Pediatric Anesthesiology PDF

Pediatric Anesthesiology
Contributors
CONSULTING EDITOR
LEE A. FLEISHER, MD, FACC, FAHA

Robert D. Dripps Professor and Chair of Anesthesiology and Critical Care, Professor of
Medicine, Perelman School of Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania
EDITORS
ALAN JAY SCHWARTZ, MD, MSEd

Director of Education & Program Director, Pediatric Anesthesiology Fellowship,
Department of Anesthesiology and Critical Care Medicine, The Children’s Hospital
of Philadelphia; Professor of Clinical Anesthesiology and Critical Care, Perelman
School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania
DEAN B. ANDROPOULOS, MD, MHCM

Chief of Anesthesiology, Texas Children’s Hospital; Professor, Anesthesiology and
Pediatrics, Baylor College of Medicine, Houston, Texas
ANDREW DAVIDSON, MBBS, MD, FANZCA

Associate Professor, Royal Children’s Hospital, Parkville, Melbourne, Victoria, Australia
AUTHORS
RICHARD J. BANCHS, MD
Assistant Professor of Anesthesiology, Department of Anesthesiology (MC515), University
of Illinois Medical Center, Children’s Hospital University of Illinois, Chicago, Illinois
DAVID BUCK, MD, MBA

Advanced Fellow Quality Improvement and Safety, Department of Anesthesiology,
Cincinnati Children’s Hospital, Cincinnati, Ohio
KATRIN CAMPBELL, MD
Assistant Professor of Anesthesiology and Pediatrics, Director, Division of Sedation,
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
NICHOLAS P. CARLING, MD
Assistant Professor of Pediatrics and Anesthesiology; Director of Neuroanesthesia, Texas
Children’s Hospital, Baylor College of Medicine, Houston, Texas
NICHOLAS M. DALESIO, MD
Assistant Professor, Division of Pediatric Anesthesiology, Department of Anesthesiology
and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore,
Maryland
iv Contributors
SABINA DICINDIO, DO
Department of Anesthesiology and Critical Care Medicine, Nemours/Alfred I. duPont
Hospital for Children, Wilmington, Delaware; Assistant Professor of Anesthesiology,
Department of Anesthesiology, Jefferson Medical College, Thomas Jefferson University,
JOHN E. FIADJOE, MD
Assistant Professor, Department of Anesthesiology and Critical Care, Children’s Hospital
of Philadelphia, Perelman School of Medicine at the University of Pennsylvania,
ROBERT H. FRIESEN, MD
Professor, Department of Anesthesiology, University of Colorado School of Medicine,
Colorado
CHRIS D. GLOVER, MD
Assistant Professor of Pediatrics and Anesthesiology; Director of the Acute Pain Service,
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
C. DEAN KURTH, MD
Professor, Department of Anesthesiology, Cincinnati Children’s Hospital, University of
Cincinnati College of Medicine, Cincinnati, Ohio
MARY LANDRIGAN-OSSAR, MD, PhD

Senior Associate in Perioperative Anesthesia, Department of Anesthesiology,
Perioperative and Pain Medicine, Boston Children’s Hospital, Instructor of Anaesthesia,
Harvard Medical School, Boston, Massachusetts
GREGORY J. LATHAM, MD
Assistant Professor, Department of Anesthesiology and Pain Medicine, Seattle Children’s
Hospital, University of Washington School of Medicine, Seattle, Washington
JERROLD LERMAN, MD, FRCPC, FANZCA

Clinical Professor of Anesthesiology, Department of Anesthesia, Women and Children’s
Hospital of Buffalo, SUNY at Buffalo, Bufffalo; Department of Anesthesia, Strong Medical
Center, University of Rochester, Rochester, New York
ERICA P. LIN, MD, FAAP

Assistant Professor of Clinical Anesthesia & Pediatrics, Department of Anesthesiology,
Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of
Medicine, Cincinnati, Ohio
ANDREAS W. LOEPKE, MD, PhD, FAAP

Associate Professor of Clinical Anesthesia & Pediatrics, Department of Anesthesiology,
Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of
Medicine, Cincinnati, Ohio
JAGROOP MAVI, MD
Assistant Professor, Clinical Anesthesia and Pediatrics, Department of Anesthesia,
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
CRAIG D. MCCLAIN, MD, MPH

Senior Associate in Perioperative Anesthesia, Department of Anesthesiology,
Perioperative and Pain Medicine, Boston Children’s Hospital, Assistant Professor
of Anaesthesia, Harvard Medical School, Boston, Massachusetts
Contributors v
DAVID L. MOORE, MD
Associate Professor, Clinical Anesthesia and Pediatrics, Department of Anesthesia,
Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
AMOD SAWARDEKAR, MD
Assistant Professor of Anesthesiology, Department of Pediatric Anesthesiology, Ann &
Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois
DEBORAH A. SCHWENGEL, MD
Assistant Professor, Division of Pediatric Anesthesiology, Department of Anesthesiology
and Critical Care Medicine; Department of Pediatrics, Johns Hopkins University School of
Medicine, Baltimore, Maryland
RAVI SHAH, MD
Assistant Professor of Anesthesiology, Department of Pediatric Anesthesiology, Ann &
Robert H. Lurie Children’s Hospital of Chicago, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois
SULPICIO G. SORIANO, MD, FAAP

Professor of Anaesthesia, Endowed Chair in Pediatric Neuroanesthesia, Department of
Anesthesiology, Perioperative, and Pain Medicine, Boston Children’s Hospital, Harvard
Medical School, Boston, Massachusetts
STEPHEN STAYER, MD
Professor of Anesthesiology and Pediatrics, Medical Director of Perioperative Services,
Associate Chief, Pediatric Anesthesiology, Texas Children’s Hospital, Baylor College of
Medicine, Houston, Texas
TRACEY L. STIERER, MD
Assistant Professor, Departments of Anesthesiology and Critical Care Medicine, and
Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine,
Baltimore, Maryland
PAUL A. STRICKER, MD
Assistant Professor, Department of Anesthesiology and Critical Care, Children’s Hospital
of Philadelphia, Perelman School of Medicine at the University of Pennsylvania,
SANTHANAM SURESH, MD, FAAP

Anesthesiologist-in Chief, Professor of Anesthesiology & Pediatrics, Department of
Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Feinberg
School of Medicine, Northwestern University, Chicago, Illinois
MICHAEL SURY, MB, BS, FRCA, PhD

Department of Anaesthesia, Great Ormond Street Hospital, London, United Kingdom
MARY C. THEROUX, MD
Pediatric Anesthesiologist and Director of Research, Anesthesiology Division,
Department of Anesthesiology and Critical Care Medicine, Nemours/Alfred I. duPont
Hospital for Children, Wilmington, Delaware; Professor of Anesthesiology and Pediatrics,
Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
LAURA TORRES, MD
Associate Professor of Anesthesiology and Pediatrics, Chair, Sedation Oversight
Committee, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
vi Contributors
MARK D. TWITE, MB BChir

Associate Professor, Department of Anesthesiology, University of Colorado School of
Medicine, Colorado
ANNA VARUGHESE, MD, MPH

Associate Professor, Department of Anesthesiology, Cincinnati Children’s Hospital,
University of Cincinnati College of Medicine, Cincinnati, Ohio
BRITTA S. VON UNGERN-STERNBERG, MD, PhD, DEAA, FANZCA

Chair of Pediatric Anesthesia, Department of Anesthesia and Pain Management, Princess
Margaret Hospital for Children; Winthrop Professor, Chair of Pediatric Anesthesia, School
of Medicine and Pharmacology, The University of Western Australia, Perth, Australia
Preface
Alan Jay Schwartz, MD, Dean B. Andropoulos, MD, Andrew Davidson, MBBS, MD,
MSEd MHCM FANZCA
Editors
Pediatric anesthesiology presents clinicians with recurring management issues that

warrant review and updating. This issue of Anesthesiology Clinics provides “just
what the doctor ordered” for a review of key topics in pediatric anesthesia patient care.
This issue is divided into 5 topical areas: (1) preanesthesia and postanesthesia con-
siderations, (2) neurophysiology and neuroanesthesia, (3) cardiothoracic anesthesia,
(4) regional anesthesia, and (5) practice management. The articles in each area are
current considerations of patient care issues that have had an evergreen timeframe
of interest.
As examples, Jerry Lerman and Richard Banchs offer a current perspective on
preoperative anxiety and emergence agitation of pediatric patients and Steve Stayer
brings us up to date on safe, effective, and efficient sedation of children in the nonop-
erating room environment. Sulpicio Soriano and Andreas Loepke present a most timely
consideration of anesthetic neurotoxicity. Paul Stricker and John Fiadjoe review the
high acuity care of children undergoing craniofacial surgery. The article devoted to
regional anesthesia originates from Santhanam Suresh and Jennifer Rhodes, placing
focus on the use of ultrasound to enhance safe care of children. Last, Dean Kurth,
Anna Varughese, and David Buck remind readers about the modern day concern
with quality assurance, also providing information from the Wake Up Safe initiative.
There are 15 articles in total covering many of the “hot topics” about which readers
are eager to learn.
We encourage you to read these up-to-date articles on some of the key issues con-
fronting pediatric anesthesiologists and get the latest word on safe anesthetic
management!
Alan Jay Schwartz, MD, MSEd

Department of Anesthesiology and Critical Care Medicine
The Children’s Hospital of Philadelphia
34th Street and Civic Center Boulevard
Room 9327
Philadelphia, PA 19104-4399, USA
Anesthesiology Clin 32 (2014) xiii–xiv

http://dx.doi.org/10.1016/j.anclin.2013.11.002 anesthesiology.theclinics.com
1932-2275/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
xiv Preface
Dean B. Andropoulos, MD, MHCM

Texas Children’s Hospital
6621 Fannin Street
Houston, TX 77030, USA
Andrew Davidson, MBBS, MD, FANZCA
Royal Children’s Hospital
Flemington Road
Parkville
Melbourne, Victoria
3052 Australia
E-mail addresses:
schwartza@email.chop.edu (A.J. Schwartz)
dbandrop@texaschildrens.org (D.B. Andropoulos)
andrew.davidson@rch.org.au (A. Davidson)
Pediatric Anesthesiology xi
ANESTHESIOLOGY CLINICS
FORTHCOMING ISSUES RECENT ISSUES

June 2014 December 2013
Ambulatory Anesthesia Abdominal Transplantation
Jeffrey Apfelbaum and Claus U. Niemann, Editor
Thomas Cutter, Editors
September 2013
September 2014 Obstetric Anesthesia
Vascular Anesthesia Robert Gaiser, Editor
Charles Hill, Editor
June 2013
December 2014 Cardiac Anesthesia
Orthopedic Anesthesia Colleen G. Koch, Editor
Nabil Elkassabany and Edward Mariano,
Editors
RELATED INTEREST
Oral and Maxillofacial Surgery Clinics, August 2013 (Volume 25, Issue 3)
Anesthesia
Paul J. Schwartz, Editor
NOW AVAILABLE FOR YOUR iPhone and iPad

Contents
Preface xiii
Alan Jay Schwartz, Dean B. Andropoulos, and Andrew Davidson
Preoperative Anxiety Management, Emergence Delirium, and

Postoperative Behavior 1
Richard J. Banchs and Jerrold Lerman
Preoperative anxiolysis is important for children scheduled for surgery. The
nature of the anxiety depends on several factors, including age, tempera-
ment, past hospitalizations, and socioeconomic and ethnic backgrounds.
A panoply of interventions effect anxiolysis, including parental presence,
distraction, and premedication, although no single strategy is effective for
all ages. Emergence delirium (ED) occurs after sevoflurane and desflurane
in preschoolage children in the recovery room. Symptoms usually last
approximately 15 minutes and resolve spontaneously. The Pediatric Anes-
thesia Emergence Delirium [PAED] scale is a validated scale to diagnose ED
and evaluate therapeutic interventions for ED such as propofol and opioids.
Anesthesia and Sedation Outside the Operating Room 25

Katrin Campbell, Laura Torres, and Stephen Stayer
The volume of pediatric invasive and noninvasive procedures outside the
operating room continues to increase. The acuity and complexity of patient
clinical condition has resulted in the expansion of the anesthesiologist’s
role in remote sites. The anesthesia provider must ensure patient safety
by assuring appropriate patient preparation, having available required
equipment for monitoring and rescue, planning careful sedation/anesthesia
management, continuing vigilance and observation into the recovery
phase, and requiring strict discharge criteria. A quality improvement pro-
gram for the department of anesthesiology should review anesthetic and
sedation outcomes of patients both inside and outside the operating room.
Respiratory Complications in the Pediatric Postanesthesia Care Unit 45

Britta S. von Ungern-Sternberg
This article focuses on common respiratory complications in the post-
anesthesia care unit (PACU). Approximately 1 in 10 children present with
respiratory complications in the PACU. The article highlights risk factors
and at-risk populations. The physiologic and pathophysiologic background
and causes for respiratory complications in the PACU are explained and
suggestions given for an optimization of the anesthesia management in
the perioperative period. Furthermore, the recognition, prevention, and
treatment of these complications in the PACU are discussed.
Major Surgical Procedures in Children with Cerebral Palsy 63

Mary C. Theroux and Sabina DiCindio
There are 3 surgical procedures that patients with cerebral palsy (CP)
undergo that may be considered major procedures: femoral osteotomies
viii Contents
combined with pelvic osteotomies, spine fusion, and intrathecal baclofen

pump implant for the treatment of spasticity. Many complications are
known to occur at a higher rate in this population, and some may be
avoided with prior awareness of the preoperative pathophysiology of the
patient with CP.
Challenges in Pediatric Neuroanesthesia: Awake Craniotomy, Intraoperative

Magnetic Resonance Imaging, and Interventional Neuroradiology 83
Craig D. McClain and Mary Landrigan-Ossar
This article gives a review of 3 challenges in caring for children undergoing
neurosurgical and neurointerventional procedures. Anesthesiologists may
have experience with certain aspects of these situations but may not have
extensive experience with each clinical setting. This review addresses
issues with awake craniotomy, intraoperative magnetic resonance imag-
ing, and neurointerventional procedures in children with neurologic dis-
ease. Familiarization with these complex clinical scenarios and their
unique considerations allows the anesthesiologist to deliver optimal care
and helps facilitate the best possible outcome for these patients.
Neuromonitoring for Scoliosis Surgery 101

Chris D. Glover and Nicholas P. Carling
The use of intraoperative neuromonitoring (IONM) during pediatric scoliosis
repair has become commonplace to reduce the risk of potentially devastat-
ing postoperative neurologic deficits. IONM techniques include somato-
sensory evoked potentials, motor evoked potentials, electromyography,
and intraoperative wake-up tests. Special considerations for scoliosis re-
pair in pediatric patients include preexisting neurologic deficits and young
patients with immature neural pathways in whom neurophysiologic moni-
toring may prove difficult or unreliable.
Brain Monitoring in Children 115

Michael Sury
Applying scalp sensors in the operating theater, intensive care, or resusci-
tation scenarios to detect and monitor brain function is achievable, prac-
tical, and affordable. The modalities are complex and the output of the
monitor needs careful interpretation. The monitor may have technical
problems, and a single reading must be considered with caution. These
monitors may have a use for monitoring trends in specific situations, but
evidence does not support their widespread use. Nevertheless, research
should continue to investigate their role. Future techniques and treatments
may show that these monitors can monitor brain function and prevent
harm.
Anesthetic Neurotoxicity 133

Erica P. Lin, Sulpicio G. Soriano, and Andreas W. Loepke
All routinely utilized sedatives and anesthetics have been found neurotoxic
in a wide variety of animal species, including non-human primates. Neuro-
toxic effects observed in animals include histologic evidence for apoptotic
Contents ix
neuronal cell death and subsequent learning and memory impairment.

