tions of 10–22% and a perioperative mortality of
Studies have also shown that children who are 1–5% (Saltzman et al. 2002). Meticulous preop-
obese have a greater incidence of difficult mask erative assessment and optimization are critical
ventilation, bronchospasm, major oxygen to avoid complications. Preoperatively, an
assessment of the severity of the patient’s disease be discussed in detail in the chapter on fetal
must be undertaken. Preoperative chest X-ray, surgery ▶ Chap. 7, “Fetal Surgery”.
pulmonary function tests, and chest computed There have been significant advances in modes
tomography scan might be required to aid estima- and techniques for prenatal diagnosis in recent
tion of illness severity. Patients with CF who are years. These modes include amniocentesis,
chronically hypoxemic are at risk of pulmonary amniography, fetoscopy, fetal sampling, fetal
hypertension and cor pulmonale. An echocardio- magnetic resonance imaging (MRI), and ultraso-
graphic evaluation should be performed in this nography. The latter, enabling direct imaging of
subset of patients (Zuckerberg and Maxwell fetal anatomy, is a noninvasive technique, safe for
2013). Identification of active respiratory tract both the fetus and the mother (Hirata et al. 1990).
infection may necessitate preoperative admission However, it is important to remember that sonog-
for intravenous antibiotics and chest physiother- raphy is operator dependent. With further
apy. A high dependency or intensive care bed is advances in screening techniques, and combining
often required for the child’s postoperative care. various antenatal screening modalities, such as the
Once again, informed consent is critical due to the Serum, Urine, and Ultrasound Screening Study
risk of anesthetic complications in this group of (SURUSS) for Down’s syndrome (Alfirevic and
children. Neilson 2004), the efficacy and safety of antenatal
screening have improved. Important information
on fetal malformation, fetal movement, and fetal
Preoperative Assessment of the vital functions, such as breathing movements and
Neonate heart rate variability, may be captured by real-time
sonographic imaging. This information may
The neonate poses a significant and unique chal- guide postnatal intervention, and serial sono-
lenge to the pediatric surgeon as it is in this graphic evaluations are particularly useful in fol-
neonatal period that most congenital abnormal- lowing the progression or regression of any fetal
ities are identified, frequently requiring correc- disease. All this important information is an inte-
tive surgery. However, many of these gral part of the preoperative assessment of a new-
abnormalities can be identified in the antenatal born with any type of congenital malformation.
period, and therefore there is the potential for Neonates born with congenital malformations
antenatal counselling for parents providing them are usually in urgent need of surgery and may also
with information regarding the child’s condi- suffer from a multitude of medical problems. Fur-
tion, the management options that are available, thermore, they are at a period when significant
and allowing them to opt for termination of physiological and maturational changes of transi-
pregnancy, in some countries, in cases of serious tion from fetal to extrauterine life are occurring.
malformations that are incompatible with life. Surgical and anesthetic intervention at this time
Prenatal diagnosis also improves prenatal care may affect this transition by interfering with nor-
by ensuring that antenatal and perinatal care is mal homeostatic controls of circulation, ventila-
provided in an appropriate center, delivering the tion, temperature, fluid balance, and metabolic
baby in the timing and mode that are appropriate balance. To facilitate a smooth preoperative
for the specific fetal malformation. Multi- course, multidisciplinary care is fundamental.
disciplinary meetings in which obstetric, neona- All neonates undergoing surgery must be care-
tal, and pediatric surgical expertise are present fully assessed preoperatively, giving particular
are commonplace in most large pediatric institu- attention to the following:
tions. They improve postnatal outcome and
encourage effective communication between all • History and clinical examination
disciplines. Prenatal intervention for certain • Temperature regulation
congenital anomalies is also possible; however, • Respiratory function
this is beyond the remit of this chapter and will • Cardiovascular status
Table 11 Principle features of prematurity Table 12 Common physiological and clinical problems
associated with prematurity
Principle features of prematurity
A head circumference <50th percentile Common physiological and clinical problems associated
A thin, semitransparent skin with prematurity
Soft, malleable ears Apneic spells
Absence of breast tissue Bradycardia
Absence of plantar creases Hypothermia
Undescended testicles with flat scrotum and, in females, Sepsis
relatively enlarged labia minora Hyaline membrane disease
Blindness and lung injury due to use of high levels of
oxygen
Patent ductus arteriosus
• Metabolic status
• Coagulation abnormalities
• Laboratory investigations
Table 13 Clinical and physiological problems of SGA
• Fluid and electrolytes and metabolic infants
responses.
Clinical and physiological problems of SGA infants
Higher metabolic rate
Hypoglycemia
History and Clinical Examination Thermal instability
Polycythemia
Antenatal history forms a significant component Increased risk of meconium aspiration syndrome
of the initial assessment of the surgical neonate.
One must document all antenatal diagnoses and
any antenatal pediatric surgical input. Anatomical physiological and clinical problems associated
and structural anomalies are important but even with prematurity are highlighted in Table 12.
more so are the metabolic or chromosomal abnor- In the SGA infant, although the body weight is
malities, which must be diagnosed prenatally or low, the body length and head circumference
soon after birth. approach that of an infant of normal weight for
Fundamental to the initial assessment of the age. These babies are older and more mature and
neonate is the condition in which the child is have different clinical and physiological problems
born in, the assessment of the degree of prematu- (see Table 13). In relation to these differences,
rity, and the identification of the congenital defect three important observations have been reported:
and its severity. The normal full-term infant has a
gestational age of 37 weeks or more and a body • LBW infants have a mortality ten times that of
weight >2.5 kg. Infants born with a birth weight full-sized infants.
<2.5 kg are defined as being of low birth weight • More than 75% of overall perinatal mortality is
(LBW). Those with a birth weight of <1.5 kg are related to clinical problems of LBW infants.
defined as very low birth weight (VLBW), and • The rate of anatomical malformation in LBW
those with a birth weight of <1 kg are defined as infants is higher than for infants at term (Avery
extremely low birth weight (ELBW). Babies may et al. 1748).
be of LBW because they are preterm or because of
intrauterine abnormalities affecting growth
(growth retardation). “Small-for-gestational-age”
(SGA) infants are those whose birth weight is less Temperature Regulation
than the tenth percentile for their age. Infants may,
of course, be both growth retarded and preterm. Temperature regulation in newborn infants, par-
The principal features of prematurity are ticularly preterm neonates, is a critical aspect of
outlined in Table 11, and the common their management as they have poor thermal
stability. A high surface area/weight ratio, a thin 12 days. The normal skin temperature for a full-
layer of insulating subcutaneous fat, and a high term infant is 36.2 C, but because of many benign
thermoneutral temperature zone are factors that factors such as excessive bundling, ambient tem-
contribute to this temperature variability. The perature may affect body temperature (Puri and
newborn readily loses heat by conduction, con- Gillick 2011). Thus the control of the thermal
vection, radiation, and evaporation, with the pre- environment of the newborn is of the utmost
dominant mechanism being radiation. Shivering importance to the outcome.
thermogenesis is absent in the neonate, and the
heat-producing mechanism is limited to non-shiv-
ering thermogenesis through the metabolizing of Respiratory Function
brown fat (Silverman and Sinclair 1966). Cold
stress in these neonates leads to increased meta- Respiratory failure is the leading cause of death in
bolic rate and oxygen consumption, and calories the neonate. Therefore, assessment of respiratory
are used to maintain body temperature. If pro- function is essential in all neonates undergoing
longed, depletion of the limited energy reserve surgery. The main clinical features of respiratory
occurs and predisposes to hypothermia and distress are restlessness, tachypnea, grunting,
increased mortality. Hypothermia can also sug- nasal flaring, sternal recession, retractions, and
gest infection and should trigger diagnostic eval- cyanosis. There are several common surgical con-
uation and antibiotic treatment if required. ditions that may present with respiratory distress
Temperature control becomes even more sig- in the newborn period, and these include pneumo-
nificant in neonates that have a condition that thorax, congenital diaphragmatic hernias, esoph-
predisposes them to excessive heat loss. The clas- ageal atresia, and congenital pulmonary airway
sic example used is omphalocele or gastroschisis. malformations (CPAM). A chest X-ray should
Priorities in these babies are to minimize heat loss be obtained with a nasogastric tube passed imme-
by wrapping the defect in cling film or a bowel diately after the resuscitation of an infant if there
bag and nursing them within a controlled temper- are any signs of respiratory distress to determine
ature in an incubator. It is desirable that most sick the etiology. Blood gas studies are essential in the
neonates be nursed in incubators as they are effi- diagnosis and management of respiratory distress
cient in maintaining the baby’s temperature but and can be obtained by repeated sampling from an
may not allow adequate access to the sick baby for umbilical artery catheter. Arterial PO2 and PCO2
active resuscitation and observation. Overhead indicate the state of oxygenation and ventilation,
radiant heaters, controlled by a temperature respectively. Noninvasive monitoring techniques
probe on the baby’s skin, are an excellent option with transcutaneous PO2 monitors or pulse
as they are effective and allow adequate access for oximeters can also be used. Monitoring of arterial
nursing and medical procedures. Hyperthermia pH is also essential in patients with respiratory
should be avoided, because it is associated with distress. Acidosis in the neonate produces
perinatal respiratory depression and detrimental pulmonary arterial vasoconstriction and myocar-
outcomes in the short-term period post-delivery dial depression. Respiratory alkalosis causes
(Laptook and Watkinson 2008). The environmen- decreased cardiac output, decreased cerebral
tal temperature must be maintained near the blood flow, diminished oxyhemoglobin dissocia-
appropriate thermoneutral zone for each individ- tion, and increased airway resistance with dimin-
ual patient because the increase in oxygen con- ished pulmonary compliance (Philippart et al.
sumption is proportional to the gradient between 1980). High-frequency ventilation, use of surfac-
the skin and the environmental temperature (Hey tant, use of inhaled nitric oxide (iNO), and extra-
1969). This is 34–35 C for LBW infants up to corporeal membrane oxygenation (ECMO) have
12 days of age and 31–32 C at 6 weeks of age. been shown to improve survival dramatically
Infants weighing 2,000–3,000 g have a thermo- in selected neonates (Ford 2006). Extracorporeal
neutral zone of 31–34 C at birth and 29–31 C at life support (ECLS) provides long-term
cardiopulmonary support for patients with revers- of the vessels with expansion of the lungs and also
ible pulmonary and/or cardiac insufficiency. because of the vasodilatory effect of inspired oxy-
Congenital diaphragmatic hernia represents gen. However, during the first few weeks of life,
one of the most common surgical conditions the muscular pulmonary arterioles retain a signif-
requiring the intervention of ECMO. (Cross-ref- icant capacity for constriction, and any
erence with “ECMO” chapter). constricting influences such as hypoxia may result
Respiratory failure secondary to surfactant in rapid return of pulmonary hypertension.
deficiency is a major cause of morbidity and mor- The management of neonates with congenital
tality in preterm infants. Surfactant therapy sub- malformation is frequently complicated by the
stantially reduces mortality and respiratory presence of congenital heart disease. At this time
morbidity for this population. Secondary surfac- of life, recognition of heart disease is particularly
tant deficiency also contributes to acute respira- difficult. There may be no murmur audible on first
tory morbidity in late preterm and term neonates examination, but a loud murmur can be audible a
with meconium aspiration syndrome, pneumonia/ few hours, days, or a week later. A newborn
sepsis, and perhaps pulmonary hemorrhage; sur- undergoing surgery should have a full cardiovas-
factant replacement may be beneficial for these cular examination and a chest X-ray. The presence
infants (Engle and the Committee on Fetus and of cyanosis, respiratory distress, cardiac murmurs,
Newborn 2008). abnormal peripheral pulses, or congestive heart
iNO is available for treatment of persistent failure should be recorded. If there is suspicion
pulmonary hypertension of the neonate (PPHN). of a cardiac anomaly, the baby should be exam-
It decreases pulmonary vascular resistance lead- ined by a pediatric cardiologist. In recent years the
ing to diminished extrapulmonary shunt and has a use of the noninvasive technique of echocardiog-
microselective effect which improves ventilation/ raphy allows accurate anatomical diagnosis of
perfusion matching. Unfortunately, the beneficial cardiac anomalies, in many cases prenatally.
effects of iNO in premature infants are less clear
cut, with a risk of intracranial hemorrhage being
observed in some studies (Barrington and Finer Metabolic Status
2007). In newborns with severe lung disease,
high-frequency oscillatory ventilation (HFOV) is Acid–Base Balance
frequently used to optimize lung inflation and
minimize lung injury. The buffer system, renal function, and respiratory
In summary, the type of respiratory care in function are the three major mechanisms respon-
neonates will always depend upon clinical and sible for the maintenance of normal acid–base
radiological findings supported by blood gas balance in body fluids. Most newborn infants
estimations. can adapt competently to the physiological
stresses of extrauterine life and have a normal
acid–base balance. However, clinical conditions
Cardiovascular Status such as respiratory distress syndrome (RDS), sep-
sis, congenital renal disorders, and gastrointesti-
At birth, there is a rapid transition from the fetal nal disorders may result in gross acid–base
circulation to the neonatal circulation. The ductus disturbances in the newborn. In a newborn under-
arteriosus normally closes functionally within a going surgery, identification of the type of
few hours after birth, while anatomical closure acid–base disturbance, whether metabolic or
occurs 2–3 weeks later. Prior to birth the pulmo- respiratory, simple or mixed, is of great practical
nary arterioles are relatively muscular and importance to permit the most suitable choice of
constricted. With the first breath, total pulmonary therapy and for it to be initiated in a timely
resistance falls rapidly because of the unkinking fashion.
Hypoglycemia they are premature or associated with a compli-

cated pregnancy or delivery. Asymptomatic hypo-
The mechanisms of glucose homeostasis are not calcemia can be effectively treated by a
well developed in the early postnatal period. This continuous infusion of 10% calcium gluconate
puts the neonate at risk of both hypoglycemia and 75 mg/kg/day and can be prevented by adding
hyperglycemia. Hypoglycemia is usually defined calcium gluconate to daily maintenance therapy.
as a serum glucose level <1.6 mmol/L in the full- The symptomatic patients should be treated by
term neonate and <1.1 mmol/L in the LBW infant slow intravenous administration of 10% calcium
during the first 3 days of life. After 72 h, serum gluconate, 6 mL in a LBW infant and 10 mL in a
glucose concentration should always be above full-term infant, with monitoring of heart rate.
2.2 mmol/L. Hypoglycemia may be asymptom- Serum calcium levels should be maintained
atic or associated with a number of nonspecific within the 2.0–2.63 mmol/L range.
signs such as apathy, apnea, a weak or high-
pitched cry, cyanosis, hypotonia, hypothermia,
tremors, and convulsions. The possibility of hypo- Hypomagnesemia
glycemia must be anticipated to prevent avoidable
brain damage. Prenatally, the glucose require- Hypomagnesemia may occur in association with
ments of the fetus are obtained almost entirely hypocalcemia in SGA infants and neonates with
from the mother, with very little derived from increased intestinal losses. If there is no response
fetal gluconeogenesis. Following delivery, the to correction of calcium deficiency, a serum mag-
limited liver glycogen stores are rapidly depleted, nesium level should be obtained. The treatment is
and the blood glucose level then depends on the by intravenous infusion of 50% magnesium sul-
infant’s capacity for gluconeogenesis, the ade- fate 0.2 mL/kg every 4 hours until the serum
quacy of substitute stores, and energy require- magnesium level is normal (0.7–1.0 mmol/L).
ments. Surgical stress and concomitant feeding ▶ Chap. 15, “Fluid and Electrolyte Balance in
practices may further exacerbate matters. Infants and Children”.
All neonates undergoing surgery should have
an infusion of 10% glucose at a rate of
75–100 mg/kg body weight per 24 h, and blood Hyperbilirubinemia
glucose levels should be monitored every 4–6 h.
Blood glucose level should be maintained above Jaundice in the newborn is a common physiologi-
2.5 mmol/L at all times. The symptomatic infant cal problem seen in 25–50% of all normal newborn
should be treated urgently with 50% dextrose, infants and in a considerably higher percentage of
1–2 mL/kg intravenously, and maintenance intra- premature and SGA infants (Maisels and GB
venous dextrose 10–15% at 80–100 mL/kg/24 h. 2005). It is the result of a combination of shortened
red cell survival, with a consequent increase in
bilirubin load, and an immature glucuronyl trans-
Hypocalcemia ferase enzyme system with a limited capacity for
conjugating bilirubin. This results in transient
Hypocalcemia is usually defined as a serum cal- physiological jaundice that reaches a maximum at
cium value <1.8 mmol/L. Hypocalcemia occurs the age of 3–4 days but returns to normal levels at
usually during the first few days of life, with the the end of the first week.
lowest levels of serum calcium seen during the Hyperbilirubinemia in the newborn may have a
first 48 h. The most common causes of neonatal pathological basis such as severe sepsis, Rh and
hypocalcemia include decreased calcium stores ABO incompatibilities, and congenital hemolytic
and decreased renal phosphate excretion. The anemia. Neonatal hemolytic jaundice usually
LBW infants are at greater risk, particularly if appears during the first 24 h of life. Other causes
for prolonged hyperbilirubinemia, including those Laboratory Investigations

often associated with surgical conditions, such as
biliary obstruction, hepatocellular dysfunction, A newborn undergoing surgery should have blood
and upper intestinal tract obstruction. Extrahe- drawn on admission for the various investiga-
patic biliary obstruction should be identified as tions, including full blood count, serum sodium,
early as possible, as early operations for biliary potassium and chloride, urea, calcium, magne-
atresia are essential to obtain good short- and sium, glucose, bilirubin, and group and
long-term results. crossmatch. Blood gases and pH estimation
The major concern in neonatal hyper- should also be obtained to assess acid–base state
bilirubinemia is the risk of kernicterus resulting and the status of gas exchange. The coagulation
in brain damage. status of infants who have been asphyxiated may
Predisposing factors for jaundice include: be abnormal and should be evaluated. Neonatal
sepsis can result in disseminated intravascular
• Hypoalbuminemia (circulating bilirubin is clotting and severe thrombocytopenia. A platelet
bound to albumin) count <50,000/mm (Nicoll 1902) in the neonate
• Hypothermia is an indication of preoperative platelet transfu-
• Acidosis sion. Blood cultures should be obtained wherever
• Hypoglycemia there is any suspicion of sepsis.
• Hypoxia
• Caloric deprivation
• Use of drugs (e.g., gentamicin, digoxin, Fluid and Electrolytes and Metabolic
furosemide) Responses
When the serum bilirubin concentration Estimation of the parenteral fluid and electrolyte
approaches a level at which kernicterus is likely requirements is an essential part of management of
to occur, hyperbilirubinemia must be treated. In newborn infants with surgical conditions. Inade-
most patients, other than those with severe hemo- quate fluid intake may lead to dehydration, hypo-
lysis, phototherapy is a safe and effective treat- tension, poor perfusion with acidosis,
ment method. When the serum indirect bilirubin hypernatremia, and cardiovascular collapse. Exces-
level rises early and rapidly, hemolysis is often the sive fluid resuscitation may result in pulmonary
reason, and exchange transfusion is sometimes edema, heart failure, opening of ductal shunts,
indicated. bronchopulmonary dysplasia, and cerebral intra-
ventricular hemorrhage. Precise calculation of
fluid and electrolyte requirements of each individ-
Coagulation Abnormalities ual newborn and accurate estimation of excess
losses is the cornerstone of fluid management.
Coagulation abnormalities in the neonate should Hydration status must be assessed, and any deficit
be sought preoperatively and treated. The new- must be replaced. Consideration of the electrolyte
born is deficient in vitamin K, and this should be content of specific fluid losses is also essential as
given as 1 mg prior to surgery in order to prevent this guides electrolyte monitoring and replacement.
hypoprothrombinemia and hemorrhagic disease In fetal life around 16 weeks’ gestation, total
of the newborn. Neonates with severe sepsis, body water (TBW) represents approximately 90%
such as those with necrotizing enterocolitis, of total body weight, and the proportions of extra-
may develop disseminated intravascular cellular and intracellular water components are 65%
coagulopathy with a secondary platelet defi- and 25%, respectively. However, fluid shifts occur
ciency. Such patients should be given fresh fro- during fetal life, so that at term, these two compart-
zen plasma, fresh blood, or platelet concentrate ments constitute about 45% and 30%, respectively,
preoperatively. of total body weight (Friis-Hansen 1983).
In very small premature infants water consti- Accurate measurements of urine flow and
tutes as much as 85% of total body weight, and in concentration are fundamental to the manage-
the term infant it represents 75% of body weight. ment of critically ill infants and children, espe-
The total body water decreases progressively dur- cially those with surgical conditions and
ing the first few months of life, falling to 65% of extensive tissue destruction or with infusion of
body weight at the age of 12 months, after which it high osmolar solutions. In these situations, it is
remains fairly constant (Statter 1992). recommended that urine volume be collected and
Maintenance fluid requirement consists of measured accurately ▶ Chap. 15, “Fluid and
water and electrolytes that are normally lost Electrolyte Balance in Infants and Children”.
through sweat, urine, stool and insensible losses.
Numerous factors contribute to the volume of
insensible water loss. These include the ambient Conclusion and Future Directions
temperature, metabolic rate, respiratory rate, ges-
tational maturity, body size, surface area, fever, In summary, the pre-assessment of neonates is a
and the use of radiant warmers and phototherapy. multifaceted complex process that requires care-
In babies weighing less than 1,500 g at birth, ful consideration of multiple factors, including
insensible loss may be up to three times greater maternal antenatal care, antenatal diagnoses,
than that estimated for term infants (Bell et al. perinatal problems, presence of congenital
1980). Respiratory water loss is approximately defects, and the physiology of early life and its
5 mL/kg per day and is negligible when infants impact on the child’s care. Multidisciplinary
are intubated and on a ventilator. Water loss care is extremely important, and maintenance
through sweat is generally negligible in the new- of solid relationships with neonatology col-
born. Fecal water losses are 5–20 mL/kg per day. leagues will help to ensure that these children
The kidneys are the final pathway regulating are managed optimally. Clear communication
fluid and electrolyte balance. Urinary output is with our anesthetic colleagues and early referral
dependent on water intake, the quantity of solute for assessment preoperatively encourage all to
for excretion, and the concentrating abilities of have an active role in the successful handling of
the kidney. Renal function in the newborn infant these patients. In children, emphasis is on the
varies with gestational age (Abitbol et al. 2016). efficiency and accuracy of the assessment,
Very preterm infants younger than 34 weeks’ informed consent, the delivery of preoperative
gestational age have reduced glomerular filtra- instructions, such as fasting instructions, and the
tion rate (GFR) and tubular immaturity in the minimization of any distress to the patient and
handling of the filtered solutes when compared their carer, ultimately leading to a safe procedure
to term infants. The full-term newborn infant can performed in a timely fashion with the child and
dilute urine to osmolarities of 30–50 mmol/L and parent having had a good experience overall.
can concentrate it to 550 mmol/L by approxi- Further experience in day case surgery will
mately 1 month of age. If the volume of fluid allow more complex procedures to be performed
administered is inadequate, urine volume falls, in an ambulatory setting.
and concentration increases. With excess fluid
administration, the opposite occurs. We aim to
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kg (Engle and the Committee on Fetus and New- Children
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Principles of Pediatric Surgical
Imaging 23
David Rea, Clare Brenner, and Terence Montague
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Effects of Radiation on Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Environmental Issues for a Pediatric Radiology Department . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Sedation and Anesthesia in the Radiology Department . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379
Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Natural Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
General Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Consent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Personnel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Contrast Media and Use in the Pediatric Radiology Department . . . . . . . . . . . . . . . . . 381
Barium Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Iodinated Contrast Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Contrast Use in the Fluoroscopy Suite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Contrast Use in the CT Suite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Contrast Use in the MRI Suite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Contraindications/Side Effects/Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382
Pediatric Interventional Radiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
D. Rea (*) · C. Brenner Abstract

Department of Radiology, Our Lady’s Children’s Hospital, Imaging of children differs to the imaging of
Dublin, Ireland adults despite using very similar equipment.
e-mail: david.rea@olchc.ie Infants and young children are often poorly
T. Montague cooperative to keep still, stay in a particular
Department of Anesthesia, Our Lady’s Children’s position or hold their breath. This varies with
Hospital, Dublin, Ireland

https://doi.org/10.1007/978-3-662-43588-5_25
376 D. Rea et al.
the age of the patient and affects all types of radiologist and the child, on a level that both can
pediatric imaging examinations. Children suf- understand.
fer from different diseases and require different Significant improvements in surgical tech-
treatments. The care prior to, during, and fol- niques, anesthesia, and intensive care in the last
lowing the examination differs from the care 20 years have advanced and improved the care of
provided in adults. Most examinations require the pediatric patient. Imaging modalities have
specific adjustments in children so the study is reached higher levels of sophistication, and the
obtained optimally, safely, and with the least range of invasive and interventional radiology
radiation exposure where possible. procedures has also increased. These advances
have placed greater demands on pediatric radiol-
Keywords ogy departments which must be well staffed,
Pediatric radiology · Effects of radiation on funded, and equipped to keep pace with these
children · Pediatric contrast agents · Sedation/ developments. Due to this vast increase in avail-
anesthesia in pediatric radiology · Pediatric able tests, it is essential that both conventional
interventional radiology radiographic and high-technology imaging facili-
ties be used efficiently and rationally. A logical
sequence of investigations should be applied com-
Introduction mencing with the simplest and least invasive and
where possible minimizing exposure to radiation.
Diagnostic imaging in children remains different At all times the as low as reasonably achievable
to imaging of adults. There are many unique (ALARA) principle should be foremost in the
issues and challenges in the imaging of children mind of the radiologist. This approach may pro-
compared to adult imaging. Children suffer from vide the diagnosis and obviate the need for more
different diseases and require different treatments. complex invasive and expensive studies. Dupli-
The diagnostic strategies employed using the cation of information from multiple imaging
same equipment used in adult imaging are differ- modalities which does not improve the manage-
ent. The care prior to, during, and following the ment of the patient should be avoided.
examination differs from the care provided in
adults. Most examinations require specific adjust-
ments in children so the study is obtained opti- Effects of Radiation on Children
mally, safely, and with the least radiation exposure
where possible. Imaging in medicine is a vital tool, and with
Interactions between pediatric radiologists/ increased technologic advances and potential
radiographers/technologists (pediatric imagers) new applications, the benefits to patients and soci-
and pediatric patients are different to the interac- ety continue to become more diverse and continue
tion between adult radiologists and adult patients to increase. However, there are inherent risks for
as there are two interactions to be considered: the pediatric patient for modalities which impart
between the imager and the child and between ionizing radiation such as radiography, fluoros-
the imager and the child’s parents or guardians. copy, and computed tomography (CT). One of
This interaction is somewhat unique in medical these risks is the possibility of cancer develop-
interactions as the communication is mostly ment. Assignment of this risk generally follows a
between the radiologist and the parents rather linear, no-threshold model. Where possible, pedi-
than with the patient. Where relevant, parents atric radiologists try to use diagnostic modalities
need to give consent for the sedation and general which do not impart ionizing radiation such as
anesthesia required for the procedure as well as for ultrasound and magnetic resonance imaging
the procedure itself. This requires a good level of (MRI). When modalities require ionizing radia-
communication to be established between the tion, radiologists should be guided by the guiding
radiologist and the parents and between the principles of radiation protection which are
23 Principles of Pediatric Surgical Imaging 377
justification, optimization, and dose limitation. less than 1 in 1,000 (Brenner et al. 2001). Radia-
Any activity involving the use of ionizing radiation-induced cancers have been described for
tion needs to be justified to ensure that benefits many organs including the brain, bone marrow,
from using ionizing radiation outweigh the detri- digestive tract, thyroid, breast, and lung. This
ment that exposure to radiation may cause. The excess cancer risk due to medical radiation needs
radiation protection and safety concerns require to be compared to the overall one in five lifetime
that the relevant examination is tailored or opti- risk of developing cancer in the general popula-
mized so that individual doses, the number of tion (Brody et al. 2007). Exposure to the low
people exposed, and the probability of exposure radiation doses delivered during pediatric diag-
are all kept as low as reasonably achievable nostic procedures or exams may pose a risk, albeit
(ALARA) and that radiation doses for individuals small, of inducing cancer. However, the benefits
from all justified activities fall below defined for children far outweigh the relatively small radi-
limits. ation risks when the examinations are appropri-
The global average annual per person radiation ately prescribed and performed. Children remain
dose from all sources in the environment is more sensitive to radiation exposure than adults.
3.0 mSv per year. Of this, 80% (2.4 mSv) is due This increased sensitivity is inversely propor-
to naturally occurring sources of radiation (back- tional to age with the youngest children being
ground radiation). There is a large variability in most at risk. When considering the need to use
the dose received by individuals dependent on ionizing radiation to image children, several
where in the world they live. For several coun- issues need to be considered:
tries, radiation exposure from medical imaging
has for the first time in history replaced naturally
– Children are more vulnerable due to the higher
occurring sources as the largest contributor to
percentage of dividing cells.
human radiation exposure. Medical radiation
– Immature organ systems are more radiosensi-
now accounts for up to 50% of the total radiation
tive than fully mature tissues.
exposure for the US population which two
– Children have a long life expectancy thereby
decades earlier had been approximately 15%
resulting in a longer latency window for
(UNSCEAR 2008).
expressing long-term radiation-induced health
Within the modalities imparting radiation dose
effects.
to children, CT is the modality which imparts the
some of the largest radiation doses individually
and is also the modality that has the highest cumu- Radiation-induced cancers may have a long
lative global population “collective” dose. CT is latency period which varies dependent on the
also the modality with the highest increase in type of malignancy. This period may be shorter
utilization since the late 1990s. It is estimated for pediatric leukemias and longer for solid organ
that worldwide more than ten million CT exami- tumors. Similar exposure levels can result in
nations are performed annually in patients less higher relative doses and relative risks for smaller
than 18 years of age (Henoy-Bhangle et al. 2010). children compared to larger children or adults.
There is no controversy regarding the carcino- Frequently these doses can be reduced by care-
genic effects of intermediate to high doses of fully altering the parameters used to acquire the
ionizing radiation. However, there is growing evi- exam while not reducing the sensitivity of the
dence to support the theory that the low levels of exam or dramatically altering image quality.
radiation doses used in pediatric imaging may Advances in genetics mean that we now know
have a small risk of inducing cancer. The lifetime that some children with specific medical condi-
risks of a radiation-induced fatal cancer are age tions are even more susceptible than the general
and gender dependent. It has been estimated that pediatric population to radiation exposure. Refer-
the lifetime risks of radiation-induced fatal cancer ring surgical and medical specialists and radiolo-
associated with one pediatric CT scan might be gists alike need to be aware that children with
378 D. Rea et al.
hyper-radiosensitive syndromes such as ataxia MRI and ultrasound technology and techniques
telangiectasia or Nijmegen breakage syndrome which allows these modalities to replace some
or Fanconi’s anemia are genetically extremely radiation imparting tests done in previous years,
radiosensitive and therefore have a significantly it remains likely that for the foreseeable future,
greater risk of radiation-induced injury. plain radiography, fluoroscopy, and CT will con-
Referring surgical and medical specialists need tinue to be required in the medical investigations
to liaise with their pediatric radiology colleagues of pediatric patients.
to identify:
1. What is the clinical question to be answered? Environmental Issues for a Pediatric

2. How does doing the test alter the current man- Radiology Department
agement of the patient?
3. Can the question be answered by reviewing Provision of imaging services for children
prior imaging studies? requires a holistic approach influenced by a wide
4. Is a radiological imaging investigation variety of considerations. These considerations
necessary? may vary depending if the examination is under-
5. If an examination is necessary, can the question taken in general hospitals that deal with adult and
be answered appropriately and safely by use on pediatric patients or a specific pediatric radiology
a nonionizing radiation examination such as department in a specialist children’s hospital. In
ultrasound or MRI? (This question needs also general, hospitals that deal with adult and pediat-
to be balanced with the question of what is the ric patients, a dedicated pediatric room or com-
best investigation for the specific clinical plete sessions dedicated to pediatric radiology
problem.) should be available. Children should not be com-
6. If an ionizing radiation examination is peting with adults for radiology room time. It
required, it is the responsibility of the pediatric would not be uncommon for a pediatric exam to
radiologist to ensure that the study is tailored to take up to 50% longer than a similar study in a
only image the area of clinical concern and that compliant adult. It is very important to have expe-
the specific pediatric parameters used are rienced staff members who can obtain the child’s
appropriate to answer the clinical question confidence and cooperation in a secure and child-
while maintaining some element of image friendly environment to allow patient and carer
quality. comfort, produce an optimal quality exam, and
reduce the radiation dose to the child.
The need for imaging in the diagnosis and
treatment of pediatric disorders is unquestioned. Patient Preparation
However, there are multiple opportunities by Prior preparation of the child and the parents is
many specialists to reduce the potential radiation essential to facilitate this process. This may
burden to the child. Hospitals and clinics that involve review of the information provided to
image pediatric patients need to adopt a multi- parents in appointment letters to ensure that the
disciplinary approach in reducing the radiation letter explains in simple language what type of test
burden delivered to individual pediatric patients. parents are attending for, specific directions to the
This requires the input of appropriately trained room where the test will take place, clear feeding/
radiologists and radiographers/technologists and fasting instructions, and a contact number if there
input from medical physics specialists who should are queries in advance of the investigation. Many
be part of the radiology department team. Con- dedicated pediatric radiology departments have
stant monitoring of equipment and audit of doses colorful child-friendly picture booklets explaining
delivered and techniques used will over time drive their more common procedures in a friendly and
down the doses of radiation imparted to individual unthreatening way, what the exam will involve,
patients. While there continues to be advances in and how long a study might take. These books are
often authored by the clinical radiographic spe- (pacifiers) for younger children and if necessary
cialist of the relevant area and answer the common dipping the soother in glycerine may allow a fasted
questions children will ask about the exam. hungry baby to remain quiet long enough to allow
an exam such as an ultrasound be performed.
Order of Examinations Control of room temperature is very important
If multiple tests are to be performed on the same given the age range of children seen in a radiology
day, consideration should be given to performing department. While computer and ultrasound
the exams which require patient cooperation first machines generate large amounts of heat, these
before doing invasive procedures like cannulation devices often require air conditioning to try to
or blood work. An upset child who has had an IV cool the room. In contrast, newborn babies need
inserted and bloods drawn will be less likely to to be kept warm. Rooms for examinations in new-
cooperate for ultrasound than one who has an borns should be kept around 27 C (80 F), and
ultrasound beforehand. babies should be removed from the warm protec-
tive environment of the incubator for the shortest
Waiting Area possible time to allow the exam to take place
The waiting areas are one of the most important successfully and safely.
areas of a pediatric radiology department. Children Undressing children for examinations often
of all age ranges should be catered for. Ideally there makes them unhappy and vulnerable. Many
should be soft play areas for infants, interesting exams can be accomplished without having to
activities for older children, and games for older get the child undressed. Unless these are specific
adolescents. A child who comes to the department artifacts on clothing which would preclude acqui-
and plays happily while waiting for an exam is sition of an appropriate quality exam, clothing can
much more likely to cooperate in the environment often be rolled up or down as appropriate.
of an ultrasound or screening room than a child For younger children distraction devices such
who has sat on a parent’s lap in an uninteresting as musical toys, rattles, CD players, music, and
and cramped waiting room with no toys or enter- flashing toys can be useful in gaining a few short
tainment. Larger dedicated pediatric hospitals may minutes to complete an exam. After examinations
have play therapists who can explain the exam to are completed, most dedicated pediatric radiology
the child using toys and reduce the fear and anxiety departments give certificates of bravery or age-
in both the child and the parent. If present, play and gender-appropriate stickers as rewards for
therapists can sometimes reduce or shorten the being brave or cooperative.
length of time required to do an examination by It has been repeated many times in multiple
facilitating patient compliance. pediatric textbooks, but children are not small
adults. They have specific needs which may be
Examination/Procedure Rooms physical, emotional, and social. Prior thought as
All exam/procedure rooms need to be child to satisfying these needs will go a significant way
friendly and welcoming. Most departments have to minimizing the stresses upon the patient and
familiar and recognizable cartoon characters on their parent to optimize patient care and allow the
the walls or ceilings. Mobiles on the ceiling are radiologist to obtain the necessary data which in
also a good distraction object for younger chil- turn satisfies the needs of the clinician.
dren. For examinations like ultrasound, a television
screen placed above the examination couch can
often distract children to facilitate performing Sedation and Anesthesia in the
examinations. This is particularly valuable in the Radiology Department
toddler age group who can be a challenge to image
even for experienced pediatric staff. In ultrasound Radiological procedures for children may be pro-
use of a gel warmer is vital. Cold gel is a guaranteed longed with a requirement to remain still so
way to reduce patient compliance. Soothers images of sufficient quality may be obtained.
380 D. Rea et al.
Other procedures are uncomfortable or painful General Anesthesia

with compliance impossible to achieve in a child
who is awake (Jaimes and Gee 2016). Increas- This obviously requires the assistance of a trained
ingly, these challenges are managed with the use anesthetist which clearly has resource implications
of sedation or general anesthesia. for the service. Modern anesthetic techniques are
Each department should have a written policy generally safe with a low incidence of significant
which is available to the users of the service as adverse events. A general anesthetic will always
well as the providers of the sedation. This policy result with a patient in an ideal state for the proposed
should include an outline of the sedation/anes- investigation. Patients with significant comorbidities
thesia service with clear guidance of fasting or who may be unsuitable for sedation or indeed may
requirements and how particular categories of have failed attempted sedation can have a safe gen-
patients might be excluded from procedures/ eral anesthetic. Some procedures can only be carried
investigations under sedation and who would out on children under general anesthesia, e.g., inter-
definitely require a general anesthetic, e.g., ventional procedures, painful procedures, or pro-
patients with unstable airways or patients who longed procedures or investigations.
have significant learning difficulty or behavior
problems.
Assessment
Each patient needs to be assessed prior to a deci-

Techniques sion about which technique should be employed.
Suitability for sedation should be established tak-
Natural Sleep ing into account the requirements and duration of
the procedure and the individual patient factors.
Neonates often sleep soundly after a feed, Patients requiring a general anesthetic should be
and this time of natural sleep can be used to reviewed by the anesthetist. This allows for proper
attempt to obtain various non-stimulating planning for that patient and for the list.
investigations.
Consent
Sedation After a full explanation to the parent and where
relevant to the patient, proper consent is possible.
The aim is depress the central nervous system to a Written consent is sought for a general anesthetic
level where the patient can tolerate the procedure but is generally not taken for the administration of
but maintain their airway and continue to breathe sedation.
and remain hemodynamically stable. The person
administering the sedation should be able to main-
tain verbal contact with the patient, and the patient Monitoring
should be able to respond. This is called conscious
sedation. This is seen as less invasive and more All patients should be appropriately monitored
convenient, but in reality it is often difficult to during procedures under sedation or anesthesia.
titrate sedation appropriately. There is a not insig- This monitoring begins with an experienced pro-
nificant failure rate (Thomas et al. 2015) with this fessional who is observing the patient and is famil-
technique as the effects of these oral agents are iar with the medications or techniques employed.
unpredictable. The medications commonly for This person should be free to exclusively monitor
this type of sedation include chloral hydrate or the patient – the radiologist or radiographer should
oral midazolam. An experienced nurse is required not be simultaneously monitoring the patient while
to administer the sedation. they carry out the investigation.
Other monitoring includes an oxygen satura- in MRI. Gadolinium-based products are used for
tion monitor and pulse oximeter, an ECG, and IV contrast; for enteral filling, a mixture of
blood pressure monitoring. An oxygen supply carobel and mannitol in a water based solution
and appropriate oxygen delivery devices should is used. When performing magnetic resonance
be available. In case of an untoward event, emer- cholangiopancreatography (MRCP), the bright
gency assistance should be immediately available, fluid signal from the duodenum and stomach is
and the staff present must know how to access this minimized with pineapple or blueberry juice as
help. Patients need to be monitored until the CNS negative contrast agents to allow maximum
depressant effects of whichever technique is visualization of pathology. IV contrast is used
employed have worn off and the patient is stable. in both CT and MRI for delineation of vascular
structures, vascularity, and perfusion of organs
and to maximize visualization of pathology.
Equipment Natural contrast agents such as air have a role
in pediatrics in air reduction of intussusceptions.
If general anesthesia is to be employed, an anes- While air can be used in double-contrast barium
thetic machine with piped gases needs to be avail- examinations, these are rarely performed in the
able. A monitor capable of invasive and pediatric population.
noninvasive monitoring should also be available.
In this way patients from ICU can also generally
be safely anesthetized for procedures. The same Barium Preparations
anesthetic monitoring can be used for patients
receiving sedation. Barium sulfate is available in a number of com-
mercially available preparations: usually in a
powder form, including an anti-clumping
Personnel agent, which is made into a solution prior to
use with water and flavoring agents. The latter
Experienced staff will need to be available for both is optional but generally improves the taste and
elective and emergency investigations. A trained compliance, and children usually prefer a more
nurse can manage a sedation program. Anesthetic familiar tasting drink. Barium preparations are
staff are required for the administration of general typically used for the stable patient undergoing a
anesthesia, and the radiology department ideally standard upper or lower gastrointestinal
should have dedicated consultant time. investigations.
Contrast Media and Use in the Iodinated Contrast Agents

Pediatric Radiology Department
These are called “ionic” or “nonionic” depending
Oral and intravenous (IV) contrast media are on the substrate binding the iodine. They are
widely used in pediatric radiology examina- generically known as “water-soluble contrast
tions, under several guises. Contrast is used for agents.” Many different preparations are commer-
enteric evaluation either upper or lower gastro- cially available. Ionic agents, e.g., Hypaque
intestinal examinations using fluoroscopy. (diatrizoate) or Isopaque (metrizoate), typically
While barium sulfate products are usually used, have higher osmolality. These are associated
nonionic agents may be substituted. Contrast with increased risk of side effects (Stacul 2001)
agents used for CT, both oral and IV prepara- and are therefore now used less frequently. Meco-
tions, are iodinated. Contrast agents used in MRI nium ileus is the one specific clinical indication in
are non-iodinated and specially formulated to pediatric radiology which requires the use of a
take advantage of the complex physics involved high osmolarity ionic contrast agent. The most
382 D. Rea et al.
frequently used agent for this indication is Contrast Use in the CT Suite
diatrizoic acid (Gastrografin). By its chemical
nature it is hypertonic; this can be used to advan- For investigation of the abdomen and pelvis, con-
tage in cases of meconium ileus where the hyper- trast can be administered orally or via nasogastric
tonicity promotes water influx into the lumen thus tube to delineate the bowel. This also can be
helping loosen the tenacious meconium adhering flavored to improve compliance and ensure that
to the walls, thereby resolving the obstruction. the required volume is taken during the required
Nonionic lower osmolality agents such as time frame. A mixture of dilute nonionic contrast
Omnipaque (iohexol) or Ultravist (iopromide) is used for over a period of several hours prior to
have fewer associated side effects (Stacul 2001). the CT to optimally fill bowel loops. The addition
The choice of the agents used is decided by the of oral CT facilitates identification of bowel loops
local radiology department. and reduces the risks of an indeterminate exami-
Iodinated contrast agents can be used in oral/ nation. For children with bowel obstruction,
enteric exams, especially in the acute setting administration of oral contrast, while very incon-
where there is either concern of perforation or venient, can allow assessment of the level of
high likelihood of surgery immediately following obstruction.
the radiological investigation. They are used in In modern pediatric CT, IV contrast when used
CT, both as an oral agent to delineate bowel and is almost exclusively of the nonionic variety. Pedi-
IV for delineation of vascular structures, vascu- atric radiology departments use a weight-based
larity and perfusion of organs, and pathology. scale to determine the volume of IV contrast to
Warming the iodinated contrast in a standard be administered. Many departments use 2 mls/kg
warmer reduces its viscosity allowing it to flow of nonionic contrast for most indications some-
more freely and more importantly is less of a times increasing to 3 mls/kg when angiographic
shock than injecting colder than body temperature information is required.
contrast when trying to get a child to stay still for a
complex examination.
Contrast Use in the MRI Suite
Contrast Use in the Fluoroscopy Suite The principal IV contrast agents in MRI are gad-
olinium-based paramagnetic agents. There are
The standard upper or lower gastrointestinal (GI) various types, depending on the exact clinical
examination in a stable patient is usually information required: blood pool agents, extracel-
performed with barium; the exact preparation lular fluid agents, and organ-specific agents (Hao
and strength will depend on local radiology pref- et al. 2012). There are eight different types of
erences. An acutely ill patient who may be going gadolinium-based agents available in Europe and
to theater or in whom there is concern of a perfo- nine in the USA. In Europe only gadoteric acid
ration will usually have the examination using (Dotarem) is European Medicines Agency
nonionic contrast. (EMEA) licensed for pediatric use. There are
Micturating cystograms are usually performed other types of MRI contrast agents which include
with either ionic or nonionic contrast; again the iron oxide, iron platinum, and manganese-based
use comes down to local departmental preference. products, but none of these agents are licensed for
Retrograde urethrograms and/or ureterograms pediatrics.
will also most commonly use nonionic contrast.
The renal excretion of iodinated contrast agents
also allows for use in intravenous pyelograms Contraindications/Side Effects/Adverse
(IVP); however, most modern European radiol- Reactions
ogy departments do not currently perform this
examination any more, preferring to do ultrasound Oral contrast: There are no contraindications to
instead. the use of oral contrast. Anaphylactic reactions to
gastrointestinal contrast media are exceptionally based MR contrast agents were gadobenic acid,
rare. gadodiamide, gadopentetic acid and
IV iodinated agents: These are generally well gadoversetamide. The macrocyclic agents, are
tolerated. Informing the radiology department believed to be more chemically stable and have a
about a history of asthma is helpful as these much lower propensity to release gadolinium. In
patients may benefit for pre-procedural steroid the EU the macrocyclic agents are gadoteridol,
therapy as per local departmental policies. Any gadobutrol and gadoteric acid.
prior history of previous anaphylactic reaction to Angiographic-type sequences can be acquired
iodinated contrast is a contraindication to repeated in MRI without the use of contrast by use of
exposure. Such children should have their inves- specific MR techniques such as time of flight or
tigations performed using modalities that avoid phased contrast MR angiography. However, these
iodinated contrast media. often lack the spatial resolution which can be
Contrast media-induced nephrotoxicity (CIN) achieved with contrast-enhanced MR imaging.
is well described especially in patients with Patient size and the location where in the body
increased creatinine or reduced GFR (Stacul et angiographic images are to be acquired can also
al. 2011). For iodinated contrast media, risks are limit the accuracy and benefit of the non-contrast
reduced if prehydration of the patient is under- angiography MR techniques. Allergic reactions to
taken prior to the contrast load. For children who iodinated IV contrast can range from minor to
have GFR less than 30 ml/min, most radiologists full-blown anaphylaxis. All radiology depart-
will not administer gadolinium-based contrast ments should have immediate access to an emer-
agents due to the risk of nephrogenic systemic gency trolley in the room in which contrast is
fibrosis (NSF) also known as nephrogenic being administered and staff should be familiar
fibrosing dermopathy (Weinreb and Kuo 2009). with resuscitation. Use of corticosteroid prophy-
There is controversy about the use of gadolinium laxis is mandated in those with previous
in children with GFR values between 30 and documented moderate/severe reactions to contrast
50 ml/min. If administration of contrast media is media and in those with asthma.
deemed important to the utility of the radiological
examination, consultation with the local nephrol-
ogy service is advised prior to contrast adminis- Pediatric Interventional Radiology
tration. Possible means of reducing the
nephrotoxic effects of iodinated contrast include Pediatric interventional radiology (PIR) encom-
prehydration of the patient and using a reduced passes a range of minimally invasive procedures,
dose of contrast or for children on dialysis, to which are performed using image guidance; pro-
organize dialysis after the use of IV contrast. cedures may be for diagnostic or treatment pur-
Dialysis after administration of gadolinium does poses. Within the field of pediatrics, PIR has an
not necessarily reduce or prevent the possibility of increasingly significant role to play in the delivery
NSF in adult patients with poor renal function. of safe and effective care by reducing risks,
There has not yet been a proven case of pediatric decreasing length of stay, and lowering costs.
NSF after gadolinium administration in children Techniques performed by interventional radiolo-
with poor renal function. Gadolinium based MR gists include central venous access, gastrointesti-
contrast agents are chemically manufactured in nal intervention (such as gastrostomy and
two forms, as linear agents and as macrocylic esophageal dilatation), aspiration or drainage of
agents. In March of 2017, the Pharmacovigilance fluid collections nephrostomy, angiography
and Risk Assessment committee of the European including arterial embolization, and the treatment
Medicines Agency (EMA) recommended the sus- of vascular malformations.
pension of the marketing authorizations for four It should not be acceptable for children to be
linear gadolinium contrast agents because of evi- treated by open surgery when they could undergo
dence that small amounts of gadolinium are minimally invasive percutaneous image-guided
deposited in the brain. These linear gadolinium therapy to achieve the same outcome. However, at
384 D. Rea et al.
present, PIR remains a significantly less advanced best example of interdisciplinary collaboration in
subspecialty in Europe compared to North Amer- PIR is the management of children with vascular
ica, and in this context many European pediatric malformations, which in most large centers is
surgical centers continue to provide operative sur- carried out by teams including radiologists, der-
gical treatments where North American centers matologists, pathologists, various types of sur-
have moved to an image-guided therapy approach. geon, and other healthcare professionals.
Pediatric interventionists are currently drawn
from several disciplines. In many hospitals, adult
interventional radiologists provide services. Inter- Conclusion and Future Directions
ventional radiologists with a special interest in
pediatric intervention are less common as training The role of the radiology department and of the
opportunities are limited. Diagnostic pediatric pediatric radiologist in the management of the
radiologists with a special interest in intervention pediatric surgical patient continues to evolve.
sometimes provide a limited service. Pediatric Pediatric surgeons should consider them as inte-
surgeons or pediatricians occasionally provide gral to the team approach to care. Close collabo-
image-guided interventions and often do so suc- ration among all those caring for the surgical
cessfully in a limited way. To date, most surgical patient will avoid inappropriate requests for imag-
training programs provide little or no formal training. A pediatric surgeon will get the best from a
ing in image-guided procedures, image interpre- pediatric radiology colleague if a specific question
tation, or catheter and guidewire skills. Most PIR is posed. In turn the pediatric radiologist should,
procedures involve a set of core skills: access to where possible, review the available clinical, lab-
the appropriate site under image guidance (often oratory, and most importantly prior radiological
using a needle and/or catheter and guidewire) investigations to see if a further radiological
followed by some type of intervention (such as investigation is necessary and if so how this can
biopsy, embolization, or balloon dilatation). There be performed optimally with the least (or no)
is a transferability of skills between different body radiation exposure to the child while minimizing
systems, which explains why PIR has made an stress and discomfort to the child and its
impact on practice in so many areas of hospital caregivers.
pediatrics. This transferability of skills helps the With adequate investment and with the appro-
interventionist with a relatively low caseload priate training pathways (for radiologists and
maintain his or her competence. It is recognized surgeons alike), it is likely that more minimally
that the requirement for pediatric intervention in invasive image-guided interventions will
nonspecialist pediatric centers may be relatively become the norm in pediatrics. Open procedures
low, especially if pediatric intervention is spread that are currently performed in the operating
across disciplines. The advantages of image- theater will in future be performed in a controlled
guided minimally invasive techniques are well image-guided setting by either an appropriately
known. However, these benefits have not been trained radiologist or surgeon. This has been the
fully realized, with many children not receiving experience of adult vascular surgery/vascular
PIR, even where national guidelines exist. Future interventional radiology and will be the future
developments in surgical care will increasingly for many surgical specialties including pediatric
rely on cooperation and cross discipline team surgery.
working providing more minimally invasive pro-
cedures with shorter lengths of stay at less cost
than traditional open cases. This lesson has Cross-References
already been learned with respect to laparoscopic
surgery and now will be reinforced with respect to ▶ Anesthesia and Pain Management
pediatric interventional radiology. Perhaps the ▶ Vascular Access in Infants and Children
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Hematological Problems in Pediatric
Surgery 24
Ciara O’Rafferty and Owen Patrick Smith
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Hematological Basic Science . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Blood Formation (Hematopoiesis) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Mechanisms of Hemostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389
Natural Anticoagulation Control Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Platelets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Blood Groups and Antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390
Hematological Disorders Encountered in Pediatric Practice: A Surgical
Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Hemophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Central Venous Access Devices (CVADs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 393
von Willebrand Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Platelet Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Immune Thrombocytopenia Purpura (ITP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
Disseminated Intravascular Coagulation (DIC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396
Thrombotic Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Asplenia/Splenectomy/Hyposplenism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 398
Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Hereditary Spherocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400
Sickle Cell Disease (SCD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Disease-Modifying Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Thalassemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403
Neutropenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
Leukemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405
Blood Products and Their Transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
C. O’Rafferty (*)
Department of Haematology, Our Lady’s Children’s
e-mail: orafferc@gmail.com
O. P. Smith
Department of Haematology, Our Lady’s Children’s
e-mail: owen.smith@olchc.ie

https://doi.org/10.1007/978-3-662-43588-5_26
388 C. O’Rafferty and O. P. Smith
Other Adverse Reactions to Blood Product Transfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Severe hemophiliacs require recombinant fac-
tor replacement perioperatively to secure Hematology is a broad specialty. It encompasses
hemostasis. Many require placement of a cen- disorders of red cells such as sickle cell disease
tral venous access device for delivery of factor (SCD), disorders of platelets such as Bernard-
replacement throughout the preschool years. Soulier syndrome, and disorders of white cells
Patients with thrombocytopenia, platelet func- such as severe congenital neutropenia. In addi-
tion defects, von Willebrand disease, or tion, deficiencies of the coagulation proteins
acquired coagulopathy may need blood prod- including hemophilia A and von Willebrand dis-
uct replacement and special precautions prior ease fall under the general remit of hematol-
to invasive procedures. ogy (Arcesi et al. 2006).
Children with sickle cell disease The majority of the pediatric hematologist’s
(SCD) may require splenectomy, cholecys- inpatient workload relates to the treatment of malig-
tectomy, or adenotonsillectomy and are nancy, usually acute leukemia, but also high-grade
at risk perioperatively of an acute sickling lymphomas. In contrast, much of the consultative
event. work is centered around children with
Leukemic patients often require blood prod- coagulopathies or hematological manifestation of
ucts or growth factor support before surgery systemic diseases. The hematology day ward is an
and frequently in the operating theater through- active place, where children with hemoglobinopa-
out their treatment course for lumbar punc- thies attend for transfusion, hemophiliacs present
tures, bone marrow biopsies, and central following a bleed, and children on chemotherapy
venous access-related issues. attend for treatment and supportive care. In addition
Children who are splenectomized are ren- to clinical work, a hematologist usually heads the
dered susceptible to overwhelming infection hematology laboratory, reporting on bone marrow
by Gram-positive encapsulated organisms. biopsies and blood films; overseeing the automated
They require vaccination prior to splenec- blood counts, pre-transfusion compatibility testing,
tomy and should receive postoperative anti- and coagulation testing; and ensuring that a quality
biotic prophylaxis up to the age of 16. Where control system is in place for delivering precise,
possible, splenectomy should be deferred accurate, and internationally standardized blood
until >6 years of age, although this latter test reports.
recommendation does not apply to children Surgical issues may arise in hematology inpa-
with SCD, who are functionally asplenic tients such as the neutropenic patient on treatment
from a young age. for leukemia who develops an acute abdomen or
the need for an implantable central venous access
Keywords device in a hemophiliac with inhibitors who needs
Sickle cell disease · Thalassemia · to embark upon immune tolerance therapy
Thrombocytopenia · Leukemia · Neutropenia · (Hutchinson 2006).
Splenectomy · Hemophilia · Venous Conversely, surgical patients may manifest
thromboembolism · Disseminated hematological disturbances such as the neonate pre-
intravascular coagulation · Transfusion senting with a rapidly enlarging vascular mass who
24 Hematological Problems in Pediatric Surgery 389
is noted to be severely thrombocytopenic or the self-renewal and are low in number and divide
postoperative child who develops wound sepsis, infrequently. It is the committed progenitors
oozing from tracheostomy and cannulation sites, that are responsible for the massive amount of
and a disseminated intravascular coagulation. cell proliferation required to maintain blood
A knowledge of hematological basic science cell production in numbers as outlined above.
and the pathophysiology and management of The common lymphoid progenitors produce T-
common hematological disorders (McCann et al. and B-cells, whereas the common myeloid pro-
2005) is a prerequisite for the competent pediatric genitors give rise to erythrocytes, megakaryo-
surgeon (Blood 2005). cytes, monocytes, and granulocytes.
Hematological Basic Science Mechanisms of Hemostasis
Blood Formation (Hematopoiesis) Normal blood coagulation is a complex sequence

of interrelated events by which the body prevents
The bone marrow is a mesenchymal-derived tissue blood loss from the vascular tree. This is achieved
divided into irregular interconnective spaces by by a multi-pathway interactive system with mul-
bone trabeculae. It consists of a complex hemato- tiple negative and positive feedback loops, which
poietic cellular component that continuously goes ultimately ensure that blood is fluid within the
through self-replication and/or differentiation pro- vasculature while also ensuring that it can be
cesses. These cells are supported by a microenvi- transformed into a clot when there is a breach in
ronment composed of stromal cells (endothelial the integrity of the vascular tree. The protein and
cells, fibroblast-like cells, adipocytes), extracellular cellular (endothelial cells, monocytes, and plate-
matrix, and vascular structures. lets) components have also been shown to be
intimately involved in the inflammatory response,
• Embryonic hematopoiesis begins in the yolk sac vasculogenesis, metastasis, cellular proliferation,
at the end of the third week of gestation where it and tissue repair.
declines to an insignificant level by the end of the
first trimester. By then, the liver is the dominant • Tissue factor, a cell surface glycoprotein, is the
source of hematopoiesis. Hepatic hematopoietic principal biological initiator of blood
activity reaches its maximum level at around the coagulation.
third month and gradually declines from the sev- • Exposure of circulating plasma factor VIIa to
enth month until birth. Bone marrow hematopoi- tissue factor triggers the coagulation cascade in
esis begins around the fifth month of gestation vivo, which results in thrombin generation
and continues to increase thereafter. (Fig. 1).
• Every day, in normal adult bone marrow, • Thrombin converts soluble fibrinogen to a
approximately 2.5 billion red cells, 1 billion fibrin network, activates platelets, and
granulocytes, and 2.5 billion platelets are pro- stimulates coagulation by positive feedback
duced per kg of body weight. activators of cofactors, factors V and VIII,
• Hematopoiesis is sustained by a complex cel- and the zymogens II, VII, IX, X, XII, and
lular interaction of hemopoietic and stromal XIII.
elements and a network of cytokine growth • Under physiological conditions, coagulant
factors including the interleukins and colony- mechanisms are balanced in favor of anti-
stimulating factors. coagulation; however, at sites of vascular dam-
• All the cells of the hemopoietic system origi- age resulting from inflammation, trauma, etc.,
nate from a pluripotent hemopoietic stem cell the anticoagulant system is downregulated and
(HSC). HSCs have the intrinsic capacity for thus procoagulant forces prevail.
TF
+
VIIa
IXa
VIIIa
X
Va
PT APTT
Xa
Pro-thrombotic
II IIa [ Thrombin ] Pro-inflammatory
TT Pro-angiogenic
I Ia [ Fibrin ]
I Insoluble
[ Fibrinogen ]
insoluble
Fig. 1 Blood coagulation is initiated (initiation phase) converts soluble fibrinogen to insoluble fibrin. Thrombin
when tissue factor (TF), expressed after injury to cell is not only prothrombotic but activates platelets and is pro-
(endothelial, monocytic cells, etc.) wall, is exposed to inflammatory and promotes new vessel formation. Shown
FVIIa in the bloodstream. TF-FVIIa complex in turn acti- in gray are three global coagulation screens and the part of
vates FIX to FIXa and FX to FXa. FIXa with its cofactor the coagulation cascade that each represents: prothrombin
FVIIIa in turn also activates FX to FXa (amplification time (PT); activated partial thromboplastin time (APTT)
phase). FXa with its cofactor FVa activates prothrombin and thrombin time (TT) (Puri and Höllwarth 2009).
(II) to thrombin (IIa) (propagation phase). Thrombin
Natural Anticoagulation Control hemostasis (adhesion, aggregation, and release).

Mechanisms Platelets may also have functional defects.
These disorders cause primary hemostatic bleed-
Several natural anticoagulant mechanisms have ing (mucocutaneous) ranging from mild to
been discovered that exert dampening effects severe.
upon pro-coagulation and in turn halt the genera-
tion of thrombin. The major anticoagulant inhib-
itors of blood coagulation include tissue factor Blood Groups and Antibodies
pathway inhibitor, antithrombin, and the protein
C pathway (Fig. 2). There are 35 blood group systems corresponding to
red blood cell (RBC) surface antigens. The ABO
system is the most important. Antibodies against
Platelets blood group antigens A and B occur naturally in
people who lack these antigens, for example,
Platelets derived from megakaryocytes play an patients who are Group A will have naturally
essential role in thrombosis and hemostasis. occurring anti-B antibodies, while patients who
Megakaryopoiesis in the bone marrow is are Group O will have anti-A and anti-B. These
governed by a complex interaction of cytokines antibodies are predominantly IgM and so can cause
(e.g., thrombopoietin) and their receptors (e.g., complement activation and acute intravascular
c-mpl). Platelets play a major role in primary hemolysis. Other clinically important antibodies
Fig. 2 The initiation phase

of coagulation is controlled
TF TFPI
by inhibiting the complex of +
TF, FVIIa, and FXa by
tissue factor pathway VIIa
inhibitor (TFPI). The
amplification phase of
IXa
coagulation is blocked by
VIIIa
the protein C pathway.
Protein C (PC) is activated
X
by a complex of thrombin, Va
thrombomodulin (Tm), and AT +
endothelial protein C
receptor (EPCR) to APC
which in association with
protein S (PS) inactivates
FVa and FVIIa. The Xa APC
thrombin formed in the PS
propagation phase is
controlled by antithrombin EPCR
(AT) (Puri and Höllwarth II IIa [ Thrombin ] Tm
2009)
PC
I Ia [ Fibrin ]
Insoluble
[ Fibrinogen ]
insoluble
do not occur naturally and require exposure to an • Hemophilia A and B are X-linked recessive
antigen – either by a blood product transfusion or disorders. Thus, males are affected and females
via feto-maternal exposure. These antigens vary in can be carriers.
their immunogenicity, e.g., the RhD and the Kell • One third of cases of FVIII deficiency have no
antigen are highly immunogenic. family history (spontaneous mutations).
• When there is no family history, infants with
moderate/severe disease usually present as
Hematological Disorders Encountered follows:
in Pediatric Practice: A Surgical – Post circumcision bleeding (Fig. 3).
Perspective – Bad “toddler bruising.”
– Soft tissue/muscle or joint bleeds at
Hemophilia 6–18 months of age (once the child
becomes mobile).
Factor VIII deficiency (hemophilia A) is the – Intracranial, ilio-psoas, and intra-abdominal
second most common inherited bleeding dis- bleeds and hematuria occasionally occur.
order with a frequency of approximately 1 in
500 male births. Factor IX deficiency (hemo- • In children presenting with bruising/severe
philia B) is approximately one sixth as bleeding, it is not uncommon for the first pre-
common. sumed diagnosis to be non-accidental injury
(NAI). True coagulation defects need to be
Clinical Features excluded. A normal coagulation screen does
• The majority of severe and moderate (factor not exclude all significant coagulation disor-
VIII levels <1% and 1–5%, respectively) cases ders, e.g., von Willebrand disease, FXIII
present in the first few years of life. deficiency, and platelet function defects.
Fig. 3 Hemophilia A: (a)

Postcircumcisional
hematoma in an infant with
no family history of
hemophilia. Mutational
analyses showed the
presence of the inversion 22
mutation. (b) Full
hematoma resolution
1 week later following
replacement with
recombinant FVIII (Puri
and Höllwarth 2009)
The presence of a bleeding disorder does not

necessarily mean that NAI is excluded.
Treatment
• The aim of modern management includes:
– Prevention of chronic joint damage (Fig. 4)
– Prevention of “life-threatening” bleeds
– Facilitation of social and physical well-
being and helping children to achieve their
full potential
– Provision of a comprehensive service to the
family (genetic counseling, training in self-
administration of factor, education on how
to prevent and manage bleeds)
• Successful treatment of a bleed involves the

prompt and sufficient intravenous replacement
of FVIII/FIX to hemostatic levels (Berntorp
et al. 2016).
• Prophylactic administration of factor concen- Fig. 4 Hemophilia B: Chronic severe hemophiliac
trate converts a child who has severe disease to arthropathy of the right knee joint. The quadriceps muscle
is severely wasted. This adolescent was only treated inter-
a child with mild disease. The child should no mittently with plasma throughout the first 5 years of life
longer have spontaneous bleeds, and prophy- (Puri and Höllwarth 2009)
laxis protects against hemophilic arthropathy.
Because of the varied half-lives of coagulation
factors, FVIII is given three times per week, child to facilitate regular intravenous
and FIX is given twice a week in prophylactic administration.
programs. Prophylaxis can be timed immedi- • Recombinant factor concentrates are now the
ately prior to sporting activities, thus allowing gold standard.
the child to live a relatively normal • Minor surgical procedures such as endoscopic
life (Keeling et al. 2008). biopsies will require factor levels to be brought
• Prophylaxis usually requires a central venous up to 100% of normal levels by giving a bolus
access device (see below) to be placed in the dose of factor concentrate immediately
preoperatively. More major procedures, such A viral vector introduces the FIX gene into
as PortaCath placement or cardiac surgery, hepatocytes. Sustained production of FIX has
may require a continuous infusion of factor ensued, which converts the patient’s phenotype
concentrate, preceded by a loading bolus. from a severe hemophiliac to that of a mild or
Levels are monitored periodically and rate of moderate hemophiliac, such that they may no
infusion titrated. In the postoperative days longer require prophylaxis and no longer bleed
once hemostasis has been achieved, the infu- spontaneously. Progress in FVIII gene therapy
sion may be tapered or may be replaced with is not quite as advanced as the factor VIII gene
bolus once or twice-daily dosing. is larger and more difficult to introduce into the
• The formation of neutralizing antibodies to host using a viral vector.
FVIII/IX (known as inhibitors) is the single
biggest complication to modern management
of hemophilia. Fifteen to 20% of hemophiliacs Central Venous Access Devices (CVADs)
will develop an inhibitor. These patients cannot
usually be treated with FVIII or FIX anymore, The intravenous administration of factor concen-
but require bypassing agents such as FEIBA or trate twice or three times per week is fraught with
NovoSeven. FEIBA is plasma derived and so difficulty in the majority of young children when
runs the theoretical risk of being able to trans- only using peripheral veins. Similarly, immune
mit novel blood-borne diseases. NovoSeven is tolerance therapy (ITT) is almost impossible with-
very costly. Neither agent can secure hemosta- out regular venous access.
sis as readily as simple factor replacement can These devices can be fully implantable
in a hemophiliac without inhibitors. No routine (PortaCath™, Deltac USA) or externalized and
laboratory test is available to monitor efficacy tunneled (single- or double-lumen Quintan™
of treatment; thus, efficacy must be judged catheters). The use of a port is preferable to an
clinically, and a change from one agent to external device because it causes fewer limitations
another may be required. Refractory bleeding to the child’s lifestyle and there is a lower infec-
may respond to concurrent treatment with both tive risk. However, despite the obvious attractions
agents (Astermark et al. 2007). of these devices, they carry the risks of thrombosis
• Immune tolerance induction therapy is used to and infection, both of which may lead to morbid-
eradicate inhibitors soon after they develop. It ity/mortality and permanent removal of the
involves giving large daily doses of FVIII or device. The rate of infection is higher in children
FIX, usually through a CVAD for many with inhibitors.
months or years with or without immunosup- There is now a growing consensus that long-
pressants. It is effective in about 80% of cases, term indwelling devices are necessary to facilitate
but is extremely costly. the modern intensive treatment of congenital
• A number of long-acting FIX products have coagulation disorders. With improved manage-
proven safe and efficacious at preventing ment of the perioperative period and regular, fre-
bleeding in severe FIX deficiency. They quent re-education, particularly in those children
include pegylated FIX and FIX fusion proteins. with inhibitors, many of the complications may be
They are expected to reduce the need for fre- avoided. Central venous access devices are gen-
quent IV accessing and will likely improve erally removed after the age of 5 with the devel-
compliance with therapy, thus reducing hemo- opment of robust peripheral veins that can be
philia-related complications. Increasing the readily accessed.
half-life of factor VIII has proven more diffi- More recently the use of arteriovenous fistulae
cult, but advances are being made (Oldenburg (AVF) as a reliable means of vascular assess in
and Albert 2014). children with hemophilia has been reported. Com-
• Gene therapy for FIX deficiency has been suc- plication rates are reported to be minimal. The
cessfully trialed in a small number of patients. majority of children (>95%) achieved functional
AVF that are still regularly used for home treat- thrombocytopenia is sometimes accompanied by
ment over a median period of 29 months, dysfunctional platelets (Bolton-Maggs et al.
suggesting that the creation of AVF as the first 2006).
option for achieving permanent venous access in The following is a list of inherited causes of
children with severe hemophilia is warranted. thrombocytopenia:
• Disorders of platelet number

von Willebrand Disease – MYH9 disorders, e.g., May-Hegglin
anomaly
von Willebrand factor is a large plasma protein – Congenital amegakaryocytic
involved in tethering the platelets to the capillary thrombocytopenia
walls at sites of minor vessel injury (primary – Amegakaryocytic thrombocytopenia with
hemostasis). It also protects FVIII from premature radioulnar synostosis
proteolytic cleavage within the circulation. – Thrombocytopenia-absent radius syndrome
A quantitative defect in VWF is termed type 1 – X-linked thrombocytopenia with
VWD if partial or type 3 VWD if complete (no dyserythropoiesis
circulating VWF). A qualitative defect in VWF is • Severe disorders of platelet function
termed type 2 VWD. Patients with VWD may or – Bernard-Soulier syndrome
may not have an abnormal platelet count or APTT. – Glanzmann’s thrombasthenia
Most patients with VWD are diagnosed in – Wiskott-Aldrich syndrome
adulthood. Children may come to clinical atten- • Disorders of receptors and signal transduction
tion after positive screening results with a family – Platelet cyclooxygenase deficiency
history of the disorder, or they may be investi- – Thromboxane synthase deficiency
gated after excessive surgical bleeding or muco- – Thromboxane A2 receptor defect
cutaneous bleeding such as easy bruising, gum – ADP receptor defect (P2Y12)
bleeding, epistaxis, or menstrual bleeding. • Disorders of platelet granules
For a subset of patients without a significant – Idiopathic dense granule disorder
personal or family history of bleeding, mild func- – Hermansky-Pudlak syndrome
tional deficiencies of VWF, or undergoing minor – Chediak-Higashi syndrome
procedures, treatment may not be required preop- – Gray platelet syndrome
eratively. For some patients tranexamic acid pre- – Paris-Trousseau syndrome
operatively and for 5–7 days postoperatively may – Idiopathic α- and δ-granule storage pool
be sufficient. A preoperative DDAVP infusion can disease
be used for minor procedures in patients with mild • Disorders of phospholipid exposure, e.g., Scott
disease. Some patients will require plasma- syndrome
derived VWF concentrates such as Wilate ® pre-
and postoperatively. It is important to confirm that the low platelet
count is genuine by careful inspection of the blood
sample and smear to exclude platelet clumps
Platelet Disorders before initiating further investigations.
Once established, the approach to the diagnosis
The normal range of the platelet count in child- of the thrombocytopenia should be tailored to the
hood is similar to that seen in adult life, being individual child or infant and mother if dealing
about 150–400 109/L. with neonatal thrombocytopenia. For example,
Neonatal thrombocytopenia may have been assessment of the child’s general well-being is
acquired in the antenatal or perinatal period or very important as healthy children usually have
may be an inherited thrombocytopenia. Inherited an immune or an inherited etiology, whereas the
Clinical Features
• It is predominantly seen in children aged
between 2 and 5 years.
• Bleeding is uncommon when the platelet count
>50 109/L.
• Spontaneous bleeding (minor) is frequent
when the platelet count <30 109/L.
• It is a diagnosis of exclusion. Typically chil-
dren will have a normal physical examination
(with the exception of purpura) and a normal
blood smear (with the exception of thrombo-
cytopenia). Laboratory workup is usually lim-
ited to FBC, coagulation screen, renal profile,
liver profile and bone profile, and LDH all of
which are otherwise normal. An autoimmune
screen is sometimes performed if a secondary
ITP is suspected. A virology screen including
hepatitis A, B and C, HIV, CMV, or EBV
serology may be helpful in some cases.
Fig. 5 Capillary hemangioma in a 2-month-old boy with • Bone marrow examination is not generally
Kasabach-Merritt syndrome (KMS). The lesion involuted required for the diagnosis to be made.
after 4 months of therapy involving vincristine, predniso- • The vast majority of children will have had a
lone, and antiplatelet agents (aspirin and ticlopidine) (Puri
preceding viral infection or will have been
vaccinated in the previous month.
presence of lymphadenopathy, hepatosple- Pathophysiology

nomegaly, mass lesions, hemangiomas (Fig. 5), • Antiplatelet antibody production leads to pre-
bruits, and congenital anomalies point toward a mature platelet destruction in the spleen and
different spectrum of causes. also impaired platelet production from
In neonates, it should also be emphasized that megakaryocytes.
obtaining a detailed maternal history, including • T-cell-mediated cytotoxicity also contributes
bleeding problems, preeclampsia, and drug to platelet destruction.
ingestion in the present and past pregnancies
and any history of viral infections (cytomegalo- Clinical Course and Treatment
virus, rubella, herpes simplex, and HIV) or con- (Provan et al. 2010)
nective tissue disease (systemic lupus • In the majority of children, ITP will resolve
erythematosus), will save time and unnecessary spontaneously within 6–12 months.
investigation. • The rate of major bleeding is low (<3%) even
when platelet counts are severely depleted.
• For these reasons, management of a child with
Immune Thrombocytopenia Purpura newly diagnosed ITP presenting with cutane-
(ITP) ous bleeding alone, even with a platelet count
<20, is usually conservative (Rodeghiero and
ITP is defined as an isolated platelet count Ruggeri 2014).
<100 109/L in the absence of other causes of • Platelet transfusions are ineffective due to
thrombocytopenia. It is the most common cause rapid platelet consumption and are generally
of thrombocytopenia in childhood. contraindicated.
• If treatment is required (e.g., more serious Disseminated Intravascular

bleeding at diagnosis, other risk factors for Coagulation (DIC)
bleeding, parental anxiety), then intrave-
nous immunoglobulin and prednisolone are DIC is a clinicopathological entity resulting in
frontline treatments. The majority will respond. simultaneous and un-regulated activation of the
• A certain degree of lifestyle restriction will be coagulation and fibrinolytic pathways. It is a
required until platelet counts rise above 50 or syndrome of serious clinical consequences
75, e.g., contact sport should be avoided, as which is encountered in all area of pediatrics
should rough play. Parents should be warned to particularly in the intensive care unit. DIC is
present urgently with any new bleeding and to not a primary disease entity; it is secondary to
avoid nonsteroidal anti-inflammatory drugs an underlying usually severe systemic illness.
(NSAIDs) such as ibuprofen which interfere DIC is a progressive, pathological process
with platelet function and thus increase the resulting in profuse thrombin formation and
risk of bleeding. excessive activity of the fibrinolytic pathway,
• Second-line treatments include rituximab (a and its most prominent clinical feature is a bleed-
monoclonal anti-CD20 antibody which ing tendency.
depletes antibody-producing B-cells), anti-D
immunoglobulin, azathioprine or cyclospor- • Possible causes include sepsis; malignancy, e.
ine, various other immune-modulating agents, g., acute promyelocytic leukemia; burns; pan-
or splenectomy. creatitis; serious complications of pregnancy;
• Romiplostim and eltrombopag are novel drugs trauma, e.g., crush injuries; surgery; and
that stimulate the thrombopoietin receptor and poisoning.
induce increased platelet production by mega- • In DIC with hemorrhage, bleeding is typically
karyocytes. Although they produce sustained from multiple sites, indicating the systemic
platelet responses in 60–70% of patients, nature of the process.
relapse tends to occur on treatment cessation. • Purpura fulminans is seen in disseminated
They are used in children in persistent or meningococcemia. The skin lesions appear
chronic ITP. There is a small risk that either hemorrhagic; however, microthromboses
agent may cause bone marrow fibrosis, thus are underlying histological findings (Thachil
regular bone marrow biopsies are required for et al. 2012) (Fig. 6).
children on longer term treatment. • Diagnostic tests in DIC include PT (pro-
• One third of children may develop a chronic longed), APTT (prolonged), fibrinogen
form of ITP (thrombocytopenia lasting greater (reduced), D-dimer (raised), platelet count
than 12 months) that can be symptomatic. (reduced), blood smear, and natural
Treatment can be problematic and hence sple-
nectomy is worth considering. Eighty percent
of children with chronic ITP will remain in
remission after 4 years. The downsides to sple-
nectomy are discussed in the relevant section.
• Emergent bleeding requires a different approach
to treatment, as some agents require weeks or
months before a response is seen. Rapid-acting
treatments include intravenous immunoglobulin
(effect seen within 24–48 h), high-dose IV meth-
ylprednisolone, IV vincristine, emergency sple-
nectomy, or some combination of these Fig. 6 Purpura fulminans secondary to severe acquired
approaches. Platelet transfusions are occasionally protein C deficiency in association with meningococcal
used in the emergency setting only. septicemia (Puri and Höllwarth 2009)
anticoagulant factor levels. Not all of these Table 1 Acquired thrombotic tendency (Puri and
tests may be deranged, and an evolving clinical Höllwarth 2009)
picture should be accompanied by repeat Indwelling vascular
testing. catheters
Renal artery and vein
thrombosis
Treatment Acquired natural Nephrotic syndrome !
• The patient and not the numbers should be anticoagulant deficiency antithrombin deficiency
treated, i.e., blood product replacement is Purpura fulminans !
varicella and protein S
required only in the setting of active bleeding
deficiency and
or prior to a surgical intervention (Levi et al. meningococcemia and
2009). protein C deficiency
• In the above settings, fresh frozen plasma Necrotizing enterocolitis
(FFP) is used if the PT and APTT are >1.5 (NEC)
times the upper limit of normal; fibrinogen Respiratory distress
syndrome
concentrate is used if fibrinogen is <1.0 g/dL,
Heparin-induced
and platelets may be transfused to keep platelet thrombocytopenia/
count >50. thrombosis syndrome
• Other forms of intervention such as heparin (HIT/HITTs)
and natural anticoagulant concentrates have Maternal anticardiolipin
antibodies (lupus
been used in the past, but the current evidence
anticoagulant)
does not support their recommendation. Extracorporeal membrane
• Treatment should be directed toward the under- oxygenation (ECMO)
lying process causing the consumption. Hemolytic uremic
syndrome/thrombotic
thrombocytopenic purpura
(HUS/TTP)
Thrombotic Disorders Birth asphyxia
Thrombotic disease in children is much less com-

mon than in adults. Idiopathic thrombosis in Children with idiopathic thrombosis should be
childhood is rare, and 95% of pediatric venous screened for an inherited gene defect predisposing
thromboembolisms (VTEs) occur in the context to clot formation. The prevalence of
of serious illness. However, the incidence of thrombophilic defects in children with VTE varies
childhood VTE is increasing, largely because of between studies from 10% to 78%. It is not clear-
better imaging modalities and advances in neona- cut whether children presenting with secondary
tal care and tertiary pediatric care such as ECMO, VTE, e.g., CVAD-related thrombosis, should
cardiopulmonary bypass, hemodialysis, and the have thrombophilic testing performed. It is expen-
use of intra-arterial and intravenous indwelling sive, can cause significant concern for parents and
catheters. other family members, and does not affect clinical
The peak incidence of thrombotic events is management of the child and so is often felt to be
in the neonatal period. When venous thrombo- unnecessary.
sis does occur in childhood, it can be fatal or
associated with several sequelae such as ampu- Treatment
tation, organ dysfunction, and post-phlebitic • Unfractionated heparin (UH), low molecular
syndrome. weight heparin (LMWH), and VKAs (e.g.,
Thrombotic tendency is seen in a warfarin) have all been used safely and exten-
number of clinical scenarios as outlined in sively in childhood. Heparin in childhood is
Tables 1 and 2. monitored with anti-Xa levels. Warfarin is
Table 2 Inherited thrombotic tendency (Puri and deficiencies, factor concentrate replacement is
Höllwarth 2009) sometimes used.
Defects within the High circulating levels of • For children who develop heparin-induced
protein C pathway FVIII thrombocytopenia (HIT), a rare prothrombotic
Protein C deficiency complication of heparin therapy, recombinant
Protein S deficiency
hirudin (lepirudin), danaparoid, or argatroban
APCR and FVR506Q (factor
V Leiden)
should be used.
FIIG20210A (prothrombin • An array of oral anticoagulants that do not
gene variant) require laboratory monitoring are now avail-
Hyperhomocysteinemia Cystathionine-B-synthase able for the treatment of VTE in adults.
Methionine synthase Many of these agents are currently being
Thermolabile trialed in children, e.g., dabigatran,
methylenetetrahydrofolate apixaban, and rivaroxaban. Unlike warfarin,
reductase
no agent exists to rapidly reverse their anti-
Antithrombin
deficiency coagulant effect.
Fibrinolytic pathway PAI-1 (4G/5G polymorphic
status)
Plasminogenemia Asplenia/Splenectomy/Hyposplenism
Dysfibrinogenemia
Hemoglobinopathy The most common form of asplenia or hypo-
Platelet defects splenism is surgical splenectomy. The usual hema-
tological indications for splenectomy include:
monitored using the INR. Home testing kits are • Repeated splenic sequestration in children with
available for parental use, with dosing super- SCD
vised by a warfarin clinic, so that the child does • Thalassemia major with associated
not have to attend clinic. hypersplenism
• VKAs take several days for anticoagulant • Hereditary spherocytosis
effect to be manifest; therefore, in the setting • Refractory immune cytopenias
of acute thrombosis, bridging anticoagulation
is required with UH or LMWH Splenectomy can be open or laparoscopic, the
• UH requires continuous intravenous infusion latter being preferred where appropriate facili-
plus frequent phlebotomy for monitoring pur- ties and expertise exists. The downside of sple-
poses. It is rapidly cleared in infants, meaning nectomy is a lifelong risk of overwhelming
that very large doses may be needed. In this sepsis from Gram-positive encapsulated organ-
population, less time is spent in therapeutic isms. Vaccination should be performed a mini-
range, and more bleeding complications are mum of 2 weeks prior to elective splenectomy to
seen than with use in adults. Antithrombin minimize this risk or 2 weeks after emergency
may need to be replaced concurrently with splenectomy. Daily antibiotic prophylaxis
UH therapy to achieve a heparin effect. against pneumococcus is recommended up to
• LMWH is emerging as the initial anticoagulant the age of 16 and, in some cases, for life. There
of choice for most episodes of acute thrombo- is also a possible increased long-term risk of
sis, although UH is still used extensively dur- venous thromboembolic disease and pulmonary
ing cardiopulmonary bypass and other such artery hypertension.
procedures. LMWH is given subcutaneously, Congenital absence of the spleen can be asso-
usually once daily (Newall et al. 2009). ciated with multiple abnormalities including car-
• In more specific disease states such as inherited diovascular and visceral, and some of these have a
or acquired protein C or antithrombin genetic basis.
normal range is 11–13.5 g/dL from 1 year to

puberty.
• Anemia can be caused by increased destruction
of red cells, e.g., acute blood loss or hemolysis.
This will be accompanied within a few hours
by a compensatory reticulocytosis, i.e., the
reticulocyte count (the number or proportion
of immature red cells) will be high.
• Conversely, a low or normal reticulocyte count
in the setting of anemia indicates inadequate
bone marrow activity or failure of red cell
production.
• Several factors are required for healthy eryth-
ropoiesis. Certain nutrients are prerequisite
Fig. 7 The arrowed red cell shows a dark dense inclusion
“Howell-Jolly body.” Howell-Jolly bodes are most com- including vitamin B12, folate, and iron. A cer-
monly seen in splenectomized (surgical or “auto”) patients, tain growth-promoting balance of cytokines is
severe forms of megaloblastic and hemolytic anemias, and required. This can be disrupted by inflamma-
hemoglobinopathies (Puri and Höllwarth 2009) tion. The hormone erythropoietin, produced in
the kidneys, is required. The bone marrow pre-
Loss of splenic substances as a result of infarc- cursors need space to expand, and an infiltrat-
tion is seen in SCD and is usually accompanied by ing malignancy can cause anemia. Hereditary
functional hyposplenism. or acquired genetic defects in the hematopoi-
etic precursors can cause abnormal erythropoi-
• Assessment of splenic filtration function is esis, e.g., Diamond-Blackfan anemia and
made by examination of the blood smear for myelodysplastic syndrome. Aplastic anemia
evidence of red cell inclusions which are pitted is thought to have an immune-related patho-
out during filtration by the normally function- genesis. Infection can directly interfere with
ing spleen (Fig. 7). The presence of Howell red cell precursors, e.g., parvovirus B19, or
Joly bodies usually reflects significant splenic through immune stimulation and can inhibit
hypo-function and the risk of overwhelming red cell precursors, e.g., transient
infection. erythroblastopenia of childhood. Toxins can
• Immune-mediated conditions associated with inhibit hematopoiesis, e.g., chemotherapy.
functional hyposplenism include: • Hemolytic anemias are usually accompanied
– Chronic graft-versus-host disease (cGvHD) by raised reticulocyte counts, indirect biliru-
– HIV/AIDS bin, and lactate dehydrogenase (LDH). Hapto-
– Coeliac disease/dermatitis herpetiformis globins will be low. Raised urinary
– Rheumatoid arthritis/SLE hemosiderin suggests that hemolysis is intra-
– Thyroid disease vascular (e.g., thrombotic thrombocytopenic
– Ulcerative colitis/Crohn’s disease purpura, hemolytic uremic syndrome, mechan-
ical heart valves) as opposed to taking place
within the spleen and reticuloendothelial sys-
Anemia tem. A direct Coombs test will help determine
whether there is antibody-mediated red cell
• Hemoglobin (Hb) values vary with age. Neo- destruction. Table 4 lists causes of hemolysis.
nates are relatively polycythemic with an Hb • The mean corpuscular volume (MCV), a
range of 15–21 g/dL. This gradually drops to marker of red cell size, can also provide useful
a nadir of 9.5–12.5 g/dL by 2–3 months of information. Iron deficiency and thalassemia
age. Thereafter, the Hb climbs such that the cause a low MCV. A high MCV accompanies
Table 3 Causes of anemia Table 4 Causes of hemolysis

Increased red cell Intrinsic to red cell Extrinsic to red cell
Decreased red cell production destruction Hb variants, e.g., HbSS, Mechanical hemolysis, e.
Nutritional: e.g., B12, folate, iron Acute blood loss HbSC, HbSβ0Thal g., mechanical heart valve
deficiency Globin gene deficiency, e. Burns, toxins, others
Space related: bone marrow Hemolysis g., thalassemia
infiltration, e.g., leukemia/other Paroxysmal nocturnal Microangiopathic
malignancies hemoglobinuria hemolytic anemia, e.g.,
Toxin related, e.g., chemotherapy TTP, HUS
Hormone related: EPO deficiency Red cell enzyme defects, Autoimmune
with chronic renal disease e.g., G6PD deficiency, PK
Immune related: aplastic anemia, deficiency
pure red cell aplasia, transient Red cell membrane Alloimmune, e.g., Rh
erythroblastopenia of childhood defects, e.g., hereditary hemolytic disease of the
Acquired genetic disorders of spherocytosis, hereditary newborn
erythropoiesis: myelodysplastic elliptocytosis, Southeast
syndrome Asian ovalocytosis
Hereditary genetic disorders of Parasites, e.g., malaria,
hematopoiesis, e.g., Diamond- babesiosis
Blackfan anemia, congenital
dyserythropoietic anemias
Cytokine related: anemia of
chronic disease, e.g., TB, protein 4.2). It is the most common hereditary
connective tissue disorders anemia in Caucasians. There is impaired interaction
between the red cell membrane and cytoskeleton.
Removal of redundant areas of membrane takes
a B12 or folate deficiency, some cases of MDS, place in the spleen so that the red cell loses its
and any cause of reticulocytosis. biconcave shape and becomes spherical, with resul-
• Examining the blood film can give further tant splenomegaly. The abnormally shaped red
pointers toward the cause of anemia, e.g., cells are incapable of traversing the narrow capil-
spherocytes in hereditary spherocytosis and lary network of the spleen and hemolysis ensues.
pencil cells in iron deficiency anemia. The spectrum of clinical severity varies among
• An FBC will help to determine if the process is different kindreds (Bolton-Maggs et al. 2004):
restricted to the erythrocyte lineage only, e.g.,
hereditary spherocytosis, or involves the • Some patients may be transfusion dependent.
hematopoiesis more generally, e.g., acute • Other patients require transfusion during
leukemia. infancy, puberty, intercurrent illness, or in
• A bone marrow aspirate and biopsy are helpful pregnancy only.
in select cases only. • Neonates may present with prolonged neonatal
• Many cases of anemia are multifactorial, e.g., jaundice.
combined nutritional deficiencies in inflamma- • Early pigment gallstones are a feature.
tory bowel disease coupled with anemia of • There may be a family history of splenectomy
chronic disease. Table 3 lists causes of anemia. or early cholecystectomy.
Children with severe disease require splene-

ctomy, which usually “cures” the anemia.
Hereditary Spherocytosis Those with moderate disease may benefit from
splenectomy. In the setting of asymptomatic gall-
This is an autosomal dominant hemolytic anemia stones, controversy exists over whether those
caused by a deficiency of a red cell membrane undergoing splenectomy may also benefit from
protein (α or β spectrin, ankyrin, band 3, or cholecystectomy.
Sickle Cell Disease (SCD) required if there is doubt about the nature of the
abnormal Hb. Many countries including the USA
Epidemiology: SCD occurs mainly in sub-Saha- and UK now have universal neonatal screening
ran Africans and in African-Americans, but also programs.
in South and Central Americans and people from
the Middle East and Mediterranean countries. It Clinical Features and Management
affects nearly 100,000 people in the USA. (Yawn et al. 2014)
Pathogenesis: Sickle hemoglobin (HbS) • Vasoocclusion is often precipitated by cold,
results from a point mutation in the β-globin dehydration, or infection. It causes severe
gene. Sickling disorders are seen when two HbS pain. Infants may experience their first vaso-
genes are inherited or when HbS is coinherited occlusive event, often dactylitis, at around
with certain other β-chain variants: HbC, HbE, 6 months of age, when HbS replaces Hb F as
HbD, HbOArab, and β-thalassemia. Sickle cell the predominant form of Hb.
trait is the term given to asymptomatic carriage • Vasoocclusion most frequently causes bone
of a single HbS gene. pain, but it can also cause nonspecific abdom-
HbS polymerizes on deoxygenation, interfering inal pain (may mimic an acute abdomen) or
with RBC membrane structure and deformability. chest pain. Pain control is essential – parenteral
The distorted RBCs cannot traverse small blood opiates are frequently required. Patients should
vessels in the microcirculation, and thus be well hydrated and antibiotics given if there
vasoocclusion occurs leading to ischemia, pain, is any suspicion of infection.
and local tissue damage. Hemolysis of affected • Chest Crisis: This can be rapidly progressive
RBCs also occurs, and the presence of free hemo- and life-threatening. Children present with
globin in the microvasculature that acts as a nitric dyspnea, fever, cough, and/or chest pain. Phys-
oxide scavenger contributes to the pathogenesis. ical examination may reveal reduced air entry,
Diagnosis: Blood smear is characteristic crepitations, or wheeze. CXR may show pul-
(Fig. 8). High-performance liquid chromatogra- monary infiltrates. Infection often underlies the
phy (HPLC) confirms the diagnosis and Hb elec- pathogenesis. Bone marrow embolus or intra-
trophoresis, or isoelectric focusing may be pulmonary vasoocclusion may also contribute.
Treatment is with supplemental oxygen, hydra-
tion, antimicrobials, top-up or exchange trans-
fusion, incentive spirometry, analgesia, and
supportive care.
• Cerebral Disease: Up to a third of children will
have silent cerebral infarcts visible on MRI
brain that lead to progressive cognitive impair-
ment (Fig. 9). This may present as behavioral
difficulties or a decline in school performance.
Ten percent of children will have overt stroke.
Raised middle cerebral artery velocity by
transcranial color Doppler (TCD) ultrasound
scanning is a predictive factor for stroke.
• Splenic or Hepatic Sequestration: Sequestra-
tion is usually seen in those under 5 years.
The spleen or liver becomes engorged by sick-
Fig. 8 A 9-year-old Nigerian boy with HbSS. The
led RBCs and may cause rapid hemodynamic
arrowed cells are markedly elongated with two pointed
ends. Also note the other classic findings of target cells collapse, and transfusion is usually required.
(TC), microcytes (MC), spherocytes (SC), and polychro- The more common splenic sequestration is a
matophilic cells (PC) (Puri and Höllwarth 2009) major cause of mortality in young children.
Fig. 9 About 25% of

patients with SCD develop
cerebrovascular
complications and about
80% of these are under
15 years of age. The MRI
brain shows an area of
infarction (I) secondary to
vessel occlusion (stenosis
(S) and absence (A)) (Puri
Parents should be taught to palpate the child’s From early infancy, patients should take daily
spleen daily, as sequestration can occur with- prophylactic penicillin, and all patients should
out warning. be vaccinated with Pneumovax.
• Priapism mainly occurs in adolescents and • Aplastic Crisis: Parvovirus infection sup-
adults with SCD and can lead to impotence. presses erythropoiesis and in SCD can cause
Up to 5% of prepubertal boys may be affected. an acute drop in Hb with an accompanying
• Hyposplenism: Autoinfarction of the spleen reticulocytopenia.
occurs in early childhood, resulting in functional • Other complications include obstructive sleep
hyposplenism. This puts patients at risk of over- apnea with nocturnal hypoxia, nocturnal
whelming sepsis from encapsulated organisms, enuresis, and increased incidence of preg-
most frequently Streptococcus pneumoniae. nancy-related complications.
Chronic Complications Surgery in Sickle Cell Disease

• Pulmonary hypertension • Any child of the correct ethnic origin who is to
• Chronic renal impairment undergo surgery and whose sickle status is not
• Chronic osteomyelitis or avascular necrosis known should have a preoperative screening
(AVN) test performed, e.g., sickle solubility test and
• Pigment gallstones HPLC. The “SICKLEDEX,” a solubility test,
• Proliferative retinopathy is unreliable in children under 6 months old or
• Chronic leg ulceration in young adults in those who have been recently transfused.
• Common surgeries performed in SCD include
splenectomy for recurrent splenic sequestra-
Disease-Modifying Therapy tion, cholecystectomy for pigment gallstones,
and adenotonsillectomy for obstructive sleep
• Chronic Transfusion Therapy: Patients are apnea.
placed on a transfusion program after a stroke • Surgery and anesthesia can precipitate sick-
or if they have abnormal TCDs. They are trans- ling. Anemia and obstructive sleep apnea also
fused every 3–4 weeks, which suppresses HbS contribute to surgical risk. Mortality rates vary
production. Recent evidence indicates that in the literature from 1% to 10%.
chronic transfusion therapy may preserve cog-
nitive function in patients with silent infarc- Key Principles of Perioperative Management
tions. Transfusion therapy is also used for • Keep the child well hydrated and maintain an
other indications. However, the benefits of adequate ambient temperature.
transfusion must be weighed against the • Maintain adequate oxygen saturations using
impracticalities of such programs and the com- supplemental oxygen.
plications that include iron overload and red • Consult with hematology and anesthetic col-
cell antibody formation. leagues regarding the need for preoperative
• Hydroxyurea: Originally used as an oral che- top-up or exchange transfusion. There is only
motherapy, hydroxyurea functions in SCD to one randomized controlled trial, which showed
increase the quantity of HbF synthesized, thus that a conservative transfusion regimen that
reducing the relative proportion of HbS in the raised hemoglobin to 10 g/dl was as effective
circulation. Hydroxyurea can reduce the num- in preventing perioperative complications as
ber of painful episodes suffered. It can also an aggressive exchange regimen which
reduce the incidence of dactylitis and ACS reduced HbS to <30%. A randomized trial is
and reduce the frequency of hospitalization currently being run in the UK that compares
and blood transfusion. For many children, it those who receive no transfusion with those
brings about a marked improvement in quality who receive transfusion.
of life, although not all children respond and • Incentive spirometry postoperatively reduces
some lose their response over time. It is now the frequency of ACS.
recommended in the USA for all children
above the age of 9 months with SCD.
• Hematopoietic Stem Cell Transplantation: This Thalassemia
is potentially curative, although the procedure
is more complicated for those with a more Thalassemia is a hemoglobinopathy caused by
complex SCD history, who paradoxically are deletion of either an α- or β-globin gene. Thal-
those most in need of cure. HSCT is not feasible assemia is found most frequently in Southeast
in every patient and is generally considered for Asia, but it also occurs in Northern Africa, the
those with previous stroke, severe sickle- Middle East, Mediterranean Europe, India,
related pain, or recurrent chest crises with a and Central Asia. Children with the mildest
fully histocompatible unaffected sibling donor. forms show only a microcytosis without
anemia. At the other end of the spectrum, dele- intravenous broad-spectrum antibiotics.
tion of all four alpha globin genes results in Chronic severe neutropenia renders patients
hydrops fetalis and is incompatible with extra- susceptible to deep-seated fungal infection.
uterine life. • Acquired transient causes of neutropenia
Children with β-thalassemia major present in include infections (viral, bacterial), burns,
infancy with transfusion-dependent microcytic drugs (e.g., chemotherapeutics, carbimazole),
anemia and failure to thrive. In the first decade hemodialysis, and B12 or folic acid deficiency.
of life, they develop the complications of • Acquired chronic causes include bone marrow
chronic transfusion-related hemosiderosis infiltration (e.g., leukemia), myelodysplasia,
including diabetes, hypoparathyroidism, and immune-mediated (alloimmune and autoim-
osteoporosis. They may have delayed puberty. mune), hypersplenism, viral bone marrow sup-
In order to prevent death in the teenage years, pression, and idiopathic.
an aggressive iron chelation program must • Severe congenital neutropenia (Kostmann syn-
accompany chronic transfusion therapy. drome) can be caused by mutations in several
In addition to oral iron chelators, this usually different genes encoding mitochondrial proteins
involves nocturnal subcutaneous desfer- (HAX1, AK2), endoplasmic reticulum proteins
rioxamine therapy, which is administered five (ELANE/ELA2 and G6PC3), cytoskeletal regu-
to seven nights per week for 8–15 h (Standards lator proteins, (WAS) and transcriptional repres-
for the clinical care of children and adults with sor proteins (GFI1). Affected children have
thalassemia in the UK; 2008.). Adherence to severe neutropenia and recurrent bacterial infec-
therapy often becomes an issue. Even with tions. The untreated mortality is high (70%).
maximal chelation therapy, affected persons >20% of children treated with GCSF will go
can develop hepatic and cardiac failure in later on to develop acute myeloid leukemia within
life. Bone marrow transplantation is potentially 10 years.
curative. • Other causes of isolated neutropenia are cycli-
cal neutropenia, WHIM syndrome (warts,
hypogammaglobulinemia, infection, and
Neutropenia myelokathexis), and benign chronic neutrope-
nia (BCN). BCN is autoimmune in etiology
Newborns often have neutrophilia for the first and is associated with a much milder pheno-
2 weeks, mean count 11 109/L, whereas chil- type than SCN. It is a transient cytopenia
dren between 1 month and 8 years have mean occurring in the preschool years that lasts an
levels of 3.6 108/L. Above this age counts are average of 20 months and is associated with
similar to adult levels. minor ENT and skin infections. It is the most
common cause of chronic neutropenia in
• Neutropenia can be inherited or acquired and childhood.
transient or chronic. • Neutropenia may also be associated with com-
• The workup for a child with neutropenia plex syndromes including cartilage-hair hypo-
requires documentation of the neutropenia plasia, Chediak-Higashi syndrome, dyskeratosis
over time and elimination of possible precipi- congenita, primary immunodeficiency syn-
tating causes by history and bone marrow dromes (e.g., X-linked immunodeficiency with
examination. hyper-IgM), Fanconi anemia, Shwachman-Dia-
• Children with neutrophil counts of mond syndrome, and metabolic disorders, e.g.,
<0.5 109/L are at increased susceptibility glycogen storage disease type 1B.
to bacterial infections. An untreated bacterial • Treatment involves supportive measures such
infection in a severely neutropenic patient can as antibiotics, G-CSF (a recombinant cytokine
progress within hours to septic shock and that stimulates granulopoiesis), and, in some
death. Treatment usually involves dual cases, bone marrow transplantation.
Leukemia chemotherapy without evidence of minimal

residual disease (MRD) by molecular tech-
Leukemia is the most common pediatric malig- niques at the end of induction are treated on a
nancy. Eighty percent of these children have acute less drug-intense regimen. Those who have
lymphoblastic leukemia (ALL), 15% have acute MRD at the end of induction are escalated to
myeloid leukemia (AML), and the remainder pre- a more intense regimen. This allows individu-
sent with rare pediatric leukemias such as chronic alized treatment to maximize cure while mini-
myeloid leukemia and juvenile myelomonocytic mizing toxicity.
leukemia. • Treatment for ALL lasts for approximately
3.5 years in boys and 2.5 years in girls. There
• Acute leukemia presents with a prodromal ill- is an initial induction phase of therapy,
ness lasting a few days to a few months. Symp- followed by consolidation, delayed intensifica-
toms include lethargy, anorexia, general tion, and maintenance therapy. Maintenance
malaise, dislike of being handled (bone pain), therapy involves daily oral chemotherapy
fever and infection, and bruising or bleeding. with intermittent pulses of intravenous chemo-
Untreated acute leukemia is fatal within days to therapy and is delivered as an outpatient. All
weeks. phases of treatment are generally accompanied
• White cell count may be high or low at presen- by intrathecal chemotherapy, drugs delivered
tation, and there are usually blasts (leukemic usually by lumbar puncture directly into the
cells) circulating in the blood. Pancytopenia CNS to prevent CNS relapse.
(anemia, neutropenia, and thrombocytopenia) • >85% of cases of ALL can be cured by che-
is common. Biochemistry may show an ele- motherapy alone.
vated LDH and urate. • Relapse treatment involves salvage chemother-
• Examination may reveal hepatosplenomegaly, apy with or without a bone marrow transplant.
palpable adenopathy, gum hypertrophy, skin
infiltration, petechiae, or purpura. Papilledema Surgical Issues in the Leukemic Patient
may be present with central nervous system • CVAD: The child requires the urgent placement
(CNS) involvement. of a tunneled CVAD for ease of delivery of
• A preliminary diagnosis can usually be made supportive care, but also to allow safe delivery
from the blood smear. The lineage (myeloid or of vesicant chemotherapy. If a vesicant (e.g.,
lymphoid) of the leukemia is then confirmed daunorubicin) is administered through a
by flow cytometry. In cases of pancytopenia, a peripheral vein, thrombophlebitis and associ-
bone marrow aspirate or trephine biopsy may ated extravasation can occur, with extensive
be needed to make a diagnosis. localized tissue destruction. This is a limb-
threatening complication. Prior to CVAD
Management of Acute Leukemia placement, the child may require blood product
• Hyperhydration to prevent tumor lysis syn- replacement to achieve Hb >8.0 g/dL, platelets
drome (TLS) on commencement of chemo- >50 109/L, or plasma replacement to cor-
therapy. TLS is manifest by electrolyte rect a coagulopathy.
disturbances and accumulation of uric acid • Typhlitis or neutropenic colitis (inflammation
crystals in the kidneys with acute renal failure. of the cecum due to Gram-negative bacteria of
• Blood product support. the gut flora) is a diagnosis unique to the neu-
• Broad-spectrum antibiotics intravenously if tropenic patient. Its diagnosis is relatively com-
there are infectious issues. mon on the hemato-oncology wards where
• Urgent placement of a tunneled CVAD and the intensive chemotherapeutic protocols are rou-
commencement of cytotoxic chemotherapy. tinely used. Patients are febrile and usually
• Treatment of ALL is now response stratified, have right-sided or generalized abdominal
i.e., those who respond promptly to pain. It should be remembered that no clinical
findings differentiate typhlitis from other histological diagnosis and are therefore only
abdominal diseases. CT and ultrasound imag- used pre-biopsy if the patient is in a critical
ing show distention and thickening of the condition. Early senior anesthetic involvement
cecum and bowel wall thickening with associ- is imperative in order to protect the airway
ated marked pseudopolypoid formation of the during surgery.
mucosa. Neutrophil recovery is a good prog-
nostic factor. Conservative management with
broad-spectrum antibiotics and antifungals Blood Products and Their Transfusion
with or without bowel rest is the treatment of
choice. Surgical intervention should only be A list of blood products used in children in the
considered in the most severe cases. surgical setting is shown below:
• Asparaginase-associated pancreatitis
(AAP): Asparaginase is a cornerstone drug • Red blood cells (RBCs): Dose (ml) = (desired
in ALL therapy; however, in 5–10% of rise in Hb) 3 recipient weight (kg).
cases, it can cause pancreatitis (Raja et al. The selection of a unit of blood is geared to
2012). The pathogenesis of AAP is prevent inadvertent exposure to a foreign anti-
unknown. As with other causes of pancrea- gen and consists of:
titis, patients present with abdominal pain 1. ABO and RhD grouping of the recipient
and vomiting and may have deranged blood 2. Antibody screen of the recipient (or
biochemistry including an elevated amylase mother in the case of neonatal transfusion)
or lipase, low calcium, and a raised CRP. – serum is tested against a “panel” of com-
Ultrasound or CT confirms the diagnosis, mercially available RBCs which carry all
and serial imaging may be required to detect clinically important antigens between
the emergence of complications. Manage- them
ment involves drug cessation, antibiotics 3. A comparison of these results with any
until sepsis can be excluded, initial bowel available historical record (a “group and
rest, total parenteral nutrition, and support- screen” finishes at this point)
ive care. There may be a role for octreotide 4. Testing of patient serum against the RBCs
and continuous regional arterial infusion of to be transfused (a crossmatch)
protease inhibitors. Complications include • Platelets: Dose =15 ml/kg. Usual maximum
systemic inflammatory response syndrome dose is one unit (“adult dose”) unless the
and multiorgan failure, pseudocyst forma- patient is bleeding or a specific target platelet
tion, insulin-dependent diabetes mellitus, count must be achieved.
and chronic pancreatitis. • Frozen Plasma (FP): Usual dose 15 ml/kg,
• Mediastinal mass at presentation: Acute lym- used as source of clotting factors in DIC and
phoblastic lymphoma is a variant of ALL hemorrhagic disease of the newborn. “Patho-
which may present with a mediastinal mass gen-reduced plasma” is standard, which has
without derangement of the FBC. The differ- undergone a viral inactivation process.
ential diagnosis includes a variety of other • Fibrinogen Concentrate: This has replaced
malignancies, and a histological diagnosis cryoprecipitate as the product of choice for
may be required. Sometimes mediastinoscopy fibrinogen replacement as it can be rapidly
can be avoided if flow cytometry of microscop- reconstituted in a small volume, is virally
ically normal bone marrow or of pleural fluid inactivated, and contains a standardized
or biopsy of an enlarged peripheral node fibrinogen content. In a massive hemorrhage
reveals the diagnosis. Patients may develop situation, fibrinogen can be the most signifi-
superior vena cava obstruction syndrome and cantly depleted clotting factor; therefore,
airway encroachment. Steroids may shrink the levels must always be checked. Usual dose is
mass; however, they may also obscure the 70 mg/kg.
• RBCs and platelets are leukodepleted to (g) Repeat crossmatch and antibody screen.
remove WBCs which can cause immune reac- (h) Alert the hematology laboratory to the possi-
tions and harbor infections (e.g., CMV). bility of a transfusion reaction as another prod-
• CMV-negative and/or irradiated products are uct recall may be necessary.
usually required for immunosuppressed
patients – refer to local guidelines.
Other Adverse Reactions to Blood
Acute Complications of Blood Product Transfusion
Transfusion
• Hemolytic reaction: fever, dyspnea, back pain, • Delayed hemolytic reactions occur after
and hemoglobinuria. 5–10 days – there is evidence of hemolysis
• Allergic reaction (urticarial and anaphylactic (decreased Hb, raised LDH, raised bilirubin,
reactions). reduced haptoglobins) and possibly renal
• Bacterial contamination – usually seen with impairment.
platelets (stored at 22 C). • Infection can be bacterial, viral, protozoal
• Transfusion-related acute lung injury (Chagas’ disease), or prion related (vCJD).
(TRALI): occurs due to anti-WBC or HLA • Iron overload is seen with chronic RBC trans-
antibodies in donor or recipient. This causes fusion, e.g., thalassemia major.
an ARDS-like picture. • Post-transfusion purpura: there is a reaction to
• Febrile non-hemolytic reaction: nonspecific an antigen on transfused platelets that the
reaction to foreign antigen. These must be dif- recipient’s immune system recognizes as for-
ferentiated from more serious reactions eign. Severe thrombocytopenia ensues
• Volume overload: Deaths have been described 7–10 days later. This is rare.
in the Serious Hazards of Transfusion (SHOT) • Transfusion-associated graft-versus-host dis-
report. All children should be medically ease is a rare but universally fatal complication
assessed for risk factors prior to transfusion, of blood transfusion. It occurs in immunocom-
blood volumes should be carefully calculated, promised hosts or where the donor shares HLA
and patients should be continuously assessed types with the host. It can be prevented by
throughout transfusions. irradiating blood for certain immunocompro-
mised recipients and avoiding interfamily
The various acute reactions have similar presen- donations.
tations (Bolton-Maggs et al. 2015). In practice, all
the above possibilities need to be considered.
When faced with a suspected transfusion reaction: Conclusion and Future Directions
(a) Stop the transfusion. Hematology is a rapidly evolving field of medi-

(b) Assess hemodynamic stability – resuscitate if cine with many advances in recent decades in the
necessary. molecular understanding of hematological disor-
(c) Check the patient identification against the ders. Pharmaceutical companies invest large pro-
blood product. portions of their drug development budgets in
(d) Examine the product for abnormal appearance hemato-oncology drugs. This has a knock-on
suggesting contamination. effect on government healthcare budgeting. Due
(e) Order full septic screen (include product if to the need for extensive experience of a drug in
bacterial contamination a possibility), and adults before it can be considered for use in chil-
check a FBC, renal profile, and coagulation dren, there is some delay before changes in adult
screen (looking for indices of hemolysis, renal practice filter into pediatrics. The following is a
failure, and DIC), summary of treatments on the horizon for the most
(f) Order CXR if dyspnea/hypoxia. common pediatric hematological disorders.
ALL is now curable in >85% of cases with In spite of improved survival in SCD through
chemotherapy alone. Current clinical trial focus is neonatal screening programs, screening to prevent
on reducing long-term toxicities of treatment regi- complications, and hydroxyurea therapy, the cur-
mens for patients with low-risk disease. For those rent life expectancy in the USA is only 50 years.
children with high-risk disease who cannot afford a Fifty percent of patients will not benefit in the long
de-escalation of therapy, biologically targeted ther- term from hydroxyurea therapy, either through poor
apies offer the potential to increase cure rates with- response, reluctant therapists, inadequate dosing,
out contributing much in the way of toxicity toxicities, or noncompliance. More widespread
(Sadelain et al. 2015; Ai and Advani 2015). use of hydroxyurea, coupled with optimization of
Blinatumomab, a bispecific T-cell engager, directs dosing, should further impact on mortality. Novel
the immune system to target B-ALL cells that therapies are needed, and treatments in the pipeline
express surface CD19. A substantial proportion of focus on modifying effects downstream of sickling
adults with relapsed or refractory ALL achieved a such as vascular adhesion, inflammation, and
complete response in early-phase clinical trials. hemolysis. Increasing experience in transplanting
Phase III trials are underway in children and adults, patients with SCD will likely make transplant
and blinatumomab has received early FDA safer. SCD patients may benefit in the future from
approval for B-ALL. Inotuzumab is a cytotoxic gene therapy. Likewise, more patients with thalas-
agent conjugated to a humanized monoclonal anti- semia may benefit from transplant, and gene ther-
body directed against CD22, often expressed on the apy may one day provide a curative solution.
surface of ALL blasts. It can induce molecular In the 1950s, children with leukemia died
remissions in relapsed or refractory ALL. One of within weeks of diagnosis, hemophiliacs were
the most exciting new developments for the treat- bed-bound throughout childhood and died in
ment of B-ALL is chimeric antigen receptor (CAR) early adulthood, patients with thalassemia major
T cells. These are T-cells taken from the patient died in early childhood, and patients with SCD
(autologous) or from a third party (allogeneic) that died in infancy or childhood. Advances in the
are genetically engineered in vitro to recognize a understanding of these disorders mean that in
marker expressed on the blasts of the patient's leu- hemophilia, thalassemia, and SCD, long-term sur-
kemia (e.g., CD19 or CD22). Results of early phase vival is expected, and focus of treatment has
trials in children have shown a very high response moved toward reducing long-term complications
(60-100%) and cure rate, including in patients with and improving quality of life. Elective surgeries
disease that would previously have been considered are now more frequently performed in these
incurable. At present, CAR T cell therapy for ALL populations, and emphasis should be on reducing
is only available in certain countries as part of a perioperative morbidity.
clinical trial, although it is likely to change the
landscape of ALL treatment in the years ahead.
Drug development for hemophilia aims to Cross-References
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Surgical Safety in Children
25
George G. Youngson and Craig McIlhenny
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Background: The History of Surgical Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Tackling Concerns – Improvement
Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
Improvement Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
Policy-Based Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Human Factors in Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
Definitions and Examples in Other Industries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415
The Evolution of Non-technical Skills in Aviation:
Crew Resource Management (CRM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
From Aviation to Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416
NOTSS (Non-technical Skills for Surgeons) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417
NOTSS and Implications for Surgical Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418
Personal Awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Surgical Checklists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Surgical Briefings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 425
Abstract dramatically in recent years, with the figure of

Awareness of the scale of unintended harm 10% of hospital admissions suffering an
during healthcare delivery has increased adverse event now being generally accepted.
Surgical care poses unique risks to patients,
with approximately 50% of untoward surgical
G. G. Youngson (*) outcomes occurring in the operative phase. In
Department of Paediatric Surgery, University of Aberdeen, accordance with other high-risk industries such
Royal Aberdeen Children’s Hospital, Aberdeen, Scotland, as commercial aviation, the majority of these
UK
e-mail: ggyrach@abdn.ac.uk adverse events are not caused by failures of
technical skill on the part of the individual
C. McIlhenny
Forth Valley Royal Hospital, Larbert, Scotland, UK surgeon but rather lie within the wider
e-mail: c.mcilhenny@nhs.net healthcare team and environment. Lapses and

https://doi.org/10.1007/978-3-662-43588-5_27
412 G. G. Youngson and C. McIlhenny
errors in communication, teamworking, lead- the efficacy of surgical treatment, as it is on the

ership, situation awareness, or decision- need to ensure that the intended treatment is
making all feature highly in post hoc analysis delivered as planned and without any unintended
of surgical adverse events. consequences of the treatment process resulting
While system-based improvement pro- in harm. Observations into healthcare systems in
grams can help reduce adverse events, they the last 10–20 years has revealed an existing level
are not of themselves sufficient, and the pos- of harm which initially appeared barely credible
session and deployment of good non-technical and which continues to attract skeptical if not
skills by individual surgeons are now known to frankly critical comment. Yet, repeated research
play a key role in optimizing outcomes for the and evaluation of unintended consequences of
surgical patient. The Non-Technical Skills for care highlight the constant nature of surgical
Surgeons (NOTSS) program has been devel- error occurring through a range of mechanisms.
oped to describe and assess these non-technical These range from inadequacies in care delivery
skills in the intraoperative environment. The from resource limitation, incomplete knowledge
NOTSS classification describes categories of or a lack of diligence, through to a lack of orga-
situation awareness, decision-making, nizational reliability.
teamworking, and communication and leader- Hazards in the operating theater/room (OR)
ship. Combined with an awareness of human have traditionally been seen as being associated
performance limitation and tools to help with the risks imposed by the physical character-
improve teamworking and non-technical skills istics of that environment (temperature control,
such as briefings and checklists, patient safety fires, fluids, sharps, radiation, etc.). Errors, how-
can be improved. ever, produced by either the individual surgeon,
the surgical team collectively, or the health orga-
Keywords nization and its infrastructure are now appreciated
Safety · Error · Human factors · Decision- as being equally, if not more, relevant in produc-
making · Communication · Teamworking · ing patient harm. At an individual level, the non-
Leadership · Improvement · Non-technical technical (as opposed to the technical skills) con-
skills tributes significantly to error. Characterizing these
behaviors and processes allows analysis of error-
prone circumstances and situations and possibly
Introduction identification of periods when surgeons find them-
selves vulnerable to their environment and to
Surgical intervention in sick newborns, infants, “normal” human performance limitations. Appro-
children, and adolescents is accompanied by var- priate and increasing appreciation of these influ-
ious levels of risk, associated in the main with the ences has been promoted by the implementation
disease process itself and its systemic effects. of surgical briefings, checklists, and standard pro-
This is particularly the case in surgical neonates, tocols such as the universal protocol, all of which
by virtue of the finite resources and limited phys- have gone some way to reducing morbidity and
iological resilience possessed by these patients improving outcome following operation
(see ▶ Chap. 8, “Specific Risks for the Preterm (Macdonald and Sevdalis; Bliss et al. 2012; de
Infant”). The term “surgical safety” is therefore, Vries et al. 2010; Haynes et al. 2009). However,
at first sight, perhaps counterintuitive when that quite why these effects are achieved without any
“safety” is determined primarily by the features obvious change in the skill set of the surgical team
of the disease process and also by the magnitude and its constituent individual members remains ill
of the surgical intervention required. The recent defined. Additionally, in some circumstances,
focus placed on safety in surgery is, however, less these measures have failed to completely control
concerned with the natural history of the illness or the more severe forms of error. Harm in healthcare
25 Surgical Safety in Children 413
is ubiquitous. The impact of surgical error is sub- published. This highlighted that deaths due to
stantial, but crucially as in the case of adverse medical error actually exceeded combined num-
events in other high-risk domains and industries – ber of deaths from breast cancer, motor vehicle
it is also preventable. Surgical disciplines have accidents, or AIDS. By aggregating the individual
been the early adopters within medicine of the adverse events occurring in every ward, every
lessons learned from such high-risk and safety- hospital, and every region, international statistics
critical industries. projected forward the true magnitude of this prob-
This chapter outlines the scale of the problem lem on a global scale. Lucian Leape, an eminent
of surgical error along with the ingredients in American pediatric surgeon in the field of safety,
human factors and surgical practice that are rele- began to investigate patient safety concerns by
vant to prevention of harm, with particular performing a large epidemiological retrospective
emphasis on intraoperative non-technical skills case note review in New York State. He created a
and those items which provide countermeasures reliable database to understand the incidence and
and mechanisms to mitigate against failings in prevalence of injury and its preventability,
self, team, and the environment/organization, looking from the point of view of possible future
and those other areas which contribute to negligence claims. This was published as the
underperformance and error. Non-technical skills pioneering Harvard Medical Practice Study in
are applicable in all surgical settings and particu- the NEJM in 1991 (Brennan et al. 1991) and
larly where the pressures of time are most keenly attracted much attention and, simultaneously, crit-
felt as in emergency surgery for trauma and fast- ical comment. The case records of over 30,000
track surgery (see ▶ 31, “Fast-Track Pediatric patients treated in New York State hospitals were
Surgery”). reviewed. This study demonstrated a major
adverse incident rate of 3.7% of all patients
treated. Almost half of these events were associ-
Background: The History of Surgical ated with surgery. Similar studies have subse-
Error quently been conducted in Utah and Colorado
(Gawande et al. 1999), Denmark (Schiøler et al.
Ernest Codman, a surgeon from Boston, assessed 2001), New Zealand (Davis et al. 2002), and
and classified adverse outcomes in surgery as Canada (Baker et al. 2004). The rates of adverse
early as 1916 (Codman 1916). In 1960, Elihu events in all of these studies are remarkably sim-
Schimmel at Yale carried out one of the first ilar, with an adverse event rate of between 8% and
explicit, systematic studies of the complications 12%, and this range is now generally accepted as
of hospitalization, with a reported adverse out- being typical of healthcare systems in developed
come in 20% of the patients studied (Schimmel countries. Throughout these studies about half of
1964). However, apart from small groups of pio- all these adverse events are deemed to be
neers like those above, both the public and the preventable.
medical profession did not appear to recognize the On a global scale, according to the World
extent or the seriousness of the problem for some Health Organization (WHO), surgical complica-
time. This began to change in the 1990s with tions contribute to approximately one million
several high-profile cases of medical error deaths around the world each year. While this
reported in the USA and in the UK, such as research focuses on adult care, there is at the
reported by the enquiry into perioperative deaths same time, a surprising lack of information relat-
from pediatric cardiac surgical care in Bristol ing to the care of children, but where it does exist,
Royal Infirmary (Kennedy 2001). it indicates that there is no immunity conferred on
The scale of problem was underreported until pediatric practice against the prevalence of patient
the 1990s when the Institute of Medicine report harm (Ligi et al. 2008), and, indeed, Cincinnati
“To Err is Human” (Kohn et al. 2000) was Children’s Hospital has been pivotal in
emphasizing that children are equally, if not more, (NOTSS) aspires to enhance performance of the
susceptible to the scale and impact of error in care surgical team by improving the skill set of its indi-
delivery (Steering Committee on Quality vidual members. Both human factors and improve-
Improvement and Management and Committee ment methodology can work side by side to
on Hospital Care 2011). improve patient safety.
In the UK, a review of 1,014 patients records
and found that 10.8% of patients experienced an
adverse event (Vincent et al. 2001). This equates Improvement Programs
to 850,000 adverse events nationwide per year. Of
those events, 50% of the events were deemed as Improvement programs utilize a range of tools for
preventable, and 3% led to moderate or greater identifying and measuring adverse events. These are
disability or death. designed to track adverse events over time and are a
useful way of identifying whether any care interven-
tion is likely to have an effect on any emerging
Tackling Concerns – Improvement pattern of harm. Key to success of any intervention
Methodology is the need to measure and remeasure following an
analysis and implementation of an action – the
The need to react to this scale of medical error has so-called PDSA cycle (plan, do, study, act). This
produced a variety of initiatives including attempts approach seemed initially to be at odds with the
to detect adverse events and introduce voluntary traditional scientific method of evaluating large-
reporting and tracking of errors. However, only scale interventions through an evidence-based, sys-
10–20% of errors are ever reported, and of those, tematic approach involving randomization and
90–95% cause no harm to patients (Kohn et al. meta-analysis. Instead the PDSA cycle simply
2000). Models such as root cause analysis are used involves small tests of change and by using run
when investigating serious untoward incidents in an charts, held at each ward level and therefore a very
attempt to produce organizational learning (Taylor- locally based feedback; it can be seen at an early
Adams and Vincent 2004). Such protocols help stage, whether or not a change in care policy is
define and attribute causality and identify mecha- having an effect. Simultaneously attempts at stan-
nisms at fault when adverse events occur. However, dardizing care on large-scale interventions (e.g., a
this approach does not necessarily identify mecha- stringent policy on the use of particular forms of
nisms for prevention, and the Institute for Healthcare antiseptic solutions during central line insertion,
Improvement among others has designed a range of patient positioning during ventilation in ITU set-
improvement programs which target specific areas tings, strict hand hygiene policies in clinical set-
in order to quantify the extent of potential harm and tings) all have provided standardized operating
to attempt to produce preventative and mitigating policy settings in healthcare in general but in the
policies. These are intended to reducing variation acute surgical care setting in particular. Control
and are able to establish standards of care, measure charts are widely used as part of improvement
them, and evaluate and analyze. method, and examples such as early warning sys-
Other approaches have focused on analyzing the tems are designed to document early deterioration in
potential inconsistency that is an integral part of physiological status and are used across adult and
human behavior and reactions and is best children’s surgery in an attempt to not only detect
represented in the science of human factors, includ- deterioration at an earlier stage than was previously
ing the non-technical skills of surgeons’ cognitive the case but to ensure that action is taken when a
and interpersonal behaviors (see below). By focus- critical score is obtained. Specific interventions
ing on consistency and obliterating error in areas of include establishing rapid response teams, the use
judgment, decision-making, use of options, as well of severity scoring, and reduction in medication
as leadership, communicating, and team manage- errors through education in medicine reconciliation
ment, the use of non-technical skills for surgeons (ensuring that the medicines patients were taking
before admission are not inadvertently omitted or Policy-Based Care

altered after admission or discharge). Communica-
tions between staff have been ensured by the use of Outwith the operating room, the areas of care
specific communication tools such as SBAR (situa- which pose most threat to patient safety and
tion, background, assessment, recommendation; see patient well-being are during transitions in care,
below) such that information is communicated in an be that between teams, between services, or the
efficient, timely, and structured manner. Addition- handover process from doctor to doctor (particu-
ally, safety briefings at shift changes have allowed larly in a shift-based rota system as part of critical
staff members to be aware of relevant information care cover arrangements) (Catchpole et al. 2007).
promoting continuity of care. These communication Additionally, admission to and discharge from
tools have become increasingly important with the hospitals, while providing an opportunity for a
emerging trend of shift working and handoffs or review of care plans, also carry the risk of
handovers being an integral part of the safety pro- unplanned change to care and particularly errors
grams, given that the patient is most vulnerable in prescribing (so-called medicines reconciliation)
during transition in care from one level to another, (Kripalani et al. 2007) with the complexities of
when critical information concerning the patient is prescribing weight-related drug regimens in chil-
susceptible to discontinuity through failure of trans- dren adding substantially to that risk (Hicks et al.
mission (Arora et al. 2005). 2006).
Finally, the development of perioperative care Venous catheter-related sepses (central and
bundles has been an integral part of surgical safety peripheral) have bloodstream infection with the
programs in the UK. The integration of the use of attendant metastatic sepsis risk as the commonest
the WHO surgical checklist, suitably amended for nosocomial infection, and a standard policy for
pediatric surgery, is an essential ingredient of this insertion and line replacement reduces the sepsis
pediatric perioperative care bundle (http://www. rate considerably (Marsteller et al. 2012). Simi-
scottishpatientsafetyprogramme.scot.nhs.uk/pro larly hand hygiene and compliance with aseptic
gramme/paediatric-programme). The purpose of techniques have reduced healthcare-associated
such developments is avoidance of never events infections substantially but a high level of com-
as published by the National Quality Forum in mitment needs to remain to avoid breakthrough
2004, e.g.: infection, and the commitment of many can be
undermined by the violating behaviors of a few
• Surgery or other invasive procedure performed who either choose or unintentionally failed to
on the wrong site adhere to workplace-based policy. The universal
• Surgery or other invasive procedure performed acceptance of policies in the workplace has
on the wrong patient required a culture change which has been slower
• Wrong surgical or other invasive procedure to achieve with some clinical groupings than
performed on a patient others.
• Unintended retention of a foreign object in a
patient after surgery or other invasive
procedure Human Factors in Surgery
• Intraoperative or immediately postoperative/
post-procedure death in an ASA Class 1 patient Definitions and Examples in Other
Industries
This list has now been extended, but in spite of
implementation of mitigating mechanisms such as Enhancing clinical performance through an under-
the WHO safety checklist and the universal standing of the effects of teamwork, tasks, equip-
protocol for preoperative verification, such events ment, workspace, culture and organisation on
human behaviour and abilities and application of
persist and persist on an unwelcome scale (Stahel that knowledge in clinical settings. (Catchpole and
et al. 2010). McCulloch 2010)
Making it easy to do the right thing. (Bromiley among these was the Tenerife disaster of 1977 in
2011.) which two Boeing 747s collided on the runway,
These are but two definitions that allude to the fact killing 582 people. Both aircraft were perfectly
that human factors are a process which encompass serviceable, and the crews were all experienced
individuals; teams; organizations, but crucially and adequately trained. The cause of the tragedy
the tools; and the instrumentation used in pursuit was deemed to be not due to a lack of technical
of task completion. Moreover, it refers to the aircraft handling skills on the part of the pilots, but
complex and dynamic integration that exists was due to a lack of what came to be known as
between any and all of these component parts of non-technical skills an important component of
operative teams. While originally the science was human factors.
applied to ergonomics, its application to the anal- The National Aeronautics and Space Adminis-
ysis of various disasters (e.g., Ladbroke Grove tration (NASA) took the lead in exploring these
train crash , oil spills, fratricide in military com- issues and revealed the alarming statistic that
bat) has been extended into healthcare in general 60–80% of all aviation accidents were attributable
and surgery in particular. The pressures faced by to human error (Cooper et al. 1980). In the vast
police marksmen acting in a hostage crisis or majority of these cases, the accident was not due
those pressures faced by oil platform managers to the pilot’s lack of technical flying ability or
contending with an oil well blowout and a poten- from mechanical failures or defects in the aircraft,
tial ecological disaster, these scenarios share some but due to errors caused by failures of leadership,
of the same features as can be found at the oper- breakdown in interpersonal communication, poor
ating table, namely, limited time to make high- teamworking, and poor decision-making in the
stake decisions, sometimes with incomplete infor- cockpit. Other studies confirmed that the better
mation or without access to the preferred kit and the crew resources were utilized and the more
an acute awareness of a potential for a loss of life. effectively the crews communicated, the better
While human factors can be applied across a range the crew performed (Sexton and Helmreich 2000).
of domains, those examples highlight the rela- The discovery of the importance of non-tech-
tively late entry of the surgical profession into nical skills in aviation led to the development of a
this kind of analysis in identifying contributing new type of training then designated Cockpit
factors when considering untoward events and Resource Management, now referred to as Crew
adverse outcomes. While surgical morbidity and Resource Management (CRM), which resulted in
mortality reviews analyze contributory factors in full integration of CRM concepts into flight oper-
determining poor patient outcome on a case-by- ations training and with the description of specific
case basis, there is as yet no reference body con- behaviors to CRM checklists.
stituted by surgeons at national level that under-
take the equivalent of an industry accident review
system. From Aviation to Surgery
Although there are significant similarities

The Evolution of Non-technical Skills between aviation and healthcare, there are also
in Aviation: Crew Resource substantial differences. Pilots and surgeons both
Management (CRM) operate in complex environments where teams
interact with technology, and in both domains,
Flight training traditionally consisted of acquiring risk can be high with threats coming from a
“stick and rudder” technical skills only. However, variety of sources within the working environ-
a series of aviation disasters in the 1970s triggered ment. However the practice of surgery is perhaps
the realization of the importance of so called more complex than that of aviation in that surgi-
“non-technical skills” in aviation safety. Chief cal practice is much less protocol-based than
flying an aircraft. In surgery professional groups NOTSS (Non-technical Skills

are also more heterogeneous – anesthetists, scrub for Surgeons)
nurses, radiographers, etc. – and the composition
of surgical teams is rarely static; there may be The framework that emerged from this research
several changes of staff sometimes even within consisted of four main categories (subdivided into
one procedure. In the early 1990s, several anes- two social skills (teamwork, communication, and
thetists saw the parallels between team issues in leadership) and two cognitive skills (situation
aviation and those in the operating theater and awareness, decision-making) (Fig. 1). Other
sought to transfer the aviation approach to med- items such as personal awareness, conflict resolu-
icine. Underlying their efforts was a desire to tion, stress, and fatigue, while relevant to the
develop techniques to deal with imperfect team- NOTSS taxonomy and intraoperative perfor-
work and the conflict that may arise in the oper- mance, were not included given the practical chal-
ating theater. David Gaba, an anesthetist from lenges of observing and rating on a regular basis.
Stanford, developed a program (Anesthesia Cri- Instead focus was placed on these four categories
sis Resource Management) and designed one of to be observed and rated during the intraoperative
the first behavioral ratings systems (adapted and phase of surgical care. These skills, while proba-
developed from aviation simulation training) to bly relevant to the remainder of surgical practice,
rate anesthesia teams managing simulated criti- have not as yet been studied outwith the operative
cal events (Gaba and DeAnda 1988). This led to surgery environment and currently relate to the
the development of a classification for non-tech- “scrubbed up/gloves on” aspect of performance.
nical skills for anesthetists, which was developed Subsequent research has endorsed the validity and
from the literature, interviews, observations and reliability of the use of this taxonomy (Yule et al.
surveys, and incident analysis, Anesthetists 2008) which comprises at the first level, the four
Non-Technical Skills taxonomy (ANTS) categories referred to above; secondly, three ele-
(Fletcher 2003) and a system for surgeons, ments subtending each category (see below); and
NOTSS (Non-Technical Skills for Surgeons) thirdly, identifying indicative behaviors which
(Yule et al. 2006). constitute good or poor examples of performance
Fig. 1 NOTSS taxonomy Category Element

(version 1.2.) (Reproduced
with the permission of the Situation Awareness Gathering information
University of Aberdeen and
Understanding information
Royal College of Surgeons
of Edinburgh) Projecting and anticipating future state
Decision Making Considering options
Selecting and communicating option
Implementing and reviewing decisions
Leadership Setting and maintaining standards
Supporting others
Coping with pressure
Communication and Teamwork Exchanging information
Establishing a shared understanding
Co-ordinating team
within each element. Finally there is rating of environment (the potential for distraction by
elements and category by reference to these indic- loud noises/chatter/music/pages, etc. may reduce
ative behaviors. It was noted that while the social attention and hence situation awareness), but it
skills and behaviors (generally in the form of also depends on past experiences. This selective
communication) could be directly observed, cog- attention process forms the basis of situation
nitive skills are more difficult to evaluate given awareness. Information is interpreted and pro-
the challenges of appreciating what goes on in cessed in the memory system a bipartite process
somebody else’s thinking. Hence for the purposes with a short-term “working memory” and a “long-
of evaluation, cognitive processes need to be term” component. This working memory has a
inferred from observable behaviors. limited storage capacity, and holding information
The NOTSS taxonomy can be accessed at http:// in this system requires effort or it may be lost.
www.abdn.ac.uk/iprc/notss and is reproduced Distraction tends to exacerbate such loss. This
below with the permission of The University of limited space for monitoring our current state,
Aberdeen and the Royal College of Surgeons of data interpretation, and planning future actions is
Edinburgh. easily overwhelmed (Miller 1956). Operating the-
aters are frequently noisy and complex environ-
ments with multiple competing sensory inputs,
NOTSS and Implications for Surgical not least changes in the current surgical task.
Performance That changing state or developing situation may
simply not be noticed or absorbed by the surgeon
Situation Awareness or surgical team until problematic, particularly if
This important cognitive category has the follow- there are concurrent tasks or competing demands
ing definition: “the perception of the elements in made on the surgeon’s attention.
the environment within a volume of time & space, The capacity of an individual to pick up new
the comprehension of their meaning and the pro- information, process that information correctly,
jection of their status in the near future.” Alterna- and maintain a mental awareness of it is finite.
tively, it can best be simply described as knowing Surgeons, as well as using their cognitive
what is going on around you by collecting the resources to scan and update their mental models
available information, comprehending it, and in a highly dynamic and changing environment,
using it to project forward, the so-called three also need to maintain process integrity (i.e.,
phases of “what – so what – now what.” keeping the operation progressing safely) and
That awareness of what is going on around you hence rely on having spare mental capacity to
at any one time, the correct understanding of those deal with the new problems that can occur during
observations, and thirdly, projection into the surgery; one of the major surgical skills therefore
future of what is likely to happen next are outlined is knowing when to use the correct proportion of
in the three-level model of situation awareness attention for each process, i.e., knowing when to
(SA) described by Mica Endsley (Endsley and concentrate principally on assessing the environ-
Garland 2000). The concept of knowing what is ment or on making a decision or on performing a
going on around you in the operating theater may technical task. Utilizing “thinking space” effec-
seem to be so obvious as not to merit any specific tively becomes particularly important when deal-
attention or commentary. However at any one ing with crisis situations. This (human
time, the amount of information available is of a performance) limitation in cognitive capacity is
magnitude such that in order to make sense in much more pronounced in the novice surgeon
handling that information, the surgeon can (Hsu et al. 2008). Characterized by a lack of
become very selective in what is consciously experience, trainees have not developed the
attended to, particularly if high levels of concen- same degree of confidence in their technical per-
tration are required for completion of the technical formance; they cannot rely on pattern recogni-
task. That focus of attention depends on the tion in perceiving the environment nor in making
decisions. All these processes are effortful and Decision-Making

demanding for the trainee, and so there is much The hallmark of surgical attitudes and behaviors is
less free cognitive space to deal with new prob- the willingness to make and follow through on
lems. In crisis situations trainees are thus at high decisions, sometimes taken as a matter of urgency,
risk of becoming cognitively overloaded, sometimes with incomplete information and yet
with subsequent deterioration in technical with a full awareness of the associated level of
performance. procedural risk. While the risk usually relates to
However, alternatively, (and more commonly patient well-being, professional and reputational
for all surgeons) a presumed familiarity with the risks are also concepts emerging from the recent
procedure involved can lead to a certain level of surgical literature which bear an impact on the
automaticity and a loss of attention (Moulton et al. choice of decisions made (Leung et al. 2012).
2007). The potential risk of this automaticity Decision-making is contingent upon accurate sit-
needs constant attention such that cues which uation awareness and frequently acts as a sequitur
convert automaticity into mindfulness can be rec- to that third – “now what” – phase. The mode of
ognized and increased vigilance of impending decision-making processes can utilize one or
difficulty or hazard is a feature of good surgical more of four common methods. These are:
performance.
It is notable in a legal review of medical • Recognition-primed decision-making (RPD,
records successfully awarded indemnity costs a.k.a. intuitive, pattern recognition)
that the reviewers identified risk to reside in the • Rule based
commonly performed operations and rarely in • Analytical
the extraordinary or complex (Rogers et al. • Creative
2006). Resilience against the loss of vigilance
and maintenance of good levels of situation Recognition-primed decision-making (RPD) is
awareness demand a disciplined approach to sur- used by the expert as opposed to the novice. It is
gical practice at all times. Anticipation (the third dependent on “having been there before” and
step of situation awareness) is predicated entirely being able to match the actions used successfully
by the preceding two elements of collecting in the past to the current task or problem. By its
information appropriately and an appreciation nature, it has a high accuracy and success rate and
of the tasks facing the operating surgeon. Any is often used in time-limited, higher-risk circum-
situation which therefore threatens to encroach stances. It is known as “fast and frugal” by virtue
on cognitive capacity threatens the maintenance of the low requirements for cognitive effort. That
of SA. Fatigue and stress are both ubiquitous in ability to match actions to circumstances is depen-
surgery and are well known in other high-risk dent on a “store” or “library” of past experiences
industries to reduce the ability to deal with new and also creates a thinking space that is liberated
information (de Vries-Griever and Meijman by the use of this type of decision-making
1987). They effectively shrink the working allowing mental capacity for other purposes –
memory and any ability to detect, deal with, and hence its value is in those urgent, high-risk
and process new information. Fatigue is respon- circumstances when stress has the effect of poten-
sible for diminishing cognitive capacity and tial impacting upon thinking.
hence reduces our ability to detect new cues By contradistinction, analytical decision-
from our environment and also the ability to making requires time, more cognitive effort,
retain valuable information in our working mem- and is an obligate process for those with no
ory. Stress has a similar detrimental effect. access to pattern matching by virtue of lack of
Retention of information in working memory is previous experience. For the inexperienced/nov-
effortful, and so distractions and interruptions ice surgeon, this mode of decision-making
can have a drastic effect in reducing crucial situ- requires more effort, leaves less available cogni-
ation awareness. tive resource for other tasks, and has a greater
stress effect with the potential for overload and quality of supervisory leadership has been related
freezing. It is in such circumstances, therefore, to decreased errors, reduced costs, improved
that slowing down and introducing an safety, and an increased compliance with safety
intraoperative pause to spread the demands of standards (Mullen and Kelloway 2010). As vari-
the situation allow a review of the situation in ous theories demonstrate, effective leadership
order to allow consideration of options. The ele- involves a combination of traits, behaviors, styles,
ments in the NOTSS taxonomy on decision- and influence. These theories also illustrate that
making encourage disclosure and sharing of the leadership can be trained and improved by train-
options to ensure optimal selection and that again ing. One of a surgeon’s main responsibilities is to
uses time to good effect. maximize effective team performance and ensure
Rule-based decision-making is knowledge safe and effective team functioning in the comple-
dependent and is algorithmic in its nature. It is tion of the surgical task.
therefore accessible to all with the appropriate Classifications of team leadership in other
information base. It is less time dependent than industries have identified functions such as defin-
the analytical decision-making method and ing the team’s mission, establishing expectations
should require little discriminating thinking in its and goals, providing feedback, monitoring the
implementation other than recognition of the cir- team, and solving problems among others. So,
cumstances being appropriate for application of effective leadership behaviors encompass not
that rule or guideline. only behaviors focused on completing the task
Finally, and used only very occasionally, is the safely but should also comprise behaviors focused
method of creative decision-making, which on developing the team. While the existing litera-
requires significant amounts of time to originate ture on leadership in surgery is not in any way
solutions which are not stored in either memory or comprehensive, many publications point to the
knowledge banks. This demands the use of a fact that surgeons’ leadership behaviors in the
pragmatic solution to often a unique problem operating theater may be less than perfect. Good
and needs both time and attention. In practice leadership behaviors are associated with
these methods are not mutually exclusive but decreased OR time and better outcomes (Catch-
may be blended to cope with the challenges of pole et al. 2008). However, Hendrickson Parker
the operative task. et al. observed that while surgeons exhibited more
leadership behaviors in higher complexity sur-
Leadership gery, the overall rate of leadership behaviors was
Leadership is one of the two social categories low (Parker et al. 2012). A significant proportion
outlined in the NOTSS taxonomy and relates to: of the leadership behaviors documented (approx-
imately one third) were solely directed at the
• Setting and maintaining standards surgical trainee. When the surgeon did communi-
• Supporting others cate with the wider scrub team, comments were
• Coping with pressure most commonly made to the room at large rather
than to a specific individual and, in most cases,
Leadership: the art of getting someone else to do
something you want done because he wants to do
leading to delays or repeated requests because
it. – Dwight D. Eisenhower there was no individual designated to complete
the request. Flin et al. showed discrepancies in
This social skill is critical to effective team perceived leadership style between professions –
performance, and the quality of a leader depends while most surgeons viewed their leadership style
on the success of the leader’s relationship with the as consultative, a similar proportion of nurses
team. Good leadership has been consistently iden- viewed it as autocratic (Flin et al. 2006). Demon-
tified as a key component for the safe and success- strating a positive leadership style through model-
ful functioning of the team in high-risk ling positive behaviors has been shown to have a
environments (Klein et al. 2006). In industry, the major impact on how patient safety initiatives are
viewed and accepted among the other members of The third element of coping with pressure
the medical or surgical team (Künzle et al. 2010). requires among other things an outwardly calm
Leaders who are considered engaging, transfor- demeanor during episodes of increased pressure
mational, and rewarding seem to have the most and stress. At this time, it is essential in empha-
influence on improving safety culture. The sur- sizing to the rest of the team that this is indeed a
geon who demonstrates positive attitudes toward high-pressure situation but one that is under con-
protocols and models attention to detail and trol. This may also mean adopting a forceful and
adherence to best surgical practice will be instructive manner (transactional leadership) if
rewarded with a more positive attitude toward such is appropriate in urgent or emergency situa-
safety within the team. A lack of such behaviors, tions but without undermining the role of the other
or even worse, the demonstration of opposing team members. This last part is vital as the sur-
attitudes or behaviors, will provide a hidden cur- geon who fails to identify urgency even during an
riculum for the rest of the team, especially sur- emergency situation and who does not convey
geons in training, that positive behaviors that urgency or seriousness of the situation is not
regarding safety are not necessary, and a degrada- demonstrating positive behavior in this situation.
tion in quality will ensue (normalization Temperament and loss of composure are also
of deviance occurs, with lack of adherence to associated with poor leadership behaviors. In
protocols becoming the norm within that theater). emergency situations, emphasis of the urgency
The time when modelling the behavior of of the situation, for instance, may be achieved by
others and being a role model is perhaps most vocal tone and volume; however, the margins
important during the pre-op briefing. This is the between assertive behavior and demonstration
surgeon’s chance to provide a positive role model of abusive personality can be blurred. Rosenstein
for the entire team around the subject of patient and O’Daniel (2006) reported that disruptive
safety. The introduction can be used to set the tone behavior such as shouting and the use of abusive
for the team regarding hierarchy and encouraging language are still observed in the operating
other team members to speak out if unsafe or theaters, and this increases frustration and
potentially unsafe events or behaviors emerge. Pos- stress and stifles further communication and
itive role modelling in this regard, which is carried interprofessional collaboration. This behavior
further and echoed at each surgical pre-op pause, has a profoundly negative effect on teamworking
and post-op debrief emphasize the focus on safety and communication often at a time when it is most
and becomes the norm for the operating team. crucial to optimize the outcome of the patient. The
In addition to setting and maintaining stan- impact of bullying and rudeness in the workplace
dards within the OR, a vital aspect of leadership is explored below.
is the surgeon’s support of others within the team.
Availability is key in providing support to help the Communication and Teamwork
other members of the surgical team as is the ability Wrong site and wrong-side surgery, a so-called
to judge different team members’ abilities and “never event,” is carried out by the surgeon in
then allocate tasks accordingly, also taking the full view of other members of the team. In effect,
current situation into account. Recognition of the other team members observe the operating sur-
limitations and strengths of individual team mem- geon perpetrate a significant error, but without
bers is essential. Being seen to recognize individ- effective intervention from themselves. These
ual team members and to delegate appropriately team members are frequently highly experienced.
within that team is a very positive leadership and Why that relationship between surgeon and team
team-building behavior. Providing good construc- permits the error to go unchecked is unclear. A
tive feedback to team members and giving credit number of potential reasons may exist:
for tasks performed well signify positive behav-
iors in this element and help build team rapport • Incomplete or different mental models across
and improve team functioning. the team members
• Steep hierarchy or chain of command S The situation is . . . .

suppressing and inhibiting “speak up” policy B The background to that situation is. . .
• An expectation that “some other person” will A My assessment is that. . .
make the intervention R My recommendations are that. . .
• A lack of situation awareness of the rest of the
team as to the implications of what is happening
• A lack of confidence to intervene of cultural or Finally, the third element of the teamwork and
linguistic origin communication category in the NOTSS taxonomy
coordinating the team – is best achieved by person-
specific briefing when the situation demands it, so
Deference to status may mistakenly denote a
that the social redundancy effect outlined above is
form of respect. This needs active management. A
minimized ensuring each team member is aware of
“speak up” or graded assertiveness policy should
his or her specific responsibilities.
be in place for all to use rather than “hoping and
There are a number of intrinsic and extrinsic
hinting” that an incipient error will be diverted.
factors prevalent in the operating room that can
One mnemonic that has found favor is the “CUS”
compromise good communication, just as they
tool featuring keywords indicative of escalating
can have an effect upon situation awareness.
levels of concern.
Examples include:
Intrinsic
• C – “I am Concerned about what is happening.”
• U – “I feel Uncomfortable about progressing.”
• Language difference
• S – “Stop this is a Safety issue.”
• Culture
• Motivation
Communication within high-performing teams
• Expectations
is an expansive topic with a rich literature on the
• Past experience
effect on outcomes following surgery (Greenberg
• Status
et al. 2007) but there are also lessons to be learned
• Emotions/moods
from adverse events in other high-risk domains as
a consequence of communication failure. In par-
Extrinsic
ticular the factors that contribute to fratricide –
mortality as a consequence of friendly fire in battle
• Noise
situations – point to the fact that low volumes of
• Low voice
communication may not themselves result in poor
• Deafness
team performance, but excessive communication,
• Electrical interference
particularly if indiscriminate and poorly directed,
• Separation in space and time
may be ineffective or possibly even hazardous
• Lack of visual cues (body language, eye con-
(e.g., distracting for the team, so-called “commu-
tact, gestures, facial expressions, etc.)
nication masking”) (Rafferty et al. 2012).
Structured tools have been developed to pro-
mote effective communication. SBAR is one such The impact of communication failure is widely
model that ensures effective transmission of crit- accepted as being responsible for a significant
ical information in a time-efficient and succinct number of adverse events occurring in the operat-
manner. Again it has its origins in military proto- ing room with 43% of adverse events being attrib-
col (nuclear submarines) and is of particular value uted to this element of failure in behaviors
in urgent or unanticipated communications (e.g., (Gawande et al. 2003).
the need to request assistance in the OR), provid- The notion that the surgical team represents the
ing both context and signaling to the nature of the ultimate example of teamworking and elite
problem in hand. interprofessional performance within healthcare
is at odds with the daily tensions experienced in rudeness has a scattered effect, and the cognitive
operating departments, and disagreement and ability of those observing, as well as those who are
aggression between team members are not an the primary recipients of the target of rudeness,
infrequent occurrence but are one which is poorly will result in shrinkage of the cognitive space of
represented in surgical literature. This aspect of those involved (Porath and Erez 2009; Bradley
team communication failure is ubiquitous but its et al. 2015). An outburst or reprimand of a junior
management is often left to the discretion of those team member, perhaps intended to “improve” the
involved rather than being subject to a more performance of the recipient, may have quite a
policy-driven approach. Moreover, it is clear contrary effect. This rudeness effect constitutes a
from studies that the issuing and receipt of aggres- significant distraction for observers and bystanders
sion is not the preserve of any one rank or group- as well as the target of the rudeness and can pose a
ing within the surgical team (Rosenstein and significant risk to intraoperative safety.
O’Daniel 2008). These factors clearly compro-
mise the potential for producing an expert team
in spite of the team possibly being constituted by Surgical Checklists
experts in their field.
. . . Improve the outcomes with no increase in
skill. That is what we are doing when we use the
checklist
Personal Awareness The Checklist Manifesto. Dr A Gawande
The original process of attempting to codify and The adoption of the WHO surgical checklist has
rate pilot’s non-technical skills in the cockpit been made obligate in health policy across many
(NOTECHS) intentionally avoided an impact countries including the UK. In spite of some
assessment of external influences such as fatigue initial skepticism surrounding its use, the signif-
and personal stress. However these and other exter- icant impact of a checklist process and compli-
nal influences sound may have a significant effect ance with use have improved (Bliss et al. 2012).
upon any individual’s day-to-day performance, and The reasons for success may appear opaque in
the Federal Aviation Authority produced a useful the first instance but cross-reference to the
mnemonic (I’m SAFE) to allow pilots to reflect NOTSS taxonomy demonstrates how the check-
upon their state of well-being at any point in time. list improves the situation awareness of the
This tool can be used for self-calibration. Compo- entire team, helps create a shared mental model,
nents of the I’m safe mnemonic are set out below: contributes to leadership communication and
I – Illness teamwork, and importantly allows prediction of
M – Medication (e.g., antihistamines for a potential problems and preparation for mitiga-
coryzal illness) tion. It is equally important however to recognize
S – Stress (personal relationships, time the limitations of checklist usage and to
pressures) acknowledge that it will not constitute a panacea
A – Abuse, substance/alcohol (or its against all intraoperative hazards. Indeed the first
aftereffects) 5 years of use of the universal protocol – a
F – Fatigue similar verification checklist for patient identifi-
E – Emotion (rudeness, anger, aggression, per- cation and laterality – failed to reduce the inci-
sonal grief) or “E” for eating (hypoglycemia dur- dence of wrong site and wrong-side surgery
ing protracted procedures) (Stahel et al. 2010). Perhaps incomplete commit-
All these affect various aspects of performance ment and, in some cases, no commitment at all to
– especially situation awareness – and due note checklist usage rendered those previously sus-
should be taken that these effects may also be ceptible to this kind of “never event” open to
shared by other team members. In particular continuation of that same risk of surgical error.
Surgical Briefings organizational barriers such as perceived lack of

time, facilities, or limited physical or fiscal
In addition to WHO checklist usage, pre-op brief- resources.
ings and post-op debriefings have the potential to A postsurgery debrief should also take place at
address a variety of communication and team- the end of each day or the end of each operating
work issues and improve team performance and list. Again this should involve all staff and should
safety culture. It is important to note that pre-op lead to a structured discussion about both positive
briefings are not synonymous with the surgical and negative points from the day. Following the
pause or the use of the WHO checklist. Briefings conclusion of the “Bristol inquiry,” a strong rec-
are meetings that are conducted before the patient ommendation from its chairman, Sir Ian Kennedy,
enters the anesthetic room and involve a discus- indicated that “it should be the norm for surgical
sion of the forthcoming case or theater list with all teams (the surgeon, anesthetist, theater nurses,
of the relevant team members. ODPs) to have time together and with those in
At this briefing the order of the theater list may other teams such as in the ITU, to review and
be finalized, and the anticipated requirement for develop their performance as a team.” However
equipment is discussed; any anticipated anesthetic documenting the debriefing also provides a
or surgical issues are also discussed. These brief- method of tracking the learning points for theaters
ings allow the development of a shared mental over time helping to identify common themes and
model of the upcoming day’s surgery to be devel- recurrent problems.
oped. It also allows other team members to ask
questions and clarify uncertainties. Another
aspect of the pre-op briefing is the setting of the Conclusion and Future Directions
tone for the day. It is a chance to focus the entire
team on safety vigilance and improve Building safety into the care plans for individual
teamworking and communication. Taking the infants, children, and young people should not be
lead in informal introductions is also essential to a random nor opportunistic process. Safe practice
break down hierarchy within the team and encour- can be systematized such that the care applied to
ages more junior members of the team to speak each patient is delivered in a timely fashion, care-
up. This can be explicitly enhanced by verbalizing fully with the process and content which was
that all personnel are required to speak up if they intended such that any potential for harm is iden-
see or suspect unsafe acts or behaviors. tified and neutralized. Improvement science
The introduction of surgical briefings separate focuses on reliability and consistency and the
from the WHO checklist has been shown to prescription of standardized operating policies
decrease wrong-site surgery, increase staff percep- and protocols which are understood and
tion of safety culture and teamwork quality, and a implemented by all without exception; deviation
significant reduction in surgical flow disruptions from standard operating policy can then be iden-
in cardiac surgery (Henrickson et al. 2009). tified and remedied or the policy changed with the
Despite the potential benefits of pre-op briefings, intention of improving care.
and their recent endorsement by the WHO (2008), While good patient selection, careful preoper-
their utilization remains low within many surgical ative planning, and sound technique are prerequi-
specialties. This may be due to a lack of a stan- sites for a good outcome following surgery, so is
dardized protocol for conducting pre-op briefings an understanding of how to cope with the com-
– each surgical specialty has unique issues that plexities inherent in our healthcare system and
may need to be addressed prior to each operation how to accommodate the unexpected, frequent
so a generic “off-the-shelf model” may not suf- changes in team members resulting in the loss of
fice. Other barriers almost certainly include indi- familiarity and varying levels of experience of
vidual attitudes or resistance to change, as well as supporting staff. Early recognition of problems
and confident and decisive interventions accom- Catchpole KR, de Leval MR, McEwan A, Pigott N, Elliott
pany careful deliberations and prudent choice MJ, McQuillan A, et al. Patient handover from surgery
to intensive care: using formula 1 pit-stop and aviation
when selecting from the available surgical models to improve safety and quality. Paediatr Anaesth.
options. The need to persevere and press on or 2007;17(5):470–8.
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Anesthesia and Pain Management
26
Aidan Magee and Suzanne Crowe
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428
Preoperative Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Fasting Prior to Anesthesia and Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
The Operating Theater and Anesthetic Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Breathing System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Laryngoscopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Ventilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Cardiovascular Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Respiratory Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Temperature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Neuromuscular Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Induction and Maintenance of Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Fluid Balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Postoperative Pain Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Pain Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Regional Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Special Considerations in the Premature Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
Anesthesia and the Developing Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Anesthesia for Specific Surgical Conditions in the Newborn . . . . . . . . . . . . . . . . . . . . . . . 437
Esophageal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Congenital Diaphragmatic Hernia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
Intestinal Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
Exomphalos and Gastroschisis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
A. Magee · S. Crowe (*)

Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
e-mail: suzanne.crowe@olchc.ie

https://doi.org/10.1007/978-3-662-43588-5_28
428 A. Magee and S. Crowe
Herniotomy for the Ex-premature Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438

Postoperative Admission to Surgical NICU/PICU . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
Abstract been a growing body of research on the clinical

Due to developments in surgical techniques and pharmacology and clinical outcomes of these
equipment, surgical repairs in smaller infants agents in neonates and infants. Developments in
and young children became feasible in the last surgical techniques and equipment available have
decades. This has been linked to new anesthetic facilitated challenging surgical repairs in smaller
drugs and new anesthesia modalities such as infants and young children (Smithers et al. 2016;
regional anesthesia. Increased operative inter- Nose et al. 2016). This has been coupled with new
vention in preterm and low birth-weight infants anesthesia modalities, in particular with regard to
has led to increased demand for postoperative regional anesthesia, and rapidly metabolized med-
high dependency and intensive care. ications such as desflurane and remifentanil
The success of major pediatric and neonatal (Davidson et al. 2015a; Sale et al. 2006;
surgery depends on the cooperation between Sammartino et al. 2011). Increased operative
surgeon, anesthetist, and nursing and allied intervention in preterm and low birth-weight
professions to optimize anesthetic and surgical infants has increased the demand for postopera-
management. Basic techniques for maintaining tive high dependency and intensive care
a favorable physiologic milieu in the face of (Brusseau and Koka 2009).
surgical intervention while at the same time Equally important has been the increased
ensuring adequate analgesia and anesthesia is understanding of the need for an efficient
essential. Besides intraoperative management, smooth-working team. The success of major pedi-
adequate postoperative care is crucial for the atric surgery depends on maximum cooperation
surgical pediatric patient. The best postopera- between surgeon, anesthetist, pediatrician, and
tive care should take place in an environment nursing and allied professions. It is appropriate
where the healthcare staff are skilled and therefore that everyone involved in the care of
trained to manage the challenges presented by the hospitalized child, whether working inside or
neonatal and pediatric physiology in the peri- outside the operating theater, should be familiar
operative period. with the basic techniques used in maintaining a
favorable physiologic milieu in the face of surgi-
Keywords cal intervention while at the same time ensuring
Anesthesia · Analgesia · Cardiovascular adequate analgesia and anesthesia.
monitoring · Cardiovascular monitoring · A newborn requires constant vigilance, rapid
Perioperative care · Respiratory management · recognition of the events, and swift intervention
Preterm infant during anesthesia. The anesthetic considerations
in neonatal surgical emergencies are based on the
physiological immaturity of various body sys-
Introduction tems, poor tolerance of the anesthetic drugs, asso-
ciated congenital disorders, and considerations
Historically, the use of anesthetics and analgesics regarding the use of high concentrations of oxy-
in neonates and infants has been based on extrap- gen. The main goal is for titration of anesthetics to
olations from studies performed in adults and desired effects while carefully monitoring the
older children. Over the past 20 years, there has
26 Anesthesia and Pain Management 429
cardiorespiratory status (Millar 2005). Advance- Communication and cooperation between the
ments in neonatology have resulted in the entire healthcare team, including the surgeons,
improvement of the survival of the premature anesthesiologists, neonatologists, and pediatri-
and critically ill newborn babies (Eicher et al. cians, are of utmost importance to ensure the
2012; Greenough et al. 2008). Most children best possible care of the child (Taneja et al.
with congenital anomalies that can be corrected 2012). This has implications in terms of operating
by surgery are now stabilized and optimized theater resources, intensive care resources, and the
before the procedure. Most of the disorders perioperative care of the newborn. Examples of
previously considered as neonatal surgical common surgeries include closure of a patent
emergencies in the past no longer require imme- ductus arteriosus and laparotomy for necrotizing
diate surgery due to new technology and new enterocolitis in the extremely preterm infant. In
methods of treating sick neonates (Greenough the term neonate, release of posterior urethral
et al. 2008). valves, duodenal atresia repair, and tracheoe-
This chapter describes the common neonatal sophageal fistula or atresia all must be carried
surgical emergencies and focuses on factors that out in the first days of life.
affect the anesthetic management of patients with The cornerstones of preoperative anesthetic
these disorders. There is a brief review of pediatric management are a detailed knowledge of the
physiology and pharmacology relevant to anes- child’s personal and family history, combined
thesia. There is an emphasis on preoperative with a physical examination. Consideration must
optimization, controlling the operating room envi- be given to the specific surgical procedure to be
ronment, and the importance of managing pain to undertaken and its implications in terms of poten-
suppress the stress response to surgery. tial blood loss, monitoring requirements, analge-
Most of the current general anesthetics have sia requirements, and postoperative care.
been associated with anesthetic neurotoxicity in The efficient recognition and prompt manage-
juvenile mammals, and several epidemiologic ment of illness in the neonatal period may be
studies in human infants and toddlers have linked lifesaving. The infant’s history includes gesta-
surgery occurring in the first 3 years of life with tional age, significant events at birth (asphyxia,
neurocognitive delays in school-age children meconium aspiration, Apgar score), and previous
(Johnson et al. 2008; Vutskits 2012). These con- or current mechanical ventilation. The physical
cerns are discussed in this chapter. Practical con- examination should pay particular attention to
siderations about pediatric intubation, line the respiratory and cardiovascular systems. Air-
placement, and intraoperative fluid management way anatomy should be assessed so that potential
are also reviewed. difficulties with airway management can be antic-
ipated. The physical examination includes hydra-
tion status and coexisting diseases.
Preoperative Optimization Laboratory examinations include a recent
hematocrit, glucose, and calcium. Glucose
Surgery will be postponed until the infant has metabolism is immature in the newborn period,
grown and gained weight if possible, to reduce and the sick infant may develop hypoglycemia
morbidity related to gestation and to make surgery rapidly. This is as a result of diminished glycogen
less technically challenging. However, it is not stores (inadequate hepatic stores in the premature
possible to postpone some operations, which are infant or depletion from catecholamine-stimulated
lifesaving for the neonate. Newborns undergoing breakdown in stress) or due to hyperinsulinism in
emergency operations present several difficult diabetic mothers. Infants born with intrauterine
challenges for the anesthesiologist. Many surgical growth retardation are also vulnerable to develop-
emergencies in the neonate are life-threatening ment of hypoglycemia due to reduced hepatic
and are frequently accompanied by multiple gluconeogenesis. Failure to recognize and treat
organ system compromise or failure. neonatal hypoglycemia results in seizures and
cerebral injury. Neonates who are not fed require pediatric anesthesia is reported as 0.02% in one
maintenance fluid containing dextrose, usually series (Tan and Lee 2016). Of the various preven-
10%. Blood glucose measurement should be tative measures that have been advocated to
performed regularly as part of normal nursing reduce the incidence of this complication, the
care. Glucagon and steroid administration is occa- preoperative fast has long since achieved univer-
sionally required to bring the blood sugar level sal acceptance with the result that patients are
into the normal range (2–6 mmol). Children required to abstain from food and drink prior to
receiving intravenous dextrose or total parenteral induction of anesthesia. Excessive fasting leads to
nutrition may experience rebound hypoglycemia dehydration and hypoglycemia, however, and
if the infusion is stopped abruptly due to increased may accentuate the risk of hypotension at induc-
blood insulin levels. tion of anesthesia. Furthermore, fasting leads to
Hypocalcemia is common in the newborn infants and children becoming hungry, thirsty, and
period, especially in critically ill newborns, infants fractious. Point-of-care ultrasound examination of
of diabetic mothers, and infants who have received the stomach may be useful in demonstrating resid-
large volume blood transfusion. Measurements of ual gastric volumes (Van de Putte and Perlas
total serum calcium do not accurately reflect the 2014). Current recommendations for infants are
level of ionized calcium in the blood. Reduced a 2-h fast from clear fluids, 4 h for breast milk, and
circulating calcium levels can cause seizures, 6 h for formula milk, milk, and solids. Infants and
apnea, and low cardiac output as the neonatal myo- children at particular risk of regurgitation, e.g.,
cardium is very sensitive to changes in calcium pyloric stenosis, intussusception, or perforated
serum levels. Replacement using intravenous cal- appendix, must fast from all oral or nasogastric
cium infusion must be carried out using central intake for 6 h (Brady et al. 2005).
venous access, as calcium is extremely irritant to
small peripheral veins and tissues.
A discussion with parents includes the planned The Operating Theater and Anesthetic
conduct of anesthesia, pain relief, regional anesthe- Equipment
sia, postoperative monitoring, blood transfusion,
invasive monitoring, and potential admission to the The primary objectives of anesthesia are the pro-
high dependency unit (HDU) or the pediatric inten- vision of sleep, analgesia, life support, intensive
sive care unit (ICU) (Hiller and Krishna 2004). surveillance, and appropriate operating conditions
Postoperative overnight admission and apnea for the surgery, irrespective of the patient’s age. In
monitoring are required in infants less than order for these to be achieved, it is imperative that
56 weeks corrected gestational age (CGA) and both operating theater environmental conditions
must be planned as part of the surgical admission. and anesthetic equipment must be appropriate for
Surgical neonates and infants are not generally infants and children.
administered sedative premedication due to Measures must be taken to minimize heat loss,
the risk of airway compromise. Children older using passive warming by manipulation of the
than 12 months may occasionally require a seda- ambient temperature and active warming through
tive premedication before separating from their fluid warmers, heated mattresses, and forced air
parents. warmers. With a large body surface area to body
ratio, the neonate tends to lose heat rapidly by
conduction, convection, evaporation, and radiation.
Fasting Prior to Anesthesia and Surgery The newborn has a limited ability to raise its body
temperature through heat production from metabo-
Pulmonary aspiration of gastric contents has long lism of brown fat stores and glucose. This inability is
been recognized as a cause of morbidity and mor- exaggerated in the premature infant, who is poikilo-
tality in patients of all ages undergoing anesthesia thermic and vulnerable to cold-induced metabolic
and surgery. The incidence of this complication in acidosis, hypoglycemia, increased oxygen
consumption, and weight loss. Critically ill neonates anticipated that video laryngoscopy will become
need to be nursed in a warm environment to protect established as a key tool in achieving intubation
them from the effects of cold stress. Due to the risk efficiently and safely (Lingappan et al. 2015).
of overheating and even burns, the child’s core There should be a “difficult airway trolley” avail-
temperature should be measured and thermostat- able in every operating department (Calder et al.
regulated equipment employed (Nesher et al. 2001). 2012).
Breathing System Ventilators
An appropriate anesthetic circuit for use in infants Most children can be ventilated using standard
and children needs to be light, has minimal resis- adult ventilators provided the ventilator is of low
tance and dead space, allows for warming and internal compliance and equipped with pediatric
humidifying of inspired gases, and be adaptable breathing tubes. The ventilator should be capa-
to spontaneous, assisted, or controlled ventilation. ble of delivering small tidal volumes and rapid
The most widely used system is the circle system, respiratory rates and have an adjustable inspira-
which allows inspiration and expiration via a dual- tory flow rate and inspiratory to expiratory ratio
limbed length of tubing. Connectors and tubes so that peak airway pressure is kept as low as
should also offer minimal flow resistance and possible. Pressure-controlled ventilation is fre-
dead space. Knowledge of the probable diameter quently used to minimize the risk of pulmonary
and length of the endotracheal tube appropriate for barotrauma. A suitable temperature-controlled
any given infant is essential. The use of an endo- humidifier should be incorporated in the inspira-
tracheal tube (ETT) of too large a diameter may tory limb of the ventilator circuit. The ability
result in tracheal wall damage, while excess length to deliver air and oxygen mixtures through the
leads to endobronchial intubation. Cuffed ET tubes ventilator or the anesthetic circuit should be
are now used as standard for managing the neonatal available.
airway and ventilation of the lungs during major
surgery (Spitzer and Sims 2016). Facemasks may
be used for short surgeries but are limited in use by Anesthesia
the neonatal propensity to develop apnea and the
need for a tight seal on the face. Laryngeal mask Monitoring the cardiorespiratory and metabolic
airways (LMAs) are used widely in pediatric anes- status of small children during anesthesia is usu-
thesia but less in small infants due to their ally difficult because the child is not physically
unreliability in maintaining an adequate and safe accessible. Specific monitoring techniques that
airway during surgery and due to their inherent provide accurate measurements are discussed.
inability to prevent aspiration of gastric contents General anesthesia is usually required for surgery;
(Bradley et al. 2013). the airway must be secured and anesthesia man-
aged with a combination of inhalational and intra-
venous agents. Regional anesthesia and opioids
Laryngoscopes may be included to decrease the intraoperative
anesthetic requirements and prevent pain in the
Because of the anatomical differences in the infant postoperative period.
airway, most anesthetists prefer to use a laryngo-
scope with a straight blade, lifting the epiglottis up
directly to expose the vocal cords. Curved blades Monitoring
are also used, especially in bigger children. The
video laryngoscope is increasingly employed in The clinical condition of the anesthetized infant
the management of pediatric airways, and it is can deteriorate more rapidly and with less
warning than that of patients of an older age replacement are expected, and during surgery
group. It follows that continuous and careful mon- for correction of congenital cardiac disease. The
itoring is required. The monitoring is employed right internal jugular vein is the easiest major
and interpreted by a meticulous and experienced vein to cannulate. Monitoring of left atrial pres-
pediatric anesthetist. The incidence of periopera- sure and pulmonary capillary wedge pressure is
tive pediatric cardiac arrest has been linked rarely indicated in children and infants.
inversely to the training and experience of the
anesthetist in a number of retrospective studies
(Zgleszewski et al. 2016).
Respiratory Monitoring
1. Pulse Oximetry: Hypoxia is the most common

critical incident in pediatric anesthesia. As
Cardiovascular Monitoring
detection of cyanosis in infants and young chil-
1. Electrocardiograph (ECG) is used to detect dren is difficult, the routine use of pulse oxim-
etry is now mandatory. Thermal injury and
bradycardia and arrhythmias. Primary arrhyth-
mias are uncommon except in infants with pressure necrosis have been reported when sen-
congenital cardiac disease. Bradycardia sec- sor probes have been applied too tightly.
2. Capnography: The measurement of pCO2 in
ondary to hypoxia, hypercarbia, deep anesthe-
sia, and surgical stimulation, e.g., strabismus inspired and expired gases is also mandatory.
surgery, is very common and must be Capnography is not only a monitor of the ade-
quacy of ventilation but gives warning of dis-
responded to immediately as the newborn’s
cardiac output is directly related to their heart ruption in gas supply, inadequate fresh gas
rate. The neonate cannot compensate for a low supply, and esophageal intubation and is an
indirect measure of cardiac output.
cardiac output by increasing their stroke vol-
ume, so a sudden decrease in heart rate to
60 beats per minute or less is an indication to Temperature
initiate chest compressions and resuscitation.
The ECG is increasingly important in the con- Monitoring temperature is important in pediatrics
text of the enhanced role of regional anesthesia because of the increased risk of both hypo- and
in neonatal practice. Prolongation of the QRS hyperthermia. Common sites for perioperative
complex is a sign of local anesthetic toxicity temperature probes include the nasopharynx,
and may indicate intravascular injection. esophagus, bladder, and rectum.
2. Blood Pressure: Routine noninvasive monitor-
ing of blood pressure during anesthesia and
surgery is carried out with an automated Neuromuscular Blockade
device, which uses oscillometry. The appropri-
ate cuff size must be used in order to obtain Monitoring neuromuscular blockade using a
accurate measurements. Direct intra-arterial peripheral nerve stimulator is routine practice
monitoring is the most accurate measurement when non-depolarizing muscle relaxants have
of blood pressure and provides “beat to beat” been administered.
assessment. Its use is generally restricted to
very ill children or those undergoing major
surgery. All the proximal and distal arteries of Induction and Maintenance
the legs and arms may be used. of Anesthesia
3. Central Venous Pressure: Central venous pres-
sure is useful in infants and children who are The induction agents employed in infants and
undergoing major surgery with anticipated large children are identical to those used in adults. The
fluid shifts, if significant blood loss and choice of induction technique depends on the age,
Table 1 Anesthesia medications in the newborn

Inhalational
agents Pharmacological effects Physiological effects
Sevoflurane Sedation, anesthesia, rapid Respiratory depressant, bronchodilator, causes hypotension,
emergence bradycardia, decreases cardiac output, increases serum inorganic
fluoride
Desflurane Sedation, anesthesia, rapid Respiratory depressant, causes hypotension, bradycardia, decreases
emergence cardiac output
Isoflurane Sedation, anesthesia Respiratory depressant, causes hypotension, bradycardia, decreases
cardiac output
Halothane Sedation, anesthesia Respiratory depressant, bronchodilator, causes hypotension,
bradycardia, arrhythmias, decreases cardiac output
Intravenous Pharmacological effects Physiological effects
agents
Fentanyl Analgesia, sedation, Respiratory depressant, bradycardia
anesthesia
Propofol Sedation, anesthesia Respiratory depressant, causes hypotension
Ketamine Analgesia, sedation, Respiratory stimulant, increases airway secretions, causes tachycardia
anesthesia
Remifentanil Ultrashort acting analgesia, Respiratory depressant, causes bradycardia
sedation, anesthesia
size, and physical status of the child. The relative blockage within 2 min of administration to an
risk of regurgitation and the personal preference infant. Their duration is 20–30 min, and they
of the anesthetist are also considerations. Intrave- require reversal with neostigmine when surgery
nous induction of anesthesia is often preferable in has finished.
a critically ill child, to allow slow titration of Anesthesia is maintained throughout the surgi-
induction medications, and administration of cal procedure. This may be done by continuous
vasoactive drugs such as atropine, and neuromus- administration of inhalational agents via the breath-
cular blockers. Inhalational induction may be pre- ing system (Table 1) or continuous infusion of
ferred in a more stable patient, in an infant with intravenous medication (Table 1). Mechanical ven-
airway concerns, or when securing intravenous tilation is used to support the infant in all but the
access is anticipated to be difficult. The inhala- shortest of surgeries, due to the rapidity with which
tional and intravenous anesthesia agents are sum- the infant’s muscles of respiration tire. A reduction
marized in Table 1. in tidal volume during spontaneous ventilation will
Anesthesia is combined with neuromuscular cause alveolar collapse, atelectasis, and ventilation/
blockade if muscle relaxation is necessary for tra- perfusion mismatch. This issue is easily prevented
cheal intubation and for optimum operating condi- by mechanically ventilating the infant lungs with
tions. Medications available for this purpose are pressure-controlled ventilation. Small increments
divided into depolarizing and non-depolarizing of positive end expiratory pressure (PEEP) may
agents, the difference being how they interact be added to recruit collapsed lung segments. A
with neuromuscular junction. Depolarizing agents mixture of oxygen and air is generally supplied
such as succinylcholine provide rapid onset, and through the breathing system and ventilator. The
short duration muscular blockade, but have many fraction of inspired oxygen is determined by the
significant side effects. These side effects include anesthetist, taking into account the age of the
hyperkalemia, bradycardia, and the triggering of patient, potential cardiac and/or respiratory mor-
malignant hyperpyrexia. bidities, and the proposed surgical procedure.
Non-depolarizing agents, e.g., atracurium, Reversal and extubation occur at the end of the
pancuronium, and rocuronium, produce reliable surgery. Prior use of neuromuscular agonists
requires reversal before safely proceeding to wake delivery to tissues at a time when normal physio-
the patient. Neostigmine is combined with atro- logic functions are altered by surgical stress and
pine or glycopyrrolate to offset the bradycardia anesthetic agents. The composition of the fluid
produced by neostigmine. Residual neuromuscu- will vary according to the maturity of the child
lar block may be associated with delayed return of and the preoperative electrolyte and glucose
spontaneous respiration and extubation. Delayed levels. All infants should have their blood sugar
emergence may occasionally be attributed to checked following induction of anesthesia and a
hypothermia, prolonged surgery, acidosis, hypo- bolus of 2 ml/kg 50% dextrose administered if the
calcemia, and opiates. blood sugar is less than 2 mmol/L (R). Surgical
stress, opiates, and anesthetic medications stimu-
late increased release of antidiuretic hormone
Recovery (ADH), which causes the retention of free water
at the renal glomerulus. This may lead to the
Following completion of surgery, the child is development of hyponatremia if hypotonic solu-
transported, fully monitored, to the recovery tions such as 0.45% normal saline are used as
room. Intubated patients are nursed one to one intraoperative maintenance fluid. Normal saline
by trained pediatric recovery nurses. Monitoring 0.9% or lactated Ringer’s solution is now used
of vital signs, adequacy of protective airway as standard, with the addition of 5–10% dextrose
reflexes, and correct positioning to prevent airway as necessary (Choong et al. 2006).
obstruction, regurgitation, and aspiration are key
priorities. The recovery room nurse also monitors
the wound site for bleeding, checks the security of Postoperative Pain Management
the dressings, and administers prescribed pain
relief. When infants and children are awake, they Pain Assessment
may be offered clear fluids or milk to drink. Com-
fort may be provided by breastfeeding in the To optimize pain management in the surgical
recovery room. Exceptions to early feeding patient, treatment is titrated to their degree of
should be made following some dental or oral discomfort. The American Academy of Pediatrics
procedures, and when local anesthesia has been has issued the following statement on pain treat-
applied topically to the vocal cords. In addition to ment: “To treat pain adequately, ongoing assess-
post-discharge instructions provided by the surgi- ment of the presence and severity of the pain and
cal team, parents or guardians need to be given the child’s response to the treatment is essential”
verbal and written instructions regarding postop- (Chou et al. 2016). Self-report remains the “gold
erative pain relief and what to do if problems arise. standard” for pain assessment. However, as new-
borns are nonverbal, they require a different
method of assessing their pain, usually focusing
Fluid Balance on posture, cry, and consolability. As they are less
able to communicate pain, they may be vulnerable
Healthy children undergoing minor operations to distress, anxiety, and poor pain management.
can reasonably be expected to tolerate oral fluids Pain assessment can be incorporated into routine
a short time after completion of surgery and do not monitoring as a vital signs measurement so that
require intraoperative intravenous fluids. The goal pain assessment becomes standard practice. A
of intraoperative fluid management in those who range of validated pain assessment tools for non-
are dehydrated preoperatively or those who are verbal children is available (American Academy
undergoing major surgery is to sustain homeosta- of Pediatrics Committee on Psychosocial Aspects
sis by providing the appropriate amount of paren- of Child and Family Health and Task Force on
teral fluid to maintain adequate intravascular Pain in Infants, Children, and Adolescents 2001).
volume, cardiac output, and ultimately, oxygen Postoperative pain experienced by the infant is
assessed using a variety of validated pain assess- bolus or continuous infusion remain the most
ment tools, including the FLACC, and the common modality for the treatment of periopera-
COMFORT-behavior scale (Crellin et al. 2015; tive pain. Intravenous infusions are administered
Boerlage et al. 2015). using the nurse-controlled analgesia system,
Early recognition is important as it facilitates where small doses of opiate are given following
prompt and adequate management. It may also pain assessment and sedation assessment
prevent long-term sequelae (Taddio and Katz (Czarnecki et al. 2014). Patient-controlled analge-
2005). Stress hormone levels have been studied sia infusions may be used in older children. Con-
in premature neonates who underwent surgery tinuous infusions are used only in a high
without perioperative analgesia; levels of corti- dependency or intensive care environment. Para-
sol, aldosterone, and other corticosteroids were cetamol has a promising role in decreasing opioid
markedly increased indicating significant stress requirement (Padda et al. 1997). Among infants
(Anand et al. 1990; Bouwmeester et al. 2001). In undergoing major surgery, postoperative use of
the recovery room and intensive care unit (ICU) intermittent intravenous paracetamol compared
setting, stress and agitation resulting from pain with tramadol resulted in a better recovery profile
and anxiety can lead children to accidentally (Uyasal et al. 2011). Routine use of ketorolac or
remove medical devices endangering the child’s other nonsteroidal anti-inflammatory drugs
safety. (NSAIDs) is not usually recommended in the
newborn, but NSAIDs are frequently used to aug-
ment analgesia in older children with normal renal
Analgesia function.
The majority of preterm neonates are capable
After assessment of pain, the treatment of pain is of glucuronidating morphine, but birth weight
the next step, and standard treatment is a balanced, and gestational and postnatal age influence the
multimodal combination, which frequently glucuronidation capability. Term neonates,
includes opioids. Treatment with opioids means infants, and children are able to produce mor-
balancing between effective dosages and pre- phine glucuronides. Pharmacokinetic studies
venting oversedation, seeing that opioids have have demonstrated that drug half-life and clear-
sedative properties as well. Oversedation may ance were found to be related to age, but volume
lead to longer duration of mechanical ventilation of distribution was unchanged. Half-life was
and ICU admission. Inadequate dosages may estimated to be 9.0 +/ 3.4 h in preterm neo-
cause a wide range of endocrine, metabolic, and nates, 6.5 +/ 2.8 h in term neonates aged
inflammatory reactions leading to increased sym- 0–57 days, and 2.0 +/ 1.8 h for infants and
pathetic activity. Besides inadequate pain relief, children aged 11 days to 15 years (Kearns et al.
this may result in prolonged recovery times after 2003). Longer half-lives mean smaller doses per
procedures, complications, and longer admission kilogram are necessary to produce analgesic
duration. Finally, inadequately treated postopera- effects. The rate of morphine infusions need to
tive pain poses a risk for the development of be reduced in the neonatal and newborn period,
chronic pain. particularly if the neonate is jaundiced. There is a
Current literature lacks systematic data on large variability associated with infusion rates,
acute perioperative pain management in neonates which means that infusion rates may need to be
and mainly focuses only on procedural pain man- adjusted, depending on feedback from pain
agement. The usual stress response to surgery scores, adjuvant medications, and adverse
through hormone release and metabolic modula- effects. If the child is feeding, oral morphine
tion is altered in the newborn, which has implica- may be used instead of intravenous. Combining
tions for cardiovascular monitoring, support, and opiate administration with regular sedation and
sedation and analgesia. Intravenous opioids such pain assessment and apnea and oxygen satura-
as morphine or fentanyl as either intermittent tion monitoring is recommended.
Regional Anesthesia solution may result in burns to the fragile neonatal

skin or absorption of alcohol into the bloodstream
With the advent of ultrasound and improvements (Sathiyamurthy et al. 2016). Nerves and nerve
in equipment, the applications of regional anes- plexuses are frequently visualized using ultra-
thesia in the pediatric population have continued sound, before specialized needles inject the local
to expand. Although frequently used for postop- anesthetic, or introduce a catheter to administer
erative analgesia or as a means of avoiding gen- medication over a longer period of time. The
eral anesthesia in patients with comorbid catheter is secured in position on the skin with
conditions, the adjunctive use of regional anesthe- adhesive tape. The other end of the catheter is
sia during general anesthesia may effectively attached to a filter to prevent entry of glass parti-
decrease the intraoperative requirements for intra- cles or bacteria. Dilute concentrations of
venous and volatile agents, thereby providing a levobupivacaine are infused continuously over a
more rapid awakening and earlier tracheal period of hours to days, depending on individual
extubation and enhanced pain scores (Hamill patient requirements. The rate of infusion of
et al. 2016). More recently, the limitation of the levobupivacaine should be reduced over a period
requirements for volatile and other anesthetic of days to prevent accumulation and a rise in
agents may be desirable, given concerns regarding plasma levels (Lerman et al. 2003). Adjunct med-
the potential impact of these agents on ications such as clonidine may be added to
neurocognitive outcome in neonates and infants increase the effectiveness and duration of the
(Johnson et al. 2008). Several authors have dem- regional block (Lak et al. 2012).
onstrated the potential utility of combining a Subarachnoid anesthesia is utilized in awake
neuraxial technique (spinal or epidural anesthesia) babies for short surgeries on the lower abdomen or
with general anesthesia in neonates and infants perineum, e.g., circumcision and orchidopexy,
undergoing intraabdominal procedures (Goeller especially in ex-premature infants (Jones et al.
et al. 2014; Adler et al. 2015). 2015). Avoiding general anesthesia in
Regional anesthesia techniques are often com- ex-premature infants is preferable due to their
bined with light general anesthesia in infants and higher incidence of chronic lung disease, oxygen
children. Regional blocks provide prolonged and dependency, and apnea. The risk of postoperative
predictable postoperative pain relief, using local apnea with regional anesthesia is decreased but
anesthetics. These local anesthesia-based blocks not eliminated (Davidson et al. 2015b).
avoid the side effects associated with opiates (e.g.,
respiratory depression, nausea, vomiting, ileus)
and reduce the hormonal stress response to sur- Special Considerations
gery (Abu Elvazed et al. 2016). The regional in the Premature Infant
block usually produces a mixed sensory and
motor blockade and may be suitable for use as Congenital defects occur more commonly in pre-
the sole anesthesia mode, e.g., for inguinal term infants, so that surgery is frequently required.
herniotomy (Mueller et al. 2016). There is a Organs and enzyme systems are immature, and
greater potential for local anesthetic toxicity in meticulous attention to detail during anesthetic
infants as reduced protein binding with alpha and surgical management is imperative if survival
(Smithers et al. 2016) acid-glycoprotein means a rates are to be high. The large body surface area
greater free fraction of the active drug in the and lack of subcutaneous fat make maintenance
bloodstream (Gunter 2002). of body temperature very difficult, so that a high
Monitoring and secure intravenous access neutral thermal environment is essential. Respi-
must be in place before performing the local anes- ratory fatigue occurs very easily and may be
thetic block. The skin requires cleaning with 0.5% exacerbated by residual lung damage following
alcohol containing solution before commencing. mechanical ventilation, persistent fetal circula-
Higher concentrations of alcohol in the cleaning tion, and oxygen dependency. The response to
exogenous vitamin K is less satisfactory than in identifying the location of a fistula, if there is one,
term infants, and there is an increased risk of or indeed multiple fistulae (Atzori et al. 2006).
bleeding. In addition, anemia is common Anesthesia is similar to that for other neonatal
because of reduced erythropoiesis, a short eryth- procedures, but special care must be taken to
rocyte life span and iatrogenic causes such as maintain spontaneous respiration until the endo-
frequent blood sampling. Fluid and electrolyte tracheal tip is placed below the level of any fistula.
management can be difficult – insensitive losses This prevents gastric distension, which may
are high and hypoglycemia and hypocalcemia induce bradycardia. The fiberscope is useful in
occur easily, while renal function and the ability accurately positioning the ETT tip above the
of the cardiovascular system to tolerate fluid carina, but below any anomalous openings to the
loads are reduced. trachea. Surgical retraction during operative
mobilization of the esophagus may compromise
either respiratory or cardiac function, so that accu-
Anesthesia and the Developing Brain rate monitoring is essential. Extubation may be
planned shortly after completion of surgery if
Studies conducted over the last two decades on there has been no contamination of the mediasti-
animal models have suggested that inhalational num or if the anastomosis is not especially tight. A
agents, such as isoflurane and sevoflurane, may pleural drain is usually left in place until a contrast
have a detrimental effect on later development of study has been performed a number of days later
the infant brain (Johnson et al. 2008). Population- (Kinottenbelt and Skinner 2010). Regional anes-
based longitudinal research has not reinforced this thesia using an epidural or paravertebral catheter
hypothesis (Vutskits 2012; Davidson et al. 2016). may assist in early weaning from mechanical ven-
Concerns exist around the neurological and devel- tilation and extubation (Bosenberg et al. 1992).
opmental effects of additional medications such as
midazolam, ketamine, and morphine. These con-
cerns must be interpreted cautiously in the light of Congenital Diaphragmatic Hernia
the requirement for lifesaving surgeries in the
newborn period. Parents may ask for further infor- The surgical repair of this condition is now
mation on the matter and should be provided with planned for 5–10 days postdelivery, to allow ade-
balanced, informed advice. quate time to optimize the pulmonary pressures.
Pulmonary hypertension related to lung hypopla-
sia and vasculopathy of the lungs, in addition to
Anesthesia for Specific Surgical the normal relative pulmonary hypertension of the
Conditions in the Newborn early neonatal period, may be challenging to man-
age. Sustained significant pulmonary hyperten-
Esophageal Atresia sion causes dilatation and failure of the right
ventricle, with resultant impairment of left ven-
When the diagnosis of esophageal atresia is made tricular function. If not aggressively managed
(with or without a fistula to the trachea), the blind with pulmonary vasodilators, this may lead to
upper pouch should be continuously aspirated hypotension, renal impairment, and gut hypo-
using a Replogle or similar tube. In general, the perfusion. Preoperative admission to the PICU,
operation may be safely delayed pending further ventilation, and hemodynamic support are
investigation – echocardiography is the most required for all but the most minor defects.
important – as there are frequently associated Inhaled nitric oxide, high frequency oscillation,
cardiac anomalies. Aspiration pneumonia should intravenous sildenafil, and extracorporeal life sup-
be treated, and surgery may then proceed when port (ECLS) may be required to support the infant.
the infant is in good condition. Pre-thoracotomy Surgical repair may be performed on ECLS, but
fiber-optic bronchoscopy is ideal, as it assists in bleeding may be problematic as the infant is fully
anticoagulated. Prior to intubation, positive pres- taken to keep heat loss to a minimum. Fluid
sure ventilation should be avoided to prevent requirements are much greater than in normal
expansion of the viscera contained within the neonates, and there is an increased need for elec-
hernia. Surfactant should not be administered as trolyte replacement. Monitoring the changes in
it may cause overdistension of the “good” lung, peak inspiratory pressures and central venous
predisposing the infant to developing a pneumo- pressure during primary closure can be useful in
thorax. Anesthesia is conducted with the support advising the surgeon whether primary closure is
of nitric oxide and inotropes, muscle relaxation, feasible. A proportion of infants, especially after
and fentanyl 2–5 mcg/kg. Volatile anesthetic repair of gastroschisis, require postoperative
agents are used cautiously. After surgery, the mechanical ventilation. Large defects may be
infant returns to the PICU for postoperative care. managed in a staged manner, by placing the exter-
nal gut into a silo, which hangs above the patient’s
abdomen. Gravity assists in the gradual return of
Intestinal Obstruction the gut to the abdomen. Establishing enteral feed
may be slow due to ongoing gut dysmotility,
The various forms of neonatal intestinal obstruc- which may persist for a considerable length of
tion account for approximately 35% of all surgi- time after closure.
cal procedures in the newborn. The major
anesthetic problems are those of fluid and elec-
trolyte imbalance (which must be corrected pre- Herniotomy for the Ex-premature
operatively), abdominal distension (causing Infant
respiratory impairment by splinting diaphrag-
matic movement), and the risk of regurgitation Improved survival rates in premature and low
and aspiration of gastric contents. Following birth-weight infants have led to increased numbers
four-quadrant decompression of the stomach, a of them presenting for inguinal hernia repair. While
modified rapid sequence incorporating a small the surgical procedure may be relatively straight-
dose of an intravenous induction agent and a forward, these babies represent a considerable chal-
muscle relaxant is performed. The lungs may be lenge for the anesthetist. They must be managed by
ventilated using low pressures (<10cmH2O) anesthetists and surgeons with adequate training
until the trachea is intubated. Many pediatric and experience, in hospitals with appropriate facil-
anesthetists do not use cricoid pressure in this ities and personnel. Ex-premature infants up to
context, as it may make intubation more difficult, 56 weeks postconceptual age are at risk of life-
leading to a need to mask ventilate at higher threatening apnea after anesthesia and surgery and
pressures, for longer, than if the ETT is placed should have apnea and oxygen saturation monitor-
in the trachea without undue delay. Anesthesia is ing for at least 12 h postoperatively. They are not
then maintained in the usual fashion. Placement suitable for day-case surgery. Regional anesthesia
of paravertebral or rectus sheath blocks may techniques such as spinal and caudal anesthesia
facilitate a reduction in opiate needed for post- may be used to augment or replace general anes-
operative pain relief (Bosenberg 1998). thesia, but they do not completely remove the risk
of postoperative apnea (Davidson et al. 2015b).
Exomphalos and Gastroschisis

Postoperative Admission to Surgical
Anesthetic concerns with large abdominal wall NICU/PICU
defects include heat and fluid loss from the
exposed bowel, and the primary closure of the As each year passes, there are advances in the
defect, which may impair respiration as the dia- perioperative management of critically ill children
phragm, is pushed cephalad. Special care must be who require surgery. Increased operative
intervention in preterm and low birth-weight on age, size, and physical status of the patient.
infants has increased the demand for postopera- Research on clinical pharmacology and clinical
tive high dependency and intensive care. Alterna- outcomes in children and infants helped to
tive respiratory and cardiovascular support in the develop new anesthesia modalities and rapidly
form of extracorporeal life support, inhaled nitric metabolizing medications during the last decades,
oxide, and high frequency oscillation have facilitating operations in even preterm and very
expanded the potential to support these severely low weight infants. Further technical and pharma-
compromised infants and children. ceutical improvements will allow operations and
Differences in physiology and pharmacology interventional procedures in the future, which are
in the preterm and term neonate have a direct currently not feasible due to technical or physio-
impact on their capacity to adapt to surgical inter- logical limits.
vention and to recover in the postoperative period.
Pulmonary vascular resistance (PVR) is elevated
in the first 10 days of life, which increases the
Cross-References
potential to develop right to left shunt through the
ductus arteriosus or a patent foramen ovale. This
response occurs particularly in response to hyp-
▶ Esophageal Atresia
oxia or metabolic acidosis.
▶ Gastroschisis
There are distinct differences in the coagulation
▶ Omphalocele
system as plasma levels and activities are low at the
▶ Pediatric Respiratory Physiology
time of birth and then increase in the first few
▶ Specific Risks for the Preterm Infant
months of life. Total body water is higher in the
newborn, especially the premature infant, and glo-
merular filtration rate (GFR) is low in the first few
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Immunology and Immunodeficiencies
in Children 27
Saima Aslam, Fiona O’Hare, Hassan Eliwan, and
Eleanor J. Molloy
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
Monocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
Toll-Like Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Mucosal Immunity, Human Milk, and Necrotizing Enterocolitis (NEC) . . . . . . . . . . 447
Neonatal Innate Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Pediatric Adaptive Immune Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
S. Aslam (*) · F. O’Hare · H. Eliwan

e-mail: saimaaslam@ymail.com; oharemarie@yahoo.co.uk;
aliwandr@gmail.com
E. J. Molloy
Department of Neonatology, Paediatrics, National
Maternity Hospital, Dublin, Ireland
UCD School of Medicine and Medical Sciences,
Neonatology, Our Lady’s Children’s Hospital, Dublin,
Ireland
Paediatrics, Royal College of Surgeons in Ireland, Dublin,
Ireland
e-mail: elesean@hotmail.com

https://doi.org/10.1007/978-3-662-43588-5_29
444 S. Aslam et al.
Lymphocyte Phenotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451

B-Cell Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451
Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
The Inflammatory Response Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 452
Clinical Outcomes in Neonatal Sepsis and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 453
Pediatric Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Primary Immunodeficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
B-Cell Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
T-Cell Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Combined B- and T-Cell Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Complement Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Phagocytic Cell Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Acquired Immunodeficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
Immunomodulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 457
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Abstract immunodeficiencies · Acquired

The immune system in neonates is different to that immunodeficiencies
of adults and evolves in the first few years of life
to achieve adult-like responses. This chapter high-
lights the response of the immune system to sepsis
both in pediatric and neonatal age groups and the Introduction
intricate balance between pro-inflammatory and
anti-inflammatory responses to limit the damage Sepsis remains a prominent cause of neonatal mor-
secondary to infections. Immunodeficiencies pri- tality especially among preterm neonates. The first
mary or acquired are described in detail including line of defense against infection is the innate
their common presentations, common pathogens immune system, and activation occurs when a path-
involved, the cell type involved, mechanism of ogen breaches the host’s natural barriers. The innate
deficiency, treatment, and prognosis including immune system developed before the separation of
specific considerations for these patients prior to vertebrates from invertebrates and is the primary
surgery. Immunomodulation of immune system immune response for most multicellular organisms
either by alteration in ligand receptor binding or (Janeway and Medzhitov 2002).
intracellular signal can help to modulate the dis- It responds instantaneously to microbes and is
ease process and may alter the prognosis for composed of both soluble (the alternative and
children with sepsis in the future. mannan-binding lectin pathways of the comple-
ment system, acute-phase proteins, and cytokines)
and cellular elements (monocytes, macrophages,
Keywords neutrophils, dendritic cells, and natural killer
Innate immune system · Neutrophils · cells). Careful modulation of the innate immune
Lymphocytes · Toll-like receptors · Systemic system is vital to prevent either uncontrolled
inflammatory response syndrome · Natural microbial growth or devastating inflammatory
killer cell · Dendritic cells · responses with tissue injury, vascular collapse,
Immunomodulation · Primary and multi-organ failure.
27 Immunology and Immunodeficiencies in Children 445
HUMORAL IMMUNITY CELLULAR IMMUNITY
Intracellular microbes
Extracellular microbes (e.g., viruses)
(e.g., bacteria) Helper
T cell Antigen-presenting
cell
B Lymphocytes
T
B
T cell
B receptor
Cytokines
Secreted
antibody Cytokine
receptor
Proliferation
and activation
of effector cells
(cytotoxic T cells,
natural killer cells,
macrophages)
Neutralization
Lysis
(complement)
Phagocytosis Lysis of
(PMN, macrophage) Infected cells
Fig. 1 Immune function: humoral and cellular immunity. microorganisms. Cellular immunity is mediated by T lym-
Humoral immunity is mediated by B lymphocytes which phocytes. Cytotoxic T cells directly lyse pathogens. Helper
produce soluble antibody proteins. These antibodies can T cells produce cytokines which stimulate other immune
either (a) directly neutralize extracellular microbes or (b) cells to remove microorganisms
activate complement, neutrophils, and macrophages to kill
Detection of invading microorganisms is Recognition in cell-mediated immunity depends

mediated firstly by recognition, then activa- upon interaction between major histocompatibil-
tion and response of immune system leading ity molecules, macrophages, and helper and cyto-
to destruction of invading microorganisms. toxic antibody-mediated immunity; the process of
The process of recognition is complex and recognition depends on macrophages, helper T
depends upon structures common to many cells, and B cells (Fig. 1). Several intracellular
microbial pathogens called pathogen-associated signaling pathways are activated when a PAMP
molecular patterns (PAMPs), antigen or epitopes binds to a pattern recognition receptor, resulting in
such as endotoxins (lipopolysaccharide: LPS), activation of transcription factors (NF-kB, AP-1,
peptidoglycan, lipoteichoic acid, lipopeptides, Fos, Jun). These transcription factors control the
flagellin, mannan, and viral RNA, which are expression of immune response genes and the
essential for survival of the microorganisms release of numerous effector molecules, such as
and therefore do not undergo major mutations. cytokines. Cytokines are chemical mediators with
Pattern recognition receptors have been evolu- an essential role in orchestrating the innate and
tionarily conserved not to recognize any self- acquired immune responses to an invading path-
structure. Autoimmunity is prevented when the ogen (Calandra 2001).
only available recognition system is the innate The acquired immune system has evolved rel-
immune system. atively recently and is built upon the
446 S. Aslam et al.
phylogenetically older innate immune system, by shown to be deficient in IL-12 (p35) expression,
which it is controlled and assisted. The principal a key regulator of Th1-type T-cell responses.
mediators of acquired immunity are the highly
evolved lymphocytes, which express an enor-
mous array of recombinant receptors, immuno- Neutrophils
globulin, and T-cell receptors. They can
recognize any potential pathogen with which the The critical role of the neutrophil in host defenses
host may come in contact. This response takes against microbial infection has long suggested
from days to weeks to develop optimally. that defects in this particular cell type might be
Newborns acquire passive immunity from the cause of the increased susceptibility of the
their mothers by maternally derived IgG cross- newborn to serious bacterial infections. Impaired
ing the placenta. Transferable maternal immu- neonatal neutrophil function at birth has also been
nologic memory is essential for the survival of implicated in neonatal inflammatory disorders
the fetus, newborn, and infant. Moreover, the (Cairo 1989). Recent advances in the understand-
attenuation of infection by transferable maternal ing of the molecular basis of cell adherence and
immunity permits microbial agents to immunize phagocytosis have provided greater insight into
the child under optimal conditions. This pro- the role of the neutrophil in the newborn’s defense
vides protection for up to the first 6 months of system. Numerous in vitro abnormalities include
life at which time neonatal acquired immunity decreased chemotaxis, leukocyte adherence, bac-
has developed. terial killing, and depressed oxidative metabolism
(Carr 2000). However, most of these neonatal
neutrophil functions have been found in the cord
Monocytes blood, which contains immature forms of the
cells, and therefore care must be taken in
The crucial role of monocytes/macrophages in the interpreting some of the data. Oxidative metabolic
immune response resides in immunoregulatory function of cord blood monocytes, measured by
functions of both humoral and cellular immunity. chemiluminescence, has been shown to be
They are important for phagocytosis, antigen pre- depressed 12–36 h after birth. Cytoskeletal actin
sentation, and cytokine production. Human polymerization is also altered in neonates.
umbilical cord blood contains almost three times Neonatal neutrophils exhibit normal phagocy-
as many monocytes as adult blood does, and tosis of opsonized particles as well as particles that
major changes occur in the levels of monocytes required no opsonization. The major opsonic role
during the first few weeks of life. Newborn mac- of neutrophils for the uptake of antibody or
rophages show poor resistance against facultative complement-coated microorganisms is reflected
intracellular organisms. Newborn monocytes in their expression of a number of receptors both
exhibit marked heterogeneity with respect to den- for antibody (Fc receptors) and complement
sity and function. Neonatal blood monocytes are (CR receptors). In newborn cord blood, the levels
also characterized as having a much lower fre- of these receptors are similar to those in adult
quency of class II molecular expression than neutrophils. The level of expression of Fc recep-
adult monocytes, which may be related to the tors is significantly more upregulated in response
selective incapacity of neonates to secrete signif- to in vitro stimuli such as f-met-leu-phe (FMLP)
icant levels of interferon-γ (IFN-γ). The precise on adult neutrophils compared to newborn
role of the monocyte in the newborn’s unique neutrophils.
susceptibility to infections with various agents Neonatal neutrophils have diminished function
remains a challenging area for future study. Den- (Koenig et al. 2005) and delayed apoptosis (pro-
dritic cells are the primary antigen-presenting grammed cell death) compared with adults. In
cells for optimum sensitization of naive T cells addition, neonatal neutrophil lipopolysaccharide
to antigen. Newborn dendritic cells have been (LPS) responses are altered (Bonner et al. 2001;
Henneke et al. 2003) which may further increase promote defense against intracellular pathogens
susceptibility to sepsis in this population. The (O’Hare et al. 2013). TLR4, TLR2, and CD14
effects of granulocyte colony-stimulating factor (cluster differentiation 14) are increased on neo-
(GCSF) and granulocyte macrophage colony- natal immune cells, and cytokine release is
stimulating factor (GM-CSF) on neonatal neutro- decreased to a greater extent than adults with
phils are altered compared with adults showing TLR-4 antagonists. During infections, pathogens
that GCCF may improve neutrophil survival bind to TLR-4 and CD14 receptors and induce
whereas GM-CSF augments function (Molloy cytokine release, leading to inflammation. Neona-
et al. 2005). tal IL-10 and TNF-α release depends on LPS
NETs are lattices of extracellular DNA, chro- binding not only to CD14/TLR-4 but also to
matin, and antibacterial proteins that mediate CD14 associated with another TLR. There is a
extracellular killing of microorganisms and are differential expression of TLR-2 but not TLR-4
thought to form via a unique death pathway sig- in the course of neonatal sepsis (Viemann et al.
naled by nicotinamide adenine dinucleotide phos- 2005). Decreased levels of MyD88 have been
phate (NADPH) oxidase-generated reactive described in neonatal monocytes in response to
oxygen species (ROS). Neutrophils from term LPS (Yan et al. 2004). There have been few stud-
and preterm infants fail to form NETs when acti- ies on neonatal neutrophils. Wynn et al. have
vated by inflammatory agonists in contrast to leu- recently demonstrated improved survival follow-
kocytes from healthy adults reflecting a deficit in ing polymicrobial sepsis induced by TLR4 ago-
extracellular bacterial killing (Yost et al. 2009). nist pretreatment which enhanced peritoneal
Recently, Raymond et al. (Raymond et al. neutrophil recruitment with increased oxidative
2017) investigated neutrophil chemotaxis and burst production. Similarly TLR-7/TLR-
transcriptomics of both term and preterm neonates 8 agonism also enhanced peritoneal neutrophil
using whole blood samples obtained in the first recruitment with increased phagocytic ability.
few days of life. They demonstrated that preterm However, these outcomes were independent of
infants have significant differences in neutrophils, the adaptive immune system and type I interferon
compared to term neonates and adults including signaling. Labor upregulates TLR-2 and TLR-4
reduced percent neutrophil migration and velocity on cord blood monocytes at the protein level,
in response to a microbial product, as well as suggesting that labor may be immunologically
transcriptomic evidence of impaired pathogen beneficial to normal newborns (DiGiulio et al.
recognition, cytokine production and antimicro- 2008). Augmenting innate immune function
bial activity. using TLR signaling may be a potential future
adjunctive therapy in neonatal sepsis.
Toll-Like Receptors
Mucosal Immunity, Human Milk,
The toll-like receptors (TLR) are vital transmem- and Necrotizing Enterocolitis (NEC)
brane receptors that provide the critical link
between microbial immune stimulants and initia- Although the intestinal tract of the fetus is consid-
tion of host defense. TLR-4 is the transmembrane ered to be sterile, recent studies suggest that many
LPS receptor that initiates the innate immune preterm infants are exposed to microbes found in
response to common Gram-negative bacteria. the amniotic fluid, even without a history of rup-
Neonates have an equivalent if not enhanced ture of membranes or culture-positive chorioam-
capacity compared with adult white-blood cell nionitis (Wolfs et al. 2009). Infants are colonized
TLR-mediated response to support Th17- and during vaginal delivery and subsequent
Th2-type immunity, which promotes defense breastfeeding with maternal vaginal and fecal
against extracellular pathogens. However neo- flora. The fecal microbial profile of infants deliv-
nates have reduced Th1-type responses, which ered vaginally versus caesarean section showed
448 S. Aslam et al.
no colonization with Bacteroides sp. before death after the first 2 weeks of life among
2 months of age in infants in the latter group and extremely low birth weight infants. Human milk
Bacteroides colonization that was half that of influences neonatal microbial recognition by
vaginally delivered infants by 6 months of age. modulating TLR-mediated responses specifically
The common use of antibiotics, type of feeding and differentially. Fresh human milk contains
(human milk versus formula), mode of delivery many immunoprotective factors, such as immu-
(vaginal versus caesarean section), decreased noglobulins (Igs), lactoferrin, neutrophils, lym-
maternal-infant direct skin contact, and various phocytes, lysozyme, and PAF acetylhydrolase
manipulations in the neonatal intensive care unit (which inhibits PAF). Human milk also is
(nursing in an incubator versus under radiant believed to promote intestinal colonization with
warmers) have the potential to alter the intestinal Lactobacillus. The efficacy of banked human
microbiota. In response to pathogenic intestinal milk is less clear because freezing and pasteuriza-
microbiota, pro-inflammatory cytokines can tion reduce the cellular components and
increase barrier permeability, facilitating bacterial immunoglobulins.
translocation with elaboration of the systemic
inflammatory response syndrome (SIRS) and
multiple organ failure. Neonatal Innate Immunity
Necrotizing enterocolitis is one of the most
devastating diseases in newborns. It is associated Newborns rely on their innate immune system
with loss of gut integrity and immune dysfunc- initially following birth as there are deficiencies
tion. NEC is thought to develop following com- in the adaptive response due to lack of previous
bination of prematurity, formula feeding, and exposure to antigens in utero (Levy 2007). The
adverse microbial colonization. Many studies in intrauterine environment is usually sterile, and
recent years support an important role of a height- transition postnatally to the foreign antigen-rich
ened mucosal immune response initiating a pro- external world starts with colonization of skin
inflammatory signaling cascade which can lead to and gut with microorganisms. The fetus is con-
the destruction of the intestinal epithelium and sidered to be immunologically naive and exists
translocation of pathogenic species (Mara et al. in a state of immune privilege in utero, to pre-
2018). One of the major cornerstone in under- vent rejection by the maternal immune cells. The
standing the development of NEC is the role that in utero defense system is largely unknown
TLR-4 signaling plays in the pathogenesis although recent evidence hints at a powerful
(Hodzic et al. 2017). Activation of TLR-4 within fetal system of innate immunity. The anti-
the intestinal epithelium in the setting of prema- bacterial properties of vernix caseosa, the
turity results in decreased enterocyte proliferation, creamy white substance covering the skin of
increased enterocyte apoptosis, disruption of term babies, have also been recognized and in
intestinal barrier integrity and bacterial transloca- particular the presence of antimicrobial peptides
tion, resulting in a systemic inflammatory including alpha defensins and inflammatory
response (Hodzic et al. 2017). As a result of bac- mediators. Antimicrobial peptides may be an
terial translocation, TLR-4 is activated on the adjunctive compensatory mechanism in the neo-
endothelium of the premature gut, leading to nate as adaptive immunity evolves (Dorschner
impaired blood flow and subsequent ischemia et al. 2003). Neonates are immune competent
via reduction of endothelial nitric oxide synthase but with a predominant Th2 profile being geared
(Yazji et al. 2013). Increased intestinal expression toward immune tolerance instead of toward
of TLRs (especially TLR-2 and TLR-4) and cyto- defense from microbial infections (Th1
kines precedes histological injury in the skewed). Th1 responses are suppressed by pla-
experimental NEC. cental products such as progesterone, prosta-
There is a dose-related association of human glandin E2, and cytokines such as IL-4 and
milk feeding with a reduction of risk of NEC or IL-10.
Pediatric Adaptive Immune Response The basis of an adequate immune response

resides in the capacity of individual cells of the
The adaptive immune system consists of B cells, immune system to recognize and react to the myr-
T cells, and their products. T cells or lymphocyte iad antigens in the environment. The hemopoietic
clones each bear a unique T-cell receptor (TCR) system of pluripotent stem cells is the source of all
which recognizes peptides, derived from foreign the major cell types, which are involved in the
or self-proteins, bound in a molecular complex to immune response. These cells include various
the major histocompatibility complex (MHC) pro- lymphocyte subsets, macrophages, natural killer
teins on the surface of other cells. T cells are cells, monocytes, and polymorphonuclear leuko-
divided into subsets based on their expression of cytes. These cells are involved in a complex reg-
different proteins, which are assigned cluster dif- ulatory network of cell interactions which
ferentiation (CD) numbers. Killer T cells express constitute an immune response and whose func-
CD8 and are important to kill virally infected tion is to eliminate both self-aberrant molecules
cells. Helper T cells express CD4 and orchestrate and cells as well as to protect the host from micro-
the overall immune response by secreting cyto- bial attack (Fig. 2).
kines and providing co-stimulatory signals to Lymphocyte development occurs along two
CD8+ cells and B cells. distinct pathways leading to the production of
BLOOD STEM CELL
Myeloid Stem Cell