Several cohort studies in neonates with significant comorbidities requiring
surgical procedures early in life have also demonstrated abnormal neuro-
developmental outcomes. This article provides an overview of the cur-
rently available data from both animal experiments and human clinical
studies regarding the effects of sedatives and anesthetics on the develop-
ing brain.
The Anesthetic Management of Children with Pulmonary Hypertension in the

Cardiac Catheterization Laboratory 157
Mark D. Twite and Robert H. Friesen
Children need cardiac catheterization to establish the diagnosis and mon-
itor the response to treatment when undergoing drug therapy for the treat-
ment of pulmonary arterial hypertension (PAH). Children with PAH
receiving general anesthesia for cardiac catheterization procedures are
at significantly increased risk of perioperative complications in comparison
with other children. The most acute life-threatening complication is a pul-
monary hypertensive crisis. It is essential that the anesthesiologist caring
for these children understands the pathophysiology of the disease, how
anesthetic medications may affect the patient’s hemodynamics, and
how to manage an acute pulmonary hypertensive crisis.
Anesthesia and Analgesia for Pectus Excavatum Surgery 175

Jagroop Mavi and David L. Moore
The technique of choice for surgical correction of pectus excavatum is
the Nuss procedure, a minimally invasive technique in which rigid metal
bars are placed transthoracically beneath the sternum and costal
cartilages until permanent remodeling of the chest wall has occurred.
Intraoperatively, anesthesia focuses on three areas: the potential for
catastrophic blood loss caused by perforation of large capacitance
vessels and the heart, the potential for malignant arrhythmias, and the
consequences of bilateral iatrogenic pneumothoraces. Postoperatively,
analgesia is institutionally dependent and controversial, based on
usage and type of regional anesthesia. The necessity of multimodal
analgesic techniques creates a common ground across different hospi-
tal systems.
Anesthesia for the Child with Cancer 185

Gregory J. Latham
Children with cancer undergo a host of surgeries and procedures that
require anesthesia during the various phases of the disease. A safe anes-
thetic plan includes consideration of the direct effects of tumor, toxic
effects of chemotherapy and radiation therapy, the specifics of the surgical
procedure, drug-drug interactions with chemotherapy agents, pain
syndromes, and psychological status of the child. This article provides
a comprehensive overview of the anesthetic management of the child
with cancer, focuses on a systems-based approach to the impact from
both tumor and its treatment in children, and presents a discussion of
the relevant anesthetic considerations.
x Contents
Anesthesia for Craniofacial Surgery in Infancy 215

Paul A. Stricker and John E. Fiadjoe
Anesthetic management of infants undergoing craniofacial surgery can be
challenging. Primary concerns for the anesthesiologist include blood loss
and its management. The evolution of procedures to treat craniosynosto-
sis has resulted in improvements in perioperative morbidity, including
decreased blood loss and transfusion, shorter operations, and shorter
hospital stays. An understanding of the procedures performed to treat cra-
niosynostosis is necessary to provide optimal anesthetic management.
Descriptions of current surgical techniques and approaches to anesthetic
care are presented in this review.
Pediatric Obstructive Sleep Apnea 237

Deborah A. Schwengel, Nicholas M. Dalesio, and Tracey L. Stierer
Obstructive sleep apnea syndrome (OSAS) is a disorder of airway obstruc-
tion with multisystem implications and associated complications. OSAS
affects children from infancy to adulthood and is responsible for behavioral,
cognitive, and growth impairment as well as cardiovascular and perioper-
ative respiratory morbidity and mortality. OSAS is associated commonly
with comorbid conditions, including obesity and asthma. Adenotonsillec-
tomy is the most commonly used treatment option for OSAS in childhood,
but efforts are underway to identify medical treatment options.
Ultrasound for Regional Anesthesia in Children 263

Santhanam Suresh, Amod Sawardekar, and Ravi Shah
The use of regional anesthesia in children is increasing. Rapid advance-
ment in the use of ultrasound guidance has allowed for a greater ease in
performing peripheral regional anesthesia in pediatrics. Successful periph-
eral nerve blockade provides children with analgesia that will improve their
operative experience.
Perspectives on Quality and Safety in Pediatric Anesthesia 281

David Buck, C. Dean Kurth, and Anna Varughese
Organizational culture underlies every improvement strategy; without
a strong culture, a change, even if initially successful, is short lived. Chang-
ing culture and improving quality require commitment of leadership, and
leaders must play an active and visible role to articulate the vision and
create the proper environment. Quality-improvement projects require
a consistent framework for outlining a process, identifying problems, and
testing, evaluating, and implementing changes. Wake Up Safe is a patient
safety organization that strives to use quality improvement to make anes-
thesia care safer. Root cause analysis is a methodology in safety analytics
based on a sequence of events model of safety.
Index 295
P re o p e r a t i v e A n x i e t y
M a n a g e m e n t , Em e r g e n c e
D e l i r i u m , an d P o s t o p e r a t i v e
Behavior
a b,c,
Richard J. Banchs, MD , Jerrold Lerman, MD, FRCPC, FANZCA *
KEYWORDS
Anxiety Children Distraction Emergence delirium Parental presence
Pediatric Premedication
KEY POINTS
Preoperative anxiolysis is of utmost importance for children undergoing surgery.
Preoperative educational materials, parental presence at induction of anesthesia (PPIA),
distraction, and pharmacologic interventions are effective anxiolytics.
Emergence delirium (ED) resurfaced with the newer insoluble anesthetics, sevoflurane and
desflurane, as a nuisance and potentially serious sequela in young children in the recovery
room.
Research and investigation into the treatments of ED was stymied by the absence of a
validated scale for ED until the Pediatric Anesthesia Emergence Delirium (PAED) scale
was published.
Causative factors for ED have not yet been elucidated, but several strategies have been
described to attenuate ED, including propofol infusion and use of a2-agonists, opioids,
and others.
INTRODUCTION
As the views and understanding of the factors that affect a child’s anesthetic experi-
ence evolve, preoperative anxiety, postoperative behavior, and parental participation
in the child’s health care experience have become important considerations. In
a
Department of Anesthesiology (MC515), University of Illinois Medical Center, Children’s Hos-
pital University of Illinois, 1740 West Taylor Street, Suite 3200 West, Chicago, IL 60612-7239,
USA; b Department of Anesthesia, Women and Children’s Hospital of Buffalo, SUNY at Buffalo,
219 Bryant Street, Buffalo, NY 14222, USA; c Department of Anesthesia, Strong Medical Center,
University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA
* Corresponding author. Department of Anesthesia, Women and Children’s Hospital of Buffalo,
SUNY at Buffalo, 219 Bryant Street, Buffalo, NY 14222.
E-mail address: jerrold.lerman@gmail.com
Anesthesiology Clin 32 (2014) 1–23

2 Banchs & Lerman
children, preoperative anxiolysis is important not only for compassionate reasons but
also for improving postoperative behavior such as ED. Parents and society expect not
only effective but also patient- and family-centered care. This review summarizes the
current state of the art of perioperative management of children.
PREOPERATIVE ANXIETY
Framework
Parental separation and induction of anesthesia is one of the most stressful experi-
ences for a child undergoing a surgical procedure. Stress may be manifested not
only during the induction period but also during the postoperative period.1 Although
all children are vulnerable to stress, preschool children and toddlers aged 1 to 6 years
seem to be the most vulnerable. Evidence suggests that children who are anxious in
the holding area and during the induction experience a greater distress during the im-
mediate postoperative period.1–4 Preoperative anxiety is an independent predictor for
postoperative negative behaviors.2 Common postoperative negative behavior include
nightmares, waking up crying, separation anxiety, and temper tantrums,2,5 whereas
more serious behavioral changes such as new-onset enuresis are uncommon.5 The
risk of postoperative negative behavior is 3.5-fold greater in children who experienced
preoperative anxiety.2 Of these children, 67% will develop negative behaviors on the
first day after surgery, 45% on the second day, and 23% within 2 weeks.2 Negative
behaviors persist for up to 6 months in 20% of the children and for up to 1 year in
7.3% of the children.5 In addition to a surgical procedure, any other health care
encounter that proves to be traumatic may increase the likelihood of an anesthesia
phobia when the child returns to the hospital. How perioperative anxiety affects later
emotional and intellectual development remains unclear, but negative memories of
hospitalizations and anesthetic care may persist well into adulthood.6
Measuring preoperative anxiety in a child is challenging. However, quantifying the
degree of anxiety experience by a child may be a worthy pursuit to understand the
magnitude of the problem and to stratify appropriate therapeutic interventions to miti-
gate its effects. Several scales have been developed to measure preoperative anxiety
and have been used for both clinical and research purposes. However, because self-
reporting scales are unsuitable for preverbal children, there are currently no scales for
children younger than 2 years. Clinical parameters such as heart rate and blood pres-
sure have been used in the past to assess anxiety, but these clinical parameters have
shown a low validity and reliability. Plasma cortisol concentrations7 after induction
have also been used to quantify perioperative anxiety, but these are also insensitive
measurements and impractical for every pediatric clinical practice.
Factors that Contribute to Preoperative Anxiety

Several factors contribute to preoperative anxiety and postoperative behavioral
changes in children, including age, gender, temperament and ethnicity, previous hos-
pital experience, type of anesthetic induction, type of surgery, and postoperative pain.
Age
The studies of the effects of age on anxiety during the induction of anesthesia have
yielded inconsistent results. Younger children seem to be more anxious at separation
from their parents8 and less cooperative during induction of anesthesia than older
children.9,10 They also suffer from a greater incidence of postoperative behavioral dis-
turbances,9,11,12 which may last up to 6 months after surgery.5 However, an observa-
tional study of 2122 children undergoing ambulatory surgery determined that distress
at induction did not vary significantly with age.13 Infants younger than 1 year may or
Preoperative Anxiety & Emergence Delirium 3
may not express anxiety on separation from their parents and, depending on the in-
fants, may be easily distracted. Paradoxically, another study noted that children older
than 7 years were actually more anxious in the preoperative holding area than those
aged 4 to 7 years, although anxiety was not measured during induction of anesthesia.5
The inconsistent results regarding the relationship between anxiety and distress and
age may, in part, be attributed to imprecise metrics that were used to measure the
anxiety in children, a paucity of prospective randomized controlled trials, and small
sample sizes.
Perioperative anxiety in children may depend primarily on their stages of develop-
ment.14 Each age group roughly correlates with a stage of development, and each
stage manifests different psychological issues that require different and specific ther-
apeutic approaches.14 Infants are less likely to experience separation anxiety, children
1 to 3 years experience separation anxiety but respond positively to distraction and
comforting measures,14 and children aged 4 to 6 years seek explanations and a desire
to maintain control of their environment. Furthermore, older children between the ages
of 7 and 12 years have strong desires to be involved in the decision-making process.14
Adolescents fear losing face and are concerned with their inability to cope.14 The last
2 age groups respond well to explanations, to maintain control of events, and to pre-
serve their privacy and independence as coping mechanisms to decrease anxiety.14
Gender
Gender has not been found to be a factor involved in preoperative anxiety or in
postoperative behavioral problems in prepubescent children.5,12
Temperament and ethnicity

Perioperative anxiety is influenced by a child’s temperament. Temperament is the
behavioral makeup of a child that influences the reaction to surrounding stimuli and
stressful environments. Four temperament components have been identified:
emotionality, activity, sociability, and impulsivity.15 Temperament has been measured
using the EASI scale (emotionality, activity, sociability, impulsivity scale), which is an
observer-based measurement tool that uses the parents to assess their child’s
temperament.15 Parents score each of 5 patterns of behavior between 1 and 5 for a
total score between 5 and 25. In a prospective study of 183 children aged 2 to 10 years
undergoing elective surgery, situational anxiety of the mother, temperament and age
of the child, and quality of previous medical encounters significantly correlated with
preoperative anxiety.5 Previous surgery, premedication, and lack of enrollment in a
day care were predictors of child’s anxiety at separation from the parents.5 The Post-
hospitalization Behavior Questionnaire (PHBQ) is a tool to assess behavioral changes
in children after health care encounters. The PHBQ is a parental questionnaire that in-
cludes 27 items in 6 categories: general anxiety, separation anxiety, sleep anxiety,
eating disturbances, aggression toward authority, apathy, and withdrawal.16 Each
item is graded on a scale from 1 to 5. Low scores indicate a positive behavioral change
and high scores indicate a negative behavioral change. The PHBQ has good test
validity and reliability, although it has not been studied in all age groups and is subject
to parental bias.
Recent evidence suggests that cultural differences, including language and
ethnicity, may contribute to changes in behavior, specifically behavior during the
recovery period.17
Previous hospital experience