Lymphoid Stem Cell
Myeloblast Lymphoblast
Granulocytes
Eosinophil
B Lymphocyte Natural killer

cell
Basophil T Lymphocyte
Red blood
cells Neutrophil
Platelets
White blood cells
Fig. 2 Blood cell development. Blood stem cells released or platelets. The lymphoid stem cell becomes a lympho-
from the bone marrow develop into mature blood cells over blast which then differentiates into one of the following
time. The blood stem cell may become a myeloid stem cell lymphocyte types: B lymphocyte, T lymphocyte, natural
or a lymphoid stem cell. The myeloid stem cell can further killer cell
differentiate into either red blood cells, white blood cells,
450 S. Aslam et al.
the two major lymphocyte populations, T cells Table 1 Cell-surface antigens which identify leukocyte
and B cells, which have very different biological subtypes in the newborn
effector functions. The thymus is the site of devel- Antigen Function
opment of T cells, which are responsible for the T cells
range of effector functions collectively termed CD2 LFA-3 receptor (adhesion)
cell-mediated immunity. Cell-mediated immunity CD3 Associated with cell receptor
ranges from the release of soluble factors such as CD4 Class II and HIV receptor
cytokines, which regulate the activity of all cells CD5 Co-stimulatory
CD7 Unknown
of the immune system, to direct cytopathic effect
CD8 Class I receptor
of cytotoxic lymphocytes on viruses or tumor
B cells
cells. B lymphocytes, on the other hand, have a
CD19 Signal transduction
more restricted effector function, confined to the
CD20 Unknown
synthesis and secretion of humoral antibodies in
CD21 C3d and EBV receptor (CR2)
each of the immunoglobulin classes, IgG, IgA, CD72 Ligand for CD5
IgM, IgD, and IgE. NK cells
The heterogeneity of cell types forms the basis CD16 IgG receptor (FcRIII)
for an international leukocyte typing classification CD56 Isoform of N-CAM
system (CD, cluster differentiation), utilizing CD94 Unknown
monoclonal antibodies which recognize specific Myeloid/monocytic cells
cell-surface markers in order to define individual C14 Unknown
leukocyte subsets. The more widely used CD C15 Unknown
antigens, for classifying immune effector cell CD32 IgG receptor (FcRII)
types, are described in Table 1. CD35 C3b receptor (CRI)
It is now well established that T lymphocytes IFN interferon, IL interleukin
do not recognize native antigen on any pathogen,
but rather a processed form of the antigen, in
association with self-major histocompatibility As already mentioned, the difference between
antigens (MHCs), class I (HLA-A, HLA-B, neonatal and pediatric immune responses is the
HLA-C), or class II (HLA-DR/Ia) molecules. skewed response from Th1 to Th2. There is
This important processing of foreign antigen is decreased production of interferon (Cant et al.
carried out by one of a group of antigen- 2003); as a result, there is decreased Th1 cyto-
presenting cells which include macrophages, den- kines (IL-1 and IL-12) with decreased cell-
dritic cells, Kupffer cells, and some B cells. The mediated immunity in neonates. There are dif-
proper functioning of these accessory cells is ferent theories as to why there is skewed Th2
therefore as central to an adequate immune response. We know with certainty that it is
response as that of specific effector cells, such as related to decreased production of IL-12.
the T lymphocytes. When antigen becomes local- Although Th1 response can be induced in neo-
ized and processed by the antigen-presenting cell nates by using exogenous IL-12 or using adult
(APC), the complex interaction of APC, T cells, rather than neonatal APC (antigen-presenting
and B cells begins, which eventually leads to cells) which signifies that the rate-limiting step
specific immunological memory, both of T cells is the maturity of APC. If neonatal APC are
and B cells as well as to antibody production. stimulated by an effective antigen, these cells
Although B cells can be directly activated by are able to produce IL-12, e.g., in response to
antigen, under experimental conditions, concom- BCG vaccination. While response to DPT is Th2
itant activation of T cells is required for the clonal skewed.
expansion of antigen-specific B cells, leading to Several studies in the literature have
the generation of long-lived memory B cells and questioned the stage of maturity of circulating
immunoglobulin-secreting plasma cells. lymphocytes in the newborn. Some parameters
of T-cell function in cord blood, however, have newborn cells compared to adult lymphocytes
been shown to be normal or similar to those of (Crespo et al. 2012).
healthy older children. These include the quantity
and proportion of T lymphocytes, lymphocyte
response to mitogens, and production of certain B-Cell Responses
cytokines such as IL-2.
The newborn’s capacity to produce antibody is
significantly reduced, both quantitatively and
Lymphocyte Phenotype qualitatively, compared to that of an adult. New-
born B lymphocytes poorly differentiate into
There has been a reported incidence of up to 25% immunoglobulin-producing cells. The mecha-
of cord blood lymphocytes co-expressing both nisms controlling this aspect of B-cell immuno-
CD4 helper T-cell and CD8 suppressor T-cell competence in the newborn are unknown. Many
surface markers. Cells of this double-positive studies have focused on the ability of cord blood
phenotype are common in the thymus, where lymphocytes to terminally differentiate into
they are considered to be the precursors of IgG-, IgA-, and IgM-producing plasma cells in
mature helper and suppressor T cells. The response to mitogens. However, a delay occurs
CD38 antigen, which is a marker of immature in B-cell differentiation, resulting in decreased
thymus-derived T cells, as well as activated lym- production of plasma cells, markedly diminishing
phocytes, is present in the majority of newborn the secretion of antibody and restriction of
cord blood lymphocytes. This thymocyte-like secreted antibody to IgM isotype. Cord blood B
membrane phenotype can be modulated by the lymphocytes, unlike adult B cells, usually are
influence of thymic hormones in vitro. In addi- unable to differentiate into immunoglobulin
tion to the presence of CD38 thymocyte- plaque-forming cells when cultured with poke-
associated antigen, human cord blood contains weed mitogen alone or with killed Staphylococcus
T cells of the unusual phenotype which include aureus alone. However, it appears that these two
peanut agglutinin-positive/CD8-positive as well stimuli can act synergistically to induce a signifi-
as some CD3-positive CD1a-positive lympho- cant in vitro plaque-forming cell response in cord
cytes. Like CD38, CD1a is a marker present on blood B cells.
early thymocytes. CD1a-positive cells are espe-
cially present in preterm and antenatally stressed
infants. While the neonate has adequate numbers Immunoglobulins
of CD4 helper T cells, cord blood T cells are
deficient in their ability to provide help for anti- The presence of physiological hypo-
body production, probably at the level of altered gammaglobulinemia has been noted by several
cytokine production. The cellular basis for this investigators in preterm and term infants. Neonates
functional defect is reflected in other phenotypic have low levels of IgA and IgM immunoglobulins
markers of functional activity. More than 90% of because of the poor ability of these immunoglobu-
cord blood T cells carry the CD45RA+ “virgin” lin classes to cross the placenta. Furthermore, all
cell phenotype marker, compared with 50% of IgG subclasses are not equally transferred across
adult T cells which express CD45RA+. In con- the placenta, especially the IgG2 and IgG4 subclass
trast, less than 10% of cord blood lymphocytes levels, which are therefore also relatively low in the
express the CD45RA “memory” T-cell marker newborn. The neonate is consequently very sus-
compared to a 50% level of expression in adult T ceptible to pyogenic bacterial infections since most
cells. This major imbalance in the ratio of of the antibodies that opsonize capsular polysac-
CD45RA+/CD45RA, CD4-positive T cells in charide are contained in the IgG2 subclass and IgM.
the newborn compared to adults may help Neonates, even during overwhelming sepsis, do
explain some of the functional differences of not produce type-specific antibodies. This
452 S. Aslam et al.
impairment in antibody production appears to be Table 2 Cytokines and their functions

secondary to the defect in the differentiation of B Principal cellular Principal cellular
lymphocytes into immunoglobulin-secreting Name source target
plasma cells and T-lymphocyte-mediated facilita- IL-1 Macrophages, Thymocytes,
tion of antibody synthesis. There is a marked lim- fibroblasts, endothelial cells,
endothelial cells neutrophils,
itation in infant antibody responses to most T cells, B cells
bacterial capsular polysaccharides. This limitation IL-2 T cells T-cells, B-cells
prevents successful infant immunization with Hib IL-3 T cells Multipotential
polysaccharide vaccines, which fortunately can be stem cells
circumvented by use of conjugate vaccines shown IL-4 T helper cells T cells, B cells,
to be immunogenic in infants. mast cells,
macrophages
IL-5 T helper cells B cells,
eosinophils
Cytokines IL-6 Fibroblasts B cells,
fibroblasts,
Among the major molecular components of the hepatocytes
immune system are the immunoglobulins, cyto- IL-7 Stromal cells B cells
kines, and proteins of the acute-phase response IL-8 Macrophages Neutrophils
and complement system. The term “cytokine” is IL-10 T cells, activated T-cell subsets,
monocytes macrophages
used to describe a group of peptides with potent
IL-12 Macrophages T cells, NK cells
immunoregulatory effects, which are produced IL-13 T helper cells B cells
and utilized, by individual cells of the immune TNF-α Macrophages, Many cell types
system, to communicate with each other and to fibroblasts
control the environment in which they operate. A TNF-α T cells Many cell types
description of some of the major characterized IFN-β Macrophages, Many cell types
cytokines is listed in Table 2. fibroblasts
Present evidence suggests that cytokines are of IFN-β Fibroblasts Many cell types
immense importance in controlling both local and IFN-β T cells, NK cells Macrophages,
T cells, B cells
systemic immune responses, inflammation, and
TGF-β T cells, macrophages, Many cell types
the regulation of hematopoiesis. Their most platelets
important function appears to be at local level, GM-CSF T cells, endothelial Multipotential
modulating the behavior of adjacent cells in a cells stem cells
paracrine fashion, or the cells that secrete them,
in an autocrine fashion. In addition, especially in
the case of TNF-α, IL-1, and IL-6, cytokines may cytokines in almost unlimited quantities and the
effect endocrine-like activity on distant organs or production of specific antagonists such as soluble
tissues. Cytokines have important biological cytokine receptors and IL-1 receptor antagonists
activity, which can be of major clinical benefit, are leading to new and exciting therapeutic poten-
such as stimulation of antimicrobial function, pro- tial for these molecules.
motion of wound healing, and myelostimulation.
With such diverse biological function, an exag-
gerated or prolonged secretion of these peptides The Inflammatory Response
may be detrimental for the host. Specifically, aber- Syndromes
rant secretion of cytokines, such as TNF-α and
IL-1, is thought to be responsible for the hemody- One reason for the failure of anti-inflammatory
namic changes in the host during septic shock and strategies in patients with sepsis may be a change
in cachexia of chronic disease. The availability of in the syndrome over time (Fig. 3). Initially, sepsis
recombinant DNA techniques to produce may be characterized by increases in
Fig. 3 Pro- and anti-

inflammatory responses:
SIRS
these responses eventually Immunostimulation
balance to produce
homeostasis and recovery.
If one or other response
predominates, it may
increase morbidity and
mortality. SIRS systemic
inflammatory response
syndrome, CARS
compensatory anti- An t i-in f lam m at o r y
inflammatory response
syndrome
INSULT CARS
Immunosuppression
inflammatory mediators; but as sepsis persists, Fetal and neonatal inflammatory responses
there is a shift toward an anti-inflammatory immu- (FIRS and NIRS) have been described. A sys-
nosuppressive state (Lederer et al. 1999). If the temic fetal inflammatory response is determined
initial insult is sufficiently severe, the by increased IL-6, in an independent risk factor
pro-inflammatory response can become intense for severe neonatal morbidity (Ashare et al.
and lead to a massive systemic inflammatory 2005). Preterm neonates with systemic infection
response syndrome (SIRS) and disrupt homeosta- have elevated IL-6, IL-10, and TNF-α concen-
sis. If the delay is prolonged and the resolution of trations. Severe infection is signified by
inflammation is blocked, the neutrophilia has a increased IL-10/TNF-α and IL-6/IL-10 ratios.
very high potential for causing extreme damage Transiently elevated IL-10 or IL-10/TNF-α
to healthy tissue due to the concentrated release of levels are not invariably associated with a poor
ROS and proteases. This then forces the body to prognosis (Ng et al. 2003).
produce a massive compensatory anti-
inflammatory response syndrome (CARS) that
may be inappropriate and result in tissue injury. Clinical Outcomes in Neonatal Sepsis
If this occurs, the body develops “immune paral- and Inflammation
ysis” and is more susceptible to infection. The
final stage occurs when the overwhelming inflam- Death and long-term complications are common
mation is not resolved causing multiple organ dys- sequelae of bacterial infections in newborns. Neo-
function syndrome and death of the patient (Bone nates undergoing intensive care have infection
1996). Adjunctive immunomodulatory treatments rates of 25–50% (Stoll et al. 2002), and mortality
for sepsis seek to balance these responses and has not changed from 15% to 20% over the last
restore homeostasis (Bone 1996). However discov- 20 years. Altered bactericidal mechanisms are
ering which inflammatory phase is dominant in the responsible for the increased vulnerability to sep-
patient at a certain time point remains difficult and sis in this group and mirror the pattern seen in
hinders appropriate therapeutic immunomodulation. grossly neutropenic patients. Neutropenia com-
Anti-inflammatory treatment can increase mortal- monly develops in neonatal sepsis in contrast to
ity. Following a cecal ligation and puncture model the leukocytosis in septic adults (Carr 2000). This
of sepsis in a murine model mortality was increased may be mediated by a decreased neutrophil stor-
in mice pretreated with interleukin receptor antag- age pool and a limited capacity for increased
onist (IL-1RA) increased mortality (Gomez et al. progenitor production in newborns especially
1998). preterms.
454 S. Aslam et al.
There is increasing evidence that sepsis and has been associated with organ dysfunction and
inflammation are important in the pathogenesis hypoperfusion. Nadel et al. reported the consensus
of perinatal brain injury. In preterm infants, epi- for definition of infection (International Consensus
sodes of sepsis are associated with poorer of Sepsis) as evidence of pathogen-positive blood
neurodevelopmental outcomes. In addition, culture, tissue stain or polymerase chain reaction
an association between cerebral palsy and (PCR) test, or a clinical syndrome associated with
maternal peripartum infection in term infants a high probability of infection (Nadel et al. 2007).
has been well documented (Nelson and Wil- SIRS is defined clinically by the presence of phys-
loughby 2000). Elevated pro-inflammatory cyto- iologic signs and one laboratory study that indicates
kines have also been demonstrated in activation of the immune/inflammatory response
retrospectively reviewed dried neonatal blood (Table 1; Standage and Wong 2011). Sepsis is a
spots from children aged 3 years with cerebral syndrome rather than a discreet pathologic entity
palsy. Activated leukocytes and infection have with a clear, unified, maladaptive process at its
been implicated in the pathogenesis of neonatal core. Early recognition, appropriate therapeutic
brain damage (Dammann et al. 2001). Severe response, and effective antibiotic therapy are critical
disruption of the blood-brain barrier in severe to prevent its progression to severe sepsis and septic
asphyxia may exacerbate neuronal damage allo- shock (Standage and Wong 2011).
wing infiltration of activated immune cells and Previous pediatric studies had defined the inclu-
cytokines. sion criteria for sepsis as hyperthermia or hypother-
mia, tachycardia (may be absent in the hypothermic
patient), evidence of infection, and at least one of
the following signs of new-onset organ dysfunc-
Pediatric Sepsis tion: altered mental status, hypoxemia, bounding
pulses, or increased lactate (Carcillo 2003;
Sepsis is a major cause of admission to pediatric Doughty et al. 1996; Proulx et al. 1994).
intensive care units (PICU) and is a leading cause
of morbidity and mortality in children. In the
United States, sepsis accounts for nearly 4,500 Primary Immunodeficiencies
deaths and costs almost 2 billion dollars per year
in health care. The incidence of sepsis is highest in Primary immunodeficiencies (Cant et al. 2003;
infants (5.16/1,000 per year), decreasing in older Bonilla et al. 2005, 2015) can be divided into
children to 0.20/1,000 in 10–14-year-old children four major contributors of immune system, that
(Watson et al. 2003). In the United Kingdom, the is, B cells, T cells, complement, and phagocytes
unadjusted case fatality rate for children admitted (Table 2).
to PICU is 4.1%. The cause of sepsis is multifac-
torial but can include virtually any infectious
organism, although bacterial infection is the B-Cell Deficiencies
most common. The most prevalent causes of
severe sepsis and septic shock are Staphylococcal X-linked agammaglobulinemia (Cant et al. 2003;
and fungal infections (Watson et al. 2003). Bonilla et al. 2005, 2015) is a deficiency of all
The pathophysiology of sepsis is characterized classes of immunoglobulins along with deficiency
by a complex systemic inflammatory response, of B cells. The failure is due to mutation in a gene
endothelial dysfunction, and dysregulation of coag- encoding for tyrosine kinase, which is an essential
ulation system. Sepsis in pediatric patients fre- signal transduction protein. Recurrent pyogenic
quently manifests as disseminated intravascular infections occur from 6 month of age as mater-
coagulation (DIC) with consumption of platelets nally acquired antibodies at its lowest nadir. It is
and clotting proteins (Wheeler et al. 2011). The diagnosed by measuring immunoglobulin levels
production of inflammatory cytokines during SIRS and B-cell numbers in blood. Treatment is life-
long immunoglobulin replacement therapy and by syndrome patients have high concentration of
using prophylactic antibiotics to prevent or treat IgM and lower concentration of IgG, IgA, and
infections. Patient on replacement immunoglobu- IgE. There is defect in the surface protein of T
lin can lead to relatively normal lives. Selective helper cells that interact with CD40 receptors on
immunoglobulin deficiencies are also congenital the B cells and thus B cell inability to switch from
such as IgA deficiency, commoner than IgG and production of IgM to other classes of antibodies. It
IgM deficiency. The failure to switch heavy chain presents with recurrent pneumonias, bronchiecta-
between different classes of immunoglobulins is sis, and sinusitis. Intravenous immunoglobulin is
the main cause of deficiency. IgA prevent infec- the treatment of choice.
tion of mucous membrane lining mouth, airway,
and GIT. IgA deficiency presents with suscepti-
bility to recurrent sinopulmonary infections, Combined B- and T-Cell Deficiencies
although the vast majority of children are normal
as immunity is conferred by IgG and IgM anti- Severe combined immunodeficiency disease
bodies. Children with IgA deficiency are at higher (SCID) in which both B and T cells are involved
risk of autoimmune diseases. (Cant et al. 2003; Bonilla et al. 2005, 2015) and
either the number is reduced or the function is
defective. It is considered one of the most serious
T-Cell Deficiencies primary immune deficiencies. The main causes
are defects in differentiation of early stem cells,
22q11.2 deletion syndrome (previously known as and it can be X linked or autosomal dominant. In
DiGeorge syndrome) has varied spectra of presen- X-linked SCID, the commonest cause is the defect
tation with different organs involved with varying in IL-2 receptor in T cells. In the autosomal dom-
degrees of severity. Infections occur in the infants inant forms there is defect in gene encoding tyro-
and children secondary to failure of third and sine kinase in T cells called ZAP 70. Other forms
fourth pharyngeal pouches to develop and present of SCID include adenosine deaminase and nucle-
with dysmorphic features, abnormal gland devel- oside phosphorylase deficiency that affects bone
opments, and heart defects. There is either a defect marrow differentiation as these enzymes are
in function or production of T cells. 22q11.2 dele- involved in making precursors for DNA. SCID
tion syndrome (Cant et al. 2003; Bonilla et al. presents with recurrent and severe respiratory
2005, 2015) is a life-long condition, but recurrent infections, and other symptoms include failure to
infections mostly occur in infants and children as thrive, eczema like rashes, chronic diarrhea, and
the incidence of recurrent infections decreases in thrush infection in mouth. Early detection of
late childhood and adulthood. It is diagnosed at SCID is important and has positive effect on
birth based on clinical observation and genetic long-term outcome. Diagnosis depends upon clin-
testing. As the disease has varied spectrum, mild ical suspicion, absence of thymus and lymphoid
cases of immunodeficiency related to T cell can be tissue, lymphopenia, panhypogammaglo-
managed by prophylactic antibiotics and close bulinemia, and poor response of T cells to anti-
follow-up. In severe cases, bone marrow trans- gens. Once diagnosis is established, the only
plantation is the treatment of choice. Chronic treatment available is bone marrow transplanta-
mucocutaneous syndrome is one of the recog- tion. Gene therapy for severe forms of SCID is
nized T-cell deficiencies. In chronic mucocutane- being used in clinical trials.
ous syndrome, there is specific deficiency in T Wiskott-Aldrich syndrome (WAS) is character-
cells directed toward candida which is normally ized by recurrent, severe pyogenic infection,
non-pathological in a normal host. As the name is eczematous skin eruptions, and thrombocytopenia.
self-explanatory, it presents with recurrent candi- There is T-cell lymphopenia and poor T-cell
dal infection of skin and mucous membranes. The responses. Both flow cytometry on lymphocytes
mainstay of treatment is antifungal. Hyper IgM from patient with suspected WAS and molecular
456 S. Aslam et al.
diagnosis are required. Bone marrow transplanta- reduction of reactive oxygen intermediates and
tion (BMT) is the treatment of choice. Before decreased phagocytic function. Diagnosis
BMT, intravenous immunoglobulins and prophy- depends on establishing the phagocytic oxidase
lactic antibiotics are effective treatment of choice. activity. Prophylactic antimicrobial use, granulo-
Ataxia telangiectasia is characterized by ataxia, cyte transfusion in the presence of an active infec-
dilatation of blood vessels in skin and conjunctiva, tion, and surgical debridement if poor response to
and recurrent pyogenic infections. It is autosomal medical therapy are the mainstay of treatment. It
recessive. Immunological abnormalities include can be successfully treated with bone marrow
low or elevated level of immunoglobulin, poor transplantation.
specific antibody response, and alteration in lym- Chediak-Higashi syndrome is an autosomal
phocyte proliferation. Diagnosis depends on recessive disease caused by failure of lysosomes
establishing the presence of chromosomal fragility of neutrophils to empty their contents. It presents
and pathognomonic increased level of oncofeto- with partial oculocutaneous albinism and neuro-
proteins. The treatment as for any other primary logical symptoms. It is diagnosed by the presence
immunodeficiency is antibiotic prophylaxis and of giant azurophilic granules in neutrophils. Infec-
gammaglobulin replacement therapy. tions associated with this syndrome are pyogenic
and involve skin and respiratory tract. Bone mar-
row transplantation is curative and improves the
Complement Deficiencies immune deficiency but has no effect on albinism
and neurologic manifestations.
Hereditary angioedema (Cant et al. 2003; Bonilla In hyper IgE syndrome, the main defect is the
et al. 2005, 2015) involves an absence of C1 failure to produce IFN-γ by helper T cells leading to
esterase inhibitor, it is not associated with any increase in TH2 cells and thus increase in IgE. IgE
immune deficiency, and its deficiency does not causes histamine release and blocks certain aspects
predispose to recurrent infections. A general defi- of the inflammatory response; thus “cold abscesses”
ciency of complement proteins is associated with are characteristic for this disease. Patients are prone
recurrent bacterial infections of respiratory sys- to infections with Staphylococcus aureus and
tem, associated with antibody deficiency and Aspergillus and suffer from chronic dermatitis.
higher prevalence of autoimmune diseases, and Patients with hyper IgE syndrome have involve-
especially associated with C2 and C4 deficiency. ment of skeletal system and dentition. High levels
For example, as all complement pathways acquire of IgE, Staphylococcus aureus-binding IgE, and
active C3, its deficiency can present with same eosinophilia are characteristic of this disease but
spectrum of disease as associated with severe are not considered pathognomonic. The mainstay
antibody deficiency. Deficiency of C6, C7, and of treatment is aggressive prophylactic antibiotics
C8 can present with infections with neisserial and antifungals. The use of intravenous immuno-
group of organisms. Diagnosis of complement globulin (IVIG) and immunomodulation with
deficiency for classical and alternate pathway IFN-γ is controversial in this disease. BMT is of
depends on laboratory tests called CH50 and limited value as disease recurs posttransplant.
AH50, respectively. The treatment of choice is In leucocyte adhesion deficiency (LAD) syn-
long-term antibiotic therapy. drome, there is absent or decreased expression of
CD18 (LAD1) and CD15 (LAD2) or decreased
upregulation in the presence of acute infection on
Phagocytic Cell Deficiencies the surface of neutrophils. Patients suffer from
cellulitis, abscesses, and bacterial and fungal pul-
Chronic granulomatous disease (Cant et al. 2003; monary infections. Patients with neutrophilia and
Bonilla et al. 2005, 2015) is characterized by recurrent infections in the absence of pus forma-
recurrent infection with bacteria and fungi. There tion should be investigated for this disease. The
is lack of NADPH oxidase activity leading to neutrophil count may be so high in acute infection
that a possibility of leukemia or acute leukemoid morbidity. Patients undergoing surgical proce-
reaction might be considered. The main treatment dures should be discussed with immunologist/
strategy is prevention by using prophylactic anti- infectious disease consultants with expertise to
biotics and aggressive treatment of acute infec- treat these patients prior to procedure. Other
tions. Granulocyte transfusion and surgical important clinical point is to avoid live vaccines
debridement should be considered if medical ther- in these immunodeficient patients such as BCG,
apy fails. oral polio vaccine, and MMR. These patients
should be reviewed by an immunologist on regu-
lar basis.
Acquired Immunodeficiency
Combined variable immunodeficiency (CVID) Immunomodulation

is an example of B-cell immunodeficiency
of uncertain etiology. It should be considered if Neonates especially those preterm are particularly
the patient suffers from recurrent respiratory vulnerable to sepsis. Transplacental transfer of
tract infections (Lougaris et al. 2016) with immunoglobulins from the mother to the fetus
encapsulated organisms (Haemophilus influ- occurs after 32 weeks of gestation, and endogenous
enza, Streptococcus pneumoniae) and atypical production commences at a few months of age.
organisms such as mycoplasma. There is GIT Administration of intravenous immunoglobulin
involvement as well, and infections with provides IgG that can bind to cell surface receptors,
Giardia, Campylobacter, and Salmonella are provide opsonic activity, activate complement, pro-
common. There is an increased incidence of mote antibody dependent cytotoxicity, and
autoimmune diseases, nonmalignant lympho- improve neutrophilic chemoluminescence. Term
proliferative disorders, and malignancies in neonates have low type-specific antibody and
CVID (Xiao et al. 2014). Hypogammaglobul- opsonin deficiencies. Preterm neonates also have
inemia and poor specific antibody response are severe hypogammaglobulinemia and deficient
hallmark of CVID. The treatment of choice is complement activity.
prophylactic antibiotics and IVIG. Theoretically infectious morbidity and mor-
A general approach to treatment in primary bidity could be reduced by the administration of
immunodeficiencies is medical including antibi- intravenous immunoglobulin (IVIG). Meta-
otics, immunoglobulins, and immune modulation. analysis of small trials has suggested that IVIG
In patients with humoral immune deficiency and may reduce the rate of neonatal death but
complement deficiencies, the treatment of choice Cochrane reviews could not recommend routine
is IVIG and prophylactic antibiotics. While com- use of prophylaxis against nosocomial infections
bined and cellular immune deficiencies require or for treatment in proven or suspected infection
bone marrow transplantation, most of these (Ohlsson and Lacy 2004, 2013). The International
patients might require IVIG and prophylactic anti- Neonatal Immunotherapy Study (INIS) was an
biotics as antibody function might not fully international multicenter randomized controlled
recover after BMT. Surgical treatment is required trial (RCT) studying the use of nonspecific IVIG
when medical treatment fails. Patients with recur- in addition to antibiotics in babies with suspected
rent middle ear infections and rhinosinusitis might or proven sepsis. However, in this study and also a
benefit from tympanostomy tube placement and subsequent Cochrane analysis, IVIG had no effect
adenotonsillectomy. Surgical drainage and on the rate of mortality and major morbidity (INIS
debridement might be required for infections Collaborative Group et al. 2011; Ohlsson and
with poor response to medical therapy. These Lacy 2015).
patients require more aggressive, prolonged Neonates often become neutropenic when sep-
course of combined antibiotics and at higher tic, and therefore the use of granulocyte colony-
doses post-surgery to reduce mortality and stimulating factor and granulocyte macrophage
458 S. Aslam et al.
colony-stimulating factors (GCSF and GM-CSF) of rotavirus-induced diarrhea, allergies to cow

has been studied on this population. The Cochrane milk protein, atopic dermatitis, and some inflam-
meta-analysis of trials has found no significant matory intestinal diseases. A relative reduction
improvement in outcome when CSFs were used in the risk of NEC, late-onset sepsis, and mortal-
for prophylaxis or treatment of sepsis. ity has been demonstrated with probiotics
The program multicenter RCT of prophylactic (B. infantis, Streptococcus thermophilus, and
GM-CSF to reduce systemic sepsis in preterm B. bifidus in one study and Lactobacillus aci-
neonates included 280 infants <31 weeks. When dophilus and B. infantis in another) (Nadel
GM-CSF 10 ug/kg/day was administered prophy- et al. 2007; Neu 2007). A multicenter, double-
lactically for 5 days, neutrophil counts were blind, randomized, controlled trial of the pro-
higher on days 3–12 than controls. There were biotics B. bifidus and L. acidophilus showed a
no significant differences in sepsis-free survival lower incidence of NEC in the study group than
in gnats who were neutropenic at recruitment, the controls, but sepsis was more frequent in the
number of infants experiencing one or more epi- study group, although this difference was not
sodes of culture-positive sepsis or survival to dis- significant on multivariate analyses, and none
charge. GM-CSF rapidly corrected neutropenia in of the affected patients developed sepsis with
preterm, growth-restricted neonates. Prophylactic organisms used as probiotics. There are persis-
GM-CSF and correction of neutropenia, even tent concerns about the use of probiotics in
when severe, did not reduce sepsis or all-cause immunosuppressed infants as there have been
mortality (Carr et al. 2009). Kuhn et al. described reports of preterm infants who had short gut
a multicenter, randomized, double-blind, placebo- syndrome and developed Lactobacillus bacter-
controlled trial of the prophylactic use of GCSF in emia while receiving this probiotic bacterium. A
neutropenic preterm infants <32 weeks (n = 200) recent Cochrane review has suggested that rou-
and found no differences in survival free of con- tine use of probiotics in less than 28 weeks’
firmed infection for 4 weeks after treatment with gestation neonates is not useful; the results of
either GCSF (10 mg/kg/day) or placebo for 3 days further ongoing multicenter studies are awaited.
(Kuhn et al. 2009). However activated leukocytes In addition to these immediate concerns about
may mediate neonatal brain injury (Nelson and sepsis, the long-term effects of the use of pro-
Willoughby 2000). GM-CSF stimulates neonatal biotics, especially in preterm infants in terms of
neutrophil activation unlike GCSF and both pro- immune modulation in later life, development of
long neutrophil survival (Molloy et al. 2005). immune disorders (such as insulin resistance,
However the 2-year developmental outcomes diabetes, obesity, and cancer), and neurodeve-
were equal in both groups. lopmental outcomes are not known.
APC (drotrecogin alfa activated) was studied
in the RESOLVE (REsearching severe Sepsis and
Organ dysfunction in children: a gLobal perspec- Conclusion and Future Directions
tiVE) trial evaluated sepsis for safety, pharmaco-
kinetics, and pharmacodynamics of drotrecogin In fetal and neonatal life, many aspects of the
alfa (activated) in children with severe sepsis, immune system are different to older children
and no benefit was found (Nadel et al. 2007). and adults. The molecular and cellular basis for
The patients studied were from term newborn these abnormalities, while partially explained by
to 18 years, and although similar pharm- many of the observations described in this chap-
acokinetic profiles were found, bleeding rates ter, remains relatively unclear. The prospects for
were increased. more specific and selective immunological inter-
Prebiotics are unique oligosaccharides that vention as part of the treatment of the immuno-
are not absorbed but facilitate colonization by compromised neonate undergoing surgery will
probiotic organisms (bifidobacteria and lactic benefit enormously from ongoing research into
acid-producing bacteria). Use of probiotics has the biological basis of immuno-incompetence of
been shown to decrease the duration and severity the newborn.
Designing new drugs to neutralize microbial lipopolysaccharide requires plasma in neutrophils from
products or block their interaction with specific adults and newborns. Infect Immun. 2001;69(5):3143–9.
Cairo MS. Neonatal neutrophil host defense. Prospects for
receptor on immune cells is an attractive concept immunologic enhancement during neonatal sepsis. Am
(Wynn et al. 2009, 2010). Potential targets include J Dis Child. 1989;143(1):40–6.
LPS-binding protein, CD14, TLR4, and MD-2 for Calandra T. Pathogenesis of septic shock: implications for
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bodies against CD14 are being evaluated in phase AR. Immunodeficiency chapter. In: McIntosh N,
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will therefore be essential. trial): a single-blind, multicentre, randomised controlled
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Sepsis
28
Scott S. Short, Stephanie C. Papillon, and Henri R. Ford
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Terminology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Barriers to Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Host Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Cellular Immunity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Humoral Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Complement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Immunoglobulins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 467
Bacterial Virulence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Neonatal Defenses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 469
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470
Treatment of Sepsis in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471
Neonatal Septic Shock . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474
Abstract
Sepsis in children is a complex process that
S. S. Short (*) · S. C. Papillon · H. R. Ford
Division of Pediatric Surgery, Children’s Hospital remains incompletely understood. Neverthe-
Los Angeles, Los Angeles, CA, USA less, clarification in the diagnosis of sepsis
e-mail: Scott.Short@imail2.org; dr.scottshort@gmail. and identification of host immunologic path-
com; Spapillon@chla.usc.edu; spapillon@huhosp.org; ways as well as bacterial virulence factors have
Hford@chla.usc.edu

https://doi.org/10.1007/978-3-662-43588-5_30
462 S. S. Short et al.
led to greatly improved understanding of the other parameters to increase the specificity, sensi-
disease processes. Ultimately, this has resulted tivity, and early detection of sepsis. These include
in improved management algorithms and measurement of inflammatory mediators such as
improved outcomes with more than fivefold C-reactive protein (CRP), which may be benefi-
decrement in mortality over the last 50 years. cial in diagnosing sepsis, with sensitivity reported
This chapter will outline the current under- as high as 76% and specificity of 84% (Jekarl et al.
standing of epidemiology, pathophysiology, 2013). Recently CRP and another inflammatory
management, and therapeutic strategies for mediator, procalcitonin, were included in the 2012
pediatric sepsis. Surviving Sepsis as adjunctive inflammatory
criteria for sepsis in the appropriate clinical setting
Keywords (Dellinger et al. 2013).
Pediatric sepsis · Septic shock · Neonatal
sepsis
Epidemiology
Introduction Difficulties with current consensus definitions

utilized to define sepsis and to distinguish it
Sepsis, an adverse physiologic response to infec- from systemic inflammatory response syndrome
tion, is a challenging clinical problem that is a (SIRS) and other pathology have resulted in a
leading cause of mortality worldwide, and the search for additional diagnostic tools and have
incidence is thought to be increasing. Despite left the overall incidence of sepsis unclear. A
high disease prevalence, only 332 or 1.7% of the study by Klein and colleagues highlighted the
more than 19,000 grants from the National Insti- low specificity of sepsis definitions. In their
tutes of Health in 2006 were intimately related to cohort of 1,072 patients, they determined the
critical care research and as little as $95 million diagnosis of sepsis in 22% and severe sepsis in
were invested in septicemia related research in 6% of patients when using stringent criteria.
2008 (Coopersmith et al. 2012). Furthermore, However, when using other less stringent
only a small portion of this research effort focuses published criteria, the incidence of sepsis rose
on pediatric sepsis. Consequently epidemiologic to 31% and that of severe sepsis to 27% (Klein
studies are lacking, the pathophysiology remains Klouwenberg et al. 2012).
incompletely understood, and sepsis remains a Several multicenter studies have been
challenging condition to manage in children of performed in an attempt to better characterize the
all ages. This chapter will outline the current incidence of pediatric sepsis and subsequent out-
understanding of the epidemiology, pathophysiol- comes. A 2012 prospective multicenter study
ogy, management, and therapeutic strategies for from Japan identified 127 children with severe
pediatric sepsis. sepsis requiring admission to the pediatric inten-
sive care unit (PICU) over a 3-year period. This
cohort represented 1.4% of children requiring
Terminology PICU admission and had a concomitant mortality
rate of 19% (Shime et al. 2012). Another multi-
In 2005 Goldstein and colleagues published pedi- center prospective study evaluated all children
atric-specific definitions for sepsis, severe sepsis, 16 years or younger requiring admission to 15
septic shock, and multiple organ dysfunction syn- different PICU’s in Italy over a 1-year period.
dromes (MODS), which have been incorporated They reported a 7.9% incidence of sepsis, a
into the 2012 Surviving Sepsis campaign (Table 1; 1.6% incidence of severe sepsis, and 2.1% inci-
Goldstein et al. 2005; Dellinger et al. 2013). dence of septic shock among a cohort of 2,741
While these widely accepted definitions have children. Overall mortality was 17.7% for severe
not been modified, researchers have evaluated sepsis and 50.8% for septic shock. Most cases of
28 Sepsis 463
Table 1 (continued)
Table 1 Sepsis definitions (Adapted with permission from
Tables 2 and 4 Goldstein et al. 2005 and Tables 1 and 2 from 5. Core to peripheral temperature gap >3 C
Dellinger et al. 2013) b. Respiratory
A. Systemic inflammatory response syndrome (SIRS): two i. PaO2/FIO2 <300 in absence of cyanotic heart
of the following, one must be abnormal temperature or disease or preexisting lung disease
leukocyte count ii. PaCO2 >65 torr or 20 mmHg over baseline PaC02
i. Temperature >38.5 C or <36 C iii. Proven need or >50% Fi02 to maintain saturation
ii. Heart rate >2 standard deviations above normal for 92%
age in absence of external stimulus, drugs, or painful iv. Need for nonelective invasive or noninvasive
stimuli. If <1 year: bradycardia defined as less than 10th mechanical ventilation
percentile for age in the absence of external vagal c. Neurologic
stimulus, beta-blocker, or congenital heart disease
i. Altered mental status or Glasgow coma scale
iii. Respiratory rate >2 standard deviations above (GCS) 11
normal for age or mechanical ventilation for an acute
ii. Acute change in mental status with a decrease in
process not caused by recent anesthesia or neuromuscular
GCS 3 points from abnormal baseline
disease
d. Hematologic
iv. White blood cell count elevated or depressed for age
or >10% immature neutrophils i. Platelet count <80,000/mm3 or a decline 50% in
platelet count from highest value recorded over the past
B. Infection
3 days
i. Suspected or proven infection caused by a pathogen
ii. INR >2
or a clinical syndrome associated with high probability of
infection. Evidence includes positive findings on exam, e. Renal
imaging, or laboratory studies i. Serum creatinine 2 times upper limit of normal
C. Sepsis for age or 2 fold increase in baseline creatinine or an
increase greater than 0.5 mg/dL
i. SIRS in the presence or as a result of a proven
infection f. Hepatic
D. Severe sepsis i. Total bilirubin 4 mg/dl (excludes newborns)
i. Sepsis plus one of the following: ii. Alanine transaminase (ALT) 2 times upper limit
of normal for age
1. Cardiovascular organ dysfunction
g. Gastrointestinal
2. Acute respiratory distress syndrome
i. Ileus
a. Pa02/Fi02 <250 in the absence of pneumonia
h. Other
b. Pa02/Fi02 <200 in the presence of pneumonia
i. Significant edema or positive fluid balance
3. Two or more other organ dysfunctions
(>20 ml/kg over 24 h)
E. Septic shock
ii. Hyperglycemia >140 mg/dL without alternative
i. Sepsis plus cardiovascular organ dysfunction etiology
F. Organ dysfunction criteria
a. Cardiovascular dysfunction: any of the following
despite isotonic resuscitation of 40 ml/kg of isotonic
fluid in 1 h sepsis were medically related (84.4%) and most
i. Blood pressure <5th percentile for age or systolic sources of sepsis were respiratory (47.8%),
blood pressure <2 SD below normal for age followed by blood stream infections (21%) and
ii. Need for vasoactive drugs to maintain blood central nervous system infections (16.2%)
pressure
(Wolfler et al. 2008).
1. Dopamine >5 ug/kg/min, or dobutamine,
epinephrine, norepinephrine While prospective multicenter data from the
iii. Two of the following: United States are lacking, several large retrospec-
1. Unexplained metabolic acidosis: base deficit tive studies have reported an annual incidence of
>5 mEq/L sepsis at 0.56 cases per 1,000 children each year
2. Increased arterial lactate >2 times upper limit (Watson et al. 2003). A 2009 study from Wash-
of normal ington State reported a mortality rate of 6.8% for
3. Acute oliguria: urine output <0.5 ml/kg/h for
children admitted with a diagnosis of severe sep-
greater than 2 h despite resuscitation
4. Prolonged capillary refill: >5 s
sis. While this number is much lower than the
(continued)
European reports, another 6.5% of this cohort
later died on readmissions for recurrent sepsis shedding of cells (skin, respiratory tree, gastroin-
(Czaja et al. 2009). These children generally had testinal tract). Other ubiquitous mechanisms
comorbid conditions, and their study demon- include the relative acidic environment of the
strated an overall mortality of 34.2% in children skin, gastric acidity, and intestinal peristalsis.
with significant comorbidities. Immunoglobulin-A (IgA) secretions are prevalent
Despite the uncertainty regarding its true prev- in the tracheobronchial tree and intestine and act
alence, sepsis remains one of the top four killers of to diminish bacterial adherence. For any infection
children as reported by the World Health Organi- to occur, these barriers must be breached. Numer-
zation and the cause of death for more than 25% of ous factors play a role in altering barrier function;
the general population (Watson et al. 2003). Nev- these include polymicrobial sepsis, trauma, mal-
ertheless, improved understanding of the patho- nutrition, burns, shock, immunosuppression,
physiology and treatment of sepsis has resulted in immaturity, reperfusion injury, and various medi-
dramatic decreases in sepsis-related mortality cations. These factors, combined with virulent
from reports as high as 97% in the 1960s to an bacteria, may result in loss of barrier integrity
estimated 10% today (Czaja et al. 2009). Contin- with subsequent tissue edema and epithelial acti-
ued improvements may occur if adequate resusci- vation, which may lead to progressive
tation and guidelines are effectively utilized. dysfunction.
Pathogenesis Host Response
The pathogenesis of sepsis is multifactorial, with Cellular Immunity

host defense mechanisms and bacterial virulence
factors as its principal determinants. The process The primary defense in response to infection or
is initiated by the pathogen’s ability to evade host tissue injury is the neutrophil, which follows an
defenses including mucous, lysozymes, and orchestrated sequence of events including neutro-
defensins to bind to the epithelial barrier. Subse- phil adherence, diapedesis to site of injury, and
quently, bacterial-epithelial interactions lead to activation of the neutrophil. Binding of the neu-
induction of virulence genes and expression of trophil to the epithelium is coordinated by expres-
virulence factors. This is followed by host patho- sion of selectins, integrins, and immunoglobulins.
gen recognition and activation of pro-inflamma- The process generally begins by expression of E-
tory signaling pathways. Undoubtedly, premature selectins on activated epithelium, to which the L-
infants, immunocompromised children, and chil- selectins present on neutrophils will bind. Once
dren with significant comorbidity will have this binding occurs, there is further adherence
altered host defenses and increased vulnerability with the binding of β2 integrin on the neutrophil
to infection. Progression of the inflammatory cas- with ICAM-1 on the endothelial cell, a necessary
cade can then enter a positive feedback loop char- step prior to initiation of PECAM-1-dependent
acterized by a pathologic or exuberant cytokine diapedesis (Liu et al. 2012).
response with resultant sepsis, progression to Once the neutrophil is able to reach the source
severe sepsis, MODS, and death. of infection, it engulfs microbes with subsequent
microbial death. To accomplish this task, the neu-
trophil must sufficiently differentiate the microbe
Barriers to Infection as different from self. Key to this process is the
recognition of pathogen-associated molecular pat-
There are numerous host defense mechanisms that terns or PAMPS. Examples include mannans in
limit bacterial adherence to the epithelium. These the yeast cell wall, lipopolysaccharides,
include anatomic barriers such as mucous produc- lipoteichoic acid, and formylated peptides present
tion, the commensal flora, and the routine in Gram-negative and Gram-positive bacteria.
28 Sepsis 465
Ultimately the organisms are absorbed into Under normal circumstances, B cells represent
phagolysosomes with subsequent exposure to approximately 15% of circulating lymphocytes
lysozyme, elastase, lactoferrin, cathepsin, and and are characterized by their ability to produce
defensins, which contribute to bacterial perme- immunoglobulins. To allow for recognition of a
ability and act synergistically with free radicals large variety of foreign antigens, B cells undergo a
produced with the respiratory burst of the neutro- process of differential antigen recognition from
phil. Mediators of the respiratory burst include rearrangement of their heavy and light chains
hydroxyl radicals generated by superoxide during development. Prior to antigen stimulation,
dismutase and oxidizing chloramines, which “naive” B cells will enter the periphery as IgM and
effect microbial death. IgD secreting cells. Later following stimulation
by T cells with IL-10, the B cell may undergo
antigen rearrangement, affinity maturation, and
Macrophages isotype switching for subsequent production of
IgG. Other cytokines such as IL-3 can induce
Macrophages are derived from monocytes and act isotype switching for production of IgE, and
to clear the host of cellular debris, bacteria, viruses, TGF-beta can induce secretion of IgA (Chaplin
and tumor cells. Like the neutrophil, the macro- 2010).
phage plays a critical role in host cellular defense T cells require presentation of antigen for acti-
and is activated following recognition of PAMPS. vation. Antigen presentation occurs by sensing of
Further activation occurs following stimulation by cell surface proteins known as major histocom-
inflammatory mediators such as interferon-γ, tumor patibility (MHC) proteins. These proteins come in
necrosis factor α, lipopolysaccharide (LPS), and two classes: class I are expressed by all nucleated
heat shock protein. Further, macrophages secrete cells while class II are only present on antigen
IL-12 and IL-23, activators of the humoral immune presenting cells (APC) such as macrophages, den-
response, which further promote excretion of the dritic cells, and B cells. APCs ingest foreign mate-
pro-inflammatory cytokines IL-1 and IL-6 and che- rial, cells, or microbes and process the proteins for
motactic factors. Once activated, macrophages presentation in association with MHC class II
phagocytose microbes and effect cytotoxicity by protein. CD4-positive T cells interact with class
generating reactive nitrogen and oxygen species II MHC and function to regulate cellular and
via NADPH oxidases. In some cases, such as in humoral immune responses. CD8-positive T
severe sepsis, an exuberant response can occur cells interact with class I MHC and primarily act
with overproduction of these reactive species by killing cells with alien, altered, or diminished
resulting in local injury thereby contributing to MHC class I expression. Both CD4 and CD8
hepatic and pulmonary injury seen during sepsis require activation prior to effecting responses.
(Laskin et al. 2011). For activation of the T cell to occur, its receptor
complex (CD3) must interact with the APC, and
the CD4/8 ligand must bind to the appropriate
Lymphocytes MHC class. These interactions will partially acti-
vate the T cell. Further interactions with CD28 on
While monocytes and neutrophils are key players the T cell and CD80 or CD86 on the APC result in
in the immune response, they are not without full activation (Nurieva et al. 2009). In CD4-pos-
vulnerability. Lymphocytes are derived from lym- itive cells, this activation process results in differ-
phoid progenitors in the bone marrow and com- entiation into T helper 1 or T helper 2 subsets
plement the immunologic arsenal. They come in depending on their cytokine profile, while in
three varieties: the B cell, the T cell, and the CD8-positive cells, it may lead to activation of
natural killer (NK) cell. T cells develop following kinases and release of cytotoxic granules,
maturation in the thymus, whereas B cells develop perforins, and serine proteases. Release of
in the bone marrow. perforins results in “perforations” of cells with
subsequent osmotic lysis, while serine proteases Complement

activate apoptotic pathways.
Recently, a subset of CD25-positive CD4 T The purpose of complement is to effectively
cells known as T regulatory cells (Tregs) have develop and implement the “membrane attack
been identified. They serve as additional media- complex.” This attack complex is the end result
tors of the inflammatory response to sepsis and of three different and distinct pathways of com-
are known to have strong immunosuppressive plement activation, which result in osmotic lysis
activities that are important in regulating host of foreign pathogens. The first pathway is the
response to infection. It is thought that Tregs classical pathway and is dependent upon anti-
play a role in T-cell anergy seen in major trauma gen-antibody interactions. Following these inter-
and burn injury and may be partially responsible actions, there are sequential activation of C1, C4,
for subsequent increased incidence of secondary and C2, which act to generate C3 convertase. This
infectious complications seen in these generates C3a, a potent vasodilator and
populations. Furthermore, elevated levels of anaphylatoxin, and C3b, which covalently binds
Tregs following the onset of septic shock have the activating antigen. C3b then activates C5 and
been correlated with increased mortality and forms the loci for development of the membrane
have been implicated in both reduced attack complex. In the event that the attack com-
lymphoproliferative response and Treg-induced plex fails to result in cellular lysis, C3b also acts as
immunoparalysis (Jiang et al. 2012). Several an opsonin, thereby enhancing phagocytosis by
animal studies utilizing anti-CD25 therapies macrophages and neutrophils.
have attempted to blunt or eliminate the coun- The second pathway or alternate pathway is
ter-regulatory effects of Tregs in sepsis with var- antibody independent and is stimulated by micro-
iable effect. To date the mechanisms of Treg bial structures such as mannans. These microbial
function remain unclear, and no human studies structures bind inhibitors of spontaneous comple-
modulating Treg response to sepsis have been ment activation resulting in efficient deposition of
attempted. C3b and subsequent development of the mem-
Natural killer cells (NK) differ from the other T brane attack complex. The third pathway is
cells in that they do not undergo maturation in the known as the lectin pathway and is also stimulated
thymus; rather, they develop in the bone marrow by microbial cell wall structures such as mannans.
under the influence of IL-2 and IL-15. NK cells Plasma mannan-binding lectins interact with
make up a small portion of the T-cell population microbial mannans to generate proteases that
and act as executioners only restrained by recog- sequentially activate C4 and C2 with subsequent
nition of self-MHC proteins. Cells that express generation of C3b.
either too little self-MHC or alien MHC are ter- The importance and regulation of the comple-
minated. NK cells therefore play a critical role in ment pathway should not be underestimated.
destruction of tumor cells and those infected with Uncontrolled activation of the pathway results in
virus, which are known to have altered or dimin- marked levels of C3a, which may a play a role in
ished MHC I expression. capillary leak syndromes and asthma, and with
C5a (cleavage product of activated C5) sepsis.
Overproduction of C5a has many detrimental
Humoral Factors effects including diminished neutrophil response,
consumptive coagulopathy, and increased mortal-
While cell-mediated immunity is critical in host ity (Klos et al. 2009). However, deficiencies in the
defenses, the initiation of the cellular response complement pathways are associated with patho-
which includes activation of complement and pro- logic diseases. Deficiency of C1 results in epi-
duction of immunoglobulins and cytokines is sodes of angiogenic edema. C3 deficiency is
equally crucial for effective immunologic associated with severe and often fatal pyogenic
response. infections. C2 and C4 deficiencies are associated
28 Sepsis 467
with lupus-like disease, and defects in the mem- this population remains unclear (Brocklehurst et
brane activation complex result in increased sus- al. 2011). Nonetheless, data from older
ceptibility to Neisseria (Chaplin 2010). populations suggest that significant benefit may
be obtained from IVIG administration. A 2007
meta-analysis found particular efficacy with
Immunoglobulins IgGAM and reported a 0.66 relative risk of mor-
tality following therapy (Kreymann et al. 2007).
Immunoglobulins are produced by B cells and the Nevertheless, like the neonatal study,
memory B cells (aka plasma cells) to effect a methodologic flaws in studies of IVIG have lim-
number of responses. These include opsonization, ited recommendations for its use and the 2012
a process where microbes are made more suscep- Surviving Sepsis campaign advised against its
tible to phagocytosis, complement activation, and use (Dellinger et al. 2013).
neutralization of toxins and virulence factors. IgA develops under the influence of TGF-beta
Prior to isotype switching and affinity maturation, and is particularly prevalent in the intestinal tract
only immunoglobulins IgM and IgD are pro- and tracheobronchial tree. It is secreted as a
duced. Of these, IgM is the most abundant and heterodimer with antiseptic properties and serves
accounts for more than 80% of circulating immu- as an antigenic barrier. IgA plays a critical role for
noglobulins and constitutes the major initial bacterial attachment and colonization thereby lim-
response to antigenic stimuli. B-cell interactions iting overgrowth and invasion. In addition to
with T cells and cytokines result in isotype excluding bacteria from the host, it plays a role
switching to the other major immunoglobulins in the prevention of epithelial injury and antigen
IgG, IgA, and IgE. presentation. Studies have demonstrated IgA’s
IgG is the predominant immunoglobulin or ability to counteract cholera toxin and inhibit bac-
antibody to act on viruses and bacteria. IgG terial motility and uptake of luminal antigens for
binds these organisms with its FAB (fragment presentation to lymphoid cells (Pabst 2012). It is
antigen-binding) portion, a part of the antibody thought that premature neonates in particular are
with a highly variable region, which allows bind- relatively deficient in IgA and therefore at higher
ing to a variety of foreign cells. The conserved risk of developing diseases such as necrotizing
portion of the antibody then binds the Fc receptor enterocolitis (NEC). Furthermore, analysis of
of neutrophils, monocytes, or macrophages. The breast milk indicates that TGF-beta may be impor-
FAB portions may also form immune complexes tant for stimulating production of IgA in infants
with autoantigens that can capture C3b and pre- (Ogawa et al. 2004).
cipitate activation of the complement system
(Lutz 2012).
Several human studies have evaluated the use Cytokines
of intravenous IgG (IVIG) as a therapeutic
modality. A recent Cochrane review of ten ran- Cytokines constitute an important arm of the
domized or semi-randomized controlled trials immunologic arsenal against foreign microbes.
inclusive of more than 300 neonates given They are produced by a wide variety of cells
IVIG for treatment of bacterial or fungal infec- including neutrophils, B cells, T cells, NK cells,
tions reported reductions in clinically suspected endothelial cells, and fibroblasts, to name a few.
sepsis and mortality. However, the overall meth- Cytokine effects may be pro- or anti-inflammatory
odology of the studies was poor, and as a result in nature. Pro-inflammatory cytokines include
the data do not clearly support IVIG as a benefi- TNF-alpha, IL-1, IL-6, IL-8, IL-11, and IL-18,
cial modality (Ohlsson and Lacy 2010, 2015). A whereas mediators such as IL-10 and TGF-beta
more recent study was unable to demonstrate any are anti-inflammatory. Other cytokines influence
benefit from the use of IVIG in suspected or immunogenic responses and include Il-2, IL-4,
proven neonatal sepsis; thus the use of IVIG in IL-12, and IL-13.
One of the early mediators of the infection by NK cells and T helper 1 cells following anti-
response is TNF-alpha, which has a number of genic stimulation. It is an important activator of
pro-inflammatory effects including enhanced leu- macrophages and increases cytokine production
kocyte adhesion, neutrophil response, production by antigen-presenting cells. It is known to poten-
of other inflammatory cytokines, priming of neu- tiate the efficacy of antibiotic therapy and to pro-
trophils and macrophages, up-regulation of mote intracellular production of free radicals to
thrombotic and fibrinolytic pathways, and stimu- eliminate bacteria (Smith et al. 2010). Interferon-
lation of nitric oxide release. LPS, peptidogly- gamma’s ability to control intracellular pathogens
cans, and other bacterial products stimulate its may be partially mediated by induction of induc-
release. As such, elevated levels of TNF-alpha ible nitric oxide synthase and further activation of
are often found in septic patients, and animal NK cells. This is particularly important in control-
models have demonstrated multi-organ dysfunc- ling fungal, mycobacterial, viral, and intracellular
tion following TNF-alpha therapy (Qiu et al. bacterial infections.
2011). Studies in murine models of peritonitis
and sepsis suggest that treatment with TNF-
alpha inhibitors may provide some benefit (Bojalil Bacterial Virulence
et al. 2013). While data remain limited, at least
one study demonstrates that anti-TNF alpha ther- Virulence is defined as a pathogen’s ability to
apy is associated with decreased ventilator days “enter into, replicate within, and persist in host
and ICU days among adults with severe sepsis sites that are inaccessible to commensal species”
(Rice et al. 2006). (Webb and Kahler 2008). The development of an
IL-1, another early cytokine associated with infection is relatively rare given the constant
the inflammatory response, is produced in bacterial-host interactions. This is due to both
response to LPS or TNF-alpha stimulation. IL-1 physical and immunologic barriers, as described
acts to induce IL-2, IL-6, and IL-8 and mediates earlier. Nonetheless just as the human has
the febrile response. There are two isoforms of many defensive strategies, bacteria have a
IL-1: membrane associated, or IL-1alpha, and variety of offensive strategies, some of which
membrane secreted, or IL-1 beta. Preliminary can be very effective. These offensive strategies
data demonstrate that administration of include bacterial adhesion, invasion of the
docosahexaenoic acid, an omega-3 fatty acid, is host, intra- and extracellular survival mecha-
associated with attenuated IL-1 beta response nisms, nutrient acquisition, damage to the
and modulation of sepsis in neonates (Lopez- host, motility, biofilm production, and regulation
Alarcon et al. 2012). IL-6, another pro-inflam- of virulence factors. While detailed description
matory cytokine and a key regulator of hepatic of each strategy is beyond the scope of this
acute phase reactants, stimulates B-cell differen- chapter, we will outline a few of the key
tiation and potentiates the development of cyto- mechanisms.
toxic T cells. Increased levels of IL-6 have been Bacterial adherence is critical in order for most
associated with the development of sepsis and pathogens to invade the host. A key to this inter-
may predict future sepsis (Wang et al. 2013). IL- action is the bacterial pili. Examples include
8, a pro-inflammatory cytokine produced by Enterobacteriaceae whose pili attach to d-Man-
monocytes, macrophages, T cells, endothelial nose receptor sites on epithelial cells, with some
cells, and platelets, is a potent chemotactic and species retracting their pili after binding. This
activating factor for neutrophils. In children with process drags the bacteria into the cell after bind-
sepsis, serum levels of IL-8 less than 220 pg/ml ing to surface receptors. Other bacterial species
predict survival with 94% accuracy at 28 days can expose host binding sites through breakdown
(Wong et al. 2008). of mucous following expression of sialidases.
Interferon-gamma represents another key pro- Sialidases have the added benefit of generating
inflammatory mediator that is produced primarily bacterial nutrients and can participate in biofilm
28 Sepsis 469
formation. Bacteria such as B. fragilis, V. cholera, Neonatal Defenses

P. aeruginosa, S. pneumoniae, H. influenzae, and
G. vaginalis are known to utilize sialidases (Lewis Relative to older children and adults, neonates
and Lewis 2012). Others such as S. aureus bind to have deficient immune systems, and infection is
fibronectin or other receptors on epithelial sur- responsible for more than 3,000 neonatal deaths
faces to facilitate adhesion. each day (Lawn et al. 2005).
Following bacterial adhesion to the cell, inva- Early-onset neonatal sepsis typically occurs
sion can occur via transcellular or paracellular within the first 24 h of life and is characterized
routes. Transcellular invasion may be initiated by vertical transmission of pathogens. The pre-
by the host or it may be induced by the bacteria. term infant is particularly susceptible to this form
Normally, host phagocytes will recognize bacte- of transmission because the host response is
ria by their opsonized components or by their dependent upon innate immunity, which is under-
PAMPS. This process elicits an immune developed in these children. The etiology of sep-
response that can result in bacterial killing. How- sis in this cohort can be multifactorial and
ever, some bacteria have developed methods includes preterm labor, prolonged rupture of
to avoid this cytotoxic response and elude membranes, maternal presence of group B strep-
epithelial cells and their receptors to gain tococci (GBS), and chorioamnionitis. Primary
entrance into the host. Listeria monocytogenes responsible pathogens include GBS (41%) and
uses E-cadherin and the heparin growth factor E. coli (17%) (Wynn and Levy 2010).
receptor to gain entry. Other bacteria such as N. Similar to older children, the first barriers to
meningitis, H. influenza, and P. aeruginosa pathogenic invasion are physical ones. In term or
use capsules to mask their immunogenic near-term infants, the skin has an additional pro-
properties. In contrast, others have developed tective layer provided by the vernix, something
mechanisms to evade activation of complement that may be absent in the preterm. The mucosa of
or Toll-like receptors 2/4 (Sarantis and the tracheobronchial tree and intestine provide
Grinstein 2012). Following phagocytosis, some additional barriers. However, host defense mech-
species have developed methods to inhibit anisms that are present in older children are either
maturation of the phagosome (L. pneumophilia, deficient or underdeveloped in the preterm. Exam-
B. abortus), escape from the cytotoxic effect of ples include relative surfactant deficiency and
the phagolysosome, or even survive within the increased goblet cell activity in the tracheobron-
phagosome (M. tuberculosis). Paracellular chial tree with subsequent airway irritation and
invasion is typically accompanied by dysfunc- poor mucous clearance. Furthermore, the intestine
tion of the epithelial barrier that can be precipi- is relatively deficient in IgA production,
tated by activation of the immune response or by defensins, commensal, or beneficial bacteria and
the direct cytopathic effects of some virulent has decreased activity of the migratory motor
strains. complex resulting in diminished peristalsis. This
The development of biofilms is another effec- leads to increased risk of overgrowth by patho-
tive method for bacteria to evade host defenses genic bacteria, adhesion to the epithelium, and
following invasion. A biofilm creates a protec- subsequent gut barrier dysfunction that can result
tive environment where colonies of bacteria can in the development of necrotizing enterocolitis in
thrive in an extracellular matrix that is resistant the premature infant.
to both host response and antibiotic therapy. The nature and diversity of bacterial coloniza-
Staphylococci and Pseudomonas species are tion also appear to play a critical role in intestinal
notorious for their ability to form biofilms and immunity in the preterm infant. Initial coloniza-
can be particularly problematic when they colo- tion of the gastrointestinal tract is random and is
nize foreign materials such as central venous dependent upon maternal vaginal flora at the time
catheters or endotracheal tubes (Webb and of delivery, degree of maturity, type of feeds
Kahler 2008). (breast milk vs. formula), and the local
Table 2 Age group-specific definitions for abnormal vital signs and leukocyte count
HR (beats/ RR (breaths/ SBP (mm WBC count (WBCs
Age group minute) minute) Hg) 103/mm)
Newborn (0 day to 1 week) >180 or <100 >50 <65 >34
Neonate (1 week to 1 month) >180 or <100 >40 <75 >19.5 or <5
Infant (1 month to 1 year) >180 or <90 >34 <100 >17.5 or <5
Toddler/preschool (2–5 years) >140 >22 <94 >15.5 or <6
School-age child (6–12 years) >130 >18 <105 >13.5 or <4.5
Adolescent/young adult (13 to >110 >14 <117 >11 or <4.5
<18 years)
Modified and used with permission from Goldstein et al. (2005)
HR heart rate, RR respiratory rate, SBP systolic blood pressure, WBC white blood cell
environment. Traditionally, it was thought that in the neonate is vulnerable to infection by organ-
most infants, the intestinal tract is first colonized isms for which maternal immunoglobulins are not
by facultative anaerobes such as Enterobac- protective. Furthermore, the risk of infection
teriaceae followed by anaerobes such as increases as the overall level of maternally derived
Bifidobacterium days to weeks later. However, immunoglobulins declines.
diminished gut barrier defenses in the preterm
are thought to allow for greater randomness in
colonization and less diverse colonization with Diagnosis
increased propensity for pathogenic species such
as Clostridia. Earlier in the chapter, we outlined definitions of
Although the risks are diminished compared to sepsis as well as current limitations to these terms.
preterm infants, full-term neonates still have rela- The progressive changes in size and physiology of
tive deficiencies in the adaptive immune response the neonate require modification of these defini-
that place them at risk for not only developing tions for different age groups. Abnormal values
sepsis but also for mounting an ineffective consist of those that fall two or more standard
response to sepsis. These include limited ability deviations from the norm (Table 2). Understand-
to increase the levels of circulating neutrophils ing what is abnormal for a given age will help one
following infection and decreased neutrophil define the presence or absence of sepsis, SIRS,
adhesion to the endothelium following activation. and/or organ dysfunction (Table 1).
This results in diminished neutrophil chemotaxis The premature neonate has markedly impaired
and migration to areas of inflammation. Neutro- host defense mechanisms compared to older chil-
phils are further limited by relative reductions in dren and often responds differently to infections.
opsonization secondary to deficiencies in B cells The presence of temperature instability, increased
and complement systems. This results in deficient frequency of apneic and/or bradycardic events,
phagocytosis that is further exacerbated by tachypnea, poor color, poor tone, lethargy, or
decreased free radical formation by the neutro- decreased perfusion should heighten concern for
phil. Unfortunately, despite the relative abun- sepsis. The likelihood of sepsis may be increased
dance of monocytes and macrophages, delays in by more than tenfold in the setting maternal fac-
cellular migration and overall function are simi- tors such as vaginal colonization with group
larly noted. B streptococcus or prolonged rupture of
The function of B cells and affinity maturation membranes.
are limited in the neonate. In fact, differentiation In addition to procalcitonin, CRP, and IL-8,
by somatic mutations into IgA- and IgG-produc- several other biochemical factors have been eval-
ing cells may only reach 25% of the adult rate by uated to improve the diagnosis of sepsis in the
60 weeks of life (Rogosch et al. 2012). Therefore, neonatal population. These include CD64, a
28 Sepsis 471
marker present on neutrophils, and IL-18, a cyto- However, care must be taken with the choice of
kine produced by activated macrophages. In pre- sedatives, as etomidate with its adrenal suppres-
liminary studies, both show promise as putative sive effects may increase mortality in the setting
markers of sepsis in the preterm infant, but overall of certain infections such as meningococcal sep-
utility remains unclear (Standage and Wong sis. Practice guidelines published by Brierley rec-
2011). Like most of the other factors that have ommend repeated boluses of 20 ml/kg of isotonic
been evaluated, they demonstrate insufficient pos- fluids until establishment of adequate perfusion or
itive predictive value. Nonetheless research is development of cardiorespiratory embarrassment
underway to stratify markers into groups for diag- (Brierley et al. 2009). Adequate resuscitation has
nostic purposes and for monitoring disease pro- been described as “capillary refill of 2 s, normal
gression/resolution. Wong and colleagues have blood pressure for age, normal pulses with no
developed a model using 12 candidate biomarkers differential between peripheral and central pulses,
known as “PERSEVERE” to identify children at warm extremities, urine output >1 ml/kg/h, and
risk of septic shock. This model promises to ben- normal mental status” (Dellinger et al. 2013). The
efit clinical decision-making, and further prospec- role of lactate clearance, which is clearly
tive studies are underway to validate its efficacy established in the adult literature, is unreliable in
(Wong et al. 2012). pediatrics and not currently recommended as a
Another method for diagnosing sepsis is the measurement of resuscitation.
PIRO system. PIRO, which comprises “Pre- Concomitant with the need for resuscitation is
disposing condition, the nature and extent of the the importance of source control. Current recom-
Insult or Infection, the magnitude of the host mendations are to start empiric antibiotic therapy
Response, the degree of concomitant Organ dys- within 1 h of the diagnosis of severe sepsis. When
function,” is a conceptional framework that has combined with adequate resuscitation, this
been developed to better assess sepsis and its out- approach may reduce mortality by up to 40%
comes (Opal 2005). In a prospective multicenter (Cruz et al. 2011). Ideally cultures should be
adult study, important variables for each of the obtained prior to initiation of therapy but should
PIRO components were identified and used to not delay administration of antibiotics. Choice of
determine factors predictive of mortality (Granja empiric antibiotic therapy is variable but should
et al. 2013). However, the PIRO system has not be broad enough to cover likely organisms based
yet been utilized in a prospective manner in the on the clinical picture and institutional anti-
pediatric population, and furthermore, it is more biogram. Once causative organisms are identified,
likely to be a prognostic rather than a diagnostic it is critically important to obtain source control
tool. by debriding, draining, or removing any identified
infective reservoir or source.
Aggressive resuscitation is necessary during
Treatment of Sepsis in Children the early phase of sepsis and may occasionally
require adjunctive use of inotropes. Randomized
A recent update to the surviving sepsis campaign controlled trials demonstrate marked reductions in
provides an up-to-date, data-driven, expert- mortality (40% vs. 12%) when children are
reviewed analysis of sepsis management, among actively resuscitated to obtain central venous oxy-
pediatric patients in resource-rich environments gen saturations greater than 70% (de Oliveira et al.
(Workman et al. 2016) (Table 3). 2008). Fluid resuscitation should occur even in
The cornerstone of initial management follow- normotensive children given unreliability of
ing the diagnosis of sepsis is resuscitation. This blood pressure readings and should continue
includes the use of supplemental oxygen and the until adequate tissue perfusion is achieved, or
administration of intravenous fluids. In the setting signs of volume overload become evident (e.g.,
of worsened pulmonary function or embarrass- hepatomegaly, rales, etc.). When fluid resuscita-
ment, endotracheal intubation may be necessary. tion fails to achieve these objectives, adjunctive
Table 3 Approach to pediatric sepsis (Adapted with Per- Table 3 (continued)

missions from Surviving Sepsis Campaign, 2012 Dellinger
d. C. difficile colitis should be treated with enteral
et al. 2013)
antibiotics if possible
A. Initial resuscitation C. Blood products
a. Respiratory distress/hypoxemia a. Use plasma to correct thrombotic purpura disorders,
i. Start with facemask oxygen, high flow nasal disseminated intravascular coagulation, secondary
cannula, or nasopharyngeal CPAP thrombotic microangiopathy, and thrombocytopenic
ii. Mechanical ventilation purpura
1. If possible resuscitate prior to intubation to b. Platelet therapy when:
limit cardiovascular instability i. 10,000/mm3 in absence of bleeding
b. Therapeutic end points ii. 20,000/mm3 with risk of bleeding
i. Capillary refill 2 s, normal blood pressure for iii. 50,000/mm3 for active bleeding, surgery, or
age, normal pulses with no differential between invasive procedures
peripheral an central pulses, warm extremities, urine c. Blood products
output >1 ml/kg/h, appropriate mental status i. If under-resuscitated and ScvO2 70% transfuse
ii. SCVO2 70%, cardiac index between 2.2 and to hemoglobin >10 g/dl
6.0 liter/min/m2 ii. If stable transfuse to keep hemoglobin >7 g/dL
c. Review and implement American College of D. Extracorporeal membrane oxygenation
Critical Care Medicine-pediatric life support guidelines
a. Refractory septic shock and respiratory failure
for resuscitation (Kissoon et al. 2010)
E. Ventilation strategies
i. Recognition of ill child (diminished perfusion,
altered mental status) a. Utilize lung protective strategies
1. Begin oxygen supplementation, and establish F. Glycemic control
IV/IO access a. Control hyperglycemia if 180 mg/dL
ii. Resuscitate b. Add glucose to insulin infusion in newborns and
1. Boluses of 20 ml/kg of isotonic saline or children
colloid until improved perfusion or development of rales G. Diuretic therapy
or hepatomegaly a. Following resolution of shock diuretics may be used
2. Correct hypoglycemia and hypocalcemia to prevent >10% total body weight fluid overload
3. Begin antibiotic therapy H. Deep vein thrombosis prophylaxis
iii. Fluid refractory shock a. No recommendations in prepubertal children with
1. Start inotropes severe sepsis
2. Obtain central intravenous access and establish I. Stress ulcer prophylaxis
a definitive airway (if needed) a. No recommendations in prepubertal children with
3. Cold shock: dopamine þ/ epinephrine severe sepsis
4. Warm shock: norepinephrine J. Nutrition
iv. Catecholamine resistant shock a. Provide enteral nutrition when possible
1. Hydrocortisone should be considered
v. Therapeutic goals
1. Attain normal mean arterial pressure or central inotrope or vasopressor therapy is indicated.
venous pressure for age Choice of therapy depends on the clinical state
2. ScvO2 70% of the patient, which may be “cold shock” char-
d. Evaluate for pneumothorax, pericardial tamponade,
acterized by low cardiac index (CI) with or with-
or adrenal crisis
B. Antibiotics
out presence of hypotension and “warm shock”
a. Empiric therapy should start within 1 h of characterized by high CI and hypotension.
identification of severe sepsis In children there are multiple options for ino-
i. When possible and without delaying antibiotic tropic support, and these include dopamine,
therapy attain cultures dobutamine, or (nor)epinephrine. Dopamine is
b. Clindamycin and anti-toxins should be considered generally used at moderate rates of infusion
for toxic shock syndromes
(5–9 μg/kg/min) for inotropic support and at
c. Obtain source control as soon as possible
higher rates (>9 μg/kg/min) for vasopressor
(continued)
effects. This commonly used drug works well
28 Sepsis 473
for fluid-resistant hypotensive shock with low in children with severe sepsis and 47–74% surviv-
systemic vascular resistance (SVR). Dobutamine ing to discharge (MacLaren et al. 2011).
offers inotropic support but may be associated Other therapies include the use of corticoste-
with hypotension. Norepinephrine, a first-line roids, which are particularly effective in children
medication in adults, is often reserved for children with adrenal insufficiency and the 25% with rela-
resistant to dopamine therapy. Other suggested tive insufficiency. The use of etomidate during
therapies include the agent terlipressin, a vaso- intubation is an increased risk factor of adrenal
pressin-like drug, and thyroid hormone. insufficiency, has been associated with increased
Terlipressin is a catecholamine receptor agonist mortality, and has prompted studies to evaluate
that has been evaluated in several series, but effi- the efficacy of steroid therapy following the use of
cacy has not yet been established; neither etomidate in septic patients (Chan et al. 2012).
terlipressin nor vasopressin has been incorporated However, randomized controlled trials have only
into current treatment algorithms. Children and demonstrated decreased vasopressor require-
adults with sepsis are known to be relatively thy- ments with no changes in ICU length of stay or
roid deficient, and it is though that hypothyroid- mortality (Payen et al. 2012). Recommendations
ism may diminish catecholamine responsiveness for steroid therapy have been limited to catechol-
to shock (Todd et al. 2012). Nonetheless, reports amine-resistant shock or suspected adrenal insuf-
on thyroid therapy for sepsis are lacking. ficiency with initial dosing recommendations of
The use of blood products during the resusci- 50 mg/m2/day.
tative phase is not clear, and optimal hemoglobin Previous sepsis guidelines had recommended
level in children with sepsis is unknown. The activated protein C for select adult populations
TRIPICU trial, a randomized non-inferiority clin- early on in the sepsis course. However, the
ical trial demonstrated that a hemoglobin of 7 g/dl PROWESS shock trial, which was published in
or greater would be safe in stabilized children with 2012 failed to demonstrate any benefit in more
sepsis (Lacroix et al. 2012). Another recent ran- than 1,600 patients with septic shock, and the drug
domized prospective trial assigned children to has now been withdrawn from the market (Ranieri
superior vena cava oxygen saturation (ScVO2) et al. 2012).
goal-directed therapy or control. Their protocol
for children with ScVO2 <70% started with crys-
talloid resuscitation of 10–20 ml/kg, inotropes Neonatal Septic Shock
and transfusion for hemoglobin <10 g/dl. The
use of this goal-directed therapy resulted in Compared to older children, neonates have a more
increased rates of resuscitation, inotropic support, variable presentation of shock. While assessment
and blood product use within the first 6 h of of shock still depends on assessment of pertinent
diagnosis. This also resulted in decreased 28-day hemodynamic, laboratory, and clinical factors >2
mortality (11% vs. 39%) and decreased incidence standard deviations from the mean, the unique
of multi-organ dysfunction (de Oliveira et al. physiology of these children including frequent
2008). As a result current recommendations presence of a patent ductus arteriosus and transi-
include blood transfusion for hemoglobin <10 g/ tion from fetal life require modification of man-
dl with ScVO2 <70% or any child with hemoglo- agement. Additional pathology not commonly
bin <7 g/dl. present in the older child may be confused with
Failure to respond to resuscitative and medica- septic shock such as cyanotic congenital heart
tion efforts may precipitate the need for extracor- disease or primary pulmonary hypertension of
poreal membrane oxygenation, particularly in the newborn.
those children with refractory respiratory failure. In some infants, evaluation of hemodynamic
Originally, sepsis was felt to be a contraindication resuscitation may be difficult. Very low birth
to ECMO given concerns for circuit contamina- weight (<1,500 g) infants and extremely low
tion. However, studies have demonstrated utility birth weight infants (<1,000 g) may have
unreliable mean arterial pressures (MAP) and dif- Cross-References

ficult assessment of capillary refill. In these
instances, ultrasound to measure SVC flow ▶ Fluid and Electrolyte Balance in Infants and
(>40 ml/kg/min) or to calculate a cardiac index Children
(>3.3/min/m2) may suffice to verify adequate ▶ Immunology and Immunodeficiencies in Children
resuscitation (Caresta et al. 2011). ▶ Necrotizing Enterocolitis
Like older children, prompt initiation of resus-
citation should occur following identification of
shock but with several distinct differences. First,
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Principles of Minimally Invasive
Surgery in Children 29
Steven Rothenberg and Samiksha Bansal
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Patient Selection and Preoperative Workup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478
Ergonomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Advances in Technology and Intraoperative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . 480
Technical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Risks and Benefits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
Evolution of Single Site Laparoscopic
Surgery (SILS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484
Role of Robotics in Pediatrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485
Abstract population. This chapter gives an overview of

The development of MIS has revolutionized the basics of MIS in infants and children
surgery over the last 30 years. MIS in pediatric
surgery was slow to advance but over the last 20 Keywords
years has rapidly expanded to include all major Minimal invasive surgery · Laparoscopy ·
pediatric surgical procedures in infants and chil- Thoracoscopy · Robotic surgery
dren. The benefits to the patient are great but
the technical hurdles are many because of
the varied size and physiology of this patient Introduction
The advent of minimally invasive surgery (MIS)

has been one of the greatest surgical develop-
S. Rothenberg (*) · S. Bansal
ments of the twentieth century. The first experi-
Department of Pediatric Surgery, Rocky Mountain mental laparoscopy was performed in an animal
Hospital for Children at Presbyterian/St. Luke’s, Denver, model by George Kelling, a German surgeon, in
CO, USA 1901 by the introduction of a visualizing scope in
e-mail: steverberg@aol.com; foldervip@yahoo.com

https://doi.org/10.1007/978-3-662-43588-5_31
478 S. Rothenberg and S. Bansal
the peritoneum of a dog. It was followed by first diseases, cavitary lesions, bullous disease, seques-
clinical description of laparoscopy and trations, lobar emphysema, congenital
thoracoscopy in humans by Jacobsen in 1911. adenomatoid malformations, and neoplasms. It
These initial attempts were greatly assisted by also allows excellent excess and visualization for
development of fiber optics, electronic CO2 insuf- biopsy and resection of various mediastinal
flators, and electronic miniature cameras, among masses such as lymph nodes, thymic lesions,
others, which gradually led to the modern laparo- cystic hygromas, foregut duplications, gangli-
scopic era. Today, the benefits of MIS are well oneuromas, and neuroblastomas. In recent years,
recognized including, but not limited to, the sur- its use has been extended to more advanced
geon’s ability to perform major intracavitary pro- thoracoscopic procedures like repair of diaphrag-
cedures with significantly less pain and morbidity matic hernia, repair of tracheoesophageal fistula,
than associated with traditional open surgery. ligation of patent ductus arteriosus, and division
While MIS techniques were embraced by adult of vascular rings. Furthermore, advanced laparo-
general surgeons soon after the first laparoscopic scopic and thoracoscopic skills combined with the
cholecystectomy was performed in 1987 by availability of appropriately sized instruments
Philippe Mouret, its utilization in pediatric com- have made these minimally invasive procedures
munity has progressed much more slowly. This feasible for neonates and infants, even those
was due to poorly adaptable equipment for use in weighing less than 5 kg.
children in earlier years, combined with the tech-
nical complexity of operating in small spaces in
most pediatric surgical patients. Additionally, it Basic Principles
was initially difficult to prove whether infants
undergoing laparoscopy, who are unable to artic- The general principles for MIS include the appro-
ulate their distress, have less postoperative dis- priate patient selection, operating surgeon’s com-
comfort and stress than those undergoing fort with the procedure involved, knowledge of
conventional surgical procedures. However, over available technology, and the appropriate
the last decade, many of these initial obstacles intraoperative management. Indication and nature
have been overcome with increasing surgeon’s of the procedure, port sites, and alternate
expertise, marked improvements in video equip- approaches along with the risks and benefits for
ment, and instrumentation. Laparoscopic proce- the surgery should be discussed with the parents
dures that can now be performed safely include, and patients, if old enough.
but are not limited to, pyloromyotomy, appendec-
tomy, fundoplication with or without gastrostomy
for gastroesophageal reflux disease, duodenal Patient Selection and Preoperative
atresia repair, Ladd’s procedure for malrotation, Workup
colonic pull-through for Hirschsprung’s disease
or anorectal malformation, cholecystectomy, Prior to any laparoscopic or thoracoscopic pro-
Kasai procedure for biliary atresia, and cedure, all children should undergo preoperative
choledochal cyst excision. The scope of evaluation, same as those required prior to any
thoracoscopy in the pediatric population is also open surgical procedure with special attention to
expanding with refinements in technology and their cardiorespiratory status. There are no abso-
technique. Initially used primarily for decortica- lute contraindications for performing laparo-
tions in tuberculosis, empyema, and diagnostic scopic or thoracoscopic procedures in children.
intrathoracic lesions, thoracoscopy is now used However, when the patient is hemodynamically
extensively for lung biopsy and wedge resection unstable, is not on conventional ventilation, can-
in patients with interstitial lung disease (ILD) and not be safely transported to the operating suite,
metastatic lesions. More extensive pulmonary or is of extremely low birth weight, the pros and
resections, including segmentectomy and lobec- cons of an MIS approach must be considered.
tomy, have also been performed for infectious Relative contraindications for MIS approaches
29 Principles of Minimally Invasive Surgery in Children 479
include difficulty to achieve pneumoperitoneum MIS are absence of direct three-dimensional

or pneumothorax and adhesions from previous vision, loss of depth perception, loss of peripheral
surgery precluding optimum visualization. With vision, loss of tactile feedback, fulcrum effect
increasing surgical expertise with MIS, proce- with tremor enhancement, and decoupling of the
dures which were considered impossible in visual and motor axes. Furthermore, it has been
these difficult situations and in small neonates observed that the operating room surgeon
only a few years ago are now routinely assumes a more static posture during MIS com-
performed at many centers. pared to traditional open approach, potentially
For most thoracoscopic procedures, similar causing disabling and harmful effects. To over-
principles apply for the preoperative work-up. come these factors, it is advisable to follow few
Most intrathoracic lesions require routine radio- basic rules of laparoscopy:
graphs as well as computed tomographic scan or
magnetic resonance imaging. A thin-cut, high- • Choose an ergonomically convenient operat-
resolution CT scan is especially helpful in evalu- ing position for yourself.
ating patients with ILD or infectious conditions to • Adjust the operating table height to keep
identify the optimal site for biopsy. Intraoperative instruments at your elbow level.
endoscopic ultrasound is an emerging technology • Adjust the monitor image at or within 25 opti-
which can prove to be extremely helpful in cases mal degrees below the horizontal plane of the
with deeper small lesions and can potentially eye to avoid neck strain.
compensate for the lack of tactile sensation. Pre- • Second monitors should be used as necessary
operative imaging should also be used to deter- for assistants.
mine patient position and optimal port placement • Port positioning is dictated by the individual
for both laparoscopy and thoracoscopy. surgeon but should follow the rule of triangula-
tion (Fig. 1) to allow the instruments to work at
60–90 angle with the target tissue without inter-
Ergonomics ference with each other and the abdominal wall.
• Adjust manipulation angle ranging from 45 to
The importance of ergonomics in the setting of 75 with equal azimuth angles when possible.
MIS cannot be overemphasized. Ergonomic inte- • Arm should be slightly abducted, retroverted,
gration and suitable laparoscopic operating room and with inward rotation at shoulder level. The
environment are essential to improve efficiency, elbow should be bent at about 90–120 .
safety, and comfort for the operating team. Few of • Last but not the least, do not hesitate to convert
the challenges faced by the training surgeons in to open procedure when needed.
Fig. 1 Ergonomics,
principle of triangulation in
laparoscopy Target organ
Retracting port
Operating port
Ta
Optical port
Advances in Technology children in the 1990s was difficult and potentially

and Intraoperative Considerations life threatening due to high insufflation pressures
and problems with overdistension. With the advent
Besides the surgical skills of the operating sur- of highly sensitive neonatal insufflators releasing
geon, choosing correct instruments and settings small puffs of air over shorter period of time, the
plays a crucial role in successfully performing any issue of overinsufflation is resolved. These units
MIS procedure. In earlier years, most of the cen- can flow at levels of 1/l/min or less and can also
ters were using the equipment and instrumenta- heat the CO2 helping prevent unwanted cooling of
tion designed for adults and large children. smaller patients. The process of creating the ideal
Instruments were either available in 5 or 10 mm instrument for children less than 5 kg took many
diameter or were too long (30–35 cm), making it years to refine and is still in evolution.
difficult to manipulate safely in smaller spaces in One should try to use the best technology avail-
young children and neonates. As more pediatric able if feasible, especially while performing MIS in
surgeons began performing minimally invasive neonates in confined spaces, including high-
surgery in infants, manufacturers developed an resolution cameras, 10–15 magnification on the
interest in development of minilaparoscopy optical system to reduce the visual challenge, and
(3 mm and 5 mm) instruments. Additionally, tele- use of modern CO2 insufflators. Operations should
scopes have also evolved in quality, length, diam- be performed using specially designed 3 mm wide,
eter, and angulation. Originally, only a long 18–20 cm long instrumentation for children and
(35 cm) 10 mm scope with 0 angulation was smaller-diameter (4.0 mm, 2.7 mm) telescopes.
available, which now is available in much smaller Insufflation pressures ranging between 8 and
diameters and length. The advent of greater scope 15 mmHg and flow rates of 1–3 l/min are
angulation up to 70 can be of great asset in the recommended for laparoscopy and should be
performance of more advanced procedures. Most adjusted based on patient’s age, size, and
of the procedures in children can be performed comorbidities. Valved cannulas of the appropriate
using short 20 cm, 4–5 mm, 30 , and 45 tele- size (3 mm, 4 mm, 5 mm) should be used to prevent
scopes. Some like using a 70 angulation scope to CO2 escape. It is often difficult to keep these trocars,
evaluate the presence of contralateral inguinal especially the reusable ones without screws or
hernia in a child while performing an open repair ridges, from sliding in and out because of the thin
for the known unilateral defect. Other major abdominal wall of most infants and small children.
advancements in the field include availability of The trocar can be stabilized by placing a small
improved energy sources for vessel and tissue section of rubber or silastic catheter on the shaft of
sealing. These devices use radio-frequency (RF), the trocar at the desired height. This rubber “stop”
bipolar, or ultrasonic technology and can safely can then be sutured to the skin to prevent slippage
seal and divide vessels up to 5 mm or cut across (Fig. 2). Again, pediatric insufflators should be
lung or liver with relatively hemostatic and air- used, if available, to avoid problems with accidental
tight seals. These devices have played an espe- overinsufflation and distension and related compli-
cially important role in the advancements of MIS cations. All patients should be carefully monitored
procedures in children eliminating the need for intraoperatively by electrocardiogram, pulse oxim-
suture ligation and division, a technically eter, and end tidal CO2 monitor.
demanding task especially in these smaller For patients undergoing thoracoscopic proce-
patients. However, these devices are still not dures, single lung ventilation may be desired in
made in smaller sizes for neonatal MIS, and so some cases. This can be achieved in most
their use in this patient population can be difficult. instances by selective intubation on the opposite
Probably of greatest import was the evolution side. Occasionally a bronchial blocker or a double
of the CO2 insufflator. Use of less sensitive adult endoluminal endotracheal tube can be used to
insufflators to perform MIS procedures in young achieve collapse of the lung. However, these
Nurse Monitor
Monitor
Lat Decub Head
Assist Surgeon
Fig. 3 Operating room setup for thoracoscopic lung

resection
place between all the supporting teams prior to

starting the surgery for optimal intraoperative
environment and safe patient outcomes. Preoper-
ative bladder decompression can frequently be
Fig. 2 Stabilizing 3 mm trocar with stitch in a small child obtained by manual pressure in children after
they are anesthetized. Foley catheterization
procedures require more technical expertise by the should be considered for procedures involving
anesthesiologist to place fast and effectively, and pelvic dissection including laparoscopic pull-
the smallest double lumen is a 24 Fr and cannot be through and imperforate anus in anticipation of a
used in smaller patients. We have found the main prolonged operation.
stem intubation to be the most reproducible and Patient positioning is of paramount importance
efficient technique. and should be guided by the nature of the proce-
In many patients CO2 insufflation alone is dure. In general, gravity can be used to assist with
enough to give adequate access. The patients can the exposure of the desired area. For most upper
have a standard tracheal intubation, and a low-flow gastrointestinal procedures, patient is positioned
(1 L/min), low-pressure (4–6 mmHg) CO2 insuffla- at the end of the table with surgeon standing
tion can be used to assist with collapse of the between the patient legs with patient in reverse
involved lung. Pressures and flow can then gradu- Trendelenburg position (Fig. 4). For lower
ally be adjusted to improve visualization depending abdominal surgeries, the monitors are placed at
on patient’s physiologic status. This is the preferred the bottom of the table with the surgeon standing
technique for mediastinal masses, esophageal atresia at the right or left side of the table. For many
repair, and other non-lung parenchymal procedures. procedures in small infants, such as pull-through,
Operating room setup for thoracoscopy is the infant can be placed crosswise on the table
shown in Fig. 3. Problems with overinflation and giving the surgeon the ability to stand at the
associated hemodynamic consequences have child’s head or feet depending on which part of
been minimized by optimal anesthetic manage- the procedure is being performed.
ment and availability of modern CO2 insufflators. For thoracoscopic procedures, positioning to
allow gravity to act as a retractor is the key for
obtaining good exposure for the procedure. For
Technical Considerations anterior mediastinal operations, the patient is
placed supine with the operative side elevated
General technical principles for any MIS proce- 30–40 to allow access for trocar placement. A
dure remain the same as open surgery. Communi- modified prone positioning provides a good expo-
cation, describing the procedure, should take sure for posterior mediastinal masses, esophageal
Fig. 4 Operating room

setup for upper abdominal Assist Monitor
laparoscopic procedures
Surgeon
Monitor
Supine at end of bed Head
Nurse
largest port. Alternatively, a cutdown or Hassan

approach can be used depending on surgeon’s
comfort and familiarity with the technique. In
younger children, often there is an umbilical her-
nia, and the initial trocar can safely be introduced
through the hernia defect. Special care should be
exercised when inserting ports in the pliable, thin
abdominal wall of infants and young children to
avoid inadvertent injury to underlying viscera. For
complex procedures the anesthesiologist should
ensure that the patient is adequately paralyzed or
relaxed to help with intra-abdominal visualiza-
tion. For 3 mm ports, stab incision technique can
be used. A stab incision is made in the skin and
peritoneum to create a tract using no. 11 Bard-
Parker blade followed by insertion of 3 mm can-
nula in the same tract. Occasionally, instruments
Fig. 5 Port placement for Nissen fundoplication can be placed directly through the stab incision
tracts, which is ideal for assisting or retracting
instruments. This technique is also helpful during
atresias, and other posterior structures. For decor- decortication where direct insertion of instrument
tications, lung biopsy, and lobectomy, a lateral is helpful in removing the inflammatory peel and
decubitus position is optimal. for introduction of staplers and retrieval bags
Ports should be widely placed to allow ade- when the space is limited. At the conclusion of
quate working space and should especially be the procedure, it is advisable to close the fascia for
planned wisely in smaller neonates. Port place- all ports 5 mm and above. For 3 mm ports, usually
ment for fundoplication and thoracoscopic pro- only the skin needs to be closed but hernias have
cedures is shown in Figs. 5 and 6. In general, been reported at these smaller sites. One should be
camera port should be in the middle and “above” careful to ensure omentum is not pulled into the
with two working ports on either side, directed tract with removal of the ports.
toward the area of interest. The optimal angle for To reiterate, basic operative principles, similar
the two working ports in relation to the point of to open surgery, should be followed to perform any
greatest dissection is 90 , as this improves the MIS procedure and knowledge of anatomical
ability to perform complex maneuvers such as planes and ability to visualize the same structures
suturing. Insufflation is obtained through insertion in a different orientation is the key to success.
of the Veress needle in the umbilicus for laparos- Additionally, importance of familiarity with instru-
copy which is followed by placement of the ments and basic operative setup cannot be
Fig. 6 Port placement for

thoracoscopic lung
resection: think of a
baseball diamond: telescope
should be at the home base
with two working ports at
first and third bases and
target organ at the
second base
overemphasized. In the incidences with instrument Average complication rate varies based on the
or equipment malfunction, surgeon should be able experience of the operating surgeon and has been
to troubleshoot or use an alternative plan. between 1% and 3% in our experience. Complica-
tions unique to a MIS approach include trocar
related-injuries, trocar site bleeding or hernia, and
Risks and Benefits wound infection but are extremely rare. Most of
the intraoperative complications can be managed
Laparoscopic procedures in neonates are not laparoscopically but depend on the technical
only safe and effective but result in significantly expertise and comfort level of the operating sur-
decreased morbidity with an earlier return of geon. There is a steep learning curve for MIS in
gastrointestinal function, quicker recovery, neonates, and surgeon should be prepared to con-
improved cosmesis, and reduced overall hospital vert to an open procedure when needed. Conver-
cost. It causes reduced physiologic stress and sion rate to open in expert hands is less than 2% but
postoperative pain leading to fewer pulmonary conversion to open to complete a procedure safely
complications. This includes improved rates of should not be considered to be a complication.
extubation, shortened postoperative ICU stays, Significant hemodynamic changes may occur
fewer days of supplemental oxygen, and following intraperitoneal or intrathoracic insuffla-
decreased postoperative pneumonias. Pulmo- tion and change of patient position during laparos-
nary benefits afforded by minimally invasive copy or thoracoscopy, especially in children with
approach play a significantly greater role in neo- congenital heart disorders. Use of MIS procedures
nates with congenital cardiac disease where the in this population is controversial secondary to
ability to avoid respiratory complications has a potentially deleterious effects of the
dramatic benefit. For some procedures, like pneumoperitoneum on cardiac index and pulmo-
fundoplication, operative times are much shorter nary vascular resistance on an already
due to improved operative visibility. Multiple compromised cardiopulmonary system, leading
procedures can be performed simultaneously to cardiopulmonary instability. However, mini-
with minimal additional morbidity. The long- mally invasive procedures can be safely performed
term benefit of decreased adhesion formation in these high-risk patients with preoperative opti-
and scar tissue may be the strongest argument mization of hemodynamic status and appropriate
for pursuing this approach in neonates. perioperative monitoring and care, with excellent
outcomes. A multidisciplinary approach should be other. Although most surgeons prefer to have
utilized which includes the availability of an expe- these commercially available SILS-specific
rienced cardiac anesthesia team, skilled laparo- instrumentations, it can be performed by passage
scopic surgeon to avoid long operative times, of multiple conventional laparoscopic instru-
keeping insufflation pressures to a minimum ments through a single umbilical skin incision
required, and effective communication between or using the yin-yang incision described by Dutta
the team members. All of these components are in 2009. This is done by making a transverse or
critical to optimize surgical outcomes in these vul- vertical incision through the umbilical skin
nerable children. extending to the very edge of the umbilical
ring. The incision is carried through the center
of the umbilical stalk, and each half of the stalk is
Evolution of Single Site Laparoscopic detached from the underlying fascia and then
Surgery (SILS) deflected around the umbilical ring to either
side to create a yin-yang appearance. It is advis-
Constant strive for improvement led the surgeons able to use the instruments with low-profile back
to develop techniques like natural orifice trans- ends to avoid instrument collision at the abdom-
luminal endoscopic surgery (NOTES) in which inal wall. An additional 3 mm port can be added
the access to the peritoneum is achieved by passing which is placed through a separate stab wound
an endoscope through a natural orifice (mouth or incision either at the pelvic brim or in the mid-
vagina), and the entire procedure is performed via epigastrium depending on the area of pathology.
multichannel endoscopes. However, considering Use of this additional single-port maintains the
this approach, one has to weigh the risk of visceral triangulation at the area of interest without
perforation needed for peritoneal cavity access compromising the cosmetic benefit of the SILS.
vs. the cosmetic benefit offered by such technique. Surgeons considering SILS should first get
These concerns led to the evolution of single-site sound with conventional MIS technique. A sim-
laparoscopic surgery, also known as LESS (laparo- ple procedure with relatively easy dissection like
scopic single-site surgery), SAS (single-access site appendectomy is a recommended SILS to start
surgery), and SPA (single-port access surgery). with such practice. Similar to any other proce-
This technique involves passage of multiple lapa- dure, a good assistant well versed with camera
roscopic instruments through a single umbilical manipulation and coordination is an essential
incision either through a single-port device with tool to complete the procedures using SILS
multiple conduits or through multiple closely technique.
spaced ports. Since its introduction, it has become Although this technique has generated a lot of
the new paradigm in the field of MIS that promises excitement, true benefit of SILS seems to be
virtually scarless procedures. SILS has been well mostly cosmetic when compared with the stan-
described in adults for appendectomy, cholecystec- dard laparoscopic surgery. Additionally, there are
tomy, nephrectomy, splenectomy, and adrenalec- many limitations to this technique. Larger single
tomy and for appendectomy, cholecystectomy, umbilical incisions may be associated with more
and splenectomy in the pediatric literature. pain, and it carries a higher risk for incisional
Basic principles for the SILS remain the same hernias, and the technique requires expensive
as the MIS techniques. However, it frequently instrumentation specifically designed for SILS.
requires the use of flexible, high dexterity instru- Use of conventional laparoscopic instruments,
ments with additional degrees of freedom and a with single-incision multiple-port technique to
multichannel single-port device. The instrument reduce the cost, has its inherent difficulties of
shafts are typically crossed to achieve the trian- having the camera and instruments all operating
gulation needed to perform these surgeries and to in line, causing instrument dueling and very little
avoid the constant instrument collision with each triangulation.
Role of Robotics in Pediatrics ▶ Congenital Malformations of the Lung

With the advent of da Vinci robot, adult surgeons ▶ Fast-Track Pediatric Surgery
have readily incorporated this surgical technique ▶ Hirschsprung’s Disease
into their practices. However, use of robot-assisted ▶ Infantile Hypertrophic Pyloric Stenosis
laparoscopic surgery (RALS) in the pediatric world ▶ Innovations in Minimally Invasive Surgery in
has been looked upon with skepticism, and only a Children
few centers are utilizing this approach, especially for
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Innovations in Minimally Invasive
Surgery in Children 30
Todd A. Ponsky and Gavin A. Falk
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
From Open to Laparoscopic in Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Laparoscopes and Hand Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Trocars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Insufflators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Neonatal Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Needlescopic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Laparoscopic Inguinal Hernia Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Hiding the Scars . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Single-Incision Laparoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Single-Incision Laparoscopic Techniques in Pediatric Patients . . . . . . . . . . . . . . . . . . . . . . . . 492
Single-Port Laparoscopic Cholecystectomy: Considerations in Children . . . . . . . . . . . . . 492
“22” Laparoscopic Cholecystectomy: Scarless Surgery in Children . . . . . . . . . . . . . . . . . 493
Single-Incision Laparoscopic Gastrostomy: Utilizing an Operative Hysteroscope . . . . 494
Appendectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
Natural Orifice Endoluminal Surgery (NOTES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
Other Innovations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Robotic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Technical Benefits of Robotic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Technical Limitations of Robotic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498
Patient Benefits of Robotic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Learning Curve . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Telemedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
Gastric Stimulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
T. A. Ponsky (*)
Division of Pediatric Surgery, Akron Children’s Hospital,
Akron, OH, USA
e-mail: TPonsky@chmca.org; tponsky@gmail.com
G. A. Falk
Division of Pediatric Surgery, Miami Children’s Hospital,
Miami, FL, USA
e-mail: gavin.falk@mch.com; gavfalk@gmail.com

https://doi.org/10.1007/978-3-662-43588-5_32
488 T. A. Ponsky and G. A. Falk

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 502
This chapter provides an overview of recent
innovations in pediatric minimally invasive The first known laparoscopic procedure was in
surgery that have enabled pediatric surgeons 1901 when Kelling performed a celioscopy
to operate safely on their smallest patients using a cystoscope on a dog. In 1985, Erich
through tiny incisions. The development of Muhe described the first laparoscopic cholecys-
size appropriate laparoscopes and instru- tectomy, which, within a decade, became the stan-
ments has been key in the development of dard of care for the treatment of cholecystitis and
this specialty. We also discuss NOTES, tele- symptomatic cholelithiasis. Since then laparos-
medicine, and robotic surgery in our pediatric copy has developed dramatically, and now surgi-
population. cal procedures that could only be achieved with
The numerous MIS techniques, originally large painful incisions are possible by minimally
used in the adult population, have been suc- invasive techniques.
cessfully applied to our pediatric patients. While initially slow to be widely accepted and
MIS has become routine for the treatment of adopted by pediatric surgeons because of the large
many pediatric surgical disease processes, instruments, laparoscopy has become the standard
due to the numerous benefits these techni- of care for many procedures. Pediatric surgeons
ques confer on the patient: decreased wound continue to look for innovative technologies and
complications, shorter length of stay, and methods to perform their operations while both
improved postoperative pain. Inherent in the minimizing incisions and maximizing patient safety.
application of these complex techniques to This chapter provides an overview of recent
infants and children are many risks due to innovations in pediatric minimally invasive sur-
the size of these patients. Pediatric surgeons gery that have enabled pediatric surgeons to oper-
must be aware and understand these risks if ate safely on their smallest patients through tiny
they are to successfully and safely incisions.
practice MIS.
MIS will continue to develop as long
as industry is committed to developing From Open to Laparoscopic in Pediatric
pediatric equipment to provide better Surgery
care for our patients. Surgical training must
continue to evolve, to ensure that the next Laparoscopic surgery brought in an era of mini-
generation of surgeons is adequately mally invasive surgery, affording benefits such as
trained in these complex techniques. The decreased wound complications, shorter length of
future of pediatric MIS is exciting for our stay, and improved postoperative pain. While the
patients and indeed the specialty of pediatric benefits are certainly realized in the pediatric pop-
surgery. ulation, adopting laparoscopic techniques for
infants and children comes with a unique set of
Keywords costs and risks.
Minimally invasive surgery · Inguinal hernias · First, the size of the patient dictates the size of
Laparoscopy · NOTES · Telemedicine · the working space, and the relationship is not a
Robotic surgery linear one (Blinman and Ponsky 2012). For
30 Innovations in Minimally Invasive Surgery in Children 489
example, a pediatric patient one half as tall as an for adult patients. These included 10 mm laparo-
adult patient leaves only one eighth of the working scopes and cumbersome (5–10 mm) laparoscopic
volume in either the chest or abdomen (Blinman instruments, which made operating in the confines
and Ponsky 2012). The same principle extends to of a pediatric abdominal cavity very difficult.
the increased risks of electrical energy injury from Eventually industry took note and developed
use of electrosurgical instruments, as well as smaller scopes allowing for the progression of
increased proportion of non-visible space due to pediatric minimally invasive surgery (MIS). In the
the close proximity of the laparoscopic or mid-1990s, smaller instruments (2–3 mm) were
thoracoscopic camera. developed, allowing pediatric surgeons to work
Second, physiologic changes related to laparo- more safely and with greater ease in the limited
scopic surgery also vary nonlinearly, often space of the pediatric abdominal cavity.
demanding exponential increases in attention to
physiologic changes as size decreases. In particu-
lar, pediatric patients are at increased risk of Trocars
developing hypothermia and hypercarbia from
laparoscopic techniques. The CO2 generally used In addition to the need for 5 mm or smaller trocars,
for insufflation, which is relatively cool and dry, pediatric patients have other unique characteristics
leads to a large fraction of an infant’s metabolic that require special attention. The working space
rate being consumed by heat production, without inside the pediatric peritoneal cavity is much
a sufficient compensatory mechanism, which can smaller than in adults, and their abdominal wall
result in subsequent hypothermia. Therefore, much thinner. This can result in trocars being fre-
humidification of the gas and diligent adherence quently dislodged during the case. The advent of
to reducing evaporative losses by minimizing radial expanding trocars or trocars with anchoring
leakage around the laparoscopic instruments is capabilities have somewhat mitigated this problem.
paramount, particularly for long cases. With Furthermore, these newer access systems offer
appropriate humidification of the CO2 used for cause less tissue trauma and a tighter fascial seal
insufflation, the hypothermic side effect on an (Lam et al. 2000), which helps minimize tissue
infant of the laparoscopic technique is virtually damage in small children with delicate tissues and
eliminated. a thin abdominal wall. In the very small patient, in
The reluctance of pediatric surgeons to adopt which 3 mm instruments are used, many surgeons
the minimally invasive techniques being used and forgo the use of trocars and place the instruments
developed by their adult colleagues was mostly directly through 3 mm stab incisions.
due to technical factors. The equipment that had
been developed for adults was not simply trans-
ferable to the pediatric patient. Innovation which Insufflators
led to the development of four key changes in
equipment allowed the meteoric rise and wide- One of the major hurdles to the developmental
spread adoption of minimally invasive techniques pediatric laparoscopy was the standard adult
in pediatric surgery, namely, laparoscopes, hand insufflators. Recently, pediatric and even neonatal
instruments, trocars, and insufflation devices. insufflators were developed. In contrast to adult
insufflators, neonatal insufflators deliver CO2 in
small, controlled puffs. This technology reduced
Laparoscopes and Hand Instruments the risk of over-insufflation that was often associ-
ated with using the oversized adult insufflators in
In the early 1990s when a few pediatric surgeons small children. Over-insufflation can often be
began performing laparoscopy on small children, accompanied by a significant increase in
they had no choice but to use instruments designed end-tidal CO2, or the measurement of the amount
of CO2 in the expired air. The anesthesiologist While the hidden scar of single-incision surgery
must adjust for this, as over-insufflation can lead is desirable, its technical difficulty along with the
to significant pulmonary complications in already potential increase in postoperative pain has forced
fragile neonates (Kalfa et al. 2005). Close partner- surgeons to seek other options. The 2–3 mm
ship with pediatric-trained anesthesiologists to needlescopic instruments have been available for
ensure that insufflation pressures are kept low many years, but many surgeons felt they were too
(8–10 mmHg) is of key importance in being able flimsy for use in larger patients. However, with the
to safely perform laparoscopic surgery in even the increased emphasis on cosmesis and hiding the
smallest of infants (Blinman and Ponsky 2012; scars, combined with development of stronger,
Lam et al. 2000; Kalfa et al. 2005; Fujimoto more versatile, minilaparoscopic instruments,
et al. 1999). many surgeons have added these to their toolbox
While much has been published detailing the even for larger patients. A 5 mm trocar and instru-
tools available in the pediatric surgeon’s toolbox ment used to be the standard-sized instrument used
(Blinman and Ponsky 2012; Lam et al. 2000; in a cholecystectomy, yet current reports show it can
Krpata and Ponsky 2011, 2013; Ponsky 2009), be done safely with 2 and 3 mm instruments (Frank-
the area needs continued attention from industry lin et al. 2006; Tagaya et al. 2007; Lee et al. 2005).
to allow full realization of minimally invasive While the advantage of a 3 mm scar over a 5 mm
techniques in the pediatric population. In particu- scar may not be readily apparent, there are two
lar, development needs to focus on designing main advantages: while 5 mm scars are smaller
stiffer 2 and 3 mm instruments, ultrasonographic than 10 mm scars, a 3 mm scar is essentially invis-
instruments in pediatric sizes, and improving ible, making it almost impossible to notice that the
optics for smaller cameras. patient underwent a major operation. The second
advantage is that with 3 mm laparoscopy, the inser-
tion of instruments is essentially percutaneous,
Neonatal Laparoscopy meaning that muscle fibers are spread rather than
cut, and this helps to minimize pain.
The development of smaller laparoscopic com- In addition to the development of more sturdy,
bined with the development of pediatric surgeons’ versatile minilaparoscopic instruments, there are
skills enabled operations to be performed on many new devices that have recently entered the
smaller and smaller children. When these laparo- marketplace or are in the pipeline. Companies are
scopic techniques were applied to infants 28 days also working with different materials to develop
old or less, and weighing up to 5,000 g, the sub- novel 2–3 mm instruments with the strength and
specialty of neonatal laparoscopy was created. functionality of the currently available 5 mm
The laparoscopic and thoracoscopic approaches instruments.
to many neonatal surgical problems have been
successfully carried out.
Laparoscopic Inguinal Hernia Repair
Needlescopic Surgery The laparoscopic inguinal hernia repair

deserves special attention as it has recently
As with many fields in surgery, necessity has been emerged as a very popular technique. Laparo-
the driving force of innovation. With the avail- scopic repair of inguinal hernias offers many
ability of 2 or 3 mm laparoscopic instruments, proposed and proven advantages over the open
surgeons can now operate with even smaller inci- repair. While some studies report improved
sions on even smaller children (Krpata and postoperative pain and cosmesis, and decreased
Ponsky 2013). The use of these “needle-sized” risk of recurrence, the current authors feel that
instruments is frequently called either the primary benefit is the ease of repair in diffi-
needlescopic surgery or minilaparoscopy. cult hernias such as a recurrent hernia, meaning
less chance of injury to the floor, and “no-touch” less pain, shorter hospital stays, and improved
of the cord structures. Additionally, in the case cosmesis, there was still a drive for advancement.
of possible bilateral inguinal hernias, laparo- This led to the advent of single-incision laparo-
scopic repair permits exploration of the contra- scopic surgery as an approach to limit the number
lateral groin without an additional incision. A of incisions required to complete laparoscopic
high percentage of open inguinal hernia repair procedures. This technique involves placing all
recurrences are direct hernias, which are either of the instruments through a single small incision
missed at initial repair or caused by the open hidden within the umbilicus.
hernia repair. The laparoscopic repair should This minimization of incision quantity is
eliminate this frequent cause of open hernia achieved in one of two ways. First, multiple com-
repair recurrence. panies have developed single, multiport trocars
There are two basic laparoscopic approaches for that have three or four working ports for instru-
inguinal hernia repair – intracorporeal and extra- ments (Blinman and Ponsky 2012; Krpata and
corporeal. The authors use the percutaneous, extra- Ponsky 2011; Kalfa et al. 2005). These trocars
corporeal approach, which involves passing a require a 2 cm incision in the skin and fascia,
circumferential suture percutaneously around the usually located in the base of the umbilicus. Alter-
patent processus vaginalis between the peritoneum natively, multiple small trocars can be placed
and the cord structures. This is done after through separate fascial openings but hidden in
bupivacaine or saline has been used to hydro- one incision in the skin. With this option, at the
dissect the peritoneum away from the spermatic completion of the procedure, the holes in the
cord, thereby avoiding injury to delicate cord struc- fascia are connected and then closed in a tradi-
tures when ligating the defect. The authors obtained tional manner. By placing the single skin incision
very convincing data from their rabbit hernia in the umbilicus, the surgeon enables the patient to
model, that intentionally causing iatrogenic injury have no visible scar.
to the anterior hernia sac with a scissors or electro- However, single-incision laparoscopy has a
cautery leads to a more durable repair than if number of inherent mechanical disadvantages
sutures alone were used (Blinman and Ponsky that have limited its use. Because they are so
2012; Blatnik et al. 2012). Consequently the hernia close together, instruments tend to clash and the
sac is cauterized from the 3 to 9 o’clock position classic “triangulation” of the instruments is lost.
anteriorly prior to percutaneous repair. The authors While instruments that can articulate (i.e., bend
have also demonstrated in their rabbit model that and flex) overcome some limitations, they
braided, nonabsorbable, suture results in a more require the surgeon to work backward and with
durable repair than a monofilament suture. reduced degrees of freedom (Blinman and
Other techniques involve the placement of an Ponsky 2012; Krpata and Ponsky 2011;
intracorporeal, purse-string stitch. Some experts Fujimoto et al. 1999). These constraints increase
argue that the defect can also be repaired operating time and restrict the complexity of case
intracorporeally by resecting the hernia sac without type that can be successfully performed. In addi-
ligation (Lam et al. 2000; Riquelme et al. 2010). tion the umbilical incision must be relatively
large to fit the port and multiple instruments,
which may lead to increased risk for herniation
Hiding the Scars in the future.
In the pediatric patient, single-incision laparo-
Single-Incision Laparoscopy scopic surgery has found daily use in multiple
procedures. The first reported use of single-
Initial opponents of laparoscopy stated that incision laparoscopy in children was in 2009
instead of one larger scar, patients were now hav- when an initial experience of 72 single-incision
ing multiple smaller scars. Despite multiple stud- laparoscopic procedures was reported and showed
ies showing that laparoscopic surgery resulted in to be a safe alternative to traditional laparoscopy
and open surgery (Ponsky et al. 2009). Many that enable an improved operative experience in
pediatric surgeons around the world now perform our unique patient population: cholecystectomy,
many procedures by a single-incision approach, appendectomy, and gastrostomy.
including splenectomy, adrenalectomy, For several years, single-incision techniques
pyloromyotomy, cholecystectomy, appendec- for cholecystectomies have been used success-
tomy, and gastrostomy tube placement (Ming fully in children. This section will look at how
et al. 2016; Ponsky and Krpata 2011; Ponsky the standard single-incision procedure has been
2009; Rothenberg et al. 2009; Agrawal et al. adapted successfully for the pediatric population.
2010). A newer alternate approach, the “22” method,
Studies in pediatric single-incision laparos- will then be outlined which uses an amalgamation
copy have shown equivalent results to standard of needlescopic techniques with single-incision
laparoscopic techniques with regard to both cost techniques to offer a scarless cholecystectomy.
and outcomes (Saldaña and Targarona 2013; Extracorporeal appendectomy using a small
Islam et al. 2012), and a recent long-term follow- umbilical incision will then be outlined, a proce-
up from a prospective randomized controlled trial dure widely performed daily on patients of all
(RCT), which compared single-incision laparo- ages and body types. The section concludes with
scopic surgery to standard four-port laparoscopic a method for single-incision gastrostomy tube
cholecystectomy in 60 pediatric patients, found placement, successfully used in the smallest of
that single-incision laparoscopic surgery patients patients.
perceived a superior scar assessment at long-term
follow-up compared with the four-port cohort
(Ostlie et al. 2013). Despite this, widespread Single-Port Laparoscopic
adoption has not occurred, likely due in part to Cholecystectomy: Considerations
the inherent technical challenges of the technique, in Children
with the only proven benefit when compared to
standard laparoscopy being aesthetics due to Standard laparoscopy utilizes a 10–12 mm
decreased visible scarring. umbilical port and either three 5 mm ports or
For this reason, we have strongly stood by the two 5 mm ports and a 10 mm port at the sub-
mantra that single-incision laparoscopy, and, for xiphoid location. In classic single-incision lapa-
that matter, standard laparoscopy, should be roscopic surgery, all three working ports are
attempted only when the approach is able to be brought to the umbilicus, and a multiport system
performed safely and effectively without is used. In the pediatric patient, the various
compromising the completeness and accuracy of single-port systems are often too large and cum-
the surgery. Conversion from a single-incision to a bersome to be feasibly employed. In addition,
standard laparoscopic approach or an open the decreased intra-abdominal working space
approach should not be viewed as a failure, but leads to increased frequency of instrument and
rather as a necessary step for certain difficult cases hand collisions without dedicated solutions to
to ensure the safety of the patient. increase extracorporeal freedom. For these rea-
sons, modifications used include separate umbil-
ical ports that are then connected for extraction
Single-Incision Laparoscopic of the specimen and a 50 cm long laparoscope
Techniques in Pediatric Patients with 90 angled video cord adapter. The tech-
nique allows the surgeon to take advantage of
Given the vast breadth of cases described in single-incision benefits without being limited to
infants and children using single-incision laparo- a single-product system while freeing up work-
scopic techniques, this chapter will look at three ing space for the surgeon’s hands.
relatively common single-port minimally invasive Various techniques for single-incision laparo-
procedures that highlight specific modifications scopic cholecystectomy have been described,
including 3-trocar techniques, 3-trocar and a gall- 11. The mini-lap is secured to the drapes and
bladder stitch, use of curved versus purely straight covered by a towel so that it is out of the
instruments, and use of an operative laparoscope. way of the surgeon’s hands.
Many techniques may add complexity to the case, 12. A reticulating endograsper is used to grasp
lead to collisions of the hands, not be easily repro- the infundibulum of the gallbladder. The han-
ducible by other surgeons, and not be easily dle is reticulated to the patient’s left and
performed by residents in a training environment. handed off to the assistant. The assistant man-
The technique described here is cost-effective, ages the camera and this grasper.
learned quickly, and easily reproducible and 13. The operating surgeon performs the dissec-
results in no bumping of the hands and relatively tion of the triangle of Calot. The critical view
short operative times. The technique has been is identified, and the cystic duct ligated with
quickly learned and performed by over 150 sur- endoclips and divided.
geons and trainees with good success. 14. The cystic artery is identified, ligated with
endoclips and divided.
Key Steps 15. The gallbladder is taken off of the cystic plate
1. The patient is placed supine on the operating and the gallbladder fossa.
table. 16. Once free, the umbilical port sites are
2. Following induction of general anesthesia, connected using electrocautery, and the spec-
the patient is prepped and draped in the imen is removed via the umbilicus.
usual sterile fashion, and pre-incision local 17. The fascia is closed with figure-of-eight
anesthetic is injected. stitches, and the skin closed using monofila-
3. A 1.5 cm curvilinear umbilical incision is ment suture.
made along the inferior umbilical stalk.
4. A Veress needle is used for insufflation of the
abdomen. “22” Laparoscopic Cholecystectomy:
5. A 5 mm umbilical trocar is placed. Scarless Surgery in Children
6. Inspection of abdominal contents is performed
to assure safe entry was achieved and no adhe- Ponsky et al. have evolved their thinking with
sions or abdominal contents are obstructing regard to minimally invasive techniques applied
entry of a second 5 mm port at the umbilicus. to gallbladder surgery and currently endorse a
A 50 cm long laparoscope (5 mm, 30 scope) mixed single-incision and needlescopic approach
with a right-angle light cord adapter is used to in the pediatric patient, which they call the “22”
ensure the assistant’s hands are behind and technique. This technique aims to adhere to the
away from the operating surgeon’s hands. principles set forth by single-incision pioneers
7. The second and third umbilical trocars are while improving the safety and working mechan-
introduced into the abdomen. ics of cholecystectomy. In the pediatric popula-
8. The trocars are situated at the 10 o’clock, tion, the technical difficulties of four instruments
2 o’clock, and 5 o’clock positions. The sited at the umbilicus are formidable. While the
depth of each port is adjusted so that the procedure has been performed safely for several
heads are all at different levels, maximizing years, the amount of infundibular and dome
working degrees of freedom. retraction is limited given the physics of a central
9. The mini-lap gator which is both a grasper fulcrum. The difficulties of gaining adequate
and trocar is inserted into the inferior aspect exposure and retraction without the instruments
of the incision and does not require its own contesting each other, given the space constraints
trocar. of a pediatric patient, have been a driving force
10. The gallbladder is grasped at its dome, leading to nominal adoption of this technique.
twisted 90 , and retracted cephalad toward Needlescopic surgery is technically defined as
the patient’s right shoulder. minimally invasive surgery with instruments that
are 3 mm in diameter or less, sometimes also 7. A second 5 mm umbilical trocar is placed.

referred to as minilaparoscopy. Over time, 3 mm 8. A 2 mm stab incision in the right
incisions tend to be nearly invisible and have hemiabdomen, two fingerbreadths below the
significant cosmetic benefits over 5 mm incisions. costal margin and at dome of the gallbladder,
Moving from 10 to 5 mm incisions decreases the is made, and a 3 mm straight alligator grasper
risk of herniation due to the physics of incision is inserted under direct visualization. This
strength, but moving from 5 to 3 mm incisions grasper is used to retract the dome of the
decreases scars from noticeable to practically gallbladder cephalad toward the patient’s
invisible. Gagner and Garcia-Ruiz described a right shoulder.
series of 60 needlescopic cholecystectomies and 9. A second 2 mm stab incision in the inferior-
showed improved postoperative analgesia and lateral position is made, and a second 3 mm
cosmesis over standard laparoscopy (Gagner and alligator grasper is introduced into the abdo-
Garcia-Ruiz 1998). The “22” hybrid technique men under direct visualization. This grasper
adopted and further modified these techniques to is used to retract the infundibulum of the
make them applicable to infants and children; the gallbladder laterally.
steps of the procedure are outlined below. Of note, 10. Dissection of Calot’s triangle is accomplished
a 50 cm long camera with an angled light cord via the umbilical port with identification of
adapter is utilized, as well as an access insertion the cystic duct and artery. The critical view of
needle built into 3 mm instruments that allow for safety can be seen clearly using this
trocar-less insertion of our alligator graspers. The technique.
alligator graspers are curved, allowing them to be 11. A ductotomy can be performed for
far left of the working space, even in pediatric intraoperative cholangiogram via the umbili-
patients. The “22” hybrid technique combines cal port, and an additional port or incision is
the triangulation advantages of standard laparo- not needed.
scopic techniques with the cosmetic benefits of 12. The gallbladder is dissected off of the cystic
single-incision techniques. The result is essen- plate using electrocautery.
tially scarless surgery and a clear sphere of work- 13. Before removing the gallbladder completely,
ing space for safe removal of the gallbladder. the gallbladder fossa is inspected for bleeding
or biliary leak, and the clips are inspected to
Key Steps ensure they are secured.
1. The patient is placed supine on the operating 14. The last attachments between the gallbladder
table. and cystic bed are ligated.
2. Following induction of general anesthesia, 15. Before extraction of the gallbladder, the two
the patient is prepped and draped in the 5 mm umbilical port sites are connected to
usual sterile fashion, and injection of form one incision.
pre-incision local anesthetic is performed. 16. The fascia of the umbilical incision is closed
3. A curvilinear umbilical incision is used along with a figure-of-eight stitch, and all skin inci-
the inferior umbilical stalk. sions are closed using monofilament subcuta-
4. A Veress needle is used for insufflation of the neous stitches.
abdomen.
5. A 5 mm umbilical trocar is placed.
6. Inspection of abdominal contents is Single-Incision Laparoscopic
performed to assure safe entry was achieved, Gastrostomy: Utilizing an Operative
and no adhesions or abdominal contents are Hysteroscope
obstructing entry of a second 5 mm port at the
umbilicus. A 50 cm long laparoscope (5 mm, Numerous methods are published for placement
30 ) with a right-angle (90 ) light cord of a gastrostomy tube, including open Stamm
adapter. gastrostomy, open Janeway gastrostomy,
percutaneous endoscopic gastrostomy (PEG), lap- 7. The stomach is visualized and is inflated and
aroscopic gastrostomy, and radiologically guided deflated via the patient’s nasogastric tube
gastrostomy. PEG tube placement is the standard (NGT) by anesthesia to confirm the anatomy.
technique utilized in children; however, PEG 8. The stomach is grasped on the greater
requires blind placement of the tube through the curvature.
peritoneal cavity. The maneuver creates opportu- 9. The abdomen is desufflated, and the stomach
nity for injury to the surrounding viscera that is pulled up through the incision site.
could be avoided using techniques that allow for 10. The stomach is grasped using an Adson for-
direct visualization. Furthermore, in children and ceps or a hemostat.
infants with severe micrognathia, foregut anoma- 11. A stay suture is placed to maintain traction on
lies, macroglossia, or prior abdominal surgeries, the stomach.
PEG placement may be difficult to perform. In 12. A purse-string suture is placed.
these situations, most surgeons default to an 13. Lateral and then medial fascial-gastric
open gastrostomy with gastropexy or to a standard stitches are placed.
three- to four-port laparoscopic technique. A min- 14. Inferior and superior fascial-gastric stitches
imally invasive approach is to perform a single- are placed.
incision laparoscopic technique utilizing an oper- 15. A needle is placed through the middle of the
ative laparoscope. The procedure can be purse-string.
performed quickly and safely and has a very 16. Electrocautery is used over the needle to cre-
short learning curve. The procedure is also appli- ate the gastrotomy.
cable to adults and has been used successfully on 17. The gastrotomy is dilated by a hemostat.
patients of all ages and body habitus. 18. The button is placed using the Veress needle
In infants, a 4 mm Storz operative hystero- as an obturator.
scope, which comes with a 3 mm, zero-degree 19. A 3–5 cc of sterile water is instilled into the
camera and two working ports, can be utilized. balloon.
Wire instruments can be inserted into the 20. Betadine solution is injected through the but-
working channel and a biopsy forceps used for ton and is aspirated via the NGT by anesthesia
this procedure. The external diameter of the to confirm intragastric placement of the button.
scope is 5 mm, which easily fits down a 5 mm 21. The sutures are tied down.
trocar. 22. The button is secured with steri-strips, serv-
ing a dual function of decreasing the chance
Key Steps of button dislodgement, as well as increasing
1. The patient is placed supine on the operating granulation tissue formation by decreasing
table. button movement.
2. Following induction of anesthesia, the patient
is prepped and draped in the usual sterile
fashion, and injection of pre-incision local Appendectomy
anesthetic is performed at the site deemed
suitable for gastrostomy, usually just below Standard laparoscopic appendectomy is
the costal margin, midclavicular line. performed with a 10 mm umbilical port for the
3. A 5 mm stab incision is created at this site. laparoscope and introduction of the stapler with
4. A Veress needle is inserted, and the abdomen two 5 mm working ports. The two additional ports
is insufflated. are classically super-pubic and left lower quad-
5. A 5 mm short step trocar is placed. rant, with additional ports added as needed. The
6. The operative laparoscope is inserted. ligation of the appendiceal vessels and the appen-
Because the scope occupies the entire channel dix is performed intra-abdominally using laparo-
of the trocar, the CO2 insufflation is moved to scopic staplers, and the specimen is extracted
the operative hysteroscope. through the umbilicus, usually with a collection
bag. The size of the umbilical port is limited by the 6. Inspection of abdominal contents is
need for a 10–12 mm port for introduction of a performed to assure safe entry was achieved,
stapler device. and diagnosis is confirmed.
Single-port appendectomy is performed 7. The patient is rotated left and put in
according to one of two conceptual techniques: Trendelenburg.
intracorporeal versus extracorporeal ligation of 8. A 3 mm trocar-less bowel grasper is intro-
the appendiceal stump. The intracorporeal tech- duced directly into the abdomen immediately
nique follows the exact same steps as standard inferior to the umbilical trocar along the mid-
laparoscopic appendectomy but utilizes a single- line and within the same skin incision.
port system. Extracorporeal ligation has been 9. The appendix is grasped, elevated, and
performed on pediatric patients of all sizes, brought to the umbilical port site.
including obese patients. In this approach, the 10. The abdomen is desufflated, and a hemostat is
appendix is identified and brought up to the placed on the appendix.
umbilical incision using a 5 mm laparoscope 11. The appendix is fully elevated out of the
and 3 mm instrument, both introduced through umbilical port, and clamps and scissors are
the umbilicus. The appendix is ligated and used to take the appendiceal vessels which are
returned to the abdomen as in the classic open tied in bulk.
appendectomy performed through a right lower 12. The base of the appendix is identified and
quadrant incision. The technique utilizes the suture ligated.
benefits of laparoscopic visualization and umbil- 13. The cecum is returned to the abdomen, the
ical entry but obviates the need for additional trocar replaced, and the abdomen inspected
laparoscopic working ports and a 10–12 mm once more.
umbilical port. The technique is well established 14. The umbilical port site is closed with a figure-
and has been tested in a randomized controlled of-eight stitch in the fascia and subcutaneous
trial by St. Peter and colleagues (2011). The monofilament suture for the skin.
single-incision appendectomy approach was
shown to have no difference regarding morbidity
and mortality outcomes with some question of Natural Orifice Endoluminal Surgery
increased costs when compared to standard lap- (NOTES)
aroscopy likely related to equipment charges.
Importantly, there was no increased risk of In the past decade, many centers have gone a step
surgical site infection with the single-site further than single-incision surgery and have
technique. started to perform “incisionless surgery.” With
the development of natural orifice transluminal
Key Steps endoscopic surgery (NOTES), surgeons have
1. The patient is placed supine on the operating found a way to utilize the endoscope to perform
table (hands tucked or along the patient’s side, surgery without any incisions in the abdominal
based on size). wall. With the use of multichannel endoscopes,
2. Following induction of general anesthesia, the peritoneal or thoracic cavity is accessed
the patient is prepped and draped in the through a natural orifice – the mouth, vagina,
usual sterile fashion, and injection of urethra, or anus, and then, by passing instruments
pre-incision local anesthetic is performed. through the working channels, basic procedures
3. A curvilinear umbilical incision is used along can be performed.
the inferior umbilical stalk. In the adult literature, this technique has been
4. A Veress needle is used for insufflation of the described in the literature for numerous surgical
abdomen. procedures including appendectomies and chole-
5. A 5 mm umbilical trocar is placed. cystectomies and recently even a transanal
NOTES total mesorectal excision with retroperi- 2007). Recently, initial experience using these
toneal sigmoid mobilization and coloanal side-to- magnetic instruments to perform appendectomy
end anastomosis (Leroy et al. 2013). in a pediatric population was published.
Although NOTES has not won overwhelming Of 23 patients who underwent this procedure,
support throughout the pediatric surgery commu- there were no conversions to an open procedure,
nity, the technique has been applied successfully and just four cases required an additional 5 mm
in some specific instances. A recent report by trocar placed. The authors note that magnetic
Velhote et al. described combining a NOTES instruments provide excellent triangulation,
technique with transanal endorectal pull-through improve the ergonomics of single trocar surgery,
(TAEPT) surgery for a patient with and can be used to perform single-site surgery
Hirschsprung’s disease (Velhote and Velhote without the aid of a surgical assistant (Padilla
2009). This alleviated the need for the abdominal et al. 2013). The current authors are using an
incision that is usually required to mobilize the animal model to develop a new technique using
sigmoid safely. hybrid NOTES to repair esophageal atresia.
Transoral incisionless fundoplication (TIF) has Although NOTES has developed relatively
been used as an alternative to the standard surgical quickly, continued investigation with long-term
treatment of laparoscopic Nissen fundoplication results will be required to determine whether it
for gastroesophageal reflux disease (GERD). This will be a technique that provides improved care
minimally invasive technique shows promise in and outcomes to patients. It is difficult to assess
treating patients who are neurologically impaired and remains to be seen if the risk of creating an
or perhaps requiring a re-operative procedure due intentional visceral injury is worth the cosmetic
to failure of their fundoplication. A special benefit of incisionless surgery (Mintz et al. 2008;
designed endoscopic device is inserted trans- Pearl and Ponsky 2008).
orally, full-thickness plications are created, and
then fasteners are placed approximately 270
around the gastroesophageal junction (Cadière Other Innovations
et al. 2008a, b). In adults, the recently reported
3-year results of a multicenter prospective study Robotic Surgery
of TIF recently showed long-term safety and dura-
bility of the procedure (Muls et al. 2013). When robotic surgery was first introduced, it was
Surgeons are doing “hybrid NOTES” proce- with great expectations that it would change the
dures – techniques combining NOTES with lapa- way surgeons operate. Robotic surgery uses the
roscopy or needlescopic surgery to perform basic basic techniques of laparoscopic surgery; how-
procedures within the peritoneal cavity (Shih et al. ever, these techniques are used through robotic
2007). Improved retraction in NOTES procedures arms, which are designed to mimic more accu-
has been described with the use of noninvasive rately the motion and dexterity of human hands.
techniques, such as with magnets. The magnetic The operating surgeon sits at a remote console and
anchoring and guidance system has been used for uses a 3D viewer to direct the robot through hand
visceral retraction and manipulating the telescope and finger controls. Because of its significant cost,
in single-site surgery (Dominguez et al. 2009; widespread use of robotic surgery is limited. The
Park et al. 2007; Padilla et al. 2011). This tech- first robotic surgical procedure in a child was a
nology uses magnetic intracorporeal graspers and Nissen fundoplication in 2000 (Meininger et al.
an extracorporeal magnet that is manipulated over 2001), and the first robotic urological procedure
the abdominal wall to adjust and control the was performed in 2002 (Lee et al. 2006; Peters
instruments and has been used to perform single- 2004).
site (Dominguez et al. 2009) and transvaginal There have been reports of pediatric proce-
NOTES cholecystectomy in adults (Scott et al. dures performed with the assistance of robotics.
Albassam et al. reported on 50 children who were precise dissection with increased magnification
in need of Nissen fundoplication. Twenty-five and visibility. The intuitive controls of the robot
children had the procedure performed in the stan- are purported as providing the ability to perform
dard laparoscopic method, while the other laparoscopic procedures in an “open” fashion. In
25 underwent robotic Nissen fundoplication. The pediatric surgical procedures, these technical abil-
results showed no significant differences in post- ities may have the potential to surpass the physical
operative complication rates, postoperative anal- capabilities of human performance in the tight
gesic requirements, or lengths of hospital stay operative fields encountered in children (Bruns
between the groups. They concluded that robotic et al. 2015).
surgery is feasible and safe but, given the signif-
icant cost, should be limited to specific cases.
With further investigation, robotic surgery may Technical Limitations of Robotic
allow operations on neonates who at one time Surgery
were thought to be too small to undergo laparo-
scopic surgery. Many of the most challenging and complex pro-
A recent systematic review was conducted cedures, where robotic MIS may hold the most
looking at all reported cases of robotic surgery potential, are performed in newborns. It might be
in the literature from the first reported case in assumed that the surgical robot would be very
2001 to 2012 (Cundy et al. 2013). One hundred useful in the small operative spaces encountered
thirty-seven articles were included in the review, in pediatrics. However, its technical requirements
reporting 2,393 procedures in 1,840 patients. can make it cumbersome or not feasible for
The most common gastrointestinal, genitouri- smaller patients. The manufacturer of the da
nary, and thoracic procedures performed were Vinci surgical robot recommends an 8 cm distance
fundoplication, pyeloplasty, and lobectomy, between each port, which is difficult if not impos-
respectively. There was an obvious trend of sible to achieve in many neonatal cases. The size
increasing number of publications over the and length of the instruments can also be an issue.
period reviewed. The net overall reported con- Neonatal surgical procedures are often performed
version rate was 2.5% and the rate of reported with 3 mm instruments and endoscopes, which are
robot malfunctions or failures was low at just smaller than the smallest instruments and endo-
0.5%. There were however no RCTs for inclu- scopes available currently for robotic surgery.
sion in the study, and the authors conclude that Currently, there are two endoscopes available for
future evolution and evaluation should occur the da Vinci Surgical System: 12 mm 3D and
simultaneously so that wider uptake may be led 8.5 mm 3D scope. The 8.5 mm scope may be
by higher quality and level of evidence (Cundy more versatile for smaller children, but it is still
et al. 2013). large for the intercostal space of a small child
(Meehan 2013).
Instruments are available in two sizes: 8 and
Technical Benefits of Robotic Surgery 5 mm. The 8 mm instruments articulate with a
pitch-roll-yaw mechanism, whereas the 5 mm
The advocates of robotic MIS systems claim instruments articulate in a snakelike manner
many inherent useful feature magnification (Berlinger 2006).
(up to 10), stereoscopic vision, operator- The difference in articulation results in the
controlled camera movement, and the elimination 5 mm instruments being longer than their 8 mm
of the fulcrum effect when compared to conven- counterparts, losing workspace within a small
tional laparoscopy (Bruns et al. 2015). The body cavity. For infants and toddlers, 3 mm
wristed laparoscopic instruments used in robotic instruments are routinely used for many basic
surgery provide seven degrees of freedom. For the and advanced laparoscopic procedures. The
surgeon, these features may allow for more lack of commercially available 3 mm
instruments is a significant limitation of the cur- with respect to laparoscopic surgery. There are no
rent robotic surgical platforms and a disincentive RCTs in the pediatric population.
for their use in small children. There are a limited
number of instruments from which to choose;
there are forty 8 mm instruments and twelve Costs
5 mm instruments. For many pediatric surgeons,
creating the smallest possible incision is a major Robotic surgery has higher costs than open and
advantage of laparoscopic procedures. The laparoscopic procedures. This is due to the high
absence of 3 mm and the few options for 5 mm costs of purchasing and maintaining a robot,
instruments may limit the use of the robots in increased operative time, and costs of disposable
infants and toddlers. surgical supplies (Geller and Matthews 2013). In a
retrospective analysis of 368,239 patients from the
Nationwide Inpatient Sample database, there was
an increase in total charges of $1,309 per robotic-
Patient Benefits of Robotic Surgery assisted case (Anderson et al. 2012). The da Vinci
Surgical Systems typically cost between $1.0 and
The patient benefits of robotic surgery are $2.3 million and require an additional maintenance
thought to be essentially the same as conven- contract of $100,000–$170,000 per year in addition
tional laparoscopy: decreased length of stay, to variable disposable instrument costs. In the US
decreased blood loss, decreased pain, quicker medical system of reimbursement, these extra costs
return to work, and improved cosmetic result may result in robotic procedures being financially
through smaller incisions (Mattei 2007). In pedi- unfeasible given the slim operating margins
atric urology, there is evidence that robot- (<1%) on patient care of most US hospitals.
assisted pyeloplasty may be superior to open
and laparoscopic approach with decreased
length of stay, decreased narcotic use, and Safety
decreased operative times (Lee et al. 2006; Yee
et al. 2006). In an analysis of the Nationwide The overall reported conversion-to-open-proce-
Inpatient Sample that compared robotic to lapa- dure rate is low. It has been reported as 2.5% in a
roscopic and open surgery, among most proce- meta-analysis of robotic pediatric surgery
dure types, there was a significant decrease in the (Cundy et al. 2013). When broken into sub-
length of stay and likelihood of mortality for the groups, it was 3.9%, 1.3%, and 10% in gastroin-
robotic surgery group when compared to the testinal, genitourinary, and thoracic cases,
open and conventional laparoscopic surgery respectively (Cundy et al. 2013). This is compa-
groups (Anderson et al. 2012). rable to the conversion rate in conventional pedi-
However, the effect was significantly dimin- atric minimally invasive surgery (Adikibi et al.
ished when comparing robotic to laparoscopic sur- 2012). However, the real conversion rate for
gery alone. In the robotic surgery group, the length robotic pediatric surgery may be higher due to
of stay was 0.6 days shorter with increased charges citation bias. There has been evidence of
of $1,300 (Meehan 2013). A recent RCT in adults underreporting of complications following
comparing open to robotic surgery showed no dif- robotic surgery in both the media and medical
ference between the groups in terms of complica- literature. Over a 12-year period, a review that
tion rate and length of hospital stay for radical cross-referenced device-related complication
prostatectomy (Bochner et al. 2014). There was a databases with the FDA revealed eight cases
significant difference in operative time: the open that were either unreported or incorrectly
group was 2 h shorter. These findings suggest some reported (Cooper et al. 2015). This is especially
potential benefits to robotic surgery, but additional concerning because the true incidence of device-
study is needed to verify the benefits, especially related complication is unknown.
Learning Curve Telemedicine
Laparoscopy has been adopted for advantages The advances in telecommunication over the last
that include decreased adhesion formation, century have enabled us to overcome our logisti-
improved cosmesis, decreased postoperative cal constraints and communicate with others over
pain, and shorter recovery times (Mattei 2007). any distance. In surgery, new technologies have
A skilled laparoscopic surgeon may see no addi- made possible long-distance mentoring, pro-
tional benefit when compared to robotic surgery. ctoring/teaching, consultation, and even remote
In a study comparing novice and expert surgeons procedures. The term “telemedicine” is an
that completed tasks on laparoscopic and robotic umbrella term for the use of audiovisual technol-
simulators, there was a significant improvement ogy to facilitate patient care, administration, or
in speed and smoothness of performance in the education related to the field of medicine (Tsuda
novice group when using the robot that was not 2012). There are many different subcategories of
replicated in the expert group (Chandra et al. telemedicine but there are a number which have
2010). This suggests that the novice laparosco- important and exciting applications to surgery,
pist may realize the greatest benefit of robotic namely, teleproctoring, telementoring, tele-
surgery. There is evidence that a learning curve is education, and telesurgery (Rosser et al. 2007).
encountered when adopting robotic surgery as Teleproctoring is the term applied to the use of
demonstrated by decreasing operative times as audiovisual technology at any distance to conduct
case volumes increased. This learning curve may examinations or certifications between proctors
be more difficult to surpass for the most complex and students, while telementoring applies the
neonatal congenital surgical cases such as same technology to provide mentoring or teaching
tracheoesophageal fistula repair where even the (Tichansky et al. 2012; Tsuda 2012). An example
busiest pediatric surgeons do only a handful of of telementoring is an expert pediatric laparo-
such cases per year due to the low incidence of scopic surgeon in the USA, using videolink to
the condition. guide a less experienced surgeon in another coun-
try, through a single-incision cholecystectomy.
However, while great advances have been made
Future in technology and surgical technique, there is still
a lag behind in skills transfer. In other words, the
Over time, there are more higher-level-of-evi- optimal method for surgeons with advanced tech-
dence studies being completed in the area of nical skills such as MIS to teach others their
pediatric robotic surgery (Cundy et al. 2013). unique skill has yet to be identified. The technol-
The largest RCT completed, to date, showed no ogy is available to support the development of
benefit for robotic surgery for radical prostatec- telementoring; however, medicolegal and finan-
tomy (Bochner et al. 2014). However, there is a cial constraints have slowed progress. There has
need for additional randomized trials comparing been recent collaboration between surgeons, med-
robot-assisted surgery to open or traditional lap- ical device companies, and legal teams to address
aroscopic surgery. In a survey of 117 pediatric the existing constraints and move toward making
surgeons, the majority felt that robotic surgery telementoring a reality.
has a future role, although over 80% of respon- The Internet has enabled the development of
dents had no personal experience with robotic surgical teleeducation through live telesymposia,
surgery (Jones and Cohen 2008). Robotic sur- during which surgeons from around the world
gery has established itself in the adult popula- discuss, learn, and share ideas on current topics
tion, but due to technical and financial in their field of interest. These telesymposia have
limitations specific to pediatrics, it may be allowed surgeons to circumvent the geographic or
some time before we see the same popularity in financial barriers to education that they would
pediatric surgery. otherwise have faced. The authors have
conducted many virtual symposiums, mainly in impaired myoelectrical activity. Standard thera-
the field of pediatric surgery in which surgeons pies used to treat gastroparesis are dietary modifi-
and allied professionals discuss contemporary cations, and medications to increase gastric
management of complex diseases. Well over contractility thereby accelerate gastric emptying.
1,000 pediatric surgeons typically join each sym- Some patients however do not get symptom relief
posium, making this one of the largest avenues for from dietary modifications and prokinetic therapy
surgical education in existence. and are termed drug refractory (Forster et al.
The term telesurgery is given to the act of 2001).
actually operating on a patient from a distance, A new technology that is gaining popularity is
usually through robotic technology. One of the the use of gastric electrostimulation (GES) to
first demonstrations of this was by Marescaux treat this drug refractory gastroparesis. It has
et al. when they performed a robotic-assisted lap- been shown that high-frequency, low-energy
aroscopic cholecystectomy on a 68-year-old gastric stimulation is an effective treatment for
woman in Strasbourg, France, while sitting at a gastroparesis (Abell et al. 2002), and in an adult
console in New York (Marescaux et al. 2002). population, that short-term placement of an elec-
Even using the high-speed connection of the trode with GES is predictive of long-term
time, which seems somewhat slow and antiquated response to GES (Islam et al. 2008; Hyman
to us now, the operation was a performed in et al. 2009; Ayinala et al. 2005). The electrical
54 min (Marescaux et al. 2002). stimulator device is implanted in the abdominal
The most obvious application of telemedicine wall and then connected to the stomach by wires.
is allowing access to expert consultation where It is unclear exactly how the stimulator relieves
none is available. Previous barriers to expert sur- symptoms, but many believe it is due to
gical treatment, such as geographic constraints, or improved receptive relaxation of the stomach,
limited surgical expertise no longer have to limit or improved gastric motility. Some institutions
patients’ choices. Through the use of new tech- first perform endoscopic temporary stimulation
nology, a patient can receive the best operation for for several weeks to assess symptomatic relief
their condition, such as new minimally invasive prior to surgically implanting the permanent
technique. The potential implications of this on device.
healthcare in developing countries are exciting,
where healthcare is often provided by volunteers
who are generalists, lacking expertise in many Conclusion and Future Directions
areas of medicine and surgery.
As MIS techniques continue to develop rap- The numerous MIS techniques discussed above,
idly, surgical trainees’ work hours are limited, and originally used in the adult population, have been
patients demand the highest quality of healthcare, successfully applied to our pediatric patients. MIS
there will continue to be an expanding role for has become routine for the treatment of many
teleproctoring, telementoring, teleeducation, and pediatric surgical disease processes, due to the
telesurgery. numerous benefits these techniques confer on the
patient: decreased wound complications, shorter
length of stay, and improved postoperative pain.
Gastric Stimulators Inherent in the application of these complex tech-
niques to infants and children are many risks due
Gastroparesis is a disorder defined by symptoms to the size of these patients. Pediatric surgeons
and evidence of gastric retention or delayed gas- must be aware and understand these risks if they
tric emptying in the absence of any structural or are to successfully and safely practice MIS.
mechanical obstruction (Parkman et al. 2004; MIS will continue to develop as long as indus-
Park and Camilleri 2006). This disorder can be try is committed to developing pediatric equip-
caused by either impaired motor activity or ment to provide better care for our patients.
Surgical training must continue to evolve, to Chandra V, et al. A comparison of laparoscopic and robotic
ensure that the next generation of surgeons is assisted suturing performance by experts and novices.
Surgery. 2010;147(6):830–9.
adequately trained in these complex techniques. Cooper MA, et al. Underreporting of robotic surgery com-
The future of pediatric MIS is exciting for our plications. J Healthc Qual. 2015;37(2):133–8.
patients and indeed the specialty of pediatric Cundy TP, et al. The first decade of robotic surgery in
surgery. children. J Pediatr Surg. 2013;48(4):858–65.
Dominguez G, et al. Retraction and triangulation with
neodymium magnetic forceps for single-port laparo-
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Fast-Track Pediatric Surgery
31
M. Reismann and Benno Ure
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
Historical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
Current Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
The Evolution of Fast-Track Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506
The Concepts and Components of Fast-Track Pediatric Surgery . . . . . . . . . . . . . . . . . 507
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
Abstract Numerous studies confirmed the safety and

Fast-track surgery was developed by the Dan- effectiveness of fast-track concepts and a sub-
ish surgeon Henrik Kehlet in the 1990s. It was stantial reduction of hospital stay compared with
initially termed enhanced recovery after sur- conventional strategies in children and adoles-
gery (ERAS) and represents a comprehensive cents. These studies showed that the use of fast-
perioperative therapeutic concept with the aim track achieves an improvement in patients, com-
to reduce discomfort, the physiological post- fort and quality of care. The acceptance of fast-
operative stress response, postoperative pain, track by patients and parents is excellent.
and complications by means of combining This chapter contains a description of the
organizational and therapeutic measures. conceptual background, the development, and
the current status of fast-track pediatric
surgery.
M. Reismann (*)
Department of Pediatric Surgery and Urology, Astrid Keywords
Lindgren Children’s Hospital, Karolinska University
Hospital, Stockholm, Sweden
Fast-track surgery · Children · Enhanced
e-mail: marc.reismann@karolinska.se; recovery after surgery · Clinical pathways ·
marc.reismann@charite.de Pain therapy protocol
B. Ure
Center of Pediatric Surgery Hannover, Hannover Medical
School and Children’s Hospital Bult, Hannover, Germany
e-mail: ure.benno@mh-hannover.de

https://doi.org/10.1007/978-3-662-43588-5_33
506 M. Reismann and B. Ure
Introduction stay could be reduced from 8 to 2 days, and the

complication rate was significantly lower when
Surgical concepts are often characterized by tra- compared with conventional care (Basse et al.
ditions, personal preferences, and habits. The dog- 2004). Since these reports fast-track concepts
matic application of measures without scientific have also been established in e.g. major upper
evidence is not an exception. The use of preoper- gastrointestinal surgery, cardiac surgery, genito-
ative enemas, long-lasting postoperative fasting urinary, and orthopedic procedures (Azhar et al.
and immobilization, postoperative drains, and 2016; Bond-Smith et al. 2016; Mir et al. 2015;
nasogastric tubes may be some examples of such Mohamed et al. 2004; Moller et al. 2001;
habits. In addition, insufficient analgesia may be Mulholland et al. 2005; Ottesen et al. 2002;
associated with a delayed postoperative recovery Pecorelli et al. 2016; Husted et al. 2011; Vricella
and increased incidence of complications. et al. 2000).
Historical Aspects Current Concept
Initial fast-track studies have been performed by Today, colorectal surgery has remained the most
general surgeons in adult patients. The primary aim common application of fast-track concepts. In a
of this concept was to reduce the stress response recent Cochrane review, it was confirmed that
and organ dysfunction during the postoperative fast-track can be applied safely with a signifi-
period and to increase the comfort of patients. The cantly reduced hospital stay (Spanjersberg et al.
prerequisite for achieving these goals is as simple 2011). However, there is a considerable diversity
as effective. An effective pain therapy is considered in the design of many of the available descriptive
as essential, while simultaneously avoiding factors studies. It was assumed that it remains difficult to
that cause discomfort, pain, and stress and counter- meet the requirements of evidence-based medi-
act mobilization such as drains, catheters, and cine for every of the up to 20 different fast-track
tubes. Opioids should be avoided to bypass rele- components. Seghal et al. (2012) viewed the most
vant side effects such as nausea, fatigue, respiratory relevant fast-track components reported from six
problems, and bowel and bladder dysfunction. randomized controlled trials: preoperative instruc-
Minimally invasive techniques as well as epidural tions and psychosocial support by a multi-
and regional anesthesia should be preferably used disciplinary team, minimally invasive
(Basse et al. 2002, 2004; Kehlet 2011). techniques, fasting, fluid management, and con-
The beneficial effects of single elements of cepts of anesthesia. Positive effects of minimally
fast-track have been described decades before invasive techniques, reduced fasting periods, a
the term was established (Kehlet 1997). The needs-based fluid administration, and regional or
Danish surgeon Henrik Kehlet could rely on spinal anesthesia were demonstrated in patients
this evidence when he combined these single undergoing colorectal surgery. The authors con-
measures to a highly effective concept. His phi- cluded from the effectiveness of single compo-
losophy was to reduce the duration of hospital nents that also the overall concept is beneficial.
stay and perioperative complications such as
thrombosis and pneumonia by means of an accel-
erated convalescence (Basse et al. 2004). Kehlet The Evolution of Fast-Track Pediatric
introduced major changes in perioperative Surgery
patient care and integrated new concepts of nurs-
ing and anesthesia (Basse et al. 2002; Wilmore Fast-track concepts are especially suitable in chil-
and Kehlet 2001). dren. Young patients and their parents perceive
Initially, fast-track strategies have been medical measures and the hospitalization as par-
applied in colonic surgery. The mean hospital ticularly stressful, and the recovery in children is
31 Fast-Track Pediatric Surgery 507
generally faster than in adults. Therefore, fast- Another study focused on patients who could
track/ERAS programs will be increasingly not undergo the full fast-track protocol for various
implemented in the pediatric population as it reasons. The applicability of the single fast-track
aims to combine both surgical outcomes and effi- measures was specifically assessed in 203 children
ciency of care (Leeds et al. 2016). using defined success criteria (Reismann et al.
First systematic attempts to evaluate fast-track 2012). The majority of the objectives were
in children have been reported by pediatric anes- achieved with a success rate of more than 75%.
thesiologists and cardiac surgeons more than The postoperative survey revealed again a high
10 years ago (Patel et al. 2001; Vricella et al. acceptance rate with 94% of patients and parents
2000). Further fast-track experience was gained being satisfied with the treatment.
in children who underwent appendectomy Recently, several authors reviewed current
(Grewal et al. 2004; Serour et al. 2005; Vegunta fast-track and ERAS approaches, stating that
et al. 2004), pyeloplasty, and nephrectomy although there is a paucity of high-quality litera-
(Mohamed et al. 2004; Mulholland et al. 2005; ture for the pediatric population, the available
Metzelder et al. 2006; Jesch et al. 2006). Since literature indicates that these protocols are safe
2004, fast-track studies have been performed in and beneficial (Shinnick et al. 2016; Pearson and
routine pediatric surgery. Hall 2016).
A first pilot study from Germany included
frequent procedures such as appendectomy,
bowel anastomosis, fundoplication, hypospadias The Concepts and Components
repair, pyeloplasty, and nephrectomy. Successful of Fast-Track Pediatric Surgery
implementation of the fast-track concepts could
be achieved in more than two-thirds out of As a result of numerous studies, the following
159 children (Reismann et al. 2007). The mean criteria have been elaborated for pediatric surgical
hospital stay (2.3 days) was substantially reduced institutions to ensure successful and safe applica-
compared with corresponding data from other tion of fast-track (Table 1; Reismann and Ure
hospitals regarding similar procedures and 2009):
patients with a similar case mix index. Complica-
tions did not occur. A drawback was a high inten- 1. Fast-track surgery is a concept with defined
sity of pain at the evening of the day of surgery measures. Therefore, fast-track should be des-
due to minimal use of opioids. However, patients ignated as a special focus within the
and parents were highly satisfied with fast-track department.
treatment, and 96% of the respondents would 2. Fast-track is interdisciplinary and may be sum-
have decided for fast-track again. marized as “comprehensive.” A network of
In a subsequent study, 20 types of routine pro- pediatric surgeons, pediatric anesthesiologists,
cedures were investigated, and the concepts of
pain therapy were optimized (Reismann et al.
2009). Thirty-six percent of patients could be Table 1 General requirements for the implementation of
fast-track pediatric surgery (Hannover criteria acc. to
treated according to the fast-track regimen, and (Reismann et al. 2009))
analgesia was substantially improved. Again,
Designation of fast-track pediatric surgery as a special
there were no fast-track-associated complications. focus
The mean hospital stay was significantly reduced Network of pediatric surgery, pediatric anesthesia,
compared with data from other institutions (4.6 vs pediatric nursing, and other areas with appointment of
9.7 days, p < 0.01). The first school or kindergar- responsible persons who are focused on fast-track
ten visit was on average 6 days after discharge. A Detailed clinical pathways for all fast-track procedures
detailed comparative analysis of urological pro- Equipment and expertise for minimally invasive surgery
cedures (pyeloplasty and (hemi-) nephrectomy) Pain management protocols, routine pain measurement,
and 24 h pain therapy service for children
confirmed these results (Dingemann et al. 2010).
pain therapists, nurses, and coworkers from special regard to immediate mobilization and
other areas should be created. Responsible per- early nutrition. This can be done by a specially
sons who are focused on fast-track may be trained nurse. A booklet or video-CD may be
designated. helpful to explain the protocols. Patients are
3. Clinical pathways are essential. They comprise admitted on the day of surgery, preferably 2 h
detailed information regarding the treatment before the operation, and may be instructed
from the preoperative diagnostics in an outpa- again. Stressful preoperative measures such as
tient setting to the postoperative treatment after colonic irrigation and long fasting periods are
discharge for every type of procedure/operation. omitted.
4. Minimally invasive techniques are essential to Fast-track concepts include minimally inva-
minimize the adverse effects of the surgical sive techniques whenever applicable. Tubes and
trauma. Equipment and expertise for mini- drains are not used routinely. Immediate postop-
mally invasive surgery are mandatory. erative mobilization is supported by a combina-
5. Effective pain treatment is a central tion of nonsteroidal anti-inflammatory drugs
aspect. Routine pain measurement using vali- (NSAIDs) for basic pain treatment and very
dated scales and a 24 h pain service are essential. reluctant use of opioids. Pain medication should
be in first line given regularly; application on
demand can be started after 24 h. The need for
Detailed clinical pathways on preoperative analgesics is adjusted according to an elaborated
diagnosis and management, operative and periop- pain treatment scheme with closely monitored
erative procedures, and the postoperative care pain measurements. Certain combinations of
should be established by the interdisciplinary drugs should be reserved for specific pain levels.
team of all involved fields (Table 2). The interdis- We recommend a “rescue medication” for situa-
ciplinary team is involved in training and instructions with sudden pain, e.g., nalbuphine. The
tion of all caretakers. pain scales used are age appropriate. We recom-
In detail, diagnostic measures are performed in mend the use of the children’s and infant’s post-
an outpatient setting. Emphasis is placed on the operative pain scale (CHIPPS) (Büttner et al.
instruction of patients and parents to ensure their 1998) for children under the age of 4 years, the
cooperation during the postoperative course with smiley scale (Keck et al. 1996) for children up to
9 years of age, and the visual analogue scale
(VAS) (LaMontagne et al. 1991) for older
Table 2 Fast-track pathways/protocols (Reismann et al.
2007, 2012) children.
Nutrition and mobilization are initiated at the
Diagnostic procedures in an outpatient setting
day of operation. In addition, the use of specific
Specific instructions of patients and parents (additional
use of videos and brochures) discharge criteria may be helpful: no fever, a pain
Admission 2 h before surgery score lower than 3 on a 10-point scale without the
No specific preoperative preparation/no bowel use of opioids, advanced mobilization with a
preparation mobilization score of 2 or above (Table 3), full
Specific anesthesia concepts/minimally invasive oral nutrition without nausea and vomiting, good
methods whenever applicable, minimal operative wound conditions without signs of infection, and
handling/routine pain measurements with validated
scales parent and patient’s agreement on discharge. For
Analgesia according to pain protocol/24 h pain service the successful continuation of fast-track after dis-
Early postoperative mobilization and nutrition charge, the close communication between pediat-
Discharge from day 1 on after the operation according to ric surgeons and the pediatrician, who takes care
discharge criteria of further treatment, is essential. Finally, some
Protocols for cooperation with pediatricians after procedures suitable for fast-track are shown in
discharge Table 4.
Conclusion and Future Directions Table 4 Examples of types of procedures with confirma-
tion of excellent feasibility of fast-track concepts
In conclusion, children are generally suitable for Abdominal procedures:
fast-track surgery due to their capacity for quick Fundoplication
recovery. Fast-track concepts can be applied to Pyloromyotomy
Appendectomy
Splenectomy
Table 3 Fast-track elements and criteria of their success- Heller’s cardiomyotomy
ful application in the German setting. The elements are
Cholecystectomy
considered feasible when successfully applied to at least
75% of the patients (Reismann et al. 2012) Choledochal cyst resection and biliodigestive
anastomosis
Definition of successful Resection/deroofing of cysts of the liver or spleen
Element application
Resection of mesenteric cyst
1. Analgesia Pain intensity of <1/3 of the
Urogenital procedures:
maximum scale pointsa at the
evening of the operation day Pyeloplasty
(18.00 h) Nephrectomy
2. Postoperative Full oral nutrition at the Hypospadias repair
nutrition 2. postoperative day at Varicocelectomy
18.00 h (two full meals Operation for intra-abdominal testis/Fowler-Stephens
without nausea and vomiting) procedure
3. Postoperative 2 score pointsb at the Ureteral reimplantation
mobilization 2. postoperative day at Interventions on the internal genitalia (ovary, tubes,
18.00 h uterus)
4. Applicability of No conversion and no Heminephrectomy
minimal invasive postoperative complication
surgery with adverse effect in Urachal cyst resection
procedures suitable for Thoracic procedures:
minimally invasive Resection of pulmonary sequestration
techniques Wedge resection of the lung
5. Hospital stay Significantly shorter hospital Lung lobe resection
stay compared to G-DRG data Biopsy/resection of tumors and cysts
on similar patients in
hospitals with similar case
mix index and similar
structure
children undergoing various routine procedures.
6. Postoperative No nausea or vomiting
symptoms Even those patients who cannot undergo the full
7. Complications No complications fast-track pathway may benefit from single fast-
8. Patient’s/parent’s Satisfaction of patients/ track measures.
judgment parents, no readmission
(>90%)
a
Pain scales:
For children aged <4 years: children’s and infant’s post- Cross-References
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(VAS) (LaMontagne 1991)
b
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1: Sitting on the edge of the bed or short mobilization out ▶ Infantile Hypertrophic Pyloric Stenosis
of the bed (infant)
▶ Innovations in Minimally Invasive Surgery in
2: Short walk in the patient’s room or feeding outside the
bed Children
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Ethical Considerations in Pediatric
Surgery 32
Jacqueline J. Glover and Benedict C. Nwomeh
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
Defining the Best Interests Standard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514
Applying the Best Interests Standard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Guidelines for Ethical Decision-Making . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 518
Informed Consent and Assent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
Multiculturalism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 519
Prenatal Surgical Consultation and Fetal Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 520
Ethical Issues in Pediatric Bariatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 521
Surgeons and Industry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
Surgical Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
Best Interests and Innovation and Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526
Abstract
Ethical issues arise in pediatric surgery when
J. J. Glover (*) difficult decisions must be made in the pres-
Department of Pediatrics and Center for Bioethics and ence of uncertainty or conflict, and stake-
Humanities, University of Colorado Anschutz Medical holders are concerned about quality of life,
Campus and The Children’s Hospital Colorado, Aurora, informed decision-making, and access to
CO, USA
e-mail: Jackie.Glover@ucdenver.edu scarce medical resources. This chapter pro-
vides the pediatric surgeon with a framework
B. C. Nwomeh
Department of Surgery, Ohio State University College of for ethical decision-making that relies on a best
Medicine, Columbus, OH, USA interest standard and includes a definition of
Nationwide Children’s Hospital, Columbus, OH, USA this standard and also the appropriate applica-
e-mail: Benedict.Nwomeh@nationwidechildrens.org tion and limitations of the best interest

https://doi.org/10.1007/978-3-662-43588-5_34
514 J. J. Glover and B. C. Nwomeh
standard. Decision-making for adolescents makes the decision and what decision is
includes a discussion of informed consent and appropriate.
assent. The best interest standard is discussed This best interest standard is based on several
in the context of multiculturalism. Other issues ethical principles and virtues. Beauchamp and
include prenatal surgical consultation and fetal Childress have articulated certain principles that
surgery, bariatric surgery, conflicts of interest, are foundational in biomedical ethics (Beauchamp
errors and innovation, and clinical research. and Childress 2013). These principles include
beneficence, non-maleficence, autonomy, and jus-
Keywords tice. The first two of these principles, beneficence
Ethical decision-making · Best interest and non-maleficence, refer to the obligation to
standard · Informed consent and assent · promote the well-being of patients and to “do no
Multiculturalism · Fetal surgery · Bariatric harm.” The other two principles are based on
surgery · Conflicts of interest · Surgical errors · relatively recent concepts. Respect for autonomy
Innovation and research (self-rule) refers to the obligation to respect the
right of competent persons to give informed con-
sent for medical treatment and have control over
Introduction their bodies, and justice refers to non-
discrimination or involves the fair and equitable
In caring for the extremely premature neonate, the distribution of the benefits (and risks) of medical
infant with multiple, life-threatening congenital care to all persons.
anomalies or the child or adolescent with surgical Although principle- and duty-based ethics are
disease, pediatric surgeons often encounter diffi- prominent in contemporary bioethics, some ethi-
cult ethical decisions about the use of advanced, cists make a strong case for virtue-based ethics.
life-sustaining treatments and operative interven- Pellegrino and Thomasma argue that virtue is
tions. The imperative to utilize new technology is derivable from the nature of medicine as a
tempered with concerns about quality of life, human activity and is an irreducible element in
informed parental decision-making, and access medical ethics (Pellegrino and Thomasma 1993).
to scarce medical resources. Pediatric surgeons, While ethical principles focus on the action or
families, and communities ask the difficult ethical actions that give rise to ethical issues, virtue ethics
question: “We can do this particular intervention, emphasizes the moral character of agents (physi-
but, should we?” This chapter provides the pedi- cians). Pellegrino and Thomasma cite the rele-
atric surgeon with ethical guidelines to utilize in vance of such virtues as trust, compassion,
clinical situations in which therapeutic decisions prudence (cautiousness), justice, courage,
contain uncertainty or conflict and the next steps phronesis (practical wisdom or common sense),
in the management of an infant, child, or adoles- fortitude, integrity, honesty, and self-effacement
cent pose challenges for the patient, parents, and (Pellegrino and Thomasma 1993). In practice, a
physicians. surgeon’s behavior is shaped both by the core
ethical principles and by the special bond that
sickness and the response to it creates between
Defining the Best Interests Standard healer and patient. Additionally, pediatric sur-
geons are challenged by issues that are unique to
Since neonates, infants, and children cannot make surgery and the care of infants and children.
decisions about the appropriate use of technology One of the most unique factors in pediatric
based on their own personal values, the central ethics is that infants and children cannot decide
ethical question is framed in pediatrics as, “What for themselves. In the USA, parents are presumed
is in the best interests of this infant or child?” An to be the appropriate decision-makers for their
answer requires a unique and complex ethical infants and children (American Academy of Pedi-
framework that combines a concern for who atrics Committee on Bioethics 1995), but they are
32 Ethical Considerations in Pediatric Surgery 515
not unqualified decision-makers. Parents and per se. Just as the presence of pain unable to be
pediatric surgeons must work together to make relieved can preclude the attainment of those basic
decisions that are in the “best interests” of infants human goods that make life worth living, so the
and children (American Academy of Pediatrics absence of fundamental human capacity can ren-
Committee on Bioethics 1996). The term “best der a life devoid of the same basic human goods.
interests” is meant to capture a balancing of the For the last few decades, the best interest stan-
benefits and burdens to this infant or child of a dard has enjoyed prominence in pediatric ethics in
particular intervention. the USA, although its limitations have also been
In the mainstream medical culture in the USA, clearly articulated. Critics argue that an infant’s
the term “best interests” was developed to focus interests are unknowable, that an interest’s appeal
attention on the need to assess the benefits and can yield counterintuitive results, and that others’
burdens of treatment for a particular infant or child interests also deserve consideration.
from the infant’s or child’s perspective. In an An expanded understanding of best interests
effort to be as objective as possible, only the direct must take into consideration several competing
pain and suffering associated with an infant’s or ethical values. One value is respect for family
child’s condition and/or proposed treatment was autonomy or self-determination. Families ought
to be considered in conjunction with the benefit of to have the freedom to make important choices
continued life. The standard was proposed as a about family welfare independent of others. It is
very strict one, regarding treatment as beneficial not so much that families have a right to make
and in the infant’s or child’s best interest unless important decisions for their infants, as it is that
the infant or child were dying, the treatment was families have the responsibility to make decisions
medically contraindicated, or continued life and provide the necessary financial and other
would be worse for the infant/child than an early types of support. Families are an essential unit of
death. A central feature of this narrow understand- care that is both valuable in themselves and instru-
ing of best interests includes its child centered- mentally valuable to meet the social goal of caring
ness, understood to mean the exclusion from for children. Since families are presumed to love
consideration of the negative effects of an their children and desire to do what is best for
impaired infant’s or child’s life on other persons, them, they have a unique claim to the decision-
including parents, siblings, and society. making role. Also, families have to live with the
A second key feature is its emphasis on the consequences of the health-care decisions that are
infant’s/child’s concrete experience of burden in made (American Academy of Pediatrics Commit-
the form of pain and suffering. In addition to the tee on Hospital Care, Institute for Family-
difficulties associated with assessing the burdens Centered Care 2003).
experienced by an infant/child, a narrow best In a very real sense, the families’ interests are
interest standard cannot be applied to neonates linked with the interests of the neonate or infant/
and infants/children with neurological deficits so child. An attempt to starkly separate infant/child
severe as to exclude the possibility of experience and family interests is artificial and diminishes
of any sort. Infants and children, who are not rather than enhances an understanding of the
responsive to outside stimuli, for example, cannot infant’s or child’s well-being. One can understand
experience pain and therefore cannot be burdened how the best interest standard developed in the
in the same way as conscious infants and children. context of imperiled newborns, where there is
Some ethicists have appropriately pointed out great uncertainty and no one has a longstanding
that absence of pain is not the only morally rele- relationship with the infant. The objectivity
vant feature (McCormick 1974). A “relational sought is comprehensible only because the infant
potential” standard is necessary to augment a is a stranger to all. Yet even in the case of new-
best interest standard. It is not morally obligatory borns, most authors agree that parents should be
to sustain life without any capacity for human the primary decision-makers. If family interests
relationship, even though life is not burdensome were irrelevant, it would be difficult to make sense
of such a presumption. Given this presumption in are vulnerable to the neglect and abuse of their
favor of parental decision-making and the fact that families. All infants deserve a certain level of
most infants are not strangers to their parents, a health care, independent of what their families
best interest standard would be better understood might choose for them.
to include a more comprehensive understanding An expanded “best interests” standard is an
of a child-centered decision, one made by a family attempt to balance the benefits and burdens of a
whose daily lives involve the love and care of health-care intervention according to the values of
their infant or child. the parents, pediatric surgeons, and the larger
Another value that is in tension with respect for society. It should be clear that the model described
family decision-making is respect for professional represents its application in the dominant medical
integrity. Since “best interests” also contain an culture in the USA. Firstly, other cultures and
important focus on the uniquely medical interests countries may have a different understanding of
of the infant, professional judgment plays an what constitutes family and necessarily include
important role in describing and evaluating the others besides parents. Perhaps others, such as
benefits and burdens of health-care interventions family elders, are the persons designated as
(Baylis and Caniano 1997). Pediatric surgeons decision-makers. Secondly, this particular model
have independent obligations to the infants who is based on Western notions of the importance of
are their patients, to promote their well-being and informed consent and respect for the autonomy
protect them from harm. They have a professional (self-determination) of the patient and the family
obligation to promote life and quality of life and to in the case of pediatrics. In other cultures and
avoid such harms as killing, premature death, countries, families may not see their role as
pain, and suffering. Little (2001) has identified decision-makers at all but only in terms of doing
five pillars of the surgeon-patient relationship: what the doctor orders. Also, other cultures and
rescue, proximity, ordeal, aftermath, and pres- countries may emphasize other core values such
ence. Although present in other therapeutic rela- as responsibility to the larger family and commu-
tionships as well, they have a special intensity in nity rather than autonomy (self-determination).
surgery. The term rescue acknowledges the ele- Finally, the model described presumes a certain
ments of surrender and dependency that patients access to technology that is primarily available in
and their families experience when they have little developed nations. A concern for quality of life is
control over the proposed surgical remedy. Prox- different in developed nations where the issue
imity refers to the surgeons’ acknowledgment of may be the result of technology that is able to
the close, intimate interactions they have with save life of diminished quality, as opposed to
their patients. Presence refers to both the virtue developing nations where diminished quality of
and duty to be visible and engaged throughout the life may be primarily a consequence of inadequate
entire surgical experience. In pediatric surgery, access to basic health-care services.
this professional obligation extends to the long-
term follow-up of their patients, often into young
adulthood. Applying the Best Interests Standard
A third important value in the discussion of
best interest is that of justice as nondiscrimination How does the best interest standard work in prac-
(McCormick 1974). How do we understand the tice? It must be remembered that the term is just a
interests of a child in himself or herself, indepen- placeholder for a complex structure of values that
dent of how others may value him or her? What must themselves be interpreted and applied. It is
does society owe its children as a matter of jus- not possible to use the label “best interests” and
tice? Infants do not only belong to their families, expect it to do the moral work for us. It is always
but they also are members of their community. necessary to discuss the particular benefits and
Communities have an obligation to protect the burdens of an intervention, according to the eval-
most vulnerable among them, especially if they uations of all the parties involved. No one party
has a privileged view of the best interests of the operation that leaves 15 cm of small intestine,
infant. the infant develops a grade IV intraventricular
Consider, for example, an infant born with an hemorrhage, worsening lung disease, renal fail-
intestinal atresia. There are no associated anoma- ure, and ongoing sepsis. In this case, the mortality
lies and the infant cannot survive without opera- rate of the condition is very high, and the infant’s
tive correction. The pediatric surgeon quality of life is affected by the associated neuro-
recommends surgery to the parents because sur- logical, renal, and pulmonary complications. A
gery would be in the best interests of their infant. pediatric surgeon and parents would be justified
The pediatric surgeon means, by the use of the in withdrawing life support and instituting com-
term, that the possible benefits to the infant (life, fort care for this infant. It could be argued that it
restoration of function, reduction of pain, and would be inappropriate to subject this already
suffering) outweigh the possible burdens (time in vulnerable infant, with little or no potential to
the hospital away from family, risk of death asso- interact with the environment, to the substantial
ciated with anesthesia, pain and suffering associ- burdens of life-sustaining technology for devas-
ated with testing and interventions, and risk of tating bowel disease and compromised pulmonary
compromised function). The calculation of best and renal function. None of the treatments for
interests is based on the infant’s diagnosis, prog- devastating bowel disease, such as further surgery,
nosis, available treatment options, and the likeli- the use of total parenteral nutrition (TPN), or a
hood of their success. The anomaly is fatal bowel transplant, would improve the infant’s neu-
without intervention, and the surgery is relatively rological condition. With little or no opportunity
low risk with a high likelihood of success. The to experience things such as pleasure or comfort
pediatric surgeon wishes to preserve professional that we regard as benefits, inflicting pain or sepa-
integrity by fulfilling the ethical obligations to ration from family could be viewed as
promote the infant’s welfare by saving the infant’s disproportionally burdensome or not necessary
life and restoring function and protecting the according to a relational potential standard.
infant from harm. The pediatric surgeon is acting Although most health-care professionals and
upon the values of what it means to be a “good parents would agree that further interventions are
physician.” not in this infant’s best interests, some parents
Most parents would agree that surgery for an would disagree and insist that “everything possi-
intestinal atresia is in the best interests of their ble be done.” In the USA, it is a very difficult
infant. Out of their values to be “good parents,” matter both ethically and legally to stop life-
they strive to promote their infant’s welfare and sustaining treatment over the objections of the
cope with the burdens placed on their infant and parents. Conflict resolution depends on a trusting
upon themselves. Most parents would agree that relationship between the pediatric surgeon and the
the outcome is good (life and restored function) family. The family must be able to trust the pedi-
and the surgery has a high likelihood of success atric surgeon so that they can rely on the pediatric
with minimum burden (surgery, recovery time, surgeon’s judgment. This trust begins with the
and associated costs). Parents who refused such pediatric surgeon’s honesty: the commitment to
surgery in the USA would most likely be accused disclose all relevant information, to insure that
of medical neglect, and the power of the state families understand what is being said and to
would most likely be used to insure that the infant respond to the questions and concerns of the fam-
received the necessary care. ily. Pediatric surgeons must also be compassion-
In other situations, a pediatric surgeon and ate, feeling for the infant and with the family as
parents may agree that stopping life-sustaining they endure this critical illness. The family needs
treatment would be in the best interests of a par- to know not only that the pediatric surgeon cares
ticular infant. For example, consider the case of a for and about them and their infant, but that the
23-week-old infant weighing 600 g who develops pediatric surgeon will not abandon them on this
necrotizing enterocolitis (NEC). Following an difficult journey. It is vital in these so-called
“futility” cases, to understand just what the family a decision? Who are the involved clinicians? Is
means when they say “everything possible should the parent a mature minor?
be done.” The conflict may be a matter of misun- 2. Gather the relevant medical facts. What is the
derstanding the diagnosis and prognosis, and such diagnosis? What is the prognosis? Are addi-
false expectations can be often corrected with tional tests necessary for further clarification?
open, ongoing communication. But sometimes Is there necessary information to be gathered
there is a real conflict between the values of the from other clinicians?
pediatric surgeon, the entire neonatal health-care 3. Solicit value data from all involved parties. Do
team, and the values of the family. conflicts exist among the values of the patient,
Because families may differ in how they make parents, other family members, and the physi-
value judgments about what constitutes an accept- cians? Has the basis for the conflict been
able quality of life for their infants, it is essential to identified?
be able to elicit information about values and 4. Define the available treatment options. With
preferences from families. The authors have each option, what is the likelihood of cure or
found the following questions useful. The ques- amelioration? What are the risks of an adverse
tions are intended as subject guides only; each effect? What is a minimum level of profession-
clinician must translate the questions into his or ally acceptable treatment?
her own style: 5. Evaluate possible treatment options and make
a recommendation. Justify your choice
1. What is your understanding of your baby’s/ according to the values of the various parties.
child’s current condition? 6. Achieve a consensus resolution. Have all
2. How has your baby’s/child’s illness affected parties articulated their viewpoint? Would
your family? more factual information help to resolve any
3. What is most important in the care of your disputes? Would a mediator (ethics consultant,
baby/child? ethics committee, or other trusted third party)
4. What do you fear the most? What would you be helpful?
like to avoid?
5. What are your family’s sources of strength and Most of the time, ethical conflicts between
support? pediatric surgeons and parents can be resolved
with further communication, negotiation, and
accommodation. But sometimes the conflict is so
Guidelines for Ethical Decision-Making severe that the pediatric surgeons should consider
appealing to an outside resource such as an ethics
Ethical dilemmas most often arise when parents committee or withdrawing from the case based on
and pediatric surgeons disagree about what con- conscientious objections.
stitutes an acceptable quality of life or what con- The threshold is high for involving the courts
stitutes the best interest of the infant or child. in a decision about surgery for a neonate, infant, or
Whose judgment should prevail? child. Pediatric surgeons should invoke the power
Pediatric surgeons can help insure that their of the state to secure treatment for an infant or
ethical judgments are reliable through the appli- child only when that treatment is universally
cation of an organized process (Little 2001). regarded as beneficial and the appropriate stan-
There are multiple versions available in the ethics dard of care, making parental refusal equivalent to
literature, but they generally all contain the fol- medical neglect, as in the previously cited case of
lowing components: the infant with an intestinal atresia (Glover and
Caniano 2000). The classic case for court inter-
1. Identify the decision-makers. Are the parents vention involves treatment for a life-threatening
involved? Are there nonparental legal guard- condition in which the benefits are substantial and
ians? Do the parents have the capacity to make the burdens minimal, such as court-ordered blood
transfusions for pediatric patients (American drugs, treatment for sexually transmitted infec-
Academy of Pediatrics Committee on Bioethics tions, and the use of contraception and pregnancy
1997). Courts are also not the appropriate venue care (English et al. 2010). These instances of
when parents demand treatments that the pediatric minor consent are based not only on respect for
surgeon regards as not being in the best interests privacy and confidentiality but on the public
of the infant. Conflicts are resolved best at the health values of treating diseases and stopping
bedside among the parties who know the infant their spread (infectious diseases). However,
and the circumstances and those who will live when an adolescent’s consent to or refusal of
with the consequences of the decision. surgery is in direct opposition to parental wishes,
the assistance of an ethics committee, social ser-
vices, or legal counsel may be required.
Informed Consent and Assent The concept of pediatric assent is also impor-
tant. There is wide support that the assent of the
When the pediatric surgeon is dealing with ado- pediatric patient should be sought as appropriate
lescents or young adults, the doctrine of informed to their development, age, and understanding, in
consent is important. This doctrine is based pri- conjunction with informed permission from the
marily on the ethical principle of respect for indi- parent or legal guardian (American Academy of
vidual autonomy but also involves beneficence Pediatrics Committee on Bioethics 1995). Pediat-
and justice. Respect for patient’s autonomy recog- ric surgeons have an ethical duty to familiarize
nizes the right of each person to make their own themselves with their own institutional guidelines
decisions, while the principle of beneficence and appropriate local statutes for decision-making
refers to the obligation to promote the well-being by minors.
of the patient. Justice refers to the obligation to act
in a nondiscriminatory fashion and to treat
patients in the same manner as other patients Multiculturalism
under similar circumstances.
In some jurisdictions, and in certain specific The ethical concept of best interests that has been
circumstances, adolescent patients may be articulated is largely dependent upon the authors’
granted authority to make their own decisions own experiences in the medical culture in the
about the health care they receive. There are two USA. Some of the most difficult ethical issues
relevant concepts – the mature minor and the that the authors’ have personally faced involve a
emancipated minor. Ethically, health-care profes- conflict between this Western medical notion of
sionals are obligated to involve mature minors in best interests and families making decisions for
decision-making insofar as the minors are able. A their infants and children from other cultures.
mature minor is a person under the age of 18 who However, there is something particularly compel-
has the capacity to make informed health-care ling about such cases that call participants to value
decisions – based on a clinical assessment of the and respect cultural differences. Both the parents
person’s emotional maturity, age, experience, and pediatric surgeons are struggling to fulfill
intelligence, and the decision to be made. An their role-specific obligations to be good parents
emancipated minor is a person under the age of and good physicians. But they literally see their
18 who has sole or primary responsibility for roles quite differently. It is culture that provides
his/her own support, is married and living away the “lens” for each of us to view the world. One
from parents or guardians, or is in the armed definition of culture states:
services. Mature and emancipated minor statutes
Culture is a set of guidelines (both explicit and
may vary by local jurisdiction (English et al. implicit) which individuals inherit as members of
2010). In addition, there are other treatments that a particular society, and which tells them how to
a minor can consent to by federal and/or state view the world, how to experience it emotionally,
statute – treatment for addiction to or use of and how to behave in it in relation to other people,
to supernatural forces or gods, and to the natural context and relationship in an ethical analysis, and
environment. It also provides them with a way of to those working in clinical settings. As Carl Elliot
transmitting symbols, language, art and ritual. To
some extent, culture can be seen as an inherited writes:
“lens”, through which individuals perceive and
understand the world that they inhabit, and learn Ethical concepts are tied to a society’s customs,
how to live within it. Growing up within any society manners, tradition, institutions – all of the concepts
is a form of enculturation, whereby the individual that structure and inform the ways in which a mem-
slowly acquires the cultural “lens” of that society. ber of that society deals with the world. When we
Without such a shared perception of the world, both forget this, we are in danger of leaving this world of
the cohesion and the continuity of any human group genuine moral experience for the world of moral
would be impossible. (Helman 1990) fiction – a simplified, hypothetical creation less
suited for practical difficulties than for intellectual
convenience. (Elliot 1992)
It seems obvious from this definition that
there is no way to talk about best interests from The authors wish to support an ethical analysis
outside a cultural perspective. All of our discus- that includes culture as an important feature but
sion, then, is in some sense cross-cultural. The also acknowledges the role of the application of
narrow explication of best interests represents universal ethical principles. Like Pellegrino, the
the perspective of the USA and perhaps predom- authors accept that there are some ethical princi-
inantly the powerful status of its medical and ples that apply to all humans based on their
legal culture. humanity. Culture is necessary to understand
The central question is not really whether or what these principles mean and how they are
not we have a cultural perspective but whether we applied with respect to each of the parties in the
can judge some perspectives as better than others. conflict. It is possible to be respectful of cultural
This raises the difficult ethical question of cultural differences and at the same time acknowledge that
relativity. Cultural relativity refers to the follow- there are limits. What remains critical is the per-
ing claims: (1) all moral judgments are relative to ceived degree of harm; some cultural practices
the culture in which they arise, (2) moral judg- may constitute violations of fundamental human
ments across cultures are significantly different, rights (American Academy of Pediatrics Commit-
and (3) there is no way to rank moral judgments tee on Bioethics 1994).
across cultures (Garcia 1992).
The well-respected physician – ethicist,
Edmund Pellegrino – accepts that culture is Prenatal Surgical Consultation
essential in the context of medical and ethical and Fetal Surgery
decisions but that there are also features of
human beings as human beings according to With the emergence of routine prenatal screening
which we can judge among cultures (Pellegrino with ultrasonography (USA) and biochemical
1992). It can be argued that there are some uni- markers and maternal/fetal centers, there comes
versal features that all cultures either should or the need for increasing attention to the ethical
would accept. An example would be that moral issues that may arise with the prenatal diagnosis
communities must allow democratic processes of fetal anomalies. Such issues may include (1) the
and cannot be oppressive. Other ethicists iden- possibility of prenatal intervention or termination
tify universal moral principles that underlie our of pregnancy; (2) the timing, location, and mode
commitments to be tolerant of cultural diversity of delivery; and (3) potential postnatal surgical
(Beauchamp 1992; Macklin 1998). Without intervention (Caniano and Baylis 1999).
some principle of respect for persons, for exam- A prenatal surgical consultation should be
ple, there would be no reason to prefer tolerance guided by the same ethical principles of benefi-
of cultural differences. cence, non-maleficence, and justice that we have
A cultural perspective is particularly important been discussing. And in addition, respect for the
to ethical theorists, who support the inclusion of woman’s choice and her reproductive freedom
(respect for autonomy) takes on a profound rele- offer recommendations that balance maternal
vance. There is disagreement about the role of and fetal interests.
termination of pregnancy within the fetal therapy 3. Foster an atmosphere that facilitates the
discussion (Ville 2011). Because these issues exchange of medical information and helping
involve the unique situation of having one patient the prospective parents make decisions that are
physically located within another patient, consistent with their own beliefs, goals, and
balancing the values of the stakeholders can be values.
particularly difficult (Mattingly 1992). Some 4. Promote responsible efforts to improve access
would argue that the moral status of the fetus to the full-range of prenatal services available
should almost never trump the autonomy of the at high-risk perinatal centers for women from
mother (ACOG Committee on Ethics 2004). all socioeconomic, ethnic, and cultural
Chervenak and McCullough have proposed a groups.
framework that includes the fetus as a patient
with beneficence and non-maleficence claims The potential for the maternal and fetal inter-
based on the fetus’ ability to live independently ests to diverge can be a major concern as everyone
or the mother’s presentation of the fetus as a involved seeks the best interests of the mother and
patient (Chervenak and McCullough 2009). The the fetus, respectively. As with other issues in
benefits of a proposed fetal surgery always must pediatrics, judicial review should be viewed as
be considered in the context of the risk of the only a last resort to resolve intractable conflict
surgery for both mother and fetus. The informed (American Academy of Pediatrics Committee on
consent process is particularly important and chal- Bioethics 1999). Establishing institutional ethical
lenging. The role of other family members, guidelines and the assistance of an ethics commit-
including fathers, is debated. Family can be both tee consult may be helpful.
a source of support and also of problematic coer-
cion (Howe 2003).
But what is the role of the surgeon? Some Ethical Issues in Pediatric Bariatric
would argue that the proper role of the pediatric Surgery
surgeon is not only to give information but also
provide a supportive, caring environment for With the recent success of adult bariatric surger-
informed decision-making. “Value neutrality and ies, it is no surprise that bariatric operations in the
moral detachment on the part of the surgeon cre- pediatric population are increasingly
ates an obstacle to forming a professional relation- recommended. Clinical evidence supports the
ship with prospective parents who are seeking need to address the serious comorbidities of child-
compassion, honesty, and integrity, virtues cited hood obesity such as type 2 diabetes, cardiovas-
by Pellegrino and Thomasma as being essential cular dysfunction, hypertension, obstructive sleep
components of the physician-patient relationship” apnea, and dyslipidemias (Caniano 2009). But
(Nwomeh and Caniano 2011). these surgeries are still innovative and much
One of the authors has suggested elsewhere the research remains to be done, especially about
following as guidelines for pediatric surgeons long-term outcomes with children.
during a prenatal surgical consultation (Nwomeh The ethical issues are complex. The decision to
and Caniano 2011): proceed with bariatric surgery should be made
only after it is determined that the patient’s
1. Empathize with the inevitable grief and sorrow comorbidities could not be treated with less inva-
that the prospective parents feel upon the sive means and there is a favorable risk/benefit
recent unexpected and frightening diagnosis profile, pre-surgery counseling and robust
of a fetal malformation. informed consent, and a comprehensive system
2. Candidly disclose the benefits, harms, and of short- and long-term follow-up care (Caniano
alternatives for the given fetal condition, and 2009).
Robust informed consent may be difficult in and Native American children of both genders
this population of morbidly obese adolescents (Blacksher 2008). It is the socially and economi-
considering bariatric surgery. There can be severe cally disadvantaged children who fare the worst
pressure from the media, lay publications, and the on most childhood health indicators. Pediatric
Internet, which highlight the benefits of this sur- bariatric programs must consider issues of justice
gical intervention to achieve a socially desirable as fairness as they develop programs and provide
body habitus. Patients may not be able to appre- access to the children most in need, in spite of
ciate the real operative risks and the irreversible their ability to pay.
nature of some of the proposed procedures. It
seems like a “quick fix” when it actually involves
many, if not all, of the lifestyle changes that are so Surgeons and Industry
difficult to make. Raper and Sarwer have
described the elements of informed consent to be Patients have benefited from the cooperative work
discussed with prospective adolescent bariatric of physicians with industry in the development of
patients and their families (Raper and Sarwer new tests, drugs, and devices. Many have argued
2008). that the improvements in the quality of medical
Bariatric surgery may uphold the principle of care have been the direct outcome of industry
beneficence for some adolescents. Although support for medical education, research, and inno-
beneficence would favor less invasive measures vation. However, these industry relationships may
such as caloric restriction diets, exercise pro- also create conflicts of interest (COI), unduly
grams, and behavioral therapy, these are not influencing professional judgments and inducing
always effective. In one study, adolescent patients physicians to perform unnecessary tests and treat-
whose BMI exceeded 40 kg/m2 had only a 3% ments that may be harmful to patients and con-
reduction in BMI after 1 year of intensive medical tribute to rising health-care costs (Brennan et al.
weight management, a result that was insufficient 2006). The 2009 report “Conflict of Interest in
to reverse comorbidities (Flum et al. 2007). The Medical Research, Education, and Practice”
principle of beneficence would require a “reason- issued by the Institute of Medicine (IOM) has
able” trial of medical/behavioral weight loss treat- urged serious consideration of this issue (Institute
ment, continuation of such treatment if proven of Medicine 2009). The IOM stresses the impor-
effective, and surgery only if less invasive means tance of preventing bias and mistrust rather than
prove ineffective. trying to remedy damage after it is discovered and
The principle of non-maleficence also is encourages the enactment of policies and laws
important because of the well-known risks of that identify, limit, and manage conflicts of inter-
surgery and such complications as lengthy hospi- ests without negatively affecting constructive col-
talizations, reoperative surgery, and other unantic- laborations between the medical profession and
ipated problems. And adolescents may have industry (Institute of Medicine 2009).
difficulty balancing immediate benefits and low Most medical institutions and professional
risks against the possible complications that may organizations have adopted conflict of interest
develop several years later and the uncertainty of (COI) policies (Glover et al. 2012). A conflict of
outcomes decades after the operation. interest exists when a person entrusted with the
The principle (and virtue) of justice is also interests of a patient, dependent, or the public
implicated in bariatric surgery given the signifi- violates that trust by promoting their own self-
cant disparities in access to adult bariatric surgery interest or the interest of third parties, such as
for African-Americans, Hispanics, low-income hospitals, physician groups, or insurance plans.
individuals, and males (Flum et al. 2007). Pediat- Some COIs are financial, like reimbursement
ric obesity in the USA affects one in three socially incentives or personal investments in health-care
disadvantaged children, with particularly high facilities. Other COIs are personal or involve pro-
rates among African-American girls and Hispanic fessional roles like responding to mistakes,
dealing with impaired colleagues, or the need to professionals, and result in increased malpractice
learn invasive procedures (Lo 2000). liability. But now disclosure is regarded as an
COIs are ethically problematical for physicians ethical imperative. Disclosure respects and bene-
because they can put at risk many important eth- fits patients and benefits physicians (maintaining
ical principles, particularly those of fidelity (keep- their sense of integrity and increasing knowledge
ing promises), beneficence, and non-maleficence. and skills from the mistakes). It is now thought
If a physician’s professional judgment is that nondisclosure, rather than disclosure, is in
compromised, the well-being of the patient could fact, harmful. It harms the physician’s reputation
be compromised as well. There are two main ways and undermines public trust.
that physicians can manage their COIs – disclo- When a surgical error has occurred, the pedi-
sure and avoidance. Disclosure of COI tends to atric surgeon should explain in clear language
dominate policies adopted by many institutions how the error occurred, the anticipated conse-
and professional bodies. However, there are dis- quences, how the error will be managed in this
tinct limitations to the power of disclosure alone patient, and what will be done to prevent the same
as an effective way to manage COIs. Disclosure error from harming others. In some institutions, it
can actually give patients a false sense of security is routine practice to offer compensation for
because patients can assume that a professional expenses incurred or early settlements. This prac-
who discloses is actually more trustworthy, when, tice can dramatically reduce malpractice claims,
in actuality, the COI is not really managed but which are much less common in countries with
only disclosed. Telling someone you have this no-fault compensation systems (Wei 2007).
conflict doesn’t necessarily mean that patients’ It is also important that the surgeon offer an
interests are not being put at risk – only that the apology with the disclosure of the error. “Apology
potential is now visible (Cain et al. 2005). Even a laws” have been enacted in more than 30 US
full disclosure may be too ambiguous to help states and several Canadian provinces and enable
patients determine whether bias is present. Some physicians to say they are sorry without the fear of
would argue that the only way to eliminate indus- increased liability (Wei 2007).
try bias is to avoid it whenever possible. However, The culture of medicine has changed and so,
avoidance is not always possible, especially in too, has the culture of medical education. To meet
light of industry-funded research that has the the education needs of the next generation of
potential to benefit patients. physicians, medical schools and residency train-
ing programs are using simulation modules, vir-
tual patients, and other novel educational
Surgical Error strategies to promote quality and safety (Bell
et al. 2010). The Accreditation Council for Grad-
The culture of medicine has changed to now uate Medical Education (ACGME) has made the
require robust quality and safety programs and identification of medical error recognition and
the routine disclosure of errors. The groundbreak- disclosure a core competency in medical educa-
ing 1999 Institute of Medicine (IOM) report “To tion (Christmas and Ziegelstein 2009).
Err Is Human” (Kohn et al. 2000) focused atten-
tion on the high incidence of medical errors
(as many as 98,000 patient deaths in the USA Best Interests and Innovation
each year) and other serious negative effects on and Clinical Research
patient outcomes (prolonged hospitalizations,
unnecessary suffering, and increased health-care The best interest standard with its balancing of
costs). benefits and harms for individual patients and
In the past, disclosure of errors was not com- their families rests on the assumption of good
mon and thought to be harmful both to patients information about the best proven surgical care
and their surrogates, and to the health-care in a shared decision-making process. Good
information relies on clinical research to validate or treatment, medication, or device to benefit the
the best approach, and in the current environment individual patient. Pediatric surgeons have been
of cost containment, to validate the approach that among the most notable surgical innovators,
brings the best outcome with the least costs, including procedures like appendectomy and
including financial costs. There is strong support pyloromyotomy, which may have never passed
for a professional and ethical obligation of pedi- the rigor of randomized trials. Many innovative
atric surgeons to be involved in clinical research. procedures have been widely adopted, without
According to the Committee on Pediatric much evidence to support their advantage over
Research of the American Academy of Pediatrics, standard techniques. In spite of the widespread
all subspecialists, including surgeons, should be acceptance of innovation, some worry that too
encouraged and supported to pursue research little regulation creates the potential for abuse
activities (American Academy of Pediatrics and can be harmful and dangerous (Nwomeh
Committee on Pediatric Research 2001). The and Caniano 2011). The authors cite examples
needs of newborns, infants, and younger where such innovative procedures like sympa-
children are unique and cannot be extrapolated thectomy for Hirschsprung’s disease and
from other research involving older children jejunoileal bypass for morbid obesity were subse-
and/or adults. quently abandoned and may never have been
But there are barriers to participation in widely used in the first place if a stricter regulatory
research for pediatric surgeons as well as for par- regimen were in place. They argue that pediatric
ents and their infants or children. Caniano has surgeons must be conservative guardians in sur-
noted elsewhere “that surgery, in contrast to gical innovation. They cite the work of
other areas in medicine, has been historically McKneally who claims that the terminology of
free to develop new operations and treatments innovation has a seductive connotation of added
without the stringent requirements of animal test- value that attracts patients seeking the “latest and
ing and rigorous, prospective multi-institutional greatest” treatment (McKneally 1999). Instead,
clinical trials in humans. The boundaries are Robert Levine proposes that it should be replaced
often blurred between an operation that should by the term nonvalidated, because it more accu-
be evaluated by a clinical trial before it is rately reflects the ethical and medical hazard
recommended for general implementation and an entailed in new procedures (Levine 1988). This
operation that is considered to be a refinement of concept of a nonvalidated operation may be more
an accepted procedure, and therefore not needing transparent and honest because it communicates
rigorous testing” (Caniano 2004). Other barriers clearly the fact that the proposed operation has not
include a misunderstanding of the meaning of been subjected to rigorous investigation. With this
“equipoise,” a concept necessary for the ethical awareness, both parents and pediatric surgeons
conduct of research. Equipoise requires that the may move toward supporting the ideal of RCTs,
researcher believes that one surgery or treatment when a state of clinical equipoise exists and before
is no better or worse than another or even the use it is widely imposed on vulnerable and trusting
of placebo, because there is no evidence patients and their families.
supporting one over the other. Surgeons treating Even though there is support for this obligation
critically ill children are often in a position of of pediatric surgeons, and even patients, to be
rescue and believe that doing something, even if involved in research, there may be great hesitation
it is not proven, is better than doing nothing and because of the obvious vulnerability of the family
better than enrolling a child in a trial where they and the infant or child. Researchers struggle to
may not get the proposed treatment. apply the standard of best interests by expanding
In pediatric surgery, there have been many the evidence base for pediatric practice for future
advances through research and the development patients on the one hand while also protecting the
of innovative surgical techniques. Innovation vulnerable patients in their care on the other hand.
involves the introduction of a new method, idea It is quite difficult to obtain parental permission
that is informed and voluntary under conditions of 1. Social or scientific value

duress and within a short therapeutic window. It is 2. Scientific validity
also very difficult to balance the risks and poten- 3. Fair subject selection
tial benefits of the research itself. Research stan- 4. Favorable risk-benefit ratio
dards in both the USA and Europe state that any 5. Independent review
child should only be enrolled in research when it 6. Informed consent
is absolutely necessary to answer an important 7. Respect for potential and enrolled subjects
scientific question. An important issue in both
the USA and Europe involves whether and how Because of the special vulnerabilities of chil-
pediatric research has to provide benefit to the dren, and especially newborns, three procedures
participating children. In the USA, children can have been proposed to improve protection of pedi-
be involved in research that offers no direct ben- atric research participants (Flotte et al. 2006).
efit, but only if the risks of participation are min-
imal. Children may also participate in research 1. Pediatric data and safety monitoring
that involves a minor increase over minimal risk, committees
but only if there is a reasonable expectation of 2. Robust assent processes
future benefit to those with the same condition 3. Decision monitoring that could verify the
(Flotte et al. 2006). Research guidelines from the “informed” nature of the consent
Ethics Working Group of the Confederation of
European Specialists in Paediatrics (CESP) state A final issue for consideration is what special
that “Children should not be involved in research protections should be in place for research in devel-
that serves only scientific interests and does not oping countries, as an increasing amount of
provide any benefit to them” (Gill 2004). In a research is, in fact, multinational. Emanuel and
discussion of the ethical principles and legal colleagues have proposed an eighth principle –
requirements for pediatric research in the EU, collaborative partnership – to be added to the
Pinxten and colleagues state “...the principle of seven requirements listed above (Emanuel et al.
beneficence requires that biomedical interven- 2004). This principle emphasizes the need to
tions contribute to the welfare of these persons develop partnerships among researchers, makers
(in research). This can be achieved in two ways. of health policies, and communities. It recognizes
First, biomedical interventions can generate ben- the importance of respecting the community’s
efits in the research subjects themselves. Second, values, culture, traditions, and social practices.
the drawbacks of biomedical interventions can be And perhaps most importantly, this principle
balanced with a newly generated benefit, either seeks to ensure that the recruited participants and
directly to the minor research subject or to another communities receive benefits from the conduct and
beneficiary” (Pinxten et al. 2009). A requirement results of the research. Raising the issue of research
for direct benefit has serious implications for the in developing countries also raises the more general
selection of control groups and research designs question of the role of culture in decision-making in
that include a placebo. For the regulations in the practice, as well as in research.
USA, determining what counts as minimal risk or
a minor increase over minimal risk is very com-
plex. If protecting children in research is not to be Conclusion and Future Directions
translated into excluding children from research,
special protections must be put in place. The best interest standard is a complex amalgam
In general, what are the requirements for ethi- of the values of pediatric surgeons, families, and
cal research? Emanuel and colleagues have pro- broader societies (Bowyer 2016; Noritz 2015;
posed seven requirements for determining Rhodes and Holzman 2014). The ethical princi-
whether a research trail is ethical (Emanuel et al. ples of beneficence, non-maleficence, autonomy,
2000). and justice and the virtues such as trust,
compassion, prudence, justice, courage, committed to universal access to health care.

phronesis, fortitude, integrity, honesty, and self- A global cross-cultural perspective is essential to
effacement provide a sound basis to navigate the help expand the concept of “best interests” to
ethical issues we encounter in pediatric surgery include a necessary public health focus.
practice and research. Although there is no uni-
versal solution to a given ethical problem, we
believe that an acceptable solution can be reached
if these principles are followed. Formal teaching
Cross-References
of clinical bioethics has been lacking in most
▶ Childhood Obesity
pediatric surgery training programs (Robin and
▶ Clinical Research and Evidence-Based Pedia-
Caniano 1998). However, in recent years, several
tric Surgery
pediatric surgery training programs in North
America have introduced formal case-based, prac-
▶ Fetal Surgery
tice-oriented ethics teaching sessions. In addition
▶ Innovations in Minimally Invasive Surgery in
to all the topics discussed in this chapter, we
Children
suggest that such case studies include important
▶ Patient- and Family-Oriented Pediatric Surgical
ethical concerns related to child abuse, conflict
Care
resolution, and the disruptive surgeon.
▶ Surgical Safety in Children
As health care itself becomes increasingly mul-
ticultural and international, the need for cross-cul-
Acknowledgments This chapter is based on a previous
tural ethical dialogue increases. There are no published chapter – Glover, Jacqueline and Caniano,
ultimate trump cards, just a genuine need for what Donna. Ethical Considerations in Newborn Surgery in
one philosopher calls “communitarian Newborn Surgery 3rd edition, Prem Puri editor. pages
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itself to self-evaluation and evaluation by others. In
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Childhood Obesity
33
Regien Biesma and Mark Hanson
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530
Measuring Overweight and Obesity in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Indices Based on Weight for Height Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
Consequences of Different Growth Standards . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Skinfolds and Body Circumference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Global Burden of Childhood Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532
Childhood Obesity in LMICs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Childhood Obesity and Social Economic Class . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Pathways to Childhood Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 533
Developmental Mismatch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Maternal Obesity and Gestational Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Health Consequences of Childhood Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
Childhood Obesity and Surgery Related Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
How Early Should Prevention for Childhood
Obesity Start? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 536
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Abstract
Childhood obesity can be measured with vari-
ous national and international standards and
cutoff points resulting in important differences
R. Biesma (*) in prevalence estimates. However, across all
Department of Epidemiology and Public Health Medicine,
data there is a rapid increase globally in the
Royal College of Surgeons in Ireland, Dublin, Ireland
e-mail: rbiesma@rcsi.ie numbers of children affected. Although still at
a high level, childhood obesity levels seem to
M. Hanson
Institute of Developmental Sciences, Faculty of Medicine, have stabilized in some high-income countries.
University of Southampton, Southampton, UK However, the prevalence of obesity in children
e-mail: m.hanson@soton.ac.uk

https://doi.org/10.1007/978-3-662-43588-5_35
530 R. Biesma and M. Hanson
is rapidly increasing in many low- and middle- Children who are overweight or obese can
income countries (LMICs), particularly those suffer from emotional and social problems, and
undergoing rapid demographic and socioeco- it has become a daily social problem for health
nomic transitions. There is substantial evi- professionals, teachers, and parents (Lobstein
dence that early life influences, in particular et al. 2003). The burden of childhood obesity not
prenatal environmental conditions such as only involves increasing prevalence levels in chil-
maternal adiposity, play an important role in dren but also the much earlier onset of
the development of obesity in children. Child- comorbidities such as type-2 diabetes, heart dis-
hood obesity is a serious health concern itself ease, and some types of cancer (Han et al. 2010).
and children have an increased risk of devel- Overweight and obese children are likely to stay
oping asthma, bone and joint problems, type obese into adulthood and more likely to develop
2 diabetes, hypertension, and cardiovascular noncommunicable diseases like diabetes and car-
disease later in life. Pediatric surgeons have to diovascular diseases at a younger age (Nader et al.
manage a greater number of obese children 2006).
who are more likely to have surgery related The alarming rise in obesity levels in children
complications. Identification by and awareness and the health problems that follow have pro-
among pediatric surgeons will be crucial in found economic consequences, such as the bur-
optimizing the hospital stay and outcome of den on health services, rise in medical costs and
these children. Obese children are more likely impact on national budgets, as well as loss of
to become obese adults and have an increased personal income (John et al. 2010). Although the
risk for noncommunicable diseases (NCDs) increasing levels of obesity prevalence in many
later in life. Early prevention interventions are developed countries, such as the United States,
needed to break the cycle of obesity one gen- may have stabilized (Ogden et al. 2012), obesity
eration to another and will be most cost- levels are rapidly increasing in most parts of the
effective, both in low- and high-income world, especially LMICs (Han et al. 2010; Ng
societies. et al. 2014).
Overweight and obesity, as well as their
Keywords related diseases, are largely preventable, and
Childhood obesity · Epidemiology · prevention of childhood obesity therefore needs
Interventions · Life-course · to be given a high priority (WHO 2014). There is
Noncommunicable diseases · Prevention now substantial evidence on the influence of
early life risk factors and the risk of childhood
obesity (Mameli et al. 2016) and disease later in
Introduction life and the time before conception offer perhaps
one of the most promising targets for preventive
The worldwide prevalence of childhood obesity interventions (Hanson et al. 2012). LMICs need
has increased at an alarming rate and is now one immediate action to implement effective public
of the major public health threats (WHO 2014). health programs from high income countries,
Globally, the number of overweight children adjusted to their local context, to prevent further
under the age of five is estimated to be over 42 mil- increases in childhood overweight and obesity
lion. Close to 35 million of these are living in rates and possibly reach a plateau at a lower level
developing countries (WHO 2014). There is some (Wabitsch et al. 2014). This chapter will discuss
evidence that the prevalence of childhood obesity the different measures and main mechanisms of
now seems to have stabilized in developed coun- childhood obesity, international growth stan-
tries, whereas it is rapidly increasing in developing dards, health consequences, and prevention
countries (Wabitsch et al. 2014). The reasons for strategies and also compare obesity rates across
this apparent stabilization are not known. the world.
33 Childhood Obesity 531
Measuring Overweight and Obesity such as 110–120% of ideal weight for height, or
in Children weight-for-height greater than 1 or 2 standard
deviations above a predefined mean, or gender-
Overweight and obesity are generally defined as specific 85th and 95th percentiles of body mass
abnormal or excessive fat accumulation in adi- index-for-age (Ogden et al. 2010). There are inter-
pose tissue that may impair health (WHO 2000). national (International Obesity Task Force (IOTF)
Ideally, adipose tissue would be measured and World Health Organization (WHO)) and
directly, but this is not possible in vivo (Lobstein national growth references (Center for Disease
et al. 2003). In the past, obesity was defined as Control (CDC), Spain-SRS, Italy-Luciano) to
visible excess of body fat and while clinically describe and assess overweight and obesity in
evident obesity was diagnosed easily it was not children. These growth references show weight,
that straightforward for determining overweight height, and BMI for children by age and gender in
children (Lobstein et al. 2003). Several indirect use, with different cutoff values and give therefore
methods have been developed to evaluate body slightly different estimates of overweight and obe-
composition and specifically total fat mass, such sity prevalence (Quelly 2014). In 2002, the Inter-
as underwater weighing, magnetic resonance national Obesity Taskforce (IOTF) developed
imaging (MRI), and dual-energy X-ray absorpti- international standards for classifying overweight
ometry (DEXA) (Lukaski 1987). However, many and obesity which enabled comparison of preva-
of these laboratory techniques are expensive and lence globally (Nader et al. 2006). The IOTF
invasive and not suitable for large population- recommend using these international growth
based studies or screening programs (Lahti- charts and age and gender specific cutoff points
Koski et al. 2004). Anthropometric measures are because, on average, they correspond to the adult
thus the most widely used methods for defining thresholds. The IOTF classification has been
overweight and obesity in large-scale population shown to have high specificity but low sensitivity
studies. Body mass index (BMI) is most com- (Han et al. 2010). However, many countries con-
monly used as a surrogate for body fat content tinued to use their own country-specific charts,
and a simple index of weight-for-height to classify including the United States (CDC), where stan-
overweight and obesity in adults. BMI has inter- dards are based on a national survey from early
nationally agreed thresholds, with overweight a 1960s, i.e., before the current epidemic.
BMI between 25 and 30 kg/m2 (WHO) and obe- In 2006, the World Health Organization
sity a BMI greater than 30 kg/m2. For children and released new international Child Growth Stan-
adolescents, anthropometric measures for diag- dards for children 0–5 years, based on data from
nosing overweight and obesity is more difficult international optimally nourished breast-fed
because of the influence of age, gender, pubertal infants (WHO Multicentre Growth Reference
status, and race/ethnicity on growth (Han et al. Study Group 2006). The standards depict normal
2010). The most used ones are subcutaneous early childhood growth under optimal environ-
skinfolds, different ratios of height and weight, mental conditions and can be used to assess chil-
and body circumferences (WHO Multicentre dren everywhere, regardless of ethnicity,
Growth Reference Study Group 2006). socioeconomic status, and type of feeding. Natu-
rally, there are individual differences among chil-
dren, but across large populations, regionally and
Indices Based on Weight for Height globally, the average growth is remarkably simi-
Measures lar. For example, children from India, Norway,
and Brazil all show similar growth patterns when
A variety of different terms, metrics, and cutoff provided healthy growth conditions in early life.
points have been used to define childhood over- The WHO 2006 Child Growth Standard shows
weight and obesity based on weight and height, that differences in children’s growth to age five are
more influenced by nutrition, feeding practices, WHO standards, the CDC charts reflect a heavier,
environment, and healthcare than genetics or eth- shorter sample than the WHO standards (O’Neill
nicity (WHO Multicentre Growth Reference et al. 2007). The WHO standards weight-for-age
Study Group 2006). There are also reference charts mean Z-score seem to better track healthy breast-
available for children aged 5–19 years (based on a fed infants track and would be the better tool for
revision of US data collected in 1977 adapted to monitoring the rapid and changing rate of growth
match the standards for 0–5-year-olds). Since in early infancy (de Onis et al. 2007).
2006, there are 125 countries that have adopted
the WHO standards, and many countries switched
from weight-for-age only to multiple indicators. Skinfolds and Body Circumference
Weight-for-age was adopted almost universally,
followed by length/height-for-age (104 countries) BMI is of limited use in capturing subtle alter-
and weight-for-length/height (88 countries). Most ations in growth and body composition, such as
countries opted for sex-specific charts and the total and regional body fatness, limb/trunk length,
z-score classification (22). and skeletal muscle mass (SMM), which are
needed to establish the early life origins of non-
communicable diseases such as type 2 diabetes
Consequences of Different Growth (Lobstein et al. 2003; McCarthy 2014). Triceps
Standards and subscapular skinfold measurements assess the
thickness of subcutaneous tissue and reflect fat-
There are important differences in the prevalence of ness primarily and are a useful addition to the
overweight and obesity between the WHO, IOTF, battery of growth standards for assessing child-
and national reference standards due to the choice hood obesity (O’Neill et al. 2007). Waist circum-
of cut-offs and to design and characteristics of used ference is a validated measure to measure deep
samples (de Onis et al. 2007; Monasta et al. 2011). subcutaneous as well as intra-abdominal fat accu-
Overweight and obesity prevalence estimates mulation, which represents risk of ill health (Cole
among children based on IOTF and CDC defini- et al. 2000). Waist circumference is a measure of
tions are substantially lower than estimates based abdominal fatness in children and is associated
on WHO definitions (Monasta et al. 2011; with higher fasting glucose and insulin concentra-
Wijnhoven et al. 2013). This means that using the tions and altered lipid profiles (Brambilla et al.
WHO standards will result in lower rates of under- 2013). Waist circumference is now endorsed by
nutrition (except during the first 6 months of life) the International Diabetes Federation and
and higher rates of overweight and obesity than National Institute for Clinical and Health Excel-
when CDC or IOTF standards are used (de Onis lence for diagnostic and monitoring purposes
et al. 2007). This finding was confirmed in a study (McCarthy 2014). In addition, chest circumfer-
comparing the WHO 2006 Child Growth Standard ence is associated with obesity in young children
and the UK 1990 growth standard. It showed by the and is positively correlated with rapid growth.
WHO 2006 that standard infants were less likely to Therefore, chest circumference may be a useful
be classified as underweight or having poor weight marker for rapid growth and may help clinicians
gain in the first year but more infants would be to identify obese children at 3 years of age
classified as overweight in the preschool years (Akaboshi et al. 2012).
(Wright et al. 2008).
Several studies reporting on the prevalence of
childhood obesity in high income countries have Global Burden of Childhood Obesity
used the IOTF cutoff points. However, IOTF can
only be applied to children 2–18 years old where There are only a few datasets describing the cross-
the WHO reference covers the full spectrum of sectional development of BMI values in children
childhood. When comparing the CDC with the over several decades before 1980. These data
show a rather stable or slowly increasing prevalence Many LMICs are undergoing rapid demo-
of childhood obesity (Wabitsch et al. 2014). Since graphic and socioeconomic changes that have
1980, however, there has been a dramatic increase in caused changes in dietary habits and sedentary
prevalence of overweight and obesity in children lifestyles. This has led to a shift in consumption
and adolescents in developed countries: the Global patterns from a traditional low fat and high
Burden of Disease Study 2013 reported that 24% of fiber diet to more “Western” diets that are energy
boys and 23% of girls were overweight in 2013 dense, low fiber diet, the “nutrition trans-
compared to 17% of boys and 16% of girls in ition”(Drewnowski et al. 1997; Popkin 2001). Ini-
1980 (Ng et al. 2014). Along with the increase in tially, it was thought that in high-income countries
obesity prevalence between 1980 and 2000, the obesity levels would be highest in poor people and
overall mean BMI values in children increased and rural areas and that the opposite was to be observed
the heaviest children had become even heavier in low and middle income countries. However,
(Skinner et al. 2014). Starting at around the year emerging evidence suggests that the burden of
2000, childhood obesity levels seem to have stabi- childhood obesity in developing countries is
lized in several developed countries (Han et al. shifting toward the urban poor (Popkin et al. 2012).
2010; Olds et al. 2011; Wabitsch et al. 2014). This
was in contrast to projections of continued increases,
such as in the United States where prevalence rates Childhood Obesity and Social
of obesity in children were expected to reach 30% Economic Class
by 2030. The plateauing of childhood obesity rates
was more marked in girls than boys and prevalence The causal direction of the relationship between
was declining in most preschool children (aged 2–5 childhood obesity and social economic class is
or 6 years) (Olds et al. 2011). It is unclear why complex (Wang et al. 2012). In general, socioeco-
saturation has been reached in developed countries, nomic groups with greater access to energy-dense
but it might result from cumulative public health diets are at increased risk of being obese than their
programs for obesity prevention (Waters et al. 2011; counterparts. Since 2005, the prevalence of child-
Wabitsch et al. 2014). However, it should be noted hood obesity is increasing in children in all socio-
that prevalence rates are still at a high level and still economic groups in developed countries, but
significantly higher than before 1980. Also, extreme mostly in children from low socioeconomic groups
obesity is still increasing, despite the declining rates (Grow et al. 2010). Initially, there was a greater
for lower obesity categories (Wang et al. 2011; increase among higher-SES children in developed
Skinner et al. 2014). countries, especially after 1997, when income
inequality dramatically increased (Singh et al.
2008; Wang et al. 2012). However, it seems that
Childhood Obesity in LMICs in developed countries the gap has closed in the
wrong way and children in more deprived popula-
In contrast to these findings in high income coun- tion groups have now overtaken those in least
tries, the prevalence of overweight and obesity is deprived population groups (Brunt et al. 2008).
still rising in children and adolescents in many Obesity, overweight and central obesity, and sed-
LMICs (Popkin et al. 2012). From 1980 to 2013, entary behavior coexist with undernutrition, such
prevalence rates in these countries have increased as in urban areas in India (Singh et al. 2007).
from 8% to 13% for both boys and girls (Ng et al.
2014). However, there are now several LMICs
countries that describe prevalence rates of child- Pathways to Childhood Obesity
hood obesity of more than 15% in children and
adolescents, such as Mexico (42%), Brazil (22%), It is now recognized that there are several path-
India (22%), and Argentina (19%) (Gupta et al. ways to childhood obesity, which can be summa-
2012). rized in the categories below. These are often
based on the concept that aspects of the prenatal this is associated with gender equality issues; in
environment and even aspects of parental lifestyle developed countries, despite plentiful food diets
and nutrition preconception (Dean et al. 2013) are often unbalanced in relation to both macro-
lead to childhood adiposity and obesity. In turn, and micronutrients (Hanson et al. 2009). Even
childhood obesity tracks into obesity in adoles- within the normal range of Western diets in the
cents and adults, conveying greater risk of NCDs UK, a less prudent diet before and in early preg-
(Nader et al. 2006). It should be noted, however, nancy is associated with alterations in fetal hemo-
that measurement of adiposity in young children dynamics leading to greater hepatic blood flow
in the postinfant phase may not give reliable esti- and less shunting through the ductus venosus,
mates of risk, as it is normal for children to lose and this is associated with greater adiposity at
and then regain weight (the so-called adiposity birth and age 4 years in the child (Godfrey et al.
rebound) at different rates, making comparative 2012). The improvements in socioeconomic sta-
measurements hard to interpret. tus, migration, and urbanization lead to nutritional
transitions which exacerbate this problem (Popkin
et al. 2012).
Developmental Mismatch Studies of the biology of fetal growth have
now shown that the process of maternal con-
One of the pathways leading to childhood obesity straint (evolved maternal and uteroplacental fac-
involves developmental mismatch. The theory of tors limiting fetal size to minimize risk of
predictive adaptive responses (PARs) posits that obstructed labor occurs in all pregnancies to a
prenatal environmental conditions such as mater- greater or lesser degree (Gluckman et al. 2004).
nal diet induce phenotypic changes in the devel- Greater maternal constraint predisposes the off-
oping offspring, which uses these cues about the spring to mismatch. Such constraint is greater in
current environment to predict aspects of its future primiparous pregnancies of great relevance to
postnatal environment (Gluckman et al. 2005). countries such as China where family size has
PARs have arguably evolved because this oppor- been limited (Reynolds et al. 2010). Greater con-
tunity to alter phenotype may provide a Darwinian straint is also associated with shorter maternal
fitness advantage in the predicted environment stature, multiple conception, at the extremes of
(i.e., survival to reproductive age and successful maternal age, and with unbalanced diet,
reproduction). PARs may therefore potentially smoking, or some drugs. Each of these situations
become maladaptive later in life should there be has been associated with a greater risk of child-
a disparity between the anticipated and actual hood overweight or obesity.
environment. This may arise from cues being
inaccurately transmitted (due perhaps to placental
dysfunction), or not reflecting the later environ- Maternal Obesity and Gestational
ment, due to socioeconomic and nutritional tran- Diabetes Mellitus
sition between generations. The latter can occur in
the case of maternal ill-health such as preeclamp- There is now much concern about the effects of
sia, because the mother consumes an unbalanced maternal adiposity and gestational diabetes
diet not representative of the population or, most mellitus (GDM) on risk of overweight or obesity
importantly in the contemporary context, because in the offspring (Gaillard et al. 2014). Pregnancy
diet and lifestyle influences change between one is a state of modest insulin resistance, which
generation and the next. The outcome is a situa- favors hyperglycemia and adiposity in the off-
tion of developmental mismatch, where the offspring (Hanson et al. 2012; Ma et al. 2013).
spring phenotype is not best suited to its Maternal obesity is also associated with increased
environment, leading to greater risk of disease birthweight independent of GDM (Black et al.
(Gluckman et al. 2007). Maternal undernutrition 2013) with fetal hyperinsulinemia and obesity
is relatively common in developing countries, and from the neonatal period through to childhood
and young adulthood, graded across the whole obese children become obese adults (Freedman
range of maternal BMI (Modi et al. 2011). Higher et al. 2001). There are many reviews of the health
gestational weight gain is also correlated with consequences of childhood obesity which sum-
BMI in early adulthood independently of maternal marize the conditions and comorbidities associ-
obesity. Once again these processes appear to ated with it and which are, or predispose to, NCDs
operate across the range of BMI and gestational (Lobstein et al. 2006; Han et al. 2010). Some
weight gain, at least in Western populations; there conditions occur in childhood, others later. Most
does not appear to be a threshold BMI or weight body systems are affected, and the list includes:
gain at which a pathological as opposed to a
physiological process operates. • The pulmonary system (obstructive sleep
The mechanisms underlying these pathways apnea, asthma, exercise intolerance)
are now increasingly recognized to involve epige- • CNS/psychological effects (intracranial hyper-
netic processes – work which was first demon- tension – pseudotumor cerebri, reduced quality
strated in animal studies (Lillycrop et al. 2005) but of life, depression, low self-esteem, social
is now shown to be applicable to human develop- discrimination)
ment. For example, maternal diet in early preg- • The cardiovascular system (hypertension,
nancy is associated with changes in the dyslipidemia, atherosclerosis, chronic inflam-
methylation of part of the genome associated mation, coagulopathies, left ventricular
with the RXRa gene and in turn with degree of hypertrophy)
fat mass in the child at age 6 or 9 years (Godfrey • The renal system (hyperfiltration,
et al. 2011). Epigenetic changes in metabolically glomerulopathy); orthopedic effects (lower limb
relevant genes are now also reported for the off- misalignment, slipped capital femoral epiphysis,
spring of GDM pregnancies (Ruchat et al. 2013). Blount’s disease – tibia vera, osteoarthritis, flat
Some epigenetic marks, even in blood, appear to feet, ankle strains, increased fracture risk)
be stable through childhood and to relate to child- • The gastrointestinal system (NAFLD, gastro-
hood fat mass (Clarke-Harris et al. 2014). These esophageal reflux, cholelithiasis, vitamin D
may therefore be valuable biomarkers of risk and and iron deficiency)
potentially useful for monitoring their efficacy of • Endocrine systems (insulin resistance/IGT,
interventions. type 2 diabetes, PCOS, menstrual abnormali-
Reviews on pathways linking overweight/obe- ties, hypercortisolism, pubertal advancement)
sity to NCDs show that inflammatory processes
are particularly important (Singer et al. 2014). There are also links to various cancers, par-
Wider social issues related to pathways involve ticularly of the esophagus, colon, rectum, and
ethnic differences (Taveras et al. 2013) and ampli- kidney (Ezzati et al. 2005; World Cancer
fication by migration in childhood Schooling et al. Research Fund/ American Institute for Cancer
2004). The mechanisms by which these process Research 2007). Apart from these distinct clini-
occur, which involve in part mismatch, possibly cal conditions, the quality of life is reduced in
some genetic factors, and other influences, are not obese children (Tsiros et al. 2009), making them
known (Popkin 2001; Han et al. 2010). less likely to be happy and productive adults.
The detrimental effects of obesity in terms of
social exclusion or victimization in children
Health Consequences of Childhood should also not be underestimated (Voigt et al.
Obesity 2014). Most of the reviews on health conse-
quences of obesity are derived from developed
Childhood obesity is closely associated with adult countries, although the same risks clearly oper-
obesity, hypertension, and cardiovascular disease. ate in developing countries (Kelishadi 2007) and
Obese preschool children are likely to be obese there are more data for China and Korea (Li et al.
later in childhood (Nader et al. 2006); 77% of 2008; Song et al. 2010).
Childhood Obesity and Surgery 2013). Surgical-site infections following various

Related Complications surgical procedures are more common in obese
children compared with nonobese patients. Sev-
The increased risk of complications faced by eral studies have reported that obesity is associ-
obese children undergoing surgery is well ated with significant changes in cutaneous
documented. Obesity is associated with a variety microcirculation and microcirculation which
of physiological changes which may impair a may contribute to the increased incidence of
patient’s response to surgery. While children and surgical-site infections (Wagner et al. 2012).
adolescents may experience serious health issues With the increasing rates of childhood obesity,
associated with their weight – including asthma, pediatric surgeons must appreciate differences in
obstructive sleep apnea, bone and joint problems, the management and outcomes of these patients
hypertension, cardiovascular disease, and type with surgical disorders (Ogden et al. 2014).
2 diabetes – they are even more at risk during a
surgical procedure (Mortensen et al. 2011;
Philippi-Hohne 2011). Anesthetic management How Early Should Prevention
of the obese child can be challenging and associ- for Childhood Obesity Start?
ated with a higher incidence of critical incidents
during anesthesia (El-Metiny et al. 2011). Admin- Even though recent data suggests that childhood
istering anesthesia to children is complex because obesity rates have been stabilizing in several high
their airways are still developing and are prone to income countries, no countries have had signifi-
collapse during the administration of anesthesia, cant decrease in obesity prevalence in the past
and the risk is increased by obesity. Although 33 years (McPherson 2014). Furthermore, rates
children and adolescents receive anesthesia by are increasing dramatically in developing coun-
both inhalation and intravenously, anesthesia is tries (Ng et al. 2014).
most often given by mask to younger patients, Given such high prevalence rates globally, and
which can pose more risk when the patient is that we now have identified modifiable early risk
obese. It can also be difficult to find a vein to factors and plastic phases of development, the
administer intravenous anesthesia in an obese question arises what early prevention interven-
child. Furthermore, obese children and adoles- tions could reduce childhood obesity (Pandita
cents are susceptible to other potential complica- et al. 2016). Consideration of where most effec-
tions when undergoing surgery, such as difficult tively to break the cycle will be based on evidence
mask ventilation, airway obstruction, oxygen of efficacy of intervention, but also on pragmatic
desaturation, bronchospasm, and prolonged issue of fastest route to impact, given limited
awakening from anesthesia. It has been reported resources. However, recognition of the impor-
that the obese children have a higher rate of oxy- tance of developmental plasticity as an important
gen desaturation requiring supplemental oxygen factor in influencing later life health – particularly
and unplanned overnight hospital admission than within the medical and public health communities
normal weight children (Olutoye et al. 2011). – is low, and it can be argued that this indifference
Obese children are also more likely to have a cannot be sustained in light of the growing under-
prolonged stay in the postanesthetic care unit standing of developmental processes and the rapid
probably a reflection of the increased incidence rise in the prevalence of obesity and metabolic
of upper airway obstruction (Olutoye et al. 2011; disease globally. The United Nations Political
Gleich et al. 2012). Declaration of the High-level Meeting of the Gen-
Childhood obesity has also been shown to be eral Assembly on the Prevention and Control of
associated with increased risks of complications Non-Communicable Diseases (Political Declara-
and technical difficulties during and after operation of the High-level Meeting of the General
tive procedures. It is associated with longer hos- Assembly on the Prevention and Control of
pital stay and higher morbidity (Kutasy et al. Non-communicable Diseases 2011) and the
World Health Organization (WHO) Global Strat- public awareness of the necessity to engage in
egy on Diet, Physical Activity and Health (WHO community intervention programs at many
2008) both identify population-based prevention levels. This turn requires programs to promote
as being vital to addressing rising levels of NCDs, self-efficacy and empowerment, especially in
with specific emphasis on childhood obesity. The disadvantaged groups of the population, if a vir-
realization that developmental plasticity, depen- tuous circle of intergenerational obesity preven-
dent on environmental factors during prenatal and tion is to be established to counter the vicious
early postnatal life, sets in part an individual’s circle generating increasing obesity burden
responses to later challenges such as living in an which currently operates both in low and high
obesogenic environment gives new impetus to income societies.
focusing preventive strategies on this time in the
life course (Godfrey et al. 2010). Approaches for
population-based obesity prevention can be
Cross-References
divided into three broad components:
▶ Metabolism of Infants and Children
• Structures within government to support child-
▶ Preoperative Assessments in Pediatric Surgery
hood obesity prevention policies and
▶ Surgical Safety in Children
interventions.
• Population-wide policies and initiatives that
help to create environments that support
healthy diets and physical activity, and dis-
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Surgical Problems of Children with
Physical Disabilities 34
Casey M. Calkins and Keith T. Oldham
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
Multidisciplinary Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
Family-Centered Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Non-accidental Trauma: Abuse and Neglect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
General Perioperative Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Ethical Complexity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543
Perioperative Considerations in Specific CSHCN Conditions . . . . . . . . . . . . . . . . . . . . . . 544
Cerebral Palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545
Down Syndrome: Trisomy 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Spina Bifida . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556
Abstract pediatric surgeon are cerebral palsy, Down

Disabled children with special health-care syndrome, and Spina bifida.
needs (CSHCN) may have a variety of medical Surgical care providers need to evaluate
conditions requiring often a multidisciplinary issues that may impact perioperative decision-
treatment. The most commonly faced by the making carefully when treating CSHCN as
they have or are at risk for chronic, physical,
developmental, behavioral, or emotional con-
ditions. The surgeon caring for these children
C. M. Calkins (*) must not only anticipate the unique
Division of Pediatric Surgery, Medical College of intraoperative and postoperative potential chal-
Wisconsin, The Children’s Hospital of Wisconsin,
Milwaukee, WI, USA
lenges for CHSCN but also the impact of the
e-mail: ccalkins@chw.org child’s condition on the whole family life.
K. T. Oldham
Division of Pediatric Surgery, Medical College of Keywords
Wisconsin, Children’s Hospital of Wisconsin, Children’s Cerebral palsy · Spina bifida · Down
Corporate Center, Milwaukee, WI, USA syndrome · Pediatric surgery · CSHCN
e-mail: koldham@chw.org

https://doi.org/10.1007/978-3-662-43588-5_36
542 C. M. Calkins and K. T. Oldham
Introduction suit and advances in health care continue to allow

us to offer innovative therapies for once thought-
According to the Americans with Disabilities to-be life-ending conditions. In this chapter, we
Act of 1990, a person with a disability is defined will focus on several areas of import to the pedi-
as a person with a physical or mental impairment atric surgeon when caring for the CSHCN patient
that substantially limits one or more major life with a potential surgical issue.
activities, including the ability to work, has a
record of such impairment, or is regarded as
having such an impairment. For the purposes of Multidisciplinary Management
this chapter, we will focus on disabled children
with special health-care needs (CSHCN) who are Much as a requirement of care for CSHCN is good
defined as those that have, or are at risk for, communication between the physician and family,
chronic physical, developmental, behavioral, or it is also essential that effective communication
emotional conditions and require health-care ser- exists between the numerous involved specialists
vices of a type or amount not typically required and the child’s primary care physician (Hamonet-
by children in their peer group (Stille and Torny et al. 2016). When numerous specialists are
Antonelli 2004). Not only are the health-care caring for a child in a complex situation, a central
histories of these children more complex, but provider acting as the child’s “medical home” and
they are often ill defined and further complicated coordinating care is preferred (Stille and Antonelli
by participation from multiple providers. Chil- 2004; Forrest et al. 2000). Typically, the provider
dren with special health-care needs remain more that assumes this role is the child’s general pedi-
likely to seek emergency care than their peers atrician or family practitioner. Specialists and gen-
and often for more complicated issues related to eralists need to be educated on successful means
their unique needs. of interaction and shared management of patients.
In order to address how to teach surgical care Lack of useful exchange between these physicians
providers how to address the unique pre- and leads to disorganized, lower-quality care and
perioperative issues that are presented by the spe- reduced satisfaction of both specialist and gener-
cial needs population, it is important to delineate alist alike (Forrest et al. 1999). Children with
which pediatric patients have special needs. Argu- multiple providers need a carefully planned out
ably all of our patients are “special,” yet we division of responsibility negotiated between phy-
acknowledge the fact that some patients present sicians in order to meet all of the child’s needs
medical and surgical complexities that go well efficiently (Stille et al. 2003). While a dialogue
beyond the scope of the otherwise healthy child. about division of responsibilities in a child’s care
The Maternal and Child Health Bureau has takes time on all physicians’ parts initially, in the
defined this pediatric subgroup as “Children with long run it saves duplication of efforts and pre-
Special Health Care Needs” (CSHCN) vents delay in meeting the needs of a child
(McPherson et al. 1998). CSHCN have or are at because of assumptions that “someone else will
increased risk for developing a chronic physical, handle it.” Specialists understand the importance
developmental, behavioral, or emotional condi- of articulation of the reason for referral and any
tion and require health and related services of a specific questions by the referring physician prior
type or amount beyond that required by children to a consultation. Generalists see the importance
generally. Based on a national survey of children of a prompt letter, phone call, or other form of
with special health-care needs published in 2002, communication from the specialist following a
approximately 40,000 children have a special consultative appointment that describes the likely
health-care need, and one in five homes in the diagnosis and recommended course of therapy.
USA house a child or youth with a special Without both of these forms of communication
health-care problem (van Dyck et al. 2002). This occurring, it is the patient who suffers (Calkins
number is likely to grow as our population follows et al. 2008).
34 Surgical Problems of Children with Physical Disabilities 543
Family-Centered Care USA have one or more disabilities. Additionally,

up to 80% of intellectually impaired children may
Families always play an important role in seeing be sexually abused at some point during their
through health-care directives delineated by pro- lifetime (Sullivan and Knutson 1998). Shock-
viders. For CSHCN, these issues go well beyond ingly, maltreatment in disabled children
administering a course of antibiotics for an ear approached a prevalence rate of 31%. Disabled
infection. In a survey on children with special children are three times more likely to be abused
health-care needs, 40% indicated that the patients’ than children without special needs. Known risk
condition significantly impacted to family finan- factors for abuse in disabled children include eco-
cial situation, and over 13% of respondents stated nomic disadvantage, single-parent homes, and
they spend over 11 h a week coordinating care for younger age groups. Although the overwhelming
their child (van Dyck et al. 2002). Furthermore, majority of children with special health-care
over 50% of caregivers either cutback on working needs have caretakers who ferociously advocate
or stopped working altogether to care for their and care for them, there remain children within
CSHCN. The American Academy of Pediatrics this population who are abused by caretakers.
(AAP) issued a policy statement which declared Pediatric surgeons should be vigilant about
that family-centered care is “based on the under- screening for and referring suspicious cases in
standing that the family is the child’s primary this vulnerable pediatric population.
source of strength and support; and the perspec-
tives and information provided by families, chil-
dren, and young adults are important in clinical General Perioperative Issues
decision making” (Committee on Hospital Care.
American Academy of Pediatrics 2003). For Ethical Complexity
CHSCN, the experience of negotiating illness or
a chronic condition is made more bearable by The principles upon which medical decisions are
partnership with a physician practicing family- made for CSHCN are the same as for any other
centered care. When family-centered care is pro- child: autonomy, beneficence, justice, non-
vided effectively, all parties involved benefit – the maleficence, veracity, and fidelity (American Acad-
child, the family, and the physician. emy of Pediatrics Committee on Bioethics 1996). It
is important for pediatric surgeons to discuss their
approaches toward the treatment of CSHCN with the
Non-accidental Trauma: Abuse parents and the entire treatment team. Agreement on
and Neglect principles prior to engaging in a discussion with the
family is often helpful to provide the best care, so as
The National Center on Child Abuse and Neglect to not to confuse the caregiver with differing opin-
reported that children with special needs or dis- ions from separate members of the health-care team.
abilities are at a greater risk of maltreatment and If conflicts persist over specific cases, then formal
abuse than their nondisabled peers (Lindberg consideration by the hospital ethics committee can
1999). This includes all forms of maltreatment: help with resolution although this is rarely required.
physical abuse, sexual abuse, neglect, and verbal/ For CSHCN who are hopelessly ill, or who
emotional abuse. While the estimated general have a progressive degenerative neurologic dis-
incidence of child abuse is between 6 and 14%, ease, it is important to determine in advance if
experts estimate that children with special needs parents want care to be limited. If parents request
are between 2 and 3.5 times more likely to expe- do not resuscitate (DNR) status for their child, it is
rience abuse or maltreatment during their child- useful to have them sign a physician signed DNR
hood than children without special needs statement in the medical record, both for clarity
(Sullivan and Knutson 2000). Up to 15% of chil- and for legal protection of physicians. In
dren evaluated by Child Protective Services in the discussing limitations of care, a distinction should
be made between initiation of life support and anesthesiologist should still make an attempt to
prolongation of life support. A distinction should discuss the situation with the patient’s parent or
also be drawn between DNR and palliative care. designated surrogate and come to an agreement
DNR orders generally limit care in circumstances about DNR status. Once a decision is made, the
of cardiopulmonary collapse. The ultimate goal of surgeon must continue his or her leadership role in
treatment prior to such an event is still to prolong documenting and conveying the patient’s advance
life. Palliative care is the active, all-encompassing directive and DNR status to the members of the
care of people to provide relief of and prevention operating room team and, if necessary, finding an
of pain and discomfort. Patients in a palliative care alternate team member to replace an individual
program may still be resuscitated in the event of who has an ethical or professional conflict with
cardiopulmonary arrest. “Comfort measures only” the patient’s advance directive instructions.
status is reserved for the patient with a terminal Advances in technology and in the application
condition, and the goal of treatment is no longer to of technology have improved the longevity of
prolong life but only to prevent suffering (i.e., no children with even the most severe disabilities.
further diagnostic or therapeutic interventions) Parent advocacy groups are quick to point out
and must be accompanied by a DNR status. that denying care to a child because of the child’s
Some patients with DNR status become candi- disability is tantamount to discrimination and is,
dates for surgical procedures that may provide therefore, a denial of civil liberty. Many of these
them with significant benefit, even though the same advocates believe that quality of life consid-
procedure may not change the natural history of erations should not be taken into account when
the underlying disease. Cardiopulmonary resusci- making medical decisions about surgical interven-
tation (CPR) in the OR carries a very different tions in CSHCN. However, physicians do not
medical prognosis than CPR administered in other have an ethical obligation to institute treatment
hospital areas. While it is rare for a patient to to try to change the course of a condition in
survive to discharge after CPR in the hospital CSHCN with a hopeless prognosis if the treatment
ward, some 50–80% of patients resuscitated in would be futile in prolonging life. Presentation of
the OR return to their former level of functioning. available data regarding the natural history, the
In the OR, the event of arrest is always witnessed, risks of surgery for mortality and morbidity, and
and the proximate cause usually known, allowing the complications of surgery should be made
rapid, effective intervention which is directed empathetically. If, in his experience, the surgeon
toward the specific cause of arrest. Also, causes considers a child not to be a surgical candidate
of arrest in the OR are often reversible effects of because of the futility of surgery to prolong life,
anesthesia or hemorrhage and not usually due one does not have the obligation to perform sur-
primarily to the patient’s underlying disease. gery. In this circumstance, it is important for the
Thus, automatic enforcement of DNR orders surgeon to explain that the decision not to perform
without discussion and clarification may not ade- surgery is not due to the child’s disability, but
quately inform patients or their authorized repre- rather given the futility of surgery for the purpose
sentatives about the new risks associated with of prolonging life. For parents who continue to
surgery and anesthesia and may lead to inappro- insist on surgery, a second opinion from another
priate perioperative and anesthetic management. specialist is recommended.
A discussion should occur as early as practical
after a decision is made to undergo surgery. This
discussion may result in the patient or surrogate Perioperative Considerations
agreeing to suspend the DNR order during surgery in Specific CSHCN Conditions
and the perioperative period, retaining the original
DNR order, or modifying the DNR order. In CSHCN can have a variety of medical conditions;
urgent or emergent situations or when the patient however, we have chosen to focus on those con-
lacks decision-making capacity, the surgeon and ditions most commonly faced by the pediatric
surgeon: cerebral palsy, Down syndrome, and implanted in the subcutaneous or subfascial tis-
spina bifida. The preoperative evaluation of any sues of the lower abdomen, and the location of
CSHCN should address common issues that may this large device must be taken into consider-
impact perioperative decision-making, and the ation when planning an appropriate laparotomy
surgeon caring for these children must anticipate incision, stoma site localization, or port place-
the unique intraoperative and postoperative ment in laparoscopic surgery. In addition, con-
potential challenges for CHSCN. sultation with the physician responsible for
management of the IBP prior to elective surgery
is wise to ensure that the pump has adequate
Cerebral Palsy baclofen.
Surgical correction of scoliosis is one of the
A consensus definition of cerebral palsy (CP) is more commonly performed elective surgical
that it is an umbrella term covering a group of procedures in patients with CP. Although
nonprogressive, but often changing, motor advances in surgical instrumentation and tech-
impairment syndromes secondary to lesions or nique have allowed for more patients to be
anomalies of the brain (O’Shea 2008). Most treated by posterior fusion alone, the anterior
cases of CP are caused by abnormal brain approach for intervertebral discectomy remains
development in the first trimester, not birth valuable in select circumstances. The pediatric
asphyxia or prematurity, as was previously surgeon is often called upon to provide exposure
believed. Cerebral palsy is classified according for the necessary disk spaces to be addressed by
to the pattern of motor involvement of extremi- the orthopedic surgeon (Janik et al. 1997). Pre-
ties (hemiplegia, one side; diplegia, lower operative planning with the orthopedic surgeon
extremities involved, upper extremities only is essential to ensure that the planned exposure
mildly so; quadriplegia, all extremities will be adequate to allow for optimal anterior
involved) and by the type of neurologic dysfunc- release and ensure the expected outcome. Sur-
tion (spastic, hypotonic, dystonic, athetotic, or a geons charged with providing anterior exposure
combination). are referred to two excellent references when
planning for these operations (Benzel and
Spasticity, Body Habitus, and Scoliosis AANS Publications Committee 1995;
For the surgeon, it becomes essential that patient Hoppenfeld et al. 2009). Thoracoscopic
body habitus and its effect on the planned surgi- approaches to anterior discectomy have also
cal approach be considered. For instance, in a been performed successfully (Norton et al.
patient with severe lower extremity contractures, 2007; Holcomb et al. 1997). Children undergo-
a laparoscopic operation may not be feasible ing surgical correction of spinal deformities may
if body habitus does not allow for adequate occasionally experience the superior mesenteric
extracorporeal clearance of laparoscopic instru- artery syndrome, with rates after corrective spi-
mentation. Alternatively, such an operation may nal surgery reported between 0.5% and 2.4%.
be possible, but the port sites must be altered Symptoms of superior mesenteric artery syn-
from their generally accustomed position. drome typically include nausea, bilious emesis,
Although treatment for spasticity may be initi- abdominal pain, early satiety, and anorexia. Ini-
ated using oral medications, these drugs have tial treatment focuses on gastric decompression,
limited use because of adverse effects. CHSCN maintaining euvolemia and electrolyte balance
with spasticity are often treated with injections and nutritional support. The duodenal obstruc-
of botulinum toxin (Delgado et al. 2010) or an tion should be bypassed for feeding by a
intrathecal baclofen pump (IBP) (Dan et al. nasoduodenal or gastroduodenal tube advanced
2010). Continuous infusion of baclofen into the beyond the point of obstruction. Gastrostomy
CSF concentrates the drug locally where it feedings may be necessary after resolution of
achieves its therapeutic effect. An IBP is often gastric distention to prevent recurrence. Other
surgical intervention is not usually indicated, Nutrition, Feeding,

although parenteral nutrition may also be and Gastroesophageal Reflux
helpful. The usual causes of malnutrition in children with
CP are inadequate caloric consumption due to
General Perioperative Neurologic poor oral-motor function (neurologic dysphagia),
Considerations increased metabolic demand due to a hyperkinetic
Associated neurologic problems in patients with movement disorder, food aversion as a learned
CP include seizure disorders, strabismus, visual response to the discomfort of eating caused by
field defects, sensorineural hearing loss, learning either gastroesophageal reflux or chronic aspira-
disabilities, and emotional problems. Patients tion (or both), and rarely parental neglect. Some
with a seizure disorder are often considered at patients have combinations of the above causes.
high risk during procedures, based primarily on The general definition of malnutrition is a
the risk of seizures occurring during or shortly chronic nutritional state resulting from protein-
after the procedure and, to a lesser degree, on the calorie consumption that is inadequate to meet
potential interaction between drugs for the proce- metabolic needs for health maintenance and growth
dure and for seizure control. The surgeon must over time. Malnutrition is associated with poor
make an appropriate plan for the perioperative somatic growth, diminished bone mineral density,
management of antiepileptic drugs (AEDs) that abnormal progression through puberty, limited
involves the continued use of medications right societal participation, and poor health (Kuperminc
up to the point of a planned operation and the and Stevenson 2008). Growth charts for adequately
provision of postoperative antiepileptic treatment. nourished children with cerebral palsy are now
Oral doses of AEDs should be administered the available as standard weight for height percentiles
morning of surgery with a small sip of water. If the perform poorly to identify malnutrition in children
duration of the surgical procedure exceeds the with cerebral palsy (Brooks et al. 2011). Advanced
half-life of the maintenance AED, some AEDs methods for determining nutritional status such as
can be administered intravenously. Serum drug measurement of triceps skinfold thickness and
levels may be significantly altered by anesthetics mid-arm circumference require expertise, expen-
and by the physiologic changes resulting from sive measuring tools, availability of tables of
surgery; thus, AED levels should be monitored age-appropriate norms, and substantial time and
closely in the perioperative period. Some children are not especially practical. Furthermore, patients
with a seizure disorder have had implantation of a with CP have an altered body composition
vagal nerve stimulator (VNS). This device is gen- such that the fat mass is maintained more
erally implanted subcutaneously in the upper centrally as compared with able-bodied peers
chest and serves to prevent seizures by sending (Tomoum et al. 2010).
regular, mild pulses of electrical energy to the
brain via the vagus nerve. Electrocautery or Neurologic Dysphagia and Aspiration
radio-frequency ablation may damage the gener- Causes of nutritional failure in children with cere-
ator; however, a VNS does not necessarily need to bral palsy can typically be ascribed to poor oral
be deactivated or inhibited during surgery. motor function (neurologic dysphagia), high met-
Recommended maneuvers to minimize damage abolic demands due to a hyperkinetic movement
to the electrical circuitry from electrocautery disorder, oral aversion secondary to pain from
include positioning grounding pads so as to pre- chronic aspiration and/or gastroesophageal reflux,
vent current flow through the system and as far or rarely caregiver neglect. Ultimately, nutritional
away from the VNS generator as possible. Never- failure is defined as protein-calorie consumption
theless, consultation with the neurologist respon- that is inadequate to meet metabolic needs. The
sible for management of the device is severity of neurologic dysphagia can be roughly
recommended prior to an elective surgical judged by the time it takes to feed a child. Chil-
procedure. dren who require more than 60 min to be fed a
typical meal and who are fed four meals or more order to propose an individualized treatment
per day are rarely adequately nourished. Calorie plan. Under fluoroscopic observation, children
counts can be used to confirm the suspicion of are fed four textures of food (thin liquids, thick-
inadequate nutrition. Typical findings associated ened liquids, pureed foods, and chopped foods),
with neurologic dysphagia are hypotonic lips, all mixed with barium. Phases of swallowing are
poor lingual function, delayed swallow reflex, observed and abnormalities noted. The therapist
and poor esophageal peristalsis. These neurologic attempts to determine the optimal circumstances
abnormalities lead to slow oral-pharyngeal transit for oral nutrition, and a feeding program is
time (Jones 1989). A recent epidemiological study devised. If weight gain is not achieved in an
among 1357 children between 1992 and 2009 agreed upon time frame, then enteral access
showed a dysphagia prevalence of 43% in chil- should be considered. Parents generally accept
dren with CP in any degree (Parkes et al. 2010). In the need for enteral access if they have exhausted
addition, particular care is necessary to avoid all resources to improve the ability of the child to
overfeeding and the associated morbidity take oral feedings.
(Andrew et al. 2012). Prior to consideration of surgically placed
The fundamental cause of aspiration in chil- enteral access, an upper gastrointestinal
dren with cerebral palsy is inability to protect the (GI) series should be obtained, as it is important
airway. This is due to either glossopharyngeal to ensure surgical candidates do not have an
dysfunction, immobility resulting in inability to esophageal stricture, hiatal hernia, malrotation,
roll from supine to side after vomiting, or both. A or other GI anomaly that may alter the plan for a
history of choking during meals, especially when gastrostomy. In addition, a liquid-phase radionu-
drinking liquids, suggests aspiration. A gag reflex clide gastric emptying study is useful to measure
that is both difficult to elicit and has little palatal gastric emptying time. Although a 24-hour pH
movement is associated with neurologic dyspha- probe study is considered to be the “gold stan-
gia and aspiration. Alternatively, an extremely dard” for diagnosis of GER, Heine et al. found
active gag reflex with repeated retching may also that the sensitivity of an abnormal pH study as a
be associated with dysphagia and aspiration. Hyp- predictor of esophagitis was only 38.5% and the
oxemia during feeding is a useful indicator of specificity was only 71.4% (Heine et al. 1995).
significant aspiration (Rogers et al. 1993). Pulmo- Esophagoscopy can be useful in evaluating chil-
nary problems caused by aspiration include dren for erosive esophagitis and its consequences,
chronic asthma, bronchitis, recurrent pneumonia, and we believe it is a valuable part of the preop-
atelectasis, bronchiectasis, hoarseness, stridor, erative evaluation. This can often be accom-
and apnea. Video fluoroscopic study of plished under the same general anesthesia when
swallowing (VFSS) has demonstrated pulmonary plans for a gastrostomy have been made.
aspiration in up to 70% of patients with severe CP
(Mirrett et al. 1994), and frequently aspiration Gastrostomy
occurs without coughing so-called silent aspira- Indications for gastrostomy in malnourished chil-
tion (Kim et al. 2013; Weir et al. 2011). Repeated dren with cerebral palsy are controversial. There
pulmonary aspiration leads to chronic coughing, is general agreement among physicians who care
sleep-disordered breathing, impaired clearance of for these children that both aspiration and under-
airway secretions, colonization of the respiratory nutrition associated with any adverse health con-
tract by pathogenic bacteria, a high risk of pro- sequence should be treated by gastrostomy
gressive parenchymal lung damage, and potential feedings. Progressively worsening nutritional sta-
mortality. tus in an already undernourished child is an indi-
cation for gastrostomy feedings. Feeding
Evaluation of a Possible Feeding Disorder problems that are present early in life in children
Videofluoroscopic investigation is helpful in with cerebral palsy tend to persist (Motion et al.
defining the nature of the feeding disorder in 2002). Feeding efficiency will not improve in
these children in proportion to their increasing esophageal motility, gastric contraction, and
need for calories as they grow; therefore, under- delayed gastric emptying occur much more fre-
nourishment will only worsen with time. Finally, quently than in neurologically normal patients
aspiration of oral feedings even in the absence of with GER (Del Giudice et al. 1999). In addition,
pulmonary disease can be an indication for enteral GERD in children with CP may also result from
feedings because it places a patient at great risk. direct lesions in cortical areas that modulate
The method by which a gastrostomy is placed is brainstem activity, increased intra-abdominal
beyond the scope of this chapter, but will likely be pressure due to abdominal muscle spasticity
covered in another chapter. and/or retching, constipation, and/or scoliosis.
Conventional medical therapy of GERD is less
Jejunostomy effective in children with CP, and surgical treat-
Children with cerebral palsy may require post- ment, while associated with high operative risk
pyloric feeding access for a variety of reasons – and significant morbidity, ultimately has an
as a primary method of enteral access, after a acceptable outcome for many (Wilkinson et al.
failed fundoplication with resultant GERD, gas- 1981). Neither vomiting nor aspiration of refluxed
tric dysmotility, or microgastria. Various tech- gastric contents is prevented by medical treat-
niques have been advocated. A Witzel ment. The use of histamine receptor 2 antagonists
jejunostomy is technically simple to perform; and proton pump inhibitors alkalinize gastric acid,
however, the feeding tube is prone to dislodge- but alkaline GER still occurs (Malthaner et al.
ment making it a poor choice for long-term enteral 1991), and persistent GER may cause erosive
access in a neurologically impaired child. Crea- esophagitis, leading to pain, oral aversion,
tion of a Roux-en-Y jejunostomy in order to place hematemesis, esophageal stricture, and even
a secure feeding access device avoids this prob- Barrett’s metaplasia and dysplasia.
lem, but the procedure is slightly more involved There is considerable uncertainty regarding
and requires a jejunojejunostomy (Williams et al. the optimal treatment for the neurologically
2007). We prefer a loop jejunostomy technique impaired child with GERD who requires a
performed either through a small laparotomy inci- gastrostomy for nutritional support. Surgical
sion or laparoscopically and placement of a bal- options range from gastrostomy alone, gastroje-
loon button access device (Ruiz-Elizalde et al. junostomy, partial or complete fundoplication,
2009). In children who require long-term jejunal gastrostomy and/or fundoplication along with a
feeding access, some children are managed by gastric emptying procedure, feeding
placement of an image-guided gastrojejunostomy jejunostomy, or esophagogastric disassociation.
tube placed through a gastrostomy tract. When The most controversial question is whether
applicable, we prefer a surgically placed fundoplication is necessary for the neurologi-
jejunostomy to long-term image-guided gastroje- cally impaired child when performing a
junostomy as surgically placed jejunostomy tubes gastrostomy. Efficacy of fundoplication in neu-
require fewer adjustments and result in fewer hos- rologically impaired children may be similar to
pitalizations per year (Raval and Phillips 2006). normally developed children; however, the lack
of high-quality prospective studies on antireflux
Gastroesophageal Reflux and Delayed surgery in children with neurologic impairment
Gastric Emptying prohibits a universally accepted approach
Neurologically impaired children have a high (Mauritz et al. 2011; Vernon-Roberts and Sulli-
prevalence of gastroesophageal reflux disease van 2013). However, there are certain groups for
(GERD) compared to typical children. The etiol- whom a fundoplication should be highly consid-
ogy of GERD in this population may be due to ered. Inability to protect the airway is perhaps
lesions in the neuronal-anatomic swallowing cen- the most important factor in deciding if a
ter located in the medulla oblongata leading to an fundoplication is necessary when performing
altered vago-vagal reflex. Indeed, abnormalities in gastrostomy. Even intermittent GERD or rare
vomiting in a child with the inability to protect 1994). Decreased retching and “gas bloat” may be
the airway can result in aspiration pneumonia realized if a pyloroplasty is done along with a
and death. Children who are completely immo- fundoplication in patients with neurologic impair-
bile are at great risk for aspiration when they ment and preoperative delayed gastric emptying.
vomit, even without diagnostic proven aspira- Patients with gastroparesis are less likely to do
tion or GERD. Patients with cerebral palsy well after gastrostomy and fundoplication, and a
older than 3 years of age who have no symptoms surgically created jejunostomy should be consid-
of GERD or of aspiration yet who can protect ered. Total esophagogastric dissociation has been
their airway, but have an abnormal pH probe described as both a primary and a rescue proce-
study (pH 4.0 for 10% of a 24-h study), should dure for neurologically impaired patients with
be considered for fundoplication because it is severe gastroesophageal reflux. Esophagogastric
unlikely that the GERD will resolve (Sullivan dissociation is associated with adequate nutri-
1999). Patients who develop GERD after tional rehabilitation, reduction in respiratory
gastrostomy are also surgical candidates for a infections, and improved quality of life (Gatti
fundoplication because the alternative is lifelong et al. 2001; Peters et al. 2013).
medical management and endoscopic surveil-
lance (Ponsky et al. 2013) (30). Complications of Gastrostomy
Neurologically impaired patients who require a and Fundoplication
gastrostomy for nutritional support, but who have Complications most frequently encountered in
no preoperative evidence for gastroesophageal patients with feeding tubes include dislodgement,
reflux or aspiration, may do well without a tube obstruction or leakage, and wound issues
fundoplication. In patients who have no risk factors associated with the tube exit site. When a child
for aspiration, a trial of tube feedings can be helpful presents with premature dislodgement of a feed-
in selecting those who will tolerate bolus feedings ing tube, the most important history to gather is
without vomiting. For patients who aspirate and the type of tube and how long ago it was placed.
who have had a gastrostomy alone and develop This determines the level of urgency of tube
GERD, long-term gastrojejunal feedings are asso- reinsertion and whether or not it is safe to do
ciated with a high rate of complications and are not so. When a tube is dislodged, the stoma should
superior to an antireflux procedure (Wales et al. be investigated for bleeding or obvious disrup-
2002). However, neurologically impaired patients tions of the tract from which it emanates. When
with preoperative retching may have abnormal acti- tubes are dislodged within 6 weeks of placement,
vation of the emetic reflex rather than classic providers must be concerned that the stomach has
GERD. Postoperative retching continues after a fallen away from the abdominal wall, making
fundoplication in 75% of such patients. One may peritoneal contamination from leaking gastric
consider this to be a relative, yet not absolute, secretions a possibility. If the tube has been in
contraindication to antireflux surgery and other sur- place for more than 6 weeks, prompt placement
gical strategies such as jejunostomy feedings or an of a Foley catheter into the existing stoma will
esophagogastric disassociation may be considered. prevent rapid closure of the site, allowing for
Delayed gastric emptying, defined as greater replacement of the appropriate tube once it
than 50% gastric retention of an isotope at 90 min, becomes available. It is important to verify
was found in 75% of neurologically impaired intraluminal position once the tube has been
children who required a fundoplication, as com- replaced. This can be done through simple phys-
pared with 25% of normal children undergoing ical examination – auscultation of air in the stom-
fundoplication (Fonkalsrud et al. 1995). Improved ach and aspiration of gastric contents. If there is
surgical results after pyloroplasty accompanying any concern about the tube reinsertion, the use of a
fundoplication for patients with cerebral palsy and simple contrast study will verify tube position,
delayed gastric emptying have been reported by and we advocate doing so if there is any question
some authors, but not by others (Maxson et al. about the tube location.
Tube obstruction is another common compli- paraesophageal hernia, bowel obstruction, and
cation associated with feeding tubes, secondary to esophageal stricture. Several complications
kinking of the tube or solidification of formula deserve specific comment. Retching can be
within the tube. Gentle flushing with warm water caused by either delayed or overly rapid gastric
usually is sufficient to reestablish patency, and the emptying and may be a preexistent condition.
use of carbonated beverages to accomplish the Delayed gastric emptying after surgery is often a
same goal is commonplace in many institutions. transient problem. Continuous infusion of for-
When flushing fails to clear the obstruction, mula can improve feeding tolerance until gastric
replacement of the feeding tube is indicated. emptying improves. Some children with normal
Leaking around a feeding tube causes skin irrita- gastric emptying preoperatively, however,
tion and breakdown, often leading to nonhealing develop delayed gastric emptying after
wounds in an already fragile population. Tube gastrostomy and fundoplication and require a sub-
sites and stomas may enlarge over time, promot- sequent pyloroplasty. Patients with the dumping
ing drainage of gastric or jejunal contents around syndrome often present with retching associated
the tube. The answer is not to replace the tube with diarrhea and symptoms of hypoglycemia
with a larger diameter tube, as this will only widen (pallor, sweating, and tachycardia). Their symp-
the stoma site. Replacement of the tube with one toms can often be controlled satisfactorily by
of smaller diameter, and application of protective feeding with an elemental formula by continuous
skin barrier, allows skin constriction around the infusion or adding cornstarch or another thicken-
tube and healing of the compromised skin. The ing agent to the formula. An appropriately sized
skin around a feeding tube can become irritated button feeding device for a gastrostomy virtually
due to leaking, tube anchors, and granulomas. eliminates the complication of gastrostomy tube
Cleansing and drying of the skin is important in migration into the duodenum and associated small
allowing the site to heal. Though these issues bowel obstruction, but if the gastrostomy is placed
rarely pose an emergency, persistent cellulitis too close to the pyloric channel, gastric outlet
may require admission for skin care and intrave- obstruction can occur regardless of the device
nous antibiotic therapy. utilized. Adhesive small bowel obstruction is a
Occasionally, children with feeding tubes pre- significant early and late complication, usually
sent with signs and symptoms of bowel obstruc- presenting with abdominal distention. Early oper-
tion. These children are at higher risk for adhesive ative intervention should be considered when
obstruction due to their past surgical history; how- small bowel obstruction is suspected in a patient
ever, it is important to remember that distal migra- who has had a fundoplication.
tion of balloons can occur, causing obstruction of
the pylorus and jejunal lumen. A contrast study Surgical Outcomes of Enteral Access or
can further define the cause of a child’s obstruc- Fundoplication
tion. Jejunostomy balloons should be filled with Gastrostomy feedings (with or without an anti-
the minimal amount of water to allow for adequate reflux procedure) have beneficial effects on the
tube placement to prevent this complication. nutritional state of undernourished children with
The complication rate of fundoplication in cerebral palsy (Samson-Fang et al. 2003). A num-
children with cerebral palsy is higher than in typ- ber of studies of undernourished children with
ical children (Caniano et al. 1990). Early compli- cerebral palsy suggest that quality of life generally
cations include pneumonia, wound infection or improves and frequency of hospitalization dimin-
dehiscence, obstructive wrap, esophageal or gas- ishes (Wilkinson et al. 1981; Sullivan 1999;
tric perforation, bowel obstruction, pancreatitis, O’Loughlin et al. 2013; Bui et al. 1989). Overall,
splenic injury, and vagal nerve dysfunction. Late “good to excellent” results after gastrostomy and
complications include gas bloat, delayed gastric fundoplication have been reported in up to 84% of
emptying, retching, dumping syndrome, neurologically impaired children with a less than
fundoplication disruption or migration, 1% operative mortality rate (Fonkalsrud et al.
1995). The true incidence of wrap failure is the avoidance of morbidity associated with treat-
unknown but can range from 10 to 50%. How- ment (Evans et al. 2013; Mathiesen et al. 2013).
ever, the complication rate for fundoplication is
no longer as high as previously reported in older
studies. Furthermore, re-operative fundoplication Down Syndrome: Trisomy 21
can be successful when the initial fundoplication
fails. In 101 neurologically impaired children who Down syndrome (DS) results from meiotic non-
underwent a redo fundoplication after an initial disjunction of chromosome 21and resultant tri-
fundoplication failed, 71% experienced adequate somy of the entire chromosome or a portion of
results (Dalla Vecchia et al. 1997). If a third anti- it. It is one of the most common developmental
reflux procedure is necessary in a neurologically disabilities and occurs in 14.47 per 10,000 US live
impaired child, we recommend consideration for births (Parker et al. 2010). Approximately 6000
an alternative operative strategy such as feeding infants per year in the USA are born with DS.
jejunostomy or an esophagogastric dissociation. Although many patients with DS lead produc-
tive and fulfilling lives well into adulthood, men-
Decubitus Ulcers tal deficiency is almost universal. Forty percent of
The prevalence of decubitus ulcers in the pediatric patients have a cardiac anomaly. The most com-
population is lower than that in the adult popula- mon of these, in decreasing order of frequency, are
tion, yet has been reported as high as 25% in atrioventricular canal, ventricular septal defect,
vulnerable ICU patients (Sullivan and Knutson patent ductus arteriosus, atrial septal defects, and
2000). CHSCN with spinal cord injury, cerebral aberrant subclavian arteries. Thyroid disorders, a
palsy, or spina bifida are at higher risk. In the USA 10- to 20-fold higher risk of acute leukemias, a
alone, more than 40,000 patients with spinal cord markedly lower incidence of solid tumors, and a
injury develop new pressure sores every year, and higher incidence of congenital gastrointestinal
management of these ulcers can require pro- anomalies, are also hallmarks of DS.
longed, complex treatment (Atiyeh and Hayek
2005). The most common sites for skin break- Gastrointestinal Malformations
down include the gluteal region, soles of the and Down Syndrome
feet, and upper extremities. The majority of pres- Duodenal stenosis or atresia is the most common
sure ulcers are diagnosed during an early stage gastrointestinal anomaly that occurs in patients
(partial thickness), and rates have markedly with DS, and this is discussed in detail elsewhere.
decreased as awareness of skin fragility has The overall surgical mortality rate of this is
increased. Whether treated with conservative slightly higher than for typical infants, but this is
wound care measures or surgery, pressure ulcers largely attributable to associated cardiac
recur in a large number of spinal cord injury malformations and immune compromise. Devel-
patients (Niazi et al. 1997). For the pediatric sur- opment of oral-motor function in children with
geon, one must document the presence of pre- DS lags behind intellectual development and
existing pressure ulcers prior to surgical may ultimately require placement of an enteral
intervention and take appropriate steps to address access device. However, we do not routinely
caring for such a lesion in the perioperative place a gastrostomy at the time of duodenal atresia
period. This is also of import from a financial repair, reserving to do so at a later date if the child
standpoint, as pay for performance measures is unable to tolerate enteral feedings after repair.
have made reimbursement for pressure ulcers The most frequently reported anorectal malforma-
acquired while in the hospital difficult if not tion associated with DS is a low-lying rectal
impossible to obtain. The use of nursing care pouch without a genitourinary or perineal fistula,
“bundles” has been shown to dramatically reduce although the presence of DS is not a contraindi-
the incidence of hospital-acquired pressure ulcers cation to standard surgical management (Torres
which translates into significant cost savings and et al. 1998). The association of Hirschsprung
disease (HD) with DS is well recognized. A large Patients with DS are particularly susceptible to
number of patients with DS continue to have infectious diseases during childhood as a result of
persistent bowel dysfunction after surgical treat- the association of the syndrome with an immuno-
ment of HD, higher rates of postoperative entero- deficiency of multifactorial origin and the coexis-
colitis, poorer functional outcomes, and increased tence of structural anomalies, particularly in the
mortality (Friedmacher and Puri 2013). However, respiratory tract. The immune dysfunction in DS
others have shown that the coexistence of HD and is generally not a contraindication for currently
DS does not influence outcome after the manage- available vaccines (Green 1988). Of particular
ment of HD (Hackam et al. 2003). concern to the surgeon is that the hepatitis B
infection carrier state is more common among
Other Operative Considerations noninstitutionalized children with DS. Up to
in Patients with Down Syndrome 20% of those with Down syndrome who test pos-
Gastrointestinal dysmotility is common in chil- itive for hepatitis B surface antigen have no overt
dren with DS, particularly encountered in the clinical or laboratory signs of liver disease. There-
esophagus and colon (Martinelli and Staiano fore, we recommend that all older children with
2011). There is a high prevalence of severe Down syndrome who have not been immunized
GERD with the occurrence of serious complica- and are undergoing surgery should be tested for
tions, such as aspiration and pneumonia in up to hepatitis B surface antigen.
40% of DS patients (Hillemeier et al. 1982). When
medical treatment is ineffective in managing
severe GERD in children with DS, an antireflux Spina Bifida
procedure can be offered; however, one must con-
sider the possibility of preexisting esophageal Spina bifida (meningomyelocele) occurs as a
dysmotility, and an appropriate preoperative result of failure of the neural tube to close during
esophageal motility evaluation should be sought. the first trimester. The vertebral bodies are splayed
Indeed, Zarate and colleagues have shown a open, and the spinal cord is malformed. The defect
greater retention of both liquid and semisolid can occur at any vertebral level, and neurologic
boluses in DS patients, and others have shown consequences depend on the pattern of innerva-
that achalasia is more common in DS patients tion at and beyond the level of lesion. Surgical
when compared with the general population closure of the spinal lesion is traditionally under-
(Zarate et al. 2001). taken on the first or second day of life; however, in
Atlantoaxial instability occurs in approxi- select circumstances, the defect may be closed in
mately 15% of children with DS, and hyperexten- utero. Traditionally, 80–90% of patients have
sion of the neck for endotracheal intubation has hydrocephalus that requires placement of a ven-
resulted in acute paralysis due to spinal cord tricular drainage shunt, although prenatal repair is
injury. However, cervical spinal cord injury can associated with a decrease in the need for a shunt
occur without evidence of subluxation on cervical postnatally (Adzick et al. 2011). We believe that
radiographs. Therefore, the surgeon should obtain children with spina bifida are best followed in a
a careful history with a focus on signs of cervical multidisciplinary clinic staffed by a pediatric neu-
instability and attempt to elicit readily detectable rosurgeon, a pediatric orthopedic surgeon, a pedi-
neurologic signs on a preoperative physical exam- atric urologist, and a pediatrician. Issues in this
ination. It is also prudent for the anesthesiologist population that are pertinent to the pediatric gen-
to treat all children with DS as if they might have eral surgeon are discussed.
cervical spine instability, taking this into consid-
eration while positioning and performing intuba- Latex Allergy Resulting in Intraoperative
tion. If there are concerning signs or symptoms Anaphylaxis
preoperatively, radiographic evaluation of the cer- Twenty to 40% of patients with spina bifida are
vical spine is warranted (Dedlow et al. 2013). allergic to latex (Bui et al. 1989). A relation exists
between the number of surgical procedures and shunt). Proximal and distal catheter occlusion,
the incidence of latex allergy, suggesting that disconnection, and infection are the most com-
intraoperative latex exposure sensitizes patients. mon reasons for shunt malfunction (Stone et al.
Some patients who have never had surgery, how- 2013). Mechanical failures are related to either
ever, are also allergic to latex, possibly as a con- improper functioning of the shunt or improper
sequence of exposure to latex catheters or gloves. placement of the device and include shunt
It is possible that there is some predilection obstruction, fracture or disconnection of the
toward the development of latex allergy that is device components, and migration. Migration of
intrinsic to patients with spina bifida. the shunt can occur from the site of its initial
Intraoperative anaphylaxis from latex allergy placement into a position where it can no longer
exposure may occur in patients with spina bifida. effectively drain CSF. Cerebrospinal fluid malab-
Most institutions have instituted hospital wide sorption may lead to abnormal accumulation of
latex avoidance for all patients with spina bifida, the fluid and may result in functional failure of the
regardless of whether they have had a previous shunt. Infectious complications typically occur
reaction to latex. This practice has been shown to within 6 months of shunt insertion and occur in
prevent latex sensitization as well as ensure no up to 10% of patients in some series. Most are due
allergic child has an anaphylactic reaction while in to inoculation with skin flora at the time of surgery
the hospital. In years past, one significant problem or seeding from sites of distal infection. These and
with first-generation latex-free gloves was that other complications may prompt consultation by a
surgeons found them to be prohibitive for use pediatric surgeon.
due to limitations in tactile sensation. But today, The general surgeon would be wise to have a
latex-free gloves are widely available that offer firm understanding of shunt tubing location in a
equal tactile sensation such that discomfort should patient with a VP shunt prior to elective or emer-
not be considered an obstacle for using them. gent abdominal surgery. We do not consider the
Latex exposure resulting in anaphylaxis is com- presence of a VP shunt to be a contraindication to
mon enough and well enough described in this creation of a pneumoperitoneum necessary for
population to be a considered a medicolegal risk. laparoscopy (Fraser et al. 2009). Planning for an
For patients with a known latex allergy, strict latex appropriate incision or port placement is neces-
precautions should be followed, and pre- sary to avoid damaging indwelling shunt tubing.
medication before surgery with antihistamines Furthermore, in patients who have peritonitis
and methylprednisolone should be considered from another source (i.e., perforated appendicitis),
(Mazagri and Ventureyra 1999). neurosurgical consultation is recommended to
discuss the possibility for temporary exterioriza-
Hydrocephalus Drainage and Shunt tion. Abdominal conditions that may render the
Considerations peritoneal cavity unsuitable for peritoneal tubing
While cerebrospinal fluid (CSF) shunting proce- placement include a history of peritonitis, dense
dures have significantly lowered the morbidity adhesions, ascites, or the need for peritoneal dial-
and mortality due to hydrocephalus, it has been ysis. Laparoscopy can be utilized to determine the
estimated that 40–50% of children will experience genesis of distal shunt dysfunction, to lyse adhe-
shunt failure within the first year after placement. sions, or to disrupt an intraperitoneal CSF pseudo-
Ventriculoperitoneal (VP) shunt placement cyst. In addition, some authors have advocated for
remains the most common site for placement of the use of laparoscopy routinely for initial shunt
the ventricular drainage catheter due to the large placement citing the advantage of fewer distal
absorptive surface area of the peritoneal lining and shunt obstructions (Naftel et al. 2011). Bacterial
the ease/comfort of insertion. Alternative drainage peritonitis may occur as a result of an infected
sites described include the atrium (ventriculoatrial CSF pseudocyst or perforated viscus from an
shunt), the pleural space (ventriculo-pleural indwelling shunt. Early recognition appropriate
shunt), or gallbladder (ventriculo-cholecystic antibiotic therapy may avert major abdominal
surgery in selected cases, but typically requires misleading, the list of possible etiologies is
urgent externalization of the shunt. Anal extrusion greater, and kyphoscoliosis may distort normal
may be present when the catheter perforates the anatomical relationships. Three factors unique to
colon, but the diagnosis of perforation is often the spina bifida population, present in most
difficult. A CT scan of the abdomen and pelvis is patients, are necessary to keep in mind when
often helpful in making the diagnosis. The major- evaluating such a patient: (1) the potential of a
ity of patients can often be treated with a new VP VPS malfunction, infection, or complication.
shunt after exteriorization of the catheter and suit- (2) Neurogenic bowel often results in constipation
able treatment of the perforation and infection. and the potential for morbid complications such as
When the peritoneal cavity is no longer suit- sigmoid volvulus. (3) The neurogenic bladder
able to accommodate the distal shunt tubing, other predisposes to both pyelonephritis and urolithiasis
locations may be utilized. Ventriculoatrial shunts and, in patients who have undergone surgical
can be typically placed into the great venous sys- bladder augmentation, to potential perforation.
tem in a percutaneous manner similar to that uti- In our experience, abdominal computed tomogra-
lized for central line placement. Complications phy with intravenous contrast is recommended
from ventriculoatrial shunts include tubing migra- when the diagnosis is elusive, as it confers the
tion with arrhythmia, shunt nephritis, pulmonary best chance of securing a diagnosis.
embolism, atrial thrombus, and endocarditis.
Ventriculo-pleural shunts in children have been
Esophagitis
used infrequently in the management of hydro-
Although GERD is often present in infants with
cephalus but may be suitable for the older child.
spina bifida and causes mild symptoms, esopha-
This form of CSF diversion offers a safe and
gitis and hematemesis are predominantly prob-
simple method of drainage, and the catheter can
lems of older children and adolescents. There are
be safely placed percutaneously or with the aid of
three probable causes of GERD in patients with
thoracoscopy. A small asymptomatic pleural effu-
spina bifida: abnormal innervation of the lower
sion is typically visible on the chest radiography
esophagus from the brain stem, anticholinergic
that does not imply malfunction. However, a
effects of oxybutynin (used in the treatment of
symptomatic pleural effusion can occur, and for
neurogenic bladder, but which also relaxes the
that reason, we do not recommend it for infants
lower esophageal sphincter), and increased intra-
and toddlers unless there are no reasonable alter-
abdominal pressure related to posture and immo-
natives. Ventriculo-cholecystic shunting is a via-
bility. If hematemesis or other severe symptoms
ble alternative with reasonably good outcomes.
recur after medical management, fundoplication
The distal catheter could be conceivably placed
may be necessary.
into the gallbladder percutaneously using retro-
grade cholangiography or by laparoscopy or lap-
arotomy (Demetriades et al. 2013). The historical Neurogenic Bowel
practice of placing a ventriculo-vesical shunt is Nearly 70% of patients with spina bifida can
discouraged as this technique is considerably achieve fecal continence using conservative mea-
more difficult and carries a high complication sures (Velde et al. 2013). Patients with intact
rate (urinary calculi and electrolyte disturbances bulbocavernosus and anocutaneous reflexes are
are common). more likely to achieve continence on a simple,
consistently timed, reflex-triggered bowel man-
Spina Bifida and the Acute Abdomen agement program. Beginning with glycerin sup-
The evaluation of abdominal concerns in the spina positories when the child is younger than 3 years
bifida patient is more difficult that in typical chil- of age results in a greater success rate than waiting
dren due to a variety of factors. Patients may have until later. Bisacodyl enemas can be used every
absent or abnormal perception of abdominal pain, other day beginning at 5 or 6 years of age to help
results of diagnostic tests and procedures may be establish a bowel habit. Large-volume saline
enemas, 20 mL per kg up to 1 L once per day we strive to treat the child and not the parent, there
administered by a nonlatex delivery system, are an are situations in which younger children may be
option, effective in two-thirds of patients with suitable candidates if parents are highly motivated
flaccid anal sphincters. Saline is made by adding and the younger child can engage in an antegrade
table salt to tap water in the ratio of 1 tsp. to washout program. Potential lack of capability to
500 mL. Administration of these enemas can adhere to management recommendations and
cause autonomic dysreflexia. morbid obesity are relative contraindications to
an ACE program. Patients who have episodes of
Antegrade Colonic Irrigation autonomic dysreflexia with retrograde enemas
In 1990, Malone and colleagues published a pre- may also have them with antegrade washouts.
liminary report on the use of antegrade “enemas” The usual washout fluid administered is tap
administered by catheter passed into the cecum water, in a volume of 250–1000 ccs. It is
through an appendicostomy – what is now com- recommended to be administered once daily to
monly referred to as the ACE (antegrade conti- begin but can be tailored as necessary. If tap
nence enema) procedure (Malone et al. 1990). water enemas are unsuccessful, then saline poly-
Commonly performed variations of the surgery ethylene glycol can be used in the solution volume
include appendix disconnection with necessary to achieve colonic washout.
reimplantation, appendicostomy with no anti- Continence is achieved by the ACE procedure
reflux component, tubularized cecal flap, in some 80% of patients (Yerkes et al. 2003).
cecostomy, or appendico-cecostomy with an Performing the enemas is frequently associated
indwelling low profile “button” device, placement with transient abdominal pain and sometimes
of a chait tube placed directly into the cecum with emesis. The median time needed for the
(Curry et al. 1999). ACE washout is 1 h per day. ACE-related com-
Patients with spina bifida constitute the major- plications include hypernatremia, adhesive bowel
ity of children receiving this procedure in most obstruction, cecal volvulus, stomal necrosis,
institutions. Diminished anal sphincter tone and appendiceal necrosis, hyperphosphatemia, cecal
abnormal rectal emptying reflexes are almost uni- perforation, fecal fistula, and volvulus around
versal features for those with any lower extremity the fixed appendix (Ekmark and Adams 2000).
weakness. Paradoxically, in those patients with Serious complications occur in less than 5% of
the lowest-level lesions (S2–5) and the least patients, although minor complications are more
motor impairment, anal sphincter tone is the frequent. Dey and colleagues reported stomal ste-
most lax and fecal continence the most difficult nosis in 41% of patients and stomal prolapse in
to achieve. Of patients with spina bifida, about 4.5% (Dey et al. 2003), although many authors
two-thirds of those 8 years of age and older are today have achieved rates of stenosis and the need
able to achieve continence with a total expendi- for revision in fewer patients (VanderBrink et al.
ture of time defecating less than 1 h per day. Of the 2013; Furlan et al. 2007). Fecal leakage occurs in
remaining one-third, about half are incontinent less than 10% of patients. For previously inconti-
principally due to lack of adherence to recommen- nent patients made continent by the ACE proce-
dations and about half because of anatomic and dure, self-esteem is improved, and patient and
physiologic limitations. caregiver satisfaction is high (Imai et al. 2014;
The typical candidate for the ACE procedure is Ibrahim et al. 2016).
at least 8 years old and has had an attempt to
achieve fecal continence by an aggressive bowel
management program. It is generally not devel- Conclusion and Future Directions
opmentally appropriate to expect a younger child
to demonstrate the rigid discipline required to Optimal treatment for children with special
meet our definition of successful use of the ACE health-care needs remains challenging and can
(Ekmark and Adams 2000). However, although often only be utilized with a multidisciplinary
approach. Health-care providers and caretakers Committee on Hospital Care. American Academy of Pedi-
must bear in mind associated disorders and poten- atrics. Family-centered care and the pediatrician’s role.
Pediatrics. 2003;112(3 Pt 1):691–7.
tial complications to the child’ disease. The Curry JI, Osborne A, Malone PS. The MACE procedure:
treating pediatric surgeon involved should care- experience in the United Kingdom. J Pediatr Surg.
fully plan the child’s procedure and implement 1999;34(2):338–40.
individual pre-, peri-, and postoperative care for Dalla Vecchia LK, Grosfeld JL, West KW, Rescorla FJ,
Scherer 3rd LR, Engum SA. Reoperation after Nissen
the child’s best interest. fundoplication in children with gastroesophageal
reflux: experience with 130 patients. Ann Surg.
1997;226(3):315–21. discussion 321-313
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Clinical Research and Evidence-Based
Pediatric Surgery 35
Dennis K. M. Ip, Kenneth K. Y. Wong, and
Paul Kwong Hang Tam
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560
Common Types of Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Concept of Evidence-Based Medicine (EBM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
The 5As of an EBM Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 563
Asking an Answerable Clinical Question in the “PICO” Format . . . . . . . . . . . . . . . . . 564
Searching for and Selecting the Best Available
Evidence for a PICO Question . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 564
Critical Appraisal of the Identified Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 565
Interpreting the Internal Validity of a Study
Result by Assessing the Role of Chance, Bias, and Confounding . . . . . . . . . . . . . . . . . . 565
Look Out for Possibility of Bias in Relation to Different Study Designs . . . . . . . . . . 566
Have Potential Confounding Factors Been Addressed? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 567
Examining the Role of Chance and Statistical Significance of the Result . . . . . . . . . 568
Examining the Clinical Significance of the Result . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Causality Assessment of the Result by Bradford Hill’s Criteria . . . . . . . . . . . . . . . . . . . 569
Is the Conclusion Applicable to the Patient in the Clinical Question? . . . . . . . . . . . . 569
D. K. M. Ip (*)
School of Public Health, The University of Hong Kong,
Hong Kong, China
e-mail: dkmip@hku.hk
K. K. Y. Wong · P. K. H. Tam
Department of Surgery, Li Ka Shing Faculty of Medicine,
The University of Hong Kong, Hong Kong, China
e-mail: kkywong@hku.hk; paultam@hku.hk

https://doi.org/10.1007/978-3-662-43588-5_38
560 D. K. M. Ip et al.
Clinical Research in Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