A previous health care experience may influence a child’s preoperative level of anxi-
ety. Children who have had previous negative health care encounters experience
4 Banchs & Lerman
greater anxiety in the holding area and at separation from parents.5,12,18 Reducing a
child’s anxiety during the preoperative period may not only benefit the current periop-
erative process but also decrease anxiety at subsequent anesthesia encounters.
Stressful life experiences close in time to a hospital admission can also affect how a
child reacts to anesthesia and the overall surgical experience.
Type of anesthesia
The effects of the type of anesthesia induction on preoperative anxiety and other
behaviors are unclear. In children aged 2 to 7 years who were premedicated with
midazolam, anxiety was least in those anesthetized by inhalational anesthesia
compared with an intravenous (IV) or rectal induction with methohexitone.19 Postop-
erative behavior was similar among the 3 groups, although negative memories
occurred more frequently in the inhalational group compared with the other 2 groups.
At present, there is insufficient evidence to determine whether one type of anesthesia
decreases perioperative anxiety any more or less than another.
Type of surgery
Whether the type of surgery influences the incidence of preoperative anxiety and postop-
erative behavior is unclear. Several studies concluded that the type of surgery does not
increase the risk of postoperative maladaptive behaviors,9,12,13,20 whereas other studies
found that surgery of the genitourinary system2 and inpatient surgery18 were associated
with an increased risk of postoperative behavioral changes. Preoperative anxiety is
similar for elective and emergency procedures.13 The effect of postoperative pain on
the risk of postoperative maladaptive behavior is not well understood either. Using the
PHBQ, one study found that pain was a significant predictor of behavioral changes
that lasted up to 4 weeks,19 whereas another reported a poor correlation between the
severity of postoperative pain and behavioral changes.5 The effect of the type of surgery
on preoperative and postoperative anxiety and behavior remains unresolved.
INTERVENTIONS
The purpose of preoperative anxiolysis is to reduce a child’s anxiety and decrease the
risk of negative postoperative behavioral changes. Preoperative anxiolysis also im-
proves cooperation during induction and may contribute to increased parental satis-
faction. Several strategies have been used to reduce preoperative anxiety, including
PPIA, preoperative educational programs, sedative premedication, and distraction
techniques. Additional studies are needed to determine the optimal intervention for
each age group. Several tools have been used to assess preoperative anxiety. The
Yale Preoperative Anxiety Score (YPAS) is an observer assessment tool designed
for children between the ages of 2 and 6 years. The YPAS has shown good validity
and reliability in several clinical trials.21 A modified version of the YPAS, the modified
Yale Preoperative Anxiety Score (mYPAS), has been developed for children between
the ages of 5 to 12 years. The mYPAS is based on the total score from 5 behavioral
categories: the child’s activity, facial expressions, alertness and arousal, vocalization,
and interaction with adults. The mYPAS has shown good validity and intraobserver
and interobserver reliability in numerous clinical trials.22 Cooperation of a child during
the induction phase of anesthesia has also been used as a surrogate measure of anx-
iety. The Induction Compliance Checklist (ICC) measures the cooperation of a child
using a checklist of 10 items.23 The ICC has excellent interobserver and intraobserver
variability, but the validity of this scale to measure preoperative anxiety has not been
validated. A visual analog scale has also been used to assess cooperation of a child at
induction.
PPIA
PPIA is a common practice in many countries but more common in Europe than in the
United States. In a survey of US and UK anesthesiologists, 58% of US anesthesiolo-
gists agreed with PPIA but in only 5% of the cases were parents routinely allowed in
the operating room.24 In contrast, 84% of British anesthesiologists allowed PPIA in
more than 75% of the cases. Contrary to US anesthesiologists, most British anesthe-
siologists believed that PPIA decreased children’s anxiety, increased their coopera-
tion, and benefited both the parent and the anesthesia provider.24 Fear of litigation
has often been cited as an impediment to PPIA. Apart from isolated anecdotal cases,
there is no evidence to support the notion that PPIA increases the risk of a lawsuit
should an untoward event occur. Safety has also been cited as an impediment to
PPIA.25,26 Concerns over the safety of a child during PPIA are generally not substan-
tive, although even when PPIA is routinely practiced, unusual circumstances may
occur.7,27 Acceptance of PPIA is mainly a function of a provider’s experience, exper-
tise, and available operating room logistical support. The level of anxiety of an expe-
rienced anesthesiologist is not increased by the presence of a parent at induction.7
The unavailability of an induction room or of an operating room staff member to
accompany the parent back to the holding area is often cited as the main cause pre-
venting the routine presence of parents at induction. Several studies concluded that
perioperative anxiety is decreased by the presence of a parent during induction.28–30
However, these studies have been criticized for their lack of randomization and the use
of tools to assess anxiety that had not been previously validated.28–30 A total of 8 addi-
tional trials assessed PPIA, and none showed a significant difference in anxiety or
cooperation during induction when parents were present.31 One study showed that
PPIA was significantly less effective than midazolam in reducing children’s anxiety
at induction.31 In a study using a visual analog score for cooperation,7 PPIA did not
improve cooperation in children during induction. PPIA does not affect anxiety in
infants younger than 1 year.32 In 2 studies of PPIA and preoperative anxiety in the
holding area, on entering the operating room and during induction of anesthesia,
the investigators found no correlation between parental presence and anxiety.7,10 A
single measurement after induction showed reduced plasma cortisol levels in children
of calm parents, shy and inhibited children, and in children older than 4 years.7 PPIA
does not reduce the risk of postoperative behavioral changes as determined by the
PHBQ,10,28,29 even with 6-month follow-up evaluations.7
Several reasons may in part explain the lack of effect of PPIA on preoperative
anxiety.
1. First, many studies have not addressed high anxiety levels experienced by parents,
which are known to affect a child’s anxiety level and overall temperament.10
2. The simple presence of a parent may be insufficient to decrease a child’s anxiety.
3. Even if a parent were present, the lack of a specific active role for the parent may
actually contribute to the child’s anxiety.33
It has also been shown that parents experience preoperative anxiety when they
witness their child in distress.34,35 Parent anxiety has been well documented using a
visual analog score and the State Trait Anxiety Inventory (STAI), which is a gold stan-
dard for measuring anxiety in adults. There are several sources of anxiety for parents.
These include the following:
1. Concerns about how their child reacts to a new environment
2. Concerns about their child’s well-being
3. Concerns on witnessing their child’s loss of consciousness and immobility34–36
6 Banchs & Lerman
4. Concerns that they are abandoning their child when they leave the operating room
after the induction
Parents who are particularly vulnerable to experiencing anxiety during PPIA include
1. The parents of young children
2. Parents of a single child
3. Parents in the health care field35–37
4. Mothers of a child undergoing a surgical procedure34,36,37
If given a choice, parents generally prefer to accompany their child during the induc-
tion of anesthesia, regardless of their level of anxiety.35 Parents believe their presence
benefits their child. However, parental anxiety could actually negatively affect their
child. Using the Global Mood Scale and the STAI, several studies have shown that
children of anxious parents experience more anxiety than those of calm parents.5,10
A child’s anxiety in the holding area and after separation from the parent is greater
if the parent is anxious.5 A child of an anxious parent is 3.2 times more likely to
have persistent behavioral problems up to 6 months after a surgical procedure,
compared with a child of a calm parent.5
Although the role of PPIA in decreasing a child’s anxiety during induction is still
debated, what is clear is that PPIA does not decrease the parent’s level of anxiety.
In a study of parental anxiety, the level of anxiety was the same when measured in
the holding area (control group) or after PPIA (intervention group).10 Some anxious par-
ents found that separation from their child actually relieved their own anxiety.10 Only
parents who were calm before induction of anesthesia felt less anxious when partici-
pating in their child’s induction.10 A single study demonstrated that PPIA reduces
parental anxiety, but this study has been criticized for a lack of randomization.30 In
the current environment of family-centered care, many advocate for parental involve-
ment in all aspects of a child’s hospital experience as a strategy to increase overall
parental satisfaction. However, even this assertion has been challenged as 2 studies
noted that satisfaction with the perioperative experience did not improve with PPIA.7,32
PREOPERATIVE PREPARATION PROGRAMS
Preoperative preparation programs to decrease preoperative anxiety have had mixed

results, stemming from the inherent immaturity and lack of reliability in children and the
variability of interventions needed to successfully address every age group, tempera-
ment, and baseline personality.38 In a study of 143 children aged 2 to 6 years, children
who were randomized to the preoperative interactive book exhibited greater anxiety
on the day of surgery but fewer behavioral changes 2 weeks after surgery than those
who received the routine preoperative treatment.39 Parents in the intervention group
reported that preoperative interactive book helped their child (87%) and themselves
(83%). Children who were randomized to routine preoperative preparation were signif-
icantly more aggressive postoperatively than those who received the interactive
teaching book preoperatively. In another study, children were randomized to either
a preoperative preparation program that consisted of information, a tour and role
play with child-life specialists, or no intervention. The anxiety of the children in the pre-
operative period was significantly less in the intervention group but did not reach sta-
tistical significance for the induction and postoperative periods.39,40 Children aged
2 to 3 years, those who were emotionally labile and those with previous hospital expe-
rience, were more anxious after the preoperative preparation program. Children older
than 6 years were least anxious if they participated in the preoperative preparation
program more than 5 days before surgery and most anxious if they participated
1 day before surgery.39 Anxiety increased in children younger than 8 years who had a
previous hospital experience and who viewed a preoperative videotape of hospital-
related material the night before their surgery compared with those who viewed a
nonmedical video.41,42 Children older than 8 years did not experience this increase
in anxiety. Younger children become more anxious after participating in preoperative
preparation programs because they have difficulty distinguishing fantasy from reality.
Reality-based preparation programs may sensitize young children undergoing surgi-
cal procedures.33 To stratify the effects of different interventions on perioperative anx-
iety, one study compared the effects of a tour of the operating room plus a videotape
plus role play with a tour of the operating room and video and with a tour alone in chil-
dren aged 2 to 12 years.40 Those who participated in a tour of the operating room plus
a videotape plus role play exhibited reduced anxiety in the holding area compared with
the other 2 groups.40 However, beyond the holding area, the interventions did not
affect perioperative anxiety.40 The investigators also determined that preoperative
preparation program exerted no effect on postoperative behavior in children 2 weeks
after their surgical experience.
Anxiety has also been measured in children after their parents read to them an age-
appropriate interactive teaching book explaining the anesthesia process 1 to 3 days
before surgery.43 Perioperative anxiety in the study and control groups was similar.
The investigators reported a significant decrease in aggressive behavior after surgery
in the teaching book group compared with the control group.43
Children who have undergone a psychological intervention-targeted behavioral
strategy for surgery supervised by a pediatric psychologist are less anxious and
more cooperative in the preoperative period and during the induction of anesthesia
than controls.44 This psychological program has also shown to be more efficient in
reducing a mother’s anxiety and increasing her satisfaction.
A novel preoperative preparation program is the ADVANCE family-centered behav-
ioral preparation program which is an acronym for Anxiety-reduction, Distraction,
Video modeling and education, Adding parents, No excessive reassurance, Coaching,
and Exposure/shaping.45 This program is a multicomponent behavioral preparation
program that in addition to standard preoperative management provides strategies
and instructions to reduce preoperative anxiety, teach parents distraction techniques,
video modeling and education before the day of surgery, PPIA, avoid excessive reas-
surance at induction of anesthesia, coach to reinforce the skills needed to succeed
during induction, and exposure/shaping to familiarize the child with induction by
mask.45 The effectiveness of ADVANCE, family-centered behavioral preparation, on
preoperative anxiety and postoperative outcome measures was compared with
PPIA alone, oral midazolam, and control groups.45 Anxiety in parents and children
in the ADVANCE group was significantly less than that in the other 3 groups in the
holding area. Furthermore, anxiety in children in the ADVANCE group was less than
in those in the control and PPIA groups during induction of anesthesia.45 Anxiety
and compliance in children in both the ADVANCE and midazolam groups were similar
during induction of anesthesia. In terms of postoperative recovery, the incidence of ED
and analgesic requirements in the recovery room in children in the ADVANCE group
were less than those in the other groups. Discharge times for children in the ADVANCE
group were less compared with times in the 3 other groups.45 In a postscript, the in-
vestigators conceded that a major obstacle in operating a program like ADVANCE was
the large operational costs.
The effects of information or preparation programs for parents have also been stud-
ied. In a randomized study, discussing either routine or detailed anesthetic risk infor-
mation and discussion regarding their child’s anesthetic did not affect anxiety levels
8 Banchs & Lerman
before the surgical intervention, on the day of surgery in the holding area, after sepa-
ration from their child, or immediately after the intervention.46 The results were unaf-
fected by both parental educational level and baseline parental anxiety.
Preoperative preparation programs to decrease preoperative anxiety in children can
also reduce parental anxiety.43 Parents who watched a preanesthetic video to facili-
tate parental education and anxiolysis before pediatric ambulatory surgery were
less anxious compared with the control group.47 Preoperative preparation programs
also increase parental satisfaction.43 For example, children of parents who had
acupuncture demonstrated more anxiolysis and were more cooperative during the in-
duction of anesthesia compared with those whose parents had sham acupuncture.31
Moreover, the parents who received acupuncture were significantly less anxious than
parents in the sham group.31 However, in 2 trials that reported the impact of audiovi-
sual aids on preoperative and postoperative outcomes, preoperative videos did not
significantly affect the anxiety of either the child or the parent.31
PERIOPERATIVE INTERVENTIONS
The perioperative dialogue is a holistic intervention aimed at reducing perioperative

anxiety in children. Perioperative dialogue is based on the beneficial effects of dia-
logue and continued support throughout the perioperative encounter.48,49 In children
undergoing ambulatory surgery, perioperative dialogue reduces perioperative anxiety
as determined by salivary cortisol concentrations and decreases postoperative
morphine consumption.49
PHARMACOLOGIC ANXIOLYSIS
Midazolam
The use of pharmacologic premedication varies widely among practices, age groups,
and geographic location.24 The most commonly used agent for anxiolysis is midazo-
lam. The major appeal of oral midazolam stems from its safety record, effectiveness,
and reliability in reducing preoperative anxiety in children. The only substantive draw-
back of oral midazolam is its bitter taste, which may cause children to refuse to finish
drinking it or to cause them to expectorate it.
Randomized controlled trials have established midazolam’s effectiveness as a
preoperative anxiolytic in children.50–57 The dose of oral midazolam has not been
clearly understood over the ages of children who need it, and this has led to underdos-
ing or prolonged times to reach maximum effect. Most clinicians administer doses of
0.5 mg/kg without regard for the child’s age. The dose of oral midazolam for anxioly-
sis, analogous to inhalational anesthetics, increases with decreasing age. That is, a
dose of 0.5 mg/kg will suit children aged 3 to 5 years, but for children aged 1 to 3 years,
doses as large as 0.75 or 1 mg/kg may be required to achieve anxiolysis in 95% of chil-
dren. This point has been studied from at least 2 perspectives, the pharmacologic and
the neurobehavioral.58,59 To ensure a greater than 95% success in anxiolysis for chil-
dren 3 years or younger, a dose of 0.75 mg/kg should be administered. This dose usu-
ally achieves a maximum effect within 10 to 15 minutes. For older children, an oral
dose of 0.4 mg/kg is suitable for children 6 years or older and a dose of 0.3 mg/kg
for those 10 years or older.
In addition to decreasing perioperative anxiety, midazolam decreased the incidence
of negative behavioral changes, including separation anxiety and postoperative eating
disturbances,57 although in one study, it actually increased negative postoperative be-
haviors.56 Preoperative midazolam may decrease the incidence of negative behavior
by 2 postulated mechanisms, either by reducing preoperative anxiety or by causing
anterograde amnesia.60 Midazolam has been shown to confer anterograde amnesia in

as little as 10 minutes.60 No serious complications have been reported after oral mid-
azolam administration in doses between 0.2 and 1.0 mg/kg,50,51,53–57 although 2 chil-
dren experienced dysphoric reactions after 0.75 and 1.0 mg/kg oral midazolam.52
Children with sleep-disordered breathing undergoing tonsillectomy have been given
premedication with oral midazolam, 0.5 mg/kg, without serious sequelae. In an obser-
vational study, one of the 70 children who were enrolled experienced a transient desa-
turation to 77% for 5 seconds, awakening from the midazolam spontaneously, without
stimulation or other intervention.61
The effects of midazolam on the quality of emergence, discharge times, and postop-
erative behavioral disturbances have also been studied yielding conflicting results.62
Oral midazolam in a dose of 0.5 to 0.75 mg/kg delayed recovery from anesthesia in
3 studies,50–52 but another study found no delay in recovery and hospital discharge
after 0.2 to 0.3 mg/kg of oral midazolam in surgeries lasting 10 minutes.54 In a study
that compared oral midazolam, 0.5 mg/kg, with PPIA, children who received midazo-
lam were less anxious on entering the operating room and at induction of anesthesia
compared with those with PPIA.23 The times to recover from anesthesia and the inci-
dence of negative behavioral changes were similar in the 2 groups.23 Parental anxiety
was significantly less when children who received midazolam were separated from
their parents. In children undergoing an inhalational induction, oral midazolam was
more effective in reducing preoperative anxiety than PPIA.23 When oral midazolam
(0.5 mg/kg) was compared with oral midazolam plus PPIA,63 the incidence of periop-
erative anxiety was similar in the 2 groups. Parental anxiety postinduction was reduced
and satisfaction with the perioperative process increased in the midazolam/PPIA
group compared with the midazolam only group.
Midazolam has also been administered intranasally (IN) in a dose of 0.2 to 0.3 mg/kg
in a 0.5 mL volume, with a time to peak effect of 15 minutes but a 2.5-hour elimination
half-life.64,65 The most serious problem with this route of administration is a burning
sensation in the nasopharynx after recovery from anesthesia. Midazolam has also
been administered sublingually, rectally, and intramuscularly (IM), although these
routes offer no particular advantages in children.
Midazolam interacts synergistically with propofol to reduce the propofol require-
ments during induction of anesthesia, a characteristic attributed to midazolam’s
effects on the g-aminobutyric acid (GABA) receptors.63 Midazolam also provides
more favorable conditions for inserting laryngeal mask airways in the presence of
propofol.66 Both characteristics have been cited as advantages to using midazolam
for anxiolysis in the perioperative period.
Other Pharmacologic Agents