Constructing a Research Question and Designing the Study . . . . . . . . . . . . . . . . . . . . . . . 570
Planning the Logistics for a Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Data Acquisition and Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
Sample Size Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
Preparing for a Grant Application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 572
Communicating the Research Findings in an Evidence-Based Format . . . . . . . . . . . 574
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
Abstract to incorporate the best available evidence into

Evidence-based medicine (EBM) is the pro- their clinical practice.
cess of acquiring the best available research
evidence and applying this evidence to inform
the best practice in a defined problem in clini- Keywords
cal practice. The widespread popularization of Clinical research · Evidence-based medicine ·
the concept of EBM since its first introduction Randomized controlled trial (RCT) · Study
more than three decades ago has resulted in a design · Critical appraisal · Hierarchy of
paradigm shift in biomedicine from a largely evidence
experience- and opinion-based practice toward
one based increasingly on objective scientific
evidence. Introduction
Properly designed and implemented clinical
research represents the best way to provide The concept of evidence-based medicine (EBM)
high-quality scientific evidence for informing has evolved since the 1980s and gradually
the practice of EBM. Among different study becomes an essential element in many specialties
designs, prospective randomized controlled of clinical practice. The aim of practicing EBM
trial (RCT) is regarded as the gold standard of is to support important clinical decision-making
clinical research and gives the highest level of and policy recommendation in an objective, fully
evidence (Class I evidence). For specialties justifiable, and evidence-based manner by the
that are progressing faster in the practice of best and most updated research findings. Over
EBM, the rapid accumulation of research find- the years, clinical research and evidence-based
ing also highlights the importance of critical medicine have developed hand in hand within
appraisal skill for assessing the quality of avail- many clinical specialties, as EBM needs to be
able evidence. In many surgical settings informed by the best available research evi-
including pediatric surgery, however, impor- dence, which in turn will shape further directions
tant barriers that may hinder the proper design of research.
and implementation of RCTs are still common. As illustrated best with the case of drug trials,
A better understanding of the concept of clin- clinical research nowadays can involve rigorous
ical research and EBM would thus serve to experimental study designs with large sample
equip researchers in these settings to produce size, complicated logistics, and very technical
better scientific evidence and for practitioners statistical analysis. Most of these, however, are
35 Clinical Research and Evidence-Based Pediatric Surgery 561
unfamiliar to pediatric surgeons working busily at of new and emerging diseases. Although case
the very clinical frontline. This is shown by the reports are anecdotally based and ranked low in
predominance of observational and retrospective the evidence hierarchy with their generally less
studies, descriptive case reports or case series, and rigorous evidence for establishing general princi-
the lack of prospective trials in the body of scien- ples in disease causation or treatment effective-
tific literature of the specialty. While these obser- ness, those reporting carefully observed original
vational studies do serve to broaden the collective and unexpected findings can contribute signifi-
experience of the pediatric surgery community, cantly to medical knowledge or even as the first
they are inherent to bias and generally do not line of evidence for revolutionary medical
provide strong supportive evidence for defining advance. By the current standard of law and
best practice. The aim of this chapter is to present ethics, most journals would regard the patient’s
an introductory concept on evidence-based medi- explicit written consent as mandatory for any arti-
cine and clinical research and their relevance in cle that contains personal medical information
the setting of the specialty. about a living individual particularly if this can
potentially identify the patient.
Cross sectional, case control, and cohort study
Common Types of Study Design are all observational studies, in the sense that the
exposure or intervention of interest is chosen by the
Before embarking on a detailed discussion on subjects themselves rather than being assigned by
evidence-based medicine and clinical research, a the researcher. One major problem of observational
basic understanding of the different kinds of studies is the potential for biases to be introduced,
study design and the hierarchy of evidence is which can affect the validity of the conclusion to be
essential. Medical research generally aims to made. Cross-sectional study generally aims to be
establish the relationship between a cause and descriptive, while the latter two are analytical
an effect of interest in a particular setting. The involving a comparison between groups of patients
cause, generically referred to either as the “expo- (intervention and control groups).
sure” or “explanatory/predictor variable,” may Case-control studies are always retrospective
include different risk factors or therapeutic inter- in nature, with the study subjects identified by
ventions, and the effect, generally referred to as their outcome status (e.g., having or not having a
the “outcome” or “response variable,” may particular disease or clinical consequence). After
include status like disease incidence or other data on exposure is ascertained, the groups are
clinical consequences. Different study designs compared. In order to ensure comparability of
employ different approaches for ascertaining the cases and controls to avoid selection bias,
these two components, which may consequently they should be drawn from exactly the same pop-
be subjected to different methodological ulation. As subjective recall by participants is
concerns. commonly depended upon the ascertainment of
Study designs commonly encountered in med- exposure in a case-control study, differential recall
ical research include case report, cross sectional, in the comparison group, as affected by the out-
case control, cohort study, and randomized con- come status (having or not having the disease),
trolled trial (RCT). may be a significant source of bias (recall bias).
Case reports are stories of individual patient Case-control study allows for the simultaneous
reporting unique or unexpected clinical findings. investigation of multiple exposures or risk factors
This can include unusual mode of disease presen- and is especially suitable for studying rare out-
tation or clinical course, unreported side effects or comes (e.g., rare diseases), which may take too
unusual treatment responses for known disease, or long for a sufficient sample size to be recruited in a
the presentations, diagnoses, and/or management prospective cohort.
Cohort studies are longitudinal studies involv- variables among the two groups and to ensure
ing the comparison of two or more groups of they are comparable to start with, thus minimizing
participants (cohorts) characterized by their dif- the possibility for the observed outcome to be
ferent exposure status (e.g., smokers versus biased by confounding factors (allocation bias).
non-smokers or individuals who had received dif- Besides randomization, the clinicians and
ferent treatment options) and assessed for their researchers responsible for the enrollment process
respective outcome of interest (e.g., incidence of should also be concealed from the randomization
disease or other clinical outcomes). This can be sequence to avoid potential bias to be introduced
done prospectively by following up the cohorts by conscious or unconscious selection or altering
over time or retrospectively by identifying them on the enrollment order of participants into differ-
from existing clinical data or medical records. In a ent groups (allocation concealment). This can be
clinical setting these cohorts may include patients done either simply with the use of opaque enve-
receiving different therapeutic options for the lopes or more elegantly using a remote call center
same condition. As the intervention is not being for assigning patients during the enrollment pro-
randomized, bias can be introduced by a combi- cess. This is essential even if the intervention itself
nation of factors such as patient or clinician pref- can be blinded and different from the actual pro-
erences, referral pattern, or institutional policy. In cess of blinding that happens after randomization.
consequence, the observed difference in outcomes Blinding refers to the situation where study par-
may be contributed by some known or unknown ticipants, researchers, and data collectors are not
confounding factors rather than the treatment aware of which group each participant has been
itself. Cohort studies are particularly suitable for allocated, so as to ensure the comparison groups
the study of rare exposures. would be handled similarly in the conduction of
Randomized controlled trial (RCT)is generally the study. Blinding helps to avoid any possibility
considered to be the gold standard to give the “best of bias to be introduced due to differential percep-
evidence” for medical research. RCTs are com- tion or expectation, either by the patient or the
monly used to compare the clinical efficacy of a researcher.
new therapeutic intervention with an existing one, Systematic review, which is not clinical
or in the case of a disease without any existing research per se, is a literature review employing
effective treatment, comparing with a placebo. a systematic approach of identifying, appraising,
For a RCT to be scientifically and ethically justi- selecting, and synthesizing all high-quality
fied, there should be enough underlying evidence research evidence relevant to a particular
from early studies (phases 1 and 2) to support the focused research question from several studies
potential effectiveness and safety of the interven- employing a comparable study design. The pur-
tion in human while still having a clinical equipoise pose is to sum up the best available research
with genuine doubt about the comparative effec- evidence on a specific question. Bias in the
tiveness of those interventions to be assigned in the review process is minimized by the use of trans-
comparison groups. When properly designed and parent, predefined, and reproducible methods for
conducted with a large enough sample size, RCT each of the steps involved. Whenever appropri-
can minimize the potential impact of bias and ate, results from different studies can be pooled
confounding on the study validity. by a statistical technique called meta-analysis to
One key feature of RCT is randomization, give a more precise estimate on the overall effect
which allocates study participants to the interven- size based on a larger sample size or to address
tion and comparison groups for receiving one or controversies due to contrasting results from dif-
other of the alternative treatments under study ferent studies.
based on pure chance. This is commonly done Besides knowing the common study designs, it
by the use of a randomization table or a is also important to understand that not all “evi-
computer-generated randomization code. Its aim dence” is equal. Research employing different
is to balance any known or unknown prognostic study designs can generally be ranked in a
by an explicit integration of the best available

evidence, the doctor’s clinical expertise and
Meta- experience, and the patient’s wishes in clinical
analysis
decision-making. One of the most widely
adopted definition of evidence-based medicine
RCT was given by David Sackett et al. (1996) who
Cohort study
founded the first department of clinical epidemi-
ology at McMaster University in Canada and
Case-control study pioneered the concept of EBM as “the conscien-
tious, explicit and judicious use of current best
Case report / series evidence in making decisions about the care of
individual patients or the delivery of health ser-
Expert opinion
vices.” Current best evidence is up-to-date infor-
mation from relevant, valid research. These
Fig. 1 The hierarchy of evidence apply to all relevant decisions in different
levels of healthcare settings, including the
potential for harm from exposure to particular
hierarchy of evidence according to the potential agents, the accuracy of diagnostic tests, and the
validity of their findings as related to the strengths predictive power of prognostic factors
of different study designs (Fig. 1). Generally, the (Cochrane 1972).
strength of evidence can be categorized into three
major classes. Class I evidence refers to those
from prospective RCTs; Class II evidence
includes those from prospective observational The 5As of an EBM Cycle
studies, cohort, prevalence, and case-control stud-
ies; and Class III evidence includes those from As medicine is an ever-changing field, keeping
retrospective clinical series, databases/registry, up with the most current clinical evidence in a
case reports, and expert opinion. Prospective busy practice can be daunting. Understanding
RCTs represent the gold standard of clinical trials the approach and familiarization with the skills
and are considered more suitable and capable for involved would be a crucial step in the successful
hypothesis testing. Systematic reviews of RCTs practice of EBM in any specialty. The five
serve to contribute to the best valid scientific sequential key steps (commonly referred to as
evidence for informing EBM. On the other hand, the “5As” cycle) in the practice of EBM are as
cohort, case-control studies, and case series and follows (Fig. 2):
reports are more likely subject to biases and are
considered at best for hypothesis generating. 1. Assess – The first step should start with a
While this hierarchy is not absolute and other thorough clinical assessment of the patient
issues such as the quality of individual research and the problem to determine the pertinent
also need to be considered, it does help to provide issues, which may include a differential diag-
a guide to the strength of the available evidence. nosis, treatment decisions, or prognosis.
2. Ask – Formulating a clear and answerable
clinical question for the patient’s problem.
Concept of Evidence-Based Medicine 3. Acquire – Searching for appropriate and rele-
(EBM) vant evidence from the literature.
4. Appraise – Critically appraising the informa-
Initially emerged as the discipline of clinical tion for its validity and usefulness.
epidemiology, EBM aims to inform clinical 5. Apply – Applying the new knowledge in the
practice in a responsible and accountable manner clinical management of patients.
Fig. 2 The 5As cycle in

EBM practice
comparison), confer any additional survival ben-

Asking an Answerable Clinical
efit at 90 days after the surgery (the outcome)”
Question in the “PICO” Format
(Moss et al. 2001).
The ability to formulate a clinical question in the
“PICO” (patient, intervention, comparison, out-
comes) format is a fundamental skill in the EMB Searching for and Selecting the Best
process (Robson 2016). The PICO question is an Available Evidence for a PICO Question
answerable question focused on a clinical prob-
lem, formulating around the specific problem Searching for the best evidence to answer a spe-
identified from the patient history and clinical cific clinical question is not a pure numbers game.
examination. Depending on the context, this can In contrast to a broad and very inclusive search,
be a question regarding the outcome difference the aim here is to nail down and obtain the best
between two contrasting scenarios, as evidence that is specific to a particular clinical
defined, for instance, by different treatment question.
approaches, exposure to different risk factors, One of the commonest tools for EBM literature
or having different prognostic factors. Generally search is the PubMed/MEDLINE database (http://
a PICO question is defined by four basic com- www.ncbi.nlm.nih.gov/entrez/query.fcgi). A basic
ponents, including the patient, the intervention, search can begin with the use of Boolean opera-
the comparison, and the outcome, as detailed in tors (e.g., AND/OR, etc.) to link up key elements
Table 1. in the PICO question as the query search terms.
For example, when considering what may be The use of MeSH terms (Medical Subject Head-
the best operative approach for necrotizing ings) can help to increase precision of the search
enterocolitis in children, one possible PICO result by running the search in the MeSH Data-
question may be like this: “For children suffering base. Search results can be saved, emailed, or
from necrotizing enterocolitis with perforation exported into common citation management soft-
(the patient), does laparotomy (the intervention), ware program such as EndNote, Reference Man-
when compared with peritoneal drainage (the ager, and ProCite.
Table 1 The four components of a PICO question can be quickly located, by searching specifically
Components Details for “systematic review” or “meta-analysis” or
P = patient or problem This part describes salient specifying the “therapy” category and search by
and important “clinical study category” for RCTs. The Cochrane
characteristics of the patient Library, available at http://www.thecochra
that may be important in
defining the current nelibrary.com/view/0/index.html, is a collection
problem. This may include of six databases where reports of systematic
the primary problem, reviews for a large variety of clinical problems
disease and coexisting can be found.
conditions, and sex, age,
and race of a patient that
might be relevant to the
diagnosis or treatment of a Critical Appraisal of the Identified
disease Evidence
I = intervention/indicator This includes the main
(e.g., certain exposures or factors which are being
prognostic factors) considered, which may be Once the best potential evidence for a PICO ques-
some intervention, tion is identified, the manuscript needs to be crit-
prognostic factor, or ically evaluated with a systematic framework. The
exposure as defined by the main aim is to assess the quality of the presented
context of the problem
evidence in terms of its validity, its potential clin-
C = comparison/control This refers to the main
alternative to compare with ical significance, and its applicability to the par-
the intervention, which may ticular patient. Figure 3 shows a flowchart of the
be an intervention, key steps in a critical appraisal.
exposure, or some
prognostic factors. Some
clinical question may not
need a specific comparison Interpreting the Internal Validity of a
group Study Result by Assessing the Role
O = outcomes The main outcome measure of Chance, Bias, and Confounding
of current interest, which
may be a treatment or
disease outcome Internal validity of a study refers to whether it is
designed and conducted to measure what it is
intended to measure and to produce a “truthful”
A search on any clinical problem, even result. Consideration of any study finding will
targeted to be very specific, can easily generate only be meaningful after the study validity can
hundreds of returns, and one has to read through be reasonably established, as the result from an
the title, the abstract, and sometimes the entire invalid study could hardly be trusted and based
article to select the best potential evidence for upon for making a clinical decision. Rather than
answering the specific clinical question. A quick being explicitly stated somewhere in the report, an
assessment of the objectives and rationale of the assessment of the internal validity can only be
study is needed to make sure this is in line with the done by a detailed examination of the study meth-
PICO question to avoid wasting time and effort on odology and analysis approach, to specifically
something irrelevant. During this selection pro- look out for hint or evidence that the study result
cess, preference should generally be given to may be affected by bias, confounding, or chance.
newer reports and those being ranked higher in While chance findings are caused by random var-
the evidence hierarchy (i.e., RCTs or meta- iation, bias and confounders represent systematic
analysis), so as to get the most updated and valid errors that may jeopardize the internal validity of a
evidence as far as possible. Clinical queries is study by leading to false conclusions regarding
another feature where evidence-based literature the true relationship between the intervention and
Yes
Bias in study design?
No
No
Confounding factors Problem in internal validity
addressed?
Yes
Result of No
statistical significance?
Yes
No Problem in external validity

Result applicable
to the patient?
Yes
Result of No
clinical significance? Problem in potential clinical impact
Yes
Apply the result onto the Have to be cautious if there are

patient/ problem in question limitations to the evidence
taking into account all available information
and potential problems identified
Fig. 3 Key steps in the critical appraisal process in the practice of EBM
outcome (e.g., false-positive or false-negative of bias, with different study designs more prone to
conclusion regarding the performance of a new their specific and inherent types of bias. As rigorous
surgical approach comparing with a traditional attention to study design and conduction is required
approach). for eliminating or minimizing their potential impact
on study validity, evidence for these elements need to
be specifically examined during the appraisal to see
Look Out for Possibility of Bias how good they have been done to prevent potential
in Relation to Different Study Designs bias (see Table 4 in the following section).
Randomized controlled trials and systemic
Bias refers to systematic error caused by the reviews represent the preferred source of valid
design or conduct of a study that may affect a evidence in EBM. Their appraisal will be consid-
true inference on the relationship between the ered in greater details here. Major methodological
intervention and outcome. The two common cat- elements that may affect the quality of a RCT
egories of bias include selection bias, which include randomization, allocation concealment,
relates to how study subjects are selected, and blinding, and follow-up of patients. During the
information bias. This is a result of error in data appraisal, questions that need to be asked include:
measurement or variable assessment.
As mentioned previously, observational study 1. Was the randomization done properly by an
designs are generally more vulnerable to the problem appropriate method?
2. Was allocation concealment being performed benefit in patients who receive treatment
properly and effectively? exactly as planned.
3. Was the study intended to involve blinding?
And if this was the case, who were those the For systemic review, the main issue to assess is
study was trying to blind, and how successful whether all potentially relevant literatures were
was the blinding? identified and considered, whether they were
As previously explained, the process of ran- selected and included in a systemic and unbiased
domization, together with allocation conceal- manner to avoid the risk of selection bias and
ment and blinding, can help balance out any whether these original studies were themselves
known or unknown confounding to ensure the of reasonable quality. With meta-analysis, compa-
two comparison groups are comparable to start rability of these studies in terms of study design
with and to avoid bias to be introduced during and settings, inclusion and exclusion criteria, and
the whole study. end-point measures all need to be assessed.
4. Were the study groups really comparable to Ideally the review should be focused on a
start with? specific clinical question relevant to the PICO
This can be reflected by an examination of question rather than being a very broad review
the baseline characteristics of both groups, which is less likely to provide a useful answer to
which is usually displayed in a table in the the clinical problem. Completeness of the search
manuscript. This gives a good indication on process can be assessed by details regarding the
how successful the randomization and alloca- search strategies and covered databases. This
tion concealment process are. should preferably also include consideration of
5. How complete was the follow-up? cited references at the end of articles and other
Ideally all participants in each group should non-published sources. The selection and assess-
complete the whole study, and good studies ment process should be checked for any hint of
should be able to follow up at least 80% of selection bias. These steps need to be guided by
their patients for the primary outcome of inter- reasonable and objective criteria and to be done by
est. Dropping out of patients in general may more than one researcher. An assessment of meth-
affect the precision of the study. Differential odological quality and validity of selected pri-
lost-to-follow-up in different comparison mary studies also needs to be included, as this
groups may lead to an overestimation of the will also have a direct impact in the validity of
effectiveness of the intervention and invalidate the review finding.
the study conclusion. Sensitivity test with the
worst-case outcome being assumed for those
missing patients will help to give a more con-
servative approach to the analysis. Have Potential Confounding Factors
6. Were patients analyzed by intention-to-treat Been Addressed?
analysis?
This refers to the approach where patients Sometimes being referred to as the third major
were analyzed according to the groups to class of bias, confounding are any variables that
which they were randomized to, regardless of may be associated with the outcome (e.g., death or
whether they received or adhered to the allo- recovery from a disease) but themselves not being
cated intervention. This approach helps to pre- a part of the causal pathway between the interven-
serve the effect of randomization from the tion and the outcome. Uneven distribution of
problems of non-compliance, crossover, and confounding in comparison groups, especially
dropout and give a pragmatic and more con- common in observational studies, may cause spu-
servative estimate of the benefit of a treatment rious association between the intervention and
option in real life rather than the potential outcome of interest and invalidate the result in a
study. Confounding can be controlled in the study cannot be confidently excluded, at least with the
design level by randomization, restriction of study current power of the study as determined by its
entry to individuals with certain confounding fac- sample size. Many journals now prefer the
tors, or matching of individuals or groups to reporting of confidence interval rather than the
equalize distribution of confounders. In the anal- p-value, which gives an estimated range of values
ysis level, they may be controlled by stratification that is likely to include the true effect size with a
analysis according to confounding or statistical specified probability level. A 95% confidence
adjustment by multivariate analysis. A well- interval not including the effect of null (0 for
performed randomization in RCT is by far the absolute difference or 1 for relative difference) is
best approach to eliminate the problem from equivalent to a p-value < 0.05 and reflects statis-
both known and unknown confounding by tical significance. The range of the interval can
balancing out their occurrence between study also convey a rough idea about the sample size, as
groups. a larger sample size will generally give a more
precise estimation with a tighter confidence inter-
val, while a wide interval may reflect an inade-
Examining the Role of Chance quate sample with a poor power.
and Statistical Significance Statistical significance should, however, be
of the Result interpreted with flexibility and consideration of
the context rather than being used as a rigid cutoff.
Any reported difference between the comparison For instance, a very large reported effect size with
groups, such as a lower complication rate with a a confidence interval marginally including the
new versus a traditional operative approach, may effect of null, such as an odds ratio of 14.3 (95%
reflect a true improvement or arise just by pure CI 0.96–28), or a mean increase in surgical com-
chance. Based on a study sample to draw a con- plication rate of 85% (95%CI 0.32%–154%),
clusion about the population, a clinical study may should reflect the need of a more powerful study
commit an error either by finding an effect or a with a larger sample size to properly demonstrate
relationship when there is in fact none (a false- a potentially important finding rather than being
positive result, or a Type I error, α) or failed to simply disregarded as statistically insignificant.
demonstrate the effect or relationship when there
is a real one (a false-negative result, or a Type II
error, β), just because of random variation or pure Examining the Clinical Significance
chance. The contribution of random variation to a of the Result
reported study result can be assessed by its statis-
tical significance, which is essentially a process of As a statistical property, a very small difference
hypothesis testing regarding the compatibility of may still attain statistical significance when the
the observed results with the null hypothesis sample size is large enough. This should not be
(which states that there is no real difference confused with its clinical significance, which
between the comparison groups). This is usually refers to the practical value of such a difference
reported with either a p-value or a confidence in clinical practice (e.g., a 0.2% difference in
interval. A p-value 0.05 (5%) has been custom- survival rate with a new surgical approach in
arily chosen as an indication for a strong argument comparison with an existing one). To a consider-
against chance and being referred to as a statisti- able degree, what constitutes a minimal clinically
cally significant result. Technically this translates important difference (MCID) involves a subjec-
into a chance of less than 1 in 20 in committing a tive judgment made by the clinician and needs to
Type I error by incorrectly rejecting a true null be balanced with any potential harm and deter-
hypothesis and concluding that a real effect of mined with the context in different scenario. For
relationship existed. On the other hand, a p-value instance, how much improvement in function or
larger than 0.05 means that the role of chance reduction in complication rate is good enough to
justify the new treatment approach? How much Table 2 Bradford Hill’s criteria for causality assessment
additional survival would be considered worth- Criteria Details
while (weeks/months/years) in the face of a new Strength Although a small association does not
treatment? preclude a causal effect, causality is
considered more likely with a larger
reported association/effect size
Dose response Also called “biological gradient,”
Causality Assessment of the Result by meaning that a greater level of
Bradford Hill’s Criteria exposure leading to greater incidence
of the outcome
In the setting of a surgical clinical trial, especially Temporality Occurrence of the cause (the exposure/
intervention) before the outcome
with a RCT design, the causal relationship
Consistency The observation of consistent findings
between the intervention (e.g., a new surgical by different studies in different places
procedure) and the outcome (e.g., a reduction in with different samples
mortality or complication) is usually pretty Biological The availability of a plausible
straightforward and not too difficult to be plausibility mechanism to explain the observed
established. An inference regarding whether the relationship between cause and effect
Coherence Coherence between all studies
result reflects only an association or points toward
adopting different study approaches,
a causality may be more difficult to establish in the e.g., epidemiological/laboratory/and
setting of an epidemiological study (e.g., to look experimental studies
for risk factors for a surgical disease), especially Specificity The specific association between a
those adopting an observational and non- factor and a particular outcome but not
other outcomes, but may not always be
experimental approach. A common approach as
the case
proposed by Sir Bradford Hill (1965) involves a
consideration of the criteria as listed in Table 3.
Generally, a stronger argument for causality can
be established with more criteria. Some of the to which the results of a study can be applied to
criteria, such as biological plausibility, may not other situations and to other people in the wider
always be available even for a really novel finding population. An assessment of this external valid-
as limited by the state of current knowledge. ity requires a careful examination of the setting
Many authorities have considered that the pres- where this study was conducted and details of the
ence of an appropriate temporality with the occur- initial inclusion and exclusion criteria for subject
rence of the exposure prior to the outcome may be enrollment. The question to ask is whether these
one of the most essential criteria to be established criteria, such as ethnicity, disease stages, or
in most scenarios (Table 2). comorbidity, may have in some way restricted
the relevance of the result to other patients
encountered in clinical practice. For the particu-
Is the Conclusion Applicable lar patient in the PICO question, this can be
to the Patient in the Clinical Question? assessed by examining the likelihood for this
particular patient to be enrolled as a subject in
After establishing the internal validity of a study, this study if he/she had presented himself/herself
the applicability of its result to the clinical prob- in the recruitment setting.
lem in question also needs to be considered. As
clinical studies are usually performed on a small
group of sample patients defined by very specific Clinical Research in Pediatric Surgery
inclusion and exclusion criteria, the results may
not always be generalizable to all patients Clinical research is defined by the National Insti-
encountered in the clinical setting. External tutes of Health as research conducted with human
validity, or generalizability, refers to the extent subjects and includes patient-oriented research,
epidemiologic and behavioral studies, outcomes also help him to focus on the central theme of the
research, and health services research. It seeks to specific argument and avoid an “all-about” study.
extend potentially promising basic scientific
understanding from laboratory studies using ani-
mal or cell lines into research involving human Planning the Logistics for a Clinical
subjects through different phases according to Research
established protocols. One main aim of clinical
research in pediatric surgery is either to validate The choice regarding which may be the most
existing clinical practices or to investigate new suitable study design depends on a number of
treatment approaches in an evidence-based man- factors including the specific aim of the study
ner. While a detailed discussion of the theory and and other practical constraints such as data avail-
conduction of clinical research would constitute a ability and funding. While observational design is
whole book in itself and is beyond the scope of commonly adopted for epidemiological and
this chapter, some important issues for consider- behavioral studies, they are less commonly used
ation during the planning of clinical research in in a surgical setting. As the evaluation of new
the setting of pediatric surgery are presented here. therapeutic approach represents a common aim
for clinical research in a surgical setting, RCT
would naturally be the best experimental approach
Constructing a Research Question for the purpose. Although clinical trials on phar-
and Designing the Study macological product underdevelopment are typi-
cally conducted in four sequential “phases” with
The ability to ask a proper research question is the each serving a different and specific purpose, a
first important step for ensuring a successful phase 3 trial using a proper RCT design is actually
research. A good research question should be the only common stage encountered in a surgical
centered around an issue the researcher is genu- setting. Justification for conducting a RCT is usu-
inely curious about and which represents an ally available in the form of early successful case
important gap in the current knowledge of the series in the case of a novel operative approach.
area. This research gap needs to be identified and Many of the important components of RCT for
properly shaped by an exploratory approach from ensuring the study validity may be logistically dif-
current literature on the field, to identify the cur- ficult if not impossible in a surgical setting and
rent state of knowledge, controversies, and impor- present problems not seen in pharmaceutical trials.
tant unanswered questions, and areas as yet While randomizing patients to receive either a new
unexplored surrounding the particular problem. operative approach or existing one for a particular
Similar to the PICO question, the research disease may still be plausible, the comparison of a
question should be constructed in a clear, focused, novel operative approach to placebo may be ethi-
concise, and arguable format. Using the same cally difficult to justify as the new approach may be
example quoted previously for the PICO question, the only existing hope for the patient even still
clear identification of the target intervention under being an experimental procedure lacking solid evi-
investigation (laparotomy), the intervention/pla- dentiary support. The existence of preconceived
cebo to be compared with (peritoneal drainage), bias among either patients or investigators is rec-
the target patient population in question (children ognized to be a major hurdle for the conduction of a
suffering from necrotizing enterocolitis with per- RCT that examines a surgical technique.
foration), and the outcome of interest (survival While it would never be possible to blind the
benefit at 90 days) would help to clearly highlight surgeon, blinding of the patient using a sham
the objective of the study (Moss, et al. 2001). operation as the placebo arm is theoretically pos-
Besides helping the researcher to choose a suit- sible but rarely ethically justifiable due to the
able study design and plan for the appropriate invasiveness and potential harm of the procedure.
logistics, a well-developed research question can In some situation where it may also be logistically
or ethically difficult to blind the patient, blinding Table 3 Selection of statistical tests for different data
of the data collector and interpreter would still be types
a valuable option to minimize potential bias. For Explanatory/ Outcome/response variable
instance, very simple method like putting an iden- predictor Categorical (two Ordinal/
tical set of postoperative dressings on the possible variable categories) continuous
wound sites had been used in previous RCTs to 2 categories Chi-squared test t-test, Mann-
Whitney U test
blind the postoperative observers to the type of
3 categories Fisher’s exact test, ANOVA,
operation that the patients had received (Chan McNemar’s test Kruskal-Wallis
et al. 2005). Likewise, even though blinding Ordinal Logistic test
may be difficult or imperfect, it is always advis- Continuous regression Regression/
able to conceal the randomization sequence to correlation
colleagues responsible for patient enrollment to
minimize the potential impact of selection bias. research questions can generally be selected
Another common problem in a surgical setting, according to the type of data in question, that is,
especially for less prevalent conditions, is the whether we are dealing with some categorical, ordi-
scarcity of sample size to attain sufficient power nal, or continuous data, respectively, for the explan-
for demonstrating an outcome difference of small atory and outcome variable, as outlined in Table 3.
or even moderate size. Collaborative multicenter
trial conducted at more than one medical center or
clinic may be a possible approach to include a Sample Size Estimation
larger number of participants within a shorter
study period. This may also enhance the general- Besides properly designed and conducted, a study
izability of the findings as a wider range of popu- needs to have a sufficient sample size to attain an
lation groups from different geographic locations adequate statistical power, which is the probabil-
are included. For efficacy outcome that may vary ity to detect a significant difference between the
significantly between population groups as a comparison groups when there truly is one. When
result of different genetic, environmental, or cul- no statistically significant difference is detected
tural backgrounds, a really large sample size from between two comparison groups in a study, there
a geographically dispersed trial would normally may either be truly no difference (true negative) or
be needed. However, quality assurance to ensure there in fact is a difference but the study is not able
proper conduction with strict protocol compliance to detect it (false negative). A conclusion can only
for processes like admission, treatment, and be drawn in this situation when the study is of
follow-up in multicenter trials may not be a trivial sufficient power to detect such a difference with
challenge and generally requires an experienced statistical significance.
and highly developed coordinating center. One of the commonest questions encountered
by most investigators is how to determine the
power and thus the required sample size. Consul-
Data Acquisition and Analysis tation with a statistician in an early phase of the
study planning would be tremendously helpful
In a clinical research setting, the aim generally is to and is always advisable.
make comparison between groups on some relevant Generally, the power of a study will be affected
clinical characteristics and outcomes, which may by five common parameters, including the effect
either be measured by some continuous variables size, estimated measurement variability, desired
that can be summarized by the means or some statistical power, significance criterion, and the
nominal or ordinal variables that can be measured planned analysis approach (a one- or two-tailed
by proportions. While a detailed account of statisti- statistical analysis). When estimating the sample
cal analysis methods is beyond the scope of this size, the investigator needs to decide on the first
chapter, a suitable statistical test for different two parameters. Then the power and the
significance criterion are commonly being set cus- (i.e., a chance of 1 in 20 for committing a Type I
tomarily at 80% and 0.05, respectively. error).
Effect size – This refers to the smallest differ- One- or two-tailed statistical analysis – While
ence in outcome between comparison groups that a two-tailed analysis tests generally for a differ-
the study is intended to detect. While a moderate ence in the result between the comparison groups,
sample size may be good enough for detecting a a one-tailed analysis tests specifically for a differ-
sizable difference, an increasing sample size is ence in only one specific direction (being larger/
generally required to detect a smaller difference. smaller). When the scenario is truly appropriate,
Results from a pilot study or a relevant previous the use of a one-tailed statistical analysis would
literature may give some guidance regarding the generally require a smaller sample size than a
effect size to be expected. Clinical experience and two-tailed analysis, as the sample size giving a
judgment may also be helpful in deciding what significance criterion of α in the former will gen-
should be the minimal amount of improvement to erally give one of 2α in the latter design.
be achievable by the new intervention for it to be Once the five issues have been decided, these
justified (e.g., 10% improvement in survival or can be used in estimating the sample size required.
20% reduction in complication rate). Online tools are commonly available for
Measurement variability – This refers to the researchers to quickly estimate the sample size
estimated variability in the outcome parameter they may need in common situations involving
within each comparison group and is commonly comparison of means, proportions, or other
expressed as a measurement of dispersion by the parameters with an assumed parametric distribu-
standard deviation (SD). Generally a large sample tion. One user-friendly example is the Java
size would be required for demonstrating a certain Applets for Power and Sample Size by Lenth,
effect size for a measurement with a larger degree R. V. retrievable from http://www.stat.uiowa.
of variability. Again data from some pilot or pre- edu/~rlenth/Power, where the simple calculator
vious study from a similar study population may “piface.jar” may also be downloaded to run in a
be useful for its estimation. When no such data is local computer with the Java Runtime Environ-
available, a range of values may be assumed bas- ment (JRE) installed.
ing on subjective experience to assess its likely Additional allowance should be given to the
impact on the estimated sample size. For an out- number of likely attrition by loss to follow up
come expressed as a proportion, the SD can be after enrollment, to make sure the estimated
statistically estimated. power can still be attained by the final sample
Statistical power (1-β) – This refers to the size after some dropping out. It is also important
probability of the study for detecting the effect to understand that the use of intention to treat in
size as specified if there truly is a difference the analysis may also cause some reduction in the
between the comparison groups. While a higher estimated power by counting subjects with sub-
power is always desirable, the obvious trade-off is optimal compliance in their assigned treatment
the resource implications associated with the group. As it is not uncommon for researchers to
larger sample size that is needed. In a RCT, a overestimate their ability to recruit, it is thus
power of at least 0.80 is customarily required, important to be realistic in the planning of the
meaning a < 20% chance of committing a Type study and have all potential logistical hurdles
II error and failing to demonstrate a true effect or properly considered.
relationship.
Significance criterion (α) – As the chosen cut-
off for p-value associated with a result to be con- Preparing for a Grant Application
sidered statistically significant, a more stringent
criterion (small p-value) would require a larger Different forms of funding opportunities are avail-
sample size. It is customarily set at 0.05 (5%) to able to support scientific research studies in dif-
give a reasonably strong argument against chance ferent settings. Common sources include
governments, NGOs, scientific and educational the randomization be done, how will the alloca-
organizations, business sectors, or charity funds. tion sequence be concealed, how to ensure
As they generally vary widely in their funding blinding, etc. would be needed to properly dem-
amount and target research projects, the impor- onstrate the study validity.
tance of an initial examination of the aim and In order to demonstrate that the study is ethi-
scope of the funding can never be overemphasized cally justifiable, a detailed assessment of the
in order to ensure aiming the nontrivial effort at potential benefits and harms or risks, including
the right target. Specific eligibility criteria for any physical, psychological, social, or legal
different funding sources also need to be met risks, to the participants or the study workers,
before a funding application will ever be consid- should be included. A justification on why these
ered. Compliance to procedural, scheduling, and risks to the participants is reasonable in relation to
formatting requirements, although sometimes the anticipated benefits of the study findings that
being highly tedious, is also effort well spent to can be reasonably expected should also be given;
avoid the greater effort of putting up the whole this is especially important if the study involves
application being wasted. people who are particularly likely to be vulnerable
Although the details required by different by participating in a study, such as fetuses and
application varies, funding sources generally try children, pregnant women, cognitively impaired
to fund proposals that are targeting to solve an individuals, or prisoners. Details of any proce-
important scientific question by employing a dures to monitor, minimize, or manage any poten-
methodologically valid and ethically justified tial harm or protect against these risks should also
study method and to be conducted by a group be given. A proper sample size estimation should
with suitable track record to ensure the delivery. always be included as it is both ethically and
To enhance the chance of success, the preparation financially unjustifiable to conduct a study with
of a grant application therefore should not be too few patients and thus underpowered to detect
regarded as a passive process of information pro- what it is supposed to look for or with too many
vision regarding details of the study and the inves- patients and thus unnecessarily exposing more
tigator, but to be taken actively as a platform to patients than what is required to the risk and
explicitly highlight the above four important inconvenience of the study.
issues and impress the reviewers. Details regarding the experience of investiga-
Firstly, a succinct summary of the current level tors and availability of appropriate resources,
of knowledge regarding the specific area of study infrastructure, equipment, and collaborating part-
should be presented as the background. This ners for the proposed study should then be pro-
needs to be centered around the specific question vided to show that the investigator and his/her
to be investigated, with the aim to have the team are the best candidates for conducting this
research gap properly highlighted, so as to justify study and thus for the funding to be
the conduction of the current study. The precise entrusted upon.
objectives need to be clearly stated, preferably in A number of practical constraints such as data
the form of a testable hypothesis. availability and funding may affect decisions
A description of the study plan and methods is regarding the study design and logistics. Once
usually needed. The details to be included here these are decided, the investigator should come
depend on the study design, but the main aim is to up with a reasonable budget to convince the
show the reviewers that due consideration and reviewers that any single dollar being asked is
attention is being paid to minimize the potential justified and will be sensibly and carefully spent.
impact of any possible bias and confounding on Having said that, it is generally not advisable to
the study validity. For instance, for a RCT pro- opt for a less valid approach just for the sake of
posal, it would not be good enough to just mention budget cutting, as most grant reviewers would
that participants will be randomized and blinded, probably prefer to fund an expensive but well-
but details on these procedures including how will designed RCT that can give a definitive answer
to an important question rather than funding detailed results and to establish the statistical
another cheaper study compromised on design validity of the conclusions. Whenever being
and validity. used they should be equipped with appropriate
descriptive headings, legends, and with abbrevia-
tions and symbols clearly defined for each to be
Communicating the Research Findings capable of standing alone. The main aim of this
in an Evidence-Based Format section is to highlight and guide the readers into
important points and thoughts that are relevant to
Scientific paper is the main channel for research the study purpose.
findings to be communicated effectively to The discussion section should include an inter-
healthcare professionals. While the exact details pretation of the results and stating the main con-
need to be reported varies with different types of clusions of the study. Comparing the findings with
study designs and the targeted journal, generally previous similar work will help to highlight the
three basic issues always need to be properly specific contribution achieved and how our scien-
addressed: Why is the research important? How tific understanding has progressed as a result of
was the research carried out? And what was findings from this study. A brief appraisal of the
found? potential limitation and remaining gaps with a
Structurally four basic parts are always needed: discussion of potential areas for improvement or
introduction, methods, results, and discussion, for future researches should also be included.
with each carrying an important aim that has to A number of reporting guidelines have been
be explicitly highlighted. Introductions should be developed by consensus opinion of experts to
short and clearly tell the reader why this study has facilitate proper reporting of research findings,
been undertaken. A background literature review including one on uniformed requirement in gen-
should tell what is already known in this subject eral and a number of others for reporting studies
area, with a problem statement to highlight the employing different common study designs
research gap as what else is still unknown and (Table 4). Most medical journals nowadays
need to be learnt and with a purpose statement to
clearly explain what is intended to achieve in the
current study. Table 4 Common guidelines for health research reporting
The methods section should contain enough URM Uniform Requirements for Manuscripts
information regarding how the study was Submitted to Biomedical Journals
Prepared by the International Committee
designed and carried out and how the data was of Medical Journal Editors (ICMJE)
collected and analyzed. Enough details should be http://www.icmje.org
given on original methods or proper references CONSORT Consolidated Standards of Reporting
should be included. Comparison groups and out- Trials
comes should be clearly described and defined. http://www.consort-statement.org
STARD Standards for Reporting Studies of
Relevant special steps taken to minimize potential
Diagnostic Accuracy
impacts of risk and confounding should be Bossuyt et al. (2003). Clin Chem. 49
highlighted. Sample size estimation and statistical (1):7–18
approaches should be suitably presented to justify STROBE Strengthening the Reporting of
the power of the planned study. The main aim is to Observational Studies in Epidemiology
http://www.strobe-statement.org/
describe what has been done, and how was it
PRISMA Preferred Reporting Items for Systematic
being done, (but not what was found) in a logical Reviews and Meta-Analyses
and chronological manner so as to convince http://prisma-statement.org/
readers about the validity of the study result. MOOSE Meta-analysis of Observational Studies in
The results of data analysis should then be Epidemiology
clearly presented. Tables, figures, and illustrations Stroup DF et al. (2000). JAMA 283
(15):2008–2012
can be used where appropriate to present the
require authors to comply with these established well-conducted prospective RCTs may not be
reporting guidelines for manuscript submission. available for many surgical conditions, it is impor-
Besides the reporting of all relevant details as tant to reiterate that the practice of EBM in pedi-
guided by these guidelines, the need for key study atric surgery must take into consideration
findings to be reported succinctly to reach and information from all three sources, including evi-
update the busy clinicians has also increasingly dence from clinical research, clinical expertise
been recognized. One example is the use of a and skills of individual surgeon, and the patient’s
one-page abridged format in the print journal of and society’s choice.
BMJ (called BMJ pico), for research papers to be
published in an evidence-based manner to make
research results more inviting and useful to
Cross-References
readers (BMJ 2008). By emphasizing the clear
and succinate reporting of the four main compo-
▶ Ethical Considerations in Pediatric Surgery
nents of a study (the patient/problem, interven-
tion, comparison, and outcomes), this approach
has once again highlighted the importance of
References
framing and understanding a research problem in
the PICO format for the practice of EBM, the Bossuyt PM, Reitsma JB, Bruns DE Gatsonis PP, Glasziou
conduction of clinical research, and the reporting PP, Irwig LM, Moher D, Rennie D, De Vet HC, Lijmer
of research results. JG. Standards for reporting of diagnostic accuracy. The
STARD statement for reporting of diagnostic accuracy:
explanation and elaboration. Clin Chem. 2003;49
(1):7–18.
Conclusion and Future Directions Chan KL, Hui WC, Tam PKH. Prospective, randomized,
single-center, single-blind comparison of laparoscopic
As for any other clinical specialties, there is little vs open repair of pediatric inguinal hernia. Surg
Endosc. 2005;19:927–32. https://doi.org/10.1007/
doubt that clinical research and evidence-based s00464-004-8224-3.
practice are the two most important elements for Cochrane AL. Effectiveness and efficiency: random reflec-
the continuous advancement of the specialty of tions on health services. London: Nuffield Provincial
pediatric surgery. The generation of the best scien- Hospitals Trust; 1972. Reprinted in 1989 in association
with the BMJ. Reprinted in 1999 for Nuffield Trust by
tific evidence by properly conducted clinical the Royal Society of Medicine Press, London, ISBN
research and the utilization of this evidence to 1-85315-394-X
inform the best clinical practice is reciprocally Hill AB., The environment and disease: association or
interlinked and mutually dependent. The four causation? Proc R Soc Med. 1965;58:295–300.
Lenth RV. Some practical guidelines for effective sample
PICO components of a study (the patient/problem, size determination. Am Stat. 2001;55:187–93.
intervention, comparison, and outcomes) consti- Moss RL, Dimmitt RA, Henry MC, Geraghty N, Efron
tuted the core considerations which need to be B. A meta-analysis of peritoneal drainage versus lapa-
properly addressed in all sequential activities in rotomy for perforated necrotizing enterocolitis. J
Pediatr Surg. 2001;36(8):1210–3.
the cycle, including when designing a good RCT, New format for BMJ research articles in print. BMJ.
identifying the most appropriate research evidence 2008;337:a2946.
in EBM, succinctly reporting the research finding, Robson B. Studies in using a universal exchange and
and drafting an effective grant application. inference language for evidence based medicine.
Semi-automated learning and reasoning for PICO
Given that RCTs for surgical problems are methodology, systematic review, and environmental
much more difficult to design and implement epidemiology. Comput Biol Med. 2016;79:299–323.
and may not always be feasible, consideration Sackett DL, Rosenberg WM, Gray JA, et al. Evidence
and effort should also be paid to improve the based medicine: what it is and what it isn’t. BMJ.
1996;312(7023):71–2.
quality of nonrandomized comparative studies Stroup DF, et al. Meta-analysis of observational studies in
and other studies, both in terms of their internal epidemiology: a proposal for reporting. JAMA.
and external validity. While Class I evidence from 2000;283(15):2008–12.
Tissue Engineering and Stem Cell
Research 36
Paolo De Coppi
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Embryonic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Somatic Cell Nuclear Transfer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
Induced Pluripotent Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
Fetal Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 583
Adult Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 584
Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 585
Naturally Derived Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
Synthetic Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
Natural Acellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Cell-Derived ECM Scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Regenerative Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 588
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Abstract or organs. So far, there has been success in the

Congenital or acquired surgical conditions are production and surgical replacement of organs
associated to high morbidity and mortality, and such as the urethra, bladder, and trachea.
most of the time functional replacement of the While regenerative medicine encompasses
missing or damaged organ remains an unmet a number of different disciplines, when it is
clinical need. Regenerative medicine has aimed toward organogenesis, the important
recently been established as an emerging inter- components are appropriate cells and an appro-
disciplinary field focused on the repair, priate scaffold. The employment of induced
replacement, or regeneration of cells, tissues, pluripotent cells may overcome the use of
immunosuppression associated with embry-
onic stem cells. Moreover, amniotic fluid
stem cells may be specifically relevant to the
P. De Coppi (*)
Great Ormond Street Hospital and UCL Institute of Child
cure of congenital malformation and reduce the
Health, London, UK hazards associated with pluripotent cells such
e-mail: p.decoppi@ucl.ac.uk; paolo.decoppi@gosh.nhs.uk

https://doi.org/10.1007/978-3-662-43588-5_39
578 P. De Coppi
as tumorigenesis, rejection, difficulty in isola- (De Coppi 2013). If children with severe congen-
tion, and ethical issues. Research on scaffold- ital diaphragmatic hernia undergo respiratory fail-
cell interaction has indicated that beyond the ure, the only option is lung transplantation, which
need for suitable biomechanical properties and is associated with a poor outcome because of
micro-architecture, an optimal scaffold must limited organ supply and immunosuppression.
support cell-matrix signaling; decellularized The first clinical applications of regenerative
scaffolds may hold an advantage toward this. medicine have recently become a reality, after
The success obtained so far in transplanting years of basic science research and proof of prin-
tissue-engineered structures has paved the way ciple experiments on animal models of disease.
for the regeneration of more complex and solid The rapid development of the field has been
organs. Herein, regenerative medicine could driven by the unmet clinical needs of patients
represent a valid solution to the shortage of requiring healthy tissues and organs, but for
donors for organ transplantation. whom allotransplantation is not an option mainly
due to the limited availability of appropriate grafts
Keywords of human origin. So far, scientists around the
Regenerative medicine · Stem cell · Congenital world have been successful in tissue engineering
malformation · Tissue engineering · structurally simple organs with the main functions
Transplantation · Organ decellularization of allowing passage (i.e., trachea, urethra) or stor-
age (i.e., bladder) in the body, but it is likely that in
the next few years, more complex structures will
Introduction be prepared in bioreactors before being trans-
planted into patients. Alternatively, it is possible
We are certainly going through the biggest revo- that regeneration may occur directly in patients
lution in medicine since the introduction of anti- using their own body as a bioreactor (Elliott et al.
biotics. While medicine of the XVIII century was 2012). This would simplify the experimental
about discovering disease and, in the XIX, doctors design, avoid risks related to in vitro cell expan-
devoted their career to develop new medicine and sion, and reduce cost. Ultimately, tissue engineer-
operations that could stop the evolution of dis- ing may provide a long-term solution to the
eases, the future generation of physician will problem of shortage of organs available for trans-
have the instruments for regenerating tissues and plantation (Table 1).
organs when they are absent or damaged. This Congenital and acquired surgical conditions
new paradigm in medicine will change forever represent a major cause of morbidity and mortality
the way we treat diseases. Regenerative medicine during the first years of life and childhood. In
will dramatically change the way we look at both those complex conditions, prosthetic materials
congenital and acquired disease (De Coppi 2013). are used because of the lack of biocompatible
Regenerative medicine can offer the opportu- tissues able to replace or regenerate damaged
nity to functionally restore tissues and organs with organs. Besides the risk of infection, the major
the aim of giving patients a better and longer life. drawback of using a prosthetic patch closure is the
In 2014, we are still unable to restore the majority risk of dislodgment and subsequent recurrence of
of congenital malformations with functional tis- the initial problem. Moreover, foreign body reac-
sues. Patients born with a large diaphragmatic tions and implant rejection occur when synthetic
defect receive a patch of synthetic material that, polymers are used. Regeneration of natural tissue
in the best scenario will integrate with the native from living cells to restore damaged tissues and
muscle but it will never function as the native organs is the main purpose of regenerative medi-
muscle, giving the chance for the hernia to cine. This relatively new field has emerged by the
reoccur. And even when the diaphragmatic hernia combination of tissue engineering and cell trans-
can be effectively repaired, we are unable to plantation as a possible strategy for the replace-
replace or regenerate the underdeveloped lung ment of damaged organs or tissues. So far, most of
36
Table 1 Summary of clinical applications of tissue engineering

Scaffold Cells Patient
Organ Type Size Type Number number Follow-up Results References
Bronchus Decellularized 7 cm Epithelial 1*106/mL 1 4 months Normal mechanical properties and appearance of Macchiarini
trachea cells graft, improved quality of life, no et al. (2008)
Chondrocytes 1*106/mL immunosuppression
Trachea Decellularized 7 cm Epithelial 2.5*108 1 2 years Normal CT scan, appropriate growth, patient well Elliott et al.
(whole) trachea cells Patches (2012)
Tissue Engineering and Stem Cell Research
Epithelial
cells
Vagina Intestinal 7 10 cm Epithelial 1*107 cells 4 up to Normal structural and functional variables Raya-Rivera
submucosa cells per cm2 8 years et al. (2014)
segments Smooth 1*107 cells
muscle cells per cm2
Bladder Collagen matrix 70–150 cm2 Urothelial 50*106/cm3 7 46 months Volume and compliance increase, preservation of Atala et al.
or collagen-PGA cells renal function, adequate structural architecture (2006)
matrix Smooth 50*106/cm3 and phenotype
muscle cells
Urethra PGA-PLGA 5 cm Epithelial 1*107/mL 4 71 months Maximum urinary flow rate 27.1 mL/s, no Raya-Rivera
matrix cells strictures, normal architecture et al. (2011)
Smooth 1*107/mL (biopsy, 3 months)
muscle cells
PLCA poly-carpolactone, PLA polylactic acid, PGA polyglycolic acid, PLGA polylactic/glycolic acid
579
580 P. De Coppi
the attention has been focused on degenerative embryonic sources have the ability to give rise to
diseases such as Parkinson or Alzheimer, while cells that not only proliferate and replace them-
very little has been done for the treatment of selves indefinitely but also have the potential to
congenital conditions. However, the knowledge form any cell type. Embryonic stem (ES) cells are
acquired in the last years from stem cell biology derived from the inner cell mass of preimplanta-
and regenerative medicine strategies could lead to tion embryos, are pluripotent, and demonstrate
new ways of repairing or replacing injured organs germ line transmission in experimentally pro-
and systems, even during fetal development, and duced chimeras (Thomson et al. 1998). More
therefore pediatric patients could largely benefit recently, cells with intermediate potential could
from the evolution of this new exciting field. In be derived from the amniotic fluid (fetal SCs)
order to give rise to a new functional organ-like (De Coppi et al. 2007) or reprogramed from
structure, several variables, such as local environ- adult SCs using various factors implicated with
ment, nutrients, and metabolites, are pivotal. the maintenance of pluripotent potential of ES
These variables, in the contest of tissue engineer- cells (Takahashi and Yamanaka 2006). This chap-
ing, are mainly dependent on the provision of a ter would like to offer an insight on the latest
three-dimensional growth structure termed “scaf- evolution of SCs with a glance at their possible
fold.” Scaffolds are usually made by natural mate- application for regenerative medicine and the
rials, which are essentially bioactive but lack recent clinical translations, particularly in the
mechanical strength, or synthetic materials, pediatric surgery field.
which lack inherent bioactivity but are mechani-
cally strong and can be engineered with the desir-
able macrostructure and microstructure and might Stem Cells
possess desired bioactive properties to make pos-
sible cellular growth and organogenesis. Despite Embryonic Stem Cells
scaffolds could ultimately represent the exclusive
tool for tissue engineering and several attempts to ES cells derive from the inner cell mass of a
generate whole organs, such as liver, have been blastocyst stage embryo. They are pluripotent
done by developing structures with vascular chan- and give rise during development to all deriva-
nels to ensure an adequate network of vascular tives of the three primary germ layers: ectoderm,
supply, major developments in regenerative med- endoderm, and mesoderm; hence, they possess the
icine have been achieved after the discovery of potential to develop into most of the cell types
cells capable to be isolated and expanded in num- within the body (Thomson et al. 1998). The field
ber outside the body. Stem cells (SCs) are of ES cell research began with the study of terato-
unspecialized cells with the capacity of undergo- carcinoma cells in the 1950s and continued with
ing to asymmetric division which offer them the the first mouse ES cell lines derived from the inner
unique power of self-renewal and to give rise to cell mass of blastocysts using culture conditions
multiple different specialized cell types. Three are (fibroblast feeder layers and serum) in 1981 and
the main source SCs in human and animals: from expanded in 1998 when Thomson et al. (Thomson
embryonic, fetal, and adult tissues. Adult SCs et al. 1998) first derived human ES (hES) cells.
have a limited cellular regeneration or turnover The maintenance of pluripotency in the hES is
that could represent a limitation for tissue engi- assured by the presence of different transcription
neering application where a large number of cells factors like Oct-4, Nanog, and SOX2 that are
is necessary. They can be identified in many adult essential to ensure the suppression of genes that
mammalian tissues, such as bone marrow, skeletal lead to differentiation. The cell surface antigens
muscle, skin, and adipose tissue, where they con- most commonly used to identify hES cells are the
tribute to the replenishment of cells lost through glycolipids stem cells embryonic antigen-3 and -4
normal cellular senescence or injury (Pittenger et (SSEA3 and SSEA4) and the keratan sulfate anti-
al. 1999). In contrast, SCs derived from gens Tra-1-60 and Tra-1-81. ES cells could be
36 Tissue Engineering and Stem Cell Research 581
used not only to generate tissues but also could be derivation; and (c) research and regenerative med-
employed as “cellular models” to study a range of icine. The first is scientifically and ethically
human diseases and to test new drug candidates condemned. The second has important implica-
for efficacy and toxicity. ES cells, being pluripo- tions for the future of ES therapies, allowing the
tent, require specific signals for correct differenti- production of non-immunogenic ES lines.
ation, and if injected in vivo prior commitment, Besides, these cells could be stored and used
they will give rise to many different types of cells, subsequently for the treatment of future medical
causing teratomas. So far their potentials, together conditions. As a consequence this could be rele-
with the difficulties related to their allogenic ori- vant for the creation of autologous tissues also in
gin, have limited their possible clinical applica- children who are born with complex
tions. In particular, the political debate malformations in which tissue viability represents
surrounding SCs began suddenly after hES crea- a problem. Patient-specific cells could be created
tion because of the destruction of the derivative in vitro. ES cells derived using SCNT would have
embryo. Recently, researchers opened the possi- the same genetic background of the patient who
bility of generating ES cell lines without has donated the initial genetic material, and the
destroying embryos by deriving cells from the tissue created would not be rejected after trans-
early development of the embryo without plantation. ES cells have in fact the advantage of
impairing their further development. Moreover, being extremely plastic facilitating the in vitro
in the last few years, ES cells have been used as engineering of complex organ such as the heart,
a model for tissue differentiation, and rudimental liver, and kidney. Nevertheless, in spite of the
organs derived from ES cells have been ethical considerations, the limitation of this tech-
engineered. Understanding the signaling neces- nique is related both to the low efficiency, leading
sary for terminal differentiation has been impor- to a high loss in cell yield and the inadequate
tant to define lineage-specific transcription factors supply of human oocytes.
which can potentially be used to genetically engi-
neer and terminally differentiate pluripotent stem
cells increasing the chance of producing function- Induced Pluripotent Stem Cells
ally differentiated tissues.
Since the major objection to hES research is their
immunogenicity, it would be advantageous to
Somatic Cell Nuclear Transfer develop a method of creating SCs from autolo-
gous tissue. Generation of induced pluripotent
Somatic cell nuclear transfer (SCNT) has also stem (iPS) cells, described by Yamanaka et al. in
been adopted to create patient-specific SCs and 2006, avoids both the immunological and the
avoid problems related to the creation of allogenic ethical problems (Fig. 1). iPS cells can be devel-
tissue. This procedure entails specifically the oped from non-pluripotent cells, usually adult
removal of an oocyte nucleus in culture, followed somatic cells, by causing a forced expression of
by its replacement with a nucleus derived from a several genetic sequences such as Oct4
somatic cell obtained from a patient. Cells yielded (POU5F1), the transcription factor Sox2, c-Myc
by this induction would be genetically identical to proto-oncogene protein, and Klf4 (Krueppel-like
the donor and would not be rejected by the patient. factor 4) as key genes, sufficient to reprogram
SCNT can potentially be used for three purposes: fibroblasts which are able to produce viable chi-
(a) reproduction, leading to generation of an meras if injected into developing embryos and
embryo for continuation of life (a notable example teratomas in immunocompromised mice
in 1996 was the generation of the first mammal, a (Takahashi and Yamanaka 2006). In 2007, suc-
sheep named Dolly, derived from an adult somatic cessful iPS cells were obtained from human fibro-
cell by the use of this technique (Campbell et al. blasts both using Oct3/4, Sox2, Klf4, and c-Myc
1996)); (b) therapy, generating blastocysts for SC with a retroviral transfection and using OCT4,
582 P. De Coppi
Fig. 1 Tissue engineering combines expertise on the fields of cell biology and material science aiming to generate tissues/
organs that could be used in alternative to allotransplantation
SOX2, NANOG, and a different gene LIN28 combine any of its own genes with the targeted
using a lentiviral system, improving transduction host, the danger of creating tumors is eliminated
output (Yu et al. 2007; Takahashi et al. 2007). The (Meissner et al. 2007). Yamanaka et al. have since
viral transfection systems used to insert the genes demonstrated that reprogramming can be accom-
at random locations in the host’s genome created plished via plasmids without any virus transfec-
concern for potential therapeutic applications of tion system at all, although at very low
these iPS cells, because it might increase the risk efficiencies. IPS cells show morphological resem-
of tumor formation. To overcome these dangers, blance to hES cells, express typical human ES
some studies have used adenovirus to transport cell-specific cell surface antigens and genes, give
the four sequences into the DNA of mouse rise to multiple lineages in vitro, and form terato-
somatic cells. Since the adenovirus does not mas when injected into immunocompromised
mice. The efficiency of reprogramming adult Moreover, iPS cells can be generated from fetal
fibroblasts has been low (<0.1%). However, cells without any genetic manipulation. It was
since reprogrammed clones could consistently be recently described that iPS cells can be easily
recovered and expanded with existing gene com- derived from first-trimester amniotic stem cells
binations, for practical applications, the low when grown on Matrigel in hES cell medium
reprogramming efficiency itself was not really supplemented with the histone deacetylase inhib-
considered an issue, unless reprogramming itor valproic acid (VPA) (Moschidou et al. 2012).
selects abnormal genetic or epigenetic events It is possible that, because of their fetal origin,
that were stably propagated in the resulting iPS amniotic fluid stem (AFS) cells (discussed in
cell lines (Yu and Thomson 2008). Recently, detail later) could be the ideal for cell banking of
Jaenisch’s group found an elegant way to derive patient-specific pluripotent cells and possible
iPS from somatic cells of patients, free from applications in pharmaceutical screening.
reprogramming factors using Cre-recombinase
excisable lentiviruses. The efficiency of
reprogrammed iPS is very high with a low number Fetal Stem Cells
of proviral vector integrations, and the cells main-
tain a gene expression profile more similar to hES Fetal cells may represent the ideal source for
than to hiPS and can be subsequently differenti- therapy (Fig. 2a, b). Like ES cells, they are still
ated into dopaminergic neurons, such that plastic and easy to expand, and, in common with
Parkinson’s disease patient-derived induced plu- their adult counterparts, they are less controver-
ripotent stem cells can be free of viral sial, not tumorigenic, and can be accomplished in
reprogramming factors. Interestingly to the surgi- an autologous setting. The latter is particularly
cal community, it has been recently demonstrated important in the context of congenital malforma-
the possibility to derive and isolate of enteric tion as surgical treatment is often complicated by
nervous system (ENS) progenitors from human insufficient available tissue at time of repair. Reg-
pluripotent stem cells and their further differenti- ularly, artificial materials have been the only
ation into functional enteric neurons. ENS pre- option for reconstruction in such cases, with
cursors derived in vitro are capable of targeted high rates of morbidity. Recently, fetal tissue engi-
migration in the developing chick embryo and neering has emerged as a promising concept in
extensive colonization of the adult mouse colon. surgical reconstruction of birth defects.
Fig. 2 Schematic
representation of the tissue-
engineered trachea
transplanted at Great
Ormond Street Hospital in
2010. During surgery the
airway was found to be
severely stenotic with
multiple stents including
one entering the ascending
aorta. (a and b) The old
homograft trachea was
removed and replaced by
the engineered graft (c)
Elliott et al. (2012)
584 P. De Coppi
Redundant or purposely obtained fetal cells could fully reprogrammed without using any genetic
be harvested, cultured, and manipulated in vitro manipulation (Moschidou et al. 2012). AFS cells
during the remainder of pregnancy and later used can be used as carrier for congenital monogenic
for tissue engineering of graft material that will be disease, which could be theoretically corrected by
applied in postnatal reconstruction. Indeed, in the a combined approached gene-cell therapy (Fig.
case of prenatal diagnosis of structural defects, 2a). Following this approach, AFS cells could be
there is the possibility of obtaining homologous isolated, the defect identified and corrected using
cells at the time of invasive sampling such as the corrected sequence, and injected back to the
chorionic villi biopsy, cordocentesis, or amnio- donor avoiding both fetal and maternal
centesis. Sampling of amniotic fluid (AF) is ideal immunorejection. Alternatively, in case of struc-
for prenatal/neonatal applications with the advan- tural anomalies, AFS cells could be expanded and
tages of being (i) relatively easy to perform; (ii) used to engineer the missing tissue/organ (Fig.
low risk for both the mother and fetus; and (iii) a 2b). Mesenchymal stem cells derived from amni-
widely accepted method of prenatal diagnosis. otic fluid have already been used in large animal
AFS cells represent about 1% of all whole cells models for the repair of surgically created dia-
in cultures of human amniocentesis specimens phragmatic defects (Fuchs et al. 2004), and
obtained for prenatal genetic diagnosis and can engineered diaphragmatic tendon graft using mes-
be immunoselected using c-Kit (CD117). AFS are enchymal amniocytes has obtained preclinical
described as broadly multipotent stem cells that validation and may soon become a clinical reality
can differentiate into adipogenic, osteogenic, (Turner et al. 2011).
myogenic, endothelial, neurogenic, and
hepatogenic lineages, inclusive of all embryonic
germ layers. In contrast with mesenchymal cells, Adult Stem Cells
AFS cells show hematopoietic engraftment
(Ditadi et al. 2009) and a functional and stable At the farthest end of the spectrum, we have stem
integration into the skeletal muscle stem cell cells, which are present in the postnatal life, are
niche, highlighting their value as cell source for more committed, and classified as either multi-
the treatment of muscular pathologies and skeletal potent or unipotent (Fig. 1). Classically, hemato-
muscle defects (Piccoli et al. 2012). This group of poietic stem cells (HSC) have successfully been
cells can be steadily expanded in cultures without used for more than 25 years and transplantation of
a feeder layer and has a typical doubling time of bone marrow (BM) and cord blood (CB) HSC is
36 h. Sub-confluent cells show no evidence of routinely performed for hemato-/oncological dis-
spontaneous differentiation, but nevertheless, orders. Following preliminary studies by
under specific inducing conditions, these cells Friedenstein et al. (Friedenstein et al. 1968),
are able to differentiate and, if injected in vivo, other cells, defined as mesenchymal stem cells
show no evidence of tumor growth in severe com- (MSC), distinguishable from HSC because of the
bined immunodeficient mice. AFS cells are posi- capacity to grow in adherent culture, were
tive for a number of surface markers commonly described. MSC are multipotent stem cells with
expressed by MSC, but not by ES cells, such as fibroblast-like morphology, which can differenti-
CD29, CD44 (hyaluronan receptor), CD73, ate into osteogenic (bone), chondrogenic (carti-
CD90, and CD105 (endoglin) (Cananzi et al. lage), and adipogenic (bone marrow stroma)
2009). Human AFS cells are also positive for lineages “in vitro.” Their existence was first
stage-specific embryonic antigen (SSEA)-4, also hypothesized when tissues biopsied (skeletal
expressed by ESC, and >90% of the cells express muscle, skin, heart, and even brain) from patients,
the transcription factor Oct4, which has been asso- who previously received a BM transplant, showed
ciated with the maintenance of the donor cell engraftment. To date, MSC have been
undifferentiated state and the pluripotency of ES isolated both in the fetus and postnatally from the
and EG cells. First-trimester AFS cells can also be blood, liver and bone marrow, amniotic fluid,
lung, pancreas, dental pulp, and periosteum. They tissues is not sufficient for any downstream MSC
have been isolated also from the umbilical cord application in clinical settings. In vitro expansion
blood, Wharton’s jelly, and the placenta. These can affect biological properties of the cells, and
parts, previously considered a “biological waste” MSC go through very significant changes in phe-
today are among the most interesting for MSC notype and gene expression as a result of cell
isolation. Three major criteria have been intro- culture adaptation. Although considered a safer
duced to define MSC by the International Society source compared with ES, the prospective clinical
for Cell Therapy (Horwitz et al. 2005): applications of MSC require meticulous
examination.
(i) The cells must be plastic adherent when
maintained under standard culture
conditions. Scaffolds
(ii) >95% of the MSC population must express
CD73 (ecto 50 -nucleotidase), CD90 (Thy-1) In order to develop a tissue-engineered construct
and CD105 (SH2 or MCAM or endoglin), to replace missing or damaged tissue, the combi-
LNGFR (low-affinity nerve growth factor nation of appropriate cellular engineering and
receptor), CD166, ALCAM adhesion pro- material science is needed. Material science is
tein, CD146 (P1H12), CD29, and CD106 concerned with the production of acellular scaf-
(vascular adhesion molecule-1, VCAM-1), folds that can be seeded with cells, allowing and
and >98% MSC should be negative for promoting their growth. General attributes that a
hematopoietic cell surface antigens: CD45, scaffold must fulfill include:
a pan-leukocyte marker; CD34, a marker of
primitive hematopoietic progenitors and (i) Biocompatibility that does not lead to an
endothelial cells; either CD11b or CD14, immunogenic response from the host
markers for monocytes; either CD19 or (ii) Biodegradation in a suitable time period
CD79a, B-cells markers; and human leuko- that permits sufficient cellular growth
cyte antigen (HLA Class 2). while not producing harmful degradation
(iii) MSC should be capable of differentiating products
into osteoblasts, chondroblasts, and adipo- (iii) Mechanical properties that are in line with
cytes when placed into an appropriate induc- tissue growth; a significant amount of three-
tion/differentiation medium. dimensional support in the early stages with-
out obstructing cellular ECM production in
Adult stem cells or progenitors have already the later stages
been used clinically to engineer urological con-
structs such as bladders and urethras, blood ves- More specific scaffold attributes are related to
sels, cornea, esophageal epithelium, bronchi, and aiming to recreate the nonmechanical attributes of
tracheas. Moreover, MSC have been tested for the ECM. These properties include the mediation
cellular therapy in pediatric patients for several of cell adhesion via integrin receptors, as well as
clinical indications, such as inborn errors of positive influence on cell survival and prolifera-
metabolism (metachromatic leukodystrophy, tion by means of growth factors and cytokines.
Hurler syndrome, infantile hypophosphatasemia), What is more, the ECM has been argued to be
osteogenesis imperfecta, and GVHD (Horwitz et involved in mechanochemical transduction, as
al. 1999; Le Blanc et al. 2005). However, in con- shown by the differentiation MSC to neurons,
trast with the aforementioned cells, MSC also muscle cells, and osteoblasts when seeded on
have a limited life span and become senescent substrate mimicking the elasticity of each of
when cultured in vitro. This is a major problem those host tissues respectively.
for therapy since, regardless of the isolation pro- Materials used thus far for tissue engineering
cedure, the MSC quantity obtained from primary have been traditionally divided in three
586 P. De Coppi
categories, namely: (2A) naturally derived mate- as biomaterials in other areas of medicine. They
rials (e.g., collagen and elastin), (2B) synthetic are advantageous because they are (i) easily and
materials (e.g., poly(L)-lactic acid [PLA], poly- (ii) cheaply manufactured, (iii) can be formed in
glycolic acid [PGA], and polylactic-co-glycolic many different structures with the required
acid [PLGA]), and (2C) natural acellular dimensions, the microstructure and nanostruc-
scaffolds. ture can be well controlled, and (iv) they can be
produced with a range of different mechanical
properties and done so reproducibly. For all
Naturally Derived Materials these reasons synthetic polymers should be the
best choice for clinical translation; however, it
Materials composed of naturally occurring mac- has been clearly very difficult to replicate in the
romolecules, in particular those that formulate laboratory the millions of years of evolutions
the ECM, have been tested for tissue engineering that has taken to design structure and composi-
purposes. They have the advantage of having a tion of our tissues and organs. Some of those
specific structure with which cellular integrins synthetic polymers, such as the polyester poly-
bind well to, promoting cellular adhesion. A mers, have been firstly used already and
classical example is collagen, the most abundant employed as sutures and orthopedic fixatives
protein found in the ECM, making up a quarter such as pins, rods, and screws. The advantage
of the total protein content in many animals. of those scaffolds is related to scaffold degrada-
There have so far been 29 different types of tion that occurs through hydrolytic attack of the
collagen that have identified, though 90% of ester bond, and its rate is affected by adjusting
the collagen in the body is types I, II, III, and various properties of the scaffold including crys-
IV. In vertebrates approximately 22% of the total tallinity, molecular weight, and porosity. The
protein content is of collagen type I, and in existing wide clinical application of polyesters
vascular tissue, such as the aorta, 80–90% of supports their biocompatibility, although some
the collagen content is of type I or III. Collagen studies have suggested that there can be prob-
extracted from animal and human tissues has lems due to their propensity to disintegrate into
been used due to its influence in cell adhesion small particles or toxicity associated with acidic
and proliferation as well as low inflammatory degradation (Taylor et al. 1994). A commonly
and immunogenic responses. Mechanical prop- used biodegradable synthetic polymer is poly-
erties of the collagen-based scaffolds, including glycolic acid (PGA). Its degradation product,
resorption rate, may be altered according to glycolic acid, is a natural metabolite and can
porosity, fiber orientation, and cross-linking con- therefore be readily metabolized without toxic
ditions. Elastin is another ECM protein and it is effect and is already in use as a material for
mainly found in blood vessels, making up a large resorbable sutures. PGA is polyester with high
part of the ECM content of arteries. It provides crystallinity and as such is a stiff and brittle
the arteries with their elastic properties and also material. It also has a fast degradation rate of 6
has antithrombogenic properties. For example, to 8 weeks when fabricated as a mesh. When
in vascular tissue engineering production of a smooth muscle cells (SMCs) are cultured on
tubular scaffold containing both collagen and PGA mesh in a bioreactor, it was observed
elastin allowed smooth muscle cells to orientate a complete loss of PGA after 8 weeks and pro-
themselves in line with the fibers. duction of ECM products like collagen.
Additionally, polylactic acid (PLA) is a semi-
crystalline polymer with a similar rate of
Synthetic Materials degradation to that of PGA and along with
PGA is one of the few biodegradable polymers
Synthetic materials were considered as a possi- with Food and Drug Administration (FDA)
bility for tissue engineering following their use approval for clinical use.
Natural Acellular Matrix in the prevention of stenosis. A successful example

of natural acellular tissue currently used in the
Natural acellular matrices are organs from humans clinic is small intestinal submucosa (SIS) harvested
or animals that have been treated to remove cells from mammalian small intestine and treated with
and immunogenic material, producing natural scaf- peracetic acid, followed by antibiotic or radioactive
folds that maintain their architecture of origin sterilization. Beyond preservation of the ECM
(Fishman et al. 2013). Following decellularization structure, GAG, and collagen content, SIS has
these scaffolds may be implanted with or without been demonstrated to contain growth factors such
prior cell seeding, aimed at regenerating a complete as vascular endothelial growth factor (VEGF),
organ or improving tissue repair respectively. The FGF-2, and tumor growth factor-β (TGF-β)
benefits of this technique include the preservation (Voytik-Harbin et al. 1997). VEGF stimulates
of the ECM that favorably influences cell fate as angiogenesis of the tissue, whereas TGF-β has
well as of the macro- and micro-architecture. The immunomodulatory properties, suppressing T-
macro-architecture is important in recreating the helper response and reducing inflammatory or
three-dimensional structure of the organ to be tissue immune reactions. Collectively, these properties
engineered as well as maintaining a vascular tree provide an environment for tissue growth and vas-
that will allow for cell and nutrient delivery and cularization while maintaining sufficient mechani-
waste removal. The micro-architecture is of value cal strength until endogenous ECM production
toward maintaining the mechanical properties and occurs. Clinical uses of SIS include various types
porosity of the tissue that will be optimal for cell of hernia repair (Franklin et al. 2008), anal fistula
seeding and growth. Since ECM components are closure (Champagne et al. 2006), and dural repair
preserved across species, immunogenic responses (Bejjani et al. 2007). Similar materials that are
are removed (Totonelli et al. 2013). The being examined for clinical use in tissue repair
decellularization process can be performed in a include amniotic membrane tissue, cadaveric fas-
variety of manners including mechanical, chemical, cia, and acellular dermis (which has been used for
and enzymatic methods. The aim is to remove full-thickness burns since 1995). Decellularized
cellular material while preserving the integrity and esophageal scaffolds have been used with good
constituents of the ECM. Mechanical methods such reported results in both preclinical and clinical
as snap freezing, direct pressure, and sonication studies (Badylak et al. 2011). Significant heteroge-
have been reported to disrupt ECM. The major neity exists among studies, both with respect to the
chemical methods used for decellularization type of scaffold, extent of surgery, and species
include ionic detergents such as sodium dodecyl used, which partly explains the range of results
sulfate and sodium deoxycholate, nonionic deter- reported. Thus, regeneration of the muscularis pro-
gents such as Triton X-100, and zwitterionic deter- pria layer is seen to take place in some studies.
gents such as CHAPS. Our experience with Badylak et al. laid sheets of SIS onto the raw
intestinal and bladder decellularization have internal surface of esophagus following endoscopic
suggested that a combination of Milli-Q water, submucosal resection in five patients with superfi-
sodium deoxycholate, and DNase is superior to cial cancers (Badylak et al. 2011). With a follow-up
the use of Triton X-100 in preserving ECM struc- of 4 to 24 months, the scaffold promoted physio-
ture and collagen/GAG content while removing logical remodeling as evident by endoscopy and
cellular material (Totonelli et al. 2013). Comparing histological characterization following biopsy.
the benefits of each method is beyond the scope of Strictures still formed but only at areas outside
this review, and when they are looked at, they those lined by SIS, suggesting possible technical
should be examined in a tissue-specific manner. improvements in scaffold delivery. In fact, when
They have the added hypothetical advantages SIS was used to completely cover a 3 5-cm
over synthetic scaffolds of not producing poten- mucosal defect in the cervical esophagus, there
tially toxic degradation products or inducing was no stenosis or other complications, and endos-
inflammation, characteristics that may be important copy at 4 weeks demonstrated good integration of
588 P. De Coppi
the scaffold (Clough et al. 2011). Hypothetically, greater degree of control can be had over the
decellularized esophageal tissue should retain the manufacture, increasing reproducibility. This is
signals, both chemical and structural, that will an important factor in good manufacture practices
direct the appropriate migration and differentiation (GMP), necessary if one wishes to take a tissue-
of host cells, in a way unlikely to occur with scaf- engineered device from lab to clinic. Dermal of
folds originating outside the esophagus, such as saphenous vein fibroblasts were cultured for
SIS. Ozeki et al. compared two methods of 21 days and then washed with deionized water
decellularization of adult rat esophagus based on and dried at room temperature for 8 h. The fibro-
deoxycholate and Triton X-100, respectively blasts can produce a large amount of ECM, which
(Ozeki et al. 2006), and assessed the resultant tissue autologous SMCs seeded on to it might not be
using routine histology and biocompatibility. able to do, depending on patient age, history, and
Those treated with deoxycholate showed superior site of extraction. The Niklason group at Yale
mechanical properties, maintenance of the ECM, have seeded SMCs from pigs, canines, or humans
and a lower DNA content than those treated with (Dahl et al. 2011) on to PGA scaffolds and cul-
Triton X-100. Bhrany et al. found a combination of tured them in a biomimetic bioreactor for
0.5% sodium dodecyl sulfate (SDS) and Triton X- 10 weeks, before decellularizing the scaffold
100 to be effective in decellularization, albeit with a with a detergent treatment. The scaffolds can
loss of tensile strength as measured by burst pres- then be seeded with cells or implanted directly.
sure studies (Bhrany et al. 2006) (Fig. 3).
Regenerative Medicine
Cell-Derived ECM Scaffolds
In order to give rise to a new functional organ-like
Instead of decellularizing blood vessels to obtain structure, several variables, such as local environ-
vascular ECM for cell seeding, some groups have ment, nutrients, and metabolites, are pivotal.
taken the approach of culturing vascular cells to These variables, in the contest of tissue engineer-
produce vascular ECM and then decellularizing. ing, are mainly dependent on the provision of a
The cells can be allo- or xenogeneic and a much three-dimensional growth structure termed a
Fig. 3 Engineering of esophageal tissue for the repair of and the neo-esophagus is conditioned in specific bioreac-
infants born with esophageal atresia. Decellularized pig tors before transplantation. The use of xenogeneic
esophagus is prepared using detergent enzymatic treatment decellularized tissue has the advantage of not requiring
(DET). Autologous cells are derived from affected infants, immunosuppression Fishman et al. (2013)
“scaffold.” Scaffolds are usually made of natural of the distal trachea and main bronchi, who
materials, which are essentially bioactive but lack underwent excisional surgery followed by a
mechanical strength, or synthetic materials, which reconstruction of his airway with a tailored
lack inherent bioactivity but are mechanically bioartificial nanocomposite previously seeded
strong and can be engineered with the desirable with autologous bone marrow mononuclear cells
macro- and microstructure and might possess via a bioreactor for 36 h (Jungebluth et al. 2011).
desired bioactive properties to make possible cel- More complex organs, such as the liver or the
lular growth and organogenesis. Although scaf- kidney, may require more time before being
folds could ultimately represent the exclusive tool applied for therapy. Atala’s group has described
of tissue engineering and several attempts have a perfusion decellularization technique for the
been made generating whole organs, such as the liver and kidney generating decellularized organ
liver, by developing structures with vascular scaffolds for organ bioengineering (Baptista et al.
channels to ensure an adequate network of blood 2011). In an analogous fashion, Uygun et al. have
supply, major developments in the clinic have reported a successful approach of decellularizing
been achieved in the last few years using relative rat livers and recellularizing them with rat primary
simple scaffolds. Atala et al. presented in 2006 a hepatocytes, showing promising hepatic function
series of seven children with myelomeningocele, and the ability to transplant heterotopically these
aged 4–19 years, with high-pressure or poorly bioengineered livers into animals for up to 8 h
compliant bladders, who successfully received (Uygun et al. 2010; Uygun et al. 2011). The
an engineered bladder tissues (Atala et al. 2006). decellularization approach was pioneered in the
Briefly, after undergoing a bladder biopsy, heart by Ott et al. who showed that it was possible
urothelial and muscle cells were grown and then not only to generate whole organ scaffolds using a
seeded onto a biodegradable bladder-shaped scaf- perfusion decellularization system but also that
fold made of collagen or a composite of collagen neonatal rat cardiomyocytes (delivered through
and polyglycolic acid. About 7 weeks after the transmural injection) and endothelial cells
biopsy, the autologous engineered bladder con- (injected through the aorta) could generate a con-
structs were implanted and wrapped in omentum tractile construct (Ott et al. 2008). Using a similar
with good long-term (mean 46 months) results approach, lungs have also been regenerated
(Atala et al. 2006). The same group described in through the seeding of pulmonary epithelium
2011 their experience with five boys who, follow- and vascular endothelium on rat lung ECM (Ott
ing trauma, between 2004 and 2007 underwent et al. 2010). Among unmet clinical needs, intesti-
urethral reconstruction using tubularized urethras nal engineering is particularly relevant, particu-
seeded with autologous cells which remained larly because of the relatively poor outcome of
functional for up to 6 years (Raya-Rivera et al. intestinal transplantation. However, although
2011). In 2001 a 4-year-old girl with a single right pioneering investigations in the field of intestinal
ventricle and pulmonary atresia, who underwent bioengineering date back to the 1980s, initial
the Fontan procedure at the age of 3 years, was excitement has been blunted by the considerable
transplanted with a polycaprolactone-polylactic limitations and roadblocks encountered in the
acid copolymer (weight ratio, 1:1) reinforced course of experimental investigations. The main
with woven polyglycolic acid seeded with autol- culprit of such stagnation is the complexity of
ogous cells to bypass the total occlusion of the intestinal anatomy and the various functions of
right intermediate pulmonary artery. Ten days the intestine. Vacanti’s group showed that rodent
after seeding, the graft was transplanted with no organoid units seeded on a nonwoven poly-
postoperative complications, and at seven months glycolic acid (PGA) fiber and implanted in rats
the patient was doing well, with no evidence of having undergone the resection of 85% of their
graft occlusion or aneurysmal changes on chest native intestine were able to partially replace gut
radiography (Shin’oka et al. 2001). More recently, function (Choi and Vacanti 1997; Kim et al. 1999;
a 36-year-old man, with recurrent primary cancer Grikscheit et al. 2004). Bioengineered intestinal
590 P. De Coppi
constructs were also successfully transplanted in of surgical approaches to malformations and

pigs (Sala et al. 2009) but this technology is inef- organ transplantation and the totally new possibil-
ficient because several centimeters of bowel are ity of correcting them using autologous tailor-
needed to obtain a sufficient number of organoid made functional tissue.
units able to repopulate just a few centimeters of
engineered intestine (Dunn 2008). Intestinal stem
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Patient- and Family-Oriented Pediatric
Surgical Care 37
Katelynn C. Bachman, Ronald C. Oliver, and Mary E. Fallat
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Core Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
History of Patient and Family-Oriented Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Additional Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Delivering News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
The Prepared Messenger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Pre-managing One’s Personal Story and Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Physical Presence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Communicating News . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598
What to Say . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599
K. C. Bachman
University of Louisville School of Medicine, Louisville,
KY, USA
e-mail: kcbach01@louisville.edu
R. C. Oliver
Norton Healthcare, Norton Children’s Hospital, Louisville,
KY, USA
e-mail: ronald.oliver@nortonhealthcare.org
M. E. Fallat (*)
University of Louisville School of Medicine, Louisville,
KY, USA
Hiram C. Polk, Jr. Department of Surgery, Division of
Pediatric Surgery, University of Louisville School of
Norton Healthcare, Norton Children’s Hospital, Louisville,
KY, USA
e-mail: mefall01@louisville.edu

https://doi.org/10.1007/978-3-662-43588-5_40
594 K. C. Bachman et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
Abstract patients, families, physicians, and other

Patient- and family-oriented care is a healthcare professionals (Eichner and Johnson
healthcare approach that influences policies, 2012; Ayub et al. 2016). Healthcare professionals
programs, facility design, and everyday inter- that embrace patient and family-oriented care
actions among patients, families, physicians, understand the importance of this balanced part-
and other healthcare professionals. Although nership and readily orchestrate these relationships
a consensus of its definition has not been met, with their patients. They also recognize that the
there is significant agreement on the general family is the child’s primary and constant source
principles of (1) open and objective informa- of strength and support. Consequently, children
tion sharing, (2) cultural competence, (3) part- and their families’ perspectives and information
nership and collaboration including joint they provide are instrumental in clinical decision-
decision-making, (4) negotiation and flexibil- making. Patient and family-oriented care goes
ity while upholding medically appropriate beyond good intentions by including the patient’s
decisions, and (5) incorporation of families at and family’s perspectives. Physicians cannot sim-
all levels of care, including personal encoun- ply assume they know what is right for the patient
ters, program development, and professional but should engage in discussions where the
education and resuscitation and end-of-life patient and family define it.
decisions. Surgeons should not take on the
daunting task of providing quality patient and
family-oriented care alone but should unite
Core Principles
with fellow multidisciplinary team members
to achieve optimal health and healing for the
Although a consensus of its definition has not
patient. Therapeutic play, a capacity of child
been met, there is significant agreement on the
life curricula, utilizes age-appropriate activities
general principles of patient and family-oriented
to allow self-expression, provide distraction
care. Groups such as the American Academy of
during treatments, and establish a near-normal
Pediatrics, Family Voices, and the Maternal and
environment to decrease the anxiety of pediat-
Child Health Bureau share the following princi-
ric patients. The trajectory of parents’ stories,
ples (Kuo et al. 2012):
hopes, confidences, and grief rests on these
twin pillars: competence and compassion.
• Information sharing: Open and objective
information sharing between families and
Keywords providers
Patient · Family · Family-oriented care · • Respect and honoring differences: Respect for
Integrative health · Child life · Death · Bad family preferences, skills, expertise, cultural
news · Communication and spiritual beliefs, and linguistic differences
• Partnership and collaboration: Joint decision-
making to meet the needs of the patient while
Introduction honoring the requests, strengths, and values of
the individuals involved
Patient and family-oriented care is an approach to • Negotiation: Participants have a willingness to
healthcare that influences policies, programs, be flexible, while upholding medically appro-
facility design, and everyday interactions among priate decisions
37 Patient- and Family-Oriented Pediatric Surgical Care 595
• Care in context of family and community: groups supported patient and family-oriented care
Incorporation of families at all levels of care, in its infancy and continue to have an influence on
including personal encounters, program devel- developing healthcare policies and procedures.
opment, and professional education Restricted visitation became 24-h parental visita-
tion, and soon, parents held an even more active
role in care-by-parent units. Here, nurses and phy-
History of Patient and Family- sicians would teach parents how to take efficient
Oriented Care care of their children’s medical needs under hos-
pital staff supervision. These care units were espe-
To understand fully what patient and family- cially beneficial for breastfeeding and chronically
oriented care concept entails, it is imperative to ill patients. However, partnership-in-care where
acknowledge its history and progress. This ideol- the parents became a contributing equal in their
ogy has drastically evolved since the child’s care did not emerge until the early 1990s
mid-twentieth century, when healthcare profes- (Jolley and Shields 2009). Today, patient and
sionals began to recognize the trauma that ensued family-oriented care is considered by healthcare
from child/family separation in the inpatient set- professionals as the standard of care in pediatrics
ting. Oftentimes, patients were admitted to the and is implemented at facilities and programs
hospital without their parents and had limited worldwide.
visitation hours due to the supposed risk of
spreading infection during this era devoid of anti-
biotics. Pediatric patients of the early 1900s retro- Additional Resources
spectively described their fear of hospital staff and
the affectionless environment that they created. Surgeons should not take on the daunting task of
Had parents been present, these experiences of providing quality patient and family-oriented care
hospitalization would likely have been vastly dif- alone but should unite with fellow multi-
ferent (Jolley and Shields 2009). Researchers disciplinary team members to achieve optimal
thereafter began to observe the negative effects health and healing for the patient. Physicians are
that hospitalization had on children, yet advance- primarily taught to diagnose and alleviate the
ments toward family-oriented care remained iso- physical ailments of their patient, while other
lated. Tangible improvements toward family- trained professionals (i.e., child life therapists)
oriented care began when two influential British work exclusively with patients and family mem-
researchers and theorists, John Bowlby and James bers to lessen emotional distress, impart coping
Robertson, combined their efforts on mother and strategies, and minimize the trauma that may fol-
child separation (Alsop-Shields and Mohay low hospitalization. For example, when parents
2001). Bowlby was considered the leading expert are unable to be present during emergency situa-
in the field of maternal care and child develop- tions, child life therapists become that compulsory
ment. While working as Bowlby’s research assis- support, which allows other hospital staff mem-
tant, Robertson’s own daughter was admitted to a bers to successfully address the medical needs of
hospital. Robertson and his wife, Joyce, were so the patient.
distressed by their toddler’s behavioral changes Even though most pediatric hospitals in the
that they decided to focus solely on the effects of United States and Canada have implemented child
separation of mother and child due to hospital life programs (Thompson and Stanford 1981), there
admission. They created educational videos and are multiple discrepancies between what healthcare
spoke to communities worldwide calling for professionals perceive as child life responsibilities
parental presence in hospitals. Parent-driven and what child life professionals consider to be their
advocacy groups were formed on the basis of role (Cole et al. 2001). Therapeutic play, a capacity
Bowlby and Robertson’s theories (Alsop-Shields of child life curricula, may appear as mere enter-
and Mohay 2001). These parent-driven advocacy tainment to the external eye; however, this program
utilizes age-appropriate activities to allow self- Table 1 Integrative health services

expression, provide distraction during treatments, Child life services
and establish a near-normal environment to Expressive therapy
decrease the anxiety of pediatric patients. These Music therapy
interventions provide normalcy for a child, as play Animal-assisted therapy
is both proverbial and comforting for children. Fur- Child psychology services
thermore, giving pediatric patients the power to Pastoral care services
choose what activities they prefer can compensate Massage therapy
for perceived vulnerability while hospitalized. Lymphatic drainage therapy
Some play can be medically directed and allows Reflexology
the patient to explore relevant equipment prior to Craniosacral therapy
Exercise physiologist or physical therapist
an upcoming procedure. Through this didactic
Nutritional therapy
interaction, pediatric patients are given the tools
Yoga instruction
to approach intimidating situations with knowl-
Guided imagery
edge and confidence, leading to a stronger founda-
Aromatherapy
tion to manage more difficult experiences in the Energy therapy
future. When performed in front of parents and Healing touch
other siblings, these activities provide an opportu- Reiki
nity to rectify any misconceptions prior to surgery. Biofeedback therapy
As a result, child life programs are known to have Acupuncture and acupressure
positive effects on the recovery of pediatric surgi-
cal patients. In an experimental study of a model
child life program, children spent less time on reducing pain in children when approved by the
initial narcotics, returned to a regular diet sooner, patient, family, and hospital staff (Braun et al.
had a shorter recovery, and had improved parental 2009). Other examples of services that may fit
satisfaction (Wolfer et al. 1988). under the umbrella of child life programs or inte-
Child life therapists are instrumental in grative health are listed in Table 1. These alterna-
implementing the patient and family-oriented tive therapies may prove most advantageous to
care method. These specialists have an extensive patients who are frequently hospitalized or those
background in child development and acknowl- staying for an extended period when parents are
edge how hospitalization can affect a pediatric unable to stay with their child at all times
patient. They work to prevent psychological (Kaminski et al. 2002). Complementary therapies
trauma, become communication liaisons between have also proven effective in outpatient and
the family and physician, and educate other ambulatory care settings. These specialists focus
healthcare staff on developmental challenges hos- on treating the whole person, making them an
pitalized children face. Therefore, they are valu- essential component of patient and family-
able consultants and should be thoroughly oriented care. When the strengths of all team
involved in a child’s treatment plan. members are properly utilized and valued, the
Programs that emphasize integrative health in pediatric surgical team can more effectively pro-
conjunction with child life services may also be vide care for patients and their families.
beneficial to pediatric surgical patients. One,
expressive (art) therapy, provides inpatient chil-
dren, adolescents, and their families a safe envi- Delivering News
ronment to express their feelings. This form of
psychotherapy uses art as the focus of communi- It is a well-regarded view that a significant amount
cation, helping the patient or family member feel of what listeners hear is conveyed nonverbally.
less threatened. Another is pet therapy, which can This axiom absolutely applies to the physician
decrease anxiety and be an effective method in delivering news. In the medical environment,
quite often the complexity of the medical infor- uncaring, unfeeling, or unaffected by the situa-
mation exceeds the comprehension capacity of the tion. Emotional walls set up as intrapsychic bar-
listener. As well, the stress imposed by the situa- riers also tend to manifest themselves as
tion further limits parents’ ability to grasp infor- interpersonal barriers.
mation that may be technical as well as
emotionally difficult to bear. As such, it is incum-
bent upon the physician to do more than say the Pre-managing One’s Personal Story
right words when conveying information. The and Pain
physician’s emotional demeanor needs to be con-
gruent with the content of the message. The phy- It has been said that “we do not see the world as it
sician must have “pre-managed” any personal is, but as we are.” A physician who will have to
pain and anxiety in order to be empathically pre- share difficult to receive bad news must have
sent with the parents, and the physician’s physical spent some time examining, understanding, and
presence in the room needs to support interper- appreciating how that kind of news intersects his
sonal connection and convey a relational tone. or her own inner life. If not adequately done, these
pivotal encounters with others will be riddled with
unintended consequences. Namely, the physician
The Prepared Messenger may come across as so distant and detached that
listeners experience the moment as robotic. Or the
Congruent emotional demeanor: when presenting situational pain combines with personal pain that
news express an emotional demeanor that sup- leaks out as anger or depression. Alarmingly, in
ports the news. One of the authors was party to either case, these reactions (and many others)
an occasion when a surgeon spent a good deal of typically operate completely outside the aware-
time carefully explaining the details of a very ness of the physician. The physician will be emit-
serious brain surgery (later the patient died). At ting “radioactive emotions” without knowing that
the end, the surgeon thoughtfully asked, “Do you everyone in the situation is being contaminated.
have any questions?” There were none. Moments Defining the precise contours of an intrapsy-
after the surgeon left the room, the grandfather chic reflective and integrative process is outside
summed up the conversation this way, “I don’t the scope of this brief chapter. Suffice it to say that
know if what he said was good or bad news, but he the goal is not to expunge personal feelings and
sure seemed pleased about it.” This family had no memories but to understand them, value their
experience whatsoever with that complex medical influence in life, reframe them as necessary, and
information, but they had a life filled with experi- identify how they shape stressful interactions with
ence reading the emotional demeanor of the mes- others (Marcellus and MacKinnon 2016). As
senger – which is what they did. George Santayana thoughtfully noted, “Those
When the news is good, a smile and some soft who cannot remember the past are condemned to
laughter can convey that the news is good. When repeat it.” The physician and those depending on
the news is bad, there is no need to overdramatize the physician’s news both deserve a whole, inte-
that fact with the surgeon’s own emotional grated, and non-anxious human helper.
response. However, a serious (but not detached)
and somber tone will help listeners grasp the grave
nature of the situation. There is a tendency for Physical Presence
messengers in these situations to retreat to a
place of their own emotional safety. This internal When the family is waiting for definitive news,
positioning allows the messenger to get through their hopeful expectations become palpable. Here
the news without feeling its pain. While such a are some tips for managing that moment.
stance may be necessary, the messenger needs to First and foremost, appreciate that most parents
provide the information without coming across as will be completely deferential to the physician. As
such, it is within the physician’s purview to create prepare the family by disseminating information
an experience that supports the exchange of infor- during the treatment process. A chaplain, social
mation and leaves the parents feeling cared for worker, patient liaison, or sometimes a well-
and believing their child is being well cared for. trained volunteer should be available to handle
Try to be in a location that minimizes distractions. this role. This becomes more important the
Colleagues, other healthcare workers, patients, worse off the predicted outcome and/or when the
and their families that see the physician “in pub- treatment process becomes prolonged. In these
lic” may consider that moment their opportunity dire situations, the following messages will signal
to ask their question or just share a hello. Given the direction of the event:
that it’s unlikely that they know the nature
(or gravity) of the conversation with a family, it’s • “We are having trouble keeping his heart
understandable that they can assume that their beating.”
initiative is inbounds. Additionally, a private loca- • “We’ve started cardiopulmonary resuscitation
tion is respectful to parents as it shields them from or CPR because the heart is not beating on its
a public display of their emotions. own.”
Certain behaviors can suggest that the physi- • “The injuries are severe and are causing her
cian is present with and attentive to the family. heart to stop.”
Unhurried speech, head nods, steady eye contact, • “There may be no way to control the severe
sitting down, and hands clasped and at ease in bleeding. The bleeding is life-threatening.”
front of one’s body are some of the behaviors
that support connecting with parents. In contrast, Updates help the family titrate their hopes,
crossed arms, hands on the doorknob, checking gather supporters, and seek spiritual resources.
the pager or smartphone, looking at the chart Second, when meeting the family waiting for
while talking, and avoiding eye contact can sug- news, know that first and foremost, what they
gest emotional discomfort and/or desire to be want is the answer to this one question: “How is
somewhere else. The sacredness of the patient- my child?” Knowing this, rapidly get to the infor-
physician relationship requires interpersonal con- mation as quickly as possible, preferably within
nection that supports two-way communication. the first 20 seconds after meeting them. Some-
Without it, there is no meaningful relationship. times well-intentioned physicians want to have a
Here’s one strategy for “bracketing” personal brief conversation to bond with the family or
anxieties and the attendant reluctance about deliv- believe that the family will be helped by knowing
ering hard or bad news: remember, it’s about the process before learning the outcome. This
them; it’s not about the experience of the messen- approach can actually backfire.
ger. Ask, “As uncomfortable as I am with needing To illustrate, the authors are familiar with an
to have this conversation, would I want to trade instance where a child died in the emergency
places with the people I am about to deliver this department (ED) after being hit by a large com-
news to?” Almost always the answer is “No.” In mercial vehicle. In all likelihood, he died
this empathic shift into the inner world of the other instantly. However, he was transported by a heli-
person, healthcare providers often feel a measure copter to the pediatric trauma center where it was
of release from the inner-psychic pain and anxiety. quickly determined that he was dead and that no
amount of intervention could have saved him. The
family had witnessed the event, which occurred in
Communicating News front of their home. Once the family assembled,
the physician entered the consult room, knelt in
There are three basic categories of news: (1) good, front the parents, and thoughtfully asked, “Can
(2) outcome uncertain, and (3) bad. While each is you tell me what happened?” Immediately their
very different, there are components of the news countenance improved and their angst abated to
communication process shared by all three. First, some degree. They heard the physician’s question
as a request for information to aid treatment so • Good news: “Hello, I’m Dr. Smith. I have been
they began spewing their account of the tragic taking care of (name of child) since she/he
event. Unfortunately, the question had the arrived. Your child is okay and will be fine.
unintended consequence of spiking their hope I’m sure this is a relief. This is what we
upward. As such, just a few minutes later, after know. . . This is the plan. . .”
they concluded sharing what they had witnessed, • Outcome uncertain: “I’m Dr. Smith. I have
when the physician delivered the news that their been taking care of (name of child) since
son was dead, their emotional fall was greater. she/he arrived. Your child is in critical condi-
The third shared component is the need for tion due to. . . At this point the outcome cannot
congruence between the type of news and the be known. I’m sorry the news is not better or
demeanor of the messenger. While previously clearer. This is the plan. . .”
addressed, it bears repeating that family-centered • Death likely: “I’m Dr. Smith. I have been tak-
care is not well-supported by a “one-size-fits-all” ing care of (name of child) since she/he arrived.
response by the physician. When the news is I so regret to tell you that the injury/condition
good, let the family see this. When the news is experienced by (child’s name) is not surviv-
less than what was hoped, it’s okay to reflect this able. The team and I are so sorry.”
in relational way. • Death: Assuming the parents have been receiv-
Fourth, know the child’s name (know name – ing updates as noted above, with a gentle
go; no name – stop!). Write the name on the top of cadence proceed by saying, “I’m Dr. Smith. I
papers or instruct support staff to provide the have been taking care of (name of child) since
name before entering the room. While parents she/he arrived. I so regret to tell you that
typically assume the physician worked hard to (child’s name) died. The team and I are so
help their child, knowing and using their child’s sorry.”
name suggests this was the case – that everyone
was up close and personal. They can believe that When death is likely or has occurred, expect an
in their relationship with the physician and by emotional outburst (Iserson 1999; Gilliam and
extension, the team, their child is not a diagnosis Chester 1991; Fallat et al. 2016). Typically, the
or a problem but a person. family will be so overwhelmed that giving the
Fifth, use support staff to provide a summary of additional process information will be of no use
who is in the room, where the parents are posi- to the family. If they do not have capacity and
tioned, and how they can be identified. This over- presence to hear more, wait. While giving news in
view and notations about any major concerns can that moment probably better suits the physician’s
usually be provided in about 30 seconds – maybe schedule, information that is not comprehended is
about the amount of time it takes to walk from a no different than it not having been given at all,
treatment room to the consult room. Having this and the physician cannot believe that their work is
information will help protect the physician and done. Additionally, don’t give process informa-
team members from being blindsided by issues tion to someone who, while with the family, may
or questions, can enhance the formation of a bond not be well-positioned to receive it. The parents
with the family, and will ensure that the conver- deserve to hear the most profound information
sation happens with the right people. they are likely ever to hear firsthand from the
physician who took care of their child (Fallat
et al. 2016).
What to Say When the time for questions and answers is
right, ask: “What questions do you have?” rather
As noted earlier, as quickly as possible get to the than “Do you have any questions?” The former
news most desired by the parents at that moment: assumes there are questions and can feel encour-
the outcome. Depending on the outcome, here’s a aging of them. Open-ended questions invite dia-
template for each type of conversation: logue and deepen the relationship.
Frequently, physicians wonder if using the say them. If I could give you something that
words “death” and “dead” are harsh and uncaring. would make this better I would give it to you.
As words, they are not. These terms are clear, I’m sorry that this situation is bigger than all of
definitive, and universally understood. In us. I am sorry.”
moments gripped by a strong emotional pall, However a child’s medical situation concludes
words need to penetrate and be clear. In contrast, – whether they leave and live happily ever after or
one of the authors was with a family who was told they die, the hope is that the parents will say, “We
that their child “had not made it.” No family know that everything that could be done was done
member did anything because they did not know and everyone here was so kind.” The trajectory or
what “didn’t make it” meant. In another instance, parents’ stories, hopes, confidences, and grief rest
a surgeon reporting the results of a brain flow on these twin pillars: competence and compassion.
study said, “He didn’t pass the flow study.” Like
the previous example, none of the family mem-
bers responded because they didn’t know what the Conclusion and Future Directions
terminology meant. It was left to a support staff to
ask the surgeon, “That doesn’t sound very good, As patient and family-oriented care becomes more
would you explain it some more?” integrated into the medical system of care around
While the terms themselves are not harsh, the the world, there will be further opportunities to
way they are delivered can make them harsh. refine communication skills of providers, empa-
Words sit in context. They are held by other thy for patients and families, and cooperation
words and they are spoken by a messenger. If toward the common goal of providing safe and
either is badly off, then “dead” comes off with quality care that is also compassionate and goal-
brutal effect. Drawing each element of the con- directed.
versation into a congruent whole is the goal.
Never say, “I know just how you feel” or “God
only takes the best of us” or “At least you had
them as long as you did” or “At least you have Cross-References
other children” or name your cliché. While cer-
tainly well-intended, they actually cause pain, ▶ Anesthesia and Pain Management
create distance between individuals, and come ▶ Specific Risks for the Preterm Infant
off sounding silly and unkind. Insert a pause ▶ Surgical Problems of Children with Physical
after the intention to say words crafted to “fix” Disabilities
the pain of a situation and before actually saying ▶ Transport of Sick Infants and Children
the words. In that moment, reflect empathically by
asking, “How will the parent hear this? Does the
statement really help? Do these words even make References
sense? Would I want someone to say these words
Alsop-Shields L, Mohay H. John Bowlby and James Rob-
to me?” Typically, that reflection-filled pause will
ertson: theorists, scientists and crusaders for improve-
result in less being said and the parents will feel ments in the care of children in hospital. J Adv Nurs.
kindly regarded by a sensitive physician. 2001;35(1):50–8.
Finally, there are circumstances that are bigger Ayub EM, Sampayo EM, Shah MI, Doughty
CB. Prehospital providers’ perceptions on providing
than any human’s ability to fix. Recognize the
patient and family centered care. Prehosp Emerg
limits of the capacity to heal. The pain of a broken Care. 2016;18:1–9. [Epub ahead of print]
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this limitation is an expression of maturity; caring assisted therapy as a pain relief intervention for chil-
dren. Complement Ther Clin Pract. 2009;15(2):105–9.
in the face of this limitation is compassion. In the
Cole W, Diener M, Wright C, Gaynard L. Health care
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2016;20(6):798–807. Marcellus L, MacKinnon K. Using an informed
Gilliam G, Chesser BR. Fatal moments: the tragedy of the advocacy framework to advance the practice of
accidental killer. Lexington: Lexington Books; 1991. family-centered care. J Perinat Neonatal Nurs.
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den unexpected deaths. Tucson: Galen Press, Ltd; Thompson R, Stanford G. Child life in hospitals: theory
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and emotional impact of child-life and pet therapy 1988;16(4):244–54.
Surgical Implications of Human
Immunodeficiency Virus Infection 38
in Children
Alastair J. W. Millar, Jonathan Karpelowsky, and Sharon Cox
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 604
Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605
Gastrointestinal Tract Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 607
Perineal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 608
Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609
Medical Aspects of Pediatric HIV Infection and
Their Effects on Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 610
Outcomes of HIV Infected Children Undergoing Surgery . . . . . . . . . . . . . . . . . . . . . . . . . 610
Factors Influencing Post-surgical Complications in HIV Infected Children . . . . . . 611
HIV Exposed Uninfected (HIVe) Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613
Abstract
According to the joint United Nations Program
A. J. W. Millar (*) on HIV/AIDS (UNAIDS), 34 million people
Emeritus Professor of Paediatric Surgery, Faculty of Health worldwide were estimated to be living
Sciences, Department of Paediatric Surgery, University of
Cape Town, Red Cross War Memorial Children’s Hospital,
with HIV or acquired immune deficiency syn-
Cape Town, Rondebosch, South Africa drome (AIDS) at the end of 2011 (UNAIDS_
e-mail: alastair.millar@uct.ac.za Global_Report_2012_en.pdf. Accessed 19
J. Karpelowsky Feb 2013). Most reside in the developing
Paediatric Oncology and Thoracic Surgery, Children’s world, with approximately two-thirds in
Hospital at Westmead Children’s cancer research Unit, sub-Saharan Africa. The annual rate of incident
University of Sydney, Sydney, Australia
e-mail: jonathan.karpelowsky@health.nsw.gov.au
(new) HIV infections is believed to have
peaked at >3 million in the late 1990s and
S. Cox
Division of Paediatric Surgery, Faculty of Health Sciences,
was 2.5 million in 2011 (UNAIDS_
University of Cape Town, Red Cross War Memorial Global_Report_2012_en.pdf. Accessed 19 Feb
Children’s Hospital, Cape Town, South Africa 2013; Karpelowsky J, Millar AJ Semin Pediatr
e-mail: sharon.cox@uct.ac.za

https://doi.org/10.1007/978-3-662-43588-5_41
604 A. J. W. Millar et al.
Surg 21(2):125–135, 2012). Approximately Introduction

12 percent of these infections (330,000 cases)
occurred in children younger than 15 years Pediatric HIV (Human immune deficiency virus)
of age (UNAIDS_Global_Report_2012_en. infection is a pandemic predominantly in sub-
pdf. Accessed 19 Feb 2013). Thus pediatric Saharan Africa. Approximately 2.2 million chil-
HIV infection is a pandemic affecting children under 15 years are infected with HIV,
dren predominantly in sub-Saharan Africa representing almost 95% of the total number of
but is also seen in Asia and sporadically else- children globally infected with HIV
where (UNAIDS_Global_Report_2012_en. (Karpelowsky and Millar 2012). Pediatric HIV is
pdf. Accessed 19 Feb 2013). The number of largely transmitted from an HIV infected mother
children newly infected with HIV has to her infant either at the time of delivery or
decreased dramatically. This decrease is a through breast feeding. The risk of transmission
consequence of the success of interventions can be substantially reduced by mother to child
to prevent mother-to-child transmission transmission prevention (MTCT) programs that
(PMTCT) of HIV. These interventions include include use of antiretroviral therapy and formula
early identification of HIV infection in preg- feeding (Roider et al. 2016; Cotton and Rabie
nant women through routine antenatal testing, 2015). However in many areas of Sub Saharan
provision of antiretroviral medications to the Africa access to these interventions is unavailable
pregnant woman and her infant, delivery by or unaffordable and may be accompanied by
elective Caesarean section when indicated unacceptable morbidity and mortality from
and the complete avoidance of breastfeeding. enteric infection. Hence mother to child preven-
In addition the widespread availability of edu- tion programs have changed to emphasize that
cational programs addressing HIV infection, exclusive breast feeding is best provided the
prevention of HIV perinatal transmission and mother has been identified and treated antenatally
HIV counselling and testing services have fur- with anti-retroviral therapy and does not have a
ther reduced the incidence. HIV infected chil- low CD4 count. With the introduction of a
dren may require surgery either as an breastfeeding-only policy late in 2011 in
emergency to deal with a life threatening con- South Africa, staff working in prevention of
dition or a complication of the disease, mother to child transmission [PMTCT] programs
non-emergency procedures where surgery is now face the challenge of educating HIV-positive
required to assist is the diagnosis of an HIV mothers on the correct care and dosing throughout
related condition or for elective surgery for the period of breastfeeding.
routine childhood procedures. Surgical prob- Whilst mothers previously had the option of
lems associated with HIV infection are formula feeding to minimize their babies’ expo-
described under categories of soft tissue or sure to HIV, they are now encouraged to
organ specific infections requiring drainage or breastfeed exclusively as a means to reducing
debridement, gastrointestinal tract disease and overall infant mortality from gastroenteritis (John-
complications, infections in the perineal area, son et al. 2016). However, this necessitates daily
and malignancies. Although surgical outcomes dosing with nevirapine syrup, and continued anti-
are compromised in children with AIDS, cur- retrovirals for the mother, and requires that
rent HAART (Highly Active Anti-retroviral breastfeeding is exclusive i.e. no formula feeding
Therapy) prognosis is, in the short term, at all. Where these PMTCT programs have been
excellent. introduced transmission of HIV from infected
mother to infant has been drastically reduced.
Keywords Although the numbers have been considerably
Children · HIV · Surgery · Complications reduced, HIV infected or exposed but uninfected
38 Surgical Implications of Human Immunodeficiency Virus Infection in Children 605
children still present and can be expected to be low and the child’s immune system should
require a surgical procedure for the following have reconstituted. If the child in question is
reasons: infected with an opportunistic organism e.g.
mycobacterium tuberculosis one must be aware
1. Emergency procedures to deal with a life of the added potential complication of the immune
threatening condition or a complication of the reconstitution inflammatory syndrome (IRIS)
disease where in the first instance the infection should be
2. Non-emergency procedures where surgery is treated and controlled before starting HAART.
required to assist is the diagnosis of an HIV The term IRIS describes a collection of inflamma-
related condition tory disorders associated with paradoxical wors-
3. Elective surgery for routine childhood proce- ening of pre-existing infectious processes
dures (UNAIDS 2012) following the initiation of highly active antiretro-
viral therapy (HAART) in HIV-infected individ-
Most studies on the outcome of HIV infected uals especially if the CD4 count is <200 cells/μL.
patients undergoing surgery have been in adults Pre-existing infections in individuals with IRIS
(Yii et al. 1995; Shelburne et al. 2005; Horberg may have been previously diagnosed and treated
et al. 2006; Madiba et al. 2009). These have or they may be subclinical and later unmasked by
reported conflicting results but several suggest the host’s regained capacity to mount an inflam-
an increased morbidity associated with HIV infec- matory response. Pathogens particularly associ-
tion with little or no impact on mortality. In con- ated with IRIS are Mycobacterium tuberculosis,
trast there is limited information on surgical Mycobacterium avium complex, Cytomegalovi-
presentations and outcomes in HIV infected rus, Cryptococcus, Pneumocystis, Herpes sim-
children. plex, Hepatitis B and Human herpes virus
For children presenting with a life threatening 8 (associated with Kaposi sarcoma).
complication of HIV/AIDS the same indications Surgical problems associated with HIV infec-
for surgery in HIV unexposed children exist. The tion may be described under four major categories
emergent nature of these cases does not allow (Table 1)
pre-operative correction of co-morbidities such
as nutritional deficits or management of the 1. Soft tissue or organ specific infections requir-
immune-suppression with highly active antiretro- ing drainage or debridement
viral therapy (HAART). Surgical procedures are 2. Gastrointestinal tract disease and
frequently undertaken to assist in the diagnosis of complications
an HIV/AIDS related pathology or complication. 3. Infections in the perineal area
Most of these allow time for pre-operative correc- 4. Malignancies
tion of pre-morbid conditions (Stefanaki 2002;
Shelburne et al. 2005; Madiba et al. 2009). Lastly
there are an increasing number of HIV infected
children who require routine pediatric surgical
procedures. In children who are considered for Infections
elective surgery the health status and life expec-
tancy should be taken into account when consid- Approximately 90% of HIV infected children will
ering the timing and need for surgery. If surgery develop mucocutaneous disease, which may be
can be delayed then treatment with HAART infectious or non-infectious (Stefanaki et al.
should commence immediately and surgery 2002). Children with symptomatic HIV infection
should only be performed after a period of have an increased incidence of soft tissue infec-
8–12 weeks at which time viral levels should tions. The cutaneous manifestations of HIV are an
Table 1 Presentation, differential diagnosis and indications for surgery in HIV-infected children
Clinical presentation Differential diagnosis Surgical Indications
Surgical Abscess Staphylococcus, Streptococcus Drain pus
infection Necrotizing fasciitis Candida Debride necrotic tissue
Septicemia Herpes, CMV Obtain culture to direct antibiotic
Tuberculosis therapy
Molluscum
Gram negative e.g. Pseudomonas
Esophageal Esophagitis Candida Contrast swallow to identify
diseases Esophageal stricture CMV, Herpes strictures
Idiopathic ulcers (HIV) Endoscopy with biopsy for histology
Malignancy e.g. Kaposi and culture
Non-HIV related pathogens
GOR
Intra- Gastrointestinal CMV Endoscopy to diagnose GI bleeding
abdominal bleeding Mycobacterium tuberculosis and Surgery for perforation and
problems Gastrointestinal avium-intracelularae obstruction
perforation Candida
Gastrointestinal Malignancy e.g. lymphoma
obstruction
Perineal Ano-cutaneous fistula CMV Colostomy for sepsis with
disease Condyloma Papilloma virus rectovaginal, rectourethral fistulae
Rectovaginal fistula Cryotherapy or laser for
Rectourethral fistula Condylomata
Malignancy Depend on site and Non-Hodgkins lymphoma Biopsy of mass
extent of disease Karposisarcoma Surgical excision
Leiomyosarcoma
B-cell lymphoma
indicator of underlying immune status. Bacterial

skin infections are often recurrent, in atypical sites
or due to atypical organisms (Prose 1991).
The most common organisms causing skin
infections are Staphylococcal and Streptococcus
species. These usually present as cellulitis,
ecthyma, erysipelas, furunculosis (occasionally
of disseminated nature), persistent and recurrent
folliculitis and impetigo. Pyomyositis is also
increasingly reported possibly associated with an
increased rate of Staphylococcus aureus coloniza-
tion. Gram negative organisms may also cause
severe skin infection in HIV infected children.
Pseudomonas organisms may produce cutaneous Fig. 1 Necrotizing fasciitis in a newborn infant with an
manifestations, including ecthyma gangrenosum ano-rectal malformation
and a papular rash, often in the perineal area
(Flores et al. 1993) (Fig. 1).
The principles of management of bacterial skin specifically as the immune compromised patient
infection are as for HIV unexposed children may not mount a clinically evident initial systemic
including the use of appropriate antibiotics and response.
surgical drainage or debridement when needed. A Infection with Molluscum contagiosum, a
high index of suspicion for rapidly spreading common viral infection due the DNA poxvirus is
infection or necrotizing fasciitis must be frequent and is identical in appearance to HIV
maintained (Pijnenburg and Cotton 2001) unexposed patients but tends to be more extensive
Fig. 2 An HIV infected child with florid facial Molluscum Fig. 3 BCG-associated ulcerating caseous axillary
Contagiosum lymphadenopathy
and recurrent, usually occurring on the face and and lead to increased morbidity and mortality
neck (Prose 1992) (Fig. 2). (Fantry 2003). Esophageal symptoms rank second
Complications after BCG (Bacillus Calmette only to diarrhea in frequency of gastrointestinal
Guerin) vaccination are also commonly seen complaints in children with acquired immune
(Alexander and Rode 2007). Following vaccina- deficiency syndrome (AIDS) (Fantry 2003).
tion with BCG (routinely given in developing Esophageal disease may be a predictor of poor
countries at birth) children may present with a long-term prognosis, as it reflects severe underly-
local reaction and localized non progressive axil- ing HIV immunodeficiency. Opportunistic infec-
lary lymphadenopathy. HIV infected children tions are the leading cause of esophageal
however may develop complications of ulcerating complaints. Treatment for most etiologies of
lymphadenopathy especially when starting esophagitis generally has a high degree of suc-
HAART due to the immune reconstitution inflam- cess, with a resultant improvement in quality of
matory syndrome (Puthanakit et al. 2006) (Fig. 3). life especially with HAART (Cooke et al. 2009).
A conservative approach to treatment is The differential diagnosis for esophageal dis-
recommended (Zar 2004) but large ulcerating ease includes:
caseating lymph nodes are best treated by excision
or curettage. Disseminated BCG disease may (a) Esophagitis or ulceration. The causes are usu-
occur in HIV infected children and may be indis- ally infective in origin, Candida species being
tinguishable from miliary tuberculosis. the most frequent infection, followed by cyto-
megalovirus (CMV), herpes simplex virus and
idiopathic infective ulceration. Due to overlap
Gastrointestinal Tract Disease of symptoms, endoscopy and biopsy are
essential in identifying the pathology (Cooke
Esophagitis is a common problem in HIV infected et al. 2009). The growing number of effective
children that can cause prolonged discomfort and antiviral and antifungal agents has mandated a
malnutrition, compromise adherence to HAART more goal directed approach to therapy. As
with all severe esophageal infections the

motility of the esophagus is adversely affected
and this may lead to acid gastro-esophageal
reflux which compounds the inflammatory
process.
(b) Esophageal strictures. The end result of
untreated or extensive ulceration is likely to
be stricture formation, occurring in approxi-
mately 10% of patients (Cooke et al. 2009).
Strictures can be difficult to treat as they
respond poorly to dilation and may require
esophageal replacement surgery (Issa et al.
2004).
Fig. 4 Multiple perforations of both small and large bowel
Intra-abdominal Pathology in an HIV infected infant presenting with peritonitis. CMV
The diagnosis and management of children with as the cause was identified on biopsy
intra-abdominal surgical pathology can be chal-
lenging. Localizing signs and symptoms are fre- Gastrointestinal perforations may be second-
quently misleading due to underlying immune- ary to CMV, TB, or lymphoma. CMV infections
suppression, debilitation, and antibiotic use. Gas- frequently lead to multiple areas of ulceration and
trointestinal (GI) bleeding, distension, obstruc- perforation with peritonitis (Fig. 4).
tion, perforation with abdominal pain and Infants with chronic diarrhea may also develop
tenderness are the most common clinical presen- peritonitis due to intestinal perforation (Kahn
tations associated with intra-abdominal diseases 1997). HIV infected and HIV exposed uninfected
in HIV infected children (Bowley et al. 2007). neonates with necrotizing enterocolitis may have
Gastrointestinal bleeding represents an impor- a higher mortality and develop more extensive
tant source of morbidity and can result from disease than unexposed infants (Karpelowsky
opportunistic infections (CMV or Candida infec- et al. 2010). Likewise, infants outside the neonatal
tion), HIV associated malignancies, (Kaposi’s sar- period may develop necrotizing enterocolitis type
coma, leiomyosarcoma or lymphoma) or may be pathology after acute gastroenteritis with shock,
unrelated to HIV infection (Balderas and Spechler which can result in extensive small and large
2006). Lower GI bleeding may be caused by bowel necrosis.
CMV colitis, Mycobacterium tuberculosis (TB), Abdominal pain as a presenting symptom may
malignancy or idiopathic colonic ulceration. be due to medical or surgical causes. Both infec-
Aggressive investigation with endoscopy to find tive and neoplastic conditions may present with
the source of bleeding is required due to the wide abdominal pain. Several unique problems arise
differential diagnosis (Zanolla et al. 2001). however. The taking of HAART may lead to
Abdominal distension may develop secondary abdominal pain due to pancreatitis or lactic acido-
to chronic diarrhea, ileus or obstruction. There are sis. Pain in the HIV infected child must be fully
many causes for obstruction including inflamma- investigated for medical, drug induced or surgical
tory and infective causes with TB predominating. causes.
Less commonly neoplastic obstruction develops
secondary to lymphoma or Kaposi’s sarcoma. The
obstruction may present due to invasive bowel Perineal Disease
infiltration by the tumor or from more localized
disease and intussusception (Cairncross et al. HIV infected children have an increased rate of
2009). In neonates, the use of HAART may peri-rectal abscess and ano-cutaneous fistula.
mimic functional bowel obstruction. There are several reports of recto vaginal fistula
and recto urethral fistulae or multiple fistulae with

an increased rate of sepsis (Wiersma 2003;
Banieghbal and Fonseca 1997). Management
includes debridement and antibiotics and on occa-
sion stool diversion with a proximal divided
colostomy. Definitive repair without previous
anti-retroviral therapy has been reported to have
poor results but after several weeks of HAART
may be successful.
Anal condylomata are rare in children but an
increased incidence has been noted in HIV
infected children presenting with extensive and
recurrent lesions. Most cases of anal condylo-
mata can be managed with cryotherapy, electro-
coagulation or ideally CO2 laser ablation under
general anesthesia, taking care not to include the
whole anal circumference to avoid anal stricture.
A staged approach may be indicated if the
lesions are very extensive and may require Fig. 5 Small bowel Kaposi sarcoma presenting as intus-
prior stool diversion with colostomy (Johnson susception in an HIV infected child
et al. 1997).
leiomyosarcoma and Kaposi sarcoma (Stefan
2014; Stefan et al. 2011).
Malignancy In developed countries 2–3% of HIV infected
children will develop an HIV-associated malig-
Children with HIV infection are at higher risk than nancy of which B-cell lymphomas constitute
HIV unexposed children for malignancy, with about 80% and Kaposi sarcoma 20% of cases. In
tumors representing 2% of AIDS defining events contrast Kaposi sarcoma, followed by Burkitt’s
(Hadley and Naude 2009). It is important to lymphoma, represent the most significant
exclude with tissue biopsy mycobacterium- HIV-associated malignancies in African children
avium-intracellulare infection associated pseudo- due to the epidemiology of herpes virus-8 and
tumor or other viral induced lymphadenopathy in Epstein-Barr Virus. Surgery is usually limited to
any child presenting with a mass. Therefore, for tissue biopsy or to the treatment of complications
any spindle cell lesion in the setting of HIV infec- (Fig. 5).
tion, it is important to order an acid fast stain to see Incidental solid tumors must be treated as for
if these S100- and CD68-positive spindle cells HIV unexposed children, although coexisting dis-
contain mycobacterial organisms. A high inci- ease, specifically TB, should be considered during
dence of EBV-related smooth muscle neoplasms the investigation of solid tumors for metastatic
including leiomyomas and leiomyosarcomas has spread (Hadley and Naude 2009). This group of
also been reported in various anatomic sites co-infected patients has been reported to have a
(mainly central nervous system, but also the gas- high mortality independent of the primary tumor
trointestinal tract, liver, spleen, lung, adrenal, and type. An HIV infected child with a malignancy
skin) in HIV-infected adults and children. Detec- should be started on HAART as soon as possible.
tion of EBV (e.g., EBER in situ hybridization) The widespread introduction of HAART has
along with smooth muscle markers (e.g., smooth greatly lengthened life expectancy, which may
muscle actin) may be of diagnostic aid. result in an increased lifetime incidence of solid
HIV-associated malignancies include B-cell lym- organ malignancy in HIV infected children
phoma, mixed-cellularity Hodgkin’s disease, (Biggar et al. 2000; Caselli et al. 2000).
Medical Aspects of Pediatric HIV make post-operative fluid management and feed-
Infection and Their Effects on Surgery ing challenging. Furthermore odynophagia and
dysphagia may be secondary to lesions which
HIV infected children have a greater risk of com- are friable and thus easily traumatized during air-
munity and nosocomial acquired bacterial infec- way instrumentation or insertion of a naso-enteric
tions which are more severe, and have a worse tube causing bleeding or perforation.
outcome than their HIV unexposed counterparts. Children experience mouth pain from oral
Bacterial infection can involve any organ system, lesions and aphthous ulcers associated with can-
and concomitant bacteremia is common. Infec- didiasis. Abdominal pain is very common, caused
tions may be polymicrobial and drug resistant, by pancreatitis or colitis. Acute pancreatitis causes
which has implications for use of prophylactic severe and diffuse abdominal pain with distention
antibiotics given at surgery (Zar 2004; George and vomiting. Chronic diarrhea is common in
et al. 2009). HIV disease and is associated with abdominal
Reduced pulmonary reserve and an increase in cramping. Pain in the mouth and gut may lead to
pulmonary complications are of concern after reduced food intake, malnutrition and failure to
major surgery (Zar 2004). HIV infected children thrive. Even in the early stages of HIV disease,
have a high incidence of pulmonary complica- difficulties with oral intake can have a significant
tions which may be infective or non-infective. impact on a child’s quality of life.
Respiratory involvement in HIV infected children Malnutrition is one of the most frequent and
can involve either the upper or lower airway with severe complications of pediatric HIV infection,
implications for airway management during anes- increasing morbidity and mortality. Malnutrition
thesia (Bosenberg 2007). Adeno-tonsillar enlarge- has been reported to be an independent risk factor
ment can cause upper airway obstruction and for an adverse surgical outcome.
difficult endotracheal intubation. There is an HIV infected children are at risk for the devel-
increased incidence of chronic lung disease in opment of metabolic complications, which may
HIV infected children; this may impact on the be secondary to HIV or to HAART. The surgical
anesthetic and peri-operative management and anesthetic implications of such complications
(Leelanukrom 2007). Lastly the increased risk of must be considered (Bosenberg 2007;
infection may lead to nosocomial pneumonia Leelanukrom and Pancharoen 2007).
complicating the post-operative course. Post-operative pain control in HIV infected
Hematological manifestations of HIV include children can also be challenging. For adequate
anemia, neutropenia, lymphopenia and throm- pain control a combination of medications may
bocytopenia (Calis et al. 2008; Eley et al. be needed, increasing the potential for drug inter-
2002). Anemia has been repeatedly identified actions in children who are often taking HAART
as a strong, independent risk factor for HIV or other drugs (Abuzaitoun and Hanson 2000).
disease progression and death. Severe thrombo-
cytopenia and anemia correlate with advanced
disease and poor prognosis. Thrombocytopenia Outcomes of HIV Infected Children
can complicate surgical procedures by increas- Undergoing Surgery
ing bleeding and the need for blood products,
leading to increased complications in the peri- Few prospective data exist on the outcomes on
operative period. HIV infected children undergoing surgery (Nel-
Gastro-intestinal dysfunction including diar- son et al. 2009; Mattioli et al. 2009). The first
rhea, nausea and vomiting, dysphagia or reports of surgical outcomes in children with
odynophagia causes significant morbidity among HIV infection were brief, focusing on the proce-
HIV infected children. Abdominal surgery may dures performed and risk of transmission of HIV
result in a post-operative ileus. This together to health care workers. Subsequently a few case
with pre-existing intestinal dysfunction can series reported HIV specific surgical conditions in
children without describing the outcome or com- investigated the use of HAART as an independent
plications of surgical intervention, although a neo- predictor of surgical complications. Both defined
natal subgroup were reported to have a high post- the use of HAART as three drugs for at least
operative mortality of 30%. Most of these children 2–3 months prior to surgery. Neither found that
reported on did not receive HAART. the use of HAART reduced post-operative com-
Several case reports or case series of proce- plications. In pediatric studies HAART was not
dures have been published, raising concerns of found to be associated with a statistically signifi-
poor wound healing, breakdown of anastomoses cant decreased rate of post-operative complica-
and surgical site infections (Kleinhaus et al. 1985; tions, thus delaying elective surgery for the
Beaver et al. 1990). A recent series of 48 HIV institution of HAART, which is currently a stan-
infected children undergoing minimally invasive dard of care may not be warranted although intu-
surgery (MIS) for diagnostic and therapeutic pro- itively restoring a compromised immune system
cedures (Banieghbal 2009) concluded that MIS prior to surgery and reducing viral load would
could be safely performed on HIV infected chil- seem sensible (Karpelowsky et al. 2011a).
dren but that certain routine procedures such as Few studies have addressed the clinical stage
fundoplication were more difficult and prone to of HIV as a predictor of surgical complications.
complication. The largest series of HIV infected Earlier studies, in the absence of CD4 counts or
and HIV exposed children undergoing surgical HIV viral load, used CDC clinical definitions to
admission was published in 2009 but the report stratify patients (Tran et al. 2000).
focused on the disease presentations and only Indicators of the stage of HIV infection include
alluded to a higher morbidity, furthermore no an absolute CD4 T-lymphocyte count, percentage
control group existed in that study (Karpelowsky of CD4 lymphocytes, and plasma HIV viral load.
et al. 2009). There is only one prospective cohort Most work on the prognosis in HIV infected
study undertaken comparing the outcomes of HIV adults has been based on absolute CD4 counts.
infected and HIV unexposed children which noted Studies assessing the role of CD4 counts in pre-
that HIV infection was the most important risk dicting wound healing have drawn conflicting
factor for development of a complication post- results. A postoperative CD4 count of <18 cells/
surgery, associated with an almost 12-fold higher mm3 and a pre to postoperative CD4 percentage
risk. There was also a significantly higher mortal- change of 3% were shown to be independent risk
ity and longer length of stay (Karpelowsky et al. factors for postoperative morbidity (Lord 1997).
2012). CD4 counts of <50 cells/mm3 or an absolute CD4
count of <200 cells/mm3 i.e. in severe immune-
suppression are predictive of an increased inci-
Factors Influencing Post-surgical dence of complications. Apart from AIDS other
Complications in HIV Infected Children conditions such as severe intra-abdominal infec-
tions or trauma can lead to low CD4 counts. There
Several factors may impact on the incidence of is thus little agreement as to the level of CD4
post-operative complications in HIV infected chil- count that might be predictive of complications
dren (Desfrere et al. 2005; Karpelowsky et al. in adults.
2012). Highly active antiretroviral therapy Viral load indicates the intensity of HIV
(HAART) has reduced mortality and morbidity infection. A postoperative viral load greater
and improved the quality of life of HIV infected than 10,000 copies/ml have been found to be
children (Violari et al. 2008). Use of HAART independent risk factors for complications.
increases the CD4 cell count and reduces the However, acute medical conditions may tran-
plasma HIV viral load, thus restoring immune siently increase viral load. No published study
function, reducing the direct cytotoxic effect of to date focuses on the combination of low CD4
the virus on some tissues and slowing the progres- counts and a viral load to predict the risk of
sion of HIV disease. Two adult studies have complications.
Poor nutrition has long been associated with a amongst HIVe children was highest in cases of
poor surgical outcome. Increased complications maternal death, low maternal CD4 count or low
may manifest as higher rates of infection, poor birth weight.
wound healing and an increased postoperative The increased morbidity and mortality in HIVe
mortality rate. No study on the outcomes of HIV children is multi-factorial relating to maternal,
infected patients undergoing surgery has investi- environmental and immunological factors all
gated nutrition as a co-morbid factor for adverse playing significant roles in the morbidity and
outcome. Albumin as a surrogate marker has been mortality of HIVe children. These include
used and was found to be a predictor of poor impaired passive immunity from an HIV infected
outcome in several studies, but was refuted in mother, exposure to a higher disease burden
another as an independent risk factor. Albumin innate immune abnormalities and concomitant
levels, however may be affected by acute stress impact of maternal HIV illness on child health
and hepatic or adrenal disease thus making them (Slogrove et al. 2010). T-Cell immunity cytokine
an inaccurate surrogate of nutrition. abnormalities and antibody function in the HIVe
Only one pediatric study has assessed predic- child have also been implicated in the pathogene-
tors of post-operative complications in sis. Currently maternal CD4 count seems to be the
HIV-infected children undergoing surgery. strongest variable correlated to the outcomes of
Although this study was limited by sample size HIVe children.
and a high proportion of children with advanced In a prospective study it was noted that HIVe
HIV disease it found only age less than 1 year and children had a risk of postoperative complications
major surgery to predict post-operative complica- and mortality higher than that of HIV unexposed
tions. There was no association between poor children but less than HIV infected children
nutrition, clinical or immunological stage of dis- (Karpelowsky et al. 2011b).
ease or the use of HAART with post-operative
complications (Karpelowsky et al. 2011b).
HIV Exposed Uninfected (HIVe) HIV infected children may present with both con-
Children ditions unique to HIV infection and surgical condi-
tions routine in pediatric surgical practice. HIV
Children who are HIVe have a higher risk of exposure confers an increased risk of complications
morbidity and mortality compared to HIV and mortality for all children following surgery,
unexposed children (Slogrove et al. 2010; whether they are HIV infected or not. This risk of
Karpelowsky et al. 2011a). HIVe children have complications is higher in the HIV infected group of
a greater susceptibility to infections including patients. These findings seem to be independent of
opportunistic infections that tend to be more whether patients undergo an elective or emergency
severe than in HIV unexposed children procedure, but the risk of an adverse outcome is
(Karpelowsky et al. 2011a). Susceptibility to higher for a major procedure. Early treatment with
infections may increase the risk for developing HAART is associated with reduced mortality in
complications in the post-operative period. HIV infected infants and children. The incidence
Poorer growth and nutrition in HIVe compared of infected children presenting for surgery should
to HIV unexposed children have been reported. be significantly reduced by the effective implemen-
Thus, HIVe children are more likely to be at risk tation of PMTCT programs. The danger is one of
for malnutrition which may impact on outcomes complacency as although once infected by HIV
post-surgery. there is yet to be a cure but HAART therapy can
HIVe children have an increased mortality virtually clear virus and enable children to live near
compared with HIV unexposed children but normal lives. Great emphasis should be placed on
lower than that of HIV infected children PMTCT. The hope for the future is the development
(Karpelowsky et al. 2011a). The risk of death of an effective vaccine.
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Part II
Newborn Surgery: Head and Neck
Choanal Atresia
39
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
Suggested Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
Endoscopic Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
Transpalatal Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Controversies in Choanal Atresia Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Nasal Stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Mitomycin C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622
Abstract choanae) connecting the nasal cavity to the

Choanal atresia or stenosis is the most common pharynx. Bilateral choanal atresia presents at
craniofacial defect of the nose. In choanal atre- birth with life-threatening airway obstruction,
sia there is either partial or complete obstruc- as neonates are obligate nasal breathers. The
tion of the one or both openings (posterior etiology of choanal atresia is largely unknown.
Infants with bilateral choanal atresia will
E. Phelan (*) · J. Russell

Our Lady’s Children’s Hospital Crumlin, Dublin, Ireland
e-mail: eimearphelan@hotmail.com;
Jdrussell.russell@gmail.com

https://doi.org/10.1007/978-3-662-43588-5_42
require stabilization of their airway soon after

birth. Surgical repair should be performed
early in bilateral choanal atresia if there are
no medical contraindications.
Keywords
Choanal atresia · Choanal stenosis · Airway
obstruction
Introduction
Choanal atresia or stenosis is the most common

craniofacial defect of the nose occurring in 1in
8000–10,000 births (Burrow et al. 2009; Harris et
al. 1997). In choanal atresia there is either partial
or complete obstruction of the one or both open- Fig. 1 Image demonstrating choanal atresia
ings (posterior choanae) connecting the nasal cav-
ity to the pharynx. In the neonate the most
common cause of nasal obstruction is choanal
atresia or stenosis (Figs. 1 and 2). Bilateral
choanal atresia presents at birth with life-threaten-
ing airway obstruction, as neonates are obligate
nasal breathers. The reflexes to facilitate breathing
through the open mouth in response to nasal
obstruction develop only weeks to months after
birth – although an infant will mouth breath if the
mouth is opened either during crying or with the
help of an artificial airway.
Epidemiology
Fig. 2 Image demonstrating choanal stenosis
• 1 in 8000–10,000 births
• Unilateral more common than bilateral 2:1
(right side > left) extend posteriorly from the nasal cavity, which is
• More common in females than males separated from the oral cavity by a thin
• Affects all races equally nasobuccal membrane. This eventually ruptures
• Chromosomal abnormalities found in approxi- at approximately 6 weeks forming the posterior
mately 6% infants choanae.
Embryology Suggested Etiology
The nasal placodes are derived from ectoderm and The etiology of choanal atresia is largely
appear during the third week of gestation. Around unknown. However, a number of theories have
week 5, these placodes invaginate into pits that been proposed including the following:
39 Choanal Atresia 619
• Persistence of the buccopharyngeal membrane (especially if bilateral). They often present with
• Failure of the bucconasal membrane of snorting and nasal flaring. Cyanotic episodes are
Hochstetter to rupture frequent which may be alleviated by episodes of
• Medial outgrowth of vertical and horizontal crying (permits ventilation – infant turns pink
processes of the palatine bone when crying as the infant breathes through an
• Abnormal mesodermal adhesions forming in open mouth – a phenomenon known as cyclical
the choanal area cyanosis). This is classical in infants with bilateral
• Misdirection of mesodermal flow due to local choanal atresia. In addition, in children with
factors choanal atresia, there is a high incidence of con-
comitant craniofacial and developmental anoma-
More recently, some studies have suggested that lies, e.g., CHARGE association.
the use of certain antithyroid medications (i.e., The CHARGE association (Coloboma, Heart
methimazole, prodrug carbimazole) during preg- defect, Atresia choanae, Retarded growth, Genital
nancy may increase the risk of having an infant hypoplasia, Ear anomalies) is associated with
with choanal atresia. It is not clear whether this is choanal atresia in 30% of cases. Additional
due to the drug itself, maternal thyroid disease, or malformations have been reported in up to 49%
abnormal thyroid hormone levels (Barbero et al. of children with choanal atresia. This rises to
2008; Clementi et al. 2010). Lee et al. demonstrated approximately 75% in bilateral choanal atresia
a significant association between low levels of thy- cases (Freng 1978a). Other associated syndromes
roid hormone at birth and the risk of choanal atresia include CHARGE, Crouzon, Pfeiffer, Antley-
among infants with no known thyroid disease (Lee Bixler, Marshall-Smith, and Treacher Collins
et al. 2012). Further studies are needed to clarify the (Burrow et al. 2009; Harris et al. 1997; Freng
role of thyroid hormones in the development of 1978a).
choanal atresia. It is essential to establish a secure airway which
The obstruction of the posterior choanae may be will need to be done before any investigative pro-
bony, membranous, or both. Ninety percent of chil- cedures. If there no associated lung or
dren with choanal atresia have a bony component, laryngotracheal abnormalities, the placement of
and 10% are membranous. However, modern imag- an oral airway or McGovern nipple (a nipple
ing would suggest a mixed bone/membranous from a feeding bottle with nipple end opened to
obstruction in 70% and a pure bony obstruction on allow respiration) may be sufficient. Alterna-
30% (Brown et al. 1996). The choanal orifices nor- tively, orotracheal intubation with ventilatory sup-
mally measure >3.7 mm in children younger than port may be required to maintain adequate
2 years, and the vomer does not exceed 3.4 mm in ventilation. Most infants with unilateral choanal
children younger than 8 years. Computed tomogra- atresia are asymptomatic and may not present
phy (CT) typically demonstrates medial bowing and until later or adulthood with unilateral nasal
thickening of the lateral walls of the nasal cavity, obstruction, unilateral nasal discharge, or as an
which are fused with the enlarged vomer. Some incidental finding.
degree of narrowing of the bony nasal passage and
vomer thickening are usually present with membra-
nous atresia (Hasegawa et al. 1983). Diagnosis
The initial diagnosis can be suggested by the

Clinical Features inability to pass an 8F nasal catheter through the
nose into the pharynx, which can be confirmed by
Infants are initially obligate nasal breathers for the the inability to see patent posterior choanae or
first few months of life. Nasal obstruction fre- pass a flexible nasal endoscope into the postnasal
quently causes severe respiratory distress space. Other simple tests which can be performed
include assessing for fogging of a mirror/metal obtained. The nasal cavity is decongested with
spatula when held at the nostril or using a stetho- 1:10,000 adrenaline patties, and the atretic plate
scope to listen for airflow at the nares. However, is injected with 1% lignocaine with 1:200,000
fine-cut (1–2 mm thick) CT images of the para- adrenaline. The atretic plate is then perforated
nasal sinuses and skull base with the bone and soft with a small urethral sound under endoscopic
tissue windows provide valuable information on visualization which is passed through the mouth
the anatomy of the posterior nasal cavity and at the time of perforation. The urethral sound is
posterior choanae such as the composition and passed in an inferior medial direction to avoid
severity of the obstruction. The nasal passages damage to the sphenoid or skull base. Progres-
should be suctioned prior to performing the CT sively larger sounds are introduced to dilate the
to eliminate retained secretions that can obscure perforated atretic plate. The endoscopic drill
the true thickness of the soft tissue component of (Medtronic) is then inserted through the nose
the anomaly (Brown et al. 1996; Hasegawa et al. until it reaches the nasopharynx. The drill has a
1983; Keller and Kacker 2000). Imaging will also specially designed sheath to prevent trauma to
differentiate choanal atresia from other causes of normal tissue/structures in the nasal cavity. The
bilateral nasal obstruction such as pyriform aper- drilling is performed medially over the vomer and
ture stenosis and bilateral nasolacrimal duct cysts. laterally over the medial pterygoid plates. The
posterior aspect of the vomer is also removed
using a backbiter forceps. This creates a common
Management cavity posteriorly which minimizes the risk of
restenosis. Currently the authors insert bilateral
Infants with bilateral choanal atresia will require soft stents (nasopharyngeal airway stents) which
stabilization of their airway as outlined above. are cut to size so they sit at the nostril anteriorly
Surgical repair should be performed early in bilat- and extend 2–3 mm posteriorly beyond the
eral choanal atresia if there are no medical contra- newly formed choanae. These are secured anteri-
indications. Infants with unilateral choanal atresia orly with silk sutures (through flange of stent
can usually wait until they are older (>1 year) only) which are then taped to the infants’
unless it is causing significant airway issues and face. Postoperatively these stents are kept patent
will therefore require early intervention. A num- by the use of regular saline flushes and humidified
ber of surgical techniques have been described; air. These stents are left in situ for 1 week. The
the first repair was performed in 1854 by Carl child is then brought back to theater for removal
Emmert. Transnasal puncture using urethral plus or minus removal of granulation tissue if
sounds was initially performed blindly. However, required. It is the authors’ practice to routinely
with the availability of endoscopic technology, the schedule the child for a second endoscopic exam-
vast majority of choanal atresia repairs are ination under general anesthetic as a day-case
performed endoscopically using powered instru- procedure approximately 1 week later, during
ments (Ramsden et al. 2009). which patency of the newly formed choanae is
assessed and granulations removed as necessary.
It is common for a child post choanal atresia repair
Endoscopic Technique to require multiple microdebridements and dilata-
tions – one large series reported an average of 4.9
This approach allows for excellent visualization procedures (Samadi et al. 2003). Other transnasal
of the operative field. A Boyle-Davis mouth gag is techniques have been described including the use
inserted and a suture placed through the uvula and of mucosal flaps which have been suggested to
clipped to assist with retraction of the soft palate. improve reepithelization (Dedo 2001; Nour and

A 120 4 mm endoscope is passed through the Foad 2008). However, the authors’ experience is
mouth into the nasopharynx, and a view of the that these flaps are difficult to perform in a new-
posterior surface of the obstructed choanae is born’s nose.
Transpalatal Technique • Stents that are too tightly secured to the septum
can likewise cause septal cartilage necrosis and
This technique provides good exposure to the permanent perforation.
posterior choanae/nasopharynx and was the main- • Stents may also contribute to localized tissue
stay of surgical repair until the advent of endo- inflammation and infection, leading to
scopic technology. A U-shaped incision was made increased pain, granulation tissue, and syn-
on the hard palate 5 mm from the dental arch. A echia formation.
posteriorly based subperiosteal flap is raised to
gain access to the nasopharynx. The inferior In addition stents demand intensive management
vomer is encountered and removed prior to dril- by caregivers with frequent irrigation and suctioning
ling of the lateral atretic plate. This technique to prevent obstruction with secretions (Hengerer et
remains useful in children with a low skull base al. 2008; Van Den Abbeele et al. 2002).
or small nasopharynx or where an endoscopic Those who advocate for no stenting argue that
technique has failed. This approach is associated due to the use of endoscopes and smaller nasal
with higher complication rates than the endo- instruments, there is less damage to surrounding
scopic technique such as postoperative pain, pal- mucosa and less risk of exuberant granulation
atal fistula, and reduced midface growth leading to tissue, thus obviating the need for stents.
a high-arched palate and dental malocclusion Schoem describes a series of 13 children with a
which occurs in approximately 50% of patients mix of unilateral and bilateral atresia. Seven of
(Freng 1978b). these patients were found to have some granula-
tion or synechiae formation at a routine endos-
copy 3–4 weeks after the initial repair. After
Controversies in Choanal Atresia microdebrider excision of the granulation tissue,
Management all were patent at the last follow-up (12 months
post repair). Only four patients from this series
Nasal Stents did not have to return to the operating room and
were found to be patent via flexible endoscopy in
Currently there is evidence in the literature which the office (Schoem 2004). Ibrahim et al. reported
supports both stenting and no stenting post on a substantial series of 21 patients managed
choanal atresia repair. Nasal stenting post choanal without postoperative stents. Three patients
atresia repair began as a way to prevent the reste- required revision, with one patient having a sec-
nosis seen after simple transnasal puncture. Cur- ond revision, for a success rate of 86% (Schoem
rent advocates of stenting suggest that nasal stents 2004). In both series, aggressive nasal irrigation
aid in the support and healing of mucosal flaps regimens with saline as well as a steroid-
around the neo-choanae and allow for nasal containing nasal drop were used. Schoem
patency until scarring has occurred. Others use added oral antibiotics and steroids. Patients
nasal stents in infant patients due to concern of were able to feed immediately after surgery,
postoperative nasal airway obstruction due to and hospital stays were relatively short (Schoem
edema. There are variable stenting practices 2004; Ibrahim et al. 2010).
among those who stent with regard to duration
and stent material used with overall good success
rates of >80% (Bedwell and Choi 2012).
The use of postoperative stenting carries with it Mitomycin C
associated risks including:
Mitomycin C is an aminoglycoside which by the
• Pressure by the stents can cause pressure bacteria Streptomyces. It cross-links DNA and
necrosis of the columella or alar rim, causing causes cell apoptosis. When applied to healing
cosmetic deformity. tissue, it has an antiproliferative effect which
inhibits fibroblast growth and proliferation. Mito- Cross-References

mycin C is widely used in ophthalmic and laryn-
geal surgery to prevent scar formation and was ▶ Congenital Airway Malformations
proposed for use in choanal atresia surgery to ▶ Embryology of Congenital Malformations
reduce restenosis. However, several small studies ▶ Pediatric Airway Assessment
have not shown it to be effective in improving ▶ Pediatric Respiratory Physiology
long-term outcomes, and there is concern on reuse
of a potentially oncogenic medication in children
(Kubba et al. 2004). References
Barbero P, Valdez R, Rodriguez H, et al. Choanal atresia
associated with maternal hyperthyroidism treated with
Outcomes methimazole: a case control study. Am J Med Genet A.
2008;146:2390–5.
The primary outcome measure in choanal stenosis Bedwell JR, Choi SS. Are stents necessary after choanal
is restenosis and the need for reoperation. atresia repair? Laryngoscope. 2012;122:2365–6.
Brown OE, Pownell P, Manning SC. Choanal atresia: a
Reported revision rates vary from 0% to 36%
new anatomic classification and clinical management
(Ramsden et al. 2009; Kubba et al. 2004). Reste- applications. Laryngoscope. 1996;106:97–101.
nosis rates appear more likely in patients who Burrow TA, Saal HM, de Alarcon A, et al. Characterization of
undergo surgery in the neonatal period for bilat- congenital anomalies in individuals with choanal atresia.
Arch Otolaryngol Head Neck Surg. 2009;135:543–7.
eral disease and suffer from gastroesophageal
Clementi M, Di Gianantonio E, Cassina M, et al. Treatment
reflux disease. Favorable outcomes may be pre- of hyperthyroidism in pregnancy and birth defects.
dicted by the absence of associated facial anoma- J Clin Endocrinol Metab. 2010;95:E337–41.
lies, higher weight at the time of surgery Dedo HH. Transnasal mucosal flap rotation technique for
the repair of bilateral choanal atresia. Otolaryngol Head
(>2.3 kg), and larger stent size (Kubba et al.
Neck Surg. 2001;124:674–82.
2004; Teissier et al. 2008). Eladl M, Khafagy YW. Endoscopic bilateral congenital
choanal atresia repair of 112 cases, evolving concept
and technical experience. Int J Pediatr Otorhino-
laryngol. 2016;85:40–5.
Conclusion and Future Directions Freng A. Congenital choanal atresia: etiology, morphology
and diagnosis in 82 cases. Scand J Plast Reconstr Surg.
Choanal atresia or stenosis is the most common 1978a;12(3):261–5.
craniofacial defect of the nose. Bilateral choanal Freng A. Growth in width of the dental arches after partial
extirpation of the mid palatal suture in man. Scand J
atresia presents at birth with life-threatening air-
Plast Reconstr Surg. 1978b;12:267–72.
way obstruction, as neonates are obligate nasal Harris J, Robert E, Källén B. Epidemiology of choanal
breathers. Infants with bilateral choanal atresia atresia with special reference to the CHARGE associa-
will require stabilization of their airway as previ- tion. Pediatrics. 1997;99(3):363–7.
Hasegawa M, Oku T, Tanaka H, et al. Evaluation of CT in
ously discussed. Surgical repair should be
the diagnosis of congenital choanal atresia. J Laryngol
performed early in bilateral choanal atresia if Otol. 1983;97:1013–5.
there are no medical contraindications; infants Hengerer AS, Brickman TM, Jeyakumar A. Choanal atre-
with unilateral choanal atresia can usually wait sia: embryologic analysis and evolution of treatment, a
30-year experience. Laryngoscope. 2008;118:862–6.
until they are older (>1 year) unless it is causing
Ibrahim AA, Magdy EA, Hassab MH. Endoscopic
significant airway issues. A number of surgical choanoplasty without stenting for congenital choanal
techniques exist for the management of choanal atresia repair. Int J Pediatr Otorhinolaryngol.
atresia in the newborn as discussed (Eladl and 2010;74:144–50.
Keller JL, Kacker A. Choanal atresia, CHARGE associa-
Khafagy 2016; Kwong 2015). Due to the rarity
tion and congenital nasal stenosis. Otolaryngol Clin
of this condition, there is still controversy as to North Am. 2000;33:1343–51.
whether nasal stents should be used or not Kubba H, Bennett A, Bailey CM. An update on choanal
(Strychowsky et al. 2016). atresia surgery at Great Ormond Street Hospital for
children: preliminary results with mitomycin C and KTP Schoem SR. Transnasal endoscopic repair of choanal atre-
laser. Int J Paediatr Otorhinolaryngol. 2004;68:939–45. sia: why stent? Otolaryngol Head Neck Surg.
Kwong KM. Current updates on choanal atresia. Front 2004;131:362–6.
Pediatr. 2015;3:52. Strychowsky JE, Kawai K, Moritz E, Rahbar R,
Lee LJ, Canfield MA, Hashmi SS, et al. Association Adil EA. To stent or not to stent? A meta-
between thyroxine levels at birth and choanal atresia analysis of endonasal congenital bilateral
or stenosis among infants in Texas, 2004–2007. Birth choanal atresia repair. Laryngoscope.
Defects Res A Clin Mol Teratol. 2012;94(11):951–4. 2016;126(1):218–27.
Nour YA, Foad H. Swinging door flap technique for endo- Teissier N, Kaguelidou F, Couloigner V, et al.
scopic transeptal repair of bilateral choanal atresia. Eur Predictive factors for success after transnasal
Arch Otorhinolaryngol. 2008;265:1341–7. endoscopic treatment of choanal atresia. Arch
Ramsden JD, Campisi P, Forte V. Choanal atresia and choanal Otolaryngol Head Neck Surg. 2008;134:57–61.
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Samadi DS, Shah UK, Handier SD. Choanal atresia: a endoscopic treatment of choanal atresia without pro-
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Macroglossia
40
Abdulrahman Alshafei and Thambipillai Sri Paran
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 625
Etiology and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 627
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 628
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 629
Abstract surgical techniques of glossoplasty to achieve

Macroglossia is generally a clinical feature that reduction in the size of the tongue while pre-
helps in the diagnosis of certain syndromes but serving its function. Overall, surgery for chil-
rarely can become the primary clinical chal- dren with severe macroglossia has shown
lenge for pediatric surgeons, otolaryngologists, favorable functional and cosmetic outcomes.
and anesthetists.
This chapter details various causes and Keywords
associations of this condition and current Macroglossia · Beckwith-Wiedemann
syndrome · Lymphangioma · Glossectomy ·
Wedge resection · Key-hole incision ·
A. Alshafei (*) Tracheostomy
e-mail: ar.alshafei@hotmail.com
Introduction
T. S. Paran
Crumlin, Dublin, Ireland True macroglossia is diagnosed when tongue mar-
gins expand beyond the teeth or, in the case of a
e-mail: sriparan80@hotmail.com neonate, the alveolar ridge (Gupta 1971).

https://doi.org/10.1007/978-3-662-43588-5_43
626 A. Alshafei and T. S. Paran
Apparent or pseudomacroglossia is diagnosed lymphangiomas and hemangiomas (Costa et al.

when the tongue is normal in size but protrudes 2013; Eivazi et al. 2009; Perkins 2009; Prada
beyond its natural cavity due to abnormalities in et al. 2012; Sunil et al. 2012; Usha et al. 2014;
the skeletal structures of the oral cavity (Murthy Nagpal et al. 2015). Malignant tumors of tongue
and Laing 1994). In the vast majority of children, are extremely rare (Harirchi et al. 2012).
macroglossia is only a cosmetic concern and does True secondary macroglossia can be due to
not cause any clinical problems. However, when acquired conditions which include infective causes
significant enlargement of the tongue is present, it (diphtheria, candidiasis, pemphigus vulgaris, acti-
can interfere with feeding, speech, dental growth, nomycosis), metabolic/endocrine causes (hypothy-
and even breathing (Costa et al. 2013; Prada et al. roidism, acromegaly, myxedema, cretinism), or
2012). Description of macroglossia is seen in lit- traumatic causes (hemorrhage, repetitive biting,
erature since 1600 BC, and many treatments intubation injury) (Balaji 2013; Costa et al. 2013;
including leeches and muscular entrapment Gupta 1971; Murthy and Laing 1994; Prada et al.
devices have been attempted with little success 2012; Wolford and Cottrell 1996). The presenta-
(Ring 1999). Sclerosing agents and vascular tion, severity, and management of secondary true
embolization techniques have been tried in the macroglossia will vary on the causative factor. Sec-
last decades, again with partial success and sig- ondary macroglossia can also be caused by a lesion
nificant complications (Perkins et al. 2010; Slaba within the oral cavity adjacent to the tongue such as
et al. 1998; Usha et al. 2014). Currently, surgical tumors (rhabdomyosarcoma, teratoma), neurofibro-
approach with reduction of the volume of tongue matosis, lingual thyroglossal cyst, lingual thyroid,
tissue, while preserving the functions, is the gold ranula, or myositis (Gupta 1971; Harirchi et al.
standard in those with symptomatic macroglossia 2012; Murthy and Laing 1994; Perkins 2009;
(Balaji 2013; Costa et al. 2013; Davalbhakta and Prada et al. 2012; Wolford and Cottrell 1996).
Lamberty 2000; Heggie et al. 2013; Kadouch Maxillary bone hypoplasia leading to mandibular
et al. 2012; Wolford and Cottrell 1996). prognathism and smaller oral cavity in Down’s syn-
drome is a cause of apparent or pseudomacroglossia
(Gasparini et al. 2002; Guimaraes et al. 2008).
Etiology and Pathology
True primary macroglossia is usually a result of Presentation

muscular hypertrophy or due to pathological
lesions within the tongue parenchyma (Costa When macroglossia is evident during the newborn
et al. 2013; Prada et al. 2012). Muscular hyper- period and associated with syndromes such as
trophy or hyperplasia can be associated with Beckwith-Wiedemann (omphalocele,
syndromes such as Beckwith-Wiedemann syn- visceromegaly, gigantism, hypoglycemia, and
drome, hemihyperplasia, Behmel, Laband or as a macroglossia) or Down syndrome, then the diag-
result of unknown etiology (Idiopathic) (Balaji nosis is easy to make. Intraglossal lesions such as
2013; Costa et al. 2013; Prada et al. 2012). lymphangioma or hemangioma leading to an
Between 80% and 99% children born with enlarged tongue can be diagnosed by identifying
Beckwith-Wiedemann syndrome will have cystic lesions on the surface of tongue or by the
macroglossia, and vast majority will be asymp- bluish discoloration (Murthy and Laing 1994; Sunil
tomatic and will not need any intervention et al. 2012; Usha et al. 2014). The physical presen-
(Kadouch et al. 2012; Tomlinson et al. 2007). tation will be obvious and may also be accompa-
Familial autosomal dominant macroglossia has nied by noisy breathing, difficulty feeding, and
also been described within the literature (Prada drooling (Costa et al. 2013; Gasparini et al. 2002;
et al. 2012; Reynoso et al. 1986, 1994). Other Prada et al. 2012; Wolfordand Cottrell 1996).
common causes of true primary macroglossia When feeding difficulties are profound, then failure
include vascular malformations such as to thrive and poor weight gain will be evident.
40 Macroglossia 627
Obstructive sleep apnoea could be associated with abovementioned primary and secondary causes.
macroglossia in some children (Perkins 2009). Investigation, following thorough physical exam-
Macroglossia from a lymphangioma may lead ination for secondary causes of macroglossia,
to verrucous lesions on the surface of the tongue, comprises thyroid function testing, echocardiog-
and these can ulcerate and exude a serous discharge raphy, and karyotype analysis (Gupta 1971;
(Sunil et al. 2012; Usha et al. 2014). If Murthy and Laing 1994; Prada et al. 2012;
unrecognized or untreated in the neonatal period, Wolford and Cottrell 1996). Magnetic resonance
the lesion may become more problematic in imaging to detail the extent of tongue involvement
infancy or later in childhood when it may present is indicated particularly when the volume of lin-
with minor trauma, e.g., to a lingual lymphangioma gual tissue affected is not clinically apparent
(Leboulanger et al. 2008). In Ludwig angina abrupt (Balaji 2013; McKenna et al. 1990).
enlargement may compromise the airway and pro-
duce a life-threatening emergency necessitating
tracheostomy and gastrostomy until definitive Management
tongue reduction can be carried out (Rajendran
and Sivapathasundaram 2009; Tasca et al. 1999). Mild macroglossia as seen in most children with
Other causes of secondary macroglossia such Beckwith-Wiedemann syndrome and smaller oral
as hypothyroidism and infective or traumatic lesions do not need any special care (Tomlinson
causes will have the appropriate accompanying et al. 2007). When associated with systemic dis-
symptoms and signs. However, postoperative orders such as hypothyroidism, management of
(following oral/palate surgery) or traumatic the primary condition alone is what is needed.
causes of macroglossia can be acute and severe Moderate enlargements can be managed by nurs-
that the enlarged tongue could potentially obstruct ing the infant in the lateral or prone position to
the oropharynx and lead to severe respiratory assist the airway and drooling. Multidisciplinary
compromise and/or death (Denneny 1985; approach including dietician, speech therapist,
Rajendran and Sivapathasundaram 2009). and pediatric dentist will be useful (Weksberg
When the macroglossia is significant and the et al. 2010).
treatment is inappropriately delayed, protracted When severe macroglossia with airway com-
dental defects develop including prognathism, promise is present, early involvement of anesthe-
anterior open bite, and an increased angle between tist or intensivist and otolaryngologist is
the ramus and body of mandible (Wolford and necessary (Weksberg et al. 2010). Airway may
Cottrell 1996). Speech defects occur and articula- have to be secured by a tracheostomy and feeding
tion is subsequently defective, especially expres- with a formal gastrostomy (Denneny 1985;
sion of consonants which are precluded by Kadouch et al. 2012; Rajendran and Sivapatha-
inadequate tongue movement as a consequence of sundaram 2009). Biopsy is rarely indicated with
the increased bulk in a limited cavity (Van Lierde histology becoming available on the resected
et al. 2002, 2010; Maas et al. 2016). Regression of specimen. Needle aspiration, however, of intra-
macroglossia is not a regular feature when due to lingual cystic lesions may be a useful temporizing
lymphangioma, and a conservative approach to the procedure (Eaton et al. 2001) but requires confi-
lesion has little merit (Gupta 1971; Murthy and dent exclusion of vascular anomalies by pre- or
Laing 1994; Sunil et al. 2012; Usha et al. 2014). postnatal imaging.
Intravascular photocoagulation (Chang et al.
1999) and embolism of vascular tongue anomalies
Diagnosis (Slaba et al. 1998) are useful in the management
of some children. Steroid treatment may confer
Physical examination should include not only the temporary benefit during an acute airway obstruc-
tongue but also of the head and neck, oral cavity, tion early in life. Glossitis and sepsis from tongue
and maxilla/mandible to differentiate between the lesions are seen later in life and will need
penicillin-based antibiotic treatment. Surgery

with glossectomy, preferably before 7 months of
age, confers optimal opportunity for rehabilitation
of tongue movement and will avoid complications
such as glossitis, hemorrhage, and secondary
speech and maxillofacial abnormalities (Balaji
2013; Tomlinson et al. 2007). However, surgery
is best avoided during the newborn period in order
to minimize unnecessary morbidity (Heggie et al.
2013; Kopriva and Classen 1998).
Surgery
Fig. 1 Traction on the apex suture delivers the necessary
Reduction glossectomy is the mainstay of treat- exposure for a central wedge resection
ment, and options include central wedge resec-
tion, circumferential wedge resection, or a
combined transoral and transcervical approach
for a massive infiltrative lymphangioma (Balaji
2013).
The aims of reduction are to allow intraoral
position of the tongue in the floor of the mouth,
to restore normal tongue movement, and to permit
speech and deglutition (Balaji 2013; Kadouch
et al. 2012; Wolford and Cottrell 1996). Implicit
in these objectives is the fact that surgery should
be conservative and a repeat tapering procedure is
preferable to removal of excess tissue. The prin-
ciples involve careful hemostasis by the use of a
tourniquet or, alternatively, by the use of a CO2 Fig. 2 Wedge of tissue is removed incorporating more of
laser (Ylmas et al. 2009), harmonic scalpel (Kittur the dorsal than the ventral aspect of the tongue
et al. 2013) or YAG laser (Tasar et al. 1995). We
recommend a V-shaped wedge resection of the with the tongue in a resting position, to the apex,
anterior tongue as has been previously described and this incision is beveled such that more ventral
(Balaji 2013; Davalbhakta and Lamberty 2000; than dorsal tissue is removed. This recreates the
Kadouch et al. 2012). natural concavity of the central tongue (Fig. 2). A
Nasal intubation or tracheostomy secures air- straight needle is a useful adjunct to creating this
way protection. The head is placed in a silicone bevel.
ring and the neck extended. A suture placed on the The divided lingual arteries are ligated. Resto-
apex of the tongue and two hemostatic/traction ration of the tongue flaps at the midline is
sutures tied over silicone rubber dams at the base performed incorporating mucosa and a few mm
of the tongue provide the requisite traction. Trac- of muscle (Fig. 3). Alternatively, a key-hole inci-
tion on the apex suture delivers the necessary sion can be employed and has been shown to
exposure for a central wedge resection (Fig. 1). provide excellent functional and cosmetic results
The resection should not usually extend into the (Fig. 4; Balaji 2013; Costa et al. 2013).
posterior one-third where the extrinsic muscles of Surgical complications include edema, bleed-
the tongue are inserted. The lateral margins of the ing, and infection (Balaji 2013; Kadouch et al.
incision extend from the level of the anterior gum, 2012; Wolford and Cottrell 1996). Excessive
40 Macroglossia 629
Early diagnosis and exclusion of associated con-

genital, infective, or metabolic pathology are
crucial when managing a child with suspected
macroglossia. Involvement of a multi-
disciplinary team, including a pediatric surgeon
and otolaryngologist, anesthetist, dietician, and
speech and language therapist, should not be
delayed. Anticipation of a difficult airway is a
focal point in the perioperative management, and
the need for a tracheostomy should be tailored to
each individual child. Surgery provides good
results for children with severe symptomatic
Fig. 3 The remaining lateral segments of the tongue macroglossia and should be considered early on
approximated in the midline in its management. In the future, other modalities
such as laser therapy may offer more definitive
options.
Cross-References
▶ Access for Enteral Nutrition

▶ Pediatric Airway Assessment
▶ Tracheostomy in Infants
▶ Pierre Robin Sequence
References
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Kopriva D, Classen DA. Regrowth of tongue following Otorhinolaryngol. 1999;15:201–5.
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Pierre Robin Sequence
41
Udo Rolle, Aranka Ifert, and Robert Sader
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Airway Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Nutritional Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
Cleft Palate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Micrognathia/Retrognathia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Skeletal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Ear Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Cardiovascular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Ocular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Nasal Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
U. Rolle (*)
Department of Pediatric Surgery and Pediatric Urology,
Goethe University Frankfurt, Frankfurt, Germany
e-mail: udo.rolle@kgu.de
A. Ifert
Carolinum, Institute of Dentistry, Frankfurt, Germany
e-mail: aranka_ifert@yahoo.de
R. Sader
Department of Oral, Maxillofacial, and Plastic Facial
Surgery, Goethe University Frankfurt, Frankfurt, Germany
e-mail: robert.sader@kgu.de

https://doi.org/10.1007/978-3-662-43588-5_44
632 U. Rolle et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 638
Abstract 1 in 3,120 live births. In other countries, the inci-

Pierre Robin sequence is a rare cause of dence is 1 in 8,060 live births in Germany, 1 in
neonatal airway obstruction considered to be 8,500 live births in the UK, and 1 in 14,000 live
“surgical,” and some of the affected patients births in Denmark.
truly require surgical procedures to achieve PRS may occur as an isolated anomaly or in
appropriate airway and nutritional manage- conjunction with a recognized syndrome. In large
ment. The clinical presentation, diagnostics, series, it has been reported that almost half of
and the subsequent conservative or surgical the patients with Pierre Robin sequence are syn-
treatment of Pierre Robin syndrome will be dromic, and the three most common associated
described in this chapter. syndromes are Stickler, velocardiofacial, and
Treacher Collins (Cote et al. 2015).
Keywords Mortality rates for Pierre Robin sequence were
Pierre Robin sequence · Airway management · found to range from 3.6% to 21%. Infants with
Distraction osteogenesis · Tracheostomy · associated anomalies or syndromic cases have
Stimulation plate higher mortality. In the recent study from the
USA, the overall mortality rate was 16.6% in
isolated cases, whereas infants with cardiac or
Introduction central nervous system anomalies had higher mor-
tality, 39% and 33%, respectively (Costa et al.
Pierre Robin sequence (PRS), which is named 2014).
after the French dental surgeon Pierre Robin, is a
triad of micrognathia, glossoptosis, and upper air-
way obstruction (Robin 1923, 1934). The major- Etiology
ity of patients with PRS also have a cleft of the
secondary palate. Typically, it is a wide U-shaped The exact cause and the pathophysiology of
cleft palate and has been reported in 73–90% of Pierre Robin sequence are still unclear
patients (Insalaco et al. 2018; Cote et al. 2015). In (Cote 2015). Hypoplasia of the mandible, either
newborns with PRS, the tongue is ptotic and its from a primary growth disturbance or from
base is retropositioned against the posterior pha- hyperflexion of the neck, before 9 weeks in utero is
ryngeal wall, resulting in upper airway collapse thought to be the inciting factor in Pierre
during inspiration, which worsens in the supine Robin sequence. There are three major hypotheses
position (Khansa et al. 2017). Severe airway to explain the sequence of events in Pierre Robin
obstruction results in feeding difficulties, reflux, sequence (Tan et al. 2013): (a) hypoplastic
and failure to thrive (Cladis et al. 2014). mandible, (b) oropharyngeal and muscular defi-
ciencies, and (c) compression of the mandible in
utero. The hypoplastic mandible theory is the
Epidemiology most widely accepted theory. The primary defect
is thought to be in Meckel’s Cartilage, the
Various studies have been published about the embryonic structure involved in the formation
incidence of Pierre Robin sequence. The highest and growth of the mandible. The subsequent man-
incidence has been reported from the USA with dibular hypoplasia is thought to lead to a small
41 Pierre Robin Sequence 633
mouth volume, abnormal position of the tongue, It should be mentioned that cleft palate does
and the secondary impairment of the palatal not have a complete penetrance and can only be
closure (Hanson and Smith 1975; Cote et al. seen in about 80% of the Pierre Robin patients
2015). Regarding the oropharyngeal and muscu- (Sadewitz 1992).
lar deficiency hypothesis, it is believed that hypo- Some infants with PRS exhibit minimal respi-
tonia of the oropharyngeal muscles could result ratory symptoms at birth, whereas others have
in hypoplasia of the mandible. The mandible severe airway obstruction with stridor, retractions,
compression theory probably plays a role in a and even cyanosis. The airway obstruction in
small proportion of neonates with Pierre Robin Pierre Robin sequence requires early and proper
sequence. management, since it may lead to hypoxia, cor
pulmonale, failure to thrive, and cerebral impair-
ment. Generally, syndromic cases are more severe
Genetics and have worse prognosis than non-syndromic
Pierre Robin sequence. Generally, it is expected
There is a high incidence of twins with PRS that patients with non-syndromic Pierre Robin
reported. Furthermore, family members of PRS sequence will show catch-up growth of the
patients have a higher incidence of cleft lip and mandible.
palate (Gangopadhyay et al. 2012). SOX9 gene, a Feeding difficulties are not uncommon in PRS.
critical chondrogenic regulator, has been linked to Feeding difficulties are thought to be secondary to
non-syndromic Pierre Robin sequence in families both the airway obstruction and the associated
with more than one member affected (Cote et al. cleft palate which prevents the formation of ade-
2015; Gordon et al. 2014). The relationship of quate intraoral pressure required for the extraction
PRS with so many different syndromes suggests of milk from the breast or the bottle (Cote et al.
a probable genetic component in the etiology 2015).
of PRS. However, the most common syndromic
Pierre Robin sequence cases have different
genes including Stickler syndrome that is associ- Airway Management
ated with mutations in COL genes (Acke et al.
2012), velocardiofacial syndrome that arises Airway obstruction due to glossoptosis can
from a microdeletion of chromosome 22q11.2 occur at or immediately after birth but may
(Buchanan et al. 2014), and Treacher Collins take much longer (up to 3 weeks) to become
syndrome that is associated with mutations in apparent (Ogborn and Pemberton 1985). Most
the TCOF1, PLOR1C, and POLR1D genes neonates present with an isolated Pierre Robin
(Buchanan et al. 2014; Trainor and Andrews sequence and not one of the syndromes, which
2013; Kadakia et al. 2014). typically present more significant clinical
problems, i.e., airway and feeding difficulties.
The airway obstruction in Pierre Robin sequence
Clinical Features is due to the narrowing or complete obstruction
of the pharyngeal space by the posteriorly
Pierre Robin sequence consists of three essential displaced tongue. This airway obstruction
components (Breugem et al. 2016): could be intermittent. Most of the complications
and unfavorable outcomes of Pierre Robin
Micrognathia or retrognathia sequence are directly related to delayed or inap-
Glossoptosis, possibly accompanied by airway propriate airway management (Myer et al. 1998).
obstruction Therefore, special vigilance is required, even in
Cleft palate (usually U-shaped, but V shape is also patients with only minor defects. Typical clinical
possible) signs of upper airway obstruction are increased
634 U. Rolle et al.
respiratory effort, stridor, subcostal retractions, (d) Tracheostomy

and cyanotic or apneic spells. In an otherwise Tracheostomy should be avoided if possi-
asymptomatic child, choking attacks, cyanosis ble, and it should only be employed if all
during feeding, or repeated aspiration events other techniques fail. Tracheostomy should
may be due to intermittent airway problems. be performed by an appropriately skilled sur-
Since PRS infants may also have short or geon who is familiar with infantile airways.
collapsing epiglottis, laryngomalacia, and/or Tracheostomy requires closed monitoring but
segmental tracheal stenosis, nasoendoscopy and enables oral feeding. Tracheostomy could be
bronchoscopy might be necessary to assess the removed after the child’s airway obstruction
child. has resolved which usually happens within the
Every child with symptoms of airway obstruc- first year of life.
tion should be nursed prone with the head to (e) Distraction Osteogenesis of the Mandible
one side. The head should be maintained in level Distraction osteogenesis comprises a rela-
position to prevent either glossoptosis or gastro- tively new technique. The mandible needs to
esophageal reflux (GER). Usually, affected children be cut near the angle of the mandible on both
can be successfully fed by mouth in this position. sides. A specialized mechanical device dis-
Persistence of airway difficulties requires fur- tracts these two portions every day by approx-
ther intervention (Albino et al. 2016; Kam et al. imately 1.5–2 mm. Using this technique, the
2015). mandible gradually elongates over a period of
2–3 weeks. Timing of performing a mandibu-
(a) Nasopharyngeal Tube lar distraction can be in newborns to prevent
The nasopharyngeal airway bypasses tracheostomy or at a later stage to remove a
the oral pharynx and the obstruction due to tracheostomy tube.
the glossoptosis. A regular endotracheal tube, Distraction osteogenesis has been carried
cut to the appropriate length, is inserted by out only during the last 5–10 years. Therefore,
nasal route and securely strapped in place. long-term follow-up results of this promising
The nasopharyngeal airway is a very effective, technique are not available. Nevertheless, the
temporary form of airway management within distraction osteogenesis technique should be
the intensive care unit (ICU). Usually, patients reserved for severe cases of non-syndromic
with nasopharyngeal tubes in place would not and syndromic Pierre Robin sequence, since
be sent home, as dislodgement of the tube can in most cases of non-syndromic Pierre Robin
result in an acute airway obstruction. sequence physiologic catch-up growth of the
(b) Endotracheal Tube mandible occurs.
Endotracheal intubation serves as a short- (f) Tongue Positioning and Stimulation Plate
term support if the nasopharyngeal airway is During the last decade, a new, nonsurgical
not successful or during resuscitation or technique was developed by orthodontists that
anesthesia. guarantees, in most cases, a free airway space
(c) Tongue-Lip Adhesion/Glossopexy and treats the hypoplastic mandible causally.
Essentially, in this technique, the tongue is Immediately, a palatal plate is produced, sim-
sutured to the lower lip. After the child has ilar to the feeding plate for cleft palate new-
demonstrated catch-up growth, the tongue-lip borns, but with a dorsal spur that goes shortly
adhesion can be released. The efficacy of the to the epiglottis (Fig. 1a–c). Sometimes endo-
tongue-lip adhesion technique remains a con- scopic control is necessary during positioning
troversial issue. to avoid irritation of the epiglottis. To accom-
Glossopexy consists of suturing the tongue plish this, the tongue is positioned anteriorly,
base to the mandible. Due to the relatively and the airway is kept patent. Moreover,
soft consistency of the mandible, a permanent via functional stimulation of the tongue, the
glossopexy is difficult achieve; therefore, this mandible starts to grow during the following
technique is also controversial. months and will be quite normal when the
Fig. 1 (a–c) Stimulation plate
palatal closure is performed at the age of about slightly elevated. This method of feeding is
6 months (Fig. 2a–e). Feeding is also appropriate in children with catch-up growth
supported, but problems remain in some of the mandible.
cases (Brosch et al. 2006). If this is not satisfactory, gavage or feeding
(g) Noninvasive Ventilation tubes can be used temporarily to improve nutri-
There is a growing evidence that noninva- tion. If the feeding is still not successful, the child
sive respiratory support (NRS) could improve might need a gastrostomy, which could be
breathing patterns and respiratory outcomes removed after gaining the ability to be feed orally.
for infants with severe upper airway obstruc- It has been shown clearly that infants with
tion due to PRS. Subsequently the rate of Pierre Robin sequence require adequate caloric
necessary tracheostomies was reduced. Some intake. It is important to achieve the maximum
authors consider this the first-line treatment growth rate of the mandible since the resolution
(Leboulanger et al. 2010; Amaddeo et al. of the airway problems is directly related to
2016). mandibular growth. Only recently has increased
work of breathing been appreciated as an impor-
tant component of calorie consumption. It may
be necessary to provide these children with sev-
Nutritional Management eral times the normal caloric requirement of an
infant to compensate for up to a tenfold increase
Children with Pierre Robin sequence have in respiratory work. Indeed, failure to gain
feeding difficulties in 38–62% (Evans et al. weight despite maximum nutritional intake
2011). Initial treatment consists of bottle- should suggest the need for more aggressive
feeding in a prone position with the head airway management. The availability of total
636 U. Rolle et al.
Fig. 2 (a) Pierre Robin sequence patient before the inser- stimulation plate. (d) PRS patient after 4 months of treat-
tion of stimulation plate. (b) PRS patient with stimulation ment with stimulation plate. (e) PRS patient after closure of
plate. (c) PRS patient after 2 months of treatment with cleft palate at the age of 8 months
parenteral nutrition should prevent any instances corrects the tongue position by moving it anteri-
of failure to thrive, but it is rarely needed if other orly. In patients with a cleft of the soft palate
aspects of the condition are managed correctly. alone, a palatal plate has no positive effect on
It has been additionally proven that PSR feeding, but it can improve the tongue position
infants have a higher incidence of GER, and and stimulate mandibular growth. To enhance this
even empiric reflux treatment may be indicated effect, the plate can be modified by an anterior
to improve breathing and feeding. stimulus according to Castillo Morales (Hohoff
and Ehmer 1999).
Surgical protocols differ from center to
Cleft Palate center, and cleft closure is performed not only by
different techniques (i.e., Langenbeck, Furlow,
Cleft palate is present in at least 80% of patients Wardill) but also at different ages, ranging from
with Pierre Robin sequence. Cleft palates are typ- 4 to 36 months.
ically repaired while patients are infants. A palatal It is currently assumed that early surgery will
plate can be used in patients with a cleft of the provide a better chance of normal palatal function
hard palate to improve feeding. The plate also and speech development.
Micrognathia/Retrognathia to undertake the intubation of such patients.

Orthopedic and radiological consultation should
The first described functional therapy for microbe sought in children with suspected skeletal
gnathia was the use of the orthodontic palatal plate problems. Rare neuromuscular defects can also
to achieve growth stimulation of the mandible. occur, resulting in a tendency for glossoptosis to
It was not clear until today whether the growth persist despite mandibular growth (Carey et al.
potential of the mandible after this stimulation 1982).
is sufficient to achieve the normal dimensions.
However, it has been shown, based on physical
examinations until age 5, that the mandible can Ear Problems
barely regain its growth in relation to a normal
population (Daskalogiannakis et al. 2001). A ret- Malformations of the ear have a frequency of
rospective longitudinal study by cephalograms 10.5% and consist of defects in the auditory
and lateral photographs of American patients capacity and anomalies of the shape of the ear.
with Pierre Robin sequence and cleft of the soft One main concern is the frequently recurring
palate showed that the mandible achieved only infections of the middle ear, which also occur in
partial catch-up growth, and, in adults, a smaller patients with a cleft palate and are based on dis-
maxilla, mandible, and a narrow respiratory air- turbed function of the Eustachian tube. Therefore,
way space persisted (Figueroa et al. 1991). Stud- a hearing screening has to be performed at birth.
ies in the Finnish population showed the same At a later date, control of the middle ear tube
result (Laitinen et al. 1997). An increased man- function has to be achieved and grommets placed,
dibular growth was seen during the first 2 years if necessary (Handžić et al. 1996).
of life, but normal craniofacial dimensions were
never achieved. At the young adult stage, even if
the patient’s profile appeared less retrognathic Cardiovascular Anomalies
due to masking by the overlying soft tissues or
the patient’s teeth showed neutral occlusion, Intrinsic cardiac defects are found in up to 20%
cephalograms revealed retrognathia and caudal- of infants with Pierre Robin sequence (Pearl
dorsal rotation of the mandible. Thus, it seems 1982). Septal defects are common, but more
in accordance with today’s knowledge that the complex lesions can also occur. A thorough car-
microgenia in Pierre Robin sequence can be diovascular examination should be performed in
balanced only partially by growth processes. PRS babies, particularly since airway difficulties
Frequently, orthodontic therapy is necessary in may aggravate the cardiac status (Dykes et al.
childhood. In severe cases, surgical advancement 1985).
of the mandible combined with a genioplasty can
be beneficial as well.
Ocular Anomalies
Skeletal Anomalies Retinal detachment and micrognathia occur as

part of Stickler syndrome (Opitz et al. 1972), but
Around 11–21% of children with Pierre 10% of infants with non-syndromic PRS also
Robin sequence have limb defects (Williams have eye defects, such as strabismus, ptosis, and
et al. 1981). Common anomalies are talipes microphthalmia. More severe defects such as
equinovarus, syndactyly, short or absent digits, cataract and congenital glaucoma have also been
and hypoplastic long bones. Occipito-atlanto- reported, and ophthalmologic consultation is
axial instability has also been described, empha- recommended in all cases (Smith and Stowe
sizing the need for very experienced clinicians 1961).
638 U. Rolle et al.
Nasal Obstruction cardiac defects or an underlying syndrome.