Clonidine, dexmedetomidine,67 ketamine, and sufentanil have all been used as anxio-
lytics in the preanesthetic period. Clonidine is an a2-adrenergic agonist with analgesic,
anxiolytic, and sedative properties and decreases the anesthetic and postoperative
analgesic requirements.68 Despite these properties, children who were scheduled
for tonsillectomy surgery and who were premedicated with clonidine (4 mg/kg)
exhibited more anxiety during separation from their parents, increased opioid require-
ments postoperatively, and greater postoperative pain scores compared with those
who were premedicated with oral midazolam (0.5 mg/kg).69 In a meta-analysis of 10
studies of healthy children undergoing ambulatory surgery who were premedicated
with oral clonidine, a dose of 2 to 4 mg/kg decreased both anxiety at induction of
anesthesia and the incidence of ED.70 This meta-analysis neither addressed the effects
of preoperative clonidine for surgeries of prolonged duration nor did it stratify for
10 Banchs & Lerman
confounding factors such as the effects of clonidine on postoperative nausea and

vomiting (PONV).70 The major advantages of the a2-agonists include an absence of
respiratory depression and fewer paradoxic reactions compared with midazolam.
However, there are several major disadvantages of clonidine use, including its slow
onset of action (>60 minutes), prolonged duration of action, and its sedation effects.
At a dose of 4 mg/kg, the clinical effects and peak blood concentration of oral clonidine
occur at 60 and 90 minutes, respectively.69 This slow onset of action precludes the use
of clonidine in many busy ambulatory pediatric anesthesia practices.
Dexmedetomidine is another a2-adrenergic agonist that has also been used for
preoperative anxiolysis. Its a2 receptor specificity is 8-fold greater than for clonidine,
reducing the frequency of side effects.71,72 Despite dexmedetomidine’s slow onset
time (30–60 minutes), its duration of action (85 minutes) is less than that of clonidine,
which makes it a candidate for use in ambulatory surgery. IN dexmedetomidine has
also been used for premedication in children. IN dexmedetomidine, 1 mg/kg, provides
more effective sedation than oral midazolam, 0.5 mg/kg,71,73 or oral dexmedetomi-
dine, 1 mg/kg. In a dose response study of IN dexmedetomidine, 2 mg/kg provided
better sedation in children 5 to 8 years old than 1 mg/kg. In children 1 to 4 years old,
1 or 2 mg/kg provided equivalent anxiolysis.74 To further exploit combination pre-
medications, the combination of IN dexmedetomidine (2 mg/kg) and oral ketamine
(3 mg/kg) provided easy separation from their parents, accepted IV cannulation,
and did not lead to side effects and postoperative complications when compared
with smaller doses of IN dexmedetomidine, larger doses of ketamine, and oral
ketamine alone (5 mg/kg).75
Ketamine has been developed as a premedication for cognitively impaired children
who are uncooperative and for healthy unimpaired children. For cognitively impaired
children, IM ketamine, 2 to 5 mg/kg, is administered from a stock solution of
100 mg/mL. It has an onset time of approximately 10 minutes. The children should
be seated on a gurney before IM ketamine is administered to avoid having to lift the
child from the recumbent position once the child is completely unconscious. Oral
ketamine (5–6 mg/kg) was developed as an alternative to oral midazolam, although
emesis has proven to be a problem with ketamine.76 Some prefer a 50–50 mixture
of midazolam (0.3 mg/kg) and ketamine (3 mg/kg) to mitigate the side effects of the
medications.77
IN sufentanil (2 mg/kg) is an effective premedication, although one study reported a
23% incidence of desaturation (<90%).78 Chest wall rigidity occurred in 45% of
children after administration of 4.5 mg/kg IN.79
ADDITIONAL NONPHARMACOLOGIC STRATEGIES
Several nonpharmacologic strategies have been found to be effective for anxiolysis in

children. Clowns, hypnosis, low sensory stimulation, and handheld video games all
reduce preoperative anxiety. In a systematic review of 17 trials involving 1796 children,
anxiolysis after several nonpharmacologic strategies was evaluated.31 Video games
given to children in the preoperative period significantly reduced anxiety at induction
compared with no intervention or premedication. Clowns have also been shown to
reduced anxiety in children. In contrast, hypnosis and music therapy did not reduce
anxiety at induction of anesthesia.31 PPIA caused no anxiolysis in 8 trials and
was significantly less effective as an anxiolytic than oral midazolam in one study.31
Other distraction techniques such as playing with a favorite toy, viewing animated
cartoons, listening to humorous stories, role playing, creative reinterpretation of the
environment, and magic tricks reduced anxiety and increased the level of
cooperation compared with controls.80–82 Certain provider behaviors have been

shown to exacerbate anxiety. Repetitive reassurance, excessive talk, apologizing,
and adult-appropriate medical explanations all increase perioperative anxiety in chil-
dren,83 although parental reassurance may not prove to be as harmful as originally
believed.84 Other language such as empathy, distraction, and assurance may be
effective to promote coping.83 To address this issue and to train health care providers
to improve their behaviors, the Provider-Tailored Intervention for Perioperative Stress
(P-TIPS) was developed to promote children’s coping and decrease behaviors that
may exacerbate children’s distress. In a trial of the effectiveness of P-TIPS, the rate
of desired behaviors increased and the rate of undesired behaviors decreased in par-
ticipants compared with control.85 Furthermore, parents who were in contact with
trained providers also demonstrated an increase in their rates of desired versus unde-
sired behaviors.85 The study of the effectiveness of P-TIPS in preventing anxiety and
improving the recovery process (in terms of postoperative pain, recovery room stay,
nausea and vomiting, ED, maladaptive behavioral change, and parental anxiety and
satisfaction) in children undergoing surgery is currently underway.86
ED
Definition and Incidence
ED is a complex of perceptual disturbances and psychomotor agitation that occurs
most commonly in preschool-aged children in the early postanesthetic period. The
term ED is often used interchangeably with emergence agitation and postanesthetic
excitement. For the purposes of this review, the authors refer to this complex as ED.
ED has been defined as a dissociated state of consciousness87 in a child who is
crying, inconsolable, and thrashing. In this state, children typically do not recognize
familiar objects or people such as parents or caregivers.87 It occurs in the recovery
room, in the early recovery period. Wells reported paranoid ideation as a component
of ED in an adult and children.88 In general, combative behavior more aptly describes
the behavior found in children with ED rather than restlessness and incoherence.89 The
authors define ED as “a disturbance in a child’s awareness of and attention to his/her
environment with disorientation and perceptual alterations including hypersensitivity to
stimuli and hyperactive motor behavior in the immediate postanesthesia period.”90 The
time course of ED usually begins as the child awakens from general anesthesia (typi-
cally in the first 30 minutes of recovery), lasts 5 to 15 minutes, and resolves spontane-
ously. The incidence of ED ranges from 5.3% to 50% and depends on several factors:
the metric used to measure it, age group, anesthetic technique, and type of surgery.91
ED is a cause for concern because it may result in injury to the child, disruption of the
surgical site, and accidental removal of the IV catheter and surgical drains. In addition,
a child experiencing ED requires extra nursing care and may require the use of supple-
mental sedatives that may delay discharge from the recovery room. The underlying
cause of ED has not been clearly elucidated. Several factors have been suggested
as potential causes of ED, including factors related to patient characteristics, anes-
thetic technique, and type of surgery.
Assessment Tools
More than 16 rating scales have been used to measure ED. The lack of consensus on a
single tool with which to assess ED demonstrates the inherent difficulty in interpreting
maladaptive behavior in small children, and especially in children who are not able to
verbalize pain or anxiety. Most scales assess emotional distress and agitation, which
are associated features rather than core features of a true ED.92 Crying, agitation, and
12 Banchs & Lerman
lack of cooperation have been included in several scales, but these behaviors are not
specific to ED. They may also characterize children who are in pain, as many are after
surgery, or who are frightened during the early emergence period from general anes-
thesia.90 These behaviors do overlap with behaviors measured in behavioral pain
scales such as the Faces Legs Activity Cry and Consolability scale, the Children’s
and Infants’ Postoperative Pain Scale, and the Children’s Hospital of Eastern Ontario
Pain Scale.92 Hence, it is fair to state that agitation does not always indicate ED.
However, agitation and thrashing requiring restraint93,94 are the most frequently
used parameters to define ED in children.95–97
The PAED scale was developed to specifically assess ED in young children. It con-
sists of 5 psychometric items: the child makes eye contact with the caregiver, pur-
poseful movement, awareness of the surroundings, restlessness, and whether the
child is inconsolable. Items are each scored on a scale from 0 to 4. When the total
score exceeds 10, ED is likely present, although some have suggested that a score
greater than 12 more likely confirms ED. The PAED scale has good reliability and val-
idity, having been used in more than 90 studies to date.90 A PAED score of 5 does
not mean there is half a chance of ED, but rather any score less than the threshold
of 10 (or 12) has no meaning in terms of ED. PAED has been compared with other
scores98,99 with variable results.100
Efforts have been undertaken to further refine the behaviors associated with ED.
Activity; nonpurposefulness; eyes averted, stared, or closed; no language; and
nonresponsivity appears to be significantly associated with ED.92 These behaviors
are not significantly associated with pain or tantrum and are believed to reflect the
true Diagnostic and Statistical Manual of Mental Disorders IV/V diagnostic criteria
for delirium. A logistic regression showed that eyes averted or stared and nonpurpose-
fulness were significant predictors of ED, whereas no language and activity did not
significantly predict ED.92
Causative Factors
Age
Children between the ages of 2 and 5 years are more likely to experience ED on recov-
ery from general anesthesia, with no gender predeliction.95 The psychological imma-
turity of a child’s nervous system and the rapid awakening from general anesthesia in
an unfamiliar environment may be responsible for the genesis of ED.95 It has also been
proposed that delirium in children and in the elderly may have a similar pathway.101
Immaturity of the cholinergic centers and the hippocampus and low levels of neuro-
transmitters may provide an explanation for the susceptibility of younger children to
ED.101 It has been suggested that the GABAA receptor could be excitatory rather
than inhibitory in early infancy, explaining this paradoxic reaction to anesthesia in
young children. As the child matures, the GABAA receptor transforms into an inhibitory
neurotransmitter, and the reaction no longer occurs, as in the adult.102 These recep-
tors could be excitatory rather than inhibitory in early infancy because of a switch from
high to low chloride content in the neurons.102 Other evidence, however, provides a
conflicting view leaving the mechanism behind the ED behavior unexplained.103
Preoperative anxiety and temperament

Preoperative anxiety has been associated with an increased likelihood of a restless
recovery and postoperative maladaptive behaviors. However, a clear relationship be-
tween preoperative anxiety and ED has not been established. The odds of experiencing
ED increases 10% for each increment of 10 points in a child’s preoperative anxiety
score (mYPAS).104 The odds ratio of having new-onset postoperative maladaptive
behavior is 1.43 for children with marked ED, as compared with children with no symp-
toms of ED.104 A 10-point increase in the preoperative anxiety scores increase the odds
that a child will have a new-onset maladaptive behavior after surgery by 12.5%.104
Despite these data, a statistically significant relationship between preoperative anxiety
and postoperative maladaptive behaviors such as ED remains unconfirmed.104
It is likely that the underlying emotional temperament of a child determines his
responses to outside stimuli and the degree to which preoperative anxiety and
postoperative agitation are manifested. Children who are emotional, impulsive, or
withdrawn104 are at increased risk for developing ED.
Anesthetic technique
ED has been reported in children after both inhalational and intravenous anesthesia.
Sevoflurane, desflurane, isoflurane,5,16,20,51 and to a lesser extent halothane93,105
have all been implicated as causative agents for ED. Most of the intravenous agents
(midazolam, remifentanil, propofol, ketamine, and barbiturates) have also been asso-
ciated with ED, although the incidence with these latter agents is far less than it is with
inhalational anesthetics. Research into the etiology of ED has been made difficult
when investigators have selected a surgical model that is associated with pain in
the recovery room, a behavior that is often difficult to distinguish from ED, and
when scales are used to diagnose ED that have not been validated to measure ED.
In children undergoing magnetic resonance imaging (MRI), the incidence of ED after
use of sevoflurane may be up to 7-fold greater than with that of halothane. ED occurs
more commonly after ether inhalational anesthetics than after alkanes like halo-
thane,89,94–97,106–115 suggesting that this is a class action. Considering that the
electroencephalogram changes that are associated with sevoflurane are similar to
those observed with either desflurane or isoflurane116 but different from halothane,117
it is possible that ED is related to the interference with the balance between neuronal
synaptic inhibition and excitation in the central nervous system produced by the ether
anesthetics.118
Sevoflurane has been shown to potentiate GABAA-receptor-mediated inhibitory
postsynaptic currents at high concentrations and to block these currents at low con-
centrations.119 This biphasic effect of sevoflurane on GABAA–receptor-mediated post-
synaptic currents may be a contributing factor to the genesis of ED in young children.120
Specific brain metabolites may also contribute to ED in young children. The meta-
bolic signature of sevoflurane shows greater brain concentrations of lactate and
glucose than that of propofol. Lactate and glucose correlate positively and total
creatine negatively with ED.121 The association between ED and serum lactate con-
centration suggests that anesthesia-induced enhanced cortical activity in the uncon-
scious state “may interfere with rapid return to coherent brain connectivity patterns
required for normal cognition upon emergence of anesthesia.”121
Several other factors have also been implicated as causes of ED. Depth of anes-
thesia122 and rapid awakening112,114,123–127 were postulated as contributing factors,
but subsequent studies determined they were not associated with ED. Although
some have suggested that the type of surgery (such as head and neck) may be asso-
ciated with ED, there is no evidence to support this claim either.128
Pain
The presence of postoperative pain may contribute to the genesis of ED in preschool-
aged children. Several studies reported that the incidence of ED in children decreased
after analgesic/sedatives were administered intraoperatively. For example, the inci-
dence of ED in children who were anesthetized with halothane or sevoflurane
14 Banchs & Lerman
decreased 3- to 4-fold when ketorolac was administered intraoperatively.111 Similarly,

ED was prevented when fentanyl, 1 or 2.5 mg/kg, was administered intraoperatively to
children undergoing ambulatory surgery, although the fentanyl preserved the rapid
recovery associated with desflurane anesthesia.98,129 The incidence also decreased
after IN fentanyl was administered intraoperatively.99,130 The incidence of ED
decreased after administration of clonidine 3 mg/kg IV or via the caudal space131 or
2 mg/kg IV132 and dexmedetomidine 0.2 mg/kg IV. The possibility that these analgesics
sedate the child to prevent or attenuate ED rather than provide pain relief has not been
clarified. To further investigate the role of pain in this phenomenon, the incidence of
ED has been determined in children aged 1 and 6 years undergoing inguinal hernia
repair. Two studies demonstrated that agitation occurred significantly more
frequently after use of sevoflurane anesthesia than that of halothane anesthesia
despite the presence of an effective but preemptive caudal block.95,97 Similarly, the
incidence of ED after sevoflurane or desflurane was similar when analgesia was pro-
vided by a caudal block.133 However, to completely remove pain as a confounding
variable, the incidence of ED was determined in children undergoing diagnostic
MRI. ED occurred in 33% of young children anesthetized with sevoflurane compared
with 0% of those anesthetized with halothane.96 The same group determined that the
incidence of ED decreased from 56% to 12% when IV fentanyl, 1 mg/kg, was admin-
istered to children anesthetized with sevoflurane for MRI 10 minutes before discontin-
uation of the anesthetic suggesting the sedative effect of fentanyl may be contributory
to attenuating ED.129
Inadequate pain control remains a potential cause of or contributor to the incidence
of ED after brief surgical procedures for which the peak analgesic effect of the agent
administered is delayed until the child is awake.111 Although pain cannot be entirely
excluded as a contributing factor to the presence of ED, current evidence suggests
the influence of other mechanisms in the cause of ED. It is likely that several factors
combined and specific characteristics of a child’s temperament contribute to the
development of ED.
PREVENTION AND TREATMENT OF ED
The only strategy that could prevent ED from occurring at all is to use a total intravenous
anesthetic approach for the anesthetic procedure. The authors generally use a propofol
infusion, supplemented with opioids and/or midazolam, with analgesia provided by
either a regional block or opioid. This approach may be supplemented with nitrous
oxide as well. Using this technique, the incidence of ED approaches zero.
Propofol, either as a single bolus or administered as an infusion has been shown to
decrease the incidence of ED after sevoflurane anesthesia.134,135 Preoperative admin-
istration of midazolam may decrease the incidence of ED,69,94 although the evidence
is still conflicting.103,134,136 Clonidine137,138 and dexmedetomidine139,140 have also
been noted to decrease the incidence of ED. Clonidine may exert its effect centrally
by reducing the noradrenaline content in adrenergic areas of the brain observed
with all the inhaled anesthetics. This increase in noradrenaline content is prominent
during sevoflurane or isoflurane anesthesia and persists in some areas of the brain
during the recovery phase.132 Magnesium sulfate infusion reduces the incidence of
ED during tonsillectomy in children with a number needed to treat of 3.141 Chloral hy-
drate has not shown to decrease the incidence of ED.142 Preemptive analgesia with
opioids, ketorolac, and a2-agonists and regional anesthesia have all been shown to
decrease the incidence of ED in children. Their effects may be due to combinations
of analgesia and sedation.97,98,111,131,132,143–146 Melatonin,147 oxycodone,148 oral
ketamine,149 and oral transmucosal fentanyl citrate150 have also been used to
decrease the incidence of ED. Remifentanil151,152 however, has yielded conflicting ef-
fects on the incidence of ED. A meta-analysis134 of the pharmacologic prevention of
ED after sevoflurane and desflurane in children reported that propofol, ketamine, fen-
tanyl, and preoperative analgesia successfully prevented ED.
The decision to treat ED in the recovery room is often influenced by the severity and
duration of the symptoms and by concerns over the safety of the child, disruption of
the surgical site, and the accidental removal of IV access and drains. There is no ev-
idence, however, that if left untreated ED has long-term sequelae in children. However,
steps should be taken to protect the child from self-injury and to provide a quiet and
dark environment where the child can recover. Parental presence has not been shown
to affect either the incidence or the severity of ED, except in one study.153 If parents
are present during ED, they should be appropriately reassured and be made aware
that the situation is self-limiting and that the child will return to his or her normal
behavior in due course. If treatment of ED becomes necessary, a single bolus of
propofol (0.5–1.0 mg/kg IV),134,135,154 fentanyl (1–2.5 mg/kg IV),129,143 or dexmedeto-
midine (0.5 mg/kg IV)134,139,140 has been successful in decreasing the severity and
duration of the episode.
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873–9.
A n e s t h e s i a a n d Se d a t i o n O u t s i d e
the Operating Room
a b c,
Katrin Campbell, MD , Laura Torres, MD , Stephen Stayer, MD *
KEYWORDS
Pediatric Anesthesia Sedation Procedure suite Pediatric radiology
Quality improvement
KEY POINTS
The volume and clinical complexity of patients requiring procedures outside the operating
room (OR) continues to increase.
The demand for pediatric sedation is too great for pediatric anesthesiologists to exclu-
sively deliver procedural sedation for healthy children outside the OR.
The decision to deliver a general anesthetic with a secured airway versus deep sedation
for most procedures outside the OR is based on special requirements for the procedure,
the pain of the procedure, the child’s comorbidities, and the experience and comfort of the
anesthesiologist with deep sedation techniques.
Risk related to sedation and anesthesia outside the OR can be broken down into inade-
quate sedation, oversedation/adverse response to sedatives, and failure to rescue.
Hospital systems are benefited by anesthesiology participation and leadership of a seda-
tion committee, whose charter is the oversight of effective, efficient, and safe sedation
throughout the institution.
INTRODUCTION
The provision of anesthesia and sedation for children undergoing procedures outside
the operating room (OR) continues to evolve. The volume of invasive and noninvasive
procedures is increasing, as is the clinical complexity of patients requiring these pro-
cedures.1 Practices strive to eliminate the use of physical restraints for painful and
frightening procedures. In addition, the requirements for appropriate personnel to
administer and monitor sedation have dramatically changed. It is no longer acceptable
to administer a cocktail of meperidine, promethazine, and chlorpromazine in an un-
monitored environment. As an example of growth, at our institution, 2578 patients
a
Division of Sedation, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin St, Suite
A300, Houston, TX 77030, USA; b Department of Pediatrics, Sedation Oversight Committee, Texas
Children’s Hospital, Baylor College of Medicine, 6621 Fannin St, Suite A300, Houston, TX 77030,
USA; c Pediatric Anesthesiology, Texas Children’s Hospital, Baylor College of Medicine, 6621
Fannin St, Suite A300, Houston, TX 77030, USA
* Corresponding author.
E-mail address: sstayer@bcm.tmc.edu