These facts must be considered when counselling
Choanal atresia is a rare accompaniment of Pierre parents of affected children. With good medical
Robin sequence (Borovik and Kveton 1987), but and nursing care, the prognosis for children with
it may complicate the respiratory difficulties in isolated Pierre Robin sequence should be excel-
small infants who do not mouth breathe. It is lent (Bull et al. 1990).
important to ensure nasal patency, especially if
one nostril is to be utilized for a nasogastric feed-
ing tube. Choanal obstruction by itself can lead to Cross-References
glossoptosis, with consequences identical to those
of Pierre Robin sequence (Cozzi and Pierro 1985). ▶ Access for Enteral Nutrition
▶ Choanal Atresia
Conclusion and Future Directions ▶ Congenital Airway Malformations
In isolated Pierre Robin sequence, the long-term ▶ Pediatric Respiratory Physiology
outcome is directly related to the quality of man- ▶ Stridor in the Newborn
agement at the onset of symptoms. With adequate ▶ Tracheostomy in Infants
nutrition, mandibular growth will achieve normal
or near-normal proportions and the glossoptosis Acknowledgments This chapter has been adapted from a
will resolve. chapter in the following publication: Copyright © 2017
The previously documented high incidence of From Newborn Surgery by Prem Puri. Reproduced by
permission of Taylor and Francis Group, LLC, a division
mental retardation in PRS patients was almost of Informa plc.
certainly due to unrecognized episodes of hyp-
oxia, and with good airway management, this
complication is uncommon. References
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positive airway pressure for upper airway obstruction
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Lymphatic Malformations in Children
42
James Wall, Karl Sylvester, and Craig Albanese
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 642
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Prenatal Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Postnatal Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643
Operative Approach to Classic Neck Lymphatic Malformation . . . . . . . . . . . . . . . . . . . . . . . 645
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
Abstract remove certain lesion in their entirety. Sclero-

Lymphatic malformations present as a wide therapy has been successful in the reduction of
spectrum of lesions of the lymphatic system. size and symptoms of macrocystic lesions,
Despite their benign nature, they can cause while medical therapy has limited success in
significant morbidity due to growth in and management of diffuse lesions. Morbidity of
around critical structures. Only complete sur- all interventions remains high and must always
gical resection has proven curative to date, but be weighed against goals of treatment. Surgical
the morbidity of resection limits the ability to management of the classic posterior neck tri-
angle cystic lymphatic malformation is
detailed.
J. Wall (*)
Pediatric General Surgery, Stanford University, Stanford, Keywords
CA, USA Lymphatic malformations · Cystic hygroma ·
e-mail: jkwall@stanford.edu Macrocystic · Microcystic · Sclerotherapy
K. Sylvester
Lucile Packard Children’s Hospital at Stanford University,
Stanford, CA, USA
e-mail: sylvester@stanford.edu
C. Albanese
New York Presbyterian Hospital, New York, NY, USA
e-mail: albanese@nyp.org; calbanese@lpch.org

https://doi.org/10.1007/978-3-662-43588-5_45
642 J. Wall et al.
Introduction of these anomalies and their wide-ranging mani-

festations, the preferred all-encompassing term is
Lymphatic malformations are a broad range of lymphatic malformations. Fetal cystic hygroma is
lymphatic lesions, including the most common used in the perinatology literature to describe the
cystic lymphatic lesions, lymphangiomatoses, specific lymphatic malformation of an enlarged
lymphangiectasias, and lymphedema (Elluru septated nuchal translucency found on prenatal
et al. 2014). Cystic lymphatic malformations are ultrasound, which is associated with Down syn-
congenital lesions characterized by a complex of drome, Turner syndrome, and Noonan syndrome
multiple cysts lined with lymphatic vascular (Malone et al. 2005). Fetal cystic hygromas are
endothelium. The incidence is estimated at 1 in found in the posterior midline and should not be
5,000 live births. Lymphatic malformations have confused with lymphatic malformations found
been reported in almost every type of tissue in the throughout the fetus later in gestation. Unlike
body with the notable exception of the central non-nuchal lymphatic malformations, fetal cystic
nervous system. Most are found in areas rich in hygromas are associated with chromosomal
lymphatic channels including the head, neck, and anomalies.
axillary regions. Lymphatic malformations are Of all lymphatic malformation, cystic lym-
pathologically characterized as vascular lesions phatic malformations are the most common.
lined with lymphatic endothelium that are They are benign and tend to enlarge slowly over
immunopositive for podoplanin and LYVE-1 time. They typically present as a soft, spongy,
(Florez-Vargas et al. 2008). non-tender mass noticeable in infancy. Cutaneous
manifestations can include peau d’orange, skin
weeping, small blue-discolored blebs, as well as
Classification evidence of subcutaneous vein engagement,
effacement, and stasis. Rapid enlargement is asso-
Traditionally, vascular malformations involving ciated with infection, hemorrhage, or trauma.
the lymphatic vessels were called by a variety of Modern classification is focused on characterizing
terms including cystic hygroma, lymphangioma, the cystic component as macrocystic, microcystic,
or hemolymphangioma. Given the benign nature or mixed (Fig. 1) and the extent as superficial
Fig. 1 Left – cervical lymphatic malformation with predominantly macrocystic components. Right – cervical lymphatic
malformation with predominantly microcystic components
42 Lymphatic Malformations in Children 643
versus deep and localized versus diffuse. Both potential to create airway obstruction upon deliv-
characteristics are clinically useful in determining ery. The ex utero intrapartum treatment (EXIT)
management. Two additional entities of lymph- procedure has been used in select cases in order to
edema and lymphangiectasia are in the spectrum enable the establishment of a definitive airway or
of lymphatic malformations but are considered a resection of the compressive mass (Lazar et al.
distinct clinical entities. 2011). For the fetus whose airway may be in
The genetic basis of lymphatic malformations jeopardy, it is important to try to differentiate, by
remains elusive (Boon et al. 2011) and most prenatal MRI, between the soft and usually
cases seem to be sporadic. The consistent asso- non-compressive lymphatic malformation from
ciation of cystic hygroma with genetic syn- the firm and often airway compressing teratoma
dromes suggests an underlying genetic cause. (Steigman et al. 2009). The prenatal tracheoe-
In addition, lymphedema syndromes have been sophageal displacement index may be useful in
associated with mutations in vascular endothelial predicting the need for surgical airway manage-
growth factor receptor 3 (VEGFR3) as well as ment at birth (Lazar et al. 2012).
other specific gene mutations (Ghalamkarpour
et al. 2009a, b; Irrthum et al. 2000, 2003; Connell
et al. 2010). Postnatal Management
In cases where there is no airway compression

Diagnosis prenatally, the morbidity of lymphatic
malformations after delivery is related to their
The diagnosis is made based on a combination of extent and effect on surrounding anatomic struc-
history, physical examination, and diagnostic tures. For example, macroglossia is seen with floor
imaging. The best imaging modalities for lym- of the mouth lesions/encroachment and can have
phatic malformations are ultrasonography, MRI, profound effects on ventilation and feeding
and contrast lymphography. Ultrasound is valu- (Fig. 2). Proptosis can result in permanent vision
able in differentiating lymphatic malformations loss in up to 40% of cases (Greene et al. 2005).
from other vascular malformations that contain Over time cystic lymphatic lesions can develop
blood flow (e.g., hemangioma). Ultrasound is fur- bleeding, infection, and cutaneous vesicles. Recur-
ther able to characterizing the size and extent of rent infections and chronic wounds are common
superficial localized lesions. MRI offers an addi- with superficial lesions. Secondary bony over-
tional advantage of axial imaging that can further growth can cause craniofacial disfigurement.
identify the extent of large diffuse lesions and Goals of treatment for lymphatic mal-
highlight the precise relationship between formations in childhood are to minimize symp-
malformations and adjacent anatomical struc- toms and accomplish realistic cosmetic goals.
tures. Lymphography with both conventional con- These benefits must be weighed against the risks
trast and specialized MRI sequences has been of disfigurement and disability.
described (Notohamiprodjo et al. 2012; Laor Lymphatic malformations are amenable to
et al. 1998). Lymphography is most helpful in multiple therapeutic modalities including sclero-
looking for a source of lymphatic leak in cases therapy, surgery, and medical therapy. Symptoms,
of ongoing chylous output from cysts or a variety location, extent, and characteristics of the lesion
of body cavities (e.g., pleura, peritoneum). determine the best individual or combination of
therapies. Sclerotherapy is ideally suited for
superficial macrocystic lesions (Fig. 3). However,
Prenatal Management deeper macrocystic lesions in the chest and abdo-
men have also been treated successfully with
Large lymphatic malformations involving the sclerotherapy (Russell et al. 2014; Chaudry et al.
head and neck identified in utero have the 2011). The preferred approach to sclerotherapy
644 J. Wall et al.
Fig. 2 Cervical lymphatic malformation with airway (c) Coronal MRI demonstrating complex cystic lesion (d)
compromise and macroglossia. (a) Sagittal MRI Cutaneous and soft tissue manifestation of cervical lym-
highlighting narrowing of the trachea (b) Macroglossia phatic malformation
Fig. 3 Large cervical lymphatic malformation with significant macrocystic component. (a) Pre-intervention (b) Imme-
diately post-sclerotherapy (c) 3 months post-sclerotherapy
utilizes ultrasound guidance with cyst aspiration (Mathur et al. 2005), OK-432 (Gilony et al.
followed by injection of a sclerosing agent. Mul- 2012), and sodium tetradecyl sulfate. There is no
tiple agents have been reported including ethanol, level I or II evidence to guide specific agent(s),
doxycycline (Nehra et al. 2008), bleomycin dwell times, or size criteria for sclerotherapy.
Complications associated with sclerotherapy Preoperative planning will usually demon-

include nerve damage, systemic toxicity, and strate a safe plane of attack and may set expecta-
skin necrosis. tions with regard to a complete excision or a
Surgical resection is typically required for the debulking operation. Loupe magnification is
treatment of microcystic lesions. These lesions often helpful, as is a bipolar cautery when work-
can encase major structures and great care must ing close to nerves. Microvascular lesions tend to
be taken to avoid significant vascular and nerve infiltrate tissue planes, are more likely to bleed,
damage. It is often stated that large microcystic and have a high rate of recurrence. Macrocystic
lesions in the neck can be the most challenging lesions tend to spread along fascial planes and
benign lesions to safely resect for pediatric sur- around neurovascular structures. Intraoperative
geons. Some lesions can be well vascularized and rupture decreases the likelihood of complete
transfusion may be required. Staged resections for resection. Any residual cystic tissue will increase
large tumors have been advocated but bring addi- the likelihood of recurrence. Because this is not a
tional risks associated with a scarred resection bed malignant lesion, it is seldom necessary to sacri-
(e.g., adjacent nerve damage). Recurrence is fice essential local structures. It is commonly nec-
reported from 15 to 50% after surgical resection. essary to place a closed suction drain, particularly
Recurrence is associated with incomplete resec- when the lesion is incompletely excised. We will
tion, which is often due to the need to preserve now detail the operative approach to the most
critical structures that the cyst is adherent to, such common lesion, a cervical lymphatic malforma-
as nerve tissue. Resection and particularly recur- tion. A first-generation cephalosporin is adminis-
rences are associated with fat hypertrophy possi- tered perioperatively prior to using a transverse
bly due to the excess lymph fluid and leak that skin crease incision that extends the length of the
exits post resection. mass (Fig. 4).
There are multiple novel medical therapeutics
reported and under investigation for the treatment
of lymphatic malformations. Sildenafil was
reported to produce subjective decrease in large
inoperable lesions, but the effect was lost once the
drug was stopped (Swetman et al. 2012).
Sirolimus has been reported as both a primary
treatment and adjunct to surgery for lymphatic
malformations (Hammill et al. 2011; Azizkhan
2013; Yesil et al. 2016; Triana et al. 2016). At
best, the level of evidence for novel therapeutics is
based on case reports and small series. However,
certain lesions are so diffuse or anatomically unfa-
vorable for resection that trails of medical therapy
is warranted.
Operative Approach to Classic Neck

Lymphatic Malformation
General anesthesia is required for resection of large

lymphatic malformations. Consideration should be
given to withholding the use of neuromuscular
blockade if there is any anticipated motor nerve
involvement. Intraoperative nerve monitoring can Fig. 4 Incision for resection of cervical lymphatic
be utilized for identification of nerves. malformation
646 J. Wall et al.
Fig. 7 Exposure of the carotid sheath laterally

Fig. 5 Subplatysmal skin flaps
If the lymphangioma demonstrates dermal infil-

tration, an ellipse of skin is removed. Otherwise,
generous subplatysmal skin flaps are raised (Fig. 5).
The external jugular vein and ansa cervicalis are not
considered essential and may be sacrificed.
Dissection of cervical lesions begins at the
superior margin of the mass, near the ramus of
the mandible. Upward reflection of the facial
artery and vein allows the precise visualization
necessary to preserve the marginal branch of the
facial nerve (Fig. 6). Bipolar cautery may be used
and optical magnification is often helpful.
The dissection proceeds medially, lifting the cyst
from the surrounding alveolar tissue. It may be
necessary to divide the middle thyroid vein and
artery as the carotid sheath is approached (Fig. 7).
Deep dissection frequently involves the contents of
the carotid sheath and sometimes the following
nerves: the vagus, spinal accessory, hypoglossal,
sympathetic trunk, phrenic, and the brachial plexus.
Care is taken to preserve the hypoglossal nerve
Fig. 6 Location of the facial nerve and vessels as it passes through the bifurcation of the carotid
Fig. 8 Location of the hypoglossal nerve

Fig. 9 Closure of the platysma
artery (Fig. 8). The mass must then be freed from has proven curative to date. Sclerotherapy has
the hyoid bone and submandibular gland. It is been successful in the reduction of size and
rarely necessary to remove the submandibular symptoms of macrocystic lesions, while medical
gland en bloc with the mass, sacrificing the facial therapy has limited success in management of
artery. The mass may be adherent to the brachial diffuse lesions. No therapy has reached an
plexus in the floor of the anterior triangle or the acceptable level of efficacy for all lymphatic
spinal accessory nerve as it courses through the malformations, and diffuse microcystic lesions
posterior triangle. Extension of the mass under the remain very difficult to treat. Ongoing research
clavicle may lead to axillary or mediastinal into the fundamental mechanisms of vascular
involvement (requiring sternotomy if the lesion malformations is needed to drive more effective
proceeds deeply). These combined masses may therapy.
be delivered either above or below the clavicle.
The platysma is reapproximated with fine
absorbable sutures and the skin closed with sub- Cross-References
cuticular sutures of similar material (Fig. 9).
Closed suction drainage is used for most lesions. ▶ Chylothorax and Other Pleural Effusions in
Neonates
Conclusions and Future Directions

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Stridor in the Newborn
43
Sam J. Daniel
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Laryngeal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Laryngomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 650
Vocal Cord Paralysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 652
Subglottic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
Subglottic Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Other Laryngeal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Laryngeal Clefts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 654
Laryngeal Web . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Congenital Laryngeal Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Laryngeal Lymphangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Tracheomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Other Airway Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 656
Abstract The vast majority of stridor in newborns is

Stridor is an abnormal sound caused by turbu- caused by laryngomalacia, which is also the
lent airflow through a partially obstructed air- most common congenital laryngeal anomaly.
way. It can be inspiratory, expiratory, or biphasic In laryngomalacia, the inspiratory stridor often
depending on the location of the obstruction. does not present until 2 weeks after birth and
resolves by 18–24 months of age. While most
cases are managed with watchful waiting,
severe cases require surgery. Vocal cord paral-
S. J. Daniel (*)
ysis is the second most common cause of neo-
Department of Pediatric Surgery, Montreal Children’s natal stridor. Bilateral vocal cord paralysis is
Hospital, McGill University, Montreal, QC, Canada usually idiopathic. In certain cases, paralysis
e-mail: sam.daniel@mcgill.ca

https://doi.org/10.1007/978-3-662-43588-5_47
650 S. J. Daniel
may occur secondary to central nervous system obstruction at the supraglottic or glottic level.
abnormalities that include Arnold-Chiari mal- Biphasic stridor suggests a narrowing between
formation, cerebral palsy, hydrocephalus, the glottis and the extrathoracic trachea, while
myelomeningocele, spina bifida, or hypoxia. expiratory stridor is generally secondary to turbu-
Severe cases may necessitate endotracheal lent airflow in the intrathoracic trachea or main
intubation and/or tracheostomy. Congenital bronchi.
subglottic stenosis is defined as a diameter of The newborn has a much narrower airway
less than 4 mm of the cricoid area in a full-term compared to the child or adult. The average diam-
infant and less than 3 mm in a premature infant. eter of the subglottis is around 4.0 mm. Several
This condition is the third most frequent laryn- types of congenital malformations leading to ana-
geal anomaly and the most common laryngeal tomical and/or functional airway obstruction are
anomaly requiring a tracheotomy in newborns. associated with stridor. The most prevalent
Laryngotracheoplasty with cartilage grafting, pathologies are highlighted below.
or stenotic segment resection, and anastomosis
may be required to repair the airway. Other rare
etiologies of neonatal stridor include subglottic Laryngeal Anomalies
hemangiomas; laryngeal webs, clefts, and
cysts; and tracheomalacia. Laryngomalacia
The clinical history is of paramount impor-
tance in orienting the surgeon to the appropriate Laryngomalacia is the commonest cause of neo-
pathology. Flexible fiber-optic endoscopy natal stridor, and the most frequent congenital
performed on the patient, while awake, often laryngeal anomaly, accounting for over 60% of
confirms the diagnosis. Management is tailored all cases (Daniel 2006; Reinhard 2014; Cheng and
to each condition and its degree of severity. Smith 2015). It usually presents with inspiratory
stridor which typically worsens in the supine posi-
Keywords tion as well as with feeding, agitation, excitement,
Upper airway · Newborn · Stridor · Congenital crying, and during the course of an upper respira-
malformations · Laryngomalacia · Vocal cord tory tract infection (Thompson 2010).
paralysis · Subglottic stenosis · Laryngeal Laryngomalacia is twice more common in males
cleft · Laryngeal cyst · Tracheomalacia than in females. Symptoms often present within
the first 2 weeks after birth, worsen at 4–8 months,
improve between 8 and 12 months, and usually
Introduction resolve by 18–24 months of age. Laryngomalacia
is thought to be the result of neuromuscular alter-
Stridor can be defined as a harsh sound caused by ation in laryngeal tone with resultant prolapse of
turbulent airflow through a partially obstructed supra-arytenoid tissue and supraglottic collapse
laryngotracheal airway. Stridor is only a sign; it causing airway obstruction (Thompson 2007).
is neither a diagnosis nor a disease, and its loud- Most children experience laryngopharyngeal
ness is not necessarily an indicator of the severity reflux with a quoted incidence of 65–100%
of the underlying condition. Stridor has to be (Olney et al. 1999; Giannoni et al. 1998; Mat-
considered with the rest of the history and physi- thews et al. 1999). While this may be the result
cal examination. It is usually the severity of of very negative intrathoracic pressure, reflux
accompanying respiratory distress and/or feeding itself can contribute to the airway compromise
issues that determine the urgency with which by causing edema. Also some patients may have
investigations and interventions are required. a secondary airway lesion such as tracheomalacia
The anatomical location of the obstruction can or subglottic stenosis. Even though bronchoscopy
be suspected based on the character of the stridor. should not be routinely performed in all
Inspiratory stridor generally points to an laryngomalacia patients, it is warranted in patients
43 Stridor in the Newborn 651
necessitating surgical treatment in order to diag- redundant arytenoid mucosa over the laryngeal
nose synchronous airway lesions that require fur- inlet during inspiration; an omega-shaped epiglot-
ther intervention (Olney et al. 1999; Schroeder tis; and a retroflexed epiglottis sitting on the laryn-
et al. 2009). geal inlet. In severe cases the vocal cords cannot
The diagnosis is best confirmed by performing be visualized. Of note, an omega-shaped epiglot-
a flexible fiber-optic laryngoscopy in the patient tis can also be present in up to 50% of normal
while awake. The infant is seated in the lap of the infants (Richter and Thompson 2008).
parent, and the endoscope is passed through the Most cases of laryngomalacia are managed
nostril, allowing simultaneous assessment of the with watchful waiting (Daniel 2006). In cases
nasal passage, nasopharynx, oropharynx, and lar- where laryngopharyngeal reflux is noted on
ynx. A number of laryngeal anomalies could be endoscopy, anti-reflux treatment is started. Sur-
noted in various combinations (Video 1). These gery is reserved for very severe cases with asso-
include shortened aryepiglottic folds; prolapse of ciated failure to thrive, apnea, hypoxia, recurrent
the cuneiform and corniculate cartilages and cyanosis, pulmonary hypertension, or cor
pulmonale (Thompson 2010). Blood gas analysis
can be useful for the detection of impending respi-
ratory failure, requiring rapid intervention
(Panduranga Kamath et al. 2010). The surgical
correction of laryngomalacia has evolved over
the past century from open tracheostomy to endo-
scopic modalities. A surgical treatment algorithm
is shown in Fig. 1. Depending on the etiology of
the obstruction, the current endolaryngeal
approach consists of a single or more commonly
a combination of any of the following four pro-
cedures: (1) cutting or removing a wedge of the
aryepiglottic folds unilaterally or bilaterally,
(2) trimming the epiglottis, (3) removing the
corniculate and/or cuneiform cartilages, and
(4) removing the redundant arytenoid mucosa.
The procedure can be performed using laser,
Video 1 Flexible nasolaryngoscopy of a patient with sharp microsurgical instruments, or powered
moderate laryngomalacia. Notice the short aryepiglottic
blade instruments (microdebrider) (Richter and
folds and the omega-shaped epiglottis
Thompson 2008; Groblewski et al. 2009).
Fig. 1 Surgical treatment

Shortened
algorithm for Release Inspiratory collapse of
Aryepiglottic folds
laryngomalacia supraglottic mucosa
Supraglottoplasty
LARYNGOMALACIA
Posterior displacement of epiglottis
Epiglottopexy
652 S. J. Daniel
It has been shown that 69–94% of infants can occur secondary to traumatic intubation, post
undergoing supraglottoplasty have resolution of cardiac surgery particularly post aortic arch sur-
their symptoms (Richter and Thompson 2008; gery (Dewan et al. 2012), and post tracheoe-
Cheng and Smith 2015). Stridor seems to improve sophageal fistula repair. Recent series have
sooner than dysphagia, and infants with medical reported symptomatic vocal cord paralysis in
comorbidities and neuromuscular disorders are at less than 5% of infants operated for esophageal
a higher risk of feeding difficulty than otherwise atresia and/or tracheoesophageal fistula (Morini
healthy infants (Richter and Thompson 2008; et al. 2011; Mortellaro et al. 2011). In certain
Eustaquio et al. 2011). Postoperative complica- cases, paralysis may be secondary to a central
tions are rare. These include persistent disease, nervous system abnormality including Arnold-
increased risk of aspiration, lower respiratory Chiari malformation, posterior fossa tumor, cere-
tract infections, and rarely supraglottic stenosis. bral palsy, hydrocephalus, myelomeningocele,
Another cause of supraglottic obstruction in spina bifida, or hypoxia. Arnold-Chiari (also
newborns is caused by a mucus retention cyst in known as Chiari II) malformation is the most
the vallecula (Hsieh et al. 2000). This cyst could common congenital central nervous system
displace the epiglottis posteriorly causing stridor abnormality resulting in vocal cord paralysis
and apparent life-threatening episodes. In fact, (Ada et al. 2010). It is characterized by downward
when a retroflexed epiglottis is seen, even in the displacement of inferior cerebellar vermis and
context of laryngomalacia, a coexisting vallecular cerebellar tonsils and medulla through the fora-
cyst should be excluded (Ku 2000). men magnum into the upper cervical canal, often
This condition is readily corrected with a associated with a myelomeningocele and hydro-
marsupialization procedure of the cystic lesion cephalus. Sleep apnea is highly prevalent in
which can be performed endoscopically with Chiari malformation, and polysomnography
microscissors or laser. should also be considered in patients to determine
whether the sleep apnea is central or peripheral
(Dauvilliers et al. 2007). Early decompression is
Vocal Cord Paralysis recommended to improve the outcome (Choi et al.
1999). Finally, rare cases of familial congenital
Vocal cord paralysis (VCP) is the second most bilateral abductor vocal fold paralysis have also
common congenital laryngeal anomaly. It can be been reported (Raza et al. 2002).
either congenital or acquired and either unilateral Unilateral paralysis is generally well toler-
or bilateral. VCP results from dysfunction of the ated and often unnoticed presenting with dys-
nerve supply to the laryngeal muscles (Chen and phonia (hoarseness), mild stridor, and
Inglis 2008). This could be easily confused with occasional aspiration. On the other hand,
vocal cord fixation which can occur secondary to patients with bilateral paralysis can present as
scarring. an airway emergency with respiratory distress
Many cases of VCP are idiopathic. Important and a high-pitched inspiratory stridor. Paradox-
causes to rule out include compression or injury of ically, these patients often have a normal voice,
the recurrent laryngeal nerve. This may occur because their vocal cords usually are in a para-
during breach or vertex delivery because of median position due to the abductor paralysis
stretching of the neck, or secondary to neck com- (Chen and Inglis 2008). In severe cases, obstruc-
pression by a looped umbilical cord or the use of tion may require immediate airway manage-
forceps. Fortunately, over 70% of unilateral vocal ment. Aspiration is common with bilateral
cord paralysis secondary to a difficult delivery vocal cord paralysis, often resulting in recurrent
have been shown to recover spontaneously pulmonary infections.
(de Gaudemar et al. 1996). Other causes of com- On examination, the child with bilateral VCP
pression include intrathoracic pathology such as may or may not be in significant respiratory dis-
mediastinal lesions or tumors. Iatrogenic injuries tress. Awake flexible laryngoscopy establishes the
diagnosis by demonstrating the vocal cord paral- intubation followed by tracheostomy in severe
ysis. In certain cases, particularly after prolonged cases. In recent series, less tracheostomies are
intubation, bilateral vocal fold fixation secondary being performed with only approximately 50%
to scarring may mimic vocal cord paralysis. of children with bilateral VCP as compared to
The work-up of patients with VCP includes a higher percentages in older series (Chen and
magnetic resonance imaging of the brain to rule Inglis 2008; Daniel 2008). The tracheostomy
out intracranial causes of brainstem compression tube is kept in place for a minimum of
such as Arnold-Chiari malformation. Chromo- 1.5–2 years while monitoring the cords for poten-
somal abnormalities should be ruled out, particu- tial spontaneous recovery. Procedures to help
larly in children with dysmorphic features. decannulate the patient in cases of non-recovery
Suspension laryngoscopy is occasionally include vocal cord lateralization procedures,
performed in the operating room with arytenoid arytenoidectomy, posterior cricoid cartilage graft
palpation in order to rule out fixation. Laryngeal augmentation, and laser cordotomy (Daniel 2006;
electromyography under light anesthesia can also Lagier et al. 2009; Ozdemir et al. 2013; Gerber
be helpful to differentiate vocal fold immobility et al. 2013; Aubry et al. 2010). A multicentric
secondary to nerve paralysis from that caused by retrospective review of operation-specific
cord fixation (Scott et al. 2008; AlQudehy et al. decannulation rate among primary procedures
2012). While the patient is under anesthesia, a for pediatric vocal cord paralysis found lateraliza-
bronchoscopy is performed to exclude synchro- tion procedures with partial arytenoidectomy to
nous airway lesions, such as subglottic stenosis have the highest success (Hartnick et al. 2003).
and tracheomalacia.
The management of unilateral cord paralysis is
usually conservative as many eventually recover Subglottic Stenosis
spontaneously, and in most cases, there is an
effective compensation by the contralateral vocal This is the third most common laryngeal anomaly
fold. Vocal fold augmentation is an effective ther- and the most common laryngeal anomaly that
apeutic option in the management of symptoms requires a tracheotomy in newborns. It is defined
related to laryngeal incompetence, as it improves as a diameter of less than 4 mm of the cricoid
the voice quality and decreases the risk of aspira- region in a full-term infant, and less than 3 mm in
tion (Patel et al. 2003). When a paralyzed vocal a premature infant. A narrowing of the subglottic
cord does not recover, a recurrent laryngeal nerve diameter of 1 mm will decrease the cross-sectional
to ansa cervicalis anastomosis can be considered area by 75% and increase airway resistance
(Smith et al. 2012). The goal of this reinnervation 16-fold (Boudewyns et al. 2010).
procedure is to restore the tone of the paralyzed Subglottic stenosis can be congenital or
vocal cord, thereby medializing it to a position acquired, and most treatment decisions are based
wherein the contralateral cord can make adequate on the severity of the stenosis. Congenital sub-
contact for suitable glottal closure (Setlur and glottic stenosis can be classified into two types,
Hartnick 2012). The effects of the reinnervation membranous or cartilaginous. The membranous
may take 3–6 months to be appreciated and are type results from submucosal hypertrophy with
maintained long term. Medialization thyroplasty excess fibrous connective tissue and is a more
is also an option in children with long-term vocal common as well as milder type. The cartilaginous
fold paralysis. In this procedure a window is made type is the result of an abnormally shaped cricoid
in the thyroid cartilage at the level of the vocal cartilage. Acquired subglottic stenosis is usually
folds; Silastic or other material is inserted through secondary to airway trauma from prolonged
the window to medialize the vocal fold. intubation.
The management of bilateral VCP is more Severe subglottic stenosis results in biphasic
difficult. The degree of airway obstruction is stridor, dyspnea, and labored breathing. Plain
often severe. Initial management is endotracheal anteroposterior radiographs can demonstrate the
654 S. J. Daniel
narrowing at the level of the subglottis. Rigid good safety profile and proven efficacy of this
bronchoscopy establishes the diagnosis. medication (Mahadevan et al. 2011; Raol et al.
Unlike acquired cases, most cases of congeni- 2011; Denoyelle and Garabedian 2010; Leaute-
tal subglottic stenosis resolve spontaneously as Labreze et al. 2008). Not all patients respond
the child grows. Severe cases may necessitate a however to propranolol, and the latter is to be
tracheostomy. Endoscopic techniques have an used with great caution in many patients with
increasing role in the management of subglottic PHACE syndrome due to the risk of an acute
stenosis (Brigger and Boseley 2012). Treatment ischemic stroke (Drolet et al. 2013).
options include balloon dilation of the stenotic
segment, laser or resection of the scar, anterior
cricoid split, laryngotracheoplasty with anterior Other Laryngeal Anomalies
and/or posterior cartilage graft augmentation, tra-
cheal resection with end-to-end reanastomosis, Laryngeal Clefts
and slide tracheoplasty.
This is a rare condition affecting approximately
one baby out of 10,000. Symptoms can include
Subglottic Hemangioma coughing with feeds, stridor, hoarseness,
increased secretions, feeding difficulty, failure to
Subglottic hemangioma is a benign congenital thrive, aspiration, respiratory distress, and recur-
vascular tumor characterized by cellular hyperpla- rent pneumonias. A high degree of clinical suspi-
sia of endothelial-like cells in the subglottic area, cion is required with rigid endoscopy under
leading to airway obstruction. The child is usually anesthesia being the standard for diagnosis.
asymptomatic at birth. Biphasic stridor usually Endoscopy should include palpation of the
develops when proliferation of the lesion interarytenoid area. Contrast studies may reveal
heightens, around 6–12 weeks of age. Symptoms laryngeal penetration and/or aspiration.
can also include barking cough, respiratory dis- Posterior laryngeal clefts may be classified
tress, hoarse cry, and feeding difficulties. according to anatomic or clinical criteria. The
Untreated, a symptomatic subglottic hemangioma most commonly used classification system is the
carries a mortality rate of almost 50% (Perkins one developed by Benjamin and Inglis (Benjamin
et al. 2009). Cutaneous hemangiomas of the and Inglis 1989). A type 1 laryngeal cleft is lim-
head and neck may be present in up to half of ited to the supraglottic interarytenoid area and
the patients. does not extend below the true vocal folds; a
Anteroposterior neck films reveal asymmetric type 2 cleft extends below the level of the true
subglottic narrowing. MRI or CT scans can dem- vocal folds to partially involve the posterior cri-
onstrate the extent of the lesion, including its coid cartilage (Fig. 2); a type 3 is a complete cleft
extension into the neck or mediastinum. of the cricoid lamina with or without extension
The diagnosis is confirmed on endoscopy, and into the cervical trachea, and a type 4 cleft
in certain cases, a bronchoscopy with a biopsy involves the posterior wall of the thoracic trachea
may be required. The management of subglottic with extension as far as the carina.
hemangiomas has evolved tremendously over the The management of type 1 and some type
past few years. Established treatment options 2 clefts involves feeding and medical therapy
include systemic steroids, endoscopic including diet texture modification and anti-reflux
intralesional steroid injection, endoscopic laser medication. When this fails, endoscopic repair is
excision, transcervical open excision, and trache- possible in type 1, type 2, and selective type
ostomy. More recently, propranolol has been 3 laryngeal clefts (Watters et al. 2012). The repair
shown to be effective in treating airway hemangi- of type 4 cleft requires an open approach.
omas, and this has become the preferred therapeu- Recently, Injection laryngoplasty, in which the
tic modality in a number of institutions due to the posterior glottic defect is filled with a synthetic
submucosal salivary ducts. When these arise from

the vallecula, they are termed vallecular cysts, and
occasionally they can be found in the subglottic
area. Saccular cysts, which represent swelling of
the laryngeal saccule filled with mucous, are
thought to arise due to atresia of the ventricular
orifice. They can either extend posteriorly and medi-
ally from the saccule between the true and false
cords causing obstruction of the laryngeal lumen
(anterior cyst) or extend laterally progressing in a
posterosuperior direction causing distension of the
false vocal cord and aryepiglottic fold. Lateral
extension through the thyrohyoid membrane may
also occur, resulting in a neck mass. Diagnosis is
established by laryngoscopy, and imaging is useful
in cases of extralaryngeal extension. Treatment by
endoscopic marsupialization is safe and successful
Fig. 2 Patient with grade 2 laryngeal cleft extending in the majority of cases without extralaryngeal
below the level of the vocal cords
extension. An external approach is required in lat-
eral cysts with extension into the neck.
injectable material, has been shown to have favor-
able outcomes in patients with type 1 laryngeal
cleft (Cohen et al. 2011). Laryngeal Lymphangioma
This is a rare congenital anomaly originating from

Laryngeal Web lymphatic vessel malformations. Patients with laryn-
geal lymphangioma may be asymptomatic or may
This is caused by the failure of recanalization of present with significant airway obstruction. Other
the larynx during embryogenesis. Depending on structures of the neck, chest, and mediastinum are
the location and size of the web, patients usually also often involved. Management options include
present with symptoms ranging from mild dys- tracheotomy, sclerosing injection therapy, laser abla-
phonia to stridor and significant airway obstruction, and microsurgery often used in combination.
tion. Patients with anterior glottic webs should be
evaluated for velocardiofacial syndrome
(Miyamoto et al. 2004). Treatment varies from Tracheomalacia
simple monitoring to endoscopic incision with
keel placement. Severe cases may require a tra- This anomaly is characterized by dynamic collapse
cheostomy or laryngeal reconstruction. of the trachea during breathing leading to airway
obstruction. Extrathoracic lesions in the cervical tra-
chea lead to collapse during inspiration, while intra-
Congenital Laryngeal Cysts thoracic, airway collapse occurs during expiration.
Tracheomalacia may be subdivided into two
These are a rare cause of neonatal airway obstruc- categories: primary tracheomalacia, which is
tion. They include in order of frequency ductal caused by an intrinsic defect in the cartilaginous
cysts, saccular cysts, and lingual thyroglossal duct portion of the trachea with the lack of sufficient
cyst (Aubin et al. 2011; Prowse and Knight 2012). rigid support resulting in airway collapse, and
Ductal cysts, which account for the majority of secondary tracheomalacia, which is caused by
cases, are thought to arise from obstruction of extrinsic tracheal compression by cardiovascular
656 S. J. Daniel
structures (most common), tumors, or other conditions, if missed, can lead to neonatal
masses. Tracheomalacia is also a frequent com- death. Most of these anomalies present with stri-
plication of surgical repair of esophageal atresia dor and can cause a variety of other symptoms
and tracheoesophageal fistula. including voice abnormality, dysphagia, aspira-
Symptoms depend on the severity of the air- tion, and failure to thrive. In the majority of
way narrowing and include a brassy cough, stri- cases, awake fiber-optic endoscopy establishes
dor, respiratory distress, and cyanosis. Chest the diagnosis. However, a thorough laryngos-
radiographs are often normal. Definitive diagnosis copy and bronchoscopy may have to be
usually is made by bronchoscopy under general performed under general anesthesia to rule out
anesthesia with the infant breathing spontane- a laryngeal cleft or other airway anomalies. Man-
ously. The symptoms of primary tracheomalacia agement is tailored to each condition and its
tend to improve as the child’s airway grows in degree of severity. Future directions in neonatal
caliber. Severe cases may require stenting. airway surgery include the use of robotic
Patients with secondary tracheomalacia may surgery for laryngeal cleft repair, fetal airway
require surgical correction to alleviate the airway surgery for specific conditions, and tracheal
compression. stem cell use.
Other Airway Pathology Cross-References
While the focus of this chapter is on congenital ▶ Embryology of Congenital Malformations

laryngeal anomalies, it is crucial for the surgeon ▶ Esophageal Atresia
not to dismiss other causes of airway obstruction. In ▶ Hydrocephalus
particular, newborns are obligate nasal breathers; ▶ Lymphatic Malformations in Children
therefore nasal obstruction can lead to airway com- ▶ Spina Bifida and Encephalocele
promise and respiratory distress. The etiologies are ▶ Tracheostomy in Infants
varied and include choanal atresia, pyriform aper-
ture stenosis, nasolacrimal duct cyst, and rarely
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Part III
Newborn Surgery: Esophagus
Esophageal Atresia
44
Michael E. Höllwarth and Holger Till
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
Incidence and Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Associated Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Prenatally . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Postnatal Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
Radiological Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Preoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Operative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Early Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
Late Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
Long-Term Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
Abstract the newborn baby. Today, survival rates are

Esophageal atresia is one of the most common around 95% and mortality is related mainly to
life-threatening congenital malformations of extreme prematurity or severe associated
malformations, predominantly cardiac anoma-
lies. Operative reconstruction of the continuity
M. E. Höllwarth (*) · H. Till
Department of Paediatric and Adolescent Surgery, Medical
University of Graz, Graz, Austria
e-mail: michael.hoellwarth@medunigraz.at;
holger.till@medunigraz.at

https://doi.org/10.1007/978-3-662-43588-5_48
662 M. E. Höllwarth and H. Till
of the esophagus or replacement by other closure of an existing fistula or esophageal

organs are surgical options. A large variety of replacement if necessary.
operative strategies have been elaborated and
proposed in the past to achieve this goal. Most
of the reports are retrospective and there is a Incidence and Etiology
definite need for multicenter prospective pro-
tocols to evaluate the methods and results. The incidence of an esophageal atresia is 2.44 in
Long-term complications are strictures of the 10,000 births (95% CI, 2.35–2.53), ranging
anastomotic region, esophageal, gastric reflux between 1.77 and 3.68 according to a recent inter-
with esophagitis, and tracheomalacia. Despite national surveillance program; among them are
these problems, the overall health-related qual- 68.6% with fistula and 25.5% without fistula
ity in adult persons is good. However, long- (Nassar et al. 2012). The mean incidence from a
term follow-up investigations into adulthood Swedish national registry between 1987 and 2007
including esophageal endoscopy are indicated. was 3.3 in 10,000 live births with little or no
significant changes over time (Oddsberg et al.
Keywords 2012). According to a French national registry,
Esophageal atresia · Associate malformations · the prevalence in 2008 and 2009 was 1.97/
Replacement · Anastomotic stricture · 10,000 live births. There is a 1.3 slightly higher
Anastomotic fistula · Recurrence · incidence in males, which is not significant (Sfeir
Dysmotility · Gastric reflux · Tracheomalcia · et al. 2013).
Follow-up Most cases occur sporadically, and therefore,
the etiology is likely to be multifactorial. A high
number of associated anomalies points to a very
Introduction early disturbance of the developing embryo caus-
ing anomalies in multiple organ systems while
The term congenital atresia of the esophagus disturbances in the later phase of the organogen-
describes a large group of variant malformations, esis may be responsible for rather isolated forms
which share a defect of the esophageal continuity of esophageal atresia. A number of environmental
with or without a fistula to the trachea or to the risk factors such as infectious diseases or terato-
bronchi. It is one of the most life-threatening gens are discussed in the literature including
anomalies in a newborn baby, and quality of sur- exposure to thalidomide, statins, alcohol,
vival depends from early diagnosis and appropri- smoking, contraceptive pills, hormones, as well
ate therapy. The first successful surgery of a as maternal diabetes or higher maternal age
12-day-old female baby was performed by (Oddsberg et al. 2010; Felix et al. 2009). Recent
Cameron Haight at the University of Michigan studies show a 4.5 times higher risk after an
in 1941. As an adult, this patient gave birth to a assisted reproductive technology (Källén et al.
newborn who suffered, just like its mother, from 2010). There is ample evidence from human and
an esophageal atresia that was successfully oper- animal studies that the anomaly can be genetically
ated at the same institution by Arnold Coran. determined. A large number of different syn-
The history of surgical therapy of babies with dromes have been reported in association with
esophageal atresia after Cameron Haight is a esophageal atresia. The Feingold syndrome is
story of success starting with survival rates caused by mutations of the MYCN gene and
around 50% but reaching today nearly 100% 30–40% of these patients have an esophageal
when associated life-threatening malformations atresia. Furthermore, gene deletions and muta-
are excluded. The mainstays of this success are tions such as the SOX2 (AEG syndrome), MID1
appropriate diagnosis, preoperative therapy, and (Opitz G syndrome), GLI3 (Pallister–Hall syn-
reconstruction of the esophageal continuity with drome), CHD7 (CHARGE association –
44 Esophageal Atresia 663
coloboma, heart disease, atresia choanae, retarded (Mc Laughlin et al. 2013). Tracheal cartilages
development, genital hypoplasia, and ear defor- and also esophageal muscle layers have been
mities with deafness), and X-linked Opitz syn- identified in the fistula wall (Mc Laughlin et al.
drome are connected to a higher incidence of 2013). The today existing major theories have
esophageal atresia (Felix et al. 2009). Chromo- been recently summarized (Merei and Hutson
somal anomalies occur in 6–10% of all cases 2002).
including Trisomy 13, 18, and 21, and the 22q11 Significant insights have been provided by the
deletion syndrome (Felix et al. 2009; Reutter and Adriamycin-induced rat/mouse model of esopha-
Ludwig 2013). Finally, the recurrence risk for a geal atresia (Mc Laughlin et al. 2013). The model
second child in parents with one affected child is produces a range of malformations similar to the
around 0.5–2.0%, and the risk for a newborn born VACTERL association thereby providing new
from an affected parent is around 3.0–4.0% (Sol- insights into the organogenesis and regulation of
omon et al. 2012). gene expression of tracheoesophageal anomalies.
The so-called VATER association was first The dorsal–ventral of the signaling molecules and
described by Quan and Smith (1973) as a non- transcription factors prior to separation of the
random coincidence of Vertebral anomalies, Anal common foregut is important for the subsequent
atresia, Esophageal atresia, Tracheo-esophageal separation. There is strong evidence of a close
fistula, and Renal malformation. The acronym relationship between an abnormal notochord and
was later expanded to VACTERL association in disturbed somatic segmentation resulting finally
order to include Cardiac anomalies and Limb dys- in vertebral anomalies, cardiac malformations,
plasia. The prevalence is about one in 40,000 and foregut anomalies such as esophageal atresia
neonates. The involvement of genetic factors in (Hajduk et al. 2012; Jacobs et al. 2012; Felix et al.
the etiology of this association is supported by an 2009). Further experiments have shown a major
increased prevalence in first-degree relatives and role of the Sonic hedgehog (Shh) signaling path-
higher incidences in monozygotic twins, as well way, and it seems to be obvious that Shh gene and
as gene mutations, mitochondrial factors (Bartels the signaling glycoprotein are involved in the
et al. 2012; Brosens et al. 2013; Siebel and Solo- normal morphogenesis of organ systems such as
mon 2013). However, since most of the esopha- notochord, vertebra, and differentiation of trachea
geal atresia cases occur sporadically there is most and esophagus (Ioannides et al. 2003, 2010;
likely a heterogeneous and multifactorial patho- Hajduk et al. 2011). Sox2 is another transcription
genesis involving different or multiple genes and factor playing an important role in the separation
signaling pathways. of the foregut. From these experiments, one must
conclude that there is either a primary gene-
related defect or any exogenous pathogenic insult
Embryology must occur already within the first 10 days of
pregnancy causing notochord dysfunction and
The normal foregut embryology is still controver- leading secondarily to the manifestation of anom-
sial. Within the fourth week of human gestation, alies such as esophageal atresia (or anorectal atre-
the separation of the esophagus and trachea takes sia, renal malformations, and others).
place by folding of the primitive foregut. The
theories include malformation of a lateral
in-growing septum dividing the foregut from the Associated Malformations
airways. Deviation of the septum in one or the
other direction results in esophageal atresia or Babies with an early-affected organogenesis and
tracheal atresia. The fistula is lined with respira- esophageal atresia suffer from a high number of
tory epithelium leading to the hypothesis that it associated malformations within a range of
arises as a posterior branch of the trachea 40–80% (Sfeir et al. 2013; Oddsberg et al. 2010;
Stoll et al. 2009; van Heurn et al. 2002). The most (coloboma, heart defect, atresia choanae, retarda-
frequent associated anomalies are musculoskele- tion, genital hypoplasia, and ear deformities), and
tal malformations (20–70%), followed by cardio- many others.
vascular (20–50%), genitourinary (15–25%),
gastrointestinal (15–25%), and chromosomal
anomalies (5–10%). The wide range of given per- Classification
centages in the literature comes from differences
in the diagnostic workup. A careful X-ray of the Classifications usually take their orientation on
whole vertebral spine, counting the ribs and ver- occurrence and type of tracheoesophageal fistula.
tebra in the different segments, will show up to The commonly used systems are those described
70% associated skeletal malformations and/or by Vogt (1929) and Gross (1953). Vogt’s
numerical variations in patients with esophageal extremely rare type 1, characterized by a more or
atresia. For a successful treatment strategy, it is less total lack of the esophagus is not included in
important to take care about a detailed diagnostic Gross’ classification. An isolated tracheoe-
workup which has a significant impact onto the sophageal fistula (H-type fistula) is classified as
outcome. The incidence of the VATER or type 4 or D, although it may belong to a different
VACTERL associations is around 20% in the spectrum because the esophagus is patent. In
esophageal atresia population, but two or more Gross’ classification, congenital esophageal ste-
anomalies occur in nearly half of the patients. nosis constitutes type E (Table 1 and Fig. 1). A
Associated cardiovascular anomalies have a complete list of all published variations of esoph-
significant impact on the overall survival of ageal atresia is summarized in the dissertation
infants with esophageal atresia, reducing the sur- work of Kluth (1976).
vival rate to 67% compared to 95% without car- Additionally to the anatomical classification,
diac anomaly (Leonard et al. 2001). The most there are risk classifications based on birth weight,
common cardiac anomaly is the ventricular septal cardiac anomalies, and/or pneumonia, which
defect (19%), which is associated with an up to allow comparing the results of different institu-
16% mortality rate. Other common anomalies tions. The best known classification is named after
include atrial septal defect (20%), tetralogy of Waterston et al. (1962). He suggested three groups
Fallot (5%), coarctation (1%), or right descending based on birth weight, moderate associated anom-
aorta (4%). It is important to realize that only a alies, and severe, mostly cardiac malformations.
few days after delivery some of these cardiac A more recent classification adapted to the pro-
defects lead to a clinically evident heart insuffi- gress in neonatal surgery and medicine based on
ciency. Therefore, all patients with esophageal the experiences with 357 cases has been published
atresia should have an early echocardiography as by Spitz et al. (1994). In this classification, only
well as ultrasound exams of the renal tract and the birth weight and cardiac anomalies are the
brain. The most common gastrointestinal-
associated anomaly is anorectal atresia (9%) Table 1 Anatomical classification
followed by duodenal atresia (5%), malrotation
Vogt- Gross- Percentage
(4%), and other intestinal atresia (1%) (Stoll types types (%)
et al. 2009; Deurloo et al. 2002). Further associ- Absent esophagus 1 – –
ated malformations may involve nearly all organ EA without fistula 2 A 8.5
systems leading to omphalocele, neural tube EA with fistula:
defects, diaphragmatic hernia, and other anoma- Proximal 3a B 1.0
lies. As mentioned above, association with at least Distal 3b C 85.0
18 different syndromes are described in up to 10% Proximal and 3c D 1.5
of patients including Holt–Oram syndrome, distal
DiGeorge syndrome, Goldenhair syndrome, H-type fistula 4 E 4.0
without atresia
Trisomy 13, 18, 21, CHARGE syndrome
Fig. 1 The most common

different forms of
esophageal atresia (From
Höllwarth ME in Puri P,
Höllwarth ME, “Pediatric
Surgery”; Springer Surgery
Atlas Series, 2006)
predicting factors for the prognosis (Table 2). is 56%, and the sensitivity of prenatal ultrasound
Thus, still today associated cardiac malformations was found to be 42% (Stringer et al. 1995). In
have a significant influence on the survival rate of cases of a large tracheoesophageal fistula, the fluid
patients. swallowed by the fetus might pass through the
trachea into the stomach, thereby preventing a
polyhydramnion. Recently, fetal magnetic reso-
Diagnosis nance imaging (MRI) has gained more attention
for prenatal diagnosis of congenital anomalies.
Prenatally
The earliest symptom of esophageal atresia is a Postnatal Symptoms

polyhydramnion in the second half of pregnancy.
Polyhydramnion is generally an unspecific mani- Postnatal presentation is characterized very soon
festation either of swallowing disorders or of dis- by the typical drooling of saliva, choking,
turbed passage of fluid through the uppermost part coughing, and cyanotic attacks. The abdomen
of the intestinal tract of the fetus. Prenatal ultra- rapidly distends due to the passage of air during
sound may further reveal forward and backward inspiration through the fistula into the stomach.
shifting of fluid in the upper pouch and an absent These symptoms are highly suggestive for esoph-
stomach bubble. The positive predictive value of ageal atresia, and therefore, any feeding trial is
an absent stomach bubble and a polyhydramnion contraindicated because it causes early aspiration
Table 2 Risk classification

Survival
Waterstone (%)
Birthweight >2,500 g A 100
otherwise healthy
Birthweight 2,000–2,500 g B 85
or higher mild pneumonia or
with moderate cardiac
anomalies
Birthweight <2,000 g or C 65
higher, severe pneumonia, or
severe associated cardiac
anomalies
Survival
Spitz (%)
Birthweight >1,500 g otherwise I 97
healthy
Birthweight <1,500 g or major II 59
cardiac anomaly
Birthweight <1,500 g, major III 22
cardiac anomaly
and pneumonia. The appropriate diagnostic step is

to pass a 12 F (firm and X-ray visible) feeding
tube into the stomach. If this is not successful, the
diagnosis of an esophageal atresia is almost cer- Fig. 2 In this case, a very small feeding tube was used to
diagnose an esophageal atresia. It resulted in a curling up in
tain. However, small tubes must be avoided the upper esophageal pouch misleading to the diagnosis of
because they may curl up in the upper pouch a normal esophagus. Therefore, a rather firm and thicker
thereby giving the illusion that they have been tube should be used for this procedure
pushed forward into the stomach (Fig. 2). Very
rarely, a small tube may pass through the trachea levels are suspicious for an additional duodenal or
and through the fistula into the stomach, thus an intestinal atresia. A gasless abdomen indicates a
esophageal atresia is erroneously excluded. If pure esophageal atresia without a lower fistula
symptoms persist, a contrast radiograph should (Fig. 3). A long distance between the segments
be performed demonstrating the atresia or even a is to be expected, but extremely rarely, a tiny or
small laryngotracheal cleft. If an esophageal atre- secondary occluded fistula may be present. The
sia is suspected, a physical examination of the translucency of the lungs provides the first infor-
entire body must be performed in order to detect mation whether aspiration occurred – either from
or exclude further associated malformations. saliva or from refluxed gastric acid through the
lower fistula – is present. Some authors inject
0.5–1.0 ml water-soluble contrast material
Radiological Diagnosis through the tube into the upper pouch under fluo-
roscopic control to detect a proximal tracheoe-
The next step is to perform a plain X-ray including sophageal fistula. Unrelated to the result, a
neck, thorax, and abdomen. The approximate preoperative tracheoscopy is always indicated to
length of the upper pouch can be estimated via identify an upper fistula. Cardiologic assessment,
the length of the X-ray visible tube in it. Air below including echocardiography, forms part of routine
the diaphragm can be seen in the presence of a preoperative workup in order to recognize associ-
lower tracheoesophageal fistula. Abdominal fluid ated congenital cardiac anomalies or the presence
Management
Preoperative Management
The babies are nursed in the ICU. Immediate

surgery is rarely required, so that all the above-
mentioned investigations can be performed step
by step. An oro- or nasoesophageal insertion of a
double-lumen Replongle tube is mandatory for
continuous or intermittent aspiration of saliva to
prevent aspiration. The baby should be positioned
upright to minimize gastroesophageal reflux
through the fistula into the trachea and lungs via
the fistula. Intubation and ventilation is only nec-
essary in cases of respiratory distress, severe
pneumonia, or severe associated malformations
demanding respiratory therapy. In these cases,
the endotracheal tube should be possibly posi-
tioned beyond a distal tracheoesophageal fistula
to avoid insufflation of gas into the stomach with
Fig. 3 Esophageal atresia without lower esophageal fis-
the risk of gastric perforation. If the latter problem
tula indicating a long distance between esophageal cannot be avoided due to a very low opening of
segments the fistula into the carina or the right main bron-
chus or due to a very large fistula, a gastrostomy
with an underwater seal may ameliorate the prob-
of a right descending aorta, which might influence lem. Gastrostomy and emergent surgical closure
the surgical approach. Brain, abdominal, and of the fistula by a thoracotomy is the best strategy
urogenital ultrasounds are performed routinely. to avoid severe respiratory distress and is also
Finally, the skeletal X-ray should be analyzed used in unstable or very premature babies. Broad
carefully whether or not structural or numerical spectrum antibiotics, intravenous fluid therapy,
anomalies exist along the vertebral column or the and vitamin K analogue are administered before
ribs. Blood samples, as well as tissue samples, surgery. If a severe pneumonia exists, surgery has
during surgery should be stored in a biobank for to be postponed until the lung recovers. In the case
genetic and chromosomal analysis even if the of severe associated malformations (e.g., dia-
external aspect of the baby is not suspicious for phragmatic hernia or cardiac malformation), it
a genetic defect. needs to be decided which surgical procedure
The history of a patient with an H-type fistula comes first or whether they are performed in one
without atresia is different: there is no passage step. Again, a preliminary closure of the fistula
problem, but leading symptoms are recurrent saves time, but the anastomosis can be postponed
coughing and cyanotic attacks during feeding if necessary.
due to aspiration through the fistula. Presenta-
tion is usually more protracted and sometimes
delayed beyond the first year of life. Diagnosis is Operative Management
made by esophagography with water soluble
contrast material that shows the spillage of Esophageal Atresia with Distal
parts of the contrast material through the fistula Tracheoesophageal Fistula (85%)
into the trachea. Tracheoscopy confirms the Surgical repair is performed under general anes-
diagnosis. thesia with endotracheal intubation. As mentioned
above, the endotracheal tube is advanced close to as good as possible. The fistula is closed near to
the tracheal bifurcation and the infant is ventilated the trachea but avoiding any narrowing of the
manually with rather low inspiratory pressure and airway. The anastomosis of the esophagus is
small tidal volumes. It is advisable to start the performed with 6/0 absorbable sutures. To facili-
procedure routinely with a tracheobronchoscopy tate the identification of the upper pouch, the
using a rigid 3.5 mm endoscope. The trachea and Replongle tube can be pushed forward by the
main bronchi are briefly inspected, and the fistula anesthetist. After incision, the upper pouch
to the esophagus is localized, which is usually mucosa often retracts and can be missed if the
5–7 mm above the carina. Exceptionally, it may surgeon does not take particular care with the
be found at the carina or even in the right main anastomosis. Once the posterior wall is sutured,
bronchus indicating a short lower segment and a 5 F feeding tube is introduced into the stomach
most likely a longer esophageal gap. The next with one end and back to the mouth with the other
step is to look for an upper fistula. The dorsal end to allow early postoperative feeding. The
membranous region of the tracheal wall is routine use of an intercostal drain (ICD) is a
inspected carefully up to the cricoid’s cartilage. matter of debate today. A recent analysis of
Small upper fistulas can be missed. To avoid this 96 consecutive patients without ICD did not
pitfall, irregularities of the dorsal tracheal wall are show any disadvantage by omitting the drain
gently probed with the tip of a 3 F ureteric catheter (Paramalingam et al. 2013). Suture closure of the
passed through the bronchoscope. If a fistula is ribs supports the development of synostosis and
present, the catheter will glide into it. possibly scoliosis but is not needed since align-
The goal of the surgical procedure is to divide ment of the ribs occurs within a few days.
the fistula, to close it on the tracheal side, and to In the majority of the cases with a distal fistula,
perform an end-to-end anastomosis between the the goal of a tension-free anastomosis can be
esophageal segments. Essential of the surgical achieved. Occasionally, the distance between a
part is a very careful and not tissue traumatizing short upper pouch and the lower esophageal seg-
procedure. The standard approach is through a ment is very long and anastomosis is only possible
right-sided laterodorsal thoracotomy via the forth by mobilization of both segments. If the tension
intercostal space. Muscle-sparing thoracotomy appears just a bit too much despite extensive
between the latissimus dorsi and the anterio mobilization of the lower esophagus and the
serratus muscle reduces postoperative muscle upper pouch, further length may be gained with
function and pain (Mortell and Azizkhan 2009). a circular myotomy (Livaditis et al. 1972; Lindahl
Some authors use a high axillary skin crease inci- 1987; Fig. 4). A serious complication that might
sion for better cosmesis (Bianchi et al. 1998). A occur is the ballooning of the mucosa and the
right-sided aortic arch is diagnosed preoperatively development of a pseudodiverdiculum (Otte
only in 20% and then a left-sided approach is et al. 1984). Another way to reduce inappropriate
recommended (Babu et al. 2000). If an
unsuspected right-descending aorta is encoun-
tered, the procedure can be continued in most
cases, establishing the anastomosis to the right
of the aortic arch; however, the incidence of anas-
tomotic fistulas seems to be higher (Babu et al.
2000). While in earlier times the procedure has
always been performed extrapleurally, recent pro-
gress in surgical techniques and suture material as
well as sophisticated perioperative management
Fig. 4 The circular myotomy according to Livaditis can
allows operating transpleurally without any dis- lengthen the upper esophageal pouch for 0.5–1.0 cm (From
advantage. The azygos vein is divided between Höllwarth ME in Puri P, Höllwarth ME, “Pediatric Sur-
ties and the fibres of the vagal nerve are preserved gery”; Springer Surgery Atlas Series, 2006)
Fig. 5 If a very large upper

esophageal pouch is
present, a flap can be
fashioned to bridge the
distance to the lower
esophagus (From Höllwarth
ME in Puri P, Höllwarth
ME, “Pediatric Surgery”;
Springer Surgery Atlas
Series, 2006)
tension to the anastomosis is to fashion a mucosa- perform an open, mostly extrapleural repair
muscular flap from a rather large upper esopha- (71%) of the atresia, despite that endoscopic sur-
geal pouch (Fig. 5). Collis gastroplasty or gical procedures are performed routinely in most
Schärli’s division of the lesser curvature are rarely of these institutions (Zani et al. 2014).
considered as useful options (Schärli 1992; Evans
1995). If there is no chance to achieve an accept- Esophageal Atresia with Proximal
able anastomosis, the strategy should be for a and Distal Tracheoesophageal Fistula
delayed anastomosis after closing the fistula and (1.5%)
performing a gastrostomy. Both segments are As mentioned above a careful endoscopic exam-
approximated by sutures as close as possible. ination of the dorsal tracheal wall using a 3 F
Some authors published successful ureteric catheter along the membrane enables the
thoracoscopic repair of the esophageal atresia, surgeon to detect an upper fistula which can be as
which is necessarily transpleural (Rothenberg high as the cricoid cartilage. The catheter can be
and Flake 2015; Rothenberg 2013; Holocomb left in the fistula to facilitate the identification
et al. 2005). Meta-analyses comparing open and when the upper pouch is separated from the tra-
endoscopic repair show similar complication rates chea. Any damage to the membranous trachea
regarding leaks and strictures but an earlier time to should be carefully avoided. The recurrent laryn-
extubation and oral feeding as well as a shorter geal nerve runs in the groove between trachea and
hospital stay after thoracoscopic approach (Yang esophagus and must be identified and protected.
et al. 2016; Borruto et al. 2012). However, the The fistula is divided flush to the trachea and
thoracoscopically performed anastomosis is cer- closed on both sides with 6/0 sutures.
tainly a very demanding procedure and needs
great experience of the endoscopic surgeon. A Esophageal Atresia with a Proximal
carefully balanced discussion comparing the Tracheoesophageal Fistula Only: A Long
thoracoscopic repair with results of more recent Gap Problem (1%)
carefully performed open surgical procedures In these cases, a long gap between the upper
concludes that the latter is still the “gold standard” pouch and the lower esophagus has to be
for most of the surgeons, while thoracoscopy may expected; therefore, a primary thoracotomy is
be appropriate for very experienced teams not indicated. The first step is to perform a
(Laberge and Blair 2013). This opinion is con- gastrostomy and to insert a radioopaque tube
firmed by a recent international survey showing into the lower esophagus. The X-ray shows either
that 90% out of 178 contributing institutions a rather short lower esophageal pouch with a long
distance between the segments or even a tiny measure the gap length, e.g., at birth or later or
anlage of esophagus which cannot be used for an at the time of surgery, without pressure or with
anastomosis. The gastrostomy is needed for feed- gentle or with strong pressure, pressure on one or
ing the baby and, depending from the choice of on both segments, including a dynamometer to
the surgeon, for the longitudinal bougienage (see estimate forces, or with gas insufflation into the
later in this chapter). stomach (Table 3; Bagolan et al. 2013, Brown and
The upper fistula can be approached and iden- Tam 1996). Thus, the terms long gap, very long
tified via a right neck incision. A 3 F catheter that gap, and ultra-long gap are used quite differently;
has been inserted during tracheoscopy allows an therefore, cases and results from different institu-
easy identification of the fistula, which is then tions cannot easily be compared. The use of a
divided and closed on both sides. The recurrent retrograde esophagoscopy of the lower segment
laryngeal nerve should be identified and pre- is useful not only to identify the length of the
served. The Replongle probe allows continuous lower pouch but also to exclude the existence of
suction from the upper pouch until the final pro- a so-called nipple-like distal esophageal remnant
cedure will be performed. (Yeh et al. 2010).
Two basic surgical strategies are available in
H-Type Fistula (4%) cases of a long gap esophageal atresia: either the
The fistula is identified by endoscopy and a 3 F preservation of the patient’s own esophagus with
ureteric catheter is passed across the fistula into delayed repair or esophageal replacement. There
the esophagus. Most H-type fistulas can be is consensus that all efforts should be directed to
approached from the right side of the neck the salvage of the child’s own esophagus because
because they are usually situated at or above the an ideal graft does not exist. Concerning the
level of the second thoracic vertebra. Palpation of preservation of the native esophagus, three strat-
the ureteric catheter facilitates the identification of egies exist: the first is to await spontaneous
the fistula. Again, the upper laryngeal nerve must growth for 2–3 months; the second is to promote
be identified and carefully preserved. elongation within 3–6 weeks by bougienage of
the lower and/or upper segment; and third is
The Long Gap Problem (8.5%) characterized by using internal or external trac-
An airless abdomen on thoracoabdominal X-ray tion forces in order to achieve an anastomosis
leads to suspicions of an esophageal atresia with- within 8–12 days. In any case, it is essential to
out a lower fistula, and a long gap can be prove that a lower esophageal segment truly
expected between the segments. The surgical exists and is significantly different from a tiny
management of this situation represents a major nub at the upper end of the stomach. In the latter
challenge which is extensively discussed in the case, elongation procedures are useless and
literature. esophageal replacement should be planned
The primary procedure consists of the place- primarily.
ment of a gastrostomy tube to allow early enteral
feeding. During this procedure, the distance 1. Delayed primary anastomosis
between the pouches can be estimated by inserting Basis of this strategy is to wait for sponta-
a radio opaque tube in the upper pouch and in the neous elongation of the esophageal segments
lower pouch via the gastrostomy. A distance of that occurs at a faster rate than overall somatic
three to four vertebral bodies on a chest film is growth due to the swallowing reflex and recur-
considered as a “long gap,” a distance of five rent reflux of the gastric content. The maximal
vertebral bodies in the newborn is about 35 mm, growth occurs within 8–12 weeks, and there-
and in the 6-month-old child 47 mm (Fig. 6a, b) fore, the ideal time for the delayed anastomosis
However, there is no consensus about the defini- was suggested at about 12 weeks. The distance
tion of a long gap in the literature, and addition- between the segments is then usually <2.0 cm
ally, there exist many technical variations to (Puri et al. 1992). A recent meta-analysis of
Fig. 6 (a) The length of five vertebral bodies in the newborn is approximately 35 mm. (b) The length of five vertebral
bodies in the 6-month-old child is approximately 47 mm
Table 3 How long is a long gap? when compared with other methods (Ein et al.
AD Santos (1983): 2.5–4.5 cm (EA with lower fistula) 1993; Paran et al. 2007).
S Hagberg (1986): >2 cm under tension = 100% 2. Delayed anastomosis and longitudinal
complications bougienage
EM Boyle Jr. (1994): >2.6 cm is long gap and Bougienage of the esophageal segments as
>3.5 cm = ultra-long gap a stimulus for growth, additionally to the
AK Brown (1996): >3 cm during surgery under normal effects of the swallowing reflex and gastric
conditions
reflux is a further option aimed to reduce the
N Myers (1997): all babies without a lower fistula
P Bagolan (2004): > 3 cm or 3 cm vertebral bodies
time till the anastomosis is possible. The
L Spitz (2009): >4 vertebral bodies under bougienage of the upper pouch has first been
tension = > 4.0 cm reported by Howard and Myers (1965). Many
CJ Hunter (2009): Any distance too wide to perform a further publications followed supporting this
primary repair technique (Mahour et al. 1974). In 1966,
Lafer and Boley reduced the waiting period to
6 weeks by bougienage of the upper and lower
451 cases reported about a 50% leak rate, sec- esophagus (Lafer and Boley 1966). Technical
ondary resection of the anastomosis due to modifications have been published by Hendren
intensive stricture was necessary in 26/121 and Hale (1976) using electromagnetic devices
(21.5%), and esophageal replacement in for the longitudinal bougienage. Recent expe-
13/92 (14%) patients (Friedmacher and Puri rience shows that daily bougienage of the
2012). The clear advantage of this strategy is upper and lower pouch for a few minutes
that it needs only one thoracotomy, but a dis- within the incubator and under light sedation
advantage of the method is the long waiting allows to achieve an overlap of the segments
time, increasing the financial load and the risk on the X-ray within 3–4 weeks until the anas-
of aspiration pneumonia. However, survival tomosis can be performed (Fig. 7). Although
rates as well as long-term results are excellent not widely accepted as a useful method, the
Fig. 7 Longitudinal
bougienage of the upper and
the upper and lower
esophageal pouch (metal
probes within plastic tubes).
A near overlapping of the
esophageal segments was
achieved within 3 weeks
experience shows that the time span till an In contrast to the internal traction method,
anastomosis is performed can be significantly an external traction technique was intro-
reduced and secondary resection are rarely duced by Foker et al. (1997). During thora-
needed. cotomy, tissue-pledgetted traction sutures
3. Forced traction methods are placed extramucosally in the upper and
Extensive tension at the anastomosis can lower segment and brought out to the skin
lead to severe leakage or even disruption of below and above the incision. Daily external
the esophageal segment. To circumvent this traction of these sutures brings the segments
problem – but still to be able to perform an together within 14 2.9 days and the anas-
anastomosis and preserving the child’s own tomosis can be performed by a second tho-
esophagus – forced traction methods have racotomy. Recently, even a thoracoscopic
been developed. Rehbein was the first to pub- elongation of the esophagus was success-
lish a method of intraesophageal forced trac- fully performed, thus avoiding the two rou-
tion by means of silver olives in each segment tine thoracotomies (van der Zee et al. 2007).
which are pulled together along a nylon thread According to Foker, the technique success-
(Rehbein 1976). A nearly identical procedure fully elongates esophageal segments which
with Teflon balls instead of silver olives was are separated even by ultra-long gaps up to
proposed by Harrison (2010). Originally the 12 cm. However, the complication rate is
thread was inserted into the esophageal seg- significant: in 28.5% of 42 patients addi-
ments by thoracotomy, later this procedure tional rethoracotomies were needed due to
was performed endoscopically (Booss et al. pulled out traction sutures, replacement of
1982). The aim of the technique was to bring traction sutures, or adhesions, and in two out
the two segments together and to create an of ten patients a secondary resection of the
autoanastomosis within 10 days. The resulting anastomosis was performed due to stenosis
stenosis needed long-term bougienage and in (Foker et al. 1997, 2009). A recent survey of
50% secondary resection. Recently, a similar 88 international surgeons showed that 39%
technique creating an autoanastomosis by are using the Foker technique, but 24% of
means of a thread was successfully applied in those were not satisfied with the results (Ron
five patients (Stringel et al. 2010). et al. 2009).
In 1994, Kimura and Soper developed a tech- that the colon has no propulsive peristalsis
nique of extrathoracic elongation of the upper and the passage of ingested food is entirely
pouch. First, a right-sided esophagostomy is by gravity. A typical complication is then an
created in patients with a long-gap atresia. This intrathoracic redundant colon with delayed
stoma is advanced subcutaneously after emptying and unpleasant stasis of ingested
2–6 months several times until the proximal food. Typical complications of the gastric
esophagus is long enough. In 12 patients, a transposition are anastomotic leaks or stric-
final anastomosis was possible after 30 months tures and ulcers, delayed gastric emptying,
(range 13–61 months); none of them needed a and occasionally dumping syndrome.
rethoracotomy or secondary replacement. In
three patients the procedure was performed To conclude in regard to the long-gap problem,
thoracoscopically (Tamburri et al. 2009). Expe- many different strategies and techniques have
riences of combining the Foker technique with been reported, but so far no consensus has been
Kimura’s method resulted, however, in a high achieved which method is to be preferred. There is
complication rate (Sroka et al. 2013). definite lack of prospective studies between cen-
4. Esophageal replacement ters, which should be based on the same categori-
It is generally accepted that the preserva- zation of cases and the use of a comparable
tion of the child’s own esophagus is the pre- technique measuring the distance between the
ferred method. With the development of esophageal segments.
sophisticated techniques, the need to replace
the esophagus is becoming rare. However,
there are patients in whom substitution of the
Complications
esophagus is required either because the dis-
tance between the segments is too long or the
Today, a newborn with esophageal atresia is
primary procedure failed. For esophageal
diagnosed in most centers shortly after birth by
replacement there are five options: reverse or
the probe test thereby preventing an early
isoperistaltic gastric tube, colon interposition,
pneumonia and aspiration after milk feeding.
jejunal interposition, and gastric pull-up.
Additionally, surgical techniques have been
Today is no agreement on a single organ or a
refined, and the quality of the suture material is
single route. While gastric tubes or free and significantly better than in the past. Finally, the
pediculed or free transplanted jejunal tubes
progress in pre- and postoperative care as well as
are used in some centers only, more accepted
excellent anesthesia techniques, intraoperative
techniques are colon interposition and gastric survey, and postoperative pain control contribute
transposition (Spitz and Coran 2012). A
largely to excellent outcome rates in the
detailed overview of the different replacement
Waterston A and B groups. Long-term survival
techniques has been published by rates are around 95%, and mortality is related
Loukogeorgakis and Pierro (2013). A recent
to extreme prematurity and to major associated
meta-analysis including 470 patients showed
cardiac malformations.
that the colon interposition has been used in However, there are a large number of early and
73%, gastric pull-up in 26%, and jejunal inter-
late complications which need special care and
position in 6% (Gallo et al. 2012). According
attention.
to this analysis, the colon interposition and the
gastric pull-up are comparable in regard to
postoperative mortality (4 and 9%), anasto-
motic complications (16 and 18%), anasto- Early Complications
motic leaks (17 and 31%), and graft loss
(4 and 5%), respectively. A disadvantage of The incidence of early complications has been
the colon interposition comes from the fact reduced significantly in the last few decades. Not
surprisingly, they occur significantly more often filling up the fistula either with synthetic tissue
in babies with perioperative problems and in long- adhesives or fibrinogen. Since the adhesives eas-
gap cases with increased tension at the anastomo- ily glide into the esophagus due to the shortness of
sis (Castilloux et al. 2010; Mortell and Azizkhan the fistula, additional destruction of the epithelial
2009; Friedmacher and Puri 2012). They include layer either with diathermia or laser, mechanical
minor anastomotic leaks which occur in 6–28% in abrasion or sclerosants, and subsequent use of
long gap cases. An esophagogram with water tissue glue is advised (Lal and Oldham 2013).
soluble contrast material may show a tiny fistula An anastomotic stricture is a common finding.
from the anastomosis indicating the anastomotic The typical caliber difference of the esophageal
leak. If the patient’s condition is stable, oral feed- segments shows in the esophagogram often a mild
ing is possible because spontaneous closure of the narrowing at the anastomosis. This finding is dif-
fistula can be expected. The early sign of larger ferent from a true stenosis, and in most cases, oral
fistulas is the excretion of saliva through the tho- feeding is tolerated without symptoms. Real stric-
racic drain. In these cases, oral feeding is post- ture development might be a consequence of too
poned until the radiological control shows the many anastomotic sutures or anastomosis under
closure of the fistula. Most of them will heal tension, both impairing the local circulation or an
spontaneously. Major leaks (3–5% up to 25% in anastomotic leak. Recurrent exposure to acidic
long gap cases) with subtotal anastomotic insuffi- reflux aggravates the stricture development
ciency create a life-threatening problem. Very (Parolini et al. 2013). A true cicatriceal stenosis
early reoperation might be helpful, but excluding (30 up to 57% after a long gap) does not improve
the esophagus by esophagostomy and a spontaneously and causes earlier or later a signif-
gastrostomy can be lifesaving. icant feeding problem. Minimal stenosis can be
An early but fortunately rare complication treated successfully with one to three careful dila-
(5–10%) is the recurrence of the tracheoe- tations – to avoid esophageal rupture. In the first
sophageal fistula (Bruch et al. 2010; Kovesi and line, balloon dilatations as well as proton pump
Rubin 2004). It follows usually a significant anas- inhibitor therapy are needed. In refractory cases,
tomotic leak and/or juxtaposition of the esopha- intralesional steroid injections or local application
geal and tracheal suture line, respectively. In of Mitomycin additionally to the dilatations may
larger fistulas, air bubbles are coming out of the be helpful. Recently, covered esophageal stents
drain. On the thoracic X-ray, a pneumothorax and are used but proper location, tolerance by the
a more or less extensive shadow can be recog- patient, and possible migration of the stent are
nized. Small fistulas are often diagnosed later typical problems (Lévesque et al. 2013).
when symptoms of coughing, chocking, and aspi-
ration occur during feeding. A spontaneous clo-
sure cannot be expected. Early open surgical Late Complications
closure of the fistula is not easy due to the local
inflammatory process and a reduced tissue quality. The most common late complication in nearly half
Additionally, either a large pleural flap from the of all patients with esophageal atresia is gastro-
mediastinum or a vascularized pericardial flap esophageal reflux that may lead to chronic esoph-
should be interposed between the trachea and the agitis and Barrett esophagus (Schneider et al.
esophagus. Addition of fibrogen glue may also be 2013, 2016; Tovar and Fragoso 2013). Severe
helpful. Nevertheless, the surgical procedure is reflux may cause feeding problems, vomiting,
associated with a significant morbidity and failure reduced weight gain or dystrophy, and/or due to
rate (Lal and Oldham 2013). Thus, tracheoscopic night time aspiration recurrent respiratory tract
strategies closing the fistula from the internal site infections. The causes of reflux are multifactorial
have gained popularity. They are successful in and include developmental neuronal dysfunction
small fistulas, but several endoscopic sessions in the lower esophagus, effects of the surgical
are often necessary. The strategies consist of mobilization of the lower pouch, and the vagal
Fig. 8 Typical manometric result in a child after esophageal atresia repair: normal propulsive peristalsis in the upper
esophagus but only weak and simultaneous contractions in the lower esophagus
innervation as well as disturbance of the cough and an inspiratory stridor, which is in

esophagogastric junction and the Hiss angle. most cases self-limiting after a few months. How-
Thus, reflux is very typical when the lower seg- ever, severe forms of tracheomalacia may lead to
ment of the esophagus had to be pulled-up to be respiratory insufficiency, apneic spells, and to
able to perform a primary anastomosis. sudden infant death syndromes. In these cases,
An additional complication is dysmotility. an aortopexy is the most often performed proce-
Propulsive peristalsis in the lower segment of the dure, either by an open approach or by
esophagus is disturbed or missing while peristal- thoracoscopy with a more than 80% success rate
sis in the upper esophagus till the anastomosis is (Torre et al. 2012). An alternative is the use of a
often normal (Fig. 8). Recent investigations metal stent to stabilize the trachea (Fig. 9). The
showed a significant lower density of interstitial stent is introduced endoscopically and the respi-
cells of Cajal in the esophagus (Midrio et al. ratory problems are normalized immediately.
2010). In 80% of the patients, the dysmotility However, if the stent is not dilated sufficiently,
causes a prolonged clearance time of the refluxed recurrent granulation tissue is a typical complica-
material. In contrast to otherwise normal babies, tion due to the movements of the stent relative to
there is no chance for spontaneous maturation of the trachea. In contrast, if the stent is in a firm
the disturbed esophageal function. Chronic expo- contact with the trachea, the mucosa tends to grow
sure of the anastomosis to refluxed gastric acid is over and removal after the period of a few months
known as trigger of refractory stenosis at the anas- may be difficult. Different types of stent are today
tomosis and chronic esophagitis. Whether initially available, but experience to use them is still small.
proton pump inhibitor therapy is useful to prevent
stricture is a matter of debate (Hagander et al.
2012). However, up to 50% of all patients with Long-Term Follow-Up
esophageal atresia need finally a fundoplication
(Tovar and Fragoso 2013). Long-term respiratory problems and recurrent
Tracheomalacia is a common finding after respiratory tract infections are reported in
esophageal atresia patients with lower fistula. 40–60% and may be associated with reflux driven
The weak part of the trachea is in the region of microaspirations or tracheomalacia (Pedersen
the former fistula. It causes a typical barking et al. 2017; Ijsselstijn et al. 2013). Abnormal
esophageal atresia and distal fistula have been

collected from the literature by Rintala and
Pakarinen (2013). Routine follow-up endoscopies
with extensive biopsies are recommended on all
adult patients (Table 4).
Spinal abnormalities exist in a significant
number of adult patients. Vertebral anomalies
have been detected in 45%, most often vertebral
fusions, and scoliosis in 56%, being 13-fold
higher when compared with healthy population
(Sistonen et al. 2011). In this study, radial ray
anomalies have been found in 25%, shoulder
asymmetry in 80%, chest wall deformities in
15%, and rib fusion in 30% of patients.
Quality of life investigations show that the
QoL score is significantly lower when compared
with healthy children. The factors associated
with lower scores are prematurity, barky cough,
and gastroesophageal reflux disease (Legrand
Fig. 9 A Palmaz-stent used for severe tracheomalacia et al. 2012). In adult atresia patients, health-
with life-threatening spells. The stent stabilized the trachea related quality of life is generally normal, but in
immediately and was removed after 8 months 15% gastrointestinal or respiratory disorders may
impair quality of life (Ijsselstijn et al. 2013). In
another study, patients reported significantly
airway reactivity is often associated with atopy decreased general health perception and
but only in 15% compatible with asthma. (Kovesi increased bodily pain, but health-related quality
2013; Sistonen et al. 2011). Pulmonary function of life was nearly comparable with the healthy
tests showed obstruction in 21%, restriction in controls; age and associated anomalies predicted
21%, and both in 36% of patients (Sistonen et al. poor gastrointestinal QoL, and associated anom-
2011). alies and tracheomalacia predicted poor respira-
Symptoms of dysphagia are reported in tory symptoms QoL (Sistonen et al. 2011).
38–85% of patients and only 19% have been In a previous study of the same institution,
described as free of digestive symptoms after adults with esophageal atresia achieved a gastro-
10–20 years (Mahoney and Rosen 2016; Legrand intestinal QoLI score similar to healthy controls
et al. 2012). Swallowing disorders are reported and there was no difference in health-related QoL
often but most patients learn to coop with this despite that the patients had more dysphagia and
problem and are used to drink fluid together with reflux and a lower respiratory symptom-related
their meals as soon as they feel that a bolus does quality of life (Koivusalom et al. 2005).
not pass easily through the esophagus. In conclusion, neonates with esophageal atre-
Chronic reflux is common and may recur after sia have an excellent prognosis if no severe
fundoplication. Symptoms in adults are usually additional malformations are present. Still a
rare and therefore chronic esophagitis may exist problem exists in babies with a long gap atresia
for a long time. The incidence is up to 19% in and the ideal method has not been found, so
patients accepting regular endoscopy (Maynard far. Both strategies, to preserve the patient’s
and Bouin 2013). Chronic reflux may finally own esophagus or to replace the organ have
lead to intestinal metaplasia and Barrett esopha- significant morbidities and more long-term
gus with the risk of esophageal cancer. So far, complications. More prospective studies are
eight cases of adenocarcinoma in patients with needed to compare the different techniques
Table 4 Follow-up controls. Long-term follow-up strategy proposed by Rintala and Pakarinen (2013)
Findings at surveillance No Any of the following: Barrett Barrett with dysplasia
upper endoscopy at findings 1. Erosive esophagitis without
15 years 2. Gastric (columnar) dysplasia
metaplasia
3. Esophageal stricture
4. Tracheoesophageal
refistula
5. Severe GER
symptoms
6. Continuous GER
medication
Next surveillance upper 30 years Repeat after 5 years Repeat Confirm dysplasia grade and
endoscopy 40 years after 1 year consider local or operative ablative
50 years treatment
60 years
based on equal data and statistics. In general, the ▶ Prenatal Diagnosis of Congenital
today’s outcome for neonates with esophageal Malformations
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and an acceptable esophageal function enabling
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esophagoscopy in delayed primary esophageal
Congenital Esophageal Stenosis
45
Masaki Nio, Shintaro Amae, and Motoshi Wada
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 682
Epidemiology/Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
Nonsurgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
Management of Complications Following Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
Abstract esophageal wall, fibromuscular thickening of

Congenital esophageal stenosis (CES) is a rare the esophageal wall, and membranous mucosal
condition. There are three pathological types of diaphragm or web. Congenital esophageal
CES: with tracheobronchial remnants in the atresia is the most common associated anom-
aly. Symptoms of CES include vomiting or
regurgitation, dysphagia, recurrent respiratory
M. Nio (*) · M. Wada
tract infections, and growth retardation.
Department of Pediatric Surgery, Tohoku University Esophagograms of stenosis exhibit tapered or
Graduate School of Medicine, Sendai, Japan abrupt narrowing of the esophagus with vari-
e-mail: mnio@ped-surg.med.tohoku.ac.jp; ous degrees of dilatation of its suprastenotic
wada@ped-surg.med.tohoku.ac.jp
portion. Esophagoscopy, manometric study,
S. Amae and pH monitoring are helpful tools for differ-
Department of Surgery, Miyagi Children’s Hospital,
Sendai, Japan
ential diagnoses in distinguishing CES from
e-mail: amae@miyagi-children.or.jp achalasia and secondary esophageal stricture

https://doi.org/10.1007/978-3-662-43588-5_49
682 M. Nio et al.
due to gastroesophageal reflux (GER). Balloon diagnosis as well as understand the pathological
dilatation is the first choice of treatment in basis of CES to employ the most appropriate
CES. When patients fail to respond to repeated treatment strategy.
attempts of bougienage, surgical intervention
should be considered. Resection of the stenosis
followed by end-to-end esophageal anastomo- Pathology
sis is a general surgical treatment. Good out-
come of circular myectomy has been also CES is defined as an intrinsic stenosis of the
reported. Complications, including an iatro- esophagus caused by congenital malformation of
genic esophageal perforation following the esophageal wall. There are three pathological
bougienage and leakage after segmental resec- types of CES: with tracheobronchial remnants in
tion and reconstruction of the esophagus, have the esophageal wall (Frey and Duschl 1936;
been reported. While good prognosis has been Bergmann and Charnas 1958; Kumar 1962;
reported following dilatation and/or surgery Paulino et al. 1963; Ishida et al. 1969; Rose et al.
when needed, it was also reported that dyspha- 1975; Ohkawa et al. 1975; Ibrahim and Sandry
gia occurred frequently regardless of the ther- 1981; Deiraniya 1974; Fekete et al. 1987; Sneed
apeutic option at follow-up. Close, long-term et al. 1979; Spitz 1973; Briceno et al. 1981;
follow-up is highly recommended. Tubino et al. 1982; Shoshany and Bar-Maor
1986), fibromuscular thickening of the esopha-
Keywords geal wall (Fekete et al. 1987; Bonilla and Bower
Congenital esophageal stenosis · Esophageal 1959; Mahour et al. 1971; Tuqan 1962; Vidne and
atresia · Tracheobronchial remnant · Levy 1970; Todani et al. 1984), and membranous
Fibromuscular thickening · Dilatation · End- mucosal diaphragm or web (Ohkawa et al. 1975;
to-end esophageal anastomosis · Circular Fekete et al. 1987; Beatty 1928; Huchzermeyer
myectomy · Esophageal perforation et al. 1979; Overton and Creech 1953; Schwaetz
1962; Grabowski and Andrews 1996; Takayanagi
et al. 1975; Sarihan and Abes 1997; Komuro et al.
Introduction 1999; Roy et al. 1996).
Stenosis due to tracheobronchial remnants is
Congenital esophageal stenosis (CES) is a rare the most common type of this anomaly and is
condition. Gross (1953) reviewed 38 cases of localized at the distal esophagus (Sneed et al.
CES from the records of the Boston Children’s 1979). Fibromuscular thickening is observed in
Hospital in 1953 and reported that repeated dila- the middle or lower portions of the esophagus
tation provided complete relief in most cases; (Fekete et al. 1987; Todani et al. 1984), and mem-
however, he later stated that CES cases that did branous webs are observed in the upper or middle
not respond after six attempts at dilatation levels of the esophagus (Fekete et al. 1987;
should be strongly considered for surgical resec- Grabowski and Andrews 1996; Takayanagi et al.
tion or revision of the strictured area. Since then, 1975; Sarihan and Abes 1997; Komuro et al.
a number of treatment modalities have been 1999; Roy et al. 1996). The stenotic area in
devised, but there is no consensus regarding cases with tracheobronchial remnants is usually
which treatment modality could be the best. localized, and the area of fibromuscular stenosis
Although the efficacy of the conservative treat- varies from one to several centimeters in length
ment varies on case-by-case basis, the surgical with circular thickening of the esophageal wall. In
treatment, which is expected to provide prompt cases of membranous web, single webs were
relief from symptoms, carries certain risks of observed in children (Grabowski and Andrews
postoperative complications including leaks, 1996; Sarihan and Abes 1997; Roy et al. 1996),
stricture, and gastroesophageal reflux (GER). whereas plural webs, termed as multiple trachea-
The surgeons should consider the differential like rings, were observed in young adults (Younes
45 Congenital Esophageal Stenosis 683
et al. (1995) reported a significant reduction of

myenteric nitrinergic neurons and fibers in the
muscle layer of two young adults diagnosed with
fibromuscular variant of CES. Lack of submu-
cosa (Takayanagi et al. 1975), loose vascular
connective tissue, and diffuse lymphocytes
(Grabowski and Andrews 1996) have been
observed microscopically in specimens of mem-
branous web.
Epidemiology/Etiology
Fig. 1 CES with tracheobronchial remnants. Mature or
CES occurs in 1 in 25,000–50,000 live births
immature cartilages, the seromucous tracheobronchial
glands, and ciliated epithelium are usually seen in CES (Fekete et al. 1987; Bluestone et al. 1969).
with tracheobronchial remnants Although the reason is unknown, the incidence
of CES is higher in Japan than elsewhere (Ohkawa
et al. 1975; Nishina et al. 1981). Nevertheless,
there is no sex-associated predisposition.
Regarding the etiology of CES, stenosis
caused by tracheobronchial remnants and
fibromuscular thickening is believed to be a devel-
opmental disorder during the formation and sepa-
ration of the primitive foregut into the trachea and
esophagus by the end of the first fetal month. The
membranous mucosal diaphragm or web is
believed to be a result of incomplete reformation
of the esophageal lumen upon recanalization of
the esophagus between the sixth and eighth week
of gestation.
The incidence of anomalies associated with
Fig. 2 Fibromuscular thickening of the esophageal wall. CES has been reported as 17–33% (Fekete et al.
Circumferential proliferation of smooth muscle fibers with
moderate fibrosis is seen in fibromuscular stenosis 1987; Nishina et al. 1981); among these, congen-
ital esophageal atresia is the most common
(Ibrahim and Sandry 1981; Deiraniya 1974;
and Johnson 1999; Katzka et al. 2000; Pokieser Fekete et al. 1987; Mahour et al. 1971; Tuqan
et al. 1998). 1962; Overton and Creech 1953; Nishina et al.
In CES with tracheobronchial remnants 1981; Sheridan and Hyde 1990; Yeung et al. 1992;
(mature or immature cartilages), the seromucous Neilson et al. 1991; Kawahara et al. 2001;
tracheobronchial glands and ciliated epithelium Takamizawa et al. 2002; Amae et al. 2003), and
were usually reported during microscopic exam- 4.9–14% tracheoesophageal fistula (TEF) cases
ination of the stenotic esophageal wall (Fig. 1) are associated with CES (Kawahara et al. 2001;
(Paulino et al. 1963; Fekete et al. 1987; Murphy Newman and Bender 1997; Vasudevan et al.
et al. 1995). On the other hand, in fibromuscular 2002). Surgeons should be aware of the high
stenosis, circumferential proliferation of smooth incidence of association of congenital esophageal
muscle fibers with moderate fibrosis has been atresia with distal CES with tracheobronchial
observed (Fig. 2) (Fekete et al. 1987; Todani remnants. Moreover, cardiac anomalies (Fekete
et al. 1984; Murphy et al. 1995). Singaram et al. 1987; Overton and Creech 1953), intestinal
684 M. Nio et al.
Fig. 3 Esophagograms of CES. An abrupt (a) or tapered narrowing (b) of the esophagus evident on an esophagogram
atresia (Fekete et al. 1987; Huchzermeyer et al. surgical repair or during the postoperative course
1979), anorectal malformation (Deiraniya 1974; of esophageal atresia before presenting any symp-
Nishina et al. 1981), and chromosomal anomalies toms of CES.
(Rose et al. 1975; Fekete et al. 1987; Todani et al.
1984; Huchzermeyer et al. 1979) can be also
associated with CES. Diagnosis
Difficulties in determining the differential diagno-

Symptoms ses of CES to distinguish it from achalasia and
secondary esophageal stenosis and particularly
Symptoms of CES include vomiting or regurgita- from a stricture due to reflux esophagitis (Blue-
tion, dysphagia, recurrent respiratory tract infec- stone et al. 1969) have resulted in various clinical
tions, and growth retardation. problems during its treatment.
Although the etiology of CES usually has con- First, achalasia, inflammatory esophagitis, and
genital origins, the symptoms rarely develop in stenosis caused by tumor or extrinsic compression
newborns (Schwaetz 1962). Characteristically, of the esophagus should be excluded. The locali-
the onset of regurgitation coincides with the intro- zation of the stenosis varies with the type of pathol-
duction of semisolid and solid foods around the ogy, as we mentioned in the earlier section.
age of 6 months in patients with tracheobronchial Patients who develop symptoms such as
remnants (Murphy et al. 1995). In some patients, a vomiting and dysphagia should be administered
foreign body in the esophagus might be the first a barium swallow test to obtain esophagograms.
symptom observed (Bluestone et al. 1969). When Esophagograms of stenosis exhibit tapered or
esophageal peristalsis is preserved, the presenta- abrupt narrowing of the esophagus with various
tion of CES might be delayed until adulthood degrees of dilatation of its suprastenotic portion
(McNally et al. 1990). (Fig. 3a, b). Most of the stenoses due to tracheo-
Patients with CES associated with esophageal bronchial remnants are visible on esophagograms
atresia are sometimes diagnosed at the time of as abrupt esophageal narrowing, whereas
fibromuscular stenosis usually exhibits as tapered

esophageal narrowing (Kawahara et al. 2001;
Amae et al. 2003). Following surgery of esopha-
geal atresia with or without TEF, an
esophagogram should be evaluated with great
care as it is easy to overlook a narrowing at the
mid-distal esophagus.
To evaluate the exact site and extent of the
stenosis, fluorography using a balloon catheter
can be employed. The balloon catheter is inserted
through the esophagus. The location and shape of
the inflated balloon provides a clear image of the
esophageal stenosis (Figs. 4 and 5a, b).
Esophagoscopy, manometric study, and pH
monitoring are helpful tools for differential diag-
noses in distinguishing CES from achalasia and
secondary esophageal stricture due to GER.
Esophageal endoscopy can directly evaluate not
Fig. 4 Fluorography using a balloon catheter. A low- only the stenotic area and the site of the gastro-
compliance balloon catheter (Rigiflex™ II, Boston Scien- esophageal junction but also the presence and the
tific LTD, UK) is placed at the stenosis and gradually severity of esophagitis. The mucosa distal to the
inflated, and then the location and length of the stenosis
stenosis is normal in CES. In addition to
are clearly visible
Fig. 5 (a) An esophagogram of a patient with abrupt narrowing. (b) A Foley catheter inserted through the esophagus is
inflated and pulled up to locate the stenosis
686 M. Nio et al.
esophagoscopy, endoscopic ultrasonography has varies with the type of pathology and that cases
been recently employed to evaluate the fine struc- with membranous web of the esophagus and some
ture of CES and is useful in choosing the treat- cases of fibromuscular stenosis can be treated by
ment strategy: balloon dilatation or surgical suitable dilatation (Fekete et al. 1987; Grabowski
treatment (Takamizawa et al. 2002; Kouchi et al. and Andrews 1996; Sarihan and Abes 1997;
2002; Usui et al. 2002). Komuro et al. 1999). It has been also believed
In cases of CES, preoperative esophageal that the efficacy of balloon dilatation in CES
manometry demonstrates a normal pattern of the with tracheobronchial remnants is limited. How-
lower esophageal sphincter and a small high- ever, it is difficult to precisely assess the efficacy
pressure zone in the resting pressure profile, of balloon dilatation in CES of each type of
which corresponds to the stenotic area of the pathology, because histological findings of the
esophagus. This small high-pressure zone disap- stenotic lesions of the patients who respond to
pears after the corrective surgery. Moreover, an dilation are not confirmed. Currently, the respon-
esophageal motility study would reveal a peristal- siveness of CES with tracheobronchial remnants
sis corresponding to the stenosis. Further, pH to dilatation is uncertain.
monitoring can reveal a significant positive reflux, Recently, successful treatment of membranous
which is not observed in patients with CES, unlike web with the use of endoscopic instruments
in patients with GER. (electrocauterization, high-frequency-wave snare/
CES associated with esophageal atresia is often cutter) has been reported (Nose et al. 2005; Chao
overlooked at the time of the initial esophageal et al. 2008).
surgical repair and diagnosed sometime later.
Ibrahim et al. (2007) recommended taking a sur-
gical specimen routinely for histopathological Surgery
studies from the tip of the lower esophageal
pouch during primary repair of esophageal atresia. When patients fail to respond to repeated (four to
six times) attempts of bougienage, surgical inter-
vention should be considered. Surgical resection
Treatment of the stenosis followed by end-to-end esophageal
anastomosis is a general surgical treatment for
The principal aims of CES treatment are the allevi- many cases with tracheobronchial remnants
ation of symptoms and maintenance of antireflux (Ishida et al. 1969; Ohkawa et al. 1975; Deiraniya
mechanism of the gastroesophageal junction. This 1974; Fekete et al. 1987; Sneed et al. 1979; Spitz
condition can be treated either conservatively or by 1973; Briceno et al. 1981; Tubino et al. 1982;
surgical intervention. Nonsurgical methods include Shoshany and Bar-Maor 1986; Nishina et al.
balloon dilatation and endoscopic treatment 1981; Neilson et al. 1991; Kawahara et al. 2001;
(Dall’Oglio et al. 2016; Terui et al. 2015). Takamizawa et al. 2002; Amae et al. 2003) and
some cases with fibromuscular thickening
(Todani et al. 1984; Murphy et al. 1995).
Nonsurgical Treatment Most cases of CES can be operated upon using
the thoracic approach. However, when the steno-
Balloon dilatation is the first choice of treatment sis is localized in the abdominal esophagus, the
in CES. This method should be employed not only abdominal approach might be utilized. In a few
for patients with tapered esophageal narrowing cases of CES, a complete resection of the stenotic
but also with abrupt esophageal narrowing when segment using the thoracoscopic (Martinez-Ferro
a balloon catheter can be passed safely through the et al. 2006) or laparoscopic approach (Deshpande
stenotic area. Low-compliance balloon catheters and Shun 2009) has been reported.
are commonly used (Amae et al. 2003). It has In the thoracic approach, right thoracotomy is
been reported that the effect of balloon dilatation employed for stenosis in the middle esophagus,
a that the phrenic and vagal nerves are not damaged

during the surgery.
Other options for surgical treatment are simple
excision of cartilaginous remnants, longitudinal
myotomy, circular myectomy, and esophageal
Diaphragm Lung replacement.
Among these procedures, simple excision of
the cartilaginous remnants and subsequent repair
of the esophageal wall have been reported
(Paulino et al. 1963; Fekete et al. 1987; Amae
et al. 2003). However, these methods are rarely
employed because they failed to provide sufficient
relief from symptoms in most cases of CES with
b
tracheobronchial remnants.
The longitudinal myotomy, which is a standard
procedure for esophageal achalasia than for CES,
has been employed for fibromuscular stenosis.
However, postoperative dilatation is frequently
required, and its efficacy is still unconfirmed.
Diaphragm Lung
Moreover, development of esophageal perforation
after myotomy has been reported as well
(Takamizawa et al. 2002).
Circular myectomy for CES with tracheobron-
chial remnants has been described (Maeda et al.
2004; Saito et al. 2008), and it might be employed
Fig. 6 Resection of the stenotic esophagus using a balloon for fibromuscular stenosis as well. During this
catheter. A Foley catheter inserted from the mouth is used surgical procedure, the lower margin of the ste-
to determine the lower margin of the stenosis (a). After
cutting the esophagus at the lower margin, another sterile
notic segment is determined by pulling up a bal-
Foley catheter is inserted from the lower opening of the loon catheter inserted through the mouth, which is
esophagus and used to determine the upper margin of the similar to the technique followed during the resec-
stenosis (b) tion of the stenotic portion. The upper margin is
determined by pushing down the balloon catheter
and left thoracotomy is employed for stenosis in inserted through the mouth or by pulling down the
the lower part of the esophagus. After exposing balloon catheter inserted through a small incision
the esophagus, a balloon catheter is inserted from at the esophageal mucosa into the esophageal
the mouth to locate the stenotic segment. The lumen. The muscular layer is incised up to the
catheter is then inflated and pulled up to confirm submucosal layer at the lower and upper margins.
the lower margin of the stenosis. Following the Subsequently, the abnormal muscular layer is dis-
cut in the distal end of the stenosis, a sterile sected circumferentially using sharp scissors or by
balloon catheter is passed through the stenotic cautery (Fig. 7). If the incision at the esophageal
area from the oral stump of the esophagus. The mucosa is made to evaluate the upper margin of
upper margin of the stenosis is determined by the stenosis, it is closed horizontally with absorb-
pulling down the catheter (Fig. 6a, b) (Amae able monofilament sutures, and the muscular layer
et al. 2003). is closed horizontally with interrupted absorbable
The stenotic area is completely removed, and sutures. Circular myectomy is expected to prevent
end-to-end anastomosis is achieved using the postoperative leakage and restenosis of the esoph-
single- or double-layer interrupted sutures of ageal anastomosis (Maeda et al. 2004; Saito et al.
absorbable materials. The surgeons should ensure 2008).
688 M. Nio et al.
reconstruction of the esophagus (Fekete et al.

1987), have been reported. The rate of esophageal
perforation after dilatation has been reported as
10.6–44% (Kawahara et al. 2001; McNally et al.
1990; Romeo et al. 2011) (Dall’Oglio et al. 2016).
Lung Perforations and large leakages might require sur-
Diaphragm
gical drainage and/or repair, but minor leakages
can be successfully treated by maintaining the
patient on total parenteral nutrition.
When GER develops following a simple resec-
tion or circular myectomy, an antireflux procedure
is required.
Fig. 7 Circular myectomy. The muscular layer is
circumferentially removed, keeping the mucosal layer
intact Prognosis
While thoracotomy has been the standard Favorable results have been reported following
approach for surgical correction, the less invasive appropriate treatment. Amae et al. (2003) reported
approach by thoracoscopy was recently reported the treatment outcome of 14 patients with CES, in
(van Poll and van der Zee 2012). which 11 and 3 patients became asymptomatic
Among various methods of surgical treatment following surgery and dilatation, respectively.
for CES, segmental resection with end-to-end On the other hand, according to the recent report
anastomosis of the esophagus is currently a stan- of 61 cases of CSE by Michaud et al. (2013),
dard procedure, and circular myectomy is a prom- dysphagia occurred frequently regardless of the
ising alternative. therapeutic option, and it remained in 36% of
Both procedures pose substantial risk of devel- patients at follow-up. Close, long-term follow-up
oping GER when anastomosis is performed under is highly recommended.
tension. When the stenosis is situated close to the
gastroesophageal junction, and the surgery is
performed through laparotomy, an antireflux pro- Conclusion and Future Directions
cedure (e.g., a Nissen fundoplication) might be
employed as well to prevent postoperative reflux CES is very rare condition. It is frequently asso-
(Amae et al. 2003). ciated with esophageal atresia but often over-
If the vagal nerve is accidently severed, a looked at the time of the initial surgery. When
pyloroplasty is performed. dysphagia persists after the surgery for esophageal
Patients with extensive CES, necessitating the atresia, association of CES should be suspected
resection of more than 3 cm of the esophagus, and assessed in order to avoid delayed diagnosis.
might require esophageal replacement using the As CES is revealed, dilatation is the first-line
colon, jejunum, or a gastric tube. therapeutic modality, which is likely to be effec-
tive for fibromuscular type of CES. In case
repeated dilatation cannot improve the symptoms,
Management of Complications employment of surgical treatment should be con-
Following Treatment sidered. While surgical resection of the stenotic
esophagus and end-to-end esophageal anastomo-
Complications, including an iatrogenic esopha- sis is the most common procedure, favorable
geal perforation following bougienage (Deiraniya results of circular myectomy have been reported.
1974; Takamizawa et al. 2002; Romeo et al. 2011) Endoscopic surgery for CES was also recently
and leakage after segmental resection and employed.
Good prognosis has been reported following Fekete CN, Backer AD, Jacob SL. Congenital esophageal
dilatation and/or surgery when needed. However, stenosis. A review of 20 cases. Pediatr Surg Int.
1987;2:86–92.
it was also reported that dysphagia occurred fre- Frey EK, Duschl L. Der Kardiospasmus. Erge Chirurg
quently regardless of the therapeutic option at Orthopaed. 1936;29:637–716.
follow-up. Thus, close long-term follow-up is Grabowski ST, Andrews DA. Upper esophageal stenosis:
essential. two case reports. J Pediatr Surg. 1996;31:1438–9.
Gross RE. The surgery of infancy and childhood. Philadel-
CES with extensive stenosis or severe esopha- phia: WB Saunders & Co.; 1953.
geal dysmotility may require esophageal replace- Huchzermeyer H, Burdeiski M, Hruby M. Endoscopic
ment, which is highly invasive and associated therapy of a congenital oesophageal stricture. Endos-
with considerable risk of morbidity. Due to recent copy. 1979;11:259–62.
Ibrahim NBN, Sandry RJ. Congenital esophageal stenosis
advancement of regenerative medicine (Sommer caused by tracheobronchial structures in the esophageal
et al. 2013), tissue-engineered esophagus is wall. Thorax. 1981;36:465–8.
expected to be utilized for the most severe type Ibrahim AH, Al Malki TA, Hamza AF. Congenital
of CES in the near future. esophageal stenosis associated with esophageal
atresia: new concepts. Pediatr Surg Int.
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Ishida M, Tsuchida Y, Saito S, et al. Congenital esophageal
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Esophageal Duplication Cyst
46
Dakshesh Parikh and Melissa Short
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
Relevant Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
Clinical Features and Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
Antenatal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
Incidental . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
Symptomatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 698
Thoracoscopic Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Thoracotomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Surgical Management of Various Types of
Esophageal Duplication Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Cervical and Suprasternal Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 699
Left-Sided Thoracic Inlet Duplication Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700
Right-Sided Thoracic Duplication Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Intra-abdominal Esophageal Duplication Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Neuroenteric Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 701
Surgical Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
D. Parikh (*)
Birmingham Children’s Hospital NHS FT, Birmingham,
UK
e-mail: dakshesh.parikh@bch.nhs.uk
M. Short
Department of Paediatric Surgery, Birmingham Children’s
Hospital, Newcastle upon Tyne, UK
e-mail: mshort1@doctors.net
# Her Majesty the Queen in Right of United Kingdom 2020 691

https://doi.org/10.1007/978-3-662-43588-5_50
692 D. Parikh and M. Short
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Esophageal duplications and bronchogenic
cysts are aberrations of primitive foregut devel- Esophageal duplications and bronchogenic cysts
opment. Duplications can be found along the come under the spectrum of foregut duplications,
entire length of the esophagus with varying as both take their origins from the primitive fore-
presentation depending on their location and gut (Ponsky and Rothenberg 2009). Esophageal
pressure effects on neighboring structures. duplications account for up to 20% of benign
Although duplications can remain asymptom- esophageal lesions and may be associated with
atic, they may get discovered incidentally dur- other duplications of the intestinal tract and ver-
ing unrelated investigations. The complicated tebral anomalies (Stringer et al. 1995). Further-
duplications can present with life-threatening more, one in five cases of alimentary tract
symptoms. duplications is esophageal in origin (Holcomb
Differential diagnosis of posterior mediasti- et al. 1989; Beardmore and Wiglesworth 1958).
nal rounded opacity on radiological investiga- Esophageal duplications are situated close to and
tion should include esophageal duplication in contact with the esophagus but rarely commu-
cyst. Investigations such as an upper gastroin- nicate with it. They are generally isolated con-
testinal contrast study and computed tomogra- genital malformations in the posterior
phy of the chest are not diagnostic but can mediastinum and are occasionally seen with
suggest duplication cyst. Once identified and esophageal atresia (Hemalatha et al. 1980;
investigated, the duplications should be Snyder et al. 1996). Esophageal duplications
resected. seen in association with cysts within the verte-
Thoracoscopic surgery is recommended bral column are called Neuroenteric cysts.
for resection of all uncomplicated and some Esophageal duplication cysts were first
complicated cysts. Thoracoscopic surgery described by Blasius in 1711. They were further
reduces the hospital stay, postoperative anal- defined by Roth in 1881 who described esopha-
gesia requirement, and morbidity compared geal duplications as a simple epithelial lined
to open surgery. Although thoracotomy can cysts and cysts covered by muscle coat. Often
achieve resection, it should be reserved for asymptomatic in nature, their true incidence is
the complicated cysts. The outcome after difficult to establish but is estimated at a fre-
complete resection is excellent. Surgical com- quency of 1:8200 from autopsy studies (Arbona
plications can be avoided by optical magnifi- et al. 1984).
cation and careful dissection close to the cyst.
Incomplete resection results in recurrence.
Surgical complications are related to inadvertent
accidental injury to the surrounding vessels, Embryology
nerves, thoracic duct, esophagus, and neighbor-
ing trachea. This chapter attempts to give an During week 4 of gestation, the primitive gut
overview of the esophageal duplication and its develops an anterior diverticulum which eventu-
current management. ally becomes the trachea and respiratory system.
At the same time, a posterior bud appears which
Keywords goes on to become the esophagus. With time,
Esophageal duplications · Mediastinal cysts · these two systems are separated by the tracheoe-
Thoracoscopic surgery · Neuroenteric cyst sophageal septum. As development continues,
46 Esophageal Duplication Cyst 693
epithelium obliterates the esophagus before it thoracic duct, trachea, and pulmonary vessels.
re-cannulizes. Simple cysts are duplications of Neuroenteric cysts are associated with vertebral
the epithelium alone. Several embryological the- anomalies, in particular hemivertebra, cranial to
ories have attempted to explain the origins of its location in the mediastinum. The intravertebral
mediastinal duplications. The esophageal duplica- and esophageal components may or may not com-
tion cysts may develop from an accessory diver- municate with each other. The recurrent laryngeal
ticulum that may or may not communicate with nerve should be identified and preserved in cases
the esophageal lumen or the failure of appropriate of an esophageal cyst in the upper and cervical
canalization of the gastrointestinal tract. Though esophagus.
these theories may be attractive, neither is able to
explain the entity known as Neuroenteric cysts
where there is associated vertebral anomaly and Pathology
a connection between esophageal duplication
cysts and cyst within the spinal canal. The split Esophageal duplication cysts are described as
notochord theory attempts to address this by being Neuroenteric, cystic, or tubular. They are
describing a time in embryogenesis where there either encased with a thin layer of muscle or
is persistence of endodermal-ectodermal tract embedded within the esophageal wall itself
leading to an endomesenchymal tract between (Snyder et al. 1996). Esophageal duplications usu-
amnion and yolk sac (Veeneklass 1952). The pos- ally replicate histology of the gastrointestinal tract
tulation in this theory is an incomplete separation with two layers of muscularis surrounding the
of the notochord from the endoderm, and the luminal epithelial lining and enteric nervous sys-
traction from the developing primitive gut forms tem but do not contain cartilage (Whitaker et al.
a tract between the vertebral column and the 1980). Esophageal duplication endothelial lining
duplication. This is described as Neuroenteric can be either squamous, gastric, pseudostratified,
cyst. During development, the communication cuboidal, columnar, ciliated respiratory, pancre-
may be lost developing into two distinct cysts: atic, or mixed epithelial. The presence of cartilage
one inside the vertebral column and one close to within its wall indicates bronchogenic origin.
the alimentary tract. Those cysts not associated Cysts contain either clear mucoid or brown or
with vertebral column anomalies or cysts within blood-stained serous fluid. The spinal component
the vertebral column may arise during separation of a Neuroenteric cyst has a thin fibrous wall and
of primitive foregut and may give rise to both is lined by single cuboidal layer or pseudo-
simple esophageal duplications and bronchogenic stratified epithelium.
cysts. These can explain a variety of epithelia Sudden increase in cyst size may occur
observed during histological examination. related to intraluminal bleeding by eroding pep-
tic ulcers related to heterotopic gastric mucosa or
infection. These complications can cause
Relevant Anatomy retrosternal pain. Erosion or fistulation into the
tracheobronchial tree or esophagus can be life-
Esophageal duplication cysts can occur anywhere threatening and may present as recurrent pneu-
along the length of the esophagus but most com- monia or hemoptysis (Rhaney and Barclay 1959;
monly occur in the lower esophagus (66%). In the Parikh and Samuel 2005). Malignant transfor-
superior mediastinum, duplications can be found mation has been reported in the esophageal
on either side of esophagus or in between the duplications as either well-differentiated adeno-
trachea and the esophagus. Distally the duplica- carcinoma or as squamous cell carcinoma arising
tions are situated in the posterior mediastinum and in the cyst. The malignant change is rare (Olsen
mainly on the right side. They therefore lie in et al. 1991; Chuang et al. 1981; Tapia and White
close proximity to the vagus and phrenic nerves, 1985).
Esophageal duplications occasionally share a Antenatal

common muscular wall with the native
esophagus. Rarely duplications may be tubular Parikh and Singh describe up to 5% of antenatally
along the entire length of the esophagus and diagnosed cystic thoracic lesions as being esoph-
have abdominal extension with duplication ageal duplication cysts, with sudden infant death
of the stomach (Cocker et al. 2006; being reported in those cysts in close proximity of
Shepherd 1965). tracheobronchial tree (Parikh and Singh 2011;
Fig. 1a, b).
Clinical Features and Presentation Incidental
Esophageal duplications may remain asymp- A large number of cysts are asymptomatic from
tomatic and present as an incidental finding. birth. Radiological investigations for unrelated
Symptoms are known to develop once symptoms or blunt chest trauma may therefore
secretions accumulate within its cavity thus reveal a previously unknown duplication cyst
producing a pressure effect on the surrounding (Fig. 2a, b).
organs and esophagus. A sudden increase in
the size of the esophageal cyst either as a
result of infection or intra-cystic hemorrhage, Symptomatic
perforation results in its acute presentation
(Nakhara et al. 1990). Symptoms are related to pressure effect from
Routine antenatal scans detect with increasing an enlarged esophageal cyst against visceral
accuracy intrathoracic cystic lesions. The postna- mediastinum causing stridor, breathlessness,
tal investigation may distinguish some to be dupli- wheezing, or dysphagia (Kawashima et al.
cations or Neuroenteric cyst. 2016). Anemia in 10 of 25 cases, melena in
Fig. 1 (a) Antenatal MRI scan: Antenatal US and subse- MRI scan confirmed the diagnosis (Acknowledgment
quent MRI showed a tubular paraspinal cystic mass with for Copyright permission: Parikh D, Singh M. Esophageal
vertebral anomaly (arrow). Antenatal scan also showed Duplication Cysts in Prem Puri (ed) Newborn Surgery 3rd
intraspinal component of Neuroenteric cyst. (b) Postnatal Edition; Hodder Arnold 2011; 406–412. Fig. 41.1)
Fig. 2 (a) A 12-year-old child with blunt chest trauma: related to this esophageal duplication. (b) Contrast study
(arrow) on chest AP and lateral x-ray showing rounded and CT and subsequent thoracoscopic resection confirmed
posterior mediastinal opacity. There were no symptoms esophageal duplication
8/25, vomiting in 8/25, pain in 5/25, and

failure to thrive in 4/25 patients were observed Investigations
by Pokorny and Goldstein 1984. Younger infants
are more likely to present with respiratory The order of the radiological imaging is generally
symptoms. The gastric epithelium may cause guided by the clinical suspicion and presenting
peptic ulceration, intra-cystic hemorrhage, and symptoms. Antenatally detected cystic lesions
fistulation into the tracheobronchial tree should undergo a CT scan of the chest with intra-
resulting in hemoptysis and pneumonia venous contrast. If the postnatal CT identifies a
(Fig. 3a, b). Fistulation into the esophageal posterior mediastinal cyst/ duplication in the
lumen leads to hematemesis and melena. chest, an additional abdominal ultrasound,
The Neuroenteric cysts with an intravertebral although not specific, may help diagnose associ-
component may present with meningitis or ated other gastrointestinal duplications (Fig. 4a).
neurological symptoms (Piramoon and
Abbassioun 1974). Chest X-ray A well-circumscribed or a tubular
smooth shadow/opacity may suggest a mediastinal
mass. Recurrent infections from a communicating
Malignancy cyst to either tracheobronchial tree or esophagus
may show as a cavitatory lesion or pneumonic
Adenocarcinoma and squamous cell carcin- shadow in the lung (Fig. 3a). Partial compression
oma have both been described in adults arising of bronchus may result in emphysema of the lobe or
from esophageal duplication cysts (Olsen et al. a tracheal narrowing (Fig. 3c). Chronic compres-
1991; Chuang et al. 1981; Tapia and White sion may result in recurrent infection of the lobe
1985). and bronchiectasis seen as chronic collapse.
Fig. 3 : Esophageal duplications presented with compli- lobe. Thoracoscopic esophageal duplication was carried
cation. (a) A 10-year-old girl presented acutely with out. (c) An infant presented with recurrent infections;
hematemesis requiring blood transfusion. Chest x-ray chest x-ray showed emphysematous right upper lobe.
showed a cavitatory lesion on the right side. (b) CT scan (d) CT scan showed duplication cyst compressing right
showed a cavitatory lesion with fluid levels in posterior upper lobe bronchus causing emphysema
mediastinum with collapse consolidation of the right lower
Contrast Swallow A focal smooth compression surgery as it may result in esophageal mucosal
or displacement may be visible in association with injury and leak after resection.
the contrast passing through the esophagus
(Fig. 5a–c). Occasionally displacement of esoph- Computed Tomography of the Chest with
agus is seen by a posterior mediastinal space Intravenous (IV) Contrast If an intrathoracic
occupying lesion. Contrast studies cannot differ- mass is suspected from preliminary investigations
entiate between the type of lesion causing the or presenting symptoms, a CT scan is indicated.
external compression and an intramural lesion. This will allow the definition, location, and rela-
Thinly lined contrast on the compressing lesion tionship of the mass to be identified, which is
side (Fig. 5c) may suggest a common mucosal wall important for the surgeon before resection
and should warn operator to be vigilant as during (Figs. 3b, d and 6).
Fig. 4 (a) Intra-abdominal duplication near gastroesoph- of the stomach (arrow). (c) CT scan confirmed a cyst at
ageal junction discovered after a routine ultrasound of gastroesophageal junction (arrow). (d) Laparoscopic view
abdomen in a child with thoracic esophageal duplication. of the duplication near gastroesophageal junction (arrow)
(b) Contrast study showing a filling defect near the fundus resected successfully
Duplication cysts on CT scan show as homog- cyst is suspected to define the spinal component
enous, smooth bordered, and of low attenuation. (Fig. 1b).
In adults, a necrotic paraesophageal posterior
mediastinal mass or an abscess is difficult to dif- Endoscopy Flexible endoscopy is not routinely
ferentiate by the CT scan alone. indicated for the diagnosis of the esophageal
duplication cysts. Endoscopy carried out while
MRI Scan Some radiologists recommend MRI investigating dysphagia may demonstrate exter-
to better delineate posterior mediastinal soft tis- nal compression; however, intramural swelling
sue masses. MRI showing low T1- and such as leiomyoma may be seen causing obstruc-
T2-weighted images of the wall and high- tion. Intraoperative endoscopy, while performing
intensity T1-weighted images of the contents of resection aids complete resection, helps reduce
the paraesophageal soft tissue mass as cyst in esophageal mucosal injury and diagnose acci-
nature. The only drawback of MRI is the need dental mucosal injury.
for sedation or general anesthesia in infants and Transesophageal ultrasound can diagnose
children. It is, however, vital if a Neuroenteric duplication cysts in adults as compressing cystic
Fig. 5 (a) Contrast swallow lateral view shows a cyst stridor and dysphagia. As the contrast continually thins out
between trachea and esophagus presented with stridor as in the area of the cyst, it is likely that the esophageal cyst
well as wheeze. (b) A left apical large cyst causing dys- may have a common wall with the native esophagus
phagia and stridor. (c) A right apical duplication causing
lesion containing echogenic material. This inves- fistulations. Thoracoscopic resection is gaining pop-
tigation is generally not indicated in children. ularity and has the advantage of less time for recov-
ery and hospital stay, reduced requirement for chest
tube drainage, opioid analgesia, and less disfiguring
Management than open operations (Michel et al. 1998; Bratu et al.
2005; Merry et al. 1999).
Esophageal duplications should be resected in Two types of esophageal duplications can be
symptomatic patients and also in asymptomatic encountered; both require slightly different tech-
cases to prevent potential life-threatening compli- nique during resection. The esophageal duplica-
cations (Holcomb et al. 1989; Dresler et al. 1990; tion with its own separate muscle wall attached
Benedict et al. 2016). Although malignancy is with the native esophagus with loose connective
rare, its late presentation causes a significant diag- tissue. A second variety is rare but may pose a
nostic dilemma in adults. Once the diagnosis has surgical challenge during its resection. This dupli-
been made and location confirmed, complete exci- cation on the side of the native esophagus is not
sion should be undertaken as incomplete resection covered by the muscle coat and attached to each
results in its recurrence. Operative resection can other by their mucosa.
be open or thoracoscopic depending on position Thoracoscopic approach is ideally suited for
of cyst and surgical expertise. the resection of esophageal duplications as it is
Antenatally diagnosed as well as symptomatic associated with low morbidities (Bratu et al. 2005;
cases in most instances are suitable for thoracoscopic Merry et al. 1999). Many including our center
resection with the exception of infected cases with have stopped placing a postoperative chest drain
in uncomplicated resections. Infradiaphragmatic Complicated duplications can cause particular

duplications are resected laparoscopically. difficulty while dissecting from the surrounding
Thoracotomy is advised for complicated dupli- normal structures. The infective fistula between
cations involving fistulation into the tracheobron- the tracheobronchial tree and the cyst should be
chial tree. Previous inadequate resection with dissected out and sutured securely. A test for air
recurrence may require an open approach for a leak should be performed after closure of the
complete resection. Cervical duplication will fistula. Surgery for infected esophageal cysts is
require a cervical incision for its resection. associated with more postoperative morbidity and
often requires placement of chest drains. Phrenic
nerve injury with eventration of the diaphragm,
Thoracoscopic Surgery chylothorax, Horner’s syndrome, and esophageal
leak are notable complications.
Thoracoscopy is carried out with 3 or 5 mm
instruments under general anesthesia in a lateral
position. Central endotracheal intubation is used Surgical Management of Various
in most cases with the exception of older chil- Types of Esophageal Duplication Cysts
dren where single lung anesthesia is possible.
Bronchial blockers are rarely necessary in youn- Cervical and Suprasternal Cyst
ger children to allow single lung ventilation. The
first port is generally placed in the mid-axillary Duplication cysts within the superior mediasti-
line followed by two or three other ports under num may appear in the suprasternal or anterior
thoracoscopic vision for the best possible manip- triangle of the neck, particularly when the child
ulation. Resection in infants can easily be carried cries. Cervical esophageal duplications are rare
out using 3 mm instruments. The carbon dioxide but are encountered (Fig. 6a). These are within
is set at a pressure of 5–7 mmHg and insufflated the deep cervical fascia adjacent to the esophagus
at flow rates of 1.5 L/min to collapse the ipsilat- and cause compression on the trachea and esoph-
eral lung and expose the posterior mediastinal agus. These are invariably symptomatic with vis-
cyst. Thoracoscopic surgery in complicated ible neck swelling, significant stridor, and
cysts can be performed but requires expertise, dysphagia. Cervical excision is achieved in
experience, and advanced skills (Sundararajan supine position with neck extension. The carotid
and Parikh 2007; Partrick and Rothenberg and internal jugular and sternomastoid muscle
2001). are retracted laterally. The surface of the esoph-
ageal duplication cyst is reached and dissection
is continued, staying close to its surface. The
Thoracotomy recurrent laryngeal nerve in particular is at risk
of injury as it travels along the tracheoesophageal
Open operations are indicated for recurrence and grove. The recurrent laryngeal nerve is known to
infected cysts. Lateral thoracotomy, preferably travel on the surface of the esophageal duplica-
muscle sparring through the bed of the fifth or tion. The nerve should be carefully dissected off
sixth rib, is ideally suited for an open approach. the duplication and preserved. The cervical inci-
Adhesions, either inflammatory or from previous sion is then closed keeping a small suction drain
attempted resections, may cause difficulty during in the space, in layers. The drain is kept for
dissection and bleeding. The posterior mediasti- approximately 48 h or until drainage stops. Post-
num and duplication cyst is exposed by operative analgesia can be achieved by local
dissecting lung parenchyma and retracting it anesthetic infiltration in the wound and if neces-
anteriorly. Meticulous dissection of lung paren- sary narcotic and anti-inflammatory medications.
chyma from adhesions avoids bleeding and air Invariably patient can be discharged on day
leaks. 3 after surgery.
Fig. 6 CT scans with IV contrast delineates relationships subclavian vessels. (b) Lower right-sided posterior medi-
with neighboring relevant anatomical structures. (a) A astinal esophageal duplication. (c) Right-sided esophageal
cervical duplication with significant symptoms entering duplication near the lower trachea and carina. (d) Large
into the superior mediastinum compressing jugular and tubular neurenteric duplication with vertebral anomaly
Left-Sided Thoracic Inlet Duplication vision. The dissection may require sharp and
Cyst electrocoagulation. The vessels and nerves are pro-
tected during dissection. Care should be taken while
Surgery of a cyst in this area is challenging because dissecting the cyst from the esophagus. If they share
of its location in the superior mediastinum in close a common wall, the native esophagus and its
proximity to major vessels (left subclavian, carotid, mucosa should be protected. Diathermy should be
arch of the aorta, and left pulmonary artery), the used sparingly as its excessive use may cause con-
phrenic and left recurrent laryngeal nerves, and the duction or thermal injury to the nerves.
thoracic duct. The cyst in this position causes pres- Hemostasis is checked, and carbon dioxide is
sure symptoms, namely, stridor, breathlessness on evacuated from the thoracic cavity after removal
exertion, wheezing, and dysphagia (Figs. 5b and of the cyst from one of the port sites. In most
6a).Thoracoscopic dissection is carried out by iden- instances, postoperative chest drain placement is
tifying and protecting vital structures, dividing the not required. The child is allowed to feed and
overlying parietal pleura, and exposing the left lat- analgesia is administered as required. An erect
eral cyst wall. The dissection is gradually carried out chest x-ray is usually performed the following day
staying close to the cyst wall under thoracoscopic to confirm full expansion of the lung and no
collection within the pleural cavity. A residual post- by intravenous paracetamol and oral anti-
operative pneumothorax generally gets reabsorbed inflammatory drugs. The majority of thoracos-
spontaneously and does not require drainage. A copically resected cases can be discharged the fol-
fluid collection may indicate chylothorax, blood, lowing day after a normal chest x ray.
or leaking saliva. If the child is symptomatic from
increasing pleural fluid accumulation, intervention
and investigation are required to identify the cause. Intra-abdominal Esophageal
Chest x-ray also delineates the position of the left Duplication Cyst
diaphragm as eventration would suggest left
phrenic nerve injury. Intra-abdominal infradiaphragmatic esophageal
duplication lying near the gastroesophageal
junction can cause dysphagia and invariably
Right-Sided Thoracic Duplication Cyst contain heterotopic gastric mucosa. The cyst
may lie posterior to the esophagus and stomach
A right-sided thoracic cyst can be at the apex, near and can be difficult to separate from the gastro-
the carina, or inferior to carina (Figs. 3c, d, 5a, c, esophageal junction (Fig. 4a–d). The continua-
and 6b–d). Depending on its position, it may tion of an intrathoracic duplication’s tail is found
cause symptoms and complications. The posterior located on the right side and parallel to the
mediastinal pleura near the cyst is incised either esophagus and seen coming out of the diaphrag-
with scissors or a diathermy hook. The separation matic crus. This cyst can be dissected
of the duplication with the esophagus can easily laparoscopically using a similar principle to the
be carried out by either diathermy scissors or one described above. A separate intra-abdominal
ultrasonic harmonic device. Care should be cyst is successfully resected either at the same
taken during dissection, and structures such as sitting or at a subsequent laparoscopic resection
the vagus nerve, azygous vein, and trachea should (Dresler et al. 1990).
be protected. The right inferior pulmonary vein,
thoracic duct, and azygous vein are at the risk of
injury during right-sided lower esophageal Neuroenteric Cyst
duplications.
Intraoperative endoscopy during resection is Neuroenteric cysts are associated with vertebral
advisable and may help avoid inadvertent resec- anomalies (Figs. 1b and 6d) and may or may not
tion of mucosa and the wall of the native esopha- communicate with the intraspinal component.
gus. The duplication cyst should be resected These cysts are ideally investigated by MRI scan
completely preferably keeping the native esopha- (Fig. 1b). The esophageal component can be
geal mucosa intact. Leaving the duplication cyst resected thoracoscopically as described above.
mucosa usually results in recurrence. The esoph- The communication entering in through the spinal
ageal muscle after resection of the cyst is sutured foramina can be ligated at its entrance into the
with absorbable sutures. Injury to esophageal spinal canal. The intraspinal component can either
mucosa can be detected by an intraoperative be resected at the same time or subsequently by
endoscopy, by keeping saline in the thoracic cav- posterior laminectomy. Rarely anterior spinal
ity and blowing air through an endoscope. The approach is required for its resection. Infected
specimen is decompressed by aspiration and intraspinal components are difficult to resect, and
delivered by expanding one of the anterior ports. at times the wall of the cyst left behind in fear of
Most esophageal duplications following resec- damaging the spinal cord inevitably results in recur-
tion do not require postoperative chest drains. A rence. Specific complications are related to incom-
chest drain is placed only if the esophageal mucosa plete resection and neuronal injury during
is breached during the resection (Piramoon and resection. Late sequel of scoliosis is related to ver-
Abbassioun 1974). Postoperative pain is managed tebral column anomaly.
Fig. 7 Surgical complications: (a) a contrast study inves- cervical duplication. (b) A chest x-ray showing elevated
tigating intermittent dysphagia showing a pharyngeal diaphragm following a resection of a recurrent duplication
pouch formation after complete resection of a left-sided from left apical region
results in stricture formation that may respond

Surgical Complications
to dilation. Late esophageal pseudo-
diverticulums can be a consequence of inappro-
Postoperative-specific morbidities are secondary
priate esophageal repair and incoordination
to esophageal cyst location and surgical approach:
(Parikh and Singh 2011). Rarely motility disor-
der of the esophagus and swallowing difficulties
1. Recurrence is inevitable after an incomplete
are noted in some cases after resection and
resection. Often, there is the need for further
improve with time. After resection of a cervical
surgery.
duplication, a pharyngeal pouch can be a long-
2. Unrecognized injury to the native esophagus
term consequence as a result of tight
may occur following either an open or
cricopharyngeus (Fig. 7a).
thoracoscopic surgery. This often occurs follow-
3. Tracheobronchial injury results in a persistent
ing the repair of an esophagus after the resection
air leak and continuous postoperative bubbling
of an esophageal duplication sharing a common
through intercostal drains. This invariably will
wall. An unrecognized leak can result in a post-
require thoracotomy and formal repair of the
operative pyrexia, mediastinitis, and/or empy-
bronchus or trachea (Bratu et al. 2005). Com-
ema. A minor leak can be managed
plicated esophageal duplications are more
conservatively with a period of parenteral nutri-
likely to cause postoperative air leak either
tion, antibiotics, and chest drainage. However,
from lung parenchyma or from a tracheobron-
significant esophageal injury resulting in signif-
chial injury.
icant leak will result in significant infection and
4. Postoperative bleeding is generally anticipated
will require thoracotomy, esophageal repair, and
in complicated cysts from the dissection of
chest drainage (Michel et al. 1998; Bratu et al.
vascular adhesions or from the lung
2005). Esophageal injury in most instances
parenchyma. In cases when postoperative Cross-References

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Esophageal Perforation
in the Newborn 47
David S. Foley
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
Classification and Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
Diagnosis and Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 706
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
Abstract With early diagnosis and close monitoring,

Esophageal perforations in newborns can even more distally located iatrogenic perfora-
occur for a multitude of reasons and are best tions can often be managed conservatively
classified as iatrogenic or spontaneous. Spon- with good outcomes. Early diagnosis of this
taneous perforation is extremely rare and more condition allows for further surgical treatment
commonly encountered in full-term infants. options such as closed-chest drainage, primary
Iatrogenic perforations are more often seen in repair, or stenting. Delayed diagnosis may
premature, small for gestational age infants and result in the inability to repair the injury pri-
usually occur in the cervical esophagus or marily, a significant increase in mortality, and
hypopharynx. Frequent causes for iatrogenic the eventual need for esophageal replacement
perforation include pharyngeal suctioning, lar- among survivors.
yngoscopy, attempted esophageal intubation,
and digital manipulation of the neonatal head Keywords
during breech delivery. Esophageal perforation · Boerhaave’s
syndrome · Cervical esophagus ·
Hypopharynx · Hydropneumothorax ·
Pneumomediastinum · Esophagography ·
Thoracostomy
D. S. Foley (*)
Department of Surgery, University of Louisville School of
e-mail: dsfole01@louisville.edu

https://doi.org/10.1007/978-3-662-43588-5_51
706 D. S. Foley
Introduction of these maneuvers have the potential to cause

injury to the delicate hypopharynx and proximal
Esophageal perforation can occur for a multitude esophagus in premature neonates, and all have
of reasons in neonates. This condition was first been reported in the literature (Astley and Roberts
reported in the literature by Eklof and colleagues 1970; Su et al. 2009; Lee and Kuhn 1976;
(Eklof et al. 1969). Over the past 40 years, perfo- Wychulis et al. 1969).
ration of the esophagus in extremely premature During instrumentation, particularly when the
neonates has become increasingly recognized and neck is hyperextended, perforation may occur at
reported. Spontaneous perforation of the esopha- the level of the cricopharyngeus muscle, as a
gus (neonatal Boerhaave’s syndrome) is result of compression of the posterior esophageal
extremely rare, and Fryfogle performed the first wall against the cervical vertebrae. The initial
successful repair (Fryfogle 1952). Although non- injury by a laryngoscope blade or endotracheal
operative management techniques are often suc- tube may be submucosal, resulting in a pseudo-
cessfully employed, neonatal esophageal diverticulum. The associated cricopharyngeal
perforations may be fatal without early diagnosis spasm predisposes the weakened area to full
and treatment, and aggressive surgical therapy is thickness perforation during subsequent manipu-
occasionally warranted (Michael et al. 1981; Van lations. Endotracheal intubation, especially in pre-
der Zee et al. 1966; Gander et al. 2009; Hesketh mature, SGA neonates, may further compromise
et al. 2015; Garey et al. 2010). Surgeons must the esophageal introitus. Subsequent oropharyn-
continue to play an early and active role in the geal suctioning or insertion of a nasogastric tube
individualization of care in these patients. may similarly extend the submucosal injury into a
full thickness perforation (Girdany et al. 1969).
Iatrogenic injury to the mid-esophagus is usu-
Classification and Etiology ally associated with dilatation of a stricture or a
postoperative anastomotic leak following esoph-
Esophageal perforations in newborns are best ageal atresia repair (Sloan and Haight 1956;
classified as iatrogenic or spontaneous. Spontane- Eraklis and Gross 1966). An improperly placed
ous perforations are extremely rare and are more chest tube may cause disruption of a fresh esoph-
commonly encountered in full-term infants. The ageal anastomosis or may penetrate a proximal
most common site of perforation is the lower third myotomy site (Johnson and Wright 1990). Chest
of the esophagus. Although the exact cause in tube-related direct pressure necrosis of an other-
individual cases may remain unclear even after wise normal esophagus has been reported in a
treatment, possible etiologies for spontaneous premature neonate (Cairns et al. 1999). As trans-
perforation include increased intra-abdominal esophageal echocardiography has become
pressure at delivery, existing weakness in the increasingly used in the evaluation and manage-
esophageal wall (either congenital or from an ment of congenital heart disease in neonates, per-
perinatal ischemic event), and reflux-associated forations of the proximal and middle esophagus
peptic esophagitis (Aaronson et al. 1975). have been reported with this procedure (Miller
Iatrogenic perforation of the esophagus is more et al. 2015; Mukerideen-Russell et al. 2001).
commonly seen in premature, small for gesta-
tional age (SGA) infants and usually occurs in
the Pharyngoesophageal junction or cervical Diagnosis and Clinical Manifestations
esophagus (Rentea et al. 2017; Mileder et al.
2016; Geoghegan et al. 2014, Ducharme et al. Newborns with iatrogenic esophageal injury fre-
1971). Specific causes in this setting include pha- quently present with hypersalivation, choking or
ryngeal suctioning, laryngoscopy, attempted coughing. Many will have overt respiratory dis-
esophageal intubation, and digital manipulation tress, either from aspiration of oral secretions or
of the neonatal head during breech delivery. All the development of hydropneumothorax. The
47 Esophageal Perforation in the Newborn 707
examiner will have difficulty passing a nasogas-

tric tube, either as the inciting event or as a result
of swelling or a false tract created by prior instru-
mentation. In patients who are not acutely symp-
tomatic, abnormal position of the nasogastric tube
on post-placement chest X-Ray is commonly the
first indication of esophageal perforation
(Ducharme et al. 1971; Soong 2007).
In neonates, the presence of blood-tinged oral
secretions after endotracheal intubation indicates
the potential for iatrogenic injury and justifies
serial X-ray examinations of the chest. The proper
diagnosis often will be missed in the absence of
such an examination. The symptoms of perfora-
tion may not become evident until the child
develops esophageal obstruction and may be dif-
ficult to distinguish from esophageal atresia if the
event occurred close to the time of birth
(Ducharme et al. 1971; Su et al. 2009; Wychulis
et al. 1969).Esophageal perforation may be differ- Fig. 1 Lateral radiograph showing aberrant course of
entiated from atresia of the esophagus by an nasogastric tube, coiled in pericardial sac
asymptomatic interval after birth, a history of
repeated attempts at intubation or vigorous
suctioning, absence of prenatal polyhydramnios,
and the position and course of the nasogastric tube
on chest X-ray (Ducharme et al. 1971). Some
perforations of the esophagus create respiratory
distress secondary to the development of hydro-
or pneumothorax. In these cases, the right pleural
space is most commonly affected (Michael et al.
1981; Gander et al. 2009; Su et al. 2009; Wychulis
et al. 1969). Thoracentesis or tube thoracostomy
will typically yield serosanguinous fluid or the
contents of the previous feeding. In the case
where persistent cloudy drainage occurs follow-
ing chest tube placement, chylothorax should be
suspected (Kairamkonda 2007).
Anteroposterior and lateral X-rays of the chest
and neck are indicated in any suspected case of
perforation. Hypopharyngeal and cervical perfo-
rations frequently demonstrate extraluminal air in
the neck, without pneumomediastinum initially. Fig. 2 AP radiograph demonstrating aberrant course of
Mid-esophageal perforations may demonstrate nasogastric tube, with tip positioned on right side of
pneumomediastinum, pneumothorax, or hydro- mediastinum
thorax. An unusual course of the nasogastric
tube (pleural cavity, pericardial cavity (Fig. 1) or of the mediastinum and blurring of the mediasti-
right side of the mediastinum (Fig. 2)) supports nal margin indicate the development of
the diagnosis and may be confirmatory. Widening mediastinitis but are later findings. The absence
708 D. S. Foley
of these findings does not rule out an injury, but Endoscopic evaluation of the esophagus is typ-
the demonstration of these changes, in the absence ically not indicated at the time of diagnosis, as it
of other confirmatory signs, should prompt con- has the potential to worsen the injury.
trast esophagography. Three types of injury pat- Spontaneous perforation of the neonatal
terns are seen in premature neonates undergoing esophagus usually presents with respiratory dis-
contrast evaluation of the esophagus: (1) a pha- tress, which presents within minutes to hours after
ryngeal diverticulum created by a local cervical the perforation occurs. These patients are usually
leak; (2) a mucosal perforation extending posteri- quite symptomatic. In contrast to the pattern typ-
orly in parallel to the esophagus; and (3) a free ically seen in older children and adults, there is a
intrapleural perforation where there is obvious greater predilection for right-sided hydropneu-
leakage of air and esophageal contents into the mothorax in neonatal Boerhaave’s syndrome
pleural cavity (Mollit et al. 1981). (Aaronson et al. 1975). This may be explained
In cases where chest X-ray demonstrates the by the close adherence of the aorta to the left
nasogastric tube to be located in the pleural cavity side of the esophagus in neonates, which provides
or pericardium, the diagnosis of esophageal per- an additional mediastinal barrier on the left side. If
foration can be confirmed. Localization of the site the perforation remains undiagnosed, respiratory
of perforation may be unnecessary in these cases, distress will worsen with subsequent feedings.
unless the patient’s clinical condition deteriorates Esophagography must be performed in all
after removal of the nasogastric tube appropriate suspected cases of spontaneous perforation with
conservative management. If symptoms suggest hydropneumothorax to evaluate the extent and
esophageal obstruction, esophagography should location of the injury.
be performed by administering a small quantity
of diatrizoate meglumine (Hypaque), diatrizoate
sodium (Renografin), or metrizamide into the Management
proximal esophagus; Gastografin and barium
should be avoided due to the risk of worsening The overall mortality rate in neonates with esoph-
mediastinitis from extravasation or pneumonitis ageal perforation (4%) is significantly less than
from aspiration. In cases of pharyngeal-esophageal that in older children and adults (25–50%).
perforation, cricopharyngeal spasm may be so (Hesketh et al. 2015; Garey et al. 2010; Engum
severe that no contrast material will enter the native et al. 1996). The management of this condition
esophagus. In these cases, several clues may help should follow a selective approach which depends
to differentiate submucosal perforation with sec- upon the size of the patient, the location and
ondary esophageal obstruction from congenital nature of the injury, the time between injury and
esophageal atresia (Blair et al. 1987). initiation of therapy, and the neonate’s response to
These include: initial conservative management when this is
employed (Garey et al. 2010; Mollit et al. 1981;
– An increased distance between the posterior Johnson et al. 1982; Krasna et al. 1987). Despite
wall of the trachea and opacified tract on lateral the frequency with which conservative therapy is
X-ray, as the pouch in congenital esophageal successful in this condition, esophageal perfora-
atresia is usually closely associated with the tion can be a rapidly fatal condition that requires
trachea immediate recognition and aggressive manage-
– A longer, narrower, and more irregular opacified ment for a successful outcome. As a result, pedi-
tract then is seen in esophageal atresia, which atric surgical involvement is warranted early in
typically shows a bulbous uniform pouch the evaluation process. Small submucosal perfo-
– Lack of compression of the posterior trachea rations of the hypopharynx and esophagus, lim-
by the opacified tract on lateral X-ray, as the ited to the mediastinum and without systemic
proximal pouch in esophageal atresia typically symptoms, may be managed by nonoperative
causes tracheal compression methods. Actual localization of the perforation is
not essential in these infants. If the nasogastric chest drainage does not handle the leak, direct
tube is noted in the mediastinum or pericardial repair of the perforation is indicated.
cavity, the tube can be withdrawn and a new Long, linear perforations to the lower end of
tube placed under fluoroscopic control. A broad the esophagus typically require thoracotomy,
spectrum antibiotic should be administered for debridement of the necrotic edges, and primary
7–14 days. IV fluids and hyperalimentation repair of the defect with pleural flap coverage. A
should be given, as oral feedings are withheld. gastrostomy tube may be inserted in these situa-
Esophagography should be performed 7–10 days tions to facilitate gastric decompression and limit
after the injury. If the perforation is completely gastroesophageal reflux during healing. When a
healed, oral feeding may be resumed. If the per- secure direct repair of the perforation is not tech-
foration has not healed during this interval, con- nically feasible because of scarring, inflammation,
servative treatment for another week will often and tissue friability, diverting cervical
lead to complete healing. esophagostomy with closure of the perforated
Routine surgical intervention does not appear area and concomitant gastrostomy is indicated. If
to improve the rate of survival in these newborns. at all possible, efforts should be made to preserve
Tube thoracostomy should be placed when the the native esophagus in an effort to avoid future
chest X-ray indicates pneumothorax (Fig. 3), esophageal replacement.
hydrothorax, or increasing pneumomediastinum. If there is a delay of more than 48 h in the
All newborn infants with esophageal perforation diagnosis of a spontaneous perforation of the
must be carefully monitored during treatment esophagus, unprotected primary repair often can-
(Ramareddy and Alladi 2016), including the use not be safely accomplished. After adequate
of white blood cell counts or C-reactive protein debridement, local esophagectomy with closure
levels, platelet counts, blood gas analyses, and of the proximal and distal esophagus, proximal
chest X-ray evaluation. If there is clinical deterio- esophagostomy, and gastrostomy tube placement
ration or respiratory compromise, and closed should be considered. Critically ill newborns can
be successfully managed with chest tube drainage,
cervical esophagostomy (with or without ligation
of the cardio-esophageal junction), and
gastrostomy (Urschel et al. 1974). Broad spec-
trum antibiotics, IV fluids, and hyperalimentation
should be continued until clinical signs of sepsis
resolve. When the cardio-esophageal junction is
closed, gastrostomy feedings may be attempted
after 48 h. In cases where extensive debridement
or resection is necessary and adequate native
esophagus cannot be preserved, esophageal sub-
stitution will ultimately be necessary. This is typ-
ically done after an interval of at least 6 months, to
allow growth and resolution of mediastinal
inflammation.
Perforations that occur following dilation of
esophageal anastomotic strictures are usually
managed nonoperatively, as long as the leak is
contained or can be adequately drained by tube
thoracostomy. These perforations may take some
Fig. 3 AP radiograph demonstrating nasogastric tube time to heal if there is obstruction distal to the site
coiled in right pleural space, with corresponding of perforation. In the last decade, endoscopic
pneumothorax stenting has been reported as a means of
710 D. S. Foley
containing leakage and promoting healing in these selective management, thereby limiting both mor-
cases. The use of this technique is currently lim- tality and long-term morbidity.
ited in the neonatal population by the size con-
straints of commercially available stents (Ahmad
et al. 2016; Rico et al. 2007). Cross-References
Onwuka et al. (Onwuka et al. 2016) recently
reported the largest series of neonates treated for ▶ Anesthesia and Pain Management
esophageal perforations and found that non- ▶ Congenital Esophageal Stenosis
operative management with bowel rest, parental ▶ Esophageal Atresia
nutrition and antibiotics was successful in 96% of ▶ Specific Risks for the Preterm Infant
neonates.
References
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Blair GK, Filler RM, Theodorescu D. Neonatal pharyngoe-
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performed on premature infants in the modern Cairns PA, McClure BG, Halliday HL, et al. Unusual site
NICU. Gentle laryngoscopy with proper visuali- for oesophageal perforation in an extremely low birth
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Part IV
Newborn Surgery: Chest
Congenital Airway Malformations
48
Richard G. Azizkhan
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Patient Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Medical History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Signs and Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Diagnostic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
Congenital Laryngeal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Laryngomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Subglottic Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
Vocal Fold Paralysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 719
Posterior Laryngeal Cleft . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
Laryngeal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
Subglottic Hemangioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
Anomalies of the Trachea and Bronchi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Tracheal Agenesis and Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Tracheal Stenosis and Webs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
Tracheal Diverticulum and Tracheal Bronchus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
Airway Malacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
Esophageal Bronchus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
Bronchogenic Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
Bronchial Atresia and Bronchial Lobar Agenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
Bronchial Stenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
Abstract
Congenital airway malformations comprise a
broad array of anomalies extending from the
larynx to the distal airway, presenting either
R. G. Azizkhan (*) acutely postnatally or remaining asymptomatic
Children’s Hospital and Medical Center, University of and therefore undiagnosed for years. Clinical
Nebraska College of Medicine, Omaha, NE, USA
symptoms vary widely, depending on the level
e-mail: Razizkhan@childrensomaha.org

https://doi.org/10.1007/978-3-662-43588-5_52
716 R. G. Azizkhan
where the obstruction occurs and its severity. cardiac surgery should be carefully reviewed. All
Due to the distinct anatomy of the pediatric of this information may provide important clues
airway and the possibility of airway symptoms as to the underlying etiology and may impact or
rapidly progressing into life-threatening condi- determine the overall management strategy.
tions, early detection, diagnosis, and treatment
are imperative.
Signs and Symptoms
Keywords
Congenital airway malformations · Patients with mild airway compromise may
Laryngomalacia · Subglottic stenosis · present with subtle symptoms such as irritability,
Subglottic hemangiomas · Vocal fold restlessness, and feeding difficulties. Those with
paralysis · Laryngeal cleft · Congenital high more severe obstruction frequently present with
airway obstruction syndrome · Tracheal severe suprasternal and intercostal retractions,
stenosis · Tracheal rings · Bronchogenic cysts tachypnea, lethargy, and cyanosis. Stridor, defined
as a harsh sound caused by turbulent airflow
through a partially obstructed airway, can mani-
Introduction fest during the expiratory or inspiratory phases
of the respiratory cycle or can be biphasic.
Congenital airway malformations comprise a Inspiratory stridor usually indicates an airway
broad array of anomalies extending from the obstruction in the extrathoracic airway, whereas
larynx to the distal airway. Presentation varies expiratory stridor generally indicates a problem
widely and is influenced by the level at which in the intrathoracic airway. Biphasic stridor
obstruction occurs as well as the severity of typically signifies a fixed glottic or subglottic
obstruction. Given the distinct anatomy of the lesion.
pediatric airway and the possibility of airway The pitch of stridor, as well as its relationship
symptoms rapidly progressing to life-threatening to the respiratory cycle, is generally helpful in
airway compromise, early detection, diagnosis, establishing a differential diagnosis and determin-
and treatment are imperative. The aim of this ing priorities for patient assessment. Clinicians
chapter is to provide an overview of these anom- should, however, be mindful of the fact that that
alies, briefly discussing symptomatology, patient the degree of stridor does not necessarily reflect
assessment, and current management strategies. the severity of airway obstruction. Even minimal
stridor can reflect the lack of airway movement
across a critical airway.
Patient Assessment
Medical History Diagnostic Studies
Assessment of respiratory compromise should The most critical component of the airway assess-
begin with a meticulous review of the child’s ment after physical examination is endoscopic
history of airway symptoms. Clinicians should evaluation. Depending on the type of suspected
explore circumstances that may elicit the onset airway lesion, either flexible or rigid bronchos-
of symptoms and should question parents regard- copy or both are performed. To adequately assess
ing the duration of symptoms and symptom the dynamic aspects of some suspected airway
progression. They should also explore possible lesions (e.g., tracheomalacia), endoscopy should
swallowing or feeding problems, the nature be performed with the patient spontaneously
of the child’s cry, and the possibility of foreign- breathing. Because 17% of patients have a syn-
body aspiration. Additionally, any history of chronous airway lesion, evaluation of the entire
endotracheal intubation, trauma, or previous airway is essential. Given that up to 45% of
48 Congenital Airway Malformations 717
children with congenital airway obstruction first few days of life. Although stridor is generally
also have significant non-airway anomalies, mild, it can be exacerbated by feeding, crying,
all patients require a thorough overall evaluation. or lying in a supine position. Symptoms generally
Imaging studies are helpful in diagnosis as worsen at 4–8 months, improve between 8 and
well as patient management (Javia et al. 2016). 12 months, and resolve by 12–18 months, with
Computed tomography (CT) and magnetic reso- the majority of affected patients amenable to non-
nance imaging (MRI) provide a rapid and precise operative management (Richter and Thompson
way of assessing and measuring the extent and 2008). When the disorder is severe, however,
length of airway narrowing or displacement. children may exhibit apnea, cyanosis, severe
These investigations are also helpful in detecting retractions, and failure to thrive, thus requiring
associated mediastinal and pulmonary anomalies. surgical intervention (Rutter 2006). In extremely
Magnetic resonance angiography (MRA) is valu- severe cases, cor pulmonale can develop. Clinical
able in assessing the relationship of mediastinal studies indicate that secondary airway lesions
great vessel anomalies (e.g., vascular rings, lead to an increased incidence of surgical inter-
pulmonary artery slings) to the airway. Computer vention and gastroesophageal reflux disease
software now allows for three-dimensional image (GERD) (Dickson et al. 2009).
reconstruction and is helpful in planning surgical Flexible transnasal fiber-optic laryngoscopy
procedures. Echocardiography is valuable in is used to confirm the diagnosis. Pathognomonic
identifying intracardiac defects and most associ- findings include short aryepiglottic folds, with pro-
ated great vessel anomalies. Contrast swallow lapse of the cuneiform cartilages. Collapse of the
studies are valuable in assessing esophageal supraglottic structures is seen on inspiration, and
motility, aspiration, and some mediastinal lesions inflammation indicative of reflux laryngitis is also
that affect the airway. Fiber-optic endoscopic frequently seen (Fig. 1). In some patients, a tightly
evaluation of swallowing (FEES) is performed curled (omega-shaped) epiglottis is observed.
to evaluate structural and functional disorders of The decision as to whether to intervene
swallowing and to identify functional problems of surgically is based more so on symptom
the larynx, pharynx, epiglottis, and proximal severity than on the endoscopic appearance of
esophagus. the larynx. For patients with severe symptoms,
Congenital Laryngeal Anomalies
Laryngomalacia
Laryngomalacia is the most common congenital

laryngeal anomaly and the most common cause
of stridor in newborns. This condition is charac-
terized by laxity of both the glottic and supra-
glottic tissues, which causes the epiglottis,
arytenoids, and aryepiglottic folds to collapse
and partially obstruct during inspiration. The
reported incidence of secondary airway lesions
in infants with laryngomalacia varies, with some
authors documenting rates as high as 50%
(Dickson et al. 2009) and 64% (Cohen et al.
1977).
Fig. 1 Endoscopic view of laryngomalacia in an infant
Inspiratory stridor is the hallmark symptom; it showing partial collapse of the supraglottic structures dur-
typically presents soon after birth or within the ing inspiration
718 R. G. Azizkhan
Table 1 Myer-Cotton Level of airway obstruction

grading system for
Classification From To
subglottic stenosis
Grade I No obstruction 50% obstruction
Grade II 51% obstruction 70% obstruction
Grade III 71% obstruction 99% obstruction
Grade IV No detectable lumen
supraglottoplasty (also termed epiglottoplasty) is

the preferred operative procedure, with a reported
surgical success as high as 94% (Richter and
Thompson 2008; Loke et al. 2001; Martin et al.
2005). Both aryepiglottic folds are divided, and
one or both cuneiform cartilages may be removed.
If the aryepiglottic folds alone are divided, post-
operative intubation is usually not required.
Patients should be observed overnight in the
intensive care unit. Antireflux management is
advisable for helping to minimize laryngeal
edema. This is especially important in patients
with a synchronous airway lesion, who, as men-
tioned earlier, have an increased incidence of Fig. 2 High-grade subglottic stenosis in a symptomatic
GERD (Dickson et al. 2009; Richter and Thomp- neonate
son 2008). Synchronous airway lesions as well as
neurologic conditions and preexisting laryngeal
edema can adversely affect operative outcomes syndrome (Azizkhan 2005). In the premature
(Schroeder et al. 2009). Occasionally, an infant’s infant, SGS is considered present when this
obstructive symptoms continue despite an lumen measures 3.0 mm or less in diameter at
adequate postoperative appearance of the larynx. the level of the cricoid, whereas in the full-term
These infants may have an underlying neurologic neonate, SGS is defined as a lumen of 4.0 mm or
problem that may become more evident over time, less in diameter at this level.
and they are therefore more likely to require Levels of SGS severity range from mild to
tracheotomy placement. severe and are graded based on the Myer-Cotton
grading system (Table 1). Patients with mild SGS
(no obstruction to 50% obstruction) may present
Subglottic Stenosis with recurrent upper respiratory infections, often
misdiagnosed as croup. In a young child,
Subglottic stenosis (SGS) is an anomaly that the greatest obstruction is usually 2–3 mm below
involves a narrowing of the subglottic lumen. the true vocal folds (Rutter 2006). Patients with
Although it can be either congenital or acquired, more severe narrowing may present with acute
the latter is far more common and is generally airway compromise and require endotracheal intu-
a sequela of prolonged intubation of the neonate. bation or tracheotomy placement at delivery
Congenital SGS is thought to be caused by failure (Fig. 2). However, many of these infants, even
of the laryngeal lumen to recanalize during those with grade III SGS (71–99%), may not be
embryogenesis. It may occur as an isolated anom- symptomatic for weeks or months. When stridor is
aly or may be associated with other congenital present, it initially occurs during the inspiratory
head and neck lesions and chromosomal anoma- phase of respiration. As SGS severity increases,
lies such as a small larynx in patients with Down stridor becomes biphasic.
Radiologic evaluation of the non-intubated Vocal Fold Paralysis

airway can provide information regarding the
site of the stenosis and its extent. Chest X-ray, Vocal fold paralysis can be congenital or acquired
inspiratory and expiratory lateral soft tissue neck and can occur either unilaterally or bilaterally.
films, and fluoroscopy are helpful in revealing Unilateral paralysis is usually an acquired condi-
the dynamics of the trachea and larynx. High- tion caused by damage to the recurrent laryngeal
kilovoltage airway films identify the classic nerve (RLN). Because of the length and course of
steeplelike configuration seen in patients with the left RLN, this is far more likely to be damaged
SGS as well as possible tracheal stenosis than the right RLN. Acquired paralysis thus gen-
and are therefore of utmost importance. erally affects the left vocal fold. Unlike unilateral
Flexible endoscopy and rigid endoscopy are vocal fold paralysis, bilateral paralysis is usually
used in a complementary fashion for evident at birth. It is generally idiopathic but often
airway evaluation and are both essential. is seen with central nervous system conditions
Flexible endoscopy provides critical infor- such as hydrocephalus and Chiari malformation
mation regarding the structural dynamics of air- of the brainstem.
flow in the hypopharyngeal and laryngeal The diagnosis is made by flexible laryngos-
airways. Rigid endoscopy provides an assess- copy with the patient awake. Investigation aimed
ment of the entire laryngotracheobronchial at finding the underlying cause is then carried out.
airway. Stabilization can be achieved with intubation,
In children with mild-to-moderate disease continuous positive airway pressure (CPAP), or
(grade I or II), congenital SGS improves with high-flow nasal cannula as an alternative tempo-
age. Children with a minor degree of SGS who rizing measure. Almost all infants with bilateral
experience mild symptoms may, nevertheless, paralysis require tracheotomy placement to ensure
benefit from endoscopic intervention. Endo- a safe and adequate airway. However, up to 50%
scopic options include radial laser incisions of children with congenital idiopathic bilateral
through the stenosis and laryngeal dilatation paralysis experience spontaneous resolution of
(Monnier et al. 2005). Outcomes are improved their paralysis by age 1 (Miyamoto et al. 2005).
when mitomycin C is used concomitantly with In view of possible resolution, decannulation is
this approach (Smith and Elstad 2009). Less than almost always delayed to allow time for this to
50% of these patients require tracheotomy place- occur. Children with acquired bilateral paralysis
ment to maintain their airway. Children with may also experience spontaneous recovery, pro-
more severe disease are best managed with vided that the RLN was stretched or crushed but
open subglottic airway reconstruction. Costal otherwise intact.
cartilage grafts can be placed through either the Because no single surgical approach offers a
anterior or posterior lamina of the cricoid carti- universally acceptable outcome, a number of sur-
lage or both. This may be carried out as a single- gical approaches have been used for children with
stage laryngotracheoplasty (White et al. 2009; de bilateral paralysis. These approaches include laser
Alarcon and Rutter 2008) or as a two-stage pro- cordotomy, partial or complete arytenoidectomy,
cedure, requiring stenting and placement of a and vocal cord medialization or lateralization
temporary tracheostomy (Monnier 2007). For (open or endoscopically guided) (Sipp et al.
severe SGS, good results have been achieved 2007; Chen and Inglis 2008). Recently, endo-
by performing partial or complete cricotracheal scopic percutaneous suture lateralization has
resection and reconstruction; however, this is a been reported to be a safe and effective nonde-
demanding procedure with considerable structive primary treatment modality for neonatal
risks. Successful outcome depends on the man- bilateral vocal fold immobility (Montague et al.
agement of comorbidities such as GERD, eosin- 2018). The aim of each of these procedures is to
ophilic esophagitis, and low-grade tracheal achieve an adequate decannulated airway while
infection. maintaining voice and preventing aspiration.
720 R. G. Azizkhan
Fig. 3 Posterior laryngeal cleft classification
Posterior Laryngeal Cleft transient cyanosis, and recurrent chest infections

(Rutter 2006; Rutter et al. 2003a). Airway
Posterior laryngeal cleft is a rare congenital obstruction manifested by stridor may also be
anomaly that results from failure of the present and is caused either by redundant mucosa
laryngotracheal groove to fuse during embryo- on the edge of the cleft or a small cricoid ring. In
genesis. This anomaly comprises four anatomic patients with severe tracheomalacia, especially
subtypes that differ with respect to involvement those with an associated TEF, the airway may be
of the larynx and/or trachea (Fig. 3). Patients significantly compromised. Contrast swallow
frequently have coexisting anomalies, many studies may demonstrate aspiration; however,
of which affect the airway. Associated airway rigid laryngoscopy and bronchoscopy are essen-
anomalies include tracheomalacia (almost tial for definitive diagnosis. The interarytenoid
always present in varying levels of severity), area is specifically probed to determine if a poste-
tracheoesophageal fistula (TEF) formation rior laryngeal cleft is present.
(20%), laryngomalacia, vocal fold paralysis, In children who are symptomatic and do not
SGS, and innominate artery compression. have other more severe anomalies, repair of
Associated non-airway conditions include the posterior laryngeal cleft should be performed
anogenital anomalies, cleft lip and palate, congen- as soon as possible to prevent chronic micro-
ital heart defects, and GERD, which affects aspiration with long-term pulmonary sequelae.
most children. The most common associated Depending on the extent of the airway anomaly,
syndrome is Opitz-Frias syndrome, characterized tracheotomy and gastrostomy tube placement
by hypertelorism, anogenital anomalies, and may be required before definitive surgical repair
posterior laryngeal clefting. of the airway. Because of the high incidence of
Diagnosis can be extremely difficult, as pre- GERD, fundoplication is often required and is
senting symptoms vary greatly. In type I and preferably performed prior to surgical repair.
type II clefts, symptoms are often subtle and Most type I and some type II clefts are amenable
may mimic those of other disorders such as to endoscopic surgical repair, whereas clefts
GERD. Nonetheless, aspiration is a hallmark clin- that extend into the cervical or thoracic trachea
ical feature of this spectrum of disease. With more require open repair. A transtracheal approach is
severe clefts, gross aspiration may occur with advised, as it provides optimal exposure of the
associated apnea, cyanosis, and even pneumonia. cleft while protecting the recurrent laryngeal
For milder clefts, the symptoms are those of nerves. A two-layer closure is recommended,
microaspiration, with choking episodes, with the option of performing an interposition
graft if warranted. Type IV long clefts, which

extend to the carina or beyond and are often
associated with multiple congenital anomalies,
are exceedingly difficult to repair and are
prone to anastomotic breakdown (Rutter et al.
2003a). Success rates for cleft repair vary
significantly (50–90%) depending on both the
severity of the cleft and the presence of
comorbidities.
Laryngeal Atresia
Congenital High Airway Obstruction

Syndrome
Congenital high airway obstruction syndrome
(CHAOS) is a rare, life-threatening, prenatally
diagnosed condition caused by complete or near-
complete obstruction of the larynx and trachea.
Fetal lung fluid becomes trapped, causing the
lungs to become abnormally distended. This cre-
ates massive lung expansion that characteristi-
Fig. 4 Fetal ultrasonography at 27 weeks gestation dem-
cally everts the hemidiaphragms. onstrating findings consistent with the diagnosis of con-
This type of fetal airway obstruction may be genital high airway obstruction: enlarged echogenic lungs,
caused by multiple etiologies, including laryngeal dilated airway (white arrow), flattened or everted dia-
phragms, and fetal ascites (white star) and hydrops. Fetal
atresia, laryngeal web, tracheal atresia, and laryn-
liver and intestines marked with a black arrow
geal cyst (Marwan and Crombleholme 2006).
Prenatal findings on ultrasonography include dif-
fuse and enhanced echogenicity of the lungs, For the newborn diagnosed with CHAOS,
dilated airways, and flattened or everted dia- securing and maintaining the airway are the
phragms with associated fetal ascites and non- highest priority. These patients are almost always
immune hydrops (Fig. 4). A fetus identified with extremely ill and require a prolonged period of
these sonographic features is at significant risk of critical care and ventilatory support. Once the
intrauterine death and faces a high likelihood infant’s cardiorespiratory status is stable and
of mortality should the pregnancy progress to other critical or potentially life-threatening anom-
delivery. Although US provides a good initial alies are ruled out, careful endoscopic evaluation
assessment of CHAOS, MRI is clearly superior of the airway precedes elective laryngotracheal
in identifying severity and the level of airway reconstruction; however, consensus has not
obstruction and optimizes planning for airway been reached as to optimal timing of airway
management at delivery (Mong et al. 2008). reconstruction. Although a functional airway can
These patients all require delivery by the ex be constructed, patients do not always attain intel-
utero intrapartum technique (EXIT) procedure ligible speech capabilities.
(Laje et al. 2016). This procedure maintains pla- Diagnosis in the middle of the second trimester
cental circulation to the fetus while securing the generally correlates with a poor perinatal out-
airway at the time of delivery (Marwan and come. A fetus presenting in the third trimester
Crombleholme 2006). Securing the airway may with CHAOS in the absence of associated anom-
include a full endoscopic diagnostic assessment alies or hydrops is likely to have incomplete
and tracheostomy. obstruction and is therefore more likely to survive.
722 R. G. Azizkhan
Subglottic Hemangioma eye abnormalities (Perkins et al. 2009; O-Lee and

Messner 2008).
Hemangiomas of infancy (also referred to as As a subglottic hemangioma undergoes prolif-
infantile hemangiomas) are the most common eration, progressive worsening of the airway
vascular tumors, affecting one in ten white usually occurs. Presenting symptoms include
infants in North America (Mulliken et al. 2000) biphasic stridor with retractions. The degree of
and occurring with a threefold female preponder- obstruction varies and can be exacerbated by
ance. These benign lesions usually follow certain positions or crying, both of which increase
a predetermined phase of growth (proliferation) venous pressure and lead to vascular engorge-
and later tumor regression (involution). The ment. When airway narrowing is severe, apnea,
involutive phase occurs at 12–18 months and cyanosis, and “dying spells” may result.
is generally complete by the first decade of life. The diagnosis is based on medical history and
Hemangiomas generally present cutaneously findings on airway endoscopy. Lesions are
but can occur in any organ or anatomic site. typically asymmetric and may be covered by a
Airway hemangiomas most frequently occur in normal smooth mucosa (Fig. 5b). Because of the
the subglottis; however, they are also seen in the risk of hemorrhage, biopsy is not advised. Most
glottic and supraglottic regions. Their natural patients require treatment, and combining various
history generally mirrors that of cutaneous treatment modalities is often essential. At Cincin-
lesions. More than 50% of patients with a sub- nati Children’s Hospital Medical Center,
glottic hemangioma also have cutaneous heman- symptomatic patients with significant stridor are
giomas, which provide an indication for the currently managed with systemic steroids com-
possible presence of a synchronous subglottic bined with propranolol, a nonselective beta-
lesion. Patients at the highest risk for a subglottic blocker used to treat infants with cardiovascular
hemangioma include those with a hemangioma conditions. In recent years, numerous publica-
occurring in a beard distribution (Orlow et al. tions have documented dramatic results with
1997) (Fig. 5a) and those with PHACE syndrome, the use of propranolol for severe subglottic
which is characterized by posterior fossa abnor- hemangiomas (Truong et al. 2010; Jephson et al.
malities, hemangiomas of the cervicofacial region 2009; Léaute-Labrèze et al. 2008; Denoyelle
that are usually plaque-like and segmental, arte- et al. 2009; Gunturi et al. 2013; Leboulanger
rial defects, cardiac and aortic arch defects, and et al. 2010), thereby changing the paradigm of
Fig. 5 (a) Patient with multiple cutaneous lesions in a beard distribution. (b) Endoscopic view of a subglottic
hemangioma
both pharmacologic and surgical treatment. the trachea differ in the degree and extent of
A systematic review of 41 propranolol studies stenosis, which can range from extremely thin
published between June 2008 and June 2012 that webs to more severe long segments of stenosis
collectively included more than 1200 patients affecting the entire airway.
(mean age, 6.6 months) with a spectrum of poten-
tially life- or function-threatening hemangiomas Tracheal Webs
at various anatomic sites showed an impressively Tracheal webs involve an intraluminal soft tissue
high efficacy rate (98%) and a low rate of serious stenosis of the trachea. These webs may be mem-
adverse advents (Marqueling et al. 2013). branous or consist of thick, relatively rigid tissue.
For critical airways, some surgeons still advocate Patients typically present with biphasic stridor
laser fulguration or translaryngeal resection, whereas or expiratory wheezing, and the severity of these
others place a tracheotomy below the lesion, with the symptoms depends on the degree of the stenosis.
expectation of removal following involution of the Thin webs can be easily managed by hydrostatic
hemangioma (Perkins et al. 2009; Bajaj et al. 2006). balloon dilatation (Ganzer 1987). For thicker
webs that are not associated with underlying
cartilage deformity, laser ablation is often used
Anomalies of the Trachea and Bronchi (Azizkhan et al. 1990). The carbon dioxide
(CO2) or potassium-titanyl-phosphate (KTP)
Tracheal Agenesis and Atresia laser is beneficial for treating lesions in the prox-
imal trachea. Lesions in the distal airway are
Tracheal agenesis is very rare, occurring in 1 in best managed with the KTP laser, which can be
50,000 to 1 in 100,000 live births and usually used through small fiber-optic cables. For children
results in fatal outcome (Boogaard et al. 2005; with a web greater than 1 cm in length or those
Varela et al. 2018). The cervical trachea is usually in whom the airway cartilage is thought to
absent. The bronchus or the carina is connected to be structurally deficient or anomalous, operative
the esophagus. Floyd proposed an anatomic clas- treatment with segmental tracheal resection or
sification in three types (Floyd et al. 1962): slide tracheoplasty is usually carried out.
Type I: representing the 20%. There is agenesis of Cartilaginous Ring Aplasia

the upper trachea. Bronchus is normal. There is Cartilaginous ring aplasia is an extremely rare
a tracheoesophageal fistula. anomaly in which only a small region of the
Type II: the most frequent representing 60% of all trachea lacks cartilage, creating a distinct ana-
the cases reported. There is a complete tracheal tomic area that is both malacic and stenotic. The
agenesis. Bronchus is normal, and there is a remainder of the trachea is unaffected, and most
fistula between the carina and esophagus. children do not have coexisting congenital
Type III: the bronchus arises from the esophagus anomalies. Management entails segmental resec-
separately. tion of the trachea, which successfully restores the
The presence of a tracheoesophageal or bronchoe- airway.
sophageal fistula is important for salvage treat-
ment of a critically ill neonate with tracheal Tracheal Cartilaginous Sleeve
agenesis, because it allows esophageal intuba- Tracheal cartilaginous sleeve is also extremely
tion and mechanical ventilation. rare. In children with this anomaly, discrete carti-
laginous rings are replaced by a fused cartilagi-
nous cylinder, with or without a membranous
Tracheal Stenosis and Webs portion. It is typically seen in children with
craniosynostosis syndromes such as Pfeiffer,
Tracheal stenosis encompasses a broad spectrum Apert, Crouzon, and Goldenhar (Davis et al.
of rare tracheal anomalies. Affected segments of 1992; Hockstein et al. 2004; Elloy et al. 2006).
724 R. G. Azizkhan
Neonates usually exhibit respiratory illness. the perinatal period to subtle symptoms of airway
Patients presenting in early infancy often experi- compromise in older children. Most symptomatic
ence acute respiratory symptoms, which infants exhibit deterioration of respiratory func-
may include biphasic stridor with respiratory dis- tion over the first few months of life. Symptoms
tress, cough, and frequent respiratory infections. include stridor, retractions, cough, and alterations
Because of tracheal rigidity, the mechanism for of cry. Atypical and persistent wheezing and rhon-
clearing secretions is impaired. chi and sudden death can also occur. More than
On endoscopy, the anterior tracheal wall 80% of children with complete tracheal rings have
appears smooth, though the membranous poste- other and often multiple congenital anomalies;
rior tracheal wall may be normal, stenotic, or 50% have congenital heart disease with or without
absent. CT and MRI are sometimes useful in great vessel anomalies (Rutter 2006).
determining the extent of the lesion. Tracheotomy In some patients, placement of an endotracheal
placement may be used as a temporizing measure; tube may further exacerbate respiratory distress
however resection and repair are imperative to by causing acute swelling and inflammation of
achieve normal function. the mucosa. Partially obstructing tracheal lesions
also may become life-threatening following
Complete Tracheal Rings the onset of a respiratory infection. In an infant
Although rare, complete tracheal rings are the or child with an abnormal trachea, the cross-
most common congenital tracheal stenosis sectional area of airway can be significantly
(Windsor et al. 2016). With this spectrum of decreased with as little as 1 mm of edema. This
potentially life-threatening anomalies, either the accounts for the rapid worsening of symptoms in
trachea alone or both the trachea and bronchi are some children with acute inflammatory conditions
significantly narrowed. The tracheal cartilage in and coexisting tracheal narrowing.
these patients is abnormally shaped and forms Prompt diagnostic evaluation to define tra-
complete rings (Fig. 6). More than 50% of cheobronchial anatomy is essential. An initial
infants have a segmental stenosis. The clinical high-kilovolt airway film may indicate stenosis;
manifestations of complete tracheal rings vary however, bronchoscopy is required to reveal the
from life-threatening respiratory distress during precise location and extent of the stenosis.
Fig. 6 Congenital tracheal stenosis. (a) Endoscopic view demonstrating complete tracheal rings. (b) Histology showing
cartilaginous rings that are circumferential
Bronchoscopy should be performed with extent and length of airway narrowing or dis-
extreme caution, using the smallest possible tele- placement. Three-dimensional reconstruction of
scopes, and any airway edema in the region of the airway and its relationship to the great ves-
the stenosis may turn a narrow airway into a sels aids in operative planning. Furthermore,
critical airway (Rutter 2006). CT scans provide with new software enhancements, virtual bron-
a rapid and precise method of measuring the choscopic images can be obtained. These images
are particularly useful in assessing the airway
distal to the obstruction (Fig. 7). MRI is also
valuable in evaluating the relationship of
the mediastinal great vessels to the airway. Echo-
cardiography is used mainly to determine
whether intracardiac defects are present and can
identify most coexisting pulmonary artery
slings.
Approximately 10% of patients with complete
tracheal rings are minimally symptomatic and
can be managed nonoperatively, though they
require ongoing observation. Most children must
undergo tracheal reconstruction (Rutter et al. 2004).
Repair of coexisting anomalies such as pulmonary
artery sling or vascular ring should be carried out
concurrent with the tracheal repair. Although patch
tracheoplasty was historically the preferred proce-
dure for long segments of narrowing, slide
Fig. 7 CT scan with three-dimensional reconstruction to
tracheoplasty is now the procedure of choice for
demonstrate anatomy of the trachea in a patient with con- both short- and long-segment stenosis (Fig. 8)
genital tracheal stenosis involving a significant portion of (Rutter et al. 2003b; de Alarcon and Rutter 2012).
the trachea This approach results in significantly less morbidity
Fig. 8 Slide tracheoplasty. The trachea is transversely portion of the caudal tracheal segment are incised. The two
divided at the midpoint of the tracheal stenosis. After tracheal segments are then overlapped and obliquely
proximal and distal tracheal mobilization, the posterior sutured together
portion of the cephalic trachea segment and the anterior
726 R. G. Azizkhan
than other tracheal reconstruction techniques and is with a rudimentary lung. Tracheal bronchus most
adaptable to all anatomic configurations of com- often affects the right upper lobe bronchus and may
plete tracheal rings. Slide tracheoplasty uses only connect to an isolated intrathoracic lung segment or
autologous tracheal tissue and is performed by the apical segment of an upper lobe. Both anoma-
transecting the trachea into two equal segments. lies frequently occur along with other tracheal,
The anterior wall of the lower half of the trachea esophageal, and pulmonary anomalies. Diagnosis
and the posterior wall of the upper trachea are is established by airway endoscopy. Most children
incised. These segments are then slid over each are asymptomatic and do not require treatment.
other and anastomosed with 5-0 monofilament Pneumonia and respiratory distress may be the
and absorbable sutures. Postoperatively, the cross- presenting symptoms during the neonatal period.
sectional area of the airway has a fourfold increase, These symptoms are almost always associated with
and the length of the involved airway decreases by stenosis of a bronchus or other lung anomalies.
half. Airflow is increased 16-fold. Resection of involved lobe and bronchus in these
Postoperatively, endotracheal intubation is gen- patients is generally curative.
erally required for 1–2 days, though some patients The most common cause of tracheal diverticu-
with parenchymal pulmonary disease require longer lum is iatrogenic, following division of a TEF
ventilatory support. During the perioperative period, where a small remnant of the esophagus is left on
unnecessary movements of the endotracheal tube or the tracheal side. These defects can be readily man-
unplanned extubation must be avoided so to mini- aged with endoscopic resection (Cheng and Gazali
mize the risk of damage to the newly reconstructed 2008; Shah et al. 2009; Johnson et al. 2007).
airway. Nasotracheal intubation is preferred, as the
endotracheal tube can be more securely stabilized.
Patients require continuous monitoring, careful pul- Airway Malacia
monary toilet, and endoscopic removal of any
obstructing granulation tissue. Immediately prior to Airway malacia is a condition in which the struc-
extubation, the integrity and patency of the tural integrity of either the trachea or bronchi or
reconstructed airway are assessed by flexible fiber- both is weakened and the cartilaginous rings of the
optic endoscopy through the endotracheal tube, thus airway lack the rigidity required to avoid airway
ensuring a safe extubation. collapse during expiration. Malacia may be local-
Although airway configuration following ized or occur diffusely throughout the airway.
slide tracheoplasty may resemble a figure Tracheomalacia is the most common congenital
eight, this does not indicate airway obstruction. tracheal anomaly. This condition may occur in
The trachea generally remodels to a normal oval isolation or in conjunction with other congenital
shape within 1 year of reconstruction. Long- anomalies. TEF, esophageal atresia, and posterior
term survival is currently 90% in our institution. laryngeal clefts are particularly common associa-
Mortality is usually associated with severe tions (McNamara and Crabbe 2004). Premature
comorbidities such as cardiac disease rather neonates and children with chronic lung disease
than airway complications. are at high risk for developing combined severe
tracheobronchomalacia.
Presenting symptoms vary depending upon
Tracheal Diverticulum and Tracheal the severity, duration, and region of airway
Bronchus involvement. Most children are either asymp-
tomatic or minimally symptomatic, and most
Tracheal diverticulum and tracheal bronchus are cases involve posterior malacia of the trachealis,
relatively common embryologic abnormalities of with associated broadening of the tracheal rings.
early tracheal budding. Tracheal diverticulum Presenting symptoms may include a honking
resembles a bronchus, though it originates from cough, stridor, wheezing, respiratory distress
the trachea and ends blindly or communicates when agitated, and cyanosis. Some children are
misdiagnosed with allergic asthma and unsuc- Inadequate bronchial drainage usually results in
cessfully treated with bronchodilators. Diagno- recurrent pulmonary infection and parenchymal
sis is best established by bronchoscopy, with the damage (Tsugawa et al. 2005). Nonetheless, some
patient breathing spontaneously; this demon- patients remain undiagnosed until adolescence or
strates dynamic distortion and compression of adulthood despite recurring pneumonias and persis-
the trachea. In children who are minimally symp- tent radiographic abnormalities. Although radio-
tomatic, symptoms often resolve by age 3. These graphic findings vary with the segment of the lung
children are managed with observation alone. affected by the anomaly, collapse, consolidation,
Children who experience symptom progression cavitation, and cyst formation within the pulmonary
require medical or surgical intervention (McNa- parenchyma are commonly seen. The diagnosis is
mara and Crabbe 2004). For some patients, confirmed by a contrast study of the esophagus,
respiratory monitoring with nasal CPAP may be though false-negative results sometimes occur.
sufficient to effect improvement. Excision of the abnormal lung and closure of the
Segmental tracheal involvement is managed bronchoesophageal fistula is the treatment of choice
with endoscopic or open aortopexy, with thymec- in patients beyond the neonatal period. Prognosis
tomy and anterior suspension of the ascending depends on early diagnosis and treatment and the
arch of the aorta to the posterior periosteum of severity of associated anomalies. Bronchotracheal
the sternum (Perger et al. 2009). More diffuse reconstruction has been successfully accomplished
malacia may require tracheotomy placement in neonates diagnosed with esophageal bronchus
with positive pressure ventilation over a long (Michel et al. 1997).
duration. For patients with severely problematic
tracheobronchomalacia that is unresponsive to
nonoperative therapy or unsuitable for surgical Bronchogenic Cyst
treatment, intratracheal stents are placed; how-
ever, this approach is associated with serious Bronchogenic cysts stem from aberrant embryo-
complications such as stent collapse, stent dis- genesis of the bronchial tree in which a segment of
lodgement, or, rarely, stent erosion into the great the lung bud develops independently. The walls of
vessels (Wallis and McLaren 2018). Additionally, the cyst often contain fibrous tissue and cartilag-
stent removal can cause tracheal tearing or major inous remnants, while the internal surface consists
hemorrhage. of ciliated columnar epithelium (Stocker 2009).
Lesions usually expand, causing extramural com-
pression of the airway. The most commonly seen
Esophageal Bronchus symptom in infants is respiratory distress.
Coughing, wheezing, or chest pain also may be
Isolated bronchial connection between the esoph- present. A plain chest radiograph may suggest the
agus and the airway is extremely rare and occurs presence of a bronchogenic cyst. A CT scan or
more frequently in females (2:1). Associated car- MRI is valuable in establishing a definitive diag-
diac, genitourinary, vertebral, and diaphragmatic nosis (Fig. 9a). Patients are successfully managed
anomalies are common. Esophageal bronchus is by open or thoracoscopic resection (Fig. 9b)
thought to develop from a supernumerary lung (Koontz et al. 2005; Hirose et al. 2006).
bud arising from the esophagus. Most commonly,
a lower lobe is aerated by this ectopic bronchus;
however, an entire main bronchus and lung may Bronchial Atresia and Bronchial Lobar
be affected. As in pulmonary sequestration anom- Agenesis
alies, the pulmonary vasculature may be abnor-
mal, with the arterial supply coming off the aorta Bronchial Atresia
and venous drainage going into either the sys- Localized bronchial atresia is a rare abnormality
temic or pulmonary veins. in which the atretic bronchus impedes the flow of
728 R. G. Azizkhan
Fig. 9 (a) MRI demonstrating a right-sided bronchogenic view of a bronchogenic cyst. The parietal pleura has been
cyst just below the right main bronchus. (b) Thoracotomy opened in the process of removal
secretions and air from the distal lung to the Diagnosis is established by chest radiographs
main tracheobronchial tree. This condition may and airway endoscopy. Most patients can be
mimic lobar emphysema or a mediastinal managed nonoperatively. Bronchial agenesis is
mass (Morikawa et al. 2005). At birth, the important to identify, as it may mimic other air-
affected lung retains fluid. A CT chest scan way and cardiovascular anomalies requiring
may show a cystic central mucocele and is treatment (e.g., bronchial stenosis or extra-
valuable in distinguishing bronchial atresia luminal airway obstruction by tumors or
from a bronchogenic cyst or lobar emphysema. masses).
Although children may initially be asymptom-
atic, secretions trapped in the lung may result in
serious pulmonary infection. Surgical resection Bronchial Stenosis
of the affected lobe restores normal lung
function. Isolated congenital bronchial stenosis is
extremely rare, with causality including compres-
Bronchial Lobar Agenesis sive vascular, cardiac, and congenital cystic
Bronchial agenesis is more commonly seen lesions or soft tissue cartilaginous stenoses.
than tracheal agenesis, and unlike tracheal Symptoms and treatment vary, depending on
agenesis, it is compatible with life. Several ana- both the severity and anatomic location of the
tomic configurations have been described; these lesion. Surgical management includes resection
include lobar, bronchial, and parenchymal and reconstruction of the bronchus and slide
agenesis. In the most severe form, complete bronchoplasty (Antón-Pacheco et al. 2007; Grillo
agenesis of the lung and its bronchus and blood et al. 2002).
supply may occur (Morikawa et al. 2005). Acquired bronchial stenosis is more common
Also, there may be a rudimentary bronchus and than its congenital manifestation and is a signifi-
aplasia of the lung. As with most airway cant cause of morbidity and mortality in infants
malformations, children may have coexistent who have undergone prolonged intubation and
congenital anomalies. Most commonly, these respiratory support. Most cases can be managed
anomalies involve the skeletal, cardiovascular, with endoscopic balloon dilatation or laser resec-
gastrointestinal, and genitourinary systems. tion (Azizkhan et al. 1990).
Conclusion and Future Directions Chen EY, Inglis AF Jr. Bilateral vocal cord paralysis.
Otolaryngol Clin N Am. 2008;41:889–901.
Cheng ATL, Gazali N. Acquired tracheal
Congenital airway malformations may be a diverticulum following repair of tracheo-oesophageal
diagnostic and therapeutical challenge as they fistula: endoscopic management. Int J Pediatr
include a wide array of anomalies, some of Otorhinolaryngol. 2008;72:1269–74.
them extremely rare, with a broad spectrum of Cohen SR, Eavey RD, Desmond MS, May BC. Endoscopy
and tracheotomy in the neonatal period: a 10-year
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Vascular Rings
49
Benjamin O. Bierbach and John Mark Redmond
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Definition and History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
Frequency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
Forms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
Double Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
Right Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
Pulmonary Artery Sling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
Vascular Rings Associated with Left Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
Clinical Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
Associated Syndromes and Noncardiac Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Laboratory Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Chest Radiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741
Barium Esophagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Echocardiography and Color Flow Doppler . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 742
Computerized Tomography Scan, Magnetic Resonance Imaging, and Digital
Subtraction Angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
Bronchoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
Indication for Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
Surgical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744
B. O. Bierbach (*)
Department of Paediatric Cardiac Surgery, German
Paediatric Heart Center Sankt Augustin, Sankt Augustin,
Germany
e-mail: bier.bach@gmx.de
J. M. Redmond
Our Lady’s Children’s’ Hospital, Dublin, Ireland
Mater Misericordiae University Hospital, Dublin, Ireland
e-mail: mark@redmondireland.com

https://doi.org/10.1007/978-3-662-43588-5_53
734 B. O. Bierbach and J. M. Redmond
Division of a Double Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744

Video-Assisted Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
Right Aortic Arch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745
Pulmonary Artery Sling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
Left Aortic Arch with Anomalous Origin of the Innominate Artery . . . . . . . . . . . . . . . . . . . 746
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 746
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 747
Abstract not compromise the blood flow to the head

Vascular rings are rare congenital anomalies vessels. In patients with right-sided aortic
caused by an anomalous configuration of the arch, the ligamentum arteriosum is divided.
aortic arch or associated vessels surrounding Division of the left subclavian artery is not
the trachea and esophagus to form a complete generally necessary for relieving tracheal
or incomplete compressing ring around them. compression. Patients with an anomalous left
They make up less than 1% of all congenital subclavian artery and Kommerell’s diverticu-
cardiac defects. The most common forms are lum may additionally have resection of the
double aortic arch, right aortic arch, pulmonary diverticulum and reimplantation of the left sub-
artery sling, vascular rings associated with left clavian artery to the left carotid artery as a
aortic arch, and cervical aorta. primary operation.
Patients often present with symptoms in the Excellent results have been achieved in
first few months of life and require surgery recent years without operative mortality in
early in life. The classic sign is the “seal- high-volume centers. Most of the patients are
bark” cough. In addition noisy breathing may essentially free of symptoms in the long term,
be heard both during inspiration and expiration and only a very small number need further
(biphasic stridor). A common finding in all interventions or supportive treatment.
forms of vascular rings is the increased occur-
rence of respiratory infections. Keywords
Diagnostic tests for visualization of the rel- Biphasic stridor · Cervical aorta · Double
evant pathology and the exact location of the aortic arch · Dysphagia · Pulmonary artery
obstruction include computerized tomography sling · Kommerell’s diverticulum · Right-sided
scan, magnetic resonance imaging, and digital aortic arch · Seal-bark cough
subtraction angiography. Echocardiography is
useful in the diagnostic workup of associated
congenital cardiac defects. Introduction
In patients with pulmonary artery sling,
repair is undertaken via median sternotomy Vascular rings are congenital vascular anomalies
utilizing cardiopulmonary bypass and of the aortic area system that compress the esoph-
reimplanting the left pulmonary artery agus and trachea, causing symptoms related to
onto the left side of the main pulmonary these two structures. There are two types of vas-
artery. If necessary, tracheal repair can be cular rings: those that are complete and have
performed concurrently. All other lesions are vascular structures completely encircling the
usually approached via a left-sided thoracot- trachea and esophagus and rings that are incom-
omy. The goal of surgical therapy in patients plete and only compress a portion of esophagus or
with a double aortic arch is to divide the trachea without encircling as a complete ring
smaller of the two arches at a site that does (Licari et al. 2015). The most common complete
49 Vascular Rings 735
vascular rings are double aortic arch and right predominance exists. Some vascular rings are
aortic arch, representing 95% of vascular rings associated with other congenital heart defects,
(Licari et al. 2015). Incomplete vascular rings while others may be isolated malformations.
include pulmonary artery sling, innominate artery The two most common types of complete vas-
compression syndrome, and aberrant right subcla- cular rings are double aortic arch and right aortic
vian artery. The clinical manifestations of vascular arch with left ligamentum arteriosum. These make
rings are the result of the compressive effects on up 85–95% of cases. Two other complete vascular
the adjacent trachea or esophagus. rings that are extremely rare (<1%) include right
aortic arch with mirror image branching and left
ligamentum arteriosum and left aortic arch with
Definition and History retroesophageal right subclavian artery, right-
sided descending aorta, and right ligamentum
The first vascular ring described was that arteriosum.
of a double aortic arch by Hommel in 1737 Other anomalies that produce symptoms but do
(Hommel 1962). Subsequently, Bayford reported not form a complete anatomic vascular ring make
a retroesophageal right subclavian artery in 1794 up the remainder and include the anomalous
after performing an autopsy on a woman who innominate artery and the anomalous right subcla-
had experienced dysphagia for years and died vian artery with left-sided aortic arch and left
of starvation. Maude Abbott described five cases ligamentum arteriosum.
of double aortic arch in 1932 and made the sug- The anomalous left pulmonary artery or pul-
gestion that surgical intervention should be under- monary artery sling makes up about 10% of cases,
taken in such cases. and, although it is not associated with anomalies
The term “vascular ring” was first used by of the aortic arch or its branches, it arises from an
Dr. Robert Gross in his report describing the abnormality of the sixth branchial arch and pro-
first successful division of a double aortic arch duces a complete ring. This anomaly is associated
(Gross 1945). with intracardiac defects in 10–15% of cases.
Potts and Holinger coined the term “pulmo-
nary artery sling ” when they reported the first
successful repair of this anomaly in a 5-month Embryology
old with wheezing and intermittent episodes of
dyspnea and cyanosis (Potts et al. 1954). This Vascular rings form as a result of abnormal devel-
anomaly was, however, first reported in a post- opment of the aortic arch system. In 1922
mortem study in a 7-month-old infant with severe Congdon reported his extensive experience with
respiratory distress (Glavecke and Döhle 1897). the study of the embryogenic development of
Although innominate artery compression syn- the human aortic arch system (Congdon 1922)
drome and pulmonary artery sling are not com- (Fig. 1). Edwards developed a schematic model
plete anatomic rings, they have been traditionally with a double aortic arch system and bilateral
classified with classic vascular rings because ductus arteriosus (Edwards 1948).
of the similarities in patient presentation, diagno- Vascular rings are a group of congenital anom-
sis, and surgical therapy. alies caused by different regressions and involu-
tions from the embryonic aortic arch system.
Several recent papers report the close association
Frequency of band 22q11 deletion with anomalies of the
aortic arch as well as other congenital cardiac
Vascular rings are uncommon anomalies abnormalities. In the embryonic aortic arch sys-
and make up less than 1% of all congenital tem, the ventral and dorsal aortae are connected
cardiac defects. They occur with about equal by six primitive aortic arches. The embryo then
frequency in both sexes. No geographical or racial utilizes the mechanism of programmed cell death
Ventral
aortae LSA LCCA
RSA
1 RCCA
2 LPA
R Ductus
L Ductus
3 RPA
5 Ao
Dorsal Double aortic arch

6
aortae LCCA
RCCA
LSA
LCCA RSA
RSA
RCCA LSA
Embryonic
aortic arches LPA
LPA
L Ductus
RPA
RPA
Ao Ao
Right aortic arch Left aortic arch
Fig. 1 Diagram of the embryonic aortic arches. Six pairs right aortic arch, or the normal left aortic arch. Ao aorta,
of aortic arches originally develop between the dorsal and LCCA, RCCA left or right common carotid artery, LPA,
ventral aorta. The first, second, and fifth arches regress RPA left or right pulmonary artery, LSA, RSA left or right
completely. Preservation or deletion of different segments subclavian artery
of the rudimentary arches results in a double aortic arch, a
(apoptosis) to eliminate redundant and unneces- form bilaterally, each with its own aortic arch
sary components. The multiple branchial arches in communicating from the aortic sac to the dorsal
the human embryo are an excellent example. They aortas.
represent the blood supply of gill-breathing At this point in development, multiple vascular
organisms which lie in our phylogenetic past. rings are present. The first and second arches
They are transiently present during human devel- largely resorb and contribute only to minor facial
opment but either partially or completely disap- arteries, while the third arches form the carotid
pear as the pulmonary circulation develops and arteries. The left fourth arch forms distal aortic
connects with the heart. Only a few segments arch and aortic isthmus from the origin of the
usually remain. In case unnecessary segments left common carotid artery to the origin the
persist, anomalies such as vascular rings may descending thoracic aorta, which itself represents
result. a persistence of the left dorsal aorta. So, if the right
The paired right and left dorsal aortae, one of fourth arch involutes, a normal left arch is formed,
which will eventually become the descending which results in the aorta passing from the anterior
thoracic aorta, are present in the embryo by to posterior mediastinum to the left of the trachea
approximately the 21st day of intrauterine life. and esophagus. If the left fourth arch involutes, a
Subsequently, the first to sixth branchial arteries right aortic arch is formed. In this case, the aorta
courses to the right of the trachea and esophagus Double Aortic Arch
from the anterior to the posterior mediastinum.
Proximally, septation of the conotruncus pro- Double aortic arch is an anomaly in which both
duces the ascending aorta, which joins with the right and left arches are present and may be one
fourth left arch. The right dorsal aorta ultimately of several variations (Fig. 2):
contributes to the right subclavian artery. The first,
second, and fifth arches involute to form Edward’s (a) Both arches widely patent
classic double aortic arch. (b) Hypoplasia of one arch (usually the left)
Stewart et al. summarized these pathologic, (c) Atresia of one arch (usually the left)
embryologic, and roentgenographic correlations
of the lesions contributing to anomalies of the
aortic arch (Stewart et al. 1964). Double aortic arch represents a persistence
of both right and left embryonic fourth
branchial arches joining the aortic portion of the
Forms truncoaortic sac to their respective dorsal aorta.
The ascending aorta bifurcates anterior to the
Different variations of vascular anomalies exist trachea and each arch course either to the left or
(listed by incidence): to the right of the trachea or esophagus. The larger
of the two arches usually crosses posterior to
1. Double aortic arch the esophagus and joins with the other arch in
2. Right aortic arch the posterior mediastinum to form the unified
3. Pulmonary artery sling descending aorta. Thus a complete vascular ring
4. Vascular rings associated with left aortic arch is formed. Note that the right recurrent laryngeal
5. Cervical aorta nerve has to pass around the right aortic arch,
Fig. 2 Division of a double RCCA RSA

aortic arch (from left to
right). Double aortic arch
with a dominant right aortic Trachea
Oesophagus
arch. The lesser left aortic R Arch
arch is divided between two
applied vascular clamps. L Arch
LCCA LSA
The stumps are oversewn
Ligamentum
and this opens up the arteriosum Recurrent
desired space for trachea Ao PA laryngeal
and esophagus. Ao aorta, nerve
LCCA, RCCA left or right
common carotid artery, PA
pulmonary artery, LSA, RSA
left or right subclavian
artery
Divided
ligamentum
rather than being in its usual position around the arteriosus can vary. Several of these configura-
right subclavian artery. Double aortic arch is tions can produce a vascular ring.
rarely associated with congenital heart disease,
but when present, tetralogy of Fallot and transpo- Right Aortic Arch with Aberrant Left
sition of the great vessels are most common. Subclavian Artery and Left Ligamentum
Arteriosum
In this anomaly, the right arch first gives off the
Right Aortic Arch left carotid artery, which travels anterior to the
trachea. It then gives off the right carotid,
In cases of individuals in whom the left fourth followed by the right subclavian artery, and, lastly,
branchial arch involutes and the right remains, the left subclavian artery, which courses in a
a right aortic arch is present (Fig. 3). Right aortic retroesophageal position and gives rise to the
arch occurs less frequently than 1 in 100,000 ligamentum arteriosum from its base. The
times in the general population and may exist ligamentum arteriosum connects the left subcla-
in the absence of any other anomalies. Its pres- vian or descending aorta to the left pulmonary
ence is suggestive of the existence of an associ- artery. The trachea and esophagus are surrounded
ated anomaly. About 30% of patients with by the ascending aorta anteriorly, the aortic arch
tetralogy of Fallot have an associated right aortic on the right, the descending aorta posteriorly,
arch. Persistence of the right arch with involu- and the ligamentum arteriosum and left pul-
tion of the left creates a situation in which the monary artery on the left. Almost 10% of these
origins of the left subclavian artery and ductus defects are associated with an intracardiac defect.
Fig. 3 Right aortic arch types. (a) Retroesophageal left ligamentum arteriosum to the left innominate artery. Ao
subclavian artery, ligamentum arteriosum to descending aorta, LCCA, RCCA left or right common carotid artery,
aorta. (b) Mirror image branching, ligamentum arteriosum MPA main pulmonary artery, LSA, RSA left or right sub-
to descending aorta. (c) Mirror image branching, clavian artery
Right Aortic Arch with Mirror Image Pulmonary Artery Sling

Branching and Retroesophageal
Ligamentum Arteriosum Typically the left pulmonary artery arises
In these cases, only partial resorption of the directly from the right pulmonary artery and
distal left fourth arch occurs. The first passes leftward between the trachea and the
brachiocephalic vessel originating from the esophagus (Wolman 1941) (Fig. 4). The
right arch is the left innominate artery, which, ligamentum arteriosum passes posteriorly from
in turn, branches into a left carotid and left the origin of the right pulmonary artery where
subclavian artery. These vessels course anterior it arises from the main pulmonary artery to the
to the trachea. Following these, a right carotid undersurface of the aortic arch, thus creating a
artery and then a right subclavian artery arise. vascular ring surrounding the trachea but not the
The ligamentum arteriosum is the final struc- esophagus. The left pulmonary artery is often
ture arising from the arch in this sequence. It relatively hypoplastic. In opposition the right
originates from an area called Kommerell’s pulmonary artery appears larger than normal and
diverticulum, which represents the non- almost like a direct extension of the main pulmo-
resorbed remnant of the left fourth arch and nary artery. The small caliber of the left pulmo-
is situated at the point of merger between the nary artery may explain the high incidence of
right arch and the proximal descending thoracic anastomotic problems that have been observed
aorta. The ligamentum passes leftward and in the past with attempts to reimplant the vessel
behind the esophagus and then travels anteri- at the main pulmonary artery.
orly to join with the left pulmonary artery and This lesion is often associated with hypoplasia
complete the ring. and other abnormalities of the tracheal and bron-
More commonly, in cases of right aortic arch chial cartilages. Most patients are symptomatic
with mirror image branching, the ligamentum by 1 month after birth. Respiratory symptoms
arteriosum travels from the mirror image innomi- predominate, as the most severe compression is
nate or left subclavian artery to the left pulmonary on the trachea. More than 50% of infants also
artery. A complete ring is not present in these have severe tracheobronchial anomalies such as
cases. Most importantly this type of vascular absence of the posterior membranous component,
ring has a more than 90% association with intra- tracheomalacia, stenosis, webs, or complete
cardiac defects. tracheal rings.
Fig. 4 Pulmonary artery

Oesophagus
sling. MPA, LPA, RPA main
pulmonary artery, left
pulmonary artery, right
pulmonary artery, inset LPA
lateral view of anterior
compression of the
esophagus
LPA
Trachea
RPA
MPA
Vascular Rings Associated with Left positioned ligamentum arteriosum is present on

Aortic Arch the left.
Two extremely rare complete rings occur in the

presence of a left aortic arch, and both are associ- Clinical Findings
ated with a right-sided descending thoracic aorta.
Clinical manifestations are related to the nature
Left Aortic Arch with Right Descending of malformation and tightness of the ring. Most
Aorta and Right Ligamentum Arteriosum children with vascular rings present with symp-
The first arch vessel to exit the left aortic arch is toms in the first few months of life and require
the right common carotid, which passes anterior to surgery within the first year of life (Backer et al.
the trachea. The left carotid is next, followed by 1989). The classic sign of a child with a vascular
the left subclavian artery. The right subclavian ring is the “seal-bark” cough. In addition noisy
artery arises more distally as a branch of the breathing may be heard both during inspiration
proximal right-sided descending aorta. The and expiration (biphasic stridor), while in asthma,
ligamentum arteriosum arises from the base of the noise is mainly at the end of expiration.
the right subclavian artery or a nearby diverticu- A common finding in all forms of vascular rings
lum and travels to the right pulmonary artery. is fact that recurrent respiratory infections occur.
In children with double aortic arch, if both
Left Aortic Arch and Left Ligamentum arches are widely patent, the rings are tight and
Arteriosum with Retroesophageal Right patients present with biphasic stridor in the first
Subclavian Artery weeks of life. In case one arch is hypoplastic or
This is the most common of the arch vessel anom- atretic, the rings are usually looser, with presenta-
alies, occurring in about 0.5% of the population tion at 3–6 months of age. Rarely, does double
(Fig. 5). In these cases, the right subclavian artery aortic arch present in adulthood. Children with
does not arise from an innominate trunk with double aortic arch are often small and poorly
the right carotid artery but originates as the last developed and hold their head in hyperextension.
brachiocephalic branch from the descending aorta Repeated severe respiratory infections may occur.
and takes a retroesophageal route to its destina- Children with a pulmonary artery sling and/or
tion, as depicted in the image below. A normally complete tracheal rings often have severe
Fig. 5 Left aortic arch with

aberrant right subclavian
artery compressing the
esophagus. Ao aorta, LCCA,
RCCA left or right common
carotid artery, PA
pulmonary artery, LSA, RSA
left or right subclavian
artery
respiratory distress requiring emergent intubation vertebral, anal, cardiac, tracheal, esophageal,
and ventilation. renal, and limb (VACTERL) or posterior
Children with the innominate artery compres- coloboma, heart defect, choanal atresia, retarda-
sion syndrome often present with apnea as initial tion, genital, and ear (CHARGE) associations.
symptom. Double aortic arch has also been reported in asso-
Feeding difficulties are occurring when solid ciation with other chromosomal anomalies, such
feeding is tried to be introduced to the infant. This as trisomy 21 and other syndromes.
results in dysphagia and only tends to occur in One of the more important noncardiac features
older children. Gastroesophageal reflux with con- that sometimes are found in association with dou-
comitant pain or fear of food intake is observed. ble aortic arch is esophageal atresia, insofar as an
Cyanotic spells in these young patients may have undiagnosed arch anomaly may complicate repair
caused episodes that are termed apparent life- of the esophageal atresia, which is usually recog-
threatening events (ALTE) or death spells, in nized earlier than the double aortic arch.
which acute apneic or severe obstructive events Another noncardiac anomaly that may be asso-
are accompanied by cyanosis. ciated with vascular rings is a congenital laryngeal
Physical exam may be within normal limits, web, which may present with the same symptoms
but one may see coughing, dyspnea, drooling, or and signs as a vascular ring. Accordingly, patients
dysphagia (Tola et al. 2016). Infants will feed with persistent stridor or upper airway obstruction
poorly due to respiratory distress and may have after repair of a vascular ring, particularly
life-threatening episodes of apnea and cyanosis. those with a chromosome 22q11 deletion, should
Cardiac exam will most often be normal. be evaluated for the presence of a congenital
Lung exam may or may not show evidence of laryngeal web.
pneumonia.
Diagnostic Tests
Associated Syndromes and Noncardiac
Conditions Laboratory Studies
Double aortic arch is associated with a chromo- No laboratory screening or diagnostic study exists
some band 22q11 deletion in approximately 20% for this abnormality.
of patients (see Causes). Band 22q11 deletion is
responsible for DiGeorge, velocardiofacial, and
conotruncal anomaly face syndromes, which are Chest Radiography
often referred to using the unified terms CATCH-
22 syndrome or chromosome band 22q11 deletion Children usually present with symptoms of respi-
syndrome. In patients with double aortic arch, ratory difficulty; therefore, chest radiography is
the frequency of phenotypes satisfying the clinical always the first and most commonly performed
criteria for these various syndromes is not known. test. Look for the position of the aortic arch, which
Rather, the important point is that double aortic is usually identifiable on the plain chest radio-
arch may be associated with band 22q11 deletion, graph. The identification of a right aortic arch on
which has various other possible manifestations. chest radiograph in a child with airway difficul-
These include, but are not limited to, palatal ties, respiratory distress, or dysphagia should alert
abnormalities, laryngotracheal anomalies, speech the clinician to a higher likelihood of a vascular
and learning delay, characteristic facial features, ring. An ill-defined arch location is often observed
hypocalcemia, abnormalities of T-cell-mediated in patients with double aortic arch. Such a finding
immune function, and neurologic defects. should raise the suspicion of an arch anomaly in
Occasionally, patients with double aortic arch a symptomatic child. Other radiographic
may have anomalies consistent with either findings that may be noted with vascular rings
include compression of the trachea and hyperin- right to left. Patients having anomalies in which
flation and/or atelectasis of some of the lobes the right subclavian artery takes a retroesophageal
of either lung. A specific finding associated with course have a posterior defect slanting upward
anomalous left pulmonary artery is hyperinflation from left to right. The posterior defect in these
of the right lung. In general, chest radiography is cases is usually not as broad as that found in
not very sensitive in the diagnosis of vascular double aortic arch. In opposition in patients with
rings. left aortic arch and aberrant subclavian artery, the
oblique filling defect is mirror imaged. An
experienced radiologist can usually distinguish a
Barium Esophagram double aortic arch from the retroesophageal sub-
clavian artery based on the esophageal impression
Most authorities consider barium esophagram to (Neuauser 1946).
be the most important study in patients with a An anterior indentation of the esophagus is,
suspected vascular ring, and it is diagnostic in however, typical of an anomalous left pulmonary
the vast majority of cases (Fig. 7). However, in artery or the so-called pulmonary artery sling. No
most recent years, computer tomography and posterior compression is present with this anom-
magnetic resonance imaging have replaced this aly. Cases of abnormally located innominate
imaging modality as the primary source of artery causing tracheal compression have normal
information. findings on esophagram.
Vascular rings surrounding the esophagus
cause an extrinsic esophageal indentation visual-
ized by barium swallow. Double aortic arch Echocardiography and Color Flow
(Fig. 6) produces bilateral and posterior compres- Doppler
sions of the esophagus, which remain constant
regardless of peristalsis. The right indentation is Echocardiographic studies have been increasingly
usually slightly higher than the left, and the pos- used for the diagnosis of a vascular ring (Gould
terior compression is usually rather wide and et al. 2015). This study has replaced pulmonary
courses in a downward direction as it goes from angiography at many centers to determine the
Fig. 6 Barium esophagram

in anteroposterior
projection in a patient with
double aortic arch
presence of an anomalous left pulmonary artery. It another (Leonardi et al. 2015). These modalities
is essential in the diagnostic workup of associated provide excellent delineation of all of the asso-
congenital cardiac defects. Some limitations in ciated structures, thus allowing precise surgical
diagnosis using this study exist. Structures with- planning of the surgical strategy (Gould et al.
out a lumen, such as a ligamentum arteriosum or 2015). MRI has been proposed as an excellent
an atretic arch, have no blood flow and are diffi- substitute for angiography. All of these studies
cult to identify with color flow echocardiography. have drawbacks. CT scan and DSA expose the
Also, identification of compressed midline struc- patient to radiation and require intravenous con-
tures and their relationship to encircling vascular trast. MRI requires patients to remain very still,
anomalies may be difficult to detect, especially for so very young patients who are unable to under-
the less experienced echocardiographer. stand verbal instructions require sedation. This
may be particularly risky in young children with
existing airway compromise. The expense
Computerized Tomography Scan, encountered with these investigations must also
Magnetic Resonance Imaging, be considered.
and Digital Subtraction Angiography
Computerized tomography (CT) scan, magnetic Bronchoscopy

resonance imaging (MRI) (Fig. 7), and digital
subtraction angiography (DSA) can be useful This diagnostic study has been used in the evalu-
diagnostic tools because they reveal the posi- ation of children with symptoms of airway
tions of vascular, tracheobronchial, and esopha- obstruction or compression. It is an essential part
geal structures and their relationships to one of the workup for congenital tracheal stenosis. It is
rarely required in the diagnosis of the various
types of complete vascular ring. In case a simple
vascular ring was diagnosed by other tests, a
bronchoscopy should not be performed due to
the added risks and costs.
In the presence of a vascular ring, pulsatile
external tracheal compression is easily
observed. Note that compression of the airway
by a vascular structure in the pediatric patient
does not represent an unyielding obstruction and
should not pose a problem for passage of the
bronchoscope. In cases of an abnormally placed
innominate artery, obvious pulsation is observed
in the anterior wall of the trachea corresponding
to the area of compression. A Kommerell’s
diverticulum produces a pulsating tracheal
obstruction placed in the membranous part of
the trachea.
Indication for Intervention

Fig. 7 Magnetic resonance imaging in left anterior
Surgical division of the vascular ring is indicated
oblique projection in a patient with double aortic arch.
Both aortic arch segments are of equal caliber and widely in any patient who is symptomatic with airway or
patent esophageal compression.
Surgical Therapy Table 1 Surgical management

Double aortic arch
Surgical division of vascular rings causing clinical Left thoracotomy in muscle-sparing technique – fourth
signs is the only appropriate form of therapy (see interspace
Table 1). Surgery should be performed promptly Division of lesser of the two arches at insertion with
descending aorta
after the diagnosis is made, especially in patients
Preserve blood flow to head and neck arteries
with stridor, apnea, or other symptoms of respira-
Ligate and divide ligamentum arteriosum
tory distress. Delay in operative intervention can
Leave pleura open
result in complications of a serious nature. Left
Right aortic arch with left ligamentum arteriosum
thoracotomy is the surgical approach of choice Left thoracotomy in muscle-sparing technique – fourth
for the division of a vascular ring in the majority interspace
of cases. Anomalous left pulmonary artery sling Ligate and divide ligamentum arteriosum
has been corrected using the left thoracotomy If present, resect Kommerell’s diverticulum and transfer
approach in the past. More recently, the use of left subclavian to left carotid artery
median sternotomy and cardiopulmonary bypass Lyse adhesive bands
has been shown to produce better long-term Leave pleura open
results. The extremely rare configurations associ- Pulmonary artery sling
Median sternotomy
ated with left aortic arch and right descending
Commence extracorporeal circulation
thoracic aorta are the lesions that should be
Resect left pulmonary artery (LPA) at its origin at the
approached via a right thoracotomy for division right pulmonary artery (RPA)
of the ring. General anesthesia with a single- Oversew resulting defect in RPA
lumen nasotracheal or orotracheal tube is used Reimplant LPA into the main pulmonary artery anterior
for infants and small children. Bilateral radial to the trachea
arterial lines and a femoral arterial line together Tracheal sliding plasty for affected segment of tracheal
with oxygen saturation probes on all extremities stenosis
are ideal. Innominate artery compression syndrome
Right anterolateral thoracotomy (left-sided thoracotomy
also possible) – third or fourth interspace
Resect right lobe of the thymus
Division of a Double Aortic Arch Suspend innominate artery to posterior sternum
Postoperative bronchoscopy
Traditional Thoracotomy Approach
The surgical approach to a double aortic arch is
through a left thoracotomy in the fourth intercos-
tal space with a muscle-sparing technique, and the arch is at its point of juncture with the descending
components of the vascular ring are visualized. aorta. Identify and avoid the recurrent laryngeal
The pleura overlying the vascular ring should and vagus nerves. Before dividing the arch, it
then be opened and careful dissection performed should be temporarily occluded and the anesthe-
to clearly identify all the pertinent vascular struc- siologist asked to check right and left radial and
tures (Fig. 8). The right, or posterior, arch does not carotid pulses. Arch division should always be
require mobilization unless it is the lesser of the done between vascular clamps with oversewing
two arches and is to be divided. In such cases, of the divided stumps with nonabsorbable sutures.
the proximal descending aorta should be reflected Simple ligation and division have been associated
anteriorly to visualize the area where the right arch with ligature slippage and subsequent cata-
enters. strophic hemorrhage. The divided stumps
The goal of surgical therapy is to divide the typically separate by 1.5–2 cm and disappear
smaller of the two arches at a site that does not into the posterior mediastinum making precise
compromise the blood flow to the head vessels. hemostasis quite important. The operative repair
A likely site for division of the minor, or atretic, is completed by freeing up all adhesive bands
and esophagus. The thoracotomy incision is

closed without a chest tube by evacuating air
from the plural space with a small suction catheter.
It may take up to 1 year for the child’s noisy
breathing to disappear as the tracheobronch-
omalacia caused by the ring resolves.
Video-Assisted Technique
A number of groups now advocate this technique

as the method of choice for treatment of vascular
rings, unless preoperative studies suggest that a
patent segment of a double aortic arch is present
(Burke et al. 1995a; Koontz et al. 2005; Kogon
et al. 2007). Riggle et al. (2017) recently reported
their experience of thoracoscopic division of
vascular rings in 31 patients and found this
approach feasible alternative to open division
Fig. 8 Operative photograph taken during dissection after
posterolateral thoracotomy in a patient with double aortic and associated with comparable rates of symptom
arch. The parietal pleura is opened and the vascular struc- resolution and decreased length of hospital stay
tures are dissected. The left-sided ductus arteriosus is and chylothorax.
looped by a silk tie The patient is placed in right lateral decubitus
position following single-lumen endotracheal
intubation. Four small stab incisions are made in
the posterolateral chest wall to admit from medial
to lateral a grasping forceps, a lung retractor,
a video scope, and an L-shaped cautery probe.
Exposure is achieved by retracting the inflated
left upper lobe inferiorly and medially. The medi-
astinal pleura is incised over the left subclavian
artery which leads to the other components of
the vascular ring. The ring is dissected free from
the esophagus and surrounding structures. The
atretic segment of the vascular ring and
ligamentum are identified. Clips are placed and
the ring and the ligamentum are divided between
Fig. 9 Operative photograph taken after division of a
double aortic arch via posterolateral thoracotomy. The clips. Fibrous bands over the esophagus are
parietal pleura is opened and the anterior arch is divided also freed. A small chest tube is placed under
and oversewn. The left-sided ductus arteriosus is tied, and direct vision, and the wounds are closed with
only the aortic component is still visible. Note the resulting Steri-Strips (Burke et al. 1995a, b).
gap between the two stumps of the anterior aortic arch
surrounding the esophagus in the area of the Right Aortic Arch

divided ring (Fig. 9).
Closure of the mediastinal pleura is not Surgical treatment of this condition also consists
performed to avoid the development of adhesive of dividing the ductus arteriosus or
scarring in the already affected area of the trachea the ligamentum arteriosum. Division of the left
subclavian artery is not generally necessary for (1986). Different techniques are utilized for
relieving tracheal compression. Patients with tracheal repair depending on the length and site
an anomalous left subclavian artery and of the tracheal stenosis. Over recent years, many
Kommerell’s diverticulum (Kommerell 1936) are different types of repair have been undertaken,
at risk of developing severe tracheal compression. ranging from simple end-to-end repair (Jonas
Backer et al. have recommended resection of et al. 1989; Cotter et al. 1999), various forms
the diverticulum and reimplantation of the left of patch tracheoplasty (Bando et al. 1996; Idriss
subclavian artery to the left carotid artery as et al. 1984), tracheal homograft implantation
a primary operation (Backer et al. 2002, 2005, (Schlosshauer 1975; Herberhold et al. 1999), and
2012, 2016; Shinkawa et al. 2012). Surgery is slide tracheoplasty (Grillo 1994; Tsang et al.
performed through a muscle-sparing left lateral 1989; Dayan et al. 1997; Elliott et al. 2008,
thoracotomy in the fourth intercostal space. After 2003; Beierlein and Elliott 2006). In recent years
dissection of the vascular structures and division slide tracheoplasty has been favored by most
of the ligamentum arteriosum, the patient is groups.
anticoagulated. Any adhesive bands are lysed,
and the recurrent laryngeal and phrenic nerves
are carefully identified and protected. The base Left Aortic Arch with Anomalous Origin
of the Kommerell’s diverticulum is taken in a of the Innominate Artery
side-biting clamp, and the distal subclavian
artery is occluded with a vascular clamp prior to The surgical treatment of this anomaly is based on
its division. The diverticulum is resected and its the suspension of the innominate artery from
base oversewn. The left subclavian artery is then the posterior aspect of the sternum. This operation
anastomosed to the origin of the left carotid artery. can be performed from either side (Gross and
Neuhauser 1948; Moes et al. 1975). The thymus
lobe of the corresponding side is resected and
Pulmonary Artery Sling the pericardium opened respecting the phrenic
nerve. The ascending aorta or the innominate
Although the traditional approach has artery is approximated to the posterior aspect
been through a left-sided thoracotomy with of the sternum by two or three interrupted
reimplantation at the original site of the left pledget-supported heavy sutures. Bronchoscopy
pulmonary artery as performed in 1953 by Potts is then performed to confirm the tracheal relief.
(Potts et al. 1954) and then reimplantation of the Other authors have described using a median
left pulmonary artery on the left side of the main sternotomy with division of the innominate artery
pulmonary artery as described by Hiller and and reimplantation into the ascending aorta at a
MacIean in 1957 (Hiller and Maclean 1957), cur- site more rightward and anterior to the native site
rently the preferred method is to undertake repair (Hawkins et al. 1992). This technique sacrifices
via median sternotomy. With this approach and the active suspending mechanism on the tracheal
utilizing cardiopulmonary bypass, reimplantation wall provided by the classical suspension maneu-
of the left pulmonary artery onto the left side of ver. In addition there seems to be some risk of
the main pulmonary artery without application of cerebrovascular accident, although Grimmer et al.
side-biting clamp is carried out without aortic report no cerebrovascular injury in a long-term
cross-clamping. If tracheal repair is necessary, it follow-up study (Grimmer et al. 2009).
can be performed thereafter, or tracheal repair is
performed on cardiopulmonary bypass, and the
left pulmonary artery is relocated in front of the Results
trachea after extensive dissection of the left pul-
monary artery into the left hilum. This technique The outcomes of surgical intervention are
was introduced by Kirklin and Barratt-Boyes excellent, and most patients have complete
resolution of symptoms over a period of time developed, but further technical advances are nec-
(Backer et al. 2016; Naimo et al. 2017). One of essary to promote a wider dissemination of these
the largest reports of vascular anomalies causing techniques.
tracheoesophageal compression comes from
Backer et al. from the Children’s Memorial
Hospital in Chicago, USA, published in 1989 Cross-References
(Backer et al. 1989) and updated in 2005 (Backer
et al. 2005). The authors described 204 infants ▶ Congenital Airway Malformations
and children with a mean age of 13 months who ▶ Embryology of Congenital Malformations
had undergone surgical procedures for tracheoe- ▶ Extracorporeal Membrane Oxygenation for
sophageal obstruction. Of these, 113 patients Neonatal Respiratory Failure
had a vascular ring, 61 with a double aortic arch, ▶ Fast-Track Pediatric Surgery
and 52 with a right aortic arch and left ▶ Pediatric Respiratory Physiology
ligamentum. The operative mortality rate was ▶ Stridor in the Newborn
4.9% with a late mortality rate of 3.4%. However,
there were no operative deaths within the Acknowledgement Republished with permission of
last 28 years. At a mean follow-up of 8.5 years, Taylor and Franciss Group LLC books, from Newborn
Surgery, PD. Dr.med. Benjamin Bierbach and Professor
92% of the patients were essentially free of
Mark Redmond, Vascular rings, chapter 39, fourth edition,
symptoms. 2017; permission conveyed through Copyright Clearance
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Pulmonary Air Leaks of the Neonate
50
Prem Puri and Jens Dingemann
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
Pneumothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 754
Pulmonary Interstitial Emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
Pneumomediastinum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 756
Pneumopericardium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 757
Pneumoperitoneum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 758
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 759
Abstract
Pulmonary air leaks of the newborn can be life-
threatening emergencies and may lead to
severe respiratory compromise. In order of
P. Puri (*) descending incidence, pneumothorax, intersti-
Department of Pediatric Surgery, Beacon Hospital, Dublin, tial emphysema, pneumomediastinum, and
Ireland
pneumopericardium are the main presentations
School of Medicine and Medical Science and of neonatal pulmonary air leaks. Combinations
Conway Institute of Biomedical Research, University
College Dublin, Dublin, Ireland of the different entities are frequently observed.
e-mail: prem.puri@ncrc.ie Pathophysiologically, all of them are commonly
J. Dingemann caused by uneven ventilation, air trapping, and
Centre of Pediatric Surgery Hannover, Hannover Medical high transpulmonary pressure swings. The final
School and Bult Children’s Hospital, Hannover, Germany common pathway of the four groups is alveolar
e-mail: dingemann.jens@mh-hannover.de

https://doi.org/10.1007/978-3-662-43588-5_54
752 P. Puri and J. Dingemann
overdistension and rupture of the alveolar sacs hypothesis suggests that the air enters the pleural
allowing the intrapulmonary air to evade into the cavity through a rupture of a subpleural bleb
different intrathoracic spaces. (Plenat et al. 1978). A rare but usually fatal com-
The diagnostic gold standard is the chest plication of neonatal pulmonary air leak is sys-
x-ray. In asymptomatic children, pulmonary temic air embolism. In the preterm and severely
air leaks may be managed conservatively by respiratory compromised infant, an alveolar-
reduction of ventilator pressures and increased capillary or broncho-venous fistula develops
inspired oxygen concentration favoring resorp- under very high ventilatory pressures (>40 cm
tion of the extra-alveolar gas. However, careful H2O), allowing intrapulmonary air to escape into
observation of the neonate is recommended, the central pulmonary blood vessels. This may be
and the threshold for drainage should be low, a sudden and catastrophic terminal event of pul-
particularly in ventilated babies. monary air leaks.
Keywords
Pulmonary air leak · Pneumothorax · Pneumothorax
Pulmonary interstitial emphysema ·
Pneumomediastinum · Pneumopericardium · Symptomatic pneumothorax (PT) occurs in 0.08%
Pneumoperitoneum · Respiratory distress of all live births (Trevisanuto et al. 2005). It is
syndrome · Bronchopulmonary dysplasia · strongly associated with primary lung disease, con-
Mechanical ventilation (complications) tinuous positive airway pressure (CPAP), and
assisted ventilation. PT predominantly occurs in
patients with hyaline membrane disease, meconium
Introduction aspiration syndrome, pulmonary hypoplasia, and
infants requiring vigorous resuscitation at birth. In
Pulmonary air leaks of the neonate commonly the earlier days of neonatal mechanical ventilation,
present as pneumothorax, pulmonary interstitial the overall incidence of PT in the newborn with
emphysema, pneumomediastinum, or pneumoper- respiratory difficulties has been reported to be as
icardium. Also pneumoperitoneum can be the high as 34% of those who are ventilated (Madansky
result of pulmonary air leak. The incidence of et al. 1979). In the last decades, the incidence of
pulmonary air leaks in the neonate has increased neonatal PT has decreased due to the use of surfac-
constantly in recent years, most probably because tant, neuromuscular paralysis of the ventilated new-
more preterm babies and infants with severe respi- born and modern ventilation modes. Today, the
ratory distress on mechanical ventilation are sur- incidence of PT in ventilated babies should be less
viving and develop this complication. than 10% (Greenough and Milner 2012). However,
All pulmonary air leaks share the same patho- it is still far more frequent in the newborn period
physiological sequence of alveolar overdistension than in any other period of life. Another strong risk
and rupture, regardless of whether it is caused by factor for PT is prematurity. In ventilated preterm
uneven ventilation, air trapping, or high trans- infants, it has been shown to be attributed to high
pulmonary pressure swings. Through the ruptured peak inspiratory pressure low FiO2, pulmonary
terminal air sacs, the pulmonary air tracks along hemorrhage and high arterial CO2, while a
the sheaths of pulmonary blood vessels to the decreased risk was associated with high positive
roots of the lung and from there into the pleura, end-expiratory pressure (Klinger et al. 2008).
mediastinum, or pericardium (Macklin 1939). In Besides mechanical ventilation, there are other
pulmonary interstitial emphysema, the air escapes reasons for iatrogenic PT of the newborn. It may
directly into the pulmonary interstitium where it is develop as a complication of repeated endotracheal
trapped in the parenchyma by the extensive con- intubation, deep endotracheal tube suction, or cen-
nective tissue matrix and increased interstitial tral venous catheter placement. Spontaneous neo-
fluid, characteristic for the preterm lung. Another natal PT has also been described as a rare
50 Pulmonary Air Leaks of the Neonate 753
complication of congenital cystic adenomatoid method helps to diagnose a PT very quickly and
malformation and common pulmonary vein atresia. can save important time in an emergency situation.
However, transmission of light may also be
increased in pulmonary interstitial emphysema.
Presentation and Diagnosis Chest x-ray remains the gold standard for the
diagnosis of PT. In a large PT, the collapsed lung
The common finding in neonates with PT is sudden and absent marginal lung markings are obvious
respiratory deterioration. Pallor, tachypnea, (Fig. 1a). Small PTs may only be recognized by a
grunting, chest retractions, and cyanosis represent difference in the radiolucency compared to the
the typical clinical signs. At physical examination, nonaffected side. In these cases, lateral decubitus
diminished or absent breath sounds and an cross-table views are very helpful in showing the
increased resonance on percussion can be found rise in pleural air to the lateral or medial side of the
on the affected side. The initial signs of tension hemithorax. Tension PT commonly presents with
PT are arterial hypotension, bradycardia, and mediastinal shift, eversion of the diaphragm, and
apnea. Sometimes a shift of the cardiac impulse to bulging intercostal spaces in the chest radiography
the unaffected side and abdominal distension due to (Fig. 1b). Rarely, lobar emphysema, congenital
the displacement of the ipsilateral diaphragm may cystic adenomatoid malformation, or congenital
be noted. Monitoring on the neonatal intensive care diaphragmatic hernia may resemble PT in the
unit (NICU) will show decreased oxygen satura- chest x-ray (Greenough and Milner 2012).
tion, blood pressure and heart rate such as rising
pCO2, and acidosis in the blood gas analysis.
A bedside method suitable to diagnose PT in Treatment
newborns and preterm infants is thoracic transillu-
mination with a cold-light probe. It shows increased Asymptomatic PT does not need any other treat-
transmission of light on the affected side. This ment than observation and monitoring in a
Fig. 1 (a) Anteroposterior chest x-ray showing right be seen. (b) Anteroposterior chest x-ray showing left ten-
pneumothorax in a ventilated newborn with severe respi- sion pneumothorax in a newborn on mechanical ventila-
ratory distress syndrome. Note air lucency around right tion. Mediastinal shift to the right, ipsilateral eversion of
lung with absence of lung markings. The left lung is totally the diaphragm, and bulging intercostal spaces are obvious.
opaque and can hardly be separated from the heart border The left lung shows diffuse pulmonary interstitial emphy-
because of widespread atelectasis. An air bronchogram can sema (see also Fig. 2a)
neonatal intensive care unit, even in ventilated to be connected to an underwater seal with or
neonates (Litmanovitz and Carlo 2008). However, without a low-grade suction of 5–10 cm H2O. At
due to the risk of tension PT, the threshold for a the time the lung is constantly expanded and there
chest drain should be kept low. The adjustment of is no evidence of persisting air leak, the tube can
ventilatory management is mandatory. The aim is then be removed. The insertion site should be
to keep ventilatory pressures as low as possible. closed with a waterproof adhesive plastic film to
High-frequency positive pressure (HPPV) is most avoid any air leak. A routine chest x-ray is not
favorable, whereas the use of patient-triggered necessary and should only be done when recur-
ventilation (PTV) and high-frequency oscillation rence of the PT is clinically suspected.
(HFO) have not been shown to be beneficial The main risk of chest drain insertion is dam-
(Greenough et al. 2008; Henderson-Smart et al. age of intrathoracic organs. Lung perforation,
2007). Neuromuscular paralysis with chylothorax, and phrenic nerve injury have been
pancuronium might have a beneficial effect in reported. Soft pigtail pleural drainage catheters
preventing PT in neonates on mechanical ventila- can be used to prevent iatrogenic damage of intra-
tion (Cools and Offringa 2005). thoracic organs. However, even these soft cathe-
Absolute indications to drain a neonatal PT are ters may cause pulmonary injury in premature
infants. Another option is the insertion of ordinary
• Cardiorespiratory deterioration 18G venous catheters which have been proven to
• Signs of tension PT on chest x-ray be a quick, effective, and safe alternative to drain
neonatal PT.
To avoid the risk of lung damage, the infant
should be temporarily disconnected from the ven-
tilator during the introduction of a chest drain or Prognosis
aspiration of a PT.
In the emergency situation of a tension PT, The mortality of neonatal PT, though not the inci-
needle aspiration can be done before formal inser- dence, varies with birthweight and is in general
tion of a chest drain. A butterfly or i.v. cannula double that of babies who have respiratory dis-
(18G) connected to a three-way tap and a 20 ml tress syndrome (RDS) but no air leak (Greenough
syringe can be used for decompression. The and Milner 2012). Thus, PT considerably aggra-
pleura is punctured at the second intercostal vates the course of RDS particularly in preterm
space in the midclavicular line. In order to avoid babies weighing <1,000 g in whom mortality rate
the entry of air once the needle is removed, the has been reported to be more than 50%
direction of insertion of the needle is oblique (Greenough and Robertson 1985). Cases with
through intercostal muscle. The single aspiration PT without underlying lung disease have a good
must be followed by close clinical observation prognosis.
and follow-up x-rays as most neonates will Arterial hypotension attending PT in the neo-
require a surgical thoracostomy during follow-up. nate increases the risk of severe intraventricular
For tube thoracostomy in neonates, a chest hemorrhage (IVH). The incidence of IVH grades
drain (10–14G) is inserted through the second 3 and 4 reaches 89% as compared with IVH rate in
intercostal space in the midclavicular line or the neonates with PTs and normal blood pressure,
sixth space in the midaxillary line under local which is only 10% (Mehrabani et al. 1991). This
anesthesia. The tip of the chest drain should be may have a detrimental effect on the neurological
placed anteriorly retrosternally to achieve the best outcome. In an attempt to produce a reliable index
possible drainage, as the (ventilated) neonate’s of the severity of the disease, Mandal and
position is usually supine. A purse-string stitch co-workers have investigated the outcome of
at the insertion site of the drain is not necessary 54 infants with pneumothorax in the first 24 h of
in neonates. The drain must be firmly fixed to the life. They found that response to inspired oxygen
skin with a stitch or adhesive plaster. Finally, it has <70% and a low positive end expiratory (<6 cm
H2O) were associated with favorable outcome (sur- Milner 2012). However, PIE has also been described
vivor group), whereas CO2 retention, additional in neonates under spontaneous breathing conditions.
pneumopericardium, pulmonary interstitial emphy- The incidence of PIE correlates with low birth
sema, or pneumomediastinum were displayed in weight and prematurity. In very low-birthweight
patients of the non-survivor group of their study preterm infants (<1,000 g), PIE has been reported
(Mandal et al. 1990). Thus, ventilatory parameters to affect up to 35% of the patients (Yu et al. 1986).
and severity of RDS may be helpful prognostic
markers of neonatal PT.
Presentation and Diagnosis
Pulmonary Interstitial Emphysema As in all pulmonary air leaks, respiratory deterio-

ration with hypoxia, acidosis, and hypercapnia
Pulmonary interstitial emphysema (PIE) is defined despite mechanical ventilation are the clinical
as trapped gas in the pulmonary interstitium. Fol- signs of PIE. Transillumination of the chest with
lowing alveolar rupture distal to the termination of diffuse PIE will give the same appearance as a
their fascial sheath, the air dissects along the peri- large pneumothorax (Greenough and Milner
vascular sheaths and spreads across the lungs within 2012). However, chest x-ray is the method of
the pulmonary interstitium. The trapped gas inter- choice to diagnose PIE. Hyperinflation of the
feres with ventilation compresses the pulmonary affected pulmonary areas and multiple cyst-like
vessels. This results in hypoxemia and CO2 reten- lucencies that appear to radiate outward from the
tion. PIE may be lobar in distribution but more hilum of the lung are diagnostic for PIE. At a later
commonly involves both lungs. It occurs mainly in stage, large bullae may appear (Fig. 2a, b). As PIE
infants with severe RDS requiring mechanical ven- may be diffuse or localized, the localized form
tilation and a combination with pneumothorax or may be misdiagnosed as cystic adenomatoid mal-
pneumomediastinum is frequent (Greenough and formation of the lung.
Fig. 2 (a) Anteroposterior chest X-ray of a preterm infant blurred. (b) Pulmonary interstitial emphysema at a later
requiring prolonged mechanical ventilation for neonatal stage showing decreased diffuse small-cystic pattern but
respiratory distress syndrome. The x-ray shows typical large rightsided pulmonary bulla which may be mis-
signs of pulmonary interstitial emphysema. Note gross diagnosed as cystic adenomatoid malformation of the
bilateral hyperinflation with characteristic diffuse small- lung. Note also mediastinal shift to the left due to right
cystic, non-confluent radiolucencies. Both diaphragms sided hyperinflation and tension
are everted due to hyperinflation. The heart shadow is
Treatment Prognosis
No specific surgical treatment is available to treat PIE significantly aggravates the clinical course of
PIE. The use of appropriate ventilation strategies children with respiratory distress syndrome. Even
is the main remedy in preventing and treating PIE. in specialized centers, the mortality rate is high.
The aim is to keep ventilatory pressures at a safe Almost a quarter of patients (24%) with diffuse
minimum while keeping blood gas values at PIE die (Greenough et al. 1984). The survivors in
acceptable levels (PaO2 >6–7 kPa, PaCO2<8 kPa, Greenough’s series (210 preterm infants) had a
and pH>7.25 have been suggested) (Greenough significantly lower maximal peak inspiratory
and Milner 2012). Additionally, to minimize the pressure and FiO2 on the first day of ventilation.
risk of extension of PIE, neuromuscular paralysis However, no other predictive factors could be
should be applied. The most recent meta-analysis identified investigating neonatal parameters
has demonstrated an advantage of high-frequency between infants who died or survived (Greenough
positive-pressure ventilation (HFPPV, ventilator et al. 1984).
rates 60 bpm) and triggered ventilation over In another large series of 315 patients with
conventional mechanical ventilation (CMV, venti- RDS, fatal outcome of PIE was almost invariably
lator rates <60 bpm) with regard to reduction of fatal (mortality rate of this subgroup 94%) in
PIE and a shorter duration of ventilation (Gree- preterm infants with a birth weight below
nough et al. 2016; Greenough et al. 2008). Another 1,600 g, need for oxygen >60% on the first day
meta-analysis revealed that prophylactic of ventilation, and appearance of bilateral pulmo-
intratracheal administration of surfactant improves nary interstitial emphysema within the first 48 h of
clinical outcome of RDS. The incidence of pneu- life. High-positive inspiratory pressure on day
mothorax, PIE, and overall mortality were 1 was found to be the most significant parameter
decreased. However, this comes at the risk of associated with fatal pulmonary interstitial emphy-
persisting patent ductus arteriosus and pulmonary sema. A cutoff level of 26 cm H2O was found to be
hemorrhage (Soll and Ozek 2010). discriminant (Morisot et al. 1990). In preterm
Decompression of the affected segments in infants, additional application of surfactant signif-
unilateral or localized PIE can be achieved by icantly reduces mortality of PIE (Soll and Ozek
placing the infant with his hyperinflated lung 2010). In the survivors, diffuse PIE greatly
dependent in the lateral decubitus position or increases the incidence of bronchopulmonary dys-
selective bronchial intubation. The intentional plasia, contributing to the long-term sequelae of
atelectasis of the desired segment can consider- RDS in preterm infants (Greenough and Milner
ably improve the respiratory distress of the neo- 2012).
nate with PIE. When the affected lung is
reventilated, the PIE does usually not recur.
For patients in whom conservative manage- Pneumomediastinum
ment fails, an aggressive approach has been
described. Therapeutic lung puncture using a pig- Pneumomediastinum (PM) is trapped extra-
tail catheter achieves consecutive tension release alveolar air in multiple independent lobules of
by the creation of artificial pneumothorax. After the mediastinum. Mostly, it is associated with
re-evacuation of the pneumothorax, mechanical extrapulmonary air at other sites. Neonatal PM is
ventilation could be discontinued within 3 days usually attributed to pulmonary infection, imma-
in all infants (Dördelmann et al. 2008). Surgery is ture lungs, and mechanical ventilation
reserved for patients in whom conservative ther- (Hauri-Hohl et al. 2008). However, also sponta-
apy failed. However, localized PIE has been suc- neous pneumomediastinum without any history of
cessfully treated by atypical wedge resection mechanical ventilation or concomitant lung dis-
(Messineo et al. 2001) and lobectomy (Matta ease has been reported (Monteiro et al. 2015;
et al. 2011). Franco et al. 2014; Lawal et al. 2009). Most
neonatal cases present with symptoms of respira- ventricular inflow. These cases will require urgent
tory distress. If the collection of air is small, it ultrasound-guided needle aspiration of the anterior
remains asymptomatic. Clinical investigation of mediastinal compartment via repeated subxiphoid
the infant reveals muffled heart sounds. In cases puncture. Successful chest tube insertion into the
with large amounts of mediastinal air, the sternum anterior mediastinum under ultrasound guidance
may appear bowed. Rarely the air dissects into the has also been described in a preterm infant with
soft tissues of the neck and into the abdomen, tension PM in whom initial needle aspiration had
presenting as pneumoperitoneum. not led to relief of symptoms.
Chest x-ray is the diagnostic gold standard to
identify PM. Typical radiologic finding is the
“angel-wing” or “spinnaker sail” sign (ante- Pneumopericardium
roposterior view) (Lawal et al. 2009) rising from
mediastinal air to extend to both sides, elevating Pneumopericardium (PPC) is a rare form of pul-
the thymic lobes. The lateral view may show monary air leak in the neonate. It is strongly
marked retrosternal hyperlucency (Fig. 3). Ultra- associated to mechanical ventilation, prematurity,
sound has been reported to be superior to x-ray and RDS. However, very rarely PPC occurs in
under certain conditions and should be considered neonates under CPAP respiratory support or spon-
if PM is clinically suspected and x-ray shows no taneously. Neonatal PPC is mostly combined with
typical findings (Megremis et al. 2008). pulmonary air leaks at other sites. Its frequent
In asymptomatic cases of PM, no specific treat- association with PIE and PM suggests that a
ment is necessary but high inspired oxygen con- defect in the pericardium serves as entrance for
centration can accelerate resorption of the extra- pre-existing interstitial air, probably at the peri-
alveolar air. Symptomatic (tension) PM can range cardial reflection near the ostia of the great vessels
from sudden respiratory deterioration to severe (Greenough and Milner 2012).
cardiac compromise with obstruction of left Clinically, symptomatic PPC resembles car-
diac tamponade in hemopericardium. Sudden car-
diorespiratory deterioration with cyanosis, arterial
hypotension, bradycardia, and muffled, arrhyth-
mic heart sounds may represent the main findings
in neonatal patients with PPC. Electrocardio-
graphic changes (axis and voltage) may be
observed. A small PPC may be asymptomatic.
All children with suspected PPC must receive a
chest x-ray. The anterior-posterior view demon-
strates pericardial air completely surrounding the
heart (Fig. 4). The radiolucent band outlines the
base of the pulmonary vessels cranially and
extends caudally to the diaphragmatic surface of
the heart. This allows differentiation of PPC from
PM in which the mediastinal gas is limited inferi-
orly by the attachment of the mediastinal pleura to
the central tendon of the diaphragm. The trans-
verse diameter of the heart can be reduced in
severe cases of PPC. Pulmonary air leaks at
Fig. 3 Anteroposterior chest x-ray of a preterm infant of other sites (mainly PIE and PM) are present in
34 weeks of gestation showing pneumomediastinum. The
the vast majority of patients.
image demonstrates the characteristic “angel-wing” or
“spinnaker sail sign” rising from bilateral mediastinal air Asymptomatic cases of neonatal PPC do not
elevating the thymic lobes require any intervention. However, they should be
PM. A large PP can be seen on the anteroposterior

view of the abdominal x-ray (“football sign”);
small amounts of air may only be detected in
lateral x-ray. It is difficult to differentiate between
PP deriving from gut perforation and pulmonary
air leak. The latter should be considered in cases
with pre-existing pulmonary air leak at other sites,
absent bloody stools or intestinal obstruction, and
a normal gut gas pattern on the abdominal plain
film. As an additional method to differentiate
ventilator-induced pneumoperitoneum from
intestinal perforation, it has been suggested to
measure the pO2 of aspirated intraperitoneal gas.
Fig. 4 Anteroposterior chest x-ray showing pneumoper- In transdiaphragmatic air dissection pO2 will be
icardium. The radiolucency at the cardiac margin outlines rather high, depending on the inspiratory O2 con-
the base of the pulmonary vessels cranially and extends
centration. In contrast, the pO2 in PP caused by
caudally to the diaphragmatic surface of the heart, allowing
differentiation from pneumomediastinum (Printed with intestinal perforation will be similar to that of
permission of Taylor & Francis Group, Abingdon, room air (Vanhaesebrouck et al. 1989). However,
UK. From: Newborn Surgery 3rd edition, Part 33, “Pulmo- in case of any doubt, PP must always consider the
nary Air Leaks”, pp333–338 (Puri and Dingemann)
result of bowel perforation, and surgical explora-
tion of the abdomen should be indicated with a
monitored closely on a NICU. Symptomatic PPC low threshold. Ventilator-induced PP must only
must be drained immediately. In most cases peri- be drained or aspirated in patients with significant
cardial puncture via the subxyphoid route will be abdominal tension or respiratory deterioration due
the appropriate therapy. If clinical signs of cardiac to compromised diaphragmatic movements.
tamponade reoccur, placement of a pericardial
catheter for continuous drainage of air may be
necessary. Conclusion and Future Directions
PPC can be masked by other pulmonary air
leaks and should be considered if drainage of the Pulmonary air leaks of the neonate are potentially
primarily obvious site does not improve the car- life-threatening events frequently requiring imme-
diorespiratory status of the infant (Cools et al. diate treatment. They are strongly associated with
2008). Mortality rate of PPC is very high and respiratory distress syndrome and mainly occur
reaches 80–90% in preterm infants, and many during mechanical ventilation. The incidence has
survivors have neurological sequelae (Greenough decreased with recent developments in ventilation
and Milner 2012). strategies and the use of surfactant. However, with
increasing number of surviving extremely low-
birth-weight preterm infants, pulmonary air leaks
Pneumoperitoneum will continue to be a matter of neonatal care.
Pneumoperitoneum (PP) is mostly the presenta-

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Chylothorax and Other Pleural
Effusions in Neonates 51
Richard G. Azizkhan
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Anatomy and Embryology of the Lymphatic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Pathophysiology of Chyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 763
Etiology and Presentation of Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Congenital Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Acquired Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Clinical Features of Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Presenting Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Consequence of Continuous Chylous Flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Confirming the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Management of Chylothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Nonoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
General Management Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 768
Fetal Chylothorax (Hydrothorax) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 769
Other Pleural Effusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Hemothorax . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
Abstract Chylothorax results from the accumulation of

Pleural effusion is a general term for the accu- lymphatic fluid within the pleural space and
mulation of fluid in the pleural space. may occur spontaneously, traumatically, iatro-
genically, or as malignant infiltration. Whether
congenital or acquired, chylothorax frequently
R. G. Azizkhan (*) resolves with nonoperative measures aimed at
Children’s Hospital and Medical Center, University of optimizing ventilation and maintenance of nutri-
Nebraska College of Medicine, Omaha, NE, USA tion. Surgical options such as pleuroperitoneal
e-mail: Razizkhan@childrensomaha.org

https://doi.org/10.1007/978-3-662-43588-5_55
762 R. G. Azizkhan
shunting, thoracic duct ligation, pleurodesis, morbidity continues. This chapter provides a basic
pleurectomy, and intrapleural fibrin glue can be foundation for understanding the anatomy and
chosen for severe and persistent cases. embryology of the lymphatic system and subse-
quently presents an overview of the pathophysi-
Keywords ology, clinical characteristic, diagnosis, and
Congenital chylothorax · Acquired management of chylothorax and other less com-
chylothorax · Pleural effusion · Hydrothorax · mon pleural effusions in neonates and children.
Hemothorax · Empyema
Anatomy and Embryology

Introduction of the Lymphatic System
Pleural effusions are the general designation for Lymph is a fluid which originates in the interstitial
the accumulation of fluid in the pleural space. spaces of the body and is collected in the cisterna
Although rare, chylothorax is a well-established chyli, located between the aorta and the vena cava
clinical entity and the most common cause of in front of the first lumbar vertebral bodies. The
pleural effusion in the fetus and neonates (Vain lymph then reaches the thoracic duct that ascends
et al. 1980; Van Aerde et al. 1984; Curci and in the posterior right mediastinum between the
Debbins 1980), resulting from the leakage of aorta and the azygos vein, then crosses to the left
chyle from the thoracic duct into the pleural cav- behind the aortic arch, and finally opens itself into
ity. It may occur spontaneously or may be a com- the major circulation at the level of the left sub-
plication of a thoracic surgical procedure, clavian and jugular veins. In the thorax it receives
non-iatrogenic trauma, or malignant infiltration lymph from the parietal pleura of both sides via
(Beghetti et al. 2000). Whether congenital or several collecting trunks. Lymphatic branches
acquired, chylothorax frequently resolves with from structures in the posterior mediastinum and
nonoperative measures aimed at optimizing ven- from the left lung and its pleura join to form the
tilation and maintenance of nutrition. For more left bronchomediastinal trunk; this trunk opens
than a decade, pharmacologic agents (e.g., into the thoracic duct or directly into the great
somatostatin and its analogue octreotide) have veins. There are also several potential
successfully been added to the nonoperative ther- lymphovenous communications that may func-
apeutic armamentarium (Roehr et al. 2006; Lim tion when the main duct is traumatized or blocked
et al. 2005; Chan et al. 2006; Das and Shah 2010; (Fig. 1).
Rosti et al. 2002, 2005; Caverly et al. 2010; The lymphatic system, a diffuse network of
Cheung et al. 2001). When nonoperative mea- endothelial channels, appears during the sixth
sures fail to effect spontaneous healing, operative week of development. The growth of this system
management becomes imperative. For patients in is a phenomenon of consecutive centrifugal bud-
whom resolution does not occur, persistent ding from original lymph sacs. In the early 1900s,
chylothorax can become a life-threatening disor- Sabin (1916) demonstrated that these sacs origi-
der with profound respiratory, nutritional, and nate from the endothelium of the adjacent veins,
immunologic consequences. Although early diag- establishing venous endothelium as the primor-
nosis, aggressive initiation of nonoperative man- dial structure of the lining of the lymphatic sys-
agement options, and a number of alternative tem. She further recognized that all lymphatic
surgical procedures have significantly decreased channels are developed as outgrowths of the
the mortality rate from 50% before the 1950s venous endothelium in six original lymph spaces:
(Schackelford and Fisher 1938; Lampson 1948) two jugular lymph sacs, two iliac sacs, a single
to more recent estimates of less than 10% retroperitoneal sac, and the cisterna chyli. These
(Beghetti et al. 2000; Chan et al. 2006), significant sacs invade the tissues by continuous growth and
51 Chylothorax and Other Pleural Effusions in Neonates 763
Fig. 1 Anatomy of the

lymphatic system
branching. The lymphatic system arises by con-

fluence of perivenous mesenchymal spaces to Pathophysiology of Chyle
form larger spaces. These in turn join to form
continuous vessels that eventually drain into the Chyle has three primary functions: (1) the trans-
venous system. portation of lipids and lip-soluble vitamins
Although the thoracic duct is usually a singular absorbed from the small bowel via lymphatic
structure, its embryology underscores the poten- capillaries, (2) the collection of excess fluid and
tial for anatomic variations and congenital anom- extravasated proteins from the interstitial space,
alies. It may develop in different anatomic and (3) the return of lymphocytes to the systemic
patterns with several lymphaticovenous anasto- circulation (Zuluaga 2012).
moses. Variation in lymphatic pathways and the At birth, chyle is clear and straw colored. Soon
presence of accessory lymphatic channels can after milk feeding begins, chylomicrons (emulsi-
account for chylous effusions resulting from sur- fied fat globules) render it milky white.
gical procedures that do not expose the main Depending on the amount of milk ingested, the
thoracic duct. Trauma to the duct in the posterior fat content of the fluid varies from 0.4 to 5.0 g/dl,
mediastinum can produce a unilateral or bilateral with a triglyceride content of >110 mg/dl (Rocha
chylothorax. Increased intraductal tension leads to 2007). Although the protein and electrolyte con-
drainage of chyle into the thorax. A lesion to the tents of chyle are similar to those in plasma, chyle
thoracic duct below the level of the fifth lumbar is rich in T-cell lymphocytes, with a lymphocyte
vertebra will result in a right-sided chylothorax; a count of 80–100%. The volume of chyle loss per
left-sided chylothorax occurs with lesions above day can exceed 1.7 times the patient’s blood vol-
this level. ume, resulting in a serious state of depletion
764 R. G. Azizkhan
characterized by hyponatremia, hypoproteinemia, (Williams and Josephson 1997; Easa et al. 1991;
metabolic acidosis, and lymphocytopenia (Curci Ibrahim et al. 1999). A genetic abnormality in the
and Debbins 1980). ITGA9 allele may be associated with more severe
fetal chylothorax and hydrops (Yeang et al. 2012).
Etiology and Presentation

of Chylothorax Acquired Chylothorax
Congenital Chylothorax Acquired chylothorax occurs due to trauma to lym-

phatic vessels and can occur after any thoracic
Congenital chylothorax is an accumulation of procedure. Several studies have reported preva-
chyle within the pleural space, and may be lence of postoperative chylothorax ranging from
detected prenatally or within the neonatal period. 2.5–4.7% (Beghetti et al. 2000; Chan et al. 2005;
It is estimated to occur in 1 in 10,000 live births Be et al. 2004). Recently, Costa and Saxena (Costa
and is the most common cause of pleural effusion and Saxena et al. 2018) performed a systematic
in the newborn (Bellini 2013; Attar and Donn. review of postoperative chylothorax in neonates
2017). Males are affected twice as frequently as found that the type of surgery that resulted in
females, and 60% of cases involve the right side of postoperative chylothorax in 107 neonates
the chest (Yancy and Spock 1967). The occur- included congenital diaphragmatic hernia repair
rence of chylothorax in the absence of other in 71%, correction of cardiac malformations in
demonstrable disease suggests the existence of 23.4%, esophageal atresia repair in 4.6% and pul-
congenital malformations of the lymphatic sys- monary sequestration in 1%. Acquired chylothorax
tem. Congenital atresia of the thoracic duct or also manifests as a complication of both subclavian
congenital fistulae due to failure of peripheral and internal jugular venous cannulation and/or
lymphatic channels to communicate with the obstruction, superior vena caval obstruction sec-
major lymphatic network have moreover been ondary to central venous catheters, or elevated
assumed on the basis of diffuse chyle leakages central venous pressures (Adiotomre et al. 1994;
seen during surgery (Van Aerde et al. 1984). Dhande et al. 1983; Ruggieto and Caruso 1985;
Congenital defects of the lymphatic system Seguin 1992; Kramer et al. 1981; Blalock et al.
that may become evident with chylothorax are 1936; Liote et al. 1990), chest tube insertion
well documented in the literature, presenting clin- (Kumar and Belik 1984), and traumatic delivery
ically as generalized lymphangiomatosis (Yeager (Wilson-Storey and MacKinlay 1987). Addition-
et al. 2008; Chen et al. 2013; Thomas et al. 1990; ally, it may be caused by a blunt blow to abdomen
Dutheil et al. 1998) or congenital pulmonary associated with child abuse. Chylothorax/
lymphangiectasis (Moerman et al. 1993; Steven- chylopericardium is a rare complication, occurring
son et al. 2006; Lee et al. 2002; Bellini et al. primarily following surgery for congenital heart
2004). Congenital chylothorax is also associated diseases (Nguyen et al. 1995) or extensive medias-
with hydrops fetalis (Deurloo et al. 2007; Mussat tinal/pulmonary lymphatic malformations.
et al. 1995; Aguirre et al. 1995; Ahmad et al.
1996; Laberge et al. 1991) and various syn-
dromes, such as trisomy 21 (Yoss and Lipsitz Clinical Features of Chylothorax
1977; Hamada et al. 1992; Foote and Vickers
1986), Turner syndrome, and Noonan syndrome Presenting Symptoms
(Fisher et al. 1982; Goens et al. 1992; Van Aerde
et al. 1984). The occurrence of chylothorax in Tachypnea, dyspnea, retraction of chest, and cya-
combination with other uncommon disorders, nosis mark the onset of chylothorax, with dullness
such as autosomal recessive lymphatic anomalies, and diminution of breath sounds on the affected
mediastinal neuroblastoma in neonates, and neo- side and displacement of the heart and mediasti-
natal thyrotoxicosis, also has been documented num to the opposite side (Lopez-Gutierrez and
Tovar 2014). In cases of congenital chylothorax, premature infants may, however, be difficult.
symptoms of respiratory distress may be noted Most of these infants already have significant
shortly after birth or at any time up to 2 weeks of pulmonary disease, and chest X-rays may appear
life. In contrast, the interval between surgery and to have areas of increasing consolidation rather
the occurrence of acquired chylothorax can vary than the more typical layering of pleural fluid seen
from 1 to 25 days. The time is shortest when there in older children. Sonography is a reliable method
is a direct injury to the duct (5–7 days) and longest of detecting chylothorax in these cases, and its use
when there is high pressure or thrombosis of the in obstetric practice as the primary method of
vena cava (10–14 days). Chyle may accumulate in imaging the fetal chest has led to the increasing
the mediastinum for several days before extrava- frequency with which fetal chylothorax is being
sating into the pleural space. diagnosed (see section below on “Fetal
Chylothorax (Hydrothorax)”). Computed tomog-
raphy (CT) or magnetic resonance imaging (MRI)
Consequence of Continuous can also be helpful, particularly for identifying
Chylous Flow loculated pulmonary parenchymal disease in
complex patients.
The loss of large quantities of chyle over a period Diagnosis is confirmed after analysis of the
of time produces nutritional failure, sepsis, meta- pleural fluid drained by thoracentesis or chest
bolic acidosis, and renal failure. Considerable loss tube placement. Initially, this fluid is serous; it
of protein and large numbers of lymphocytes may turns chylous only after milk feedings have
result in immunodeficiencies, including hypo- begun. Chyle is characterized by elevated total
gammaglobulinemia and abnormal cell-mediated protein and albumin levels, a specific gravity of
immune responses. >1.012, the presence of white blood cells with a
predominance of lymphocytes (80–100%) and
Confirming the Diagnosis elevated triglycerides, cholesterol, and total fat
levels if the infant is milk fed (Brodman 1975).
X-rays of the chest typically show opacification of In the unfed neonate, the fat content of the
one or both hemithoraces, with compression of chylothorax may be quite low, and the fluid does
lung and displacement of mediastinal structures in not have the characteristic milky appearance. The
unilateral chylothorax (Fig. 2). X-ray diagnosis in protein content is somewhat less than that of
serum and the electrolytes approximate those of
serum.
Management of Chylothorax
Nonoperative Management
The goal of the treatment is to decrease the

chylothorax volume to keep the pleural space
clear and to allow time for injured lymphatic
vessels to heal or develop enough collateral con-
nections (Tutor 2014; Attar and Donn 2017). The
treatment is typically stepwise, starting with con-
servative therapy, such as MCT diet, TPN, chest
tube drainage or repeated aspirations, administra-
tion of octreotide, somatostatin and/or steroids
Fig. 2 Chest radiograph in a term neonate demonstrating (Matsuo et al. 2013; Costa and Saxena 2018).
bilateral chylothorax An initial trial of nonoperative management
766 R. G. Azizkhan
relying on adequate drainage of chyle, coupled (Al-Hussaini and Butzner 2012; Rosti et al. 2002;
with nutritional supplementation via Cheung et al. 2001; Goyal et al. 2003). OCT is
MCT-enriched diets and/or TPN, should be well tolerated at dosing ranges of 40–100 μg/kg
given in order to optimize the chance of recovery per day for 3–6 weeks, and the earlier use of
without surgery. Using this regimen, the majority higher doses may be preferable to gradual upward
of cases of congenital chylothorax and up to 77% tapering of the dose (Helin et al. 2006). A recent
of cases with traumatic chylothorax (postopera- review reported that octreotide is a relatively
tive) resolve spontaneously (Chan et al. 2006; effective and safe treatment option in neonates
Robinson 1985; Rubin et al. 1977). with chylothorax especially for the congenital
Some investigators have observed no differ- forms. Potential adverse effects include cholelithi-
ence in MCT or TPN in regard to duration or asis, liver impairment, renal impairment, transient
amount of drainage (Allen et al. 1991; Nguyen glucose intolerance (Rimensberger et al. 1998;
et al. 1995). Others have found that for patients Tibballs et al. 2004), hypothyroidism (Maayan-
with superior vena caval obstruction and congen- Metzger et al. 2005), and necrotizing enterocolitis
ital lymphatic malformation, MCT alone is not as (Lam et al. 2001). It is thus prudent for patients to
effective; they thus recommend the rapid admin- undergo routine monitoring of liver function,
istration of TPN (Le Coultre et al. 1991). blood glucose, and thyroid parameters during the
Numerous case studies suggest that somato- course of treatment.
statin (SST) and octreotide (OCT) exert a positive Costa and Saxena (Costa and Saxena 2018)
effect on persistent congenital and postoperative reported results of treatment in 107 cases of post-
chylothorax (Roehr et al. 2006; Chan et al. 2006; operative chylothorax and found that MCT alone
Das and Shah 2010; Rosti et al. 2002; Cheung was effective in 27 (25.3%) cases and TPN, either
et al. 2001; Pessotti et al. 2011; Al-Hussaini and as first line or second line treatment modality,
Butzner 2012). SST is a polypeptide with mainly resulted in the resolution of chylothorax in 42
inhibitory actions on the release of various hor- (39.3%) cases respectively.
mones (e.g., growth hormone and insulin) and
lymph fluid excretion (Lamberts et al. 1996;
Tauber et al. 1994). OCT is a synthetic SST analog Operative Management
with antisecretory properties similar to those of
SST. It is thought that octreotide may act directly The percentage of neonates requiring surgery and
on somatostatin receptors in the splanchnic circu- the timing of surgical intervention vary widely
lation to reduce lymph fluid production (Cheung among reported series and are dependent upon the
et al. 2001; Goyal et al. 2003). Thoracic duct patient population being studied, etiology, and the
lymphatic flow depends on splanchnic vascular clinical status of individual patients. Operative man-
tone as well as gastric motility (Nakabayashi agement has, however, been the mainstay of treat-
et al. 1981). OCT decreases the volume of gastric, ment for a number of clinical conditions that have a
pancreatic, and biliary secretions, thus reducing high failure rate with standard nonoperative man-
the volume and protein content of fluid within the agement; these include postsurgical cases in which
thoracic duct. It offers a number of advantages there is injury to the thoracic duct and massive
over SST, including a longer half-life in the circu- lymph leakage, caval obstruction, or elevated central
lation (1–2 h vs. 2–3 min), a higher potency, and venous pressures (Nguyen et al. 1995; Le Coultre
good bioavailability after subcutaneous adminis- et al. 1991; Higgins and Mulder 1971; Puntis et al.
tration (Al-Hussaini and Butzner 2012). In view 1987; Nath et al. 2009). Congenital chylothorax
of these advantages, OCT has largely supplanted associated with superior vena caval thrombosis in
SST as an adjunctive pharmacologic agent for the premature neonate is also particularly refractory
chylothorax. Moreover, published data indicate to standard nonoperative therapy (Dhande et al.
that it shortens the duration of TPN and hospital 1983). Since failure is associated with a high mor-
stay and avoids the need for surgical intervention tality rate, some investigators maintain that surgical
intervention should be considered early in the man-

agement of such cases (Le Coultre et al. 1991; Nath
et al. 2009; Rheuban et al. 1992; Engum et al. 1999).
Several surgical options exist, and they are
often used in combination. These options include
pleuroperitoneal shunting, thoracic duct ligation
(open thoracotomy or thoracoscopy), chemical
and mechanical pleurodesis with various agents,
pleurectomy, and intrapleural fibrin glue.
Pleuroperitoneal Shunts
Pleuroperitoneal shunts, first used by Azizkhan
et al. in 1983 (Azizkhan et al. 1983) to treat five
ventilator-dependent infants with persistent
chylothorax, remain a viable treatment option
(Rheuban et al. 1992; Engum et al. 1999; Murphy
Fig. 3 Chest radiograph showing resolution of a
et al. 1989). chylothorax after pleuroperitoneal shunt placement
The procedure avoids the risks associated with
a more complicated, open surgical procedure in
high-risk infants and is considered safe, highly subcutaneous valve reservoir is available. Once
effective, and easy to perform. Nonetheless, it is the chylous effusion clears, parents are taught the
associated with several drawbacks. These include technique of pumping the chamber, and the
having to manually press a pumping chamber patient is discharged from the hospital. Over the
several times a day and having the valve and ensuing 2–3 months, the frequency of pumping is
pumping chamber become dysfunctional after further reduced. When the chylous effusion
several weeks due to an accumulation of fibrin completely resolves, the catheter is removed.
and protein in the valve mechanism. It thus is This approach offers less interruption of the
ideal for patients who require a relatively short sleep cycle and may facilitate a shorter hospital
or stabilizing procedure. stay. Although this approach carries an increased
A postoperative chest X-ray is obtained to make risk of infection, this risk has not been
certain that the pleural catheter is properly placed. documented in clinical studies.
During the immediate postoperative period, the Although there has been concern that elevated
pumping chamber is compressed 50–100 times right atrial pressures transmitted to the venous and
per hour in order to completely clear the lymphatic bed of the peritoneal space may impair
hemithorax of chyle. As the infant’s clinical status absorption of shunted pleural fluid, the successful
improves, a gradual decrease in the frequency of use of pleuroperitoneal shunting with this patient
shunt compression is begun. Noninvasive transcu- population, even in the face of moderate eleva-
taneous oxygen saturation monitoring, arterial tions in right atrial pressure, has been reported
blood gas determination, and serial chest X-rays (Rheuban et al. 1992). Failure to resolve chylous
are used to assess shunt efficacy (Fig. 3). Manual effusions is associated with occlusion of the shunt
compression of the shunt valve is discontinued catheter or significant intra-abdominal chylous
when it is clear that chylothorax is resolved. This ascites. When the latter occurs, a pleuroperitoneal
often occurs within 2–3 weeks. However, some shunt and a peritoneovenous shunt combination
infants require a more prolonged period of manual have been successfully used in some cases.
compression, lasting 6–8 weeks. The same principle has been applied in the
A high-flow externally located valve reservoir management of patients with chylopericardium.
designed to avoid some of the discomfort and Case reports indicate that pericardial–peritoneal
positioning problems associated with a shunting provides an easy and effective alternative
768 R. G. Azizkhan
to prolonged pericardial draining, thoracotomy, or Also, it may be difficult to correctly visualize

thoracic duct ligation in patients with chyloper- leaks in the presence of a massive chylous
icardium of various etiologies (Chan et al. 1990). effusion.
Other Surgical Alternatives