26 Campbell et al
received anesthesia or deep sedation outside the OR in 2003, representing 11% of

total cases; by 2012, that number had increased to 8695 (24% of cases).
In contrast to OR anesthesia, the approach to providing sedation and anesthesia
outside the OR varies among institutions and even among different providers in
the same institution.2–7 Anesthesia providers are commonly requested to care for chil-
dren who need sedation, but have significant comorbidities, such as obstructive sleep
apnea, obesity, craniofacial abnormalities, and significant pulmonary or cardiac dis-
ease. Many (nonanesthesia) pediatric specialists provide procedural sedation, with
similar goals of analgesia and immobility to optimize procedural conditions. In order
to accomplish these goals, pediatric sedation practitioners administer sedative and
anesthetic medications that produce deep sedation. There is controversy about the
training and qualifications of sedation specialists. There is also controversy about
the types and doses of anesthetic medications that they administer. Anesthesia
departments have a responsibility to their institutions to ensure the safe and effective
delivery of sedatives and anesthetics, no matter the location or the personnel, and fed-
eral authorities dictate that anesthesiologists should provide oversight and credential-
ing of sedation practices.8,9 Failed sedations frustrate families and add cost, and
therefore, sedation services must also develop practices to minimize this occurrence.
The demand for pediatric sedation is too great for pediatric anesthesiologists to exclu-
sively deliver this care. In addition, fellowship trained pediatric anesthesiologists are
skilled in providing anesthetic management of children with life-threatening medical
conditions undergoing complex surgical procedures (eg, a child undergoing repair
of a diaphragmatic hernia while supported with extracorporeal membrane oxygena-
tion). Using such highly trained specialists to provide sedation for an otherwise healthy
child could be considered a wasteful use of resource.
GOALS
The goals for procedural sedation/anesthesia are7:

First, ensure safety.
The anesthesia provider should be trained in administration of sedative med-
ications and rescue from adverse events.
The anesthesia provider is not the individual performing the procedure.
The anesthesia provider administers medications and monitors and records
vital signs.
Careful monitoring should continue after the procedure until discharge criteria
have been met.
Minimize pain and discomfort.
Minimize psychological discomfort and anxiety for both the patient and family.
Control movement to optimize imaging studies and to improve safety for invasive
procedures.
Develop systems that are efficient and cost effective for the patient and for the
health care system.
ANESTHESIA VERSUS SEDATION
The decision to deliver a general anesthetic with a secured airway versus deep seda-
tion for most procedures outside the OR is based on special requirements for the pro-
cedure (breath holding), the pain of the procedure, the child’s comorbidities, and the
experience and comfort of the anesthesiologist with deep sedation techniques. Even
though strong evidence supporting a particular technique is lacking, anesthesiologists
Anesthesia Outside the Operating Room 27
should consider the advantages of providing sedation for many procedures and not
simply use general endotracheal anesthesia for every patient. The anesthesia provider
should choose a technique that best meets the goals, as stated earlier. For example,
the laryngeal mask airway (LMA) can be used to maintain a patent airway with spon-
taneous ventilation and requires a lower dose of anesthesia, and, therefore, there is a
more rapid emergence from anesthesia. Patients with upper respiratory tract infec-
tions, and those with asthma, may have fewer respiratory complications when an
LMA is used.10 Patients undergoing imaging studies who do not have a history of
airway compromise can be managed with a natural airway and a shoulder roll with
slight head extension to maintain pharyngeal patency during deep sedation. Propofol
is one of the shortest-acting anesthetics and has been used as an antiemetic; there-
fore, this technique may be optimal in terms of recovery characteristics. A propofol
infusion for these procedures with routine noninvasive monitors and nasal cannula
CO2 monitoring can provide a safe and efficient method of providing a motionless
examination. If the child develops some degree of airway obstruction not relieved
by improved positioning and an oral airway, an LMA can be used. The anesthesiologist
has the means of providing immediate tracheal intubation to safely complete the im-
aging study. It is challenging to clearly distinguish deep sedation versus general anes-
thesia in a spontaneously breathing patient receiving a propofol infusion for imaging
studies. Therefore, in our institution, we differentiate deep sedation from general anes-
thesia by the need for an invasive airway device (LMA or endotracheal tube [ETT]). Pa-
tients managed with a nasal cannula and propofol infusions are classified as
undergoing deep sedation, no matter the dose of propofol.
PATIENT PREPARATION
A complete evaluation of the patient is paramount to conducting a safe procedure.

This strategy is essential for every patient managed in the OR but is absolutely
required in a procedure outside the OR, where limitation of space and challenging ac-
cess to ancillary services (blood bank, pharmacy) and emergency personnel may
exist.
A thorough evaluation of the patient’s clinical history must include:
Current medical or surgical diagnosis requiring the scheduled diagnostic or ther-
apeutic procedure
Current clinical condition of the patient with respect to hydration, airway compro-
mise, respiratory symptoms, cardiac hemodynamics, hematologic status, infec-
tious disease, mental status, and immunologic risk
Review of past medical history
Review of previous procedures requiring anesthesia or sedation and noted
complications
Current and recent medications, including other sedative/analgesic drugs; in a
study analysis of 264 preventable and potential adverse drug events,11 lack of
patient information accounted for 18% of errors
Review of allergies to medicines, latex, and foods
Review of laboratory data and imaging studies
Plan for additional laboratory analysis, imaging studies, or other diagnostic tests
to reduce risk
A physical examination, with focus on the airway, lungs, heart, and neurologic sta-
tus, must be performed. The specific procedure determines additional aspects of the
physical examination, which must be assessed.
28 Campbell et al
Careful attention to fasting status must be made. Except for emergency procedures,
the standard American Society of Anesthesiologists (ASA) nil-by-mouth guidelines
should be followed to avoid the risk of aspiration. An exception to these guidelines
should be considered for patients undergoing computed tomography (CT) scanning
of the abdomen with oral contrast. In our institution, we proceed with sedation/anes-
thesia 1 hour after ingestion of oral contrast. Although it is controversial, suboptimal
CT images are commonly obtained from a prolonged delay after contrast ingestion,
requiring a repeat of the CT scan, with the associated radiation exposure. We have
used this shortened fasting guideline in CT for the past 7 years without a single inci-
dence contrast aspiration.
Informed consent should include detailed information about planned management,
concerns, potential risks, and benefits. The anesthesiologist should also include an
explanation of the potential need for deepening sedation, inducing general anesthesia
and placing an airway device, should the need arise.
To reduce the risk of postprocedure adverse behavior, the administration of an-
xiolytic or analgesic medications should be considered. A variety of distraction
techniques that alleviate the stress of separation may also be used. Although the op-
portunity to induce deep sedation or general anesthesia with parental presence may
be limited in many OR settings, the remote anesthesia site can commonly accommo-
date parental presence.
The Universal Protocol (preprocedure verification, site marking, and time-out)
mandated by the Joint Commission and performed in the OR environment must be
adopted in sites outside the OR.
SPECIFIC EXTRAMURAL SITES AND BEST PRACTICES
Essentially, every medical system that manages pediatric patients undergoing inva-
sive procedures has developed unique processes to provide sedation for children.
Sedation is commonly provided in clinics, such as oncology, orthopedics, and dental;
on inpatient wards; in the emergency center; in burn centers; intensive care units; in
postanesthesia care units; in radiology areas and procedure suites. In order to provide
a safe environment for children undergoing deep sedation or anesthesia, these out of
OR areas should be set up to provide12:
Equipment and monitoring similar to the OR environment
Backup airway equipment such as oral and nasal airways, LMA, laryngo-
scopes and ETTs, and adequate suction
Standard ASA monitors including end-tidal CO2 (ETCO2) monitoring
Difficult airway cart
Malignant hyperthermia cart
Scavenging system
Anesthesia providers who are familiar with the environment and assistants, such
as nurse anesthetists, anesthesia technicians, sedation nurses, or respiratory
therapists to assist with patient management when needed
Effective communication system in order to obtain immediate skilled assistance
from the OR when needed
Radiology
The radiology suite is commonly the busiest remote anesthesia site. Providing anes-
thesia and sedation in this site creates many unique issues and challenges. Some
of the anesthesia equipment used in these locations must be modified or specially
ordered for the specific environment, and any practitioner providing sedation or anes-
thesia must be familiar with the specific constraints of each site. However, regardless
of the location, minimum standards for equipment, monitors, and conditions of anes-
thetic delivery set by the ASA must be in place. Specifically, the ASA requires off-site
locations to have 2 sources of oxygen, suction, a self-inflating hand resuscitator bag,
anesthesia machine with scavenging system for volatile agent administration, and
standard-of-care monitors and equipment. Anesthesiologists should be involved in
the development of these areas to ensure that standards are met as well as advocate
for adequate space for the various equipment, monitors, and induction/emergence
areas that are needed.
CT
CT uses ionizing radiation to differentiate between high-density and low-density struc-
tures.13 The growth of CT use in children has been driven primarily by the decrease in
the time needed to perform a scan (now <5 seconds, in some instances), largely elim-
inating the need for anesthesia to prevent the child from moving during image acqui-
sition. Situations in which sedation or general anesthesia may be required include
unstable respiratory or cardiovascular status, emergent situations (ie, head trauma),
uncooperative children (young age or developmental delay), unstable airways, and
the need for breath holding during imaging (ie, dynamic airway studies to evaluate
tracheobronchomalacia).
In many cases, distraction techniques (colored lights and toys) and parental pres-
ence may obviate anesthesia. Varying levels of sedation (minimal to moderate to
deep) can be accomplished using midazolam, propofol or dexmedetomidine.14
CT uses ionizing radiation

Procedures are short (uncommonly require sedation)
Oral contrast administered for abdominal CT requires a deviation from ASA nil-by-mouth
guidelines in order to obtain adequate imaging
Breath holding may be required for chest CT, which typically requires sedation and assisted
ventilation in younger patients
One area of controversy that anesthesiologists face in sedating children for CT is

necessary violation of nil-by-mouth guidelines with oral contrast administration. Gas-
trografin (Bristol-Meyers Squibb, Princeton, NJ), 3% concentration at full strength, is
hyperosmolar and hypertonic. If aspirated, it can cause pulmonary edema, pneumo-
nitis, and death. For this reason, it is diluted to an isotonic 1.5% solution before inges-
tion. Even so, to be effective, images must be taken between 30 and 90 minutes after
administration, falling outside usual nil-by-mouth guidelines of 2 hours for clear liquids.
In addition, the volume of contrast required can be large (60–90 mL in neonates and
250–350 mL in children aged 1–5 years). In these cases, there are no data to suggest
optimal sedation technique to account for theoretic aspiration risk. Care for these
patients includes intravenous (IV) sedation with spontaneous ventilation and natural
airway; inhaled induction and LMA placement; and rapid sequence induction and
endotracheal intubation.15
For CT scans of the chest or abdomen that require breath holding for optimal image
quality, anesthetic techniques include general anesthesia with volatile agents, mask
ventilation with intermittent hyperventilation, apnea breath holding, and general endo-
tracheal intubation with muscle relaxation. Because atelectasis is more frequent and
30 Campbell et al
severe in children undergoing general anesthesia compared with IV pentobarbital

sedation, consideration should be given to the use of forced inspiration in children
anesthetized for CT scan of the chest.16
Magnetic resonance imaging

Magnetic resonance imaging (MRI), including magnetic resonance angiography and
magnetic resonance venography, is rapidly becoming one of the most frequently
used diagnostic tools since its introduction in 1990. It is used in the diagnosis of neo-
plasms and vascular/cardiac malformations, evaluation of sleep apnea, developmental
delay, seizures, stroke, behavioral disorders, autism, hypotonia, and metabolic/mito-
chondrial disorders, as well as infectious processes such as meningitis/encephalitis,
osteomyelitis, and abscess formation.
One of the most commonly used imaging tools