Thoracic duct ligation has historically been the General Management Principles
most common surgical therapy and has been
successfully utilized in resolving chylous leaks The general principles of management for
in many patients. However, the risk that a chylothorax include the following:
compromised, frail, or premature neonate must • Thoracentesis is performed to provide
endure a major surgical procedure is not insig- immediate relief of respiratory failure and to con-
nificant. Despite this drawback, thoracic duct firm the diagnosis through chemical analysis of
ligation is currently an option when pleural fluid specimen.
pleuroperitoneal shunting fails to resolve the • Supportive ventilation is instituted as
chylous leak or when chylothorax is due to pen- required.
etrating trauma (Zuluaga 2012; Nath et al. 2009; • Thoracostomy tube drainage is carried out if
Matsuo et al. 2013). Giving a small bolus of pleural fluid reaccumulates after one or two
“cream” through the nasogastric tube several thoracenteses. (Repeating this procedure carries
hours before operations may help to identify a risk of producing pneumothorax and introduc-
the sites of leakage of the milky white fluid. ing infection; chest tube drainage keeps the lungs
Major leaks from the thoracic ducts can be fully expanded, which is necessary for sealing
closed by direct suturing or by ligating the duct chyle leakage.)
above and below the leak. Pleurodesis and pari- • Nutritional losses are replaced through a
etal pleurectomy have been used when there is high protein diet, rich in MCTs that are absorbed
generalized seeping of chyle from parietal directly into the portal venous system.
pleura; however, these are extensive surgical • Parenteral feeding is instituted. (When supe-
procedures that may increase the possibility of rior vena caval thrombosis is present with
pulmonary lymphedema, fibrosis, and further chylothorax, TPN may need to be delivered via a
pulmonary compromise. Fibrin glue applied to peripheral vein.)
the leakage site after patent ductus arteriosus • The albumin, gamma globulin, and fibrino-
ligation has been reported to successfully man- gen that are contained in chyle, as well as
age chylothorax in both a 3.5-month-old infant fat-soluble vitamins, are adequately replaced.
(Stenzl et al. 1983) and a premature infant • Full expansion of the lungs is maintained by
weighing 600 g (Nguyen and Tchervenkov continuous chest tube drainage of chyle. (These
1994). The choice of either an open or tubes may become obstructed and require replace-
thoracoscopic approach to thoracic duct ligation ment as necessary.)
depends on the experience of the surgeon. • Prophylactic antibiotics are given when
Video-assisted thoracoscopic procedures chest tubes are in place, since many of these
(VATS) are being used with increasing frequency. infants have an acquired immune deficiency
These procedures offer the advantage of access to caused by lymphocytopenia. Some infants
the entire hemithorax, with excellent visualization may also need salt restriction, diuretics, and
of the mediastinal structures (Beghetti et al. 2000). digoxin.
This approach allows application of clips to the • Octreotide may be used for cases recalcitrant
thoracic duct at the hiatus or to the thoracic duct to other medical therapies or as an adjunct to
injuries or pleural defects. It also facilitates standard medical therapy.
mechanical or chemical pleurodesis and applica- • Surgical intervention is warranted when
tion of fibrin glue. Despite its advantages, its use medical therapies fail to significantly diminish
is limited by an infant’s size and pulmonary status. chylous drainage for more than 14 days or if
Chylothorax
Progressive effusion Stable effusion

Chest tube
Failure Improvement
High output Decreasing output MCT-rich feedings

> 7 days 7-10 days
Failure Improvement
Surgical options TPN Failure MCT-rich feedings

Failure 3 weeks 21 days
Success Success
Effusion
resolving
Postoperative Bilateral chylothorax, SVC obstruction Regular diet

chylothorax Congenital lymphangiectasia
Thoracoscopic
Thoracic duct ligation Primary
+ fibrin glue approach
Failure
Pleuroperitoneal shunt
Failure Success
Pleurectomy Shunt remains until

Direct open ligation effusions resolve (2-3 months)
Lymphatic leaks
Fig. 4 Algorithm of management principles. SVC superior vena cava, MCT medium chain triglycerides, TPN total
parenteral nutrition
there is obvious deterioration in the patient prior 2007). Owing to the growth of routine prenatal
to that period of time (Fig. 4). ultrasonography over the past several decades, it
has been diagnosed with increasing frequency
from as early as 16 weeks’ gestation to an average
Fetal Chylothorax (Hydrothorax) of 30 weeks’ gestation (Nygaard et al. 2007). In
contrast to chylothorax diagnosed at birth, fetal
As mentioned earlier in this chapter, primary fetal chylothorax is associated with an overall mortality
chylothorax (also known as hydrothorax) is the rate as high as 50% (Longaker et al. 1989). Never-
most common fetal pleural effusion, occurring in theless, its clinical course is highly variable, ranging
1 in 10,000–15,000 pregnancies (Nygaard et al. from complete spontaneous resolution (10–20%) to
770 R. G. Azizkhan
progression into hydrops fetalis and/or lung hypo- 2008; Picone et al. 2004). Several case reports ema-
plasia and perinatal death (Weber and Philipson nating from Europe and Japan have documented the
1992; Aubard et al. 1998; Devine and Malone successful use of intrapleural injection of OK-432
2000). Survival depends on multiple factors, for the treatment of severe fetal chylothorax associ-
including the presence of associated anomalies ated with pronounced hydrops (Jorgensen et al.
and the gestational age at which diagnosis is first 2003; Tanemura et al. 2001; Okawa et al. 2001).
made. In fetuses with isolated pleural effusions and From a broad perspective, antenatal diagnosis
low gestational age, spontaneous resolution rates is significant not only in that it can often identify
are reportedly as high as 50% (Nygaard et al. the need for potentially helpful intrauterine inter-
2007; Aubard et al. 1998; Klam et al. 2005). Prog- vention and facilitate preparation of appropriate
nosis is poor when effusion is associated with chro- postnatal outcome but also in that it is a reliable
mosomal aberrations, multiple malformations, and predictor of fatal outcome. As such, it facilitates
fetal hydrops (Yinon et al. 2008). the communication of a more accurate prognosis
The management of fetal chylothorax has been to parents. Since most large pleural effusions dis-
controversial, and the optimal treatment approach covered in utero lead to hydrops and pulmonary
remains unclear. Dissension is primarily focused hypoplasia, such effusions have a high mortality
on the following issues: (Vain et al. 1980) whether rate. Retrospective research indicates that the
treatment should be attempted in utero or the absence of hydrops predicts 100% survival and
infant should be delivered and treated after birth, that fetuses that initially present without hydrops
(Van Aerde et al. 1984) under what clinical cir- and subsequently develop it have only a 38%
cumstances antenatal intervention should be car- survival (Laberge et al. 1991).
ried out, and (Curci and Debbins 1980) whether
pleurocentesis or pleuroamniotic shunting should
be used for thoracic decompression. Other Pleural Effusions
Despite the dissension, there is a general consen-
sus that fetal chylothorax with rapid progression Hemothorax
warrants intervention. Although reports of success-
ful management with pleurocentesis or Although massive hemothorax is uncommon, acci-
pleuroamniotic shunting have appeared in the liter- dental injury to the intercostal artery during
ature (Longaker et al. 1989; Klam et al. 2005; Yinon thoracentesis or closed intercostal drainage can
et al. 2008; Rodeck et al. 1988; Roberts et al. 1986; result in intrapleural bleeding (Haller 1986).
Blott et al. 1988; Mandelbrot and Dommergues Hemothorax has been reported as a complication
1992), pleurocentesis has been associated with of a variety of congenital malformations (e.g.,
rapid reaccumulation of the effusion and is therefore sequestration, patent ductus, and vascular anoma-
unlikely to be advantageous (Weber and Philipson lies) and of subclavian vein catheters (Tetsuka et al.
1992; Aubard et al. 1998; Klam et al. 2005; Yinon 2009; Webber and Rescorla 2012; Feliciano et al.
et al. 2008). Thoracoamniotic shunting has been 1979; Casado-Flores et al. 2001; Lee et al. 2010). It
effective in selected patients with progressive pleu- is also an occasional manifestation of intrathoracic
ral effusions, especially when there is evidence of neoplasms and blood dyscrasias, as well as bleeding
intrathoracic hypertension (Yamamoto et al. 2007). diatheses. Additionally, it can occur spontaneously
Most commonly, a Harrison double-pigtail catheter in neonates, sometimes in association with a pneu-
is used. Both techniques are associated with serious mothorax. Symptoms reveal respiratory embarrass-
pregnancy risks, including preterm labor, prerupture ment similar to that seen in tension pneumothorax.
of the membranes, intrauterine infection, bleeding, However, the percussion note is dull, and chest
and maternal or fetal organ trauma. Additionally, X-rays show opacification. More importantly, the
technical failures such as shunt displacement and infant may show signs of hypovolemic shock.
blockage are common (Longaker et al. 1989; Weber Blood transfusion and urgent tube thoracostomy
and Philipson 1992; Klam et al. 2005; Yinon et al. generally provide adequate control of bleeding. To
avoid sudden circulatory collapse, transfusion of systemic administration of antibiotics, anaer-

should precede intercostal drainage. If massive obic infection tends to be multilocular and may
blood loss continues, urgent thoracotomy and iden- thus require debridement. Based on a compre-
tification and securing of the bleeding site are hensive review of evidence to date, the Ameri-
required (Webber and Rescorla 2012). can Pediatric Surgical Association Outcomes
and Clinical Trials Committee recommends the
following management strategy: (Islam et al.
Empyema 2012) (1) chemical debridement with a fibrino-
lytic agent (e.g., deoxyribonuclease) should be a
Empyema (purulent effusion) is a relatively first line of therapy; (2) if a child is persistently
uncommon condition in children thought to evolve ill after the chest tube drainage is diminished and
from a parapneumonic fluid collection subse- imaging demonstrates significant pleural space
quently infected by an adjacent lung infection. disease, VATS should be considered; (3) paren-
Although many organisms cause pediatric empy- chymal abscess and lung necrosis should be
ema, the most common is Streptococcus managed nonoperatively; and (4) antibiotic ther-
pneumoniae (Krenke et al. 2016); other frequently apy should continue for at least 10 days after
identified organisms include Staphylococcus resolution of fever.
aureus, Pneumococcus, and Haemophilus
influenzae. This condition can also be incurred
through the introduction of skin bacteria during Cross-References
thoracentesis or thoracotomy and may be accom-
panied by anaerobic infection. Although empyema ▶ Embryology of Congenital Malformations
in children is less serious than empyema in adults, it ▶ Fetal Counseling for Congenital Malformations
nevertheless poses a considerable burden on hos- ▶ Fetal Surgery
pitals and families and complicates the course of ▶ Lymphatic Malformations in Children
2–8% of children hospitalized for pneumonia in the ▶ Pediatric Clinical Genetics
United States (Gates et al. 2004; Tan et al. 2002). ▶ Principles of Minimally Invasive Surgery in
Symptoms include indications of respiratory dis- Children
tress in addition to abdominal distension, lethargy,
and, at times, a septicemic state. The size of effusion Acknowledgments The author wishes to acknowledge
typically correlates with the presence of symptoms the assistance of Aliza P. Cohen, MA, in the writing of
(Bradley et al. 2011). In symptomatic patients, chest this chapter.
radiographs are helpful in identifying the effusion
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Congenital Malformations of the Lung
52
Keith T. Oldham and Kathleen M. Dominguez
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
Congenital Pulmonary Airway Malformations/Congenital Cystic
Adenomatoid Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
Radiographic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Fetal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Postnatal Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
Pulmonary Sequestrations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784
K. T. Oldham (*)
Division of Pediatric Surgery, Medical College of
Wisconsin, Children’s Hospital of Wisconsin, Children’s
Corporate Center, Milwaukee, WI, USA
e-mail: koldham@chw.org
K. M. Dominguez
Pediatric Surgery, Marshfield Clinic, Marshfield, WI, USA
e-mail: dominguez.kathleen@marshfieldclinic.org

https://doi.org/10.1007/978-3-662-43588-5_56
776 K. T. Oldham and K. M. Dominguez
Congenital Lobar Emphysema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788
Bronchogenic Cysts and Congenital
Lung Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
Pulmonary Hypoplasia, Aplasia, and Agenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
Lung Surgery in Newborns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792
Complications and Long-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
Abstract emphysema · Pulmonary sequestration ·

Congenital lung malformations are uncommon Bronchogenic cyst
but extraordinarily diverse in their presenta-
tion. Potential consequences may be life-
threatening; therefore, an understanding of
Introduction
the diagnosis and treatment of these anomalies
is important to all physicians and surgeons who
Congenital lung malformations are uncommon
care for infants and children. These lesions
but extraordinarily diverse in their presentation.
vary from asymptomatic to immediately life-
Given that the potential consequences may be life-
threatening in nature and may present antena-
threatening, an understanding of the diagnosis and
tally or well into adulthood. Lung development
treatment of these anomalies is important to all
and anatomy are important fundamentals in the
physicians and surgeons who care for infants and
discussion of these malformations and aide in
children. The presentation of these lesions occurs
understanding the pathophysiology which
in a spectrum, from antenatal diagnosis to presen-
occurs. The most common congenital
tation in adulthood. These lesions may also vary
malformations include congenital pulmonary
from asymptomatic to immediately life-
airway malformations, pulmonary sequestra-
threatening in nature. To begin to understand the
tions, lobar emphysema, and bronchogenic
pathophysiology of these malformations, one
cysts.
must first start with a basic understanding of
lung development, as well as respiratory anatomy
Keywords and physiology, which are presented below. The
Congenital pulmonary airway malformations · most common congenital malformations such as
Congenital cystic adenomatoid congenital pulmonary airway malformations, pul-
malformations · Congenital lobar monary sequestrations, lobar emphysema, and
52 Congenital Malformations of the Lung 777
bronchogenic cysts, as well as a number of less malformations are evident. If one considers
common anomalies will be discussed. the rapid expansion of pulmonary parenchyma
during this period of development, it is easily
understood how a congenital pulmonary
Embryology lesion can have a significant impact on fetal
lung development and postnatal respiratory
Development of the respiratory system begins physiology. Development and maturation of
during the third week of gestation as a diverticu- the alveoli occur during the third trimester.
lum of the ventral foregut. This diverticulum is The number and size of the alveoli continue
primarily endodermal in origin but derives carti- to increase during this time, but it is important
laginous and muscular elements from the sur- to recognize that this process is not complete
rounding splanchnic mesoderm. During the until well into childhood. An additional six
fourth week, the esophagotracheal septum forms divisions of the airways occur during early
through fusion of the esophagotracheal ridges, postnatal life, and lung development con-
completely separating the developing respiratory tinues until approximately 8 years of age
system and foregut except at the larynx. As devel- (Thurlbeck 1975). When considering congen-
opment progresses, the endodermal diverticulum ital lung lesions and their treatment, this is
will become the epithelial lining of the larynx, critical: because of continued lung develop-
trachea, bronchi, and alveoli. By the end of week ment well into childhood, pulmonary
6, the trachea has undergone division into the right resection in infants and children is extraordi-
and left main-stem bronchi. Proliferation of mes- narily well tolerated, with little impact on
enchyme in the mediastinum provides the meso- long-term respiratory physiology (Gray and
derm which eventually develops into the Skandalakis 1972).
cartilaginous, smooth muscle, and connective tis-
sue of the lung.
The pulmonary vasculature develops in paral-
lel to the surrounding lung tissue. This tissue is Anatomy
derived from the mesoderm around the primitive
lung buds and begins to develop at 7–8 weeks of A brief discussion of relevant anatomy is pre-
gestation. Pulmonary blood flow slowly matures, sented. For a more detailed review, several excel-
and by the seventh gestational month, gas lent references are available (Agur and Dalley
exchange is possible. 2013; Netter 2011). The location of the carina is
The endodermal diverticulum continues to dependent on age, but in a term infant is located at
progressively branch; segmental and lobar the fourth or fifth vertebral body. The main stem
branching is complete by the ninth week of bronchus of the right lung is larger in diameter,
gestation and coincides with closure of the shorter in length, and more vertical in direction
pleural peritoneal canal and the formation of than the left main stem bronchus; these anatomic
the diaphragm. As the lung continues to differences account for the preference of aspirated
expand and grow, the lung buds come to material and deep endotracheal tubes to enter the
nearly completely fill these canals, leaving right main stem. In the infant and child, the hilum
only a small residual space which becomes of either lung is beneath the fifth intercostal space
the pleural cavity. By the sixth month of ges- on the lateral chest wall. A thoracotomy through
tation, approximately 17 generations of sub- this space provides optimal exposure for pulmo-
divisions have been formed, giving rise to nary resection. The relationship of the hilum to
the respiratory bronchioles. At this point in other mediastinal structures is demonstrated in
gestation, many congenital pulmonary Fig. 1. The mature right lung is composed of
Vagus nerve
Left recurrent
laryngeal nerve
Esophagus
Right recurrent Trachea

laryngeal nerve
Ligamentum
arteriosum
Vagus nerve
Bronchial arteries
originating from
descending thoracic
aorta
Aorta
Pulmonary
artery
Fig. 1 Key anatomic relationships of the structure of the pulmonary hilum (Modified from Oldham 2005, p. 952)
three lobes, in contrast to two lobes on the left; the

lungs are further subdivided into anatomic Congenital Pulmonary Airway
segments. Malformations/Congenital Cystic
The pulmonary artery circulation is dedicated to Adenomatoid Malformations
gas exchange; the vascular supply of the trachea,
bronchi, and lung parenchyma is systemic in nature. Pathology
The trachea is supplied by branches of the inferior
thyroid arteries, which anastomose with the bron- In 1949 Ch’in and Tang described a mass lesion of
chial blood supply, derived from the aorta on the left gland-like (adenomatoid) alveoli, coining the term
and the third intercostal artery on the right. Venous “congenital adenomatoid malformation.” Over the
drainage is by the azygous and hemiazygous sys- next 30 years, a variety of lesions, both cystic and
tems. This arterial supply and venous drainage gen- not, were grouped together under the heading of
erally follow the segmental architecture of the lung congenital cystic adenomatoid malformation
and bronchial tree (Agur and Dalley 2013; Netter (CCAM), with subdivisions based on the size of the
2011; Oldham 2005). cysts. The term congenital pulmonary airway
Fig. 2 CPAM
0
classification based on
presumed site of
development of the
malformation.
0 = tracheobrohial, 1
1 = bronchial/bronchiolar, 2
2 = bronchiolar,
3 = bronchiolar/alveolar, 3
4 = distal acinar (From 4
Stocker 2009)
malformations (CPAMs) was developed by Stocker, of normal architecture. A component of bronchial

attempting to better clarify and subdivide this disease atresia is identifiable in most CPAM lesions and
process based on the presumed origin of the abnor- may contribute to their pathogenesis. These lesions
mal lung tissue (Fig. 2). This classification system typically communicate with the normal bronchial
carries both descriptive and prognostic significance, tree and have a normal vascular supply (Rashad
given that certain subtypes (1 and 4) carry increased et al. 1988). A single lobe is generally affected;
risk of malignancy (MacSweeney et al. 2003; there is a slight predilection for the lower lobes,
Stocker 2009). with right and left sides affected equally.
Today, these terms are used somewhat inter-
changeably, though inconsistency continues to
exist regarding the correct nomenclature. For the Diagnosis
purposes of this chapter, this group of lesions will
be referred to as CPAM and is generally defined as Radiographic
benign hamartomatous or dysplastic tumors char-
acterized by overgrowth of terminal bronchioles in Currently, the majority of cystic lung lesions are
a glandular or adenomatoid pattern. These lesions identified on prenatal ultrasound (US), which
are relatively uncommon, with an estimated inci- demonstrates an echogenic pulmonary mass with
dence of 1 in 25,000 to 1 in 35,000 (Duncombe displacement of adjacent structures. The location
et al. 2002), but constitute up to 50–70% of of the stomach bubble is helpful in distinguishing
bronchopulmonary foregut malformations in some between CPAM and congenital diaphragmatic
reports (Adzick et al. 1998; Wolf et al. 1980). hernia (CDH), though some difficult cases may
CPAMs are thought to result from marked over- require prenatal magnetic resonance imaging
growth of terminal bronchioles at the expense of (MRI) for definitive diagnosis (Hubbard et al.
alveolar development. Grossly, these lesions are 1999). Adzick and colleagues used antenatal US
large, firm multicystic masses and are characterized and defined CPAM as either macrocystic (greater
by interconnected disorganized cysts. Histology of than 5-mm diameter cysts) or microcystic (solid or
CPAM lesions demonstrates ciliated cuboidal or less than 5-mm diameter cysts); however, overall
columnar cells lining the cysts and a notable lack size and degree of compression of adjacent
structures ha a greater impact on the natural his- 28 weeks. These are performed twice weekly if
tory of CPAM than does gross appearance. Phys- the CVR is greater than 1.6 and once weekly if the
iologic consequences may be severe, with CVR is 1.6 or less, to evaluate for an increasing
significant compression of the mediastinum, CVR or the development of hydrops.
resulting in hydrops fetalis and fetal demise. Con- Postnatal diagnosis can often be made by plain
versely, serial US exams may show shrinkage or chest radiographs; a nasogastric tube is helpful in
even spontaneous resolution in up to 40% of pre- distinguishing between CPAM and CDH, as an
natally identified CPAMs (Adzick et al. 1998; van intrathoracic stomach is common with left CDH.
Leeuwen et al. 1999). In a stable patient, CT and MRI are helpful to
The differential diagnosis of cystic and mass define anatomy and identify aberrant systemic
lesions noted on prenatal US includes CPAM, blood supply that is more suggestive of a pulmo-
CDH, pulmonary sequestration, and broncho- nary sequestration (Fig. 3). A CT scan is more
genic cyst. Differentiation between these entities accurate than plain chest radiography in
can often be made by the associated findings: confirming complete resolution of an prenatally
CPAMs are associated with polyhydramnios diagnosed congenital pulmonary lesion that is not
(thought to be secondary to esophageal compres- apparent on postnatal plain chest radiography, as
sion and impairment of fetal amniotic fluid residual parenchymal abnormalities may still be
swallowing), pleural effusions, and fetal hydrops present (van Leeuwen et al. 1999).
(resulting from mediastinal shift and diminishing
cardiac output from caval obstruction) (Adzick
et al. 1998). Any of these findings during preg- Clinical Features
nancy are associated with a poor outcome. Con-
versely, mortality approaches zero for a fetus with The natural history of a CPAM diagnosed prena-
a CPAM and no associated hydrops. tally is highly unpredictable and variable.
Crombleholme et al. developed and proposed Approximately one third of patients will be symp-
US determination of the CPAM volume ratio tomatic in the neonatal period (Wang et al. 1999).
(CVR) to aid in predicting risk of developing These patients may demonstrate tachypnea, dys-
hydrops fetalis. CVR = (CPAM Length pnea, cyanosis, or even impending respiratory
Height Width 0.52)/head circumference. A failure as a consequence of mass effect. The pre-
CVR of 1.6 (lesions with a dominant cyst sentation in these patients can be dramatic and
excluded) predicts a low risk (<3%) for the devel- may demand intervention in the neonatal period.
opment of hydrops, whereas a CVR >1.6 predicts However, the majority of patients are asymptom-
fetal hydrops in 75% of patients. In their series, atic at birth and present instead with recurring
postnatal intubation was required in fewer than persistent respiratory infections during the first
7% of patients with a CVR 1.6, and the survival few years of life. This may result in the formation
rate was 94%. In contrast, when CVR was >1.6, of pulmonary abscesses or development of reac-
intubation was required in 88% of patients and tive airway disease. In a small cohort of patients
survival was 53%. They also observed that the with unresected CPAM, Aziz et al. found a 10%
greatest increase in CVR occurred between 20- incidence of infectious complications by the age
and 26-week gestation, and thereafter the CVR of 3 years (Aziz et al. 2004). The long-term inci-
plateaus or diminishes with continued fetal dence of infections is likely higher. Ultimately,
growth (Crombleholme et al. 2002). Further stud- these chronic pulmonary problems may also lead
ies have confirmed these findings, citing a strong to failure to thrive. In those patients who require
correlation between the CVR, the development of respiratory support or fail to thrive as a result of
hydrops, and the need for fetal intervention (Cass increased work of breathing, neonatal surgical
et al. 2011). For these reasons, surveillance US is resection is indicated.
suggested in fetuses with a known CPAMs which Less commonly, a CPAM is diagnosed in a
are less than the estimated gestational age of child or during adulthood in association with a
Fig. 3 Term female infant with prenatally diagnosed (b) demonstrates the CPAM (white arrow) but also iden-
CPAM. CXR (a) shortly after birth demonstrates left tifies an extralobar sequestration (black arrow), adjacent to
lower lobe CPAM. Preoperative CT angiogram the left lower lobe
pulmonary malignancy. More than 40 cases of trimester. In fetuses with US evidence of fetal
CPAM associated with a bronchoalveolar carci- hydrops, intervention should be considered.
noma (BAC), sarcoma, pleuropulmonary Maternal steroid administration to any affected
blastoma (PPB), mesenchymoma, or mucinous fetus less than the estimated gestational age of
adenocarcinoma are reported in the literature. 34 weeks is reasonable (Curran et al. 2010).
When hydrops develops during the third trimester,
one option is an ex utero intra partum therapy
Management (EXIT) procedure with thoracotomy and lobec-
tomy using placental bypass, permitting safe
Fetal Therapy resection and avoiding respiratory collapse. Cass
et al. recently reported a 100% survival rate for
Fetal treatment of surgical disease remains one of infants undergoing an EXIT procedure; fetuses
the more controversial areas in pediatric surgery were identified as high risk either because of
due to the high risk of complication and mortality fetal hydrops or CVR >1.6, and EXIT was
for both fetus and mother. For CPAMs, it is clear performed in those who demonstrated persistent
from the literature that treatment should be expec- mediastinal compression near birth (Cass et al.
tant management with term delivery and postnatal 2013). Conversely, of the patients who did not
evaluation, except in those cases where the fetus undergo EXIT, all required emergent surgery as
develops hydrops or physiologic distress. What, if neonates, and two died. If the fetus is in the second
any, treatment should be offered to fetuses who trimester, several options exist for fetal interven-
demonstrate fetal hydrops or distress is less clear. tion. Intrauterine thoracoamniotic shunting may
As stated above, previously published experience be performed with US guidance for a CPAM
demonstrated universal fetal demise in fetuses with a large cyst; this intervention has the best
with cystic pulmonary lesions and hydrops. outcome with the lowest fetal and maternal risk.
More recently, published reports indicate that the Of 23 such patients treated with this approach in
development of hydrops in a fetus with a CPAM one series, the volume reduction of the CPAM
may not be uniformly fatal, and the risk of fetal was 70%, and survival through the neonatal
loss may be further decreased by systemic mater- period was 74% (Wilson et al. 2006). Open
nal steroid administration during the second maternal-fetal surgery with pulmonary resection
of a large CPAM yields a >50% probability of children who present with acute pulmonary infec-
survival to discharge from the NICU, but given tion, it is appropriate to treat first with antibiotics
the technical complexity, this should only be and then plan for elective lobectomy. Tradition-
performed in a center with experience in open ally, resection was performed through open thora-
maternal-fetal surgery. Due to the complexity of cotomy, but recent reports have demonstrated
this decision making process and the expertise excellent outcomes for minimally invasive pul-
necessary to make any needed intervention, refer- monary resection (Mattioli et al. 2016). This will
ral to a tertiary care center is appropriate at the be further discussed later in the chapter.
time of diagnosis of any CPAM. While the majority of surgeons recommend
resection of these lesions even in asymptomatic
patients due to the risk of infection and malig-
Postnatal Therapy nancy, there is controversy regarding this
approach. Proponents of expectant management
Any symptomatic newborn necessitates prompt point out that little is known about the natural
surgical intervention. Some infants who did not history of these lesions, particularly in the age of
show evidence of compromise in utero will dete- prenatal US diagnosis, when more lesions are
riorate as the abnormal lung tissue becomes pro- being diagnosed than ever before. Operative ther-
gressively distended with the postnatal apy inherently carries a risk of morbidity and
phenomenon of air trapping related to breathing mortality, while little is known about the true
or positive pressure ventilation. Many infants risk with expectant management. Some reviews
remain asymptomatic in the newborn period, and of the literature have suggested that the incidence
delaying resection until later in infancy is reason- of malignancy in those with CPAMs is no higher
able. This approach allows somatic growth and than that in the population without CPAMs
may facilitate the ease of pulmonary resection. (Hammond et al. 2010). While pleuropulmonary
Delaying resection until later in infancy does not blastoma (PPB) may occur at a young age and be
appear to pose an increased risk of complications difficult to differentiate from CPAM without a
(Colon et al. 2012) and allows the opportunity for pathologic specimen, certain patients who are at
spontaneous resolution to occur. Complete spon- increased risk can be identified and offered elec-
taneous resolution of a CPAM identified on post- tive resection. Patient characteristics such as
natal imaging is rare but may occur in more than multifocal/bilateral lesions, associated pneumo-
4% of patients (Butterworth and Blair 2005). thorax or renal cystic nephroma, and a family
Because congenital pulmonary lesions may history of various tumors (including PPBs, renal
become undetectable by ultrasound and plain nephromas, bladder rhabdomyosarcomas,
radiograph, axial imaging using chest CT or gonadal germ cell tumors, papillary carcinomas,
MRI is necessary to ensure complete resolution. and nodular hyperplasia of the thyroid gland) are
Asymptomatic but persistent CPAM generally all associated with PPB (Hammond et al. 2010).
should be resected during infancy to prevent com- Bronchoalveolar carcinoma (BAC) may also be
plications of recurrent infections or malignant seen in association with CPAM but is typically
degeneration (Kapralik et al. 2016; Singh and seen in older children and adults, with low overall
Davenport 2015). incidence. BAC is only associated with the type
Resection typically includes formal lobectomy 1 CPAM subtype (MacSweeney et al. 2003);
and is very well tolerated in infants and children. however, the lesions must be resected and undergo
For small CPAM, nonanatomical resection is a histopathologic examination in order the diagno-
reasonable option and does not appear to have sis. Other types of malignancy are extremely rare.
increased risk of perioperative morbidity (John- Arguments in favor of early resection include a
son et al. 2011). Nonanatomic resection may also lower risk of perioperative complications, as dem-
be useful when multilobar disease is present. onstrated in a meta-analysis (Stanton et al. 2009),
Occasionally, pneumonectomy is required. For and better long-term long function in younger
patients who were resected before symptoms arose Table 1 Intralobar versus extralobar pulmonary
(Komori et al. 2009). The exact risks or potential sequestration
advantages of expectant management in the setting Intralobar Extralobar
of CPAM cannot be defined without a prospective Gross Invested in pleura Separate pleura
trial. That is unlikely to occur given the concerns findings of normal lung from normal lung
by many in the medical community regarding the Location Lower lobes Left lower
(90%) hemithorax(75%);
implications of recurrent infectious complications may occur outside
and malignancy. thorax
Sex (M: F) 1:1 4:1
Associated Rare Frequent (60% of
Pulmonary Sequestrations anomalies patients): CHD,
other congenital
lung
Pathology malformations,
CDH
Pulmonary sequestrations account for roughly one Arterial Descending aorta Descending aorta
third of cystic bronchopulmonary foregut supply (95%), celiac or (75%)
splenic (20%)
malformations (Ryckman and Rosenkrantz 1985;
Venous Pulmonary veins Systemic veins
Schwartz and Ramachandran 1997). The majority drainage (95%) (75%)
of these lesions are intrathoracic and are further Age of Usually over <6 month or
classified as intralobar or extralobar based on presentation 1 year prenatally
whether the lesion is within the visceral pleura of Presentation Typically Incidental finding,
the normal lung or invested by its own pleura recurrent respiratory
infection; rarely: distress, CHF
(Table 1). In both types of pulmonary sequestra- CHF, failure to
tion, there is no bronchial communication with the thrive, PTX
normal tracheobronchial tree. Also, the sequestra- CHD congenital heart disease, CDH congenital diaphrag-
tion receives its blood supply from an aberrant matic hernia, CHF congestive heart failure, PTX
systemic arterial vessel, typically the aorta. Pulmo- pneumothorax
nary sequestrations may also occur in extrathoracic
locations. Histologically, pulmonary sequestrations Extralobar sequestrations are completely sepa-
demonstrate immature lung development, often rated from the normal lung and are invested in
resembling more peripheral lung parenchyma. separate visceral pleura. As such, they are also
Intralobar sequestrations account for 50–70% of completely separate from the functioning airways.
pulmonary sequestrations, and most often involve These lesions are most commonly found adjacent
the posterior or basal segments of the left lower to the left lower lobe but can occur anywhere in
lobe (Frazier et al. 1997). These intralobar lesions the chest; extrathoracic locations have also been
are surrounded by normal lung parenchyma and described, including intradiaphragmatic and sub-
share the visceral pleura. The arterial supply is diaphragmatic locations. As with intralobar
typically from the descending thoracic aorta but sequestrations, the typical arterial supply is from
can also be from intercostal, brachiocephalic, or the descending thoracic aorta, though approxi-
abdominal aortic aberrant branches. Venous drain- mately 20% have anomalous blood supply from
age is usually via the pulmonary vein that is an infradiaphragmatic vessel. Venous blood drain-
draining the accompanying normal lung tissue. age is typically into systemic veins, such as the
Though by definition these lesions lack normal azygous, hemiazygous, or portal system, and
communication with the tracheobronchial tree, occasionally directly into the atrium. These
there may be communication via abnormal air- lesions are prone to hemorrhage or arteriovenous
spaces. These abnormal communications can lead shunting; patients may present with high-output
to air trapping within the lesion, as well as provide cardiac failure. In addition, extralobar sequestra-
a route for colonization with infectious pathogens. tions are associated with CPAM and CDH
(Conran and Stocker 1999), as well as many other by US, though anomalous blood supply is often
congenital anomalies (Oldham 2005; Ryckman identified on Doppler examination and may aid in
and Rosenkrantz 1985). Figure 3 demonstrates identifying these lesions. Like intralobar seques-
an infant with a left lower lobe CPAM and extra- trations, these lesions may cause symptoms sec-
lobar sequestration. ondary to mass effect, particularly if large.
The embryologic origin of pulmonary seques- Mediastinal shift, hydrops fetalis, or fetal demise
trations remains unclear. Theories include abnormal can occur. Congestive heart failure may result
budding of the tracheobronchial tree or accessory from arteriovenous shunting within the lesion.
budding from the primitive foregut, either leading These lesions are also more commonly noted pre-
to an orphaned lobe. The stimulus is unknown. natally or early in infancy due to the association of
Regardless of the embryologic origin, these lesions other anomalies and the evaluation required for
are clearly congenital in nature, as evidenced by these other problems.
their presence in neonatal autopsies, evermore fre- Postnatal plain chest radiography will occa-
quent prenatal US diagnosis, and frequent associa- sionally be diagnostic for a sequestration. More
tion with other congenital anomalies in up to 40% commonly, plain films demonstrate a retrocardiac
of patients. Rarely, pulmonary sequestrations com- posterior mediastinal mass if extralobar (Fig. 4) or
municate outside the respiratory tract with the a nonaerated mass within the lung if intralobar.
esophagus or stomach, as all these structures share Neither finding is specific for a sequestration, and
derivation from the embryonic foregut. additional imaging is required to make a definitive
diagnosis. Ultrasound may be helpful, but axial
imaging such as CT and MRI provides greater
Diagnosis anatomic detail as well as identifying anomalous
arterial supply. The differential diagnosis often
Intralobar sequestrations typically are not diag- includes CPAM, CDH, and other posterior medi-
nosed until symptoms develop. Given that these astinal masses such as neuroblastoma. Despite
lesions are surrounded by normal lung parenchyma, modern imaging advances, these lesions may be
they are often difficult to distinguish on imaging difficult to differentiate and sometimes cannot be
studies until pathologic events develop. Patients differentiated without surgical excision.
with intralobar sequestrations most often present
with pulmonary infections which occur secondary
to abnormal airspace connections and poor drainage Management
(Fig. 5). These lesions can also cause compressive
atelectasis of adjacent normal lung parenchyma, The hallmark for treatment of pulmonary seques-
leading to infection. Most commonly, diagnosis is trations is surgical excision of the abnormal lung
later in childhood or adulthood, in a patient with tissue. Abnormally developed lung tissue is not
recurrent pneumonias, lung abscess, or hemoptysis. beneficial to the patient. Although some lesions
With the now commonplace use of antenatal US, may remain asymptomatic, the risks of hemor-
these lesions are increasingly diagnosed prenatally rhage, infection, arteriovenous shunting, or late
and may appear similar to a CPAM or CDH. They malignancy are real and may result in significant
may be associated with pleural effusion, poly- morbidity or mortality for the patient.
hydramnios, or hydrops fetalis. Sixty percent of Prenatal management is identical to that for
these lesions occur on the left side and most com- CPAM. In cases where fetal compromise is occur-
monly involve the left lower lobe. ring due to the lesion, such as tension hydrothorax
Extralobar sequestrations are often diagnosed or hydrops fetalis, fetal interventions such as
on antenatal ultrasound. These lesions appear as thoracoamniotic shunting and drainage may be
an echogenic thoracic mass, 90% of which occur helpful but remain controversial. Although a few
on the left in the posterior mediastinum. They can observational studies of small cohorts of patients
be difficult to differentiate from a CPAM or CDH with unresected extralobar sequestrations
Fig. 4 Preoperative plain chest radiography (a) and chest demonstrate signs of resolution on serial chest CT and
CT (b) of a patient with an extrapulmonary sequestration. was resected at 4 months of age (Modified from Puri
Chest CT demonstrates a well-circumscribed solid mass in 2009, p. 301)
the left posterior mediastinum. The lesion failed to
followed over a short period of time appear to identification and control of anomalous vascula-
have a low risk of complications, in general, ture and preservation of the phrenic nerve. Preop-
postnatal resection of a sequestration is indicated erative imaging can be helpful in identifying blood
for the reasons outlined above. As in the CPAM supply and preoperative planning. Some lesions
population, resection is recommended before have arterial supply from an infradiaphragmatic
symptoms develop, generally before the age origin and course through the inferior pulmonary
of 1 year. Arterial embolization has also been ligament; if this is unrecognized prior to division,
reported but is not widely practiced (Curros or not properly controlled, the vessel may retract
et al. 2000). into the abdomen with significant blood loss. Addi-
For extralobar sequestration, resection is accom- tionally, abnormal foregut communications must
plished by either thoracotomy or thoracoscopy. be recognized and appropriately controlled
As the lesion is separate from normal lung, the intraoperatively.
procedure is relatively straightforward. Intralobar
sequestration may present more of a challenge; this
lesion is generally treated with lobectomy either via Congenital Lobar Emphysema
thoracotomy or thoracoscopy. In some cases, par-
ticularly where prenatal diagnosis has led to dis- Pathology
covery in an asymptomatic patient, segmentectomy
may be an option. While the goal of resection is to Congenital lobar emphysema (CLE), also known
remove only abnormal lung tissue, in patients who as congenital lobar overinflation, is characterized
have become symptomatic due to infection, the by air trapping within the affected lobe, which
degree of inflammation usually necessitates lobar usually otherwise anatomically normal. The air
resection. Preoperative treatment with antibiotics is trapping leads to overdistension of the affected
advisable if infection is presents and may help lobe and compresses the adjacent lung and medi-
decrease inflammation. Figure 5 demonstrates a astinal structures, which may lead to hemody-
patient with an extralobar sequestration and pneu- namic or respiratory compromise. The lung
monia and the response to antibiotic treatment. parenchyma is typically normally developed.
Technical aspects important in the surgical Though an etiology is not identified in up to half
resection of pulmonary sequestrations include of reported cases (Lewis 1980), it is believed to
Fig. 5 A 16-year-old male presented with fevers, cough, the normal lung had improved significantly, though con-
and hemoptysis. CXR (a) demonstrated a large left lower solidation remained in the sequestration. A CT angiogram
lobe (LLL) cavitary pneumonia. Chest CT (b) at that time (4) was performed to identify vascular supply, and a large
revealed an infected pulmonary sequestration, with pneu- feeding vessel off the thoracic aorta was identified
monia in the adjacent LLL. After antibiotic treatment (c),
result from bronchial collapse secondary to defi- unnecessary lung resection. In addition, extrinsic
ciency or absence of the cartilaginous components compression can also result in air trapping and
of the bronchus, resulting in air trapping within occur as a result of mediastinal lymphadenopathy,
the affected lobe (Haller et al. 1979). Other poten- anomalous or enlarged blood vessels, congenital
tial etiologies, which typically are only seen out- heart disease, and bronchogenic or enteric cysts or
side the newborn period, include endobronchial tumors (Coran and Drongowski 1994).
obstruction due to secretions, granulation tissue, Rarely, an apparent CLE is found histologi-
foreign bodies, or tumors, all of which similarly cally to have a proliferation of normal alveoli
lead to air trapping. For this reason, broncho- within the affected lobe without bronchial
scopic evaluation is recommended to avoid obstruction. This is termed polyalveolar
morphology. Similarly to CLE, the increase in flattening of the hemidiaphragm (Fig. 6). Ten-
alveoli leads to expiratory air trapping and over sion pneumothorax may appear similar on chest
distension with respiratory compromise. The radiograph but is differentiated by complete col-
diagnosis and treatment of polyalveolar morphol- lapse of the entire ipsilateral lung into the hilum
ogy is the same as that for CLE. with absent peripheral lung markings. In CLE
The incidence of CLE is estimated at 1 in compressed normal lung is seen on the affected
20,000–30,000 live births (Thakral et al. 2001) side. Further imaging beyond plain chest radi-
and is most commonly seen in the Caucasian ography is rarely necessary in newborns and
population with a 2:1 or 3:1 male predominance. infants and in some cases contraindicated due
The left upper lobe is most commonly affected to the need for emergent operative intervention.
(40–50%), followed by the right middle lobe In older children, CT, MRA, and bronchoscopy
(30–40%) (DeLorimer 1986; Murray 1967). are helpful to evaluate for reversible causes of
Lobar emphysema may be associated with con- lobar emphysema and may prevent unnecessary
genital heart disease or abnormalities of the great lung resection.
vessels in 15% of infants (Buntain et al. 1974); for
this reason, screening echocardiography is
recommended in all infants with CLE. Clinical Features
Congenital lobar emphysema is most commonly

Diagnosis found in term infants; however, acquired emphy-
sema can occur in premature infants as a result of
Presentation and Diagnosis barotrauma, oxygen toxicity, and lung immaturity
and may have very similar clinical consequences.
In contrast to other congenital pulmonary Following birth, spontaneous respiration leads to
malformations, the diagnosis of CLE is rarely progressive over distension of the affected lobe
made by antenatal US or MRI as the process of and compression of normal lung. Initial symp-
air trapping occurs postnatally. This diagnosis can toms include tachypnea and wheezing. Cyanosis
be difficult to differentiate from a microcystic occurs when oxygenation is sufficiently impaired.
CPAM as both may appear as an echogenic mass As the infant becomes more distressed, air trap-
prenatally. Despite this, there have been reports of ping is worsened by excessive respiratory effort.
prenatal diagnosis of this lesion. This process can be exacerbated by the need for
Contrary to the name, CLE does not occur positive pressure ventilation and may in fact lead
immediately at birth, as breathing is a postnatal to rapid decompensation. Half of affected infants
phenomenon. Symptoms develop as lobar dis- will demonstrate develop respiratory distress in
tension progresses over time. Severity of disease the first few days of life; the remainder develops
is generally related to the age of presentation, symptoms within the first few months or years of
with the most threatening presentations occur- life. Rapidly progressive respiratory failure occurs
ring in newborns. Most commonly, the diagnosis in up to 10–15% of newborns. In those patients
of CLE is made by plain chest radiography in a with rapidly progressive symptoms, emergency
newborn with respiratory distress. Shortly after thoracotomy allows for decompression of the tho-
birth, a lobe affected by CLE may appear con- rax, followed by definitive lobectomy.
solidated on chest radiography as a result of Physical findings of congenital lobar emphy-
inadequate clearance of amniotic fluid from the sema include diminished breath sounds and focal
affected lobe. As distension of the affected lobe hyperresonance on the affected lobe, an asymmet-
progresses, radiographic findings include hyper- ric thorax, and shift in the apical impulse to the
inflation of the affected lobe, mediastinal dis- contralateral side. As these findings are not diag-
placement, atelectasis of the adjacent lung, and nostic or specific, the diagnosis is best established
Fig. 6 Preoperative plain chest radiography (a) and chest of the normal lung parenchyma. Postoperative plain chest
CT (b) of congenital lobar emphysema of the left upper radiography (c) demonstrates resolution of the mediastinal
lobe. Note the hyperinflation of the left upper lobe, shift and re-expansion of the normal lung parenchyma
resulting in mediastinal shift and compressive atelectasis (Modified from Puri 2009, p. 302)
with plain chest radiography. Additional imaging preceding thoracotomy to evaluate for reversible
is reserved for older children or those cases in endobronchial lesions not requiring pulmonary
which the diagnosis is unclear. resection. Causes of extrinsic compression
should also be sought but are generally associ-
ated with a focal cartilaginous defect such that
Management relief of the extrinsic compression will not
relieve the bronchial obstruction. Bronchoplasty
Lobectomy is indicated in any symptomatic is theoretically attractive; however, the size of
patient with CLE. This may be safely achieved the bronchus in an infant or child makes bron-
by either traditional open thoracotomy or chial reconstruction technically unsuccessful,
thoracoscopy. In a newborn with severe respira- while lobectomy in the infant population is
tory distress as a result of CLE, emergent thora- very well tolerated.
cotomy with delivery of the affected lobe can be In premature infants who develop acquired
lifesaving. Although generally unnecessary in emphysema, the treatment is generally medical
infants, children should undergo bronchoscopy and supportive. These infants often have a
multitude of other problems and, in contrast to treatment; however, in contrast, parenchymal lung
CLE, have disease involving multiple areas of cysts arise from the distal airways, alveoli, or may
the lung. Strategies used for treatment include be pleural in origin. The histology is variable but
selective ventilation of nonemphysematous areas resembles the structure of origin. Differentiation
or the use of alternative ventilator modes such as of parenchymal cysts from bronchogenic cyst
high-frequency oscillatory ventilation or jet ven- tends to be difficult short of resection. The fea-
tilation. Lobectomy may be beneficial in select tures of presentation and principals of manage-
patients who have disease isolated to one lobe, ment are similar to those for bronchogenic cysts,
but carries significantly more morbidity than in except when the cyst is lymphatic in origin. When
patients with CLE, as the premature infants with the cyst is lymphatic in origin, widespread pulmo-
acquired emphysema do not have remaining nor- nary lymphangiectasis may be present and is asso-
mal lung parenchyma, rather chronic lung disease. ciated with diffuse bilateral cystic lung
In one series, infants requiring lobectomy demon- involvement and a poor prognosis (Oldham
strated prompt physiologic improvement follow- 2005). Although collectively parenchymal lung
ing surgery, but one third of the patients died cysts are rare, infection of these cysts is not
within the following 3 years due to respiratory uncommon as a result of communication with
insufficiency (Azizkhan et al. 1992). the airways.
Bronchogenic Cysts and Congenital Presentation and Diagnosis

Lung Cysts
Some patients with bronchogenic cysts or paren-
Pathology chymal lung cysts are asymptomatic. Presentation
ranges from an incidental finding on imaging to
Bronchogenic cysts are developmental cysts aris- life-threatening respiratory distress, though the
ing from the trachea or bronchus and are included latter is rare. As with other congenital cystic
in the spectrum of bronchopulmonary foregut lung lesions, physiologic injury occurs due to
cystic malformations, accounting for up to one compression of adjacent structures, such as the
third this category of malformations in some proximal airways or esophagus, or from impaired
reports (Evrard et al. 1999; Wesley et al. 1986). drainage of secretions in the lesion or adjacent
These cysts are typically thick walled, unilocular tissue leading to infection. If a patent connection
cysts filled with mucus. The cyst wall is composed to the tracheobronchial tree is present, infection
of the structural elements of the airway: smooth may develop, and presentation with fever, chills,
muscle, cartilage, elastic tissue, and mucous productive cough, or hemoptysis is typical. Most
glands and respiratory epithelium. Typical loca- commonly, infants present respiratory symptoms
tions include the cervical or thoracic trachea, hilar related to obstruction/compression of adjacent
bronchi, or more distal intraparenchymal bronchi. structure or, less commonly, failure to thrive.
Ectopic locations have also been reported and Older children usually present with infectious
include paravertebral, paraesophageal, pericar- complications. Rarely, cysts may enlarge to the
dial, subcarinal, and subcutaneous locations. point of causing significant mass effect with medi-
Bronchogenic cysts arise from the airway and astinal displacement, airway compression, and
typically remain intimately attached; however, cardiorespiratory compromise. Secondary malig-
the communication with the airway is typically nancy of these lesions has also been reported.
lost during development. Bronchogenic cysts are Plain chest radiography typically demonstrates
believed to occur as a result of abnormal budding a smooth, roughly spherical mass in either a para-
of the tracheobronchial tree. tracheal or hilar mass without calcification
Parenchymal lung cysts are similar to broncho- (Fig. 7). Displacement of adjacent airway is rela-
genic cysts in terms of clinical significance and tively common, and evidence of distal air trapping
Fig. 7 Preoperative plain chest radiography (a) and chest middle mediastinal lesion displacing the trachea and great
CT scan (b, c) of a 9-month-old patient presenting with vessels. The mass was resected through a median
cough. Plain radiography demonstrates a smooth, round, sternotomy; pathology was consistent with a
mediastinal mass causing significant tracheal deviation. bronchogenic cyst
Chest CT demonstrates a large, well-circumscribed,
may be noted even in asymptomatic patients. If duplication cysts, neuroblastoma, neurenteric

the cyst is infected or communicates with the cysts, pericardial cysts, and lymphoma are
airway, an air fluid level may be present. CT and included in the differential diagnosis depending
MRI are useful adjuncts for defining pertinent on cyst location.
anatomy and will demonstrate a cystic lesion
without calcification (excluding a neuroblas-
toma). Contrast-enhanced studies will demon- Management
strate a nonenhancing mass lesion, which helps
to differentiate bronchogenic cysts from an aber- Resection is indicated to alleviate symptoms, pre-
rant pulmonary artery (pulmonary sling). Addi- vent infection, provide pathologic identification,
tionally, anatomic relationships to adjacent and prevent future malignancy. Rarely, acute
mediastinal structures can be defined (particularly decompensation from a large bronchogenic cyst
the spine) and allow differentiation between bron- or parenchymal cyst may require emergent treat-
chogenic cysts and neurenteric cysts. An ment with needle decompression or tube
esophagram can be helpful in selected cases to thoracostomy placement as a temporizing mea-
evaluate for foregut communication. Foregut sure. Generally, simple local resection can be
accomplished with preservation of adjacent nor- severe and include pulmonary hypertension, per-
mal lung parenchyma. In cases where infection of sistent fetal circulation, and respiratory failure.
the cyst or pneumonia is present at the time of Significant clinical support, such as high-
diagnosis, treatment with antibiotics preopera- frequency oscillatory ventilation, inhaled nitric
tively is appropriate. Resolution of active infec- oxide or extracorporeal membrane oxygenation,
tion prior to resection is helpful to minimize is frequently required, and mortality may result
unnecessary pulmonary resection. Formal pulmo- despite these interventions.
nary resection may be required due to the ana- Pulmonary agenesis is the complete absence of
tomic location of the cyst (particularly for one or both lungs. The cause of this is unknown
parenchymal lung cysts) or secondary to inflam- but appears to result from a failure of organogen-
mation from previous infections. In some cases, it esis when the trachea divides into two lung buds,
is not possible to remove the cyst without sacrific- during the fourth week of gestation. Bilateral
ing vital structures; in these cases, partial involvement is very rare and is not compatible
cystectomy with fulguration of any remaining with survival. Unilateral involvement is rare, is
cyst wall is indicated. Long term follow-up is seen with roughly equal incidence on right and left
necessary as recurrences have been reported for sides, and is frequently associated with other con-
partially resected lesions. genital abnormalities. There may be significant
As with the other previously described con- management issues in the neonatal period, not
genital pulmonary malformations, resection can only due to respiratory insufficiency but also due
often be accomplished with a minimally inva- to the associated anomalies (Booth and Berry
sive approach and may be associated with 1967; Hoffman et al. 1989; Osborne et al. 1989).
shorter duration of thoracostomy drainage and This disorder is sometimes diagnosed in older
hospital stay (Tölg et al. 2005). If a minimally children who present with nonspecific respiratory
invasive approach is planned, it is important to symptoms, failure to thrive, exercise intolerance,
establish anatomic relationships preoperatively, chest asymmetry, or scoliosis. For unclear rea-
as bronchogenic cysts are often invested in the sons, these children also often present with pneu-
mediastinal pleura and require pleural incision monia or bronchitis, though functional
and mediastinal exploration for excision. If abnormalities of the remaining bronchus have
an open approach is planned, lateral thoracot- been postulated. On physical exam, a shift in the
omy is generally employed, although median location of heart tones and absent ipsilateral
sternotomy may be useful for more central breath sounds are notable. Plain chest radiography
lesions. demonstrates hyperinflation of the contralateral
lung, displacement of the mediastinum, and a
fluid filled cavity on the involved side. The diag-
Pulmonary Hypoplasia, Aplasia, nosis can be confirmed with endoscopy, echocar-
and Agenesis diography, axial imaging, or angiography, where
absence of the ipsilateral main stem bronchus or
Pulmonary hypoplasia is the abnormal develop- pulmonary artery is definitive. Figure 8 demon-
ment of an entire lung or both lungs, which results strates left lung agenesis in a patient with multiple
in a diminutive organ with dysfunctional gas congenital anomalies.
exchange. Most commonly, this occurs as a result Treatment of unilateral pulmonary agenesis is
of extrinsic compression during development, nonsurgical and supportive. Aggressive antibiotic
though may also occur primarily. The most com- therapy is indicated in the setting of infection. The
monly responsible lesions are CDH and CPAM. major surgical issues are related to the manage-
Pulmonary aplasia is the result of developmental ment of associated anomalies and avoidance of
arrest during organogenesis and results in a some- putting the single remaining lung in jeopardy dur-
times marked reduction in the number of alveoli. ing any necessary operative interventions. Histor-
The consequences of either derangement may be ically, these patients have a high mortality rate,
Fig. 8 Female infant with prenatal diagnosis of CDH and a blind ending left main stem bronchus. Echocardiography
congenital heart disease. Postnatal plain chest radiography confirmed the absence of left pulmonary artery or veins.
(a) with left CDH. Also notable are multiple rib anomalies, Plain chest radiography after repair of the CDH (c) demon-
and no visible left lung. In addition, the patient had a limb strates a hyperinflated right lung, tracheal shift toward the
anomaly. At the time of CDH repair, no lung was visible in side with pulmonary agenesis, and a large effusion in the
the hemithorax. A chest CT reconstruction (b) demonstrates affected hemithorax
with about one-half failing to survive beyond the approach minimizes the potential for future prob-
first 5 years of life (DeLorimer 1986). Deaths lems with scoliosis related to division of chest wall
often occur in the perinatal period, secondary to musculature, which for traditional thoracotomy
associated anomalies or due to recurrent respira- (which historically also included rib resection in
tory infections. More recently, prognosis appears many cases) has been estimated to occur in up to
to be improving. 50% of patients (Westfelt and Nordwall 1991).
Modern muscle sparing thoracotomy (described
below) is currently practiced when an open
Lung Surgery in Newborns approach is utilized in an attempt to minimize the
likelihood of scoliosis. Pain is also purportedly less
A brief discussion of thoracic surgical techniques with thoracoscopic techniques, though this has been
is appropriate. More detailed, comprehensive difficult to elucidate in the current literature due to
atlases are available (Ferguson 1997; Sugarbaker differences in evaluation and management.
et al. 1997). Lung surgery in neonates is similar to For lesions approached either through tradi-
that in adults, with the notable exception being tional thoracotomy or thoracoscopic approaches,
size of the involved structures. Technical preci- the patient is generally placed in the lateral
sion is required in any thoracic procedure, but decubitus position with the arm extended and
small infants have a notably smaller allowable placed over the head. Positioning devices are
margin of error. Technical problems may result used to optimize stabilization, expose the opera-
in serious, irreversible consequences. Despite tive field, and avoid prolonged pressure on
this, lung resection in infants is very well tolerated nerves (particularly the brachial plexus, axillary
and has an acceptable rate of complications. and peroneal nerves are at risk). Heat loss is
Resection may be accomplished by traditional always a concern in pediatric surgery and can
thoracotomy or through minimally invasive tech- be minimized with insulating coverings on non-
niques. Minimally invasive techniques operative areas as well as convective and radiant
(thoracoscopic resection) have demonstrated warmers.
shorter duration of tube thoracostomy as well as For open thoracotomy, optimal exposure is
shorter hospital stay without any difference in gained through a transverse or oblique incision
rates of complications when compared to open tho- through the fourth or fifth intercostal space. This
racotomy (Tölg et al. 2005). In addition, this is performed below and lateral to the nipple to
avoid damaging breast tissue. Care should also be Following any type of resection, air leaks can
taken to place the incision below the tip of the be identified by filling the chest with warm saline,
scapula to optimize exposure. The underlying while the anesthesiologist inflates the residual
subcutaneous tissues are divided along the line lobe. Suture repair is performed on any identified
of the incision, exposing the serratus anterior leaks. A tunneled chest tube is then placed in the
and latissimus dorsi muscles. It is desirable to pleural space for drainage and connected to a
perform a muscle sparing technique in order to closed suction system. The wound is closed in
limit postoperative morbidity from scoliosis. This anatomical layers with absorbable suture.
is accomplished by mobilizing, but not dividing Detailed thoracoscopic techniques are beyond
the musculature, so they may be retracted out of the scope of this chapter, but several useful prin-
the operative field. Following this, the scapula can cipals bear mentioning. Due to the size of the
be retracted and the chest wall exposed, allowing patient, double lumen endotracheal tubes are not
palpation of the ribs and determination of the a viable option for single lung ventilation. This
correct interspace to enter the chest. The second difficulty can at least in part be overcome by a
rib is usually the highest palpable rib in infants combination of selective main stem intubation of
and the fourth or fifth interspace desirable for the nonoperative side, the placement of a bron-
entering the chest. The incision can then be con- chial blocker (balloon catheters work well for
tinued through the interspace, taking care to do so this), or the use of low pressure insufflation of
just superior to the lower rib and avoid injury to the chest to gently decompress the lung in the
the neurovascular bundle which runs along the operative field. Pressures of 5–7 mm Hg are gen-
inferior surface of each rib. The pleura is then erally well tolerated without hemodynamic com-
carefully entered, to avoid injury to the underlying promise. The field of thoracoscopy in children
lung, and a rib spreader placed to facilitate continues to evolve rapidly as new technology
retraction. becomes available. There is considerable appeal
General principles of lobar resection include to this approach for resection of congenital
hilar dissection, vascular control, and bronchial lesions, due to possibly equivalent outcomes
stump closure. In older children and adults, bron- without the morbidity of a thoracotomy incision.
chial stump closure is most easily accomplished
with commercially available stapling devices. In
newborns and small children, the size of available Complications and Long-Term
instruments and resulting lack of precision makes Outcomes
this approach undesirable; bronchial closure in
this population is best accomplished with a careful In the absence of diffuse lung disease or hypopla-
hand sewn closure. sia, pulmonary resection is generally very well
For some types of peripheral lesions, wedge tolerated, even in newborns. Contemporary pedi-
resection is easily accomplished and techni- atric surgical series of pulmonary resection for
cally straight forward. Stapling devices work congenital malformations report a mortality rate
well on lung parenchyma even in small infants of less than 2%. It is important to anticipate which
and are generally more reliable than hand sewn infants will have increased morbidity and mortal-
closures. Segmental lung resections are also ity. These can be identified when any of the fol-
sometimes appropriate for specific lesions lowing are present: hydrops fetalis, significant
(CPAM isolated to a specific segments, and mediastinal shift, pulmonary hypertension, or
intralobar sequestrations are examples); how- other associated anomalies. Short-term complica-
ever, the available literature suggests that peri- tions following resection are infrequent and
operative morbidity in regard to air leak and include prolonged air leak, pneumothorax, hem-
hemorrhage for segmental resections may be orrhage, and infectious complications. Whether
greater than that for formal lobectomy using an open or a minimally invasive approach,
(Ryckman and Rosenkrantz 1985). short-term complications do not appear to be
any higher in infants compared to older pediatric from the antenatal period to well into adulthood.
patients. Significant progress has been made in terms of
As discussed earlier, lung development occurs earlier diagnosis, so that the majority of patients
well into childhood; because of this, pediatric seen today are diagnosed antenatally and are often
pulmonary resection is associated with excellent asymptomatic at the time of diagnosis. Minimally
long-term functional outcomes. In the absence of invasive surgical techniques continue to improve
other associated illness, most patients who and are becoming more widely used. The role of
undergo pulmonary resection as an infant or fetal intervention is still evolving but clearly
child will have normal somatic growth and normal should be reserved for those with physiologic
pulmonary function. Laros demonstrated that by compromise such that treatment after birth is not
adulthood, children who had undergone pneumo- feasible.
nectomy before age 5 had nearly fully compen-
sated in terms of total lung capacity.
Compensatory response was inversely related to Cross-References
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Congenital Diaphragmatic Hernia
53
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
Treatment Modalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 801
Prenatal Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
Preoperative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 802
Operative Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 804
Postoperative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 805
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
Congenital Eventration of the Diaphragm (CDE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 807
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Operative Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
J. Zimmer
School, Hannover, Germany
e-mail: zimmer.julia@mh-hannover.de
P. Puri (*)
Ireland

https://doi.org/10.1007/978-3-662-43588-5_57

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
Abstract located in the posterolateral diaphragm (Bochdalek

Congenital diaphragmatic hernia(CDH) is a rel- hernia) in 90% of the cases and 9% occur as ante-
atively common congenital malformation with a romedial defect (Morgagni hernia) (McHoney 2015).
poorly understood etiology. On account of Total agenesis of the diaphragm is rare.
advances in technical equipment and operative The overall prevalence of CDH is reported to
and anesthetic treatment modalities, the surgical be between 1:2500 and 1:3000 live births
repair of the diaphragmatic defect either open (McHoney 2015; Morini et al. 2006). The CDH
or minimally invasive is nowadays often prevalence in Europe is 2.3 per 10,000 births for
unproblematic. However, associated pulmonary all cases and 1.6 per 10,000 births for isolated
hypoplasia and persistent pulmonary hyperten- cases (McGivern et al. 2015). Approximately
sion lead postnatally to severe respiratory dis- 80% of the CDH cases are left sided, 15% are
tress and contribute to the high morbidity and right sided, and less than 5% are bilateral (Colvin
mortality rates in this potential life-threatening et al. 2005; Gallot et al. 2007). The size of the
condition. Therefore, optimal perioperative sta- defect varies from small (2 or 3 cm) to large ones,
bilization and management by an interdisciplin- involving most of the hemidiaphragm. The inter-
ary team of pediatric surgeons, neonatologists, national committee of the Congenital Diaphrag-
and anesthetists is crucial for these neonates. matic Hernia Study Group (CDH study group)
Nearly half of the CDH survivors beyond the created a standardized four grade (A to D)
neonatal period are able to lead a normal healthy reporting system for CDH (Lally et al. 2013):
and symptom free life. However, many survi- Grade “A” defects are completely surrounded by
vors with complex medical and surgical needs muscle. “B” defects present with a small and “C”
require a multidisciplinary comprehensive care defects with a large portion of the chest wall
for their pulmonary, neurodevelopmental, and devoid of diaphragm tissue. “D” defects are char-
nutritive long-term outcome. Clinical and basic acterized by a complete or near complete absence
research continues to identify underlying gene of the diaphragm. Increasing diaphragmatic
and protein alterations and through this provid- defect size and associated potential severe cardiac
ing a potential for new treatment options anomalies have been shown to worsen the out-
for CDH. come (Lally et al. 2013). Despite advances in
technical equipment as well as resuscitation and
Keywords intensive care treatment strategies, newborns with
Congenital diaphragmatic hernia · Pulmonary CDH continue to have high morbidity and mor-
hypoplasia · Pulmonary hypertension · tality rates, which is mainly attributed to pulmo-
Diaphragmatic repair · Animal models · nary hypoplasia and persistent pulmonary
Nitrofen hypertension (Coughlin et al. 2016; Jeanty et al.
2014; Wynn et al. 2013b). Current survival rates
in population-based studies vary between 55%
Introduction and 80% (Boloker et al. 2002; Colvin et al.
2005; Gallot et al. 2007), with survival rates up
Congenital diaphragmatic hernia (CDH) is a common to 90% in highly specialized centers (Wynn et al.
and severe congenital malformation, characterized by 2013b). However, there is a noticeable hidden
a defect in the diaphragm through which the abdom- mortality due to increasing numbers of pregnancy
inal viscera migrate into the fetal thorax. The defect is termination (Burgos and Frenckner 2017).
53 Congenital Diaphragmatic Hernia 799
Etiology ipsilateral and contralateral lung even before the

diaphragm starts to develop (Iritani 1984), which
Embryogenesis has been suggested to happen due to the so-called
dual-hit hypothesis (Keijzer et al. 2000). This
Despite ongoing research, the etiology of CDH is hypothesis proposes that the early retardation in
still not fully understood. Until now, more than lung development that occurs before the develop-
20 monogenetic disorders associated to CDH ment of the diaphragmatic defect is caused by
have been identified, but CDH usually occurs nitrofen, whereas the late-gestational increase in
sporadically with unknown cause of origin lung hypoplasia is caused by mechanical com-
(Wynn et al. 2014). CDH embryogenesis has pression from herniated viscera (Puri and Doi
been postulated as a failure of the pleuroperitoneal 2011). It has been demonstrated that rat
canals in the posterolateral part of the diaphragm pleuroperitoneal canals are too narrow to allow
to fuse during gestational week 8 (Sadler 2009). herniation of bowel loops (Kluth et al. 1996). The
Thus, abdominal organs (typically liver, bowel, or nitrofen-induced CDH rat model is a widely used
stomach) migrate into the thorax, compressing the model to investigate gene and protein alterations
growing lungs and resulting in pulmonary hypo- not only for CDH etiology but also its associated
plasia. CDH associated pulmonary hypoplasia complications of pulmonary hypoplasia and pul-
covers the whole lung, leading to less alveoli, monary hypertension (Takahashi et al. 2017;
thickened alveolar walls, increased interstitial tis- Zimmer et al. 2017b). One of these pathways,
sue, and markedly diminished alveolar air space the retinoid signaling pathway with its compo-
and gas-exchange area (Puri and Doi 2011; Sadler nents has been shown to be disrupted in animal
2009, Fig. 1a, b). These alterations usually affect models and CDH neonates likewise (Beurskens
the ipsilateral lung most severely, but also extend et al. 2010; Doi et al. 2010; Nakazawa et al. 2007;
to the contralateral lung. Similarly, the pulmonary Sugimoto et al. 2008). Furthermore, prenatal
vasculature develops abnormally with fewer ves- retinoic acid (RA) treatment has been shown to
sels, adventitial and medial thickening, and upregulate pulmonary expression levels of genes
peripheral extension of the muscle layer into the involved in lung morphogenesis in the nitrofen-
smaller intra-acinary arterioles (Levin 1978; Puri induced hypoplastic lung (Doi et al. 2009, 2010).
and Doi 2011). Although prenatal use of RA has been controver-
Experimental studies have added new findings sial, these experimental data suggest that prenatal
into this classical view of embryogenesis. The RA treatment may have a therapeutic potential to
toxicological nitrofen CDH model presents pul- revert pulmonary hypoplasia associated
monary hypoplasia with abnormalities in both with CDH.
Fig. 1 Histologic comparison of (a) normal lung vasculature. (b) Pulmonary vasculature in CDH. Note the increased
pulmonary artery muscle thickness (red color)
Several knockout models have been developed Vasoactive substances such as endothelin-1
for diaphragmatic hernia such as Wt-1 / , and endothelin A receptor are reported to be
Shh / , Slit3 / , Gli2/Gl3 / , Gata4/Gata6 / , increased in infants and animal models with
Fog2 / , Pdgfrα / , COUP-TFII / , and CDH and adversely affect vasoconstriction
RARs / (Ackerman et al. 2005; Bleyl et al. (Kobayashi and Puri 1994; Nobuhara and Wilson
2007; Clugston et al. 2006; Jay et al. 2007; 1996). The transforming growth factor β (TGFβ)
Mendelsohn et al. 1994; Molkentin 2000; pathway is known to be altered in nitrofen-
Motoyama et al. 1998; Pepicelli et al. 1998; You induced CDH pulmonary rat tissue (Burgos et al.
et al. 2005; Yuan et al. 2003). However, only 2010; Gosemann et al. 2013; Mahood et al. 2016;
mutations of WT-1, Fog2, and recently COUP- Oue et al. 2000; Zimmer et al. 2017a). Candilera
TFII have been identified in human CDH patients et al. found decreased transforming growth factor
so far (Bleyl et al. 2007; Devriendt et al. 1995; β (TGFβ) levels in the amniotic fluid of human
High et al. 2016; Scott et al. 2005). There is CDH pregnancies in comparison with normal
ongoing research to identify novel genes with pregnancies at amniocentesis (Candilera et al.
predicted deleterious de novo variants potentially 2016). Other authors, however, found conflicting
contributing to the pathogenesis of CDH and results about the role of different TGF β factors in
associated other anomalies (Yu et al. 2015). pulmonary vascular remodeling in human CDH
lung tissue (Yamataka and Puri 1997).
There are also contradictory results about the
Pathophysiology immaturity of the surfactant system which may
aggravate hypoxia and hypercarbia (Glick et al.
The degree of pulmonary hypoplasia and pulmo- 1992; Sullivan et al. 1994). It has therefore been
nary hypertension directly determine the outcome suggested that the deceptive surfactant deficiency
of a newborn diagnosed with CDH. The amount of may be secondary to respiratory failure, rather
abdominal viscera in the thorax and the associated than to a primary deficiency (IJsselstijn et al.
degree of pulmonary hypoplasia affect onset and 1998; Puri and Doi 2011). Fetal blood pro-
severity of symptoms. Respiratory distress with inflammatory and chemotactic factors may also
cyanosis, tachypnea, and sternal recession are the be involved in vascular changes resulting in pul-
usual clinical signs in the newborn CDH patient. monary hypertension in CDH patients, as recently
Pulmonary hypoplasia leads to hypoxia and hyper- published (Fleck et al. 2013).
carbia, resulting in pulmonary vasoconstriction and
hypertension. Consequently, reversal to right-to-
left shunting through the ductus arteriosus and the Diagnosis
foramen ovale occurs and the infant enters a harm-
ful and self-perpetuating cycle (Puri and Doi 2011). With proper visualization of the diaphragm, CDH
Characteristic alterations in CDH associated can be reliably diagnosed ultrasonographically at
pulmonary vascular remodeling and pulmonary around 20 weeks of gestation. Abdominal viscera
hypertension are abnormal vascular beds and in the thorax and consequential compression of
increased arteriolar muscularization similarly to thoracic organs indicate its absence indirectly
the changes seen in newborns with idiopathic (Deprest et al. 2006a).
persistent pulmonary hypertension (PPHN) CDH must be distinguished from potential dif-
(Levin 1978). Further features are dysfunctional ferential diagnosis such as diaphragmatic
endothelial cells, abnormal pulmonary smooth eventration, bronchopulmonary sequestration,
muscle cell proliferation and suppressed apopto- congenital cystic adenomatoid malformation
sis, leading to arterial medial and adventitial (CCAM), or bronchogenic cyst. Moreover, other
thickening, increased pulmonary vascular resis- anomalies such as cardiac malformations, neural
tance and venous hypertrophy (Guignabert et al. tube defects, and chromosomal aberrations need
2015; Kool et al. 2014, Fig. 1a, b). to be excluded. Half of the CDH patients present
Fig. 2 (a) Left-sided CDH

with viscera in the left chest,
pulmonary hypoplasia, and
significant mediastinal shift
to the right. (b) Right-sided
CDH with viscera visible in
the right chest and
mediastinal shift to the left
side
with additional congenital disorders (Bojanic malformations may also be found. An X-ray of
et al. 2015). Five percent to 30% of infants born chest and abdomen with demonstration of tho-
with CDH have chromosomal abnormalities, racic air-filled bowel loops and a paucity of gas
among these, trisomy 21, 18, and 13 are the in the abdomen will bring the definite diagnosis
most common (McHoney 2015). CDH may also (Fig. 2a, b). A mediastinal shift to the opposite
be part of a syndrome such as Pentalogy of side may be observed, and only a small portion of
Cantrell, Brachmann-Cornelia De Lange, lung may be seen on the ipsilateral side (Puri and
Beckwith-Wiedemann, CHARGE, Goldenhar Doi 2011).
syndrome, Pierre Robin sequence, or VACTERL
(Chandrasekharan et al. 2017), and patients must
be examined accordingly. Treatment Modalities
The grade of lung hypoplasia needs to be deter-
mined as it is a crucial factor for postnatal sur- The optimal timing of delivery of an infant with
vival. Thoracic liver herniation in left-sided CDH CDH remains controversial. Early term birth
indicates severe pulmonary hypoplasia and can be (37–38 gestational weeks) has previously been
assessed by umbilical vein and hepatic vessels shown to be associated with a less use of extra-
Doppler (Deprest et al. 2006a; Metkus et al. corporeal membrane oxygenation (ECMO) com-
1996). Ultrasonographic lung-to-head ratio pared to term delivery for infants born via
(LHR – the area of the right lung at the level of cesarean section (Chandrasekharan et al. 2017;
the four-chamber view divided by the head cir- Stevens et al. 2009). However, other studies pos-
cumference) or MRI fetal lung volume measure- tulated decreased mortality with advanced gesta-
ment can predict the degree of pulmonary tional age (40 weeks of gestation)
hypoplasia (Britto et al. 2015; Deprest et al. (Chandrasekharan et al. 2017; Hutcheon et al.
2006b; Jeanty et al. 2014). 2010).
If not detected prenatally, CDH should be Immediate postnatal endotracheal intubation
suspected postnatally in neonates with severe and mechanical ventilation is recommended in
respiratory distress at birth or within the first order to maintain cardiopulmonary stability and
hours of life. A scaphoid abdomen, an increased delay the natural progression into severe hypox-
thoracic anteroposterior diameter, and a mediasti- emia and hypercapnia (McHoney 2015; Reiss
nal shift are usually seen during physical assess- et al. 2010). Mask ventilation and CPAP should
ment with absent breathing sounds on the affected be avoided as it will distend the stomach and
side (Puri and Doi 2011). Associated congenital further compromise respiratory status. A
nasogastric tube deflates stomach and bowel. The influencing the gestational age at delivery and bal-
usage of muscle relaxants should be avoided as loon removal (Deprest et al. 2011). To deliver
part of the gentle ventilation strategy (Boloker infants with FETO, the ex utero intrapartum treat-
et al. 2002; Reiss et al. 2010). ment procedure (EXIT) has been developed. Cesar-
Previously, CDH was considered a surgical ean section is performed with maximal uterine
emergency, assuming that swift evacuation of relaxation, and while keeping the infant on placen-
abdominal thoracic viscera will allow expansion tal support, the upper airway can be instrumented
of the compressed lung tissue. Increasing knowl- (Puri and Doi 2011). However, currently there is
edge of the pathophysiology of CDH has led to only insufficient evidence to recommend in utero
the modern approach of prolonged preoperative intervention for CDH fetuses as a routine clinical
stabilization time, assuring cardiorespiratory and practice (Grivell et al. 2015). Controversially,
hemodynamic stability of the patient. However, FETO has been shown to improve survival in
several studies provided no strong advantage for a selected CDH cases but to also to increase morbid-
delayed (when stabilized) or early (within 24–48 h ity including significantly longer durations of
after birth) repair (Moyer et al. 2002; Okuyama mechanical ventilation, supplementary oxygen,
et al. 2017). and hospital stay (Ali et al. 2016; Al-Maary et al.
2016). Presently, FETO is being evaluated in a
large international randomized control trial
Prenatal Treatment (Oluyomi-Obi et al. 2017).
Various other medical strategies for lung hypo-
Any prenatal intervention able to reverse or plasia such as steroid administration with or with-
improve associated lung hypoplasia might theo- out thyrotropin releasing hormone, vitamins, or
retically improve prognosis and outcome of CDH stem cell therapy have been tested in the last
patients. Fetal surgery with primary repair of the decades in different CDH animal models, but
defect seemed to be a promising approach, but their impact on the human situation has yet to be
clinical application of anatomical fetal CDH addressed (Eastwood et al. 2015; Jeanty et al.
repair was abandoned once it became clear that it 2014). Especially, regenerative medicine includ-
was not possible in fetuses with liver herniation ing stem cell therapy and tissue engineering seem
and that those without did not benefit from the to be a promising field for further treatment strat-
intervention (Harrison et al. 1993, 1997; Puri and egies in CDH as this may play an important role
Doi 2011). both in developing a myogenic patch capable of
Experimental studies showed that tracheal restoring muscle function as well as promoting the
occlusion triggers lung growth, leading to the regeneration of hypoplastic lungs (De Coppi and
approach of fetoscopic tracheal occlusion (FETO) Deprest 2012; DeKoninck et al. 2015; Shieh et al.
in humans. The effect on lung growth by tracheal 2017a; Yuniartha et al. 2014; De Coppi and
occlusion and retention of pulmonary fluid seems Deprest 2017).
to be exerted by pulmonary stretch itself, which in
turn causes upregulation of different growth factors
(Liao et al. 2000; Muratore et al. 2000; Nobuhara Preoperative Treatment
et al. 1998; Puri and Doi 2011). Usually, the tra-
cheal balloon is placed endoscopically in one-port Any infant with respiratory distress requires endo-
technique (Deprest et al. 2006a; Harrison et al. tracheal ventilatory support. Previously, aggressive
2003). If the balloon is deflated by repeated hyperventilation strategies and hypocarbia often
tracheoscopy at 34 weeks of gestation, vaginal resulting in barotrauma were widely used, but gen-
delivery is permitted (Deprest et al. 2006a). A tle ventilation and permissive hypercarbia has been
feared and frequent complication of FETO is pre- demonstrated to decrease mortality (Logan et al.
term premature rupture of the membranes 2007; Masumoto et al. 2009; Puligandla et al. 2015;
(PPROM), potentially caused iatrogenic and Vitali and Arnold 2005). High-frequency
oscillatory ventilation (HFOV) provides effective which it is hoped that the lung and pulmonary
ventilation while decreasing barotrauma, but has vasculature will mature. Several centers advocate
not been shown to improve the mortality or mor- the use of ECMO only in patients with evidence of
bidity rates in CDH (Puligandla et al. 2015; Snoek a “honeymoon period,” i.e., patients with ade-
et al. 2016b). Any changes in HFOV settings must quate gas exchange for a period preceding the
be monitored carefully, as high airway pressures deterioration in respiratory status (Puri and Doi
may cause lung hyperinflation, with adverse effects 2011). Others use preductal blood gases, where
on venous return, pulmonary vascular resistance, only patients with a period of normal preductal
and ultimately in cardiac output (Logan et al. pO2 and pCO2 will be considered for ECMO
2007). In a recent study, ventilation outcomes (Logan et al. 2007; Puri and Doi 2011). Optimal
such as duration of ventilation time and the need patient selection for ECMO in CDH requires
for ECMO seem to favor conventional ventilation refinement of non-ECMO support techniques so
(Snoek et al. 2016b). A ventilation strategy tailored that this higher risk but higher potential reward
to the patient’s underlying physiology rather than modality is focused primarily on those patients
the mode of ventilation is a crucial issue for clini- with more severe CDH as defined by smaller
cians treating CDH patients (Morini et al. 2017). lungs, worse birth physiology, anatomy, and
Following initial ventilation settings are larger defects (Kays 2017). Although widely
recommended to achieve a target SaO2 of >85% used, a Cochrane review found that the ECMO
preductally and a PCO2 of 45–60 mmHg benefit remains unclear (Mugford et al. 2008).
(Puligandla et al. 2015; Reiss et al. 2010): Additionally to conventional mechanical ven-
For pressure controlled ventilation, a peak tilation or ECMO, surfactant replacement has
inspiratory pressure (PIP) of 20–25 cm H2O, a been experimentally used but beside its risky
positive end-expiratory pressure (PEEP) of administration its benefit is unproven
2–5 cm H2O, and a frequency (f) of 40–60/min (Chandrasekharan et al. 2017; Logan et al.
is commended. For HFOV it is advised to main- 2007). Data from the CDH Study Group showed
tain a mean airway pressure (MAP) of 13–17 cm no significant advantage of surfactant use, both in
H2O with a frequency of 10 Hz and a pressure term and preterm infants with CDH (Morini et al.
delta (Δp) of 30–50 cm H2O, based on the extent 2017).
of chest rise on the chest X-rays (Puligandla et al. Recently, the efficacy of Perflubron-induced
2015; Reiss et al. 2010). lung growth (PILG) has been studied in CDH
Nitric oxide (NO) is a direct pulmonary vaso- patients requiring ECMO (Mychaliska et al.
dilator, but its relevance for CDH patients remains 2015). PILG doubled the total lung size but had
controversial (McHoney 2015; Putnam et al. no positive effect on persistent pulmonary hyper-
2016; Tiryaki et al. 2014). Short-term improve- tension (Mychaliska et al. 2015).
ment in oxygenation in selected patients has been CDH patients need to be carefully managed by
observed with positive effect on stabilizing the intensive care physicians. Appropriate fluid and
patient during transport or awaiting ECMO can- catecholamine management, adequate sedation,
nulation; however, inhaled NO does not reduce and analgesia are crucial in these infants. Routine
the need for ECMO itself (McHoney 2015; administration of pre- or postnatal glucocorticoids
Oliveira et al. 2000; Harting 2017). is not recommended (Puligandla et al. 2015).
ECMO is a life support system used in the Alternative strategies for NO-resistant pulmo-
treatment of CDH when conventional mechanical nary hypertension are PDE inhibitors. The PDE
ventilation fails, typically considered for infants 5 inhibitor sildenafil enhances NO-mediated
with CDH 34 weeks’ gestation or with a birth vasodilatation, improving oxygenation and out-
weight > 2 kg and no associated other major come (Bialkowski et al. 2015; McHoney 2015).
lethal anomalies (Chandrasekharan et al. 2017). The PDE 3 inhibitor Milrinone has also been
ECMO allows partial heart-lung bypass providing shown to be effective in the management of NO
rest to the lungs for long time periods during resistant PH in CDH infants (Chandrasekharan
et al. 2017; Hagadorn et al. 2015). The endothelin

receptor blocker Bosentan has been used with
limited experience as adjunctive therapy for
PPHN (Chandrasekharan et al. 2017; Steinhorn
et al. 2016). Other agents with proposed benefit
are prostaglandins or novel agents like
L-citrulline; Rho-kinase inhibitors or
proliferator-activated receptor-γ agonists are cur-
rently under investigation (Lakshminrusimha
et al. 2016).
Operative Repair
For the surgical repair of the diaphragmatic

defect one can choose between open (laparot-
omy or thoracotomy) or minimally invasive (lap-
aroscopic or thoracoscopic) technique; however,
the optimal approach is still a matter of discus-
sion among surgeons (Terui et al. 2015). The
abdominal approach is commonly preferred as
the exposure is usually excellent and abdominal
viscera can be easily reduced as well as associ- Fig. 3 Operative repair of CDH. A subcostal transverse
muscle cutting incision is made on the side of the hernia
ated gastrointestinal anomalies corrected (Image from Puri and Höllwarth, Pediatric Surgery
(Fig. 3). When reducing abdominal organs, (Springer Surgery Atlas Series), 2006, Springer)
small intestine and the colon should first be
reduced on the right side and the liver is with-
drawn last (Fig. 4). After reduction of hernia an
attempt is made to visualize the ipsilateral lung.
Most diaphragmatic defects can be sutured
by direct sutures after refreshing the defect
edges (Figs. 5 and 6a, b). Although the anterior
rim of the diaphragm is usually quite evident,
the posterior rim may not be immediately
apparent and may require dissection for delinea-
tion. There is usually a layer of peritoneum
running from the retroperitoneum over the
lower edge of the defect. Division of this
tissue usually allows visualization of the
posterior edge of the diaphragm. The defect is
closed by interrupted nonabsorbable suture (Puri
and Doi 2011). Fig. 4 Gentle manual reduction of viscera into the abdo-
If the posterior rim is absent altogether, the men (Image from Puri and Höllwarth, Pediatric Surgery
anterior rim of the diaphragm is sutured to the (Springer Surgery Atlas Series), 2006, Springer)
lower ribs with either periosteal or pericostal
sutures. If the defect is too large for primary
closure, prosthetic material should be placed vs. nonabsorbable), but the ideal material has yet
(Fig. 7). Numerous types of patches are commer- to be identified (Zani et al. 2014). Right-sided
cially available (natural vs. synthetic, absorbable CDH has been found to require patch repair
Postoperative Treatment
Postoperatively, patients need to be monitored as

closely and careful as preoperatively, with spe-
cial attention on fluid management, ventilator
support, and hemodynamic monitoring (Puri
and Nakazawa 2009). Some infants may show
improvement in oxygenation in the so-called
honeymoon period but will usually deteriorate
6–24 h later, which is due to pulmonary hyper-
tension and persistent fetal circulation with
increased pulmonary artery resistance, high pul-
monary artery pressure, and right-to-left
ductal and preductal shunting leading to hypox-
emia (Puri and Doi 2011). Postoperative
pulmonary hypertension is probably caused by
various factors, such as limited diaphragmatic
excursion and increased abdominal pressure
Fig. 5 After inspecting diaphragmatic defect, posterior with impaired visceral and peripheral perfusion.
rim of the diaphragm is mobilized by incising the overlying Overdistended alveoli of the hypoplastic
peritoneum (Image from Puri and Höllwarth, Pediatric lungs with diminished alveolar-capillary
Surgery (Springer Surgery Atlas Series), 2006, Springer)
blood flow, release of vasoactive cytokines, and
deterioration of pulmonary compliance may con-
more commonly than left-sided CDH due to larger tribute as well. A sudden deterioration in the
defect size or complete agenesis (Collin et al. patient’s oxygenation status should always raise
2016). the suspicion of pneumothorax. Also, infections
An alternative is a muscle flap taken from including pneumonia and septicemia are not
the transversus abdominus, leaving the outer uncommon.
abdominal muscle layers intact. Due to the risk
of hemorrhage, this technique should not be
performed in patients with ECMO or in risk of Prognosis
ECMO treatment. Furthermore, operations
involving muscle flaps are too long and complex Certain factors can influence and predict CDH
for critically ill patients and may lead to chest associated pre- and perinatal mortality, with
deformities. The insertion of a chest drain important impact on any potential prenatal inter-
prior to closure is controversial as it may vention and the information given to the parents
increase the transpulmonary pressure gradient (Daodu and Brindle 2017). Chromosomal aberra-
(Puri and Doi 2011). tions and other lethal malformations should be
Reduced trauma and physiological distur- identified. Intrathoracic herniation of stomach
bance through surgery as well as better cosmet- and/or liver has been shown to be associated to a
ically outcome are the main advantages of higher mortality (Jeanty et al. 2014; Mann et al.
minimal invasive CDH repair. However, 2012; Sananes et al. 2016). The lung-to-head ratio
although survival and patch usage has been (LHR) is a crucial indicator for CDH outcome,
found to be similar to open surgery, neonatal and values <1 have been found to relate to a high
thoracoscopic CDH repair is associated with risk of death, ECMO, and pulmonary hyperten-
greater recurrence rates, operative times and sion at 1 month of age (Garcia et al. 2013; Jeanty
severe intraoperative acidosis and hypercapnia et al. 2014). The observed-to expected LHR (O/E
(Bishay et al. 2013; Lansdale et al. 2010; Pierro LHR) is usually associated with death if the values
2015; Weaver et al. 2016; Zhu et al. 2016). is less than ~20% (Ruano et al. 2012).
Fig. 6 (a, b) Primary

closure of the
diaphragmatic defect by
interrupted nonabsorbable
sutures (Image from Puri
and Höllwarth, Pediatric
Surgery (Springer Surgery
Atlas Series), 2006,
Springer)
or major cardiac anomalies, very low birth weight,

and suprasystemic pulmonary hypertension (Brin-
dle et al. 2014). Only recently, the CDH group
developed the Score for Neonatal Acute
Physiology-II to predict not only mortality but
also need for ECMO in CDH patients on the first
day of life by analyzing a multivariable logistic
regression adjusted for hernia side, gestational
age, liver position, Center, ventilation mode, and
observed-to-expected lung-to-head-ratio (Snoek
et al. 2016a). Furthermore, low birth weight,
patch repair, and need for ECMO correlate with
more severe pulmonary hypertension at 1 month
of age (Wynn et al. 2013b).
Golden et al. demonstrated that infants under-
going CDH repair post ECMO-decannulation
Fig. 7 Patch placement for large diaphragmatic defects have better outcomes. In their study group, sur-
(Image from Puri and Höllwarth, Pediatric Surgery
(Springer Surgery Atlas Series), 2006, Springer)
vival rate was 54% in infants undergoing extra-
corporeal life support (ECLS), 65% in those who
underwent repair, 36% in those repaired during
The observed-to-expected total fetal lung vol- ECLS, and 85% in those who were decannulated
ume (O/E TLV), percent predicted lung volumes prior to repair (Golden et al. 2017).
(PPLV) and percent liver herniation, need for Exit-to-ECMO strategy neither increased sur-
ECMO, and development of chronic lung disease vival nor long-term morbidity in severe CDH
in MRI studies were predictors of mortality patients (Shieh et al. 2017b).
(Jeanty et al. 2014; Ruano et al. 2014; Walleyo CDH survivors have lower initial PaCO2 at
et al. 2013; Oluyomi-Obi et al. 2017). 30 days than nonsurvivors (Abbas et al. 2015;
The CDH study group created a logistic equa- McHoney 2015). Additionally, neonates with
tion using birth weight and 5-minute Apgar score continuous hypercarbia have a worse prognosis
to distinguish between high, intermediate, and than those who are stabilized to a normal PaCO2
low risk of death (Congenital Diaphragmatic Her- (Abbas et al. 2015). Further biomarkers to predict
nia Study Group 2001). Later, the fetal risk was the outcome of CDH patients are the best oxygen-
further stratified by the factors absent or low ation index on day 1 (Goonasekera et al. 2016;
5-minute Apgar score, presence of chromosomal Ruttenstock et al. 2015) and a simplified formula
of postnatal blood gas (PaO2–PaCO2) to calculate factor for SNHL (Robertson et al. 2002; Tracy
need for ECMO or death (Park et al. 2013). and Chen 2014). However, several retrospective
studies found an SNHL rate of 2.3–7.5% in both
ECMO and non-ECMO CDH survivors (Dennett
Outcome et al. 2014; Partridge et al. 2014; Wilson et al.
2013), which is equivalent to the SNHL rate of all
Improvement in treatment strategies for neonates neonatal intensive care unit patients (Hille et al.
born with CDH has increased the survival rate of 2007; Tracy and Chen 2014).
more severely affected infants. Long-term follow- Many CDH survivors present with gastrointes-
up of those patients has led to the recognition of tinal symptoms such as gastroesophageal reflux
pulmonary and extrapulmonary morbidities (GER), failure to thrive (defined as weight <25th
which were not previously recognized. The most or 5th centile), and late bowel obstruction (Burgos
common problem in CDH infants surviving et al. 2017; Puri and Doi 2011; Rais-Bahrami et al.
beyond the neonatal period is pulmonary morbid- 1995; Sigalet et al. 1994). One-third of the
ity, which is even more distinct in patients treated patients require gastrostomy tubes due to nutri-
with ECMO or requiring patch repair (Burgos tional morbidity (Chiu et al. 2006; Muratore et al.
et al. 2017; Jaillard et al. 2003; Puri and Doi 2001; Tracy and Chen 2014). Treatment for
2011; Hollinger et al. 2017). BPD rate is up to GERD comprises H2-blockers, but if clinical
41% in CDH neonates who survived the first problems like pulmonary infections or choking
month of life (van den Hout et al. 2010). Further- persist, fundoplication must be discussed
more, CDH survivors with chronic lung disease (Bagolan and Morini 2007; Tracy and Chen
may require prolonged ventilator support and tra- 2014). The most frequently reported predictor
cheostomy and/or suffer from recurrent respira- for antireflux surgery is the need of diaphragmatic
tory tract infections (Bagolan et al. 2004; Jaillard patch repair (Jaillard et al. 2003; Muratore et al.
et al. 2003; Tracy and Chen 2014). Therefore, 2001), and recurrence is more common in patients
some authors recommend palivizumab (Syn- repaired with a prosthetic patch. Moreover,
agis ®) vaccination for CDH infants in fall and patients with patch repair have a higher risk for
winter (Gaboli et al. 2014; Masumoto et al. developing musculoskeletal deformities such as
2008; Resch 2014). scoliosis or pectus excavatum (Jancelewicz et al.
Neurodevelopmental outcome has been inten- 2010).
sively studied in CDH survivors. Developmental Most CDH survivors beyond the neonatal
delay; motor, behavioral, and cognitive disorders; period are able to lead a normal life; however,
as well as impaired language and neurocognitive the children with CDH should have a multi-
skills are reported frequently among these patients disciplinary follow-up and assessed regularly for
(Danzer et al. 2010; Danzer and Hedrick 2011; their pulmonary, neurodevelopmental, and nutri-
Friedman et al. 2008; Tracy and Chen 2014; tive outcome until adulthood.
Wynn et al. 2013a; Hollinger et al. 2017). Inter-
estingly, there were no significant differences
found in neurodevelopmental outcome between Congenital Eventration
right-sided and left-sided CDH survivors, with of the Diaphragm (CDE)
both groups exhibiting normal median GQ scores
at 1 year of age (Collin et al. 2016). Eventration of the diaphragm is characterized by
Ototoxic medications and prolonged mechani- an atypically high or deviated position of all or
cal ventilations with high oxygen tensions may parts of the hemidiaphragm, which can occur con-
contribute to sensorineural hearing loss (SNHL), genitally or acquired as a result of phrenic nerve
which is found frequently in CDH survivors palsy. Congenital CDE is a developmental abnor-
treated with and without ECMO, suggesting that mality in muscular aplasia of the diaphragm,
the use of ECMO is not the only predisposing which primarily has fully developed musculature,
and becomes atrophic secondary to phrenic nerve identify abnormal organs underneath the
damage and disuse. CDE occurs in 1 per 1400 eventration. Other study modalities such as
patients with higher prevalence in males (Wu et al. pneumoperitonography, contrast peritonography,
2015). radioisotope scanning, CT, or MRI scans are
rarely required.
Clinical Features
Management
Clinical characteristics may vary widely from
being asymptomatic to severe respiratory distress, Asymptomatic patients without crucial pulmo-
pneumonia, bronchitis, or bronchiectasis. Gastro- nary abnormalities can be treated conservatively.
intestinal symptoms such as vomiting or epigas- Same applies for patients with incomplete phrenic
tric discomfort have also been reported. Patients nerve palsy without paradoxical movement as
with phrenic nerve palsy may have a history of normal function usually returns. In contrast,
difficult delivery, exhibiting tachypnea, respira- symptomatic patients, especially those with respi-
tory distress, or cyanosis. Breathing sounds may ratory distress, need prompt respiratory support
be reduced on the affected side during physical and ventilation with humidified oxygen to mini-
examination and a mediastinal shift during inspi- mize the diaphragmatic excursions. A nasogastric
ration and a scaphoid abdomen may be observed. tube should be placed to decompress the stomach.
Occasionally, CDE patients exhibit associated Surgery is undertaken once the patient’s condition
malformations like hypoplastic lung, congenital is stabilized.
heart disease, or cryptorchidism (Wu et al. 2015).
Operative Repair
Diagnosis
Diaphragmatic plication is the method of choice,
A chest X-ray reveals an elevated diaphragm with increasing both tidal volume and maximal breath-
a smooth, unbroken outline on frontal and lateral ing capacity (Fig. 9a, b). For left-sided CDE, an
chest (Fig. 8a, b). Fluoroscopy is useful to distin- abdominal approach through a subcostal incision
guish a complete eventration from a hernia. Com- is usually chosen, whereas a thoracic approach
plete eventration can lead to paradoxical with a posterolateral incision in the sixth space
diaphragmatic movements. Ultrasound helps to may be used for right-sided CDE. A
Fig. 8 (a) Right-sided

CDE with liver visible in
the right chest and
mediastinal shift to the left.
(b) Lateral X-ray image of
right CDE
Fig. 9 (a, b) Plication repair of diaphragmatic eventration (Image from Puri and Höllwarth, Pediatric Surgery (Springer
Surgery Atlas Series), 2006, Springer)
transabdominal approach facilitates good visuali- molecular pathomechanisms aims to identify cru-
zation of the complete diaphragm and easier cial parts in the diaphragmatic, pulmonary, and
mobilization of abdominal contents. Plication via vascular development for further treatment strate-
laparoscopic or thoracoscopic approach is also gies. Currently, CDH management focuses
safe repair method (Fujishiro et al. 2016). mainly on postnatal surgical and medical care;
however, promising studies on stem cells and
tissue engineering may open opportunities for
Outcome prenatal treatment on diaphragmatic and lung
development likewise. Infants born with CDH
Mortality of CDE is usually related to pulmonary need to be managed carefully and interdisciplin-
hypoplasia, but patients without underlying ary by obstetrician, neonatologists, anesthetist,
pulmonary hypoplasia commonly have an and pediatric surgeons to assure optimal outcome
excellent prognosis. Timely precise diagnosis of these patients. Although most CDH survivors
and management of symptomatic CDE beyond the neonatal period are able to lead a
effectively prevents respiratory morbidity and normal life, they should have multidisciplinary
reduces complications such as recurrence, pneu- follow-up and assessed regularly for their pulmo-
monia, pleural effusions, or renal insufficiency nary, neurodevelopmental, and nutritive outcome
(Wu et al. 2015). until adulthood.
Conclusions and Future Directions Cross-References
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Extracorporeal Membrane
Oxygenation for Neonatal 54
Respiratory Failure
Jason S. Frischer, Charles J. H. Stolar, and Ronald B. Hirschl
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 818
Types of Extracorporeal Membrane Oxygenation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
Technical Equipment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 821
Patient Management in ECMO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 824
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 826
Abstract
Recent medical advances, such as permissive
hypercapnia, inhaled nitric oxide, and the use
of oscillatory ventilation, have spared numer-
ous patients from ECMO, yet many children
J. S. Frischer (*)
Colorectal Center, ECMO Program, Division of Pediatric still benefit from this modality. Patients with
General and Thoracic Surgery, Cincinnati Children’s reversible cardiopulmonary disease, who meet
Hospital Medical Center, Cincinnati, OH, USA criteria, should be considered ECMO candi-
e-mail: jason.frischer@cchmc.org dates. As of January 2015, 27,728 neonates
C. J. H. Stolar (74% survival) and 6,569 pediatric patients
Emeritus Professor of Surgery and Pediatrics, Columbia (57% survival) have been treated with ECMO
University, College of Physicians and Surgeons, New
York, NY, USA for respiratory failure and 13,124 neonatal and
pediatric patients for cardiac failure. ECMO
California Pediatric Surgery Group, Goleta, CA, USA
provides an excellent opportunity to provide
Morgan Stanley Children’s Hospital, Division of Pediatric “rest” to the cardiopulmonary systems thus
Surgery, New York, NY, USA
e-mail: cjs3@columbia.edu avoiding the additional lung or cardiac injury
which otherwise would be necessary to main-
R. B. Hirschl
Section of Pediatric Surgery, C.S. Mott Children’s tain life support. This chapter outlines the indi-
Hospital, University of Michigan, Ann Arbor, MI, USA cations, contraindications, management
e-mail: rhirschl@med.umich.edu

https://doi.org/10.1007/978-3-662-43588-5_58
818 J. S. Frischer et al.
approach, and complications associated with Candidates for ECMO are expected to have a
ECMO as well as the various bypass configu- reversible cardiopulmonary disease process, with a
rations and cannulation strategies which may predictive mortality greater than 80–90%, and
be employed. exhaustion of ventilatory and other therapies.
Obviously, these criteria are subjective and vary
Keywords between institutions. Criteria for mortality risk in
Extracorporeal membrane oxygenation · neonatal respiratory failure have been suggested to
Extracorporeal support · Respiratory failure · identify infants with a >80% mortality (Bailly et al.
Cardiac failure · ECMO · Cannulation 2017; Barbaro et al. 2016). These include (a) the
oxygenation index (OI), calculated as FiO2* mean
airway pressure * 100/PaO2(OI >25 is predictive
Introduction of a 50% mortality rate and is a relative indication
for ECMO while OI >40 equates with 80% mor-
Extracorporeal membrane oxygenation (ECMO) tality and mandates implementation of ECMO),
is a lifesaving technology that affords partial and (b) an alveolar-arterial oxygen gradient
heart/lung bypass for extended periods. ECMO (A-aDO2) >625 mmHg for more than 4 h, or an
is a supportive rather than a therapeutic modality A-aDO2 >600 mmHg for more than 12 h. Older
as it provides sufficient gas exchange and perfu- infants and children do not have as well-defined
sion in patients with acute, reversible cardiac or criteria for high mortality risk. The combination of
respiratory failure. It provides a finite period to a ventilation index (respiratory rate* PaCO2* peak
“rest” the cardiopulmonary systems at which time inspiratory pressure/1,000) >40 and an OI >40
they are spared insults from traumatic mechanical correlates with a 77% mortality, whereas a mortal-
ventilation and perfusion impairment. ECMO was ity of 81% is associated with an A-aDO2
first implemented in newborns in 1974. Most >580 mmHg and a peak inspiratory pressure of
information on the use of ECMO comes from 40 cmH2O. In general, ECMO is indicated in
the Extracorporenal Life Support Organization pediatric patients with respiratory failure when the
(ELSO). International registering ELSO has A-aDO2 is >600 mmHg on FiO2 1.0 despite opti-
recorded 50,903 neonatal and pediatric patients mal treatment. Indications for support in patients
treated with ECMO for a wide range of cardiore- with cardiac pathology are based on clinical signs
spiratory disorders. Several randomized trials in of cardiovascular failure such as hypotension
the United States and the United Kingdom found despite the administration of inotropes or volume
that ECMO support improved survival outcomes resuscitation, metabolic acidosis, oliguria (urine
when compared with conventional care and it has output <0.5 cc/kg per h), and decreased peripheral
become accepted practice in neonatal care perfusion.
(Bartlett et al. 1985; Jenks et al. 2017). In the In addition, the gestational age should be at
neonatal period the most common disorders least 34–35 weeks due to the increased risk for
treated with ECMO are meconium aspiration syn- intracranial hemorrhage (ICH) and the birth
drome (MAS), congenital diaphragmatic hernia weight at least 2 kg secondary to cannula size
(CDH), persistent pulmonary hypertension of the limitations. The length of mechanical ventila-
neonate (PPHN), sepsis, respiratory distress syn- tion, and its associated toxicity from prolonged
drome (RDS), and cardiac support. For the pedi- exposure to high concentrations of oxygen and
atric population, viral and bacterial pneumonia, elevated positive pressure ventilation prior to
acute respiratory failure (non-ARDS), acute respi- ECMO should be preferably no longer than
ratory distress syndrome (ARDS), and cardiac 10–14 days due to the development of
disease are the most common pathophysiologic bronchopulmonary dysplasia. Babies with lethal
processes requiring ECMO intervention (Butler congenital anomalies should not be considered
et al. 2017; Frenckner 2015; Campbell et al. for ECMO support. Treatable conditions such as
2003). total anomalous pulmonary venous return and
54 Extracorporeal Membrane Oxygenation for Neonatal Respiratory Failure 819
transposition of the great vessels, which may rate. It is recommended that patients who require
masquerade initially as pulmonary failure, can only respiratory support use VV or DLVV
be corrected with surgery but may require bypass and those that necessitate cardiac support
ECMO resuscitation initially. Therefore, echo- use VA ECMO. If necessary, one can convert
cardiogram should be rapidly obtained to deter- VV or DLVV to VA support.
mine cardiac anatomy. There should be no Most reports have suggested that there is no
evidence of significant neurologic injury such overall advantage with either the VA or VV tech-
as seizures. Patients with suggestion of a small nique (McHoney and Hammond 2018). VA
ICH (grades I–II) should be considered candi- ECMO seem to be the more popular of the two
dates for ECMO on an individual basis and modes according to the ECMO registries, presum-
monitored closely for worsening of the hemor- ably as the VA ECMO may give the additional
rhage. In fact, all patients with gross active benefit in the presence of severe cardiac dysfunc-
bleeding or major coagulopathy should be tion (McHoney and Hammond 2018). Size and
corrected prior to initiating ECMO. vascular anatomy may sometimes dictate the
mode use.
Types of Extracorporeal Membrane

Oxygenation Technical Equipment
The goal of ECMO support is to provide gas Blood is drained from the patient to a pump that
exchange and oxygen delivery. Three different advances blood to a membrane lung. The circuit is
extracorporeal configurations: venoarterial comprised of three main components: a roller
(VA), venovenous (VV), and double-lumen sin- pump, a membrane oxygenator, and a heat
gle cannula venovenous (DLVV) bypass are exchanger (Fig. 2). Right atrial blood is drained
available (Fig. 1a–c). VA bypass allows for sup- by gravity siphon into a venous servomechanism,
port of both the pulmonary and cardiac systems. which acts to ensure that venous return to the
Venous blood is drained from the right atrium circuit is adequate for the current pump flow. To
(RA) through the internal jugular vein (IJ), and do so, the servo detects diminished venous return,
oxygenated blood is returned via the carotid slows or shuts off the pump, and sounds an alarm,
artery (CA) to the aorta. Potential disadvantages hence stopping blood flow and relieving the risk
of this arrangement include the sacrifice of a of cavitation, introducing air into the circuit, and
major artery; risk of gaseous or particulate injury to the right atrium. Next, a roller pump,
emboli into the systemic circulation; reduced with continuous servoregulation and pressure
pulmonary perfusion; increased afterload, monitoring, perfuses the blood through the mem-
which may reduce cardiac output; non-pulsatile brane oxygenator. The oxygenator is a
flow; and perfusion of the coronaries by rela- two-compartment chamber composed of a spiral
tively hypoxic left ventricular blood. VV and wound silicone membrane and a polycarbonate
DLVV avoid these disadvantages and provide core, with blood flow in one direction and oxygen
pulmonary support but do not provide hemody- flow in the opposite direction. The size of the
namic/cardiac support. VV bypass is accom- oxygenator is chosen based on the patient’s size.
plished with drainage from the RA via the IJ The oxygenated blood flows through a heat
with reinfusion into the femoral vein or drainage exchanger and is then returned to the patient. A
from the IVC/femoral vein with reinfusion into bridge is constructed to connect the venous line
the IJ/RA. DLVV is carried out by means of the shortly after exiting the patient and the arterial line
IJ. A major disadvantage of VV and DLVV just prior to entering the patient so that during
ECMO is that a fraction of freshly infused weaning, the patient and the circuit can easily
blood recirculates back into the circuit and form two separate circuits. Technological
requires approximately a 20% increase in flow improvements and the introduction of low-
a b
IVC IVC
SVC SVC
Gravity Gravity
Lung Lung
IVC
SVC
Gravity
Lung
Fig. 1 Three different extracorporeal configurations; P., Höllwarth M.E. (eds) Pediatric Surgery. Springer Sur-
venoarterial (VA), venovenous (VV), and double-lumen gery Atlas Series. Springer, Berlin, Heidelberg 2006)
single cannula venovenous (DLVV) bypass (Source: Puri
resistance oxygenators have resulted in the transi- These systems are much simpler, cannot over
tion to centrifugal pump systems. Many centers pressurize, are at lower risk for negative pressure
now use circuits which incorporate centrifugal events which bring gas out of solution, and, there-
pumps and low resistance, blood on the outside/ fore, are much safer and require less maintenance
gas on the inside multiporous hollow fiber lungs. and supervision.
Temp Probe Connector
Arterial
Heat Exchanger
Line
Membrane
Bridge Oxygenator
Venous
Line
Oxymetrics Probe
Pump
Bladder
Fig. 2 Schematic of the ECMO circuit (Source: P. Puri and M. Höllwarth (eds.), Pediatric Surgery: Diagnosis and
Management © Springer-Verlag Berlin Heidelberg 2009)
Surgical Technique first and mobilized over proximal and distal liga-
tures. Occasionally, it is necessary to ligate the
Cannulation can be performed in the neonatal or inferior thyroid vein. The common carotid artery
pediatric intensive care units under adequate seda- lies medial and posterior, contains no branches,
tion, with proper monitoring. The patient is posi- and is mobilized in a similar fashion. The vagus
tioned with the head at the foot of the bed, supine, nerve should be identified and protected from
and the head and neck hyperextended over a injury (Fig. 4).
shoulder roll and turned to the left (Fig. 3). Local The patient is then systemically heparinized
anesthesia is administered over the proposed inci- with 50–100 U/kg heparin, which is allowed to
sion site. A transverse cervical incision is made circulate for 3 min. The arterial cannula (usually
over the sternomastoid muscle, one finger’s 10 F for newborns) is measured so that the tip will
breadth above the right clavicle. The platysma lie at the junction of the brachiocephalic artery
muscle is divided with electrocautery. Self- and the aorta (2.5 cm neonates, one-third the
retaining retractors are placed, and dissection is distance between the sternal notch and the
carried out with the sternomastoid muscle xiphoid). The venous cannula (12–14 F for neo-
retracted to expose the carotid sheath. Using nates) is measured to have its tip in the distal RA
sharp dissection and meticulous hemostasis, the (6 cm, one-half the distance between the supra-
sheath is opened, and the internal jugular vein, sternal notch and the xiphoid process). For VA
common carotid artery, and vagus nerve are iden- bypass, the carotid artery is ligated cranially.
tified. All vessels must be handled with extreme Proximal control is obtained with an angled
care as to avoid spasm. The vein is dissected free clamp, and a transverse arteriotomy is made near
Fig. 3 Patient positioned with the head at the foot of the

bed, supine, and the head and neck hyperextended over a
shoulder roll and turned to the left. Local anesthesia is
administered over the proposed incision site (Source: Puri
P., Höllwarth M.E. (eds) Pediatric Surgery. Springer Sur-
gery Atlas Series. Springer, Berlin, Heidelberg 2006) Fig. 5 Proximal control is obtained with an angled clamp,
and a transverse arteriotomy is made near the ligature
(Source: Puri P., Höllwarth M.E. (eds) Pediatric Surgery.
Springer Surgery Atlas Series. Springer, Berlin, Heidel-
Common carotid a. berg 2006)
Vagus n.
Internal jugular v.
Fig. 4 Open sheath with internal jugular vein, common

carotid artery, and vagus nerve identified (Source: Puri P., Fig. 6 The drainage catheter is passed to the level of the
Höllwarth M.E. (eds) Pediatric Surgery. Springer Surgery RA and secured in a manner similar to that used for the
Atlas Series. Springer, Berlin, Heidelberg 2006) arterial catheter (Source: Puri P., Höllwarth M.E. (eds)
Pediatric Surgery. Springer Surgery Atlas Series. Springer,
Berlin, Heidelberg 2006)
the ligature (Fig. 5). Stay sutures, using 5/0 or 6/0
prolene, are placed through the full thickness of In preparation for the venous cannulation, the
the medial and lateral proximal edges of the patient is given succinylcholine to prevent sponta-
arteriotomy to help prevent subintimal dissection. neous respiration. The vein is then ligated cranially.
The sutures are gently retracted and the clamp Gentle traction is placed on the lower ligature to
slowly released as the arterial catheter is inserted help decrease back bleeding, and a venotomy is
into the carotid artery to its proper position. The made close to the proximal ligation. The drainage
cannula is then fastened into place with two silk catheter is passed to the level of the RA and secured
ligatures (2/0), with a small piece of vessel loop, in a manner similar to that used for the arterial
on the anterior aspect, inside the ligatures to pro- catheter (Fig. 6). The cannulas are then debubbled
tect the vessel from injury during decannulation. with back bleeding and heparinized saline. Then
stabilized. Continuous inline monitoring of the

venous (pre-pump) SvO2 and arterial (post-
pump) PaO2 as well as pulse oximetry is vital.
The goal of VA ECMO is to maintain a mixed
venous PO2 (SvO2) of 37–40-mmHg and satura-
tion of 65–70%. VV ECMO is more difficult to
monitor due to variation in the degree of
recirculation, which may produce a falsely ele-
vated SvO2 assessment. Inadequate oxygenation
and perfusion are indicated by metabolic acidosis,
Fig. 7 Both cannulas are then secured to the mastoid oliguria, and hypotension. Arterial blood gasses
process using 2-0 suture (Source: Puri P., Höllwarth M.E. should be monitored hourly with PaO2 and
(eds) Pediatric Surgery. Springer Surgery Atlas Series. PaCO2 maintained as close to normal level as
Springer, Berlin, Heidelberg 2006)
possible. As soon as these parameters are met,
all vasoactive drugs are weaned, and ventilator
they are connected to the ECMO circuit and bypass levels are adjusted to “rest” settings. Gastrointes-
is initiated. Both cannulas are then secured to the tinal prophylaxis is initiated, and mild sedation
mastoid process using 2–0 suture (Fig. 7). The and analgesia is provided usually with fentanyl
wound is irrigated, meticulous hemostasis obtained, and midazolam, but the use of a paralyzing agent
and the skin closed with a running nylon. The site is is avoided. A cephalosporin is often administered
covered with a sterile dressing, and the circuit tub- for prophylaxis. Routine blood, urine, and tra-
ing is fixed securely to the bed. cheal cultures should be taken.
For VV and DLVV bypass, the procedure is Heparin is administered (typically 30–60 mg/
exactly as described above including dissection of kg per h) throughout the ECMO course in order to
the artery, which is marked with a vessel loop, so preserve a circuit free of thrombus. ACTs should
that a future switch from VV to VA ECMO can be be monitored hourly and maintained at 180–220 s.
accomplished, if necessary. The catheter tip A complete blood count should be obtained every
should be in the mid-right atrium (6 cm in the 6 h and coagulation profiles daily. In order to
neonate) with the arterial portion of the catheter prevent hemorrhage, platelets are transfused to
pointed toward the ear. This directs the oxygen- maintain a platelet count above 100,000/mm3,
ated blood flow toward the tricuspid valve. and some authors sustain fibrinogen levels above
Cannula position is confirmed by chest X-ray 150 mg/dl. The hematocrit should remain above
and by transthoracic echocardiogram when nec- 40% using red blood cell transfusions so that
essary. The venous catheter should be located in oxygen delivery is optimized.
the inferior aspect of the right atrium and the Volume management of patients on ECMO is
arterial catheter at the ostium of the innominate extremely important. It is imperative that all
artery and the aorta. With a double-lumen venous inputs and outputs be diligently recorded and
catheter, the tip should be in the mid-right atrium electrolytes monitored every 6 h. All fluid losses
with reinfusion of oxygenated blood flow toward should be repleted and electrolyte abnormalities
the tricuspid valve (Hirschl and Bartlett 2012; corrected. All patients should receive mainte-
Kim and Stolar 2003; Kim and Stolar 2000). nance fluids as well as adequate nutrition using
hyperalimentation. The first 48–72 h of ECMO
typically involves fluid extravasation into the soft
Patient Management in ECMO tissues. The patient becomes edematous and may
require volume replacement (crystalloid, colloid,
Once the cannulas are connected to the circuit, or blood products) in order to maintain adequate
bypass is initiated, and flow is slowly increased intravascular and bypass flows, hemodynamics,
to100–150 ml/kg per min so that the patient is and urine output greater than 1 cc/kg per h. By
the third day of bypass, diuresis of the excess local pressure or the placement of topical hemo-
extracellular fluid begins and can be facilitated static agents such as Gelfoam, Surgicel, or topical
with the use of furosemide if necessary. thrombin. For all sites of bleeding, the platelet
Surgical procedures, such as CDH repair, may count should be increased to >100,000 mm3 and
be performed while the child remains on bypass. the ACT lowered to 180–200 s. Sometimes the
Hemorrhagic complications are a frequent mor- temporary discontinuation of heparin and normal-
bidity associated with this situation and increases ization of the coagulation status is warranted to
mortality. To avoid these complications, prior to help stop the hemorrhage with availability of a
the procedure, the platelet count should be greater second circuit should acute clotting of the circuit
than 100,000/mm3, a fibrinogen level above occur. Aggressive surgical intervention is
150 mg/dl, an ACT reduced to 180–200 s, and warranted if bleeding persists.
ECMO flow increased to full support, and it is Neurological sequelae are a serious morbidity
imperative that meticulous hemostasis be of the ECMO population and include learning
obtained throughout the surgery. Fibrinolysis disorders, motor dysfunction, and cerebral palsy
inhibitor aminocaproic acid (100 mg/kg) just (Schiller et al. 2016; Madderom et al. 2013).
prior to incision followed by a continuous infu- These outcomes appear to be as much due to
sion (30 mg/kg per h) until all evidence of bleed- hypoxia and acidosis prior to the ECMO course
ing ceases is a useful adjunct. as due to the time on ECMO itself. ICH is the most
As the patient improves, the flow of the circuit devastating complication, occurring in 7.4% of
may be weaned at a rate of 10–20 ml/h as long as newborn patients with an associated 57% mortal-
the patient maintains good oxygenation and perfu- ity among newborns who have ICH on ECMO.
sion. Flows should be decreased to 30–50 ml/kg per Frequent comprehensive neurologic exams
min, and the ACT should be at a higher level should be performed, and cranial ultrasounds
(200–220 s) to prevent thrombosis. Moderate con- obtained daily for the first days of ECMO and
ventional ventilator settings are used, but higher then based on local protocols. Blood pressure
settings can be used if the patient needs to be should be carefully monitored and maintained
weaned from ECMO urgently. If the child tolerates within normal parameters to help decrease the
the low flow, all medications and fluids should be risk of ICH. If necessary, electroencephalograms
switched to vascular access on the patient, and the may be helpful in the neurologic evaluation.
cannulas may be clamped with the circuit bypassing Oliguria and increasing blood urea nitrogen
the patient via the bridge. The patient is then and creatinine levels, may be seen in the ECMO
observed for 2–4 h, and if this is tolerated, patient during the initial 48 h, at which time renal
decannulation should be performed. This should function is expected to improve. If this does not
be executed under sterile conditions with muscle occur, consideration must be toward poor tissue
relaxant onboard to prevent air aspiration into the perfusion. This may be due to low cardiac output,
vein. The catheters are removed and the vessels are insufficient intravascular volume, or inadequate
ligated. The wound should be irrigated and closed pump flow, all of which should be corrected. In
over a small drain, which is removed 24 h later. the event of continued renal failure, hemofiltration
or hemodialysis can be performed to maintain
proper fluid balance and electrolyte levels and
Complications are reported to be required in 14% of cases.
Extracranial bleeding is a common complication

of the heparinized ECMO patient either at the site Conclusion and Future Directions
of cannulation or at other sites and is noted in 21%
of neonatal cases, 44% of pediatric respiratory As of January 2015, 27,728 neonates (74% sur-
cases, and 40% of all cardiac cases. Bleeding at vival) and 6,569 pediatric patients (57% survival)
the site of cannulation can often be treated with have been treated with ECMO for respiratory
Table 1 ELSO registry neonatal respiratory failure cases Table 3 ELSO registry cardiac failure cases (as of January
(January 2015) 2015)
Number Percent Primary Number of Number Percent
of survived diagnosis ECLS runs survived survived
Primary diagnosis patients Survived to DC Congenital 9,807 4,757 49
Congenital 7,228 3,691 51 defect
diaphragmatic Cardiac arrest 309 117 38
hernia Myocarditis 431 290 67
Meconium 8,684 8,128 94 Cardiomyopathy 825 504 61
aspiration
Cardiogenic 286 131 46
syndrome
shock
Persistent 4,800 3,696 77
Other 2,056 1,035 50
pulmonary
hypertension of the TOTAL 13,714 6,834 50
newborn/persistent
fetal circulation
Respiratory 1,546 1,300 84 CDH (51%). Viral pneumonia is the most com-
distress syndrome/
hyaline membrane
mon etiology amongst the pediatric population
disease requiring ECMO and has a 65% survival. Aspira-
Sepsis 2,856 2,084 73 tion carries the greatest survival at 68%, where as
Other 3,007 1,835 61 non-ARDS respiratory failure has a 54% survival,
Total 28,121 20,734 74 ARDS 56%, and bacterial pneumonia 59% sur-
vival. Cardiac patients have an overall survival of
46%. Specifically, congenital defects have a 49%
Table 2 ELSO registry pediatric respiratory failure cases survival and cardiomyopathy 61%, and the
(January 2015)
highest survival rate is for myocarditis, 67%.
Primary Number of Percent While many centers have shown very good sur-
diagnosis patients Survived survived
vival employing minimal or no ECMO in CDH,
Viral 1,450 940 65
the highest overall survival rate in the sickest
pneumonia
Bacterial 686 402 59
CDH patients is reported from centers that utilize
pneumonia ECMO (Kays 2017). Several centers have
Aspiration 304 208 68 reported ECMO survival rates in CDH patients
Pneumocystis 35 18 51 in excess of 70%, substantially different from the
Acute 1,186 641 54 ELSO reported survival of 50% (Kays 2017). It is
respiratory generally acknowledged that the ECMO improves
failure
survival in babies with severe cardiopulmonary
ARDS 735 412 56
disease over and above that currently available
Other 2,306 1,195 52
by non-ECMO techniques.
Total 6,702 3,816 57
Recent medical advances, such as permissive
hypercapnia, inhaled nitric oxide, and the use of
failure and 13,124 neonatal and pediatric patients oscillatory ventilation, have spared numerous
for cardiac failure. Tables 1, 2, and 3 demonstrate babies from ECMO, yet many children still bene-
the common neonatal and pediatric respiratory fit from this modality.
and cardiac diagnoses along with survival with In summary, any patient with reversible cardio-
ECMO support (Extracorporeal Life Support pulmonary disease, who meets criteria, should be
Organization 2015). In the neonatal population, considered an ECMO candidate. ECMO provides
MAS is the most common indication for ECMO an excellent opportunity to provide “rest” to the
and carries with it a survival rate of 94%. Other cardiopulmonary systems thus avoiding the addi-
frequent diagnoses (with survival rates in paren- tional lung or cardiac injury which otherwise
theses) include PPHN (77%), sepsis (73%), and would be necessary to maintain life support.
Cross-References Extracorporeal Life Support Organization International

Registry Report of the Extracorporeal Life Support
Organization. 2015. University of Michigan Medical
▶ Congenital Diaphragmatic Hernia Center, Ann Arbor.
▶ Pediatric Cardiovascular Physiology Frenckner B. Extracorporeal membrane oxygenation: a
▶ Pediatric Respiratory Physiology breakthrough for respiratory failure. J Intern Med.
▶ Sepsis 2015;278(6):586–98.
Hirschl RB, Bartlett RH. Extracorporeal life support
in cardiopulmonary failure. In: Coran AG, Adzick
NS, Krummerl T, Laberge JM, Shamberger R,
References Caldamone A, editors. Pediatric surgery. 5th ed. -
New York: Mosby; 2012. p. 89–102.
Bailly DK, Reeder RW, Zabrocki LA, Hubbard AM, Kays DW. ECMO in CDH: Is there a role? Semin Pediatr
Wilkes J, Bratton SL, Thiagarajan RR. Extracorporeal Surg. 2017;26(3):166–70.
life support organization member centers. Develop- Kim ES, Stolar CJ. ECMO in the newborn. Am J Perinatol.
ment and validation of a score to predict mortality in 2000;17:345–56.
children undergoing extracorporeal membrane oxygen- Kim ES, Stolar CJ. Extracorporeal membrane oxyge-
ation for respiratory failure: pediatric pulmonary rescue nation for neonatal respiratory failure. In: Puri P,
with extracorporeal membrane oxygenation prediction editor. Newborn surgery. London: Arnold; 2003.
score. Crit Care Med. 2017;45(1):e58–66. p. 317–27.
Barbaro RP, Bartlett RH, Chapman RL, et al. Development Jenks CL, Rama L, Dalton HJ. Peidatric extracorporeal
and validation of the neonatal risk estimate score for membrane oxygenation. Crit Care Clin. 2017;33(4):
children using extracorporeal respiratory support. 825–41.
J Pediatr. 2016;173:56–61.e3. McHoney M, Hammond P. Role of ECMO in congenital
Bartlett RH, Roloff DW, Cornell RG, et al. Extracorporeal diaphragmatic hernia. Arch Dis Child Fetal Neonatal
circulation in neonatal respiratory failure: a prospective Ed. 2018;103(2):F178–81.
randomized study. Pediatrics. 1985;76(4):479–87. Madderom MJ, Reuser JJ, Utens EM, et al. Neuro-
Butler DF, Lee B, Molitor-Kirsch E, Newland developmental, educational and behavioral
JG. Extracorporeal membrane oxygenation associated outcome at 8 years after neonatal ECMO: a nation-
bloodstream infections in children. Pediatr Infect Dis J. wide multicenter study. Intensive Care Med.
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Campbell BT, Braun TM, Schumacher RE, et al. Impact Schiller RM, Madderom MJ, Reuser JJ, et al. Neuropsy-
of ECMO on neonatal mortality in Michigan chological follow-up after neonatal ECMO. Pediatrics.
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Part V
Newborn Surgery: Gastrointestinal
Pyloric Atresia and Prepyloric Antral
Diaphragm 55
Girolamo Mattioli and Sara Costanzo
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
Pyloric Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
Definition and Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 830
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 831
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Prepyloric Antral Diaphragm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 837
Abstract
Pyloric atresia (PA) and prepyloric antral dia-
G. Mattioli (*) phragm are two causes of congenital gastric
Department of Paediatric Surgery, Giannina Gaslini outlet obstruction.
Research Institute and University of Genoa, Genoa, Italy PA is a very rare condition, with an inci-
e-mail: girolamomattioli@gaslini.org
dence of about 1 in 100,000 newborns,
S. Costanzo representing approximately 1% of all intestinal
Department of Paediatric Surgery, University of Genoa,
Genoa, Italy atresias. The exact etiology of this condition is
not known. Commonly, PA is an isolated con-
Paediatric Surgery Unit, “V. Buzzi” Children’s Hospital,
Milan, Italy dition, but familial occurrence is also reported,
e-mail: saracostanzo@ymail.com supporting a genetic predisposition. Most of

https://doi.org/10.1007/978-3-662-43588-5_59
830 G. Mattioli and S. Costanzo
the familial cases have been reported to be GOO is a relatively common condition in pedi-
associated with epidermolysis bullosa atric age, if hypertrophic pyloric stenosis (HPS) is
(EB-PA) and are characterized by an autosomal considered. However, when HPS is excluded,
recessive inheritance. Prenatal diagnosis is GOO is quite rare, with an incidence of 1 in
possible on ultrasound (US); prenatal testing 100,000 live births (Sharma et al. 2008).
in families at risk for EB-PA can be performed. The causes of GOO may be classified as fol-
After birth, the main presenting symptoms are lows (Sharma et al. 2008):
non-bilious vomiting and upper abdominal dis-
tension. Associated anomalies are very fre- 1. Congenital intrinsic obstruction of antrum and
quent, the commonest being EB. The pylorus:
diagnosis can be made on plain abdominal (a) Aplasia
X-ray, barium meal, and abdominal US. The (b) Atresia
treatment is surgical and the prognosis is vari- (c) Diaphragms and webs
able, mostly depending on the severity of the (d) Luminal obstruction (e.g., mucosal valves,
associated conditions. heterotrophic pancreas, etc.)
Prepyloric antral diaphragm is a rare condi- 2. HPS
tion, whose prevalence and etiology are still 3. Acquired:
unknown. The age of onset and clinical pre- (a) Primary:
sentation vary depending on the degree of (i) Acquired gastric outlet obstruction dur-
obstruction determined by the diaphragm. ing infancy and childhood
The main symptoms are recurrent non-bilious (b) Secondary:
vomiting, often projectile; progressive feeding (i) Acid peptic disease (chronic duodenal
problems; epigastric pain; and failure to thrive. or juxtapyloric ulcer)
The diagnosis can be made on plain abdominal (ii) Neoplasm
films, barium meal, and abdominal US; endos- (iii) Chemical injury (ingestion of acid,
copy is helpful and may also be a therapeutic caustic, and other irritants like potas-
tool. Surgery is the treatment of choice and the sium carbonate)
prognosis is excellent. (iv) Others: chronic granulomatous dis-
ease, Crohn’s disease, eosinophilic
gastritis, gastric duplication cysts,
Keywords
and cholecystogastrocolic band
Gastric outlet obstruction (GOO) · Pyloric
(malrotation) (Nissan et al. 1997)
atresia (PA) · Prepyloric antral diaphragm ·
Epidermolysis bullosa (EB) · Hereditary
multiple intestinal atresias (HMIA) · Carmi
syndrome · Integrin gene (ITG) mutations ·
Pyloric Atresia
Plectin (PLEC) gene mutations · Pyloroplasty ·
Gastroduodenostomy
Definition and Classification
Congenital pyloric atresia (PA) was firstly

Introduction described by Calder in 1749. The first successful
surgical correction was performed in 1940 by
Pyloric atresia and prepyloric antral diaphragm Touroff (Al-Salem 2007; Ilce et al. 2003).
are two causes of gastric outlet obstruction Anatomically, it is divided into three types:
(GOO), a broad spectrum of conditions that pre-
vent the passage of gastric contents into the – Type 1, the commonest: pyloric membrane or
duodenum. web (57%)
55 Pyloric Atresia and Prepyloric Antral Diaphragm 831
– Type 2: pyloric atresia with a solid cord anatomically narrow passages, such as the
between the two ends (34%) pyloric canal.
– Type 3: pyloric atresia with a gap between the
stomach and the duodenum (9%) (Al-Salem Hereditary multiple intestinal atresias (HMIA),
2007; Ilce et al. 2003; Tomá et al. 2002). frequently associated with PA, are reported as an
autosomal recessive condition, although the can-
didate gene has not been identified yet (Al-Salem
Epidemiology 2007; Cole et al. 2010).
In patients affected by epidermolysis bullosa
Congenital PA is a very rare condition, with an and pyloric atresia (EB-PA) and Carmi syndrome
incidence of about 1 in 100,000 newborns. It (EB-PA and aplasia cutis congenita), the affected
represents approximately 1% of all intestinal atre- skin presents morphological abnormalities in the
sias (Al-Salem 2007; Ilce et al. 2003; Chung and hemidesmosomes and reduced or absent expres-
Uitto 2010; Mboyo et al. 2016). sion of the hemidesmosomal component integrin
Sex distribution is about equal (Ilce et al. 2003; α6β4, a member of a large family of α/β hetero-
Andriessen et al. 2010). dimeric transmembrane glycoprotein receptors
(Chung and Uitto 2010; Birnbaum et al. 2008;
Abe et al. 2007; Ozge et al. 2012).
Etiopathogenesis Sequence analysis of integrin genes identified
mutations in integrin β4, encoded by integrin β4
The exact etiology of this condition is not known. (ITGB4) gene, in most EB-PA cases, with few
Embryologically, it is thought to result from a cases demonstrating integrin α6 (ITGA6 gene)
developmental arrest between the 5th and 12th mutations (Chung and Uitto 2010; Birnbaum
week of intrauterine life. According to Tandler’s et al. 2008). Almost 70 distinct mutations of
theory, this anomaly is the result of a failure of the ITGB4 in EB-PA patients can be found in the
tube canalization during development (Al-Salem mutation database, while a total of 5 mutations
2007; Andriessen et al. 2010; Sencan et al. 2002). in the ITGA6 gene have been reported (Chung and
Commonly, PA is an isolated condition, but Uitto 2010). Sequencing analysis shows that
familial occurrence is also reported, supporting a ITGB4 accounts for 80% and ITGA6 for 5% of
genetic predisposition. Most of the familial cases EB-PA patients (Ozge et al. 2012).
have been reported to be associated with ITGB4 mutation database suggests that prema-
epidermolysis bullosa (EB) and are characterized ture termination codon (PTC) mutations predom-
by an autosomal recessive inheritance (Chung and inantly result in lethal forms, while missense
Uitto 2010; Birnbaum et al. 2008; Charlesworth mutations frequently associate with nonlethal var-
et al. 2013; Dang et al. 2008; Abe et al. 2007; iants (Abe et al. 2007; Ozge et al. 2012).
Natsuga et al. 2010; Usui et al. 2013). Other genetic mutations that have been linked
PA in association with EB is supposed to result to EB-PA lie in the gene for plectin (PLEC)
from two pathologic elements (Al-Salem 2007; (Charlesworth et al. 2013; Nakamura et al. 2011;
Ilce et al. 2003; Natsuga et al. 2010; Bıçakcı Natsuga 2015). Plectin is a cytoskeletal protein
et al. 2012): abundantly expressed in several cell types (epi-
thelia, muscles, and fibroblasts). It harbors bind-
1. Intrauterine sloughing of the pyloric mucosa, ing sites for several proteins, including integrin
as a result of disintegration of basement mem- α6β4. The association of PLEC mutations with
brane and hemidesmosomes EB-PA is therefore consistent with plectin’s
2. Subsequent inflammatory response which cross-linking functions with other proteins and
causes fibrous cicatrization and obliteration results in pleiotropic phenotypes (Charlesworth
of the intestinal lumen, especially in et al. 2013). Genetic findings suggest that EB-PA
is linked to mutations in the portions of plectin A new technique of immunofluorescence ana-

that mediate interactions with integrin β4 lyses of villous trophoblastus has been recently
(Charlesworth et al. 2013). Ten distinct mutations proposed (D’Alessio et al. 2008).
in the PLEC1 gene have been demonstrated in Preimplantation genetic diagnosis, for couples
patients with EB-PA (Chung and Uitto 2010). at risk of having children with EB-PA, has been
EB-PA due to PLEC mutations is considered uni- also offered to avoid abortion of possibly affected
versally lethal (Nakamura et al. 2011). pregnancies (Ozge et al. 2012).
A mutation in the ITGB4 gene has been The prognosis, the decision about whether to
recently detected in a patient affected by PA and continue or not the pregnancy, and the risks for
desquamative enteropathy, without skin disease future pregnancies should be discussed with the
(Salvestrini et al. 2008). parents, advising them about the risk of recurrence
(25% for autosomal recessive diseases) and the
prognosis associated with different types of muta-
Diagnosis tions, together with the encouraging improve-
ments of the medical therapy to treat EB
Prenatal Diagnosis and Counselling (Al-Salem 2007; Parshotam et al. 2007).
Prenatal diagnosis of PA is possible on ultrasound
(US) (Al-Salem 2007; Usui et al. 2013), with Clinical Presentation
visualization of polyhydramnios (reported in Almost all patients have a low weight at birth (Ilce
about 50% of PA cases (Ilce et al. 2003)), a dilated et al. 2003).
stomach in the absence of a double bubble After birth, the main presenting symptoms are
(Andriessen et al. 2010), and narrowing of the non-bilious vomiting and upper abdominal disten-
gastric outlet (Ilce et al. 2003). sion (Al-Salem 2007; Andriessen et al. 2010).
Cases of diagnostic confirmation by fetal mag- Congenital PA can be an isolated condition, but
netic resonance imaging have been reported associated anomalies are also very frequent
(Yu et al. 2009). (30–50% of cases). The commonest associated
The presence of EB or Carmi syndrome can be anomaly is EB (Al-Salem 2007).
suggested prenatally by the sonographic so-called EB is categorized in three major groups: EB
“snowflake” sign (echogenic particles in the simplex (EBS), junctional EB (JEB), dystrophic
amniotic fluid), associated with fetal stomach EB (DEB), and Kindler syndrome, depending on
dilation and polyhydramnios (Birnbaum et al. the depth of the dermal-epidermal junction split
2008; Usui et al. 2013). (Nakamura et al. 2011). EB-PA is classified as a
EB can be also diagnosed by electron form of JEB (Ozge et al. 2012).
microscopy or immunofluorescence of a fetal Skin lesions may not appear until as late as 48 h
skin biopsy (Al-Salem 2007; D’Alessio et al. after birth. They are associated with disruption of
2008). the intestinal mucosa, which causes malabsorp-
Identification of genetic mutations in families tion, increased antigenic sensitivity, bloody diar-
has provided molecular confirmation of diagnosis rhea, and protein losing enteropathy (Bıçakcı et al.
together with prognostication and can also pro- 2012).
vide a means for prenatal testing in families at risk The severity of skin involvement in EB-PA can
for recurrence of the disease (Chung and Uitto be variable, and both lethal and nonlethal variants
2010; Nakamura et al. 2011). have been reported (Chung and Uitto 2010; Abe
Prenatal testing in families at risk for EB-PA et al. 2007). In some patients, even on successful
can be performed from chorionic villus sam- surgical correction of the pyloric or intestinal atre-
pling, which can be performed as early as the sia, skin involvement is so severe that the children
10th week of gestation (Chung and Uitto 2010) die from complications, such as infections or elec-
or from amniotic fluid sampling (Nakamura trolyte imbalance, within a few days or weeks
et al. 2011). from birth. In others, skin fragility can be mild,
or it can improve with age, allowing them to Laboratory

conduct normal lives (Chung and Uitto 2010). During the prenatal period, elevated levels of
EB-PA can be associated to many other disor- maternal serum and/or amniotic fluid alpha-
ders including gastrointestinal, urinary, pulmo- fetoprotein can be found in EB-PA (Birnbaum
nary, and eye problems, as well as dental et al. 2008; Yu et al. 2009).
(enamel hypoplasia, dental caries), hair (alope- In patients with EB-PA, immunofluorescence
cia), and nail (toenail dystrophy) abnormalities, mapping of the affected skin usually shows
ear or nose hypoplasia, or atrophy (Dang et al. completely negative staining for integrin β4
2008; Abe et al. 2007; Bıçakcı et al. 2012). The and/or integrin α6 in lethal cases, whereas non-
associated anomaly rate is reported to be around lethal forms are usually associated with positive
30% (Ilce et al. 2003). but attenuated staining (Dang et al. 2008).
The combination of PA, EB, and aplasia
cutis congenita (PA-EB-ACC) is known as Radiologic Findings
Carmi syndrome (OMIM #226730) (Birnbaum The diagnosis can be made on plain abdominal
et al. 2008). It is characterized by congenital X-ray, which shows a single, large air bubble,
absence of skin, mostly of the limbs, involving representing the dilated stomach, with no gas dis-
all skin layers and severe neonatal mucocuta- tally (Al-Salem 2007; Parshotam et al. 2007;
neous blistering (Chung and Uitto 2010; Hermanowicz and Debek 2015).
Birnbaum et al. 2008). Most cases result in A double bubble may, however, be seen in
early death of the affected child, but nonlethal cases with prolapse of a pyloric membrane into
cases with progressive improvement of the the duodenum, thus imitating duodenal atresia.
cutaneous lesions have been described An intermittent double bubble sign has also been
(Birnbaum et al. 2008). described, probably reflecting configuration of the
In 2010 the first report of EB complicated with distended stomach (Parshotam et al. 2007).
both PA and muscular dystrophy was published, The presence of calcification raises the possi-
caused by mutations in the plectin gene (PLEC) bility of associated multiple intestinal atresias
(Natsuga et al. 2010). (Al-Salem 2007): they are homogeneous
PA can also be associated with distal duode- intraluminal calcifications, described as a “string
nal atresia forming a closed duodenal loop, of pearls,” almost resembling a contrast study,
where biliary and pancreatic secretions accumu- and are pathognomonic of this condition (Bass
late, leading to massive distention and possible 2002).
duodenal perforation (Al-Salem 2007), esopha- Barium meal can confirm the diagnosis, as it
geal atresia (Al-Salem 2007; Ilce et al. 2003), shows dilated stomach with obstruction at the
hereditary multiple intestinal atresias (HMIA), pylorus level and no contrast passing distally
with or without combined immunodeficiency (Al-Salem 2007).
syndrome (Cole et al. 2010; Bass 2002), intra- An additional lower gastrointestinal contrast
uterine growth retardation, Down’s syndrome, study (barium enema) can be done to rule out the
congenital heart disease, cleft palate, Meckel’s presence of colonic atresia (Al-Salem 2007).
diverticulum (Al-Salem 2007), Dieulafoy lesion US with high-resolution high-frequency equip-
of the stomach (Polonkai et al. 2011), ment is a useful and noninvasive technique in the
ureterovesical junction obstruction, evaluation of PA and associated anomalies, dem-
pelviureteric junction obstruction, agenesis of onstrating the abnormal sonographic pattern of
the gallbladder (Al-Salem 2007), ectopic drain- the antropyloric region, the absence of other
age of the common bile duct, annular pancreas causes of gastric obstruction, as well as many
(Scheida et al. 2009), malrotation, anorectal associated anomalies that may affect the intestinal
agenesis (Al-Salem 2007), and pylorocho- loops (distal loops’ dilatation in case of multiple
ledochal fistula (Al-Salem 2007; Sencan et al. atresias, calcifications) or other abdominal organs
2002). (Tomá et al. 2002).
Abdominal US can show bile duct dilatation strategies, including balloon dilatation, laser web
and cystic dilation of the duodenum in case of excision, and laser radial incision (Yokoyama and
both PA and duodenal or high jejunal obstruction Utsunomiya 2012).
with retention of pancreaticobiliary secretions For type 2, excision of the atretic segment with
(Bass 2002). end-to-end or diamond-shaped (proximal trans-
verse and distal longitudinal incision, Kimura
Differential Diagnosis technique) gastroduodenostomy is recommended
Non-bilious vomiting in the newborn period can as the standard technique (Andriessen et al. 2010;
be interpreted as gastroesophageal reflux, the Dessanti et al. 2004).
most frequent cause of delayed emptying in chil- A different procedure has been also proposed,
dren, leading to a delay in the diagnosis of PA the gastroduodenal mucosal advancement anas-
(Ilce et al. 2003; Polonkai et al. 2011). tomosis, which achieves an anatomic reconstruc-
Other congenital developmental anomalies, tion of the pyloric canal (Dessanti et al. 2004). The
such as hypertrophic pyloric stenosis, pyloric atretic pylorus is incised longitudinally, showing
duplication, antrum membrane, gastric volvulus, the presence of an internal muscular layer, which
gastric duplication, aberrant pancreatic tissue is separated as in Ramstedt operation. By this
plugging the pylorus, and retrograde pyloromyotomy, the mucosal cul-de-sacs on the
duodenogastric intussusception, need to be gastric and duodenal sides are isolated, mobilized,
included in the differential diagnosis of PA (Ilce and advanced into the pyloric canal and then
et al. 2003; Tomá et al. 2002; Polonkai et al. sutured into an end-to-end anastomosis. The
2011). pyloromyotomy is then closed.
A novel gastroduodenostomy procedure for
solid segment type has been recently published
Treatment (Yokoyama and Utsunomiya 2012), through
which the stomach and duodenal lumen are
The treatment of PA is surgical (Fontenot et al. anastomized end to end anteriorly to the solid
2011). segment, which is not excised.
Preoperative management should include When a gap is present (type 3), the treatment is
nasogastric tube placement, intravenous fluid gastroduodenostomy (Andriessen et al. 2010;
administration, and electrolyte correction Fontenot et al. 2011).
(Andriessen et al. 2010; Fontenot et al. 2011). Gastrojejunostomy should be avoided because
Intraoperatively, it is important to make sure it is associated with high failure and mortality
that only one pyloric diaphragm is present, as this rates (Ilce et al. 2003; Yokoyama and Utsunomiya
can be multiple (Al-Salem 2007; Zecca et al. 2012).
2010). It is also important to check the patency When PA is associated with EB, surgical inter-
of the distal intestine, passing a catheter and vention is often effective only for short-term sur-
injecting saline distally to exclude associated vival, because infants usually die within the first
intestinal atresias. few weeks or months of life, due to complications
The surgical treatment depends on the type of related to EB (Bıçakcı et al. 2012).
PA discovered at laparotomy (Al-Salem 2007; Identification of the genetic mutations
Fontenot et al. 2011). involved in EB-PA provides the basis for molec-
Type 1 is treated by excision of the membrane/ ular therapies: gene therapy, protein replacement
web with or without Heineke-Mikulicz or Finney or stem cell therapies. These approaches are
pyloroplasty (Al-Salem 2007; Ilce et al. 2003; supported by the development of animal models
Dessanti et al. 2004; Yokoyama and Utsunomiya of different forms of EB, including those with
2012). Recent advances in endoscopy have allo- targeted ablation of the ITGB4, ITGA6, and
wed the development of alternative treatment PLEC1 genes (Chung and Uitto 2010).
Some forms of desquamative enteropathies because it might alter medical and surgical man-
associated with PA have been treated with agement (Bass 2002).
immune modulatory therapy with significant clin-
ical improvement (Salvestrini et al. 2008).
Prepyloric Antral Diaphragm
Complications Syn.: (congenital) (gastric) antral (mucosal)

web/membrane/diaphragm – prepyloric
After excision of the atretic pylorus and (mucosal) web/diaphragm
gastroduodenostomy, pyloric function can be
lost with consequent duodenogastric reflux,
which can cause gastric disorders like alkaline Definition
gastritis as a result of bilious reflux into the stom-
ach (Yokoyama and Utsunomiya 2012). Prepyloric antral membrane (PAM) is a rare cause
of congenital gastric outlet obstruction (Borgnon
et al. 2003), firstly described in 1933 by Parsons
Outcome and Barling (Parsons and Barling 1933).
It is a circumferential intraluminal mucosal
The prognosis of PA is variable. septum in the prepyloric region, perpendicular
Isolated PA, particularly if type 1, if diagnosed to the long axis of the antrum (Chao et al. 2011).
and treated on time, has an excellent prognosis It consists of normal, noninflamed mucosal and
(Ilce et al. 2003; Fontenot et al. 2011). Mortality submucosal gastric mural layers (Otjen et al.
rate is higher if there is a diagnostic delay (Ilce 2012) which may or may not have a muscular
et al. 2003) and if atresia contains a solid compo- component (de Vries et al. 2011; Ferguson et al.
nent (Fontenot et al. 2011). 2004). The antral web is usually 2–4 mm thick,
The presence of associated anomalies is an located 1–7 cm proximal to the pyloroduodenal
important factor for the reported high mortality junction (Chao et al. 2011; Otjen et al. 2012;
rate, exceeding 50% (Yu et al. 2009; Fontenot Tiao et al. 2005). In most of cases, it has a
et al. 2011). central or eccentric perforation, which may
EB is generally fatal because of fluid and pro- range from 2 to 30 mm in diameter; in a few
tein loss, electrolyte imbalance and sepsis cases, the web is unperforated or complete
(Al-Salem 2007; Bıçakcı et al. 2012). This is (Chao et al. 2011).
why some surgeons think that the association of
congenital PA and EB should preclude surgical
treatment of PA. However, recent advances in the Epidemiology
medical treatment of EB, with the use of steroids
and phenytoin, have been reported to give favor- This is a rare condition, whose prevalence is
able results (Parshotam et al. 2007). unknown; only sporadic cases are described in
Congenital PA in association with hereditary the literature.
multiple intestinal atresias (HMIA) is reported as
always fatal, the cause of death being sepsis in the
majority of cases (Al-Salem 2007; Cole et al. Etiopathogenesis
2010), particularly when HMIA is associated
with immunodeficiency (Cole et al. 2010; Bass The etiology is unknown.
2002). Awareness of the pathognomonic findings PAM is considered a congenital lesion
of HMIA in plain abdominal X-ray and US must resulting from a local redundancy of the endoder-
alert the surgeon of the severity of this condition, mal tube (Borgnon et al. 2003).
A report published in 1997 (Gahukamble Radiologic Findings

1998) describes multiple occurrence of this con- Plain abdominal films show a distended gas-filled
dition in a close family unit, suggesting the stomach (Borgnon et al. 2003).
hypothesis of a genetic etiology, with autosomal Ultrasound shows a fluid-filled, dilated stom-
recessive inheritance being the most probable ach (Chao et al. 2011), with very limited passage
mode of transmission. of gastric content from the stomach to the duode-
num, active gastric peristalsis but no increase of
the pyloric wall thickness or canal length
Diagnosis (Borgnon et al. 2003; de Vries et al. 2011);
Chew et al. (Chew et al. 1992) proposed four
Clinical Presentation ultrasound diagnostic criteria of an antral web,
This condition has been described in different including demonstration of an echogenic
ages, from premature and newborn infants to diaphragm-like structure in the antral region, gas-
adults (Chao et al. 2011). The age of onset tric dilatation, delay in gastric emptying, and a
and clinical presentation vary depending on normal pylorus.
the degree of obstruction determined by the A diagnosis can be established through a bar-
diaphragm – symptoms usually correlating ium meal study in most of cases (Chao et al. 2011;
with apertures of 1 cm or less (Otjen et al. de Vries et al. 2011), with a 90% sensitivity
2012; Tiao et al. 2005), with the consistency reported (Lui et al. 2000). Upper gastrointestinal
of ingested food and with the ability of the series demonstrate a dilated stomach with delayed
gastric motility to overcome the partial lumi- gastric emptying, sometimes revealing a trans-
nal web (Chao et al. 2011; de Vries et al. verse radiolucent line in the antral region
2011). (Borgnon et al. 2003) as well as a spraying of
A complete web presents with persistent barium through a central or an eccentric aperture
vomiting commencing shortly after birth, while with “jet stream” during examination (Chao et al.
incomplete antral membranes are usually diag- 2011; de Vries et al. 2011). A “double bulb” sign
nosed at an older age (3–11 years) and exception- has been described when a thicker membrane
ally in adults (Nissan et al. 1997; de Vries et al. mimics the pylorus, creating an antral chamber
2011; Lui et al. 2000). (Otjen et al. 2012).
The main symptoms are recurrent non-bilious Endoscopy is helpful in the diagnosis of PAM,
vomiting (Borgnon et al. 2003), often projectile in the detection of other gastric pathologies (e.g.,
(Noel et al. 2000), progressive feeding problems peptic diseases, adhesions) (Nissan et al. 1997; de
particularly for solid nutrition, epigastric pain Vries et al. 2011), and may also be a therapeutic
(sometimes presenting in infants with tool (Borgnon et al. 2003).
unexplained excessive crying (Noel et al. 2000)), However, in many cases, the definite diagnosis
and failure to thrive (de Vries et al. 2011; Feng is achieved only during surgical exploration
et al. 2005). Cases are described who became (Borgnon et al. 2003).
symptomatic after foreign body ingestion (Oak
et al. 1996).
Some authors described misleading presenta- Differential Diagnosis
tion of prepyloric web with prominent pulmonary The main entities in the differential diagnosis are
symptoms due to secondary gastroesophageal pyloric stenosis, pylorospasm, redundant gastric
reflux with probable recurrent aspiration pneumo- mucosal folds, perigastric adhesions, heterotopic
nias (de Vries et al. 2011). pancreas tissue (Borgnon et al. 2003; Lui et al.
Antral webs associated with hypertrophic 2000), irregular webs, and deformity of the antrus
pyloric stenosis, distal antral hypertrophy, or duo- suggesting acquired etiologies such as ulcer (Lui
denal atresia have been described (Ferguson et al. et al. 2000) and gastroesophageal reflux (de Vries
2004; Tiao et al. 2005). et al. 2011).
One case of intramuscular circumferential pre- obstruction, because of their potential unfavorable
pyloric fibrous band in the gastric wall causing prognosis.
partial obstruction and mimicking antral web has Barium meal and abdominal ultrasound are the
recently been described (Medsinge et al. 2012). most important tools in diagnosing these entities.
Symptoms may mimic duodenal ulcer (Nissan Because each condition has a different imaging
et al. 1997). appearance and diagnosis can be challenging,
experience with the use of these modalities and a
working differential diagnosis are important for a
timely diagnosis.
Treatment
While prepyloric antral diaphragm usually
has a less severe clinical presentation and a better
For antral diaphragm with gastric outlet obstruc-
outcome, PA can be associated with a variety of
tion, surgery is the treatment of choice (Chao et al.
associated conditions, particularly skin lesions,
2011; de Vries et al. 2011). It consists of incision
that can significantly increase morbidity and
or excision of the membrane by gastrostomy
mortality. Nevertheless, an early diagnosis can
(de Vries et al. 2011; Ferguson et al. 2004), with
often improve the outcome, and a better insight
or without associated pyloroplasty (Borgnon et al.
into the genetics and the immunologic aspects of
2003; Ferguson et al. 2004; Gahukamble 1998;
this condition will probably provide the basis for
Lui et al. 2000).
a more structured and widespread use of prenatal
An endoscopic balloon dilatation or transec-
diagnosis, for the implementation of immuno-
tion of the web can be performed (Borgnon et al.
modulatory therapies, and for the development
2003; Lui et al. 2000; Feng et al. 2005).
of molecular therapies.
Complications Cross-References
A reported complication of the surgical correction ▶ Anatomy of the Infant and Child
is pyloric scarring with subsequent pyloric stric- ▶ Colonic and Rectal Atresias
ture, which has been treated through endoscopic ▶ Duodenal Obstruction
procedures (Chao et al. 2011). ▶ Embryology of Congenital Malformations
▶ Fluid and Electrolyte Balance in Infants and
Outcome Children
▶ Infantile Hypertrophic Pyloric Stenosis
The prognosis is excellent (Nissan et al. 1997). ▶ Jejunoileal Atresia and Stenosis
Persistence of minimal feeding problems ▶ Prenatal Diagnosis of Congenital
because of the secondary atonic stomach can Malformations
occur, particularly in case of late diagnosis and ▶ Principles of Pediatric Surgical Imaging
treatment (de Vries et al. 2011). ▶ Sepsis
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Parsons LG, Barling S. Diseases of infancy and childhood. ated with distal antral hypertrophy and prepyloric ste-
London: Oxford Medical Publication; 1933. p. 739. nosis mimicking hypertrophic pyloric stenosis. World J
Polonkai E, Nagy A, Csízy I, Molnár C, Roszer T, Balla G, Gastroenterol. 2005;11(4):609–11.
Józsa T. Pyloric atresia associated with Dieulafoy Tomá P, Mengozzi E, Dell’Acqua A, Mattioli G, Pieroni G,
lesion and gastric dysmotility in a neonate. J Pediatr Fabrizzi G. Pyloric atresia: report of two cases (one
Surg. 2011;46(10):E19–23. associated with epidermolysis bullosa and one associ-
Salvestrini C, McGrath JA, Ozoemena L, Husain K, ated with multiple intestinal atresias). Pediatr Radiol.
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Thomson MA, Murch SH. Desquamative enteropathy Fukuzawa M. Prenatal diagnosis of isolated congenital
and pyloric atresia without skin disease caused by a pyloric atresia in a sibling. Pediatr Int. 2013;55
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2002;37(8):1223–4. Pediatr. 2010;36:3.
Infantile Hypertrophic Pyloric Stenosis
56
Takao Fujimoto
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Genetic Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Extrinsic Factors/Environmental Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 844
Clinical Presentation and Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 845
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
Preoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
Operative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 847
Nonoperative Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850
Prophylactic Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Postoperative Feeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Other Postoperative Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 852
Abstract the etiology of IHPS remains still obscure.

Infantile hypertrophic pyloric stenosis (IHPS) Genetic, environmental, and hormonal factors
is a common surgical condition encountered in have been implicated in the pathogenesis of
early infancy. Despite the extensive research, this condition. In terms of the pathophysiology,
abnormalities of smooth muscle cells, growth
factors, extracellular matrix, nerve and
T. Fujimoto (*) supporting systems, neurotransmitter, and
Department of Paediatric Surgery, Imperial Gift intestinal cell of Cajal have been also reported.
Foundation, Aiiku Maternal and Children’s Medical The incidence is approximately 1–5:1,000 with
Center, Tokyo, Japan
e-mail: takaosg@me.com a peak incidence of 2–8 weeks. Also,

https://doi.org/10.1007/978-3-662-43588-5_60
842 T. Fujimoto
epidemiologically, wide variations of inci- muscle. Elucidation of molecular background of

dence have been reported with geographic this condition may give a clear understanding of
location, season, and ethnic origin. Although the pathophysiology and possibly lead to identifi-
extramucosal pyloromyotomy is the procedure cation of environmental risk factors that may be
of choice, the best way to approach the pylorus target for preventive factors. This chapter pro-
is debated – conventional right upper quadrant vides update on IHPS, focused on epidemiology,
open procedure, transumbilical approach, and etiology, and pathophysiology including genetics,
more recently laparoscopic procedure. This pre- and postoperative care, various surgical tech-
chapter outlines the new insights into etiology niques, complications, and medical care.
and pathogenesis and also the important ele-
ments necessary to care for the patients in safe
and effective manner. Epidemiology
Keywords The incidence of IHPS has been reported to be

Hypertrophic pyloric stenosis · Epidemiology · approximately in 1–5 per 1,000 live births. How-
Etiology · Genetics · Environmental and ever epidemiologically, the incidence of IHPS
extrinsic factors · Diagnosis · Preoperative varies widely between different regions and coun-
care · Surgical technique · Postoperative care tries. IHPS prevalence varies by maternal race/
ethnicity. IHPS occurs in approximately 2–4 per
1,000 live births in the Western population,
Introduction whereas the incidence has been reported to be
approximately four times lower in the Southeast
Infantile hypertrophic pyloric stenosis (IHPS) is Asian and Chinese populations. Studies in the USA
well known, the most common surgical condition generally report higher prevalence of IHPS among
of vomiting in infants. The first clinical descrip- white non-Hispanic mothers, with significant lower
tion of IHPS was in 1627 by Fabricius Hildanus, prevalence of IHPS among non-Hispanic black
but it was subsequently more clearly defined at a mothers and Asian mothers (Ranells et al. 2011;
conference by Harold Hirschsprung in 1888. The Wang et al. 2008). Young maternal age also
pyloric muscle is hypertrophied, and the pyloric appears to be a risk factor, according to epidemio-
channel becomes narrow and elongated, causing logic data from European surveillance of congeni-
gastric outlet obstruction. Treatment is by tal anomalies (Pedersen et al. 2008), whereas
pyloromyotomy which was introduced a century McMahon shows that there is no consistent asso-
ago. Because advances in medical and surgical ciation between maternal age and IHPS
care have resulted in minimal mortality and mor- (MacMahon 2006). The risk of IHPS is strikingly
bidity, in modern times, pyloromyotomy has been four to five times more common in male than
considered a relatively minor surgical procedure. female infants. However the prevalence of IHPS
However, despite extensive research, the etiology seems to decline with increasing birth order. Thus
or causes of circular muscle hypertrophy is not first-born white male predominance on IHPS is
fully understood. The occurrence of IHPS has well documented (MacMahon 2006). Concordance
been thought to be associated several variables rate of 46% is reported in monozygotic twins com-
such as genetics and environmental and mechan- pared with 8% in dizygotic twins (Krogh et al.
ical factors. Pyloric sphincter function and motil- 2011). Recently, declining IHPS incidence has
ity is under a complex control system which been reported in Scotland, Sweden, the USA, Den-
involves the enteric nervous system and gastroin- mark, and Germany, but the reason of this evidence
testinal hormones, and smooth muscle cells have a is still obscure (Laffoklie et al. 2012).
close relationship and interact with extracellular Regarding to the prevalence of IHPS studies,
matrix proteins. One of these factors may be a interestingly, the most recent national report on
causative factor of abnormal hypertrophied prevalence of birth defects for 2003–2007 in the
56 Infantile Hypertrophic Pyloric Stenosis 843
USA shows state-level prevalence of IHPS rang- studies identified two candidates regions with sig-
ing by almost an order of magnitude, from 0.5 to nificant linkage on chromosome 2p24 and 7p
4.21 per 1,000 live birth (National Birth defect 22 and additional suggestive linkage on chromo-
Prevention Network 2010). Thus, it gave warning some 6p21 and 12 p24 (Svenningsson et al. 2012).
that the literature on descriptive epidemiology of However in terms of the genomic evaluation, fur-
IHPS seems enigmatic at first glance, a close look ther study must be needed to conclude the clear
at the data suggests that surveillance and ascer- relation and identification of responsible gene
tainment issues may account for much of the for IHPS.
reported validity. Although no definite specific gene has been
clearly identified as the cause of IHPS, genetic
syndrome, such as Smith-Lemli-Opitz, Cornelia
Etiology de Lange, and other chromosomal abnormalities
have been associated with IHPS.
Genetic Factor
Male gender and family history of IHPS are consis- Extrinsic Factors/Environmental
tently reported risk factors and suggest a genetic Factors
predisposition to the development of this condition.
Various genetic loci associated with IHPS have On the other hand, the changes in IHPS incidence
been identified. Nitric oxide is a major inhibitory reported in several countries indicate that environ-
neurotransmitter in the gut causing smooth muscle mental factors may be also important. Younger
relaxation. The synthesis of nitric oxide is catalyzed maternal age and maternal smoking are thought
by enzyme neuronal nitric oxide synthase (NOS) to influence the incidence of IHPS, but studies
coded by the NOS1 gene (IHPS1; chromosomal have been inconclusive. Parallels between breast
locus 12q24.2-q24.31). A mouse model with feeding and IHPS risk have been documented in
targeted disruption of NOS1 gene shows a pheno- various countries raising discussion about
type consistent with IHPS with a hypertrophic pylo- whether breast feeding protects or is a risk factor
ric muscle and distended stomach (Huang et al. of IHPS. Early exposures such as feeding prac-
1993). Also, in hypertrophic pyloric stenosis tissue, tices are thought to be important risk factor
the NOS1 gene expression has been found to be because symptoms usually do not arise until the
significantly reduced (Kusafuka and Puri 1997). second or third week after birth. Study in Nigeria
NOS1 gene has therefore been subject to extensive suggests that exclusive breast feeding was associ-
investigation in IHPS patients. NOS1 is to date the ated with reduced risk of IHPS, and study in
only gene reported with evidence as an IHPS sus- Denmark suggests that bottle-feeding had a 4.6-
ceptibility locus. Linkage to chromosome 16p12- fold increased risk of developing IHPS compared
p13 and 16q24 was found in two different large with infants who were not bottle-fed (Krohg et al.
Caucasian families with autosomal dominant inher- 2012). However this observation requires confir-
itance. However this could not be replicated in any mation with a larger population-based study that
other families of same ancestry investigated, indi- includes a control group. Also recently, relation or
cating locus heterogeneity of disease (Capon et al. common cause between IHPS and sudden infant
2006; Everett et al. 2008a). 11q14-q22 and Xq23- death syndrome (SIDS) was reported from Swe-
24 were identified via genome-wide linkage analy- den. The incidence of IHPS in Sweden from 1970
sis of families with two or more affected individual to 1997 has been reported to parallel the incidence
(Everett et al. 2008b). Recently rearranged during of SIDS. The prone sleeping position has been
transfection (RET) proto-oncogene located at suggested as possible risk factor given the fact
10q11.2 of which variants are seen in that it has been associated with increased risk of
Hirschsprung’s disease was reported to be respon- SIDS, and the launch of the “back to sleep” cam-
sible of IHPS (Serra et al. 2011). Recent Swedish paign to prevent SIDS has coincidence with the
844 T. Fujimoto
decline in the incidence of both IHPS and SIDS antropyloric canal is unable to accommodate the
(Persson et al. 2001). Thus prone sleeping may be redundant mucosa, which protrudes into gastric
an environmental risk factor for IHPS, which also antrum. These anatomical abnormalities cause
could account for lower occurrence of IHPS in obstruction to passage of gastric contents.
Asian people, who routinely place infants in According to the review by Panteli, the pyloric
supine position for sleep. It has been speculated sphincter contracts tonically and phasically to
that pooling of a feed in antrum, with prone sleep effect gastric emptying (Panteli 2009). Sphincter
position, may lead to dysmotility of stomach or function is controlled by a complex system
pylorus caused by effect on function of stomach involving the enteric nervous system, gastrointes-
and pylorus via proteins sensitive to change in tinal hormones, and intestinal cells of Cajal.
volume, pressure, or solute concentration. Abnormalities in hormonal control, extracellular
Pharmaceutical agents, hormones, and growth matrix, smooth muscle fibers, growth factors,
factors have also all been linked to IHPS through intestinal cells of Cajal, and pyloric innervations
small case reports. Especially erythromycin has have been implicated in the pathogenesis of IHPS.
been associated with an increased risk of IHPS Histologically, IHPS is characterized by thick-
(Murchison et al. 2016) as it acts as a motilin ened, hypertrophied, and edematous mucosa and
agonist and induces strong gastric and pyloric its relationship to the underlying hypertrophied
contractions that may eventually thought to lead musculature, primarily involving the circular
to hypertrophy of pylorus. Infants of mothers muscle.
exposed to erythromycin during lactation have Although the exact mechanism that leads to
been reported to be at a higher risk of IHPS muscle hypertrophy in IHPS is still obscure,
(Sorensen and Skriver 2003), while prenatal expo- there is evidence that the growth of smooth mus-
sure has not been found to be associated with an cle cell is regulated by various growth factors
increased risk (Cooper and Ray 2002). Although and/or neurological stimulations. Histochemical
neonates treated with erythromycin showed a ten- analysis using surgical samples revealed abnor-
fold increase in the incidence of IHPS (Mahon mal peptidergic innervation, abnormal distribu-
et al. 2001). Prostaglandins have also been impli- tion of nerve terminals and supporting cells,
cated as causative agent of IHPS. High level of altered nitric oxide production, and abnormal
prostaglandins has been found to be present in expression of various growth factors such as
infants with IHPS, which suggests a positive asso- insulin-like growth factor-1(IGF-1), platelet-
ciation (Shinohara and Shimizu 1998). The debate derived growth factor-BB, platelet-derived endo-
over a genetic or environmental origin of IHPS thelial cell growth factor, transforming growth
has not yet reached a final condition. Multifacto- factor –alpha, and epidermal growth factor.
rial background, such as genetic/environmental Among these growth factors, histochemical
interaction as the cause of this condition, is highly expression and in situ hybridization of IGF-1
suspected. have been extensively studied. It stimulates pro-
liferation and differentiation in many tissues and
acts as the mediator of most anabolic effects of
Pathophysiology growth hormone. Using histochemical analysis,
the expression of IGF-1 and its receptor in con-
The characteristic gross pathological feature in trols was either absent or weak as opposed to
IHPS consists of thickening of antropyloric por- increased expressions in the hypertrophied mus-
tion of the stomach (“olive-like mass”) and cle in IHPS patients. Intestinal cell Cajal are non-
crowding of redundant and edematous mucosa neuronal cells that form network alongside the
within the lumen. Abnormally circumferentially enteric nervous system and serve as electrical
thickened antropyloric muscle separates normally pacemakers and mediators of motor neurotrans-
distendable portion of antrum from the duodenal mission in the gastrointestinal tract. Ultrastruc-
cap. It stops abruptly at both ends. The rigid tural abnormalities of enteric nerves and
intestinal cells of Cajal are also reported. Extra- resting or sleeping to palpate the mobile enlarged
cellular matrix (ECM) molecules have character- pylorus or “olive.” In cases with adequate passage
istic patterns: chondroitin sulfate was markedly of gas through the pylorus, abdominal distension
increased, with smaller increases in fibronectin interferes with palpation of the enlarged pylorus.
and laminin. This constellation of abnormalities Aspiration using nasogastric tube facilitates the
leads to failure of pyloric motility and then successful palpation of an enlarged pylorus.
induced subsequent muscular hypertrophy. After the edge of the liver has been identified
with a fingertip, applied gentle pressure deep to
the liver and progress caudally reveals the
Clinical Presentation and Evaluation enlarged pylorus. In most cases, an enlarged pylo-
rus is located just above the umbilicus at the
Clinical Presentation lateral border of the rectal muscle below the liver
edge. Palpating the “olive” has a 99% positive
Babies of IHPS are commonly term infants who predictive value; however in recent times, there
are otherwise healthy. The usual onset of symp- has been a shift in practice methods with an
toms occurs between 2 and 8 weeks of age with increased emphasis on imaging for diagnosis. In
peak occurrence at 3–5 weeks of age. The infant a retrospective chart review, Macdessi and Oates
presents with non-bloody, non-bilious emesis, determined that over two study periods
which is often described as projectile in nature. (1974–1977 compared with 1988–1991), the inci-
However the clinical features vary with the length dence of palpable enlarged pylorus(“olive”) being
of the symptoms. Initially the vomiting may not reported decreased from 87% to 49%, whereas the
be frequent and forceful, but over several days, it use of ultrasonographic examination
progresses to every feeding and become forceful (US) increased 20–61% (Macdessi and Oates
non-bilious vomiting described as “projectile.” 1993). Regarding the visible peristaltic wave, it
The emesis consists of gastric contents, which would be easy to observe after test feeding in
may become blood tinged with protracted warm environment; however, this approach has
vomiting and likely related to gastritis, with “cof- unacceptably high false-positive and false-
fee-ground” appearance (17–18% of cases). negative rates and is not used extensively.
Infants with IHPS do not appear ill or febrile in The assessment of hydration status is also
early stage; however significant delay in diagnosis important. This can be judged by inquiring about
leads severe dehydration and weight loss due to the vomiting pattern and frequency as well as
inadequate fluid and calorie intake. Severe starva- assessing the fontanelles, mucous membranes,
tion can exacerbate diminished glucuronyl trans- and skin turgor.
ferase activity and jaundice associated with
indirect hyperbilirubinemia as seen in 2–5% of Diagnostic Imaging
infants with IHPS. Ultrasound imaging is usually used as a substitute
or complement to physical examination or test
feeds. Although imaging is more costly, it is
Evaluation highly sensitive, with accuracy and sensitivity
approaching 100% (Aspelund and Langer 2007;
Physical Examination NIedzielski et al. 2011; Iqbal et al. 2012). The
The diagnosis of IHPS is usually based on clinical examination should be performed with high-
history of projectile vomiting, visible gastric peri- frequency linear transducers operating between
staltic waves in left upper abdomen, and palpable 5 and 15 MHZ, adjusted to the size of infant and
enlarged pylorus (“olive-like mass”). It should be depth of the pylorus. Although the US is the
possible to diagnose IHPS on clinical features standard diagnostic procedure, the pylorus is dif-
alone in 80–90%. During examination, one must ficult to visualize in patients with gastric over-
take advantage of the time when the infant is distension because of displacement of the
846 T. Fujimoto
Fig. 1 Ultrasonography of pylorus in IHPS. (a) Longitudinal orientation: red arrow indicates hypertrophied pyloric
muscle, and yellow arrow shows “nipple sign.” (b) Cross section image
pylorus dorsally by the gas- or liquid-filled stom- diagnostic methods, current guidelines may not be
ach. This problem can usually be averted by turn- sufficient for accurate diagnosis of IHPS younger
ing the patient to a right lateral decubitus position, than 3 weeks because of the thin pyloric muscle
which causes the pylorus to rise to an anterior thickness (Leaphart et al. 2008). Young infants
position, thus allowing it to be imaged. In patients should be observed and reevaluated in 1 and
with IHPS, the muscle is hypertrophied to a var- 2 days when the lesion may be more clinically or
iable degree, and intervening mucosa is crowded, radiologically evident. In a hospital where US
thickened to a variable degree and protrudes into diagnosis for IHPS is not reliable or available,
the distended portion of the antrum (the nipple the Barium meal upper gastrointestinal (UGI)
sign) and can be seen filling the lumen on trans- study is a reliable alternative. The characteristic
verse section (Fig. 1a and b). The length of the radiological feature of IHPS is narrowed elon-
hypertrophic canal is variable and may range from gated pyloric canal giving “string” or “double
as little as 14 mm to more than 20 mm. The track” sign caused by compressed invaginated
numeric value of for the lower limit of muscle folds of mucosa in the pyloric canal (Fig. 2).
thickness has varied in literature, ranging between However, barium meal study provides indirect
3.0 mm and 4.5 mm. However currently a pyloric information about the antropyloric canal status.
muscle thickness of greater than 3 mm and pyloric Failure of relaxation of antropyloric lesion,
cannel length of 15 mm or more is accepted in known as pylorospasm, demonstrates the same
most centers (Hernaz-Schulman 2009; Malcom findings as those of IHPS. The emptying speed
et al. 2009; Indiran and Selvaraj 2016). Lowe of barium meal to the distal bowel will be impor-
et al. used a definition of pyloric ratio that is the tant to differentiate these two conditions.
pyloric wall thickness to a diameter. By their
definition, a ratio of 0.27 or more had high sensi- Blood Chemistry
tivity and specificity (96% and 94%, respectively) The increasing reliance on imaging studies has
for diagnosis of IHPS (Lowe et al. 1999). Border- resulted in diagnosis being made before serious
line cases are problematic, but repeating US sev- dehydration and alkalosis have developed. Serum
eral days later may confirm diagnosis. And in sodium, chloride, potassium, and bicarbonate
cases with severe dehydration occasionally dem- value should be obtained when establishing intra-
onstrate low measurement of muscle thickness, venous access. An abnormally low chloride and
which may increase after proper fluid administra- high bicarbonate level is characteristic findings of
tion. Despite the high specificity and sensitivity of a patients with IHPS.
antral web, preampullar duodenal stenosis, dupli-

cation cyst of antropyloric lesion, and ectopic
pancreatic tissue within an antropyloric muscle,
which are all less common than IHPS.
Management
Preoperative Management
Recurrent and persistent vomiting in these patients

results in hypochloremic, hopokalemic, and meta-
bolic alkalosis. Blood chemistries are evaluated for
chloride, bicarbonate, sodium, potassium, urea
Fig. 2 Barium meal study of IHPS narrowed elongated nitrogen, and hematocrit. After determining the
pyloric canal giving a “string sign” or “double track” sign state of dehydration, and acid-base abnormalities
caused by compressed invaginated fold of the mucosa in prompt establishment of venous access, and fluid
the pyloric canal (red arrow)
administration should be commenced. Infants cur-
rently present earlier, with corresponding reduc-
Table 1 Differential diagnosis of IHPS tions in frequency of metabolic disturbances and
Surgical conditions Medical conditions moderate to severe dehydration on admission.
Pylorospasm Gastroenteritis Although there are many algorithms in initial fluid
Gastroesophageal reflux Increased intracranial administration for the patients with IHPS on admis-
disease pressure sion, maintenance fluid with 5% dextrose in 0.45%
Gastric volvulus Metabolic disease
Antral web normal saline containing 20–40 mEq/L potassium
Preampullar duodenal stenosis chloride can be administered. Initial maintenance
Duplication cyst rate of fluid administration is depending on the
Ectopic pancreas within the dehydration status of the patients, and standard
pyloric muscle
initial fluid administration doses is 120–150% of
standard maintenance doses. An initial goal is 1 ml/
Differential Diagnosis kg/h to 2 ml/kg/h of urine output. Once acceptable
Several conditions must be considered if the urine output is obtained, decreasing the input of
patient demonstrates non-bilious vomiting. fluid administration to usual maintenance dose is
Table 1 gives the list of common differential diag- appropriate. It is relevant to confirm that blood
nosis. Patient with bilious vomiting is unlikely to electrolytes and bicarbonate returned to normal
be IHPS because of the hypertrophied pylorus prior to carry out the surgery. There has been a
preventing bile reflux. Pylorospasm and gastro- debate in terms of preoperative placement of the
esophageal reflux (GERD) give similar clinical nasogastric tube. Most infants with IHPS do not
findings and may be difficult to differentiate have complete gastric outlet obstruction and can
them from IHPS without further evaluations. tolerate their gastric secretion. A nasogastric tube
However, both conditions are more easily removes additional fluid and hydrochloric acid
excluded with US than UGI study using Barium from the stomach.
meal because of ability of the former to detect and
measure the antropyloric muscle thickness. Her-
niation of gastric fundus or regurgitation of gastric Operative Care
contents in patients with GERD can also be iden-
tified by ultrasonography. Other surgical causes of A nasogastric tube must be placed before induc-
non-bilious vomiting include gastric volvulus, tion of anesthesia, and it will be useful later for a
848 T. Fujimoto
leak test to ensure that the submucosa has not been gently retracted cephalad. The stomach is identi-
injured during the procedure. Fredet first fied and is grasped proximal to the pylorus with
described a full thickness incision of the pylorus noncrushing clamp and brought through the
followed by transverse closure in 1908. Ramstedt wound. Then the greater curvature of the stomach
modified the technique in 1912 and later described can be held in a moist gauze swab, and, with
extramucosal longitudinal splitting of the traction inferiorly and laterally, the pylorus can
pyloric muscle. Since then this extramucosal be delivered through the wound (Fig. 3a). Grasp-
pyloromyotomy has been the standard surgical ing the duodenum or pylorus directly by forceps
procedure of IHPS for more than 100 years. The often results in serosal laceration or perforation,
pyloric muscle is split longitudinally which therefore should be avoided.
allows the submucosal layer to bulge out to the The surgeon should then hold the pylorus
level of serosa and the stricture will be released. between the thumb and index finger to stabilized
Since Ramstedt introduced the longitudinal and assess the extent of hypertrophied muscle. A
pyloromyotomy in 1912, the treatment of IHPS seromuscular longitudinal incision is made over
has remained essentially the same; what has the avascular area of pylorus with a scalpel, com-
changed, however, is the way in which the abdo- mencing 1 ~ 2 mm proximal to the prepyloric vein
men is opened. Nowadays, there are three surgical along the gastric antrum. The incision should go
approaches to carry out extramucosal longitudinal far enough onto the gastric antrum at least
pyloromyotomy for IHPS: right upper abdominal 0.5 ~ 1.0 cm from the antropyloric junction
open, transumbilical, and laparoscopic. where the muscle is thin. At this point, scalpel
The right upper abdominal open pyloro- handle can be used to press down on the incision,
myotomy is performed by making a 2.5 ~ 3 cm essentially cracking the muscle such that the sub-
transverse incision on a normally lateral to the mucosa is seen. Then pyloric spreader is spread
lateral border of the rectus muscle. The incision widely. Spreader should be placed at midpoint of
is deepened through the subcutaneous tissue, and incision line, and the muscle is spread perpendic-
the underlying external oblique, internal oblique, ularly, and spreading is continued proximally and
and transverse muscles are split. The peritoneum distally. Loose prolapsing of intact mucosa is evi-
is opened transversely in the line of the incision. dence of a satisfactory myotomy (Fig. 3b). The
Once the abdomen is entered, the liver edge is anesthesiologist then inflates the stomach using
Fig. 3 Operative findings of hypertrophied pyloric lesion. Loose prolapsing of intact mucosa is evidence of satisfac-
(a) Hypertrophic antropyloric lesion is delivered through tory myotomy
the surgical wound. (b) After spreading the pyloric muscle.
nasogastric tube, and passage of air through the is set at 0.5 L/min. A 3 mm trocar is used in the
pylorus to duodenum is confirmed. This operative umbilicus along with 3 mm, 30 lens laparoscope.
approach and procedure is the most common, In the right midclavicular line just below the costal
reliable, and safe for junior pediatric surgeon margin (just above the liver edge), a #11 scalpel
who is not experienced in doing laparoscopic blade is used to make a 2–3 mm stab incision under
surgery in small infants. Pyloromyotomy has a direct vision. And also second stab incision is made
low intraoperative and postoperative complica- just below the costal margin in the left mid-
tion rate. The major complications following clavicular line in the same manner. An atraumatic
pyloromyotomy are wound infection, mucosal grasper is placed directly through the right upper
perforation, and inadequate pyloromyotomy. quadrant stab wound and is used to retract the
Mucosal perforation should be rare event, but if inferior border of the liver superiorly and expose
this occurred, myotomy site is reapproximated the hypertrophic pylorus. A retractable myotomy
and rotate the pylorus 180 and perform a new knife is inserted directly through the left stab
pyloromyotomy on the posterior wall. Another wound. Working ports are usually not necessary,
option to repair is that the submucosa of perfo- and instruments are directly introduced through
rated site is approximated using fine absorbable these stab wounds. The pyloromyotomy is
suture material, and then repair site is covered performed in a similar manner to open procedure,
with the omentum. and laparoscopic pyloric spreader is then used
Because it provides a better cosmetic appear- (Fig. 4a–d). Care must be taken at this stage that
ance, transumbilical approach has been suggested. this incision is deep enough to allow the insertion
This transumbilical approach was first described by of the pyloric spreader blades and must penetrate
Tan and Bianchi in 1986 (Tan and Bianchi 1986). the pyloric muscle somewhat deeper than is usual
Since then, various modification techniques with the conventional open procedure. Pushing the
through umbilical route approach have been spreader toward the mucosa or rapid spreading can
reported. In the transumbilical approach, a supra- result in mucosal tear. To test for the mucosal
umbilical incision is made around two-thirds of the injury, the stomach is inflated through nasogastric
circumference of umbilicus and carried down to the tube as is usually done in open techniques.
abdominal wall fascia with sharp dissection. The The approach to the pylorus to perform
midline fascia was exposed in a cephalad direction pyloromyotomy is still debated, and many authors
by undermining the epigastric skin. The peritoneal in recent years have compared these three
cavity is entered in the midline. Ordinary extra- approaches looking for the best, considering the
mucosal pyloromyotomy is then carried out either operative time, complication rates, length of post-
intracavitary (in situ pyloromyotomy) or extra- operative hospital stay, time to restart feeding, and
cavitary (delivering the pylorus through the umbil- cosmetic appearance (Hall et al. 2004; Leclair
ical incision) techniques. et al. 2007; Sola and Neville 2009; St Peter et al.
Since Alain et al. first described the laparo- 2006; St Peter and Osstli 2008). A recent meta-
scopic approach in 1991 (Alain et al. 1991), the analysis showed absolute incidence of major post-
laparoscopic pyloromyotomy becomes increasing operative complications of 4.9% in laparoscopic
popular in many centers. For laparoscopic group. Also this meta-analysis showed that lapa-
approach the patients are placed in the supine posi- roscopic procedure did not lead to significantly
tion at the end of operation table or 90 to the more major postoperative complications
anesthesiologist. The access site is injected with (ARR3%, 95%CI-3 to 8%) than open procedure.
local anesthetic with epinephrine, which reduced The mean difference in time to full feed was
the postoperative pain and risk of bleeding from the significant (2.27 h 95%CI-4.26 to -0.29 h), and
stab wound. The abdominal cavity is entered via the mean difference in postoperative hospital stay
the umbilicus using either the modified Hasson or tended to be shorter, both in favor of laparoscopic
Veress needle techniques. Intra-abdominal pressure approach (Oomen et al. 2012). Another meta-
is maintained at 8–12 mmHg, and insufflation rate analysis which is reported by Sola and Naville
850 T. Fujimoto
Fig. 4 Laparoscopic procedure for IHPS. (a) Laparo- pylorus. (c) The hypertrophied muscle is splitted with
scopic view of hypertrophic pylorus. (b) Laparoscopic laparoscopic spreader. (d) Prolapsing mucosa after pylorus
knife is used to make a seromuscular incision along the myotomy
demonstrates that laparoscopic approach has a with nonoperative medical treatment for
significantly lower incidence of wound infection, IHPS have been reported over the past
shorter postoperative stay, and decreased time 50 years. However, medical treatment with oral
to feeding. The incidence of inadequate pyloro- anticholinergic drugs such as atropine sulfate
myotomy ranged between 1.4% and 5.6%. There or methyl scopolamine nitrate has not worked
was no difference in rates of mucosal perforation consistently and been virtually abandoned
(Sola and Neville 2009). In terms of the operative since 1960. Recently, researchers from Japan
time, Kim et al. reported that the transumbilical have reviewed this medical treatment with
approach had the longest operative time, com- reports of a new methods using methyl
pared with laparoscopic and open procedures atropine nitrate intravenously (IV) and
(Kim et al. 2005). Hence, laparoscopic obtained successful results (Takeuchi et al.
pyloromyotomy may preferably be performed in 2013; Koike et al. 2013). Atropine is
centers with pediatric surgeons and anesthesiolo- administered intravenously at dose of
gists with experience in various laparoscopic 0.01 mg/kg six times a day, 5 min before
procedures. feeding. Recently, Takeuchi et al. reported that
overall success rate of IV atropine was 78.9%
(142/180) and concluded that atropine
Nonoperative Treatment therapy for IHPS should be reserved for
patients who are medically unfit to undergo
Although the extramucosal pyloromyotomy is general anesthesia and surgery (Takeuchi
the gold standard therapy for IHPS, many studies et al. 2013).
Prophylactic Antibiotics feedings in infants after pyloromyotomy, and the

advantages include the simplicity of the regimen
Antibiotic policy for pyloromyotomy highlights and the potential for earlier tolerance of full feed-
wide variation in clinical practice (Tan and ings and earlier discharge from the hospital
Bianchi 1986; Alain et al. 1991; Nour et al. (Adibe et al. 2007). Withholding feeds for a day
1996; Ladd et al. 2005). The efficacy of preoper- or 12 h decreased vomiting overall but will delay
ative antibiotics in preventing wound infections the infant who is ready to progress. The ultimate
after an open umbilical approach demonstrated goal of initiating early feeding is to achieve full
that their routine use reverted the wound infection feeds more quickly and therefore safely decrease
rate back to that which would be expected for a total hospital stay. Starting feeds shortly after
clean case (Ladd et al. 2005). Katz et al. recently recovery (earlier than 6 h postoperatively) is an
reported that the use of prophylactic antibiotics accepted method for feeding and allows most
does not significantly decrease the rate of wound infants to advance to full feedings without any
infection or other wound complications after lap- complications and risk.
aroscopic pyloromyotomy (Katz et al. 2011). In
relation to the postoperative use of prophylactic
antibiotics still remains a subject to debate, and Other Postoperative Considerations
nationwide survey or controlled study must be
needed. Postoperative Apnea
Most of the infants with IHPS are in the
2–10 weeks of age and have a risk of postopera-
Postoperative Feeding tive apnea because of their immaturity. The post-
operative apnea thought to persist until 52 weeks
There has been still debate in relation to the timing of postconceptional age. For this reason, the
of initiation of the enteral feeds following patients should be monitored using a cardiac and
pyloromyotomy. Some surgeons advocated a apnea monitor for at least 24 h postoperatively.
delay of 4 or more hours before starting oral
intake, followed by gradual and strictly Postoperative Emesis
regimented increase in the volume and concentra- Important aspect of the perioperative management
tion of the feeds (Schari and Leditschke 1968; of IHPS is to inform parents that vomiting after
Georgeson et al. 1993; Turnock and Rangercroft surgery is common, expected, and essentially
1991). Other reports recommend that early, full- harmless. In most cases, when pyloromyotomy
strength feeding may decrease the average length is adequate by intraoperative testing, vomiting
of hospital stay without increasing the risk of that occur postoperatively will be because of pylo-
postoperative emesis (Garza et al. 2002; Purapong ric and antral spasm and will resolve with contin-
et al. 2002). Also ongoing debate arises over ued feedings.
whether a physician chooses a standardized,
incremental feeding regimen versus an ad libitum
feeding schedule which allows the infant to decide Conclusion and Future Directions
when and how much to eat. Most recent reports
recommend early full-strength ad libitum feeding Hypertrophic pyloric stenosis is a well-known sur-
protocol (Sullivan et al. 2016; Markel et al. 2016). gical problem within a pediatric population and is
Infants are fed ad libitum full-strength breast milk easily diagnosis by US. When prompt diagnosis
or formula when they are in awake and alert after and proper resuscitation with adequate electrolytes
operation. This feeding regimen shortened hospi- replacement and volume administration are
tal stay and also resulted that frequency of post- performed, perioperative course is usually smooth.
operative emesis is not increased. They concluded Pyloromyotomy is the treatment of choice in most
that ad libitum feeds are a safe way to advance of Western countries, with the laparoscopic
852 T. Fujimoto
approach favored, because of shorter length of hos- chromosome 16p12-p13 and evidence of genetic hetero-
pital stay, superior cosmetic result, and rather lower geneity. Am J Hum Genet. 2006;79(2):378–82.
Cooper WO, Ray WA. Prenatal prescription of macrolide
incidence of complication rates. Recently natural antibiotics and infantile hypertrophied pyloric stenosis.
orifice transluminal endoscopic surgery (NOTES) Obstet Gynecol. 2002;100(1):101–6.
has gained attention for the treatment of IHPS, and Everett K, Chioza BA, Georgoula C, et al. Linkage of mono-
various experimental studies are performing at the genic infantile hypertrophic pyloric stenosis to chromo-
some 16p24. Eur J Hum Genet. 2008a;16(9):1151–4.
several institutions (Kawai et al. 2012). Future Everett KV, Chioza BA, Georgroula C, et al. Genome-wide
advance technology will make NOTES technique high-density SNP-based linkage analysis of infantile
clinically applicable shortly. Thus the clinical treat- hypertrophic pyloric stenosis identifies loci on chromo-
ment protocol seems to be already established and somes 11q14-q22 and Xq23. Am J Hum Genet.
2008b;82(3):756–62.
matured. Although genetic and environmental Garza JJ, Morash D, Dzakovic A, et al. Ad libitum feeding
research works have explored several potentially decreases hospital stay for neonates after
causative factors of the IHPS, pathogenesis of pyloromyotomy. J Pediatr Surg. 2002;37(3):493–5.
IHPS is still not yet fully understood. The debate Georgeson KE, Corbin TJ, Griffen JW, et al. An analysis of
feeding regimens after pyloromyotomy for hypertrophic
over a genetic or an environmental origin of IHPS pyloric stenosis. J Pediatr Surg. 1993;28(11):1478–80.
has not yet reached a final conclusion. A future Hall NJ, Van Der Zee J, Tan HL, et al. Meta-analysis of
combined study of genes and environmental factors laparoscopic versus open pyloromyotomy. Ann Surg.
in different populations including monozygotic and 2004;240(5):774–8.
Hernaz-Schulman M. Pyloric stenosis: role of imaging.
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should be focused on linkage analysis and next- tion of neuronal nitric oxide gene. Cell.
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Gastric Volvulus
57
Alan E. Mortell and David Coyle
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Abstract the gastroesophageal junction to the pylorus, or

Gastric volvulus (GV) is a rare surgical emer- mesenteroaxial volvulus, occurring perpendic-
gency, defined by the abnormal rotation of a ular to the longitudinal axis, such that the pylo-
part of the stomach around another part, lead- rus and antrum come to lie above the
ing to obstruction and, in some cases, tissue gastroesophageal junction. Associated contrib-
ischemia and necrosis. Anatomically, most utory diaphragmatic anomalies are common,
cases are either organoaxial volvulus, occur- especially in neonates, while splenic anomalies
ring along the stomach’s longitudinal axis from are also frequent.
GV may present as an acute or chronic
condition. The mode of presentation varies
depending on age. Neonates and infants may
A. E. Mortell (*)
Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland present with respiratory distress, non-bilious
vomiting, excessive salivation, and regurgita-
e-mail: alan.mortell1@gmail.com; alan.mortell@olchc.ie tion of feeds. Older children may present with
Borchardt’s triad of non-productive retching,
D. Coyle
e-mail: davidcoyle@rcsi.ie

https://doi.org/10.1007/978-3-662-43588-5_61
856 A. E. Mortell and D. Coyle
localized epigastric swelling, and failure to neurodevelopmental handicap and splenic

pass a nasogastric tube. abnormalities (McIntyre et al. 1994; Cribbs
Diagnosis relies on index of suspicion and et al. 2008). Both operative and nonoperative
is aided by plain radiography of the chest and management strategies have been described in
abdomen and upper gastrointestinal contrast the literature.
series to clarify the anatomical orientation of
the stomach. Suggestive plain radiography
findings include spherically distended stomach Etiology
with two air-fluid levels or a double
retrocardiac air-fluid level, as is the case with Gastric volvulus may be defined as an abnormal
intrathoracic GV. rotation of one part of the stomach around
In acute GV, surgery is the management of another; the degree of twist varies from 180 to
choice and involves correction of any con- 360 and is associated with closed loop obstruc-
tributory anatomical abnormalities such as tion and the risk of strangulation (Tanner 1968).
diaphragmatic hernia as well as fixation of Rotation of the stomach less than 1800 is termed
the stomach to the anterior abdominal wall gastric torsion, is probably common, and is fre-
with a gastrostomy and/or anterior quently asymptomatic. Such cases may be associ-
gastropexy. Minimally invasive approaches ated with transient vomiting in infants, but
are being more frequently employed to spontaneous resolution is the rule (Eek and
achieve these goals. Hagelsteen 1958).
Gastric volvulus classically may occur in two
Keywords planes – organoaxial or mesenteroaxial (Fig. 1).
Volvulus · Organoaxial · Mesenteroaxial · In organoaxial volvulus, rotation of the stomach
Nasogastric · Gastropexy · Gastrostomy occurs along its longitudinal axis from the gas-
troesophageal junction to the pylorus. In
mesenteroaxial volvulus, rotation occurs in a
Introduction
Gastric volvulus is a rare, potentially life-

threatening surgical emergency. It occurs when
part of the stomach rotates abnormally with
respect to another part of the stomach, leading
to closed loop gastric obstruction and, in some
cases, tissue ischemia and necrosis. It was first
described in adults by Berti in 1866 and in chil-
dren by Oltman in 1899 (Sivakumar 2008).
Since then, over 640 cases of acute and chronic
gastric volvulus in children have been described
in the literature. A comprehensive review of the
world literature in 2008 found that 21% of cases
presented in the neonatal period, 37% presented
between 1 and 12 months of age, while just 14% Fig. 1 Schematic representation of stomach showing axes
present between the ages of 6 and 18 years around which gastric volvulus occurs: Organoaxial volvu-
(Cribbs et al. 2008). Associated contributory lus happens due to anterior torsion around the axis joining
anomalies are common. Congenital or acquired the gastroesophageal junction and the antropyloric region.
Mesenteroaxial volvulus occurs about the axis perpendic-
defects in the diaphragm are the most commonly ular to this, leading to “upside-down” stomach, where the
reported anomalies, while gastric volvulus in pylorus and gastric antrum rotate anteriorly to lie about the
older children is frequently associated with level of the gastroesophageal junction
57 Gastric Volvulus 857
perpendicular plane, leading to the pylorus and Pathogenesis

antrum coming to lie superior to the gastro-
esophageal junction. The majority of patients The stomach is relatively fixed at the esophageal
present with organoaxial volvulus (54%) as hiatus and at the pyloroduodenal junction and is
opposed to mesenteroaxial volvulus (41%), also stabilized by four “ligamentous” attachments
while combined volvulus occurs in only approx- – the gastrohepatic, gastrosplenic, gastrocolic,
imately 2% of cases (Cribbs et al. 2008). A and gastrophrenic ligaments (Fig. 2). Despite
mixed or combined picture occurs if the stomach these attachments, considerable changes in shape
rotates around both axes simultaneously. The and position of the normal stomach are possible.
usual direction of rotation is anterior, i.e., in This is highlighted by the gastric rotation that can
organoaxial volvulus the greater curve moves sometimes be observed during air insufflation of
upward and forward above the lesser curve, the stomach at the time of laparoscopy-assisted
causing the posterior gastric wall to face anteri- percutaneous endoscopic gastrostomy insertion
orly. The gastroesophageal junction and the (Croaker and Najmaldin 1997). Absence or atten-
pylorus may both become obstructed. In anterior uation of the normal anatomical anchors results in
mesenteroaxial rotation, the antrum comes to lie abnormal gastric mobility, which may be encour-
anterosuperior to the fundus and obstruction is aged still further by a coexistent diaphragmatic
usually in the antropyloric region. Simultaneous defect and an intrathoracic stomach (Fig. 3).
torsion at both the gastroesophageal junction Most cases of gastric volvulus in the newborn
and the pyloroduodenal region has been are secondary to diaphragmatic defects with or
described and is termed a gastric bascule without deficient ligamentous attachments
(Menezes et al. 2010). (McDevitt 1970; Campbell 1979; Komuro et al.
Gastric volvulus may be acute and complete – 2005). The contribution of the gastrocolic and
the variety most often seen in infancy – or chronic gastrosplenic ligaments to fixation of the stomach
and partial, which is seen more commonly in older is demonstrated by the observation in the cadaver
children. While no study has set out to formally that their division allows 180 rotation of the
define risk factors for gastric volvulus, certain normal stomach (Dalgaard 1952).
congenital anomalies appear to have a contribu- In patients with diaphragmatic eventration or
tory role to its pathogenesis. Eventration or herni- herniation, the presumed mechanism of gastric
ation of the diaphragm is present in about
two-thirds of all children presenting with gastric
volvulus (Cribbs et al. 2008). However, this pro-
portion is as high as 80% in some series of infants
(Cole and Dickinson 1971). Diaphragmatic her-
nias are typically paraesophageal or posterolateral
defects, but gastric volvulus within a Morgagni
hernia is also possible (Estevao-Costa et al. 2000).
Abnormal upper gastrointestinal anatomy due to
midgut malrotation, dextrogastria, or previous
gastroesophageal surgery have been implicated
in its etiology, as has aberrant splenic anatomy,
such as wandering spleen and the asplenia syn-
drome (asplenism, congenital heart disease, with
or without intestinal malrotation, and deficiency
of the gastric ligaments) (Fung et al. 1990; Garcia
et al. 1994; Cribbs et al. 2008; Aga et al. 2010; Fig. 2 Anchoring gastric ligaments: A gastrophrenic liga-
Joshi and Parelkar 2010; Mitsunaga et al. 2011; ments, B gastrosplenic ligaments, C gastrocolic ligaments,
Mirza et al. 2012). D gastrohepatic ligaments
complication in 3 of 25 patients with asplenia,

the youngest of whom was 1 month of age
(Nakada et al. 1997). Anchoring gastric ligaments
were deficient in all cases. Because of the poten-
tially fatal outcome of acute gastric volvulus in
this situation, Okoye et al. have recommended
prophylactic gastropexy in all patients with
asplenia (Okoye et al. 1997). A review of gastric
malformations in patients with the asplenic syn-
drome by Mitsunagaet al. in 2011, which included
one case of gastric volvulus, described the hugely
variable anatomy encountered in this condition
(Mitsunaga et al. 2011). Defective fixation and
ligamentous laxity also account for the associa-
tion between gastric volvulus and a wandering
Fig. 3 Contrast study demonstrating intrathoracic stom- spleen (Garcia et al. 1994). Intestinal malrotation
ach due to paraesophageal hernia, a common predisposing is associated with gastric volvulus, even in the
factor in gastric volvulus absence of asplenia (Iko 1987; Nakada et al.
1997; Gerstle et al. 2009).
volvulus is upward displacement of the transverse Gastric volvulus in children may rarely arise as
colon, which pulls up the greater curve of the a postoperative complication. It has been
stomach into the expanded left upper quadrant. described after Nissen fundoplication, presum-
Dextrogastria may further facilitate this process ably because the stomach has been extensively
(Aga et al. 2010; Menezes et al. 2010). Acute mobilized by division of gastrosplenic and
gastric volvulus may therefore present as an gastrocolic attachments (Fung et al. 1990). It has
early complication of diaphragmatic defects. also been described in two cases postoperatively
Gastric distension may encourage the develop- for tracheoesophageal fistula/esophageal atresia
ment of gastric volvulus. Infantile hypertrophic repair with no associated deficiency of anchoring
pyloric stenosis may rarely be a predisposing fac- ligaments (Joshi and Parelkar 2010). There is one
tor, as has been reported in two cases. However, recorded case of gastric volvulus developing after
diaphragmatic defects were also present in both repair of a diaphragmatic hernia and another as an
cases (Moreno Torres 1968; Anagnostara et al. iatrogenic complication of gastric transposition in
2003). Air swallowing can also cause gastric dis- infancy (Starshak and Sty 1983; Chan and Saing
tension, and intermittent gastric volvulus has been 1996). Diaphragmatic trauma from blunt injury
reported in an aerophagic, neurologically due to falling and the Heimlich maneuver have
impaired child (Komuro et al. 2005). also been reported to have predisposed to gastric
Other rare causes of gastric volvulus in the volvulus in older children (Ragavan 2010;
neonate and infant include abnormal bands or Matharoo et al. 2013).
adhesions producing an axis of rotation for the
stomach (Cole and Dickinson 1971; Iko 1987;
Gerstle et al. 2009), rectal atresia with consequent Clinical Features
overdistension of the transverse colon (Mizrahi
et al. 1988), congenital absence or resection of The clinical features depend on the degree of
the left lobe of the liver which may promote rotation and obstruction. In adults, Borchardt’s
abnormal gastric mobility (Chuang et al. 1993; triad of (1) unproductive retching, (2) acute local-
Koh et al. 2008), and congenital deficiency of ized epigastric distension, and (3) inability to pass
the gastrocolic omentum (Odaka et al. 1999). a nasogastric tube is classically diagnostic of gas-
Nakada et al. reported gastric volvulus as a tric volvulus. In neonates and infants, however,
these features are not always present in combina-

tion, and symptoms and signs may be nonspecific,
such as vomiting (usually, but not exclusively,
non-bilious, depending on the degree of pyloric
obstruction), respiratory distress (especially in
those with an intrathoracic stomach), excessive
salivation, and persistent regurgitation of feeds,
similar to gastroesophageal reflux.
Hematemesis and anemia are well described,
and occasionally the vomiting is described as
projectile (Karabulut et al. 2009). Failure to thrive
and chest infections are sometimes evident (Sam-
uel et al. 1995). Upper abdominal pain and dis-
tension may be noted in older infants and children
in whom the stomach is not intrathoracic (Camp-
bell 1979; Starshak and Sty 1983).Difficulties in
the normal placement of a nasogastric tube may
provide evidence for the diagnosis; however, fail-
ure to pass a nasogastric tube may have several
causes in the newborn, such as tracheoesophageal Fig. 4 Classical appearance of a spherical gaseous gastric
fistula/esophageal atresia or esophageal perfora- bubble in an infant with gastric volvulus on plain radiog-
tion (Soylu et al. 2013). Additionally, successful raphy, with an abnormal appearance of the diaphragm
centrally to suggest a defect
passage of a nasogastric tube does not exclude the
diagnosis (Cole and Dickinson 1971; Cameron
et al. 1995). Findings that should raise suspicion may appear as a single large spherical gastric
of gastric volvulus however include arrest of the bubble with two air-fluid levels, one in the fundus
nasogastric tube in the distal esophagus and radio- and another in the antrum (Fig. 4). These findings
graphic abnormalities on routine films. Further may be absent if there has been prior decompres-
investigation with contrast studies is indicated in sion of the stomach with a nasogastric tube. A
this circumstance. Jaundice may be part of the paucity of distal bowel gas may be present in
presenting symptom complex if one lead point cases of acute volvulus complicated by gastric
for the volvulus involves the second part of the outlet obstruction (Oh et al. 2008).
duodenum (Menezes et al. 2010). In older chil- An upper gastrointestinal series can be diag-
dren, especially those with neurological impair- nostic and clarifies the anatomy (Fig. 5) and site
ment, presenting symptoms may be intermittent, (s) of obstruction, which is usually at the pylorus,
chronic, and nonspecific (Cameron et al. 1995). giving a so-called “beak” deformity (McDevitt
1970; Garel et al. 2016). The greater curvature
of the stomach is seen to lie superiorly to the lesser
Diagnosis curvature with an inferiorly directed pylorus in
organoaxial volvulus, while in mesenteroaxial
Diagnosis depends on a combination of clinical volvulus, the pylorus is seen to lie in overlap
index of suspicion and radiological imaging. Plain with either the gastroesophageal junction or the
abdominal and chest radiographs are essential fundus. Organoaxial volvulus, which may be par-
(Garel et al. 2016). Most will reveal a diaphrag- tial, is more difficult to diagnose on plain films
matic hernia or eventration if present and will (especially if there is no associated diaphragmatic
clarify if there is an intrathoracic stomach. A defect) and may indeed be missed during a con-
distended stomach in an abnormal position should trast study. A differential (double) retrocardiac
suggest the possibility of gastric volvulus. This fluid level has been described as a radiological
Fig. 5 Contrast study demonstrating intrathoracic gastric

volvulus: Note the absence of contrast flow into the duo-
denum and the upside-down appearance of the stomach, Fig. 6 Computed tomography demonstrating a diaphrag-
with the pylorus lying above the level of the gastroesoph- matic defect, with an intrathoracic spherical viscus
ageal junction consistent with mesenteroaxial gastric containing an air-fluid level. The relationship of the indi-
volvulus vidual structures to each other can be more easily seen
using this imaging modality
sign suggestive of intrathoracic gastric volvulus,
as distinct from a single retrocardiac fluid level support. Gastric decompression wherever possi-
seen in a sliding hiatus hernia (Scott et al. 1986). ble with a nasogastric tube should be attempted,
Cross-sectional imaging with computed although vigorous attempts to pass a tube must be
tomography (CT) or magnetic resonance imaging avoided because of a risk of gastric perforation,
(MRI) has been used in cases where gastric vol- especially in those suspected of ischemic necrosis
vulus was not diagnosed on plain films. However, (Cole and Dickinson 1971). Volume and electro-
it should not be necessary if an upper gastrointes- lyte repletion are mandatory during initial
tinal contrast study is performed. Additionally, it resuscitation.
is associated with a substantial radiation dose in Definitive surgical management for acute gas-
the case of CT, and may only serve to delay tric volvulus will depend on the contributory ana-
treatment, especially if sedation or anesthetic is tomical anomaly. Although the direct thoracic
required for scanning (Oh et al. 2008; Aga et al. approach has been described (Zaki et al. 2010),
2010). Both modalities can yield further informa- an abdominal approach is recommended, even
tion about structural abnormalities, such as when the stomach lies in the chest, since this
splenic position or absence (Fig. 6). allows identification of any associated gastroin-
testinal anomalies and accurate diaphragmatic
repair if required. Occasionally, preliminary nee-
Treatment dle aspiration of the stomach may be warranted
before manipulating a tensely dilated stomach and
Acute gastric volvulus, if untreated, can lead to reducing the volvulus (Asch and Sherman 1977).
ischemic necrosis, gastric perforation, and death. Any associated diaphragmatic defect should be
Infants and neonates can present with severe repaired. Excision of hernia sacs where present
respiratory distress, especially in the presence of should be attempted, and crural repair in those
a diaphragmatic defect, and initial preoperative with paraesophageal hernia should be undertaken.
resuscitative measures should include supplemen- Fixation of the stomach to the anterior abdominal
tary oxygen therapy and, where exhaustion due to wall may take several forms and should accom-
increased work of breathing is present, ventilation pany any surgery for gastric volvulus.
Gastrostomy alone may be used for gastric Okazaki et al. 2010). Laparoscopic gastropexy,
fixation in neonates, since it provides adequate which involves securing the anterior wall of the
fixation, postoperative decompression, and a reduced stomach to the peritoneum with non-
route for postoperative feeding. A Stamm absorbable sutures, can be combined with
gastrostomy using a 10 or 12 French gauge splenopexy in those with wandering spleen by fash-
Malecot catheter secured by a double purse string ioning an extraperitoneal pouch, within which the
absorbable suture is appropriate. In infants with spleen is secured by closure of the peritoneum,
no predisposing diaphragmatic defect, an anterior leaving space for the splenic vessels (Okazaki
gastropexy should be added to the gastrostomy et al. 2010). Splenopexy alone may be sufficient
procedure. This involves suturing the greater in gastric volvulus due to wandering spleen.
curve of the stomach to the parietal peritoneum
of the anterior abdominal wall and the under sur-
face of the diaphragm by a series of non- Complications
absorbable sutures. Low recurrence rates have
been reported with this procedure in the majority A number of well-described complications can
of cases, even when the gastrostomy was removed result from gastric volvulus including prolonged
after 2 weeks (Stephenson and Hopkins 1964; gastric ileus, gastric necrosis, and perforation
Colijn et al. 1993; Bawa et al. 2012). This (Gerstle et al. 2009). Following successful sur-
approach has also been successfully employed gical treatment, ischemic sequelae can include
for infants with associated diaphragmatic defects. lower esophageal stricture, gastric outlet
Fundoplication may be necessary if there is obstruction, and microgastria. This may lead to
evidence of gross gastroesophageal reflux, but sev- long-term dependence on gastrostomy or
eral authors have achieved good results in such jejunostomy feeding and ultimately a require-
cases with a crural repair alone, and a more con- ment for a stomach substitution procedure
servative approach is warranted provided the ten- (Kulkarni et al. 2011). Examples of stomach
dency to volvulus is prevented (Samuel et al. 1995; substitution procedures include the Hunt-
Stiefel et al. 2000). Diaphragmatic crural repair Lawrence J-pouch and the ileocecal pouch. The
must be performed meticulously, as there is often former procedure entails division of the proximal
a common hiatus for the esophagus and aorta in jejunum, formation of a J-pouch with the distal
these patients (Stiefel et al. 2000). There is no limb, followed by an esophageal-jejunal pouch
justification for gastroenterostomy or the colonic anastomosis, and anastomosis of the afferent
displacement operation described by Tanner in this limb of jejunum distal to the pouch with an
age group, and gastric resection should be limited end-to-side anastomosis to reestablish continuity
to those with grossly necrotic nonviable segments of the proximal jejunum with the small bowel. A
in all patients (Tanner 1968; Lal Meena et al. 2011). feeding jejunostomy should also be formed as
A Doppler probe can be used intraoperatively to part of this operation. Alternatively, an ileocecal
evaluate for restoration of gastric perfusion in cases pouch can be utilized, with the vermiform appen-
where viability is in doubt (Gerstle et al. 2009). dix brought out as a feeding stoma. Patients with
In 1993 Blair et al. gave one of the earliest such complicated clinical courses are susceptible
descriptions of laparoscopic-guided gastropexy, to malabsorption and, in particular, vitamin B
suggesting its suitability was limited to children deficiency, and their nutrition should be
with intermittent gastric volvulus with no underly- supplemented accordingly.
ing abnormality (Cameron and Blair 1993). This is The mortality from gastric volvulus is difficult
now probably the operative treatment of choice for to assess with series reporting mortality rates of
such patients (Odaka et al. 1999). The laparoscopic 7.1% in acute gastric volvulus compared to 2.7%
approach has been reportedly effective both in in chronic cases (Gerstle et al. 2009). One review
treating neonates and those with associated splenic of 581 cases found that 28% of all infants pre-
and diaphragmatic anomalies (Shah and Shah 2003; sented with acute gastric volvulus requiring life-
saving resuscitation, with a mortality of 6.9% majority will continue to be managed surgically.
within this group (Cribbs et al. 2008). Untreated, The laparoscopic approach is gaining favor, espe-
gastric volvulus has a mortality rate of up to 80%, cially in older children, as it provides excellent
highlighting the importance of prompt recogni- exposure of the structures in the epigastrium and
tion and treatment. Deaths have been reported left hypochondrium and yields a more favorable
due to missed or delayed diagnosis, with subse- cosmetic outcome when compared to a laparot-
quent gastric necrosis and perforation, or inade- omy scar. As availability and expertise with lapa-
quate gastric fixation (Cole and Dickinson 1971; roscopy increases, it is reasonable to expect the
McIntyre et al. 1994; Gerstle et al. 2009; Kulkarni trend toward its increased use in the treatment of
et al. 2011). gastric volvulus to continue.
Most recent series report uncomplicated early
outcomes after surgery. One long-term follow-up
study of nine infants demonstrated no recurrences Cross-References
or late complications (McIntyre et al. 1994). A
more recent series included ten cases, one of ▶ Access for Enteral Nutrition
whom expired owing to multi-organ failure and ▶ Congenital Diaphragmatic Hernia
polytrauma, while the remaining nine cases, of ▶ Surgical Problems of Children with Physical
which three were primary gastric volvulus, had Disabilities
no recurrence at a median follow-up of 4 years
(Mirza et al. 2012).
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Gastric Perforation
58
Adam C. Alder and Robert K. Minkes
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 867
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
Perioperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 868
Surgical Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 869
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 871
Abstract (25–50%). Typically there is a constellation

Neonatal gastric perforation is rare and life- of symptoms which can help identify this
threatening condition period and can be condition. These symptoms include fever,
associated with overdistension, gastric intu- sepsis, abdominal distension, hematemesis,
bation, ischemia, or idiopathic causes. Infants pneumoperitoneum, and respiratory failure.
with this complication have a high mortality Recognition of the symptoms allows preoper-
ative preparation including endotracheal
intubation for respiratory failure, volume
resuscitation, administration of antibiotics,
A. C. Alder
Division of Pediatric Surgery, Children’s Medical Center - and possible abdominal decompression. Tra-
Plano, Center for Pectus and Chest Wall Anomalies, ditional operative approaches and laparos-
Division of Pediatric Surgery, Children’s Health, copy have been employed to correct this
Department of Surgery, UTSW, Dallas, TX, USA
abnormality. Operative principles include
e-mail: adam.alder@childrens.com
control of spillage, debridement of devitalized
R. K. Minkes (*)
tissue, and multiple repair techniques. Future
Division of Pediatric Surgery, Golisano Children’s
Hospital Lee Health, Fort Myers, FL, USA investigation includes improvements in the
e-mail: robert.minkes@childrens.com understanding of the underlying causes of
https://doi.org/10.1007/978-3-662-43588-5_62
866 A. C. Alder and R. K. Minkes
idiopathic and spontaneous perforation, perforation (Leger et al. 1950). Survival following
improvement in prevention of the perforations a neonatal gastric perforation was rare prior to the
of known cause, and advancement of repair 1960s. While mortality has improved since that
techniques and approaches. time, it remains significant and ranges from 25%
to over 50% in most series (Rosser et al. 1982).
Keywords
Gastric perforation · Pneumoperitoneum ·
Stomach · Trauma · Ischemia Etiology
Gastric perforations in neonates can be broadly

Introduction categorized as spontaneous (idiopathic), ische-
mic, or traumatic; however in many instances,
Gastric perforation in the neonatal period is rare; the etiology may be multifactorial. Ischemia,
however, it continues to be associated with signif- necrosis, and perforation may occur with no obvi-
icant morbidity and mortality. Spontaneous neo- ous inciting factors (Pelizzo et al. 1998). Table 1
natal gastric perforation is estimated to occur in
1 in 2,900 live births (Rosser et al. 1982) and Table 1 Causes and associations of neonatal gastric
accounts for approximately 10–15% of all gastro- perforation
intestinal perforations in neonates and children. Idiopathic
Gastrointestinal perforations occur more com- Perinatal stress
monly in males; however, there appears to be no Hypoxia
sex predilection for those occurring in the stom- Asphyxia
ach (Bell 1985). Recent series may suggest a male Prematurity (Holgersen 1981; Tan et al. 1989)
predominance, but this remains inconclusive Anatomic defect
Distal obstruction
(Duran et al. 2007). The incidence of gastrointes-
Pyloric atresia (Burnett and Halpert 1947)
tinal perforation is increasing in some
Duodenal atresia (Holgersen 1981)
populations; however, the relative incidence of
Midgut volvulus (Miller 1957)
gastric perforation is decreasing (Terui et al.
Tracheoesophageal fistula (Othersen and Gregorie
2012). The terminology used to describe neonatal 1963; Bloom et al. 1990; Holcomb 1993; Maoate et al.
gastric perforation has been inconsistent, and its 1999; Reyes et al. 1989)
etiology remains a topic of debate. Spontaneous Congenital deficiency of gastric muscle
or idiopathic gastric perforations refer to those Iatrogenic
with no identifiable underlying cause and account Nasogastric tube (Graivier et al. 1973; Jawad et al.
for the majority of gastric perforations in most 2002)
Aggressive bag ventilation with or without
reported series (Rosser et al. 1982; Kara et al.
tracheoesophageal fistula (Othersen and Gregorie 1963;
2004). Nevertheless, many pediatric surgeons Grosfeld et al. 1996; Waltsad and Conklin 1961; Zamir
believe that an underlying cause can be found in et al. 1987)
most cases of neonatal gastric perforation (Leone Cardiopulmonary resuscitation (Bush et al. 1996;
and Krasna 2000). Custer et al. 1987; Im et al. 2005; St-Vil et al. 1992)
Siebold, in 1826, is credited with the first Positive pressure ventilation
description of a gastrointestinal perforation with Inadvertent perforation during surgery
(ventriculoperitoneal shunt) (Alonso-Vanegas et al.
no demonstrable cause, the so-called spontaneous 1994; Christoph et al. 1995)
perforation (Siebold 1826). In 1929, Stern et al. Vaginal delivery (Silbergleit and Berkas 1966; Leger
(1929) reported attempts at surgical repair. Agerty et al. 1950)
et al. reported the first successful repair of a neo- Medication
natal intestinal (ileum) perforation in 1943 Indomethacin (Gray and Pemberton 1980; Rajadurai
(Agerty et al. 1943), and Leger, in 1950, described and Yu 1991)
the first successful repair of a neonatal gastric Corticosteroids (O’Neil et al. 1992)
58 Gastric Perforation 867
lists several possible causes and associations with spontaneous gastric ulceration or perforation.
gastric perforations. Spontaneous gastric perfora- Pathologic specimens from non-necrotic portions
tions most often occur on the greater curvature of the stomach in six spontaneous gastric perfora-
(Rosser et al. 1982). Neonatal gastric perforation tion patients showed a decreased number of inter-
can occur in full term, premature, and small for stitial cells of Cajal (Jactel et al. 2013). In
gestational-age neonates. Some infants appear to addition, postmortem examination of stomachs
have been healthy and medically stable prior to of neonates, who died of idiopathic gastric perfo-
the development of the perforation, whereas ration, revealed a deficiency in both C-KIT+ mast
others have underlying medical conditions or con- cells and interstitial cells of Cajal when compared
genital anomalies. There are reports of intrauter- to controls. The authors suggest that these abnor-
ine gastric perforation with no known underlying malities could result in impaired immunity and
cause (Woo et al. 2006). Unrecognized over- abnormal motility predisposing to gastric perfora-
distension or ischemic insult may result in a per- tion (Yamataka et al. 1999).
foration that is thought to be spontaneous.
Ischemic perforations occur in the setting of phys-
iologic stress such as prematurity, asphyxia, sep- Clinical Presentation
sis, and necrotizing enterocolitis. The perforations
are often associated with ulcerations and ischemic The clinical presentation of gastric perforation is
tissue. Traumatic perforation results from pneu- variable. The majority of cases present within the
matic distension during mask ventilation, positive first 7 days of life; however, later presentations are
pressure ventilation, or iatrogenic injury during reported (Bell 1985). The neonates are often pre-
gastric intubation. Several specific causes of neo- mature or have a history of asphyxia or hypoxia
natal gastric perforation have been reported (Holgersen 1981). Neonates may present with
including intestinal atresias, prenatal stress, feeding intolerance or emesis that may contain
trauma, foreign bodies or bezoars, exposure to blood. Many develop abrupt onset of rapidly pro-
corticosteroids, and nonsteroidal anti- gressive abdominal distension from pneumo- or
inflammatory agents (Table 1). Several theories hydroperitoneum (Aydin et al. 2011). These
on the etiology of spontaneous (idiopathic) gastric infants progress to respiratory distress, hemody-
perforations have been suggested, but no single namic instability, and signs of shock such as hypo-
theory is universally accepted. Theories include thermia, cyanosis, poor peripheral perfusion, and
congenital absence of the gastric muscle low urine output. The abdomen may rapidly
(Braunstein 1954), forces exerted during vaginal become tense and tender with signs of peritoneal
delivery (Silbergleit and Berkas 1966), and pneu- irritation. Ventilation may be impaired or ineffec-
matic distension (Othersen and Gregorie 1963). tive until the abdomen is decompressed. Subcuta-
Studies in dogs and human neonatal cadavers neous emphysema in the abdominal wall or
suggest that rupture is caused by overdistension pneumoscrotum may be appreciated (Aslan et al.
and is in keeping with the law of Laplace (Shaw 1999). Infants with posterior perforations into the
et al. 1965). With gastric distension, the greatest lesser sac may present with a more insidious
wall tension is exerted on the fundus, the site of course, making the diagnosis difficult.
most spontaneous perforations. In addition, over- Infants with perforation secondary to an under-
distension can cause ischemic changes, a finding lying process often have evidence of the pre-
present in many cases of perforation (Touloukian disposing condition such as findings of
1973). tracheoesophageal fistula, duodenal atresia,
Recent studies suggest a deficiency of the tyro- malrotation, or diaphragmatic hernia (Holgersen
sine kinase receptor C-KIT+ mast cells, and a lack 1981). In some instances, a secondary cause is
of C-KIT+ interstitial cells of Cajal may contribute found at the time of operation. In cases of iatrogenic
to idiopathic gastric perforation (Ohshiro et al. perforation, a history of traumatic naso- or
2000). Mice lacking C-KIT+ mast cells develop orogastric intubation, prior surgery, corticosteroid
or nonsteroidal administration, and aggressive ven-

tilation or cardiopulmonary resuscitation may be
obtained (Graivier et al. 1973).
Diagnosis
The diagnosis of gastric perforation is made from

the clinical history, physical examination, and
radiographic studies. In infants with massive
pneumoperitoneum, a plain abdominal radiograph
will demonstrate air under the diaphragm that
extends laterally, trapping the abdominal viscera
medially and producing a saddlebag appearance
(Houck and Griffin 1981). The stomach is not
visualized by plain radiograph in 90% of cases
(Pochaczevsky and Bryk 1972). Other plain
radiograph findings include subcutaneous emphy-
sema, pneumoscrotum, ascites, or an oro- or naso-
gastric tube outside the confines of the stomach. A
definitive diagnosis may not be made prior to
laparotomy. A water-soluble contrast study will
reveal extravasation from the stomach into the
peritoneal cavity (Fig. 1). Ultrasound may show
ascites or fluid collections. In premature infants Fig. 1 Diagnosis. Abdominal distension, pneumoperitone-
um seen on these two view films of the abdomen. (a) Note
with known lung disease, pneumoperitoneum can the lucency over the liver. (b) Pneumoperitoneum becomes
result from air tracking from the mediastinum. A much clearer on the lateral decubitus film. There is no
chest film demonstrating pneumomediastinum, an evidence of lung disease and no findings suggestive of
air–fluid level in the stomach, a negative perito- enterocolitis
neal aspirate, and an intraperitoneal drain that
bubbles with the ventilator cycle can help to syndrome, imperforate anus, perforated viscus,
exclude an intra-abdominal process. necrotizing enterocolitis, and midgut volvulus.
Differential Diagnosis Perioperative Care
The differential diagnosis is broad and includes Infants with gastric perforation develop septic
conditions that cause sudden deterioration in the parameters and need to be resuscitated accord-
newborn and conditions that produce vomiting ingly. Neonates may become unstable prior to
and abdominal distension. Conditions causing the development of free intra-abdominal air.
cardiovascular collapse include sepsis, pneumo- Infants who develop respiratory distress require
thorax, cardiac dysfunction, intraventricular hem- intubation, and increased ventilator support is
orrhage, electrolyte abnormalities, hypoglycemia, needed as the abdomen becomes more distended.
necrotizing enterocolitis, perforated viscus, and Appropriate laboratory investigations include
malrotation with midgut volvulus. Conditions blood cultures, white blood cell count, hemoglo-
associated with vomiting and abdominal disten- bin, hematocrit, platelet count, electrolyte profile,
sion include Hirschsprung’s disease, intestinal and blood gas analysis. Broad-spectrum antibi-
atresia, meconium ileus, meconium plug otics should be initiated. Fluid boluses and blood
transfusions are given to achieve hemodynamic umbilical vein is divided. The incision can be
stability and adequate urine output. An oro- or extended as needed. Peritoneal fluid and debris
nasogastric tube should be carefully passed and are evacuated. The abdomen is explored for the
placed on low intermittent suction. Once free, site of perforation. When a perforation of the
intra-abdominal air is identified, the patient is stomach is not found, careful exploration of the
stabilized, and a laparotomy should be performed. gastroesophageal junction, duodenum, small
Aspiration of the peritoneum with an IV cannula bowel, and colon should be performed. The lesser
when an overly distended abdomen is impeding sac should be opened and inspected for contami-
ventilation can be a life-saving measure nation and integrity of the posterior surface of the
(Touloukian 1973). In select cases, peritoneal stomach.
drainage has been reported with resolution of the The most common site of a spontaneous perfo-
peritonitis and healing of the perforation (Aydin ration is near the greater curvature. Yang et al.
et al. 2015). (Yang et al. 2018) reported that the site of gastric
perforation among the 68 patients was greater cur-
vature in 50 (73.5%) neonates, lesser curvature in
Surgical Technique 12 (17.6%) and unspecified in 6 (8.9%). The per-
foration can be small or extensive and extend high
Traditionally, open exploration and repair are on the stomach. For isolated perforations, the
required. Recently, successful laparoscopic repair devitalized edges of the perforation are debrided
of neonatal gastric perforation has been reported back to viable tissue (Fig. 3). The defect is closed in
(Gluer et al. 2006). For an open repair, an upper one or two layers and may be reinforced with an
abdominal transverse skin incision (Fig. 2) is omental patch (Fig. 4). Stapled closure of a perfo-
made and dissection carried through the rectus ration and repair around a gastrotomy tube have
muscle until the peritoneum is entered. The also been successful. A variety of techniques have
been used to manage extensive perforations or
necrosis that requires subtotal or total gastrectomy.
In a stable infant, subtotal gastrectomy can be
performed with reconstruction and esophagogastric
anastomosis (Bilik et al. 1990). Several techniques
for reconstruction after total gastrectomy have been
reported including transverse colon interposition,
Roux-en-Y esophagojejunal anastomosis, and
Hunt-Lawrence pouch reconstruction (Duran
et al. 2007). Reconstruction following total gastrec-
tomy in an unstable neonate can be delayed and
performed at a later stage.
Following repair of the perforation, the abdo-
men is lavaged with warm saline. Peritoneal
drainage is not needed for most primary repairs
and has not been shown to reduce postoperative
complications but is used routinely by some sur-
geons. The fascia and skin are closed in standard
fashions. Postoperatively, supportive and resusci-
tative care is continued. The child is maintained
on broad spectrum antibiotics, gastric acid sup-
pression therapy, and total parenteral nutrition.
Fig. 2 Incision. Upper abdominal transverse skin inci-
sion. The incision can be enlarged to gain access to the The stomach should be decompressed. Feedings
entire abdomen are held until the infant has stabilized. Many
Fig. 3 Exposure and

resection. The entire
perforation is exposed. A
variable area of the stomach
is found to be devitalized or
necrotic. The edges of the
perforation are resected
back to bleeding viable
tissue. On rare occasions,
extensive resection,
subtotal, or total
gastrectomy are required
Fig. 4 Closure. The free

edges of healthy tissue are
closed in one (depicted) or
two layers. An omental
patch may be used. Careful
inspection of the posterior
wall of the stomach and the
entire small and large bowel
should be performed to
exclude additional areas of
necrosis
surgeons obtain a contrast study prior to initiating prematurity, with the mortality being significantly
enteral feeds. higher in preterm neonates.
The surgical management of gastric perfora-
tion in neonates has remained largely unchanged.
However, the overall mortality is changing. Yang Conclusion and Future Directions
et al. (Yang et al. 2018) reported results in the
largest cohort of neonatal perforations in 68 Gastric perforation in the newborn is a rare event,
patients and found that the overall mortality had but with early recognition, appropriate care and
decreased from 100% during 1980–1989 to 16% adherence to principles of surgical management
during 2010–2016. Similarly, a Japanese study survival can be maximized. Causes of gastric per-
showed a mortality rate of 14% among 42 neo- foration may be multiple including idiopathic
nates with gastric perforations (Sato et al. 2017). and spontaneous perforation. Recognition of
Chen et al. (Chen et al. 2018) reviewed 168 cases the patterns of symptoms related to gastric perfo-
of gastric perforation in the newborn and reported ration will aid in identification of this rare clinical
that the single most prognostic factor was condition. Careful attention to preoperative
preparation will aid in a successful repair. Opera- ▶ Jejunoileal Atresia and Stenosis
tive principles include control of spill of the lumi- ▶ Necrotizing Enterocolitis
nal contents, debridement of devitalized tissue, ▶ Pyloric Atresia and Prepyloric Antral
and closure of the defect. Postoperative care Diaphragm
includes supportive measures, broad spectrum ▶ Specific Risks for the Preterm Infant
antibiotics, and gastric acid suppression. Nutrition
plays a key role in healing with TPN until the
stomach is healed. Contrast study of the stomach References
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Duodenal Obstruction
59
Yechiel Sweed and Alon Yulevich
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 876
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 877
Associated Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
Prenatal Diagnosis/History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
Clinical Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
Preoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
Operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
Incision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
Exploration and Identification of Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
“Diamond-Shaped” Duodenoduodenostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 885
Side-to-Side Duodenoduodenostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
Operative Technique for Duodenal Web . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 886
Laparoscopic Management of DO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 888
Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 889
Management of Persistent Megaduodenum by Duodenoplasty . . . . . . . . . . . . . . . . . . . . 889
Outcome and Long-Term Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 890
Y. Sweed (*)
Department of Pediatric Surgery, Galilee Medical Center,
Azrieli Faculty of Medicine, Bar-Ilan University, Safed,
Israel
e-mail: yechiels@gmc.gov.il
A. Yulevich
Department of Pediatric Surgery, Galilee Medical Center,
Bar-Ilan University, Safed, Israel
e-mail: AlonY@gmc.gov.il

https://doi.org/10.1007/978-3-662-43588-5_63
876 Y. Sweed and A. Yulevich

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 891
The duodenum is the most common site of
neonatal intestinal obstruction, accounting for Congenital DO is the most common cause of
50% of all intestinal atresias. Duodenal intestinal obstruction in the newborn period,
obstruction (DO) is often complicated by pre- occurring in 1 per 5000–10,000 live births (Best
maturity and associated anomalies. Early pre- et al. 2012; Choudhry et al. 2009; Haeusler et al.
natal ultrasonographic diagnosis of DO allows 2002; Rattan et al. 2016). DO is the result of
the mother karyotype analysis for trisomy intrinsic lesion, extrinsic lesion, or a combination
21 and other associated anomalies. Cardiac of both. These pathological lesions can cause
malformations are the major cause of morbidity complete or incomplete obstruction. Intrinsic DO
and mortality in patients with congenital DO. may be caused by duodenal atresia, stenosis, dia-
For most causes of congenital DOs, phragm, a perforated diaphragm, or a “wind-
duodenoduodenostomy via an open approach sock” web. The “wind-sock” web is a duodenal
is the preferred surgical procedure. Vidal from membrane which is ballooned distally as a result
France and Ernst from the Netherlands are of peristalsis from above (Norton et al. 1992;
credited with the first successful repairs in Rowe et al. 1968). Extrinsic DO may be caused
1905 and 1914, respectively. Over the last by annular pancreas, malrotation, or preduodenal
decade, the application of minimally invasive portal vein (Rattan et al. 2016). Although the
surgical techniques (MIS) and the advent of annular pancreas forms a constricting ring around
smaller laparoscopic instruments have the second part of the duodenum (Fig. 1), it is not
expanded the potential of laparoscopy for believed to be the cause of DO (Elliott et al. 1968;
repair of congenital DO. The first reported Escobar et al. 2004), and there is usually an asso-
laparoscopic repairs of duodenal atresia were ciated atresia or stenosis in patients with an
by Bax in 2001 and Rothenberg in 2002.
The last retrospective studies comparing the
surgical outcome of laparoscopic repair versus
open repair found that laparoscopy is a safe and
effective technique, and the results including
operative time, length of stay, time to full feed-
ing, and complication rate were similar in both
groups. The long-term survival rate of patients
with DO is excellent and greater than 95%
resulting from an early surgical intervention
combined with advancement in neonatal inten-
sive care, anesthesia, and nutritional support.
Keywords
Duodenum · Obstruction · Duodenal atresia · Fig. 1 Duodenal obstruction caused by an annular pan-
Down syndrome · Malrotation · creas associated with duodenal stenosis in a postmortem of
Duodenoduodenostomy · Duodenal web · a 14-week-old fetus with a diagnosis of Down syndrome.
ST stomach, DU duodenum, AP annular pancreas (Sweed
Laparoscopy · Endoscopy · Associated 2009). (The picture added with the courtesy of Prof.
anomaly · Ultrasound Bronshtein Moshe)
59 Duodenal Obstruction 877
annular pancreas (Girvan and Stephens 1974; “wind-sock” web (Fig. 3g), and an annular pan-
Grosfeld et al. 1979; Papandreou et al. 2004). creas (Fig. 3h).
Similarly, preduodenal portal vein has also sel-
dom been reported to be the cause of DO, and it
is often associated with other causes of intestinal Etiology
obstruction such as malrotation or duodenal atre-
sia (Kouwenberg et al. 2008; Singal et al. 2009; The underlying cause of duodenal atresia remains
Srivastava et al. 2016). Duodenal atresias have unknown although its pathophysiology has been
been classified into three types: type I bowel con- well described. Frequent association of duodenal
tinuity but with luminal obstruction or stenosis, atresia or stenosis with other neonatal
type II bowel discontinuity with a connecting malformations suggests that both anomalies are
bridge of tissue, and type III complete separation due to a developmental error in the early period of
with a mesenteric defect (Fig. 2) (Skandalakis and gestation. Tandler (1900) theorized that duode-
Gray 1994). The reported prevalence of type I is num is a solid cord during early development,
about 92%, type II is 1%, and type III is 7% secondary to exuberant epithelial growth, and
(Applebaum et al. 2006). Duodenal stenosis is lumen is formed by vacuoles which coalesce.
approximately half as prevalent as atresia (Dalla Further, he suggested that duodenal atresia results
Vecchia et al. 1998). from the failure of the solid cord to recanalize.
The obstruction of the duodenum usually Merrot et al. (2006) were the first investigators to
occurs distal to the ampulla of Vater. Pre-ampul- counter the “recanalization theory,” asserting that
lary obstruction is much less common, occurring it failed to explain the different morphological
in about 20% of cases (Knechtle and Filston types and other variability seen in patients with
1990). Occasionally there may be a bifid termina- duodenal atresia (Teague et al. 2018). Duodenal
tion of the bile duct with one limb of the duct atresia differs from other atresias of the small and
system opening into the duodenum above the large bowel, which are isolated anomalies caused
atresia and one below (Komuro et al. 2011; Reid by mesenteric vascular accidents during later
1973). stages of development (Jejuno-Ileal Atresia and
Figure 3 shows the wide spectrum of various Stenosis Essay 367,705 84/84). This theory of
types of DO. The proximal and distal segments of vascular disturbance was presented by the classic
the duodenum may be separated by a gap study of Lauw and Barnard (1955).
(Fig. 3a), be in apposition (Fig. 3b), or be joined No predisposing maternal risk factors are
by a fibrous cord (Fig. 3c). Other types include known. Although up to one third of patients with
duodenal stenosis (Fig. 3d), complete diaphragm duodenal atresia have Down syndrome (trisomy
(Fig. 3e), a perforated diaphragm (Fig. 3f), a 21), it is not an independent risk factor for
Fig. 2 Types of duodenal atresia (by Grays and artretic ends of duodenum), (c) type III (a complete sepa-
Skandalakis). (a) Type I (mucosal membrane with intact ration of the artretic ends with a mesenteric defect
muscle wall), (b) type II (fibrous cord connecting the two
(a) (b) (c) (d)
(e) (f) (g) (h)
Fig. 3 Various types of duodenal obstruction. (a) Blind (g) “Wind-sock” web. (h) Annular pancreas. (As appeared
ends separated by a gap. (b) Two ends in apposition. (c) in Fig. 49.10, page 474 of the textbook “Newborn Surgery”
Ends joined by a fibrous cord. (d) Duodenal stenosis. (e) 3rd ed. by Puri P, Sweed 2011)
Complete duodenal membrane. (f) Perforated diaphragm.
developing duodenal atresia (Applebaum et al. recently on a new familial case of annular pan-
2006). In the large California population-based creas and found one microduplication on chromo-
registry of 2.5 million infants, the risk of duodenal some 6q24 by array-based comparative genomic
atresia was found to be 265 times higher in infants hybridization (CGH) shared by the affected
with Down syndrome compared to those without mother and son (Markljung et al. 2012). This
it, and the corresponding frequencies were 46 and microduplication may be a causative aberration
0.12 per 1000 births (Torfs and Christianson or present a risk factor for the development of
1998). The association between duodenal atresia annular pancreas and duodenal atresia.
and Down syndrome suggests an underlying
genetic etiology. In mice, interruption of fibroblast
growth factor 10 (FGF10) gene signaling results Associated Malformations
in duodenal atresia in 30–50% of embryos
supporting genetic etiology (Teague et al. 2018). There is a high incidence (approximately 50%) of
Although DO is usually not regarded as a associated anomalies in patients with intrinsic
familial condition, there have been several reports DO, especially Down syndrome which occurs in
of familial cases (Gahukamble et al. 1994; Gross about 30% of these patients (Sweed 2011; Puri
et al. 1996; Markljung et al. 2012; Okti et al. 1981; Young and Wilkinson 1968).
2005) and a very rare group of hereditary multiple Table 1 presents the overall prevalence and
intestinal atresias with fatal outcome (Lambrecht distribution of associated anomalies of duodenal
and Kluth 1998). Markljung et al. reported atresia. The data are the collected statistics of
Table 1 The incidence of associated congenital anoma- 2008). The mortality rate is even higher in neo-
lies (%) (Collected statistics) (N = 1759 patients). (Data nates born with three or more anomalies of the
from Sweed 2009)
VACTERL association with an overall survival
Associated anomaly % rate of 40–77% (Iuchtman et al. 1992; Muraji
Down syndrome 28.2 and Mahour 1984; Weber et al. 1980). Spitz and
Annular pancreas 23.1 colleagues reported the combination of esopha-
Congenital heart disease 22.6
geal and duodenal atresias as particularly lethal,
Malrotation 19.7
with mortality rates ranging from 67% to 94% in
Esophageal atresia and tracheoesophageal fistula 8.5
various series (Spitz et al. 1981). Jackson et al.
Genitourinary 8.0
inferred that the majority of these deaths are
Anorectal 4.4
Other bowel atresia 3.5
caused by failure to recognize the second abnor-
Others 10.9 mality preoperatively (Jackson et al. 1983).
1759 patients with DO from a dozen large series Prenatal Diagnosis/History