Very strong magnetic field requires special safety precautions
Use of MRI-safe equipment
Screening of patient for potential implants
Most younger children require sedation for immobility
Persons inside the scanning room require auditory protection
Children with comorbidities should be managed by an anesthesiologist
The MRI system is a superconducting magnet that creates a variety of safety issues
not seen in other diagnostic/therapeutic areas. The strength of the magnetic field in
the scanner is measured in Tesla (T) or the equivalent of 10,000 G. The earth’s mag-
netic field is 0.5 G and the most common MRI machines are 1.5 to 3T. Thus, any ferro-
magnetic material brought near the machine becomes a major hazard, because it can
become a projectile from the strong attractive force created by the scanner (and the
magnet is always on). Additional patient injury can occur from implanted devices
such as cardiac pacemakers, spinal cord or vagus nerve stimulators, and programma-
ble insulin pumps or ventriculoperitoneal shunts, which may be affected by the mag-
net. Therefore, special MRI-compatible or MRI-safe equipment is frequently used in
these areas, and special screening of patients and employees must be carried out
before entering the scanner. The Web site http://www.mrisafety.com/ is a useful
resource to identify potential hazards. Auditory hazards are created from the loud
knocking sound produced by the scanner; therefore, any person remaining in the
scanner while it is running should have earplugs or headphones in place. Burns or
thermal injury can occur from coiled or frayed monitor cables (even if MRI safe),
MRI-unsafe electrocardiography leads, and skin contact with the MRI bore or cables
as they heat up during the scanning process.
MRI-compatible/MRI-safe equipment may not be available in every institution, and
special care with alternative methods must be taken to deliver a safe anesthetic.
Creating a hole in the console wall to thread necessary tubing (suction and medication
infusion tubing, ventilator circuit for an MRI-unsafe machine, ETCO2 monitoring tubing)
from outside the scanner to the patient is one option. On average, 9.15 m (30 ft) of
tubing is needed for each.17–19
Anesthetic care varies with practitioner preference, patient medical history, and
physical status, as well as availability of support staff and equipment. With the advent
of MRI-safe video goggles, many children are able to complete the examination
without sedation. When sedation is required, infusions with dexmedetomidine or pro-

pofol with spontaneous ventilation, nasal cannula O2 supplementation, and ETCO2 are
often used. General anesthesia with an LMA or ETT can be used, with careful taping of
the pilot balloon to the circuit to prevent artifact on images of the head or neck. Bivona
tracheostomy tubes may need to be replaced with MRI-safe tracheostomy tubes (ie,
Shiley) or ETTs, because the Bivona tube is not considered MRI safe by the US Food
and Drug Administration.
Interventional radiology
Interventional radiology (IR) procedures have definitely contributed to the expansion of
the anesthesiologist’s role in remote sites. With the recent advances in technology,
increasing numbers of patients are coming to radiology for a minimally invasive alter-
native to larger procedures performed in the OR. In addition, some of these patients
may be acutely ill, with a tenuous hemodynamic or respiratory status, and considered
too high risk for the surgical alternative. A variety of procedures are performed in the IR
suite, including peripherally inserted central catheter line placement, liver biopsies,
abscess drain placements, nephrostomy and chest tube placements, lumbar punc-
tures in morbidly obese patients, cerebral angiography and embolization, as well as
sclerotherapy for vascular and lymphatic malformations. Unlike diagnostic radiologic
procedures, IR procedures can pose significant procedural-related risks, similar to
surgery performed in the OR. Preprocedural planning with the radiologist must occur.
In our institution, all members of the interventional team, including the anesthesiolo-
gist, radiologist, nurses, and technicians, meet to discuss each case in a morning
rounds session. Pertinent medical history and laboratory tests, planned procedure,
including required equipment and special medications that are administered by either
the radiologist or anesthesiologist, positioning, and any further testing or treatments
required to optimize the patient before arrival are discussed. Depending on the patient
status, planned procedure, need for absolute immobility or breath holding, anticipated
procedure length, and postoperative disposition, patients may be managed using a
range of techniques, from minimal IV sedation with spontaneous ventilation and nat-
ural airway to general anesthesia with LMA or ETT.
Many procedures are performed on very high-risk patients, because IR is less invasive than
surgery
Sclerotherapeutic agents used for vascular and lympathic malformation have potential side
effects
Cerebral angiography and embolization of vascular malformations can produce profound
hemodynamic changes
With sclerotherapy and embolization of arteriovenous and lymphatic malformations,

it is important to have an understanding of the various agents and their potential com-
plications. Ethanol, polyvinyl alcohol foam, bleomycin, doxycycline, sodium tetradecyl
sulfate, ethylene vinyl alcohol, cyanoacrylate glue, balloons, and coils have all been
used. Polyvinyl alcohol foam causes direct mechanical obstruction and is often
used for tumor embolization and preoperative devascularization of lesions but can
break down over time, causing recanalization of vessel.20 Coils need to be appropri-
ately sized for the vessel or arteriovenous malformation (AVM) that is targeted. A small
coil may embolize downstream; a large coil may herniate back into the parent vessel.
Ethanol destroys the endothelial lining of the vessel, causing immediate thrombosis.
32 Campbell et al
Systemic effects can include sedation or agitation, pulmonary hypertension, cardiac

arrhythmias, and complete cardiovascular collapse.21 Therefore, total dose should
be limited to 1 mL/kg, and additional sedatives and narcotics must be cautiously
administered. Hemolysis and subsequent hemoglobinuria are a concern, and careful
attention to fluid management with aggressive hydration to flush the kidneys must
occur to prevent renal injury or failure. Administering furosemide and sodium bicar-
bonate to alkalinize the urine may also be needed to reduce this risk. Bleomycin
has been known to cause pulmonary fibrosis and skin hyperpigmentation. In our insti-
tution, a no-sting barrier is used before placement of any adhesive materials on the
patient’s skin. Special Velcro-based ETT holders are used, and eyes are protected
with lubrication. Most sclerosing agents cause some degree of swelling. This swelling
may cause airway compromise in patients with head or neck involvement, warranting
extended intubation until resolution (Fig. 1).
Cerebral angiography is often used in the diagnosis and treatment evaluation for
various medical conditions, including aneurysm, arteriovenous malformation, stroke,
and vascular disease (such as moyamoya disease). It requires absolute patient immo-
bility and controlled ventilation with intermittent breath holding and therefore is
routinely performed under general endotracheal anesthesia. Consideration should
be given to arterial line placement for blood pressure monitoring in these patients,
especially when an intervention is anticipated. Maintaining normocarbia or even
slightly hypercarbic ventilation aids in radiologic visualization by dilating the cerebral
vasculature. Similarly, avoiding hyperventilation is important, especially in patients
with a history of transient ischemic stroke or moyamoya disease, because these pa-
tients are at higher risk for perioperative neurologic complications.
Nuclear medicine
Nuclear medicine studies are used in the diagnosis of multiple disease states, including
hematologic and oncologic processes and their response to treatment, localization of
seizure foci in intractable epilepsy, and assessment of benign and malignant bone
lesions, as well as assessing cardiac, renal, and thyroid function. Unlike other imaging
modalities that focus on structures, nuclear medicine studies give functional informa-
tion through the use of radioisotope medication uptake. About 90% of worldwide radio-
isotope use is for medical diagnoses. The most common radioisotope, used in about
80% of nuclear medicine studies, is technetium 99. With a half-life of 6 hours, it lasts
long enough to examine metabolic activity but short enough to minimize radiation
exposure to the patient. Even so, all radioisotopes produce waste products, which
require special handling and storage until stabilized. These materials include medical
waste such as syringes, paper, and cloth, as well as patient substances such as urine,
Fig. 1. Facial edema after sclerotherapy.

blood, and other bodily fluids. Therefore, all members of the patient care team should
be cognizant of potential exposure to radioactive materials, and safety training should
be instituted.20,22,23
Radioactive agents are administered before scanning, and patients may need sedation in a
warming room remote from the anesthesia provider
Requires remote monitoring setup
Commonly require long periods of sedation
Anesthesia providers are challenged with increasingly longer studies requiring

sedation or anesthesia and limited access to the patient during peak levels of potential
radiation exposure. Hybrid imaging (single-photon emission CT, positron emission to-
mography [PET] CT; PET MRI) is becoming standard in nuclear medicine. These
advanced imaging studies require longer time commitments (1–3 hours in some
cases) and are very sensitive to patient movement. Often, patients need to be sedated
for a warming phase, usually 30 minutes to 1 hour, after injection of the radioisotope
before the start of the examination. During this period, risk of radiation exposure is
high, and patients may be monitored from a remote location with closed circuit cam-
eras. There is some concern that with the prolonged sedations required, patients are
at higher risk of adverse outcomes. However, recent studies with propofol sedation for
examinations lasting longer than 1 hour did not have any significant increase in
adverse events compared with shorter studies.21 Alternatively, providers may wish
to use general anesthesia with an airway device (LMA or ETT) in place.
External beam radiation therapy

External beam radiation therapy (XRT) has become one of the cornerstone treatments
in the management of malignant lesions. A linear accelerator machine is used to accel-
erate electrons to a very high energy state and then collide with material such as tung-
sten, which then releases energy in the form of radiographs, which are then focused at
specific sites on the body to destroy tumor cells. The energy deposited into the tissues
is measured in units of gray (Gy), and equal to 1 J/kg. A typical course of treatment
involves 25 to 80 Gy divided into 30 equal portions, often once per day, over a 6-
week period. Although the procedure itself is short and painless, it requires complete
patient immobility to avoid damage to surrounding normal tissues. Initially, a planning
or simulation session is undertaken, in which a plaster immobilization cast of the pa-
tient’s head or torso is created to aid patient positioning for repeated treatments. This
session also allows the radiation oncologist to plan the number and location of sites to
be treated. Although this initial simulation can last from 20 to 90 minutes, the subse-
quent daily treatments usually last only 5 to 20 minutes and are therefore mainly per-
formed under deep sedation with nasal cannula O2. One exception is the treatment of
retinoblastoma, because complete immobilization of the globe and extraocular mus-
cles often requires muscle paralysis. Anxiolysis with midazolam or deep sedation with
propofol infusion can be used to accomplish XRT.24 Initial concerns for tachyphylaxis
to propofol have not been substantiated.25 Alternative medications used for XRT
include dexmedetomidine and ketamine. However, the prolonged time required to
bolus dexmedetomidine may inhibit its use for this brief procedure. The need for moni-
toring from a distance with telemetry and cameras makes this site uniquely chal-
lenging for the anesthesiologist. The typical configuration involves 2 cameras: one
34 Campbell et al
directed at the patient to assess respiratory effort and patient motion and one directed
at the monitors (and anesthesia machine, if general anesthesia is being used).
Patients require complete immobility

Daily treatments are common
Remote monitoring is necessary
Children commonly require monitored transport to a radiation center
Radiation therapy is also used in some operating arenas with either brachytherapy
(intercavity implantation of radioactive material), intraoperative radiation therapy
(IORT), and stereotactic radiosurgery.26 In IORT, the procedure begins in the OR,
where tumor debulking occurs. The patient is then transported to the XRT suite with
the surgical site exposed for treatment. The patient is then returned to the OR for sur-
gical closure. Stereotactic radiosurgery or Gamma Knife (Elekta Instruments, Stock-
holm, Sweden) surgery uses beams of g radiation to treat various malignancies,
arteriovenous malformations, and acoustic neuromas. The patient first has a stereo-
tactic frame placed over the head and secured in place with screws. They are then
transported to the MRI scanner, where three-dimensional reconstruction of the brain
and plotting of coordinates are performed. The patient is then taken to the Gamma
Knife unit for treatment. The head frame is removed, and the patient is taken to the re-
covery area. Although Gamma Knife surgery may occasionally be performed under
deep sedation, general anesthesia is most commonly used, because these cases
can last 9 to 12 hours. It is important to remember to transport the patient with equip-
ment to rapidly remove the head frame should access to the airway be required. Both
IORT and Gamma Knife procedures require a great deal of coordination among ser-
vices to complete.
Procedure Suite
Procedure suites have been historically established for the individual medical special-
ists whose teams are charged with performing procedures and administering sedative
medications to accomplish such procedures successfully. Although the volume of
patients needing timely procedures and the advancement of technology persists,
the complexity of patient clinical condition has resulted in the expansion of the anes-
thesiologist’s role in these sites. A properly designed procedure suite functions similar
to an OR. The design should take into account the need for patient admission and
evaluation, the tools and room design needed for specific procedures, and an area
for monitoring and observation during recovery. It is our opinion that procedure suites
provide a significant advantage in safety and efficiency for patients who require mod-
erate or deep sedation compared with a system in which the sedation practitioner
travels to the bedside or clinic. Invasive procedures such as gastrointestinal endos-
copy, bronchoscopy, bone marrow aspirations, lumbar punctures, dermatologic pro-
cedures, and kidney/liver biopsies are the types of procedures performed outside the
OR in specialized procedure suites. These procedures produce strong noxious stim-
ulation for children and therefore typically require deep sedation or general anesthesia.
In our institution, the choice of sedation provider is dependent on the child’s underly-
ing medical condition, the associated risks, and the duration of the planned proce-
dure. The ideal procedure suite provides the anesthesia practitioner with the option
of using the same techniques and monitoring that are available in an OR, with backup
equipment and support systems to treat procedural complications, such as the diffi-
cult airway, hemorrhage, anaphylaxis, and cardiac arrest. Considerations for some
of these procedures are discussed.
Upper esophagogastroduodenoscopy
Upper esophagogastroduodenoscopy (EGD) in infants and small children is most
commonly performed under general anesthesia with tracheal intubation to avoid
airway compression caused by the endoscope pressing the trachealis muscle into
the trachea. An LMA can be used; the cuff is deflated to allow passage of the endo-
scope and then reinflated once the scope has entered the esophagus. When the endo-
scopist passes the scope from the oropharynx into the esophagus, there is increased
risk of dislodging the LMA or ETT, and we suggest that the anesthesiologist should
hold on to the airway device during this portion of the procedure and when the endo-
scope is withdrawn.
Many healthy children can be deeply sedated

Most stimulation occurs during passage of the scope through the oropharynx into the
esophagus
Younger children (<10 years) and those with comorbidities should have an anesthesiologist
providing care
The use of total IV anesthesia has been described for these procedures and is espe-
cially useful in endoscopy suites that do not have adequate scavenging and ventilation
to allow the safe use of inhalational anesthetics.27–29 Propofol can be used alone30 but
is more commonly combined with an opioid such as fentanyl or remifentanil31,32 or
with ketamine.33 Outcomes after deep sedation with propofol versus inhalational
anesthesia were similar.28 The time to awakening was more rapid after the inhalational
anesthetic, yet the time to hospital discharge was greater. In the propofol group, the
incidence of agitation on emergence was less and the time to hospital discharge
earlier.
Sedating a child for EGD is particularly challenging, because introducing the scope
into the pharynx is stimulating and it must be removed in order to apply bag-valve-
mask ventilation. Topical local anesthetic spray can be used to reduce stimulation,
coughing, and gagging with introduction of the scope, and most patients require a
deep level of sedation during this portion of the procedure. Once the scope is in the
esophagus, the level of sedation can be reduced. These rapid adjustments in the level
of sedation are most easily accomplished by using infusions or small boluses of short-
acting sedatives and analgesics, such as propofol and remifentanil. Passing the scope
through the pylorus is also stimulating and often requires deepening the level of seda-
tion as well. Because the endoscope is passed through the oropharyngeal airway,
there is a higher risk of apnea, laryngospasm, bronchospasm, and airway obstruction
when these cases are performed without tracheal intubation. Early recognition and
treatment by removal of the endoscope and bag mask ventilation are generally effec-
tive, although tracheal intubation may be required.34 In addition to monitoring heart
rate, blood pressure, and oxygen saturation, capnography helps the anesthesiologist
recognize these airway-related problems and should be used routinely. At completion
of the procedure, the endoscopist should aspirate the air that has been introduced into
the gastrointestinal tract. Failure to do so may impair diaphragmatic excursion and
compromise ventilation after the procedure.
36 Campbell et al
In 2007, the PEDS-CORI (Pediatric Endoscopy Database System-Clinical Out-

comes Research Initiative [the pediatric component of a national registry of endo-
scopic procedures]),35 reported outcomes from data collected between 1999 and
2003. This report included data from 13 institutions involving 10,236 encounters.
The study found an overall complication rate of 2.3%, and of these 80% were cardio-
pulmonary complications. Children with complications were younger and had a
greater ASA physical status. There were fewer complications in patients who received
general anesthesia (1.2%) compared with those who underwent sedation (3.7%).
There are insufficient data to develop definitive guidelines, and many sedation prac-
tices use criteria to select patient for sedation that include ASA physical status 1
and 2, body mass index less than 95% for age, and weight more than 10 kg.
Bronchoscopy
Pediatric pulmonologists perform flexible bronchoscopy to evaluate a variety of respi-
ratory diseases in children. In 2003, the American College of Chest Physicians pub-
lished guidelines for interventional pulmonary procedures, leaving the choice of
anesthesia versus sedation or topical anesthesia to the interventionalist. However,
general anesthesia was recommended for pediatric bronchoscopic procedures.36
Deep sedation or general anesthesia with topical anesthesia can be provided with
the natural airway and nasal cannula for oxygen administration and CO2 monitoring,
or via facemask, LMA, or ETT. Many consider the LMA to provide ideal bronchoscopic
conditions, because the large shaft more easily accommodates the bronchoscope,
without significant compromise to gas flow, with ease of visualizing laryngeal function
and the ability to administer positive pressure ventilation when needed.
Various agents can be used, including potent inhaled anesthetics or short-acting IV
anesthetics, such as propofol, remifentanil, dexmedetomidine, fentanyl, and midazo-
lam. The most stimulating portion of the procedure is the introduction of the bronchos-
copy through the vocal cords, and the vocal cords are typically sprayed with lidocaine
before passing the scope through the vocal cords. Lidocaine itself commonly causes
coughing and may produce laryngospasm in lightly anesthetized patients. If the bron-
choscopist touches the carina, a cough reflex is often produced, which is sometimes
accompanied by bronchospasm. The anesthesiologist should be prepared to treat
bronchospasm by increasing the depth of anesthesia or the administration of inhaled
bronchodilators. In more severe cases, the procedure should be interrupted, the bron-
choscope removed, and bronchodilators administered. Inhalational anesthetics have
the added benefit of producing bronchodilation and ease of titration to alter the depth
of anesthesia. However, when compared with sevoflurane, and when remifentanil was
compared with propofol and remifentanil, the propofol group had less coughing and
faster return of ciliary function.37 Remifentanil, like all opioids, blunts airway reflexes
and, because patients generally do not have pain after the procedure, some consider
this the ideal opioid to use as an adjunct for these procedures.
BONE MARROW/LUMBAR PUNCTURE
Children with oncologic conditions frequently undergo brief, painful procedures such
as bone marrow aspiration and biopsy, and lumbar puncture. A single frightful or pain-
ful experience may have long-term effects, in which every subsequent procedure is
associated with fear and anxiety by the patient and family. Therefore, it is important
to develop a process that minimizes pain and distress for the child and family.
Some patients can be effectively managed with local anesthetics, distraction, and
minimal sedation or anxiolytic medications; others require a brief general anesthetic
in a procedure suite; and patients with underlying high-risk medical conditions are
managed in an OR. At Texas Children’s Hospital, we have developed and published a

clinical algorithm to assist the decision-making process regarding the type of sedation
and the optimal environment. We use an isolation room in our postanesthesia care unit
as a deep sedation suite, where propofol or remifentanil are generally administered by
an anesthesiologist (Fig. 2).38
Anesthesia providers should practice nonpharmacologic interventions that
decrease anxiety and distress, such as nonprocedural distracting talk (eg, talk about
friends, toys), humor, and medical reinterpretation (eg, reframing medical procedures
and equipment as something fun and positive). They should be trained to provide
developmentally appropriate procedural information. Undesired behaviors from the
health care team include reassuring statements, empathizing, and apologizing.39
Fig. 2. TCH Evidence-Based Outcomes Center Clinical Algorithm for Managing Painful Pro-
cedures in the Cancer Center. BMA, Bone marrow aspiration; BMI, body mass index; BMX,
Bone marrow biopsy; CBI, Cognitive-behavioral interventions; HgB, hemoglobin; LP; MD,
medical doctor/physician; OFF, is off; PACU, postanesthesia care unit; PNP, Pediatric Nurse
Practitioner; RN, registered nurse.
38 Campbell et al
When sedation or anesthesia is required, the choice of pharmacologic agents and

airway management is dependent on the individual patient and the environment.
Rapid emergence from sedation-analgesia is desirable, significant respiratory depres-
sion should be avoided, and postoperative complications, such as nausea and vom-
iting as well as emergence agitation, should be minimized. Because of the rapid onset
and offset of actions with minimal postoperative side effects, propofol is frequently
used, often combined with other analgesics, such as fentanyl, remifentanil, and keta-
mine. Combining ketamine with propofol reduces respiratory depression and better
maintains pharyngeal tone. Therefore, this combination is commonly used by nona-
nesthesiologists, because the need for airway interventions is reduced.
MOBILE SEDATION
Tasked with the challenge of providing procedural sedation for patients in outpatient
clinics or inpatient floors because of advanced ASA classification, lack of skilled seda-
tion providers, and limited additional space to perform procedures safely, our institu-
tion established a mobile sedation service. The team travels with all required
equipment, supplies, and medications for safe administration of agents and resuscita-
tion. The anesthesiologist can manage patients in the audiology, dental, hematology-
oncology clinics. In our institution, the physical medicine and rehabilitation whirlpool
suite is indeed 18 floors away from the OR, with limited access, and is probably the
most remote anesthesia site.
SPECIFIC ISSUES
Nitrous oxide (N2O) is an inhalation analgesic, which can be used for mild to moder-
ately painful procedures in children, including laceration repair, fracture reduction,
and peripheral venous catheter insertion. It has a very rapid onset of action (minutes)
and a rapid return to baseline after discontinuation. It is sometimes delivered in a pre-
mixed tank at 50% with oxygen, or through flow meters that allow up to 70% N2O
administration with oxygen. According to American Academy of Pediatrics guidelines,
N2O delivery equipment must have the capacity of delivering 100% and never less
than 25% oxygen concentration. A delivery system that covers the mouth and nose
must be used in conjunction with a calibrated and functional oxygen analyzer.7 N2O
generally produces minimal sedation in concentrations of 50% or less.40–42 The child
should be able to maintain verbal communication throughout the procedure. If N2O is
combined with other sedatives or hypnotic agents, a deeper level of sedation may
develop, requiring an increased level of monitoring. The most common use of N2O
is in pediatric dentistry; however, some pediatric institutions report excellent success
with the use of N2O and rare side effects. Because N2O is more soluble than nitrogen,
it expands air-containing spaces in the body. Therefore, it is contraindicated for pa-
tients who have bowel obstruction or pneumothorax. In remote anesthesia sites,
where the availability of anesthesia machines might be limited, a portable N2O delivery
system managed by a trained, highly skilled nursing team or respiratory therapist team
can be used to sedate children for peripheral IV catheters in preparation for deep
sedation or general anesthesia with IV sedative medications.
DIFFICULT AIRWAY
Patients with recognized syndromes associated with difficult intubation or a craniofa-

cial abnormality on physical examination suggestive of difficult intubation are difficult
to manage outside the OR. These locations that are remote from the OR typically do
not have the full selection of tools to manage the airway in the OR such as video laryn-
goscopes and fiber-optic bronchoscopes. All sedating and anesthetizing locations
must be equipped with standard laryngoscopes, with varying sizes and shape of
blades to care for children. In addition, LMAs of all sizes must be available. The
sedating physician/anesthesiologist must decide on the optimal technique of sedation
or anesthesia and be prepared to intubate the trachea if airway obstruction or respi-
ratory depression develops. If the difficult airway is recognized before the procedure,
the anesthesiologist should consider starting the anesthetic in the OR, where addi-
tional personnel and equipment are more readily available. If difficult intubation was
not anticipated beforehand, the LMA can be lifesaving.43 There must also be a mech-
anism and protocol to call for immediate assistance (see later discussion).
CARDIOPULMONARY RESUSCITATION
The anesthesia provider directing cardiopulmonary resuscitation (CPR) in locations

other than the OR must be prepared to potentially deal with a team that is less prepared
and less practiced in these skills compared with OR personnel. Simulation has shown
these weaknesses in 1 hospital. Before undertaking sedation/anesthesia of a child in a
new location, the anesthesia provider should familiarize themselves with the location of
the closest code cart and the contents of that cart if it is not standardized in the insti-
tution. In 2009, the ASA published a practice advisory for MRI that advises initiation of
CPR in the MRI when an emergency situation develops and quickly removing the pa-
tient from the MRI scanner. The patient should be transferred to a previously desig-
nated location near the MRI that has monitoring and resuscitation equipment.17,44
POSTPROCEDURE CARE
Like procedures in the OR, careful observation and monitoring of the patient after
sedation/anesthesia should continue into the recovery phase in remote sites. Emer-
gence agitation, pain, respiratory events, and unstable hemodynamics should be
managed in a safe environment and under the vigilance of skilled personnel. Close
attention should be made to the patient’s medical condition, which may pose a risk
after sedation/anesthesia. Anticipated time of recovery (extended stay for patients
with obstructive sleep apnea), possible hospitalization (premature infant at risk for
postanesthesia apnea) or upgrade of inpatient care environment (unstable hemody-
namics or acute respiratory event requiring intubation) must be communicated to
the recovery phase nursing team, responsible medical or surgical team, and the par-
ents. Children scheduled for outpatient procedures should meet strict discharge
criteria to eliminate risk.
RISKS AND COMPLICATIONS
Risk related to sedation and anesthesia outside the OR can be broken down into inad-
equate sedation, oversedation/adverse response to sedatives, and failure to rescue.
There is a theoretic risk of neurotoxicity from sedative exposure to the developing
brain, and this is discussed in the article elsewhere in this issue.
In a study of 1140 sedations administered by nonanesthesiologists,45 the most
frequent complication was inadequate sedation, which was reported in 13.2% of pa-
tients. Even although outcomes from inadequate sedation have not been studied, they
can be inferred from evidence regarding stress and anxiety in children having surgery.
The incidence of negative behaviors 2 weeks after surgery is significantly greater in
children who are anxious and have a stressful inhalation induction.
40 Campbell et al
In 2000, Dr Charles Coté published a landmark article on the risk of oversedation

and failure to rescue children after sedation.46 This was a retrospective review of 95
cases reported over a 20-year period. Even though an incidence of severe adverse ef-
fects could not be determined, the findings from this article remain applicable. The
incidence of death or severe neurologic injury was high (60 of 95 patients), and
most of these events could have been prevented. Thirty-four of the patients received
an overdose, and when 3 medications were used in combination, the risk of overse-
dation was significantly greater. The most frequent complications began as a respira-
tory event (80%), and most of these events progressed to cardiac arrest, which
indicates an inability to rescue the child.
The Pediatric Sedation Research Consortium (PSRC) has established a large data-
base of sedation procedures, outcomes, and complications. There are more than 35
institutions, which share prospective data on pediatric sedation, and several reports
have been published from this database. In 2006, the PSRC reported an analysis of
the first 30,037 records.3 They found no deaths and only 1 cardiac arrest; unantici-
pated admission occurred in 1 per 1500 sedations; vomiting in 1 per 200, including
1 aspiration; stridor, laryngospasm, wheezing, and apnea in 1 per 400; and airway
or ventilatory manipulations occurred in 1 per 200. Failed sedations were rare, at
8.9 per 1000. In 2009, the PSRC reported the analysis of 49,386 procedures in which
propofol sedation/anesthesia was used outside the OR.4 Propofol was administered
by anesthesiologists, intensivists, emergency medicine specialists, pediatricians,
and radiologists. No deaths were recorded; however, CPR was required in 2 children
(anesthesiologists were not involved in their care), and aspiration occurred in 4 chil-
dren. Desaturation of less than 90% for more than 30 seconds developed 154 times
per 10,000 sedations/anesthetics, and 1 in 70 children required airway rescue. Unex-
pected admissions occurred 7.1 times per 10,000 sedations. No difference in major
pulmonary complications was found for anesthesiologists versus other providers.
Another report of the PSRC published in 201147 analyzed 131,751 procedural seda-
tions and found no difference in the rates of major complications among different pe-
diatric specialists administering procedural sedation. The study did not track whether
high-risk patients were referred to the anesthesia service.
QUALITY IMPROVEMENT AND OUTCOME
In the 1990s, the Centers for Medicare and Medicaid Services and the Joint Commis-
sion mandated uniform standards for all sedated patients throughout an institution,
which include standardized documentation, fasting guidelines, and informed consent
procedures. These standards hold regardless of the location of the procedure and
regardless of practitioner. The sedation personnel, monitoring equipment, and recovery
facilities must be uniform within an institution, as well as a quality improvement pro-
cess.8 In 2010, the Joint Commission mandated that anesthesia departments provide
the leadership and responsibilities for the delivery of deep sedation in addition to anes-
thesia.9 Minimal and moderate sedation are not subject to anesthesia administration re-
quirements. However, hospitals are required to develop protocols for patients receiving
all levels of sedation. A quality improvement program for the department of anesthesi-
ology should review anesthetic and sedation outcomes of patient both in the OR and
outside the OR. The types of complications that are commonly assessed include:
Aspiration events
Unscheduled admissions to the hospital, or unplanned admission to an intensive
care unit as a direct result of the sedation or anesthesia (ie, because of protracted
emesis, prolonged sedation, or respiratory or cardiac complication)
Failed procedures resulting from inadequate or problematic anesthesia or

sedation
Medication errors
Airway injury
Hypothermia
Awareness
Position injuries
Respiratory arrest and hypoxemic events
Cardiovascular compromise
Anaphylaxis
Cardiac arrest
Hospital systems have benefited from anesthesiology participation and leadership
of a sedation committee, whose charter is the oversight of effective, efficient, and
safe sedation throughout the institution. A sedation committee membership is made
up of physicians, nurses, pharmacists, and quality specialists. Physicians who are
common users of sedation, such as gastroenterologists, pulmonologists, emergency
medicine specialists, intensivists, and oncologists should be represented on the com-
mittee. This committee should produce education programs and credentialing pro-
cesses for sedating patients as well as policies on needed equipment, medications,
monitoring, assessment, and recovery from sedation.
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ology 2011;115:18–27.
40. Zier JL, Tarrago R, Liu M. Level of sedation with nitrous oxide for pediatric med-
ical procedures. Anesth Analg 2010;110:1399–405.
41. Zier JL, Liu M. Safety of high-concentration nitrous oxide by nasal mask for pedi-
atric procedural sedation: experience with 7802 cases. Pediatr Emerg Care 2011;
27:1107–12.
42. Babl FE, Oakley E, Seaman C, et al. High-concentration nitrous oxide for proce-
dural sedation in children: adverse events and depth of sedation. Pediatrics
2008;121:e528–32.
43. Schmidt U, Eikermann M. Organizational aspects of difficult airway management:
think globally act locally. Anesthesiology 2011;114(1):3–6.
44. Blike GT, Christoffersen K, Cravero JP, et al. A method for measuring system
safety and latent errors associated with pediatric procedural sedation. Anesth
Analg 2005;101:48–58.
45. Kain ZN, Mayes LC, Wang SM, et al. Parental presence during induction of anes-
thesia versus sedative premedication: which intervention is more effective? Anes-
thesiology 1998;89:1147–56.
46. Coté CJ, Karl HW, Notterman DA, et al. Adverse sedation events in pediatrics:
analysis of medications used for sedation. Pediatrics 2000;106:633–44.
47. Couloures KG, Beach M, Cravero JP, et al. Impact of provider specialty on pedi-
atric procedural sedation complication rates. Pediatrics 2011;127:e1154–60.
Respiratory Complications in the
P e d i a t r i c P o s t a n e s t h e s i a C a re U n i t
a,b,
Britta S. von Ungern-Sternberg, MD, PhD, DEAA, FANZCA *
KEYWORDS
Pediatric anesthesia Respiratory complications Risk factors
Postanesthesia care unit Recovery room
KEY POINTS
Despite a good safety record, respiratory complications are a major cause of morbidity
and mortality in pediatric anesthesia.
1 in 10 children present with 1 or more respiratory complications during their stay in the
PACU.
The risk factors can be divided into patient factors, surgical factors, and factors caused by
anesthesia management.
Rapid recognition of respiratory complications in the PACU and appropriate treatment
strategies are essential to avoid hypoxia.
INTRODUCTION
Although pediatric anesthesia is relatively safe, perioperative respiratory adverse

events (PRAE) are one of the major causes of morbidity and mortality.1–6 A large audit
in an academic center in Singapore showed that PRAE accounted for more than three-
quarters of all critical incidents in pediatric anesthesia.1 In addition, one-third of all
perioperative cardiac arrests are caused by respiratory complications.2 One-fifth of
all perioperative cardiac arrests occur during emergence from anesthesia and in the
postanesthesia care unit (PACU), with half of these the PACU arrests being caused
by respiratory problems.7 Furthermore, when comparing pediatric and adult closed-
claim legal cases with respect to the mechanisms of injury and outcome, PRAE
are more common and the rate is greater in pediatric claims that resulted in death
Funding: B.S. von Ungern-Sternberg is partly funded by the Princess Margaret Hospital Foun-
dation and Woolworths Australia.
a
Department of Anesthesia and Pain Management, Princess Margaret Hospital for Children,
Roberts Road, Subiaco, Western Australia 6008, Australia; b School of Medicine and Pharma-
cology, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western
Australia 6009, Australia
* Department of Anesthesia and Pain Management, Princess Margaret Hospital for Children,
Roberts Road, Subiaco, Western Australia 6008, Australia.
E-mail address: britta.regli-vonungern@health.wa.gov.au