(Sweed 2011). The associated anomalies in order
of frequency are Down syndrome (28%), annular Maternal polyhydramnios has been reported to be
pancreas (23%), congenital heart disease (22.6%), present in 17–75% of cases of duodenal atresia
malrotation (20%), esophageal atresia (8.5%), gen- (Cohen-Overbeek et al. 2008; Hancock and Wise-
itourinary malformations (8%), anorectal anoma- man 1989; Murshed et al. 1999) and is the most
lies (4.4%), and other bowel atresias (3.5%). common ultrasonographic finding in fetuses with
Vertebral anomalies were reported to range intrinsic DO (Irving 1990). Ultrasound is usually
between 2% (Bailey et al. 1993) and 37% (Atwell performed for suspected fetal or maternal abnor-
and Klidkjian 1982) in these patients. Reports of malities when polyhydramnios or a large-for-date
duodenal atresia have also shown a low incidence pregnancy is established. Although the majority
of musculoskeletal anomalies (Pulkkinen et al. of cases are diagnosed during the seventh or eighth
1997). month of gestation (Bronshtein et al. 2008), sono-
Other rare anomalies include Cornelia de Lange graphic detection of duodenal atresia was reported
syndrome (Bailey et al. 1993), chromosomal as early as 12 gestational weeks by Tsukerman
abnormalities (Sweed 2011), multiple intestinal et al. (1993) and 19 weeks by Romero (1988).
abnormalities (Morikawa et al. 2009), choledochal There has been an increase in prenatal ultraso-
cyst (Iwai et al. 2009; Sugimoto et al. 2004), immu- nographic diagnosis of duodenal atresia during
nodeficiency (Moore et al. 1996), tracheomalacia the last three decades, from 14% between the
(Kimble et al. 1997), and situs inversus (Nawaz years 1972 and 1991 (Grosfeld and Rescorla
et al. 2005). 1993) to 18% (Akhtar and Guiney 1992) to the
The complex cardiac anomalies among all high rate of 57% for the period of 1991–1995
other associated malformations are the major (Murshed et al. 1999).
cause of morbidity and mortality in patients with The prenatal sonographic diagnosis relies on
duodenal atresia (Choudhry et al. 2009; Dalla the demonstration of the “double bubble” sign,
Vecchia et al. 1998; Escobar et al. 2004; Piper which is due to simultaneous distension of the
et al. 2008). Dalla Vecchia et al. attributed all the stomach and the first part of the duodenum
operative mortality (4%) to associated complex (Fig. 4). In many cases this sonographic sign is
congenital heart anomalies in a group of observed in the second half of pregnancy proba-
138 patients with DO in a 25-year survey. Two bly due to hydrostatic pressure needed to dilate the
other important factors affecting higher morbidity duodenum and also to the degree of the DO.
and mortality of these patients are prematurity and Visualization of a fluid-filled double bubble
low birth weight (Escobar et al. 2004; Gourevitch (Fig. 4) on prenatal ultrasound scan is associated
1971; Hancock and Wiseman 1989; Piper et al. with DO secondary to intrinsic or extrinsic lesion.
(corresponding with the tissue of annular pan-

creas) (Dankovcik et al. 2008).
Hancock and Wiseman investigated the impact
of antenatal diagnosis of congenital DO in a series
of 34 infants, 15 of whom were diagnosed by
antenatal ultrasound (Hancock and Wiseman
1989). They concluded that although surgery
was performed sooner, the outcome of infants
with DO was not changed by providing an ante-
natal diagnosis. However, the antenatal diagnosis
of DO influenced parents positively in coping
with the anomaly, because it allowed them time
to prepare for the medical and surgical interven-
tions required after the birth of their infant. These
authors also emphasize that a normal ultrasound
in the presence of polyhydramnios does not rule
out the diagnosis of DO and is an indication for
Fig. 4 Ultrasonography (transverse view) of 24-week repeated sonography. Cohen-Overbeek et al. have
gestational age fetus showing the “double bubble” sign. also reported on 91 cases diagnosed with isolated
S stomach, P pylorus, D duodenum, g.b gallbladder or non-isolated DO. They found that the outcome
(Sweed 2011) of prenatally and postnatally diagnosed DO is not
essentially different despite the fact that more
prematurity and a lower birth weight were
This sonographic finding is known to have a low observed in the former (Cohen-Overbeek et al.
false-positive rate. Zimmer and Bronstein have 2008).
reported that in a few cases, it may represent a The rapid advancement in imaging technology,
transient finding in an otherwise healthy fetus including magnetic resonance imaging (MRI),
(Zimmer and Bronstein 1996). It is possible that should allow for diagnosis during the first and
intestinal peristalsis in a fetus may show transient early second trimester, enabling abortion
dilatation suggesting DO (Bronshtein et al. 2008). (Tsukerman et al. 1993). Alternatively, early pre-
On the ultrasound examination, it is also important natal diagnosis of DO should lead to karyotype
to demonstrate the continuity between the gastric analysis for prenatal screening for trisomy 21 and
and duodenal bubbles (Fig. 4) to exclude other other associated anomalies (Grosfeld and
causes such as choledochal cyst which lacks such Rescorla 1993; Keckler et al. 2008; Singh et al.
communication (Casaccia et al. 2002; Lawrence 2004).
et al. 2000) or duodenal duplication (Malone et al. The prenatal diagnosis allows the mother the
1997). opportunity to receive counseling and to consider
Often other anomalies can also be diagnosed delivery at or near a tertiary care facility that is
by ultrasound. Kawana et al. (1989) and able to care for infants with gastrointestinal anom-
Pameijer et al. (2000) reported on the ultrasonic alies (Haeusler et al. 2002).
prenatal diagnosis of a fetus with combined duo-
denal and esophageal atresias associated with
VACTERL anomalies. Prenatal ultrasono- Clinical Presentation and Diagnosis
graphic diagnosis of annular pancreas has also
been reported showing the coincidence of the The presenting symptoms and signs are the result
double bubble sign together with hyper- of high intestinal obstruction. About half of these
echogenic bands around the duodenum patients are premature and low birth weight
infants (Dalla Vecchia et al. 1998; Escobar et al. the proximal segment or a sharp termination of the
2004; Piper et al. 2008). Vomiting is the most dilated segment, indicating a perforated dia-
common symptom and is usually present on the phragm (Fig. 7).
first day of life. Since 80% of the obstructions are Incomplete DO usually leads to delayed onset
located in the post-ampullary region of the duo- of symptoms, and the diagnosis of duodenal dia-
denum, vomitus in the majority of cases is bile- phragm with a central aperture is sometimes
stained. In supra-ampullary atresia it is delayed for months or even years (Melek and
non-bilious. Orogastric aspiration also yields sig- Edirne 2008; van Rijn et al. 2006; Vaos and Mis-
nificant volumes of bile-stained gastric fluid. iakos 2010). Mikaelsson et al. reported on the late
There is minimal or no abdominal distension diagnosis and treatment of 8 out of 16 patients
because of the high level of obstruction. The with membranous duodenal stenosis. Their
infant may pass some meconium in the first 24 h patients were diagnosed and operated at 1 month
of life and thereafter constipation may develop. to 4 years of age (Mikaelsson et al. 1997). Occa-
Dehydration with weight loss and electrolyte sionally a duodenal diaphragm may be stretched
imbalance (hypokalemic/hypochloremic meta- and ballooned distally, giving the “wind-sock”
bolic alkalosis) soon follows if the diagnosis is appearance on a contrast study (Fig. 8; Eustace
done late and if fluid and electrolyte losses have et al. 1993).
not been adequately replaced (Kilbride et al. The most important differential diagnosis of
2010). DO is DO caused by malrotation resulting in
Incomplete DO usually leads to the delayed extrinsic compression related to Ladd’s bands
onset of symptoms. Infants with duodenal steno- across the duodenum, or volvulus of the midgut
sis and partial bowel obstruction may escape loop, although this is rare. Midgut volvulus may
detection of an abnormality soon after birth and result in gangrene of the entire midgut within
may proceed into childhood or rarely into adult- hours, and thus diagnostic investigation is
hood before a partial obstruction is noted (Escobar urgently required, though the symptoms may
et al. 2004; Grosfeld and Rescorla 1993). relent because the obstruction may be incom-
The diagnosis of DO is confirmed on X-ray plete or intermittent in malrotation. Part of
examination. An abdominal radiograph will these extrinsic obstructions exhibits the double
show a dilated stomach and duodenum, giving bubble sign with distal air on plain film, while
the characteristic appearance of a double bubble the majority can be identified from the coil
sign (the stomach and the proximal duodenum spring appearance of small bowel volvulus fol-
are air filled) with no gas beyond the duodenum lowing barium injection (Eustace et al. 1993).
(Fig. 5a–c). In partial DO, a plain film of the However, Samuel et al. observed that volvulus
abdomen will show a double bubble appearance, neonatorum was not encountered in neonates
but there is usually some air in the distal intes- with duodenal atresia and stenosis who had
tine (Fig. 6). Occasionally in cases of duodenal associated malrotation. They suggested that
atresia, air may be seen distal to the site of DO could perhaps be a floodgate that prevents
obstruction due to associated bile duct bifurca- volvulus in these children (Samuel et al. 1997).
tion (Knechtle and Filston 1990). Radiographic Preduodenal portal vein is a rare anomaly and
findings in patients with annular pancreas are generally asymptomatic. It is a rare cause of DO
usually indistinguishable from duodenal atresia and often coexists with other anomalies resulting in
or stenosis. bowel obstruction (Kataria et al. 1998; Mordehai
In some cases of partial DO, plain films may be et al. 2002; Singal et al. 2009). In most of these
normal. Upper gastrointestinal tract contrast radi- patients, it is impossible to diagnose preduodenal
ography is indicated in these patients to establish portal vein prior to surgery.
the cause of incomplete DO. This may show a The wide variety of additional congenital
stenotic segment of duodenum with dilatation of anomalies with special emphasis on cardiac
Fig. 5 (a) Abdominal radiograph showing grossly At operation duodenal membrane was found and excised.
distended stomach and duodenum with “double bubble” GB gastric bubble, DB duodenal bubble (Sweed 2011). (c)
sign with no air beyond the duodenum. GB gastric bubble, Duodenal atresia evident on upper gastrointestinal radio-
DB duodenal bubble (Sweed 2011). (b) Abdominal radiograph contrast study. S stomach, D duodenum (Sweed
graph showing the “double bubble” sign. In this case 2011)
duodenal bulb is more prominent than the gastric bulb.
malformation, often severe (Keckler et al. 2008; babies. A micturating cystourethrogram should
Piper et al. 2008), make preoperative diagnosis be performed in those babies with abnormal
imperative. Anterior-posterior and lateral chest urogenital ultrasound or an associated anorectal
and abdominal radiographs ascertaining visual- anomaly. Rectal biopsy should be taken in
ization of the entire spine should also be babies with constipation and the combination
performed. of Down syndrome and duodenal atresia, to
Soon after the X-ray, cardiac and renal ultra- exclude Hirschsprung’s disease (Kimble et al.
sound should be carried out routinely in all these 1997).
Fig. 6 Duodenal stenosis erect abdominal X-ray demon-

strating a “double bubble” sign with air beyond the duo-
denum. (As appeared in Fig. 49.10, page 474 of the
textbook “Newborn Surgery” 3rd ed. by Puri P, Sweed
2009)
Fig. 7 An abdominal X-ray contrast study showing
marked distention of duodenum terminating abruptly with
narrow caliber distally. A perforated diaphragm was found
Preoperative Management at operation
Although duodenal atresia is a relative emer-

gency, the patient should not be rushed to the Care is taken to preserve body heat and avoid
operating room until the infant’s hemodynamic hypoglycemia, since many of these newborn
and fluid and electrolyte status is stable. If the patients are premature and small for date
clinical history and findings on physical examina- (Murshed et al. 1999). Very low birth weight
tion indicate that the baby is in no distress and the infants or those with respiratory distress syn-
radiographs are consistent with the usual presen- drome and associated severe anomalies, e.g.,
tation of duodenal atresia with no air beyond the congenital heart disease, may need occasionally
second bubble (excluding malrotation), operation special preparation such as resuscitation and
should be performed on an elective basis. ventilation.
An orogastric tube decompresses the stomach,
and intravenous fluid resuscitation can be initi-
ated. Blood samples for electrolyte determination
should be obtained, and any derangements should Operation
be corrected. Prolonged vomiting can result in a
hypokalemic hypochloremic metabolic alkalosis. Duodenoduodenostomy is the procedure of
Passage of the orogastric tube rules out esopha- choice for patients with duodenal atresia, stenosis,
geal atresia, and careful inspection of anal defect and annular pancreas (Dalla Vecchia et al. 1998;
variants of imperforated anus should be obtained. Weber et al. 1986; Wesley and Mahour 1977).
Duodenoduodenostomy can be performed in long-term results (Kimura et al. 1990; Upadhyay

either “diamond-shaped” (proximal transverse to et al. 1996).
distal longitudinal) anastomosis as described by Bax et al. (2001) and Rothenberg (2002)
Kimura (Fig. 9a, b; Kimura et al. 1977) or side-to- reported on the first case and the first series,
side fashion (Fig. 10). The “diamond-shaped” respectively, on the of laparoscopic management
duodenoduodenostomy has been reported to of DO. They indicated that laparoscopic approach
allow earlier feeding, earlier discharge, and good has proven to be safe and effective and represents
an alternative to the open procedure. They also
emphasized that this minimal invasive surgical
technique should be used only if the surgeon has
appropriate instruments and suturing and laparo-
scopic skills (Bax et al. 2001; Kay et al. 2009;
Rothenberg 2002).
Incision
The baby is placed supine on the table with a small

roll under his upper abdomen on a warming blan-
ket. Endotracheal anesthesia is used. The abdom-
inal skin is prepared by cleaning with prewarmed
povidone-iodine.
A transverse supra-umbilical abdominal inci-
sion is made 2 cm above the umbilicus starting in
Fig. 8 “Wind-sock” web. Dilated duodenum demon- the midline and extending laterally into the right
strated with duodenal membrane ballooned distally, giving upper quadrant for about 5 cm. The abdominal
characteristic “wind-sock” appearance. Reflux of contrast muscles are divided transversely with cutting dia-
medium into pancreatic and common bile duct is seen.
(As appeared in Fig. 49.10, page 474 of the textbook thermy, and the peritoneal cavity is opened in the
“Newborn Surgery” 3rd ed. by Puri P, Sweed 2009) line of incision.
Fig. 9 Diamond-shaped duodenoduodenostomy. (a) A (b) A single-layer anastomosis using interrupted 5/0 Vicryl
transverse incision is made in the distal end of the proximal sutures with posterior knots tied inside the posterior wall of
dilated duodenum, and a longitudinal incision is made in the anastomosis and anterior knots tied outside the anterior
the smaller limb of the duodenum distal to the occlusion. wall is performed
(a) (b) (c)
Fig. 10 Side-to-side duodenoduodenostomy. (a) An interrupted 5/0 Vicryl sutures. (As appeared in Fig. 49.10,
upper transverse abdominal incision. (b) Parallel incisions page 474 of the textbook “Newborn Surgery” 3rd ed. by
of about 1 cm are made in the proximal and distal duode- Puri P, Sweed 2009)
num. (c) The anastomosis is performed using single-layer
The type of atresia as well as any pancreatic

Exploration and Identification
abnormality (e.g., annular pancreas) is noted. In
of Pathology
patients with an annular pancreas, the pancreatic
tissue should never be divided and should always
After exposing the peritoneal cavity, the surgeon
be bypassed. The duodenum distal to the site of
inspects the entire bowel for the presence of
obstruction is small and decompressed. The
other bowel anomalies. There may be an associ-
requirements for distal mobilization vary
ated annular pancreas, malrotation (in about one
according to the location of the atresia and to
third of the patients), or in rare cases, pre-
the gap between the two segments (Fig. 2). If
duodenal portal vein. If the colon is in normal
necessary, the ligament of Treitz is divided, and
position, malrotation is probably not a
mobilization and displacement of the distal duo-
coexisting factor.
denum are performed behind the superior mes-
The stomach and first portion of the duodenum
enteric vessels, thus allowing a satisfactory
are usually thickened and dilated. The liver is
anastomosis to be performed without any
carefully retracted superiorly. The ascending
tension.
colon and the hepatic flexure of the colon are
mobilized medially and downwards to expose
the dilated duodenum (Sweed 2006).
The duodenum is then adequately mobilized “Diamond-Shaped”
and freed from its retroperitoneal attachments – Duodenoduodenostomy
Kocher maneuver. Great care must be exercised
not to dissect or manipulate either segment of the After abdominal exploration, the duodenum is
duodenum medially, to avoid injury to the adequately mobilized. With two traction sutures,
ampulla of Vater or the common bile duct. The the redundant wall of the proximal duodenum is
tube in the stomach is then passed distally into the pulled downward to overlie the proximal portion
dilated duodenum and helps to locate the point of of the distal duodenal segment. A transverse inci-
obstruction and determine if a “wind-sock” defor- sion is made in the distal end of the proximal
mity is present (Fig. 3g). duodenum, and a longitudinal incision is made
in the smaller limb of the duodenum distal to the malrotation (Grosfeld and Rescorla 1993). In
occlusion. these patients, the cecum should be placed in the
These are made in such a position as to allow left lower quadrant to reduce the risk of midgut
good approximation of the openings without volvulus.
tension. The wound is closed in layers: the peritoneum
The papilla of Vater is located by observing and posterior fascia and the anterior fascia by two
bile flow. This is performed by gentle compres- layers using continuous 4-0 Vicryl. The skin is
sion of the gallbladder. closed with running intracuticular suture using
The orientation of the sutures in the “diamond- 5-0 Vicryl.
shaped” anastomosis and the overlapping
between the proximal transverse incision and the
distal longitudinal incision are shown in Fig. 9a, b. Side-to-Side Duodenoduodenostomy
Additionally, an 8 French Foley catheter
should be passed proximally into the stomach The dilated proximal duodenum and the distal
and distally into the jejunum and pulled back collapsed duodenum are approximated using two
with the balloon inflated, to ensure that no addi- stay sutures (5-0 Vicryl). Then parallel incisions
tional web or a “wind-sock” deformity is over- with a length of about 1 cm are made in the
looked. The distal duodenum can be distended to proximal and distal duodenum (Fig. 10). An
a larger size during this maneuver facilitating the 8 French Foley catheter should be inserted both
anastomosis. Before pulling back the catheter to the proximal dilated duodenum and to the
from the distal duodenum, the surgeon should distal collapsed duodenum in order to rule out
inject 30–40 ml of warm saline through the cath- “wind-sock” membrane and distal atresias simi-
eter to rule out distal atresias of the distal small larly as described in the “diamond-shaped”
bowel. The catheter is then removed. duodenoduodenostomy.
A single-layer anastomosis using 5/0 or 6/0 The posterior layer of anastomosis is com-
Vicryl sutures with posterior knots tied inside the pleted using interrupted 5/0 Vicryl sutures.
posterior wall of the anastomosis and interrupted At this stage, a transanastomotic 5 Fr gauge
sutures with anterior knots tied outside the ante- silastic nasojejunal tube may be inserted for an
rior wall. Before completion of the anterior part of early enteral feeding.
the anastomosis, a 5F silicon nasojejunal trans- The anastomosis is then completed using
anastomotic feeding tube maybe passed down into interrupted 5-0 Vicryl sutures for the anterior
the upper jejunum for an early postoperative layer. The abdomen is closed in the same manner
enteral feeding (Hall et al. 2011) using the same as described in the “diamond-shaped”
insertion technique as was reported for patients duodenoduodenostomy.
who underwent surgical repair for esophageal In premature infants, some surgeons prefer to
atresia and tracheoesophageal fistula (Sweed perform a gastrostomy and insert the trans-
et al. 1992). Others, however, do not use the anastomotic silicon tube via the gastrostomy.
nasojejunal tube because they suggest that it may The tip of the tube should be well down in the
delay the commencement of oral feeding (Kimura jejunum as to decrease the chance of it becoming
et al. 1990). Hall et al. reported recently that a displaced.
transanastomotic tube significantly shortens time
to full enteral feeds in infants with congenital DO
as well as significantly reducing the need for cen- Operative Technique
tral venous access and parenteral nutrition (Hall for Duodenal Web
et al. 2011). Then the right colon is returned to its
former position so that the mesocolon covers the A longitudinal incision is performed above the
anastomosis. The Ladd procedure with “inversion “transitional zone” between the wide and narrow
appendectomy” is performed in patients with segments of the duodenum (Fig. 11a), and the
a b c
Fig. 11 Operative technique for duodenal web. (a) Lon- small bowel. The white arrow points to the excisional line
gitudinal incision above the “transitional zone” of the of the membrane. (e) Intraoperative photograph of a
duodenum. (b) Excision of the web leaving the medial 2-day-old infant with Down syndrome and AV canal show-
third of the membrane intact. (c) The duodenum is closed ing: (e) An 8 French Foley catheter which was introduced
transversely (Sweed 2011). (d) Intraoperative photograph through an aperture of a duodenal membrane. M, mem-
of a 2-week-old infant born with duodenal web with an brane; the white arrow points to the aperture of the mem-
aperture. The papilla of Vater was identified at the proximal brane. (f) Excision of the membrane. (As appeared in
and medial part of the duodenal membrane (). DU, Fig. 49.10, page 474 of the textbook “Newborn Surgery”
opened duodenum; M, membrane; , papilla of Vater; SB, 3rd ed. by Puri P)
duodenum is opened. The membrane usually is damaging the sphincter of Oddi or the ampulla
located in the second part and occasionally in the of Vater and continue leaving a circumferential
third portion of the duodenum. It can be complete rim of tissue of 1–2 mm (Fig. 11b, d). The resec-
or have a hole. Anatomically, the ampulla of Vater tion line is then oversewn using continuous
may open directly into the medial part of the sutures of Vicryl 5/0, and the duodenum is closed
membrane, or posteriorly close to it; thus the transversely in one layer using Vicryl 5/0
close relationship of the membrane to papilla of (Fig. 11c). Because of the pitfalls in cases of the
Vater makes its identification mandatory, before lax membrane that may bulge downward distally
excision of the web. Excision of the web should into the distended duodenum (the so-called wind-
proceed from the lateral duodenal wall, leaving sock phenomenon), and in order to avoid missing
the medial third of the wall intact to avoid the anomaly, before closure of the duodenum, the
distal patency of the distal duodenum must be

verified by inserting an 8 French Foley catheter
through duodenotomy (Fig. 11e, f ).
The experience with fiber optic duodenoscopy
indicates the usefulness of the technique for both Scissors, needle
the diagnosis and nonoperative management of driver
Curved
duodenal membrane (Beeks et al. 2009; Camera
Dissector
Bittencourt et al. 2012; Okamatsu et al. 1989).
However, based on reports describing anomalous
entry of the pancreatobiliary channels (Adams
1986), the delineation of the ducts at endoscopic
retrograde cholangiopancreatography (ERCP) may
be necessary prior to endoscopic intervention. Fig. 12 Trocar placement and instrumentation for laparo-
Recently, Bittencourt et al. reported on three scopic repair of duodenal atresia
female patients aged between 9 and 12 months
born with duodenal membrane who were treated stands at the patient’s feet. The abdomen is
successfully by two endoscopic sessions. The first insufflated through a 5-mm umbilical port, for a
and second sessions of endoscopic treatment 30 laparoscope. 3-mm and 5-mm ports are placed
included dilatation and resection of the mem- in the right lower quadrant and left upper quad-
brane, respectively, and were carried out without rant, respectively. The left upper quadrant port is
complications (Bittencourt et al. 2012). placed for the introduction of suture.
Most surgeons however believe that a The duodenum is then kocherized, the type of
duodenotomy is preferable to the potential risk obstruction becomes easily visible, and the dilated
of inadvertent pancreatic or bile duct injury proximal and decompressed distal segments are
(Adams 1986). identified (Rothenberg 2002). A proximal trans-
verse and distal longitudinal duodenotomy is then
made. As with the open repair, stay sutures are
Laparoscopic Management of DO placed at each corner to facilitate the anastomosis.
A diamond-shaped anastomosis is performed with
The application of minimally invasive surgical either a separate running suture for the posterior
techniques (MIS) for the correction of congenital and then anterior wall or single interrupted
anomalies has increased significantly over the last stitches of Vicryl. Intracorporeal knot tying is
10 years. The ability to perform delicate dissec- used. An extra port can be placed in the right
tion and intracorporeal anastomosis has broad- upper quadrant to help retract the liver and set up
ened the scope of entities that can be approached the anastomosis. Alternatively, the apical stitch
including neonatal DO. Although most neonatal can be tied and brought out through the abdominal
conditions presenting with bowel obstruction pre- wall to assist with retraction and align the
sent a difficult problem for laparoscopy because enterotomies for the anastomosis. The distal
of the dilated bowel and limited abdominal cavity, bowel is examined in all cases to ensure that
this is not the case in duodenal atresia. The entire there are no obvious secondary atresias. Once
small and large bowel is decompressed, and there the anastomosis is completed, the ports are
is an excellent exposure of the proximal duode- removed, and the sites are closed with absorbable
num (Bax et al. 2001; Kay et al. 2009). sutures.
For the laparoscopic approach (Fig. 12), neo- The main benefits of laparoscopic approach for
natal laparoscopic instruments (3 mm) and trocars the treatment of duodenal atresia are the excellent
are used. The patient is positioned supine at the visualization of the obstruction and the ease of the
end of the operating table. The operating surgeon anastomosis. However, the possible disadvantage
of this approach may be that evaluation of the The commencement of oral feeding depends
distal bowel for other artretic segments is more on the decrease of the gastric aspirate and may be
difficult to accomplish and, if not specifically delayed for several days and occasionally for
evaluated, it is feasible that a malrotation can be 1–2 weeks or longer. Once the volume of the
missed (Hill et al. 2011). The bowel can be gastric aspirate decreases, the feeding tube is
inspected visually for distal obstructed segments, withdrawn, and the infant can be started on oral
but internal webs may be more difficult to see. feeding.
Hill et al. (2011) reported recently on their Spigland and Yazbeck (1990), in their follow-
results comparing 22 patients with DO treated by up of 33 neonates, found that bowel transit was
laparoscopy and 36 patients treated by traditional established for an average of 13.1 days, 7.5 days
laparotomy during a 9-year period (2001–2010). after partial web excision, 12.4 days following
They found no difference between groups in time duodenoduodenostomy, and 15 days after
to full feeding, postoperative length of stay, and duodenojejunostomy. Spilde et al. (2008) recently
complication rate. They found that the operative reported that the time to initial feeding was
time was slightly longer in the laparoscopic group 11.3 days for patients with an open repair of DO
(median time 116 min vs. 103 min); however, compared to 5.4 days for those who were treated
laparoscopic management appeared to allow a by laparoscopic approach. They also found that
shorter postoperative ventilator requirement. Six the average time to full oral intake was 16.9 days
patients (26%) of the laparoscopic group were for the open group compared to 9 days for the
converted to open exploration because of unclear laparoscopic group.
anatomy.
The experience with laparoscopic duodenoduo-
denostomy (Oh et al. 2017; Spilde et al. 2008; Management of Persistent
Valusek et al. 2007) demonstrates that it can be Megaduodenum by Duodenoplasty
performed safely and successfully in the neonate
with excellent short-term outcomes. Surgeons with The deformity and dysfunction of the first part of
experience in advanced laparoscopic techniques the duodenum – the megaduodenum – are the
can learn the laparoscopic duodenoduodenostomy causes of well-known morbidity (Ein and
and have good results. Shandling 1986; Spigland and Yazbeck 1990),
and occasionally these patients require
duodenoplasty (Dewan and Guiney 1990). The
Postoperative Care malfunction of the greatly dilated gut and the
absence of effective peristalsis were demonstrated
The baby is returned to an incubator (or radiant by Nixon in the small bowel (Nixon 1960), but the
heat cot) at the thermoneutral temperature for its same phenomenon is thought to occur in the
size and maturity. An intravenous infusion of the dilated duodenum proximal to the duodenal atre-
dextrose/saline is continued in the postoperative sia. Several techniques of duodenoplasty have
period, and further fluid and electrolyte manage- been described, and in all, it is of the utmost
ment depends on clinical progress, loss by gastro- importance to visualize and identify the ampulla
duodenal aspiration, and serum electrolyte levels. of Vater within the duodenal lumen prior to resec-
Postoperatively, patients may have a prolonged tion and tapering of the duodenum. Hutton and
period of bile-stained aspirate through the naso- Thomas have reported success by extensive taper-
gastric tube, which is mainly due to the inability of ing duodenoplasty (Hutton and Thomas 1988).
the markedly dilated duodenum to produce effec- Adzick et al. (1986) and Grosfeld and Rescorla
tive peristalsis. Enteral feeding through the trans- (1993) emphasized the merit of tapering
anastomotic feeding tube is generally started duodenoplasty at the primary operation of neo-
within 24–48 h postoperatively. nates with dilated duodenum, to improve the
immediate postoperative gastrointestinal function Late complications included adhesive bowel

and the prevention of further development of obstruction in 9%, megaduodenum and duodenal
megaduodenum. Other techniques include resec- dysmotility that required tapering duodenoplasty
tion and suturing (Weisgerber and Boureau 1982), in 4%, and gastroesophageal reflux requiring sur-
resection and stapling (Adzick et al. 1986), and gery in 5%.
elliptical seromuscular resection (Kimura et al. Weber et al. (1986) reported the complication
1996). rate and morbidity of 3 methods of technical
However, refashioning the anastomosis or repair in a group of 41 newborns with duodenal
bypass techniques usually fail (Ein et al. 2000; atresia. The three techniques were (1) side-to-side
Young et al. 1993). Another technique of sub- duodenoduodenostomy, (2) side-to-side duodenoje-
total duodenal resection with reconstruction of junostomy (which is rarely performed today), and
the duodenum by the proximal jejunum as an (3) diamond-shaped duodenoduodenostomy. There
onlay patch was demonstrated in two children. was no difference in the complication rate, but the
In this technique, the diseased duodenal wall is “diamond-shaped” technique was found to be supe-
completely removed, except for the area of the rior for repair, resulting in earlier feeding and dis-
ampulla of Vater, and the duodenum is charge. Kimura et al. reported on their experience
reconstructed by the jejunum (Endo et al. with 44 patients with the diamond-shaped tech-
1998). nique (Kimura et al. 1990), without the use of
gastrostomy or transanastomotic tube, and found a
Outcome and Long-Term Results

Table 2 Survival rates of patients with duodenal atresia
The survival of babies with DO has gradually and stenosis. Table shows gradual improvement in survival
improved over the last 40 years (Table 2; Bailey reported over the past 40 years. Most deaths are related to
et al. 1993; Cohen-Overbeek et al. 2008; Dalla the associated complex cardiac malformations
Vecchia et al. 1998; Hill et al. 2011; Kilbride et al. Author/year No. of patients % survival
2010; Wesley and Mahour 1977). All agree that Girvan and Stephen (1974) 158 67
the three main factors contributing to the mortality Wesley and Mahour (1977) 72 74
rate in this group of patients are high incidence of Hancock and Wiseman 34 94
associated anomalies, especially severe cardiac (1989)
malformations, prematurity, and low birth weight Akhtar and Guiney (1992) 49 94
(Choudhry et al. 2009; Escobar et al. 2004; Bailey et al. (1993) 138 93
Grosfeld and Rescorla 103 95
Grosfeld and Rescorla 1993). In a recent review
(1993)
covering 45 years (1951–1995) of management of Dalla Vecchia et al. (1998) 138 86
DO, Murshed et al. (1999) found that in the first Cohen-Overbeek et al. 91 91
15 years, survival reached 51%, in the next (2008)
15 years it was 80%, and in the last 15 years 95%. Choudhry et al. (2009) 65 96
During the latest period, mortality was almost Kilbride et al. (2010) 51 98
entirely the consequence of associated anomalies. Kay et al. (2009)a 17 100
DallaVechia et al. reported a relatively low rate Hill et al. (2011)b 58 100
a
of postoperative complications in a series of Laparoscopic duodenoduodenostomy (Years: 2004–2008),
138 infants (Dalla Vecchia et al. 1998). The N = 17 pts
b
Laparoscopic versus open repair of duodenal obstruction,
early complication rate included anastomotic (Years: 2001–2010), Lap. Group, N = 22 pts.; open group,
obstruction in 3%, congestive heart failure in N = 36 pts. One patient in the Lap group who had Down
9%, prolonged adynamic ileus in 4%, pneumonia syndrome and duodenal and jejunal atresias died because
in 5%, and wound infection in 3%. of sepsis 5 months after the initial operation
very low rate of complications and good long-term is the treatment of choice and can be performed via
results. open approach or minimally invasive. The last
Long-term results of congenital DO were retrospective studies comparing the surgical out-
reported by Kokkonen et al. (1998), who studied come of laparoscopic repair versus open repair
41 patients aged 15–35 years. They found that found that laparoscopy is a safe and effective tech-
growth and development, including body weight, nique, and the results including operative time,
were satisfactory. Although the great majority was length of stay, time to full feeding, and complica-
symptom-free, on barium meal examination, all tion rate were similar in both groups (Chung et al.
but two had abnormal findings, including mega 2017). However, for those preferring laparoscopic
duodenum in nine cases. They concluded that DO repair, duodenojejunostomy might be a feasi-
some gastrointestinal disturbances are common, ble alternative as it is easier to perform and has
even in asymptomatic patients, and careful equal clinical outcomes compared to duodenoduo-
follow-up is important. Salonen and Makinen denostomy (Zani et al. 2017).
reported previously on their experience in a small Over the last few decades, advancements in
group of nine patients at age 3–21 years (Salonen neonatal intensive care, parenteral nutrition, man-
and Makinen 1976) and found, in contrast, a nor- agement of associated anomalies, and improve-
mal barium meal in all patients except one. Their ments in operative technique including video
result was similar to the documentation by Kimura equipment, smaller instruments, and better post-
et al. (1990) with the diamond-shaped technique. operative care have improved the outlook for
Ein et al. encountered five patients with late patients born with duodenal atresia and stenosis.
complications of duodenal atresia repair that Mortality today has been reduced to 5–10% and is
appeared suddenly between the ages of 6 months now related mostly to associated cardiac
and 24 years. The duodenal repair was function- anomalies.
ally obstructed – caused by proximal, dilated duo-
denal atony. Plication of the dilated atonic
proximal duodenum was curative (Ein et al.
Cross-References
2000).
Recently, Son and Kein (2017) compared the
results of laparoscopic versus open surgery in the
▶ Jejunoileal Atresia and Stenosis
management of duodenal obstruction in 112 neo-
▶ Malrotation
nates. They reported that the laparoscopic treat-
ment is associated with lower postoperative
Acknowledgments This chapter has been adapted from
morbidity, shorter recovering time and postopera- the author’s own chapter in the following publication:
tive hospital stay, and better postoperative Copyright © 2011 From Newborn Surgery, Third Edition,
cosmesis than open surgery. Mentessidou and by Prem Puri. Reproduced by permission of Taylor and
Francis Group, LLC, a division of Informa plc.
Saxena (2017) and Chung et al. (2017) performed
systematic reviews and found that laparoscopic
repair was of comparable safety and efficacy as
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Malrotation
60
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 898
Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 899
Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
Open Ladd’s Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
Laparoscopic Ladd’s Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
Complication of Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
Controversies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903
Abstract
Intestinal malrotation comprises the spectrum
of abnormalities of midgut development asso-
A. Zani
Division of General and Thoracic Surgery, The Hospital ciated with abnormal rotation and/or fixation.
for Sick Children, Toronto, Canada Intestinal malrotation is characterized by the
Department of Surgery, University of Toronto, congenital abnormal positioning of the midgut,
Toronto, Canada narrowing the dorsal mesenteric root and put-
e-mail: augusto.zani@sickkids.ca ting the bowel at risk of midgut volvulus. It is
A. Pierro (*) usually associated to the presence of peritoneal
Division of General and Thoracic Surgery, The Hospital folds, the Ladd’s bands, which cross from the
for Sick Children, University of Toronto, colon and cecum to the duodenum and liver
Toronto, ON, Canada
and can cause duodenal obstruction.
Department of Surgery, University of Toronto, Patients with intestinal malrotation can
Toronto, Canada
e-mail: agostino.pierro@sickkids.ca remain asymptomatic or may present with

https://doi.org/10.1007/978-3-662-43588-5_64
898 A. Zani and A. Pierro
signs of acute bowel obstruction, such as col- orthopedic anomalies can be found in association.
icky abdominal pain, abdominal distention, Intestinal malrotation can be observed in patients
bilious vomiting, or shock. The surgical treat- with small bowel atresia, where this is thought to
ment is the Ladd’s procedure with derotation of be the result of an antenatal volvulus. Tradition-
the volvulus, division of the Ladd’s bands, ally, the age of symptom presentation has been
widening of the small intestine’s mesentery, reported to be during the first year of life for the
appendectomy, and correctional placement of majority of patients. However, recent studies have
the cecum and colon. shown that intestinal malrotation can occur in
patients of any age and, in contrast with traditional
Keywords teaching, nearly half of these patients may present
Intestinal malrotation · Midgut volvulus · during adulthood (Nehra and Goldstein 2011;
Ladd’s bands · Ladd’s procedure Aboagyeet al. 2014).
Introduction Pathophysiology
Intestinal malrotation is the term used to describe The intestinal develops in the utero through
the spectrum of abnormalities of midgut develop- three stages that occur during the first trimester
ment that are associated with abnormal rotation (Kluth and Fiegel 2003). During the first stage
and/or fixation. Typically, intestinal malrotation is (fifth to tenth week), the elongating bowel
characterized by the congenital abnormal posi- exceeds the abdominal cavity and herniates out-
tioning of the midgut, whereby the side the abdomen. During the second stage
duodenojejunal (DJ) flexure lies right of the mid- (10th–11th week), the bowel returns into the
line and relatively close to the ileocecal valve. abdomen and rotates 270 anticlockwise around
This makes the dorsal mesenteric root narrow the superior mesenteric artery. The third stage
and puts the bowel at risk of midgut volvulus. (12th week) is characterized by the retroperito-
Intestinal malrotation is usually associated to the neal fixation of the duodenum and colon. The
presence of peritoneal folds, the so-called Ladd’s distal duodenum comes to lie across the midline
bands, which cross from the colon and cecum to toward the left upper quadrant, attached by the
the duodenum and liver and can cause duodenal ligament of Treitz at the DJ flexure to the poste-
obstruction. rior abdominal wall. The cecum passes to the
right and downward and becomes fixed to the
posterior abdominal wall.
Epidemiology
As intestinal malrotation may remain asymptom- Clinical Presentation

atic throughout life, its exact incidence in the
normal population is unknown. Nonetheless, Patients with intestinal malrotation can remain
autopsy studies have estimated a prevalence of asymptomatic and be diagnosed incidentally
0.5–1%, with only one symptomatic case every (up to 10% of all cases).
6,000 live births. Incidence is slightly higher in Symptomatic infants, instead, may present
males than females. A higher incidence of with signs and symptoms of acute bowel obstruc-
malrotation is seen in patients with anterior tion, such as colicky abdominal pain, abdominal
abdominal wall defects (gastroschisis and exo- distention, and bilious vomiting (Millar et al.
mphalos), congenital diaphragmatic hernia, 2003). In advanced cases, patients may present
heterotaxy syndrome, biliary atresia, intussuscep- with hemodynamic instability from hypovolemia
tion (Waugh’s syndrome), and intestinal and/or septic shock, abdominal tenderness, signs
dysmotility syndromes. Cardiac and/or of peritonitis, and blood per rectum. These
60 Malrotation 899
findings are suggestive of bowel ischemia due to will be difficult on an upper gastrointestinal series
midgut volvulus. alone either because of technical difficulties or
Older children with intestinal malrotation because of difficulties in differentiating normal
without acute volvulus more often present with variations in duodenal anatomy from true abnor-
chronic episodic obstructive symptoms, failure to malities of rotation (Daneman 2009). For this
thrive, malabsorption, diarrhea, and nonspecific purpose, the next most commonly evaluated fac-
colicky abdominal pain. tor is the position of the cecum. Contrast enema
has historically been used, especially to study the
position of the cecal pole. However, in 15–30% of
malrotation cases, the cecum is normally located,
Imaging Studies and in many patients with normal intestinal rota-
tion, the cecum has an abnormal location. There-
The plain abdominal radiography is usually fore, a contrast enema is not always helpful.
aspecific, may present a wide spectrum of Since the late 1980s, several sonographic
appearances, and can be either normal or show approaches have been reported to diagnose or
features of distended stomach and proximal duo- exclude intestinal malrotation, but this modality
denum with a distal paucity of gas (Daneman is still not used as the modality of choice by most
2009). Nonetheless, most patients presenting radiologists (Daneman 2009). Inversion of the
with a suspicion of intestinal malrotation will superior mesenteric artery and vein relationship
receive a plain abdominal X-ray. However, can be indicative of intestinal malrotation. Nor-
because of this wide variation of appearances mally, the superior mesenteric vein (SMV) is
on plain radiographs, one should never rely on located to the right of the superior mesenteric
the plain film findings to diagnose or to exclude artery (SMA) in the axial plane at the level of
intestinal malrotation. the junction of the SMV with the portal vein.
If the physical examination and/or the abdom- Conversely, a SMV not lying to the right of the
inal radiography raise the suspicion of volvulus, SMA is highly sensitive for intestinal malrotation.
surgery should be expedited. Alternatively, if the However, the vessel inversion may also be present
patient is stable, further diagnostic imaging is in normal rotation, and a normal vessel relation-
recommended. ship may be present in children with intestinal
In most institutions, an upper gastrointestinal malrotation (Daneman 2009). Therefore, a normal
series (alone or in combination with a follow sonogram does not exclude intestinal malrotation,
through series) is the most used imaging modality. and this modality cannot be used as a screening
This study helps define the position of the procedure for this condition. More recently, it has
duodenal-jejunal flexure and/or the position of been suggested that a retroperitoneal third portion
the cecum and proximal colon. of the duodenum between the aorta and the SMA
Imaging findings indicative of intestinal is an indicator for normal rotation (Yousefzadeh
malrotation are the following: 2009). This observation, based on anatomical and
embryological principles, has been confirmed by
– On the frontal view, the duodenal-jejunal flex- several studies (Menten et al. 2012; Hennessey
ure lies on the right of the spine and inferior to et al. 2014; Khatami et al. 2014).
the transpyloric plane (Addison’s plane). Direct visualization of a whirlpool sign is sug-
– On the lateral view, the fourth part of the duo- gestive of an intestinal volvulus. However, this
denum lies anterior to the second part occa- sign is not present in those children without vol-
sionally showing a corkscrew appearance. vulus but who are symptomatic because of
obstruction due to bands (Daneman 2009). Fur-
Even when a technically perfect examination is thermore, the sign may be difficult to appreciate in
performed, there will remain a group of children those with volvulus and a large amount of dilated,
in whom the diagnosis of intestinal malrotation gas-filled bowel.
Cross-sectional imaging obtained with com-

puter tomography or magnetic resonance may
depict a dilated duodenum, malposition of the
DJ flexure, the whirlpool sign indicative of vol-
vulus, an internal hernia, or abnormalities of the
relationship of the superior mesenteric artery and
vein. However, these imaging modalities are not
commonly performed in children.
All symptomatic patients with positive inves-
tigative findings should undergo urgent laparot-
omy. Management of the asymptomatic patient
and indication to surgery remain controversial.
The risk of bowel ischemia due to midgut volvu-
lus is invariably present, and the majority of sur-
geons would proceed to prompt operation.
Surgery
The principles of the procedure have remained Fig. 1 Open Ladd’s procedure: right upper quadrant trans-
almost unchanged since originally described by verse incision
Laddin 1936 (Ladd 1936).
Open Ladd’s Procedure
The patient is positioned supine, and a right upper

quadrant transverse incision is made (Fig. 1). The
umbilical vein is divided and ligated. The perito-
neal fluid is examined. Frequently it is clear;
bloodstained fluid implies bowel ischemia and
volvulus; fecal staining indicates bowel perfora-
tion and should be cultured. The midgut is deliv-
ered from the wound and the base examined. Any
volvulus, if present, should be derotated anti-
clockwise, noting the number of turns (Fig. 2).
The bowel is examined for viability, and any
ischemic bowel should be wrapped in a damp
swab and reexamined after 5–10 min. Nonviable
bowel is resected and a primary anastomosis
performed.
The Ladd’s bands, if present, are divided
(Fig. 3). The superior mesenteric artery is identi- Fig. 2 Anticlockwise derotatation of a volvulus
fied, and the mesenteric base is broadened as
much as possible by division of the peritoneal position of the appendix at the end of the surgery
folds (Fig. 4). Care must be taken not to injure (left upper quadrant). However, this remains a
the superior mesenteric vessels. An appendec- matter of debate especially in neonates. Some
tomy may be performed, due to the abnormal surgeons would opt for an inversion of the
60 Malrotation 901
appendix; others would leave the appendix Ladd’s procedure usually stabilize the bowel.
untouched to prevent potential additional The abdomen is closed as routine.
morbidity. Midgut volvulus due to malrotation may result
At the end of the procedure, the small bowel is in the loss of the small bowel. Recently, it has
placed in the right hemi-abdomen and the large been proposed as a novel technique to deal with
bowel in the left hemi-abdomen. There is no need the mesenteric thrombosis, which causes continu-
to apply any fixation sutures, as adhesions and the ing ischemia of the intestine (Kiely et al. 2012).
broad base to the mesentery developed by the This includes (i) digital massage of the superior
mesenteric vessels after derotation to restore intes-
tinal perfusion and (ii) postoperative systemic
infusion of tissue-type plasminogen activator. If
extensive ischemic bowel of doubtful viability is
present, a second-look laparotomy is performed
after 24 h in the hope of minimizing the extent of
bowel resection required.
Laparoscopic Ladd’s Procedure
Laparoscopy can be performed for diagnosis of

equivocal cases of malrotation as well as for cor-
rection of the defect (Bass et al. 1998; Stanfill
et al. 2010). The principles of the procedure are
the same of the open technique. Port position is
shown in Fig. 5. Care must be taken to correctly
identify landmarks such as the duodenum and
ascending colon. To gain access to the duodenum,
it is useful to raise the head of the operating table
Fig. 3 Division of Ladd’s bands and elevate the right flank. The ascending colon
Fig. 4 Broadening of the mesentery

is more common in older patients, and it is asso-

ciated with earlier full enteral feeding, shortened
length of hospital stay, and decreased risk of post-
operative complications. However, this review
highlighted the higher incidence of postoperative
volvulus after laparoscopic Ladd’s procedure
questioning the efficacy of the laparoscopic
approach.
Complication of Surgery
Recurrence of midgut volvulus is rare, but it has

been reported and may be due to division of the
Ladd’s bands without a full derotation and
splaying of the mesentery. Adhesive bowel
obstruction is reported in about 5% of cases. Mid-
gut volvulus occurs in 45–65% of children with
malrotation and still carries a mortality rate of
Fig. 5 Laparoscopic Ladd’s: positions of ports 7–15%; necrosis of >75% of the midgut is asso-
ciated with intestinal failure.
falls toward the left side of the abdomen. The
duodenum is exposed, and Ladd’s bands are
divided. After division, the bowel is examined Controversies
along its length for any further causes of obstruc-
tion. Dividing the peritoneal folds broadens the There is still a number of controversial scenarios
root of the mesentery, and care must be taken in where it is debatable whether to look for and/or
not injuring the superior mesenteric vessels. correct rotation anomalies (Lampl et al. 2009).
Appendectomy can be carried out either using These include:
endoloops for intracorporeal ligation or by deliv-
ering the appendix through a trocar site and excis- – Patients undergoing repair of abdominal wall
ing it extra-abdominally in smaller patients. defects or diaphragmatic hernias. Some degree
Postoperatively, a nasogastric tube is left in situ of nonrotation or malrotation is invariably
for gastric aspirates. Intravenous fluids are contin- encountered in these patients, and subsequent
ued, and gastric losses are replaced milliliter for volvulus is rare.
milliliter with normal saline and potassium chlo- – Asymptomatic patients with malrotation in
ride (20 mmol/L saline). Enteral feeds are whom the diagnosis is made incidentally dur-
restarted when the postoperative ileus is resolved. ing evaluation for nonspecific complaints,
Although the principles of the Ladd’s proce- prior to fundoplication for gastroesophageal
dure for intestinal malrotation in children have reflux, and in those with heterotaxy
remained unchanged since its first description, in syndromes.
the era of minimally invasive surgery, it is contro- – Monozygotic twins with proven malrotation in
versial whether laparoscopy is advantageous over the sibling.
open surgery. Recently, a systematic review of the
literature reported that the current surgical man- Especially, the treatment of asymptomatic or
agement of infants and children with intestinal incidentally discovered intestinal malrotation
malrotation is not based on substantial evidence remains controversial. A systematic review from
(Catania et al. 2016). The laparoscopic approach the Outcomes and Evidence-based Practice
60 Malrotation 903
Committee of the American Pediatric Surgical shorter hospital stay (Catania et al. 2016; Hun-
Association revealed a paucity of prospective tington et al. 2017). However, the laparoscopic
studies evaluating patients with malrotation, and procedure has a higher risk for post-op volvulus
in particular, patients with congenital heart dis- (Catania et al. 2016).
ease and intestinal rotation abnormalities Screening of asymptomatic patients with
(Grazianoet al. 2015). The Committee heterotaxy for intestinal foregut and rotational
recommended that each major institution evalu- anomalies and prophylactic treatment are cur-
ates their current approach to patients with asymp- rently seen controversial, and further studies are
tomatic malrotation and creates a consistent necessary to define guidelines for screening and
approach or an algorithm that can be studied and prophylactic operative care (Cullis et al. 2016;
revised as needed. In particular, the Committee Tan et al. 2016; Landisch et al. 2015).]
suggested to take in consideration of three factors,
namely, the presence of symptoms, status of car-
diac disease, and age, in all patients who are
Cross-References
diagnosed with malrotation as a result of a screen-
ing ultrasound or incidentally on another study
▶ Biliary Atresia
(Graziano et al. 2015). In such patients, it is
important to maintain a multidisciplinary
approach that involves all specialists, including
▶ Gastroschisis
pediatricians, radiologists, intensivists, general
▶ Omphalocele
surgeons, and in case of patients with cardiac
▶ The Epidemiology of Birth Defects
anomalies, cardiologists and cardiovascular sur-
geons. In the era of family-centered care, it is
crucial to have the parents and potentially the
References
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Families should be educated on the arguments Aboagye J, Goldstein SD, Salazar JH, Papandria D, Okoye
for and against surgical intervention as well as MT, Al-Omar K, Stewart D, Lukish J, Abdullah F. Age
conservative management. It is not uncommon at presentation of common pediatric surgical condi-
tions: reexamining dogma. J Pediatr Surg. 2014;49(6):
that asymptomatic patients with intestinal
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malrotation experience postoperative complica- Bass KD, Rothenberg SS, Chang JH. Laparoscopic Ladd’s
tions, such as prolonged ileus or adhesive bowel procedure in infants with malrotation. J Pediatr Surg.
obstruction. 1998;33(2):279–81.
Catania VD, Lauriti G, Pierro A, Zani A. Open versus
laparoscopic approach for intestinal malrotation in
infants and children: a systematic review and meta-
Conclusion and Future Directions analysis. Pediatr Surg Int. 2016;32(12):1157–64.
Cullis PS, Siminas S, Losty PD. Is screening of intestinal
foregut anatomy in heterotaxy patients really neces-
Bowel ischemia and subsequently bowel necrosis
sary?: A systematic review in search of the evidence.
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with midgut volvulus (Langer 2017). Therefore, Daneman A. Malrotation: the balance of evidence. Pediatr
early diagnosis and prompt surgical treatment are Radiol. 2009;39(Suppl 2):S164–6.
Graziano K, Islam S, Dasgupta R, Lopez ME, Austin M,
fundamental for the treatment of intestinal
Chen LE, Goldin A, Downard CD, Renaud E, Abdullah
malrotation in symptomatic patients. Apart from F. Asymptomatic malrotation: diagnosis and surgical
the risk of intestinal failure, midgut volvulus still management: an American Pediatric Surgical Associa-
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systematic review. J Pediatr Surg. 2015;50(10):
Comparisons of laparoscopic versus open
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minimal-invasive approach with less overall com- graphic assessment of the position of the third part of
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Radiol. 2014;44(4):387–91. P. Sonographic assessment of the retroperitoneal posi-
Huntington JT, Lopez JJ, Mahida JB. Comparing laparo- tion of the third portion of the duodenum: an indicator
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patients. J Pediatr Surg. 2017;52(7):1128–1131. (8):941–5.
Khatami A, Mahdavi K, Karimi MA. Ultrasound as a Millar AJ, Rode H, Cywes S. Malrotation and volvulus in
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J Radiol. 2014;19(79):112–6. 12(4):229–36.
Kiely EM, Pierro A, Pierce C, Cross K, De Coppi P. Clot Nehra D, Goldstein AM. Intestinal malrotation: varied
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Kluth D, Fiegel H. The embryology of the foregut. Semin Stanfill AB, Pearl RH, Kalvakuri K, Wallace LJ, Vegunta
Pediatr Surg. 2003;12(1):3–9. RK. Laparoscopic Ladd’s procedure: treatment of
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Lampl B, Levin TL, Berdon WE, Cowles RA. Malrotation Tan YW, Khalil A, Kakade M, et al. Screening and treat-
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Congenital Hyperinsulinism
61
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Epidemiology and Types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Medical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
Postoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910
Abstract
Congenital hyperinsulinism (CHI) comprises a
group of disorders characterized by excessive
insulin secretion from pancreatic β-cells, resulting
in severe hypoglycemia. In neonates and infants,
A. Zani (*) CHI is considered the most frequent cause of
Division of General and Thoracic Surgery, The Hospital persistent hypoglycemia. Prompt diagnosis and
for Sick Children, Toronto, Canada treatment are crucial as a delay may cause severe
Department of Surgery, University of Toronto, brain damage and long-term neurodevelopmental
Toronto, Canada disability. Therapeutic strategies for CHI can be
e-mail: augusto.zani@sickkids.ca
medical, surgical, or combined.
A. Pierro
for Sick Children, University of Toronto, Keywords
Toronto, ON, Canada Congenital hyperinsulinism · Transient
Department of Surgery, University of Toronto, hyperinsulinism · Persistent hyperinsulinism ·
Toronto, Canada Hypoglycemia · Pancreatectomy
e-mail: agostino.pierro@sickkids.ca

https://doi.org/10.1007/978-3-662-43588-5_65
Introduction regulate insulin secretion from the pancreatic

β-cells, such as GLUD1 (encoding the enzyme
Congenital hyperinsulinism (CHI) represents a glutamate dehydrogenase), GCK (encoding the
group of disorders characterized by excessive enzyme glucokinase), HADH (encoding the L-3-
insulin secretion from pancreatic β-cells, which hydroxyacyl-coenzyme A dehydrogenase), UCP2
results in severe hypoglycemia. In the past, the (encoding the uncoupling protein2), and SLC16A1
same condition was named in several ways: (encoding the monocarboxylate transporter 1)
nesidioblastosis, islet cell adenomatosis, beta cell (Nessa et al. 2016; Stanley 2016).
dysregulation syndrome or dysmaturation syn-
drome, or persistent hyperinsulinemic hypoglyce-
mia of infancy (PHHI). Histology
CHI can be classified into three histological vari-

Epidemiology and Types ants: diffuse, focal, and atypical.
Focal forms, which are typically sporadic in
CHI is considered the most frequent cause of inheritance, are restricted to a small area of the
persistent hypoglycemia in neonates and infants. pancreas (2.5–7.5 mm), where β-cells have a large
The estimated incidence is 1 in 50,000 live births, cytoplasm and abnormal nuclei of irregular shape.
but it can be as frequent as 1 in 500 in countries Within the focal lesion several abnormal lobules are
with a high rate of consanguinity, such as Saudi interspersed with acinar foci, and a second
Arabia. endocrine-cell population can be detected. These
CHI can present in different ways. The main features are representative of an abnormal develop-
distinction to make is whether it is a transient or a mental process rather than a tumorigenic process.
persistent phenomenon. Transient hyperinsulinism Around the main focal lesion there could be satellite
is caused mainly by nongenetic factors, such as areas of abnormal pancreatic tissue. Therefore, clear
perinatal stress or small size for gestational age. resection margins are crucial to avoid recurrence.
However, some neonates, usually macrosomic, Diffuse forms, which are typically inherited in
have transient CHI due to mono-allelic inactivating an autosomal recessive or dominant manner,
mutation of hepatocyte nuclear factor 4α (HNF4A) involve every β-cells throughout the whole pan-
(Kapoor et al. 2008). Later in life, some of these creas with variable involvement of the islets. The
patients may develop maturity-onset diabetes of islet pattern is preserved but contains active
the young type 1 (MODY1) and therefore should β-cells with abundant cytoplasm and abnormal
be followed up after resolution of CHI. nuclei.
Conversely, most cases of persistent hyperinsu- Atypical forms are not well defined. The pan-
linism have recognized genetic etiologies (Yorifuji creas presents a diffuse CHI pattern in one large
2014; Rozenkova et al. 2015). The genetic forms area, but the rest of the organ is histologically
are caused by recessive or dominant mutations of normal. Some forms are due to chromosomal
regulatory genes for glucose metabolism and insu- mosaics, but their genetic basis has not been
lin secretion. The main genes involved are ABCC8 fully elucidated.
and KCNJ11 genes, which encode for subunits
(SUR1 and KIR6.2) of the ATP-sensitive K+
(KATP) channel (Nessa et al. 2016; Stanley Diagnosis
2016). Recessive inactivating mutations in
ABCC8 or KCNJ11 cause continuous β-cell mem- The inappropriate insulin secretion that is seen in
brane depolarization and subsequent calcium CHI results in increased glucose consumption,
influx, which result in unregulated insulin secre- inhibition of glycogenolysis and gluconeogene-
tion. Dominant inactivating mutations in the same sis, and ultimately hypoglycemia (Ferrara et al.
genes cause a milder form of CHI. Other genes 2016). This puts the brain at severe risk of injury,
implicated in rarer forms of CHI are those that due to the suppression of ketone body production,
61 Congenital Hyperinsulinism 907
i.e., its alternative energy substrate, secondary to infusion at >6–8 mg/kg/min. In absence of intra-
insulin-induced inhibition of lipolysis and free venous access, intramuscular glucagon may also
fatty acid production. Expedite diagnosis is cru- be administered, in order to stimulate glycogenol-
cial to avoid complication. ysis and glucose release from the liver. Patients
The diagnostic criteria for CHI include the will also be started on continuous or frequent
following: feeding regime.
Drug treatment includes diazoxide with chlo-
– Fasting and/or postprandial hypoglycemia rothiazide, nifedipine, octreotide, and new medi-
(<2.5–3 mmol/L). cines such as long-acting octreotide.
– Inappropriate plasma insulin and C-peptide Diazoxide is an inhibitor of insulin secretion,
levels concomitant to hypoglycemia. and it is used in all types of CHI. Diazoxide binds
– Increased blood glucose levels (>1.7 mmol/L to the SUR1 subunit of KATP channel, which
or 30 mg/dL) within 30–40 min following glu- activates intact KATP channels and reduces insu-
cagon administration. This is important for the lin secretion. However, patients with diffuse CHI
differential diagnosis with glycogen storage secondary to ABCC8 or KCNJ11 mutation and
disease. those with focal lesions are unresponsive to
– Inappropriately low plasma and urine ketone diazoxide, as they have no intact KATP channels.
bodies and low plasma free fatty acids for Diazoxide can cause fluid retention, which can be
fasting hypoglycemia. so severe to result in congestive heart failure espe-
cially in neonates. For this reason, chlorothiazide,
Infants with CHI have a fasting tolerance of a thiazide diuretic, is used in combination also
less than 1 h, so that they require continuous thanks to its synergistic effect on insulin secretion
intravenous glucose infusion at more than suppression.
8 mg/kg/min to maintain normal glycemic levels Nifedipine is a calcium channel blocker, which
(normal: 4–6 mg/kg/min). inhibits insulin secretion by inactivation of
voltage-gated calcium channels.
Octreotide is a long-acting analogue of
Treatment somatostatin, which naturally inhibits the insulin
release from the pancreatic β-cells. Octreotide
It is crucial to make a prompt diagnosis and insti- activates the somatostatin receptor 5 (SSTR5),
tute immediate treatment since delay in managing thus inhibiting calcium mobilization and acetyl-
CHI can cause severe brain damage and long-term choline activity, and decreases insulin gene pro-
neurodevelopmental disability (Lord et al. 2015). moter activity, which reduces insulin biosynthesis
It is essential to insert a central venous catheter to and insulin secretion.
monitor blood glucose levels and to provide a
reliable route for intravenous glucose administra-
tion. The goal of therapy is to achieve normal Surgical Treatment
blood glucose levels, considered as >63 mg/dl
or >3.5 mmol/L and to inhibit inappropriate insu- Indication for surgery is the failure to respond to
lin secretion. intensive medical treatment. Surgical procedures
Therapeutic strategies can be medical, surgical, and approaches vary according to whether the
or combined (Arnoux et al. 2011). patient has focal or diffuse CHI (Pierro and Nah
2011).
Medical Treatment Diffuse CHI

When the whole pancreatic tissue is affected, the
In the emergency setting, e.g., in case of seizures, gold standard operation is to resect the majority of
the infant should receive an intravenous bolus of it (95%), carrying out a “near-total” pancreatec-
2 ml/kg of 10% glucose, followed by a glucose tomy in order to prevent recurrent
hyperinsulinemia. In near-total pancreatectomy, process is mobilized. A sling may be placed

the tail, body, uncinate process, and part of pan- around the superior mesenteric vessels, retracting
creatic head are resected, leaving a rim of pancre- them away from the uncinate process. As the head
atic tissue surrounding the common bile duct and of pancreas is approached, attention is directed to
along the duodenum. In refractory cases, a 98% identifying the course of the common bile duct. A
pancreatectomy is performed, and only small sling is placed around the bile duct superior to the
islands of tissue are left along the pancreatico- first part of the duodenum. A blunt forceps is then
duodenal arcade bordering the duodenum. A passed from within the C-loop of the duodenum
“near-total” pancreatectomy can be performed behind the first part of the duodenum to grasp the
with an open or laparoscopic approach. sling, bringing it out superior to the head of pan-
creas. This becomes the guide to the position of
Open Near-Total Pancreatectomy the common bile duct during subsequent dissec-
The abdomen is accessed via a transverse supra- tion of the pancreas. The head of the pancreas is
umbilical incision. The lesser sac is entered mobilized, and the superior and inferior pancreati-
through the gastrocolic omentum; kocherization coduodenal vessels are divided. The pancreatic
of the duodenum allows full exposure of the pan- duct is ligated with nonabsorbable sutures and
creas. The tail of the pancreas is sent for divided. A rim of pancreatic tissue surrounding
intraoperative frozen section histology, and the the common bile duct and along the duodenum is
diagnosis of diffuse CHI is confirmed before pro- left remaining after near-total pancreatectomy
ceeding with pancreatectomy. A stay suture is (Fig. 1). The abdomen is closed in layers using
placed in the tail of the pancreas to allow traction absorbable sutures. Postoperatively, the patient
of the pancreas facilitating its dissection because has both nasogastric tube and bladder catheter.
direct handling of the pancreas results in fracture Enteral feeds are restarted after the gastrointesti-
of this friable organ. The tail of the pancreas is nal function has returned.
carefully dissected away from the hilum of the
spleen, and the short pancreatic vessels are coagu- Laparoscopic Near-Total Pancreatectomy
lated. Dissection of the pancreas is carried out in a An umbilical 10-mm Hasson port is inserted by
medial direction toward the head of the pancreas. an open technique, and a 5-mm 30 camera is
Pancreatic vessels passing from the splenic introduced. Three additional ports are placed: a
vessels into the pancreas are coagulated and 5-mm port in the left lower quadrant, a
divided using bipolar diathermy. Meticulous care Nathanson retractor at the epigastrium, and a
is taken with the splenic artery and vein, which are further working port (3 or 5 mm) in the right
closely related to the pancreas, as the spleen flank. The gastrocolic omentum is divided, and
should be preserved. Once dissection has arrived the lesser sac is entered. The Nathanson retractor
at the superior mesenteric vessels, the uncinate is used to retract the stomach. The head of the
Fig. 1 Near-total
pancreatectomy. The grey
area indicates the resected
pancreas, leaving behind an
amount of pancreatic tissue
around the common bile
duct and along the medial
border of the duodenum
patient is elevated. A stay suture is inserted into carried out, and pancreaticojejunostomy is
the tail of the pancreas, which is used to retract performed to allow drainage of the distal pan-
the pancreas superiorly. Dissection of the pancreas. In distal focal lesions, a distal pancreatec-
creas proceeds toward the head. The short pan- tomy may be done laparoscopically.
creatic vessels passing from the splenic vessels
into the pancreas are divided using a 3-mm hook Surgery for Focal CHI
diathermy at very high coagulation settings. The abdomen is accessed laparoscopically as
These vessels are the most common source of described above.
intraoperative hemorrhage, which may be con- The pancreas is inspected for a nodular area,
trolled by applying gentle pressure using an which indicates the site of the focal lesion. In focal
atraumatic bowel grasper. The pancreatic tail is CHI, the lesion is often deep within the paren-
transected using the Harmonic scalpel (Ethicon chyma of the pancreas and may not be visually
Endo-Surgery). The pancreatic tail is removed evident. An intraoperative biopsy is performed for
via the umbilical 10 mm port and sent for frozen frozen section histologic examination. Histology
section analysis to confirm the diagnosis of dif- may reveal the following: (1) the presence of the
fuse CHI. No further resection takes place until focal lesion completely resected (normal pancreas
this confirmation has been obtained. Subsequent at the resection margin), (2) focal lesion not
dissection is facilitated by the insertion of a stay completely resected, and (3) the presence of nor-
suture at the cut surface of the remaining pan- mal pancreas excluding the presence of diffuse
creas, which is resected in segments of approx- CHI and indicating that the focal lesion has not
imately 2 cm. As dissection nears the head of the yet been excised.
pancreas, stay sutures are placed in the uncinate
process and the head of pancreas, which are Focal Lesion in Head or Neck of Pancreas
retracted superiorly. A near-total pancreatec- When the focal lesion is deep in the head or neck
tomy is achieved by leaving an adequate amount of the pancreas, the procedure may be converted
of pancreatic tissue along the medial border of to open, and dissection of the head of the pancreas
the duodenum where the common bile duct is is commenced (Fig. 2a). Superficial lesions may
expected (Fig. 1). Port sites are closed using be enucleated laparoscopically.
absorbable sutures. No drains are used. A sling may be passed behind the neck of the
pancreas to facilitate traction of the pancreas away
Focal CHI from the pancreatic bed. Short pancreatic vessels
In patients with focal CHI, a localized resection of are meticulously ligated using bipolar diathermy
the focal lesion is curative. The diagnosis of focal and divided. The head of the pancreas is dissected
CHI and its localization is made using fluorine- in the direction of the duodenum, carefully
18-L-3,4-dihydroxyphenylalanine positron emis- avoiding the common bile duct. A pancreaticoje-
sion tomography (18F-DOPA-PET) scan (Shah junostomy is then constructed to allow drainage of
et al. 2014; Zani et al. 2011). This imaging tech- the distal pancreas.
nique allows an accurate differentiation between
focal and diffuse forms and, in case of focal CHI, Focal Lesion in Body or Tail of Pancreas
helps the localization of the lesions that are usu- In more distal lesions, the entire procedure may be
ally deep in the parenchyma and hardly visible completed either laparoscopically or open
macroscopically. Although the accuracy of local- (Fig. 2b). Once histologic confirmation of focal
ization in 18F-DOPA-PET-CT scan is approxi- disease is obtained, the pancreas is dissected as
mately in 70% of cases, this imaging technique described previously. Dissection is performed
is beneficial for the preoperative surgical plan- until the resected specimen includes the lesion.
ning: in focal lesions of the head or neck of the The pancreas is transacted with the Harmonic
pancreas, open resection of the lesion with a small scalpel (Ethicon Endo-Surgery, Cincinnati, OH).
rim of surrounding normal pancreatic tissue is An adequate resection margin is confirmed by
Fig. 2 Focal CHI.

(a) Lesion in the head or
neck of pancreas (zone A:
white area). Surgery: open
excision of focal lesion and
pancreaticojejunostomy.
(b) Lesion in the body or tail
of pancreas (zone B: grey
area). Surgery: laparoscopic
or open distal
pancreatectomy
further frozen section analysis. There is no need and dieticians is advisable to assure careful glu-
for drains. cose/insulin balance and optimal long-term drug
treatment. The treating pediatric surgeon should
be aware that patients who underwent near-total
Postoperative Management pancreatectomy have a high risk of developing
diabetes (Lord et al. 2015).
Enteral feeds are recommenced as early as the first
postoperative day and gradually advanced, reduc-
ing the intravenous infusion of dextrose. It is not
unusual to observe a period of gastroparesis, par- Cross-References
ticularly after excision of the head of the pancreas
for focal lesions or near-total pancreatectomy for ▶ Pediatric Clinical Genetics
diffuse CHI. This may last 2–3 days. The man-
agement of postoperative hypoglycemia may
require medical treatment. However, this is usu- References
ally transient. Further resection of the pancreas is
Arnoux JB, Verkarre V, Saint-Martin C, et al. Congenital
needed when bolus enteral feeding and cessation
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A. Biomarkers of insulin for the diagnosis of hyper-
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insulinemic hypoglycemia and maturity-onset diabetes
Congenital hyperinsulinism represents a group of the young due to heterozygous HNF4A mutations.
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Lord K, Radcliffe J, Gallagher PR, Adzick NS, Stanley
Early diagnosis and treatment are fundamental CA, De León DD. High risk of diabetes and
as delay can cause brain damage and impair neurobehavioral deficits in individuals with surgically
long-term neurodevelopment. As low or treated hyperinsulinism. J Clin Endocrinol Metab.
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undetectable insulin levels do not exclude the
Nessa A, Rahman SA, Hussain K. Hyperinsulinemic hypo-
diagnosis of hyperinsulinism, biomarkers such glycemia – the molecular mechanisms. Front Endo-
as C-peptide and insulin-like growth factor bind- crinol (Lausanne). 2016;7:29.
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(Ferrara et al. 2016).
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7(2):86–97. future perspectives. Ann Pediatr Endocrinol Metab.
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Jejunoileal Atresia and Stenosis
62
Alastair J. W. Millar, Alp Numanoglu, and Sharon Cox
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
Etiology/Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 914
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
Prenatal Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
Postnatal Radiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
Postoperative Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
Prognosis and Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
A. J. W. Millar (*) Abstract

Emeritus Professor of Paediatric Surgery, Faculty of Health Jejunoileal atresia, defined as a congenital
Sciences, Department of Paediatric Surgery, University of defect in continuity of the bowel, is a common
Cape Town, Red Cross War Memorial Children’s Hospital,
Cape Town, Rondebosch, South Africa cause of intestinal obstruction in the newborn.
e-mail: alastair.millar@uct.ac.za The incidence of jejunoileal atresia varies from
A. Numanoglu · S. Cox
1 in 330–400 live births to between 1 in
Division of Paediatric Surgery, Faculty of Health Sciences, 1500–3000 live births. Jejunoileal occlusions
University of Cape Town, Red Cross War Memorial occur more frequently than duodenal or
Children’s Hospital, Cape Town, South Africa colonic. The management of jejunoileal atresia
e-mail: alp.numanoglu@uct.ac.za; sharon.cox@uct.ac.za

https://doi.org/10.1007/978-3-662-43588-5_66
has been one of the great success stories of if not resected or tapered at the time of surgery
pediatric surgery in the twentieth century. following end-to-end anastomosis with the
Mortality of more than 90% up till 1950 was absence of parenteral nutritional support. An
turned to a >80% survival with a simple understanding of the etiology and realization that
change in surgical technique prompted by the proximal blind-ending dilated bulbous atretic
innovative surgical experiments on dog fetus bowel was the cause of poor prograde peristalsis
performed by Barnard and Louw – the first and that resection of this segment with primary
steps in fetal surgery. With improved neonatal anastomosis of proximal to distal bowel solved
and perioperative care, safe anesthesia, this problem led to a dramatic improvement in
refined surgical techniques, and better outcomes from a mortality of 90–100% to a sur-
management of short bowel syndrome, a survival of over 80% in the 1950s even without
vival rate of greater than 95% can be expected parenteral nutritional support (Haller et al. 1983;
in well-resourced centers. This chapter Louw 1967; Nixon 1955).
describes the current approach to the diagnosis
and management of jejunoileal atresia of the
newborn.
Demographics
Keywords
The incidence and type of intestinal atresia vary
Congenital · Intestinal · Atresia
widely among different countries and geographi-
cal areas. In Europe and the USA, this is around1:
3000 to 1:10,000 live births and in Africa nearer to
Introduction
1:1000 live births where types III and IV are more
frequent. There also appears to be an increased
Atresias and stenoses of the jejunum and ileum
incidence in twin pregnancies at 7.3 per 10,000
are common causes of bowel obstruction in the
live births (Adeyemi 1989). The male-to-female
neonate and account for about one third of all
ratio is equal in most reports. There have been
cases of neonatal intestinal obstruction with nec-
other familial associations reported, but to date, a
rotizing enterocolitis, midgut volvulus,
specific gene mutation has not been discovered.
anorectal malformations, cystic fibrosis, con-
genital segmental dilatation of the intestine,
and Hirschsprung’s disease as differential diag-
noses. A third of infants with these conditions Etiology/Pathophysiology
are born prematurely or small for their gesta-
tional age (Stollman et al. 2009). Stenoses are Our present understanding of the etiology of
less frequently seen, occurring in about 5% of intestinal atresias is based upon the classic
cases, and seldom present in the newborn period experimental work of Louw and Barnard
due to delay in diagnosis (DeLorimier et al. reported in1955 (Louw and Barnard 1955).
1969). These investigators observed that ligating mes-
In the early days of pediatric surgery, outcomes enteric vessels and causing strangulated bowel
after surgery, whether end-to-end anastomosis or obstruction in fetal dogs resulted in atretic
stoma formation, were associated with a generally lesions of the small intestine that were similar
poor prognosis. Factors contributing to this his- to those observed clinically in human neonates.
toric poor prognosis included delayed presenta- Thus, atresias and stenoses of the small intestine
tion, frequent ischemia, and necrosis of the are believed to be due to an ischemic insult. The
proximal bowel due to pressure-induced disten- ischemic bowel is resorbed and both ends heal
sion and/or volvulus of the proximal bulbous resulting in two blind ends. The proximal end
dilated segment and dysmotility of the dilated becomes distended in time with pressure from
segment of the bowel proximal to the obstruction prograde peristalsis of swallowed liquor and
62 Jejunoileal Atresia and Stenosis 915
intestinal secretions. This etiologic mechanism Classification

explains the frequent association of atresias with
mesenteric defects and with other conditions Atresias occur equally in the jejunum and ileum,
that may cause strangulated obstruction of the with the distal ileum and proximal jejunum being
intestinal tract (e.g., volvulus, intussusception, the most frequent sites. While most atresias are
internal hernias, and gastroschisis). An ischemic single, around 10% can be multiple and these
etiology may also explain why intestinal atresias usually involve the proximal jejunum.
are often associated with maternal smoking and The contemporary morphological classifica-
vasoconstrictor drug exposure during preg- tion into stenosis and four types of atresia was
nancy. Caffeine and ergotamine tartrate use for initially described by Martin in 1976 and later
migraines in late pregnancy, as well as the used revised by Grosfeld and colleagues (Grosfeld
of pseudoephedrine and acetaminophen, has et al. 1979). This was based initially on the
been associated with an increased incidence nomenclature of Bland Sutton and Louw and has
(Graham et al. 1983). Other suggested causes both prognostic and therapeutic implications
have been placental insufficiency or intermittent (Fig. 1).
midgut volvulus. There is a greater incidence of • Stenoses occur in 5–10%. In this situation the
cystic fibrosis and malrotation in association proximal and distal bowel are in continuity
with jejunal atresia compared with ileal atresia with an intact mesentery. At the point of steno-
(Sweeney et al. 2001). sis, there is a short rigid segment with a narrow
There have also been several case series reports but patent lumen. There is a normal length of
of familial small bowel atresia, most frequently the intestine.
type IV lesions (Mishalany and Najjar 1968). The • Type I atresia (~23%) is a transluminal septum
apple-peel variety may also be associated with a (membrane or web) with dilated proximal
familial pattern, and in this situation patients typ- bowel in continuity with collapsed distal
ically present as premature, low birth weight bowel. The bowel is usually of normal length.
babies and have associated malrotation and other
congenital abnormalities (Blyth and Dickson
1969). More recently some of the established con-
cepts of bowel development and rotation have
been questioned (Nichol et al. 2011; Shorter
et al. 2006).
Clearly the usual type of jejunoileal atresia
described is quite different from the familial mul-
tiple atresias of the whole gastrointestinal tract
seen in severe immune deficiency syndrome,
which is an autosomal recessive condition (Cole
et al. 2010).
However the localized nature of the vascular
accident occurring late in fetal life would explain
the low incidence (less than 10%) of congenital
coexisting malformations other than the intestine,
as well as the observation that bile pigments,
lanugo hair, and squamous cells may be found in
the lumen distal to the atretic segment. There is a
low incidence of less than 1% of an association of
proximal jejunal atresia and duodenal atresia, and
Fig. 1 Types of jejunoileal atresia according to the Bland-
there have been isolated reports of biliary atresia Sutton and Louw and Grosfeld classification (Bland-
and jejunal atresia. Sutton 1914; Louw 1967):
• Type II atresia (~10%) involves two blind- Distally the bowel is disused and narrow, but
ending atretic ends separated by a fibrous essentially should have normal peristaltic
cord along the edge of the mesentery with function.
mesentery intact. The total bowel lost approx-
imates the length of the atretic cord, and thus
prognosis is generally good. Prenatal Findings
• Type IIIa atresia (~15%) is similar to type II,
but there is a V-shaped mesenteric defect. The Atresias of the jejunum are frequently associated
total bowel length is always foreshortened. with polyhydramnios. The more proximal the
• Type IIIb atresia (19%) (“apple-peel” or atresia, the higher the incidence with up to 38%
“Christmas tree” deformity) consists of a prox- of cases of proximal jejunal atresia displaying
imal jejunal atresia near the ligament of Treitz, polyhydramnios. Fetal diagnosis with ultrasound
usually with malrotation and the absence of scanning may be made where, in addition to poly-
most of the mesentery. Prematurity and low hydramnios, dilated echogenic and thickened
birth weight are common. This type is the bowel with increased peristalsis and distal
result of an extensive infarction of the proximal decompressed bowel can be identified (Wax et
midgut secondary to an occlusion of the supe- al. 2006). Prenatal ultrasound, however, has a
rior mesenteric artery just distal to the middle relatively poor predictive value and is unreliable
colic origin. A varying length of ileum survives in detecting atresias with less than a third of cases
coiled around a single artery with perfusion being detected (Wax et al. 2006). As suggested by
from retrograde flow via an arcade of the the etiology, the later the ultrasound in gestation,
right colic or middle colic artery. Occasionally the more likely it will be to define the atresia. The
there may be further type I and II atresias along use of fetal MRI scanning is increasing and may
the length of the coiled bowel. There is always be more valuable in the prenatal diagnosis of
significant reduction in intestinal length; thus, bowel atresia (Veyrac et al. 2004).
these babies may develop short bowel syn-
drome and have an increased morbidity and
mortality. Familial incidence of this type has Clinical Presentation
been reported (Seashore et al. 1987).
• Type IV atresia is a multiple atresia of types I, Many of these patients are born prematurely and
II, and III and appears clinically to look like a often are small for their gestational age due to
string of sausages. The viable bowel length is inability to absorb nutrients from the amniotic
always reduced. The site of the initial atresia fluid in patients with proximal intestinal obstruc-
determines if it is a jejunal or ileal atresia. The tions (Surana and Puri 1994). The more proximal
terminal ileum, as in type III, is usually spared. the atresia, the higher the incidence of low birth
weight infants. Nearly all infants with intestinal
atresias develop symptoms within hours after
Pathology birth; however, several publications have
documented that neonates in developing countries
The intestine proximal to the atresia is subject to often do not reach definitive medical care for
increased pressure due to ongoing fetal ingestion several days. Unlike atresias, most patients with
of amniotic fluid. This may lead to a cyanotic intestinal stenoses are not diagnosed until well
appearance of the dilated segment as well as beyond the neonatal period.
some areas of necrosis. Pre- or postnatal perfo- Intestinal atresia should be suspected in any
ration may develop. Histological and histochem- newborn showing evidence of bowel obstruction
ical abnormalities have been observed up to (bilious vomiting, abdominal distension, and
20 cm proximal to the obstruction, clinically failure to pass meconium). Aspiration of
presenting as reduced or ineffective peristalsis. >25 ml of fluid from the stomach via a
nasogastric tube (NGT) is very suggestive of

obstruction. Proximal atresias may show little
or only upper abdominal distension. The more
distal the atresia, the more generalized the
abdominal distension. After aspiration of gastric
contents, the abdomen will be less distended and
visible peristalsis may be observed. There is usu-
ally a failure to pass meconium, and typically
small-volume gray mucoid stools are passed.
The passage of meconium, however, does not
exclude an atresia as meconium distal to the
atresia may be present in late-onset lesions.
Occasionally, if ischemic bowel is present, as in
type IIIb atresia, blood may be passed rectally.
Abdominal tenderness, distension, or peritoni-
tis develops only with complications of ischemia
or perforation. This commonly occurs with a
delay in diagnosis in the more distal atresias and Fig. 2 Abdominal radiograph showing several dilated
is due to increased intraluminal pressure from gas-filled bowel loops in a newborn with jejunal atresia
swallowed air and/or secondary volvulus of the
bulbous blind-ending bowel at the level of the first calcification may be seen indicating meconium peri-
obstruction. tonitis from an antenatal perforation.
A contrast enema (a) in a newborn with
jejunoileal atresia (b) showing a patent but dis-
Postnatal Radiology used micro-colon helpful to rule out other differ-
ential diagnoses and colonic atresia (Fig. 3a, b)
In most patients, an abdominal x-ray with ante- It may also demonstrate the position of the
roposterior (AP) and either cross table or left lateral cecum, thus giving information regarding bowel
decubitus projections are adequate to make the diag- rotation – which is abnormal in 10–15% of cases.
nosis based upon the presence of dilated, air-filled A high jejunal atresia associated with malrotation
intestinal loops, and air-fluid levels (Fig. 2). In addi- on contrast enema is very suggestive of type IIIb
tion, plain abdominal x-rays especially if performed atresia. Preoperative demonstration of a patent
after aspirating all fluid from the stomach via a colon is also helpful in that confirming colonic
nasogastric tube and injecting air will suggest the patency by injection of saline at operation, a some-
level of obstruction based upon the number of times tedious procedure, is not required (Fig. 3).
dilated bowel loops. A single very dilated loop In patients with intestinal stenoses, plain
with a large fluid level and no further distal gas is abdominal x-rays may demonstrate proximal
often indicative of atresia, and in patients with evi- bowel dilatation; however, in most patients a gas-
dence of a proximal complete obstruction, the dif- trointestinal contrast meal or enema is required to
ferential diagnosis is limited, and no additional confirm and locate the site of partial obstruction.
diagnostic studies are required. A contrast meal
should not be necessary and adds no further infor-
mation. The radiograph findings with more distal Differential Diagnosis
atresias demonstrate a greater number of dilated
loops with a larger loop with an air-fluid level just The differential diagnosis includes other causes of
proximal to the atresia. A prone lateral view may be intestinal obstruction in the neonate.
useful to distinguish between low ileal and colonic Malrotation with or without volvulus may be
obstruction. Occasionally dystrophic intraperitoneal suspected when there is minimal abdominal
Fig. 3 (a, b) Contrast

enema showing normal
colon with dilated proximal
small bowel in an infant
with jejunal atresia
distension accompanied by bilious vomiting. The evidence of a serious cardiac defect. Prolonged
presence of multiple dilated bowel loops without delay in operative intervention increases the risk
air-fluid levels suggests the possibility of meco- of fluid and electrolyte disturbances, ischemia of
nium ileus, particularly if the intestinal content the dilated segment, and infection (Table 1).
has a “ground-glass” appearance. In patients with Operative techniques need to be individualized
multiple dilated bowel loops, suggesting a distal according to the type of atresia, length of residual
obstruction, the differential diagnosis includes sev- bowel, presence of complications, and surgeon
eral conditions for which surgical intervention may capabilities. In addition, associated pathologies
not be required. Therefore, in these patients a con- or defects (meconium peritonitis, gastroschisis)
trast enema may be helpful to look for evidence of a may influence the procedure performed. Explora-
meconium plug or meconium ileus, which may tion is usually via a supra-umbilical transverse
respond to nonoperative management. In addition, incision although minimally invasive peri-
a contrast enema may demonstrate findings sug- umbilical incisions and laparoscopy are increas-
gestive of Hirschsprung’s disease, which would ingly employed (Banieghbal and Beale 2007;
direct initial management toward obtaining confir- Lima et al. 2009; Li et al. 2015).
matory tests for this disease. The basic concepts of the surgical procedure
are to immediately isolate the site of perforation to
avoid further contamination of the peritoneal cav-
Management ity, identify all atresias, resect and/or narrow the
proximal dilated segment, preserve sufficient
All patients should receive judicious intravenous bowel length, and restore continuity of the
fluid hydration and be well resuscitated prior to bowel. In most cases of simple atresia, primary
operative intervention. In addition, a nasogastric anastomosis is safe and stomas are not required.
or orogastric tube should be passed to empty the The entire bowel is exteriorized. The site of
stomach and decrease the risk of vomiting with the most proximal atresia is readily identified as
pulmonary aspiration. Electrolyte imbalances the site of marked change in intestinal caliber.
need to be corrected and blood crossmatch The outer wall of the intestine at the site of
performed. In general, patients with intestinal obstruction may appear intact, or there may be
atresias have a low risk of associated cardiac an associated defect in continuity of the intestine
anomalies, so that preoperative special investiga- and the mesentery. Generally, surgical treatment
tion is not required unless the patient has clinical requires excision of the ends of the intestine
Table 1 Summary of diagnostic workup and management proximal to the first occlusion encountered. This
of jejunoileal atresia and stenosis (Adapted from Haller dilated bowel, even when the obstruction is
et al. 1983)
relieved by resection and anastomosis or stoma
Prenatal Polyhydramnios, affected family: formation, remains dilated, having inefficient pro-
ultrasonography, MRI
grade peristalsis. Surgical strategies to overcome
Preoperative Gastric decompression
management this include back resection of this bowel to a near
Fluid management: maintenance
and replacement normal-caliber intestine if sufficient residual
Correction of electrolyte length (more than 75 cm plus ileocecal valve) or
abnormalities reduction in diameter by various tapering maneu-
Transfer to a pediatric surgery vers (Grosfeld et al. 1979; Thomas and Carter
center 1974).
Radiology: abdominal radiograph, After resection of the atretic segment on both
contrast enema, contrast meal if
stenosis suspected sides of the defect (~10 cm on the proximal and
Assessment for associated 2 cm on the distal side), the surgeon is faced with
malformations the sometimes difficult task of reestablishing con-
Prophylactic antibiotics tinuity between intestinal segments with marked
Operative Identify type of atresia size discrepancies. Another consideration is the
management Establish distal patency potential dysmotility of the proximal markedly
Bulbous component: resect, taper, dilated segment, which may result in delayed
or plicate if short residual length
intestinal function and problems with bacterial
De-rotate and taper if high jejunal
atresia
overgrowth (Doolin et al. 1987). Therefore, in
Preserve maximal distal bowel patients with a relatively short segment of
length – measure residual bowel severely dilated proximal intestine, resection of
End-to-end single-layer interrupted the dilated segment with reestablishment of con-
anastomosis tinuity by end-to-end anastomosis is a good
Postoperative Gastrointestinal decompression option. This is best achieved by end-to-end
management Antibiotics extra-mucosal single-layer anastomosis using
Parenteral nutrition 5–0 or 6–0 polydioxanone sutures with larger
Early graduated enteral feeds:
gaps between interrupted sutures on the dilated
breast, special, or polymeric feeds
Special Anastomotic dysfunction
segment. Prior to anastomosis, the distal end of
problems Short bowel syndrome
the bowel may need to be gently dilated by apply-
Associated congenital ing a non-crushing clamp 6–8 cm beyond the
abnormalities distal blind end and distension with normal saline
injection, being careful not to split the serosa.
Transection of the distal bowel slightly obliquely
involved in the atresia. It is also important to look and extension of this incision along the anti-
for distal sites of obstruction, which can occur in mesenteric border may render the opening about
up to 20% of patients and may not be immedi- equal to that of the proximal bowel. Discrepancies
ately obvious due to lack of caliber change in size of bowel lumen of up to 8:1 have been
beyond the proximal atresia. These distal points accommodated using these techniques. However,
of obstruction can be identified by flushing the an end-to-end anastomosis is thought to result in
distal intestinal lumen with saline to confirm earlier return of normal peristalsis and is prefera-
intestinal continuity to the level of the rectum. ble where the lumen discrepancy is 4:1 or less.
Preoperative placement of a transrectal catheter In patients with long segments of proximal
may aid in this process if a contrast enema has intestine that are significantly dilated, resection
not been performed. of the whole involved segment may result in inad-
The immediate consequence of an atresia is equate remaining intestinal length to allow
dilatation of the bowel for a variable distance absorption of enteric nutrients, i.e., short bowel
syndrome. Therefore, these patients require either length remains. In type IV atresias with multiple
imbrication or tapering enteroplasty of the proxi- segments of bowel, it is useful to pass a nasogas-
mal dilated segment. To date, no randomized stud- tric tube through these segments consecutively
ies have compared the outcomes for patients with like a string of beads. This facilitates performing
intestinal atresia with or without the addition of an the multiple anastomoses and may even act as a
enteroplasty or inversion plication. stent during the postoperative period (Chaet et al.
In patients for whom the atresia is just distal to 1994). Patients that require multiple anastomoses
the duodenojejunal flexure, it may be advanta- may experience long-term delays in return of
geous to resect the dilated bowel up to the third intestinal function. In addition, many of these
part of duodenum and de-rotate and taper the patients will have short bowel syndrome due to
duodenum with primary anastomosis (Kling inadequate residual intestinal length. The total
et al. 2000). It is important to be careful to avoid residual length of bowel should be measured
cutting back too far such that the pancreas and with a tape at operation and recorded, as this
ampulla of Vater are protected. Passage of a trans- gives some guidance as to prognosis. In general,
anastomotic feeding tube for early commence- the formation of stomas is unnecessary and should
ment of enteral feeding is a useful adjunct to be avoided because dilated bowel does not reduce
postoperative nutrient support particularly if in caliber, and fluid and electrolyte losses may be
delay in restoration of foregut function is expected severe.
due to gross dilatation of the proximal bowel and The bowel should be displayed in a position of
if parenteral nutrition is not available, a situation non-rotation keeping the free mesenteric border in
still common in many parts of the world. A trans- sight, and restrictive fibrotic bands along this free
anastomotic tube can either be passed via the edge should be divided prior to primary anasto-
nasogastric route or via a Stamm gastrostomy mosis to enhance blood supply and venous drain-
performed on the anterior aspect of the stomach. age. The mesentery from any resected bowel is
Patients who have multiple atresias (type IV) retained and may assist in closure of mesenteric
or an apple-peel deformity (type IIIb) present defect (Millar et al. 2000). This technique is very
particularly challenging management problems helpful and prevents kinking or distortion of the
(Fig. 4a, b). Multiple atresias are often localized anastomosis. Furthermore, the potential for
to a short segment of intestine, and resection with kinking the single marginal artery and vein
one anastomosis is preferred if sufficient intestinal requires careful placement of the bowel into the
Fig. 4 (a, b) Two operative

photographs of type IIIb
anomalies. In (a), there is a
high jejunal atresia,
malrotation, and viable
~100 cm of distal ileum
supplied by a single artery
arising from the right colic
arcade. In (b) a similar
anatomical anomaly type
IIIb atresia (apple-peel) has
undergone recent antenatal
volvulus with infarction
resulting in ultrashort bowel
peritoneal cavity at the completion of the Postoperative Care

anastomosis.
In infants with congenital short bowel, autolo- Postoperative care requires nasogastric decom-
gous intestinal reconstructive surgery (AIRS) pression for several days after the operation (lon-
such as the serial transverse enteroplasty proce- ger for high jejunal atresias). Therapeutic
dure (STEP) and lengthening and tailoring pro- antibiotics are usually continued for 5–7 days or
cedures (LILT, Bianchi) have no defined place at longer directed by culture of gastric aspirate and
the initial operation although sporadic reports enteric content, and an oral antifungal agent is
have appeared in the literature (Bianchi 1980; given prophylactically. Parenteral nutrition is
Wales and Dutta 2005). It would seem wiser to given initially and weaned slowly as enteral feed-
perform a primary end-to-end anastomosis and ing is increased as per protocols. There is increas-
allow for adaptation to progress before intervening evidence that keeping the daily fat load to
ing surgically when a plateau of enteral tolerance 1 gm/kg body weight and the use of fish
has been achieved and the infant is well grown oil-containing lipid will reduce the incidence and
and outside the neonatal period. The fashioning of severity of parenteral nutrition-associated liver
stomas, e.g., Bishop-Koop, Santulli, Rehbein, or disease (Hess et al. 2011).
double barrel, as practiced by some, is not rou- Gavage feeding can begin as soon as there is
tinely advocated unless there is gross intraperito- evidence of bowel peristalsis. If a trans-
neal contamination, making a primary anastomotic tube has been placed, hourly feedings
anastomosis unsafe. The Bishop-Koop stoma can commence in small volumes from the day
seems to be particularly associated with an following surgery. Oral intake is commenced
increased incidence of complications. when the neonate is alert and sucks well, and
Jejunoileal atresia associated with a there is evidence of prograde gastrointestinal
gastroschisis is treated by resection and primary function, i.e., clear gastric effluent of low volume,
anastomosis if there is limited edema and mat- a soft abdomen, and stools have been passed.
ting from amniotic peritonitis. If there is marked Surveillance should continue until the infant has
edema and matting, initial reduction of the evis- established normal gastrointestinal function. If at
cerated bowel with the atresia intact and primary any time there is suspicion of a leak at the anasto-
closure of the abdominal wall defect, if possible, mosis (suggested by ileus, abdominal distension,
is preferred (van Hoorn et al. 1985). After allo- vomiting, and peritonitis), a plain radiograph of the
wing for disappearance of the edema abdomen should be taken. If this reveals free air in
(10–14 days), a second laparotomy is performed the abdomen more than 24 h after operation, which
with resection of the atretic segment and primary is indicative of bowel perforation, laparotomy
anastomosis. In the long term, there is up to 20% should be performed immediately and the leaking
incidence of prolonged dysmotility, which may site sutured or the anastomosis redone.
benefit from surgical interventions of tapering or
imbrication. The so-called closed gastroschisis
may be associated with the both exit and entry Postoperative Complications
level atresias with loss of intestinal length. Serial
antenatal ultrasound scanning may show The most common postoperative complication is a
increasing bowel dilatation which should pro- functional obstruction at the site of anastomosis.
mpt earlier preterm delivery (Houben et al. Unfortunately, this complication may be due to the
2009). underlying intestinal dysmotility associated with
It is important to note that enteroplasties, exci- this anomaly and may not be preventable by
sion of membranes, and bypass techniques are not changes in surgical technique. Other less com-
recommended in patients presenting with monly observed complications include anasto-
jejunoileal stenosis as these procedures fail to motic leak and adhesive obstructions. HIV
remove the dysfunctional segments. infection or exposure is associated with a higher
incidence of anastomotic breakdown and wound Further study into the etiology of the familial
sepsis with dehiscence. Obstructions due to missed variety is required to understand the mechanisms
distal unrecognized atresias should not occur and of causation.
can be prevented by proper evaluation at the time
of the initial operation. Persistent bowel dysfunc-
tion or obstruction requires a full evaluation with Cross-References
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Colonic and Rectal Atresias
63
Tomas Wester
Contents
Colonic Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 926
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 927
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
Complications and Long-Term Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
Rectal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 930
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932
Complications and Long-Term Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 932
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 933
Abstract suspected on plain abdominal radiographs. A

Colonic and rectal atresias are very rare. Both contrast enema is useful to show a microcolon.
have been considered to be the result of insuf- Rectal atresia is suspected in neonates with
ficient blood supply during intrauterine life. bowel obstruction, where it is impossible to
Rectal atresia is included in classifications of pass a catheter through the rectum, although
anorectal malformations. Colonic and rectal the anus is normal. Colonic atresia is often
atresia both present as neonatal bowel obstruc- operated with resection of dilated colon and
tion. The diagnosis of colonic atresia is usually primary anastomosis. In complicated cases, it
is common to open a colostomy in the neonate
and do the anastomosis later. There are several
procedures for rectal atresias. Many investiga-
T. Wester (*)
Department of Pediatric Surgery, Karolinska University tors open a colostomy in the neonate and
Hospital, Karolinska Institutet, Stockholm, Sweden reconstruct the rectum through a posterior
e-mail: tomas.wester@karolinska.se; tomas.wester@ki.se

https://doi.org/10.1007/978-3-662-43588-5_67
926 T. Wester
sagittal approach at a later stage. Long-term

functional outcome is usually favorable in
patients with colonic as well as rectal atresia.
Keywords
Colonic atresia · Rectal atresia · Primary
anastomosis · Posterior sagittal approach ·
Outcome
Colonic Atresia
Introduction
Binninger was the first to describe colonic atresia

in 1673 (Evans 1951). The first survivor was
reported in 1922, when Gaub (1922) opened a
diverting colostomy in a child with an atresia of
the sigmoid colon. Potts (1947) successfully
performed a primary anastomosis in a neonate
with an atresia of the transverse colon in 1947.
Atresia of the colon is a rare cause of bowel
obstruction in the neonate. The incidence of
colonic atresia in live births has been difficult to
ascertain, but an incidence of approximately one in Fig. 1 (a) Type I: there is continuity of the outer layers of
the bowel wall; the lumen is obstructed by a membrane
20000 live births has been considered to be realistic covered with two layers of mucosa. (b) Type II: the bowel
based on the experience in major pediatric surgical ends are connected by a fibrous band, and the mesentery is
centers (Philippart 1986). In the Northwest of intact. (c) Type III: a defect in the mesentery is accompa-
England, isolated colonic atresia has been reported nied by a gap between the bowel ends (Reprinted with
permission from Wester T. Colonic and Rectal Atresias.
to occur in one in 66,000 live births (Davenport In Puri P (ed). Newborn Surgery 3rd ed. Hodder Arnold,
et al. 1990). Other investigators have reported that London. 2011 pp 505–511, Fig. 53.1)
colonic atresias account for 1.8–10.5% of the total
bowel atresias (Freeman 1966; Benson et al. 1968), 3. Type III atresia with separated blind ends of
the incidence of which has been estimated to be one bowel and a gap in the mesentery (Fig. 1c)
in 1500 to one in 20,000 live births (Evans 1951;
Webb and Wangensteen 1931). Colonic stenosis is Furthermore, a hereditary form with multiple
extremely rare. atresias of the gastrointestinal tract has been
Except for stenosis, three different types of described, suggested to be of nonvascular origin
intrinsic occlusion have been distinguished (Guttman et al. 1973; Puri and Fujimoto 1988).
(Louw 1964; Bland Sutton 1889): Type III atresia appears to be the most common
type proximal to the splenic flexure, whereas type
1. Type I atresia or a membrane (Fig. 1a) I and II are more common in atresias distal to the
2. Type II atresia with blind ends of bowel joined splenic flexure (Powell and Raffensperger 1982;
together by a cord-like remnant of bowel, with Boles et al. 1976). In a literature review, it was
or without a gap in the mesentery (Fig. 1b) reported that type III occurred in 60.4% of all
63 Colonic and Rectal Atresias 927
cases (Etensel et al. 2005). Most series show an vomiting is very common but is not always an early
even distribution between atresias proximal and symptom. Failure to pass meconium is the rule, and
distal to the splenic flexure (Freeman 1966; Ben- neonates that do not pass meconium within the first
son et al. 1968; Peck et al. 1963; Coran and 24 h of life should be considered for further inves-
Eraklis 1969). tigations. On examination, the abdomen is distended
and often slightly tender, sometimes with visible
bowel loops. In those who have an abdominal wall
Etiology defect, associated atresias should always be
suspected.
Colonic atresia is probably the result of intrauter- Colonic atresia is associated with abdominal
ine vascular insufficiency. The finding of bile, wall defects, such as gastroschisis, cloacal
squamous epithelium, and hair in the bowel distal exstrophy, and more rarely omphalocele, which
to the atresia supports the hypothesis that the complicates the management of these patients
vascular accident occurs late in development (Philippart 1986; Boles et al. 1976; El-Asmar
(Louw 1964). Several pathological conditions et al. 2016). Boles et al. (1976) found that four
may result in compromised blood supply to the of their 11 patients had gastroschisis. In the series
bowel, such as intussusception, volvulus, hernia- reported by Philippart (1986), 22 of 36 patients
tion, tight gastroschisis, and embolic or throm- with colonic atresia had no associated anomalies,
botic events. It appears likely that focal whereas six had cloacal exstrophy, and three had
resorption of the sterile gut occurs after ischemic other abdominal wall defects. Five of the
necrosis. Animal experiments have been 36 patients had jejunal atresia associated with
performed in which the blood supply was the colonic atresia. Rarely, colonic atresia has
interrupted to different parts of the small intestine been reported to occur concomitantly with imper-
or colon, thus inducing various types of atresias. forate anus (Benson et al. 1968). Malrotation has
These experiments confirm the etiologic role of in also been reported to be a common associated
utero vascular occlusion (Louw 1964; Barnard anomaly (Etensel et al. 2005). One important
and Louw 1956; Louw and Barnard 1955). associated anomaly is Hirschsprung’s disease,
Colonic atresia has been reported in monozy- which has been reported in a few cases
gotic twins (Kim et al. 2000). Benawraet et al. (El-Asmar et al. 2016). Although the colonic atre-
(1981) reported three cases occurring in first- sia was diagnosed at birth in these patients, there
degree relatives of a family. Fairbanks et al. was a considerable delay in diagnosing the asso-
(2005) has shown that the absence of fibroblast ciated aganglionosis. It is therefore recommended
growth factor 10 (Fgf10) or its receptor fibroblast that resected bowel is examined for Hirschsprung’s
growth factor receptor 2b (Fgfr2b) results in disease (Akgur et al. 1998). Rectal suction biopsies
colonic atresia in a mouse model, despite normal are suggested in patients that do not gain normal
mesenteric vascular development. These findings bowel function postoperatively (Kim et al. 1995).
suggest that genetic factors may play a role in the Some authors recommend that rectal suction biop-
pathogenesis of colonic atresia. sies should be routinely taken in all patients with
colonic atresia (Etensel et al. 2005; Lauwers et al.
2006). Isolated colonic atresia is sometimes asso-
Presentation ciated with skeletal anomalies such as syndactyly,
polydactyly, absent radius, and clubfoot (Philippart
Neonates with colonic atresia present with symp- 1986). Furthermore, colonic atresia has been
toms of distal bowel obstruction. Abdominal disten- reported in association with eye anomalies, such
sion is usually present at birth but otherwise as exophthalmos and optic nerve hypoplasia (Pow-
develops over the first 24–48 h of life. Bile-stained ell and Raffensperger 1982). In the series reported
928 T. Wester
by Davenport et al. (1990), one patient had trisomy reported in approximately 10% of the cases
18 and esophageal atresia. The fact that chromo- (Philippart 1986).
somal abnormalities do occur in patients with
colonic atresia makes it reasonable to recommend
chromosomal analysis, at least in those patients Management
who have other associated anomalies
Preoperative
Correction of fluid and electrolyte abnormalities is
Diagnosis started as soon as bowel obstruction is suspected.
The gastrointestinal tract is decompressed with a
Prenatal diagnosis of colonic atresia has been nasogastric tube. Prophylactic antibiotics are
reported. However, prenatally detected colonic administered. The neonate should be in a stable
dilatation may also be the result of Hirschsprung’s condition before general anesthesia and the oper-
disease or anorectal malformations (Anderson ation are started.
et al. 1993).
Plain radiographs show a distal bowel Operative
obstruction with multiple dilated loops with The two therapeutic options available are pri-
air-fluid levels. A large right-sided loop, mary resection with anastomosis and colostomy
corresponding to the proximal dilated colon, with anastomosis at a later stage. Traditionally,
has been considered characteristic in patients many authors distinguished between the man-
with colonic atresia (Fig. 2a) (Davenport et al. agement of colonic atresias distal and proximal
1990). The level of obstruction is confirmed by a to the splenic flexure. Atresias proximal to the
contrast enema, which reveals the distal micro- splenic flexure were treated with primary resec-
colon and incomplete filling of the colon tion and anastomosis, whereas the distal atresias
(Fig. 2b). Pneumoperitoneum, indicating were treated with primary colostomy and
colonic perforation, is not rare and has been delayed establishment of the gastrointestinal
Fig. 2 (a) Plain abdominal radiographs often show the hugely dilated bowel segment proximal to the atresia.
(b) A contrast enema is diagnostic of a colonic atresia showing a microcolon and incomplete colonic filling
continuity (Philippart 1986; Benson et al. 1968; performed. In patients with type II and III atre-
Powell and Raffensperger 1982; Coran and sias, with adequate bowel length, the exces-
Eraklis 1969; Defore et al. 1976). More recently, sively dilated proximal bowel should also be
it has been suggested that staged repair should resected (Fig. 4a). A few centimeters of the
be undertaken in complex cases with, for distal narrow bowel are resected. The mesenteric
instance, questionable bowel viability, colonic vessels are divided close to the bowel wall to
perforation, and peritonitis and in patients with preserve the blood supply to the adjacent bowel.
concomitant abdominal wall defects. On the The distal bowel is incised along the anti-
other hand, in uncomplicated cases, resection mesenteric border to achieve lumina of a similar
and primary anastomosis has been proposed to diameter (Fig. 4b). A single-layer anastomosis is
be the method of choice for atresias at all levels performed using interrupted 5-0 absorbable
of the colon (Arca and Oldham 2012). There is sutures (Fig. 5a–c). The wound is closed in
no evidence that this later approach increases the layers with absorbable sutures.
mortality or complication rate (Davenport et al.
1990), although the anastomosis may be techni- Postoperative
cally difficult because of the large discrepancy During the first postoperative days, parenteral
between the diameters of the proximal and distal nutrition is administered. Feeding can be started
bowel (Watts et al. 2003). when the baby is well and the gastric aspirates
The abdomen is opened through a transverse have decreased. In cases with a primary anasto-
incision a finger diameter above the umbilicus mosis, it usually takes a few days before the
and to the right. The incision may be extended as
required. Cautery is used to divide the muscle
layers of the abdominal wall, and the umbilical
vein is ligated and divided. The site and type of
atresia is assessed (Fig. 3). It is extremely impor-
tant that additional atresias are excluded. The
patency of the distal colon must always be tested
by, for instance, injection of saline. In those with
type I atresias, the bowel adjacent to the atresia
is resected, and a primary anastomosis is
Fig. 4 (a) The dilated proximal and the relatively ische-

mic portion of colon just distal to the atresia are resected.
(b) The distal colon is incised along its antimesenteric
border to match the luminal diameters of the two portions
of bowel to be joined (Reprinted with permission from
Wester T. Colonic and Rectal Atresias. In Puri P (ed).
Fig. 3 The proximal colon is hugely dilated (arrow a), Newborn Surgery 3rd ed. Hodder Arnold, London.
while the distal colon is very small (arrow b) 2011 pp 505–511, Fig. 53.3)
930 T. Wester
Fig. 5 (a–c) The anastomosis is performed with a In Puri P (ed). Newborn Surgery 3rd ed. Hodder Arnold,
single layer of interrupted sutures (Reprinted with London. 2011 pp 505–511, Fig. 53.4)
permission from Wester T. Colonic and Rectal Atresias.
neonate starts to pass stools. If a colostomy has 19 patients. Problems related to the colostomy
been fashioned, the parents are instructed how to were encountered in three of 11 patients treated
take care of the stoma. Usually, the colostomy is with colostomy and delayed anastomosis,
closed at 2–3 months of age. whereas anastomotic strictures were seen in six
of the 19 patients. Boles et al. (1976) reported
significant complications in four of 11 cases. The
Complications and Long-Term Results use of contemporary principles of neonatal sur-
gery has, however, reduced the morbidity rate,
Many factors have led to an improvement in the and Davenport et al. (1990) reported recovery
results of patients with colonic atresia, including without complications.
early postnatal diagnosis, improved neonatal
intensive care and anesthesia, and more efficient
transport facilities. Today, mortality related to the Rectal Atresia
colonic atresia or its treatment is rare. In the series
reported by Davenport et al. (1990), no deaths Introduction
occurred in the patients that underwent surgery,
although one patient, who was never operated on, Rectal atresia has been classified under the rare
died of associated abnormalities. The mortality types of anorectal malformations (ARM) in the
rate in earlier series varied from 9% to 33%, in Krickenbeck classification constituting only
many cases as a result of associated anomalies but 1–2% of ARM cases (Sharma and Gupta 2017).
also attributable to late diagnosis, nutritional defi- Rectal atresia is characterized by the presence of a
ciencies, infectious complications, and technical normally developed anus and sphincter muscles
errors (Freeman 1966; Benson et al. 1968; Powell with a proximal blind and dilated rectum, which
and Raffensperger 1982; Boles et al. 1976; Coran wends at or above the pusococcygeal line. Sharma
and Eraklis 1969). Etensel et al. (2005) recently and Gupta (Sharma and Gupta 2017) have classi-
reported a lethal outcome in 27% of the cases fied rectal atresia into five types: Type I: Rectal
collected for a literature review. stenosis: (A) Intramural (B) Web with a hole.
Powell et al. (Powell and Raffensperger 1982) Type II: Rectal atresia with a septal defect. Type
reported 15 postoperative complications in III: Rectal atresia with a fibrous cord between two
may be much more important as the possible

etiological factor.
Presentation
Neonates with rectal atresia present with distal

bowel obstruction comprising abdominal disten-
sion and failure to pass meconium. The perineum
and anal canal are normal, and the diagnosis may
therefore easily be delayed. The atresia is usually
located 1–3 cm above the dentate line.
The incidence of associated anomalies in
patients with rectal atresia has been considered
to be extremely low (Peña 1996). In the series
Fig. 6 Rectal atresia (Reprinted with permission from reported by Dorairajan (1988), associated anom-
Wester T. Colonic and Rectal Atresias. In Puri P (ed).
alies were found in 2% of the 147 cases. No
Newborn Surgery 3rd ed. Hodder Arnold, London.
2011 pp 505–511, Fig. 53.5) significant abnormalities were found in the uri-
nary tract. Patients with rectal atresia usually
have a normal perineum and a normal sacrum.
atretic ends. Type IV: Rectal atresia with a gap Rectal atresia occurs in patients with multiple
(Fig. 6) Type V: Multiple: (A) rectal atresia with atresias of the bowel (Magnus 1968). Two of
stenosis (B) multiple rectal atresia and (C) thick- Dorairajan’s (1988) patients had ileal atresia, and
ened Houston’s valves/multiple rectal stenosis. one had multiple small bowel atresias. Patients
with rectal atresia and particularly rectal stenosis
may have an associated presacral mass, and it has
Etiology been recommended that they should undergo MRI
like other patients with anorectal malformations.
The exact embryogenic process underlying this Presacral mass such as presacral teratoma or ante-
anomaly is not known, but the following theories rior sacral meningocele is the most commonly
have been postulated. reported association with rectal atresia/rectal ste-
nosis, 29% patients in Pena’s series (Hamrick et
1. >Embryological theory: rectal atresia develops al. 2012). Sharma and Gupta (Sharma and Gupta
due to a vascular accident that occurs at a 2017) reported 10 cases of rectal atresia/rectal
window in time between 13 and 14 weeks of stenosis over a 15 year period. Median age at
gestation. presentation was 1 month (1 day–96 months).
2. Genetic theory: there is high incidence of these Six patients including all five cases of rectal atre-
anomalies among consanguineous marriages, sia underwent colostomy at birth.
especially in South India. This supports the
genetic association of the condition.
3. Infective theory: this theory was supported by Diagnosis
Magnus (1968) and she believed that intrauter-
ine infection causing thrombosis of the vessels The diagnosis of rectal atresia can be challenging
could lead to acquired atresia of the already as the patients shows a normal anus. The inability
formed rectum. to pass a thermometer or a rectal tube up the anal
canal should raise the suspicion of rectal atresia.
Due to the pattern of geographic distribution After a colostomy has been opened, a contrast
noted with this anomaly, a racial or genetic defect study with simultaneous injection of contrast
932 T. Wester
Complications and Long-Term Results
In patients with rectal atresia, the anal canal,

sacrum, and sphincteric mechanisms are virtually
normal. Therefore, the prognosis with respect to
functional outcome is favorable. Although the
number of cases reported is very limited, the out-
come in patients with rectal atresia or stenosis
treated through a posterior sagittal approach is
excellent. Peña (1995) reported voluntary bowel
movements with total continence and without
soiling in a series of five cases. However, two of
the five patients had constipation. The same group
showed, in a more recent series of 17 patients, that
all 12 patients older than 3 years had voluntary
bowel movements and were clean between bowel
movements. Five (29%) of the 17 patients had
constipation that required laxatives. The authors
report that complications occurred in three
Fig. 7 Simultaneous injection of contrast material into the patients; one rectovaginal fistula and two pre-
upper pouch (via the sigmoid colostomy) and the sacral abscesses (Hamrick et al. 2012). Constipa-
anorectum clearly outlines the distance between the two tion has been reported to occur frequently after
pouches. The arrow shows the atresia
other procedures used to treat rectal atresia or
stenosis as well (Zia-ul-Miraj Ahmed et al.
1995). Upadhyaya (1990) reported an uneventful
material through the colostomy into the rectal recovery and normal continence in two patients
pouch and the anal canal clearly outlines the anat- treated with his method. Dorairajan (1988)
omy of the anomaly (Fig. 7). followed up 37 of 60 patients that were treated
with sacroperineal pull-through operations and
who had their colostomy closed. The outcome
Management was excellent in 20% of the patients, whereas
65% had occasional soiling at night, and 15%
Various procedures have been described to treat had soiling also in daytime. The mortality rate in
rectal atresia and rectal stenosis, many of which this series was 35%. A recent study reported nor-
have now become obsolete such as abdomino- mal bowel control at 3–5 years of age following
perineal and sacroperineal pullthrough opera- transanal endorectal pull-through operation for
tions (Sharma and Gupta 2017). Most rectal atresia (Gieballa et al. 2018).
commonly used procedures now a days for rectal
atresia and rectal stenosis include posterior
saggital anorectoplasty and transanal pull- Conclusion and Future Directions
through operation. Upadhyaya (Upadhyaya
1996) recommended transanal end to end recto- Colonic and rectal atresias are both very rare
rectal anastomosis. The advantage of this tech- conditions. The long-term results appear to be
nique is that the luminal continuity is restored good, although there is limited data on the out-
without causing damage to functional anatomy come in adulthood in patients with colonic and
of the region. rectal atresia. For colonic atresia, the surgical
options are mainly resection and primary anas- Dorairajan T. Anorectal atresia. In: Stephens FD, Smith
tomosis or colostomy with delayed anastomosis. ED, Paul NW, editors. Anorectal malformations in
children. New York: Liss; 1988. p. 105–10.
For rectal atresias, several techniques have El-Asmar KM, Abdel-Latif M, El-Kassaby AA, Soli-
been described. There is little evidence to show man MH, El-Behery MM. Colonic atresia: associa-
that one technique is better than another. It is, tion with other anomalies. J Neonatal Surg.
also with multicenter studies, difficult to get a 2016;5(4):47.
Etensel B, Temir G, Karkiner A, et al. Atresia of the colon.
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Fairbanks TJ, Kanard RC, Del Moral PM, et al. Colonic
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Duplications of the Alimentary Tract
64
Mark D. Stringer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
Distribution and Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 937
Lingual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
Esophageal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 939
Thoracoabdominal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
Gastric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Duodenal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Pancreatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Small Bowel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Colonic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
Rectal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
Associated Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Surgical Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
Esophageal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
Thoracoabdominal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
Gastric . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
Duodenal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 948
Pancreatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
M. D. Stringer (*)
Department of Paediatric Surgery, Wellington Hospital,
Department of Paediatrics and Child Health, University of
Otago, Wellington, New Zealand
e-mail: mark.stringer@ccdhb.org.nz

https://doi.org/10.1007/978-3-662-43588-5_68
936 M. D. Stringer
Small Bowel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949

Colonic and Appendiceal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
Rectal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951
Abstract Although most enteric duplications are cystic,

Alimentary tract duplications are rare congenital some are tubular in shape. They vary widely in
cystic or tubular malformations that are usually size. Enteric duplications have two characteristic
found adjacent to a segment of the gut, sharing a features: (i) the presence of a well-defined coat of
common wall but are occasionally located at a smooth muscle and (ii) an epithelial lining
more distant site. They are usually single, vari- consisting of some type of gut mucosa. Most but
able in size, and characterized by a well-defined not all duplications share a common muscular
coat of smooth muscle and an epithelial lining wall and blood supply with the adjacent part of
consisting of some type of gut mucosa. They the gut. They are usually single but are multiple in
may be asymptomatic and discovered inciden- 5–15% of cases, e.g., an individual with an esoph-
tally on physical examination or during imaging ageal and small bowel duplication cyst. The epi-
for unrelated conditions, e.g., at prenatal sonog- thelial lining of a duplication cyst is usually
raphy. However, the majority cause symptoms, similar to that of the adjacent gut but ectopic
most often in early childhood, but sometimes not mucosa (e.g., gastric, respiratory, and/or pancre-
until adult life. Presenting symptoms and signs atic ductal epithelium) may be present. Ectopic
are related to the site and size of the duplication gastric mucosa is found in 20–30% of duplica-
and whether it contains ectopic gastric mucosa, tions (Bower et al. 1978; Holcomb et al. 1989;
which predisposes to mucosal ulceration and Stringer et al. 1995) (Fig. 1). Ectopic respiratory
bleeding. Various associated congenital anoma- epithelium has been documented in enteric dupli-
lies have been reported, particularly vertebral cation cysts as far distally as the ileum (De Roeck
anomalies. Duplication cysts should be excised et al. 2008). While enteric duplications may com-
completely to relieve symptoms and avoid the municate with the lumen of the gut, most are
risk of complications, including malignant noncommunicating. Tubular lesions are more
degeneration in adulthood. After complete exci- likely to be communicating and contain ectopic
sion, long-term outcome is generally excellent. gastric mucosa. Occasionally, enteric duplications
are found separate from the alimentary tract, e.g.,
Keywords
Duplication cyst · Enteric cyst · Neurenteric
cyst
Introduction
Alimentary tract duplications are rare and diverse

congenital malformations found anywhere from the
mouth to the anus (Ladd and Gross 1940; Patiño
Mayer and Bettolli 2014). They are also known as
enteric cysts, enterogenous cysts, or reduplication
cysts. When associated with intradural spinal
Fig. 1 Histology of a duplication cyst showing ectopic
pathology, they are frequently referred to as gastric mucosa (top left of image) with an associated muco-
neurenteric cysts (Alrabeeah et al. 1988). sal ulcer (arrow)
64 Duplications of the Alimentary Tract 937
in the retroperitoneum or vertebral canal. Enteric Distribution and Presentation

duplications are generally classified according to
their location rather than their mucosal lining. Most enteric duplications cause symptoms in
Thus, a gastric mucosa-lined cyst lying adjacent infancy or early childhood, although they may
to the esophagus in the posterior mediastinum is remain asymptomatic until adult life. An increas-
termed an esophageal duplication cyst. ing proportion is now detected before the onset of
The incidence of enteric duplications is symptoms, presenting either as an incidental mass
unknown but a figure of 1 in 4,500 based on on physical examination or during imaging for
fetal and neonatal autopsy data is often quoted. unrelated symptoms or another condition. The
Overall, there is a slight male predominance but latter includes duplications that are detected by
colonic duplications may be more common in routine prenatal ultrasound scans.
girls (Temiz et al. 2013). The distribution of alimentary tract duplica-
tions based on the four largest single institution
series (to reduce publication bias) is shown in
Pathogenesis Table 1 and schematically in Fig. 2. Almost 80%
of all enteric duplications are intra-abdominal and
There is no satisfactory unifying explanation to approximately 50% are related to the midgut, with
account for the pathogenesis of all gastrointestinal ileal being the commonest.
duplications. They are understood to arise from Presenting symptoms and signs depend on the
defective embryogenesis. Several mechanisms location and size of the duplication, and whether it
have been proposed: contains ectopic gastric mucosa. Duplications com-
monly cause obstruction – of the airway (coughing,
(i) Partial twinning – some hindgut duplica- wheezing, and/or pneumonia), esophagus (dyspha-
tions, particularly those with complete dou- gia), or intestine (abdominal pain and vomiting)
bling of the genitalia, bladder, and colon (Erginel et al. 2017). Those lined by ectopic gastric
(Ravitch 1953) are probably an expression mucosa are prone to ulceration, hemorrhage, or
of caudal twinning. perforation. Intussusception and segmental volvu-
(ii) Split notochord theory – abnormal adher- lus are additional potential complications of small
ence of the endoderm of the developing bowel duplications. Occasionally, duplications are
gut tube to the notochord may account complicated by infection.
for enteric duplications associated with In adults, carcinoma (most often adenocarci-
vertebral anomalies (Bentley and Smith noma) has been reported as a complication of
1960). duplication cysts in the esophagus (Singh et al.
(iii) Intrauterine mesenteric vascular accident – 2001), stomach (Zheng and Jing 2012), duode-
this might explain the origin of duplication num (Chen et al. 2010), small bowel (Blank et al.
cysts associated with intestinal atresia 2012), colon (Hsu et al. 2011), and rectum
(Favara et al. 1971). (Michael et al. 1999). Many of these tumors are
(iv) Disordered foregut budding – this advanced and associated with metastases at pre-
could account for some foregut duplication sentation. To date, there have been no recorded
cysts. instances of malignant degeneration in children
(v) Disordered recanalization of the developing under 16 years of age.
gut – this may explain enteric duplications
arising at sites where the developing gut is
temporarily occluded by epithelial prolifera- Clinical Features
tion (Gross et al. 1952). This mechanism
could also explain rare cases of triplication Clinical features of alimentary tract
or even quadruplication of segments of the duplications are best considered according to
intestine. their location.
938
Table 1 Large single institution series of children with alimentary tract duplication cysts
Foregut Midgut Hindgut
Author No. of duplications Cervical Mediastinal/ Thoracoabdominal Gastric Duodenal Jejunal + Ileala Colonic Appendix Distal Rectal Other sites
(no. of patients) (oropharyngeal) esophageal colonic
Gross et al. (1952) 68 (67) 1 13 3 2 4 4 + 28 5 3 5
(Boston)
Bower et al. (1978) 74 (64) 15 1 7 3 6 + 28 8 2 2 2
(Pittsburgh)
Holcomb et al. (1989) 101 (96) 21 3 8 2 12 + 35 13 1 1 5
(Philadelphia)
Stringer et al. (1995) 77 (72) 2 15 6 10 3 5 + 16 6 3 1 6 3
(London) Retroperitoneal
1 Spinal
Total 320 3 (1%) 64 (20%) 13 (4%) 27 12 (4%) 27 (8%) + 107 32 6 (2%) 5 (2%) 18 6 (2%)
(8%) (33%) (10%) (6%)
a
Including ileocecal
M. D. Stringer
Fig. 2 Schematic
illustration of
320 alimentary tract
duplications reported in
four large institutional
series (Gross et al. 1952;
Bower et al. 1978; Holcomb
et al. 1989; Stringer et al.
1995)
hemangioma. Duplication cysts in the tongue

may be asymptomatic or present with feeding or
breathing difficulties in the newborn (Hambarde
et al. 2011). If detected prenatally, the potential for
neonatal airway obstruction should be considered;
these cases need to be followed closely with serial
ultrasound scans to anticipate problems at or after
delivery, including the small possibility of an
ex-utero intrapartum treatment procedure.
Dynamic magnetic resonance imaging of the
fetus may provide additional information
(Houshmand et al. 2011). Duplication cysts of
the tongue may be lined by gastric mucosa
Fig. 3 A tongue duplication cyst © National Journal of
Maxillofacial Surgery (Courtesy of Hambarde et al.
(Hambarde et al. 2011). Late malignant degener-
(2011)). NB. This is an open-access article distributed ation has been described (Volchok et al. 2007).
under the terms of the Creative Commons Attribution- They are best treated by complete surgical
Noncommercial-Share Alike 3.0 Unported, which permits excision.
unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
Lingual Esophageal
Most are located in the anterior two-thirds of the Esophageal duplication cysts are typically located
tongue (Fig. 3). The differential diagnosis in the posterior mediastinum, more often on the
includes lymphatic malformation, ranula, and right side, but may also be found in the neck
940 M. D. Stringer
Fig. 4 Axial CT scans of a cervical esophageal duplication cyst (left) and an upper mediastinal thoracic esophageal
duplication cyst (right). The cysts are marked with an asterisk
potential intraspinal extension should be

considered. Esophageal duplications must be
distinguished from neurogenic tumors (neuro-
blastoma and ganglioneuroma) and broncho-
genic cysts (Fig. 5).
Bronchogenic cysts are similar to esophageal
duplications but are understood to arise from
parts of the foregut destined for respiratory
differentiation. They are lined by ciliated
columnar epithelium and their walls contain
bronchial mucous glands, smooth muscle, and
hyaline cartilage (Tireli et al. 2004; Jiang et al.
2015). Bronchogenic cysts are usually unilocu-
lar and filled with clear fluid but they may con-
tain air or pus if they have a patent connection
with the airway. Most bronchogenic cysts are
located in the mediastinum, although they may
Fig. 5 Plain chest radiograph showing a mass in the upper be found in the lung parenchyma, neck, or at
right mediastinum which proved to be an esophageal more distant sites.
duplication cyst. The differential diagnosis includes a neu-
rogenic tumor (neuroblastoma/ganglioneuroma), bron-
chogenic cyst, and an anterior mediastinal mass
Thoracoabdominal
(Fig. 4). Most do not communicate with the A thoracoabdominal duplication usually descends
esophageal lumen. Esophageal duplications may as a tubular structure to the right of the esophagus
cause respiratory problems such as stridor, (but slightly separate from it) in the posterior medi-
tachypnea, chest infection, or feeding difficulties astinum. It communicates through the diaphragm
in infants (Nayan et al. 2010) and dysphagia in with the stomach, duodenum, pancreas, jejunum, or
older children. There may be palpable neck swell- ileum (Stringer et al. 1995). Thoracic and/or cervi-
ing. If the duplication contains ectopic gastric cal vertebral anomalies may be present and the cyst
mucosa and communicates with the esophageal may have an intradural connection. They are fre-
lumen, peptic esophageal stricture is a potential quently lined by ectopic gastric mucosa.
complication (Stringer et al. 1995). Thoracoabdominal duplications can therefore pre-
Associated thoracic or cervical vertebral sent with respiratory distress, gastrointestinal
anomalies should be excluded; if present, a bleeding, vomiting, and even meningitis.
Gastric Pancreatic
Gastric duplication cysts are most often located There is some confusion about the classification
on the greater curvature of the stomach or in the of duplication cysts within the pancreas. They
pyloric region. Cystic varieties are more com- are variably reported as pancreatic, gastric, or
mon and, unlike tubular lesions, these rarely duodenal duplication cysts. Some are clearly
communicate with the stomach lumen. Very intrapancreatic while others are in continuity
occasionally, a gastric duplication communi- with the stomach or duodenum. The presence of
cates with a pancreatic duct (Hoffman et al. gastric epithelium may signify a gastric origin or
1987; Moss et al. 1996). Gastric duplications may represent ectopic gastric mucosa. Since
may present as an asymptomatic mass detected enteric duplication cysts are classified by their
on abdominal examination or on ultrasound scan location rather than their mucosal lining, those
(including prenatal) or with vomiting and/or primarily associated with the stomach or duode-
bleeding. In infants, they may cause pyloric num are gastric and duodenal duplications,
obstruction and mimic infantile hypertrophic respectively even though they may communicate
pyloric stenosis. Rarely, they present with with a pancreatic duct. In contrast, duplication
perforation. cysts within the pancreas should be regarded as
pancreatic duplication cysts, irrespective of their
mucosal lining. About half are located in the head
Duodenal of the gland and they may communicate with the
pancreatic duct (Fujishiro et al. 2011).
Duodenal duplications are variable in size but Pancreatic duplication cysts most commonly
frequently measure 2–5 cm in diameter; they present with abdominal pain and vomiting, with
may be dominantly intraluminal or extraluminal or without evidence of acute pancreatitis. They
(Lopez-Fernandez et al. 2013). Most are located may be confused with a pancreatic pseudocyst or
medial or posterior to the second or third part of cystic neoplasm (Hunter et al. 2008).
duodenum and can therefore be confused with
type III choledochal cysts (choledochoceles)
(▶ Chap. 78, “Congenital Biliary Dilatation”). Small Bowel
Almost 50% communicate with the pancreatic
and/or bile duct or with a smaller pancreatic duct This is the commonest site for an enteric dupli-
or the duodenal lumen (Chen et al. 2010). There is cation (Table 1); most are ileal or ileocecal. They
one report of a duodenal duplication cyst commu- are usually cystic but can be tubular (when they
nicating with a duplicated gallbladder (Menon are more likely to communicate with the bowel
et al. 2013). lumen) and typically lie on the mesenteric aspect
Presentation is often with nonspecific symp- of the intestine (Fig. 6). Cystic duplications may
toms such as upper abdominal pain and be detected incidentally as a mobile mass on
vomiting, making delays in diagnosis common abdominal examination or as a cystic mass on
(▶ Chap. 59, “Duodenal Obstruction”). Acute ultrasound scan (or other cross-sectional imag-
pancreatitis (which may be recurrent) is a ing), particularly in the fetus. Others can present
presenting feature in more than half the cases acutely with intestinal obstruction due to luminal
(Chen et al. 2010). Other potential clinical man- compression by the mass or from a volvulus or
ifestations include biliary obstruction and intes- intussusception; such cases may be confused
tinal bleeding; the latter is related to ectopic with acute appendicitis (Fig. 7). Tubular
gastric mucosa which is uncommon according small bowel duplications are more likely to
to a meta-analysis (Chen et al. 2010) but was contain ectopic gastric mucosa and therefore
present in 6 of 11 cases in one series (Lopez- may present with intestinal bleeding or
Fernandez et al. 2013). perforation.
942 M. D. Stringer
Colonic Rectal
Hindgut duplications largely fall into three As with other duplications, these may be cystic
groups: duplication cysts of the colon, tubular or tubular. They may manifest as a perineal
duplications of the rectum and/or colon, and mucosal swelling and/or a perianal or perineal
duplication of the appendix. fistula, causing confusion with perianal sepsis
Colonic duplications may be cystic or tubular. (Flint et al. 2004; La Quaglia et al. 1990). Alter-
Ectopic gastric mucosa is uncommon (Stringer natively, they may obstruct defecation or cause
et al. 1995; Temiz et al. 2013). In the rare total rectal prolapse or bleeding. Cystic rectal dupli-
colonic duplication, the duplicated bowel is cations must be distinguished from cystic
located lateral or medial to the normal colon and sacrococcygeal teratoma, tailgut cyst, and ante-
usually has a proximal communication (Ravitch rior meningocele. When associated with an
1953). Colonic duplications tend to present with anorectal malformation and sacral vertebral
abdominal pain, constipation, and/or bleeding. anomalies, the cyst may be part of the Currarino
Cecal duplication cysts may mimic an appendix triad (Currarino et al. 1981).
mass (Temiz et al. 2013). Extensive tubular dupli-
cations of the colon and rectum may be discovered
during the investigation of associated genitouri- Prenatal Diagnosis
nary and spinal anomalies.
Enteric duplications may be identifiable as early
as 12 weeks’ gestation (Chen et al. 2002) but most
of those that are detected prenatally are first
observed at or after 20 weeks’ gestation
(▶ Chap. 3, “Prenatal Diagnosis of Congenital
Malformations”). Prenatal complications are rare
(Laje et al. 2010): There is one report of successful
thoracoamniotic shunting in a fetus with a tho-
racic duplication cyst causing mediastinal shift
and hydrops fetalis (Martínez Ferro et al. 1998)
and another of a large ileal duplication cyst in a
fetus that was drained percutaneously to relieve
umbilical vein obstruction (Ness et al. 2006). A
Fig. 6 An extensive tubular duplication of the small
bowel localized volvulus of an intestinal duplication cyst
Fig. 7 Operative appearances of two examples of ileal volvulus (note the constriction rings related to the pedicle
duplication cysts, both presenting with intestinal obstruc- of the volvulus after untwisting the affected segment of
tion. The cyst in the picture on the right had undergone a bowel)
in the fetus may be a rare cause of intestinal atresia vertebrae, hemivertebrae, spina bifida, vertebral
(Sinha et al. 1992). fusion, and scoliosis (Fig. 8). There may be asso-
Enteric duplications account for approximately ciated intradural spinal pathology including a
10% of prenatally diagnosed intra-abdominal cysts direct communication between the cyst and the
(Thakkar et al. 2015). Distinguishing these cysts dural sac (Alrabeeah et al. 1988).
from other fetal intra-abdominal cysts such as ovar- Numerous other malformations have been
ian, choledochal, and mesenteric cysts can be diffi- reported infrequently in association with enteric
cult. Some centers use prenatal magnetic resonance duplications. They include congenital cardiac
imaging to characterize these cysts (Laje et al. disease, esophageal atresia, congenital diaphrag-
2010) but this is unlikely to influence postnatal matic hernia, congenital pulmonary mal-
management. If postnatal imaging confirms an formations, and myelomeningocele with foregut
enteric duplication, symptomatic cases require pro- duplications (Stringer et al. 1995; Iyer and
mpt surgery. Asymptomatic lesions need close Mahour 1995); intestinal malrotation or less com-
postnatal follow-up and surgery is advisable during monly intestinal atresia with midgut duplications;
the first 6 months of life because of the potential for and genitourinary duplication, bladder exstrophy,
serious complications (Laje et al. 2010). and imperforate anus with hindgut duplications
(Bower et al. 1978; Holcomb et al. 1989; Stringer
et al. 1995; Gross et al. 1952).
Associated Anomalies
Associated anomalies are present in 30% to 50% Imaging

of patients with enteric duplication cysts (Stringer
et al. 1995). The choice of imaging is dictated by the site of the
Vertebral anomalies are more likely with tho- duplication, clinical urgency, and the potential for
racic and hindgut duplications (Bower et al. 1978; associated anomalies. Isolated small bowel dupli-
Stringer et al. 1995) but may be found with duplications require few preoperative investigations
cations at other sites, including the small bowel other than abdominal sonography and plain
(Li et al. 1998). Between 20% and 30% of tho- radiography.
racic duplications have associated vertebral
anomalies (Bower et al. 1978; Holcomb et al. • Plain radiography: a chest radiograph may
1989; Stringer et al. 1995). These include cleft show a posterior mediastinal mass with an
Fig. 8 Left: Cervical

vertebral anomalies in a
child with a tubular
esophageal duplication
(note the abnormal gas
shadow to the right of the
mediastinum and the
endotracheal tube in situ).
Right: Mid-thoracic
vertebral anomalies in a boy
with a thoracoabdominal
duplication cyst
944 M. D. Stringer
esophageal duplication cyst. Plain radiographs

also demonstrate vertebral anomalies.
• Ultrasound is especially useful for intra-
abdominal enteric duplications. Most duplica-
tion cysts have an anechoic center unless there
has been bleeding into the cyst. Two sono-
graphic features strongly support the diagnosis
of a duplication cyst: the “double-wall sign”
(an inner hyperechoic rim corresponding to the
mucosa/submucosa and an outer hypoechoic
layer corresponding to the muscle coat) and
the presence of peristalsis (Fig. 9). This “gut
signature” is highly suggestive but not patho-
gnomonic of a duplication cyst since it is occa-
sionally seen with other intra-abdominal cysts
such as ovarian and mesenteric cysts (Cheng
et al. 2005). Urinary tract ultrasound is often
advisable in the evaluation of pelvic duplica-
tion cysts. Endoscopic ultrasound may be
advantageous in duodenal and pancreatic Fig. 9 Ultrasound scan of an ileal duplication cyst show-
duplications (Liu and Adler 2014). ing the “double-wall sign”: an inner hyperechoic rim (thick
• Contrast studies such as a contrast swallow, arrows) corresponds to the mucosa/submucosa and an
meal, or enema may be helpful when evaluat- outer hypoechoic layer (thin arrows) corresponds to the
muscle coat
ing esophageal and gastrointestinal duplication
cysts (Fig. 10). A “fistulogram” is valuable in
investigating rectal duplications with a peri-
neal opening (Fig. 11).
• Magnetic resonance or CT cross-sectional imag-
ing offers the best method of delineating tho-
racic and pelvic duplications in particular. The
precise location and extent of a thoracic dupli-
cation cyst can be mapped together with associ-
ated vertebral and spinal anomalies. Most
duplications have low signal intensity on
T1-weighted MR images and high signal inten-
sity on T2-weighted images (Hur et al. 2007).
Magnetic resonance cholangiopancreatography
(MRCP) can provide useful information when
evaluating a duodenal or pancreatic duplication
cyst and MR angiography in large retroperito-
neal lesions. On CT, enteric duplications often
show peripheral enhancement and may need to
be distinguished from an abscess, although this
is usually evident clinically. Fig. 10 A contrast swallow in a child with a tubular
• A technetium-99m pertechnetate radionuclide esophageal duplication that was lined by ectopic gastric
scan to detect ectopic gastric mucosa (Kiratli mucosa (thin arrow) and communicated with the distal
native esophagus (thick arrow)
Fig. 11 A contrast study in a child with a rectal duplica-

tion associated with a perineal opening
et al. 2009) is useful in selected duplications:

(i) in when evaluating a child with abdominal Fig. 12 A technetium-99m pertechnetate radionuclide
pain and GI bleeding, (ii) when deciding the scan demonstrating ectopic gastric mucosa within an
urgency of surgery in a child with an asymptom- extensive thoracoabdominal duplication cyst. There is
atic duplication cyst, and (iii) when indicating the abnormal uptake of isotope in the chest and abdomen
approximate extent of a tubular duplication
(Fig. 12). mucosa. Only rarely is it necessary to leave an
• Endoscopy: endoscopic retrograde cholangio- intact part of the duplication in situ (see below).
pancreatography (ERCP) is helpful in defining If the expertise is available and the same result
the relationship of a duodenal duplication cyst to can be achieved with minimally invasive surgery,
the pancreatic and bile ducts. Flexible upper and then a thoracoscopic or laparoscopic approach is
lower gastrointestinal endoscopy may provide preferable because it is associated with reduced
additional information in selected duplications. postoperative discomfort and improved cosmesis.
However, the emphasis should be on complete
excision rather than the surgical technique.
Surgical Treatment All patients should receive prophylactic intrave-
nous broad spectrum antibiotics at induction of
The optimum treatment of alimentary tract dupli- anesthesia.
cations is complete excision. This avoids future
complications including the risk of malignant
degeneration. Occasionally, complete resection Esophageal
is deemed to be too hazardous when the aim
should be to remove the entire mucosal lining of Cervical esophageal duplications can be removed
the cyst, especially if it contains ectopic gastric via a cervical incision (Fig. 13), care being taken to
946 M. D. Stringer
Fig. 13 Operative view of

a cervical esophageal
duplication cyst excised via
a right-sided cervical
incision
Fig. 14 Excision of an
upper mediastinal
esophageal duplication cyst
via a right posterolateral
thoracotomy
avoid injury to structures such as the recurrent communication with the esophageal lumen or
laryngeal nerve. A nasogastric tube in the esopha- breach of the esophageal mucosa must be closed;
gus may assist with identification. leak testing with air injected via a nasogastric tube
Thoracic esophageal duplications can be may be helpful. The esophageal repair can be
excised via a transpleural posterolateral thoracot- buttressed with the muscular fringe of the duplica-
omy (Fig. 14). Cystic duplications are usually tion. Closing the muscular defect in the esophageal
intramural and noncommunicating and more wall probably helps to avoid the development of an
often related to the right side of the esophagus. It esophageal diverticulum (Merry et al. 1999). The
is usually possible to excise the cyst leaving the chest is closed and pleural drainage is not usually
esophageal mucosa intact. If the cyst cannot be necessary.
removed intact, then it can either be transected Video-assisted thoracoscopic resection is an
close to the esophagus with stripping of the resid- effective technique for cystic (rather than tubular)
ual mucosa or a short segment of esophagus can duplication cysts (Hirose et al. 2006; Perger et al.
be excised in continuity. Laser ablation of residual 2006). Intraoperative cyst decompression and single
cyst mucosa does not reliably prevent recurrence lung ventilation may assist with thoracoscopic
(Merry et al. 1999). The proximity of the vagus resection by creating more working space. A flexi-
nerve and the thoracic duct should be noted. Any ble endoscope within the esophagus may help to
monitor the integrity of the esophageal mucosa communicates with the vertebral canal, neurosur-
intraoperatively (Perger et al. 2006). gical input is advisable. A staged approach, excis-
ing each component sequentially, should be
avoided (Stringer et al. 1995).
Thoracoabdominal Incomplete excision is a particular risk with
thoracoabdominal duplications because of their
These are potentially very challenging resections size and complexity; the potential consequences
and detailed preoperative assessment of the medi- of this include meningitis, gastrointestinal bleed-
astinal, abdominal, and potential spinal compo- ing and perforation, and respiratory complications.
nents of the duplication is critical. The
duplication cyst may be adherent to thoracic or
cervical vertebrae and can have an intradural con- Gastric
nection (Stringer et al. 1995). The duplication may
extend distally to the stomach, duodenum, pan- Greater curvature or pyloric duplication cysts can
creas, or ileum but often appears tenuous as it usually be completely excised by dissecting the
passes behind the diaphragm. The abdominal por- cyst off the gastric submucosa and repairing the
tion most often appears as a tubular lesion com- residual seromuscular defect. Gastric mucosal
municating with the small bowel but may integrity is checked prior to seromuscular repair
occasionally end blindly along the greater curve by insufflating air via a nasogastric tube. This can
of the stomach. These duplications are generally be achieved by open or laparoscopic surgery.
best excised through separate thoracic (right-sided Small gastric duplications are occasionally
posterolateral thoracotomy) and abdominal more simply excised by a wedge resection of the
incisions, rather than a single oblique thoraco- cyst and a segment of stomach followed by a two
abdominal incision (Fig. 15). When the cyst layer gastric closure. Extensive duplications of the
Fig. 15 Surgical approach

to an extensive
thoracoabdominal
duplication cyst
948 M. D. Stringer
greater curvature of the stomach can be treated by

partial resection and stripping of the residual
mucosal lining followed by repair. A less ideal
approach is to divide the septum separating the
tubular duplication from the gastric lumen with
linear staplers introduced via proximal and distal
gastrotomies. The division should be as complete
as possible but since the mucosal lining of the
duplication has not been removed, there remains
a risk of long-term mucosal complications.
Fig. 16 Operative view of a duodenal duplication cyst in

Duodenal the medial wall of the descending duodenum (associated
with biliary obstruction). The cyst has been approached via
Some duodenal duplications are simple cystic a transverse right upper quadrant incision and a lateral
duodenotomy
lesions that can be excised easily without risk of
injury to pancreatic or biliary ducts. Those on the
medial aspect of the second or third part of the
duodenum may be complex and communicate
with the pancreatic and/or common bile duct.
Previous pancreatitis or inflammation secondary
to ectopic gastric mucosa may make surgical dis-
section more difficult. Facilities for intraoperative
cholangiopancreatography should be available
with prior positioning of the child on the operating
table allowing for image intensifier access.
In open surgery, the duodenum is approached
via a right upper quadrant incision and
“Kocherised” to elevate it into the wound. The
adjacent peritoneal cavity is isolated with swabs
and an oblique incision is made in the lateral wall
of the descending duodenum to expose the medi-
Fig. 17 Operative cholangiogram via the gallbladder in a
ally situated duplication cyst (Fig. 16). If the child with a duodenal duplication cyst (arrow) in the
opening of the common bile duct or pancreatic medial wall of the second part of the duodenum causing
duct is uncertain, intraoperative cholangiography biliary obstruction
may be helpful (Fig. 17). Alternatively, a chole-
cystectomy can be performed and a fine probe be fenestrated into the duodenal lumen, cautiously
passed distally through the cystic and common oversewing the edges of the window to achieve
bile duct into the duodenum. hemostasis. If the latter option is selected, the pres-
Once the duplication cyst is exposed, surgical ence of ectopic gastric mucosa must be excluded by
alternatives are dictated by the anatomy. They intraoperative biopsy and the fenestration must be of
include (i) complete excision of the cyst with divi- sufficient size to permit free dependent drainage
sion of any ductal communication (optimum); without forming a cul-de-sac. Pancreatoduo-
(ii) partial excision and mucosectomy of the denectomy is rarely required (Chen et al. 2010).
remaining part of the cyst (Lopez-Fernandez et al. There are recent reports of endoscopic marsupia-
2013), which can be achieved laparoscopically in lization of duodenal duplication cysts, mostly in
selected cases (Byun et al. 2014); and (iii) if the adults (Chen et al. 2010). However, the paucity of
duplication is adjacent to the ampulla of Vater, it can long-term results of this technique is a particular
concern in children because malignant degeneration (Laje et al. 2010), although a laparoscopic-assisted
has been described in adults (Seeliger et al. 2012). resection after preliminary decompression of the
cyst and exteriorization of the affected segment of
the bowel is often easier. In ileocecal duplication
Pancreatic cysts, it may be possible to preserve the ileocecal
valve by separately resecting the ileal and cecal
Surgical options include complete local excision components of the cyst (Catalano et al. 2014).
with or without Roux loop drainage of the residual Short tubular small bowel duplications may be
cavity or a Whipple-type pancreatoduodenectomy. excised in continuity with the adjacent bowel.
Roux loop drainage of the cyst alone is inadequate Care should be taken to obtain complete excision
because the mucosal lining of the cyst must be of the proximal and distal margins of the lesion
completely excised if pancreatitis is to be pre- where the normal and duplicated bowel merge;
vented. When the duplication is in the tail of the distinguishing the two can be difficult. Long tubu-
pancreas, distal pancreatectomy with splenic pres- lar duplications, where remaining intestinal length
ervation (laparoscopic or open) can be performed. is a potential problem, pose a more difficult prob-
lem. The tubular duplication runs parallel to the
native bowel between the leaves of the adjacent
Small Bowel mesentery risking ischemia of the native intestine
with complete resection of the duplication. In
Cystic lesions of the ileum or jejunum can usually these cases, submucosal resection is an alternative
be excised without difficulty using open or laparo- but difficult option. The mucosal lining is stripped
scopic techniques. The continuous muscular coats out using a series of longitudinal seromuscular
of the normal and duplicated bowel make excision incisions in the duplication. The residual
of the cyst alone more demanding than simple seromuscular sleeve of the duplication may be
segmental resection of the bowel (Fig. 18) but safely left in situ. Bleeding within the sleeve
both are acceptable methods. Excising the cyst almost always stops spontaneously. For duplica-
alone is achievable in some cases by laparoscopy tions within the mesentery but separate from the
intestine, careful separation of the two leaves of
the mesentery and division of vessels in one leaf
only may enable excision of the duplication with-
out jeopardizing the blood supply of the adjacent
bowel (Norris et al. 1986) (Fig. 19). Whichever
technique is used, the junction between the
Fig. 19 Resection of a tubular small bowel duplication

from between the leaves of the small bowel mesentery. Any
Fig. 18 Segmental resection of the bowel with a small communication with the native intestine must be identified
bowel duplication cyst and resected
950 M. D. Stringer
duplicated and normal bowel must be resected exstrophy can be retained for later use in recon-
since ectopic gastric mucosa is frequently present structive surgery.
at this site.
Associated intestinal malrotation requires a
Ladd’s procedure. Rectal
Rectal duplications may be excised using one of

Colonic and Appendiceal several approaches. Small submucosal cysts can
be excised via an endorectal route; leaving the
All cystic and most tubular duplications of the cyst intact facilitates dissection (Fig. 21). After
colon can be excised in continuity with an adjacent excision, the rectal mucosa is repaired. The pos-
segment of bowel. In long tubular duplications, terior sagittal approach provides excellent expo-
distal fenestration is possible provided there is no sure of the retrorectal space for excision of tubular
ectopic gastric mucosa (which is uncommon with and larger cystic duplications (La Quaglia et al.
colonic duplications); this is conveniently done 1990). With attention to bowel preparation and
with a linear stapler introduced through an antibiotic prophylaxis, a covering colostomy
enterotomy near the distal margin of the duplica- may be avoided. Infected rectal duplication cysts
tion (Fig. 20). The distal end of the septum must be are best treated by preliminary perineal drainage
divided completely to avoid leaving a spur. If both followed by resection once the inflammation has
colons reach the perineum, then a preliminary dou- settled. Rectal duplications should be completely
ble defunctioning colostomy may be necessary. excised because of the risk of late malignant
The duplicated bowel can later be anastomosed to degeneration (see above).
the native rectum and the mucosa of the redundant Retroperitoneal duplication cysts may be very
distal duplicated colorectal segment excised. large and are frequently adherent to retroperitoneal
Asymptomatic duplications of the appendix structures including the pancreas. Care is required
found in association with cloacal or bladder during surgery to avoid injury to mesenteric and
renal vessels and nearby viscera. Duplication cysts
in the tongue tend to be small and are usually
removed via an intraoral, sublingual approach.
Intra- or extradural duplication cysts in the verte-
bral canal are best managed in conjunction with
neurosurgeons.
All excised duplications should be examined
histologically.
The key steps in the successful surgical man-

agement of gastrointestinal duplications include
a thorough understanding of the spectrum of
these congenital malformations; careful preop-
erative assessment of the cyst and potential
associated pathology; appropriate operative
planning; complete excision whenever possible
(using open or minimally invasive approaches);
Fig. 20 Distal fenestration of a long colonic tubular dupli- and an awareness of alternative techniques and
cation (containing no ectopic gastric mucosa) potential pitfalls in complex cases where
Fig. 21 Endorectal
submucosal excision of a
small rectal duplication cyst
complete excision may be unduly hazardous. of the valve always necessary? J Pediatr Surg.
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Mesenteric and Omental Cysts
65
Suzanne Victoria McMahon, Dermot Thomas McDowell, and
Brian Sweeney
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 957
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
Outcome and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 959
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
Mesenteric and omental cysts represent a rare
intra-abdominal pathology, which should be The Italian anatomist Benevieni first described a
considered in the differential diagnosis of a mesenteric cyst in an autopsy of an 8-year-
cystic abdominal mass in a child or neonate. old boy in 1507. von Rokitansky described a
chylous mesenteric cyst in 1842, and the first doc-
Keywords umentation of an omental cyst was by Gairdner in
Mesenteric · Omental · Retroperitoneal · 1852. In 1880 the French surgeon Tillaux performed
Congenital · Acquired · Cysts the first successful surgery (a marsupialization) of a
mesenteric cyst (Tillaux 1880).
The classification of this heterogeneous group
of lesions has been based on multiple factors
including their anatomical location (Fig. 1), his-
topathology, or etiology, which has resulted in
S. V. McMahon (*) · D. T. McDowell · B. Sweeney some confusion. Moynihan endeavored to differ-
Department of Paediatric Surgery, Our Lady’s Children’s entiate these cysts based on their fluid content. He
Hospital, Crumlin, Dublin, Ireland described serous cysts with straw-colored fluid
e-mail: suzanne_mcmahon@hotmail.com;
dermcd@yahoo.com; sweenj@hotmail.com with essentially the same composition as plasma.
© Her Majesty the Queen in Right of United Kingdom 2020 955

https://doi.org/10.1007/978-3-662-43588-5_69
956 S. V. McMahon et al.
Fig. 1 Classification of mesenteric cysts: Type 1 – on a into the retroperitoneum, often incompletely resected; type
pedicle, easily resected; type 2 – sessile in the leaves of the 4 – multicentric, may require multiple complex operations,
mesentery, requires bowel resection; type 3 – extending sclerotherapy, or both (Losanoff et al. 2003)
In addition chylous cysts were described therefore have similar characteristics (De Perrot
containing both lipids and fat globules. In 1950 et al. 2000; Kurtz et al. 1986; Nam et al. 2012;
Beahrs et al. developed a classification for mes- Vanek and Phillips 1984).
enteric cysts based on their etiology (Beahrs et al. Mesenteric cysts can occur anywhere along the
1950). Mesenteric cysts are most widely consid- gastrointestinal tract from the stomach to the rec-
ered to be derived from ectopic lymphatic tissue, tum (Benevieni 1954). Omental cysts can occur in
which lacks communication with the central lym- either the greater or lesser omentum. Mesenteric
phatic system. The resultant cysts are thought to cysts are 4.5 times more common than omental
arise from lymphatic spaces associated with the cysts (Walker and Putnam 1973).
embryonic retroperitoneal lymph sac (Ricketts In a large case series in 1986, Kurtz et al. found
2006; Skandalakis et al. 1994). The role of lym- 60% of mesenteric cysts in the small bowel
phatic obstruction in their ontogeny is not mesentery (most commonly in the ileal mesen-
supported by relevant animal models (Benevieni tery), 24% in the large bowel mesentery (most
1954; Ricketts 2006; Skandalakis et al. 1994; commonly in the distribution of the sigmoid
Takiff et al. 1985; Vanek and Phillips 1984). mesocolon), and 14.5% in the retroperitoneum
Lymphangiomas comprise 90% of cysts of the (Chirathivat and Shermeta 1979; Kurtz et al.
mesentery of the neonate. Mesothelial lined 1986; Ure 2011; Vanek and Phillips 1984).
cysts, which are less common, are thought to
result from failure of the mesothelial surfaces of
the mesentery or omentum to coalesce (Ure 2011). Clinical Presentation
Ros et al. developed a histopathological classifi-
cation in 1987 (Ros et al. 1987). Mesothelial cysts Mesenteric and omental cysts occur in approxi-
are most commonly lined with cuboidal or colum- mately 1 per 20,000 admissions to pediatric hos-
nar endothelium or mesothelium (Bliss et al. pitals, with a slight male predominance (60%
1994; Ricketts 2006 Takiff et al. 1985). Their male:40% female). A quarter of cases present in
lack of lymphatic spaces and smooth muscle dif- children less than 10 years of age, with a mean age
ferentiates them pathologically from lymphan- of presentation in children ranging from approxi-
giomas of the same areas (Losanoff et al. 2003; mately 3–5 years of age (Bliss et al. 1994; Hebra
Takiff et al. 1985). Omental, retroperitoneal, and et al. 1993; Okur et al. 1997; Ure 2011). The age
mesenteric cysts are grouped together as they are of presentation is decreasing probably due to the
all derived from the same pathophysiology and increased use of imaging (Ure 2011). Mesenteric
65 Mesenteric and Omental Cysts 957
Fig. 2 (a) A plain

abdominal X-ray of a
patient suggesting a large
central abdominal mass
displacing the bowel to the
left. (b) A contrast study
performed in the patient in
Fig. 1a confirming
displacement of the bowel
by the mass without
evidence of bowel
obstruction
and omental cysts can present in a variety of

different ways. They may be detected on an ante-
natal ultrasound scan, found incidentally on radio-
logical imaging (asymptomatic), or can present
clinically with nonspecific abdominal complaints
or acute abdominal pain (Fernandez Ibita et al.
2015; Egozi and Ricketts 1997; Nam et al. 2012;
Sardi et al. 1987; Ure 2011; Vanek and Phillips
1984; Walker and Putnam 1973). The presenta-
tion varies according to the location and more
importantly the size of the cysts (Nam et al.
2012; Walker and Putnam 1973). Large cysts are
more likely to present acutely as abdominal dis-
tension, or with pain secondary to rapid increase
in size, intracystic hemorrhage, torsion, infection,
or rupture (Colodny 1986; Gross 1953; Kosir et al.
1991; Mollitt et al. 1978; Parrish and Potts 1973;
Ure 2011). Bowel obstruction resulting from sec-
ondary compression by the cyst or volvulus
around the cyst has been reported (Nam et al.
2012; Ricketts 2006; Vanek and Phillips 1984)
(Figs. 2 and 3).
Diagnosis Fig. 3 A child presented clinically with a large abdominal

mass that on imaging was consistent with a multiloculated
mesenteric cyst. At the time of surgery, a large mesenteric
In the majority of cases, a definitive preoperative lymphangioma arising from the mesentery of the ascend-
diagnosis is not possible. There is no role for ing colon was excised with evidence of hemorrhage. It was
routine laboratory studies to aid diagnosing possible to avoid a bowel resection in this case
Fig. 4 (a) An abdominal ultrasound of a complex septated unit reading of the cyst can help to determine the possible
cystic lesion consistent with a lymphangioma. (b) A CT nature of the cyst content, i.e., whether it contains chylous,
image of the patient presented in Fig. 3a. The Hounsfield blood, or proteinaceous fluid
these lesions, buy they can be used to assess the Table 1 Differential diagnosis of a mesenteric cyst
patient clinically if they present with complica- (Ricketts 2006)
tions such as torsion, hemorrhage, or rupture Intestinal duplication cyst
(Ure 2011). Omental cyst
These lesions are most commonly assessed by Ovarian Cyst
ultrasonography. This is a highly sensitive and Choledochal cyst
specific imaging modality to detect an abdominal Pancreatic, renal, or splenic cyst
cyst and can also be used to follow up these cysts Hydronephrosis
and to check for a postoperative recurrence. How- Cystic teratoma
ever, it is frequently impossible to determine the Hydatid cyst
cysts site of origin, i.e., if it is derived from the
omentum or mesentery. It can determine the mor-
phology of the lesion determining if it comprised Differential Diagnosis
of single or multiloculated cysts .Multiloculated
cysts favor the diagnosis of a lymphangioma (see There is a broad differential diagnosis for these
Fig. 4a). lesions, which includes but is not limited to cysts
Other imaging techniques may be used. A arising from the ovary, biliary tree, pancreas,
plain X-ray film of the abdomen may be used spleen, and intestine (Table 1). A large mesenteric
to demonstrate a mass effect, bowel obstruc- or omental cyst may mimic ascites (Karhan et al.
tion, bowel perforation, and ascites. Computed 2016). A non-pancreatic pseudocyst as a result of
tomography is not frequently used due to the trauma or inflammation can be confused with an
high levels of radiation. It does provide useful omental or mesenteric cyst. In the older patient,
information regarding size, location, and these benign conditions can also be mistaken for a
extension of the cysts into surrounding struc- malignant process. Distinguishing between mes-
tures. Magnetic resonance imaging could be enteric and intestinal duplication cysts can be
used to evaluate these cysts. This modality particularly challenging. Intestinal duplication
has the advantage that it does not use ionizing cysts share a common blood supply and muscular
radiation. It is however expensive and may layer with the adjacent bowel and have a well-
require the patient to undergo a general defined mucosal layer that may be appreciated on
anesthesia. ultrasound examination.
Treatment Kuga et al. 2000; Pampal and Yagmurlu 2012;

Singh et al. 2009; Wildhaber et al. 2006; Yao
In children with mesenteric or omental cysts, the et al. 1999). Port placement in patients with large
most common indication for surgical intervention cysts is challenging and utmost care is required.
is the presence of an abdominal mass with or In cases where intestinal resection is required,
without signs of intestinal obstruction. the bowel can be exteriorized through a port site
With the widespread use of prenatal ultraso- with the resection and anastomosis performed
nography, these cysts maybe diagnosed in utero. extracorporeally. It may be necessary to aspirate
No role for antenatal treatment of these lesions is the cyst to facilitate resection. Any mesenteric
currently recognized, but when they are discov- defects created at the time of surgery should be
ered prenatally, intervention during early infancy closed to minimize the risk for the development
is indicated to prevent potential complications of an internal hernia.
such as obstruction and intestinal volvulus which
may be life-threatening.
The patient should undergo standard preoper- Follow-Up
ative preparation with the insertion of an NG tube
and antibiotic prophylaxis to prepare for the need There is no clear consensus as to the type or
for possible bowel resection at the time of surgical duration of follow-up. Ultrasound is the modality
exploration. The origin of the cyst needs to be of choice for monitoring cysts that are incom-
confirmed carefully intraoperatively as preopera- pletely excised.
tive imaging may be misleading. Sometimes par-
tial decompression of the cyst facilitates this
process and also allows for a smaller wound to Outcome and Conclusion
allow delivery of the cyst post resection whether
the case is performed open or laparoscopically. Where complete excision is achieved, the long-
Complete excision is the treatment of choice as term outcome is good. The risk of recurrence is
it reduces the risk of recurrence. Omental cysts are reported up to 14% of cases. Recurrence is more
generally easily excised without interfering with likely following marsupialization and may require
adjacent organs. Enucleation is the surgical treat- a combination of re-excision, further marsupia-
ment of choice for mesenteric cysts as it avoids the lization, and injection of a sclerosing agent.
need to divide mesenteric blood vessels, which in There has been no reported incidence of malig-
turn would necessitate bowel resection. Intestinal nancy in these lesions (Fig. 5).
resection occurs in approximately 30% of adults
but is as high as 60% in children with mesenteric
cysts (Falidas et al. 2011). It is imperative that the
length of intestinal resection should be kept to a
minimum. In some cases the cyst may not be
amenable for complete resection and so a partial
resection is performed. Marsupialization of the
cyst can also be used in cases where complete
excision is not possible. This can be done in
isolation or in conjunction with a sclerosing agent.
With the advent of minimally invasive sur-
gery, these cysts have been managed success-
fully laparoscopically or with laparoscopic
assistance (Tran and Nguyen 2012; Al-Zaiem Fig. 5 An excised omental cyst containing serous fluid
2011; Esposito et al. 2009; Kenney et al. 1996; derived from the greater omentum
Cross-References Kenney B, Smith B, Bensoussan AL. Laparoscopic exci-

sion of a cystic lymphangioma. J Laparoendosc Surg.
1996;6(Suppl 1):S99–101.
▶ Lymphatic Malformations in Children Kosir MA, Sonnino RE, Gauderer MW. Pediatric abdom-
inal lymphangiomas: a plea for early recognition.
J Pediatr Surg. 1991;26(11):1309–13.
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Necrotizing Enterocolitis
66
Stephanie C. Papillon, Scott S. Short, and Henri R. Ford
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
Epidemiology of Necrotizing Enterocolitis
Worldwide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
Mechanisms of Intestinal Mucosal Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
Histopathologic Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 965
Risk Factors for NEC in the Full-Term Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
Laboratory Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
Associated Comorbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Nonoperative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Operative Indication and Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
Overall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
Postoperative Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
Long-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Neurodevelopmental Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970
Abstract
Necrotizing enterocolitis (NEC) is the predom-
inant intestinal inflammatory disorder affecting
S. C. Papillon (*) · S. S. Short · H. R. Ford
the newborn infant. Risk factors for NEC
Division of Pediatric Surgery, Children’s Hospital Los
Angeles, Los Angeles, CA, USA include prematurity, formula feeding, and bac-
e-mail: spapillon@huhosp.org; dr.scottshort@gmail.com; terial colonization of the gastrointestinal
HFord@chla.usc.edu

https://doi.org/10.1007/978-3-662-43588-5_70
964 S. C. Papillon et al.
(GI) tract. The number of neonates at risk of The incidence of NEC has been increasing
developing NEC continues to rise due to recent worldwide as a result of a steady rise in the rate
advances in neonatology that have resulted in of high-risk pregnancies and recent advances in
increased survival of extremely premature neonatology that have resulted in the survival of
infants. Clinical features of NEC are often significant numbers of extremely low birth weight
nonspecific and include evidence of physio- infants (Heida et al. 2017; Schlager et al. 2012;
logic instability, feeding intolerance, abdomi- Ahle et al. 2013). Thus, the need to understand
nal distention, and hematochezia. A cluster of this disease has never been more imperative.
key clinical and radiographic findings, known
as the Bell staging system, has been used to
characterize disease severity. Despite aggres- Pathogenesis
sive management strategies, morbidity and
mortality from NEC remain high. Thus, this Risk Factors
vexing disease will likely remain a major con-
tributor to healthcare costs and may, one day, Early studies by Santulli and colleagues suggested
become the leading cause of death among pre- that NEC develops in a susceptible or premature
mature infants. Optimal preventive strategies host as a result of various insults to the gastroin-
are needed to avert the devastating conse- testinal tract inflicted by ischemia, enteral feeding,
quences of NEC. and pathogenic bacteria (Mizrahi et al. 1965;
Santulli et al. 1975). Our current understanding
Keywords of the pathogenesis of NEC suggests that imma-
Necrotizing enterocolitis · Short bowel turity of the gastrointestinal tract in the preterm
syndrome · Ostomy, prematurity · Low birth neonate, combined with these insults, accounts for
weight infants · Peritoneal drainage · Total the cascade of events that lead to NEC. The imma-
parenteral nutrition ture intestine is characterized by poor microcircu-
latory regulation, impaired integrity of the
epithelial barrier, and various immune deficien-
Introduction cies, including decreased production of mucin,
defensins, and secretory IgA, to name a few,
Epidemiology of Necrotizing which impair the host’s ability to restrict the trans-
Enterocolitis Worldwide mucosal passage of pathogenic bacteria and
toxins. In addition, the dysfunctional motility
NEC is predominantly a disease of the premature and reduced digestive capacity of the premature
neonate. The majority of patients diagnosed with intestine further predispose to the accumulation of
NEC are less than 32 weeks of gestation. Data toxins or noxious substances that may contribute
from population-based studies worldwide esti- to or exacerbate mucosal injury (Neu and Pammi
mate the incidence of NEC to be 0.72–1.8 per 2017; Niño et al. 2016; Dominguez et al. 2014;
1000 live births (Dominguez et al. 2014). The Sylvester et al. 2012). Although a normal intesti-
incidence is highest in extremely low birth weight nal microbiota could mitigate such mucosal
infants (ELBW) weighing less than 1000 g, likely injury, the premature neonate suffers from abnor-
reflecting the degree of prematurity (Patel et al. mal microbial colonization of the gastrointestinal
2016; Sylvester et al. 2012; Holman et al. 2006; tract. Thus, breakdown of the epithelial barrier is
Llanos et al. 2002; Sankaran et al. 2004; Guthrie further exacerbated by loss of the vigorous and
et al. 2003; Christensen and Gordon 2010). NEC complex interaction between the mucosa and
decreases proportionally as birth weight intestinal microbiota, which results in an inappro-
increases, and a drastic decline occurs after priate, exuberant inflammatory response to com-
35 weeks gestation (Llanos et al. 2002; Hunter mensal and pathogenic bacteria. The
et al. 2008; Sylvester et al. 2012). inflammatory mediators released lead to further
66 Necrotizing Enterocolitis 965
epithelial injury, exaggerated systemic inflamma- analysis of resected, diseased intestine and
tion, and the resulting adverse sequelae character- autopsy specimens has historically shaped much
istic of NEC. The mechanisms that predispose the of our understanding of the pathogenesis of tissue
immature intestine to injury must be further injury in NEC. On gross morphology, the bowel
defined in order to prevent or treat NEC in the appears distended with patchy or diffuse areas of
premature neonate (Llanos et al. 2002). gray to dark discoloration. Focal lesions occur as
commonly as multisegmental disease (Nadler
et al. 2001; Dominguez et al. 2014). Examination
Mechanisms of Intestinal Mucosal of the mucosa may reveal a hemorrhagic and
Injury friable surface. Predominant histologic findings
range from acute and chronic inflammatory
Various studies describe some of the mechanisms changes to frank necrosis or perforation. These
by which mucosal injury occurs in NEC (Nadler include bowel wall edema, submucosal gas, as
et al. 2000; Sodhi et al. 2010). These studies have well as neutrophilic and lymphocytic infiltrates,
established a role for mediators such as nitric which may reflect in part the acuity or chronicity
oxide, which is made in large quantities during of the disease (Fig. 1). Subserosal or submucosal
inflammatory conditions by the inducible isoform gas, a product of bacterial fermentation also
of nitric oxide synthase (iNOS), and toll-like known as pneumatosis intestinalis, may also be
receptor 4 (TLR4) in the pathogenesis of NEC. visible and lends support to the infectious nature
These mediators are not only elevated in neonates of NEC. Rapidly progressing injury to the bowel
with NEC but also have been localized to regions is suggested by necrosis in the absence of inflam-
of mucosal injury and have been shown to inhibit mation, also known as coagulation necrosis, while
pathways necessary for restoration or repair of the more gradual progression is suggested by the
damaged intestinal epithelium (Ford 2006; Afrazi presence of chronic inflammatory changes
et al. 2011; Sodhi et al. 2010). Inhibiting the (Gould 1997; Ballance et al. 1990). Coagulation
activation of these mediators can not only reverse necrosis is often, although not exclusively, the
the inflammatory changes noted in the intestinal result of ischemia. Coagulation necrosis may be
epithelium in experimental models of NEC but limited to the mucosa; however, advanced disease
can also restore reparative pathways such as epi- may ultimately result in transmural involvement
thelial restitution through enterocyte migration and perforation. Necrosis may be accompanied by
and proliferation (Sodhi et al. 2010). Interplay hemorrhage and intramural thrombi. Reparative
between these pro-inflammatory mediators and
others such as platelet-activating factor (PAF)
has been demonstrated and could represent puta-
tive pathways essential for the development of
NEC (Soliman et al. 2010). Despite these obser-
vations, the sequence of events that lead to NEC
have yet to be established. Nonetheless, targeted
inhibition of these mediators may ultimately lead
to new therapeutic approaches to prevent or
attenuate NEC.
Histopathologic Findings
NEC can occur anywhere along the gastrointesti-

nal tract but most commonly affects the small Fig. 1 Diffuse patchy necrosis in a patient with NEC
intestine (Hackam et al. 2015). Morphological totalis. Subserosal gas can be seen
changes and granulation tissue have also been

observed along with active injury. These findings
suggest that the acute injury characteristic of NEC
probably occurred prior to the clinical manifesta-
tions that required resection of the diseased intes-
tine (Ballance et al. 1990). Patients with
transmural inflammation that do not undergo
resection may subsequently develop regions of
submucosal fibrosis that can manifest clinically
as intestinal strictures.
Risk Factors for NEC in the Full-Term

Infant
Fewer than 10% of patients who develop NEC are

full term. While the pattern of mucosal injury
reflects that of preterm infants, full-term infants
differ clinically from their premature counterparts
and, in this population, NEC “may be initiated by
different perinatal factors” (Ostlie et al. 2003).
Most studies suggest that congenital heart disease
(CHD) is the most significant predisposing risk Fig. 2 Abdominal distention and extensive abdominal
wall erythema in a patient with NEC totalis
factor for NEC in the full-term infant (Ostlie et al.
2003). Infants with CHD develop intestinal ische-
mia due to reduced blood flow to the intestine, abdominal wall discoloration, or erythema
which may result in mucosal injury and bacterial (Fig. 2). Within hours, patients can rapidly dete-
invasion, which in turn incites the inflammatory riorate and develop peritonitis with signs of car-
cascade that leads to NEC. diovascular collapse. The diagnosis is often
established by radiographic imaging. Standard
imaging consists of plain abdominal radiographs.
Clinical Features Initial findings may be nonspecific such as dilated
loops of intestine and a bowel gas pattern consis-
Presentation tent with ileus. Pneumatosis intestinalis is the
most common finding observed in patients with
At initial presentation, infants who develop NEC NEC (Dominguez et al. 2014). Portal venous gas
often exhibit nonspecific systemic signs that may is another potential finding that is associated with
prompt a workup for sepsis. Symptoms specific to pan-involvement and an unfavorable outcome.
the gastrointestinal tract are present in over 70% The NEC staging system, originally developed
of patients and include feeding intolerance by Bell et al., combines the clinical symptoms
manifested by high gastric residuals or frank with radiographic findings and has been used to
vomiting, abdominal distention, and gross or classify severity of disease and guide therapy.
occult blood in the stool, which is seen in up to
60% of patients (Sylvester et al. 2012). These
symptoms may present postoperatively following Laboratory Findings
the initial stages of cardiac repair for CHD in the
full-term infant. As NEC progresses, patients may Laboratory data, although universally used, have
develop worsening abdominal distention, not proven to be specific or reliable indicators for
the diagnosis of NEC. Metabolic acidosis, leuko- Operative Indication and Technique
penia, and thrombocytopenia are common find-
ings in patients with NEC (Sylvester et al. 2012; Up to 20–40% of patients with NEC will require
Dominguez et al. 2014). Thrombocytopenia that surgical intervention (Dominguez et al. 2014;
occurs rapidly has been associated with a poor Sylvester et al. 2012). Over the past decades,
prognosis (Sylvester et al. 2012; Dominguez indications for operation have evolved as practi-
et al. 2014). Studies have investigated potential tioners have sought to identify patients just prior
indices predictive of NEC that may also serve as to perforation; however, pneumoperitoneum
prognostic indicators; however, no inflammatory remains the only consistent and definitive indica-
marker has emerged as highly sensitive and spe- tion for surgical intervention. Relative indications
cific (Dominguez et al. 2014). for surgery include failure to respond to optimal
medical therapy, as evidenced by worsening clin-
ical status, abdominal wall erythema, or the pres-
Associated Comorbidities ence of a persistent intestinal loop on serial
abdominal radiographs. The goal of surgery is to
Several retrospective studies have reported a high resect gangrenous bowel while minimizing the
prevalence of NEC in patients who underwent risk of short bowel syndrome. The operation is
abdominal wall closure for gastroschisis (Oldham largely determined by the extent of disease found
et al. 1988; Amoury 1989; Mollitt and Golladay at laparotomy (Hansen et al. 2016). The entire
1982; Jayanthi et al. 1998). The patients described length of the gastrointestinal tract is examined
were often managed nonoperatively; however, and frankly necrotic bowel is resected. Where
recurrence was commonly observed (Oldham intestinal viability is questionable, a second look
et al. 1988). NEC was significantly more common laparotomy may be warranted. The standard sur-
in patients with severe gastrointestinal dysfunc- gical approach to the patient with NEC is resec-
tion, a characteristic of the premature gastrointes- tion of gangrenous or perforated bowel with
tinal tract. creation of a proximal ostomy. Traditionally,
enterostomy creation has been accepted as the
safest approach because primary anastomosis
Management may be tenuous in a septic infant (Pierro 2005).
For selected stable patients with localized disease,
Nonoperative resection with primary anastomosis may obviate
the need for a second operation as well as some of
Patients with NEC are initially managed with sup- the morbidity associated with ostomy creation
portive care. Upon clinical suspicion of NEC, feeds (Sylvester et al. 2012; Pierro 2005). In the past,
are withheld and the gastrointestinal tract is multiple stoma creation had been advocated for
decompressed using an orogastric tube. Intravenous patients with multifocal disease; however, this
fluid resuscitation is initiated. Laboratory data approach can lead to short bowel syndrome by
including a chemistry panel, complete blood count sacrificing viable intestine; therefore, it has been
with differential blood gas, and C-reactive protein abandoned.
(CRP) are obtained. Broad spectrum intravenous The “clip and drop back technique,” which
antibiotics are initiated once blood and urine are consists of resection of all necrotic bowel leaving
sent for culture. Close clinical observation with the remaining clipped segments within the
serial abdominal examinations as well as serial abdominal cavity without creating ostomies or
abdominal radiographs are used to monitor disease anastomoses, has been advocated for patients
progression. Clinical improvement is expected to with extensive multifocal disease. The viable seg-
occur within the first 72 h (Brunicardi et al. 2015). ments are then re-anastomosed at a second opera-
For patients who stabilize and show improvement, tion 48–72 h later. Delayed re-exploration has
antibiotic therapy is continued for 1–2 weeks. been proposed in a yet more controversial
technique, the “patch, drain, and wait.” This 1 and 6 months postoperatively between the two
approach involves irrigation of the abdominal groups. Seventy-four percent of the patients who
cavity, primary approximation of intestinal perfo- underwent drainage subsequently required lapa-
rations, placement of a Stamm gastrostomy, and rotomy for deteriorating clinical status. The
insertion of two Penrose drains beneath the dia- authors concluded that peritoneal drainage is not
phragm that course along the lateral aspect of the “a safe alternative to laparotomy and is not an
peritoneal cavity and exit from the lower quad- effective temporizing measure.” While neither
rants for continued peritoneal drainage (Moore randomized trial detected differences in primary
2000). Postoperatively patients are kept on long- nor secondary outcomes, each included a mixed
term parenteral nutrition (TPN). The drains are population of patients with focal intestinal perfo-
left in place until the drainage ceases and patients ration and NEC, and the studies did not meet the
are tolerating enteral feeds. The authors advocate minimum number of required participants for
postponing a second operation during the 2-week appropriate statistical power perhaps limiting the
period immediately postoperatively, and in cases ability to observe differences.
where return of bowel function does not occur,
reoperation may occur as late as 2 months.
In the 1970s, peritoneal drainage was proposed Outcomes
as a temporizing measure for the critically ill very
low birth weight (VLBW) patient, weighing less Overall
than 1500 g, with perforated NEC. The procedure
is typically performed under local anesthesia at NEC is associated with a high morbidity and
the bedside. The major components involve copi- mortality. Overall outcome is affected by the
ous irrigation of the abdominal cavity and place- degree of prematurity and extent of disease.
ment of a Penrose drain in the lower quadrant or Over the past decades, survival for NEC has
bilateral lower quadrants allowing for decompres- shown steady improvement. This observation
sion and removal of fecal contamination. Perito- has been most notable in VLBW infants and is
neal drainage is widely viewed as initial likely related to advances in supportive care.
treatment, and its use as definitive treatment NEC has a relatively low recurrence rate. Up to
remains controversial. There have been two ran- one third of patients with NEC will develop
domized controlled trials investigating the use of intestinal strictures. Strictures occur more fre-
peritoneal drainage versus laparotomy in VLBW quently in patients with medically treated NEC
infants with perforated NEC to determine any (Sylvester et al. 2012). Suspected patients
survival advantage. In the first multicenter trial, should undergo contrast enema and surgical
117 VLBW infants were randomized to either resection.
treatment with 55 undergoing drainage and
62 undergoing laparotomy (Moss et al. 2006).
The investigators did not observe any significant Postoperative Outcomes
differences in 90-day mortality. Similarly, no sig-
nificant differences were observed in secondary Postoperative complications occur in up to 40% of
outcome measures that included TPN dependency neonates who undergo surgical therapy for NEC.
and length of hospital stay at 90 days postopera- These include anastomotic leak, stoma complica-
tively. In the second international multicenter ran- tions such as prolapse or necrosis, and injury to
domized controlled trial (Rees et al. 2008), the liver (Sato et al. 2011). Other complications
35 patients were randomized to peritoneal drain- include intestinal strictures, sepsis, and short gut
age and 34 to laparotomy. There were no signifi- syndrome (Horwitz et al. 1995; Blakely et al.
cant differences in mortality or in secondary 2005). While mortality shows stepwise progres-
outcome measures that included length of stay sion with decreasing gestational age, Horwitz
and gastrointestinal and respiratory outcomes at et al. found the overall number of complications
to be relatively stable across all age groups patients and their families. NEC is also a major
(Horwitz et al. 1995). contributor to healthcare costs, and the economic
burden persists beyond the initial hospitalization
period. A retrospective cohort study found signif-
Long-Term Outcomes icantly higher healthcare costs for patients with
both medical and surgical NEC compared with
Gastrointestinal matched controls. These differences persisted
The most devastating complication of NEC is through the first 3 years of life for patients with
intestinal failure due to inadequate residual small surgical NEC (Ganapathy et al. 2013). Thus, for
bowel (short gut). Nearly one quarter of patients the practitioner caring for these patients and their
undergoing surgical resection for NEC will families, there is an urgent need to optimize cur-
develop short bowel, and NEC is among the lead- rent management and develop preventive
ing causes of intestinal failure in the neonatal strategies.
population. The absence of the ileocecal valve Although numerous studies have identified
does not always predict the likelihood of failure putative risk factors for NEC, preventive
of intestinal adaptation in patients with inadequate approaches are limited. Animal models have dem-
small bowel length (Duro et al. 2010). The onstrated a protective role for growth factors such
patient’s gestational age at the time of small as EGF and HB-EGF, which can promote intesti-
bowel resection is an important prognostic indi- nal restitution, and for inhibitors of
cator of the risk of intestinal failure because an pro-inflammatory mediators. Studies in human
increase in small bowel length typically occurs infants have shown a beneficial role for probiotics
during the third trimester (Goulet and Ruemmele and prebiotics in reducing the incidence of NEC
2006). and producing a fecal microbial composition that
resembles that of their breastfed counterparts
(AlFaleh and Anabrees 2014). However, there is
Neurodevelopmental Outcome insufficient evidence to recommend these inter-
ventions at this time. Restrictive feeding strategies
NEC has been found to be an independent risk have not shown any advantage. Corticosteroid
factor for adverse neurodevelopmental outcomes. administration has also been investigated as a
Analysis at 7 years for children included in the therapeutic adjunct in NEC because of its ability
ORACLE Children Group, a randomized study to induce maturation of immature organs. The
investigating the use of broad-spectrum antibi- impact of corticosteroids on the developing intes-
otics in preterm premature rupture of membranes, tine was first explored in the 1960s and was sub-
found increased risk of any functional impairment sequently shown to accelerate the maturation of
in children with a history of NEC (Pike et al. the mucosal barrier (Israel et al. 1990). Random-
2012). In a multicenter retrospective study, ized trials have demonstrated that steroids can
ELBW infants who required surgery for NEC reduce the number of patients who develop NEC
were found to have a significantly increased prev- as well as the severity of disease (Bauer et al.
alence of neurodevelopmental and neuromotor or 1984; Halac et al. 1990). However, the direct
neurosensory deficits including cerebral palsy, impact of steroids on the gastrointestinal tract
blindness, and deafness (Hintz et al. 2005). and their long-term effects on the developing
intestine are not well defined. While antenatal
steroids show benefit, the use of postnatal steroids
Conclusions and Future Directions is cautioned since long-term outcomes will
require further study (LeFlore et al. 2002). Breast
NEC remains a vexing problem for both neona- milk is the only intervention that is recommended
tologists and pediatric surgeons. The most devas- for the preterm infant by the American Academy
tating impact of this disease is its direct effect on of Pediatrics to prevent or reduce the incidence of
NEC. Clinical trials have demonstrated the ability Duro D, Kalish LA, Johnston P, Jaksic T, McCarthy M,
of breast milk to reduce the incidence of NEC and Martin C, et al. Risk factors of intestinal failure in
infants with necrotizing enterocolitis: a Glaser Pediatric
its associated mortality and morbidity among pre- Research Network study. J Pediatr. 2010;157(2):203–8.
term infants, including improved neurodeve- Ford HR. Mechanism of nitric oxide-mediated intestinal
lopmental outcomes. As studies on NEC barrier failure: insight into the pathogenesis of necro-
continue, identifying the child at risk, advocating tizing enterocolitis. J Pediatr Surg. 2006;41(2):294–9.
Ganapathy V, Hay JW, Kim JH, Lee ML, Rechtman
for the use of breast milk, and providing aggres- DJ. Long term healthcare costs of infants who survived
sive care will be key in managing this perplexing neonatal necrotizing enterocolitis: a retrospective lon-
problem. gitudinal study among infants enrolled in Texas Med-
icaid. BMC Pediatr. 2013;20:13–127.
Gould SJ. The pathology of necrotizing enterocolitis.
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Meconium Ileus
67
Pietro Bagolan, Francesco Morini, and Andrea Conforti
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 974
Definition and Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
Simple MI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
Complex MI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 975
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
Pathogenesis and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 976
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
Prenatal Detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 977
Postnatal Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 978
Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
Non-CF Related Meconium Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 980
Intestinal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Intestinal Malrotation and Midgut Volvulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Hirschsprung’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Meconium Plug Syndrome and Neonatal Small Left Colon . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 981
Nonoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
P. Bagolan (*) · F. Morini · A. Conforti

Neonatal Surgery Unit, Department of Medical and
Surgical Neonatology, Bambino Gesù Children’s Hospital,
IRCCS, Rome, Italy
e-mail: pietro.bagolan@opbg.net;
francesco.morini@opbg.net; andrea.conforti@opbg.net

https://doi.org/10.1007/978-3-662-43588-5_71
974 P. Bagolan et al.
Simple MI: Operative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 984

Complicated MI: Operative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988
Outcomes and Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 989
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 990
Meconium ileus (MI) is an intestinal
obstruction caused by thickened meconium, History
strictly linked to cystic fibrosis (CF) and
often representing its first manifestation. Baron Karl von Rokitansky described the first
Meconium ileus can be either simple report of a patient with meconium ileus
(intraluminal occlusion by stick meconium) (MI) (Hodson et al. 2007). He described the
or complex, with volvulus, atresia, necrosis, autopsy findings in male fetus found in a cemetery
perforation, meconium peritonitis, and in Vienna in 1834: “. . .In the last part of the small
pseudocyst formation. Since its first descrip- bowel there was a small ileal perforation the size
tion in the nineteenth century, progress was of a hemp seed and around the perforation there
made in the understanding of the genetic was yellow jelly-like meconium partially fast
origins of this disorder, leading to the iden- sticking to the outside of the bowel.” The pancreas
tification of the CFTR gene and its over was macroscopically normal. Although the histol-
1900 pathogenetic mutations. The diagnos- ogy of the pancreas was not recorded, this report is
tic workup has seen the evolution of prenatal considered to be an early or even the first descrip-
and postnatal imaging and laboratory studies tion of complicated meconium ileus.
improving the ability to early detect MI and In 1905, Landstainer was the first to report
CF and to differentiate MI from other causes thickened meconium obstructing the small bowel
of neonatal intestinal occlusion. Finally, the associated with pathologic changes of the pan-
development of several treatment options, creas in a newborn (Hodson et al. 2007), due
both surgical and nonsurgical, gives the sur- probably to an unknown enzyme deficiency. In
geon the opportunity to tailor the therapeutic 1936, Fanconi coined the term cystic fibrosis
strategy to the clinical presentation of each (CF) of the pancreas to describe the association
single patient. This chapter on MI will between chronic pulmonary disease of infancy
review the current knowledge about its path- and pancreatic insufficiency (Hodson et al.
ogenesis, describe the diagnostic and thera- 2007). It was only 2 years later that Anderson
peutic approaches to the fetus and newborn described the connection between MI and CF
baby with this disorder, and illustrate the reporting similar pattern of histologic pancreatic
outcomes of such patients that may aid the abnormalities in both CF and MI newborns,
pediatric surgeon in caring for these suggesting a causative link between CF, abnormal
patients. intestinal mucus secretion, and the abnormally
viscid nature of meconium in MI infants (Hodson
Keywords et al. 2007). MI was considered exclusively an
Cystic fibrosis · Meconium ileus · Meconium early manifestation of CF until the mid-1960s,
peritonitis · Neonatal surgery · Nonoperative when Rickham and Boeckman (Rickham and
management · Prenatal diagnosis · Treatment Boeckman 1965) described seven infants who
67 Meconium Ileus 975
had neonatal meconium obstruction but did not age should be offered preconception and prenatal
appear to have CF. Five survived and subse- CF carrier screening routinely (Am.Coll.Obst.
quently had normal sweat tests, and trypsin was Gynecol.Committee on Genetics 2011), thereby
present in their stools. Since then, it became clear identifying low-risk or high-risk groups. In the
that MI could exist without CF. high-risk group, diagnosis is suspected when the
MI and MI equivalent were invariably lethal up sonographic features of MI are found in a mother
to late 1940s, when Hyatt and Wilson reported the with positive CF carrier screen (Carlyle et al.
first series of five consecutive patients treated with 2012).
enemas through enterotomies, who survived Neonatal MI is commonly classified into two
(Hyatt and Wilson 1948). Between the 1950s subgroups: simple MI and complex MI.
and the beginning of the 1970s, several surgical
techniques were developed for the treatment of
MI. In 1953, Gross proposed resection and Simple MI
Mikulicz enterostomy (Gross 1953); few years
later, Bishop and Koop reported the resection Simple (uncomplicated) MI should be prenatally
with end-to-side anastomosis and distal stoma suspected when hyperechoic bowel loops, with/
(Bishop and Koop 1957). In 1961, Santulli and without intestinal dilatation, are found at prenatal
Blanc modified the technique with a side-to-end US. Nonetheless, it is usually documented after
anastomosis and proximal stoma (Santulli and birth in term newborn admitted for abdominal
Blanc 1961). Resection of the dilated bowel and distension secondary to distal small bowel
anastomosis without enterostomy was proposed obstruction, with bilious vomiting and failure to
by Swenson in 1962 (Swenson 1962), and in 1970 pass stools.
O’Neill developed the tube enterostomy (O’Neill Characteristic inspissated meconium is evacu-
et al. 1970). In 1969, Noblett introduced a novel ated after enema or found at surgery.
therapy for uncomplicated patients (Noblett
1969). She used full-strength Gastrografin
enemas. Since the introduction of nonoperative Complex MI
management of MI, the first-line approach was
progressively shifted from surgery to intervention Complex (complicated) MI is usually prenatally
radiology. Currently, survival rate of MI new- suspected for the evidence of complications (e.g.,
borns is approaching 100% in developed coun- intestinal perforation, ascites, volvulus) discov-
tries, depending mostly on management of CF ered during prenatal ultrasound screening. Calci-
complications. fications are frequently present and may be found
either prenatally or postnatally, at abdominal plain
X-rays. Clinical signs of intestinal perforation
Definition and Classification may be present.
Later in life presentation is usually referred to
Meconium ileus (MI) is defined as a unique intes- as meconium ileus equivalent or distal ileal
tinal obstruction at the level of the terminal ileus obstruction syndrome (DIOS). Complete or
caused by thick, adhesive, desiccated meconium incomplete intestinal obstruction by viscid fecal
in the bowel lumen and a failure to pass meco- material in the terminal ileum and proximal colon
nium rectally, in patients with cystic fibrosis. The is a common complication in cystic fibrosis, with
natural course of untreated MI is uniformly poor. estimates of prevalence range from 5 to 12 epi-
The importance of a precocious diagnosis, led sodes per 1000 patients per year in children, with
the American College of Obstetrics and Gynecol- higher rates reported in adults (Colombo et al.
ogy to recommend that all women of reproductive 2011).
Epidemiology long arm of human chromosome 7, band q31,

described in 1989 (Kerem et al. 1989b). CF is
The meconium syndromes occur primarily in the most common life-threatening autosomal
Caucasians and are frequently linked to CF. In recessive condition in the non-Hispanic white
particular, MI is the first clinical manifestation of population. It is a progressive, multisystem dis-
CF in up to 20% affected infants, while the preva- ease that primarily affects the pulmonary, pancre-
lence of CF in patients with MI varies from 54% atic, and gastrointestinal systems (Am.Coll.Obst.
(Gorter et al. 2010) to 100% (Casaccia et al. 2003). Gynecol.Committee on Genetics 2011). To date
No male or female preponderance is reported. 1940 CFTR mutations have been reported to the
In families with a first child affected by CF with CF Genetic Consortium (Cystic fibrosis mutation
MI, the risk of a subsequent child with the identi- database statistics 2012). The most common
cal clinical presentation of CF and MI is 39% mutation (F508del; previously termed ΔF508) is
(Carlyle et al. 2012) compared with 6% in families responsible for approximately 70% of clinical
with a first child with CF without MI (Kerem et al. cases. It acts through the CFTR protein degrada-
1989a). Cases with CF are constantly rising, from tion in the endoplasmic reticulum prior to folding
3500 at the end of 1980s to more than 7000 by the and trafficking. Nonetheless, there is wide vari-
millennium (Davenport 1998). Thus, the number ability within different ethnic and geographic
of patients with MI may be expected to increase in populations (Bobadilla et al. 2002). A direct cor-
the near future. relation between CF and MI have long been
Cystic fibrosis is transmitted as autosomal shown since Anderson in 1938 described the asso-
recessive disease with a heterozygote frequency ciation of the histologic likeness of pancreatic
estimated to be as frequent as 1 in 25 in abnormalities in both MI and CF, reporting MI
non-Hispanic whites, 1 in 58 in Hispanic whites, as an early and more severe manifestation of the
1 in 61 in African Americans, and 1 in 94 in Asian overall lung and pancreatic insufficiency.
Americans (Am.Coll.Obst.Gynecol.Committee In the intestine, CFTR mediates secretion of
on Genetics 2011). Incidence of CF phenotype is chloride, bicarbonate, and fluid. Mutations in the
very variable (Hodson et al. 2007). In Europe, the CFTR gene may result in partial or total loss of
incidence ranges from 1/1775 in the Faroe Islands function with abnormally low volume and aber-
to 1/25,000 in Finland. In the United States, it is rant electrolyte composition. It was demonstrated
1/2500–3500 live births in the general Caucasian that the localization of CFTR expression in the
population, 1/10,500 Native American births, intestine reflects the need for bicarbonate and fluid
1/11,500 Hispanic births, 1/14,000–20,000 Afri- secretion. Bicarbonate secretion is highest in the
can American births, and 1/25,000 Asian births. proximal intestine that receives a high acid load
In the Middle East population, the incidence from the stomach, than lowering through the
ranges from 1/1800 to 1/5800 depending on the intestine. Gastric acidity is normally neutralized
ethnicity. In Oceania it ranges from 1/2000 in the by bicarbonate to support optimal activity of
Australian population of British origin to 1/3700 digestive enzymes from the exocrine pancreas
in the Australian population of Greek origin. The and solubility of bile salts from the biliary tract.
incidence in Japan is 1/355,000, and in If CFTR function is deficient, gastric acid is not
South Africa it is 1/2000 in the white population properly neutralized in the intestine, and this con-
and 1/12000 in the colored one. tributes to poor digestive function (De Lisle and
Borowitz 2013).
Most of the wide range of effects of CF on the
Pathogenesis and Pathophysiology intestine are secondary to the decrease in anion
and fluid transport caused by loss of CFTR func-
CF results from mutations in the gene, which tion: Quinton proposed his hypothesis that the
codes for a cell membrane protein termed the CF lack of secreted HCO3 in the extracellular
transmembrane regulator (CFTR), localized to the medium impairs calcium removal, prevents
normal mucin expansion, and promotes stasis of Studies on the discordant phenotype observed in
mucus in the ducts or on the luminal surfaces of CF siblings argued against a major role of envi-
affected organs (Quinton 2008). Along with ade- ronmental factors and suggested that genes other
quate fluid volume, other authors advocate the than CFTR modulate the CF phenotype.
crucial role of bicarbonate to regulate the normal Rozmahel et al. (Rozmahel et al. 1996) firstly
expansion and solubility of intestinal mucus reported a modifier locus for MI on chromosome
(Garcia et al. 2009). As a matter of fact, the 7 in a murine CF model (cfm1). Subsequently
major consequence of the altered luminal environ- several markers on human chromosome 19 (the
ment is the accumulation of mucus in the CF intes- region syntenic to the mouse locus) showed sig-
tine. All this may lead to intestinal obstruction nificant linkage with the presence of MI in 185 sib-
mostly at the level of the terminal ileus caused by ling pairs (Zielenski et al. 1999). Recently, Van
thick, adhesive, desiccated meconium in the bowel der Doef et al. reported the association between a
lumen and a failure to pass meconium rectally. variant in the calcium-activated chloride channel
The analysis of meconium in infants affected regulator 1 (CLCA1) gene and meconium ileus in
by CF shows poor water contents, low levels of European CF patients (Van der Doef et al. 2010).
minerals (sodium, potassium, and magnesium are However, the causal role between human modifier
almost the half in concentration when compared genes and MI has yet to be discovered.
with controls), as well as protein-bound carbohy-
drate and trypsin contents. Meconium samples
from patients affected by CF show a greater Diagnosis
amount of albumin, mucoproteins, and calcium.
Meconium hyperviscosity is thought due to the Prenatal Detection
increased concentration of proteins (80–90% in
neonates with MI compared with 7% in normal MI may be suspected prenatally, during second
infants) and to low concentration of carbohydrates trimester ultrasound, when the presence of hyper-
(Welsh 1995). These changes seem to be due to echogenic fetal bowel loops and/or bowel dilata-
mucus hyperproduction and to luminal HCO3 tion and/or polyhydramnios may raise the
deficiency, causing an incorrect maturation of suspicion of MI (Fig. 1). Hyperechogenic fetal
mucins as they are released onto luminal surfaces bowel is a relatively common event (0.04–1.80%
(Kreda et al. 2012). Therefore, the huge mucins, of fetuses) indicating different disorders (hypo-
highly condensed Ca + rich macromolecules thyroidism, chromosomal abnormalities, infec-
(106–108 Da) in intracellular granules, released tions, gastrointestinal disorders, fetal growth
during exocytosis to protect the apical surfaces of restriction, intra-amniotic bleeding, etc.) (Scodet
epithelial tissues, are not hydrated due to the lack et al. 2002). Familial history of CF (reported in up
of HCO3- in the extracellular matrix, impairing to 33% of patients with MI), coupled with restric-
calcium removal and therefore preventing normal tion fragment length polymorphism analysis and
mucin expansion (Quinton 2008). prenatal sonographic findings, allows accurate
Different mutations in CFTR correlate with prediction of intestinal obstruction due to MI and
different percentage of infants affected by MI: CF (Culling and Ogle 2010). All types of intesti-
patients with two copies of the F508del mutation nal obstructions, including isolated intestinal atre-
have a 24.9% chance of presenting with MI, sia, may be associated to CF. Pregnant women
F508del plus any “other” CF mutation confers with fetal intestinal obstruction compatible with
16.9% chance, and two “other” CF mutations MI should be counseled for genetic screenings
confer a 12.5% chance of MI (Carlyle et al. 2012). and amniocentesis (Casaccia et al. 2003).
Although the prominent role of CFTR in etiol- In complicated MI ultrasonographic evalua-
ogy of CF is well accepted, other nongenetic risk tions may reveal dilated hyperechoic bowel
factors seem to play a role in the phenotype of CF: loops, abdominal calcifications, possibly associ-
this is the case of the so-called modifier genes. ated with ascites and/or giant pseudocysts, and
Fig. 1 Prenatal US: hyperechoic bowel and ascites (a–c); dilated bowel with hyperechogenic wall (d)
isolated ascites. In some cases, signs of meconium Complicated MI patients present with bile-
periorchitis (caused by fetal peritonitis with sub- stained gastric fluid, bile or fecal vomiting,
sequent spillage of meconium into the scrotal sac) abdominal distension, and impossibility of meco-
may be detected (Regev et al. 2009). Nonetheless, nium passage associated with bowel perforation,
complicated MI represents a minority of cases. intestinal atresia and volvulus, and abdominal
pseudocyst. In the latter case, an abdominal swell-
ing may be palpated at birth, as well as possible
Postnatal Presentation signs of peritoneal irritation and skin discolor-
ation. General symptoms of intestinal perforation,
Newborn affected by MI may be unremarkable at including hypovolemic shock and sepsis, may
birth and may also tolerate feeds for the first 24 h. rapidly occur. Occasionally prenatal intestinal
They usually develop progressive abdominal dis- perforation spontaneously heals, and bowel occlu-
tension; clear vomiting, which later becomes bil- sion is not detected at birth. In those cases, the
ious, due to failure to pass meconium. Visible only finding is the presence of calcification on
peristaltic waves are often present as well as pal- abdominal X-rays or US.
pable, thick, malleable bowel loops. Classical sign
is the “putty sign”: finger pressure over a firm loop
of bowel leads to intestine indentation. No signs Imaging
of peritoneal irritation are present at birth in case
of simple MI, and usually no meconium is Although there are no exclusive features (Carroll
expelled at rectal examination. et al. 2016), the baby with simple MI X-ray
typically shows dilated bowel loops, usually with- pneumoperitoneum, pseudocyst, and abdominal
out air-fluid levels since the thick meconium pre- calcifications.
cludes air-fluid interface, Singleton’s sign A confirmative study is the contrast enema
(granular “soap bubble”) and/or Neuhauser’s with water-soluble contrast agent whether hyper-
sign (ground-glass appearance) both secondary or iso-osmolar. Contrast studies must be
to the mix of air with the thick meconium in the performed under fluoroscopy to prevent possible
right lower abdominal quadrant (Casaccia et al. bowel perforation (Culling and Ogle 2010), show-
2003). ing a normally positioned microcolon that can be
Cases with complicated MI usually present empty, or may contain pellets of thickened meco-
with more noticeable bowel distension and radio- nium (Fig. 2a, b). If contrast enema refluxes
logical signs of intestinal perforation such as through ileocecal valve, meconium “pearls” may
Fig. 2 Draft of impacted terminal ileum before (b). Passage of some pearls is obtained in a few hours (c).
Gastrografin® hypertonic enema (a); enema showing (Atlas on “Pediatric Surgery” by Prem Puri and Michael
inspissated meconium along the left and transverse colon Hollwart edited by Springer)
be observed in the terminal ileum followed by a transport in the etiology of CF and offering the
transitional and then a dilated ileum more proxi- molecular rationale to the sweat test for
mally. The passage of contrast into the terminal diagnosing CF.
ileum may result in pellet evacuation (Fig. 2c),
with complete or partial resolution of intestinal
obstruction. When contrast fails to reflux to ter- Differential Diagnosis
minal ileum, either the diagnosis of MI or the level
of the occlusion remains unclear. In these cases, MI appears to be under nearly complete control of
surgical procedure may be required on the basis of genetic factors, as heritability of this trait
bowel obstruction. approaches 100% (Blackman et al. 2006). MI
accounts for 10–25% of all cases of neonatal
intestinal obstructions (Casaccia et al. 2003).
Laboratory Tests Therefore, excluding the presence of CF is man-
datory in each newborn infant presenting intesti-
Definitive diagnosis of CF associated with MI nal obstruction.
has always to be obtained. Several tests have been However, other relatively common causes of
historically developed. Albumin value (>20 mg/g) neonatal intestinal obstruction have to be consid-
as well as a low trypsin concentration in the stools ered: non-CF related meconium obstruction intes-
(<80 mg/g) has been reported as good indicator for tinal atresia, intestinal malrotation and midgut
MI (Culling and Ogle 2010). Nonetheless, due to volvulus, Hirschsprung’s disease, meconium
the low specificity and sensitivity of these tests, all plug syndrome, neonatal small left colon, and
current protocols rely on immunoreactive trypsin hypothyroidism.
(IRT) test as the primary screening test for CF
(Farrell et al. 2008), which is considered the gold
standard first-line screening for CF. Non-CF Related Meconium Obstruction
Once suspected, CF can be confirmed either
with genetic test or with the sweat test, A difficult diagnosis to differentiate from MI is the
which remains the standard procedure (Farrell presence of a functional gastrointestinal
et al. 2008). In fact, despite the potential dysmotility presenting as intestinal obstruction
usefulness of the information, acquiring a CF during newborn period. This is a relatively com-
genotype can be difficult, and available mutation mon condition affecting preterm or low birth-
screening panels can identify no more than 90% weight infants (Kim et al. 2015).
of CFTR mutations, the 9.7% of genotyped Recently, this condition was referred to as MI
individuals remaining with at least one in non-CF patients, due to the high correlation in
unidentified mutation in the Cystic Fibrosis presenting symptoms between the two conditions
Foundation Patient Registry. Furthermore, the (Gorter et al. 2010).
consequences of the vast majority of CFTR Intestinal immaturity is believed to be respon-
mutations remain unknown, even if the genotype sible for this condition, which may require surgi-
is identified (Farrell et al. 2008). Sweat is easily cal intervention to treat possible complications
collected from infant’s skin, and pilocarpine such as necrotizing enterocolitis and spontaneous
ionophoresis is applied to quantify chloride and perforations (Casaccia et al. 2003; Gorter et al.
sodium. The accuracy of sweat test is strictly 2010). Although no definitive data are available,
linked to the minimum amount of sweat to be intestinal dysmotility in preterm babies should be
collected (100 mg) and then generally indicated related to some degree of depletion of interstitial
in babies weighing 3.0–3.5 Kg or more. A mea- cells of Cajal (ICC). The key role played by these
sured concentration of sweat chloride higher cells in generation of pacemaker activity makes it
than 60 mEq/L is diagnostic for CF. The discov- likely that a proportion of hitherto unexplained
ery of CFTR confirmed the role of electrolyte gut motility disorders are caused by functional or
structural abnormalities in ICC (Kenny et al. Meconium Plug Syndrome

1999). and Neonatal Small Left Colon
Meconium plug syndrome (MPS) and neonatal

Intestinal Atresia small left colon syndrome (SLCS) should also be
considered and ruled out. MPS was firstly
Intestinal atresia is usually prenatally suspected described in 1956 as a distinct condition charac-
faced with fetal dilated bowel loops. At birth, terized by transient large bowel obstruction
progressive abdominal distension and consequent relieved by the passage of meconium plugs. Con-
respiratory distress, bilious vomiting, and failure versely, SLCS was firstly described in 1974 as a
to pass meconium are the main typical symptoms. neonatal obstructive condition reported in infants
A plain abdominal X-ray reveals distended of diabetic mothers in whom contrast enema
bowel loops, with air-fluid levels and typically showed a narrow left colon. Recent reports are
no air beyond that point. less prone to consider those as specific diagnoses,
due to the high incidence of overlapping between
MPS and SLCS and other well-defined diseases
Intestinal Malrotation and Midgut (e.g., Hirschsprung’s disease and cystic fibrosis)
Volvulus that impose discrimination (Burge and Drewett
2004).
Intestinal malrotation refers to all abnormalities of
intestinal position and fixation deriving from an
incomplete or absent intestinal rotation during Hypothyroidism
early stages of fetal development. This condition
may lead to chronic or acute intestinal occlusion. Hypothyroidism is not a surgical challenge;
In a classical neonatal surgical emergency, however, it may become evident during neonatal
with sudden onset of bilious vomiting in a previ- period as a delayed passage of meconium
ously healthy infant, the acute midgut volvulus beyond 24–48 h of life, with subsequent
could be associated with MI and CF (presenting as sub-occlusive clinical onset. Dosage of thyroid
complicated MI) and may lead to intestinal atre- hormones allows a correct diagnosis and substi-
sia. Infants with complete obstruction rapidly tutive therapy.
develop intestinal ischemia with a firm distended
abdomen, hypovolemia, and shock.
Treatment
Hirschsprung’s Disease CFTR dysfunction in the gastrointestinal tract

occurs earlier in the ontogeny and is present in
Hirschsprung’s disease, especially total colonic all patients regardless of phenotype. Most or per-
aganglionosis, as well as extended small bowel haps all the effects of CF on the gut are secondary
aganglionosis may mimic MI. Physical examina- to the decrease in anion and fluid transport caused
tion often demonstrates abdominal distention usu- by the loss of CF function.
ally absent at birth. Rectal examination of According to De Lisle et al., the possible cas-
newborn infant with Hirschsprung’s disease cade of events concerning the intestine, supported
reveals a tight anus that may be incorrectly diag- by CF model, is:
nosed as anal stenosis. Rectal examination usually
leads to emission of gas and fecal matter under 1. Deficient anion and fluid transport due to loss
pressure. Contrast enema may be useful to suspect of CFTR function.
HD, but definitive diagnosis depends on histo- 2. The consequent altered environment impairs
pathological examination of intestinal specimens. turnover and clearance of mucus.
3. Static mucus promotes abnormal bacterial (a) Rule out other types of neonatal intestinal
colonization. occlusion as well as complicated forms of MI.
4. Abnormal bacteria alter immune system (b) Assess intravenous hydration (one to three
behavior. times maintenance) and administer prophylac-
5. Altered immune response further stimulates tic antibiotic therapy.
mucus production and accumulation, the (c) Perform the technique under fluoroscopic con-
major consequences of the altered luminal trol and be present, as a neonatal surgeon, at
environment (De Lisle and Borowitz 2013). the radiological procedure.
(d) Be ready, patient and surgeon, for an emer-
gency surgery due to any unexpected compli-
The most serious intestinal complication is
cation (i.e., intestinal perforation).
obstruction of the terminal ileum or proximal
large intestine, which if untreated may result in
Gastrografin ® has been reported as the most
rupture and sepsis. Such obstruction, the meco-
efficacious of the enemas, and it is still frequently
nium ileus, is a unique form of congenital and
used as radiopaque hypertonic agent (Copeland
neonatal obstruction. The meconium of the fetus
et al. 2009). Gastrografin® is meglumine
forms concretions in the distal ileum that
diatrizoate, a liquefying hyperosmolar agent
completely occlude the lumen. Several other
(1900 mOsm/l), water soluble, radiopaque solu-
intestinal conditions can be associated with CF
tion containing two components: 0.1% Polysor-
at birth or later in life, but none is so typically
bate 80 (Twin 80 ®, a tension-reducing
linked to CF as MI. At birth, clinical picture may
emulsifying agent) and organically 37% bound
look like simple intraluminal bowel obstruction
iodine. Thanks to its hyperosmolar properties,
(uncomplicated MI) or as complex one (compli-
Gastrografin ® draws fluid into the intestinal
cated MI), the latter including volvulus, gan-
lumen, inducing transient osmotic diarrhea (and
grene, perforation and cystic meconium
a putative osmotic diuresis). The eventual
peritonitis, and atresia. Complicated forms affect
unblocking mechanical effect is so obtained
one half of MI patients, with sexes affected in
thanks to the hydration and softening of the
similar proportion (Escobar et al. 2005; Carlyle
inspissated meconium.
et al. 2012).
The infusion should be gently performed by
After birth, both simple and complicated MI
the radiologist, through a catheter with no balloon
should be managed as a neonatal intestinal
inflated in the rectum, at low hydrostatic pressure
obstruction. Resuscitative measures including
and under fluoroscopic control (Fig. 2a, b). The
mechanical ventilation, if needed, and intrave-
nonuse of these precautions is potentially respon-
nous hydration are initiated along with gastric
sible for bowel injury and intestinal perforation in
decompression, evaluation, and correction of any
up to 23% (Ein et al. 1987). The Gastrografin ®,
coagulation disorders and possibly with empiric
diluted to 25–50% compared to the original solu-
antibiotic coverage.
tion, is slowly infused, to reduce excessive fluid
draw and subsequent potential osmotic complica-
tion, such as hypovolemic shock, colonic inflam-
Nonoperative Management mation, ischemic enterocolitis, and perforation.
The contrast medium is so followed along the
Helen Noblett firstly reported in 1969 the use of entire colon, through the ileocecal valve till the
Gastrografin ® hypertonic enema washout in terminal ileum. Resistance is encountered as the
treating four infants with MI. Since then it has microcolon is filled, and the mold of inspissated
become the initial nonoperative procedure by meconium is outlined when the contrast medium
definition. In the original paper, H. Noblett reaches the terminal ileum. When the dilated/
reported also some main rules that require a impacted ileum is reached, the study is stopped
rigorous clinical assessment of the baby: and the baby returned to the unit.
The spontaneous passage of the meconium can cases are approached more cautiously now,
then be observed usually within the first 12 h resulting in a low complication rate that is
(Fig. 2c), and confirmed by an abdominal radio- inversely related to a high failure rate (Copeland
graph, also to rule out any unexpected perforation. et al. 2009). Possible alternatives have been stud-
Moreover, once back to the neonatal unit, warm ied to improve the current success rate of non-
saline enemas containing 1% N-acetylcysteine are operative strategies, maintaining a low risk of
administered to enhance complete evacuation complications. However, experimental studies in
(Mychaliska 2005). The administration of mice found that Gastrografin® is still the most
5–10 ml of 5–10% N-acetylcysteine is also efficacious agent in relieving constipation
suggested per orogastric tube, every 6 h, to further in vivo, that all tension-reducing agents (including
clear the meconium from above (Meeker 1964; 10% Tween-80) and liquefying agents (including
Mychaliska 2005). Burke et al. reported that 4% Gastrografin ®) resulted equally benign to intesti-
N-acetylcysteine, given as a liquefying agent, pro- nal mucosa on histologic examination, that the
duces only a 69% decrease of viscosity of human surface tension-reducing agents (including 10%
meconium in the immediate; however, after 6 h of Tween-80) and liquefying agents (including
in vitro incubation, the decrease of viscosity is over Gastrografin ®) are more efficacious than 4%
90% (Burke et al. 2002). When the spontaneous N-acetylcysteine in immediate at in vitro decreas-
evacuation is obtained but the intestinal obstruction ing the viscosity of meconium, and that the best
is only partially relieved, H. Noblett suggests liquefying activity of 4% N-acetylcysteine (over
performing a second hyperosmolar enema. 99%) in the human meconium is observed after
Up to two thirds of patients were successfully 6 h of incubation (Burke et al. 2002).
treated with her technique by H. Noblett. Early
studies treating MI with Gastrografin® enema also
reported success up to 83% (Rowe et al. 1971). Operative Management
More recent studies, using the same agent, have
substantial but smaller rate of success, closer to Surgical treatment is requested when faced with a
36–50% (Del Pin et al. 1992; Escobar et al. 2005; baby who fails conservative treatment or affected
Karimi et al. 2011; Munck et al. 2006). Recently, by complicated MI. Nearly one third to one half of
the diminishing role of contrast enema in simple patients undergoing surgery represent cases with
MI has been highlighted in a multi-institutional simple MI that failed to respond nonoperative
study that observed a significant success rate dif- treatment (Ziegler 2006). Parents should be
ference in a contemporary group compared to a informed about the main goals of the surgeon:
historic one, 39% and 5.5%, respectively (1) relieving the impacted meconium completely,
(Copeland et al. 2009). The introduction of hyper- (2) removing any surgical (even unexpected pre-
osmolar solution into the intestinal lumen was operatively) complication found at laparotomy,
considered a risk factor for severe complication and (3) restoring bowel continuity in the immedi-
such as hypovolemic shock, mucosal and submu- ate or in a later time depending on the operative
cosal inflammation, enterocolitis, and intestinal findings. As a consequence, information should
perforation. Perforation is reported approximately be done about the possibility of intestinal resec-
in 10–20% of patients in historical series com- tion, temporary stoma, or tube ileostomy as well
pared with 2.7% more recently (Ein et al. 1987). as eventual appendectomy or colorectal biopsies
This risk of iatrogenic complications probably led to rule out specifically the presence of
to the use of alternative tension-reducing and liq- aganglionosis (Mattei 2011). After the laparotomy
uefying agents. Moreover, following the same has been made, mainly transverse right lower,
logic, a trend toward a fewer enema attempts per depending also on the surgeon’s option and atti-
patients was observed in the more recent era, from tude, the cecum should be gently mobilized and
1.9 (historical group) to 1.4 (contemporary group) impacted ileum delivered (Fig. 3a–c). At that time
(Copeland et al. 2009). It is possible that these there are two main scenarios that become
Fig. 3 Overdistended abdomen (a); several pearls are visible, occluding the small hypoplastic terminal ileum (b); dilated
proximal ileum with dark meconium inside (c); small enterotomy to evacuate the sticky and inspissated meconium (d)
apparent: simple (no evidence of perforation, vol- used to protect peritoneum from contamination.
vulus, or atresia) and complicated MI. An enterotomy is made on the antimesenteric
border of the dilated ileum, and a 10–12 French
soft catheter is introduced to instill a meconium
Simple MI: Operative Management solubilizing solution (Fig. 4a). A variety of solu-
tions have been used for irrigation including
Minimal enterotomy, showing the typical thick- warmed saline, 50% diluted Gastrografin ®, 1%
ened, sticky, meconium (Fig. 3d) followed by solution of pancreatic enzymes, and hydrogen
irrigation of the impacted bowel, is the most com- peroxide (Shaw 1969; Ziegler 2006). The most
monly used technique. Moistened gauze packs are commonly used is N-acetylcysteine that is in
Fig. 4 Irrigation of the impacted terminal ileum (a). Sev- decompressing tube is in the dilated proximal loop, the
eral “pearls” have been milked from the enterotomy irrigating one in the small terminal ileum (d). (Atlas on
(b). Double-tube ileostomy in place to irrigate and decom- “Pediatric Surgery” by Prem Puri and Michael Hollwart
press the terminal impacted ileum (c). Tubes in site: the edited by Springer)
general available in two different concentrations, appendicostomy (Fitzgerald and Conlon 1989).
10% or 20%. It should be diluted with warm saline A gentle anal dilatation and rectal irrigation can
or water to a final concentration of 4%. The bowel finally be performed, in particular when a large
irrigation usually allows the mastic/tar-like amount of inspissated meconium has been milked
impacted meconium to be detached from the into the colon.
intestinal wall, gently milked and removed As a first technical variant, a “tube” enteros-
(Fig. 4b) from the intestinal lumen through the tomy, with and without resection, can be fashioned
enterotomy, through the ileocecal valve into the and left in site. Firstly described by O’Neill et al.
colon, or both. The enterotomy is then trans- in 1970 (O’Neill et al. 1970), it allows the decom-
versely closed, and appendectomy possibly pression of proximal dilated ileum and continuous
performed to rule out long segment local instillation of the small distal bowel with
Hirschsprung’s disease and to support the diagno- solubilizing agents in the postoperative period,
sis of CF by revealing mucous plugging of the avoiding in the same time a reoperation for
crypts and exuberant intraluminal mucinous mate- stoma closure, as would be required if a classic
rial at histological examination. Appendectomy enteral stoma was performed. The double-tube
can also be used for bowel irrigations, instead of enterostomy (Fig. 4c, d) is placed at the junction
the aforementioned enterotomy, the stump of the of the proximal distended bowel: a 10 Ch soft-
appendix being used to fashion an tube pluri-fenestrated/larger cut opening is
allocated in the proximal more dilated bowel, and Santulli: side (proximal)-to-end (distal) anasto-
the second one, 5 Ch soft tube, is gently advanced mosis. Proximal limb is brought out as a ter-
and placed in the small distal ileum in a T-tube- minal stoma. The distal limb is anastomosed
like fashion. A purse-string suture is performed end to side. Proximal limb doesn’t need any
around the tubes. The enterostomy is tightly fixed resection at this surgical step. Advantages are
to the appropriate part of the ventral abdominal the same mentioned for Bishop-Koop tech-
wall as is classically described for gastrostomy. nique, but irrigation of distal ileum requires
Both tubes are carefully fixed with nonabsorbable the intraoperative insertion of the soft catheter
sutures to the skin. The large tube is used to gently into the distal loop. The apparent disadvantage
drain, evacuate, and decompress intestinal con- with these techniques is the presence of a high-
tents of the proximal dilated loop; the small distal output stoma and the inherent risk of dehydra-
one is used to irrigate the ileum and the micro- tion, requiring an early closure to avoid/pre-
colon (Casaccia et al. 2003). These catheters may vent complications induced by excessive fluid
then be removed after the 14th–15th postoperative and electrolyte losses.
day once clinically and/or radiologically checked
that any solution passes freely into the colon and
the obstruction is definitely relieved. Stoma closure doesn’t necessarily require the
As a further technical alternative, a temporary operating theater either for Mikulicz, after a spe-
obstruction-relieving stoma may be performed cific externally placed clamp turned the stoma into
with or without a segmental resection of dilated a side-to-side anastomosis, or Bishop-Koop and
ileum. In the past, it was a common practice to Santulli techniques, since the ligation of the resid-
treat all babies with an ileostomy; conversely, it is ual “chimney stoma” allows that enterocutaneous
no longer used routinely. Anyway, the various remaining fistula may spontaneously close. An
stoma operations should be part of the armamen- alternative to such an extra-abdominal stoma clo-
tarium of the neonatal surgeon when faced with sure is the delayed stoma segmental resection and
these challenging cases. Historically, various end-to-end anastomosis.
stoma operations have been reported (Fig. 5): Finally, primary resection and immediate
enteral anastomosis can be considered as an alter-
Mikulicz: side-to-side enterostomy. Advantages native to the primary ileostomy and delayed stoma
associated with this option are quick operation, closure. Meconium is accurately evacuated,
intraoperative meconium evacuation not patency of the distal ileum and colon verified,
required, and minimization of intraperitoneal and resection of the dilated ileum and primary
contamination (exteriorized bowel loop can be end-to-end anastomosis performed. A higher rate
opened after the abdominal closure); intra- of complications, as anastomotic leak and perito-
abdominal anastomosis is avoided, thereby nitis, has been reported with this procedure. More
preventing the risk of anastomotic leakage. recently the necessity of adequate resection of
Bishop-Koop: end (proximal)-to-side (distal) compromised bowel, preserving an adequate
anastomosis. Distal limb is brought out as a blood supply to the anastomosis, was emphasized
terminal stoma. The proximal limb, after resec- (Escobar et al. 2005). A few studies compared
tion of the most dilated segment, is anasto- resection with primary anastomosis to resection
mosed end to side. Advantages associated with enterostomy and delayed anastomosis. Sur-
with this technique are resection of proximal gical complication in patients with primary anas-
dilated/disparate proximal ileal loop to create a tomosis ranged between 21% and 31% compared
congruent end-to-side anastomosis, good with none to more than 60% of those with primary
decompression of proximal stoma while distal enterostomy (Del Pin et al. 1992; Karimi et al.
obstruction still persists, and easy intubation of 2011).
distal stoma, allowing instillation of solubiliz- All these surgical alternatives have the disad-
ing agents postoperatively. vantage of including, sooner or later, an ileal
Fig. 5 Different possible stomas for babies affected by MI: Mikulicz and Bishop-Koop (a); Santulli and modified
Bishop-Koop (b). (Atlas on “Pediatric Surgery” by Prem Puri and Michael Hollwart edited by Springer)
resection in an infant with a disorder of intestinal have to be considered by the surgeon from time to
function up to a short bowel syndrome. As a time, including general and intraoperative condi-
consequence, minimal enterotomy and bowel irri- tions of the baby that may require a quick and
gation/disimpaction are currently considered the effective obstruction-relieving operation or allow
treatment of choice for uncomplicated MI that a more prolonged operative procedure. More rig-
fails nonoperative management. Anyway, to orous studies are needed to identify best practices
make the best technical decision, several aspects for surgical treatment of MI.
Complicated MI: Operative inflammatory membranes are gently and exten-

Management sively lysed, meconium evacuated, and the
bowel carefully inspected. The dissection may
Surgical open approach is almost always required be bloody and difficult because of dense inflam-
in babies with complicated meconium ileus. Sur- matory vascular adhesions. Necrotic and atretic
gical strategy is very variable, being dictated by bowel should be resected with the minimum
preoperative and intraoperative finding (Fig. 6): length required and residual bowel measured and
from “simple” jejunoileal atresia to intestinal per- precisely reported. A balanced judgment is then
foration and peritonitis. CF was documented in made to evaluate if a primary anastomosis is fea-
6–13% of neonates admitted with a diagnosis of sible or a stoma is needed, based on the overall
jejunoileal atresia (Casaccia et al. 2003; Farrell condition of the patient, specific condition of the
et al. 2008). Meconium peritonitis may present bowel proximal to the resection, and good patency
as: a meconium pseudocyst, with/without calcified of the distal one. When a segment of dilated atonic
fibrous wall, when meconium accumulates in a bowel pouch is found (i.e., in cases with intestinal
peritoneal pseudo cavity; adhesive meconium atresia), it can be left in place and sacrificed later
peritonitis, when meconium prenatally contami- on possibly, depending on the residual length of
nates peritoneal cavity for weeks (scattered calci- viable bowel. Those babies with inadequate
fication may be observed also in these cases); and length of the residual bowel must be considered
ascites, either noninfected or infected, when intes- for a subsequent tapering enteroplasty or bowel
tinal perforation occurs only a few days before elongation. Primary anastomosis was associated
delivery or when colonized intestinal organism to surgical complications in 31% of patients
postnatally enter from the intestinal perforation (Jawaheer et al. 2007). In a recent study, Karimi
into the peritoneal cavity, respectively. et al. reviewed 41 patients with MI and compared
As for patients with simple meconium ileus resection with primary anastomosis to resection
unresponsive to nonoperative treatment, the goal with enterostomy. They found that 21% of the
of operative management is the complete evacua- primary anastomosis group developed peritonitis,
tion of meconium and primary or delayed resto- whereas none of the resection with enterostomy
ration of bowel continuity aiming also to prevent group did (Karimi et al. 2011). Appendectomy
short bowel syndrome. may be performed to rule out the future doubt of
Surgical approach is mostly a transverse right long segment Hirschsprung’s disease. If extensive
abdominal incision, expanded to the left when bowel resection is necessary, a gastrostomy
needed (Mattei 2011). Adhesions and should be considered. In rare instances the
Fig. 6 Complicated meconium ileus: pneumoperitoneum and microcolon (a); huge intestinal dilatation, intestinal atresia,
and “pearls” in the terminal ileum (b)
surgeon is faced to adhesions so dense that also a Since intravenous aminoglycosides are com-
stoma is difficult to perform. These cases can be monly used to treat lung infections in CF patients,
temporarily drained with tubes left in places to aminoglycoside levels should be monitored while
allow the passage of meconium, waiting for a the patient is on therapy, and hearing screens
subsiding of the inflammatory process in a couple should be performed at least annually on all CF
of months (Teitelbaum and Coran 2004). patients receiving aminoglycosides. When neph-
After the operative management of meconium rotoxic antibiotics are used, drug levels should be
ileus, care must be focused to support the infant’s monitored while the patient is on therapy, serum
artificial nutrition and general physiology and to creatinine levels should be checked weekly, and
promote the evacuation of any residual proximal antibiotic doses should be adjusted accordingly.
or distal gastrointestinal inspissated meconium. Immunization for influenza should be carried out
Moreover, care must be taken to maintain salt in all children who are eligible (Borowitz et al.
and mineral balance and appropriate vitamin sup- 2009).
plementation, to minimize the risk of potential Concerning intestinal outcomes in those
pulmonary complication and to closely monitor patients presenting MI at birth, different authors
and treat possible infection and/or sepsis. suggest that MI is not associated with higher risk
for late clinical deterioration or decreased sur-
vival. Specifically it seems that precocious nutri-
Outcomes and Follow-Up tional and medical support of MI infants allows
further similar nutritional status and pulmonary
Survival rate for patients affected by CF has pro- function tests compared to other early-diagnosed
gressively increased in the last few decades CF patients (Munck et al. 2006). Nonetheless, MI
(George et al. 2011): the median predicted sur- infants are at higher risk to late development of
vival age for patients has increased from 25 years distal intestinal obstruction syndrome (DIOS)
in 1985 to 37 years in 2008 (Cystic Fibrosis Foun- defined as complete or incomplete intestinal
dation 2011). The length of survival is directly obstruction by viscid fecal material in the terminal
correlated to the decade the patient was born ileum and proximal colon. The estimate preva-
(Cohen-Cymberknoh et al. 2011), and patients lence ranges from 5 to 12 episodes per 1000
born today are expected to have a lower patients per year in children, with higher rates
MI-related morbidity (Munck et al. 2006) and a reported in adults (Colombo et al. 2011).
median survival into their sixth decade (Dodge Other common manifestations of cystic fibro-
et al. 2007). sis that should be ruled out in patients with MI
Newborn screening for CF offers the opportu- include azospermia in nearly all patients, pancre-
nity for early medical and nutritional intervention atic insufficiency in 90%, diabetes mellitus in
that can lead to improved outcomes; however, 20%, and obstructive biliary disease in 15–20%.
there is few evidence on optimal care for infants
with CF. Therefore, Cystic Fibrosis Foundation in
2009 developed recommendations based on a sys- Conclusion and Future Directions
tematic review of the evidence and expert opinion
(Borowitz et al. 2009): a dedicated CF care team In conclusion, in the last few decades, CF patients
should visit each patient at least once every experienced a dramatical improvement in survival
3 months. Physical examination by a specialized rate. This is mainly due to centralized manage-
CF physician, nutritional evaluation, and, if pos- ment of patients in specialized CF centers, more
sible, spirometry might be performed. On a yearly aggressive use of antibiotics, and intensive nutri-
basis or when clinical symptoms dictate, a chest tional support. Long-term outcomes for MI have
X-ray, blood work, and full pulmonary function also improved dramatically, and today no differ-
testing (including measurement of lung volumes ences are seen between MI and non-MI patients.
and diffusing capacity) should be carried out. Nonetheless, following the prolonged survival,
DIOS is becoming a rising issue, with a lifetime update on carrier screening for cystic fibrosis. Obstet
prevalence of 8% in pediatric CF patients and Gynecol. 2011;117(4):1028–31.
Bishop HC, Koop CE. Management of meconium ileus,
16% in adult CF patients. Early aggressive laxa- roux-en-Y anastomosis and ileostomy irrigation with
tive treatment with oral laxatives or intestinal pancreatic enzymes. Ann Surg. 1957;145(3):410–4.
lavage with balanced osmotic electrolyte solution Blackman SM, Deering-Brose R, McWilliams R, et al.
is almost always effective, making surgical inter- Relative contribution of genetic and non genetic mod-
ifiers to intestinal obstruction in cystic fibrosis. Gastro-
ventions rare (van der Doef et al. 2010). enterology. 2006;131(4):1030–9.
The goals for the future include exploration of Bobadilla JL, Macek Jr M, Fine JP, et al. Cystic fibrosis: a
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late complications. New ways are already going to with incidence data and application to screening. Hum
Mutat. 2002;19(6):575–606.
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gastrointestinal symptoms and/or disease, for fibrosis foundation evidence-based guidelines for man-
example, the use of alternative intestinal agement of infants with cystic fibrosis. J Pediatr.
unblocking agent as polyethylene glycol-based 2009;155(6 Suppl):S73–93.
Burge D, Drewett M. Meconium plug obstruction. Pediatr
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Recently, Stoltz et al. were able to demonstrate, in Burke MS, Ragi JM, Hratch L, et al. New strategies in
a new transgenic CF pig model, that expressing nonoperative management of meconium ileus. J Pediatr
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Carlyle BE, Borowitz DS, Glick PL. A review of patho-
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Meconium Peritonitis
68
Jose L. Peiró and Emrah Aydin
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 994
Clinical Findings and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 996
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
Conclusion and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
Abstract hypotheses related with ischemic events are

Meconium peritonitis (MP) is defined as most popular ones; neither of them has been
aseptic, localized, or generalized peritonitis substantiated yet. As first meconium reaches
due to leakage of meconium into the peritoneal the ileum about 16th gestational week, timing
cavity due to perforation of the fetal intestine in of the event also determines the pathological
utero. The incidence of MP is 1/30000. Even types of MP, as fibro-adhesive, generalized, or
cystic type. Intra-abdominal calcifications,
being the most pathognomonic feature of the
J. L. Peiró (*) MP, are originated from the catalytic effect of
University of Cincinnati, Cincinnati, OH, USA fatty meconial compounds on the precipitation
Pediatric General and Thoracic Surgery Division, of calcium salts. A grading system described
Cincinnati Fetal Center, Cincinnati Children’s Hospital by Zangheri et al. can be used for international
Medical Center (CCHMC), Cincinnati, OH, USA standardization of prenatal diagnosis. Antena-
e-mail: jose.peiro@cchmc.org
tal diagnosis should also include investigation
E. Aydin for congenital anatomical or structural anoma-
The Center for Fetal, Cellular and Molecular Therapy,
lies, cystic fibrosis, and chromosomal abnor-
Pediatric General and Thoracic Surgery Division,
Cincinnati Children’s Hospital Medical Center (CCHMC), malities. When there is prenatal suspicion of
Cincinnati, OH, USA MP in a patient, postnatal diagnosis is through
e-mail: emrah.aydin@cchmc.org; dremrahaydin@yahoo. abdominal and/or scrotal radiographs and
com

https://doi.org/10.1007/978-3-662-43588-5_72
994 J. L. Peiró and E. Aydin
ultrasonography. The natural history of prena- Table 1 Mortality rate in meconium peritonitis among
tally diagnosed MP is different than diagnosed 2,098 cases reported in world literature
postnatally since some prenatally diagnosed Years Total Survivors Mortality (%)
cases resolve spontaneously. While there is Before 1952 100 8 92.0
not an established treatment modality in prena- 1952–1962 102 19 81.4
tal period, postnatal treatment varies 1963–1968 145 51 64.8
depending on the signs and symptoms of the 1969–1988 752 375 50.1
neonate. 1989–1995 210 150 28.6
1996–2004 374 343 8.3
2004–2016 415 370 10.8
Keywords
2,098 1,316 37.3
Meconium · Peritonitis · Antenatal bowel
perforation · Neonate
mortality rates below 10% in some series (Chan

Introduction et al. 2005; Zangheri et al. 2007).
Meconium peritonitis (MP) is defined as asep-

tic, localized, or generalized peritonitis due to Etiopathogenesis
leakage of meconium into the peritoneal cavity
because of perforation of the fetal intestine in Meconium, generated in the third gestational
utero. Agerty was the first to successfully month, is composed of amniotic fluid with bile
operate a newborn with MP. The disease was salts, cell debris, and proteins, which have been
first reported by Morgagni in 1761 in “De shown to activate immune cells including macro-
Sedibus et Causis Morborum”; Simpson phages. Uric acid, intestinal enzymes, choles-
managed to find 25 cases in 1838. (Agerty terols, inorganic salts, and sugar also constitute
1943; Simpson 1838) MP as a term is limited to the meconium. Chemical peritonitis is triggered
the reaction caused by perforation that is already by lipases and bile salts spilled into the abdomen.
sealed or not but before the infant is born. Peri- The inflammation is mediated through phagocy-
tonitis caused by postnatal gastrointestinal per- tosis, release of chemical mediators, and
forations even when there is meconium is not antibody-dependent cell-mediated cytotoxicity
included in meconium peritonitis and excepted by macrophages those infiltrate into the perito-
as a different group of clinical problems (Cerise neum. TNF-α production is reported to remark-
and Whitehead 1969). The incidence of MP is ably increase when encountered with meconium,
reported as 1/30000, which might be an underes- which also results in fibrin deposition and severe
timation due to spontaneous recovery of intesti- intra-abdominal adhesion. The progressive
nal perforation and regression of the pro-inflammatory cytokine reaction may also
inflammatory process without neonatal clinical enhance the inflammatory reaction (Lally et al.
manifestations (Nam et al. 2007). There are more 1999; Rubin et al. 1996; Shyu et al. 1994). Inter-
than 2,000 cases presented in the literature with a leukins 6 and 8 are also associated with inflam-
total mortality 37.3% since the disease first matory response syndrome in MP. Their
reported (Table 1). While it had a mortality rate concentrations are found to increase not only in
approximately 70% in 1960s, the survival rate is patient’s plasma but also in the cyst or ascites just
over 90% today in USA but still has perinatal after birth in very high amount (Kanamori et al.
morbidity and mortality as high as 80% in third 2012). Drainage of the cystic fluid does not sup-
world countries (Saleh et al. 2009; Uchida et al. press the inflammation.
2015). Improvements in prenatal diagnostic There are many hypothesis regarding the
modalities and postnatal intensive care decrease intrauterine intestinal perforation, neither of
68 Meconium Peritonitis 995
which has been substantiated. Segmental It is called fibro-adhesive type if the site of per-
absence of muscular coats, absence of muscularis foration is effectively sealed off. In the fibro-
mucosa, vascular occlusion, and general hypoxia adhesive type of MP, intestinal obstruction by
of the fetus in the perinatal period are the most adhesive bands might be encountered. If the per-
commonly speculated ones (Lloyd 1969; foration cannot be restricted and the intestine gets
Rickham 1955; Vilhena-Moraes et al. 1964). In more inflamed and fixed, it forms a cystic cavity
an experimental study, it has been shown that formed by fixed intestinal loops and filled with
these are consequences of MP, not the cause meconium called cystic type. This entity restrains
(Boix-Ochoa 1982). The main etiological factors the inflammation from spreading to the remain-
are intestinal atresia, intestinal volvulus, and der part of the abdomen. Calcium deposits at the
meconium ileus. Hirschsprung’s disease, meco- cyst wall which is clearly be seen at prenatal and
nium plug syndrome, congenital bands, internal postnatal imaging. If the adhesions caused by
hernias, Meckel’s diverticulum, and rectal perfo- chemical peritonitis after intestinal perforation
ration might also be other etiological factors that are more fibrinous than fibrous, it is called gen-
lead to MP through intestinal perforation. Cystic eralized type which is usually the most common
fibrosis when accompanies MP is mostly a com- type (Fonkalstrud et al. 1966; Gugliantini et al.
plication of meconium ileus. Its incidence has 1979; Kolawole et al. 1973; Lorimer and Ellis
been reported to vary between 8% and 40% 1966). Calcified meconium is scattered through-
(Dirkes et al. 1995). On the other hand, neonatal out the peritoneal cavity. In an experimental
hypoxia or anoxia and fetal respiratory distress study with rats, meconium was demonstrated to
may lead to MP, 80% of which etiology cannot be give rise to a peritoneal reaction with fibroblastic
demonstrated despite pathological findings. It’s proliferation that covers the lesion, followed by
proposed that, when there is a decrease in the foreign body granulomas and calcification (Boix-
blood flow to the intestines as seen in hypoxic Ochoa 1982). There may be local or generalized
fetus, the mucin production decreases and muco- reaction, which leads adherence of intestinal
sal degenerations occur which eventually lead loops with a fibrous tissue that is difficult to
mucosa susceptible to ischemia. Thus, the dissect. The exact location of the perforation is
bowel wall is defenseless to proteolytic enzymes hard to find due to calcifications and dissemi-
of gastrointestinal system. Ileocecal region and nated meconium inclusions. Patton et al. also
splenic flexure are more vulnerable to ischemia reported systemic spreading of meconium in
as they are less vascularized. Almost 60% of all their studies (Patton et al. 1998).
idiopathic lesions are found at this location. Intra-abdominal calcifications are originated
Fetus is capable of swallowing amniotic fluid from the catalytic effect of fatty meconial
at 12th gestational week, the same time with the compounds on the precipitation of calcium
start of bile secretion. At 16th gestational week, salts. Intra-abdominal calcification could not be
meconium reaches the ileum for the first time. demonstrated in MP in animals with low serum
Whether the necrosis or perforation of the intes- levels of calcium. Light microscopic examina-
tine occurs before or after this week, it would tion of these calcifications revealed that they
result in intestinal atresia either solely or with are in response to keratin debris (Faripor 1984).
meconium peritonitis. Timing of the event also However, keratin cannot be the only source
determines the pathological types of MP, as fibro- because of the presence of granulomas devoid
adhesive, generalized, or cystic type. If the per- of keratin. Since some of these granulomas
forated area sealed off before meconium passes, resemble gouty tophi, it may be because of
there will be no spillage of meconium in to the inflammation caused by uric acid present in
peritoneum. Digestive enzymes leak from perfo- meconium.
rated area which causes chemical peritonitis The rare entity called meconium pseudocyst
which eventually leads to a fibroblastic reaction. should be differentiated from cystic type of
MP. In cystic type MP, the inflamed bowel loops MP during pregnancy is feasible (Blumental et al.
are fixed and lead to formation of an intraperito- 1982; Bowen et al. 1984; Dunne et al. 1983; Garb
neal cystic cavity with a fibrous wall. On the other and Riseborough 1980). A grading system
hand, a meconium pseudocyst does not have an described by Zangheri et al. can be used for inter-
epithelium, which is lost due to inflammation. It is national standardization of prenatal diagnosis by
made of dilated intestine filled with meconium using the information related with fetal intra-
that has a smooth muscle layer connecting the abdominal calcifications, fetal ascites, pseudo-
cyst to the normal intestine (Minato et al. 2012). cysts, and bowel dilatations (Zangheri et al.
The formation of a pseudocyst represents an 2007) (Table 2). Patients with a score greater
attempted to intra-abdominal healing process to than 1 have a high risk for urgent neonatal surgery,
confine the perforation. while the ones with 0 can be delivered at term
Another type of presentation is microscopic without any complication. Antenatal diagnosis
MP that is an incidental finding, most of the time should also include investigation for congenital
(Tibboel et al. 1981). Patients mostly presented anatomical or structural anomalies, cystic fibrosis,
with an intestinal atresia that occurred at very and chromosomal abnormalities (Chan et al.
early stage of gestation. Bile pigments and squa- 2005; Nam et al. 2007). Detection of cystic fibro-
mous cell remnants could be found when perito- sis is done by screening for the most common
neum viewed carefully which is a proof for gene mutations and sweat chloride test and also
perforation. The presence of collagen, calcium is recommended screening for congenital infec-
deposits, and giant cells surrounding meconium tions including herpes simplex virus, cytomega-
particles demonstrates that the event should have lovirus, parvovirus B19, and toxoplasmosis
taken for a considerable time ago. (Cassacia et al. 2003).
Fetal magnetic resonance imaging (MRI) pro-
vides additional data for the diagnosis of MP
Clinical Findings and Diagnosis (Fig. 2) besides ultrasonography (57.1%
vs. 42%), even it is not needed in all cases (Chan
Antenatal and postnatal ultrasounds are the pri- et al. 2005). However, it might help assessment of
mary investigation modalities for diagnosis of any accompanying disorders, which is crucial due
MP. Prenatal ultrasonography not only provides to its repercussions in the immediate postopera-
an accurate diagnosis of the disease but also esti- tive period. Even though ultrasonography is sen-
mates the severity of it and determines the need sitive, there are many diseases for the differential
for intervention (Fig. 1). Intraabdominal calcifica- diagnosis of cystic masses such as ovarian cyst,
tions use to appear early, so prenatal diagnosis of duplication cyst, or mesenteric cyst that is difficult
Fig. 1 Prenatal ultrasonography showing ascites with collapsed intestines

Table 2 Zangheri’s grading system for meconium prognosis of neonate. Twenty-four percent of
peritonitis patients’ cultures were found to be positive at
Score first 12 h, while 86% were at 72 h. Patients
0 Intraabdominal calcification operated between 36 and 48 h of life have a
1 A Intraabdominal calcification with ascites four times higher mortality rate than those oper-
B Intraabdominal calcification with ated during postnatal 24 h, while after 48 h, the
pseudocyst
mortality rates vary between 80% and 91%
C Intraabdominal calcification with bowel
dilatation
(Boix-Ochoa 1982; Tibboel and Molenaar
2 Intraabdominal calcification with any of 1984). While immediate diagnosis and surgery
two associated findings if needed is crucial, termination of pregnancy
3 Intraabdominal calcification with all is unnecessary (Wang et al. 2008). Early
associated findings detection of the disease is not associated with
poor outcome. In a study, only 22% of fetuses
with prenatally diagnosed MP required surgery
to diagnose (Aydin 2016; Degnan et al. 2010). with 11% mortality (Dirkes et al. 1995). How-
Limitations of prenatal ultrasonography in detec- ever, an elective preterm delivery by cesarean
tion of calcifications are an ultrasonographic section at 35th gestational week could be
entity. (Zangheri et al. 2007) Fetal MRI can be a recommended to prevent disease progression
useful tool for description of the exact pathology and enable an early intervention (Saleh et al.
and comorbidities. 2009).
When there is prenatal suspicion of MP in a MP might be presented also as an inguinal or
patient, postnatal diagnosis is through abdominal scrotal mass. These patients do not present any
and/or scrotal radiographs and ultrasonography. relevant history related with MP. Many of them
In patients without prenatal suspicion or diagno- present with unilateral hydrocele at birth. Scrotal,
sis, the diagnosis of MP in the postnatal period is as intraabdominal, calcifications could be demon-
based on clinical presentation and radiological strated by radiological imaging being pathogno-
findings of intestinal obstruction. A newborn monic for MP (Cook 1978; Gunn et al. 1978;
with abdominal distension is the very first sign, Heydenrych and Marcus 1976). Nodules in these
which is present at the birth or develops soon after. patients mostly regress spontaneously and do not
Bilious vomiting and stop in meconium pass can require surgery.
be other signs of intestinal obstruction. When the Differential diagnosis should be done very pre-
abdominal distention is severe, it may lead to cisely. Intra-abdominal calcifications may also be
respiratory distress. Abdominal radiographs seen in cases of multiple intestinal atresia, colonic
might reveal pneumoperitoneum or calcifications atresia, Hirschsprung’s disease, high anorectal
in the peritoneal cavity, which is pathognomonic malformations, and cloacal anomalies. On the
(Fig. 3) (Miller et al. 1988; Smith and Clatworthy other hand, adrenal and liver calcifications can
1961). In some cases, calcifications may also be also be identified with cytomegalovirus, parvovi-
seen at scrotum mimicking scrotal mass. Hyper- rus, or hepatoblastoma (Aydin et al. 2013; Boix-
echogenic concretions with posterior acoustic Ochoa 1982; Bowen et al. 1984; Sciarrone et al.
shadowing on ultrasounds confirm calcifications, 2016).
while cysts or ascites could be other findings Meconium periorchitis first reported in 1953 is
(Fig. 4). the result of MP and spillage of meconium
The natural history of prenatally diagnosed through open processus vaginalis. This entity
MP is different than diagnosed postnatally since can be diagnosed by ultrasonography during intra-
some prenatally diagnosed cases resolve spon- uterine life, but mostly incidentally at the postna-
taneously. Because the bacterial overgrowth at tal period. A detailed examination during fetal life
meconium begins just after birth, immediate is crucial to prevent any unnecessary orchiectomy
and proper diagnosis is fundamental for the in the neonate. Surgical excision might determine
Fig. 2 Fetal MRI. Abnormal meconium dilated small bowel loop in mid-abdomen extending to the left abdominal wall in
association with septation. Also shows complex ascites and small area of calcification (arrow)
the diagnosis but is not necessary (Alanbuki et al. and remove inflammatory debris (Izumi et al.
2013; Regev et al. 2009). 2011; Taba et al. 2010). Although there are
many prenatally diagnosed cases with
intraabdominal calcifications, only very few
Treatment require postnatal surgery. Associated findings
could be a good marker to decide who is a candi-
There is not an established treatment modality in date for surgery and select them for delivery in
prenatal period. There are some occasional trials tertiary neonatal surgical centers (Zerhouni et al.
such as injection of urinary trypsin inhibitor into 2013).
fetal abdomen to reduce meconium-induced While intestinal obstruction and/or perfora-
chemical peritonitis and avoid a postnatal surgery tion with MP is a definitive indication for sur-
or fetal paracentesis to diminish intraabdominal gery (Fig. 4), meconium peritonitis without any
pressure to improve mesenteric vascular supply obstruction or perforation findings is just a
candidate for follow-up. These children should

be observed at least for 48 h without enteral
feeding with appropriate antibiotic coverage.
Oral gradually progressing feedings could be
started to the ones without any clinical findings
after this follow-up period.
For the ones that require surgery, all precau-
tions should be taken to decrease morbidity and
mortality such as monitoring vital signs, control of
temperature to prevent heat loss in the operating
theater, and prophylactic antibiotic. Even if the
perforation is visible, the operative management
should be condensed on intestinal resection and
Fig. 3 Postnatal abdominal plain x-ray of a baby diag- end-to-end anastomosis of the segments without
nosed as meconium peritonitis showing calcification in the trying to repair primarily. In localized or
abdomen (arrow)
Fig. 4 Postnatal abdominal plain X-ray and US of a baby the bowel perforation with meconial intestinal and perito-
diagnosed as meconium peritonitis showing calcification neal staining
in the abdomen (arrow) and ascites. Surgical appearance of
generalized type of MP, attempts for the lysis of Complications

adhesions should only be done in purpose to
discover the perforation if possible or just relieve As most of the abdominal surgeries, ileus due to
major obstruction due to the possibility of spon- adhesions is the most frequent complication of
taneous relief of fibro-adhesive peritonitis in MP. Anastomotic leakage, necrosis of ostomy,
8–14 days. After determination of etiology, sur- enterocutaneous fistula, respiratory problems
gical technique decision should rely on the gen- related with cystic fibrosis, and sepsis are some
eral status of the patient and discordance of the other complications reported (Boix-Ochoa 1982).
intestinal calibers. Either end-to-end anastomo- Gentle and delicate operative manipulation is
sis according the Louw’s technique or two-stage required to reduce the mortality and morbidity in
operation of Rehbein, temporary enterostomy these cases.
and delayed reconstruction of intestinal integrity
might be chosen. Most of the patients with MP
could be treated with primary anastomosis but Conclusion and Future Directions
the non-stable low birth weight infants (Louw
1967; Miyake et al. 2011; Rickham 1955). In In conclusion, current survival of the patient is up
patients with cystic type MP, a two-stage opera- to 100% in some centers with the improvements in
tion should be done. Maintaining enteral and the surgical techniques and postnatal care of the
parenteral nutrition and allowing transportation neonates. Even the exact mechanism of MP is still
of contents from proximal intestine to distal is unknown; with the advances in antenatal treat-
necessary between two stages. Overall two-stage ment modalities, early diagnosis of the patients
operations have a lower mortality rate than is more frequent. As CF is one of the main known
one-stage operation (7.2% vs 22%) (Boix- causes of MP, improvements in diagnosis and
Ochoa 1982). They also have some advantages treatment of CF would decrease the incidence of
compared to one-stage operations such as: time MP and improve the outcome.
of recovery is shorter, they do not have the risk of
dehiscence of anastomosis due to infection,
fibro-adhesive bands disappear by the time of Cross-References
second operation, calibration of the intestines
becomes suitable for anastomosis, and there ▶ Anorectal Malformations
will be enough time for neuroendocrine system ▶ Colonic and Rectal Atresias
maturation. ▶ Hirschsprung’s Disease
Another treatment modality is cyst drain- ▶ Jejunoileal Atresia and Stenosis
age and late laparotomy that might be chosen ▶ Malrotation
in patients not suitable for immediate opera- ▶ Meconium Ileus
tion but require intervention due to mass
effect of the cyst. It should be accompanied
by supportive decompression treatment, par- References
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Neonatal Ascites
69
Elke Zani-Ruttenstock and Augusto Zani
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Abstract present with signs of renal insufficiency, and

Neonatal ascites is a rare condition character- the aim of treatment is to achieve decompres-
ized by the accumulation of fluid in the intra- sion of the urinary tract. Chylous ascites is an
peritoneal cavity. The most common types of accumulation of lipid-rich lymph in the perito-
ascites caused by surgical disorders in neonates neal cavity most commonly due to an obstruc-
are classified as urinary, chylous, and bilious. tion of the lymphatic system secondary to
Urinary ascites occurs mostly in boys who congenital malformation of the lymphatic
have an obstruction of the urinary tract, such channels. Diagnosis is typically achieved by
as posterior urethral valves. These patients may paracentesis to confirm the presence of chyle,
and treatment is usually conservative with
enteral diet containing medium-chain triglyc-
E. Zani-Ruttenstock
erides. Bilious ascites usually results from
for Sick Children, University of Toronto, Toronto, ON, spontaneous perforation of the bile duct, a
Canada rare condition with an unknown cause. Patients
A. Zani (*) have fluctuating mild jaundice, normal to
Division of General and Thoracic Surgery, The Hospital acholic stools, and slowly progressive ascites.
for Sick Children, Toronto, Canada Imaging studies, such as the hepatobiliary scin-
Department of Surgery, University of Toronto, Toronto, tigraphy, confirm the diagnosis. Surgical inter-
Canada vention is required.
e-mail: augusto.zani@sickkids.ca

https://doi.org/10.1007/978-3-662-43588-5_73
1004 E. Zani-Ruttenstock and A. Zani
peritoneal cavity due to a perforation above the

Keywords point of obstruction. The perforation may occur
Ascites · Chyle · Posterior urethral valves · anywhere in the urinary tract, but most often
Lymphangiomatosis · Bile duct spontaneous occurs in the upper tracts (De Vries et al. 2002).
perforation In case of obstruction, the kidney experiences
high pressure for a prolonged period of time, and
it can eventually become atrophic or dysplastic.
Introduction Urine may collect as a perinephric urinoma within
the Gerota’s fascia or as urinary ascites in the
Ascites is defined as an abnormal fluid accumula- peritoneal cavity (Sie et al. 2006).
tion in the intraperitoneal cavity. The term derives The presence of urine in the peritoneal cavity
from the Greek word “askítes,” which means leads to an autodialysis effect produced by the peri-
baglike. In neonates, this condition is relatively toneum, whereby the neonate experiences marked
rare and may occur due to a wide range of medical serum electrolyte imbalance. This effect has been
and surgical causes, some of which are specific to demonstrated experimentally in rats and has been
the newborn period. Herein, we discuss the path- documented in patients, who develop a degree of
ophysiology, clinical presentation, diagnostic hyponatremia and hyperkalemia (Clarke et al. 1993;
tests, and management of the most common sur- Oei et al. 2001). This autodialysis phenomenon is
gical conditions that cause ascites in the neonate. caused by a shift of water and solutes due to a
difference in relative osmolarity between the two
compartments (peritoneal cavity and intravascular
Etiology and Pathophysiology bed). On the one hand, the high urinary osmolarity
(high concentrations of potassium, urea, and creati-
Ascitic fluid can accumulate in the peritoneal cavity nine) causes water to move from the intravascular
as a transudate or an exudate. A transudate consists bed to the peritoneal cavity; on the other hand, the
of a fluid with low protein count and low specific sodium, contained in modest amount in the urine,
gravity, whereas an exudate is a fluid with high moves to the peritoneal cavity, causing hypo-
protein count and high specific gravity. Ascites in natremia. The low serum sodium levels activate the
neonates has specific causes that result into three renin–angiotensin–aldosterone system that acts at the
main types: urinary, chylous, and bilious. distal tubule and collecting duct of the kidney neph-
Urinary ascites accounts for up to 30% of all ron by increasing the reabsorption of sodium and
cases of neonatal ascites. It occurs almost exclu- water (which follows sodium) into the serum and the
sively in boys and can be a life-threatening condi- secretion of potassium into the urine. With time, the
tion. The main cause of urinary ascites is an solute concentration gradients promote movement of
obstruction to the urinary tract that in up to 70% potassium, urea, and creatinine from the peritoneal
of cases which is due to the presence of posterior cavity to the intravascular compartment, resulting in
urethral valves (Hoffer et al. 1990; Hirselj et al. elevated serum levels.
2009). Other causes include ureteropelvic junction Chylous ascites is a rare condition seen during
obstruction, ureterocele, lower ureteral atresia, blad- the newborn period and infancy (Cardenas and
der neck obstruction, and neuropathic bladder Chopra 2002). It refers to the accumulation of
(De Vries et al. 2002). Urinary ascites can also be lipid-rich lymph in the peritoneal cavity due to
caused by bladder rupture secondary to umbilical disruption of the lymphatic system secondary to
arterial catheterization leading to rupture of the obstruction or traumatic injury. Obstruction of the
dome of the bladder. Spontaneous rupture of the lymphatic system in neonates most commonly is
bladder has also been reported as a result of pro- the resultant of a congenital malformation of the
found hypoxia or morphine administration. lymphatic channels such as atresia or stenosis of
In case of urinary tract obstruction, the ascites the major lacteals, mesenteric cysts, or general-
results from extravasation of urine into the ized lymphangiomatosis (Levine 1989; Karagol
69 Neonatal Ascites 1005
et al. 2010). Obstruction that results in mild chy- neonates with bilious ascites are previously
lous ascites occurs due to external compression to healthy with unremarkable perinatal history but
the lymphatics, as in intestinal malrotation, incar- with signs and symptoms that appear gradually.
cerated hernia, intussusception, or inflammatory The classic subacute presentation occurs with
enlargement of lymph nodes. A traumatic injury fluctuating mild jaundice, normal to acholic
to the lymphatic vessels in neonates occurs more stools, and slowly progressive ascites. Associated
commonly due to an iatrogenic damage during symptoms may also include sepsis, lethargy, irri-
retroperitoneal procedures, and less commonly tability, anorexia, failure to thrive, persistent eme-
due to blunt abdominal trauma in the context of sis, fever, and dark urine. On the other hand, a
accidental or non-accidental injury. About 10% of smaller proportion of neonates with bilious ascites
all infants with chylous ascites present with present acutely with peritonitis, septic shock, or
lymphedema of the limbs (Guttman et al. 1983). even pulmonary collapse.
Bilious ascites in infancy is a rare condition
usually resulting from spontaneous perforation of
the bile duct (SPBD) (Davenport et al. 2003). Diagnosis
Most often, SPBD is seen in infants aged
2–20 weeks, but it has been reported in neonates The general evaluation of a neonate with ascites
as young as 3 days (Topuzlu et al. 1994; includes history taking, physical examination,
Xanthakos et al. 2003). The site of perforation is routine laboratory tests, and imaging studies,
most often the junction of the cystic duct with the such as plain radiography and ultrasonography.
common bile duct (CBD). The exact cause of Patient history should include details about the
SPBD is unknown, but numerous etiologies have pregnancy, the delivery, and the perinatal period,
been proposed, such as congenital mural weak- as well as the maternal history. It is important to
ness of the CBD, ischemia, gallstones, infection, note all antenatal tests and scans, as well as post-
distal bile duct stenosis, inspissated bile, and pan- natal growth, feeding history, color of stools, and
creatic reflux from anomalous pancreaticobiliary urine. With severe ascites, the baby’s growth
ductal union (APBDU) (Ando et al. 1995; might change dramatically, so it is important to
Xanthakos et al. 2003; Lee et al. 2010). In the have an idea of the baseline values before the
majority of cases, there is no apparent cause for ascitic process started. On physical examination,
the perforation. Some authors suggest that spon- attention should first be on the vital signs, as some
taneous bile duct perforation is not merely spon- neonates might be experiencing respiratory dis-
taneous but may be related to APBDU and tress that requires intubation or might be
choledochal cyst, i.e., the perforation of the bile decompensating due to electrolyte or fluid imbal-
duct and congenital choledochal cyst may be ance which requires resuscitation. The neonate
interrelated problems with a common pathogene- should then be evaluated head to toe: the abdomen
sis (Sai Prasad et al. 2006). can be prominent with an everted umbilicus, and
umbilical and/or inguinal hernias may be present.
Laboratory tests that include electrolytes, com-
Clinical Presentation plete blood count, and liver and renal profile
should be routinely done in all neonates with
In general, neonates with ascites present with ascites. In some neonates, a septic screen and
gross abdominal distension that if severe can viral serology tests may also be required. More
lead to respiratory compromise. Those with uri- specific laboratory tests may be performed to rule
nary ascites are typically preterm male neonates out metabolic diseases that could be the cause of
that present with signs of renal insufficiency. ascites. Finally, the ascitic fluid should be drawn
Newborns with chylous ascites, instead, may via paracentesis for examination that includes an
have additional signs of peritoneal irritation, mal- evaluation of color, cell count, gram stain, micro-
absorption, and failure to thrive. The majority of organism culture, total protein, albumin, and
glucose and LDH levels. Classically, the serum In neonates with urinary ascites, a micturating
ascitic albumin concentration (SAAG) gradient cystourethrogram (MCUG) is necessary to rule
has been used to differentiate between transudate out the presence of posterior urethral valves
and exudate: the SAAG in case of transudative and/or vesicoureteric reflux. Abdominal para-
ascites is >1.1 g/dL, whereas for exudative ascites centesis confirms the diagnosis via elevated cre-
is <1.1 g/dL (Lin and Piccoli 2016). atinine levels and urine in the fluid.
A plain abdominal X-ray typically shows diffuse In infants with chylous ascites, analysis of the
opacity, centralization of the bowel loops if still ascitic fluid obtained by paracentesis is the most
visible, bulging of the flanks, and splinting of the useful diagnostic test. Chyle has usually a milky
diaphragm (Fig. 1). Ultrasonography is the most appearance, especially if the neonate has been
sensitive imaging modality to demonstrate ascites started on oral feeds; it has a specific gravity of
in neonates, as it can detect even very small >1.012, an alkaline pH, and it contains fat glob-
amounts of intraperitoneal fluid collection (Fig. 2). ules (Lin and Piccoli 2016). Diagnosis is con-
Like in adults, the ascitic fluid usually collects in the firmed by determining high protein and
most dependent intraperitoneal spaces and recesses, triglyceride content with predominance of lym-
such as the Morrison pouch, the pelvis, and the phocytes on differential count. To determine the
paracolic gutters. Ultrasonography can also accu- causes of chylous ascites, the neonate undergoes
rately interrogate the status of the intra- and retro- routine imaging studies that include ultrasonog-
peritoneal organs that are most commonly involved raphy and gastrointestinal contrast series. Further
in the pathogenesis of neonatal ascites. diagnostic tests like lymphangiography and
lymphoscintigraphy are done with the purpose
of identifying the site of chyle leak
preoperatively.
In neonates with bilious ascites, the diagnosis
should be suspected in case of abdominal dis-
tension, intermittent jaundice, and ascites. At
ultrasonography, free or loculated intraperito-
neal fluid with normal intrahepatic and extrahe-
patic ducts will confirm the presence of SPBD
(Tani et al. 2009). A contrast upper gastrointes-
tinal study may demonstrate collection of fluid
between the liver and the stomach (Fig. 3). If
paracentesis is performed, the concentration of
bilirubin in the ascitic fluid is higher than that in
the serum. Hepatobiliary scintigraphy is highly
sensitive and specific for SPBD, and it is the
preoperative test of choice when SPBD is
suspected (Saltzman et al. 1990; Goldberg
et al. 2000; Murphy et al. 2013). It can provide
useful information about liver function, biliary
patency, site of perforation based on localized
accumulation of radiotracer, and any biliary
leakage into the peritoneum. Magnetic reso-
nance cholangiopancreatography (MRCP) is
also useful in these patients (Takaya et al.
Fig. 1 Plain X-ray showing massive abdominal disten- 2007; Krause et al. 2002). Loculated fluid col-
sion, centralization of the bowel loops if still visible, bulg-
ing of the flanks, and splinting of the diaphragm in a lection or pseudocyst formation can be more
neonatal male with urinary ascites easily visualized on MRCP than ultrasound.
Fig. 2 Sonographic
appearance of urinary
ascites in a newborn with
posterior urethral valves.
The liver is free-floating
over the large amount of
intra-abdominal fluid
collection
management of such neonates may require appro-

priate ventilation and fluid resuscitation. Pain is
not to be underestimated, as neonates with ascites
may experience severe acute abdominal
distension.
The management of urinary ascites has to be
prompt with the basic aim of achieving decom-
pression of the urinary tract. This may be accom-
plished by paracentesis, catheter drainage, or
surgical exploration and repair of the bladder
wall. In cases of posterior urethral valves, catheter
drainage by urethral route with or without
vesicostomy achieves good results in most
patients in 10–14 days. Catheter drainage may
fail in some cases of bladder rupture with large
defects and requires surgical repair (Solarin et al.
2015). Long-term outcome of bladder and kidney
function is reported to be good in cases of neona-
tal urinary ascites secondary to severe obstructive
uropathy (De Vries et al. 2002). Intrauterine pres-
sure relief in the collecting system through urinary
extravasation (“pop-off” mechanism) protects the
Fig. 3 Upper gastrointestinal contrast study shows com- renal function and prevents severe secondary
pression with downward displacement of stomach and changes to bladder function (Chun and Ferguson
duodenum. At operation, perforation of the common 1997; Silveri et al. 2002).
hepatic duct was found
Treatment of chylous ascites is usually conser-
vative (Campisi et al. 2006). The majority of
Management patients respond to paracentesis and an enteral
diet containing medium-chain triglycerides
In general, neonates with ascites requiring (MCT). MCTs are not re-esterified within the
advanced respiratory support or support of two intestinal cell and thus bypass the enteric lym-
or more organ systems may have to be admitted phatics and directly enter the portal system. It is
to the intensive care unit. In fact, the initial believed that the reduction in dietary long-chain
fats reduces lymphatic flow and pressure within drainage with or without cholecystectomy, pri-
the lymphatic system and decreases the amount of mary repair with or without external drainage,
lymph leakage. Therefore, an MCT-based diet and hepaticojejunostomy if pancreaticobiliary
reduces chyle production, thus decreasing the malformation or distal obstruction is present
amount of chyle leak in the peritoneal fluid (Liao (Saltzman et al. 1990; Bingol-Kologlu et al.
et al. 1990). For severe or complicated chylous 2000; Pereira et al. 2012). Most authors recom-
ascites or chylous ascites that persists after a mend a conservative approach of draining the
maximum of 10 weeks of diet, total parenteral abdomen to decompress the biliary tree, unless
nutrition (TPN) has been successfully used there is distal biliary tract obstruction requiring
in treating these infants by resting the gastrointes- biliary intestinal anastomosis (Kasat et al. 2001).
tinal tract (Chye et al. 1997). Somatostatin ana- Spontaneous closure is typical even with distal
logs have been demonstrated to be effective in obstruction, once the biliary tree is decompressed
reducing lymphorrhea and may be proposed (Kanojia et al. 2007). The drains should not
prior to considering the surgical approach. be removed too early, since this can lead to accu-
The exact mechanisms of somatostatin on drying mulation of bile in the peritoneal cavity. In situa-
lymphatic flow are not completely understood. tions where the surgeon encounters biliary
It has been previously shown to decrease perforation without a preoperative diagnosis, the
the intestinal absorption of fats, to lower triglyc- safest policy is to drain the area and place a T-tube
eride concentration in the thoracic duct, and through the perforation. Suture repair of the bile
to attenuate lymph flow in the major lymphatic duct or biliary reconstruction remains controver-
channels (Collard et al. 2000). Satisfactory results sial because of the potential for stricture formation
were achieved by the administration of the (Suresh-Babu et al. 1998). Reported complica-
somatostatin combined with TPN (Huang and tions have included portal vein thrombosis, bile
Xu 2008; Purkait et al. 2014). Surgical interven- leak, and cholangitis (Chardot et al. 1996). In a
tion is recommended if 1–2 months few cases, further surgery, including biliary revi-
of conservative approach has failed (te Pas et al. sion and portosystemic shunting, was reported
2004). A peritoneovenous shunt, such as the Den- (Chardot et al. 1996). Overall, the prognosis is
ver™ shunt, placed percutaneously to recirculate good with early recognition and surgical
the ascitic fluid from the peritoneal space to management.
the circulatory system, has been reported to be
successful at least temporarily following failure
of medical management (Man and Spitz 1985; Conclusions and Future Directions
Karagol et al. 2010). Successful surgical treatment
of congenital chylous ascites by resecting Ascites remains a rare condition for neonates.
the macroscopically localized anomaly or by In order to decrease the morbidity, future work
ligation of an identifiable lymphatic leak has should be directed at establishing means
been described (Laterre et al. 2000; Kuroiwa for an earlier diagnosis, avoiding invasive
et al. 2007). diagnostic procedures, and improving manage-
Surgical management of bilious ascites is man- ment outcome. Innovative techniques that enable
datory as soon as the diagnosis of SPBD is con- intraoperative recognition of minute structures,
firmed (Howard 2002). An intraoperative as well as more advanced operative tools, could
cholangiogram should be performed to delineate prevent iatrogenic injuries that result in ascites.
the location of the perforation and exclude distal
obstruction. If the perforation is in the gallbladder Cross-References
or cystic duct, simple cholecystectomy is curative
(Xanthakos et al. 2003). Several surgical ▶ Lymphatic Malformations in Children
approaches have been described, including simple
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Hirschsprung’s Disease
70
Prem Puri, Christian Tomuschat, and Hiroki Nakamura
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Historical Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Etiopathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
Cholinergic Hyperinnervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Adrenergic Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Nitrergic Innervation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Interstitial Cells of Cajal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Platelet-Derived Growth Factor Receptor α+-Cells (PDGFRα+) . . . . . . . . . . . . . . . . . . . . . . 1016
Smooth Muscle Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
Extracellular Matrix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016
P. Puri (*)
Ireland
C. Tomuschat
e-mail: c.tomuschat@posteo.de
H. Nakamura
Department Pediatric General and Urogenital Surgery,

https://doi.org/10.1007/978-3-662-43588-5_74
1012 P. Puri et al.
Genetics Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1016

Associated Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1018
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1019
Anorectal Manometry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1020
Rectal Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1021
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1022
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1023
Role of Colostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
Transanal One-Stage Endorectal Pull-Through Operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
Operative Technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
Laparoscopic-Assisted Pull-Through . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1025
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Anastomotic Leak . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Retraction of Pull-Through . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Perianal Excoriation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Enterocolitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Constipation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Soiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Long-Term Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1028
Abstract has led to an expanding field of research into

Hirschsprung’s disease (HSCR) is a relatively developing novel therapies for HSCR. During
common cause of intestinal obstruction in the the last decade, there has been an increasing
newborn. It is characterized by the absence of focus on the development of novel stem cell-
ganglion cells in the distal bowel beginning at based therapies for the treatment of HSCR.
the internal sphincter and extending proximally Research is ongoing to determine the optimal
for varying distances. The absence of ganglion source of stem cells to generate a new enteric
cells in HSCR has been attributed to a failure of nervous system in the aganglionic bowel and
migration of neural crest-derived cells. The earlier also to determine the best way to deliver stem
the arrest of migration, the longer the aganglionic cells to the affected bowel.
segment of bowel. Eighty to ninety percent of
patients with HSCR produce clinical symptoms Keywords
and are diagnosed in the neonatal period. Delayed Hirschsprung’s disease · Aganglionosis ·
passage of meconium is the cardinal symptom in Enterocolitis · Children · Constipation ·
over 90% of affected neonates. About one-third Hypoganglionosis · Rectal biopsy
of babies with HSCR present with enterocolitis
which remains the most common cause of mor-
bidity and mortality in the disease. This chapter Introduction
describes in depth the etiopathogenesis, patho-
physiology, diagnosis, and management of Hirschsprung’s disease (HSCR) is characterized by
Hirschsprung’s disease. The progress in under- an absence of ganglion cells in the distal bowel and
standing of normal gut development and motility extending proximally for varying distances (Heanue
70 Hirschsprung’s Disease 1013
and Pachnis 2007). In over 80% of patients, Incidence

aganglionosis is confined to the rectosigmoid. In
the remaining patients, aganglionosis extends The incidence of HSCR is estimated to be one in
beyond the rectosigmoid, involving descending 5000 live births (Orr and Scobie 1983; Passarge
colon, transverse colon, or the entire colon with a 1967, 2002; Spouge and Baird 1985; Wales
short segment of terminal ileum. Total intestinal 1984). Significant interracial differences in the
aganglionosis with the absence of ganglionic cells incidence of HSCR have been reported:
from the rectum to the duodenum is the rarest form 1:10,000 births in Hispanics, 1 in 6667 white
of HSCR and is associated with high morbidity and subjects, 1 in 4761 in black subjects, and 1 in
mortality (Nemeth et al. 2001; Ruttenstock and Puri 3571 Asian subjects (Kenny et al. 2010). The
2009; Senyuz et al. 1989; Ziegler et al. 1987). disease is more common in boys, with a male-to-
female ratio of 4:1 (Orr and Scobie 1983). The
male preponderance is less evident in long-
Historical Overview segment HSCR, where the male-to-female ratio
is 1.5–2.1 (Heanue and Pachnis 2007; Kenny et al.
The condition of “congenital megacolon” has 2010; Orr and Scobie 1983; Passarge 1967; Puri
been recognized for centuries. The first known 2009, 2011; Spouge and Baird 1985).
description of this condition was by the ancient
Indian surgeon Sushruta in 600 BC and later by
Fredericus Ruysch, a Dutch anatomist in 1691 Etiopathogenesis
(Fiori 1998; Raveenthiran 2011). The most in-
depth description of congenital megacolon was The most striking pathological feature in HSCR is
reported by Harald Hirschsprung, a pediatrician dilation and hypertrophy of the proximal colon
from Copenhagen, when he presented two infants with abrupt or gradual transition to narrow distal
with this condition to the society of Pediatrics in
Berlin in 1886 (Skaba 2007). His treatise was
entitled “Constipation in newborns due to dilata-
tion and hypertrophy of the colon.” During the
next 60 years, several cases of congenital mega-
colon were reported and most of these children
died. It was not until Keenohan in 1948 and
Bodian et al. in 1949 confirmed the diagnosis of
Hirschsprung’s disease by recognizing the pres-
ence of the contracted and spastic rectosigmoid
and absence of ganglion cells in the spastic distal
segment. In 1948, Swenson and Bill published
their classic paper recommending resection of
the contracted and spastic rectosigmoid with the
preservation of the sphincter as the treatment for
Hirschsprung’s disease (Skaba 2007; Swenson
1999). Although improvements in operative tech-
niques and earlier diagnosis have resulted in a
significantly improved morbidity and mortality
in patients with HSCR, the dogma stated by
Swenson that patients can only be cured by
removal of the contracted aganglionic segment Fig. 1 Typical gross pathology in Hirschsprung’s disease,
with transitional zone at rectosigmoid level
of bowel tissue, is still valid (Swenson 1996).
1014 P. Puri et al.
Fig. 2 (a) Auerbach’s plexus, containing ganglion cells. (b) Hypertrophied nerve trunks in rectal biopsy from a patient
with Hirschsprung’s disease
bowel (Fig. 1). Although the degree of dilation sandwiching the myenteric plexus after it has
and hypertrophy increases with age, the cone- been formed in the 12th week of gestation. In
shaped transitional zone from dilated to narrow addition, after the craniocaudal migration has
bowel is usually evident in the newborn. ended, the submucous plexus is formed by the
Histologically, HSCR is characterized by the neuroblasts, which migrate from the myenteric
absence of ganglionic cells in the myenteric and plexus across the circular muscle layer and into
submucous plexuses and the presence of hyper- the submucosal; this progresses in a craniocaudal
trophied non-myelinated nerve trunks in the space direction during the 12th–16th weeks of gestation
normally occupied by the ganglion cells (Fig. 2). (Burns et al. 2009). The absence of ganglion cells in
The aganglionic segment of bowel is followed HSCR has been attributed to a failure of migration
proximally by a hypoganglionic segment of vary- of neural crest cells. The earlier the arrest of migra-
ing length. This hypoganglionic zone is character- tion, the longer the aganglionic segment (Passarge
ized by a reduced number of ganglion cells and 1967; Puri 2009, 2011).
nerve fibers in myenteric and submucous plexuses
as well as a disorganized and reduced numbers of
interstitial cells of Cajal (ICCs) (Nemeth et al. Pathophysiology
2000; Puri 2009, 2011; Rolle et al. 2002b;
Vanderwinden et al. 1996). The pathophysiology of HSCR is poorly under-
The enteric ganglion cells are derived primarily stood. It has been long recognized that the obstruc-
from the vagal neural crest cells (Gershon 2008). tive symptoms in HSCR are secondary to the
During normal development, neuroblasts migrate abnormal motility of the narrow distal segment,
from the vagal neural crest along the bowel wall in but there is still no clear explanation for the occur-
a craniocaudal direction from the esophagus to the rence of the spastic or tonically contracted segment
anus. In the human fetus, neural crest-derived of bowel. Normal intestinal motility requires coor-
neuroblasts first appear in the developing esopha- dinated interaction of the enteric nervous system
gus at 5 weeks and then migrating down to the anal (ENS), smooth muscle cells (SMCs), ICCs and
canal in a craniocaudal direction during the platelet-derived growth factor receptor α+-cells
5th–12th weeks of gestation. The neural crest (PDGFRα+) (SIP-syncytium). Several abnormali-
cells first form the myenteric plexus just outside ties have been described to explain the basis for
the circular muscle layer. The mesenchymal- motility dysfunction in the contracted bowel in
derived longitudinal muscle layer then forms, HSCR (Puri 2009, 2011).
Cholinergic Hyperinnervation produces NO in nervous tissue, iNOS an inducible

NOS isoform is expressed in a variety of activated
In association with aganglionosis, there is a tissues and produces large amounts of NO or stim-
marked increase in cholinergic nerve fibers in ulation, and eNOS or endothelial NOS generates
the intermuscular zone and submucosa of the NO in blood vessels and is involved in regulating
aganglionic segment. These fibers appear as vascular function. Several investigators have stud-
thick nerve trunks and correspond to extrinsic ied NOS distribution in the ganglionic and
preganglionic parasympathetic nerves (Kakita aganglionic bowel in patients with HSCR. In nor-
et al. 2000). The continuous acetylcholine release mal and ganglionic colon from patients with
from the axons of these parasympathetic nerves HSCR, there is strong NOS staining of the sub-
results in an excessive accumulation of the mucous and myenteric plexuses, and there are a
enzyme acetylcholinesterase that is typically large number of NOS positive nerve fibers in the
found in the lamina propria mucosae, muscularis circular and longitudinal muscle as well as in the
mucosae, and circular muscle with histochemical muscularis mucosae (Rolle et al. 2002a). In the
staining technique (Tang et al. 2011). Both the aganglionic segment of HSCR patients, there are
thick nerve trunks and the increased acetylcholin- no ganglia, and there is an absence or marked
esterase activity are most pronounced in the most reduction of NOS positive nerve fibers in both
distal aganglionic rectum and progressively muscle layers and the muscularis mucosae. The
diminish proximally as normal bowel is typical hypertrophied nerve trunks in the submu-
approached (Weinberg 1975). The cholinergic cosa and between the circular and longitudinal
nerve hyperplasia has been proposed as the main muscle layers appear weakly stained. The expres-
cause of spasticity of the aganglionic segment sion of neural NOS mRNA in the aganglionic
since acetylcholine is the main excitatory neuro- segment is decreased to 1/50–1/100 of the level
transmitter (Puri 2009, 2011). expressed in ganglionic bowel (Kusafuka and Puri
1997). Furthermore, recent findings of the
upregulation of nitric oxide synthase-interacting
Adrenergic Innervation protein (NOSIP) in the aganglionic and ganglionic
bowel suggest an impairment of local NO produc-
Adrenergic nerves are increased in number in the tion (Tomuschat et al. 2017), which in consequence
aganglionic colon of HSCR and have a chaotic may prevent smooth muscle relaxation and contrib-
distribution. They are present in the circular and ute to motility dysfunction. These results suggest
longitudinal muscle layers as well as in the that the defective distribution of nerves containing
mucosa whereas they are almost absent in normal NOS as well as impaired local NO production may
ganglionic colon (Nirasawa et al. 1986). Because be involved in the pathogenesis of HSCR (Bealer
adrenergic nerves normally act to relax the bowel, et al. 1994; Puri 2009, 2011).
it is unlikely that adrenergic hyperactivity is
responsible for increased tone in the aganglionic
colon (Puri 1997, 2009, 2011). Interstitial Cells of Cajal
Abnormalities of interstitial cells of Cajal (ICC)

Nitrergic Innervation have been described in several disorders of
human intestinal motility including HSCR.
Nitric oxide (NO) is considered to be one of the ICCs are scarce, and their network appeared
most important neurotransmitters involved in the disrupted in aganglionic segments of HSCR
relaxation of the smooth muscle of the gut (Rivera (Vanderwinden et al. 1996). ICCs are also
et al. 2011). It is synthesized in a reaction catalyzed reduced in the muscle layers of patients with
by nitric oxide synthase (NOS). There are three HSCR, and only a few ICCs can be found around
NOS isoforms described: nNOS or neuronal NOS the thick nerve bundles in the space between the
1016 P. Puri et al.
two muscle layers in the aganglionic bowel Extracellular Matrix

(Yamataka et al. 1997). A disorganized and
impaired function of ICCs in the ganglionic Extracellular matrix (EM) abnormalities have
bowel proximal to the transitional zone of been described in HSCR. The lethal spotted
patients with HSCR has been suggested to con- mouse model which develops aganglionosis is
tribute to the persistent dysmotility problems characterized by an abnormal distribution of EM
observed after properly performed pull-through components including laminin, collagen type IV,
operation (Puri 2009, 2011; Rolle et al. 2002b). glycosaminoglycans, and proteoglycans (Tenny-
son et al. 1990). The laminin concentration in
aganglionic bowel has been reported to be twice
Platelet-Derived Growth Factor as high as in the normoganglionic bowel of HSCR
Receptor a+-Cells (PDGFRa+) and three times greater than an age-matched con-
trol. Also, excess collagen VI in a rodent model
Platelet-derived growth factor receptor α+-cells developed HSCR-like disease due to decreased
(PDGFRα+) have recently been documented in enteric neural crest-derived cell (ENCDC) migra-
the human colon (Kurahashi et al. 2012).These tion (Soret et al. 2015). The inhibitory effect of
cells are found to be distributed in a similar pattern collagen VI on ENCDC migration may partially
as ICCs and are found alongside neurons and explain why children with Down syndrome have
SMCs. PDGFRα+ cells have a role in neurotrans- an increased risk of HSCR since collagen VI
mission and the modulation of smooth muscle genes are on chromosome 21 (Puri 2009, 2011;
contraction. Recently a decreased expression of Soret et al. 2015).
PDGFRα+ in HSCR colon has been described,
suggesting a role of these cells in the pathophys-
iology of this condition (O’Donnell et al. 2016; Genetics Factors
Puri 2009, 2011).
HSCR is known to occur in families. The reported
overall incidence of familial cases is 7.6%, with a
Smooth Muscle Cells higher incidence of 15–21% in total colonic
aganglionosis and 50% in the rare total
Smooth muscle cells (SMC) are the effector cells intestinal aganglionosis (Angrist et al. 1995;
of the bowel, and as a result of communication Attie et al. 1995).
from the ENS, ICCs, and PDGFRα+, govern During the past 20 years, several genes have
intestinal peristalsis. The SMC cytoskeleton con- been identified that control morphogenesis and
sists of proteins whose primary function is to differentiation of the enteric nervous system.
serve as a structural framework that surrounds These genes, when mutated or deleted, interfere
and support the contractile apparatus of actin and with the enteric nervous system development. So
myosin filaments in the body of the SMC. The far, 22 genes are known to be involved in the
expression of cytoskeletal proteins in the smooth development of HSCR (Table 1). The rearranged
muscle of HSCR has been reported to be either during transfection (RET) gene, encoding a tyro-
absent or weak in the aganglionic bowel, whereas sine kinase receptor, is the major gene causing
it is moderate to strong in the smooth muscle of HSCR (Edery et al. 1994; Tomuschat and Puri
normal bowel and ganglionic bowel from patients 2015). Mutations in the coding region of RET are
with HSCR (Nemeth et al. 2002). Studies on responsible for 50% of familial HSCR cases and
surface glycoproteins revealed an altered expres- 15% of sporadic ones. The other major gene
sion, indicating disturbed cell-cell interactions which plays a dominant role in HSCR is the
between SMC in patients with HSCR (Covault endothelin B receptor (EDNRB) gene, associ-
and Sanes 1986; Moore and Walsh 1985; Puri ated with Waardenburg syndrome (Moore
2009, 2011; Thiery et al. 1982). 2017). However, the RET proto-oncogene
Table 1 Genes involved in the morphogenesis and differentiation of the ENS

Gene Phenotype Inheritance Effects on intestinal innervation
RET HSCR/HSCR-MEN2/FMTC Dominant, Absence of neuronal plexus in the
incomplete small and large bowel
penetrance TIA, renal agenesis
GDNF HSCR Dominant, low Absence of neuronal plexus in the
penetrance small and large bowel
TIA, renal agenesis
EDNRB WS4/HSCR Recessive/ Aganglionosis of the distal colon, coat
dominant spotting
SOX10 WS4/HSCR Dominant Aganglionosis, coat spotting
PHOX2B CCHS/neuroblastoma + HSCR Dominant TIA, no autonomic nervous system,
ventilatory anomalies
NRTN HSCR Dominant, low Moderate deficit of enteric neurons
penetrance
PSPN HSCR Dominant, low –
penetrance
GFRA1 HSCR Dominant, low TIA, renal agenesis
penetrance
EDN3 WS4/HSCR Recessive/ Aganglionosis, coat spotting
dominant
ECE1 HSCR with cardiac defects, craniofacial Dominant Aganglionosis, coat spotting,
anomalies and autonomic dysfunction craniofacial defects
NTF3 HSCR Dominant, low Reduced enteric neurons
penetrance
NTRK3 HSCR Dominant, low Reduced enteric neurons
penetrance
PROKR1 HSCR Dominant, low –
penetrance
PROKR2 HSCR Dominant, low Hypoplasia of the olfactory bulb and
penetrance reproductive system
PROK1 HSCR Dominant, low
penetrance
SEMA3A HSCR Dominant, low Deficit of cardiac sympathetic
penetrance innervation and stellate ganglia
malformation
SEMA3D HSCR Dominant, low –
penetrance
NRG1 HSCR Dominant, low Lethal from cardiac defect
penetrance
NRG3 HSCR Dominant, low –
penetrance
ZFHX1B MWS Dominant Lethal at gastrulation
KIAA1279 GSS Recessive –
L1CAM HSAS/MASA spectrum + HSCR X-linked Hydrocephalus
remains the most consistent with allelic loss (Moore 2017). However, all the genes which
being found in more than 80% of all cases. have been implicated in the development of
Known interactions between RET and other HSCR together account for only 20% of all
genes are common and additive/synergistic cases of HSCR, suggesting potential other
effects from another genetic variant is the most genes involved in the pathogenesis of HSCR
likely explanation in the pathogenesis of HSCR (Moore 2015; Tam 2016).
1018 P. Puri et al.
Table 2 Syndromes commonly associated with associated with congenital heart disease (CHD)
Hirschsprung’s disease has been reported in 5–8% of cases, with septation
Down syndrome (trisomy 21) defects being the most frequently recorded abnor-
Neurocristopathy syndromes malities. The overall reported prevalence of HSCR
1. Waardenburg-Shah syndrome associated with CHD in infants without chromo-
2. Yemenite deaf–blind hypopigmentation somal disorders was 3%. In infants with syndromic
3. Piebaldism disorders, the overall prevalence of HSCR associ-
4. Goldberg–Shprintzen syndrome ated with CHD ranged from 20% to 80% (overall
5. Smith–Lemli–Opitz syndrome
prevalence 51%). Septation defects were recorded
6. Multiple endocrine neoplasia 2
in 57% (atrial septal defects in 29%, ventricular
7. Congenital central hypoventilation syndrome
(Ondine’s curse) septal defects in 32%), a patent ductus arteriosus
8. Mowat–Wilson syndrome in 39%, vascular abnormalities in 16%, valvular
heart defects in 4%, and tetralogy of Fallot in 7%.
The prevalence of HSCR associated with CHD is
The relationship with Down syndrome further much higher in infants with chromosomal disorders
underlines the genetic component in the etiology compared to infants without associated syndromes.
of HSCR. Down syndrome is the most common A routine echocardiogram should be performed in
chromosomal abnormality associated with all infants with syndromic HSCR to exclude car-
aganglionosis and had been reported to occur in diac abnormalities (Duess and Puri 2015).
4.5–16% of all cases of HSCR (Friedmacher and The association of urogenital anomalies and
Puri 2013). Other chromosomal abnormalities HSCR based on the common genetic background
that have been described in association with of enteric nervous system and human urinary tract
HSCR include interstitial deletion of distal 13q, development has been well described in the liter-
partial deletion of 2p and reciprocal translocation, ature. A prevalence of 14.3% associated urologi-
and trisomy 18 mosaic (Table 2). cal and urogenital anomalies has been reported in
Recurrence risk to siblings is dependent upon HSCR and warrants a thorough urological inves-
the sex of the person affected and the extent of tigation, especially in syndromic HSCR cases
aganglionosis. Furthermore, the recurrence risk to (Hofmann et al. 2014).
siblings increases as the aganglionosis extends
and brothers of patients with rectosigmoid
HSCR have a higher risk (4%) than sisters (1%). Diagnosis
Much higher risks are observed in cases of long
segment HSCR. The brothers and sons of affected The diagnosis of HSCR is usually based on clin-
females have a 24% and 29% risk of being ical history, imaging, and rectal biopsy and con-
affected, respectively (Badner et al. 1990; firmed by histological examination of rectal
Bergeron et al. 2013). The risk of familial recur- biopsy (Jakobson-Setton et al. 2015). The vast
rence of HSCR should be discussed with families majority of patients (80–90%) are diagnosed dur-
of diagnosed patients. Genetic counseling should ing the neonatal period. The hallmark symptom in
be offered in these families and in particular for neonates is delayed passage of meconium. Over
those patients with long segment and total colonic 90% of affected patients fail to pass meconium in
aganglionosis (Mc Laughlin and Puri 2015). the first 24 h of life. Usually patients present with
constipation, increasing abdominal distension
(Fig. 3) and vomiting on the first day of life.
Associated Anomalies Some patients present later in childhood, or even
during adulthood, with chronic constipation, fail-
As the cardiac development depends on neural crest ure to thrive, and abdominal distension (Puri
cell proliferation and is closely related to the for- 2009, 2011). Although, the typical patient is a
mation of the enteric nervous system, HSCR full-term male infant, HSCR can also occur in
premature infants. Prematurity was recorded in previous years. Although rare, HSCR should be
257 cases out of a total number of 4147 infants, considered in preterm infants presenting with fea-
giving a prevalence rate of 6% of preterm infants tures of intestinal obstruction (Duess et al. 2014).
diagnosed with HSCR. Interestingly, in recent Up to one-third of babies present with fever,
years, a higher prevalence of HSCR has been bilious vomiting, abdominal distension, and diar-
reported in premature infants compared to rhea due to Hirschsprung-associated enterocolitis
(HAEC). HAEC is a life-threatening condition
and remains the commonest cause of death. Rectal
examination or introduction of a rectal tube results
in explosive evacuation of gas and foul-smelling
liquid stools.
Imaging
Plain abdominal films in a neonate with HSCR

will show signs of distal obstruction with dilated
loops of bowel, fluid levels, and airless pelvis.
Occasionally, one may be able to see a small
amount of air in the undistended rectum and
dilated colon above raising the suspicion of
HSCR (Fig. 4a). Plain abdominal radiographs
obtained from patients with total colonic
aganglionosis (TCA) may show characteristics
signs of ileal obstruction with air fluid levels or
simple gaseous distension of small loops. In
Fig. 3 A 2-day-old infant with marked abdominal disten-
patients with enterocolitis, plain abdominal radi-
tion and failure to pass meconium. Suction rectal biopsy ography may show thickening of the bowel wall
confirmed Hirschsprung’s disease with mucosal irregularity or a grossly dilated
Fig. 4 Hirschsprung’s
disease. (a) Abdominal
radiograph in a 4-day-old
infant showing marked
dilation of large and small
bowel loops. Note gas in
undilated rectum. (b)
Barium enema in this
patient reveals transitional
zone at sigmoid level
1020 P. Puri et al.
colon loop, indicating toxic megacolon. transition between the dilated proximal colon
Pneumoperitoneum may be found in those with and the distal aganglionic segment, leaving the
perforation. Spontaneous perforation of the intes- diagnosis in little doubt.
tinal tract has been reported in 3% of patients with In some cases, the findings on the barium
HSCR (Elhalaby et al. 1995; Puri 2009, 2011). enema are uncertain and a delayed film at 24 h
Barium enema performed by an experienced may confirm the diagnosis by demonstrating the
radiologist should achieve a high degree of reli- retained barium and often accentuating the
ability in diagnosing HSCR in the newborn. It is appearance of the transitional zone (Fig. 5). In
important that the infant should not have rectal the presence of enterocolitis complicating
washouts or even digital examinations before bar- HSCR, a plain film will show dilated loops of
ium enema, as such interference may distort the bowel with fluid levels and a barium enema can
transitional zone appearance and give a false- demonstrate spasm, mucosal edema, and ulcera-
negative diagnosis. A soft rubber catheter is tion (Fig. 6) (Puri 2009, 2011).
inserted into the lower rectum and held in position In total colonic aganglionosis (TCA), the con-
with firm strapping across the buttocks. A balloon trast enema is not pathognomonic and may not
catheter should not be used due to the risk of provide a definitive diagnosis. The colon in TCA
perforation and the possibility of distorting a tran- is of normal caliber in 25–77% of cases (Menezes
sitional zone by distension. The barium should be et al. 2008).
injected slowly in small amounts under fluoro-
scopic control with the baby in the lateral position.
A typical case of HSCR will demonstrate flow of Anorectal Manometry
barium from the undilated rectum through a cone-
shaped transitional zone into dilated colon The recto-anal inhibitory reflex (RAIR) is defined
(Fig. 4b). Some cases may show an abrupt as a reflex relaxation of the internal anal sphincter
in response to rectal distension and is present in
normal children.
Fig. 5 Delayed 24-h film in lateral position showing barium Fig. 6 Enterocolitis complicating Hirschsprung’s disease.
retention with accentuated transition zone at the rectosigmoid Note the fluid levels
Fig. 7 Anorectal manometry
In patients with HSCR, the rectum often shows sedation, particularly in babies and small children,
spontaneous waves of varying amplitude and fre- may overcome technical challenges encountered
quency in the resting phase and the internal in this age group (Puri 2009, 2011).
sphincter rhythmic activity is more pronounced.
On rectal distension, with an increment of air,
there is complete absence of internal sphincter Rectal Biopsy
relaxation. Both term infants and premature
babies have been shown to exhibit a well- The gold standard in diagnosis of HSCR is the
developed recto-anal inhibitory reflex (RAIR) examination of rectal biopsy specimens. A suction
and anorectal pressures (Fig. 7). In the presence rectal biopsy should involve sampling a segment
of an RAIR in children of under 1 year of age, of rectal wall 2 cm proximal to the dentate line
HSCR is very unlikely. However, the specificity along the posterior wall of the rectum. A biopsy
and positive predictive value of anorectal manom- taken too distally may obtain a specimen from the
etry (ARM) for the diagnosis of HSCR are inferior physiologically aganglionic region erroneously
to those of rectal suction biopsy. Failure to detect suggesting the presence of HSCR, whereas a
the rectosphincteric reflex in premature and term biopsy taken too proximally (i.e., 5+ cm) may
infants is believed to be due to technical difficul- miss very short segment HSCR (Muise et al.
ties and not to immaturity of ganglion cells. Light 2016). It is also important to bear in mind that
1022 P. Puri et al.
Fig. 8 Acetylcholinesterase staining of suction rectal mucosae. (b) Hirschsprung’s characterized by marked
biopsy. (a) Normal rectum showing minimal acetylcholin- staining of cholinesterase-positive nerves in the lamina
esterase staining in mucosa, lamina propria and muscularis propria and muscularis mucosae
recent enemas causing mucosal edema may influ- cells and mucosal nerve fibers has been described
ence the quality of the specimens and also a poor as an adjunctive or primary diagnostic test in HSCR.
technique such as incorrect placement of the Aganglionic segments completely lack calretinin
biopsy system and low pressure, all contribute to immunoreactivity in enteric nerves (Kapur et al.
inadequate biopsy specimens (Puri 2009, 2011). 2009). The sensitivity and specificity of calretinin
The introduction of immunohistochemical IHC are equivalent to rapid AChE and that calretinin
staining (IHC) techniques for the detection of IHC may be informative when inadequate tissue is
acetylcholinesterase (AChE) activity in the rectal available to establish an H&E diagnosis (Fig. 9). A
suction biopsy (SRB) has resulted in a reliable and recent study reported that the definite diagnosis or
simple method for the diagnosis of HSCR exclusion of HSCR by calretinin IHC alone was
(de Arruda Lourencao et al. 2013). Full-thickness more accurate than rapid AChE alone, with no
rectal biopsy is rarely indicated for the diagnosis major errors and fewer equivocal readings (Baker
of HSCR except in total colonic aganglionosis. In and Kozielski 2014). Moreover, calretinin staining
normal persons, barely detectable acetylcholines- decreased the rate of inconclusive results and
terase activity is observed within the lamina pro- increased the likelihood of a confirmed diagnosis.
pria and muscularis mucosa, and submucosal These results are in agreement with previous studies
ganglion cells stain strongly for acetylcholinester- and argue for the addition of calretinin to the usual
ase. In HSCR, there is a marked increase in ace- repertoire of stains used to diagnosis HSCR (Baker
tylcholinesterase activity in lamina propria and and Kozielski 2014).
muscularis which is evident as coarse, discrete
cholinergic nerve fibers stained brown to black
(Fig. 8) (Puri 2009, 2011). In total colonic Differential Diagnosis
aganglionosis, AChE activity in rectal suction
biopsies presents an atypical pattern, different The most common condition that must be differen-
from the classic one. Positive AChE fibers can tiated from HSCR is the meconium plug syndrome.
be found in the lamina propria as well as the Meconium plugs obstructing the colon can present
muscularis mucosae. However, cholinergic fibers as HSCR with strongly suggestive history and plain
present a lower density than in classical HSCR. films. In meconium ileus, the typical mottled thick
Recently, calretinin, a calcium-binding protein meconium may be seen. Also, clear, sharp, fluid
that functions as a calcium sensor/modulator and levels are not a feature in erect or lateral decubitus
expressed in submucosal and myenteric ganglion views. However, HSCR can sometimes simulate
Fig. 9 Calretinin staining of suction rectal biopsy
meconium ileus in plain films and may give equiv- and electrolyte imbalance by infusion of appropri-
ocal findings on Gastrografin or barium enema. ate fluids will be required as well as antibiotic
Other causes of intestinal obstruction in new- coverage. It is essential to decompress the bowel
borns such as intestinal atresia, left colon syn- as early as possible in these babies. Deflation of the
drome, and imperforate anus are also common intestine may be carried out by rectal irrigations
differential diagnoses. Rare differentials such as with saline at a volume of 20 mL/kg three times
colonic atresias give similar plain film findings to daily via a large catheter located high in the rectum
HSCR. However, it is readily excluded with barium or descending colon. Some babies may require
enema showing complete mechanical obstruction. “leveling” colostomy. The level at which the colos-
Distal small bowel atresia shows gross distension tomy is placed is determined by rapid frozen sec-
of the bowel loop immediately proximal to the tions of seromuscular biopsies obtained from the
obstruction with the widest fluid level in it. colon during the operation. One must be assured
Small left colon syndrome is associated with that there are normal ganglion cells at the site of the
maternal diabetes and presents with marked disten- proposed colostomy. Children with associated
sion proximal to narrowed descending colon and anomalies such as cardiac disease or congenital
simulates HSCR at the left colonic flexure. This central hypoventilation syndrome must be investi-
conditions usually resolve with Gastrografin enema. gated and managed before definitive surgical repair
(Puri 2009, 2011).
In recent years, the vast majority of cases of
Management HSCR are diagnosed in the neonatal period.
Many centers are now performing one-stage pull-
Once the diagnosis of HSCR has been confirmed through operations in the newborn with minimal
by rectal biopsy examination, the infant should be morbidity rates and encouraging results. The
prepared for surgery. If the newborn has enteroco- advantages of operating on the newborn are that
litis complicating HSCR, correction of dehydration the colonic dilation can be quickly controlled by
1024 P. Puri et al.
washouts and at operation the caliber of the pull- through operation can be successfully performed
through bowel is near normal, allowing for an in these patients using a transanal endorectal
accurate anastomosis that minimizes leakage and approach without opening the abdomen. This pro-
cuff infection. A number of different operations cedure is associated with excellent clinical results
have been described for the treatment of HSCR. and permits early postoperative feeding, early
The four most commonly used operations are the hospital discharge, no visible scars, and low inci-
rectosigmoidectomy developed by Swenson and dence of enterocolitis (Kim et al. 2010).
Bill, the retrorectal approach developed by Duha- A good barium enema study is essential for the
mel, the endorectal procedure developed by Soave transanal one-stage pull-through operation. A typ-
and deep anterior colorectal anastomosis developed ical study of rectosigmoid HSCR will show flow
by Rehbein (Puri 2006). The basic principle in all of barium from undilated rectum through a cone-
these procedures is to resect the aganglionic bowel shaped transition zone into a dilated sigmoid
and to bring the ganglionic bowel down to the anus colon (Puri 2009, 2011).
by preserving an intact sphincter mechanism. The
long-term results of any of these operations are
satisfactory if they are performed correctly. Operative Technique
Recently, several investigators have described and
advocated a variety of one-stage pull-through pro- The patient is positioned on the operating table in
cedures in the newborn using minimally invasive the lithotomy position. The legs are strapped over
laparoscopic techniques. Many pediatric surgeons sandbags. A Foley catheter is inserted into the
in recent years perform a transanal endorectal pull- bladder. A Denis-Browne retractor or anal retrac-
through operation performed without opening the tor is placed to retract perianal skin. The rectal
abdomen and have reported excellent results in mucosa is circumferentially incised using the cau-
rectosigmoid HSCR (Puri 2009, 2011). tery with a fine-tipped needle, approximately
5 mm from the dentate line, and the submucosal
plane is developed. The proximal cut edge of the
Role of Colostomy mucosal cuff is held with multiple fine silk
sutures, which are used for traction (Fig. 10).
It is important to recognize a stoma may still be The endorectal dissection is then carried proxi-
indicated for children with severe enterocolitis, mally, staying in the submucosal plane.
perforation, malnutrition, or massively dilated When the submucosal dissection has extended
proximally bowel, as well as in situations where for about 3 cm, the rectal muscle is divided
there is inadequate pathology support to identify circumferentially, and the full thickness of the rectum
the transition zone on frozen sections. Many sur- and sigmoid colon is mobilized out through the anus.
geons prefer right transverse colostomy; others This requires division of rectal and sigmoid vessels,
advocate performing colostomy just above the which can be done under direct vision using cautery.
transition to the ganglionic bowel. Ileostomy is When the transition zone is encountered, full-
indicated in patients who have total colonic thickness biopsy sections are taken, and frozen
aganglionosis (Puri 2009, 2011). section confirmation of ganglion cells is obtained.
The rectal muscular cuff is split longitudinally
either anteriorly or posteriorly. The colon is then
Transanal One-Stage Endorectal Pull- divided several centimeters above the most prox-
Through Operation imal normal biopsy site (Fig. 10), and a standard
Soave–Boley anastomosis is performed (Fig. 10).
Over 80% of patients with HSCR have No drains are placed. The patient is started on oral
rectosigmoid aganglionosis. A one-stage pull- feeds after 24 h and discharged home on the third
Fig. 10 Transanal endorectal pull-through. (a) Rectal the rectum and sigmoid colon is mobilized out through the
mucosa is circumferentially incised using the needle-tip anus. (c) On reaching the transition zone, full-thickness
cautery approximately 5 mm above the dentate line and rectal biopsies are taken for frozen section to confirm
submucosa plane is developed. (b) When the submucosal ganglion cells. (d) Colon is divided several centimeters
dissection is extended proximally for about 3 cm the mus- above the most proximal biopsy site. (e) A standard
cle is divided circumferentially, and the full thickness of Soave–Boley anastomosis is performed
postoperative day. Digital rectal examination is aganglionosis, a different type of pull-through

performed 2 weeks after the operation. Routine operation or ostomy may be considered. Also,
rectal dilatation is not performed unless there is laparoscopic mobilization of the intra-abdominal
evidence of a stricture (Puri 2009, 2011). segment increases the mobility of the rectum and
makes the endpoint of the endorectal dissection
more definitive (Georgeson et al. 1995).
Laparoscopic-Assisted Pull-Through Initially, three ports (Fig. 11) are placed to
visualize the transition zone and to perform biop-
Despite the fact that many of the benefits of the sies for histologic leveling. A window is then
pull-through procedure can be attained by trans- made between the colon and superior rectal ves-
anal pull-through alone, significant advantages sels, and distal dissection of the aganglionic colon
are realized by performing the laparoscopic dis- is then performed circumferentially, keeping close
section (Georgeson and Robertson 2004). Prior to to the colon wall, carefully preserving the mesen-
the irreversible step of endorectal dissection, lap- teric blood supply to the rectum. Blunt and sharp
aroscopy allows verifying the presence of gan- dissection of avascular plane posterior to the rec-
glion cells in the proximal colon pedicle by tum follows. Anteriorly, the rectum is dissected
seromuscular biopsy. In cases of total colon for about 1–2 cm below the peritoneal reflection.
1026 P. Puri et al.
Fig. 11 Position of trocar

sites for laparoscopic pull-
through
It is important to avoid too extensive lateral dis- adhesions, and ileus. Late complications include
section, where damage to the nervi erigentes can constipation, enterocolitis, incontinence, anasto-
result. Proximal mesenteric dissection of the motic problems, adhesive bowel obstruction and
colon pedicle with careful preservation of the urogenital complications (Puri 2009, 2011).
marginal artery depends on the extent of the
aganglionic segments; some patients require sig-
moid colon mobilization or division of the lateral Anastomotic Leak
colonic fusion fascia up to the splenic flexure.
After the endoscopic dissection of the colon and The most dangerous early postoperative compli-
rectum has been completed, the cation following the definitive abdominoperineal
pneumoperitoneum is released and the instru- pull-through procedure is leakage at the anasto-
ments are removed, and the procedure is com- motic suture line. Factors which are responsible
pleted with an endorectal transanal pull-through. for anastomotic leak include ischemia of the distal
Once, the anastomosis of the proximal gangli- end of the colonic pull-through segment, tension
onated colon with the anorectal cuff is completed, on the anastomosis, incomplete anastomotic suture
reinsufflation for pneumoperitoneum can be lines, and inadvertent rectal manipulation. If a leak
performed to inspect the colon pedicle for twisting is recognized in a patient without a colostomy, it is
or potential internal herniation (Georgeson et al. imperative to perform a diverting colostomy
1995; Puri 2009, 2011). promptly, to administer intravenous antibiotics
and to irrigate the rectum with antibiotic solution
a few times daily. Delay in establishing fecal diver-
Postoperative Care
sion is likely to result in a large pelvic abscess
which may require laparotomy and trans-
Most infants undergoing pull-through for HSCR
abdominal drainage (Puri 2009, 2011).
can be fed next day. The anastomosis should be
calibrated with an appropriately sized dilator
2 weeks after the procedure.
Retraction of Pull-Through
Complications Retraction of a portion or all of the colonic segment

from the anastomosis can occur and is usually seen
Early postoperative complications which can occur within 3 weeks of the operation. Evaluation under
after any pull-through operation include wound general anesthesia is generally necessary. In occa-
infections, anastomotic leak, anastomotic stricture, sional patients, resuturing the anastomosis may be
retraction or necrosis of the neorectum, intestinal feasible transanally. For those with separation of
less than 50% of the anastomosis but with adequate Constipation

vascularity of the colon, a diverting colostomy for
approximately 3 months is necessary. For patients Constipation is common after definitive repair of
with wide separation at the anastomosis, early trans- HSCR and can be due to residual aganglionosis and
abdominal reconstruction of the pull-through is high anal tone. Repeated and forceful anal dilations
recommended (Puri 2009, 2011). and intrasphincteric botulin toxin injection under
general anesthesia may resolve the problem. In
some patients, internal sphincter myectomy may
Perianal Excoriation be needed. In patients with scarring, stricture, or
intestinal neuronal dysplasia proximal to
Perianal excoriation occurs in nearly half of the aganglionic segment, treatment consists treating
patients undergoing pull-through procedure but the underlying cause (Puri 2009, 2011).
generally resolves within 3 months with local
therapy and resolution of diarrhea. It is helpful to
begin placing a barrier cream on the perianal skin Soiling
promptly after the operation and to continue after
each movement for the first few weeks. Resolu- Soiling is fairly common after all types of pull-
tion of diarrhea will often hasten the clearance of through operations; its precise incidence primar-
perianal skin irritation. ily depends on how assiduously the investigator
looks for it. The reported incidence of soiling
ranges from 10% to 30% (Ruttenstock and Puri
Enterocolitis 2010). The attainment of normal postoperative
defecation is clearly dependent on intensity of
Hirschsprung’s associated enterocolitis (HAEC) bowel training, social background, and respec-
is a significant complication of HSCR both in tive intelligence of the patients. Mental
the pre-and postoperative periods. HAEC can handicap, including Down syndrome, is invari-
occur at any time during the neonatal period ably associated with long-term incontinence.
onwards to adulthood and can be independent of Those patients with preoperative enterocolitis
the medical management and surgical procedure would also appear to have a marginally higher
performed. The incidence of enterocolitis ranges long-term risk of incontinence. In some
from 20% to 58% (Menezes and Puri 2006). For- patients in whom soiling is intractable and a
tunately, the mortality rate has declined over the social problem, a Malone antegrade continence
last 30 years from 30% to 1%. This decrease in enema procedure may be needed to stay clean
mortality is related to earlier diagnosis of HSCR (Puri 2009, 2011).
and enterocolitis, rectal decompression, appropri-
ate vigorous resuscitation, and antibiotic therapy.
It has been reported that routine postoperative Long-Term Outcome
rectal washouts decrease both the incidence and
the severity of the episodes of enterocolitis fol- The vast majority of patients treated with any one
lowing definitive surgery. In episodes of chronic of the standard pull-through procedures achieve
enterocolitis, which can develop in up to 56% of satisfactory continence and function with time
patients, anal dilatations and metronidazole have (Menezes et al. 2006). The attainment of normal
been recommended. However, before commenc- continence is dependent on the intensity of bowel
ing a treatment regime, a contrast enema should be training, social background, and respective intel-
performed to rule out a mechanical obstruction. ligence of patients. Mental handicap, including
Patients with a normal rectal biopsy and recurrent Down syndrome, is invariably associated with
episodes of enterocolitis may require a long-term incontinence (Granstrom et al. 2015;
sphincterotomy (Puri 2009, 2011). Menezes and Puri 2005).
1028 P. Puri et al.
Conclusion and Future Directions Badner JA, Sieber WK, Garver KL, Chakravarti A. A
genetic study of Hirschsprung disease. Am J Hum
Genet. 1990;46(3):568–80.
The progress in understanding normal gut devel- Baker SS, Kozielski R. Calretinin and pathologic diagnosis
opment and motility has led to an expanding field of Hirschsprung disease: has the time come to abandon
of research into developing novel therapies for the acetylcholinesterase stain? J Pediatr Gastroenterol
HSCR. During the last decade, there has been Nutr. 2014;58(5):544–5.
Bealer JF, Natuzzi ES, Flake AW, Adzick NS, Harrison
increasing focus on the development of novel MR. Effect of nitric oxide on the colonic smooth mus-
stem cell-based therapies for the treatment of cle of patients with Hirschsprung’s disease. J Pediatr
HSCR. Stem cell transplantation using laboratory Surg. 1994;29(8):1025–9.
cultured neural stem cells (NSCs) to colonize Bergeron KF, Silversides DW, Pilon N. The developmental
genetics of Hirschsprung’s disease. Clin Genet.
aganglionic intestine and restore intestinal motil- 2013;83(1):15–22.
ity has been proposed as a treatment for HSCR. Burkardt DD, Graham JM Jr, Short SS, Frykman
Transplanted NSCs may contribute to functional PK. Advances in Hirschsprung disease genetics and
improvement directly by repopulating the treatment strategies: an update for the primary care
pediatrician. Clin Pediatr. 2014;53(1):71–81.
aganglionic gut with implanted neurons and res- Burns AJ, Roberts RR, Bornstein JC, Young
toration of neural circuits, and may also release HM. Development of the enteric nervous system and
trophic factors or neurotransmitters which can its role in intestinal motility during fetal and early
improve intestinal contractile function and finally postnatal stages. Semin Pediatr Surg. 2009;18
(4):196–205.
could open a new field in the treatment of HSCR. Covault J, Sanes JR. Distribution of N-CAM in synaptic
However, the optimal source of stem cells to gen- and extrasynaptic portions of developing and adult
erate a “new” enteric nervous system in the skeletal muscle. J Cell Biol. 1986;102(3):716–30.
aganglionic bowel in HSCR has yet to be Coyle D, Puri P. Hirschsprung’s disease in children with
Mowat–Wilson syndrome. Pediatr Surg Int. 2015;31
established. Further research is needed to deter- (8):711–7.
mine the optimal source of stem cells to replace Coyle D, Friedmacher F, Puri P. The association between
ENS in HSCR and determine the best way to Hirschsprung’s disease and multiple endocrine neopla-
deliver stem cells to the bowel. sia type 2a: a systematic review. Pediatr Surg Int.
2014;30(8):751–6.
Croaker GD, Shi E, Simpson E, Cartmill T, Cass
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Hirschsprung-Associated Enterocolitis
71
Farokh R. Demehri, Ihab F. Halaweish, Arnold G. Coran, and
Daniel H. Teitelbaum
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
Incidence/Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
Radiologic Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1038
Preventive Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1040
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1041
Abstract along with emesis, fever, lethargy, and even

Hirschsprung-associated enterocolitis (HAEC) shock. The pathogenesis of HAEC, the subject
is a common and sometimes life-threatening of ongoing research, likely involves a complex
complication of Hirschsprung’s disease (HD). interplay between a dysfunctional enteric ner-
Presenting either before or after definitive sur- vous system, abnormal mucin production,
gery for HD, HAEC may manifest clinically as insufficient immunoglobulin secretion, and
abdominal distension and explosive diarrhea, unbalanced intestinal microflora. Early recog-
nition of HAEC and preventative practices,
such as rectal washouts following a pull-
Daniel H. Teitelbaum passed away in 2016 through, can lead to improved outcomes.
Treatment strategies for acute HAEC include
F. R. Demehri (*) · I. F. Halaweish · A. G. Coran · D. H.
Teitelbaum timely resuscitation, colonic decompression,
Section of Pediatric Surgery, C.S. Mott Children’s Hospital and antibiotics. Recurrent or persistent HAEC
and the University of Michigan School of Medicine, Ann requires evaluation for mechanical obstruction
Arbor, MI, USA
e-mail: fdemehri@med.umich.edu; ihalawe@med.umich.
edu; acoran@med.umich.edu; acoran@umich.edu;
dttlbm@med.umich.edu

https://doi.org/10.1007/978-3-662-43588-5_37
1032 F. R. Demehri et al.
or residual aganglionosis and may require sur- of the etiology, pathophysiology, and complexity
gical treatment with posterior myotomy/ of HD, has led to improved outcomes for patients
myectomy (POMM) or redo pull-through. with this disease. Despite these advancements,
This chapter describes the incidence, patho- HAEC remains a frequent complication of HD
genesis, treatment, and preventative strategies with real morbidity and mortality, and its etiology
in the management of HAEC. and pathophysiology remain poorly understood.
This paper provides an up-to-date review of the
Keywords epidemiology, pathophysiology, and treatment of
Hirschsprung’s disease · Enterocolitis · HAEC, including pre- and postoperative preven-
HAEC · Pathogenesis · Prevention · Treatment tive strategies (Demehri et al. 2013).
Incidence/Diagnosis
Introduction
Review of modern literature shows that HAEC
Hirschsprung-associated enterocolitis (HAEC)
occurs preoperatively or at the time of HD diag-
is a serious, life-threatening complication of
nosis in 6–26% of cases and post-pull-through
Hirschsprung’s disease (HD). Harald Hirschsprung,
surgery in 5–42% (Teitelbaum et al. 1988;
a Danish pediatrician, is credited with the first
Imamura et al. 1992; Rescorla et al. 1992;
description of congenital megacolon in 1886
Elhalaby et al. 1995b; Pastor et al. 2009;
based on his observations of two children who
Teitelbaum and Coran 2013). In a retrospective
died at 7 and 11 months of age, likely from repeated
review by Haricharan, of 52 children who
bouts of HAEC. His description of one of these
underwent pull-through surgery, HAEC admis-
children is shown here (Corman 1981):
sions decreased by 30% with each doubling of
“. . .bowel movements became copious, watery and age at diagnosis and increased ninefold when
involuntary. He vomited only once, but the emaci- postoperative stricture was present (Haricharan
ated youngster was crying and manifestly et al. 2008). Whether this older age at diagnosis
suffering. . .Rectal temperature was 38.4 C. No
stool was felt in the rectum, but evacuation followed means a different type of HD or lesser length of
with withdrawal of the finger. During the stay in the aganglionosis is uncertain; however, this finding
hospital, which lasted four or five weeks, diarrhea is in contradistinction to others who have found
alternated with inability to evacuate. The abdominal that a delay in diagnosing HD beyond the first
girth varied between 56 and 41 cm; he died with
emaciation. . .Microscopic examination of the stool month of life actually predisposes children to a
showed. . . epithelial and pus cells.” higher incidence of HAEC (Teitelbaum et al.
1988).This may be due to the fact that the inci-
His description of this unfortunate child covers dence of HAEC has varied considerably between
all of the classic signs and symptoms of enteroco- different surgical groups, most likely secondary to
litis, including the classic fever, distention, and lack of a standard definition of HAEC. Pastor
watery stools, as well as the expulsion of stool et al. developed a scoring system for diagnosis
with removal of the examiner’s finger. The asso- of HAEC through a consensus approach using the
ciation between HD and HAEC was recognized Delphi method (i.e., panel of experts in the area of
by Swenson and Fisher in 1956, and the process Hirschsprung evaluating a progressively more
was later described in detail by Bill and Chapman refined list of characteristics) by identifying clin-
in 1962 (Bill and Chapman 1962). Significant ical diagnostic criteria for HAEC from a larger
advances in the treatment of HD disease have pool of potential items (Pastor et al. 2009). Eigh-
been made in the past 50 years, starting with teen items were included in the score with the
Swenson and Bill in 1948 and later operations following criteria receiving the highest scores:
by Duhamel, Soave, and others. The success of diarrhea, explosive stools, abdominal distension,
these procedures, along with better understanding and radiologic evidence of bowel obstruction or
71 Hirschsprung-Associated Enterocolitis 1033
mucosal edema (Table 1). The frequencies of Radiologic Imaging

major presenting features of HAEC are listed in
Fig. 1. Plain abdominal radiographs will likely demon-
strate colonic dilation (90% sensitivity), but this is
nonspecific (24% specificity). Gaseous intestinal
Table 1 HAEC score (Adapted from Pastor et al. 2009)
distension with abrupt cutoff at the level of the
pelvic brim – the “intestinal cutoff sign” (Fig. 2) –
History
is both sensitive (74%) and specific (86%) for
Diarrhea with explosive stool 2
HAEC (Elhalaby et al. 1995a). If a radiographic
Diarrhea with foul-smelling stool 2
Diarrhea with bloody stool 1
contrast enema study is performed, it would dem-
History of enterocolitis 1 onstrate a spastic distal colon with spiculations of
Physical examination the mucosal lining, consistent with the presence of
Explosive discharge of gas and stool on 2 mucosal inflammation and erosions (Fig. 2c). It is
rectal examination important to note that such enema studies should
Distended abdomen 2 be avoid in the presence of HAEC due to the great
Decreased peripheral perfusion 1 risk of perforation with the application of
Lethargy 1 intraluminal pressure. Chronic HAEC symptoms
Fever 1 typically include persistent diarrhea, soiling,
Radiologic examination intermittent abdominal distension, and failure to
Multiple air fluid levels 1 thrive. In patients that present repeatedly with
Dilated loops of bowel 1
these symptoms, mechanical obstruction from
Sawtooth appearance with irregular mucosal 1
aganglionosis should be ruled out in the neo-
lining
Cutoff sign in rectosigmoid with the absence 1
rectum or a residual proximal segment. The role
of distal air of rectal biopsy in the diagnosis of HAEC is
Pneumatosis 1 controversial and not recommended during the
Laboratory acute phase given the high risk of perforation,
Leukocytosis 1 unless a diagnosis of HD has yet been obtained.
Shift to left 1 However, as will be discussed below, a strong
Total 20 consideration for retained or recurrent
HAEC aganglionosis must be pursued in a child with
10
recurrent HAEC.
Fig. 1 Frequency of the 90 83

major presenting clinical
features among patients 80
with HAEC (Adapted from 69
70
Elhalaby et al. 1995)
60
Frequency (%)
51
50
40 34
30 27
20
10 5
0
Abdominal Explosive Vomiting Fever Lethargy Rectal
Distension Diarrhea Bleeding
Major Presenting Clinical Feature
Fig. 2 Plain radiograph findings of HAEC. (a) Marked (Reprinted from Elhalaby et al. 1995, copyright, with per-
gaseous distension of the colon, with abrupt cutoff at the mission from Elsevier). (c) Contrast enema performed
level of the pelvic brim (intestinal cutoff sign, arrows) in a during an unrecognized enterocolitis episode. Note the
patient with postoperative HAEC. (b) A plain film of the spastic distal nature of the bowel, with spiculations of the
same patient after insertion of a rectal tube (arrow), with mucosal lining, consistent with mucosal inflammation and
marked decrease in amount of colonic gaseous distension erosions (arrows)
several years. While advanced colonic manome-

Differential Diagnosis
try studies might be needed, certainly frequent
stooling, without other findings of HAEC should
Certainly the diagnosis of viral enteritis is com-
help with this diagnosis. Typically, these infants
mon in infancy and, as such, must be entertained
will not respond to classic treatment approaches
whenever a child presents with diarrhea and fever.
used in enterocolitis (e.g., antimicrobials, wash-
The use of the Delphi scoring system as men-
outs, and Botox injections). Interestingly, use of
tioned above has proven useful in ruling out
antidepressant medication, with associated anti-
viral enteritis, but not uncommonly one may opt
cholinergic activity, such as amitriptyline, has
to treat for HAEC in such cases, as the conse-
proven useful in reducing the number of bowel
quences of not treating, and the subsequent
movements in these HD patients.
advancement of mucosal inflammation, outweigh
the risk of enteral antibiotics and rectal washout
therapy.
Anatomic factors such as an anastomotic Pathogenesis
narrowing may result in frequent bowel move-
ments and abdominal distension. Importantly, a Despite being the leading cause of morbidity and
careful physical examination is always important mortality in Hirschsprung’s disease, the patho-
in helping to sort out the etiology of an infant’s physiology of HAEC remains poorly understood.
symptomatology after a pull-through procedure. Historically, Swenson and Fisher in 1956 first
Another diagnosis that should be considered is postulated that this disorder was caused by a
the finding that a subgroup of patients with HD defect in water and electrolyte metabolism (Fisher
has pronounced hypermotility, without HAEC and Swenson 1956). Later theories included par-
(Kaul et al. 2011). Such children may manifest tial mechanical obstruction leading to colitis
with over 15 bowel movements per day (often (Swenson et al. 1960). Subsequent experience
squirting and small in volume as seen in children with the disorder has implicated a variety of
with HAEC), and such symptoms may persist for causes, including mucosal immunity defects,
Fig. 3 Histopathologic findings of HAEC. Top left panel – – intraluminal fibrinopurulent debris or mucosal ulcera-
normal mucosa. Top right panel – crypt dilation and tions (Reprinted from Elhalaby et al. (1995), with permis-
retained mucin. Bottom left panel – multiple crypt sion from Elsevier)
abscesses per high-power filed (HPF). Bottom right panel
disordered motility, abnormal mucin production, development of crypt abscesses. If untreated,

and infection (Austin 2012). As no single etiology more advanced stages of HAEC demonstrate
has been identified, the clinical entity of HAEC mucosal ulceration and fibrinopurulent debris. In
likely represents a common result of various dys- severe cases, ischemia, transmural necrosis, and
functions of intestinal homeostasis. perforation may occur, leading to shock and sys-
An understanding of the histopathologic temic hypoperfusion. A histological grading sys-
changes associated with HAEC may provide tem is shown in Fig. 3 and represents a
insight into its pathophysiology. Similar to other progression of pathologic changes with increasing
inflammatory processes of the colon, HAEC is severity (Teitelbaum et al. 1989; Elhalaby et al.
histologically characterized by cryptitis, the 1995b). Interestingly, these pathologic findings
appearance of neutrophils in intestinal crypts have been found in aganglionic as well as gangli-
(Teitelbaum et al. 1989). Early episodes of onic segments. This suggests that the contributing
HAEC, often captured during a rectal biopsy dur- mechanisms go beyond the simple mechanism of
ing the initial work-up for Hirschsprung’s disease distension of the bowel (see below) or the absence
is associated with crypt dilation and retained of ganglia (Murphy and Puri 2005).
mucus. Such mucin retention is unique to only Another proposed mechanism of HAEC is par-
two diseases, Hirschsprung’s disease and cystic tial obstruction, which may lead to stasis, bacterial
fibrosis. This histologic process progresses to the overgrowth, and translocation. The finding of an
anastomotic stricture or narrowing has been con- patients, and this suggests dysfunction of the
sistently observed by a number of investigators as ENS beyond the aganglionic segment. Such an
a risk factor for developing HAEC, and this may abnormal ENS may create an abnormal intestinal
well relate to its pathogenesis (Hackam et al. equilibrium, where perturbations such as partial
1998). The successful treatment of patients with obstruction or bacterial overgrowth may lead to
recurrent HAEC with internal sphincterotomy enterocolitis.
(Polley et al. 1985), or a posterior myotomy, A fundamental component of intestinal
lends support to functional obstruction as an eti- homeostasis is epithelial barrier function (EBF),
ology in some patients. As HAEC also occurs in a composite function of factors including mucin
infants without evidence of obstruction, including production, intraluminal immunoglobulins, epi-
patients with diverting stomas, other factors must thelial tight junctions, and the enteric nervous
play a role. system. Dysfunctional EBF may result in adher-
The increased risk of HAEC in patients with ence of pathologic organisms to enterocytes. Most
trisomy 21 potentially suggests a genetic role in interesting is the finding of the development of
the etiology of HAEC (Teitelbaum et al. 1988). enteroadhesive behavior in organisms during epi-
The etiology of this predisposition is not under- sodes of HAEC (i.e., microbial penetration of the
stood. However, infants with trisomy 21 have mucin layer with subsequent adherence of bacte-
immune deficiencies that span both T cell and B ria to the lining epithelial cells). This phenomenon
cell lineages, as well as dysfunction in their neu- is demonstrated with the adherence of C. difficile,
trophils. All these may greatly contribute to the Cryptosporidium, and E. coli in up to 39% of
predisposition this subgroup of Hirschsprung’s patients with HAEC in some reports (Teitelbaum
children have to develop HAEC. No genetic et al. 1989).
abnormality has been shown to cause HAEC; One of the more intriguing histologic manifes-
however some genetic variations do correlate tations of HAEC is the outpouring of mucins
with more severe disease. For example, intestinal which fill the crypt cells. This led to an early
autonomic dysfunction has been associated with investigation of nature of these mucins. Akkary
mutation in the RET proto-oncogene (Staiano et al. demonstrated that the nature of these mucins
et al. 1999), which is known to be associated shifted toward the production of neutral mucins
with HD. In addition, variations in the ITGB2 (Akkary et al. 1981). Abnormalities in the amount
immunomodulatory gene (CD18) have been and composition of mucin, a key component of
found in 66% of patients with HD, with 59% of the mucosal barrier function, may contribute to
these patients developing HAEC (Moore et al. this dysfunction. Further investigation of these
2008). More than one variation in the ITGB2 changes confirmed this shift in neutral mucins
gene was associated with more severe HAEC. (Teitelbaum et al. 1989) and a decline in acidic
Continued work on the role of genetic variation sulfomucins. This shift (increase in neutral
in HAEC may shed more light on its pathogenesis. mucins and a decrease in acidic sulfomucins)
As the primary defect in HD is the congenital was subsequently correlated to a loss of barrier
lack of intestinal ganglia, an abnormal enteric function using an in vitro approach (Aslam et al.
nervous system (ENS) remains a culprit in the 1999). A key component of mucins is the MUC
pathogenesis of HAEC. The ENS has a role in family of proteins. The production of MUC-2, the
intestinal homeostasis, including motility, epithe- predominant mucin expressed in humans, is
lial barrier function, mucosal immunity, epithelial markedly depressed in patients with HD, and for
transport, and regulation of the gut microbiome. those samples examined during an episode of
Dysfunction of the ENS may lead to the initiation HAEC, production of MUC-2 was virtually
or propagation of the inflammatory cycle of undetectable at the protein level (Mattar et al.
HAEC. Miyahara et al. (2009) demonstrated 2003). In addition, reduced total colonic mucin
markers of neuronal immaturity in the proximal, turnover correlates with an increased risk of
normal ganglionic bowel of Hirschsprung’s HAEC development (Aslam et al. 1998). Such
changes in mucin production and composition cells in the lamina propria of bowel from patients
may be secondary to abnormalities in the ENS with HAEC, with decreased luminal IgA in the
described above, as the goblet cells that secrete aganglionic segment of these same patients
mucus are regulated by submucosal neuroendo- (Imamura et al. 1992). Similar findings have
crine cells, which are reduced in patients with been seen in a mouse model of HAEC using
HAEC (Soeda et al. 1993). Other regulators of piebald-lethal mice, whereby an initial elevation
intestinal epithelial barrier function, such as mast of immunoglobulins was measured early in the
cells and enteric glial cells, are abnormal in HD, life followed by a precipitous fall near the death
but have yet to be fully investigated in HAEC of these animals (Fujimoto et al. 1988; Caniano
(Austin 2012). Finally, it is intriguing to speculate et al. 1989). Other immune changes noted in
that the altered production of mucins may actually patients with HAEC included increased distribu-
be a nutrient source to selected bacteria in patients tion of CD57+ natural killer cells, CD68+ mono-
with enterocolitis. Recently, a relatively unknown cytes/macrophages, and CD45RO+ leukocytes in
organism, Akkermansia spp., particularly, the bowel of patients with HAEC (Imamura et al.
Verrucomicrobia thrive on mucins and have 1992). To determine whether these changes are
recently been implicated in the development of primary defects predisposing to HAEC, or
inflammatory conditions, including inflammatory whether they are secondary to enterocolitis,
bowel disease (Belzer and de Vos 2012). While an Turnock et al. in 1992 evaluated suction rectal
extensive examination of the microbial biopsies of infants with HD and found similar
populations of children with HAEC has not yet levels of mucosal immunoglobulins regardless of
been done, it will be intriguing to examine for the the presence of HAEC (Turnock et al. 1992). This
expansion of such populations in the setting suggests that in patients with HAEC, mucosal IgA
of HD. production is intact but intraluminal transfer is
As deficiencies in epithelial barrier function deficient, limiting the role of IgA in mucosal
lead to loss of mucosal integrity, the mucosa of defense (Murphy and Puri 2005). These findings
patients with HAEC may exhibit diminished implicate an intrinsic immune deficiency in the
recovery. Reduced expression of caudal type development of HAEC, which may explain the
homeobox (CDX) gene-1 and gene-2 has been increased risk in patients with trisomy 21, who are
found in the mucosa of patients with HAEC (Lui known to have abnormal cytotoxic T cell and
et al. 2001). As these genes are involved in muco- humoral function.
sal proliferation and differentiation, this suggests The factors described above may create a dys-
a deficiency in mucosal healing, which may con- functional environment in which the gut micro-
tribute to prolonged mucosal damage and subse- biome is susceptible to a pathologic change in
quent enterocolitis. composition leading to HAEC. A microbial etiol-
Another component of intestinal epithelial ogy of HAEC has been investigated since the first
defense that has been implicated in HAEC is the reports of high C. difficile toxin titers in patients
mucosal immune system. Secretory IgA, the pre- with HAEC compared to those with HD only and
dominant immunoglobulin in the intestinal tract, normal controls (Thomas et al. 1982). These find-
plays a role in preventing bacterial translocation in ings were not substantiated in later studies, which
healthy intestine. Wilson-Storey and Scobie in found variable C. difficile carriage rates (Wilson-
1989 demonstrated that, in patients with HD, Storey et al. 1990; Hardy et al. 1993). While not
secretory IgA was undetectable in saliva while it currently thought to be causative, C. difficile may
was increased in buccal mucosa (Wilson-Storey flourish in the setting of HAEC (Murphy and Puri
and Scobie 1989). For those with HAEC, how- 2005), with an associated mortality rate of 50% if
ever, secretory IgA was absent from the buccal pseudomembranous colitis develops (Bagwell
mucosa altogether. Similarly, colonic resection et al. 1992). Changes in the composition of the
specimens studied by Imamura et al. in 1992 gut microbiome were evaluated by Shen et al. in
showed elevated IgA, IgM, and IgG chain plasma 2009, who found decreased colonization of
Unbalanced
secretory IgA
Abnormal
microbiome
Abnormal mucin
production
Dysfunctional enteric
nervous system
Insufficient
immunoglobulin
secretion
Colonic
dysmotility
Fig. 4 Schematic representation of the potential patho- insufficient and unbalanced immunoglobulin production,
physiologic mechanisms contributing to HAEC. Note mul- abnormal mucins, and a dysfunctional enteric nervous
tiple changes occurring in patients with HAEC. This system which may contribute to colonic dysmotility
includes an abnormal microbial population (microbiome),
bifidobacteria and lactobacilli, probiotic organ- mucin production, insufficient immunoglobulin

isms, in patients with HD versus controls, and secretion, and unbalanced intestinal microflora,
even lower colonization in those with HAEC contribute to the development of the common
(Shen et al. 2009). This finding of altered micro- clinical entity of HAEC. A summary of the poten-
bial equilibrium is supported by a recent study tial pathophysiologic mechanisms contributing to
evaluating the stool microflora of a child with HAEC is shown in Fig. 4.
HD during HAEC episodes and during remission,
finding a clustering of microbial diversity with
HAEC episodes (De Filippo et al. 2010). These Treatment
studies suggest that disequilibrium of the gut
microbiome may result in dominance of a pre- The treatment of children presenting with
disposing bacterial community for HAEC devel- suspected HAEC is resuscitation, decompression
opment, though further investigation must be of the gastrointestinal tract, and antibiotics. The
done to establish the specific organisms involved severity of the episode dictates antibiotic choice;
(Li et al. 2016; Frykman et al. 2015). mild episodes of HAEC can be treated with oral
While the elements contributing to HAEC are metronidazole alone, while more severe episodes
increasingly well described, much work remains should be treated with intravenous, broad-
in elucidating its pathophysiology. There is spectrum therapy including ampicillin, gentami-
increasing evidence that several factors, including cin, and metronidazole. Unfortunately, there are
a dysfunctional enteric nervous system, abnormal few studies comparing antimicrobials for the
treatment of HAEC. Classically, the colon is should be undertaken in infants that present with
under considerable pressure, potentially a strong repeated episodes of enterocolitis following a
causative factor for the HAEC episode. Decom- pull-through procedure. If a contrast enema is
pression of the colon is essential and can generally normal, full-thickness rectal biopsy is warranted
be done with rectal washouts. Rectal washouts to rule out aganglionosis in the pull-through seg-
with saline (10–20 mL/kg) using a large bore ment (Moore et al. 1994; Levitt et al. 2010). While
soft tube should be initiated immediately and a rare cause of HAEC, in cases of retained
repeated anywhere from two to four times per or secondary aganglionosis associated with
day until proper decompression as determined enterocolitis, such patients will need a redo pull-
by clinical examination. In the case of fulminant through (Lawal et al. 2011). In cases of anasto-
disease, washouts should be avoided due to risk of motic strictures, a trial of dilation is recommended
perforation, but gentle passage of a rectal tube to with the possibility of a redo pull-through being
decompress the bowel is critical. Bowel rest is reserved if dilations are unsuccessful.
indicated with parenteral nutrition in cases of pro- Medical approaches for treatment of HAEC
longed disease (Vieten and Spicer 2004; Levitt include antibiotics and sodium cromoglycate.
et al. 2010). Inability to adequately decompress Although there is no data to support prophylactic
the bowel or cases of sepsis with HAEC maybe an antibiotic therapy post-pull-through, the authors
indication for diversion with a leveling colostomy have recommended its use with the first signs and
just proximal to the transition zone. The use of symptoms of HAEC. Sodium cromoglycate, a mast
intraoperative frozen section histology is essential cell stabilizer, is not absorbed in the gastrointestinal
in cases where a child initially presenting with HD tract. A nonrandomized study by Rintala and
has HAEC, in order to level the colon at a site with Lindahl in 2001 showed a favorable response in
ganglion cells. three out of five patients with decrease in number of
Current surgical treatments for HD, including bowel movements and abdominal distention
one-stage endorectal pull-through (ERPT), have (Rintala and Lindahl 2001). Unfortunately, there
become standard of care (Coran and Teitelbaum have been no follow-up studies to verify these
2000). Although pull-through operations relieve results.
the obstructive symptoms of HD, there is a per- Surgical or interventional approaches for treat-
sistent risk of the development of enterocolitis, ment of HAEC include botulinum toxin injec-
occurring in up to 42% of patients (Hackam tions, sphincterotomy, and posterior myotomy/
et al. 1998; Teitelbaum et al. 2000; Vieten and myectomy (POMM) (Fig. 5). With the observa-
Spicer 2004). Compared to patients undergoing a tion that post-pull-through patients often have
two-stage approach, recent data shows a trend tight rectal sphincters, Swenson and coworkers
toward a higher incidence of enterocolitis in the initially proposed that sphincterotomy prevents
primary ERPT group compared with those with a enterocolitis. However, a follow-up evaluation
two-stage approach (42.0% vs. 22.0%). Although did not show significant improvement with such
this is thought to be primarily due to a lower procedures (Swenson et al. 1975).
threshold in diagnosing HAEC in more recent In children with recurrent HAEC over
years (Teitelbaum et al. 2000), it is possible that 1–2 years following their pull-through, the use
a tighter anastomosis in these younger infants of a POMM should be considered. The use of
undergoing a primary pull-through may be a con- this approach has been tempered by some series
tributing factor. Risk factors for post-pull-through showing poor functional outcomes. A study using
enterocolitis include anastomotic leak or stricture the transanal POMM approach showed adulthood
and postoperative intestinal obstruction due to incontinence in 4 out of 14 patients who
adhesions; such factors increase the relative risk underwent POMM procedures as children
of subsequent enterocolitis by approximately (Heikkinen et al. 2005). Small reports from vari-
threefold (Hackam et al. 1998). Ruling out a ous groups have shown mixed results (Polley et al.
mechanical cause of partial bowel obstruction 1985; Marty et al. 1995a). It is possible that the
Fig. 5 Operative approach

to a posterior myectomy
(POMM). Note a flap of
mucosa and submucosa are
raised posteriorly about
0.5–1 cm above the dentate
line. The muscularis is
incised and a one-half
centimeter wide segment is
carried as far cephalad as
possible. It is critical to keep
the segments oriented for
pathologic review
(Reproduced with
permission from
Teitelbaum et al. 2013)
etiology of incontinence in these patients is the best treatment for enterocolitis is its prevention.
transection of part, or all, of the internal anal Rectal washouts limit colonic distention and fecal
sphincter. If the performance of a POMM is stasis and should be performed when surgical
started above the level of the dentate line, damage management is delayed (Vieten and Spicer
to the internal anal sphincter can be avoided. 2004). It has been noted that a histologic grade
Wildhaber et al. in 2004 reported excellent conti- of III or higher on rectal biopsy, regardless of the
nence rates with this approach for recurrent patient’s clinical history, indicates high risk for
HAEC (Wildhaber et al. 2004). An additional potential development of clinical enterocolitis
advantage to the use of a POMM is that a redo and may be an indication for prophylactic antibi-
pull-through operation can still be performed in otics (Teitelbaum et al. 1989).
case myectomy is not successful. Postoperatively, scheduled rectal washouts
The use of botulinum injections for treatment have been shown to reduce the incidence of post-
of recurrent HAEC post-pull-through has shown operative HAEC. In a review by Marty et al. in
promise in recent studies (Minkes and Langer 1995a, 36% of patients in the nonirrigation cohort
2000) with improvement in symptoms and num- developed postoperative enterocolitis compared
ber of hospitalizations; however, long-term results with 8% of patients in the rectal irrigation cohort
have been mixed with difficulty predicting (Marty et al. 1995b). Traditionally, routine anal
response in patients. Finally, in rare cases of recal- dilations where thought to prevent stricture for-
citrant HAEC not responsive to medical and sur- mation with most pediatric surgeons
gical intervention, end ileostomy or colostomy is recommending daily dilations by parents. How-
a last resort (Estevao-Costa et al. 1999). ever, recent data has challenged this assertion. In a
retrospective review by Temple et al. in 2012,
children undergoing repair of HD or anorectal
Preventive Strategies malformation had either routine dilatation by par-
ents or weekly calibration of the anastomosis by
Some authors have noted preoperative enteroco- the surgeon, with daily dilation reserved for chil-
litis increases the risk of post-pull-through entero- dren with concern for anastomotic narrowing.
colitis (Engum and Grosfeld 2004). Ideally, the There was no significant difference in the
development of enterocolitis in children with HD HAEC. Intestinal decompression, antibiotics, and

(Temple et al. 2012). Despite these latter findings, rectal washouts remain the cornerstones of treat-
it has been our practice to start such anal dilations ment for acute HAEC, with surgical intervention
at 3 weeks post-pull-through and typically send such as POMM an effective option for patients
the infant home with a prophylactic course of with recurrent HAEC.
metronidazole for the first 2 months after surgery. Future goals in the management of HAEC
Topical isosorbide dinitrate or nitroglycerin include identification of patients at high risk and
applied to the anal canal has been shown to relax the development of patient-specific measures to
the smooth muscle of the anal sphincter. Some prevent its onset. Further understanding of the path-
authors have shown that anal application of topi- ophysiology of HAEC may provide targets for
cal isosorbide dinitrate paste leads to improve- treatment and prevention. For example, given the
ment in recurrent HAEC and “internal sphincter likely role of alterations of gut microbiology, the
achalasia”; although small patient numbers limit identification of a high-risk intestinal microbiome
the interpretation of the outcomes of these studies, in a patient may allow for early modulation of this
this approach should be studied further in the bacterial profile to prevent HAEC. In addition, fur-
future (Messina et al. 2007). ther research into the role of immune dysfunction in
Because of the potential for an altered micro- HAEC may lead to the development of strategies to
biome/epithelial cell interaction in children with modulate the enteric immune system to create a
HAEC, many have thought that probiotics may lower-risk intestinal environment. Finally, as the
confer a prophylactic benefit to such patients. outcomes of surgical intervention for HAEC con-
El-Sawaf et al. recently reported on a multicenter, tinue to be assessed, the optimal timing of surgical
prospective, randomized, controlled trial of pro- intervention (i.e., POMM) is yet to be defined.
biotics versus placebo in infants undergoing a Much knowledge has been gained over the past
pull-through for HD to determine if the use of three decades in the diagnosis, treatment, and pre-
probiotics could decrease the incidence and fre- vention of HAEC, with more progress on the hori-
quency of HAEC (El-Sawaf et al. 2013). Unfor- zon in the understanding of its pathophysiology and
tunately, the use of a high dose of orally delivered use of this understanding to develop better thera-
probiotics failed to offer any prophylactic benefit peutic and preventive strategies.
to this group of patients. Multivariate analysis,
adjusting for length of aganglionosis and age of
child, also failed to demonstrate any benefit of
probiotics to a subgroup of HD children. This Cross-References
certainly emphasizes the multifaceted aspect of
the etiology and the complexity of this disorder. ▶ Anorectal Malformations
▶ Colonic and Rectal Atresias
Conclusion and Future Directions ▶ Hirschsprung’s Disease
▶ Sepsis
HAEC remains a substantial source of morbidity ▶ Variants of Hirschsprung Disease
for children with HD. Its clinical characteristics
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1993;28(8):1063–8. 1989;24(5):462–4.
Staiano A, Santoro L, et al. Autonomic dysfunction in Wilson-Storey D, Scobie WG, et al. Microbiological stud-
children with Hirschsprung’s disease. Dig Dis Sci. ies of the enterocolitis of Hirschsprung’s disease. Arch
1999;44(5):960–5. Dis Child. 1990;65(12):1338–9.
Variants of Hirschsprung Disease
72
Prem Puri, Jan-Hendrik Gosemann, and Hiroki Nakamura
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Variants of HD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Intestinal Neuronal Dysplasia (IND) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Hypoganglionosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Internal Anal Sphincter Achalasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1051
Megacystis Microcolon Intestinal Hypoperistalsis Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 1052
Summary and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1056
Abstract
Variants of Hirschsprung disease (HD) are a
group of conditions that clinically resemble
HD despite the presence of ganglion cells in
P. Puri (*) rectal suction biopsies. The characterization
Department of Pediatric Surgery, Beacon Hospital, Dublin, and differentiation of various entities is mainly
Ireland based on histological and immunohistochemi-
School of Medicine and Medical Science and Conway cal findings of biopsies from patients with
Institute of Biomedical Research, University College functional intestinal obstruction.
Over the last decades, several groups have
e-mail: prem.puri@ucd.ie; prem.puri@ncrc.ie
focused on the investigation and definition of
J.-H. Gosemann
variant HD such as intestinal neuronal dysplasia,
Department of Pediatric Surgery, University of Leipzig,
Leipzig, Germany isolated hyperganglionosis, internal anal sphinc-
e-mail: Jan-Hendrik.Gosemann@medizin.uni-leipzig.de; ter achalasia, immature ganglia, and smooth
gosemann.jan@mh-hannover.de muscle cell disorders such as megacystis micro-
H. Nakamura colon intestinal hypoperistalsis syndrome. How-
National Children’s Research Centre, Our Lady’s ever, definition of the above-mentioned entities
remains a controversial issue and research is
Department Pediatric General and Urogenital Surgery, ongoing to standardize diagnostic criteria, spe-
cific therapy, and outcome criteria.

https://doi.org/10.1007/978-3-662-43588-5_75
1046 P. Puri et al.
This chapter summarizes the current knowl- Table 1 Diagnoses of investigated bowel specimens
edge of the above-mentioned entities of (1981–2016)
variant HD. Cases (Total:
n = 214)
Keywords Intestinal neuronal dysplasia 87
Hirschsprung’s disease · Intestinal neuronal Internal sphincter achalasia 57
Megacystis microcolon intestinal 27
dysplasia · Hypoganglionosis · Internal
hypoperistalsis
sphincter achalasia · Megacystis microcolon Hypoganglionosis 22
intestinal hypoperistalsis syndrome Immature ganglia 12
Intestinal ganglioneuromatosis 5
Absence of argyrophil plexus 4
Introduction
Patients with Hirschsprung’s disease (HD) usually Over the past several years, we have focused
present in the newborn period with delayed pas- our research interests into delineating variants of
sage of meconium and abdominal distension or as a HD on the basis of specific histochemical, immu-
young child with severe chronic constipation. The nohistochemical, and electron microscopic stud-
diagnosis of HD is confirmed by the absence of ies. Between 1981 and 2016, full-thickness
ganglion cells in the submucosa on rectal suction or bowel biopsy or resected surgical specimens
full thickness biopsies and increased acetylcholin- from 214 patients (75 boys and 103 girls) with
esterase (AChE) activity as a sign of hypertrophic clinical symptoms suggesting HD were exam-
nerve fibrils in the lamina propria and muscularis ined in the Puri laboratory. Age ranged from
mucosae (Moore 2016). There are a number of 1 day to 9 years with 65% of these patients
patients who – when evaluated for suspected HD having onset of symptoms in the neonatal period.
– show presence of ganglion cells in rectal biopsies Nearly half of the specimens were sent from
but continue having signs and symptoms of func- other countries. Various functional bowel disor-
tional intestinal obstruction. Various terms have ders were diagnosed using different histologic
been used to describe these conditions: “chronic techniques, including intestinal neuronal dyspla-
idiopathic intestinal pseudoobstruction,” “pseudo sia (IND), isolated hypoganglionosis, internal
HD,” “neonatal intestinal pseudoobstruction,” and sphincter achalasia, and megacystis microcolon
“intestinal hypoperistalsis.” The diagnosis and intestinal hypoperistalsis syndrome (MMIHS)
management of patients with rare functional intes- (Table 1). This chapter summarizes the current
tinal disorders remains a challenge for clinicians knowledge on the most frequent variants of HD.
since described histological variations of ganglia
and nerves are highly variable (Puri 2012; Puri and
Gosemann 2012). These variations include number Variants of HD
and distribution of ganglion cells, abnormal
peripheral nerves, and other features of a disor- Intestinal Neuronal Dysplasia (IND)
dered enteric nervous system (Moore 2016). Quan-
titative abnormalities of neuronal density have In 1971, Meyer-Ruge described IND as a hyper-
been shown to vary depending on the age of the plastic malformation of the enteric plexus (Meier-
child, region of the examined bowel, degree of Ruge 1971). Subsequently, Puri et al. reported the
intestinal dilation, type of biopsy/preparation, and association between IND and HD in a 5-year-old
mode of staining. Furthermore, the lack of diag- Arab boy who had rectosigmoid aganglionosis
nostic criteria and a high documented inter- combined with IND of the descending and trans-
observer variation lead to controversies regarding verse colon (Puri et al. 1977). In 1983, Fadda et al.
the definition and/or existence of variants of HD classified IND into two distinct clinical and histo-
(Schäppi et al. 2013). logical subtypes (Fadda et al. 1983): Type A is
72 Variants of Hirschsprung Disease 1047
histologically characterized by congenital aplasia or in the picture of IND with hyperganglionosis, giant
hypoplasia of the sympathetic innervation. Patients ganglia, and hypertrophied nerve fiber strands in the
diagnosed with type A IND present acutely in the submucous plexus (Boyen et al. 2002; Holland-
neonatal period with episodes of intestinal obstruc- Cunz et al. 2003).
tion, diarrhea, and bloody stools. Type B is charac- However, mutational screenings of both the
terized by malformation of the parasympathetic HOX11L1 and the EDNRB gene did not show any
submucosal and myenteric plexuses. The histolog- mutation in these genes (Costa et al. 2000; Gath et al.
ical features include hyperganglionosis, giant 2001). Furthermore, analysis of noncoding promoter
ganglia, ectopic ganglion cells, and increased ace- regions of HOX11L1 was carried out by Fava et al.
tylcholinesterase (AChE) activity in the lamina pro- and they found no alterations, such as nucleotide
pria and around submucosal blood vessels in rectal variants, small deletions, or cytogenetic alterations,
suction biopsies (Bruder and Meier-Ruge 2007; potentially impairing expression of HOX11L1, and
Meier-Ruge 1985; Puri and Gosemann 2012). thus concluded that a direct involvement of this gene
IND may also occur in association with HD. in the pathogenesis of human intestinal motility
disorders is unlikely (Fava et al. 2002).
Pathogenesis
The existence of IND as a distinct histopathologic Epidemiology
entity is highly controversial (Sacher et al. 1993; An incidence of 1 in 7500 newborns has been
Lake 1995). Some authors suggest that the patho- described by Granero Cendón et al. (2007), and
logic changes seen in IND may be normal devel- reports about the occurrence of isolated IND in all
opmental changes (Schäppi et al. 2013) or may be rectal suction biopsies vary from 0.3% to 40% in
a secondary phenomenon induced by congenital different centers (Holschneider et al. 2008; Puri
obstruction or inflammatory disease (Sacher et al. and Gosemann 2012). IND immediately proximal
1993; Milla and Smith 1993; Lake 1995). How- to a segment of aganglionosis has been described
ever, several familial cases of IND have been and suggested as a possible cause of persistent
described in the literature, suggesting that genetic bowel problems after the definitive operation for
factors may be involved in this condition (Moore HD (Kobayashi et al. 1995). Several authors
et al. 1993; Kobayashi et al. 1996; Martucciello reported IND combined with HD in up to 44%
et al. 2002). Evidence supporting IND as a real of patients with HD (Ure et al. 1997; Montedonico
entity arose from animal models: While investigat- et al. 2011; Puri and Gosemann 2012), whereas
ing the role of the homeobox gene Hox11L1, which others have rarely encountered IND in association
is expressed in neural crest cells, two different with HD (Puri and Gosemann 2012). This vari-
Hox11L1 knockout mouse models have been ability may be mainly attributed to the consider-
established. Both homozygous knockouts resulted able confusion regarding the essential diagnostic
in the development of megacolon at the age of criteria. The diagnostic difficulty is centered on a
3–5 weeks without any further major morpholog- wide variability encountered in the literature, not
ical disorders. The histopathological evaluation only in terms of the age of the patient, the type of
revealed hyperplasia of myenteric ganglia similar specimen examined, and the staining methods
to the phenotype observed in human IND type B performed but also in the diagnostic criteria used
(Shirasawa et al. 1997; Hatano et al. 1997). (Puri 2012; Schäppi et al. 2013; Moore 2016).
Another animal model resulting in IND pheno-
type was described by von Boyen et al. in 2002 Clinical Presentation
(Boyen et al. 2002). The authors investigated rats The majority of patients with IND present with
with a heterozygous mutation of the endothelin-B chronic constipation with or without abdominal
receptor (EDNRB). Whereas rats with homozygous distension. Montedonico et al. described a char-
deficiency of EDNRB show HD phenotype with acteristic clinical pattern of IND in infants less
long segment aganglionosis, a heterozygous than 1-year-old with a history of constipation
301-base-pair deletion of the EDNRB gene resulted and abdominal distention, resembling HD with
1048 P. Puri et al.
Fig. 1 AChE staining of rectal suction biopsies. (a) Normal rectal suction biopsy. (b) Rectal suction biopsy from a patient
with IND showing hyperganglionosis, giant ganglia, and increased AChE activity in the lamina propria
absence of internal sphincter relaxation in intraobserver variation (Koletzko et al. 1999;

manometry but who have a normal barium Montedonico et al. 2011; Puri and Gosemann
enema (Montedonico et al. 2002). IND in these 2012). The debate about the existence of IND as
investigated patients was classified according to a real disease entity still continues, and is mainly
the severity of histochemical changes following due to the lack of consensus in diagnostic criteria
the criteria for the diagnosis of severe IND, (Coerdt et al. 2004; Martucciello et al. 2005;
including hyperplasia of the submucous plexus Montedonico et al. 2011). IND has been tradition-
and giant ganglia with more than seven nerve ally diagnosed on the basis of AChE staining of
cells. According to Montedonico et al. intestinal nerve fibers in rectal suction biopsies (Meier-
obstruction is the most characteristic clinical Ruge and Bruder 2005; Montedonico et al. 2011;
symptom of IND in young children, whereas Puri 2012). However, since AChE activity in the
fecaloma and soiling are more pronounced in lamina propria mucosae has been shown to be an
patients with severe constipation. age-dependent phenomenon, which disappears at
A high incidence of associated pathologies in the time of maturation of the submucosal plexus,
IND patients has been reported ranging from 25% additional staining techniques have been pro-
to 30% (Puri 2012). The most common associated posed. Meier-Ruge et al. introduced lactatedehy-
pathologies include anorectal malformations, drogenase (LDH), succinatdehydrogenase (SDH),
intestinal malrotation, megacystis microcolon and nitric oxide synthase (NOS) for their diagno-
hypoperistalsis syndrome (MMIHS), congenital sis of IND (Meier-Ruge et al. 2004). Several neu-
short bowel, hypertrophic pyloric stenosis, necro- ronal and glial markers besides the initially
tizing enterocolitis, and Down syndrome recommended AChE have been suggested for
(Montedonico et al. 2002; Pini Prato et al. 2011; the evaluation and diagnosis of IND, such as
Puri and Gosemann 2012). nicotinamide-adenine dinucleotide phosphate
Pini Prato reported an association of IND, (NADPH) diaphorase (Figs. 1 and 2), neural cell
intestinal malrotation, and megacystis in their adhesion molecule, protein gene product 9.5
small series of four patients. These findings were (PGP9.5), S-100, peripherin, synaptophysin, and
accompanied by the observation of a de novo cuprolinic blue (Wester et al. 1999; Meier-Ruge
duplication detected on chromosome 12 (Pini and Bruder 2005; Puri 2012).
Prato et al. 2011). Due to the controversy in staining techniques
and age-dependent AChE expression, the most
Diagnosis commonly used diagnostic criteria to date is the
Previously, the diagnosis of IND was based on finding of more than 20% of giant ganglia with
qualitative criteria, thus resulting in a high more than eight nerve cells in the submucosa of
Fig. 2 NADPH-diaphorase staining in whole-mount preparations. (a) Normal submucous plexus. (b) Submucous plexus
in IND showing giant ganglia
30 serial sections in addition to hyperganglionosis period of 2.4 years. Sixty four percent of patients
(Meier-Ruge et al. 2004; Knowles et al. 2010; with IND had a good response to conservative
Montedonico et al. 2011; Pini Prato et al. 2011) in treatment with normal bowel habits and did not
patients older than 1 year. It is important to note that require surgical intervention. Thirty six percent,
in the first year of life giant ganglia may be mis- however, required internal sphincter myectomy
interpreted due to the fact that immature ganglia after failed conservative treatment. Seven out of
often have an incomplete differentiation in nerve these 12 patients had normal bowel habits after
cells (Meier-Ruge et al. 2004). myectomy, and two were able to stay clean with
IND patients do not display any specific radio- regular enemas. Three patients continued having
logic features in barium enemas other than persistent constipation after myectomy and subse-
rectosigmoid distension. Furthermore, the quently underwent resection of redundant and
rectosphincteric reflex has been shown to be pre- dilated sigmoid colon, resulting in normal bowel
sent, absent, or atypical in IND patients (Puri 2012). habits (Gillick et al. 2001).
Management
To date, there is a broad compliance with the Hypoganglionosis
recommendation that IND type B treatment
should be conservative in the first instance, The number of isolated hypoganglionosis
consisting of laxatives and enemas (Ure et al. (IH) cases presented in the current literature is
1997; Bruder and Meier-Ruge 2007; Puri 2012; limited due to the fact that IH is one of the rarest
Schäppi et al. 2013). The majority of patients have subtypes of intestinal innervation disorders (Puri
been shown to be manageable in this way. How- 2012), and the discussion about IH as a real iso-
ever, if bowel symptoms persist (at least lated entity remains controversial (Martucciello
>6 months of treatment (Puri 2012)) despite et al. 2005).
proper bowel management, surgical or interven-
tional options may be considered. Internal sphinc- Pathogenesis
ter myectomy and injection of botulinum toxin To date, the pathogenesis and the genetic basis of
have been reported by several authors (Puri and IH remain unclear. Several authors performed
Gosemann 2012). mutational analysis of the RET gene, which has
been reported to be associated with HD, but no
Outcome sequence variants, either causative missense
Gillick et al. reported results of treatment in mutation or neutral substitution, were found
33 patients with IND with a mean follow-up (Inoue et al. 2001; Do et al. 2011).
1050 P. Puri et al.
Epidemiology diagnostic criteria still remains to be found. A

Reports of finding IH in rectal biopsies are rare full-thickness bowel specimen is required for the
and vary from 0.3% to 6.4% (Meier-Ruge 1992; diagnosis of IH (Swaminathan and Kapur 2010;
Ure et al. 1997; Montedonico et al. 2011). Thirty Schäppi et al. 2013). The vast majority of the
two percent of all the reported IH patients reported IH cases have been evaluated by immu-
(n = 92), published between 1978 and 2009 in nohistochemical staining of AChE to visualize the
the English literature, were diagnosed in the new- previously described features of IH (Puri and
born period. However, the median age at diagno- Fujimoto 1988), such as sparse and small
sis is 4.85 years, which was attributed to the fact myenteric ganglia, absent or low mucosal AChE
that, in some patients, diagnosis was made late – activity, and hypertrophy of muscularis mucosae
at the age of 17 (Dingemann and Puri 2010). and circular muscle (Dingemann and Puri 2010).
In 1999, Meier-Ruge et al. reported significant
Clinical Presentation differences between morphometric measurements
According to the current literature, the most com- of resected bowel specimens from patients with
mon presenting symptoms of patients diagnosed hypoganglionosis compared to normal controls
with IH are intestinal obstruction, severe chronic using AChE staining: The authors found about a
constipation, ileus, and enterocolitis, thus resem- 40% decreased number of nerve cells, which was
bling classical symptoms of aganglionosis/HD. accompanied by a doubling in distance between
The median age at diagnosis is considerably ganglia and a three times decreased plexus area in
higher in patients with IH compared to patients IH tissue compared to normal controls (Meier-
with HD, which in turn is diagnosed during the Ruge et al. 1999; Zhang et al. 2008). These obser-
newborn period in the vast majority of cases. vations have been the diagnostic basis for the
Enterocolitis of the newborn has been reported majority of subsequently published evaluations
to be the most serious complication of IH, com- of IH.
parable to HD (Dingemann and Puri 2010). Several additional neuronal markers have been
suggested to facilitate the diagnosis of IH:
Diagnosis NADPH diaphorase staining has been shown to
It is unclear whether IH represents a severe form allow characterization of the muscular nitrergic
of intestinal dysganglionosis or just an enteric innervation and differentiation of mature and
nervous system abnormality that leads to consti- immature ganglia (Fig. 3). C-kit staining was
pation (Martucciello et al. 2005). Hence, diagno- performed to investigate interstitial cells of Cajal
sis of IH remains difficult and a consensus in (ICCs) to define intestinal pacemaker activity in
Fig. 3 NADPH-diaphorase staining in whole-mount preparation. (a) Normal myenteric plexus. (b) Myenteric plexus in
hypoganglionosis showing markedly reduced number of ganglion cells
IH. ICCs have been reported to be decreased in IH Pathogenesis

(Dingemann and Puri 2010; Puri 2012). Although several investigators attempted to elu-
cidate the pathogenesis of IASA, the exact path-
Management ogenesis and pathophysiology remains unclear.
Management of hypoganglionosis is similar to It has been reported that alterations in intramus-
HD. Fifty four of the 92 reported patients with cular innervation may be the pathophysiologic
IH underwent resection of the affected bowel and basis for the motility dysfunction seen in IASA
subsequent pull-through procedures with various (Doodnath and Puri 2009a). Hirakawa et al.
techniques. According to the literature, the treat- reported absence of nitrergic innervation within
ment of choice remains resection of the affected the IAS muscle as an underlying
segment. However, the management of IH should pathomechanism for IASA, leading to spasm or
be tailored to the individual findings and will also increased tone in the IAS (Hirakawa et al. 1995).
be dependent on the surgeon’s preference in this Puri et al. reported defective innervation of the
rare disease (Dingemann and Puri 2010). neuromuscular junction of the IAS in patients
with IASA (Oue and Puri 1999). Furthermore,
Outcome altered distribution of interstitial cells of Cajal
An overall mortality rate of 8% was reported with has been found in the IAS of patients with IASA
the majority of patients who died during the new- (Piotrowska et al. 2003).
born period suffering from severe enterocolitis or
complications of short bowel syndrome. Typical
Epidemiology
complications were enterocolitis, chronic consti-
A recent meta-analysis revealed a total number of
pation, overflow encopresis, and the need for redo
395 patients in the English literature, reported
pull-through for residual disease (Dingemann and
with the diagnosis of IASA from 1973 to 2009
Puri 2010; Puri 2012). Since dysmotility may also
(Friedmacher and Puri 2012). In 2002, De Caluwe
affect the urinary tract, recurrent urinary tract
et al. presented 15 patients (4.5%) diagnosed with
infections are a common problem and should be
IASA who were investigated for chronic consti-
monitored actively (Schäppi et al. 2013).
pation within their cohort of 332 children. How-
ever, the exact incidence of IASA is unknown
(De Caluwe et al. 2001).
Internal Anal Sphincter Achalasia
Clinical Presentation
Internal anal sphincter achalasia (IASA) is a con-
The clinical presentation of patients with IASA
dition with clinical presentation similar to HD but
is similar to HD patients. IASA patients usually
in contrast to HD ganglion cells are present in
present with severe constipation with or without
suction rectal biopsies. IASA was previously
soiling in the vast majority of cases. About a
referred to as ultrashort-segment HD, which in
third of the patients have a history of abdominal
turn is characterized by an aganglionic segment
distension and failure of laxative therapy
of 1–3 cm, normal AChE activity in the lamina
(De Caluwe et al. 2001; Doodnath and Puri
propria, and increased AChE activity in the
2009a).
muscularis mucosae (Meier-Ruge 1985; De
Caluwe et al. 2001). Since many patients with
abnormal anorectal manometric findings showed Diagnosis
presence of ganglion cells as well as normal Diagnosis of IASA is based on anorectal manom-
AChE activity in rectal biopsies, several investi- etry that shows absence of the rectosphincteric
gators suggested that the term IASA is more accu- reflex on rectal balloon inflation (Fig. 4), presence
rate for this pathologic entity (Lake et al. 1978; of ganglion cells and normal AChE activity in
Neilson and Yazbeck 1990; Doodnath and Puri suction rectal biopsy, and clinical symptoms of
2009a). severe constipation (Puri 2012).
1052 P. Puri et al.
Fig. 4 (a) Evidence of the rectosphincteric reflex on balloon dilatation in the normal internal anal sphincter. (b) Absence
of the rectosphincteric reflex on balloon dilatation as observed in IASA
Management injection. Furthermore, the rate of temporary

Posterior internal anal sphincter myectomy has fecal incontinence, nonresponse, and subsequent
been recommended for the treatment of IASA surgical procedures were significantly higher in
and more recently intrasphincteric injection of botulinum toxin-treated patients, whereas long-
botulinum toxin has been introduced as a less term improvements were significantly more fre-
invasive therapeutic alternative (Doodnath and quent following IAS myectomy. No differences
Puri 2009b). were found in the postoperative use of laxatives or
enemas, in overall complication rates and postop-
Outcome erative soiling, as well as in constipation between
The meta-analysis of 395 IASA patients, which both procedures (Friedmacher and Puri 2012).
compared internal sphincter myectomy to botuli-
num toxin injection, revealed that 83.5% of all
patients in which outcome was reported Megacystis Microcolon Intestinal
(n = 309) had regular bowel movements after Hypoperistalsis Syndrome
treatment independent of the therapeutic
approach. However, regular bowel movements Megacystis microcolon intestinal hypoperistalsis
were significantly more frequent after IAS syndrome (MMIHS) is a rare condition and
myectomy compared to botulinum toxin the most severe form of functional intestinal
Fig. 5 (a) Voiding

cystourethrogram showing
massively enlarged bladder
in an MMIHS patient. (b)
Contrast enema showing
microcolon in an MMIHS
patient
obstruction in the newborn. The main character- (Richardson et al. 2001) carried out in situ hybrid-
istics of MMIHS are massive abdominal disten- ization and immunocytochemistry studies to
sion caused by a largely dilated nonobstructed determine whether alpha 3 mRNA or alpha 3
bladder, microcolon, and decreased or absent subunit protein was expressed in the resected
intestinal peristalsis (Puri and Gosemann 2011, specimens of small bowel from patients with
Fig. 5). MMIHS. They found lack of α3 ηAChR staining
in most MMIHS tissues, thus suggesting that the
Pathogenesis absence of functional α3 subunit containing
MMIHS was first described by Berdon et al. in ηAChR may provide a possible explanation for
1976 in a series of five female neonates. The the underlying pathogenesis of MMIHS.
etiology of this syndrome has not fully been It has been suggested that MMIHS is inherited
understood. Several hypotheses have been pro- in an autosomal recessive manner as consanguin-
posed to explain the pathogenesis of MMIHS: ity between parents and recurrence in siblings is
genetic (Halim et al. 2016, 2017a, b; Korğalı et frequently seen (Mc Laughlin et al. 2013). How-
al. 2018), neurogenic (Granata et al. 1997; Kubota ever, since the majority of cases of MMIHS occur
et al. 1989; Taguchi et al. 1989), myogenic (Ciftci sporadically, it has been hypothesized that locus
et al. 1996; Piotrowska et al. 2003; Puri et al. heterogeneity exists, and that the genetic etiology
1983; Rolle et al. 2002), and hormonal (Jona of sporadic and familial MMIHS cases may differ.
et al. 1981). In recent years, using whole-exome sequencing, a
Familial occurrence of MMIHS has been powerful tool used to identify disease genes, four
reported. The first insights into the genetic basis genes have been found to be involved in the
of MMIHS appeared to come from transgenic pathogenesis of MMIHS. De novo variants in
mice lacking certain nicotinic acetylcholine ACTG2 gene are implicated in the autosomal-
receptor (ηAChR) subunits, which showed some dominant form of MMIHS, whereas homozygous
of the phenotypic features of MMIHS and thus variants in MYH11, MYLK, and LMOD1 cause a
suggesting a basis for this condition. Xu et al. (Xu recessive form of the disease. Heterozygous mis-
et al. 1999) produced an MMIHS phenotype in sense variants in ACTG2 gene have been reported
beta 4/alpha3 (two of the seven neuronal nicotinic as a cause of sporadic MMIHS cases in several
acetylcholine receptor subunits) knockout mice. independent studies (Thorson et al. 2014; Tuzovic
The alpha 3 and beta 4 subunits have been local- et al. 2015; Wangler et al. 2014), while homozy-
ized to human chromosome 15. Richardson et al. gous missense variant in MYH11 was identified in
1054 P. Puri et al.
a newborn patient with consanguineous parents families had two siblings with confirmed MMIHS
(Gauthier et al. 2015) and homozygous variants in and 3 families had 3 children each with MMIHS.
MYLK were found in three MMIHS patients from Consanguinity between parents was confirmed in
two consanguineous families (Halim, Brosens, 30 (6.7%) cases (18 siblings and 12 individual
2017a). ACTG2 is the main actin isoform cases).
expressed in smooth muscle cells, and changes
affecting its structure lead to severe disruption of Clinical Presentation
smooth muscle cell development and function. The clinical presentation of MMIHS is similar to
The MYH11 gene is a highly specific contractile that of other severe neonatal intestinal obstruc-
gene for smooth muscle lineages. Mice with tions. The most prominent and frequent finding
homozygous deletion of MYH11 show several is abdominal distension, which is a consequence
smooth muscle cell abnormalities including a of the massively enlarged urinary bladder with or
large and thin-walled bladder and abnormal intes- without upper urinary tract dilatation (Fig. 5). The
tinal movement, the typical features of MMIHS. majority of reported patients are not able to void
MYLK gene is an important kinase required for spontaneously and required either vesicostomy or
myosin activation and subsequent interaction with catheterization. Further frequent findings are bile-
actin filaments, and its absence leads to impair- stained vomiting, absent or decreased bowel
ment of smooth muscle cell contraction. LMOD1 sounds, and failure to pass meconium (Gosemann
gene is involved in the smooth muscle cytoskele- and Puri 2011).
tal-contractile coupling and loss of LMOD1
results in a reduction of filamentous actin, elon- Diagnosis
gated cytoskeletal dense bodies, and impaired Prenatal diagnosis of MMIHS is important, since
intestinal smooth muscle cell contractility. prenatal counseling should allow the future par-
ents to make the important decision on the con-
Epidemiology tinuation of the pregnancy, bearing in mind the
Between 1976 and 2018, a total number of 450 pathology, prognosis, therapeutic options, and
patients with the diagnosis of MMIHS have been care of this severe condition. A recent review of
reported in the literature (Nakamura et al. 2019). the diagnosis of MMIHS reported that 25% of
The overall female-to-male ratio of MMIHS cases cases were diagnosed prenatally (Tuzovic et al.
was 2.3:1, suggesting a female predominance in 2015). Enlarged bladder and hydronephrosis are
this condition. It has been reported that male the most frequent findings on fetal ultrasound of
MMIHS patients seem to have a shorter life span MMIHS patients (Gosemann and Puri 2011). Fur-
than affected females. This has been suggested to thermore, analysis of enzymatic changes in amni-
be most likely due to a more severe disorder in otic fluid, in combination with magnetic
males compared with females (Kohler et al. 2004; resonance imaging, has been shown to contribute
Young et al. 1981). Familial occurrence of to the prenatal diagnosis of MMIHS (Garel et al.
MMIHS has been frequently reported. There 2006).
were 56 (12.4%) cases in which familial
MMIHS was confirmed, 25 families with multiple Histological Findings
siblings, and 3 families with a single affected Histological evaluation of myenteric and sub-
infant. Seven further confirmed index cases of mucous plexuses revealed normal ganglion cells
MMIHS had a probable afflicted sibling and one in 77% of the reported histological findings. The
of the sibling pairs had a probable third affected remaining 23% were shown to have various neu-
sibling. The probable cases suffered intrauterine ronal abnormalities including hypoganglionosis,
death or died in the early neonatal period with hyperganglionosis, and immature ganglia (Puri
evidence of bladder and bowel pathology consis- and Gosemann 2011). Whereas the enteric ner-
tent with MMIHS, but without a confirmed diag- vous system has been studied in several reports of
nosis. Of the 25 families with multiple siblings, 22 MMIHS, the majority of reports do not mention
histologic findings in the muscle layers of bowel (1976–2004: 12.6% survival vs. 2004–2011:
and bladder wall. However, some authors found 55.6% survival) has been reported, with the
significant abnormalities in smooth muscle cells, oldest survivor being 24 years old. The most
such as vacuolar degeneration in the center of the frequent cause of death in MMIHS patients was
smooth muscle of bowel and bladder as well as shown to be overwhelming sepsis followed by
thinning of the longitudinal muscle (Puri et al. multiple organ failure and malnutrition
1983; Rolle et al. 2002; Puri and Gosemann 2011). (Gosemann and Puri 2011). Loinaz et al.
reported a 3-year survival of 50% in their series
Management with all survivors tolerating enteral feedings and
MMIHS is the most severe form of functional showing adequate gastric emptying (Loinaz
intestinal obstruction in the newborn and is genet al. 2005).
erally a fatal condition. Treatment usually Improvements in survival have been attributed
involves targeting both gastrointestinal and geni- to a more specialized care, innovations in paren-
tourinary deficits associated with the condition. teral nutrition, and the introduction of multi-
Most patients are maintained on long-term TPN visceral transplantation. However, no specialized
which may lead to serious complications such as treatment is known to date and the majority of
catheter-associated sepsis and liver failure. Surgi- survivors are either maintained by TPN or have
cal interventions have been performed frequently undergone multiorgan transplantation (Gosemann
in MMIHS patients such as gastrostomy, and Puri 2011).
jejunostomy, ileostomy, and colostomy. The
need for surgical intervention should be carefully
evaluated, and the intervention individualized
since most exploration have not been helpful and
Summary and Future Directions
probably not necessary. MMIHS patients are not
able to void spontaneously and, therefore, would
There are a number of congenital variants of the
require either a vesicostomy or clean intermittent
enteric nervous system leading to severe chronic
catheterization.
constipation and a clinical picture resembling HD
Recently, intestinal and multivisceral trans-
despite the presence of ganglion cells. These find-
plantation has been introduced as a valuable
ings include the above-described variants with
therapeutic alternative for children with irre-
abnormal number and/or distribution of ganglion
versible intestinal and total parenteral nutrition
cells. Continued research and ongoing discussion
failure (Loinaz et al. 2005). In a review, data
is crucial to enhance the understanding of variant
from 12 MMIHS patients, who underwent multi-
HD, to define normal values and to improve the
visceral transplant surgery to date, were
care of patients.
obtained (Gosemann et al. 2011) The majority
received liver, pancreas, small bowel and colon
transplants. Loinaz et al. reported a 3-year sur-
vival of 50% in their series (Loinaz and
Rodriguez 2005). The authors further reported Cross-References
that all survivors tolerated enteral feedings and
showed adequate gastric emptying. In contrast, ▶ Anorectal Malformations
bladder function did not improve and ▶ Embryology of Congenital Malformations
catheterisation had to be continued after trans- ▶ Hirschsprung’s Disease
plantation (Loinaz and Rodriguez 2005). ▶ Hirschsprung-Associated Enterocolitis
▶ Malrotation
Outcome ▶ Necrotizing Enterocolitis
The outcome of MMIHS improved in recent ▶ Sepsis
years. An overall survival rate of 19.7% ▶ Short Bowel Syndrome
1056 P. Puri et al.
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Anorectal Malformations
73
Andrea Bischoff, Belinda Hsi Dickie, Marc A. Levitt, and
Alberto Peña
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1060
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Associated Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Cardiovascular Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Gastrointestinal Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Sacral Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Spinal Cord Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1061
Vertebral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
Genitourinary Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
Gynecologic Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
A. Bischoff
e-mail: andrea.bischoff@childrenscolorado.org
B. H. Dickie
Colorectal and Complex Pelvic Malformation Center,
Department of Surgery, Boston Children’s Hospital,
Boston, MA, USA
e-mail: belinda.hsidickie@childrens.harvard.edu
M. A. Levitt
Center for Colorectal and Pelvic Reconstruction,
Nationwide Children’s Hospital, Columbus, OH, USA
e-mail: marc.levitt@nationwidechildrens.org
A. Peña (*)
Colorectal Center for Children, Division of Pediatric
Surgery, Cincinnati Children’s Hospital Medical Center,
Cincinnati, OH, USA
e-mail: Alberto.Pena@cchmc.org

https://doi.org/10.1007/978-3-662-43588-5_76
1060 A. Bischoff et al.
Anorectal Anatomy and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062

Sphincter Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
Sensation and Proprioception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Colonic and Rectosigmoid Motility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Clinical Findings and Initial Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Limited Posterior Sagittal Anorectoplasty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
Colostomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
Management After Colostomy (High-Pressure Distal Colostogram) . . . . . . . . . . . . . . . . . 1067
Anorectal Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
Basic Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
Posterior Sagittal Anorectoplasty for Anomalies in Males . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
Posterior Sagittal Anorectoplasty for Anomalies in Females . . . . . . . . . . . . . . . . . . . . . . . . . 1073
General Principles of Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1077
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Continence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
Abstract surgical procedures and have good functional

This is a brief presentation of the most com- prognosis for bowel and urinary control. On the
mon types of anorectal malformations. It has other extreme of the spectrum are complex
been written for the practicing pediatrician. It is anorectal and urogenital malformations that
meant to be a practical guide to identify and require sophisticated, technically demanding sur-
manage these pediatric problems from birth gical procedures to be repaired and have rather
until adult life. It emphasizes the importance poor functional prognosis for bowel, urinary, and
of suspecting the associated defects as well sexual function.
as to try to avoid the most common errors It is rather regrettable that a patient born with a
observed in the management of these “good prognosis” type of defect ends up suffering
malformations. It also includes information from fecal and (or) urinary incontinence due to a
that will allow the clinician to establish the deficient surgical care. That is the reason why in
functional prognosis for each specific types of this chapter, emphasis is placed in the manage-
defect. ment of the “benign” group of anorectal
The management of the sequelae is consid- malformations, which happens to include the
ered an important part of this chapter. greatest number of cases.
Keywords
Anorectal malformation · Imperforate anus · Incidence
Cloaca
Anorectal malformations occur approximately in
1 of 5000 live births (Brenner 1975). Its cause
Introduction remains unknown and it seems to be multifactorial
(Wang et al. 2015). Some types of anorectal mal-
Anorectal malformations are serious congenital formation such as recto-perineal fistula and
defects that present in the form of a wide spec- rectovestibular fistula occur more frequently in
trum, which can be treated with relatively easy families (Falcone et al. 2007). In patients with
73 Anorectal Malformations 1061
Down syndrome, the most common defect found ventricular septal defect and tetralogy of Fallot.
is imperforate anus without fistula, an anomaly The literature (Greenwood et al. 1975; Teixeira
that is uncommon in patients without Down syn- et al. 1983) mentions an incidence of 12–22%, but
drome (Torres et al. 1998). about one third of the cases were hemodynami-
The most common defect in females is cally unstable.
rectovestibular fistula, whereas the most common
defect in males is rectourethral fistula. Cloacal
malformations are more common than formerly Gastrointestinal Anomalies
thought, most likely because they were previously
misdiagnosed as rectovaginal fistulas (Rosen et al. Malformations of the gastrointestinal tract have
2002). been described occurring in 15–18% of cases of
ARM (8–9). Esophageal atresia has been reported
in 7–15% of cases of ARM (Casaccia et al. 2009;
Shin et al. 2013; Hassink et al. 1996) and duode-
Classification
nal atresia in 3–4% (Casaccia et al. 2009; Hassink
et al. 1996). Hirschsprung’s disease has been
The classification system shown in Table 1 is
found in three patients in the author’s series of
anatomically descriptive with therapeutic and
2100 cases, and overdiagnosis of this association
prognostic implications.
is probably due to the high incidence of constipa-
tion seen in patients with anorectal
malformations.
Associated Malformations
Most babies (50–60%) with imperforate anus Sacral Anomalies

have one or more abnormalities that affect other
systems (Smith and Saeki 1988; Cho et al. 2001). Sacral abnormalities are very common and have
significant implications. The quality of the sacrum
seems to have great influence on the functional
Cardiovascular Anomalies prognosis for bowel and urinary control. A sacral
ratio has been created to try to quantify the sacral
Cardiovascular anomalies are present in approxi- defect (Fig. 1) and to correlate with bowel and
mately a third of patients with imperforate anus, urinary function. A sacral ratio higher than 0.7 is
but only 10% require treatment in the author’s considered normal. A sacral ratio lower than
series. The most common lesions are atrial septal 0.4–0.7 has a rather mild influence on bowel
defect and patent ductus arteriosus, followed by control.
Table 1 Classification of anorectal malformations Spinal Cord Anomalies

Males Females
Perineal fistula Perineal fistula Approximately 25% of patients with ARM suffer
Rectourethral fistula Vestibular fistula from tethered cord (Levitt et al. 1997a). The pres-
Bulbar Persistent cloaca ence of the defect seems to have more influence
Prostatic 3 cm common channel on the urinary function and the motor activity of
Recto-bladder neck fistula >3 cm common channel the lower extremities. The diagnosis of tethered
Imperforate anus without Imperforate anus without cord can be done with a lumbosacral ultrasound
fistula fistula
during the first 3 months of life. After that, the
Rectal atresia Rectal atresia
diagnosis can only be made with an MRI of the
Complex defects Complex defects
spine (van den Hondel et al. 2016).
a b
AB AB
BC BC
GR
Normal Ratio: BC BC
= .74 = .77
AB AB
Fig. 1 Anterior-posterior (a) and lateral (b) sacral ratios
Vertebral Large intra-abdominal collections and peritonitis

can develop, or patients may have amenorrhea
Hemivertebrae are commonly seen. The implica- because of the absence of the Müllerian structures.
tion of these on bowel and urinary control has not Obstruction to menstrual flow can occur as an
been determined. However, they have important atresia at any level, such as the tube, the cervix,
orthopedic implications (scoliosis). or a hemivagina. Uterine septation abnormalities
(predominantly bicornuate uterus) vaginal septum
and associated vaginal atresia can also occur. Dur-
Genitourinary Anomalies ing the definitive repair or at the time of colostomy
closure, the intra-abdominal gynecologic struc-
Improved imaging has shown an increasing range tures must be inspected and its patency tested.
of upper and lower urinary tract anomalies (Rich The full obstetric impact of these anomalies is
et al. 1988). The incidence increases with increas- not yet known.
ing complexity of the anorectal defect.
Vesicoureteral reflux is the most common func-
tional anomaly found, and renal agenesis and Anorectal Anatomy
dysplasia is the most frequent malformation. and Pathophysiology
Bowel control is the result of a complex interplay

Gynecologic Anomalies among sphincter function, anorectal sensation,
and colonic motility. All these factors are affected
Gynecologic anomalies are a significant concern in children with anorectal malformations.
in patients with anorectal malformations (Levitt
et al. 1998). In the newborn period, hydrocolpos
can lead to urinary obstruction or can cause Sphincter Mechanism
pyocolpos, in patients with cloacas (Bischoff
et al. 2010). The sphincter mechanism is represented by a
Müllerian anomalies may manifest later when funnel-like structure. The exposure afforded by
teenagers have obstruction of menstrual flow. the posterior sagittal approach shows that the
levator musculature continues down to the anal information related to the nature of the rectal
dimple with vertical striated muscle fibers called contents (solid, liquid, or gas). Depending on the
the “muscle complex.” Electrical stimulation of surrounding social circumstances, the individual
the upper end of the levator group pushes the may contract the sphincteric mechanism to avoid
rectum forward. Stimulation of the muscle com- a bowel movement and then voluntarily relax at
plex (vertical fibers) elevates the anus, and stimu- the appropriate time. Normal defecation allows
lation of the parasagittal fibers closes the anus massive emptying of the rectosigmoid, followed
(Peña 1989). Children with anorectal by another resting period of about 24 h, during
malformations have varying degrees of striated which the rectosigmoid again acts as a reservoir.
sphincter muscle development from almost nor- Children with anorectal malformations suffer
mal to virtually no muscle at all. from rectosigmoid hypomotility of different
severity. This results into constipation of different
degrees, which is self-perpetuating and self-
Sensation and Proprioception aggravating to the point that if left untreated,
megasigmoid develops. In extreme cases, fecal
Under normal circumstances, the anal canal is an impaction and encopresis, or overflow pseudo-
exquisitely sensitive area (Duthie and Gairns incontinence, may develop. It seems that consti-
1960). It allows the individual to discriminate pation is worse with lower defects. Constipation
solids, liquids, and gas. The overwhelming major- should not be underestimated and must be treated
ities of children with anorectal malformations are aggressively.
born without an anal canal and therefore lack this Children with anorectal malformations, who
kind of sensation. There is, however, propriocep- have lost their rectosigmoid, suffer from the oppo-
tion, which is described as a vague feeling that is site problem (i.e., tendency to have diarrhea).
perceived when the rectum is distended, simulta- These children have no reservoir capacity, are
neous with stretching of the voluntary muscle that highly sensitive to certain foods, and suffer from
surrounds the rectum (Skerritt et al. 2016). The incontinence.
clinical implications are that these patients lose
control when they suffer an episode of diarrhea,
but may have the ability to be toilet trained when Clinical Findings and Initial
they can form solid stool and can learn to Management
perceive it.
Figures 2 and 3 show the decision-making algo-
rithm for the initial management of male and
Colonic and Rectosigmoid Motility female patients (van der Steeg et al. 2015).
A clinician called to see a newborn with an
The intestinal contents reach the cecum in a liquid anorectal malformation must perform a thorough
state. It then takes about 20–24 h for that liquid perineal inspection, which usually provides the
fecal material to reach the rectum and become most important clues about the type of malfor-
formed stool as a consequence of the absorption mation that the patient has (Figs. 4 and 5). It is
of water that occurs in the colon. The important to not make a decision about a colos-
rectosigmoid acts as a reservoir and holds the tomy or a primary surgery before 20–24 h of age.
fecal material for a variable period of time usually The reason for waiting is that significant
about 24 h. The anal canal (below the pectinate intraluminal pressure is required for the meco-
line) is usually empty because of the action of the nium to be forced through a fistula, which is the
surrounding sphincteric mechanism. Peristaltic most valuable sign of the location of distal rec-
waves in the colon push the fecal material toward tum in these babies. If meconium is seen on the
the anus and touch the exquisitely sensitive tissue perineum, it is evidence of a recto-perineal fis-
of the anal canal, thereby providing valuable tula. If there is meconium in the urine, the
Decision Making Algorithm for a Male Newborn with an Anorectal Malformation
Perineal inspection/ Urine analysis
1st 24 h Evaluation:
Echocardiogram, rule out esophageal and duodenal atresia (NG tube and abdominal
x-ray), AP and lateral films of the sacrum, kidney ultrasound
Undefined
Flat perineum malformation
Perineal fistula
Meconium in the urine (5 – 10% of cases)
Sub-epithelial
fistula
Cross table lateral film
Colostomy
Rectal gas bellow Rectal gas above
the coccyx the coccyx
Anoplasty
or Fistula dilation
Anoplasty or colostomy Colostomy
Fig. 2 Algorithm for the treatment of a male newborn with an anorectal malformation
Decision Making Algorithm for a Female Newborn with an Anorectal Malformation
Perineal Inspection
1st 24 h Evaluation:
Echocardiogram, rule out esophageal and duodenal atresia (NG tube and abdominal x-ray film), AP
and lateral films of the sacrum, kidney ultrasound, pelvic ultrasound in cloacas
No fistula (< 10% )

Perineal or Single perineal
Vestibular orifice
fistula Cloaca
Cross table
lateral film
Rectal gas below Rectal gas above

the coccyx the coccyx
Anoplasty Colostomy
or Fistula dilation Hydrocolpos drainage
with delayed repair * (if present)
Anoplasty Colostomy
or Colostomy*
* Depending on the experience of the surgeon and general condition of the patient
Fig. 3 Algorithm for the treatment of a female newborn with an anorectal malformation
Fig. 4 External appearance of the perineum of male patients with anorectal malformations. (a) Perineal fistula with “bucket
handle,” prone position. (b) Rectourethral bulbar fistula, prone position. (c) Flat bottom, patient in supine position
Fig. 5 External appearance of the perineum of female patients with anorectal malformations (a) Perineal fistula.
(b) Vestibular fistula. (c) Cloaca
diagnosis of a rectourinary fistula is obvious. If a and the baby should be checked for the presence
single orifice is diagnosed during the perineal of esophageal atresia. A plain radiograph of the
inspection of a female, the diagnosis of a cloaca lumbar spine and sacrum should be taken to eval-
is made. uate for hemivertebrae and sacral anomalies. A
Radiologic evaluations do not show the real spinal ultrasound helps screen for tethered cord.
anatomy before 24 h because the rectum is col- Ultrasonography of the abdomen evaluates for the
lapsed by the muscle tone of the sphincters that presence of hydronephrosis, and pelvic ultraso-
surround its lower part. Therefore, radiologic nography in females with cloaca evaluates for
evaluations done too early (before 24 h) will likely the presence of hydrocolpos. During opening of
reveal a “very high rectum” and therefore yield a the colostomy, it is mandatory that the
false diagnosis. hydrocolpos be drained when present. If the
During the first 24 h, the newborn should hydrocolpos is not large enough to reach the
receive intravenous fluids, antibiotics, and naso- abdominal wall above the bladder, to be sutured
gastric decompression to prevent aspiration. The to the skin, it can be drained with a pigtail tube.
clinician should use these hours to evaluate for the If the baby has signs of a perineal or vestibular
presence of associated defects such as cardiac fistula, a posterior sagittal repair can be
malformations, esophageal atresia, and urologic performed without a protective colostomy in
problems. An echocardiogram can be performed, the newborn period, provided the surgeon has
Fig. 6 Cross-table lateral X-ray, reachable rectum

Fig. 7 Cross-table lateral X-ray, high rectum
experience with that kind of procedure. If the

baby is ill from associated problems, or prema- The potential advantages of an early operation
ture, or if the clinician chooses to wait until the must be weighed against the possible disadvan-
baby is a little older, the fistula can be gently tages of an inexperienced surgeon unfamiliar with
dilated. The repair in such cases should not be the minute anatomic structures of an infant’s pelvis.
delayed more than several months. A trend to repair these defects without a protec-
After 24 h, if no meconium is seen on the peri- tive colostomy (Albanese et al. 1999) must be bal-
neum or in the urine, a cross-table lateral X-ray film anced against the concern that such a repair without
with the baby in prone position should be obtained. a colostomy is done without precise anatomic infor-
If the gas in the rectum is located below the coccyx mation about the patient’s specific type of anorectal
(Fig. 6) and the baby is in good condition with no defect. The most catastrophic complications
significant associated defects, depending on the occurred in patients operated on without a colos-
surgeon’s experience, a posterior sagittal operation tomy and, as a consequence, without a distal
without a protective colostomy can be considered. colostogram. While looking for the rectum, the
A more conservative alternative would be to per- surgeon might inadvertently find and injure the
form a colostomy, with the definitive repair planned urethra, an ectopic ureter, the bladder neck, the vas
for a second stage. If rectal gas is seen above the deferens, or the seminal vesicles (Hong et al. 2002).
coccyx (Fig. 7) or the patient has meconium in the With emerging advancements in perinatology
urine, single perineal orifice (cloaca), significant and prenatal ultrasound techniques, anorectal
associated defects, and/or an abnormal sacrum or malformations are more commonly being
a flat bottom, a colostomy is recommended with suspected (Bianchi et al. 2013). Prenatal sono-
postponement of the main repair for a subsequent graphic findings, such as a dilated rectum,
operation. This can be performed 2–3 months later hydrocolpos, or demonstration of an associated
after a distal colostogram delineating the anatomy is urological and spinal anomaly, can make the pri-
performed, provided that the baby is gaining weight matologist suspicious that the fetus may in fact
normally. have an anorectal malformation.
Performing the definitive repair not later than
at 2–3 months of age has important advantages
for the patient, including less time with an Limited Posterior Sagittal
abdominal stoma, less size discrepancy between Anorectoplasty
the proximal and distal bowel at the time of
colostomy closure, easier anal dilation, and no When a perineal fistula is diagnosed (Fig. 5), the
recognizable psychological sequelae from pain- anal orifice is always located anterior to the
ful perineal maneuvers. sphincter mechanism. A limited posterior sagittal
anoplasty can be performed in the newborn

period. It is advantageous to perform this opera-
tion in the first 48 h of life because the meconium
is sterile. When such an operation is delayed and
performed at several months of life, a complete
bowel preparation, including a postoperative
period of parenteral nutrition without oral intake,
is recommended to reduce the risk of perineal
infection.
The baby is placed prone. In males, a urinary
catheter is inserted. The distal end of the rectum is
intimately attached to the posterior urethra, and
urethral injury must be avoided. In females, the
clinician must acknowledge an intimal contact of
the rectum with the vagina, in cases of perineal
fistula, and a thin common wall between rectum
and vagina in cases of vestibular fistula. Multiple
6-0 silk sutures are placed at the mucocutaneous
junction around the fistula orifice. The posterior
sagittal incision divides the posterior sphincter in Fig. 8 Descending colostomy
half and is continued circumferentially around the
fistula. While traction is maintained on the bowel, colostogram requires the use of a Foley catheter
a circumferential dissection is performed to mobi- inserted through the mucous fistula of the colos-
lize and reposition the bowel within the limits of tomy. The balloon must be inflated and the radi-
the sphincter. The bowel wall is sutured to the skin ologist must pull on the catheter to allow the
with fine, absorbable sutures under slight tension. balloon to act as a plug to avoid the leakage of
The perineal body is reconstructed. contrast material. Water soluble contrast material
must be injected with a syringe, with enough
pressure to overcome the tone of the voluntary
Colostomy muscles that surround the lower rectum and to
force the contrast through the fistula. The first
Except for patients with perineal fistula, a colos- films must be taken in AP position to show the
tomy is usually performed as a first stage in the length of the bowel available for the pull through
majority of cases (Fig. 8) (Peña et al. 2006). (See and then the patient is placed in perfect lateral
▶ Chap. 21, “Stomas of Small and Large position with a lead marker in the anal dimple to
Intestine”). show the fistula.
Management After Colostomy (High- Anorectal Reconstruction

Pressure Distal Colostogram)
Basic Principles
Before proceeding with definitive reconstruction,
the anatomy of the anorectal malformation is All defects can be repaired using a posterior sag-
delineated by high-pressure distal colostography ittal approach. Approximately 10% of male
(Gross et al. 1991) (Figs. 9 and 10). This study is patients (those with a rectum–bladder neck fistula)
by far the most valuable radiologic test to deter- and about 40% of female patients with a cloaca
mine for specific type of anomaly and best surgi- may in addition require an abdominal approach
cal approach. The high-pressure distal for mobilization of a high rectum or vagina. A
Special care must be taken to cushion all the

pressure areas of the baby’s body (Fig. 11). Two
small bolsters are used in front of each
deltopectoral groove to avoid hyperextension
of the neck and shoulders. Electrical stimulation
of the perineum allows evaluation of the strength
of the sphincter contraction. A midline incision
is made, and the sphincteric mechanism is
divided exactly in the midline, leaving equal
amounts of muscle on each side. Sharp
Weitlaner retractors are used to achieve good
exposure.
Posterior Sagittal Anorectoplasty

Fig. 9 Distal colostogram showing a rectourethral bulbar for Anomalies in Males
fistula
Rectourethral Fistula (Bulbar
and Prostatic)
The incision usually extends from the lower por-
tion of the sacrum through the center of the anal
dimple and sometimes extended to the perineal
body (Fig. 12). Below the skin and running paral-
lel to the midline are the parasagittal muscle
fibers. Medial to these muscle structures and
located within the limits of the anal dimple are
other muscle structures that run perpendicular to
the parasagittal fibers. These structures extend
from the skin to the levator muscle and are called
the muscle complex. Deeper to the parasagittal
fibers, the ischiorectal fat becomes evident, and
below this is the levator, which is also divided in
the midline. The crossing of the muscle complex
fibers with the parasagittal muscle structures
defines the anterior and posterior limits of the
Fig. 10 Distal colostogram showing a recto-bladder neck
fistula new anus. These limits can be determined most
clearly with the use of an electrical stimulator.
In boys with a rectourethral bulbar fistula, upon
Foley catheter is inserted into the bladder. The opening the levator muscle, the bowel is very
catheter sometimes goes into the rectum through evident. In boys with a rectoprostatic fistula, the
the fistula rather than into the bladder. To avoid rectum is much smaller and located much higher
this, the surgeon can direct the catheter with a in the incision just under the coccyx. The distal
lacrimal probe inserted in the tip of the Foley colostogram provides information that is valuable
catheter to function as a guide. Alternatively, a at this point for determining where the rectum can
“Coudee” catheter can be used. Occasionally, the be found (Fig. 9). In the case of a recto-bladder
catheter must be positioned intraoperatively once neck fistula, the rectum is not visible through a
the fistula is exposed. The patient is placed in posterior sagittal approach and should not be
prone position with the pelvis elevated. searched for (Fig. 10).
Fig. 11 Patient in prone

position with proper
padding
Temporary silk sutures are placed in the poste- is applying traction to the rectum, the dissection
rior rectal wall for traction, and the rectum is continues in a circumferential manner. The ves-
opened exactly in the midline. The incision in sels that hold the rectum are coagulated and
the rectal wall is extended distally. As the rectum divided until enough rectal length has been
is being opened, more sutures are placed to hold achieved. The rectum has an excellent intramural
the edges of the rectal wall and improve the expo- blood supply; even in cases of a very high pros-
sure of the rectal lumen. The incision must be tatic fistula, sufficient length can be obtained with-
extended distally until the fistula site is found out making the rectum ischemic. When the rectal
(Fig. 13). wall is injured, however, this blood supply is
Because there is no distinct plane of separation damaged and ischemia may occur. Therefore,
between the rectum and urethra, the surgeon must every effort must be made to perform this dissec-
be extremely careful while separating the rectum tion as close as possible to the rectal wall but
from the urinary tract. Multiple 6-0 silk sutures are without damaging the bowel wall. Once enough
placed above the fistula site in a semicircular length has been achieved to perform a tension-free
fashion (Fig. 14). These sutures allow the surgeon bowel-to-skin anastomosis, the size of the rectum
to exert uniform traction on the rectum while must be evaluated and compared with the avail-
dissecting and separating it from the urethra. Dis- able space. If necessary, the rectum can be tapered
section of the lateral aspects of the rectum first by removing part of its posterior wall and
helps to delineate the anterior plane. The dissec- reconstructed by closing with two layers of long-
tion then proceeds in the submucosal plane, until term absorbable interrupted sutures. The urethral
the rectum and urethra gradually separate and fistula is closed with interrupted absorbable
become independent. sutures.
Once the rectum is fully separated from the The perineal body is reconstructed by bringing
urinary tract, a circumferential perirectal dissec- together the anterior limits of the external sphincter,
tion is performed to gain enough rectal length to which was previously marked with temporary silk
reach the perineum. To achieve this, the fascia that sutures. The levator muscle is sutured behind the
surrounds the rectum must be divided, including rectum (Fig. 15), and the posterior edges of the
blood vessels and nerves attached to the rectum. muscle complex are sutured together in the midline
This is a key plane to identify. While the surgeon while taking, with the same stitches, part of the
Fig. 12 Essential steps for posterior sagittal Posterior rectal wall exposed. (d) Posterior rectal wall
anorectoplasty in male patients. (a) Planned posterior sag- opened in the midline. (e) Posterior rectal wall opened
ittal incision. (b) Posterior sagittal approach with the para- going anteriorly until the rectourethral fistula is identified.
sagittal fibers and ischiorectal fat split in the midline. (c) (f) Separation of the rectum from the posterior urethra with
Fig. 13 Operative view, posterior sagittal approach. The Fig. 14 Operative view. Fine silk sutures are placed
rectourethral fistula is seen with a metallic probe in it through the mucosa of the cephalad hemicircumference
of the fistula
posterior rectal wall to anchor the rectum. This

helps to prevent prolapse (Fig. 16). The ischiorectal that the surgeon can work simultaneously in the
fossa and the subcutaneous tissue are then abdomen and the perineum. The abdomen is
reapproximated, and the skin closed. The anoplasty entered via either laparoscopy or laparotomy
is performed by placing the rectum within the (Fig. 18a, b). The sigmoid is identified and dis-
limits of the sphincter with the use of interrupted sected down to the bladder neck. It is very impor-
long-term absorbable sutures (Fig. 17). tant to remember that the vas deferens and ureters
run very close to the rectum; thus the dissection
must be carried out as close as possible to the
Recto-bladder Neck Fistula rectal wall. The rectum narrows very rapidly and
In patients with a recto-bladder neck fistula, an opens into the bladder neck in a T-shaped manner.
abdominal approach via either laparoscopy or lap- The rectum is divided at its most distal part, and
arotomy, in addition to the posterior sagittal the fistula is closed with absorbable sutures.
approach, is necessary to mobilize the rectum. The challenge, thereafter, is often the mobili-
Before beginning this operation, the entire zation to gain adequate rectal length to reach the
body surface from chest to toes is prepared so perineum (Bischoff et al. 2011, 2013a). The
Fig. 12 (continued) dissection above the fistula. (g) The mechanism. (i) Closure of the levator and tacking of the
rectum fully mobilized and in this case tapered. Sutures are posterior edge of muscle complex to the posterior rectal
placed anteriorly to close the perineal body. (h) The rectum wall. (j) Closure of the posterior sagittal incision and
pulled through and placed within the limits of the sphincter completed anoplasty
Fig. 15 Levator muscle sutured behind the rectum
Fig. 16 Sutures on the posterior edge of the muscle com-

plex which anchor the rectum
mobilization of the rectum is limited by branches
of the inferior mesenteric vessels. To gain length
surgeons have traditionally been advised to divide Imperforate Anus Without a Fistula
the inferior mesenteric vessels at their origin from Anorectal malfromations (ARMs) without fistula
the aorta. This maneuver is contraindicated here, occur in approximately 5% of all cases of ARMs.
since this is often the only blood supply of the Bischoff et al. (Bischoff et al. 2014) in a series of
rectosigmoid because the opening of the colos- 2186 cases of ARMs found 92 (4.2%) patients had
tomy may have interfered with the continuity of no fistula. Thirty-seven (40%) patients had tri-
the arcade that connects the middle colic vessels somy 21. In patients with an imperforate anus
with the inferior mesenteric vessels. Therefore, and no fistula, the blind end of the rectum is
meticulous ligation of peripheral branches of the located at the same level as in a patient with a
inferior mesenteric branches must be performed bulbar urethral fistula. Even when patients do not
being sure to leave at least two good vessels have a fistula, the rectum is still intimately
coming directly from the inferior mesenteric attached to the posterior urethra in males or vagina
(Fig. 19). in females, requiring careful dissection. The rest
With the legs lifted up, a midsagittal incision of the repair is performed as described for
is made and the presacral space dissected. Then rectourethral fistulas.
the rectum is pulled through. An anoplasty
should be performed as previously described. Rectal Atresia and Stenosis (Hamrick
Tacking of the rectum to the muscle complex is et al. 2012)
important because these patients have poor pel- Repair of rectal atresia and stenosis involves
vic musculature and are particularly prone to connecting the blind dilated end of the rectum
prolapse. proximally with the anal canal distally. Both
structures are usually separated by a few millime- particular is frequently associated with a presacral
ters of fibrous tissue. The rectum must be suffi- mass, often a teratoma, which must be
ciently mobilized to allow the performance of an screened for.
end-to-end anastomosis to the anal canal. The
wound is then closed by reconstructing all the
muscle structures, as previously described. Since Posterior Sagittal Anorectoplasty
the anal canal is normal, these patients have excel- for Anomalies in Females
lent potential for bowel control. This defect in
Vestibular Fistula
The complexity of this defect is frequently
underestimated. Patients with a vestibular fistula
are born with excellent potential for bowel con-
trol. Thus, every effort should be made to give
these patients the best opportunity to undergo a
successful reconstruction with a single operation.
A protective colostomy minimizes the chances of
these complications.
With the patient in prone position, a midline
incision is performed. The midline incision con-
tinues around the fistula into the vestibule, and
multiple 5-0 sutures are placed circumferentially
at the fistula site. While traction is placed on these
sutures, the rectum is dissected in a circumferen-
tial manner. The posterior rectal wall can easily be
identified, and the dissection must start from the
posterior aspect and be extended laterally. The last
step, separation of the rectum from the vagina, is
the most delicate part of the dissection. The com-
mon wall between the rectum and vagina in this
kind of defect is long and extremely thin. Once
fully separated, the rectum must be mobilized as
Fig. 17 Anoplasty previously described, to gain enough length to
Fig. 18 Operative view of a recto-bladder neck fistula showing the rectosigmoid ending at the bladder neck.
(a) Laparoscopic view. (b) View via laparotomy
repaired with a meticulous and delicate technique.

Fortunately, this represents more than 50% of all
cloacas. On the other hand, complex cloaca with a
common channel longer than 3 cm should be
repaired by surgeons fully dedicated to repair
these malformations. The length of the common
channel is better determined during cystoscopy.
Cloacas with a Common Channel Shorter

than 1 cm
These patients are treated almost like those that
are born with a recto-vestibular fistula (Bischoff
2016). They do not require total urogenital mobi-
lization as the urethra is perfectly visible in its
natural location, even when it is a little hypo-
spadic. The first step consists of approaching the
Fig. 19 Ligation of the peripheral branches of the inferior patient through a posterior sagittal incision, iden-
mesenteric vessels with preservation of the main trunks, in tifying the posterior wall of the rectum, clearing
order to gain length on a very high rectum
the posterior and lateral walls of the rectum, and
then performing a very meticulous dissection to
perform a tension-free bowel-to-skin anastomo- separate the anterior rectal wall from the posterior
sis. The limits of the sphincteric mechanism are vaginal wall. Once the separation is completed
electrically determined and marked with tempo- and the rectum reaches the center of the sphincter
rary silk sutures. The perineal body is then mechanism without tension, the posterior and lat-
reconstructed by bringing together the anterior eral walls of the vagina are mobilized in order to
limit of the sphincter complex. The posterior create an adequate introitus. The limits of the
edges of the muscle complex are reapproximated sphincter are delineated with the use of an electro-
taking bites of rectal wall, as described previously stimulator and the perineal body is created. An
for males. The anoplasty and wound closure are anoplasty is performed.
performed as described for males. For the
extremely unusual case of a rectovaginal fistula, Cloacas with a Common Channel Length
the technique is the same except that the rectum Between 1 and 3 cm
requires more mobilization to reach the perineum. Patients with a common channel length shorter
than 3 cm can be repaired through a posterior
Cloaca sagittal approach. The rectum is opened in the
Cloaca represents a spectrum of defects that goes midline and silk stiches are placed along the
from “benign” cloaca with a good functional edges of the posterior rectal wall. The entire com-
prognosis that can be repaired with a relatively mon channel is exposed to allow confirmation of
simple surgical technique, to very complex its length under direct vision (Fig. 20). After the
malformations with many anatomic variations separation of the rectum from the vagina, the
that require different surgical maneuvers to be surgeon should perform a maneuver called total
able to successfully reconstruct those patients urogenital mobilization. To accomplish this, the
(Bischoff 2015). posterior wall of the vagina and the entire com-
The group of patients born with a “benign” mon channel is divided to exposes the urethral and
type of cloaca will have bowel and urinary con- vaginal openings. Multiple 5-0 silk stitches are
trol, will become sexually active, and may get placed taking the edges of the vagina and common
pregnant and deliver by cesarean section. All channel. Another series of stitches are placed in a
this is possible, provided the malformation is horizontal manner, 5 mm proximal to the clitoris
Fig. 20 (a) Posterior sagittal view of a typical cloaca with a common channel of 2 cm with a visible vaginal septum. (b) A
cloaca with a very large vagina (hydrocolpos). The rectum opens higher in the vagina and is not seen here
in order to provide uniform traction (Fig. 21). of the introitus and perineal body. The anoplasty is
With the use of a needle tip cautery, the urogenital then performed.
sinus is divided between the clitoris and the trac-
tion sutures. Dissection is performed between the Cloacas with a Common Channel Longer
anterior wall of the urogenital sinus and posterior than 3 cm
aspect of the pubis. Between these two structures, When endoscopy and a cloacagram show that the
there is a natural plane, mostly avascular. The patient has a long common channel, the surgeon
dissection must be carried up until the upper must be prepared to face several significant tech-
edge of the pubis is identified. At this point, it is nical challenges. A more precise anatomic diag-
easy to identify a whitish thin membrane located nosis can be achieved with the use of a 3-D
between the upper edge of the pubis, the urogen- rotational scan (Fig. 22).
ital sinus, and the lateral walls of the vagina. We The repair of these complex defects usually
call this “suspensory ligaments of the urethra and starts with a posterior sagittal approach, separa-
vagina.” During the division of these ligaments, tion of the rectum as previously described, and a
the surgeon should try to avoid the venous plexus total urogenital mobilization. Occasionally the
located right behind the pubis. In most cases, the surgeon may find that it is possible to bring the
total urogenital mobilization is sufficient for the urethra and the vagina in cases with a common
urethra and vagina to reach the perineum together channel of 4 or 4.5 cm.
without tension. In some cases, the posterior vag- In the event that the total urogenital mobiliza-
inal walls still require some extra mobilization. tion was not enough to perform an adequate
The urethral meatus is then sutured to the tissue urethral and vaginal repair, the next step should
behind the clitoris with multiple interrupted 6-0 be a laparotomy to divide all the avascular
vicril sutures. The lateral walls of the vagina are attachments of the vagina and urethra. If that is
also sutured to the perineum and the limits of the not enough, it will be necessary to separate the
sphincter are delineated with the use of the bladder and urethra from the vagina(s). This is
electrostimulator to help and determine the size performed through the abdomen, with the
Fig. 21 (a) Total urogenital mobilization (cloaca with a placed around the urogenital complex for uniform traction
short common channel, <3 cm). (b) The intrinsic anatomy to facilitate mobilization of the urogenital sinus. (e) Uro-
of the cloaca is exposed posterior sagittally. (c) The rectum genital sinus fully mobilized. (f) Finished repair
is separated from the urogenital sinus. (d) Sutures are
bladder open, and catheters placed through the those circumstances one of the cervices can be
ureters. This separation represents the most tech- resected, the vaginal septum resected, both
nically demanding and sophisticated maneuver hemivaginas are tabularized as a single vagina,
in the repair of cloacas; it requires experience and and what used to be the dome of one of the
delicate technique. hemivaginas is switched down to the perineum
Once the vaginas have been separated from the (Fig. 23).
bladder, the surgeon must try and see if the vagina Patients with a long common channel should
reaches the perineum. If the answer is no, then the receive a total-body preparation because it is
patient will need either a vaginal replacement that likely that a laparotomy will be required. The
can be done with rectum, colon, or small bowel, presence of a very long common channel (more
depending on the specific anatomic circumstances than 5 cm) indicates that there is no way that total
of the patient. The vaginal switch maneuver urogenital mobilization will be sufficient to repair
(Bischoff et al. 2013b) is only applicable in the malformation, and therefore it is advisable to
cases with two very large hemivaginas, with leave the common channel in place, which can be
widely separated cervices, located very high in used as urethra for intermittent catheterization. In
the pelvis. The surgeon may find that the distance this situation, the vaginas are usually connected to
between on the cervix and the other is longer than the bladder neck (Fig. 24), and therefore it is
the vertical length of both hemivaginas. Under easier to separate them from the urinary tract
Fig. 22 3D cloacagram
through the abdomen. Once the vaginas have been require such diversion for less than 3 months. In
separated, a partial vaginal replacement is complex reconstructions, a vesicostomy is
performed. This can be done using the rectum recommended, particularly in cases with
(Fig. 25a, b), colon (Fig. 26), or small bowel vesicoureteral reflux and (or) hydronephrosis.
(Fig. 27a–c). Later on, the bladder function should be evaluated
Once in the abdomen, either during the main to determine the possible urologic strategy to
repair or at the time of colostomy closure, the follow.
patency of the Müllerian structures is investigated At the time of colostomy closure, endoscopy
by passing a No. 3 feeding tube through the fim- should be performed to be sure that the repair is
briae of the fallopian tubes, injecting saline, and intact, that there is no prolapse, stricture, or
observing the saline solution to come out through urethrovaginal fistula. If the cloaca repair did not
the vagina. If one of the systems is not patent, the require a laparotomy, the time of colostomy clo-
atretic Müllerian structure should be excised, with sure is the opportunity to investigate the patency
great care to avoid damage to the blood supply of of the Müllerian structures.
the ipsilateral ovary. When both Müllerian struc-
tures are atretic, they should be left in place. The General Principles of Postoperative
patient must be monitored closely and further inves- Care
tigated with ultrasound when she reaches puberty.
After the repair of a cloaca, in cases with a In the absence of a laparotomy, oral feedings may
common channel shorter than 3 cm, a Foley cath- begin when the child is awake. Antibiotics are
eter is left in place for a period of 2–3 weeks. In given for 48 h. In males who had a rectourethral
cases of longer common channels, a suprapubic fistula, the urinary catheter should be left in place
tube is left if the surgeons feel that the patient will for 7 days.
a R. TUBE
R. HEMIUTERUS
DIVIDE VAGINAL SEPTUM
R. OVARY L. OVARY
R. GIANT
HEMIVAGINA
HYDROCOLPOS
COMMUNICATION WITH
URINARY TRACT
AND/OR RECTUM
PERINEUM
PRESERVED
b PRESERVED L. HEMIUTERUS
OVARY
(RIGHT HEMIHISTERECTOMY)
RESECTED
VAGINAL SEPTUM PRESERVED
BLOOD SUPPLY
R. HEMIVAGINA
SWITCHED DOWN
Fig. 23 (a) Very large hemivaginas with a vaginal septum and long common channel. (b) Vaginal switch maneuver
An anal dilatation program is begun 2 weeks frequency of dilations is reduced to once a day for
after surgery. The anus is calibrated and a dilator 1 month, twice a week for 1 month, once a week
that fits snugly is initially used to dilate the anus for 1 month, and then once a week for 3 months.
twice a day. Every week, the size of the dilator is After the colostomy is closed, the patient may
increased by one unit until the desired size is have multiple bowel movements and perineal exco-
reached. The optimal size of dilator is shown in riation may develop. A constipating diet may be
Table 2. Once the correct size is reached, the helpful in the treatment of this problem. After sev-
colostomy can be closed which is usually eral weeks the number of bowel movements
8–12 weeks after the reconstruction. decreases, and most patients will suffer from con-
Dilatations must continue after colostomy clo- stipation. This constipation must be watched for
sure. Once the dilator can be inserted easily, the and proactively treated to avoid the formation of
megasigmoid and overflow pseudoincontinence sensation or pushing typically has a poor functional
(Peña and el Behery 1993). After 3–6 months, a prognosis for bowel control. The original type of
more regular bowel movement pattern develops. A malformation, as well as the quality of the sacrum
patient who has 1–3 bowel movements per day and spine, predicts the potential for voluntary bowel
remains clean between bowel movements, shows movements.
evidence of “feeling” during the bowel movement
and pushes, and generally has a good prognosis.
This type of patient is trainable. A patient with Outcomes
multiple bowel movements or one who passes
stool constantly without showing any signs of Complications
All the usual postoperative complications may

occur after these operations. In addition, some
specific problems develop both early and late in
the postoperative course.
Wound infection and retraction are known to
occur. When the infection affects only the super-
ficial layers of the wound, is not accompanied by
dehiscence of the structures pulled through, and is
promptly treated, it is likely that no functional
sequelae will result. On the other hand, infection
accompanied by dehiscence may reach cata-
strophic proportions and leave sequelae that
include incontinence, strictures, acquired atresias,
recurrent fistulas, and severe pelvic fibrosis.
Infections and dehiscence have occurred
Fig. 24 Extremely long common channel – hemivaginas mainly in patients operated on primarily, without
and rectum connected to the bladder neck a colostomy. Therefore, although there is the
a b
INFERIOR
MESENTERIC
VESSELS
RECTUM
(INTRAMURAL
BLOOD SUPPLY)
FUTURE VAGINA
NEW VAGINA
LINE OF DIVISION
Fig. 25 A and B, vaginal replacement with the rectum

Fig. 26 Vaginal
replacement with the
sigmoid colon
benefit to operate earlier, primarily, and without a (B) tapering a dilated rectum if necessary, and
colostomy, it must be remembered that a colos- (C) performing the anoplasty under slight tension
tomy is a very valuable adjunct in the manage- so that after the sutures of the anoplasty are cut,
ment of these defects. Every surgeon must make a the rectum retracts slightly with no mucosa being
decision regarding this issue based on his personal visible.
experience. Prolapse is managed by full-thickness trim-
It is very difficult to determine the precise ming and is performed when prolapse causes
causes of these complications; however, it seems excess mucus production and bleeding or inter-
the main contributing factors are fecal contamina- feres with the patient(s) quality of life.
tion, ischemia, and suture line tension, (often from A review revealed significant urologic injuries
the incomplete mobilization of structures). in male patients who underwent repair of
Rectal or vaginal strictures (or both) are usu- anorectal malformations (Hong et al. 2002). The
ally due to ischemia and (or) tension. posterior sagittal approach, when performed with-
An anal dilatation program is recommended to out a good preoperative distal colostogram, was
avoid strictures; however, these maneuvers pre- the most important source of these complications.
vent only minor, ringlike strictures. Difficult anal Urethral, ureteral, vas deferens, and seminal ves-
dilatations usually reflect a major problem related icle injuries can occur. The laparoscopic approach
to ischemia or tension that will result in a long when done for malformations in which the rectum
narrow stricture or even acquired atresia. ends at the bulbar urethra risks leaving behind a
Rectal mucosal prolapse may occur in less than posterior urethral diverticulum (the original distal
5% of cases; to prevent this from happening, rectum). Postoperative neurogenic bladder in
several maneuvers are recommended, including: male patients who undergo a technically correct
(A) tacking of the posterior rectal wall to the operation for the treatment of anorectal
posterior edge of the muscle complex, malformations must be extremely unusual.
Fig. 27 Vaginal replacement with small bowel (a) and (b). Using the portion of ileum with the longest mesentery.
(c) Pulling the small bowel down as a neovagina (the insert shows an anastomosis to the upper part of the vagina)
Table 2 Anal dilatation program will lead to more megarectosigmoid, resulting in

overflow pseudoincontinence. Patients appear to
Patient age Hegar dilator
be incontinent, but if their constipation is man-
1–4 months Size no. 12
aged appropriately, they become continent. Such
patients sometimes benefit from sigmoid resection
1–3 years Size no. 15 to reduce their laxative requirement (Peña and el
3–12 years Size no. 16 Behery 1993).
>12 years Size no. 17 Every effort must be made to avoid this cycle
and maintain a collapsed and clean bowel from the
moment the baby is born. Transverse colostomies
Constipation is the most common sequel after left for a long period of time lead to severe mega-
surgical repair of anorectal malformations. The rectosigmoid. Loop colostomies may also contrib-
lower the malformation, the more likely the devel- ute to distal fecal impaction, dilation, and
opment of constipation. A vicious cycle ensues subsequent constipation. An adequate treatment
with megarectosigmoid leading to more constipa- of constipation starting after colostomy closure is
tion. Constipation that is not properly managed very important.
Continence management program is implemented to keep

them artificially dry and clean, with the use of
Bowel control is achieved in about 75% of enemas. This program is used in the 25% group
patients. of patients that suffer from fecal incontinence
Results according to the type of abnormality (Bischoff and Tovilla In press; Bischoff et al.
are shown in Tables 3, 4, and 5. Patients with low 2009; Peña 1990). With the rational administra-
anomalies have done extremely well; those with tion of enemas and, sometimes, diet and drugs,
high lesions and those with associated spinal or most patients remain clean for 24 h after the
sacral problems have done less well. administration of the enema. Only patients with
All patients with anorectal malformations, non-manageable loose stool secondary to an
regardless of the complexity of the defect, can be absent or a short colon need a permanent
kept completely dry of urine and clean of stool colostomy.
after the age of 3, either because they achieve Patients suffering from fecal incontinence are
bowel and urinary control or because a bowel evaluated and classified into those with consti-
pation or those with increased motility (ten-
dency to have diarrhea). In the first group, the
Table 3 Voluntary bowel movement (VBM) and type of saline enema must be of large volume, with
defect
additives (such as glycerin, soap, and/or phos-
Patients phate) to help empty the colon. This program
with
takes advantage of the decreased bowel motility
VBMs
in constipated patients; they remain clean for the
Defect Cases n %
Atresia or stenosis 11 11 100
next 24 h. No laxatives or diets are given in these
Perineal fistula 58 56 97 types of patients. The second group (patients
Vestibular fistula 146 131 90 who suffer from increased bowel motility
Imperforate anus without fistula 40 31 78 because of loss of the rectosigmoid), require a
Bulbar fistula 112 89 79 constipating diet, medication to decrease bowel
Cloaca common channel 3 cm 99 65 66 motility, and a smaller daily saline enema
Prostatic fistula 109 71 65 (Bischoff and Tovilla In press; Bischoff et al.
Vaginal fistula 5 3 60 2009; Peña 1990).
Cloaca common channel >3 cm 69 24 35 The treatment is adjusted by trial and error over
Bladder neck fistula 49 10 20 a period of 1 week with radiologic monitoring.
Total 698 491 70
Table 5 Totally continenta patients and type of defect
Table 4 Soiling and type of defect Totally

continent
Patients with soiling Defect Cases N %
Defect Cases n % Perineal fistula 52 43 83
Perineal fistula 57 9 16 Atresia or stenosis 9 5 56
Vestibular fistula 135 49 36 Vestibular fistula 135 86 64
Atresia or stenosis 10 4 40 Imperforate anus without fistula 36 18 50
Bulbar fistula 105 51 49 Bulbar fistula 101 46 46
Imperforate anus without fistula 39 20 51 Cloaca common channel 3 cm 91 32 35
Cloaca common channel 3 cm 91 57 63 Vaginal fistula 5 1 20
Prostatic fistula 110 86 78 Prostatic fistula 105 19 18
Vaginal fistula 5 4 80 Cloaca common channel >3 cm 52 6 12
Cloaca common channel >3 cm 55 46 84 Bladder neck fistula 46 3 7
Bladder neck fistula 48 43 90 Total 632 259 41
Total 655 369 56 a
Voluntary bowel movements and no soiling
Fig. 28 Diagram showing appendicostomy
Approximately 95% of patients become clean.

Bowel management is started just before the
patient has to go to school and join their class-
mates who are already wearing regular underwear.
Most patients and parents are very happy with the
implementation of this program.
When the patient reaches the age of 7–12 years
or sometimes younger, more independence is usu-
ally desirable. At that point, creation of a conti-
nent appendicostomy (Malone procedure) is very
beneficial (Levitt et al. 1997b). This operation
creates a communication between the abdominal Fig. 29 Neoappendix made from a tabularized flap of
wall and the cecum through the patient’s appendix colon
(Fig. 28). A one-way valve mechanism is created
by placating the cecum around the appendix
which allows catheterization of the cecum but Some patients benefit from an enema program
prevents leakage of stool. Patients are able to early on, but if they have potential for bowel
administer their own enema while sitting on the control, when they are a little older, a laxative
toilet. A significant number of patients do not trial can be employed to help their colon empty,
have an appendix. In such cases an appendix is with careful radiologic monitoring. This may
made with a tubularized flap of the cecum and allow them to demonstrate the capacity for volun-
then plicate the cecum around it (Fig. 29) tary bowel movement and thus eliminate the need
(Chatoorgoon et al. 2011). The stoma is also exte- for enemas.
riorized through the umbilicus. Most patients who Certain patients in whom the rectum was mis-
have undergone this operation express a great deal located during the original operation may be can-
of satisfaction. didates for a reoperation. This is recommended
only in patients who were born with a good Bischoff A, Levitt MA, Peña A. Bowel management for
sacrum, good sphincters, and a malformation the treatment of pediatric fecal incontinence. Pediatr
Surg Int. 2009;25(12):1027–42.
with a good prognosis. The results of this proce- Bischoff A, Levitt MA, Breech L, Louden E, Peña
dure vary, with worthwhile continence achieved A. Hydrocolpos in cloacal. Malformations. J Pediatr
in more than half of patients (Peña et al. 2007). Surg. 2010;45(6):1241–5.
In patients with a cloaca, those with a common Bischoff A, Levitt MA, Peña A. Laparoscopy and its use in
the repair of anorectal malformations. J Pediatr Surg.
channel shorter than 3 cm require intermittent 2011;46(8):1609–17.
catheterization one third of the time. Patients Bischoff A, Peña A, Levitt MA. Laparoscopic-assisted
with common channels longer than 3 cm require PSARP – the advantages of combining both techniques
intermittent catheterization or a continent diver- for the treatment of anorectal malformations with recto-
bladderneck or high prostatic fistulas. J Pediatr Surg.
sion 70–80% of the time. 2013a;48:367–71.
Bischoff A, Levitt MA, Breech L, Hall J, Peña A. Vaginal
switch – a useful technical alternative to vaginal
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Congenital Pouch Colon
74
Amulya K. Saxena and Praveen Mathur
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Historical Insights . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Gross Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Histopathological Findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1091
History and Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1092
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Preoperative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1093
Operative Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1094
Postoperative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1095
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
Abstract
A. K. Saxena (*)
Department of Pediatric Surgery, Congenital pouch colon (CPC) is a rare form
Chelsea and Westminster Hospital NHS Foundation Trust, of anorectal malformation, in which the entire
Imperial College London, London, UK colon is replaced by an enormously dilated
e-mail: amulya.saxena@nhs.net
pouch that communicates with a fistula to
P. Mathur the genitourinary tract. CPC is a condition
Department of Pediatric Surgery,
which comprises of a high form of anorectal
SMS Medical College, Jaipur, Rajasthan, India
e-mail: azadanita@rediffmail.com malformation which is associated with large

https://doi.org/10.1007/978-3-662-43588-5_77
1088 A. K. Saxena and P. Mathur
variations in the size of the dilatations of Historical Insights

the affected colonic segment. Surgical
management depends on the type of CPC, Though CPC is a rare congenital malformation
and outcomes are variable depending on which is almost nonexistent outside the Indian
the length of colon affected and the anorectal subcontinent, this anomaly was initially recog-
muscle complex. nized in England during the beginning of the
twentieth century. The first description of this
Keywords anomaly was documented by Spriggs from a spec-
Congenital pouch colon · Congenital imen carefully observed at the London Hospital
malformation · Pull-through procedure · Museum in 1912 (Spriggs 1912). The specimen
Protective colostomy · Coloplasty was described by him to have an absence of
half of the large bowel and rectum, where the
dilatation was presumed to be the result of a
Introduction congenital occlusion of the gastrointestinal
tract. The following reporting of this congenital
Congenital pouch colon (CPC) is a congenital mal- malformation was published almost half a
formation of the large bowel in which the entire century later in an article from Canada in 1959.
large bowel or segments of varying lengths of the In this publication, a more accurate account
large bowel exhibit enormous dilatations in the was provided by Trusler et al. who described
form of a pouch and communicate more typical characteristics of this malformation
distally through a fistula with the urogenital system. such as the pouch-like dilatation of the shortened
CPC is a condition which comprises of a high form large bowel and its association with a high
of anorectal malformation which is associated with form of anorectal malformation (Trusler et al.
large variations in the size of the dilatations of the 1959). Later on in 1967, El-Shafie described
affected colonic segment (Fig. 1). The scarce this malformation in detail as a congenital short-
reporting of this condition in the 1980s missed its ening of the small intestines which accompanied a
inclusion in the Wingspread classification of cystic dilatation of the colon associated with an
anorectal malformations; however, with the increas- ectopic anus (El-Shafie 1971).
ing number of reports and detailed investigation of CPC was first reported from India in 1972,
the condition, CPC has been recognized as a rare when Singh and Pathak coined the term “short
form of anorectal malformation and has been colon” after observing this condition in a series
included in the Krickenbeck classification of six patients (Singh and Pathak 1972).
(Holschneider et al. 2005). The authors also speculated in this report on
Fig. 1 Distribution of anorectal malformations in 426 patients from 1995 to 2007

74 Congenital Pouch Colon 1089
the possible embryogenesis of the malforma- series of patients are being reported from the
tion. Later on, in a successive report in 1977, neighboring countries in the Indian subcontinent
a description of the anatomy of this malforma- such as Pakistan and Nepal, however, with a low
tion was published (Singh et al. 1977). An incidence reported from Bangladesh (Gupta and
important contribution to CPC was made by Sharma 2006, 2007). Sporadic cases of CPC are
Chiba et al. in 1976, who not only made the being reported from the Middle East, Far East,
first attempts to classify this malformation but Europe, and North America (Al-Salem 2008;
also reported on the management of this mal- Wester et al. 2006; Herman et al. 2000; Arestis
formation with the technique of “coloplasty” et al. 2005). The incidence of CPC is the highest in
(Chiba et al. 1976). The term “colonic reser- the North-West regions of India and is estimated
voir” was coined by Gopal in 1978 in a report to be 5–18% of the total number of neonates
with this malformation with the distal end of the managed for anorectal malformations. Among
reservoir terminating into the female genitals the Indian Tertiary Care Centers reporting on
through a rectovaginal fistula (Gopal 1978). large series of CPC, Udaipur in the Western
Further efforts to describe this malformation State of Rajasthan has reported the highest inci-
as a “short colon malformation” associated dence of CPC in India accounting for 37% of the
with an atresia of the anus were done by Li in high forms of anorectal malformations (which is
1981(Li 1981). more than double reported in Delhi, 15.2%)
Narasimha et al. in 1984 proposed the (Mathur et al. 2002). CPC more frequently affects
term “pouch colon syndrome” for this the male population with a male-female distribu-
malformation and after observing variations in tion of 4:1.
the presentation of this malformation presented
a classification based on the length of normal
colon preceding the pouch dilatation Etiology
(Narasimha Rao et al. 1984). Cloutier et al. in
1987 described this malformation as a “rectal The etiopathogenesis and embryology of CPC
ectasia” in a newborn with a low anorectal mal- are poorly understood. The widespread use
formation and reported an incidence of 5% of and direct contact with pesticides in agriculture-
terminal bowel ectasia in their patients with low based communities have been regarded as the
anorectal deformities (Cloutier et al. 1987). possible factor in the triggering of events that
Elaborate terms to describe this malformation lead to CPC. It is also important that the effect
by Wu et al. in 1991 were suggested with acro- of these factors influence the fetus after concep-
nyms such as “association of imperforate anus tion at a time when the hindgut is differentiating
with short colon” (AIASC) or “association of into the urinary and colonic tracts.
imperforate anus with exstrophia splanchnica” Various theories have been hypothesized to
(AIAES) (Wu et al. 1990). Also in 1990, explain the formation of the pouch. The chronic
Wardhan described this entity as imperforate obstruction theory proposed that the expansion of
anus with congenital short colon (Wardhan the large bowel was a result of chronic obstruction
1990). However, Chadha et al. in 1994 coined of the distal colon (Trusler et al. 1959). However,
the term “congenital pouch colon” which is the this theory has not been accepted since the dilated
nomenclature to aptly describe this anomaly pouch does not return to assume normal propor-
(Chadha et al. 1994). tions even after a colostomy placement to relieve
the obstruction. Another hypothesis is the inter-
ference of hindgut growth and migration theory
Incidence proposed by Dickinson (1967). In this hypothesis,
it was proposed that the interference in the longi-
The largest patient series in CPC are being tudinal growth of the hindgut (distal to the allan-
reported exclusively from India. Smaller tois) and failure of its migration into the pelvis
following the obliteration of the inferior mesen-

teric artery in the early embryonic life were
responsible for the formation of the short colon.
The altered hindgut stimulation theory was
hypothesized by Chatterjee (1991). This theory
proposed that the cecum and the right colon nor-
mal development was stimulated by the normal
developing hindgut and development alterations
in the hindgut resulting from a primary disorder
were responsible for the altered development of
the cecum or the right colon. The faulty rotation
and fixation theory proposed by Wu
et al. hypothesized that the faulty rotation and
fixation of the large bowel were responsible for Fig. 2 Operative view of the exteriorized grossly dilated
congenital pouch colon segment visualized from a left
the disturbances in longitudinal growth (Wu et al. lower quadrant “hockey stick” incision
1990). The vascular insult theory was proposed
by Chadha et al. in which degrees of vascular
insult at the time of the partitioning of the cloaca(b) Irrespective of the type of CPC, there is a
by the urogenital septum were deemed responsi- decrease in the length of the large bowel due
ble for the malformation and could explain its to the presence of the pouch.
variations (Chadha et al. 1994). The vascular (c) The pouch formations may differ in length and
insult theory was also supported by Mathur et al. diameter and are fecal or meconium impacted
in explanation of double pouch formation in at the time of surgery.
CPC (Mathur et al. 2002). At present, vascular (d) The pouch wall is thick with a stiff
insults best explain the formation of CPC, which consistency and is abruptly connected to the
is evident by the abnormal vascular supply to normal bowel without the presence of the
the pouch. Also, the overwhelming vascular transition zone.
support provided by the superior mesenteric (e) There is an absence of haustrations, taenia,
artery to the entire distal bowel supports this and appendices epiploicae in the pouch colon.
view, since the inferior mesenteric artery has (f) An abnormal vascular supply to the pouch
been identified only in few patients with CPC can always be identified during surgical
during surgery. Recently, Mathur et al. (2018) exploration.
performed a whole exome sequencing of CPC (g) A fistula can be identified to the urinary
samples and reported significant associations in tract in male neonates (colovesical fistula)
patients with rare mutations and variants. and to the genitourinary tract in females
(colocloacal, colovaginal, or colovestibular
fistula).
Pathology (h) Appendiceal anomalies are present and
vary from complete absence to the presence
CPC is recognized by certain pathological of double appendices.
characteristics that are solely found to be associ-
ated with this congenital malformation (Fig. 2).
Histopathological Findings
Gross Pathology Histological studies of resected pouch colon

demonstrate extreme variations in CPC. In most
(a) The presence of anorectal malformations patients, acute and chronic inflammation of the
differentiates this entity from segmental mucosal and submucosal layers are present with
dilatation of the colon. varying degrees of hemorrhage along with the
presence of disorganized muscle layers in the reported histopathological and immunohisto-

colon wall. Hypotrophy of the muscle layers has chemical findings in 49 cases of CPC which
been observed which is more predominant in showed distinct defects in the neuromusculature
the outer muscle layer of the pouch (Agarwal of CPC. The histopathological findings included
et al. 2005). Extreme variations in the disrupted muscle fibers, an additional muscle
muscle layer (both circular and longitudinal) coat, deranged SMA, myosin and desmin expres-
have also been found which range from sion, and a reduced number of ganglion cells.
fibrosis, atrophy, to hypertrophy along with Studies have also shown that pouch colon which
muscle disruption (Gangopadhyay et al. 2009). normally fails to show spontaneous contraction
Investigations have also shown variations under in-vitro conditions has shown to respond
such as the presence of normal colon wall to acetylcholine and histamine (Tyagi 2009).
with normal ganglion cells in some patients, to a
poorly developed colon wall musculature with
decreased or absent ganglion cells in others Classification
(Singh et al. 1977; Narasimha Rao et al. 1984;
Chadha et al. 1994; Wakhlu et al. 1996a). Until recently, the most widely used classification
Interestingly, heterotrophic tissue such as of CPC was that described by Narasimha Rao
gastric mucosa, small intestinal mucosa with et al. (1984) which classified CPC into four
characteristic villi, and pancreatic tissue has types based on the length of the normal colon
also been found in pouch specimens of CPC proximal to the colonic pouch. Saxena and
patients (Narasimha Rao et al. 1984; Agarwal Mathur (2008) classified CPC into five types
et al. 2005). Recently, Udawat et al. (2017) based on anatomic morphology (Fig. 3).
Fig. 3 Distribution of patients (n = 80) into five types of type 3 CPC, Normal ascending colon and transverse
congenital pouch colon according to the Saxena-Mathur colon open into pouch colon; type 4 CPC, Normal colon
classification. (type 1 CPC, Normal colon is absent and with rectosigmoid pouch; type 5 CPC, Double pouch colon
ileum opens into pouch colon; type 2 CPC, Ileum opens with short normal interpositioned colon segment)
into a normal cecum which opens into pouch colon;
History and Physical Examination Despite CPC being a high anorectal anomaly,
major associated malformations are relatively
The presence of an anorectal malformation uncommon (Chadha and Khan 2017). The most
with gross distention of the abdomen is the common associated malformations are urological
hallmark of the physical examination. In males, including hydronephrosis and vesicoureteral
the pouch usually terminates in a colovesical reflux.
fistula just proximal to the bladder neck. In male
neonates, therefore, discharge of meconium
(meconurea) or stool through the urethra via the Diagnosis
colovesical fistula is evident, and these neonates
are generally referred for treatment in the Plain erect abdominal radiographs performed to
immediate neonatal period. However, in female diagnose patients with CPC demonstrate a classi-
patients, meconium and fecal discharge through cal solitary grossly dilated air fluid bowel loop
a cloacal, uterine, or vaginal fistula may delay that occupies more than 75% of the abdominal
referral in a stable neonate. In the majority of cavity with displacement of the small intestines
female cases, the colonic pouch is reported to (Fig. 4). The position of the pouch and the dis-
open into either vagina or in a persistent cloaca placement of the intestinal loops depend on CPC
(Chadha and Khan 2017). Girls usually have a type (Wakhlu et al. 1996a). Although plain
double vagina with a wide intervaginal bridge. abdominal radiographs can predict the CPC type,
the definitive diagnosis and the CPC type can be
determined only after surgical exploration
Presentation
The majority of patients with CPC present in the

immediate neonatal period due to the anorectal
malformation. The absence of the anal canal and
excessive distention of the abdominal cavity are
the two characteristic signs that raise suspicion of
CPC. Although in CPC the pouch ends through a
fistula in the genitourinary tract, meconurea may
be present or absent. Another common symptom
in these neonates is serial episodes of bilious
vomiting which is a major symptom that leads to
the referrals. Delayed referrals or grossly
distended pouch colon are associated with colonic
perforations, which present a major challenge in
the management of the newborn with septicemia
and peritonitis which further deteriorates the
respiratory distress present due to the massive
abdominal distension. Delay in diagnosis and
late referrals even in the neonatal period have
been largely responsible for the high mortality
in CPC. Awareness of the condition and develop-
ment of proper management strategies especially
through improvement in neonatal intensive care
Fig. 4 Plain abdominal erect radiograph demonstrating
at the tertiary centers in India have drastically the classic grossly dilated pouch colon segment occupying
reduced the mortality from 40% to the present over 75% of the left abdomen, thereby displacing the small
rate of 15% (Sharma et al. 2005). intestines toward the lower quadrant in the right abdomen
(Mathur et al. 2010). False diagnosis of CPC Management

based on plain radiographs is possible in patients
with (a) significant dilatation of the sigmoid Preoperative Management
colon, (b) pneumoperitoneum after perforation in
anorectal malformations due to late presentation, The preoperative management is broadly depen-
and (c) in females, neonates with rectouterine dent on the condition of the pouch (intact versus
fistula when severe dilatation of the meconium perforated). In stable neonates, preoperative man-
filled uterus and gas exhibit the classical images agement includes gastric decompression using a
of CPC radiographs (Wakhlu et al. 1982). nasogastric tube, intravenous fluid replacement
In the majority of CPC cases, the diagnosis is to correct the effects of dehydration and
made on an abdominal radiograph. An enormous electrolyte imbalance, and placement of a urinary
gas shadow or air fluid level is seen on the left side bladder catheter. Antibiotic therapy is com-
of the abdomen, occupying more that 50% of the menced and extended depending on the state of
abdominal width and the small bowel loops are the inflammation in the pouch colon evaluated
displaced to the right. A prone cross table or during the surgery. In neonates presenting with
lateral film is better for visualizing gas within pouch perforations along with signs or either peri-
the bladder. Prior to the surgical management, tonitis or septicemia, aggressive intensive care
further investigations such as abdominal ultraso- management is necessary to stabilize the neonate
nography, intravenous pyelography, or voiding for the emergency surgical procedure which is
cystourethrography and echocardiography are limited to evacuation of the meconium or
mandatory since a wide range of genitourinary, stool from the peritoneal cavity, placement of a
gastrointestinal, and other forms of associated ileostomy or colostomy, and closure of the perfo-
anomalies have been found in patients with ration site. The intention in surgical management
CPC. (Table 1). in neonates with perforations is to perform the
Table 1 List of associated anomalies reported in congenital pouch colon patients

Genitourinary anomalies Gastrointestinal anomalies Other organ anomalies
Hydronephrosis Absent appendix Sacral agenesis
Vesicoureteral reflux Double appendix Congenital heart disease
Bicornuate uterus Malrotation Myelomeningocele
Cryptorchidism Colon duplication Prune belly syndrome
Hydroureteronephrosis Meckel’s diverticulum Hemivertebrae
Hypospadias Double Meckel’s diverticulum Congenital talipes equinovarus
Renal aplasia/agenesis Esophageal atresia Perineal teratoma
Renal dysplasia Small intestinal duplication Absent ribs
Double uterus Rectal atresia Down’s syndrome
Double vagina
Septate vagina
Ectopic kidney
Urethral duplication (males)
Urethral diverticula
Bifid penis
Megalourethra
Urethral strictures
Bladder exstrophy
Duplicate bladder exstrophy
List of associated anomalies in congenital pouch colon patients distributed under genitourinary, gastrointestinal, and other
organ manifestation categories
surgery with the smallest possible incision and to restore or partially restitute the function of the
complete the procedure in a short time. large bowel such as absorption, transportation,
and containment.
In type 1 CPC and type 2 CPC, a one-stage
Operative Management procedure (pouch excision and pull-through) or
three-stage procedure (ileostomy, pouch
Management algorithm of CPC is based on the coloplasty with pull-through, and ileostomy clo-
type of pouch according to the Saxena-Mathur sure), depending on the condition of the pouch
classification (Fig. 5) (Mathur et al. 2009). An (ischemic or healthy), can be performed. In case
abdominal incision in the lower left quadrant in of severe ischemia and perforations, resection of
shape of a “hockey stick” has been found to offer the pouch remains the only alternative. If the
optimal access to inspect the malformation with pouch is resected, either a direct pull-through of
the primary intention of fistula ligation the ileum or placing a protective ileostomy
irrespective of the CPC type. After the fistula has with delayed ileum pull-through offers the best
been exposed and ligated, the condition of the surgical options. However, if the pouch is healthy,
pouch dictates the further operative strategy. the surgical approach is focused on attempts to
Staged procedures, employing the placement of rescue and taper the pouch and to perform a
a protective ileostomy or colostomy with ligation pouch coloplasty through pouch tubularization.
of the fistula in the first stage, followed by an Pouch tubularization is performed after pouch
abdominoperineal pull-through in the second mobilization and longitudinal incision on the
stage, still offer the safest option when compared antimesenteric side (to preserve the vascular sup-
to one-stage surgery which is associated with a ply) with edge reapproximation over a catheter.
higher incidence of morbidity and even mortality. Although tubularized pouch coloplasty is
The intention of surgical management in CPC is performed in both type 1 CPC and type 2 CPC,
to evaluate the amount of large bowel affected it is not uncommonly associated with increased
and to salvage its maximum length in order to morbidity in terms of incontinence and
Fig. 5 Management overview of the various types of congenital pouch colon with outline of the operative stages (dotted
lines showing points of stagged procedure)
complications resulting from redilatation of best treated by a three-stage procedure (Mathur

the tubularized pouch (Wakhlu et al. 1996b; et al. 2002). The first procedure involves the liga-
Chadha et al. 2002). tion of the fistula, excision of the distal pouch,
The significance of the Saxena-Mathur classi- tubularization of the proximal pouch, and the
fication in differentiating type 1 CPC and type placement of a protective ileostomy. The second
2 CPC is to recognize the presence of the normal procedure involves the abdominoperineal pull-
cecum in type 2 CPC which is underestimated through keeping the protective ileostomy. In the
in the classifications on surgical approach. third procedure, the protective ileostomy is
Various investigations and experimental studies returned. Another option type 5 CPC would be
have demonstrated the significance of the to tubularize both the proximal and distal pouch.
cecum and ascending colon or parts of the Surgical management of female neonates
ascending colon in the absorption of sodium with pouch colon is complex due to the frequent
which influence the exchange of chloride association with the cloaca as well as the asso-
and bicarbonate in these tissues (Hatch and Freel ciated anomalies of the genital system (Chadha
1988; Fromm et al. 1990). However, investiga- et al. 1999, 2015; Sarin et al. 2007). Depending
tions need to be performed to validate these on the complexity of the genital anomalies, a
differences in patients and compare type 1 CPC one-stage or three-stage approach is preferred;
and type 2 CPC patients. Similarly, the absorption however, there is no consensus on the approach
of potassium, which is significant in the to date. The pouch colon has been tubularized to
descending colon in experimental studies (Yau create a neo-vagina and reconstruct the
and Makhlouf 1975; Sweiry and Binder 1990), anorectum with preserved vasculature also
highlights the difference between the type 3 CPC using the longitudinal incision technique
and type 4 CPC since the normal functioning (Wester et al. 2006). Also, pouch colon patch
descending colon is only present in type 4 CPC. graft on pulled through ileum has been reported
The presence of considerable lengths of in an isolated case with good clinical outcomes
normal colon in the type 3 CPC and type 4 CPC (Ratan and Ratan 2004).
enables total resection of the pouch and a
staged abdominoperineal pull-through of normal
colon. The approach to type 3 CPC and type 4 Postoperative
involves the ligation of the fistula, excision of
the pouch, and placement of a stoma which is The postoperative management depends on the
followed by a delayed abdominoperineal pull- condition of the pouch. In patients with pouch
through. Although it is debatable if a protective perforation, intensive care support along with
colostomy should be placed, or a prior high colos- parenteral nutrition is necessary until complete
tomy be closed during the pull-through procedure, recovery. The use of antibiotics and the duration
the authors prefer the first option and place a of treatment are also dependent on the surgical
protective colostomy during the pull-through findings. In patients with protective colostomy,
which is returned return at a later point of time. feeds are commenced earlier than those who
In type 3 CPC and type 4 CPC, if the high colos- have undergone tubularization and pull-through
tomy is opted (instead of the end colostomy), procedures. Monitoring of bowel movements is
appropriate placement of the colostomy is advo- necessary to achieve success in these patients
cated since improper placement of a high colos- (Gharpure 2007). Regular postoperative
tomy may interfere with the pull-through follow-up is necessary to document the bowel
procedure especially if the length of the colon to movements which could range from diarrhea
be pulled through is too short. when the pouch is resected to obstipation
Management of type 5 CPC requires the which could result in tubularized pouch
approach to two pouch colon segments that are redilatation and necessitate further surgical
separated by a segment of normal colon and is procedures.
Complications and the normal large bowel is pulled through. The

colonic pouch has histopathological abnormali-
Complications in the management of CPC can ties of neuromusculature and therefore not suit-
be divided into five distinct categories able for pull-through. Detailed long-term follow-
which are related to (a) window colostomy, up studies are required to properly assess conti-
(b) protective colostomy, (c) tubularized pouch nence in the patients.
colon, (d) complete pouch resection, and
(e) pull-through procedure. Window colostomy
leads to a wide range of complications such Conclusion and Future Directions
as incomplete pouch decompression, prolapse,
stoma recession, stoma stenosis, pouchitis, Surgical management depends on the type of
enterocolitis, and failure to thrive (Singhal and CPC, and outcomes are variable depending on
Bhatnagar 2006). The complications of protective the length of the colon affected and the anorectal
colostomy or pull-through procedures are general muscle complex (Shinde et al. 2017). Future
complications associated with these procedures studies will be directed to investigate the etiology
and are not specific for CPC. Tubularization of of CPC and details of colon histological
the pouch colon could be associated with compli- characteristics which were still unknown.
cations of leakage along the suture line with con-
sequent rupture. Also, redilatation after
tubularized colon has been observed after long-
term follow-up in patients with salvaged pouch
Cross-References
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▶ Anorectal Malformations
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resection is associated with the complications of
Acknowledgments Adapted with permission of Taylor
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Congenital Segmental Dilatation of
the Intestine 75
Yoshiaki Takahashi, Yoshinori Hamada, and Tomoaki Taguchi
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1100
The Clinical Features and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
Criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1102
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104
Abstract Swenson and Rathauser in 1959, and over

Segmental dilatation of the intestine (SD) is a 100 cases have been reported since then. Several
rare lesion defined as limited bowel dilatation theories were proposed to explain this malfor-
with a three- to fourfold increase in size with an mation; however, its cause remains unknown.
abrupt transition between the normal and dilated Most pediatric cases are discovered in neo-
bowel and no intrinsic or extrinsic barrier distal natal periods, so the SD cases in neonates were
to the dilatation. It was first described by frequently called congenital segmental dilata-
tion (CSD). Neonates with CSD usually pre-
sent with features of intestinal obstruction
Y. Takahashi (*) · T. Taguchi within days of birth. Older children present
Department of Pediatric Surgery, Graduate School of with anemia, hypoproteinemia, malabsorption,
Medical Sciences, Kyushu University, Fukuoka, Japan and gastrointestinal bleeding. Preoperative
e-mail: yoshiaki@med.kyushu-u.ac.jp; taguchi@pedsurg.
diagnosis is sometimes difficult because of
med.kyushu-u.ac.jp
the clinical polymorphism and the lack of
Y. Hamada
Department of Surgery, Kansai Medical University, Osaka,
Japan
e-mail: hamaday@hirakata.kmu.ac.jp

https://doi.org/10.1007/978-3-662-43588-5_78
1100 Y. Takahashi et al.
specificity of radiological investigations. SD in neonates were reported (Rantan et al. 2001;

Patients with an unexplained obstructive intes- Hosie et al. 2001; Cheng et al. 2001; Chadha et al.
tinal pattern are occasionally found at surgical 2001; Ojha et al. 2004; Mathur et al. 2004;
exploration. The usual finding on laparotomy Manikoth et al. 2004; Basaran et al. 2005; Waters
is localized dilatation of an isolated, well- et al. 2007; Morikawa et al. 2009; Thambidorai
defined segment of bowel with apparently nor- et al. 2009; Saha et al. 2009; Okada et al. 2010;
mal bowel proximal and distal to this segment. Harjai et al. 2010; Park et al. 2010; Mahadevaiah
The definitive treatment is resection of the et al. 2011; Ragavan et al. 2012; Mirza and Bux
dilated segment and anastomosis of the normal 2012; Rathod et al. 2012; Paradiso et al. 2013;
segments of intestine. Most patients have an Sakaguchi et al. 2015; Soyer et al. 2015; Rai et al.
uneventful course after surgical resection, and 2016; Sakaguchi et al. 2016; Kaiser et al. 2016).
the prognosis is excellent. In most cases, his- Despite the large number of reports, the etiology
tology of the resected segment is usually nor- of the disease remains elusive. Although the cur-
mal. However, some of the cases showed rent study attempts to evaluate the roles of inter-
hypertrophied or very thin muscle layer in the stitial cells of Cajal, the enteric nervous system,
involved segment in histopathological evalua- and the smooth muscle in segmental dilatation of
tion. The dislocation of the myenteric plexus the intestine, the etiology has not been clarified.
and the ectopic pancreatic or gastric tissues are The first and most recent retrospective cohort
reported in dilated intestinal segment. study on allied disorder of Hirschsprung’s disease
(ADHD) was performed in Japan. SD was classi-
Keywords fied as an ADHD and 28 SD cases were collected
Segmental dilatation · Intestine · Colon · (Sakaguchi et al. 2015; Taguchi et al. 2017).
Neonate · Criteria · Intestinal obstruction ·
Surgical resection · Histopathology · Allied
disorders of Hirschsprung’s disease
Etiology
Introduction The etiology of SD remains unknown. Some of

the hypotheses that have been proposed:
Segmental dilatation of the intestine (SD) is a rare
lesion defined as limited bowel dilatation with a (a) Abnormal tortuous vessels (Rossi and
three- to fourfold increase in size with an abrupt Giacomoni 1973; Komi and Kohyama 1974)
transition between the normal and dilated bowel (b) Vascular insufficiency during intussuscep-
and no intrinsic or extrinsic barrier distal to the tions (Ueda and Okamoto 1972)
dilatation. It was first described in 1959 by (c) Disturbance during splitting of the notochord
Swenson and Rathauser (Swenson and Rathauser from the endoderm (Heller et al. 1989)
1959) as “a new entity,” which is distinct from (d) Volvulus and kinking due to a long mesentery
Hirschsprung’s disease in terms of the pathologi- during the embryologic period (Balik et al.
cal findings of normal ganglion cells. Since then, 1993)
over 100 cases were reported in the world litera- (e) Interruption of the continuity of the nerve
ture, and more than 50% of the SD were neonatal fibers and the nerve plexus in islands of
discoveries (Ben Brahim et al. 2006). So it is ectopic tissue (Marsden and Glichrist 1963;
assumed that these conditions represent congeni- Rovira et al. 1989)
tal malformation, and the SD cases in neonate are (f) Entrapment by the omphalocele sac (Irving
frequently called congenital segmental dilatation and Lister 1977)
(CSD). This condition is complicated by the (g) Strangulation of the intestine in the umbilical
obstruction of the intestines or chronic constipa- ring during the early stage of development
tion from birth. From 2000 to 2016, 53 cases of (Irving and Lister 1977)
75 Congenital Segmental Dilatation of the Intestine 1101
The Clinical Features and Diagnosis
The common morphological feature of SD is the

presence of a single, well-defined segment of
dilated intestine with a more or less abrupt transi-
tion to normal bowel both proximally and distally,
with no evidence of intrinsic obstruction or defi-
cient innervation. Most cases of SD were discov-
ered in neonates who presented with symptoms of
intestinal obstruction in which the clinical picture
was hard to differentiate from more common
causes of occlusion, such as intestinal atresia,
Hirschsprung’s disease, meconium ileus, intestinal
duplication, and midgut volvulus. From the
reviews of 53 neonatal cases (Rantan et al. 2001;
Hosie et al. 2001; Cheng et al. 2001; Chadha et al.
2001; Ojha et al. 2004; Mathur et al. 2004;
Manikoth et al. 2004; Basaran et al. 2005; Waters
et al. 2007; Morikawa et al. 2009; Thambidorai
et al. 2009; Saha et al. 2009; Okada et al. 2010;
Harjai et al. 2010; Park et al. 2010; Mahadevaiah
et al. 2011; Ragavan et al. 2012; Mirza and Bux
2012; Rathod et al. 2012; Paradiso et al. 2013;
Sakaguchi et al. 2015; Soyer et al. 2015; Rai et al.
Fig. 1 X-ray showed a dilated bowel (arrow) in the right
2016; Sakaguchi et al. 2016; Kaiser et al. 2016), the side of the abdomen
common symptoms were abdominal distension
and vomiting. Rarely, the patient may present segmental dilatation of the bowel loop (Waters
with peritonitis due to peroration of the dilated et al. 2007). In segmental dilatation of the colon,
segment (Thambidorai et al. 2009; Kuint et al. the contrast enema findings are very similar to
1993). And the commonly dilated segments were those of Hirschsprung’s disease, but the two
the ileum (n = 31; 58%) and colon (n = 14; 26%). conditions can be differentiated by anorectal
Concurrent malformation were seen in 26 cases manometry. Additionally, histochemical studies
(49%) such as intestinal malformation (n = 12), demonstrate that there is no proliferation of the
omphalocele (n = 7), congenital heart disease cholinergic nerve fibers of the rectal mucosa.
(n = 6), and cleft lip and palate (n = 4). Among
them, multiple malformations were seen in five
cases. Four cases had chromosomal abnormalities: Criteria
trisomy 21 (n = 3) and 46 XY 15p + (n = 1).
Because the symptom is not specific and the The criteria for diagnosis of this entity, as pro-
definitive diagnosis is difficult, SD is usually posed by Swenson and Rathauser, are as follows
diagnosed incidentally during surgery. However, (Swenson and Rathauser 1959):
the anomaly can also be suspected or diagnosed
preoperatively on the basis of radiologic findings (a) Limited bowel dilatation with a three to four-
(Basaran et al. 2005; Waters et al. 2007). The fold increase in size
classic feature of SD on plain radiographs is the (b) An abrupt transition between the dilated and
marked segmental dilatation of the bowel loop, normal bowel
with or without an air-fluid level (Fig. 1). Contrast (c) No intrinsic or extrinsic barrier distal to the
enema studies are often useful for confirming dilatation
Fig. 2 (a) Surgical finding. Locally dilated ileum with an abrupt transition between the dilated and normal bowel. No
intrinsic or extrinsic barrier distal to dilatation. (b) Resected specimen
(d) A clinical picture of intestinal occlusion or Chadha et al. 2001; Ojha et al. 2004; Mathur et al.
subocclusion 2004; Manikoth et al. 2004; Basaran et al. 2005;
(e) A normality of the neuronal plexus Waters et al. 2007; Morikawa et al. 2009;
(f) Complete recovery after resection of the Thambidorai et al. 2009; Saha et al. 2009; Okada
affected segment et al. 2010; Harjai et al. 2010; Park et al. 2010;
Mahadevaiah et al. 2011; Ragavan et al. 2012;
The diagnosis of definitive SD occurs when all Mirza and Bux 2012; Rathod et al. 2012; Paradiso
criteria are met, and the possible SD is diagnosed et al. 2013; Sakaguchi et al. 2015; Soyer et al.
solely based on anatomical features (a–c) without 2015; Rai et al. 2016; Sakaguchi et al. 2016;
occlusive findings (Fig. 2) and surgery of histo- Kaiser et al. 2016), 8 with hypertrophic muscular
logical examination. layer were reported (Ben Brahim et al. 2006;
Hosie et al. 2001; Basaran et al. 2005; Saha et al.
2009; Sakaguchi et al. 2015; Soyer et al. 2015),
Pathology but 9 with hypotrophic or atrophic muscular layer
were collected (Ben Brahim et al. 2006; Rantan
The histopathological findings are most important et al. 2001; Chadha et al. 2001; Ojha et al. 2004;
diagnostic criteria. The presence of ganglion cells Thambidorai et al. 2009; Okada et al. 2010; Park
that are normal in number and morphology is one et al. 2010; Sakaguchi et al. 2015). Ectopic pan-
of the criteria for the differential diagnosis. creatic or gastric tissues were found in two and
Microscopy can reveal some anomalies, essen- three cases, respectively (Ben Brahim et al. 2006;
tially a hypertrophic muscular layer and a hetero- Harjai et al. 2010; Paradiso et al. 2013; Sakaguchi
topic mucosa that can include esophageal, gastric, et al. 2015). Some case reports of SD detected
or pancreatic tissue. Hypertrophy of the circular decreasing c-kit- positive cells in the dilated seg-
and longitudinal layers of the muscularis propria ment (Okada et al. 2010; Sakaguchi et al. 2016;
in the dilated segment is evident in older infants/ Katsura et al. 2011). In some cases, other
children and is probably an acquired functional immunohistological investigations, such as
adaptation that occurs secondarily to chronic fecal CD-56, S-100, and MAP5, assisted in the diagno-
distention (Helikson et al. 1982; Brawner and sis of SD (Cheng et al. 2001). Furthermore, a
Shafer 1973). recent study reported the dislocation of the
From the review of 53 neonatal cases (Rantan myenteric plexus within the circular muscle
et al. 2001; Hosie et al. 2001; Cheng et al. 2001; layer (Mahadevaiah et al. 2011) (Fig. 3). Precise
Fig. 3 Myenteric plexus shifts to the circular muscle layer (arrow) at the dilatated lesion, but not at the non-dilatated
lesion. CM circular muscle layer, LM longitudinal muscle layer
histological and immunohistological investiga- formation is always recommended for

tions in future cases of SD might provide more anorectoplasty in the second stage. A covering
detailed information about its etiology. ileostomy was also fashioned due to the presence
of multiple colonic anastomoses and rectal atresia
(Mirza and Bux 2012).
Treatment Some reports recommend the use of laparo-
scopic procedure in the surgical treatment of
The treatment of SD depends on the clinical con- SD. Laparoscopy was found to be a reliable diag-
dition of the patient, the presentation, the sur- nostic tool and is a minimally invasive procedure
geon’s experience in dealing with such that provides safe and superior cosmetic results
malformations, and the association with other (Porreca and Capobianco 2002).
malformations. The definitive surgery is resection
of the involved segment and end-to-end anasto-
mosis with/without proximal colostomy (Balik Prognosis
et al. 1993; Al-Salem and Grant 1990; Sarin and
Singh 1995). In the case of patients who are crit- Most patients who underwent surgery for SD
ically ill (such as patients with perforation or showed an uncomplicated postoperative course.
chromosomal abnormalities), an ileostomy can The survival rate is excellent unless other serious
be fashioned without excision of the segmental complications or anomalies are present. In the
dilatation (Mirza and Bux 2012). In the case of most recent retrospective cohort study, one patient
associated anorectal malformations, stoma who underwent ileocecal resection for cecal
segmental dilatation at 9 years of age died at Cheng W, Lui VC, Chen QM, et al. Enteric nervous sys-
12 years of age from catheter-related sepsis and tem, interstitial cells of cajal, and smooth muscle
vacuolization in segmental dilatation of jejunum.
liver dysfunction. Excluding the case, the survival J Pediatr Surg. 2001;36(1):930–5.
rate of SD was 100% (Sakaguchi et al. 2015). Harjai MM, Katiyar A, Negi V, et al. Congenital segmental
dilatation of jejunoileal region in a newborn: unusual
clinical and radiologic presentation. J Indian Assoc
Pediatr Surg. 2010;15(3):96–7.
Conclusion and Future Directions Helikson MA, Schapiro MB, Garfinkel DT, et al. Congen-
ital segmental dilatation of the colon. J Pediatr Surg.
Segmental dilatation of the intestine is a rare mal- 1982;17:201–2.
formation with an unknown etiology and a mis- Heller K, Waag LD, Beyersdorf F. Intestinal duplication-
segmental dilatation of intestine: a common genetic
leading clinical presentation. From the review of complex. Pediatr Surg Int. 1989;4:249–53.
53 neonatal cases, most of the clinical features Hosie S, Lorenz C, Schaible T, et al. Segmental dilatation
have been revealed, but the etiology of SD of the jejunum resembling prenatal volvulus. J Pediatr
remains unclear. In some cases, immunohis- Surg. 2001;36(6):927–9.
Irving I, Lister J. Segmental dilatation of the ileum.
tological investigations are useful for diagnosis. J Pediatr Surg. 1977;12(1):103–12.
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Short Bowel Syndrome
76
Michael E. Höllwarth
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108
Incidence and Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1109
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
Nutritional Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1112
Supplemental Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1113
Surgical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1115
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1121
Abstract patients will finally need surgical interventions

Short bowel syndrome occurs after extensive either to reduce a very fast passage time or to
loss of small bowel leading to a status of intes- lengthen the dilated intestinal remnants. Some
tinal failure characterized by significant prob- patients will need intestinal or combined intes-
lems in digesting and absorbing enteral tinal/liver transplantation either after nearly
nutrition. A very complex adaptation process total loss of small bowel or after severe com-
of the intestine allows that 90% of the patients plication such as intestinal failure-associated
can be weaned after a long-term period from liver insufficiency. The therapeutic decisions
parenteral nutrition. A small number of have to be tailored to each individual patient
depending which parts of the intestine are lost
or which dysfunctions of the intestinal rem-
M. E. Höllwarth (*) nants need a special treatment. Survival rates
Department of Paediatric and Adolescent Surgery, Medical
University of Graz, Graz, Austria
reach today nearly 90% including some
e-mail: michael.hoellwart@medunigraz.at

https://doi.org/10.1007/978-3-662-43588-5_80
1108 M. E. Höllwarth
children with long-term home parenteral sup- nutrition. These efforts resulted in significant pro-
port, additionally to the enteral nutrition. gress reducing the morbidity and improving the
survival rates. This chapter summarizes recent
Keywords insights and developments in babies with (SBS).
Short bowel syndrome · Intestinal adaptation ·
Intestinal failure · Liver insufficiency ·
Bacterial overgrowth · Dysmotility · Bacterial Definition
translocation · Central venous line · Sepsis
The term “short bowel” has been defined by
Rickham in 1967 as a small intestinal remnant of
Introduction 75 cm in the newborn, which equals 30% of
normal small bowel length in that age group
Short bowel syndrome (SBS) is a condition that (250 cm). In premature babies the term also cor-
occurs after extensive loss of digestive and responds to 30% of the total calculated length for a
absorptive surface area of the small intestine. It given gestational age (Fig. 1) (Touloukian and
results after a pre- or postnatal catastrophic event Walker 1983). However, the antimesenteric mea-
and is characterized by an intestinal failure with surement of intestinal length during surgical inter-
the need of long-term parenteral nutrition. ventions yields highly variable results due to
Whether or not a full enteral nutrition can finally enormous contractibility of the bowel in length
be achieved depends not only on the length of the and diameter. Therefore, a more functional
remaining parts of active small bowel but also on description is preferred by most authors defining
the functional quality of the intestinal remnants. short bowel as a state of significant maldigestion
Over the past decades, intensive research has been and malabsorption resulting in intestinal failure
performed in order to stimulate and support the (IF) (D’Antiga and Goulet 2013). One of the
functional capacities of the small bowel remnants causes of IF is an extensive loss of functional
as well as to control and minimize the typical absorptive intestinal surface area. Other causes
complications of long-term high caloric parenteral of IF – not included in this chapter – are disorders
Fig. 1 Normal intestinal 400 GROUP A GROUP B GROUP C

length and the ranges in
premature babies (with
permission from Elsevier:
Touloukian RJ, Smith GJ,
TOTAL INTESTINAL LENGTH (cm)
JPS 1983, 18, 720–723) MEAN MEAN

300 ± 1SD ± 2 SD
200
100
19 20 23 26 29 32 35 38 41
GESTATIONAL AGE (weeks)
76 Short Bowel Syndrome 1109
with intact intestinal length but insufficient age groups (Mugal and Irving 1986). According
enterocyte function and disorders characterized to Wallander, the incidence of extreme SBS in the
by severe motility dysfunction, such as chronic neonatal age group lies around 3–5/100,000 birth/
intestinal pseudo-obstruction. year (Wallander et al. 1992). Using Canadian cen-
The term short bowel syndrome (SBS) is sus data and Canadian Institute of Health infor-
defined as a status when the patient suffers from mation data, a population-based incidence of 24.5
a severe malnutrition due to extensive loss of per 100,000 life birth has been calculated (Wales
absorptive surface area requiring total parenteral et al. 2004). The analysis of a cohort of very low
nutrition (TPN) for more than 6 weeks or when and extremely low birth weight neonates demon-
the residual small bowel length is less than 25% strated incidences of SBS at 0.7% and 1.1%,
(Sigalet 2001). However, some babies with sig- respectively, excluding term neonates (Cole et al.
nificantly longer bowel remnants can never be 2008). However, the real incidence of SBS is
weaned from parenteral nutrition; thus bowel difficult to determine because all forms of reduced
length is not the most reliable parameter, but the small bowel length/function associated with IF are
requirement for long-term parenteral nutrition often included.
remains the best measure to define a SBS with In infancy, most of the cases of SBS occur in
IF (D’Antiga and Goulet 2013). the neonatal age group. There are many different
In the past, extensive loss of small bowel in causes which can be divided into three major
newborns and babies used to be a catastrophic groups. The first of these consists of neonates
event which was nearly always followed by IF with prenatally acquired anomalies characterized
and death. Significant progress was achieved in by a vascular injury to the intestinal tract in utero,
the early 1970s when Wilmore reviewed e.g., multiple intestinal atresias or gastroschisis
50 babies younger than 2 month with a SBS. with intrauterine volvulus of the prolapsed
He found that survival and enteral nutrition bowel. The second group comprises postnatally
were possible with 15 cm jejuno-ileum with acquired diseases necessitating extensive intesti-
ileocecal valve or with 38 cm jejuno-ileum with- nal resection, e.g., necrotizing enterocolitis or
out ileocecal valve (Wilmore 1972). It must be volvulus. A third rare group is defined by a genet-
realized that little progress has been achieved ically determined deficiency, e.g., in the embryo-
since then: today, long-term survival on logical small bowel anlage causing a “true”
enteral nutrition has been described in infants congenital short bowel, or in its innervation,
with as little as 11 cm jejuno-ileum with such as total intestinal aganglionosis (Table 1).
ileocecal valve (5% of total) or with 25 cm Extensive intestinal resection leading to SBS is
jejuno-ileum without ileocecal valve (10% of rarely required in older children. Indications may
total) (Dorney et al. 1985). be severe Crohn’s disease, traumatic avulsion of
the intestinal tract, and/or traumatic or iatrogenic
mesenteric artery lesions. The most common
Incidence and Etiology causes for SBS in adults are Crohn’s disease,
The prevalence of SBS has undoubtedly been

increased over the last two to three decades, Table 1 Over 100 causes of SBS in newborn babies
collected from the literature
since enormous progress in intensive care medi-
cine has significantly improved the initial progno- Necrotizing enterocolitis 36%
sis of newborn babies with severe intestinal Volvulus 19%
disease and/or following major intestinal resec- Intestinal atresia 21%
tion. It has been estimated that severe SBS cases Gastroschisis and atresia 10%
Hirschsprung’s disease 7%
remaining dependent on long-term home paren-
Trauma 1%
teral nutritional support amount to 2 new patients
Others 6%
per one million of population/year including all
mesenteric vascular accidents due to emboli, arte- presence of the ileocecal valve are required to
rial or venous thrombosis, intestinal tumors, or assure that passage time allows at least partial
radiation injury. absorption of bile salts, vitamins, and nutrients.
Therefore, despite different opinions in the litera-
ture, recent publications show clearly that the
Pathology presence of an ileocecal valve has a beneficial
effect on the outcome (Mayr et al. 1999; Spencer
Adequate digestion and absorption depend on et al. 2005; Goulet et al. 2005).
the active mucosal surface of the intestinal More serious consequences result from resec-
tract. Three anatomical modifications amplify tion of the ileum. The ileum is responsible for
its surface area 500–600-fold: first, the plicae absorbing all the water that has been secreted in
circulares of Kerckring which are most promi- the upper intestinal tract following a hypertonic
nent in the upper jejunum; second, the villi meal. If the ileum is resected, this water spills
which are significantly higher in the duodenum over into the colon. Although the colon can
and proximal jejunum than in the ileum (0.8 vs increase water and solute absorption up to 400%
0.5 mm); and third, the microvilli covering the of normal, there is a limit to the excess that may be
luminal surface of the enterocyte (Madara and reabsorbed (Debongnie and Philips 1978). Another
Trier 1994). Altogether, the gut has a mucosal consequence of ileal resection is lifelong malab-
surface area of some 400 m2 in the adult; basi- sorption of vitamin B12 due to loss of site specific
cally, large reserves of absorptive and digestive receptors. Furthermore, the ileum is the major site
capacity are available. Following extensive loss of bile acid absorption. Nonabsorbed intestinal
of small bowel, the symptoms of an individual contents including bile acids spill over into the
patient depend not only on the digestive and colon and may cause significant diarrhea. Finally,
absorptive capacities but also on the inborn char- loss of the ileum results in a depletion of the bile
acteristics of the remaining bowel. The major salt pool leading to a disturbed micelle formation
factors are the age of the patient, the length and and malabsorption of fat and fat-soluble vitamins
the part of the small bowel that has been lost, and (A, E, D, and K). In consequence, nonabsorbed
the functional characteristics of the remaining hydrolyzed fatty acids reach the colon. The hydro-
bowel including its adaptive capacities. lyzed fatty acids bind eagerly to calcium to form
In normal human individuals, most of the nutri- calcium stearate. Subsequently, oxalate – which is
ents are digested and absorbed within the first part normally bound to intraluminal calcium and then
of the jejunum (Höllwarth 1999). After ingestion excreted with the feces – gets absorbed in increased
of food, luminal isotonicity is rapidly achieved in amounts, leading to oxaluria and eventually kidney
the upper jejunum either by water secretion stone formation. Similarly, due to the consumption
(hypertonic meal) or water absorption (hypotonic of enteric calcium by undigested fatty acids in the
meal). An isotonic aqueous medium is essential colon, the deconjugated enteric bilirubin remains in
for proper digestion and absorption. However, the solution resulting in a significant enterohepatic cir-
capacity of water and electrolyte absorption in culation of unconjugated bilirubin and increased
SBS patients does not depend on the residual secretion rates of bilirubin in the bile responsible
amount of small intestine alone but also to a for biliary sludge formation and the typical gall-
great extent on the presence or absence of colon stone diseases in SBS patients (Vitek and Carey
as well (Goulet et al. 2009). 2003; Brink et al. 1996). Furthermore, resection of
Resection of the jejunum induces only a tran- the ileum results in a loss of the “ileal brake.”
sient reduction of absorption of all nutrients due to Consequently nutrients spend less time in the stom-
an enormous adaptive capacity of the ileum, the ach and in the upper intestinal segments. Due to the
intact enterohepatic circulation of bile salts, and shorter contact, digestion and absorption are
the preserved absorption of vitamin B12. A mini- reduced, and an unusual large fluid load imposed
mum of ileum with at least 10–15 cm and the onto the distal remnants (Höllwarth 1999).
Resection of the colon reduces the capacity of the ileum than in the jejunum, which may be
water and electrolyte absorption. The osmotic explained by the fact that the remainder of the jeju-
load of the carbohydrates contributes substantially num in a SBS patient faces the usual composition
to diarrhea if only a little colon remains. If the and osmolarity of intestinal contents, while the ileal
colon is preserved, undigested fiber, carbohy- mucosa is confronted with a substantial different
drates, and proteins undergo a fermentation pro- composition of chyme that enhances mucosal adap-
cess to yield short-chain fatty acids (SCFA), tation. A long-term stimulation of intestinal growth
which are absorbed provide a significant source enlarges the absorptive surface area and includes an
of calories (Nordgaard et al. 1994). increase in villous height, crypt depth, intestinal
Citrulline is an amino acid that became length, thickness, and diameter in rodent experi-
recently interesting as a biomarker of the viable ments (O’Brien et al. 2001). Adaptive growth in
mass of enterocytes. It is nearly exclusively pre- regard to length and diameter of the remaining
sent in the enterocytes which produce citrulline bowel also occurs in humans and is most pro-
from glutamine or from other intermediates of the nounced in premature babies (Kurkchubasche et al.
glutamine synthesis pathway, such as ornithine or 1993). Epithelial hyperplasia following massive
glutamate (Peters et al. 2011). After release from bowel resection is observed as well, while villus
the enterocytes, citrulline passes unmetabolized hypertrophy and crypt depth accretion are not
the liver and is converted to arginine in the kidney. (Porus 1965; Pironi et al. 1994). Additionally water
Clinical evidence shows that citrulline is a useful and solute absorption is enhanced in the remaining
marker for small bowel length and absorptive ileum and colon; colonic bacteria ferment undigested
capacity (Peterson and Kerner 2012). In 2005 carbohydrates and proteins into short-chain fatty
Rhoads et al. showed in a retrospective study acids, which act as additional promoters of adapta-
that the citrulline level of children who were tion (Briet et al. 1995; Tappenden et al. 1997).
later weaned from parenteral nutrition (PN) was The precise mechanisms of adaptation are not
20 μmol/L, while it was 11 μmol/L in children clear, but intraluminal nutrients and endogenous
who were never weaned with a cutoff level of intestinal secretions and humoral factors stimulate
19 μmol/L providing a predictive value for growth. In general, the higher the workload
distinguishing the children cohorts. required for digestion and absorption, the more
Intestinal adaptation is the term which character- potent is the stimulus for adaptation. In response
izes the pathophysiology which follows intensive of the nutrients and secretions, a large number of
intestinal resection and by which 90% of babies trophic polypeptides, growth factors, and other
with SBS do finally reach a normal life on entirely mediators are secreted. Over the years, some of
oral nutrition. Extensive surgical resection results in them have attracted attention regarding their possi-
substantial loss of enterocyte mass or functional ble clinical value in promoting adaptation in SBS
mucosal surface that triggers the process of bowel patients. First, gastrin was demonstrated to exhibit
adaptation (Ramos-Gonzalez and Kim. 2018). On a trophic effects on the small bowel (Johnson 1976).
macroscopic level, this process results in bowel dila- Gastrin blood levels significantly rise after jejunal
tation, which in turn results in dysmotility and ulti- resection. This might be due to the decrease of
mately leads to stasis and bacterial overgrowth. On a gastric inhibitory polypeptide and vasoactive poly-
microscopic level, adaptation is associated with peptide normally secreted from the small bowel.
enterocyte proliferation, muscle hypertrophy, Hypergastrinemia causes gastric hypersecretion
increased villous height and crypt depth (Jones et imposing a substantial fluid load onto the intestinal
al. 2013). In animal studies, an increase of blood remnants and decreases the duodenal pH thereby
flow to the remaining bowel has been observed after inactivating most of the pancreatic enzymes
80% mid-intestinal resection, and perfusion of the (Stringer and Puntis 1995). Growth hormone
ileal remnant stayed elevated for at least 4 weeks, (GH) exerts direct and indirect metabolic effects
followed by an increase of DNA content (Ulrich- on the intestine, the latter by the production of
Baker et al. 1986). The latter is more pronounced in insulin-like growth factor (IGF-I) (Inoue et al.
1994). IGF-I is synthesized in the liver and in sustaining the physiological process of bowel
intestinal tissues. Its production is stimulated by adaptation following intestinal resection. The
directly by enteral feeding and indirectly by GH, clinical course of SBS can be divided into three
and the endogenous GH-IGF-I system is supposed stages which require individual management: the
to be an important regulator of small intestinal acute phase, the adaptation phase, and the main-
growth and adaptation (Winesett et al. 1995). GH tenance phase. The acute phase – the duration of
upregulates glutamine uptake in SBS in rabbits and which depends on the underlying disease – is
has also been shown to be effective in weaning of characterized by insufficient absorption,
adult patients from TPN (Byrne et al. 2005). Epi- dysmotility, diarrhea, and gastric hypersecretion
dermal growth factor (EGF) is secreted by the and hypergastrinemia. Therapeutic measures are
salivary glands and the duodenal Brunner’s glands guided by the underlying disease and the severity
and upregulates intestinal electrolyte and nutrient of illness of the patient. They are primarily aimed
transport in SBS experiments, but extensive clinical at restoring and maintaining fluid, electrolyte, and
studies have not been performed (Salloum et al. acid-base equilibrium and minimalizing nutrient
1993; Thompson 1999). The combination of GH loss. Compensating gastrostomy and enteral fluid
and EGF significantly enhanced adaptation after and electrolyte losses is important, and a central
massive enteral resection in rabbits (Iannoli et al. venous line is required.
1997). Enteroglucagon has been shown to stimu- The following adaptation phase is slower and
late the adaptive response on the intestinal tract in often takes more than a year to reach its peak –
animal experiments and humans (Bloom and Polak unrelated to the absolute length of intestinal rem-
1982). Since monoclonal antibodies failed to block nants. Treatment strategies during this phase
this trophic effect, recently a precursor of include carefully balanced parenteral nutrition
enteroglucagon such as glucagon-like peptide 2 and stepwise increasing enteral feeding. Balanced
(GLP-2) is considered to be responsible for stimu- fluid and electrolyte solutions must cover the
lating adaptation. It is produced in the ileum and basic demands and replace losses via a nasogastric
colon by endocrine L cells regulating gastric motil- tube, from an enterostomy, or due to excessive
ity, gastric acid secretion, and intestinal hexose diarrhea. Existing nutritional deficiencies should
transport and increasing the barrier function of the be restored by adequate supplementation of car-
enterocytes (Vanderhoof et al. 2003). Prostaglandin bohydrates, protein, and fat. Calorie intake in
(Pg) E2 and polyamines have also been shown to children needs to be continuously advanced to
stimulate cell proliferation in animal experiments accommodate the increasing demands of the
by increasing blood flow and DNA synthesis growing organism. Finally, the maintenance
(Höllwarth et al. 1988; Ulrich-Baker et al. 1986). phase in patients has a constant malabsorption
Experimental evidence exists that testosterone rate of 30% or more, during which a surplus of
enhances adaptation after small bowel resection in enteral calories has to be consumed daily,
cats (Pul et al. 1991). supplemented by vitamins, trace elements, and
minerals, adapted to the individual demands.
Growth in weight, height, and head circumfer-
Management ence are the basic parameters to ensure adequacy
of parenteral nutritional solutions and enteral
Nutritional Therapy feeding. In newborns and small infants, an infu-
sion running continuously over 24 h is most
Medical management strategies for children with appropriate. In contrast, when patients take at
short bowel syndrome are centred on the provi- least 20% of their total calorie requirements by
sion of adequate fluid, electrolytes and calories to the enteral route, intermittent parenteral feeding
allow for appropriate growth and neurological can be attempted and the intervals increased as
development (Oliveira and Cole. 2018). Strate- long as serum glucose levels are maintained. In
gies have developed that allow for enhancing or the older age groups and in adults, a 12-h infusion
time is usually well tolerated. Finally, parenteral baseline, is an indication to reduce the amount
nutrition can be restricted to the nocturnal period. and/or concentration of enteral feedings. Stool
The possibility of home parenteral nutrition (HPN) samples positive for reducing substances also sug-
considerably improves the quality of life for the gest that enteral feeding should not be advanced
patients and their families allowing a more normal and carbohydrate uptake should be reduced. In
lifestyle and substantially reduces hospital costs. infants with normal colon length, a decrease of
Enteral or oral feeding is usually should be stool pH below 5.5 signals carbohydrate
started as soon as the intestinal remnants resume malabsorption.
normal motility. Continuous enteral infusion via a Dietary modifications are recommended
gastric or jejunal tube has many advantages over depending on the individual situations. Patients
bolus feeding as it enhances intestinal absorption suffering from SBS with the colon intact benefit
(Vanderhoof et al. 2003). The technique avoids from a high-soluble fiber intake because the colon
gastric distension and offers a constant load of is capable of fermenting carbohydrates into short-
carrier proteins to the microvilli. When the neo- chain fatty acids (SCFA). Studies in rats have
nate’s condition improves, oral feeding of small shown that SCFA supplementation of TPN
amounts of breast milk three of four times daily enhances morphological and functional aspects
should be attempted. Human milk is the first choice of adaptation (Tappenden et al. 1997).
because it contains among several protective fac- On the contrary, patients who have had the
tors also glutamine and EGF which support intes- large bowel removed or excluded may do fare
tinal adaptation. When this is not possible, an better with a diet rich in fat providing a high-
extensively hydrolyzed protein formula can be energy concentration and a relatively small
used (Vanderhoof and Young 2004). They are ben- osmotic load (Nordgaard et al. 1994). In animal
eficial due to their higher content of di- and tri- experiments, triglycerides with highly unsaturated
peptides. In infants up to 6 months, protein- long-chain fatty acids such as menhaden oil have
containing diets might cause a protein-sensitive exerted more trophic effects on the intestinal rem-
enteritis/allergy. Therefore, amino acid formulas nants after resection than other long-chain fatty
are preferred. A recent retrospective study reported acid-containing oils (Vanderhoof et al. 1994).
an earlier weaning from PN and a reduced rate of Adolescents with SBS and very short small
allergies (De Greef et al. 2010). Once children are bowel remnants may have growth problems and
older than 1 year, they can often be managed with health-related problems of quality of life even if
more complex diets which may induce even more they were off PN for a long time. They tend to
the adaptation process and allergic injury to the gut have low levels of vitamin D and suffer from
is less common (Vanderhoof et al. 2003). decreased bone mineral density. Blood levels of
Medium-chain triglycerides are water soluble vitamins, trace elements, and minerals must be
and can be absorbed already in the stomach with- checked regularly, and any deficient substance
out the need for bile acid micelle formation, but has to be supplemented either orally or parenter-
their efficiency in enhancing the adaptation pro- ally as appropriate. Reinitiation of nutritional sup-
cess is far lower in comparison to long-chain fatty port improved pubertal development. Therefore,
acids. Therefore, elemental diets in pediatrics con- long-term follow-up well into adulthood is neces-
tain both medium- and long-chain fatty acids, the sary according to Miyasaka et al. 2010 and
mixture probably being the most efficacious for Olieman et al. 2012.
stimulation of adaptation.
Elemental diets are started in a low concentra-
tion at 20–25 kcal/kg/day and are slowly increased Supplemental Therapy
(D’Antiga and Goulet 2013; Goulet et al. 2013).
Carbohydrate content represents a substantial Hormonal therapy intends to stimulate and sup-
osmotic load and may cause diarrhea. A stool vol- port the intestinal adaptation process. Human
ume, which increases by >50% compared to growth hormone (HGH) has been used in a large
number of studies aimed to stimulate the adapta- has a very short half-life; therefore, teduglutide
tion process. However, recently published thera- came recently into the focus because it is a degra-
peutic trials with GH have inconsistent results. dation resistant GLP-2 analogue that has a signif-
Twelve adult patients on home parenteral nutrition icantly longer half-life and might restore intestinal
(HPN) receiving a low-dose GH over 3 weeks integrity after small bowel loss. A large double-
showed a significantly improved intestinal blind, randomized, placebo-controlled multicen-
absorption (Seguy et al. 2003). A prospective, ter trial showed that patients treated with
randomized, placebo-controlled, double-blind teduglutide had a significant greater reduction in
clinical study using GH, glutamine, and diet parenteral volume support when compared with
reduced the PN requirements by 6–8 L/week and placebo; however no patient was completely
4,000–6,000 cal/week (Byrne et al. 2005). Seven weaned from PN (Jeppesen et al. 2012). An
children aged between 21 and 90 month with a important result of this study was that plasma
residual small bowel not longer than 100 cm citrulline increased significantly concordant with
received repeatedly GH for 3 weeks and gluta- an increase in intestinal mass.
mine. Six children could be weaned from PN Among the amino acids, glutamine (GL) plays a
(Guo et al. 2012). In contrast, a 4-month treatment key role in the maintenance of intestinal structure
with high-dose GH, unaccompanied by a special and function by providing the energy required by
diet or glutamine supplementation, was not effec- cells with a rapid turnover, such as macrophages
tive in weaning off 14 children with long-term PN and enterocytes. Patients after major trauma or in
dependence (Peretti et al. 2011). Administration chronic catabolic states benefit from GL supple-
of high dose of recombinant human growth hor- mentation. It has been shown that GH increases
mone (rhGH) decreased the PN needs in eight glutamine uptake after intestinal resection,
children and improved the net energy balance. supporting the evidence that glutamine exerts tro-
However, six children remained on PN, and only phic effects in the small intestine and colon of
two children could be definitely weaned from PN patients with SBS (Ziegler et al. 1996). However,
(Goulet et al. 2010). A recent Cochrane review as mentioned above, conflicting results of studies
analyzing the role of GH with or without gluta- raised some doubts whether GH and glutamine are
mine in patients with chronic SBS showed some effective in stimulating and supporting the adapta-
benefits of weight gain and fat absorption. How- tion process (Wales et al. 2010).
ever, only a small number of patients have been A number of other medications are often
enrolled in these studies, and benefits of treatment needed in this very special group of patients.
were not sustained after cessation of therapy. The Gastric hyperchlorhydria during the early phase
study concludes that routine use of GH and gluta- after extensive loss of intestine can be
mine cannot be recommended for routine use in suppressed successfully proton pump inhibitors,
patients with SBS (Wales et al. 2010). thereby improving absorption and reducing high
Glucagon-like peptide 2 (GLP-2) is produced output diarrhea. Rapid intestinal transit can be
by L cells of the terminal ileum and colon in slowed by opioid medication. In this group
response to luminal nutrients. It has trophic effects loperamide has proved effective and safe to use
on the gut mucosa increasing nutrient absorption in the pediatric age group even over a long
and improving gut barrier function and reduces period of time. Octreotide acetate, a somato-
gastric acid secretion and stimulates intestinal statin analogue, essentially inhibits all exocrine
blood flow (Jeppesen et al. 2001; Hsie et al. and endocrine gastrointestinal secretions, is apt
2009; Meier et al. 2006; Cisler and Buchmann to improve quality of life in patients with pre-
2005). Patients with low levels of GLP-2 follow- dominantly secretory losses, and has been
ing the resection of the terminal ileum and colon judged beneficial in patients on long-term treat-
may benefit from treatment with GLP-2, thereby ment (Nightingale et al. 1989). However, it has
improving intestinal absorption and nutritional more side effects in comparison to loperamide, is
status (Jeppesen et al. 2001). However, GLP-2 rather expensive, and has suppression of growth
effects in children. Cholestyramine binds bile regrowth after massive bowel resection
acids and prevents choleretic diarrhea induced (Hadjitoffi et al. 2013).
by an excess of bile salts in the colon. While thus
reducing diarrhea, it may increase steatorrhea.
Ursodeoxycholic acid is known to counteract Surgical Therapy
hepatic damage by restricting the absorption of
potentially toxic bile acid metabolites from the The primary aim of surgical interventions is
colon. Of course, the latter considerations only restoration of the bowel continuity and stoma
apply if the colon is present. In patients with ileal closure as soon as possible in order to allow
resection but an intact colon, urinary oxalate all remaining intestinal segments to take part in
levels should be monitored. Dietary oxalate the adaptation process (Höllwarth 2017). The
restriction is to be recommended in patients majority of patients will finally be able to tol-
with high levels of oxaluria. A surplus of cal- erate full enteral feeding, and no additional
cium ingestion provides additional oxalate bind- surgical procedures are needed. Further surgery
ing capacity. Another effect of a surplus of oral might be only needed to deal with complica-
calcium in these cases comes from the fact that tions such as intestinal obstruction and ileus, a
they bind to bilirubin which is then excreted too fast intestinal transit time or a dysmotility
instead of absorbed. Supplementations of the problem due to grossly dilated intestinal loops
diet with non-starch polysaccharides such as with stagnation of chyme, or if the adaptation
pectin or other soluble fibers which are process is impaired by a too small absorptive
fermented by colonic bacteria to SCFA and surface, respectively.
absorbed provide a significant additional source A variety of surgical procedures to slow intes-
of energy. Additionally, they increase prolifera- tinal transit time have been invented and applied
tion of enterocytes. in humans. Reversed (antiperistaltic) intestinal
Probiotics are live organisms with beneficial segments (Fig. 2) have been used in over
effects on the host. Experimental studies have 40 adult patients, and in most of them, a delay of
shown that probiotics decrease bacterial translo- chyme transport was achieved and increased
cation and have a stimulating effect on bowel absorption documented (Panis et al. 1997;
regrowth after massive intestinal resection Thompson and Langnas 1999). However, all of
(Mogilner et al. 2007; Eizaguirre et al. 2011). these reports are anecdotal, and so far it remains
In humans with SBS, probiotics might also sup- uncertain whether these effects will be
port intestinal adaptation, enhance barrier func- maintained. In children only a few reports have
tion, and suppress pathogenic bacteria. been published. One of them describes a baby
However, there is a paucity of clinical studies with 11 cm small bowel plus ileocecal valve
in children with SBS. A recent meta-analysis (Kurz and Sauer 1983). This patient is now
showed that evidence from some clinical studies 38 years and on full enteral nutrition. Intestinal
indicates that probiotics have a potential for ben- valves and sphincters have been crated in a few
efit, but RCT are missing. Among nine case humans, mostly children, with doubtful long-
reports, five showed beneficial effects and term results (Ricotta et al. 1981). Construction of
four reported adverse effects of probiotics valves has also been used to induce adaptation
(Reddy et al. 2013). In two studies probiotics and dilatation of the proximal bowel per-
have been effective in the treatment of forming later a lengthening procedure if needed
bacterial overgrowth and D-Lactic acidosis, (Georgeson et al. 1994). A segment of colon can
improved tolerance of enteral feeds and weaning be interposed in the small bowel, more proximally
from TPN (Vanderhoof et al. 1998; Kanamori et in the isoperistaltic direction or in an anti-
al. 2001). Dietary supplementation with vitamin peristaltic manner distally (Fig. 3). Few clinical
D has been shown in a rat model of SBS to cases have been reported in children (Glick et al.
stimulate enterocyte turnover and intestinal 1984).
Fig. 2 Reversed intestinal segment aimed to reduce intestinal transit time. Appropriate length in newborn babies about
3 cm (from Höllwarth ME in Puri P, Höllwarth ME, “Pediatric Surgery”; Springer Surgery Atlas Series 2006)
Fig. 3 Colon interposition

can be used in an
isoperistaltic manner to
increase absorption and in
the antiperistaltic manner
the decrease transit time.
The method has been used
only in a few patients (from
Höllwarth ME in Puri P,
Höllwarth ME, “Pediatric
Surgery”; Springer Surgery
Atlas Series 2006)
Lengthening Procedures Dilated intestinal motility. Bianchi introduced an interesting proce-

loops with inefficient peristalsis and stagnant dure consisting of longitudinal division of the
chyme are a common problem in patients with dilated part into two separate segments each com-
SBS, either as a consequence of the underlying prising one half of the circumference (Bianchi
pathology, e.g., remnants after multiple atresias, 1980). The principle behind the Bianchi proce-
or following initially effective adaptive growth dure is to increase exposure of chime to the intes-
that finally overshoots to result in large dilated tinal mucosa and enhance nutrient absorption by
bowel segments with insufficient and undirected increasing bowel length and reducing intestinal
Fig. 4 Bianchi method of intestinal lengthening aimed to refashion dilated loop with insufficient peristalsis and stagnant
chyme (from Höllwarth ME in Puri P, Höllwarth ME, “Pediatric Surgery”; Springer Surgery Atlas Series 2006)
Fig. 5 The effects of serial transverse enteroplasty (STEP) are aimed to improve insufficient peristalsis and digestion
(from Höllwarth ME in Puri P, Höllwarth ME, “Pediatric Surgery”; Springer Surgery Atlas Series 2006)
dilatation. Both segments remain viable because insufficiency (Bianchi 1997). Long-term results
the mesenteric vessels divide extramurally into show in some patients recurrent dilatation and
branches supplying either side of the bowel sepa- overgrowth; thus patients with inherent motility
rately. The two halves are then refashioned to disorders may not be selected for this procedure
tubes of normal intestinal diameter which are (Thomson et al. 2000; Vernon and Georgeson
lined up in the isoperistaltic direction and anasto- 2001).
mosed one to the other yielding twice the length of Serial transverse enteroplasty (STEP) (Fig. 5) is a
the original part (Fig. 4). Although this technique new procedure that gained significant attention
has been used in a larger number of patients, it has worldwide as a method to refashion dilated intestinal
only proved successful when performed in a later loops thereby improving peristalsis and motility (Kim
stage of the disease, on so-called self-selected sur- et al. 2003; Sommovilla and Warner 2014). It is
vivors, i.e., patients in stable general condition free technically much easier when compared with the
of other severe complications such as liver Bianchi method. Long-term results show that a
Fig. 6 A short dilated

intestinal loop can be
refashioned by infolding the
excessive part of the gut
without losing absorptive
area (from Höllwarth ME in
Puri P, Höllwarth ME,
“Pediatric Surgery”;
Springer Surgery Atlas
Series 2006)
majority of children can be weaned off PN except progressive liver failure and recurrent sepsis. In the
children with motility problems and/or gastroschisis past, the results of intestinal TPX have been poor,
(Javid et al. 2013). Results from an International mainly due to high rejection rate. Recently, signifi-
Registry show that 11 out of 97 patients died (11%) cant progress has been achieved by introduction of
and 5 progressed to intestinal transplantation. Forty- new immunosuppressive agents (tacrolimus,
seven percent attained full enteral nutrition, and everolimus, OKT 3) and induction therapy with
patients with primarily longer bowel were signifi- daclizumab. A survey on 500 intestinal and multi-
cantly more likely to achieve enteral autonomy visceral transplantations showed in the last era of
(Jones et al. 2013). Typical complications of both pretreatment strategies using antithymocytic globu-
bowel-lengthening techniques are bowel lin and alemtuzumab 1-year and 5-year patient sur-
re-dilatation, bleeding from the staple line, and vival rates of 92% and 70% (Abu-Elmagd et al.
bowel obstruction (Kang et al. 2012). Intestinal 2009). According to Intestinal Transplant Registry
refashioning can be achieved surgically by tailoring reports, 1,611 children were transplanted worldwide
the antimesenteric side of a dilated loop, either by between 1985 and 2013, with an overall survival
resection of abundant wall – provided that enough rate of 51% (Marino and Lauro 2018). However,
absorptive area remains available and stasis is the intestinal grafts have often a suboptimal absorption
only problem – or by infolding the excessive part of capacity which necessitates for the patients a signif-
the intestinal circumference in a longitudinal way icant higher-energy intake (Ordonez et al. 2013).
(Fig. 6).
Intestinal transplantation (TpX) either isolated
or combined with the liver is the most effective Complications
method to increase the absorptive surface. Indica-
tion for isolated intestinal TPX is given in infants Despite the progress in intensive care medicine
with very little or no small bowel at all who are and long-term parenteral nutrition, many compli-
expected to be dependent on TPN for life and/or for cations do occur in patients with SBS, some of
patients with failure of venous access. Indication for which are life threatening. Among the most
combined TPX is intestinal failure together with important ones are central venous catheter-related
problems, liver failure, and bacterial overgrowth gastrointestinal bleeding, and deconjugation of
and translocation. bile acids finally leading to malabsorption. If the
Infections related to the central venous line predominant species are lactobacilli, the resulting
have two major pathways, an external and an massive lactate production decreases intraluminal
internal route. Today, bacterial contamination of pH and causes L-lactic and D-lactic absorption.
the infusion solution has been virtually eliminated The latter is poorly metabolized and may be
by developing detailed practice guidelines for responsible for recurrent episodes of acidosis
aseptic care. Colonization of the catheter along and coma (Vanderhoof et al. 2003). Elevated
the skin, especially by coagulase negative staph- D-lactate in serum or urine can be used for diag-
ylococci, is highly resistant to antibiotic treatment nosis of lactobacilli overgrowth. Treatment of
as long as the foreign body is not removed (Cole bacterial overgrowth is either surgically if massive
et al. 2012). The incidence of this way of infec- distended loops are the cause or medically with
tions has been greatly reduced by tunneling the cyclic antibiotic intestinal decontamination for
catheter between the entrance in the skin and the 1 week/month. Development of resistance may
entry into the vein. The incidence of this problem necessitate changing the antibiotics. Probiotics
has been further reduced by using special ports have also been proposed as treatment of bacterial
which are implanted subcutaneously for patients overgrowth because they display antibiotic activ-
on home parenteral nutrition (HPN). Recently it ity against a wide variety of bacteria, fungi, and
has been shown that a 70% ethanol solution viruses. Probiotics, such as Lactobacilli and
instilled into the central vein catheter for at least Bifidobacterium, can suppress or directly kill
4 h/day either daily or three times a week pathogenic bacteria (Reddy et al. 2013).
decreases significantly catheter-related infections Bacterial translocation (BT) is the major
(Wales et al. 2011). Central venous catheter harmful consequence of bacterial overgrowth.
replacement decreased from 5.6 4.1 per 1,000 Experimental studies of a SBS model in rats
catheter days to 0.3 0.2 per 1,000 catheter days have shown a significant increase in BT after
after ethanol lock therapy. Taurolidine is an anti- jejunum (70%) or ileum resection (58%) when
microbial and antifungal naturally occurring sub- compared to sham laparotomy animals (12%)
strate. Using taurolidine as an indwelling catheter (Schimpl et al. 1999). While under normal cir-
solution in children on HPN resulted in a decrease cumstances BT to mesenteric lymph nodes takes
of catheter-related infections from 8.6 to 1.1 epi- place at a rate of 5–8% but is not clinically signif-
sodes per 1,000 catheter days (Chu et al. 2012). icant in the presence of a fully functioning
However, loss of vascular access due to recurrent immune system. However, bacterial translocation
catheter infections is one of the indications for increases up to tenfold to the portal vein, and
intestinal TpX. systemic spread occurs if bacterial overgrowth
In contrast, endogenous infections caused by impairs the intact mucosal barrier and leads to
continuous or intermittent bacteremia from a dis- intestinal permeability. The latter is associated
tant focus still impose a significant problem and with recurrent episodes of sepsis, central venous
have gained increased attention. Over two thirds line infections, and severe liver disease.
of systemic infections in neonates on TPN are Long-term parenteral nutrition is well known
caused by germs which are normally encountered to cause liver steatosis in adults. It may be directly
in the intestine (Pierro et al. 1998). Stasis of nutri- related to the delivery of an inappropriate carbo-
ents and secretions due to insufficient propulsive hydrate load and excess of calories. The course is
peristalsis in dilated intestinal loops allows bacte- usually uncomplicated with mild and often tran-
rial overgrowth. Intestinal motility, gastric acidity, sient bilirubin and liver enzyme elevations, and
the intact mucus layer, secretory IgA, and the recovery of hepatic function occurs once more
ileocecal valve are supposed to be factors pre- than 50% of calorie intake is tolerated enterally.
venting bacterial overgrowth. Bacterial over- Intestinal failure-associated liver disease
growth results in inflammation of the mucosa, (IFALD) is in contrast a serious hepatic
dysfunction with intrahepatic cholestasis. It is Dore et al. 2017). Presence of the ileocecal
mainly observed in neonates and infants with valve and a small bowel length >10% of the
SBS and long-term parenteral nutrition. It finally expected length for age are the major predictors
leads to cirrhosis and death, or it necessitates a of weaning from PN (Spencer et al. 2005; Goulet
combined intestinal/liver TpX. The causes of et al. 2005). The mainstay of the treatment of a
IFALD are multifactorial, and known risk factors newborn or child with a SBS consists of
additionally to the duration of TPN are prematu- a sophisticate enteral stimulation with an indi-
rity and recurrent septic episodes. The latter risk vidually balanced nutritional equilibrium
factor is closely associated with intestinal micro- between carbohydrates, proteins, and fatty
organisms flushed directly in to the liver in cases acids. The enteral nutrition is the best stimulus
of severe BT. Different components of lipid emul- for adaptation. The use of additional hormonal
sion used in TPN have been suspected for their therapies has not yet proved sufficiently
possible role in IFALD (Raphael and Duggan by controlled studies. Home parenteral
2012; Javid et al. 2011). Recently, lipid solutions nutrition (HPN) significantly decreases the
rich in ω-3 fatty acids (fish oil) have shown to complication rate and improves the psychologi-
improve liver function and to reverse cholestasis cal situation of the patient. Nevertheless, the
in IFALD (Puder et al. 2009). Deficiency of spe- annual costs/patients are between $100.000
cific amino acids such as taurine, serine, or methi- and $150.000 (Schalamon et al. 2003).
onine may also exert toxic effects on the Recent estimations including all costs were cal-
hepatocytes. Bacterial-driven bile salt culated to be $ 355.000–$ 600.000 (Olieman
deconjugation results in increased amounts of et al. 2010).
toxic bile salts such as desoxycholic and
lithocholic acids, which are absorbed in the
colon and impair bile flow. Ursodesoxycholic Conclusion and Future Directions
acid therapy replaces harmful bile acids and
reduces cholestasis according to experimental Treatment of babies with SBS is a challenge that
and clinical studies. Cycling of PN and prevention needs a sophisticated multidisciplinary team. The
of sepsis have been recommended to prevent length of the small bowel remnant and the pres-
and/or treat IFALD (Raphael and Duggan 2012). ence of the ileocecal valve influence the time
The duration of dependence on PN is influenced needed for weaning from parenteral nutrition.
by the residual short bowel length and the per- Crucial for a successful weaning is the presence
centage of daily enteral caloric intake of a good propulsive intestinal motility – with or
(Sondheimer et al. 1998). without adjunct surgical measures. Fish oil lipid
emulsions offer new aspects in the therapy of
cholestatic liver failure. Approximately 10% of
Prognosis patients will benefit from surgical interventions
which are indicated only in some individual as a
Survival of children with SBS has significantly helpful adjunct therapy, either by prolongation of
improved over the last decades due to collecting transit time or by remodeling parts of the intestine.
the expertise by multidisciplinary teams (Stanger These procedures should only be considered in
et al. 2013; Hess et al. 2011). Long-term survival the context of a full multi-disciplinary plan of
today is between 72% and 90% and does not care provided by a centre that specializes in intes-
only depend on the length of the remaining tinal rehabilitation. However, even after success-
bowel but on the incidence of complications ful weaning from parenteral nutrition, some of
such as IFALD, recurrent septicemia, central these patients may suffer in the adolescence from
venous line infections, and the quality of the nutritional and/or digestive problems necessitat-
motility of the remaining bowel (Spencer et al. ing long-term follow-up. Some of the may come
2005; Diamond et al. 2007; Pakarinen et al. after years either to additional HPN or to intestinal
2013; Fullerton et al. 2016; Cohran et al. 2017; TPX due to insufficient absorption of nutrients.
Progress in tissue engineering might offer future De Greef E, Mahler T, Janssen A, et al. The influence of
therapies for augmentation of the absorptive neocate in pediatric short bowel syndrome on PN
weaning. J Nutr Metab. 2010:Article ID 297575. 6 pages
surface area. Debongnie J, Philips S. Capacity of the human colon to
absorb fluid. Gastroenterology. 1978;74:698–703.
Diamond IR, de Silva N, Pencharz PB, et al. Neonatal short
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Part VI
Newborn Surgery: Liver and Biliary Tract
Biliary Atresia
77
Mark Davenport and Amy Hughes-Thomas
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1128
Extrahepatic Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1129
Cystic Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130
Etiological Heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130
Biliary Atresia Splenic Malformation (BASM) Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . 1130
Intrahepatic Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1131
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Blood Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Liver Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Cholangiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1132
Screening for Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Surgery: Kasai Portoenterostomy (KPE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1133
Options and Alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1135
Adjuvant Therapy for Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1136
Postoperative Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1137
Outcome and Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139
M. Davenport (*)
Department of Paediatric Surgery, Kings College Hospital
NHS Foundation Trust, London, UK
e-mail: markdav2@ntlworld.com;
mark.davenport@nhs.net
A. Hughes-Thomas
Department of Paediatric Surgery, Kings College Hospital,
London, UK
e-mail: aoht@doctors.org.uk
# Her Majesty the Queen in Right of United Kingdom 2020 1127

https://doi.org/10.1007/978-3-662-43588-5_81
1128 M. Davenport and A. Hughes-Thomas
Prognostic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1139

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1141
Abstract which leads to hepatic fibrosis and cirrhosis.

Biliary atresia remains one of the most chal- This leads to liver failure complicated by portal
lenging conditions in pediatric surgery. The hypertension and ascites and ultimately death.
incidence ranges from 1 in 5,000 in Asia to It can however be effectively treated in a high
about 1 in 16,000 live births in Europe with a proportion by surgery. For the remainder, liver
slight female preponderance. The cause is still transplantation is an option and indeed BA
unknown with a number of possible causes remains the single most common cause for this
giving rise to a range of different presentations. in the pediatric age group.
It is usually an isolated condition but can be
associated with other anomalies.
Currently the management is almost History
entirely surgical with an initial attempt to
restore bile flow and preserve the native liver John Thomson, a physician working in Edin-
using a Kasai portoenterostomy. Liver trans- burgh, reported an infant he felt had “congenital
plantation is an option if this fails or for those obstruction of the bile ducts” in 1891. This child
infants who present late with obvious who became deeply jaundiced had clay-colored
end-stage cirrhosis. Beyond effective surgical stool and dark urine from the time of birth and
technique, the role of adjuvant medical therapy ultimately died from liver failure or sepsis at a few
is unclear and evidence of benefit is lacking. months of age. The illustrations from the postmor-
Despite this the use of postoperative steroids, tem showed a normally formed but empty gall-
prophylactic antibiotics, and choleretic agents bladder with two small bile-filled cysts in the
such as ursodeoxycholic acid is common. porta hepatis indicating an absence of the com-
Experience from high-volume centers sug- mon hepatic duct (Thompson 1891).
gests clearance of jaundice can be achieved in The influential American pediatric surgeon Wil-
50–60% of infants with 10-year native liver liam Ladd published a series in 1928 of 11 cases of
and real survival rates of 40% and 90%, surgical jaundice he had operated upon (Ladd
respectively. 1928). He describes using restoration of bile flow
using reconstruction techniques such as hepatico-
Keywords jejunostomy. Though not all of these cases were
Biliary atresia · Kasai portoenterostomy · truly biliary atresia, some appearing to be
Surgical jaundice · Cirrhosis · BASM · Cystic choledochal cysts and luminal blockages with
biliary atresia inspissated bile, it presaged a surgical approach to
such infants. Nonetheless, with increasing surgical
experience in infants with biliary atresia, it was
Introduction quickly realized that most actually appeared to
have an entirely solid extrahepatic biliary tree and
Biliary atresia (BA) is a rare but important cause therefore were “uncorrectable” by the conventional
of neonatal jaundice. BA remains a somewhat surgical techniques available at the time.
elusive disease, confined as it is to infancy but In the 1950s, Morio Kasai, working in Sendai,
yet with its origin essentially unknown. If Japan, developed a much more radical approach
untreated it results in progressive cholestasis to the biliary dissection, advocating complete
77 Biliary Atresia 1129
excision of the extrahepatic biliary tree and anas- down. By the end of the 1970s, increasing use of
tomosis of the Roux loop to the denuded, trans- the effective immunosuppressive cyclosporine
ected, albeit “solid” porta hepatis (Kasai and allowed a resumption of liver transplantation,
Suzuki 1959). He recognized that actually most and it then became a viable proposition for ini-
retained some communication with the tially older children who had had some response
intrahepatic bile ducts via microscopic biliary to a KPE. Our own program began as a joint
channels and exposure of these could restore bile venture in the mid-1980s as the King’s College
flow in a proportion. This operation, now known Hospital – Cambridge collaboration led by Sir
as a Kasai portoenterostomy (KPE), still fails in a Roy Calne and Alex Mowat.
disappointingly high proportion but still remains
the only realistic option in most cases as an
attempt to salvage the native liver. Extrahepatic Pathology
The first liver transplant anyway was
performed in March 1963 by Thomas Starzl in BA affects both intra- and extrahepatic bile ducts
Denver, Colorado, on a child who had been born and can be described as a pan-ductular
with biliary atresia (Starzl et al. 1963). Though cholangiopathy. The commonest classification is
unsuccessful as she died on-table from uncontrol- derived from the Japanese Association of Pediat-
lable bleeding, it did mark a historical milestone. ric Surgeons and divides BA into three types
Liver transplant programs then emerged through- based on the most proximal level of occlusion of
out the world in the 1960s, but in the face of the extrahepatic biliary tree (Fig. 1).
ineffective immunosuppression and invariable In types 1 and 2, there is usually some degree
recipient demise, they were inevitably closed of preservation of structure of the intrahepatic
Fig. 1 Schematic
illustration of biliary atresia
classification
bile ducts though these are clearly still highly (Hartley et al. 2009). Three groups can be defined
abnormal with blunting, irregularity, and pruning clinically:
(and importantly absence of dilatation, even when
obstructed). Type 3 (aka “uncorrectable” BA) is the (i) Biliary atresia splenic malformation
commonest type seen where the intrahepatic (BASM) syndrome
bile ducts are grossly abnormal with myriad (ii) Cystic biliary atresia
microscopic ductules coalescing at the porta (iii) Isolated biliary atresia
hepatis. There are then two further distinct sub-
types often dependent on the appearance of the Other entities are fewer in number, but there
gallbladder. Most have an atrophic gallbladder, does seem to be a relationship with other gastro-
and these can be associated with an intact, yet intestinal anomalies such as esophageal atresia
solid biliary tree or complete absence of the and jejunal atresia in a small proportion (<2 %
common bile duct. This latter appearance is of large series) and occasional cases with a
characteristic of the extrahepatic ducts of the defined chromosomal abnormality (e.g., cat-eye
syndromic form (see later). Alternatively syndrome and chromosome 22 aneuploidy).
the gallbladder can look entirely normal and Developmental biliary atresia is a term which
be filled with a clear mucus (it is these that are we have proposed for those where the onset is
misdiagnosed on ultrasound). These typically almost certainly prenatal and evident by the time
have a normal and often patent common bile of birth. It currently includes BASM, BA arising
duct but an absence of the common hepatic with other congenital anomalies, chromosomal
duct. Finally, in some infants there is an obvi- BA, and cystic BA (Livesey et al. 2009). The
ous inflammatory reaction with edema and onset of occlusion in isolated BA is much more
hypertrophy of the adjacent lymphoid tissue; contentious, and it is widely believed that the bile
in others this appears entirely absent with trans- duct can be normally formed and even patent at
lucency of the peribiliary tissues. the time of birth becoming occluded secondarily,
perhaps by virally mediated cholangiocyte
damage.
Cystic Biliary Atresia
Extrahepatic cyst formation (containing clear Biliary Atresia Splenic Malformation

mucus or bile) occurs in about 5–10% of cases (BASM) Syndrome
and can be termed cystic biliary atresia (CBA)
(Caponcelli et al. 2008). It is distinguishable clin- While the association of BA with polysplenia had
ically and histologically from simple obstruction been recognized for some time, clarification of what
in a cystic choledochal malformation as there is constitutes BASM is only relatively recent (Daven-
preservation of an epithelial lining and retention port et al. 1993, 2007). The constellation of other
of a normal and often dilated intrahepatic biliary anomalies (Table 1) is peculiar and the reasons for
tree in the latter. Where retrograde cholangiogra- this are still obscure. The embryological insult may
phy is possible in CBA, the intrahepatic bile ducts be common to all affected developing organs and
are often seen as a primitive “cloud-like” appari- may simply be timing (20–45 days of gestation –
tion above the porta hepatis. corresponding to Carnegie stages 10–18) rather than
a specific genetic defect. There are key genes which
are important in both bile duct development (e.g.,
Etiological Heterogeneity JAG1, HNF-6) and visceral and somatic symmetry
(e.g., INV, CFC-1), although actual correlation with
BA is not a single disease, certainly not one with a the human condition is patchy. A possible genetic
single cause. In all probability it is a phenotype link has recently been reported by a French group
resulting from a number of different etiologies who found an increased frequency of mutations in
Table 1 Biliary atresia splenic malformation (BASM) 2007). Monocytes/macrophages also have an
syndrome important role as antigen-presenting cells and
Components Features also as cellular mediators perpetuating the inflam-
Splenic Polysplenia, double spleen matory process and initiating fibrosis.
Asplenia There is a parallel increase in inflammatory
Abdominal situs Situs inversus mediators (especially sVCAM) and cytokines
Cardiac e.g., ASD, VSD, Fallot’s tetralogy
(especially TNF-α, IFN-γ, IL-2, and IL-18 ) iden-
Vascular Preduodenal portal vein
Absence of vena cava
tifiable in the serum, which continues to increase
Absence of portal vein during the early postoperative period and only
Gastrointestinal Malrotation, annular pancreas abates from about 6 months (Narayanaswamy
et al. 2007).
the CFC-1 gene (on chromosome 2), compared to

controls (Davit-Spraul et al. 2008). Alternatively, we Epidemiology
identified that infants with BASM may arise as a
result of an abnormal intrauterine milieu. Certainly There is a marked geographical variation in the
maternal diabetes was a key observation in our incidence of BA across the world. It appears most
series (Davenport et al. 1993), and although the common in Asian countries such as Japan and
mechanism of its embryopathic effect is still not China. Taiwan, for instance, has the highest
known, in general it is associated with a tenfold reported incidence at 1 in 5000 live births. By
increase in birth defects and some very specific contrast it is much less common in Western
malformations such as sacral agenesis and transpo- Europe and North America with rates of 1 in
sition of the great vessels. 15,000–20,000 being reported. Our own study in
England and Wales had an overall incidence of
1 in 17,000, but there was also a markedly signif-
Intrahepatic Pathology icant variation within the country with
diminishing incidence along a north and west
Biliary atresia is not simply a mechanical extra- axis (Livesey et al. 2009). There is a female pre-
hepatic biliary obstruction – in which case there dominance in development BA, not seen in
would be dilatation of the intrahepatic bile ducts. isolated BA.
Early features include portal tract edema, plug- Seasonality in BA has been sought in a few
ging, and then duplication of biliary ductules. studies in order to strengthen a possible link with
Increasingly, fibrosis is evident ultimately leading perinatal viral infection though there was no evi-
to overt macronodular cirrhosis. There is early dence for this in the largest of such studies
portal tract inflammation and in a proportion of (Livesey et al. 2009).
cases an obvious mononuclear cell infiltrate typi- Infants who are later diagnosed with BA have a
cal of an inflammatory response. normal range of birth weights and gestational age,
There will be abnormal expression of class II even those with the developmental forms of
antigens on biliary and vascular epithelium with BA. Failure to thrive then becomes evident and
expression of cellular adhesion molecules (ICAM their postnatal weights at diagnosis are
and VCAM) in about 50% of infants (Davenport subnormal.
et al. 2001). The nature of the infiltrate is still the
subject of ongoing research but appears to be
largely CD4+ T cells and, within that genera, Clinical Features
predominantly Th1 and Th17. Polarized Th1
cells also appear to be oligoclonal suggesting Infants with BA are often otherwise healthy and
perhaps a proliferative response to a specific anti- usually present soon after birth with persistent
gen (speculatively viral proteins) (Mack et al. jaundice, acholic stools, and dark urine. Around
40% of infants with cystic BA are detected biochemistry will show a conjugated hyper-
antenatally with the cyst seen on the maternal bilirubinemia, slightly raised transaminases
ultrasound scan, typically at around 20 weeks (AST and ALT), and significantly raised
of gestation (Caponcelli et al. 2008). It is γ-glutamyltranspeptidase (GGT). Protein and
important to have prompt differentiation albumin levels are usually normal. The AST-to-
postnatally between BA and a choledochal platelet ratio index (APRi) can also be calculated
malformation to ensure prompt appropriate and has been used as a surrogate marker of liver
management. fibrosis and perhaps as a prognostic index
Infants usually demonstrate a degree of failure to (Grieve et al. 2013).
thrive by the time of diagnosis which is thought to
be due to fat malabsorption. Subsequent deficiency
of the fat-soluble vitamins A, D, E, and most impor- Imaging
tantly K can mean some infants will present with a
bleeding tendency, and in severe cases, this can be An abdominal ultrasound is a key part of the
as catastrophic as an intracranial hemorrhage. diagnostic process in order to exclude other pos-
Liver fibrosis and are time-dependent features sible surgical diagnoses. The signs in BA however
which seem to begin perinatally even in those are less specific but might include an atrophic
infants with developmental BA (Makin et al. gallbladder with no evidence of filling between
2009). Features such as obvious ascites, marked feeds and a “triangular cord sign” representing the
hepatosplenomegaly, etc. should therefore be con- sonographic appearance of the solid proximal bil-
sidered a late sign and are not seen before iary remnant in front of the bifurcation of the
80–90 days. portal vein (Park et al. 1997).
Radioisotope (technetium (Tc)-labeled
iminodiacetic acid derivatives) hepatobiliary
Diagnosis imaging was formerly quite popular in showing
absence of biliary excretion. However, it is rarely
It is important to distinguish between medical and specific, and there is considerable overlap with
surgical causes of the jaundiced infant. Table 2 neonatal hepatitis (Shanmugam et al. 2009).
illustrates the differential diagnosis of conjugated
hyperbilirubinemia (Davenport et al. 2003). The
process involves a panel of blood investigations Liver Biopsy
(to exclude α-1-antitrysin deficiency, TORCH
infections, etc.), ultrasonography (to exclude Percutaneous liver biopsy, looking for histologi-
other surgical causes such as choledochal cal features of “large-duct obstruction” as against
malformations, inspissated bile syndrome, etc.), those of “neonatal hepatitis,” is safe and well-
and at least in our center percutaneous liver tolerated but needs an experienced pathologist to
biopsy. In other centers such as those in Asia, interpret (Russo et al. 2016). Currently it is the
simple placement of a naso-duodenal tube and diagnostic method of choice in two out of the
aspiration over 24 h is the principle method of three English BA centers.
making the diagnosis.
Cholangiogram
Blood Tests
Direct cholangiography is certainly possible,
Hemoglobin and white cell counts are normal either using ERCP (Shanmugam et al. 2009) or
although the platelet count may be raised. This latter at laparoscopy (Nose et al. 2005). ERCP is tech-
observation appears to be specific for BA. Liver nically challenging even with the right equipment
Table 2 Differential diagnosis of conjugated hyperbilirubinemia

Medical Key investigation Surgical Key investigation
“TORCH” infections toxoplasma, Serology Choledochal US and MRCP
cytomegalovirus, hepatitis, syphilis malformation
α-1-Antitrypsin deficiency Protein electrophoresis Inspissated bile US, MRCP
syndrome Percutaneous
transhepatic
cholangiogram
Alagille’s syndrome Clinical features (e.g., Spontaneous US and radioisotope
abnormal facies, perforation of bile scan
echocardiography) duct
Vertebral x-rays
Genetic testing
Cystic fibrosis Sweat test Tumors US and CT scan
Genetic testing
Parenteral nutrition-associated History
cholestasis Liver biopsy
Progressive familial intrahepatic Liver biopsy
cholestasis Genetic testing
? low GGT
Family history
Metabolic causes, e.g., galactosemia Gal-1-PUT level
but can avoid laparotomy in the larger infants.

Laparoscopy and direct puncture of the gallblad- Management
der is also relatively straightforward as an access
point for a cholangiogram. Surgery: Kasai Portoenterostomy (KPE)
The operation can be divided into various steps:
Screening for Biliary Atresia (i) Confirmation of diagnosis: A limited right-

upper quadrant muscle-cutting incision allows
Screening programs have been initiated in some access to the gallbladder and a cholangiogram
countries in order to reduce the time to definitive (if possible). If there is no lumen, then that, in
surgery. The most well-developed has been that in itself, is evidence for BA. The cholangiogram
Taiwan (Hsiao et al. 2008) but other European coun- should show the complete biliary tree and
tries are also pioneering it. Mothers are issued with drain into the duodenum to exclude BA.
color-coded cards and asked to compare with their (ii) Mobilization of the liver: Our practice sug-
infant’s stool. Recognition of pale stool then pro- gests that complete porta hepatis dissection
mpts further investigation and referral. This has requires mobilization of the liver allowing it
lowered the time to surgery in Taiwan, but still it is to be everted outside of the abdominal cavity.
no quicker than in the UK even though there is no The anesthetist needs to be aware of this
such coordinated program. They do avoid the prob- maneuver as it reduces venous return and
lem of the “missed” infant presenting late (>100 requires judicious intravenous volume sup-
days old) with BA and overt cirrhosis which is still port. Alternatively, some surgeons leave the
seen in England and Wales. A recent review of our liver in situ but sling the right and left vas-
program suggested that this had fallen from 7.8% in cular pedicles and use traction to expose the
the period 1999–2004 to 4.8% in the period porta hepatis. There is a risk of portal vein
2009–2013 (personal observation). thrombosis with this technique.
Fig. 2 Kasai
portoenterostomy –
anatomy of the region
Fig. 3 Kasai
division of common bile
duct and mobilization of
gallbladder
(iii) Portal dissection: The gallbladder is mobi- coagulation diathermy to open up the
lized from its bed and the distal CBD divided recessus of Rex (where the umbilical vein
and then dissected back toward the porta joins the left portal vein). On the right side,
hepatis (Figs. 2 and 3). Division of small the division of right vascular pedicle into
veins from the back of the portal confluence anterior and posterior should be visualized.
to the porta plate facilitates downward trac- The “width” of the transected portal plate
tion of the portal vein and exposes the cau- should extend from this bifurcation and a
date lobe. On the left side, there is often an small innominate fossa on the extreme right
isthmus of liver parenchyma (from segments to the point where the umbilical vein joins
III to IV) which may need division by the left portal vein.
Fig. 4 Kasai
resection of biliary
remnants and anastomosis
with Roux loop
(iv) Porta hepatis transection: Excise remnants When there is patency of the native gallbladder
flush with the liver capsule by developing a and common bile duct, some, at least in France,
plane between solid white biliary remnant would consider a portocholecystostomy, as it does
and the underlying liver starting at the gall- have the advantage of abolishing the risk of post-
bladder fossa. Excising liver parenchyma operative cholangitis. However, the anastomosis
itself does not seem to improve bile drainage is not as flexible as a standard Roux loop, and
and the so-called deep coring adds nothing. revisions for repeated biliary obstruction have
All of the denuded area now needs to be been described (Zhao et al. 2011).
incorporated into the Roux loop. Laparoscopic KPE have been reported (Dutta
(v) Roux loop and portoenterostomy: A stan- et al. 2007), but this has not been taken up by the
dard retrocolic Roux loop measuring larger centers performing the standard KPE on a
40–45 cm should be constructed. The regular basis. It has become apparent that lapa-
jejunojejunostomy lies about 10 cm from the roscopic Kasai surgery doesn’t offer anything
ligament of Treitz and can be stapled or advantageous to the child beyond the cosmesis
sutured. The proximal anastomosis must be of a better scar and perhaps an adhesion-free
wide (~ 2 cm) and end-to-side is appropriate. abdominal cavity for the transplant surgeon,
Fine precise suturing (e.g., 6/0 PDS®) at the though even this is arguable (Hussain et al.
edge of the portal plate is satisfactory (Fig. 4). 2017).
Key outcomes such as clearance of jaundice
Options and Alternatives results are certainly not better and are rarely com-
parable to the open approach. Some initial advo-
There is of course an option not to proceed with cates in Hong Kong and Hannover have since
KPE following confirmation of the diagnosis returned to the standard open approach (Wong
though this is uncommon. In our own national et al. 2008; Ure et al. 2011). The problems seen
program, only 2.8% of 620 infants were directed are likely to be due to the difficulties with portal
toward primary liver transplantation. The usual plate dissection using currently available laparo-
reasoning is that an attempt at KPE is felt to be scopic instruments. Radical resection of all extra-
futile by reason typically of advanced cirrhosis. hepatic biliary remnants from all biliary sectors
These are usually infants who present late, per- and a wide portoenterostomy encompassing all
haps at > 100 days of age. Though even in this the margins of that resection are the key features
cohort we have shown a not insignificant 5-year to maximize results, and it can be a difficult,
native liver survival of about 40% (Hadzic et al. delicate dissection in the open operation without
2003). the constraints of laparoscopic surgery.
Sometimes, the anatomical configuration of the steroid group cleared their jaundice compared
the less common type 1 and type 2 BAs, particu- to 57% (21/37) in the placebo group, still not
larly cystic biliary atresia, will allow a hepatico- statistically different (P = 0.36), but noticeably
jejunostomy to be performed as there is still a bile the same magnitude as was found in the UK study.
duct to join to. However, given that these groups There is therefore a clear possibility of a type
do have a better long-term outcome (Davenport 2 error (i.e., accepting the null hypothesis when
et al. 1997; Superina et al. 2011), it is probably there actually is a true difference).
more sensible to dissect it higher and clear the We recently reported a follow-up study to the
portal plate as in a standard KPE than risk this original trial which now examined the use of a
approach. high-dose prednisolone cohort (starting at 5 mg/
kg/day) (Davenport et al. 2013). This showed the
same beneficial biochemical effects (now includ-
Adjuvant Therapy for Biliary Atresia ing a reduction in AST and APRi levels) with an
increased proportion of those who cleared their
A number of drugs have been highlighted to have jaundice in the steroid groups [67% (41/62) versus
the potential to improve the outcome of KPE, but 52% (47/91); P = 0.04].
there has been little hard scientific data published Dexamethasone has also been recommended
to provide real evidence for their use. by one UK center (Leeds) commencing orally
(0.3 mg/kg twice daily for 5 days, 0.2 mg/kg
Corticosteroids twice daily for 5 days, and 0.1 mg/kg twice daily
Small, uncontrolled series have suggested benefit for 5 days), beginning on postoperative day
in terms of increased bile flow post-KPE (Meyers 5 (Stringer et al. 2007).
et al. 2004; Kobayashi et al. 2005), and postoper- Despite the lack of hard research evidence,
ative steroids remain popular. many centers continue to use steroids in a variety
There have now been two prospective, double- of regimens. Its use is particularly high in Japan
blind, randomized, placebo-controlled trials. The with over 90% of the institutions using some form
first one used a low dose of prednisolone (2 mg/ of steroids after KPE. Its use in the USA is a little
kg/day) in two English high-volume centers (Dav- more restricted but still 46% of the infants were
enport et al. 2007) in 73 infants. This showed a being prescribed steroids in one survey (Lao et al.
statistically significant improvement in early bili- 2010). All three of the English specialist centers
rubin levels (especially in the “younger” liver) in use a variety of post-KPE steroid regimens.
the steroid group but did not translate to a reduced
need for transplant or improved overall survival. Ursodeoxycholic Acid (UDCA)
The other recently published study is the START This is widely thought to be beneficial, but only if
Trial (Bezerra et al. 2014). This randomized surgery has already restored bile flow to a real
70 infants from 14 North American centers to a degree. UDCA “enriches” bile and has a
steroid arm using initially IV methylprednisolone choleretic effect, increasing hepatic clearance of
4 mg/kg/day for first 3 days followed by oral supposedly toxic endogenous bile acids, and may
prednisolone (4 mg/kg/day till second week, confer a cytoprotective effect on hepatocytes. A
2 mg/kg 2 week, followed by a tapering proto- study assessed the effect of UDCA on liver func-
col over the next 9-week period). Although there tion in children >1 year post-KPE in a crossover
was a difference in the main primary endpoint study in 16 children with BA who had undergone
(clearance of jaundice) from 48.6%, in the pla- “successful” surgery defined by resolution of
cebo group, to 58.6% in the steroid group, this did jaundice 6 months after surgery. These patients
not attain statistical significance. As the median were all treated with UDCA (25 mg/kg/day in
time to KPE was relatively high in this study, they three divided doses) for 18 months at which
also did a subgroup analysis of infants <70 days point treatment was stopped and their clinical
at KPE (n = 76). This showed that 72% (28/39) in and biochemical status monitored. Six months
later only one had worsened clinically with recur- much more likely to occur in those with BA
rence of jaundice; however, all but two had compared to those with choledochal
sustained significant worsening in liver enzymes. malformations who have the same reconstruction
These were all then restarted on UDCA, and as the latter’s bile flow is so much better than even
6 months later, all of these had significant dimi- the best KPE. The risk is apparent in the first
nution in their liver enzymes (Willot et al. 2008). 2 years postsurgery although the reason for the
diminution in risk is obscure. Presumably there is
Chinese Herbs some time-dependent change in local immunolog-
Both Japanese and Chinese centers routinely pre- ical defenses. The CHiLDREN consortium
scribe the Chinese herb “inchinko-to” to infants reviewed 219 long-term survivors with a median
post-KPE, and one of the claimed benefits age of 9 years and reported an incidence of
includes inhibition of apoptosis and inhibition of cholangitis of 17% in the preceding 12 months
liver fibrosis (Inuma et al. 2003). For instance, (Ng et al. 2014).
Tamura et al. (2007) reported a prospective study Most children will present with pyrexia,
of 21 children post-KPE who had cleared their worsening jaundice, and a change in liver bio-
jaundice but who had persistent elevated liver chemistry and should be treated aggressively
enzymes and GGT. Inchinko-to was given to with broad-spectrum intravenous antibiotics
12 for up to 3 years, while the remainder persisted effective against Gram-positive organisms (e.g.,
in their standard regimen without any herb. Liver gentamicin, meropenem, Tazocin™ (piperacillin/
enzymes, bile acids, and markers of liver fibrosis tazobactam)) (Wong et al. 2004).There is some
were measured sequentially. There were no side evidence to suggest synergistic action of third-
effects of treatment. In the inchinko-to group, generation cephalosporin with aminoglycosides
markers of liver fibrosis (e.g., hyaluronic acid) (Luo and Zheng 2008).
were significantly decreased at 1 and 3 years with- Many protocols also advocate long-term pro-
out change in liver enzymes, bile acids, or phylactic antibiotic use to reduce the incidence of
bilirubin. cholangitis (Bu et al. 2003; Mones et al. 1994)
though again the evidence is thin. Bu et al. (2003)
reported a prospective randomized study of
Postoperative Complications 19 children who had had at least one previous
episode of cholangitis to evaluate the efficacy of
Continuation of the natural history of BA and trimethoprim/sulfamethoxazole or neomycin as
ineffective KPE are the most common problems oral prophylactic agents to prevent cholangitis.
postoperatively and lead invariably to end-stage Though there was no difference between the two
liver disease and cirrhosis. Jaundice deepens and treated groups, they did have a lower frequency of
is accompanied by abdominal distension and asci- cholangitis and a higher survival rate compared to
tes with failure to thrive and malnutrition. These historical controls.
infants require urgent consideration of liver trans- A number of modifications to the Roux loop
plantation. Other problems are related to the KPE have been suggested to reduce the risk of
procedure itself, and there are some specific com- cholangitis. Early surgeons suggested bringing
plications which can occur independently of this the Roux loop out as a stoma (Ohya et al. 1990),
process though. separating it from the intestinal stream, while lat-
terly others have advocated creation of a “valve”
Cholangitis in the loop by intussuscepting mucosa (Endo et al.
The direct anastomosis of bowel to the liver cre- 1999) though none have really stood the test of
ates a bilio-intestinal link which predisposes to time (Ogasawara et al. 2003).
ascending cholangitis and is seen in up to 60% There is one surgical modification which does
of large series (Ecoffey et al. 1987; Rothenberg significantly reduce the risk of cholangitis alto-
et al. 1989; Ernest van Heurn et al. 2003). This is gether by avoiding a Roux loop and draining the
denuded portal plate into the opened out native treated endoscopically with banding or in the
gallbladder as a portocholecystostomy. This has very young injection sclerotherapy. In those with
been a particular favorite of the French group in reasonable restoration of liver function, this
Bictre, Paris, and is anatomically possible in about should be all that is necessary; however, those
10–20% of KPE where the gallbladder is a who are still jaundiced may require transplant
mucocele and the common bile duct is patent. assessment. The role of propranolol in BA chil-
The subsequent cholangitis rate approaches zero, dren with portal hypertension particularly those
but the revision rate is higher as the drainage is with cirrhosis has not been formalized.
more tenuous (Matsuo et al. 2001 and personal
communication Prof. F Gautier). Ascites
This is related to and caused by portal hyperten-
Portal Hypertension and Esophageal sion in part, but other contributory factors include
Varices hypoalbuminemia and hyponatremia. It predis-
Abnormally raised portal venous pressure (i.e., poses to spontaneous bacterial peritonitis. Con-
portal hypertension) is seen at the time of KPE ventional treatment includes a low-salt diet, fluid
in about 70% of BA infants (Shalaby et al. 2012). restriction, and the use of diuretics particularly
It is caused by increasing liver fibrosis and corre- spironolactone. Often seen in settings of malnu-
lates with age at KPE, bilirubin level, and ultra- trition, consideration should be given to nasogas-
sound measured spleen size. Overall however it is tric feeding to try and increase calorie and protein
a poor predictor of outcome either in terms of intake.
response to KPE or more surprisingly even in
those who will go on to develop varices. The Nutrition and Growth Failure
result of the KPE in terms of clearance of jaundice It should be apparent that maintenance of good
and more importantly the abbreviation and per- nutrition and restoration of normal growth are
haps attenuation of the hepatic fibrotic process vital to an infant well-being. This is particularly
determines variceal formation. so (and harder to achieve) in those who have failed
Using endoscopic surveillance about 60% of to clear their jaundice and should be heading down
children who survived beyond 2 years will have the transplant pathway. There is a clear correlation
definite varices and of these about 20–30% will between improvements in nutrition and better out-
bleed (Stringer et al. 1989; Duché et al. 2010). In come following transplantation (De Russo et al.
the recently reported North American consortium 2007, Carter-Kent et al. 2007). Indeed malnutrition
study based on long-term survivors with BA, is one of the variables used in calculation of the
43 (26%) of the cohort of 163 subjects (median pediatric end-stage liver disease (PELD) score used
age 9 years) had had some form of complication in the USA to prioritize children for liver transplan-
of portal hypertension (variceal bleed, ascites), tation (McDiarmid et al. 2002).
while a further 37 (23%) subjects met their Growth failure may be defined as height or
definition of portal hypertension [i.e., spleen weight <2 standard deviations below the popula-
palpable> 2 cm below the costal margin and tion mean and is a major risk factor for poor
thrombocytopenia (platelet count < 150,000/ml)] outcome, and a recent report from the Biliary
(Shneider et al. 2012b). Atresia Research Consortium (BARC) identified
Esophagogastric varices take time to develop, this as a key measure of outcome associated with
and bleeding is unusual before 9 months of age transplantation or death by 24 months of age
and more usually occurring from 2 to 3 years. (Sokol et al. 2007). Similarly, Studies in Pediatric
Emergency treatment of bleeding varices specifi- Liver Transplantation (SPLIT) looked at 775 chil-
cally includes the use of vasopressin (e.g., dren with BA awaiting transplantation and again
terlipressin) or somatostatin analogues (e.g., identified growth failure as an independent risk
octreotide) sometimes even a Sengstaken- factor for pre-and posttransplant mortality and
Blakemore tube (Eroglu et al. 2004). Most are graft failure (Utterson et al. 2005).
The main emphasis to correct nutritional defi- quality of life and comparable attainment of edu-
ciencies has been on increasing the supply of cational standards in both countries. By contrast,
calories. Sometimes this may simply be by there is some evidence that those coming to
adopting a more reliable mode of delivery. Chin transplant may not be as fortunate.
et al. (1990) and Holt et al. (2000) achieved higher Neurocognitive function was seen to be signifi-
growth rates simply with supplemental feedings cantly deficient in 10–15%, 26% had learning
via a nasogastric tube. Overall calorie prescription disabilities, and almost 40% had special educa-
should aim for 110–160% of normal caloric intake tional needs in one long-term American study of
and may need to consist of semi-elemental for- 51 children living with a liver transplant (Mid-
mula, medium-chain triglycerides (MCT) (by up gley et al. 2000).
to 60% of fat provided), and may be supplements
of branched chain amino acids. In infants our
standard prescribed formula feed has included Outcome and Results
Heparon# Junior and Caprilon# (higher propor-
tion of MCT) (UK manufacturer, SHS Interna- Clearance of jaundice (to a bilirubin of 20μmol/L)
tional) providing approximately 120–150 kcal/ occurred in 55% of 424 infants undergoing KPE
kg/day. Short-term PN should be considered in from 1999 to 2010 in England and Wales (Dav-
those where NG feeding is not being tolerated enport et al. 2011). The 5- and 10-year native liver
then and can improve nutrition of children on the survival estimate was 47% and 43%, respectively,
transplant waiting list (Sullivan et al. 2012). with the overall survival estimate at 10 years
Virtually all infants are deficient in fat-soluble being 90% (Fig. 5). This compares well with
vitamins (D, A, K, and E) at presentation and all data from other national surveys [e.g., Japan
require active correction of this. This may forestall (Nio et al. 2003) France (Serinet et al. 2006),
complications such as rickets and pathological Switzerland (Wildhaber et al. 2008), and Canada
bone fractures (vitamin D), coagulopathy and (Schreiber et al. 2007)] and is the best argument in
spontaneous bleeding (vitamin K), and even cer- favor of centralization of management and treat-
ebellar ataxia and impaired vision (vitamin E). ment in this condition (Stagg et al. 2017). More
Supplementation and monitoring of fat-soluble recent data from Finland who have also central-
vitamins should be regarded as absolutely manda- ized their practice accord with this view (Lampela
tory and again is particularly important in those et al. 2012).
failing to clear their jaundice (Sokal et al. 1994;
Schneider et al. 2012).
Prognostic Factors
Developmental Delay
and Neurocognitive Function Though the results of surgery of BA are largely
Many of these infants and children are severely unpredictable in individual cases, a number of
affected by chronic liver disease requiring factors can be identified as important (Nightingale
extended periods of hospital stay and as such et al. 2017). These include:
have the potential to miss out on normal educa-
tional opportunities. Much is directly propor- Age at Kasai Portoenterostomy
tional to the severity and duration of illness and The effect of age on outcome following KPE is
malnutrition though there may also be more spe- still complex and incompletely understood. If a
cific impairment of normal neurocognitive func- bile-obstructed liver is left untreated, then fibro-
tion by vitamin and mineral deficiencies. sis and cirrhosis are invariable. But, the effect is
Howard et al. (2001) published a comparative neither simple nor linear. We examined the con-
study of developmental outcome from adoles- cept with respect to infants treated in our institu-
cents with their native livers in the UK and tion as an example of a relatively homogenous,
Japan. This showed actually an overall high uniform scheme of management with
Fig. 5 Actuarial native

liver (a) and true (b)
survival curves for biliary
atresia (n = 626) in England
and Wales (Jan. 1999–Dec.
2013). Five-year true and
native liver survival
estimate = 91% and 49%,
respectively
experienced surgeons in a high-volume center. Surgical Experience

We divided infants coming to KPE in the 1980s It has previously been shown in the UK that the
and 1990s into age quartiles and calculated their more KPEs a surgeon does (as a center, arbitrarily
subsequent native liver survival. Only the oldest >5/year), the better the outcome (McClement
quartile (<100 days) had a demonstrably worse et al. 1985; McKiernan et al. 2000). This has led
outcome (Davenport et al. 1997), even then not to superspecialization in England and Wales,
reaching statistical significance. We then looked Denmark (Kvist and Davenport 2011), Finland
at 225 infants from the 1990s and 2000s and (Lampela et al. 2012), and the Netherlands. Cer-
divided them again into specific age cohorts tainly each country must have a duty of care to
and also by their putative etiological group. even its smallest citizens and make provisions to
This time a significant effect on outcome was improve collaboration and communication
shown but only for those where the BA was between centers and allow the best possible
considered developmental (BASM and cystic outcome.
BA). For all those remaining infants with iso-
lated BA, there was barely any discernable effect Liver Histology and Biliary Remnant
again up until about 100 days of age (Davenport There is improved outcome in types 1 and 2 com-
et al. 2008). Throughout this period we have pared to type 3 BA and cystic BA compared to
never found any evidence of a significant cutoff non-cystic BA (Caponcelli et al. 2008; Davenport
(e.g., < 60 days, < 6 weeks, < 8 weeks, etc.), et al. 1997; Superina et al. 2011). Almost certainly
and such an arbitrary simplistic approach to this is due to improved preservation of the con-
prognosis needs to be consigned to the dustbin nections between the intra- and extrahepatic bile
of history. ducts and ductules. Infants with BASM also have
Fig. 6 Native liver

actuarial survival curves of
patients with biliary atresia
based on AST-to-platelet
ratio index (APRi)
quartiles. Higher values
suggest more liver fibrosis
(1st quartile, < 0.43; 2nd
quartile, 0.43–0.67; 3rd
quartile, 0.6 –1.1; 4th
quartile, 1.12–11)
a worse outcome and also appear at risk of sudden limit the natural life span of the Kasai survivor and
death in the first year following KPE. The cause of the specter of transplant will once more emerge.
this is unknown and may be due to an intrinsically Limitation of this process by effective antifibrotic
worse liver disease, a smaller biliary remnant tis- drugs remains tantalizingly close but none are
sue, or the effect of other anomalies (e.g., cardiac). ready for real clinical application (Czaja et al.
Prospective evaluation of the macroscopic fea- 2014). Many pharmacological agents that diminish
tures of the hepatobiliary elements (hardness of oxidative stress [e.g., S-adenosylmethionine
the liver, presence of ascites, etc.) was relatively (SAMe), N-acetylcysteine (NAC), vitamin E] and
poorly predictive of outcome with only actual size at a cellular level reduce the pro-inflammatory
of resected biliary remnants being really discrim- cytokine cascade (e.g., infliximab, etanercept) and
inatory (Davenport and Howard 1996). Micro- limit hepatic stellate cell activation and minimize
scopic examination of the transected bile duct myofibroblast proliferation (e.g., cannabinoid
remnant will show a varying amount of residual antagonists) have been identified.
ductules. Older series suggested that only those Still, although the cause of biliary atresia
showing large ductules ( >300 μm) had a dis- remains elusive, a complementary system of sur-
tinctly better outcome (Howard et al. 1982), but gical treatment has evolved, which has improved
a later evaluation showed that minimal or no duct- the overall survival to adulthood in affected
ules in the remnant were also predictive of lack of infants from around 10% to about 90%. Not
effect of KPE (Tan et al. 1994). many surgical diseases can claim such a dramatic
Among the newer prognostic indices, APRi turnaround in prognosis.
used here as a surrogate for liver fibrosis can be
used to discriminate, but only those with low
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▶ Congenital Biliary Dilatation
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Congenital Biliary Dilatation
78
Atsuyuki Yamataka, Geoffrey J. Lane, and Joel Cazares
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1146
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1147
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1148
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1150
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151
Incidental CBD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1151
Open Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1152
Intraoperative Endoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Postoperative Complications and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1154
Malignancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
Laparoscopic Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1156
Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160
A. Yamataka (*) · G. J. Lane

Department of Pediatric General and Urogenital Surgery,
e-mail: yama@juntendo.ac.jp; yama@med.juntendo.ac.jp;
geoffrey@juntendo.ac.jp
J. Cazares
Department of Pediatric General and Urogenital Surgery,
Department of Pediatric Surgery, Hospital Regional de
Alta Especialidad Materno Infantil, Monterrey, Mexico
e-mail: joel@juntendo.ac.jp

https://doi.org/10.1007/978-3-662-43588-5_82
1146 A. Yamataka et al.

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1161
Abstract births, but in the East it is far more common, with

Congenital biliary dilatation (CBD) continues rates as high as 1 in 1000 live births in some parts
to baffle researchers and surgeons because its of Japan. Female predominance is as high as 4:1
cause remains unknown. There is a female (Yamaguchi 1980).There is little doubt that CBD
preponderance and higher incidence in Asia. is a congenital lesion with a strong hereditary
It is often identified in childhood but some 20% component, which may explain the higher inci-
may remain undiagnosed until adulthood. Pre- dence seen in Asia, and its familial occurrence in
natal diagnosis has increased in recent years siblings and twins (Ando et al. 1996).
accounting for 25% of new cases. Hypotheses Anatomic features frequently associated with
for its etiology and pathogenesis include an CBD include a cystic or fusiform dilatation
anomalous junction between the pancreatic of the common bile duct, an anomalous junction
duct and the common bile duct, intrahepatic of the pancreatic duct and the common
bile duct dilatation, and hepatic fibrosis. bile duct (pancreaticobiliary malunion: PBMU),
Because there is a risk for malignancy increas- intrahepatic bile duct (IHBD) dilatation with or
ing with age and inadequate surgery, early without downstream stenosis, and various degrees
excision with Roux-en-Y hepaticoenterostomy of hepatic fibrosis. Early diagnosis and treatment
is recommended. Intraoperative endoscopy is important as relationship with malignancy is
should be performed routinely to prevent post- documented. The risk of biliary cancer increases
operative bile stone formation by washing out according to age (Mizuguchi et al. 2017).
any debris present. Early and late complica-
tions include leakage, cholangitis, anastomotic
stricture, and cholangiocarcinoma. Laparo- Etiology
scopic treatment is safe with outcomes compa-
rable to open surgery. There are two known causal factors for the etiol-
ogy of CBD – weakness of the wall of the com-
Keywords mon bile duct and obstruction distal to it. Distal
Choledochal cyst · Hepaticojejunostomy · stenosis is closely associated with cystic dilatation
Hepaticoduodenostomy · Laparoscopic of the common bile duct, and the site of stenosis is
surgery · Cholangiocarcinoma · related to an abnormal choledochopancreatic duc-
Pancreaticobiliary maljunction tal junction (Miyano et al. 1979). Jona (1979)
proposed that the pathogenesis of CBD associated
with PBMU may be related to faulty budding of
Introduction the primitive ventral pancreas (Jona et al. 1979).
Wong and Lister (1981) conducted research on
In order to gain an understanding of biliary tract human fetuses and demonstrated that the
disease, it is necessary to study the basics of the choledochopancreatic junction lies outside the
development, anatomy, and function. duodenal wall before the 8th week of gestation,
Congenital biliary dilatation (CBD) or dilata- whereupon it moves inward towards the duodenal
tion of the common bile duct was first reported by lumen, suggesting that an anomalous junction
Douglas in 1852 (Lane et al. 1999a). The condi- may be caused by arrest of this migration (Wong
tion, relatively rare in the West, occurs at an and Lister 1981), while Tanaka (1993) proposed
estimated incidence of 1 in 13,000 to 15,000 live that regression of the terminal common bile duct
78 Congenital Biliary Dilatation 1147
and canalization of the ventral pancreatic duct histological appearance of CBD is generally con-
caused by sinistral dislocation of the ventral pan- sistent although choledochoceles have duodenal
creas are responsible for PBMU (Tanaka 1993). mucosa and can resemble bile ducts in structure
Cholangiography has identified anomalies of the (Komi et al. 1986). Liver biopsies are seldom
pancreaticobiliary ductal system in association needed, and usually show inflammatory changes,
with CBD, which may allow reflux of pancreatic central venous distention, and portal fibrosis.
enzymes and subsequent dissolution of duct Postoperative liver biopsies taken after CBD
walls. This is known as the long common channel resection may actually show worsening of portal
theory and was first proposed by Babbit in 1969 fibrosis and central venous distention with little
(Babbitt 1969).This theory is further supported by evidence of regression (Sugandhi et al. 2014;
the high amylase content of fluid aspirated from Soares et al. 2014). The possibility of incipient
dilated ducts in patients with CBD. A dilated adenocarcinoma is of constant concern.
common channel and anomalous pancreatic duct
are also frequently observed, which may be
responsible for the formation of protein plugs or Embryology
pancreatic stones, often associated with pancrea-
titis. Although Babbit stressed that pancreatic The extrahepatic and intrahepatic biliary systems
fluid is the most likely factor causing edema, arise from endoderm as separated units, around the
weakness, and eventual fibrosis of the distal com- 4th week of gestation, from the hepatic bud and
mon bile duct, CBD can be diagnosed antenatally divide in two. Hepatocytes, intrahepatic ducts,
as early as 15–20 weeks’ gestation (Schroeder proximal extrahepatic ducts, and the gallbladder
et al. 1989), at which time the pancreas is regarded arise from the cranial part and the distal extrahe-
to be too immature to function (Laitio et al. 1974), patic ducts arise from the caudal part (Ando 2010).
and even in neonates, enzymes secreted by the Around the 5th week, the dorsal and ventral pan-
pancreas are not fully functional (Lebenthal and creatic buds appear. The main ventral pancreatic
Lee 1980). While weakness of the duct wall sec- bud develops near the entry of the common bile
ondary to refluxed pancreatic enzymes may be duct in the duodenum; then as it rotates in a C-
implicated, CBD is most likely to be caused by shape, the ventral pancreatic bud is carried dorsally
an anomalous choledochopancreatic duct junction with the bile duct and fuses with the dorsal pan-
combined with congenital stenosis, both of which creas, lying posteriorly to the dorsal pancreatic bud
are associated with abnormal development of the and fuse each other, giving rise to the uncinate
ventral pancreatic duct and biliary duct system. process (Roskams and Desmet 2008). The ventral
Komi (1992) suggests that PBMU can be divided pancreas is connected by two ducts to the primitive
into three types: a right angled union without hepatic duct. The left ventral duct disappears dur-
accessory pancreatic duct, an acute angled union ing development. The right ventral duct divides
without accessory pancreatic duct, and an acute into two branches, superior and inferior; the former
angled union or right angled union with an acces- joins the dorsal pancreatic duct to form the main
sory pancreatic duct (Komi et al. 1992). Another pancreatic duct, which merges with the common
theory according to Davenport suggests that CBD bile duct, inserting into the duodenum as the
is secondary to a reduced number of neurons ampulla of Vater (Baumann et al. 2008).
and ganglions; as a result, congenital cysts were
round because reduced ganglia induced distal
obstruction with proximal dilatation while bile Anatomy
stasis was responsible for chronic inflammation
(Davenport and Basu 2005). Histologically, dif- The biliary tract is the connection between the
ferent changes can be found in CBD, ranging from liver where bile is produced by hepatocytes and
fibrous connective tissue in duct walls to inflam- excreted into canaliculi that channel it into larger
mation of the mucosa and submucosa. The intrahepatic and extrahepatic ducts. Its action is to
transport stored bile into the duodenum and is without biliary dilatation. Choledochal cysts with-
regulated by the sphincter of Oddi. The portal out PBMU are classified as: (D) cystic diverticulum
triad is comprised of inter lobular or terminal of the common bile duct, (E) diverticulum of the
bile ducts, hepatic artery branches, and the hepatic distal bile duct (choledochocele), and (F)
portal vein. The bile ducts usually have a diameter intrahepatic bile duct dilatation alone (Caroli’s dis-
of <100 μm. Bile drains from hepatocytes into ease) (Miyano et al. 2005).
septal then segmental bile ducts before reaching Technical issues during surgery for cystic
the left and right hepatic ducts. The left hepatic choledochal cyst are frequently found on the prox-
duct collects bile from segments II, III, and IV; the imal side of the pathology occurring as a result of
right hepatic duct collects bile from segments V, anatomic variants of the common hepatic duct,
VI, VII, and VIII (Baumann et al. 2008). Segment uncertainty in relation to the excision level of com-
I has its own drainage or drains into both right and mon hepatic duct, dilated IHBD, debris, and/or
left hepatic ducts in 78% of individuals. Variations stenosis in the IHBD. In contrast, Technical issues
in intrahepatic bile duct anatomy can be observed during surgery for fusiform choledochal cyst most
in as many as 60% of individuals. The right and often arise on the distal side of the pathology and
left hepatic ducts join to form common hepatic are due to uncertainty in relation to the excision
duct. The left hepatic duct is usually longer than level of the distal choledochus, debris in the com-
the right hepatic duct and lies outside the liver mon channel, and complicated PBMU.
parenchyma, making it more accessible during Caroli’s disease is characterized by segmental
surgery if needed. The gallbladder and cystic dilatation of large intrahepatic ducts, involving
duct join the common hepatic duct to form the one or several segments, without an obstructive
common bile duct; several variations can be found cause (Caroli et al. 1958). In up to 40% of cases,
making it mandatory to have a good understand- dilatation is confined to the left lobe of the liver. The
ing of anatomy to prevent injuries. The common more serious form, Caroli’s syndrome, associated
bile duct is divided into 4 portions: supra- with peripheral fibrosis, portal hypertension, and
duodenal, retroduodenal, pancreatic, and liver failure, has an association with mutations in
intraduodenal, and drains into the second part of PKHD1, a gene that is linked to adult recessive
the duodenum at the papilla of Vater. At this point, polycystic kidney disease, as well as jaundice sec-
the pancreatic duct joins to form a common short ondary to obstruction of extrahepatic bile ducts by
channel (Blumgart and Hann 2008). bile plugs or stones (Desmet 1992). Differential
diagnoses include primary sclerosing cholangitis
and secondary bile duct dilatation due to distal
Classification obstruction. Treatment varies according to the pres-
ence of cholangitis or bile duct obstruction. In mild
CBD has been classified by Alonso-Lej et al. cases, conservative management with antibiotics
(1959), Todani et al. (1978), and Komi et al. for cholangitis is usually necessary; surgical inter-
(1992) according to anatomy and cholangiography vention is indicated for bile drainage but can
of the hepatobiliary duct system, but the most inter- include liver resection to reduce the risk for recur-
nationally reliable method would appear to be pres- rent cholangitis or cholangiocarcinoma. Liver trans-
ence or absence of PBMU (Fig. 1). The vast plantation should be considered for Caroli’s
majority of CBD is associated with PBMU and is syndrome (Okada et al. 2002).
commonly referred to as being cystic, fusiform, or
forme fruste. Choledochal cyst is commonly asso-
ciated with PBMU involving concurrent abnormal- Clinical Presentation
ities of the common channel, pancreatic duct, and
intrahepatic ducts. Choledochal cysts with PBMU CBD should always be considered in the differen-
are classified as: (A) cystic dilatation of the extrahe- tial diagnosis of a child with abdominal signs and
patic duct, (B) fusiform dilatation of the extrahepatic symptoms. CBD can present at any age, but
bile duct, and (C) forme fruste choledochal cyst approximately half become symptomatic in
Fig. 1 Classification of CBD according to pancreati- (d) Cystic diverticulum of the common bile duct. (e)
cobiliary malunion (PBMU). (a) Cystic dilatation of the Choledochocele (diverticulum of the distal common bile
extrahepatic bile duct. (b) Fusiform dilatation of the extra- duct). (f) Intrahepatic bile duct dilatation alone (Caroli’s
hepatic bile duct. (c) Forme fruste CBD without PBMU. disease) (From Miyano et al. (2005))
infancy. Neonatal cases have been uncommon. characteristic of fusiform or forme fruste CBD.
Clinical manifestations of CBD differ according Older children may present with the classical triad
to age. Neonates and young infants may present originally described by Alonso-Lej in 1959,
with obstructive jaundice, acholic stools, and hepa- consisting of pain, mass, and jaundice with fever
tomegaly resembling biliary atresia (BA) and may and vomiting. This “classic” triad is usually only
even have advanced liver fibrosis, but on cholangi- present in 20–30% of patients. Pain characteristi-
ography, there is a patent communication with the cally mimics that of recurrent pancreatitis, with or
duodenum and a well-developed IHBD tree. Young without raised serum amylase. In adolescence and
infants may also present with a large upper abdom- adulthood, CBD is usually misdiagnosed for many
inal mass without jaundice. Young children may years as being cholelithiasis or cholecystolithiasis,
present either with a right upper quadrant mass and both of which are secondary to bile stasis, cirrhosis
intermittent jaundice due to biliary obstruction, leading to portal hypertension, upper gastrointesti-
usually seen in patients with cystic CBD, or with nal bleeding, and splenomegaly; hepatic abscess
abdominal pain due to pancreatitis, which is and biliary carcinoma are known complications.
Spontaneous CBD perforation can occur in up to of the ducts to be detected with medium to high
12% of patients presenting with acute abdomen or degrees of accuracy (Yamataka et al. 1997a; Shi-
septic shock. mizu et al. 2000; Saito et al. 2016) (Fig. 2). MRCP
is also noninvasive and can be used to visualize
the duct system upstream to an obstruction or area
Diagnosis of stenosis, and has replaced ERCP as a diagnostic
tool. Recently, better MRCP equipment has been
Currently, abdominal ultrasonography (US) is developed, rendering three-dimensional imaging
probably the best screening method available useful for delineating anatomy. However, in chil-
even though it does not permit visualization of dren less than 3 years old, the pancreaticobiliary
the entire duct system and it is not sensitive duct system may not be visualized clearly because
enough to demonstrate an undilated common of their small caliber. Percutaneous transhepatic
channel and pancreatic duct. It is a low-cost, non- cholangiography is also available, especially for
invasive imaging study, accurate enough to detect patients with IHBD dilatation and severe jaun-
a cystic mass in the upper right quadrant that can dice, and intraductal US (Kamisawa et al. 2011)
be distinguished from gall bladder pathology or can delineate the distal parts of the common bile
pathology related to the porta hepatis. In addition, duct and pancreatic duct successfully.
it can differentiate readily between hepatic cysts, The importance of intraoperative cholangiog-
liver abscess, pancreatic pseudocysts, omental raphy (IOC) in the modern era is controversial
cysts, or duodenal duplications. In patients (Saito et al. 2016). If preoperative MRCP imaging
suspected of having CBD, US can also demon- can allow clear visualization of the entire
strate IHBD dilatation and the state of the paren- biliopancreatic ductal system, including the
chyma of the liver. However, for thorough
diagnosis, the extrahepatic bile duct, intrahepatic
ducts, anomalies of the pancreatic duct, and
PBMU should also be identified. Increased diam-
eter of extrahepatic bile duct can be identified,
requiring further investigation if needed. Normal
common bile duct diameter in infants measures up
to 2 mm and in children up to 3.5 mm (Hernanz-
Schulman et al. 1995); in adolescents and young
adults, up to 6 mm is considered normal; however,
clinical correlation is mandatory. Endoscopic ret-
rograde cholangiopancreatography (ERCP) can
accurately delineate the configuration of the
pancreaticobiliary duct system and is unlikely to
be replaced by other investigations, especially in
cases where fine detail is required preoperatively.
However, ERCP is an invasive procedure
unsuitable for repeated use and is contraindicated
during acute pancreatitis. Nevertheless, it is
performed routinely in many centers in Japan,
with reasonable success (Iinuma et al. 2000). Fig. 2 Magnetic resonance cholangiopancreatography
Magnetic resonance cholangiopancreatography (MRCP) in a patient with CBD showing fusiform dilatation
of the extrahepatic bile duct, long common channel
(MRCP) provides excellent visualization of the (between arrows), protein plugs (arrowheads), and the
pancreaticobiliary ducts in patients with CBD, pancreatic duct (From Yamataka and Kato (2009);
allowing narrowing, dilatation, and filling defects Fig. 56.2)
intra- and extrahepatic bile ducts and pancreatic internal drainage, a commonly used treatment in
duct in detail, then IOC is unnecessary. Further- the past. Some of the procedures that had been
more, if CBD is too extensive, IOC via the gall- performed are only of historical interest only and
bladder or directly via the common bile duct is include: external drainage, internal drainage opera-
ineffective and must be replaced by selective tions including choledochocystogastrostomy,
IOC of the IHBD and distal common bile duct choledochocystoduodenostomy with/without
during excision. Technetium-99m di-iso- gastrostomy, choledochocystojejunostomy,
propylphenylcarbamoylmethylimidodiacetic acid hepaticocholedochostomy, hepaticoduo-
scintigraphy scan is not used routinely; however, denostomy, intrahepatic cystoduodenostomy at
it can be useful to distinguish biliary atresia from the porta hepatis, and intrahepatic cysto-
CBD in a jaundiced child, if suspected. It is also jejunostomy at the porta hepatis. Recently, more
helpful in cases of subacute or chronic cyst perfo- attention is being given to the treatment of condi-
ration showing localized accumulation or perito- tions affecting the intrahepatic and intrapancreatic
neal spillage of radiotracer and as a follow-up ducts, such as IHBD dilatation, focal stenosis,
investigation. Abdominal computed tomography debris in the IHBD, and protein plugs or stones in
(CT) is frequently not necessary and involves the common channel. The optimum levels for trans-
radiation exposure. However, it is useful for ecting the common hepatic duct and excising the
assessing the severity and extent of pancreatitis intrapancreatic duct will affect the incidence of
and/or malignancy. It is superior to US for visual- complications and prognosis. In cases of Caroli's
izing IHBD, the distal bile duct, and the pancreas. disease, if cystic lesions are confined to one lobe of
CT is also valuable for defining the status of the liver, hepatic lobectomy should be considered,
surrounding structures such as the portal vein but if multiple lobes are involved with evidence of
and hepatic artery (Jabłońska 2012). progressive hepatic fibrosis, only palliative mea-
In recent years, CBD has been detected with sures or liver transplantation may be possible. In
increasing frequency during routine prenatal US choledochocele, the transduodenal unroofing with
at as early as 15 weeks gestation, resulting in an sphinteroplasty of the pancreatic or common bile
increasing incidence of CBD, particularly in neo- duct is the procedure of choice (Lobeck et al. 2016).
nates (Howell et al. 1983; Elrad et al. 1985). In a
recent series, some 20% of patients were detected
either neonatally or antenatally, and interest- Incidental CBD
ingly, the ratio of cystic to fusiform-type CBD
neonatally or antenatally was 20:1, in contrast to Incidental CBD identified on routine antenatal US
an overall ratio of 5:3 (Lane et al. 1999b), which should be observed during the antenatal and neo-
further supports the hypothesis that cystic dila- natal periods. Some pediatric surgeons recom-
tion of the common bile duct is a prenatal event mend CE soon after diagnosis (Burnweit et al.
and fusiform dilation begins after birth. Overall, 1996; Suita et al. 1999), while others believe
up to 60% of CBD are diagnosed in childhood there is no need for hasty excision if jaundice is
and up to 20% can remain undiagnosed until not present (Miyano and Yamataka 1997). In the
adulthood. absence of protocols for management, neonates
with incidental CBD should receive standard con-
servative medical management and nutritional
Treatment support and with thorough assessment should
they become symptomatic. Early surgery provides
Complete cyst excision (CE) with Roux-en-Y the opportunity to exclude BA, relieve obstructive
hepaticoenterostomy (HE) is the definitive treat- jaundice if present, prevent fibrosis (Burnweit
ment of choice for CBD because of the high mor- et al. 1996), reduce the risk for cholangitis by
bidity and high risk for carcinoma associated with clearing debris, as well as prevent cyst perforation
and malignancy (Howell et al. 1983; She et al. the cyst. By exposing the posterior wall directly
2009). However, in complicated neonatal cases from the inside, dissection of the portal triad is
presenting with severe cholangitis, poor general facilitated. If the cyst is extremely inflamed and
condition, or huge dilated CBD, external biliary adhesions are very dense, mucosectomy of the
drainage is recommended by either percutaneous cyst (Fig. 3) should be performed rather than
transhepatic cholangio drainage or direct percuta- attempting full-thickness dissection to minimize
neous cyst drainage. Subsequently, delayed pri- the risk for injuring the portal vein and hepatic
mary CE may be performed 3–6 months later. In artery and also to prevent the residual epithelium
cases of biliary peritonitis secondary to CBD per- of the distal portion of the cyst from undergoing
foration, either external biliary drainage or CE is malignant transformation. Otherwise, the cyst is
recommended. Outcome of surgery in neonates is transected after careful circumferential dissection
generally excellent (Suita et al. 1999). from the hepatic artery and portal vein. The distal
common bile duct should be resected as close as
possible to the pancreaticobiliary ductal junction.
Open Surgery If the distal common bile duct is resected along
line 1 (Fig. 4) over time, a cyst will re-form around
CE with biliary reconstruction to avoid two-way the distal remnant in the pancreas, causing recur-
reflux of bile and pancreatic secretions is the stan- rent pancreatitis, stone formation, or malignancy.
dard procedure of choice (Liuming et al. 2011) However, if the distal duct is resected along line 3
because of the high morbidity and high risk for (Fig. 4), that is, just above the pancreaticobiliary
carcinoma associated with internal drainage, ductal junction, there is no residual duct within the
a commonly used treatment in the past. While pancreas and a cyst is unlikely to re-form. Finally,
the essentials of management of CBD are the the common hepatic duct is transected at the level
same, treatment in early infancy has unique of distinct caliber change, ensuring there is
aspects that must be considered in relation to the enough left for HE. If CBD is fusiform with no
risks of surgery itself in a small patient with distinct caliber change, the cyst should be excised
immature physiology and immunology, while
CE in older children and adults is much more
difficult than in younger children because of com-
plications associated with repeated episodes of
chronic inflammation. Full-thickness CE is easier
in neonates and young infants, because the wall of
the dilated common bile duct is not inflamed and
there are few adhesions to surrounding structures,
such as the portal vein and hepatic artery (Filler
and Stringel 1980; Somasundaram et al. 1985).
Adhesions are usually denser with cystic CBD
than forme fruste CBD, especially in older chil-
dren; in adolescents and adults, they can be
severe. Thus, mucosectomy is rarely indicated in
neonates because there is usually little inflamma-
tion present. Aspiration of the cyst prior to dissec-
tion makes surgery easier if the cyst is large.
Specifically, the cyst should be incised in the
distal portion transversely close to the duodenum,
because anomalous right and left hepatic duct
openings may exist outside the porta hepatis in
addition to the true openings in the distal part of Fig. 3 Distal mucosectomy
HJ (Shimotakahara et al. 2005; Narayanan et al.

Cystoscope
2013). Furthermore, a recent meta-analysis com-
pared HJ with HD and reported significantly more
1 postoperative reflux and gastritis with HD (Soares
et al. 2014; Narayanan et al. 2013).
2 HE at the hepatic hilum is indicated in specific
3 cases only, such as in patients with dilated IHBD
with stenosis in the common hepatic duct or ado-
lescent patients with severe inflammation of the
common hepatic duct. HE at the hepatic hilum is
more difficult than conventional HE, particularly
in neonates and young infants without IHBD dila-
Pancreatic duct tation, and valved jejunal interposition HD is a
Common channel complicated procedure.
End-to-end anastomosis of the jejunum to the
Debris, protein plugs
upper remnant of the common bile duct is
recommended if the ratio between the diameters
of the common bile duct and the proximal Roux-
Fig. 4 Diagram of IE in a case of CBD with debris and en-Y jejunum is less than or equal to 1 (common
protein plugs in the distal bile duct and recommended level
hepatic duct) to 2.5 (jejunum) (Fig. 5). If the
of CE. Once IE has cleared any debris or protein plugs
present CE is performed. If excised at Level 1, there is risk common bile duct is too small, then end-to-side
for residual cyst and at Level 3, there is risk for injuring the anastomosis is unavoidable and the anastomosis
pancreatic duct. Level 2 is the ideal level for excision should be as close as possible to the closed end of
(From Miyano et al. 2000)
the duodenal limb (Fig. 5). If an end-to-side
anastomosis is performed far from the closed
just above the choledochopancreatic junction, and end of the proximal jejunum, a blind pouch can
the stump double-sutured, ligated, and transected. develop as the child grows and such a blind
The distal bile duct within the pancreas must also pouch has been documented to be associated
be excised entirely. In cystic CBD, the distal com- with adhesive bowel obstruction, bile stasis,
mon bile duct is often so narrow that it cannot be and stone formation (Miyano et al. 1996)
identified and the likelihood of incomplete exci- (Fig. 6a). Bile stasis in the blind pouch is also
sion is virtually nil, in contrast to forme fruste known to cause intrahepatic stone formation,
CBD where the distal common bile duct is still especially if IHBD dilatation is also present.
wide at the pancreaticobiliary duct junction, and Figure 6b shows an ideal Roux-en-Y anastomo-
the likelihood of incomplete excision is high. sis without any redundant limb. The native jeju-
Basically, the only difference between operative num should also be secured side-to-side to the
procedures available is the type of biliary reconstruc- Roux-en-Y jejunal limb from the ligament of
tion performed. Although most surgeons use a Treitz for about 8 cm proximal to the end-to-
Roux-en-Y hepaticojejunostomy (HJ), some side anastomosis to ensure smooth flow of bile
(Todani et al. 1981) recommend a wide anastomosis and bowel contents distally, ensuring the
at the level of the hepatic hilum, while others prefer jejunojejunostomy does not become T-shaped.
hepaticoduodenostomy (HD). Good outcome with Severe dilatation of the IHBD can be managed
low early morbidity is to be expected irrespective of by segmentectomy of the liver, intrahepatic
technique, but complications develop more often in cystoenterostomy, or balloon dilatation of a stenotic
the long term if dilated IHBD are present, and post- lesion at the time of CE. Stricture of the IHBD at
operative duodenogastric bile reflux appears to com- the hepatic hilum can be treated by intrahepatic
plicate HD although operative time and ductoplasty and cystojejunostomy or HJ at the
hospitalization are shorter for HD compared with hepatic hilum (Miyano et al. 1995). Stenosis of
Fig. 5 (a) End-to-end anastomosis during HJ is pouch so there will be no blind pouch at the HJ anastomo-
recommended to prevent elongation of the blind pouch if sis site; if an end-to-side anastomosis is performed far from
the ratio between the diameters of the common hepatic duct the closed end of the blind pouch, the blind pouch will
and the proximal Roux-en-Y jejunum at the proposed site grow as the child grows and an elongated blind pouch can
of anastomosis is less than or equal to 1:2.5 (common contribute to bile stasis in the pouch and IHBD (especially
hepatic duct:jejunum). (b) If end-to-side anastomosis is if they are dilated) leading to stone formation
unavoidable, the common hepatic duct should be anasto-
mosed as close as possible to the closed end of the blind
the papilla of Vater, stricture of the pancreatic duct, used to view the pancreatic and biliary duct systems
protein plugs, and septate common channel have directly at the time of CE (Yamataka et al. 2000;
been reported (Yamataka et al. 2000; Kaneko et al. Takahashi et al. 2010). In younger patients, a neo-
1997). If stenosis of the major papilla with a dilated natal cystoscope or a fine flexible scope
common channel is identified, a transduodenal (1.9–2.0 mm) with a flush channel may be required.
papilloplasty or endoscopic papilloplasty should IE is extremely effective. On long-term follow-up,
be performed (Yamataka et al. 2000). the incidence of postoperative stone formation in
postoperative CBD patients who had IE was lower
than reported in the literature (Takahashi et al. 2010).
Intraoperative Endoscopy
Intraoperative endoscopy (IE) initially performed to Postoperative Complications

examine the duct system and remove any biliary and Management
debris/stones and protein plugs in the common chan-
nel and dilated IHBD is now also used for determin- Satisfactory surgical outcome with low morbidity
ing the ideal level of resection. Briefly, a pediatric in the short- to mid-term is to be expected
cystoscope or fine fiberscope with a flush channel is after CE. Surgical outcome is better, and early
Fig. 6 (a) Inadequate Roux-en-Y HJ reconstruction. T-shaped Roux-en-Y jejunojejunostomy. (b) Appropriate
Note: HJ is far from the closed end of the blind pouch Roux-en-Y HJ reconstruction. Arrowheads: Approximated
(arrowhead). Double headed arrow in the inset: Elonga- native jejunum and distal Roux-en-Y limb. Arrows:
tion of the blind pouch. Arrow with an asterisk: Reflux of Smooth flow without reflux of small bowel contents
jejunal contents into the Roux-en-Y limb through a (From Yamataka et al. (2003))
morbidity is lower in younger children than in

older children. IE would appear to reduce compli- Table 1 Complications after cyst excision in children
versus adults
cations (Yamataka et al. 1997b). Patients with
IHBD dilatation, dilatation of the remaining distal Incidence/
200 Incidence/
bile duct, pancreatic duct, and common channel children Complications 40 adults
require more extensive follow-up, because 3 Ascending cholangitis 9
chronic inflammation could contribute to stone 3 Intrahepatic bile duct stones 5
formation and malignant change in the long-term. 3a Intrapancreatic terminal 1
Complications documented in a review of choledochus calculi
240 (200 children; 40 adults) CBD cases 1 Pancreatic duct calculus 1
(Yamataka et al. 1997b) include ascending 1a Stones in the blind pouch of 0
cholangitis, intrapancreatic terminal common an end-to-side Roux-en-Y
HJ
bile duct calculi, pancreatitis, and bowel obstruc-
9b Bowel obstruction 3c
tion, requiring revision hepaticoenterostomy, per-
0 Cholangiocarcinoma 2
cutaneous transhepatic cholangioscopic
0 Liver dysfunction 1
lithotomy, excision of the residual intrapancreatic 5 Pancreatitis 5
terminal common bile duct, endoscopic 25(18) Total 27(17)
sphincterotomy, pancreaticojejunostomy, or lapa- Note: Numbers in parentheses indicate number of patients.
rotomy (Table 1). Overall incidence of compli- Thus, 18 children and 17 adults had 25 and 27 complica-
cations was 9% (Yamataka et al. 1997b). In the tions, respectively
group of patients who had CE by the time they From Yamataka et al. (1997b) with permission
a
One patient with intrapancreatic terminal choledochus
were 5 years old, none of the abovementioned calculi also had a stone in the blind pouch of an end-to-
complications were documented, indicating side hepaticojejunostomy
b
that early diagnosis followed by CE and IE Adhesions in six and intussusceptions in three
c
would appear to be the best approach to Adhesions in all three
achieve surgical cure and prevent postoperative Laparoscopic Treatment

complications.
Minimally invasive surgery using laparoscopy is
now widely used for treating CBD. The general
Malignancy concepts are the same as for open CE; in other
words, laparoscopic CE (lapCE) is performed
Since an association between malignancy and according to the principles of our open CE and
CBD was first reported in 1944, more than includes IE (retermed intralaparoscopic endos-
100 cases of cholangiocarcinoma have been copy) as a routine procedure.
reported in CBD cases. Histopathologic findings LapCE is performed under general anesthesia,
compiled from excised CBD specimens include with the patient positioned at the foot of the oper-
erosion of bile duct mucosa, epithelial desquama- ating table in a reverse Trendelenburg position,
tion, papillary hyperplasia with regenerative the surgeon at the patient’s feet, an assistant with a
atypia, bile duct mucosa dysplasia, and presence scope at the surgeon’s left, and another assistant
of metaplastic changes such as mucous cells, gob- on the surgeon’s right (Fig. 7). An open Hasson
let cells, and Paneth cells. There is a tendency for technique through a supraumbilical incision is
hyperplasia and metaplasia to increase with age. used for a 5 or 10 mm, 30 or 45 degree laparo-
Cholangiocarcinoma has been documented in scope, and carbon dioxide pneumoperitoneum is
more than ten patients younger than 20 years at established at a pressure of 10–12 mmHg. Three
the time of initial surgery for CBD; the youngest additional 5 mm trocars are inserted in the right
case reported being a 3-year-old boy (Saikusa upper quadrant, left paraumbilical area, and left
et al. 2009). In addition, gallbladder carcinoma upper quadrant (Fig. 8). Adequate exposure is
has been reported in 10–25% of CBD cases achieved by elevating the liver by introducing a
(Soares et al. 2014; Edil et al. 2008). There are percutaneous stay-suture just below the xiphoid
also case reports of malignancies arising from the process to snare the falciform ligament and retract
intrapancreatic terminal choledochus, hepaticoje- the liver. To expose the porta hepatis, a pair of
junostomy anastomosis, and IHBD after primary Babcock forceps is inserted through the left sub-
excision. Todani et al. (2002) reported a case costal port in the anterior axillary line, to grasp
of biliary carcinoma that developed 19 years and elevate the gallbladder to allow the CBD to be
after CE and HD, which was attributed to pancre- dissected free from surrounding structures, such
atic enzymes being activated by the presence of as the portal vein and hepatic artery. To excise the
bile and enterokinase in intestinal secretions. In posterior wall of the cyst, the anterior wall is
fact, HD appears to be associated with complica- incised first to improve exposure of the posterior
tions similar to those that arise secondary to inter- wall, as in the open technique (Fig. 9). This step
nal drainage for CBD and transduodenal facilitates dissection especially if there is chronic
sphincteroplasty for cholelithiasis, two proce- inflammation and dense adhesions which tend to
dures documented to develop biliary carcinoma. be worse in cystic CBD cases.
Consequently, HD is no longer routinely used for IE is performed during lapCE by introducing a
biliary reconstruction. fine uteroscope through an additional 3.9 mm tro-
Malignant lesions are usually associated with car in the left epigastrium (Fig. 8) and its tip is
abnormal epithelium and can involve K-ras gene inserted into the common channel through the
and p53 mutations in up to 60% of carcinomas distal cyst under laparoscopic guidance to remove
in CBD patients followed by late inactivation of protein plugs or debris in the same way as IE is
the DPC-4 gene, especially in biliary tract performed during open CE (Fig. 10). A fine long
adenocarcinomas (Tomono et al. 1996; ureteroscope can also be inserted through the left
Shimotake et al. 2003). Vigilant follow-up and paraumbilical trocar for intralaparoscopic hepatic
awareness of the risk for malignancy cannot be bile duct endoscopy to remove debris in the
overemphasized. IHBD, if present (Fig. 11). In cystic CBD, the
Fig. 7 The patient is initially positioned at the foot of the assistant on the right. *Note the different positions for the
operating table, with the surgeon at the patient’s feet. An monitor and the surgeon when it is time for HJ
assistant with a scope stands on the surgeon’s left and an
distal end tapers and is often very narrow, and cholangitis and/or liver dysfunction. In general,
occasionally, the orifice of the distal end opening IE is performed in all cases unless the
into the common channel cannot be identified. In ureteroscope cannot be inserted smoothly into
such cases where even the finest ureteroscope the common channel from the distal part of the
cannot be inserted, IE cannot be performed, but CBD (Miyano et al. 2011). During lapCE, it is
debris in the common channel is also rare. Such tempting to examine the duct system with the
patients usually do not develop pancreatitis but laparoscope instead of changing to an
can present with jaundice with or without ureteroscope, but inspection and irrigation are
not possible without a constant flow of saline to initiated by removing the adjacent peritoneum
expand the lumen, and while flexible scopes do using monopolar electrocautery and a Maryland
have side channels, they are only designed for dissector to establish a plane of dissection, begin-
flushing, or introducing instruments and are not ning on the anterior wall and continuing to the
suitable for IE. medial and lateral sides, and then to the distal
To prepare for excision, the cystic artery is portion. The exact level of transection of the distal
identified and divided. Dissection of the CBD is common bile duct is easier to determine if the
orifice of the pancreatic duct in the common chan-
nel can be identified, as in the open technique
(Fig. 4). After the CBD is freed, the distal part is
divided as close as possible to the pancreati-
cobiliary junction, and the stump is ligated with
an endoloop. The proximal part is excised leaving
10 mm of common hepatic duct. Cholecystec-
tomy is then performed.
A segment of proximal jejunum distal to the
duodenojejunal flexure is then exteriorized by
extending the umbilical port incision, and a
Roux-en-Y jejunojejunostomy is constructed
extracorporeally. The length of the limb is deter-
mined by placing the jejunojejunostomy at the
umbilicus and bringing the distal end of the limb
to be 3 cm above the xiphoid process. The exteri-
orized jejunum is returned to the abdominal cavity
after the Roux-en-Y jejunal limb is approximated
to the native jejunum for 8 cm cranially. The
closed end of the jejunal limb is brought up via a
Fig. 8 Trocar positions for laparoscopic excision. Note retrocolic window to the porta hepatis. Then, an
there is a 5 mm trocar in the epigastrium for the antimesentric enterotomy, 5 mm in length, for the
ureteroscope and additional 3 and 5 mm trocars (square HJ anastomosis, is created near the closed end of
brackets) on the right required for HJ. Numbers indicate the Roux-en-Y limb to allow the common hepatic
trocar sizes
Fig. 9 Excision of the

posterior wall of the CBD
under laparoscopic control
Fig. 10 Under
laparoscopic guidance, the
tip of a fine ureteroscope
(E) has been inserted into
the common channel
through the distal CBD to
remove protein plugs. The
inset shows the IE field
Fig. 11 A fine
ureteroscope (E) has been
inserted into the IHBD to
perform IE and delineate the
transition zone into right
and left hepatic ducts. Note
the clamped cystic duct
(CD). The inset shows the
IE field
duct to be anastomosed as close as possible to the of HJ anastomosis. Two additional trocars, lateral
closed end of the blind pouch. When creating the right subcostal, and between the lateral right sub-
5 mm enterotomy, monopolar diathermy should costal and right upper quadrant trocars are
be avoided because it appears to emit considerable required for the HJ anastomosis using 5/0 absorb-
lateral thermal energy which could injure the able sutures (Fig. 8). End-to-side HJ is performed
bowel wall around the enterotomy, which could using interrupted 5/0 or 6/0 absorbable sutures
be the cause of postoperative anastomosis leakage with the right upper quadrant port as a needle
reported by many centers (Lee et al. 2009; Hong holder in the right hand, the 5 mm port for the
et al. 2008; Srimurthy and Ramesh 2006; Ure scope, and the 3 mm subcostal port as a needle
et al. 2005; Nguyen Thanh et al. 2010). The receiver in the left hand. Both the right and the left
edges of the enterotomy are apposed temporarily edge sutures are exteriorized and are used as trac-
with two 7/0 PDS sutures to prevent spillage of tion sutures during anastomosis of the anterior
bowel contents. These sutures are cut at the time wall to facilitate accuracy (Fig. 12), especially
5 years (range: 1.0–14.2), and mean weight was

16.5 kg (range: 8.0–47.0). There were 19 females
and 7 males. CBD was fusiform in 19 and cystic in
7. Five patients had IHBD dilatation. Of the
19 fusiform CBD cases, 16 had HJ diameters of
6–9 mm, while the remaining 3 fusiform CBD
cases and 7 cystic CBD cases had HJ diameters
over 10 mm. IE of both the common channel and
IHBD were performed in 16 cases (all fusiform);
the remaining 10 had IE for IHBD only because
the ureteroscope could not be inserted into
the intrapancreatic choledochus or the common
channel. During IE of the common channel, all
16 fusiform CBD cases had protein plugs
removed successfully by irrigation with normal
saline from the side channel of the ureteroscope
(massive protein plugs in 4, moderate in 10, min-
imal in 2). Debris were present in the IHBD in 13/
26 CBD cases (moderate 6, minimal 7); the
Fig. 12 Traction sutures during HJ anastomosis. Both the remaining 13 had no debris. There were no
right and left edge sutures are exteriorized and used as intraoperative complications. Mean blood loss
traction sutures during anastomosis of the anterior wall to was minimal at 20 mL. Although all are well
facilitate accuracy, especially when the diameter of the HJ
anastomosis is less than 9 mm
after a mean follow-up of 2.8 years (range:
1 months–5.2 years) with cosmetically attractive
wounds, there were three postoperative complica-
when the HJ anastomosis diameter is less than tions The first complication was pancreatitis
9 mm. A tube drain is inserted in the pouch of developing 8 months postoperatively in a case
Winslow. The resected cyst and gallbladder are with massive protein plugs probably due to resid-
extracted through the umbilical wound, trocars are ual fine debris, 3 mm 3 mm in size, even though
removed, and all wounds are closed. we thought all debris had been removed success-
fully during IE. Pancreatitis was treated conserva-
tively with no sequelae. The second complication
Outcomes was duodenal obstruction in a cystic CBD case. At
exploratory laparoscopy, the third part of the duo-
As of mid-2014, the authors had performed denum was found to be compressed by the Roux
143 Roux-en-Y HJ with IE for CBD. Anastomo- limb that had been inadequately fixed to the
ses were end-to-end in 85 cases and end-to-side colonic mesentery. Once the sutures between the
in 58 cases. All cases are well at the time of Roux limb and colonic mesentery were released
writing without any complications after a mean laparoscopically, the postoperative course was
follow-up period of 14 years (range: 4 months to uneventful. The third complication was anasto-
29 years). One hundred and fifteen of these cases motic leakage that was treated by minilaparotomy.
had open CE and 28 had lapCE. Two lapCE cases
required conversion to open CE because laparot-
omy and minilaparotomy were required, respec- Conclusion and Future Directions
tively. Thus, 117 cases had open CE and 26 cases
had lapCE. CBD is a rare pathology that affects all ethnic
A summary of these 26 lapCE treated between groups but with higher incidence in Asian
2009 and 2014 follows. Mean age at surgery was populations. Proper diagnosis and early treatment
play important roles in preventing serious compli- References

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Part VII
Newborn Surgery: Anterior Abdominal
Wall Defects
Omphalocele
79
Jacob C. Langer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
Embryology and Associated Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1168
Antenatal Diagnosis and Perinatal Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1169
Neonatal Resuscitation and Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1170
Primary Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171
Staged Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1171
Postoperative Management After Primary or Final Staged Closure . . . . . . . . . . . . . . . . . . 1173
Long-Term Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
Gastrointestinal and Nutritional Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
Respiratory Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1174
Psychological Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1175
Abstract should stimulate investigations looking for

Omphalocele is an abdominal wall defect in associated chromosomal and structural abnor-
which the abdominal viscera herniate through malities. The surgical management of
the umbilicus and are covered by a sac. omphalocele consists of closure of the abdom-
Omphalocele is frequently detected on antena- inal wall defect either primarily or with a vari-
tal ultrasound. Prenatal diagnosis may influ- ety of staged approaches. The choice of
ence mode and location of delivery and approach depends on the size of the defect,
the amount of herniated viscera, and the pres-
ence of associated comorbidities such as car-
J. C. Langer (*) diac anomalies, pulmonary hypoplasia, or
Division of General and Thoracic Surgery, Hospital for prematurity. Long-term outcome is favorable
Sick Children, University of Toronto, Toronto, ON,
Canada
e-mail: jacob.langer@sickkids.ca

https://doi.org/10.1007/978-3-662-43588-5_83
1168 J. C. Langer
in most cases; however, significant associated probably completely distinct entities. Major dif-
anomalies may result in ongoing morbidity and ferences are summarized in Table 1.
mortality.
Embryology and Associated

Introduction Malformations
Omphalocele (also known as exomphalos) is a An omphalocele occurs when the intestines fail to
congenital abdominal wall defect which is char- return to the abdominal cavity after normal
acterized by herniation of the abdominal viscera embryonic herniation into the umbilical cord dur-
through the umbilical ring. The viscera are cov- ing weeks 6–10 of development. This is typically
ered by a sac which is composed of Wharton’s attributed to a folding defect in the abdominal wall
jelly. The incidence of omphalocele is approxi- rather than to the genes involved in gut elongation
mately 1 in 4000 live births and has remained and rotation (Thieme 1992). The resulting sac
stable in most parts of the world. There is a spec- over the extruded viscera therefore consists of
trum of severity in the size of the defect and the the coverings of the umbilical cord i.e., amnion,
amount of viscera which is out, but in general Wharton’s jelly, and peritoneum. The umbilical
omphaloceles can be categorized as small without cord inserts into the sac; sometimes this insertion
herniated liver and large with herniated liver is at the apex of the sac and sometimes it is closer
(Fig. 1). Some authors have also focused on to the abdominal wall. Varying amounts of intes-
“giant” omphaloceles, with the definition of the tine, liver, bladder, stomach, ovary, and testis can
latter category determined by a defect greater than also be found within the sac.
6–10 cm, or in other reports defined as a defect The process of intestinal rotation begins during
which cannot be closed primarily. Despite the the time of intestinal herniation into the umbilical
tendency to divide omphaloceles in this way, cord, and then is completed once the intestine has
there is clearly a spectrum of abnormalities returned into the abdomen. In children with
which range from very small to extremely large omphalocele, this process does not happen, and
defects. most therefore have intestinal non-rotation.
Omphalocele was recognized in ancient times, Omphalocele is commonly associated with
but the initial description in the modern literature other structural congenital anomalies as well as
was by Ambrose Pare in the seventeenth century with various types of chromosomal abnormalities
(Ricketts 2012). Omphalocele is often confused (Table 2). There are also several recognized syn-
with gastroschisis, but the two conditions are dromes which include omphalocele. Beckwith-
Fig. 1 Typical appearance of omphalocele. (a) Small omphalocele with liver in, (b) Giant omphalocele with liver out
79 Omphalocele 1169
Table 1 Differences between omphalocele and diaphragmatic hernia, pericardial defect, sternal
gastroschisis defect, and intrinsic congenital heart disease.
Omphalocele Gastroschisis Most cases do not have all five abnormalities.
Sac Present Absent The genetic basis for Pentalogy of Cantrell is
Associated Common Uncommon unknown, although mutations in the PORCN
anomalies gene has been described in some cases (Lombardi
Location of Umbilicus Right of
et al. 2011). Donnai-Barrow syndrome consists of
defect umbilicus
Maternal age Average Younger
hypertelorism, central nervous system abnormali-
Mode of delivery Cesarean/ Vaginal ties, sensorineural hearing loss, diaphragmatic
vaginal hernia, and omphalocele and is caused by muta-
Surgical Not urgent Urgent tions in the LRP2 gene.
management
Prognostic Associated Condition of
factors anomalies bowel
Antenatal Diagnosis and Perinatal
Management
Table 2 Chromosomal and structural malformations
associated with omphalocele
Omphalocele is sometimes suspected antenatally
because of an elevated maternal serum
Chromosomal abnormalities
α-fetoprotein (Palomaki et al. 1988). Ultrasound
Trisomy 21
diagnosis may be made as early as the first trimes-
Trisomy 18
ter if three-dimensional ultrasonography is avail-
Trisomy 13
Structural organ system anomalies
able but is more commonly made on routine
Pulmonary hypoplasia 18-week two-dimensional ultrasound. In addition,
Cardiac identification of bowel in the umbilical cord
Renal before 12 menstrual weeks can be a normal find-
Neurological ing, and the diagnosis should not be made until
Limb subsequent scans confirm that the herniated vis-
Syndromes cera have not returned to the abdomen. The inci-
Beckwith-Wiedemann syndrome dence of omphalocele seen on ultrasonography at
Cloacal exstrophy (OEIS) syndrome 14–18 weeks is as high as 1 in 1100, but many of
Pentalogy of Cantrell these result in spontaneous intrauterine fetal death
Donnai-Barrow syndrome and pregnancy termination, and the incidence in
live births is approximately 1 in 4000 (Blazer et al.
Wiedemann syndrome consists of omphalocele, 2004).
neonatal hypoglycemia, organomegaly, and a pre- Once made, an antenatal diagnosis of
disposition to a variety of solid tumors and is omphalocele should be followed by a comprehen-
caused by mutations in the 11p15 location sive fetal ultrasound, as well as fetal echocardiog-
(Demars and Gicquel 2012). Cloacal exstrophy, raphy, looking for structural anomalies. Many of
which is also known as OEIS (omphalocele/ the features of associated syndromes such as clo-
exstrophy/imperforate anus/spinal malformation), acal exstrophy, Donnai-Barrow syndrome, and
particularly in the genetics and obstetrics litera- Pentalogy of Cantrell can also be suggested by
ture, consists of exstrophy of the combined blad- fetal ultrasound. Cardiac defects are the most
der and cecal plate, neural tube and spinal defects, common anomalies in this group, but such lethal
high anorectal malformation, and congenitally entities as holoprosencephaly and anencephalus,
short small bowel in approximately 10% of as well as the complete spectrum of VACTERL
cases. The genetic basis for cloacal exstrophy is (vertebral, anorectal, cardiac, tracheoesophageal,
unknown (Vlangos et al. 2011). Pentalogy of renal, and limb) defects, may be seen. Pulmonary
Cantrell consists of omphalocele, Morgagni hypoplasia is also commonly associated with
1170 J. C. Langer
omphalocele and may result in early respiratory early and placed to suction or gravity drainage. A
distress requiring intubation and ventilatory sup- thorough search for associated anomalies should
port at the time of delivery. Antenatal ultrasound then be undertaken. The high risk of associated
has been unreliable in predicting the probability of cardiac defects mandates a directed clinical car-
this problem (Kamata et al. 2008), but preliminary diac evaluation, including auscultation, four-limb
data using MRI-generated lung volumes shows blood pressures, peripheral pulse examination,
some promise for predicting neonatal respiratory and chest X-ray. Once stabilized, a more detailed
function in infants with omphalocele (Danzer evaluation can be provided by echocardiography,
et al. 2012). although a routine cardiac echo is probably unnec-
Karyotype analysis using chorionic villous essary if the clinical evaluation is completely nor-
sampling or amniocentesis should be encouraged mal (Nasr et al. 2010). An abdominal ultrasound
because of the high incidence of chromosomal should be obtained to evaluate the possibility of
abnormalities; most commonly trisomies 13, 18, associated renal anomalies. The presence of neo-
and 21. The risk of a chromosomal abnormality natal hypoglycemia raises the possibility of
appears to be more common in fetuses with a Beckwith-Wiedemann syndrome and should be
central omphalocele than those with epigastric followed by appropriate genetic testing.
omphaloceles (Brantberg et al. 2005), and para- For infants with omphalocele who require trans-
doxically chromosomal abnormalities are more port to a perinatal center, adequate intravenous
common in small omphaloceles without liver her- access should be obtained for fluid resuscitation,
niation than in larger omphaloceles (Benacerraf and specific issues related to cardiac or other asso-
et al. 1990). ciated anomalies should be addressed. Most infants
The mode of delivery for fetuses with with omphalocele have an intact sac, which pre-
omphalocele should be dictated by obstetric con- vents significant fluid and temperature losses; how-
siderations, because neither vaginal delivery nor ever, losses are higher than those with an intact
cesarean section has been shown to be superior. abdominal wall, and the omphalocele sac should
Despite the lack of data, most practitioners choose therefore be dressed with saline-soaked gauze and
to deliver neonates with large omphaloceles by an impervious dressing to minimize these losses. In
cesarean section because of the fear of liver injury cases of a ruptured omphalocele, the initial man-
or sac rupture during vaginal delivery (Heider agement of the viscera should be the same as an
et al. 2004). In addition, most authors advocate infant with gastroschisis, with rigorous attention to
delivery at a tertiary perinatal center to allow the prevention of heat and fluid loss, and a sterile
immediate access to neonatal and pediatric surgi- dressing to minimize the risk of infection and to
cal expertise. Small omphaloceles without stabilize the liver and bowel to avoid ischemia due
documented structural or chromosomal abnormal- to kinking of these organs.
ities can probably be safely delivered outside of a
perinatal center. There is no advantage to routine
preterm delivery for fetuses with omphalocele. Surgical Management
The goal of surgical management for the infant

Neonatal Resuscitation with omphalocele is to reduce the viscera and
and Investigation provide permanent abdominal wall coverage,
without causing injury to the viscera either by
The first priority in the delivery room is careful direct trauma or by decreased organ perfusion
attention to cardiopulmonary status, since chil- due to excessive intra-abdominal pressure
dren with omphalocele may have unsuspected (“abdominal compartment syndrome”). Treat-
pulmonary hypoplasia that requires immediate ment options depend on the size of the defect,
intubation and ventilation (Biard et al. 2004). A gestational age, and the presence of associated
nasogastric or orogastric tube should be inserted anomalies.
79 Omphalocele 1171
Primary Closure the incidence of abdominal compartment syn-

drome was shown to decrease from historical con-
In infants with small defects, primary closure can trols (Lacey et al. 1993). Intra-abdominal pressure
usually be accomplished easily. In most cases this can be estimated using intragastric pressure trans-
consists of excision or inversion of the sac, duced through the nasogastric tube, or using
followed by direct closure of the fascia and skin. intravesical pressure transduced through the
Care should be taken when excising the portion of Foley catheter. Although neither technique is
the sac covering the liver, as it is typically densely completely accurate, both give the surgeon valu-
adherent and excision can tear Glisson’s capsule able information to assist in decision-making dur-
leading to hemorrhage. Often it is best to leave a ing abdominal wall closure.
part of the sac on the liver; only rarely does this For cases in which the increase in intra-
result in infection or other problems. Additionally, abdominal pressure is felt to be unacceptable, multi-
there may be significant anatomic distortion of the ple techniques are available to achieve primary fas-
liver in patients with omphalocele, and the hepatic cial closure of the abdominal wall. Flaps that
veins may be located just under the sac in the mobilize the muscle, fascia, and skin of the abdom-
midline, making them susceptible to inadvertent inal wall toward the midline and allow midline fas-
injury. Similarly, the inferior portion of the sac cial closure have been used successfully (Zama et al.
covering the bladder can be quite thin, and exci- 2004). Component separation at the level of the
sion of the sac in this area can lead to accidental external oblique has also been described, with
bladder injury. In some cases an omphalome- encouraging abdominal wall function on medium-
senteric duct remnant may be associated with a term follow-up (van Eijck et al. 2008, 2013). Tissue
small omphalocele, and this should be closed expanders inside the abdominal cavity have been
during primary repair. Other anomalies that may used to reduce abdominovisceral disproportion
be encountered under the sac or along the umbil- (Tenenbaum et al. 2007). Volume is added to the
ical cord in children with a small omphalocele tissue expander over time until a primary fascial
include an allantoic cyst or an ectopic piece of closure can be performed. Some surgeons prefer to
liver tissue. Both of these should be recognized place a patch in the abdominal wall and close the
and excised at the time of closure. skin over the patch. Infection of nonabsorbable patch
In small omphaloceles without liver hernia- materials such as Marlex, Gore-Tex, and Prolene,
tion, abdominal compartment syndrome is usually leading to mesh removal, has prompted investigation
not a problem. However, primary closure of larger into the use of bioabsorbable materials (small intes-
omphaloceles may be accompanied by the risk of tinal submucosa, dura, or acellular dermis) (Rahni
acute hepatic congestion, renal failure, and bowel et al. 2008). Recurrence is relatively common with
infarction (Dunn and Fonkalsrud 1997). A high these patches, but those who recur can be
index of suspicion and careful attention to venti- reconstructed at a later time with a nonabsorbable
latory pressures, end-tidal CO2 levels, urine out- patch or a delayed primary closure (Beres et al.
put, and distal perfusion can minimize these types 2012). In many children with a large omphalocele,
of complications. In addition, many authors have part of the fascial defect can be closed primarily and
suggested the use of intra-abdominal pressure a relatively small patch can be used for the remaining
monitoring during attempted reduction as a more section of fascia. This is particularly true for high
objective way to guide closure. In a series of omphaloceles that abut the costal margin.
experiments in rabbits, Lacey demonstrated that
an intra-abdominal pressure of greater than
10–15 mm Hg was associated with decreased Staged Closure
organ perfusion using a microsphere technique
(Lacey et al. 1987). In a subsequent clinical In 1967, Schuster described the use of a silicone
study in which these criteria were applied to a plastic “silo” to provide staged reduction for chil-
series of children with abdominal wall defects, dren with omphalocele (Schuster 1967). The sac
1172 J. C. Langer
Fig. 2 Staged closure of a giant omphalocele in an other- (c) Closure of the skin with or without a biodegradable
wise healthy neonate. (a) Removal of the sac and place- patch
ment of a silastic silo; (b) Gradual reduction of the viscera;
was excised, and the silo was sewn to the rectus (Fig. 2). The aggressiveness of serial reduction
fascia and over the top of the viscera. Some sur- can be determined through clinical observation
geons created a short circumferential skin flap so of lower limb perfusion, ventilation pressures,
that the silo was sewn to the fascia only, and some end-tidal CO2, and oxygen saturation. Intra-
attached the silastic to the full thickness of the abdominal pressure monitoring, as described
abdominal wall. Some surgeons have recently above, can also be used in this setting and may
recommended the use of preformed spring-loaded provide more objective information to guide
silos in this setting, but this is usually unsuccess- reduction. Once the viscera are completely
ful owing to the relatively large size of the defect reduced, the infant returns to the operating room
that prevents the silo from remaining in place. for attempted definitive closure of the defect. In
Another option for moderate-sized omphaloceles many cases the fascial edges still cannot be
is to use sequential ligation of the sac itself for approximated, usually due to the large size of the
gradual reduction of the viscera (Hong et al. defect, and patch closure or combined primary
1994). This is most feasible if the sac is relatively and patch closure can be utilized.
thick, and if the umbilical cord inserts near the “Escharotic therapy,” which results in gradual
apex of the sac. epithelialization of the omphalocele sac, is
Once the silo has been placed or sac ligation another form of staged closure that can be used
has been initiated, serial bedside reduction is for neonates who cannot tolerate any increase in
performed on a once- to twice-daily basis intra-abdominal pressure due to prematurity,
79 Omphalocele 1173
Fig. 3 Escharotic treatment for a giant omphalocele in a hernia repair using porcine intestinal submucosa as a patch
neonate with pulmonary hypoplasia. (a) Initial application in the superior aspect of the defect. This repair should only
of silver sulfadiazine; (b) Mature eschar with partial epi- be done once the child is medically optimized
thelialization; (c) Complete epithelialization; (d) Ventral
pulmonary hypoplasia, congenital heart disease, epithelialization has occurred and the infant is
or other anomalies (Bauman et al. 2016). Histor- stable enough to undergo anesthesia and surgery,
ically, mercurochrome was used as both a the remaining ventral hernia can be repaired by
scarificant and a disinfectant; however, reports of one of the previously mentioned methods. In most
deaths due to mercury poisoning led to abandon- cases prosthetic mesh with skin flap coverage is
ment of this treatment option. Povidone-iodine required, especially at the upper end of the defect.
has also been used, but systemic absorption of Tissue expanders and component separation tech-
iodine has been associated with transient hypo- niques, as mentioned above, have also been
thyroidism. Absorption is negligible after described for definitive closure at this late stage.
escharification, but infants treated with
povidone-iodine as a scarification agent should
undergo monitoring of thyroid function Postoperative Management After
(Whitehouse et al. 2010). Silver sulfadiazine is Primary or Final Staged Closure
the most common topical applicant currently in
use (Fig. 3). Once initial cicatrization has begun, The majority of patients, particularly those with
silver sulfadiazine may be replaced with an absor- liver herniation, require mechanical ventilation
bant synthetic fiber like Aquacel™ (Convatec, for a few days after final abdominal wall closure
Canada) to keep the eschar dry, while granulation even if ventilation wasn’t necessary previously.
and epithelialization gradually occurs over the During this time, abdominal wall, liver, and
following months (Ein and Langer 2012). Once bowel edema resolve and the intra-abdominal
1174 J. C. Langer
pressure usually decreases. Careful monitoring of Gastrointestinal and Nutritional

urine output, tissue perfusion, and intra- Problems
abdominal pressure may be advisable for early
identification of abdominal compartment syn- Many children with omphalocele are initially fed
drome, which would necessitate a return to the through a nasogastric tube for a prolonged period
operating room and decompression of the of time and as a result do not learn how to eat by
abdomen. mouth. Some of these patients may require place-
An adequately sized, functioning nasogastric ment of a gastrostomy tube. This can present a
tube is important to provide gastric decompres- technical challenge for the surgeon, since surgical
sion during this period. Parenteral nutrition is access to the stomach may be difficult. Another
often necessary initially, but feeding can begin option is gastrostomy tube placement under image
when the nasogastric output is no longer bilious, guidance by an interventional radiologist. In most
the volume is minimal, and bowel activity has cases these feeding difficulties resolve over time,
resumed. with height and weight measurements becoming
similar to those of their peer group (Berseth et al.
1982).
Long-Term Outcomes Severe gastroesophageal reflux is also very
common in children with large omphaloceles. Ini-
Outcomes in children with omphalocele are pri- tial management consists of medical therapy
marily determined by the presence or absence of using acid reduction and prokinetic agents, but
associated structural or chromosomal abnormali- in many cases this is insufficient. Fundoplication
ties. Most infants with a small omphalocele, in the is often technically challenging or impossible
absence of other abnormalities, recover well and because of the large midline liver which obscures
do not have any long-term issues. However, this surgical access to the gastroesophageal junction,
may represent as few as 10% of all omphaloceles and because of techniques that may have been
diagnosed on prenatal ultrasound. Approximately used to close the abdominal wall defect. This
20% of patients with omphalocele do not live issue is especially problematic in the child who
beyond the first year of life, approximately is being managed with escharotic therapy. These
one-third die in the first week from multiple con- children may be better served by the use of a naso-
genital anomalies, and the majority of the rest do or gastrojejunal tube, which can be placed using
not survive the first year of life because of cardiac image guidance, or a surgically placed Roux-en-Y
anomalies or pulmonary hypoplasia (Brantberg jejunostomy (Langer et al. 2000).
et al. 2005). Up to a third of patients with omphalocele
A number of long-term medical problems may report intermittent abdominal pain persisting into
occur in patients with large omphaloceles (Danzer young adulthood (van Eijck et al. 2009). The
et al. 2015). Gastrointestinal issues including gas- etiology of this problem is unclear.
troesophageal reflux, feeding difficulty and failure
to thrive (Haug et al. 2016), and respiratory prob-
lems including pulmonary insufficiency, recurrent Respiratory Problems
lung infections, or asthma are reported in up to
60% of infants with a giant omphalocele (Biard Many of the infants with pulmonary hypoplasia die
et al. 2004; Koivusalo et al. 1999). In addition, during the neonatal period. Those who survive often
challenges may be presented later in life because have respiratory insufficiency and may require oxy-
of abnormal position of intra-abdominal organs gen supplementation for prolonged periods at home.
(van Eijck et al. 2010), and there are long-term However, one recent study looking at the long-term
psychological problems reported because of the cardiopulmonary consequences of large abdominal
cosmetic appearance of the abdomen in children wall defects documented normal lung volumes and
with omphalocele (Guida et al. 2013). oxygen consumption on long-term follow-up,
79 Omphalocele 1175
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1178
Prenatal Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
Preoperative Assessment and Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1179
Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
Operative Procedure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1180
Primary Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1181
Staged Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182
Postoperative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1184
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1184
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1186
Abstract
Gastroschisis is a congenital anterior abdominal
wall defect which results in herniation of intra-
abdominal contents early in utero. Prenatal ultra-
M. Z. Schwartz (*) sonography has become the optimum means of
Drexel University College of Medicine, St. Christopher’s diagnosing gastroschisis. Knowing the diagnosis
Hospital for Children, Philadelphia, PA, USA in advance allows for appropriate resources to be
e-mail: mzschwartz@msn.com available to facilitate the delivery at or near a
S. J. Timmapuri tertiary neonatal care center. Meticulous periop-
Rutgers/Robert Wood Johnson Medical School, erative management is imperative for good
Bristol–Myers Squibb Children’s Hospital, New
Brunswick, NJ, USA patient outcomes. Abdominal closure can be
e-mail: timmapsh@rwjms.rutgers.edu performed primarily or using a staged technique.

https://doi.org/10.1007/978-3-662-43588-5_84
1178 M. Z. Schwartz and S. J. Timmapuri
Congenital or acquired complications, e.g., atre- gestation), weighing 2000–2500 g. The defect is
sias, perforation, and delayed necrotizing entero- almost always to the right of the umbilicus and
colitis, must be identified promptly and managed generally measures 2–3 cm in diameter. In addition
carefully. Patient outcomes in gastroschisis are to the stomach and urinary bladder, the transverse
typically excellent, especially if close attention is and left colon may be extracoelomic. Also visible
paid to the details of perioperative management may be the testicles in males and the fallopian
and surgical technique. tubes and ovaries in females. The intestine is
foreshortened and edematous and generally has a
Keywords fibrin coating (Fig. 2). Atresia involving the small
Gastroschisis · Abdominal wall defects · or large intestine occurs more often (10–20%) than
Intestinal atresias · Silo · Prenatal diagnosis in patients with omphalocele (~1%). The most
striking difference in appearance between
omphalocele and gastroschisis is the absence of a
Introduction sac or membrane covering the herniated contents
in gastroschisis (Christison-Lagay et al. 2011).
Gastroschisis is an anterior abdominal wall defect
that occurs early in fetal development, which
results in herniation of intra-abdominal viscera History
into the amniotic sac. This typically occurs to the
right of the umbilical stalk (Fig.1). The prevailing The first successful surgical repair of
hypothesis is that the defect occurs at the site of gastroschisis was performed by Watkins in
involution of the second (right) umbilical vein. 1943. Although there were improvements in the
Because most or all of the midgut is outside of perioperative management and surgical proce-
the peritoneal cavity, this anomaly is accompanied dures for gastroschisis, the mortality remained
by nonrotation of the bowel and an increased significant and was reported to be as high as
incidence of other intestinal abnormalities, includ- 90%. Two major advances occurred in the late
ing atresia, perforation, and infarction, resulting 1960s that led to a dramatic improvement in the
from midgut volvulus or vascular thrombosis.
Gastroschisis is much more common now than
omphalocele with an incidence of approximately
2.5 per 10,000 live births. Most infants with
gastroschisis are born prematurely (35–37 weeks’
Fig. 1 An infant with gastroschisis. Note herniated con-

tents to the right of the umbilical stalk Fig. 2 Foreshortened, edematous bowel
80 Gastroschisis 1179
survival of infants with gastroschisis. In 1967, and warrant early delivery. However, the timing
Schuster et al. described a technique of staged of delivery still remains controversial. Rationale
reduction of the herniated bowel and abdominal for early delivery (36–38 weeks) includes
closure for patients in whom primary closure was decreased exposure time of the intestine to amni-
not possible. This allowed for more rapid bowel otic fluid and ability to ensure delivery at/near a
recovery and decreased risk from sepsis. tertiary care pediatric center. However, advo-
The second major advance was the evolution of cates for spontaneous delivery believe that
intravenous nutrition, which, remarkably, allo- early delivery is associated with poorer out-
wed for growth and development during the pro- comes such as increased ventilation require-
longed period that these infants could not ments from lung prematurity, prolonged time to
tolerate enteral feeding. Over the past four full enteral feeds, and prolonged hospital stay.
decades, the outcome for infants with The findings from a recent study indicate that
gastroschisis has dramatically improved, there is a decreased incidence of severely matted
resulting in a survival rate that is now greater bowel with increased gestational age, further
than 90% (Holland et al. 2010). discouraging early or preterm delivery (Youssef
et al. 2015). It has been demonstrated by numer-
ous studies that the mode of delivery (vaginal
Prenatal Considerations vs. Cesarean section) does not influence patient
outcomes in gastroschisis (Snyder et al. 2011).
Fetal ultrasonography can detect gastroschisis as Delivery at or near a tertiary pediatric facility,
early as the first trimester of pregnancy. Sono- with the availability of a pediatric surgeon and
graphic detection of extracoelomic bowel level III neonatal intensive care unit, has been
with no covering membrane strongly suggests shown to significantly improve outcomes for
the diagnosis. Other findings such as bowel dila- these patients (Savoie et al. 2014). These infants
tation and/or bowel wall thickening/edema are are likely to have more prompt surgical inte-
concerning for bowel obstruction and/or ische- rvention and successful primary closure.
mia (Kuleva et al. 2012; Long et al. 2011). How- This is likely due to shorter exposure time of
ever, the degree of bowel dilatation is not the herniated bowel resulting in decreased
necessarily indicative of the extent of intestinal swelling and perhaps the need for less bowel
complications (Badillo et al. 2007; Davis et al. manipulation. These factors likely lead to earlier
2009). Factors, such as intrauterine growth initiation of enteral feedings and decreased
restriction, thickened bowel, and stomach herni- lengths of stay.
ation, have also been proposed as parameters
predicting poor postnatal outcomes. There are
two commonly accepted explanations for the Preoperative Assessment
thickened, foreshortened, and edematous bowel and Preparation
(D’Antonio et al. 2015; Horton et al. 2010).
Continuous contact of the herniated contents Infants with gastroschisis require prompt inter-
with amniotic fluid has been proposed as one vention. Significant delays in management of the
reason. Secondly, serial fetal ultrasonography herniated contents should be avoided. Appropri-
has demonstrated that the fascial defect begins ate preoperative preparation is essential to ensure
to decrease in diameter near the end of the third a good outcome. Because heat loss from the
trimester, which could lead to venous conges- exposed herniated contents can be significant,
tion, swelling, and even infarction of the midgut. maintenance of the infant’s temperature within
Therefore, serial fetal ultrasonography in the the normal range is critical. It is well documented
third trimester is warranted to follow the appear- that hypothermia leads to poorer overall out-
ance of the bowel. Progressive worsening of comes with delayed bowel function and pro-
these findings could lead to future complications longed length of stay. There are various
methods to minimize this heat loss depending on as it diffuses into the lumen of the bowel causing
available supplies in the delivery room or inten- distension and compromises the likely success of
sive care nursery. If transport of the infant to a primary abdominal wall repair.
pediatric surgical center is needed, the patient
should have an intravenous catheter established,
the bowel should be wrapped in moist saline- Operative Procedure
soaked gauze, and the lower body placed in a
plastic bag to the lower chest or loosely wrapped The operation should be performed under condi-
in cellophane. Alternatively, dry rolls of gauze tions that maintain normothermia. Several
may be wrapped around the patient’s abdomen methods exist to accomplish this goal. An over-
after the damp gauze-covered bowel is placed to head radiant warmer, warming lights, or a
create an appropriate environment. It is impera- warming blanket should be used to maintain the
tive to stabilize the bowel to diminish the risk of infant’s temperature in the normal range during
compromising its blood supply at the fascial the procedure. Raising the temperature in the
ring. The infant should be in a warming isolette operating room may also be necessary. After the
or under an overhead radiant warmer to help induction of general anesthesia, the dressing pre-
maintain normothermia. viously placed over the herniated contents should
Most infants with gastroschisis are dehy- be removed. The bowel should be handled with
drated at birth and require at least 125% of nor- sterile gloves. The umbilical cord, which has usu-
mal maintenance fluids to regain normovolemia. ally been left long, should be clamped 2–3 cm
Eventually, almost all infants with gastroschisis above the abdominal wall and the excess cord
will require central venous access. Broad- then removed. Holding the bowel and clamp on
spectrum antibiotics are appropriate during the the umbilical cord in one hand, the bowel should
perioperative period because of exposure of the be prepared using gauze sponges soaked in a
bowel and peritoneal cavity to bacterial contam- 50:50 mixture of povidone-iodine solution and
ination at the time of birth. A nasogastric or saline. The antiseptic solution must be warm to
orogastric tube placed at the time of birth is the touch in an effort to minimize heat loss. After
necessary for gastrointestinal decompression gently washing the bowel and the anterior and
because of the bowel inflammation and resulting lateral abdominal wall, drapes are appropriately
ileus. Thus, before surgery, the infant with placed and the herniated contents are laid on the
gastroschisis should be normothermic, drapes. The surgeon should then scrub and put on
normovolemic, and hemodynamically stable gown and gloves.
and have normal serum electrolytes following At this point the umbilical stump can be ligated
adequate fluid resuscitation. allowing removal of the clamp. Next, the herniated
intestine should be carefully inspected for areas of
perforation or sites of atresia, although no effort
should be made to dissect matted loops of intestine.
Anesthesia It is sometimes necessary to extend the abdominal
wall defect to facilitate reduction of the herniated
General anesthesia is required for appropriate bowel. This is generally done by extending the
operative management of gastroschisis. The defect superiorly in the midline by 1–3 cm
choice of anesthetic agents should be made by (Fig. 3). Extending the incision caudally is not
the anesthesiologist, but there are two important recommended because the urinary bladder is in
considerations: (1) muscle paralysis is useful in close proximity to the inferior aspect of the abdom-
optimizing the chances for complete reduction of inal wall defect. The length of this incision
the herniated bowel and primary abdominal wall depends on the size of the original defect and the
closure; and (2) nitrous oxide should not be used bulkiness of the herniated bowel.
in fewer knots and greater distribution of ten-

sion. When all the sutures have been placed,
they are tied in sequence with a thin, malleable
retractor initially underneath the fascia to pre-
vent a loop of intestine from becoming entrapped
under the sutures. The umbilical stalk is retained
to create a more natural umbilical appearance
when the wound is fully closed. When the fascia
has been closed, the skin edges are approximated
using interrupted absorbable sutures or skin sta-
ples and sufficient sterile skin closure strips,
allowing distribution of skin tension over a
wider surface area and thus reducing the likeli-
Fig. 3 Vertical extension and closure of gastroschisis hood of skin disruption.
defect
About 60–70% of infants with gastroschisis
can be operatively treated in this way without
creating undue intra-abdominal pressure or ten-
Primary Closure sion in the abdominal wall closure. It is best to
avoid high intra-abdominal pressure and exces-
The herniated intestine is reduced as much as sive suture line tension. This can result in
possible, distributing the bowel to all quadrants abdominal compartment syndrome, possibly
of the peritoneal cavity. Two techniques have leading to intestinal necrosis, renal hypo-
been described to facilitate complete bowel perfusion, and difficulty in ventilation, as well
reduction and abdominal wall closure: as wound disruption. Intragastric and bladder
(1) stretching of the anterior abdominal wall pressure monitoring has been used by some pedi-
and (2) “milking” the intestinal contents into atric surgeons to determine intra-abdominal
the stomach and aspiration through the nasogas- pressure (Lacey et al. 1993). These two measure-
tric tube. Some surgeons also find milking out ments are used as a guide to monitor intra-
the colonic contents to be an effective maneuver abdominal pressure during primary or staged
for decompressing and reducing the bowel. closure of gastroschisis. The goal of therapy is
Although gentle stretching of the anterior to maintain intra-abdominal pressure below
abdominal wall can be useful, vigorous 20 mmHg, which is based on prior studies show-
stretching can lead to rectus muscle hemorrhage ing that higher pressures compromise intra-
and abdominal wall edema, producing a non- abdominal organ perfusion.
compliant, firm anterior abdominal wall. This An alternate method, utilizing abdominal wall
can result in ventilation difficulties and wound- component separation, has been described for clo-
related problems. Caution should also be taken sure of larger gastroschisis fascial defects (Levy et
when manipulating the intestine to “milk” the al. 2013). This technique has been used for many
intestinal contents into the stomach, as this can years to repair large ventral hernias in older chil-
cause further damage to the bowel wall, resulting dren and adults. It involves incising the external
in increased bowel wall thickening and addi- oblique fascia lateral to the rectus sheath and
tional delay in bowel recovery. If reduction of separating the external oblique from the internal
the herniated intestine is successful, the abdom- oblique muscle. This is done bilaterally and
inal wall is assessed for primary closure. If it can allows for tissue approximation in the midline
be closed without undue tension, 3/0 absorbable, without significant tension. Biologic mesh may
monofilament sutures are used. These sutures are be placed above or below the tissue to reinforce
placed in a figure-of-eight fashion, as this results the repair if needed.
Staged Closure silo. The optimal target for completely reducing

the bowel, removing the silo and closing the
For patients in whom complete reduction of the abdominal wall, is7–10 days. Any delay beyond
herniated bowel and abdominal wall closure are this timeframe substantially increases the risk of
not possible or appropriate, the staged reduction fascial infection, tearing away of the silo from the
technique described by Schuster in 1967 has pro- anterior abdominal wall muscle, and failure of the
ved to be very useful (Schuster 1967). Reinforced technique. The risk of failure of this technique is
Silastic sheeting (0.8–1.0 mm thick) is sutured to high if the silo is not able to be removed within
the fascial edges (Fig. 4). This is accomplished 14 days from placement. Daily reduction of the
with interrupted 3/0 silk mattress sutures. It is intestinal contents within the sac can be accom-
generally necessary to enlarge the fascial defect plished in the neonatal intensive care unit using
prior to suturing the Silastic sheet. However, sedation and sterile technique (Fig. 7). Each time
extending the fascial opening too far inferiorly
should be avoided as bladder injury may occur.
The cephalad and caudad vertical edges of the silo
are constructed with running 3/0 monofilament
sutures (Fig. 5). Before closing the top of the
silo, as much of the bowel as possible is reduced
into the peritoneal cavity by manual compression
within the sac while avoiding excessive intra-
abdominal pressure. The top of the sac is over-
sewn with a 3/0 monofilament suture placed in a
running horizontal mattres
s fashion. Suture is also placed through the skin
and looped over the silo (Fig. 6) in order to place
some tension on the skin edges to minimize skin
retraction and facilitate skin approximation at the
time of the abdominal wall closure. The silo is
covered with povidone-iodine ointment followed
by dry roll gauze to act as a protective dressing
and provide support to the silo at the fascial level.
The staged reduction technique requires daily
reduction of the herniated intestine within the Fig. 5 Silo creation using Silastic sheeting
Fig. 4 Silastic sheeting sutured to fascial edge Fig. 6 Suture placed through skin and looped over silo
Fig. 8 Preformed, spring-loaded silo
Fig. 7 Reduction of bowel in silo using horizontal suture
the procedure is performed, the sac and anterior

abdominal wall are prepared with warm
povidone-iodine solution before the reduction,
and povidone-iodine ointment is applied followed
by roll gauze after the procedure. General anes-
thesia is not necessary. When the herniated bowel
has been successfully reduced into the peritoneal
cavity and the fascial edges brought to within Fig. 9 Bowel placed within preformed silo
1 cm of each other, the infant is ready for removal
of the sac and primary abdominal wall closure in
the operating room under general anesthesia contents into a small diameter preformed silo
(Schwartz et al. 1983). can result in local or massive intestinal ischemia
An alternative method of staged reduction and/or infarction. If the defect is too small, the
which has become popular and is effective is the fascial opening should be enlarged to allow us of a
placement of a preformed, spring-loaded silo at larger diameter silo to prevent these potential
the bedside (Fig. 8) (Schlatter et al. 2003). This complications. Reduction of the bowel is accom-
can be accomplished without general anesthesia. plished in a similar fashion to that used for the
The preformed silo comes indifferent diameters sutured silo, except that a single tie with umbilical
and should be selected appropriately to accommo- tape is used to secure the reductions (Fig. 10).
date the size of the defect but more importantly to Recently, another method, referred to as
accommodate the bulkiness of the herniated con- “sutureless” or “plastic” gastroschisis closure, has
tents. The ring of the spring-loaded silo is placed been described (Sandler et al. 2004). In this tech-
underneath the fascial defect after the herniated nique, the bowel is reduced in the usual fashion
bowel is placed within it (Fig. 9). A very small either primarily or after placement in a silo. How-
fascial defect can be constrictive and may lead to ever, instead of placing sutures to approximate the
failure to reduce the herniated contents into the fascia, the defect is covered with the umbilical
peritoneal cavity. Also, placing the bowel stump or a nonadherent dressing. An occlusive
while awaiting the return of intestinal function.

Nasogastric decompression is necessary until there
is evidence of bowel function. Broad-spectrum anti-
biotics are generally continued during the perioper-
ative period (usually 3–5 days). Those infants who
undergo the staged approach require a longer period
of antibiotic treatment (usually until 1–2 days after
the silo has been removed). Once there is evidence
of gastrointestinal function, enteral feeding can be
introduced and gradually progressed using breast
milk or a low-residue elemental-type formula with
appropriate caloric intake. In the past, enteral feed-
ing in these patients was generally delayed for at
Fig. 10 Reduction of abdominal contents within spring- least 4–6 weeks after surgery, as it was thought that
loaded silo
early feeding could lead to an increased risk of
developing complications. However, this approach
dressing is then placed over the site and the wound has not been supported by clinical evidence. More
is allowed to granulate. Once granulation tissue recently, enteral feedings have been started as early
covers the wound bed, the area is covered with as 10–14 days after abdominal wall closure with no
dry dressings. Proposed advantages of this tech- increase in adverse outcomes.
nique include reduced intra-abdominal pressure
during the closure process and decreased narcotic
and sedation requirements. Nearly all infants have Complications
an umbilical hernia following this method of repair,
but many of these resolve spontaneously, similar to Complications in infants with gastroschisis are
isolated umbilical hernias (Riboh et al. 2009; Orion generally related to the gastrointestinal tract or
et al. 2011; Choi et al. 2012). the abdominal wall closure. As noted earlier, in
Negative pressure wound therapy has also utero complications from intestinal atresia or per-
been utilized to manage very large abdominal foration can occur (Fig. 11). Intestinal perforation
wall defects. This technique can be used for initial can be managed in one of several ways, depending
coverage of viscera in patients without sufficient on the specific circumstances. The options at the
abdominal domain. This negative pressure dress- time of birth include suture closure (Fig. 12), resec-
ing can also be placed above a skin graft or over a tion of the site of perforation with oversewing of
closed wound to facilitate granulation tissue and the two ends of the bowel (i.e., creating “intestinal
decrease tension on the repair site. The exact atresia”), or creation of a stoma if primary abdom-
mechanical settings are variable based on patient inal wall closure can be accomplished. It is gener-
status and goals of therapy (McBride et al. 2014). ally not recommended to attempt a bowel
anastomosis because of the marked thickening
and inflammation of the bowel wall.
Postoperative Care Intestinal atresia (Fig. 13) can be managed by
the creation of a stoma if primary abdominal wall
Patients with gastroschisis require parenteral nutri- closure is possible or by leaving the atresia in situ
tion to provide the necessary calories intravenously if staged reduction is undertaken. A stoma can be
while awaiting bowel reduction and recovery of created at the time of removal of the silo and
bowel function. This can be accomplished via a primary abdominal wall closure. Alternately, the
cuffed Silastic central venous catheter or a periph- atresia can be left in place at the time of the
erally inserted central catheter (PICC line). Paren- abdominal wall closure, especially in cases
teral nutrition is typically required for 2–4 weeks where significant intestinal wall thickening and
inflammatory peel is present. The patient will then

undergo a re-exploration in 4–6 weeks with defin-
itive surgical management of the atresia at that
time (Snyder et al. 2001).
A devastating complication of gastroschisis
can be partial or complete necrosis of the midgut
as a result of excessive intra-abdominal pressure
or kinking of the blood supply to the bowel
before or at the time of reduction of the herniated
bowel. This complication may lead to the death
of the patient or to short bowel syndrome. Thus,
excessive tension creating increased intra-
abdominal pressure should be avoided to mini-
Fig. 11 Multiple intestinal perforations in gastroschisis mize this complication. Additional complica-
bowel
tions associated with the abdominal wall
closure are wound dehiscence and intestinal-
cutaneous fistula formation. These complica-
tions are also often associated with excessive
intra-abdominal pressure. Therefore, it is prefer-
able to use the staged reduction approach when
primary abdominal wall closure might result in
excessive intra-abdominal pressure (Kunz et al.
2013).
A delayed complication is the development of
necrotizing enterocolitis. The incidence of necro-
tizing enterocolitis inpatients with gastroschisis
has been reported to be as high as 20% (Oldham
et al. 1988). It generally has a delayed onset,
usually 3–6 weeks after birth. The causes remain
unknown, but associations have been made with
Fig. 12 Suture closure of intestinal perforations total parenteral nutrition (TPN)-induced cholesta-
sis and slow recovery of bowel function. Necro-
tizing enterocolitis associated with gastroschisis
can be mild or severe and can involve a significant
portion of the bowel resulting in a high mortality.
Finally, sepsis, resulting from intra-abdominal or
wound infections and central line infections, are
additional causes of morbidity in the gastroschisis
patient (Youssef et al. 2017).
Feeding intolerance is a common finding in
gastroschisis patients and is typically a result of
gastroesophageal reflux and intestinal dysmotility.
Both of these can usually be managed medically,
with adjustment of feeds and/or medications,
including H2-blockers, proton pump inhibitors,
and prokinetic agents. In cases of severe gastro-
esophageal reflux where medical management is
Fig. 13 Intestinal atresia in gastroschisis insufficient, anti-reflux surgery may be necessary.
A recent study from one institution suggested that Cross-References

there may be a higher incidence of hiatal hernias in
gastroschisis patients and this, in turn, may con- ▶ Embryology of Congenital Malformations
tribute to more severe reflux requiring surgical ▶ Fetal Counseling for Congenital Malformations
intervention (Tsai et al. 2014). ▶ Long-Term Outcomes in Newborn Surgery
▶ Omphalocele
▶ Prenatal Diagnosis of Congenital Malformations
Outcome
The availability of neonatal intensive care units,

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Omphalomesenteric Duct Remnants
81
Kenneth K. Y. Wong and Paul Kwong Hang Tam
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
Pathology and Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
Meckel’s Diverticulum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1190
Umbilical Mucosal Polyp/Umbilical Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1191
Omphalomesenteric Duct Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Persistent Omphalo-Mesenteric Duct (Patent or Obliterated) . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Meckel’s Diverticulectomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193
Excision of Omphalomesenteric Duct . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1194
Excision of an Umbilical Polyp . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1195
Abstract chapter, the underlying embryology, pathol-

Omphalomesenteric duct malformations are ogy, clinical presentation, and management of
developmental defects relating to the closure these malformations are discussed.
of the omphalomesenteric duct. They are rela-
tively rare diseases with a prevalence of around Keywords
2% of people. The malformations can take the Omphalomesenteric · Meckel’s · Umbilical ·
form of a patent duct, a cyst, a fistula, or a sinus Diverticulitis · Laparoscopy
and may or may not be symptomatic. The usual
treatment options are by surgical means. In this
K. K. Y. Wong (*) · P. K. H. Tam

Department of Surgery, Li Ka Shing Faculty of Medicine,
The University of Hong Kong, Hong Kong, China
e-mail: kkywong@hku.hk; paultam@hku.hk

https://doi.org/10.1007/978-3-662-43588-5_85
1190 K. K. Y. Wong and P. K. H. Tam
Introduction
In the human embryo, the omphalomesenteric

duct exists as a long narrow tube that joins the
yolk sac to the digestive tube. During the 7th week
of gestation, the duct usually undergoes complete
obliteration. Incomplete obliteration results in
omphalomesenteric remnants, which may be
completely asymptomatic throughout life. Some
types of omphalomesenteric remnants can be
apparent in the newborn infant, while others may
cause various problems, such as the potential to
develop into adenocarcinoma due to scattered
glandular epithelial nests, although these are rare.
Embryology
At around 20th day in embryo, the precursors in

Fig. 1 Schematic diagram showing the omphalome-
enteric nervous system migrate and colonize to senteric duct located between midgut and umbilicus during
form the original gut(Gershon 1997), involving embryogenesis
foregut (esophagus, stomach and duodenum),
midgut (small intestine, caecum, ascending cyst and persistent omphalomesenteric duct
colon, proximal transverse colon), and hindgut (Fig. 3). It must be noted that both urachal rem-
(distal transverse colon, descending colon, sig- nant and umbilical granuloma, although not of the
moid and rectum) (Fig. 1). same embryological etiology as omphalome-
Development of the gut in the embryo is char- senteric remnants, need to be considered also as
acterized by the elongation starting at the end of differential diagnoses when a baby with umbilical
the fourth week of gestation. At the apex of the anomaly is seen.
tube, the intestinal loop remains connected and
open to the yolk sac via the omphalomesenteric
(vitelline) duct.(Larsen 1998) At the end of 5th Meckel’s Diverticulum
week of gestation, the midgut starts to be isolated
from yolk sac due to obliteration and subsequent The most common omphalomesenteric remnant
resorption of the omphalomesenteric duct. This seen is the Meckel’s diverticulum, which is the
process should be complete by the end of seventh persistence of the enteral end on the anti-
week of gestation (Fig. 2a–c). mesenteric side of the small intestine. It was first
described in 1809 by the German anatomist,
Johann Friedrich Meckel (1781–1833). This
Pathology and Clinical Presentation anomaly occurs in around 2% of the population,
with its location usually within 2 feet from
Omphalomesenteric duct may persist after birth ileocecal valve and is approximately 2 inches in
due to incomplete obliteration and resorption in length (Rule of 2 s). It affects boys equally as girls
some people, giving rise to omphalomesenteric but is more likely to be symptomatic in males.
remnants, with various anatomical anomalies. Meckel’s diverticulum is usually lined by typical
These may or may not be symptomatic and can ileal mucosa as in the adjacent small bowel.
be classified into four types: Meckel’s diverticu- Mucosa containing ectopic gastric can often be
lum, umbilical polyp, omphalomesenteric duct, seen. Other mucosal types like duodenal, colonic,
81 Omphalomesenteric Duct Remnants 1191
Fig. 2 Schematic diagrams showing normal development process of omphalomesenteric duct and yolk stalk outside
pancreatic, hepatobiliary tissues have also been incidentally detected Meckel’s diverticulum
reported. Complications of the diverticulum (Zani et al. 2008).
include bleeding (due to acid secretion from gas- For diagnosis, the presence of ectopic gastric
tric mucosa), diverticulitis, and intussusception. mucosa with the secretion of gastrin can be
The risk of the complications decreases with detected using Tc-99 radio-isotope scanning
increasing age with the highest rate of presenta- (Fig. 4), although a negative result does not
tion at around 2 years of age, with no predictive exclude the presence of Meckel’s diverticulum
factors for the development of complications. (sensitivity of Tc-99 around 80–85%).(Kiratli
Interestingly, Meckel’s diverticulitis can mimic et al. 2009; Bagade and Khanna 2015) As a result,
symptoms and signs of acute appendicitis and in patients with persistent symptoms, diagnostic
the correct diagnosis may often be made the oper- laparoscopy can be a very useful tool.
ation. Asymptomatic ones are usually found inci-
dentally at laparotomies for other conditions. A
recent study showed that resection of incidentally Umbilical Mucosal Polyp/Umbilical Cyst
detected Meckel’s diverticulum had a signifi-
cantly higher postoperative complication rate An umbilical polyp is a remnant of gastric or
than leaving it in situ, and that 758 resections intestinal mucosa at the umbilicus (Fig. 5). The
would need to be performed to prevent one death bright red, polypoid tissue produces a persistent
from the condition. As a result, there is no evi- discharge, which may be blood-stained. It is often
dence to support the routine resection of confused with an umbilical granuloma, which is a
Fig. 3 Schematic diagrams showing the different anatom- omphalomesenteric duct, (c) Omphalomesenteric duct
ical variations of omphalomesenteric remnants cyst, (d) Meckel’s diverticulum, (e) Umbilical cyst
(a) Obliterated omphalomesenteric duct, (b) Patent
Fig. 4 Photograph of a Tc-99 radioisotope scan taken at

20 min, showing the presence of gastrin secreting mucosa
in a Meckel’s diverticulum Fig. 5 Photograph showing an umbilical polyp
more common condition and is due to a failure to mainly caused by inflammatory tissue prolifera-
epithelialize after the umbilical cord has fallen off. tion due to persistent chemical stimulation of
Umbilical granuloma should respond to simple bowel content. In the newborn, the persistent dis-
cauterization treatment. The diagnosis of an charge can often result in peri-umbilical excoria-
umbilical polyp may be confirmed by biopsy to tion. Rarely, the ileum may even prolapse through
look for the presence of intestinal or gastric the omphalo-ileal fistula – giving rise to the
mucosa, while specific multinucleate giant cells so-called “steer-horn” abnormality. The diagnosis
can be noted in umbilical granuloma tissue. Clin- is confirmed clinically by passing a catheter
ically, failure of red polypoid tissue to respond to through the fistula into the small intestine and
cauterization should alert the clinician to the pos- aspirating small bowel content or by injecting
sibility of umbilical polyp. As umbilical polyp radiographic contrast medium into the fistula.
may be associated with Meckel’s diverticulum Incomplete obliteration in omphalomesenteric
because both are remnants of the omphalome- duct can result in the presence of a fibrous con-
senteric duct, the presence of the visible polyp nective cord attached to the umbilicus. Although
may serve as warning to otherwise obscure intra- most children are asymptomatic, this persistent
abdominal symptoms. obliterated omphalomesenteric duct can cause
intestinal obstruction or even volvulus.
Omphalomesenteric Duct Cyst

Management
The obliterated omphalomesenteric duct may con-
tain one or more cysts. The clinical presentation of Surgical treatment remains the best management
this is similar to obliterated duct, with a risk of option for omphalomesenteric remnants.(Snyder
small bowel volvulus. The cysts are usually lined 2007) The approaches for the various anomalies
by a columnar mucin-secreting epithelium. Thus, are described below:
the cyst can sometimes become infected with the
child presenting with pain and fever. The infant
who has this anomaly usually presents with cystic Meckel’s Diverticulectomy
mass with increasing size in middle or inferior
belly. Occasionally, the intestinal duct dislocates As mentioned previously, it is not essential to
due to cystic mass compression and infant pre- remove the Meckel’s diverticulum in otherwise
sents with obstructive symptoms correlating to asymptomatic patients, as the risks outweigh the
adhesive bowel volvulus. Diagnostic ultrasonog- benefits. However, in symptomatic children,
raphy usually confirms the potential cystic mass Meckel’s diverticulum should be excised. Nowa-
before surgery. days, the procedure is mostly performed
laparoscopic-assisted or even performed totally
laparoscopically in many centers (Fig. 6). Lapa-
Persistent Omphalo-Mesenteric Duct roscopy is also useful in helping to diagnose
(Patent or Obliterated) symptomatic patients with negative isotope
scans. The principles of laparoscopic resection
The omphalomesenteric duct may be fully patent remain the same as open surgery. Although some
and present as an omphalo-ileal fistula. Nonethe- would argue for the resection of Meckel’s diver-
less, this is a rare finding and if present, it usually ticulum alone, it is the authors’ preference to
presents in the neonatal period with gastrointesti- resect a short segment of ileum together with the
nal drainage.(Pathak et al. 2015) The fistula may diverticulum to ensure that all abnormal mucosa is
contain ectopic gastric, colonic, or pancreatic tis- removed.(Teitlebaum et al. 1994; Shier 2008)
sue. Further, an umbilical “polyp” consisting of In centers where laparoscopy is not feasible,
intestinal mucosa may also be present, which are open surgery is adopted. Here, the access to the
peritoneal cavity is via a 2-cm peri-umbilical inci- the mesenteric side are ligated and divided. Ileal
sion. With this approach, an excellent cosmetic resection with primary end-to-end anastomosis
result is postoperatively ensured. After gaining with single layer, interrupted absorbable 4–0
access into the peritoneum, the small bowel is sutures is carried out. This ensures the removal
brought out and run through. The Meckel’s diver- of all ectopic tissue. The fascia of the subumbilical
ticulum is situated around 2 feet from the ileocecal incision is closed using 3–0 absorbable sutures,
valve, on the antimesenteric border of the distal and the skin is approximated with subcuticular
ileum, and may be bound to the adjacent small 5–0 sutures reinforced with adhesive strips.
bowel mesentery by a covering of peritoneum. At
the operation, these adhesions are divided to
mobilize the diverticulum. The blood vessels on Excision of Omphalomesenteric Duct
For a patent omphalomesenteric duct, the umbilical

skin surrounding the fistula should be preserved for
better cosmesis. Thus, a circumferential incision
around the orifice of the fistula is made (Fig. 7). A
separate skin-crease incision is made below the
umbilicus. The superior skin flap, which includes
the umbilicus, is elevated and the fistula is brought
out through the subumbilical incision. The abdom-
inal wall fascia is incised transversely on either side
of the fistula. The umbilical vessels and the urachus
are individually ligated and divided as the perito-
neal cavity is entered. The fistula is then traced to its
origin at the distal ileum.
The blood supply to the fistula should be
ligated and divided near its origin on the mesen-
tery. Similar to Meckel’s diverticulum, the fistula
should be excised with a small margin of ileum,
which is then repaired with a single interrupted
layer of absorbable 4–0 sutures. The linea alba is
Fig. 6 An intra-operative photograph taken after then repaired and the subumbilical incision closed
laparoscopic-assisted dissection of Meckel’s diverticulum with subcuticular 5–0 sutures. The circular defect
Fig. 7 An intra-operative
photograph taken after
dissection of a patent
omphalomesenteric duct
in the center of the umbilicus may be left to heal diagnosis of the various conditions is important,
by secondary intention if small or may be loosely as the surgeon can then give parents reassurance
closed with a pursestring suture. The healed and advice for treatment. Minimal invasive sur-
wound should resemble the umbilicus. gery is likely to become the mainstay for Meckel’s
diverticulectomy in future.
Excision of an Umbilical Polyp
For the surgical management of umbilical polyp, Cross-References

limited exploration of the peritoneal cavity is
advisable, because of the possibility of an under- ▶ Principles of Minimally Invasive Surgery in
lying connection to the ileum by a remnant of the Children
omphalomesenteric duct. The approach is via a ▶ Principles of Pediatric Surgical Imaging
circumferential incision around the polyp, trying
to preserve as much of the normal umbilicus as
possible. The skin defect is repaired using an References
absorbable purse-string suture. A subumbilical
Bagade S, Khanna G. Imaging of omphalomesenteric duct
incision is made as described above. The abdom-
remnants and related pathologies in children. Curr
inal wall is opened transversely and the peritoneal Probl Diagn Radiol. 2015;44(3):246–55.
cavity entered. If an omphalomesenteric duct rem- Gershon MD. Genes and lineages in the formation of the
nant is present, it is resected. enteric nervous system. Curr Opin Neurobiol.
1997;7:101–9.
Kiratli PO, Aksoy T, Bozkurt MF, Orhan D. Detection of
ectopic gastric mucosa using 99mTc pertechnetate:
Complications review of the literature. Ann Nucl Med.
2009;23:97–105.
Larsen WJ. Development of the gastrointestinal tract. In
For omphalomesenteric duct remnants, if the sur-
Essentials of human embryology. Churchill Living-
gical treatment involves peritoneal access (either stone, 1998; 151–172
open or laparoscopic) and intestinal resection, Pathak A, Agarwal N, Singh P, Dhaneria M. Prolapse of
early postoperative complications would include inverted ileal loops through a patent vitellointestinal duct.
BMJ Case Rep. 2015; doi:10.1136/bcr-2015-211563.
anastomotic leak, adhesions formation, postoper-
Shier F. Laparoscopic treatment of Meckel’s diverticulum.
ative ileus, and wound infection. These are, how- In: Bax KMA, Georgeson KE, Rothenberg SS,
ever, rare (<5%). Intestinal obstruction from Valla JS, and Yeung CK (eds). Endoscopic surgery in
adhesions may present as a late event. infants and children. Springer, 2008:309–314
Snyder CL. Current management of umbilical abnormali-
ties and related anomalies. Semin Pediatr Surg.
2007;16:41–9.
Conclusion and Future Directions Teitlebaum DH, Polley TZ, Obeid F. Laparoscopic diag-
nosis and excision of Meckel’s diverticulum. J Pediatr
Surg. 1994;29:495–7.
In conclusion, although anomalies related to fail-
Zani A, Eaton S, Rees CM, Pierro A. Incidentally detected
ure of obliteration of the omphalomesenteric duct Meckel diverticulum: to resect or not to resect? Ann
are not seen commonly, prompt and correct Surg. 2008;247:276–81.
Conjoined Twins
82
Juan A. Tovar
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1198
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1198
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1199
Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1200
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
Preoperative Ethical Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1202
Preoperative Meetings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1204
Separation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1205
Wall Reconstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1207
Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1207
Early and Long-Term Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1207
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1208
Abstract surgery. The twins are classified into two

Monozygotic, monochorionic, and isosexual main groups: asymmetric and symmetric.
twins united by a part of their anatomy are Asymmetric ones are acardius acephalus,
known as Conjoined Twins. This is a rare and fetus-in-fetu, or heteropagus twins. In all
fascinating malformation that represents one of these, only one component, the autositus sup-
the more complex challenges of pediatric plying circulation, is viable. Symmetric twins
are designated craniopagus, thoracopagus,
omphalopagus, rachiopagus, ischiopagus,
J. A. Tovar (*)
pygopagus, or parapagus according to the
Department of Pediatric Surgery, Hospital Universitario La location of the joining bridge. This can be
Paz, Universidad Autonoma de Madrid, Madrid, Spain large and often contains shared organs. The
e-mail: juan.tovar@salud.madrid.org; cardiovascular systems of both components
jatovar44@telefonica.net

https://doi.org/10.1007/978-3-662-43588-5_86
1198 J. A. Tovar
of the set are communicated and the internal and ethical issues that represent one of the hardest
environment is also shared to a variable extent. challenges of pediatric surgery.
Mortality is high before and after birth This obvious condition that may involve dra-
because of frequent and severe associated matic obstetric issues was known from ancient
malformations. Viability of separation is diffi- times. Probably two-faced deities like Jano or
cult to determine and requires sophisticated multiple-headed creatures like Hydra were intro-
imaging studies. Separation not only involves duced into mythology after observation of such
lengthy and complex operations but also twins. There are pictures and carvings depicting
difficult ethical decisions with familial, medi- conjoined twins in cultures from various
cal, and even court participation. continents. Conjoined twinning raised moral
Separation, when possible, requires various dilemmas and risky definitions (for instance,
groups of specialists under a strong leadership. how many souls they have?). One of the first
Bony parts, nervous system, hearts, great ves- descriptions of esophageal atresia was based on
sels, digestive and genitourinary organs, as the autopsy of a set of conjoined twins but they
well as the skin and musculoskeletal tissues only became popular after certain sets were
have to be divided and reconstructed to achieve exhibited as freaks or circus attractions. This was
separation with preservation for each the case of Chang and Eng Bunker, the original
component of as much function as possible. Siamese twins, who were taken for this purpose
Survival is nearly impossible when the hearts from Siam to the USA, where they eventually
are united, but it is possible for one or both settled and lived for more than 50 years. Many
twins in all the other forms. Complications are examples have been publicized ever since and
frequent and long-term quality of life is often they are often addressed in the media.
burdened by fecal and urinary incontinence or Due to the complexity of the technical prob-
by abnormal limbs and genitalia that are the lems involved, it is understandable for the first
price to pay for separation. separations to be relatively recent (17th century)
The quality of a pediatric surgical group is (van der Weiden 2004). However, many unsuc-
heavily put to test by these cases that can only cessful separations were never reported and the
be managed when outstanding expertise is high mortality of this condition is still largely
available in the various specialties involved. hidden.
Keywords
Conjoined · Twin · Acardius · Acephalus · Etiology
Heteropagus · Parasitic · Craniopagus ·
Thoracopagus · Omphalopagus · Ischiopagus · The current etiology of conjoined twins is still not
Pygopagus · Parapagus · Separation · Ethics fully understood. There are two theories for the
pathogenesis of conjoined twins. The first one
asserts that incomplete fission of the early embryo
Introduction produces identical twins that shared anatomic
structures (Spitz and Kiely 2003; Arnold et al.
Conjoined twins are physically fused at birth. 2018). Monozygostic twins occur when an
They share a single chorion, placenta, and amni- embryo divides before day 13. An embryo that
otic sac (Arnold et al. 2018). Genetically identical divides on or after day 13 will not divide
individuals joined by a part of their anatomy and completely and will remain with fused organs of
often sharing one or more organs are known as various degrees, producing conjoined twins. The
“conjoined twins.” This event occurs in 1:50,000 extent of division and subsequent development
to 1:100,000 live births (Mutchinick et al. 2011), will determine the degree of shared anatomy
and it involves complex anomalies and technical between the twins. The second theory states that
82 Conjoined Twins 1199
conjoined twins are the result of secondary fusion Symmetric conjoined twins are classified
of embryos from a completely separated fertilized according to the body parts that are fused:
egg (Arnold et al. 2018; Kobylarz 2014; Spencer cephalopagus (11%, head to umbilicus),
1996). The twins are always joined by central thoracopagus (19%, thorax to umbilicus),
parts of their anatomies and they are always omphalopagus (18%, umbilicus), ishiopagus (11%,
homologous in the sense that they never have lower abdomen and pelvis), paragagus (28%, lower
the head or the lower limbs on opposite sides. abdomen and pelvis), craniopagus (5%, cranium,
This is consistent with the previously mentioned but not foramen magnum/skull based), rachipagus
interpretation of the embryonic mechanism. (2%, vertebral column), and pygopagus (6%,
Some experiments in amphibians and a few sacrum and perineum) (Arnold et al. 2018; Baken
modern molecular genetic observations suggest et al. 2013).
that fusion of two originally separated embryos
may be the explanation for some rare cases in
which there is sex discordance (Logrono et al. Clinical Presentation
1997; Martinez-Frias 2009).
Nowadays, most conjoined twins are prenatally
diagnosed by ultrasound and this allows preven-
Classification tion of potentially serious problems during vagi-
nal delivery. Except in the thoracopagus twins
The location, extent, and nature of the bridge that with common heart and in the asymmetric twins,
joins both twins vary widely and this complicates both fetal heart tones can be heard like in regular
description of the anatomy of each individual twins. The heads and the limbs of conjoined twins
set (Pierro et al. 2015). Several classifications are on the same side (this is why they are termed
attempted at simplifying description. Conjoined “homologous”) in contrast with regular twins that
twins were divided into ventrally and dorsally are usually arranged in opposite directions. This
joined and subdivided according to the level of allows fetal ultrasonographic (US) diagnosis that
fusion (Spencer 2003). It is probably simpler to leads to more sophisticated US and/or magnetic
divide them according to their asymmetric or resonance imaging (MRI) studies aimed at defining
symmetric nature and to the level of the fusion the anatomy of the fusion and the chances of sep-
that is followed by the suffix pagus. aration (Andrews et al. 2006; Lopes et al. 2013).
Asymmetric twins include “fetus in fetu,” Associated anomalies that can be diagnosed readily
acardius acephalus, and heteropagus parasitic in expert hands (Brizot et al. 2011) are more fre-
twins. The adscription of the first variety of organoid quent in regular twins than in singletons and this is
teratomata to the family of conjoined twins is only more so in conjoined ones. Since they may condi-
acceptable when they are “organoid” and contain a tion viability of the twins, their detection some-
more or less rudimentary spine (Spencer 2001). times prompts termination of pregnancy.
Acardius acephalus is a variety of parasitic twin Most sets of conjoined twins are delivered by
devoid of heart and head that is connected by mar- cesarean section and can be taken care of by
ginal placental vessels with the healthy twin (the multidisciplinary teams from the beginning. In
autositus) that accounts for circulation and nutrition cases delivered vaginally, it is frequent for lesions
of both. Heteropagus twins are usually attached to due to obstetric trauma to be present at birth:
the abdominal wall of an anatomically normal auto- intracranial hemorrhage, long bone fractures, rup-
situs twin, without or with exomphalos, and appear ture of exomphalos, evisceration, etc. The anat-
as organoid parasitic masses containing various omy varies widely according to the modality of
organs and limbs unable to sustain independent joining. Thoracopagi with common hearts almost
circulation by themselves (Bhansali et al. 2005; constantly have severe cardiovascular and arterial
Abubakar et al. 2011). anomalies that produce early symptoms and may
1200 J. A. Tovar
Fig. 1 (a) Set of

omphalopagus twins.
Severe brain hemorrhage in
twin on the right after
vaginal delivery prompted
neonatal separation. Only
the twin on the left
survived. Fourteen years
later (b), she is a bright,
normal girl whose only
concern is breast
asymmetry (Tovar 2011)
be rapidly lethal (Marin-Padilla et al. 1981; single internal environment which is hard to
McMahon and Spencer 2006). The most frequent manipulate: the healthier twin can compensate in
forms, omphalopagi and thoracopagi, have often part for the problems of the diseased one, but the
an omphalocele as a part of the joining bridge. latter may expose the former to disbalances,
Abdominal viscera, like the liver or different parts toxins, or medications (Lai et al. 1997).
of the intestine, are contained in the gelatinous
membrane that is in continuity with the umbilical
cord (Figs. 1 and 2). The livers are often fused and Diagnosis
they show amazingly complex biliary and vascular
communications. A common arrangement consists The diagnosis remains easy, even if some of the
of a more or less thick arterial trunk that communi- associated congenital abnormalities cannot
cates both aortas trough the abdominal cavity. The be seen at the early gestational stage. A compre-
intestines are usually connected or shared. The hensive understanding of the anatomy of the
more common arrangement is a fusion of both organs and the distribution of their functions
small bowels at jejunal level and an ileal divergence is necessary for planning viable separation
close to the ileo-cecal valves. Sometimes this fusion strategies. Plain X-rays, gastrointestinal (g.i.),
consists of a cystic dilatation of the bowel and or urogenital (g.u.) tract contrast studies may
occasionally there are intestinal atresias of various depict the points of junction and other features
types in either one of the small bowels. The bladder of the corresponding organs but, due to the atyp-
may be common and sometimes opens at the lower ical anatomy (Kingston et al. 2001), incomplete
part of the bridge as an exstrophy (Fig. 3). In cases understanding leads to unexpected surprises.
joined by the rump (Figs. 4 and 5), the anatomical Ultrasonographic (US) study helps at every diag-
varieties in terms of gastrointestinal and urogenital nostic step (Andrews et al. 2006). Ultrasound
openings are multiple but sometimes the urinary, enables an early and accurate diagnosis of con-
genital, and digestive tracts end in a single cloacal joined twins. The first trimester ultrasound is the
orifice shared by both twins. best method for diagnosing conjoined twins in
Serious malformations or trauma suffered by early pregnancy (Mathew et al. 2017; Melo et al.
only one of the twins may create difficult clinical 2018). Angiography, widely used in the past for
situations because crossed circulation creates a imaging the nature of the blood supply in the
Fig. 2 Four sets of

thoracopagus twins with
common heart. Separation
was undertaken only in set
A because they were joined
only by a narrow atrial
bridge. Unfortunately, the
twins did not survive (Tovar
2011)
shared organs, is currently replaced by comput- define the functional anatomy of the liver, kid-
erized tomography (CT) or magnetic resonance ney, or other organs (Rubini et al. 1995; Chen
angiography (angio-MRI) (McHugh et al. 2006). et al. 2011). However, unexpected anatomical
CT angiography is the best way for depicting the surprises that may change the order or the nature
vascular arrangement (Ohashi et al. 2012; of the participation of the different specialists
Tannuri et al. 2013). MRI is an excellent imaging involved are frequent. In most cases, the
modality for tissue characterization and better expected anatomy does not fully fit the surgical
depicts the fused neural and meningeal tissues findings and some ingenuity is required for
in craniopagus, rachiopagus, ischiopagus, improvising solutions.
pygopagus, or parapagus. Both CT and MRI are Hematologic and biochemical studies are often
crucial for imaging the anatomy of conjoined misleading due to the situation of crossed circula-
hearts. Helical CT reconstruction of the bony tion. When the vascular channels are large, para-
junctions may help in preparing strategies of biosis is complete, but when only minor territories
skeletal separation (Martinez et al. 2003) are in connection, both twins maintain some inter-
(Figs. 4 and 5). Nuclear imaging may help to nal environmental differences that can be relevant
1202 J. A. Tovar
Fig. 3 Omphalopagus
twins with incomplete
cloacal exstrophy. The
single bladder opened under
the exomphalos (a). A
single colonic opening was
visible in the middle of the
bladder plate (b). Both had
anorectal agenesis with one
single urogenital canal and
double uterus and vaginas
(c). Separation involved
division of the colon with
colostomies and bladder
closure (d). Later on,
saggital anorectoplasty with
colonic and vaginal pull-
through were performed
(Modified from Tovar 2011)
in cases in which blood tests are necessary for The principle of autonomy (the decisions
diagnosis. Other tests, like ECG, are challenging taken by the patient after honest and complete
when the hearts are connected (Carton et al. information should be respected) cannot be fully
2011). Metabolic rate may show considerable dif- applied in children for obvious reasons and has to
ferences between twins upon calorimetry (Powis be exerted by proxy by the parents. This may be a
et al. 1999). source of conflicts among them (for instance, one
may want a separation to be attempted and the
other one may refuse it) or with doctors or the
Treatment courts. Any effort to reach unanimous decisions
agreed upon after informed consent should be
Preoperative Ethical Issues made (Boudreaux and Tilden 2002).
The principle of justice (similar chances for
The principles that regulate the practice of medi- both patients) is obviously at risk when it comes
cal profession are particularly difficult to respect to separation that may involve mutilation or shar-
in conjoined twins and serious ethical dilemmas ing of organs. Choices should be made taking into
are to be expected (Atkinson 2004; Lee et al. account that distribution of organs and tissues has
2011; Spitz 2015): to be fair for both members of the set. All possible
Fig. 4 (a) Ischiopagus

tetrapus (four legs) twins.
(b) The spines and the
spinal cords were joined at
the caudal end as shown by
helicoidal CT
reconstruction. During
separation, the spines were
divided, the meningeal sacs
were reconstructed, a
quadruple iliac osteotomy
was performed for joining
both pubic bones in each
twin, the urogenital system
was reconstructed, and
colostomies were
fashioned. (c) Patients at the
age of 12. They deambulate
normally and enjoy
relatively normal lives with
permanent colostomies and
intermittent bladder
catheterization. (d) and (e):
CT reconstruction of the
bony pelvis of both twins at
the age of 11 (Modified
from Tovar 2011)
actions should attempt at complying with this and the team involved is usually so large and often
principle although the limitations are obvious. ethically discordant that keeping a unified line of
The principles of beneficiency and non- decision becomes difficult. Acknowledgement of
maleficiency (the benefit of the patients should a strong moral leadership after open discussion of
be sought and no harm should be inflicted to every issue is required before providing informa-
them), that are considered as the ethical back- tion about the chances and the consequences of
bone of medical decision-making process, separation to the caretakers. In case of serious
are also difficult to apply if separation is nec- discrepancies among all participants in the pro-
essary for the survival of only one twin, if cess of decision, the courts might be involved
distribution of organs is uneven, and if separa- (Gillon 2001).
tion involves, as it is usually the case, loss of Furthermore, the media (whose interference is
some functions that might be preserved with- difficult to avoid due to the large amount of people
out separation. involved) almost constantly creates new difficul-
When separation of conjoined twins is consid- ties. The twins and their family have to be pro-
ered, the patients are usually too young for decid- tected from these agents and, if possible, the entire
ing by themselves, the parents are heavily process of decision-making and even the separa-
influenced by information delivered by doctors, tion should be kept in the shade. Unfortunately,
1204 J. A. Tovar
Fig. 5 (a) Caudal

parapagus twins with an
extra thoracic limb irrigated
from the abdominal aorta of
twin on the left. (b) There
was a single pelvis with two
lower limbs and two spines
with communicating spinal
canals and joined cords.
Separation involved two
surgical steps. First, the
spinal cords and meningeal
sacs were separated and
subcutaneous expanders
were inserted. (c) Secondly,
the sacrum, the g.i., and
g.u. tracts were divided and
the parietal defects were
closed. In twin on the left,
the skin and muscle of the
additional limb were used
as a vascularized flap. In
twin B, a synthetic mesh
was used for this purpose.
Colostomies were
fashioned. Both twins are
able to deambulate with
braces (d) (Tovar 2009)
this is difficult to put into effect. Too many people aspects should be discussed, and the operation
are involved in the treatment of conjoined twins itself should be rehearsed because installation of
while being mesmerized by them. Corruption by the set of twins on the table, skin prep and draping,
the media can easily put unauthorized pictures and as well as transport of one twin with the
films in circulation and sometimes, the families corresponding anesthetic equipment to another
themselves cast information in exchange of table for reconstruction after separation should
economic support. All these actions may be dam- be carried out according to a previously
aging for the twins and should be prevented when- established plan (Kiely and Spitz 2015). The
ever possible. expected order and extent of the participation of
each specialist team in the separation should be
scheduled as well. The surgeon in charge of the
Preoperative Meetings direction of the operation acts as an orchestral
conductor and his/her coordinating activity
When separation has been decided, one or more extends well beyond the end of the separation
meetings with scrub nurses, nurses, anesthesiolo- itself.
gists, and surgeons of the specialties involved Recent advances, such as 3D printing, may aid
(general pediatric, orthopedic, plastic, urologic, in surgical pre-planning, thereby enabling suc-
neurologic and cardiovascular surgery) should cessful surgical separation of conjoined twins
be scheduled (Al Rabeeah 2006). Technical (Mathew et al. 2017).
Separation Separation of Craniopagus may be extremely

difficult or even impossible given the complexity
Anesthesia is a serious challenge not only because of the neural, arterial, and venous connections
of the obvious anatomical difficulties for intuba- involved. Modern imaging and sophisticated neu-
tion, insertion of lines, and invasive monitoring rophysiologic monitoring are particularly useful
but mainly because of the previously mentioned in these cases. The final amount and nature of the
situation of parabiosis in which one single inter- brain tissue and the vascular network shared by
nal environment is shared to variable extents by the twins set the limits for separation that may
the twins. The drugs administered to one pass on involve several stages (Browd et al. 2008;
into the other one and biochemical and gas mon- Staffenberg and Goodrich 2012). Serious difficul-
itoring may be confusing (Thomas and Lopez ties are to be expected for separation, particularly
2004; Szmuk et al. 2006). In difficult cases, it venous and neurologic deficits, determined by the
may be worth to proceed with preanesthetic location and size of the brain junction, are very
manipulations and line insertions one day before likely even after successful operations.
the operation itself in order to leave time enough Separation of Omphalopagus twins involves
for this. variable difficulties depending on the extent of
Asymmetric conjoined twins represent in organ sharing. These twins have more often
general surgical challenges that are not unlike fused livers and g.i. tracts. It is customary to start
other ones met in this specialty. The Acardius separation by the liver, where more difficulties are
acephalus parasitic twin is inviable and dies to be expected. A small liver bridge without major
upon clamping the umbilical cord of the host vascular connections is relatively easy to take
(autositus). Intrauterine occlusion of the umbilical down but a large mass of anatomically atypical
cord of the parasitus allows termination in cases liver with wide arterial, venous, and biliary con-
in which cardiac failure of the autositus threatens nections (Meyers and Matlak 2002) may be a
survival. It should be pointed out that a consider- formidable undertaking. Perioperative ultraso-
able proportion of host fetuses have severe cardiac nography and parenchyma dividing devices used
problems at birth as a result to adaptation of the for liver resection (ultrasonic or water jet knives)
new hemodynamic situation after separation. The are very useful for this purpose. The surgeons
Fetus in fetu is treated as a tumor. In fact, it is a should ensure that adequate arterial and portal
teratoma with organoid tissues and a more or less inflows, hepatic veins outflow, and patent biliary
rudimentary spine. Depending on size and loca- tracts are preserved in each half of the liver mass.
tion, the operation may be variably hazardous. Anatomic orientation may be difficult and all pre-
Most cases are central or paraspinal and they cautions are justified. In a number of cases, a large
may have close relationship with large vessels. arterial trunk joins the abdominal aortas of both
Heteropagus asymmetric parasitic twins are twins and temporary clamping is advisable before
removed with attention at preserving as much division. The raw liver surface is treated like in
tissue of the host as possible in order to respect any other major liver resection. Careful ligation of
the organs and allow for wall reconstruction. Sur- the vascular and biliary radicals and coverage
vival of the parasitus devoid of heart and brain is with fibrin adhesive in some cases will limit com-
impossible and this allows for a large use of its plications. As far as the gastrointestinal tract is
tissues. After excision of the membrane of the concerned, the most common form of connection
exomphalos, the abdominal wall can be involves fusion of the small bowel from the upper
reconstructed with aponeurotic and/or muscle jejunum down and divergence near the distal
flaps using skin of the parasitus for coverage. ileum. Separation consists in most cases of allo-
Sometimes, bony parts of this have to be removed. cating half the available gut to each twin. Addi-
In cases in which wall closure is impossible with tional problems may be met when atresia of one of
autologous tissues, synthetic grafts can be used as the tracts or a common cystic dilatation of the mid
in symmetric forms of conjoined twinning. bowel are present. Regular techniques used in
1206 J. A. Tovar
digestive neonatal surgery are also indicated in often malformations at other levels, including
these cases (Cywes et al. 1997; el-Gohary 1998; asymmetric vertebra, anomalies in number, or
Spitz and Kiely 2003; Rode et al. 2006). malposition, and scoliosis has to be taken into
Thoracopagus twins without connected hearts account during follow-up.
are separable in contrast with those with common Neurosurgical separation may involve divid-
myocardium (Thomas Collins et al. 2012). Only a ing a common brain tissue or a spinal cord. In
few of them are amenable to surgery under car- both cases reconstruction of the dura or dural
diopulmonary bypass. Except in very rare cases in sacs on each side directly or using biological
which narrow atrial or ventricular bridges exist, prostheses is necessary (Fieggen et al. 2004).
the only chance of separation involves using the The motor and sensitive effects of separation of
bulk of myocardial material for one of the twins. nervous tissue are variable depending on the
Even if separation is attempted, the conduction location and extent of the fused tissue. Fused
system is heterotopic, and severe arrhythmias spinal cords (end-to-end in pygopagus and
can intervene during surgery. In addition, these side-to-side in parapagus) are usually quite distal
twins often have cardiovascular defects that may and separations have limited neurological
further complicate or preclude separation (Lopes effects. The neurosurgical part of some separa-
et al. 2013). The aorta and the pulmonary arteries tions is particularly delicate because of the con-
may be hypoplastic and, as described above, there taminated environment that is unavoidable when
may be communications between the infra- the gastrointestinal or genitourinary tracts have
diaphragmatic aortas. In the very few cases suc- to be divided and particularly when enterosto-
cessfully separated, only one twin survives and mies are established and when prosthesis are
the tissues of the other one, including the sternum used for bridging dural defects.
and/or ribs, can be used for bridging the large Sharing the common lower g.i. tract between
defect created in the thoracic wall during separa- both twins entails the loss of continence for one or
tion. Of those twins that cannot be separated, most both of them. In twins joined by the lower abdomen
die of the associated heart defects in the first or pelvis, there is often a single colon. The func-
months or years of life. tional reconstruction of the colorectal area is there-
Rachiopagus, Ischiopagus, Pygopagus, and fore rarely possible. Rectal function can be seldom
Parapagus twins share to different extent parts of preserved in one twin but more often this is impos-
the spine, central nervous system, gastrointestinal, sible in both and enterostomies have to be fashioned
and genitourinary tracts and they may represent at some stage. Even if reconstruction of the anus
formidable challenges. The separation of the bony and rectum are feasible, patients will only have half
parts requires highly skilled orthopedic surgeons. the colon or less and achieving reasonable conti-
Careful design of the operation is necessary nence is often impossible. All refinements of
because osteotomies or synthesis of osseous tissue advanced bowel management (diet, enemas, ante-
should aim at reconstructing the pelvis or the grade wash-outs through a continent apendiceal
limbs, and this may require planned coverage stoma or a cecal button) are necessary to obtain
with the available tissue. In some cases, the recon- subsequent adaptation of these patients to a more
struction of the pelvic rim requires bilateral iliac or less normal social life (Kim et al. 2002).
osteotomies and pubic fixation (Fig. 4). In other The same can be said about distributing the
cases, even refashioning a bony pelvis is impos- urogenital tract structures between the twins.
sible and the subsequent prosthetic treatment is Keeping a bladder and urethra for one of them is
difficult (Kim et al. 2002; Fieggen et al. 2004) rarely possible in most frontally united sets.
(Fig. 5). When the twins are united side by side, Again, all refinements of reconstructive urology,
splitting the sacrum is necessary. Sometimes, this bladder augmentation, clean intermittent catheter-
is better performed in two operative steps: one at ization, and continent urinary diversion may help
the time of insertion of skin expanders and the to readapt these patients (Holcomb et al. 1989;
other one during separation itself. The spine has McLorie et al. 1997; Lazarus et al. 2011). The
native genital tract can be reconstructed if dupli- Early and Long-Term Results
cated but sometimes vaginal replacement is nec-
essary (Kim et al. 2002). Overall mortality in conjoined twinning is high.
When diagnosis is made during early pregnancy,
interruption of gestation is common practice in
Wall Reconstruction developed countries particularly for the forms
with poor prognosis (Martinez-Frias et al. 2009;
One of the major technical problems posed by Brizot et al. 2011). Fetal mortality or stillbirths
separation of conjoined twins is the coverage of are also frequent. Obstetric mortality or severe
the huge parietal defects left. When only one birth trauma remain a real risk when prenatal
survives, part of the wall of the other one can be diagnosis was missed, and this happens more
used to bridge the defects but in other cases, often in undeveloped countries in which preg-
additional procedures are necessary. Several nancies are not monitored. A considerable pro-
types of muscle and/or fascial flaps have to be portion of twins have multiple malformations
fashioned, and in a number of cases, only the use that cause demise in the first hours or days of
of biologic or synthetic prostheses allows closing life (Kaufman 2004). When separation is deemed
the gaps. When planning the separation, the avail- possible, it must be reminded that neonatal sep-
ability of skin and subcutaneous tissue necessary arations involve higher mortality mainly because
for the type of closure elected should be estimated. they are only indicated for life-threatening rea-
Skin expansion with subcutaneous inflatable sili- sons (for instance, one twin may be very ill or
cone expanders is often useful prior to separation. develop intestinal obstruction) but also because
However, the same limitations mentioned for neu- these complex operations are better performed
rosurgical or bone procedures apply for expanders when most anatomical and functional features
since the risk of bacterial colonization and infec- of the set have been ascertained.
tion with loss of the expansion is considerable Thoracopagus twins with a common heart
when the operative field is contaminated by rarely survive because most have severe
opening the gastrointestinal tract or simply by malformations. Of those sets in which separation
enterostomies. is attempted, only a few individual twins survive
(Chiu et al. 1994; Fishman et al. 2002). However,
thoracopagus without shared heart can be success-
Complications fully separated.
Most omphalopagus twins can be separated and
The nature of these risky operations involves a survive if no obstetric trauma or severe associated
large number and variety of possible complica- malformation are present (Fig. 1). In all other forms
tions. Intraoperative hemorrhage and damage to of conjoined twinning a high proportion of the
vital structures is always possible due to the twins can be separated and survive although with
atypical anatomy. Bone division or meningeal more or less extensive deficits that require follow-
membrane opening simultaneous to gastrointesti- up for life and often additional operations.
nal or the genitourinary procedures increase the In the long term, separation of conjoined twins
risk of serious infection. Wound closure avoiding rarely produces independent individuals without
compartment syndrome may necessitate synthetic sequelae. Some cases of asymmetrical twins and
materials that are also exposed to contamination. omphalopagi may survive separation and face a
Wound disruption and infection are therefore not normal life. Most other cases keep orthopedic or
rare. Finally, a wide range of complications not neurologic sequelae or have fecal and urinary
unlikely those seen after other major operations continence problems that become predominant
may occur: internal hemorrhage, abscesses, vas- with the passage of time. Orthopedic and motor
cular thromboses, or postoperative intussuscep- deficits may require prolonged rehabilitation and/or
tions, among others, are possible. prosthetic appliances. Permanent enterostomies
1208 J. A. Tovar
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Part VIII
Newborn Surgery: Spina Bifida and
Hydrocephalus
Spina Bifida and Encephalocele
83
Jonathan R. Ellenbogen, Michael D. Jenkinson, and
Conor L. Mallucci
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214
A Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1215
Embryological Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216
Classification and Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216
Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1216
Spinal Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217
Other Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1217
Spinal Dysraphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Spina Bifida Occulta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Spina Bifida Cystica: Meningocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Spina Bifida Cystica: Myelomeningocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1218
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219
Dietary Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1219
Diabetes and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220
Teratogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220
J. R. Ellenbogen (*)
Department of Neurosurgery, Alder Hey Children’s NHS
Department of Neurosurgery, The Walton Centre NHS
e-mail: jellenbogen@doctors.org.uk
M. D. Jenkinson
Department of Neurosurgery, The Walton Centre NHS
e-mail: michael.jenkinson@thewaltoncentre.nhs.uk
C. L. Mallucci
Department of Neurosurgery, Alder Hey Children’s NHS
e-mail: conor.mallucci@alderhey.nhs.uk

https://doi.org/10.1007/978-3-662-43588-5_87
1214 J. R. Ellenbogen et al.
Prenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220

Maternal Serum Alphafetoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1220
Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221
Amniocentesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221
Clinical Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221
Prenatal Assessment and Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1221
In-Utero Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
Postnatal Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
Inspection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1222
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224
Parental Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1224
General Management, Operative Treatment, and Technique . . . . . . . . . . . . . . . . . . . . . 1224
Postoperative Management and Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1225
Long-Term Management and Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
Medical Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1227
Lifestyle Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Intellect . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Ambulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Psychosocial Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Encephalocele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1228
Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229
Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1229
Investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1230
Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1230
Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1231
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1232
Abstract Magnetic resonance imaging (MRI) · Shunt ·

This chapter aims to explain the range of con- Neural tube defects (NTD) · Spina bifida ·
genital anomies that are encompassed by the Anencephaly · Myelomeningocele ·
term neural tube defects (NTD). Both cranial Embryology · Encephalocele · Meningocele ·
and spinal abnormalities occur which arise dur- Serum alphafetoprotein · Counseling · In-utero
ing embryological development due to defects surgery · Hydrocephalus · Arnold–Chiari type
in morphogenesis of the neural tube. They range II malformation · Craniorachischisis ·
from anencephaly to spina bifida occulta. The Dysraphism
commonest congenital nervous system defect
encountered remains spina bifida despite the
overall incidence of neural tube defects declin-
ing. The chapter explains the classification, Introduction
pathogenesis, assessment, management, treat-
ment, and prognosis related to these conditions. Neural tube defects (NTDs) arise due to aberra-
tions in the embryological development of the
Keywords neural tube and encompass a variety of congen-
Hydrocephalus · Cerebrospinal fluid (CSF) · ital anomalies ranging from spina bifida occulta
Ultrasound · Computed tomography (CT) · to anencephaly, occurring in one in every
83 Spina Bifida and Encephalocele 1215
1000 births. Geographic variations exist in the A Historical Perspective

incidence of spina bifida and neural tube
defects, for example, the incidence of spina The first reports of fetuses and infants with anen-
bifida cystica varies between 0.3 per 1000 live cephaly, myelomeningocele, and craniora-
births in Finland, and 4.5 per 1000 live births chischisis originate in ancient Egypt (Obladen
in Ireland (Leck 1984). The prevalence of NTDs 2011). Caspar Baulinin is credited with the first
in USA and many European countries is accurate description of spina bifida in the
estimated at 0.5–0.8/1,000 births, whereas early seventeenth century (Morgagni 1762).
prevalence in some regions in China and India The term “spina dorsi bifida” was coined by
has been reported to be more than 20 times Nicholas Talpius (Tulp) in 1641 (Doran and
higher (Copp 2015; Li et al. 2006; Bhide et al. Guthkelch 1961; Tulp 1672), and Virchow
2013). The incidence of spina bifida occulta introduced the term “spina bifida occulta” in
has a greater reported variation, which ranges 1875 (Virchow 1875). The association of hydro-
between 1% and 50% depending upon the cephalus and spina bifida was recognized by
age group (Boone et al. 1985). Lower socioeco- Morgagni in 1761, and he also described anen-
nomic groups have a higher incidence of cephaly and spina bifida as expressions of the
developing spina bifida, as do Caucasians same pathological process and attributed blad-
when compared to black people (Leck 1972; der, rectal, and limb abnormalities to the neuro-
Wiswell et al. 1990). There also exists a marked nal damage in the defective spinal cord
difference in prevalence between ethnic groups (Morgagni 1762).
and pregnancy order in multiparous women, Aspiration of the lesion was the time-honored
with a preponderance of anencephaly in girls method of management but had catastrophic
(Carter 1974). NTDs are thought to be multi- consequences. Forestus ligated the sac (1882),
factorial in origin with both genetic and envi- and sac excision was attempted by Tulp with
ronmental factors playing a role in their fatal results (Tulp 1672). The Clinical Society
development. of London (1882) recommended the use of a
While spina bifida remains the commonest local sclerosing technique as the preferred
congenital central nervous defect, the overall method of treatment, which was initially advocated
incidence of NTDs is in decline (EUROCAT by Morton (Morton 1872). Excision of the sac was
Working Group 1991; Kondo et al. 2009; again popularized by Bayer (Bayer 1892) and
Stevenson et al. 2000; Yen et al. 1992). Several Frazier (Frazier 1918) in the early twentieth
factors are thought to account for this century; however, the mortality rate remained
change, which include declining birth rates, high. With the advent of antibiotics and introduc-
increasing antenatal diagnosis, changing social tion of CSF shunts in the 1950s, the operative
attitudes, and improving standards of living results encouraged more surgeons to introduce
and nutrition. The most appropriate manage- comprehensive, aggressive management. In 1963,
ment strategy for these patients is a continued Sharrard proposed emergency operative closure of
source of medical, ethical, and legal debate. the back lesion to decrease mortality and improve
A multidisciplinary team approach, incorporating muscle function (Sharrard et al. 1967). This
neurosurgeons, pediatricians, neurologists, provided new hope for these patients. However,
endocrinologists, urologists, orthopedic surgeons, in the latter part of the decade, it became evident
physiotherapists, social workers, psychologists that the mortality remained high and those who
and nursing staff, must be utilized as survived had major handicaps. In 1971, Lorber
a diagnosis of a NTD may have devastating reviewed 524 cases of myelomeningocele treated
consequences not only for the patient but their actively and concluded that there were four main
family. The aim being to provide the patient criteria associated with a poor prognosis: gross
and family with the minimal disability possible hydrocephalus, severe paraplegia, kyphosis,
and therefore with the best quality of life associated gross congenital anomalies, or major
achievable. birth injury (Lorber 1971). He advocated that
patients with one or a combination of these criteria tube formed by primary neurulation (the junction
should be managed conservatively as very few between the two processes is well below the site
patients survived, and those that did would suffer of virtually all occurrences of spina bifida and so
severe mental and physically handicap. In recent cannot be considered a potential factor in the
years, the reliability and “predictive value” of these origin of the vast majority of these NTDs)
four criteria has been questioned. It has been (Sadler 2005).
suggested that the management of these infants
should be individualized and changed whenever
necessary in the best interest of the patient and Classification and Pathogenesis
family (McCarthy 1991; Surana et al. 1991;
Woodhouse 2008). All developmental defects of the central nervous
system are NTDs. They can be classified into
neurulation defects (nonclosure of the neural
Embryological Development tube resulting in open lesions), postneurulation
defects (producing skin-covered, i.e., closed
NTDs are the results of an abnormality in the lesions), or migration abnormalities (Table 1).
process of neurulation, conversion of the neural Some examples include:
plate into a neural tube by a process of folding,
which occurs in the fourth week. Failure of part
of the neural tube to close disrupts both the Brain
differentiation of the central nervous system
and the induction of the vertebral arches and Anencephaly: Failure of closure of rostral-
can result in a number of developmental anoma- neuropore. Occurs in about 1 out of 10,000 births.
lies. These malformations usually involve part of Results in absence of skull, cerebral hemispheres or
the cranial or caudal neuropore, the unfused ros- cerebellum, and facial abnormalities. There are
tral and caudal neural folds, resulting in a defect three types of anencephaly: (a) meroanencephaly,
of the cranial or lower lumbar and sacral regions where there is rudimentary brain tissue and partial
of the central nervous system (CNS) respec- formation of the cranium; (b) holoanencephaly, the
tively. These close on day 24 and on day most common type, in which the brain is
26 respectively (Larsen 1993). Once closure is completely absent; and (c) craniorachischisis, the
initiated neurectoderm cells reorganize to form most severe, where area cerebrovasculosa and
the roof of the neural tube, while overlying epi- area medullovasculosa fill both cranial defects
dermal cells form the ectodermal layer of the and the spinal column (Isada et al. 1993; Lemire
skin. Closure of the neuropores coincides with et al. 1978).
the establishment of a blood vascular circulation Encephalocele: Postneurulation disorder.
for the neural tube. Failure to close leads to Failure of the surface ectoderm to separate from
escape of α-fetoprotein from the circulation into the neuroectoderm. Occurs approximately once
amniotic fluid. This process is called primary in every 2000 births. Results in a bony defect
neurulation and it is responsible for establishing in the cranium (cranium bifidum) allowing
the brain and spinal cord regions down to the herniation of intracranial contents, most
lowest sacral levels (probably S4–5). From this commonly in the occipital region (75%) in the
level caudally, secondary neurulation forms the United States and Western Europe. Approxi-
remainder of the cord. In this phenomenon, the mately 90% of cases involve the midline. The
neural tube forms from mesoderm cells that coa- hernia may contain meninges (meningocele),
lesce and then epithelialize. These epithelial meninges and part of the brain (meningoence-
cells reorganize around a lumen forming the phalocele), or meninges, part of the brain, and part
most caudal regions of the neural tube that then of the ventricular system (meningohydroence-
becomes continuous with the remainder of the phalocele) (Moore et al. 2011).
Table 1 Classification of the commonest neural tube defects (Copp et al. 2013)
Site Lesion Sex ratio Clinical presentation Pathology
Cranial Anencephaly Female Lack of brain and cranial Failed fusion of anterior
excess vault; fetal loss, or stillbirth neuropore; degeneration of
(3:1) neural tissue and absence of
cranial vault formation
Encephalocele Female Meningeal sac, often Brain herniation through
excess in containing brain tissue, congenital opening of skull
occipital protrudes from skull; and covered by meninges and
lesions commonly in occipital, skin
parietal, or frontoethmoidal
locations
Spinal Spina bifida cystica/ Variable; Open spinal cord covered by Open cord defect at any point
aperta roughly meningeal sac or exposed; from cervical to sacral
equal most commonly Degeneration of exposed
(a) Myelomeningocele thoracolumbar, lumbar, or neural tissue after failed
(b) Meningocele lumbosacral; usually closure
livebirth; frequently Meningeal sac without neural
associated with tissue
hydrocephalus postnatally
Spina bifida occulta Skin covered. No visible Absent spinous process and
exposure of meninges or varying amounts of lamina
neural tissue (may be associated with
lipomyelomeningocele,
tethered cord, dermal sinus
tract, diastematomyelia, and
hemangioma)
Craniospinal Craniorachischisis Female Anencephaly continuous Combined anencephaly and
excess with complete open spina myelomeningocele
bifida, i.e., total dysraphism;
fetal loss or stillbirth
Spinal Cord spinal column because of tethering or as a result

of descent secondary to increased pressure of
Meningocele: Defect postneurulation hydrocephalus.
Myelomeningocele: Failure of caudal neuropore
closure. Myelomeningoceles can occur any- Other Defects
where from cervical to lumbar spine, and numer-
ous theories have been put forward to explain the Occur secondary to various postneurulation
precise mechanism of the defective neurulation. abnormalities involving the neural tube or meso-
It is either due to failure of neural folds to fuse or derm, or because of persistence of totipotent
a reopening of the normally fused neural tube. cells. These lesions are: diastematomyelia, syrin-
The normally fused neural tube may reopen gomyelia, complete anterior and posterior spina
because of increased intraluminal pressure or a bifida, butterfly vertebrae, lipoma, hemangioma,
primary defect in the neuroepithelium (Gardner dermoid cyst, and sacrococcygeal teratoma. A
1961). Defective neuroepithelium itself may be partial duplication and separation of the noto-
responsible for the failure of neural folds to fuse chord can result in herniation of the endoderm
or the defect may lie in mesoderm, which deters of the yolk sac, called split notochord syndrome.
the closure of neural folds (Patten 1952). Asso- If the hernia ruptures it may result in ectopic
ciated Arnold Chiari malformations may be sec- bowel, sinus, or fistula (Bentley and Smith
ondary to failure of ascent of the cord within 1960).
Spinal Dysraphism the meninges through this but no abnormality of

neural tissue. Meningocele, which comprises
Spina Bifida Occulta about 5% of all spina bifida cystica cases, is usu-
ally not associated with neurological deficit and
The term “spina bifida occulta” refers to the form hydrocephalus, and is most frequently observed in
of spinal dysraphism not accompanied by the the lumbar region.
extrusions of the contents of the vertebral column.
There is congenital loss of the spinous process and
variable amounts of lamina without exposure of Spina Bifida Cystica:
neural tissue. Without obvious external evidence Myelomeningocele
Spina bifida occulta is rarely diagnosed in the
newborn. The defect may be palpable, and occa- Myelomeningocele is one of the most common
sionally patients may have external evidence of congenital malformations and the commonest
spina bifida occulta such as a small dimple, sinus, form of NTD. There is a congenital defect in the
tuft of hair, or hamartomatous lesions such as vertebral arches with cystic dilatation of the
hemangioma, lipoma, and nevi. This incidental meninges with underlying structural and func-
finding is usually of no clinical importance when tional abnormality of the spinal cord (Fig. 1).
it occurs alone. Although there may be neurolog- A neural plaque is centrally placed, around which
ical deficit because of tethering of the cord, there is a cystic lesion with attenuated meninges
manifesting as urinary problems, e.g., recurrent and skin (Fig. 2). Although the pathological
urinary infection or enuresis, motor deficit with changes are obvious at the site of the lesion, addi-
pedal deformity, pelvic tilt and muscle weakness, tional changes involve the whole of the nervous
and sensory involvement in the form of trophic system and other systems, especially genitourinary
ulceration. These patients warrant careful exami- and skeletal. Nearly all infants who are born with
nation, investigation, and follow-up. Spinal X-ray myelomeningocele have the Arnold–Chiari II mal-
will show evidence of spina bifida and other formation, which includes a constellation of anom-
spinal abnormalities. Ultrasonography can be alies that include hindbrain herniation (downward
useful in the newborn period to diagnose displacement of the medulla, fourth ventricle, and
diastematomyelia (McConnell et al. 1986). The
common clinically relevant lesions are
diastematomyelia, tethered cord, lipomyelome-
ningocele, and dermal sinus tract. All of these
lesions need referral to a neurosurgical specialist
and investigation with acraniospinal Magnetic
Resonance Imaging (MRI). Many patients with
these lesions require regular follow-up and sur-
gery in the future. The increased incidence and
treatment of these lesions over the last
10–20 years probably reflects increased diagnosis
due to the more widespread availability of MRI.
Spina Bifida Cystica: Meningocele
A meningocele is an epithelial lined sac filled with

cerebrospinal fluid (CSF), which communicates
with the spinal subarachnoid space. There is a Fig. 1 A sagittal T2-weighted MRI demonstrating a
defect in the vertebral arches with distention of myelomeningocele
Fig. 2 Myelomeningocele –
a lumbosacral lesion is
demonstrated showing a
central neural plaque
surrounded by dystrophic
epidermis
cerebellum into the spinal canal), brain-stem abnor- Dietary Factors

malities, low-lying venous sinuses, and a small
posterior fossa. This malformation is also associ- Substantial data have been accumulated to sug-
ated with hydrocephalus and developmental brain gest that myelomeningocele and other neural
abnormalities (Adzick et al. 2011). defects may be reduced by improved maternal
nutritional status. Mothers of spina bifida patients
were found to have an increased incidence of
Etiology folate metabolism abnormalities and it has since
been suggested that folic acid might be involved
The precise etiology of NTDs is not known but it (Smithells and Chinn 1965). Several studies have
is likely to be multifactorial, with both genetic and reported a beneficial role of folic acid and other
environmental factors implicated. vitamins (Atta et al. 2016; Laurence et al. 1981;
Olney and Mulinare 2002; Willett 1992). The
Medical Research Council conducted a random-
Genetics ized double-blind prevention trial with factorial
design at 33 centers in seven countries to deter-
The exact mode of inheritance is not known, mine whether supplementation with folic acid or
although ethnic variation, gender (females are a mixture of seven other vitamins (A, D, B1, B2,
more commonly affected than males), increased B6, C, and nicotinamide) around the time of con-
incidence with parental consanguinity, and ception could prevent NTDs (Group 1991). The
familial tendency suggest a non-Mendelian women at risk were randomly allocated to various
multifactorial hereditary predisposition. An groups including a control group to avoid bias.
individual’s risk of having other children with This study found a significant reduction in the
spina bifida increases to one in 20–25 if there is number of children born with NTDs to high-risk
one child with spina bifida in the family mothers who had taken folic acid in the peri-
(Angerpointner et al. 1990; Carter 1974). This conceptional period. Periconceptional use of
risk is one in eight to ten if there are two children folic acid has been recommended to all women
with NTDs (Carter 1974). The risk of having with or without risk. A concern that large doses
an affected child is of lesser magnitude (one in of folic acid may delay the diagnosis of pernicious
200) if one of the parents had spina bifida than if anemia has led to the fortification recommenda-
a sibling had spina bifida (Angerpointner et al. tions being limited to a level that may add
1990). on average, only about 0.1 mg folic acid/day.
However, others feel that a daily dose of 0.4 mg/ sauna, or fever in the first trimester of pregnancy
day should be continued (Wald and Bower 1994). has also been associated with an increased risk
Indeed in recent studies published from Canada, of NTDs (Janerich 1971; Layde et al. 1980;
United States, and Australia have shown a decline Milunsky et al. 1992; Sandford et al. 1992).
in neural tube defects especially in high-risk
groups not only with folic supplementation but
also with food fortification (Bower et al. 2009; Prenatal Diagnosis
Stevenson et al. 2000; De Wals et al. 2007). Atta et
al. (Atta et al. 2016) recently performed a system- Prenatal diagnosis of myelomeningocele
atic review and meta-analysis of prevalence of allows for parental informed decision to
spina bifida by folic acid fortification status, geo- continue the pregnancy or terminate if desired,
graphic region and study population. They and also improved obstetric and neonatal care
reported that the spina bifida is significantly of the affected infant (White-Van Mourik et al.
more common in world regions without govern- 1990).
ment legislation regulating full coverage-folic
acid fortification of the food supply and that man-
datory folic acid.-fortification resulted in a lower Maternal Serum Alphafetoprotein
prevalence of spina bifida regardless of the type of
birth cohort. Alphafetoprotein (AFP) can be detected in
maternal serum in open NTDs. It is a 70 kd
glycoprotein produced initially by the yolk sac
Diabetes and Obesity but by the end of the third trimester solely by the
fetal liver. AFP is excreted in the urine by the
Mothers with preexisting diabetes and obesity fetal kidneys and thus into the amniotic fluid. It is
have each independently been found to have an an effective method for mass screening to iden-
increased risk of having a child with a NTD. A tify pregnancies requiring further evaluation.
recent paper has demonstrated a 0.7% preva- Elevated levels, 2 multiples of the median for
lence of diabetes mellitus in mothers of children the appropriate week of gestation, between
with NTD, as compared to 0.4% of controls 15 and 20 weeks gestation carries a relative risk
(adjusted odds ratio 1.84). Nineteen percent of of 224 for neural tube defects (Milunsky et al.
mothers of children with NTD were obese (Body 1989). If positive, the test is repeated a week later
Mass Index (BMI) 30) as compared with to confirm the presence or absence of NTDs. The
10.8% of control (adjusted odds ratio 1.97) (Par- sensitivity of this test is about 97% for anenceph-
ker et al. 2013). aly and 72% for spina bifida (Wald et al. 1977).
This second test requires further confirmation by
amniocentesis and prenatal ultrasonography
Teratogens after appropriate counseling. Since maternal
serum AFP rises during normal pregnancy, an
Many agents have been blamed as possible terato- underestimate of gestational age may cause a
gens responsible for the occurrence of NTDs. normal level to be interpreted as elevated, and
Exposure to the antiepileptic drugs valproate and an overestimate of gestation age may lead to an
carbamazepine in utero carries a 1.2% risk of fetal elevated AFP interpreted as normal. Maternal
NTDs, which have been reported to be more serum AFP may be elevated in many other fetal
severe open defects with a high incidence of abnormalities, including those of the abdominal
hydrocephalus (Lindhout et al. 1992; Rosa 1991; and urological systems, such as omphalocele,
1988; 1983). Certain viruses and hyperthermia gastroschisis, cloacal exstrophy, esophageal
have also been hypothesized to cause NTDs, atresia, and renal agenesis. Therefore, the diag-
and exposure to heat in the form of a hot tub, nosis should be confirmed using other tests.
fluid biochemical markers for assessment of risk

of neural tube defect and other anomalies (Kooper
et al. 2007). Using ultrasound guidance, amniotic
fluid is obtained transabdominally at about
16 weeks of gestation. Acetylcholinesterase
(AChE) levels are used to improve the diagnostic
accuracy of the amniotic AFP level to confirm the
presence of NTD (Aitken et al. 1984). A small
amount of neural AChE is released into the CSF
during fetal development. In an open NTD, the
AChE can leak into the amniotic fluid and will be
detected. If the NTD defect is skin covered the
AChE level will therefore be negative. The risk of
an open NTD is 60% if the levels are + 3 stan-
dard deviations (SD) above normal, and rises to
Fig. 3 A prenatal ultrasound scan demonstrating spinal 86% if the levels are + 5SD. Specimens contam-
dysraphism and a meningocele inated with fetal or maternal blood can cause
potential problems with interpretation of results
Imaging and repeat amniocentesis may be required. There
is approximately a 6% risk of fetal loss in this
Prenatal ultrasonography may be used as a pri- population with this procedure (Greenberg 2010).
mary screening procedure (Fig. 3). It is a safe and
effective method of antenatal screening if the
ultrasonographer is experienced, and levels of up Clinical Management
to 98% specificity and 94% sensitivity have been
reported (Romero et al. 1989; Takeuchi 1991). This section relates primarily to the management
Within Europe there are formal national ultra- of myelomeningocele as this is the commonest
sound screening policies for structural anomalies NTD that presents to pediatric neurosurgical
(Boyd et al. 2008). However detection rates are practice.
influenced by gestational age and type of NTD,
spina bifida has a higher detection rate of 92–95%
in the second trimester compared to a lower rate Prenatal Assessment and Counseling
of 44% in the first trimester (Cameron and Moran
2009). Three-dimensional sonography has an Once a prenatal diagnosis of myelomeningocele
advantage over conventional two-dimensional has been made, further detailed imaging is
ultrasound in predicting the level of lesion and performed to determine the level and extent of
this may offer a predictive morbidity (Cameron the defect (Fig. 4). This allows the neurosurgeon
and Moran 2009). Prenatal MRI screening is to predict the likely degree of neurological deficit
not currently readily available due to limited and facilitates prenatal counseling. Antenatal
resources and there is no evidence showing counseling is undertaken in specialist clinics and
superiority over ultrasound. involves fetal medicine specialists, obstetricians,
neurosurgeons, and radiologists. Parents need to
be given realistic expectations regarding the prog-
Amniocentesis nosis for intellectual development, ambulation,
and survival, as well as information on hydro-
While many now question the use of amniocentesis cephalus and neurogenic bowel and bladder. In
in the era of modern high-quality ultrasonography, the UK, a review process is underway with a view
there remains a role in some cases for amniotic to setting up national standard.
before 26 weeks of gestation or standard postnatal

repair of myelomeningocele based in the USA.
Outcomes assessed include death, the need for
cerebrospinal fluid shunting by one year of life,
and neurological function at 30 months of age.
They found that prenatal surgery for myelo-
meningocele reduced the need for CSF shunting
(40% in the prenatal-surgery group and 82% in the
postnatal-surgery group) and improved the com-
posite score for mental development and motor
function at 30 months. Prenatal surgery also
resulted in improvement in hindbrain herniation
by 12 months, and ambulation by 30 months.
However, prenatal surgery was associated with
increased fetal risks and an increased risk of pre-
term delivery and uterine dehiscence at delivery
(Adzick et al. 2011; Johnson et al. 2016). Whilst
this is positive, fetal surgery is a very complex
procedure. The centers performing fetal surgery
Fig. 4 A sagittal inter-uterine fetal MRI demonstrating a need to be very well organized with diagnosis,
Chiari malformation counseling, intervention, follow-up, and support
performed by a highly skilled and trained multi-
In-Utero Surgery disciplinary team. All fetal surgical interventions
that involve low volume and highly complex care
The rationale for fetal surgery is that the progres- should be restricted to dedicated centers with
sive damage is caused by the prolonged exposure strict regulations and a high level of quality con-
of the spinal cord and nerves to the intrauterine trol (van Lith et al. 2013, Joyeux et al. 2018).
amniotic fluid environment and a suction gradient
due to cerebrospinal fluid leakage, leading to pro-
gressive downward displacement of the hindbrain Postnatal Assessment
(Joyeux et al. 2018). There is a potential role for
fetal surgery as neural tube defects are diagnosed Inspection
prenatally. Techniques using endoscopy, percuta-
neous fetoscopic patch coverage, and via hyster- In about 80% of infants with myelomeningocele,
otomy have been described. Human prenatal the defect includes the lumbar region because
myelomeningocele repair by hysterotomy was this is the last region of the neural tube to close.
first performed in 1997, and by 2003, more than Occasionally more than one lesion can be found
200 fetuses had undergone the procedure (Adzick and there is often marked kyphosis or scoliosis
et al. 2011). However, until recently little evi- present (Thompson 2009). Most myelo-
dence as to the benefit of fetal surgery existed meningoceles contain an enlarged subarachnoid
(Sutton 2008). A randomized clinical trial named space ventrally, with the neural tissue displaced
Management of Myelomeningocele Study dorsally; in combination this creates a herniated
(MOMS trial) showed that prenatal correction of sac on the infant’s back.
open spina bifida via open fetal surgery was asso-
ciated with improved infant neurological out- Motor Assessment
comes relative to postnatal repair (Adzick et al. Motor function is assessed when the infant is at
2011). MOMS trial was a three-center randomized rest. Sharp stimulation above the level of the
prospective trial comparing prenatal surgery meningocele is administered with careful
observation of voluntary movement below the is indicated. Delayed placement of a ventriculo-

affected level. Varying degrees of paralysis peritoneal shunt is not associated with a lower
below the level of the lesion are common, except infection rate compared to placement at the time
in rarer cervical and upper thoracic lesions, which of myelomeningocele closure (Chadduck and
are usually spared. The paralysis is usually flac- Reding 1988; Parent and McMillan 1995).
cid, indicating a complete neural lesion. It must be It may reduce the risk of myelomeningocele
borne in mind that there are some abnormal reflex repair breakdown previously seen in the interval
activities in the lower extremities that have no before shunting (Greenberg 2010).
bearing on volitional motor function. Myelomeningocele repair may actually convert
a latent hydrocephalus to active as the route of
Sensory Assessment CSF egress is eliminated. Almost half of
Sensory loss is determined by pinprick test from meningocele patients shunted at birth require
distal to proximal, looking for an upper limb or shunt revision in the first year of life, mostly
facial response characteristic of those experienc- due to mechanical failure (Caldarelli et al.
ing a pain sensation. The level at which anesthe- 1996). Endoscopic third ventriculosomy (ETV)
sia starts indicates the level of the lesion and has also been used in some patients although
predicts the degree of disability. Proper care is the failure rate is high when performed as a
necessary to avoid trophic changes in anesthetic primary procedure (Fritsch et al. 2005; O’Brien
areas. et al. 2005). In patients presenting with shunt
malfunction, secondary ETV has a better success
Assessment of Bladder and Bowel rate and is therefore best reserved for later
Function management (O’Brien et al. 2005).
Over 90% of patients with myelomeningocele
have a form of neurogenic bladder. The vast Arnold–Chiari Type II Malformation
majority of these patients have disturbances of Arnold–Chiari II malformation is invariably
detrusor and sphincter balance resulting in a large, associated with myelomeningocele, often
trabeculated bladder with urinary stasis. The anal accompanied by hydrocephalus. The caudally
external sphincter and puborectalis are often displaced cervicomedullary junction, pons,
involved, resulting in patulous anus and sometimes fourth ventricle and medulla together with a
rectal prolapse. It is difficult to ascertain bladder small posterior fossa and tectal “beaking” are
involvement in the newborn but steps should be demonstrated well on MRI. Between 25 and
taken to ensure the bladder is kept empty by inter- 33% of patients are symptomatic from the Chiari
mittent catheterization. The upper urinary tract is II malformation caused by brainstem dysfunc-
usually normal but some affected patients will tion and lower cranial nerve palsies. Stevenson
experience changes in the upper urinary tract at et al. reported that apneic episodes, stridor (vocal
birth (Greig et al. 1991). These patients need cord paresis), and swallowing difficulties in
careful urological and renal follow-up. infancy were associated with a 15% mortality
rate in those affected (Stevenson 2004). Whether
Hydrocephalus early decompression improves symptoms
Hydrocephalus develops in 65–85% of patients remain controversial as surgery related morbid-
with myelomeningocele, the majority before ity and mortality is high in infants (up to
the age of 6 months, and approximately 5–10% 15–20%) and will not correct the intrinsic
have overt hydrocephalus at birth (Stein and brainstem abnormalities (Pollack et al. 1992;
Schut 1979). Assessment of the anterior fonta- Vandertop et al. 1992). From a practical point
nelle and occipitofrontal circumference are of view, symptomatic Chiari II are rare in infants
important to determine the timing of any CSF as long as the hydrocephalus is correctly man-
diversion procedures. In those infants with clear aged. Chiari II can become a secondary problem
evidence of hydrocephalus, early CSF diversion in adult life with delayed deterioration.
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With 487 Figures and 114 Tables

ISBN 978-3-662-43587-8 ISBN 978-3-662-43588-5 (eBook)

Dublin, Ireland Prem Puri

1 Embryology of Congenital Malformations .............. 3

14 Metabolism of Infants and Children . . . . . . . . . . . . . . . . . . . 231

31 Fast-Track Pediatric Surgery . . . . . . . . . . . . . . . . . . . . . . . . . 505

Part II Newborn Surgery: Head and Neck . . . . . . . . . . . . . . . . . . . 615

39 Choanal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Part III Newborn Surgery: Esophagus . . . . . . . . . . . . . . . . . . . . . . . 659

44 Esophageal Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661

46 Esophageal Duplication Cyst . . . . . . . . . . . . . . . . . . . . . . . . . 691

Part IV Newborn Surgery: Chest . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713

48 Congenital Airway Malformations . . . . . . . . . . . . . . . . . . . . . 715

Part V Newborn Surgery: Gastrointestinal . . . . . . . . . . . . . . . . . . 827

55 Pyloric Atresia and Prepyloric Antral Diaphragm . . . . . . . . 829

62 Jejunoileal Atresia and Stenosis . . . . . . . . . . . . . . . . . . . . . . . 913

Part VI Newborn Surgery: Liver and Biliary Tract . . . . . . . . . . . . 1125

77 Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1127

78 Congenital Biliary Dilatation . . . . . . . . . . . . . . . . . . . . . . . . . 1145

Part VII Newborn Surgery: Anterior Abdominal Wall Defects . . . 1165

Part VIII Newborn Surgery: Spina Bifida and Hydrocephalus . . . 1211

83 Spina Biﬁda and Encephalocele . . . . . . . . . . . . . . . . . . . . . . . 1213

Part IX Newborn Surgery: Long-Term Outcomes in Newborn

85 Long-Term Outcomes in Newborn Surgery . . . . . . . . . . . . . . 1259

Prem Puri is the Newman Clinical Research

Professor Puri is known internationally for his

Carlos E. Blanco Department of Neonatology, National Maternity Hospital,

Belinda Hsi Dickie Colorectal and Complex Pelvic Malformation Center,

John Gillick Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland

Faraz A. Khan Center for Advanced Intestinal Rehabilitation, Department

Roman Metzger Department of Paediatric and Adolescent Surgery, Paracel-

James J. O’Byrne Department of Clinical Genetics, Our Lady’s Hospital,

Owen Patrick Smith Department of Haematology, Our Lady’s Children’s

Benno Ure Center of Pediatric Surgery Hannover, Hannover Medical School

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 3

The Development of the Midgut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24

Abstract According to Haeckel’s “biogenetic law,” a

Misconceptions and/or Outdated A Shortage of Study Material (Both

A Shortage of Explanatory Images (a) Serial sectioning of embryos and time-

Scanning Electron Microscopic Atlas

In this section we want to present examples of

Normal Foregut Development

(c) Laryngo-tracheo-esophageal clefts the diaphragmatic development. For practical rea-

Abnormal Development Of these theories, failure of the pleuroperitoneal

of congenital diaphragmatic hernia (CDH) devel-

(a) Timing of diaphragmatic defect appearance.

Abnormal Development In all affected embryos, we made the following

Fig. 23 Rupture of the

Fig. 25 Phallus of a rat ED

(embryonic day 22), the bulb disappears partially

The Role of the Gubernaculum

abnormalities and their embryogenesis. Pediatr Surg

Abstract genetic investigations. Instead, it may be more

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 35

Introduction large and unknowable numbers of defects that

metabolic syndrome, but there is reason to believe

to do such work. Medicine is still taught around

# Springer-Verlag GmbH Germany, part of Springer Nature 2020 49

Abstract nization; Preterm birth. Fact sheet N 363, 2015;