46 von Ungern-Sternberg
(70%) or brain damage (30%) in previously healthy children compared with adult
claims.8,9
A study by our group of more than 9000 children showed that 15% of all children
suffered from 1 or more PRAE with oxygen desaturation; pulse oximeter saturation
(SpO2) less than 95% (10%), coughing (7%), airway obstruction (4%), and laryngo-
spasm (4%) were the most common, whereas bronchospasm (2%) and postoperative
stridor (<1%) were less common.3
Although PRAE may occur at any time in the perioperative period, they are most
frequently observed during the induction of anesthesia and the recovery period.3
Besides pain, emergence delirium, and postoperative nausea and vomiting, PRAE
are the most common problems encountered in the PACU; however, above all, the
most common reason for an emergency call from the PACU is the occurrence of
PRAE.
Our goal should therefore be to predict (even before the induction of anesthesia)
which children are at a particularly high risk for PRAE in the perioperative period,
to then adjust our anesthesia management for the individual patient in order to mini-
mize the occurrence and severity of PRAE during the entire perioperative period,
including the stay in the PACU. Most respiratory complications, if treated immedi-
ately and effectively, are not associated with any long-term negative effects for the
patient.
DEFINITIONS AND SIGNS OF PRAE
PRAE in the PACU include apnea, bronchospasm, laryngospasm, severe persistent

coughing, oxygen desaturation, and stridor/postextubation croup, with the following
definitions10:
1. Laryngospasm: complete airway obstruction associated with muscle rigidity of the
abdominal and chest walls. Warning signs for the occurrence of laryngospasm are
cough, breath holding, and straining in inspiration and expiration.
2. Bronchospasm: increased respiratory effort, particularly during expiration, and
wheeze on auscultation; in extreme cases, a silent chest can occur, making the
diagnosis more challenging.
3. Severe persistent coughing: a series of pronounced, persistent severe coughs
lasting more than 10 seconds.
4. Partial and complete airway obstruction: erratic respiratory efforts in combination
with stridor or a snoring noise or with paradoxic movement of the abdomen in
the presence of partial and complete airway obstruction, respectively.
5. Apnea: cessation of gas flow for more than 10 to 15 seconds (varying definitions)
or less if associated with bradycardia, cyanosis, or pallor. Apnea can be of either
central (no gas flow because of lack of respiratory effort), obstructive (no gas
flow despite respiratory effort), or mixed (central and obstructive) origin.
6. Oxygen desaturations: definitions vary between SpO2 of lower than 90% and 95%.
Desaturations can be the consequence of any of these signs and can lead to hyp-
oxia and cardiac arrest.
7. Stridor: a high-pitched wheezing sound, resulting from turbulent airflow in the
upper airway.
INCIDENCE OF PRAE
Recent data in our institution have shown that 1 in 10 children in the PACU present
with 1 or more PRAE.3 Although the incidence of bronchospasm and laryngospasm
Respiratory Complications in PACU 47
is low in the PACU (1%), 5% of children suffer from severe persistent coughing or
desaturation (SpO2 <95%).3 Airway obstruction, which could be relived by simple
airway maneuvers, was found in 1% of children in our institution independent of the
presence of respiratory risk factors, whereas stridor was found mainly in high-risk
children (for risk factors, see later discussion).3
Other groups have reported desaturation rates as high as 50% on arrival in the
PACU.11,12 High desaturation rates are commonly linked with the lack of oxygen
administration on transfer to the recovery area.11–13
SEVERITY AND OUTCOME OF RESPIRATORY COMPLICATIONS
Potential complications of PRAE in the PACU are negative pressure pulmonary edema,
prolonged oxygen requirements, prolonged hospital stay, behavioral problems, need
for reintubation, need for admission to the intensive care unit (ICU)/neonatal ICU
(NICU), cardiac arrest, permanent brain damage, and death. Most reintubations and
nearly half of all the unplanned postoperative admissions to ICU are related to PRAE,
the remaining mainly for surgical reasons.14,15 Most PRAE resulting in permanent brain
damage are caused by inadequate ventilation. Half of all cardiac arrests in the PACU are
caused by PRAE.2,7 Children cared for by pediatric anesthesiologists or in pediatric only
centers had better outcomes after PRAE and cardiac arrest compared with children
cared for by general anesthesiologists or in mixed population centers.3,7,16
General Risk Factors for Respiratory Complications

Although cardiac complications are mostly easy to predict in children because they
mainly occur in children with known cardiac disease, respiratory complications are
more commonly seen in previously healthy children or those with only minor comor-
bidities such as asthma or eczema. To determine who is at risk for respiratory compli-
cations, it is easiest to distinguish between factors related to the patient, the surgical
procedure, and the anesthesia management (Box 1).3,17–19
The difficulty in studying and reporting risk factors of PRAE is that most PRAE
and their risk factors are not independent from each other (eg, both bronchospasm
or laryngospasm can lead to oxygen desaturations, and asthma is a risk factor
for the occurrence of laryngospasm, bronchospasm, persistent coughing, and
desaturation).3
Patient factors and pathophysiology: why are children at such a high risk for
desaturations?
The main causes of postoperative hypoxemia in children are atelectasis and depres-
sion of respiratory drive by opioids and hypnotic agents, as well as decrease in mus-
cle tone because of the muscle relaxing properties of anesthetics and residual
neuromuscular blockade. In general, the resting volume of the lung is determined
by the balance between the chest and lung recoil pressures. Because of the
increased chest wall compliance, the functional residual capacity (FRC) is lower in
younger children compared with older children or adults.20,21 Chest wall compliance
decreases rapidly during childhood, particularly in the first year of life.20 Nearly all
anesthetic agents induce a dose-dependent relaxation of respiratory muscles, which
also reduces airway muscle activity.22–25 This induced muscle relaxation interferes
with the balance between the chest wall compliance, elastic lung recoil, and tension
of the diaphragm, leading to a decrease in lung volumes and unequal distribution of
ventilation.24–28 In small children, this anesthesia-induced muscle relaxation in addi-
tion impairs the natural dynamic increase of FRC in the expiratory phase, leading to
Box 1
Factors increasing the risk of respiratory complications in the PACU
Patient
Young age, particularly (ex-) premature babies
Current or recent upper respiratory tract infection
Passive/active smoking
Recurrent wheezing
Current/past asthma
Nocturnal dry cough
Wheezing during exercise
Allergic rhinitis
Current/past eczema
Family history of asthma, eczema, or allergic rhinitis
Obstructive sleep apnea
Obesity
Unfasted patient
Bronchopulmonary dysplasia
Cystic fibrosis
Other respiratory illnesses
Surgical Procedure
Blood or secretions in the upper airway
Procedures with shared airway (eg, ear, nose, and throat, dental, respiratory medicine)
Sudden surgical stimulation
Emergency procedure
Anesthesia/Recovery Management
Invasive airway management
Repeated attempts at airway management
Desflurane as maintenance agent
Less experienced anesthesiologist
Less experienced PACU staff
Patient ratio in PACU
Opioid management
Administration of neuromuscular blocking agents
Timing of the removal of airway device
Topical lidocaine
Premedication with midazolam
Emergence (vs induction of anesthesia)
Mixed population hospital (vs solely pediatric)
an increased tendency for small peripheral airway collapse, even during normal tidal
breathing.29
Children have lower oxygen reserves because of an increased tendency to airway
collapse (increased compliance), leading to a decrease in FRC that makes them prone
for hypoxemia.21 This situation can be counteracted by the administration of positive
end-expiratory pressure in the immediate postoperative period to prevent alveolar
collapse by increasing FRC and dynamic lung compliance and decreasing total airway
resistance.28,30–33
Age The age of the patient has a significant impact on the occurrence of PRAE, with
neonates and young infants having the highest risk.3 For example, the relative risk for
laryngospasm decreases by 11% for each yearly increase in age.3,34
Clinical studies have shown that oxygen desaturation occurs faster, to deeper levels
and with a slower recovery in infants compared with older children and adults.35 Up to
half of normally healthy infants and young children present with desaturations during
the transport from operating room to the PACU or on arrival in the PACU.11–13
Prematurity Prematurity also increases the risk for PRAE, mainly because of the
associated higher risk for apnea and bronchopulmonary dysplasia.
Bronchopulmonary dysplasia in (ex-) premature patients
Bronchopulmonary dysplasia occurs in a relatively high percentage of ex-premature
preterm babies (birth weight <1500 g).36 Even though many children are symptom-
free in everyday life by 2 years of age, they still have a higher rate of bronchial hyperre-
activity (BHR) compared with the normal population.37 Many parents are unaware of
the bronchopulmonary dysplasia that their child has, and history taking can therefore
be deceiving.37 A high index of suspicion should be used if a child was born prema-
turely, especially if ventilated in the neonatal period.38 The lack of surfactant and under-
developed lungs, artificial ventilation, and other factors of the early neonatal period
can result in inflammation and fibrosis of the alveoli and small airways.36 These children
display a hypersensitive pulmonary capillary network, which is prone to vasocon-
striction after hypothermia, pain, or acidosis, for example. The BHR in these children
with bronchopulmonary dysplasia has been shown from as early as 26 weeks after
conception and 12 days of age and decreases slowly over the years, depending on
the severity.39
Apnea in neonatal patients
Because respiratory control in neonates is not yet fully developed and needs weeks
to months to mature,10 the breathing pattern of preterm as well as term infants is often
irregular and periodic and can be associated with severe apnea.40 Brainstem respira-
tory rhythmogenesis, peripheral and central chemoreceptor responses, and other
parts of the respiratory control network are immature in premature babies, leading
to an impaired response to hypercapnia and hypoxia.10 In older children and adults,
hypercarbia leads to an increase in tidal volume and respiratory rate. These responses
are impaired in premature babies.41 Hypoxia in preterm infants shows a biphasic
response; at first, ventilation increases for approximately 1 minute and then de-
creases, with the potential for apnea.42 In the PACU, after emergence from anesthesia,
any residual anesthetic drugs decrease the respiratory control to both hypoxia and
hypercapnia.43 Risk factors for postoperative apnea are given in Box 2.
BHR BHR is defined as a tendency of the smooth muscle of the tracheobronchial tree
to contract more intensely in response to a given stimulus than it does in the response
seen in normal individuals and is commonly caused by airway inflammation.
Box 2
Risk factors for postoperative apnea
Inversely correlated to gestational age

Inversely correlated to postconceptual age
Associated with previous history of apnea
Not associated with small-for-gestational-age infants (protective)
Anemia, hematocrit level less than 30%, regardless of gestational age or postconceptual age
Preventative treatment: caffeine 10 mg/kg
Asthma, BHR, upper respiratory tract infection (URTI), or passive smoking are all
recognized risk factors for PRAE.3,44–46 The incidence of asthma and BHR is high
among children, with up to 40% of 6-year-old children having wheezing and around
20% having asthma requiring regular medication.47,48 In addition, the incidence of
URTI in children, particularly preschool children, presenting for anesthesia is
high.3,49 Although a recent URTI increases the risk of PRAE,3,34 general anesthesia
is often performed under these circumstances for several reasons: (1) URTI occurs
frequently, especially in young children and children undergoing ear, nose, and throat
(ENT) procedures, and there is clinical uncertainty for how long to postpone the pro-
cedure after an URTI3; (2) there are adverse economic and emotional impacts to
canceling surgery.50
In general, all factors that are commonly associated with an increase in BHR lead
to an increase in PRAE (Box 3). Children with BHR have an aggravated response to
airway stimulations (eg, suctioning, removal of airway device in the PACU, which
can lead to an increased risk for bronchospasm and desaturation in particular). In
young children, symptoms of BHR might not yet have been noted by the parents, or
the child might be to young to report them. Because eczema and to a lesser extent
allergic rhinitis are often seen in children who later in life develop recurrent wheeze,
asthma, and BHR, the presence of these early symptoms should alert the anesthesi-
ologist as significant risk factors for respiratory complications.
BHR after an acute asthmatic/wheezing episode persists for several weeks
beyond the presence of asthmatic symptoms.51,52 Warning signs for significant
BHR are a recent increase in asthma symptoms or treatment requirements or even
Box 3
Factors commonly associated with an increase in BHR
Lung disease with airway inflammation (eg, asthma, cystic fibrosis)

Current/recent (within 2 weeks) upper respiratory tract infections, particularly when
associated with moist cough/green runny nose
Dry nocturnal cough
Wheezing with exercise
Passive/active smoking
Atopy
Possible increase in children with eczema, allergic rhinitis, or family history of asthma,
eczema, or allergic rhinitis
hospitalization. BHR is mainly caused by underlying airway inflammation, which

should be treated and lung function optimized before surgery whenever possible.53
Children with these warning signs should receive intensified therapy for their
asthma/wheezing before elective surgery, preferably in a respiratory clinic, and sur-
gery should be postponed. In addition, if surgery has to go ahead or even after the
intensified therapy, these children can further benefit from a premedication with salbu-
tamol 10 to 30 minutes before the induction of anesthesia, which significantly
decreases the incidence of PRAE in these high-risk children.19
Obesity The incidence of childhood obesity, a risk factor for PRAE, is steadily
increasing; in Australia, 25% of children are overweight (body mass index [BMI], calcu-
lated as weight in kilograms divided by the square of height in meters >85th centile) or
obese (BMI >95th centile).44,54–57 Obese children not only have a reduced lung func-
tion via a loss in lung volume and impaired respiratory mechanics58 but also have a
higher rate of asthma and other comorbidities (eg, obstructive sleep apnea, habitual
snoring), further increasing the risk for PRAE.17,44,55,57 Furthermore, many compo-
nents of anesthesia (eg, supine positioning, anesthetic agents, and surgery) lead to
an additional decrease in lung volumes, and the changes in lung function are expected
to be greater in the obese patient.28,33,59–66 Together, these factors increase the inci-
dence of all PRAE, in particular, postoperative desaturations.
Surgical procedure
Procedures with a shared upper airway during the procedure (eg, ENT, dental, respi-
ratory medicine) are more prone to lead to airway lesions, swelling, bleeding, or
increased secretions postoperatively. Blood or increased secretions in the upper
airway lead to an increased risk for PRAE.
ADENOTONSILLECTOMY
Children undergoing ENT surgery, particularly adenotonsillectomy, have an in-

creased incidence of PRAE,3,4,67 in particular oxygen desaturations and airway
obstruction.68,69
Not only does the operation on the upper airway cause postoperative swelling,
but these children also have a high incidence of obstructive sleep apnea syndrome,
which is often the primary reason for surgery. It is therefore common practice in
many institutions to monitor these children, particularly if they also show symptoms
of obstructive sleep apnea, with continuous pulse oximetry for 24 hours after surgery.
Anesthesia Management
Airway device
Noninvasive airway management (supraglottic airway device or face mask) actively re-
duces PRAE (tracheal tube vs face mask relative risk [RR] [95% confidence interval]
5.1 [2.3–11.6], P<.0001).3 The optimal timing of removal of any airway device is a topic
of debate among pediatric anesthesiologists. However, there seem to be only minor
differences between both techniques, regardless whether a laryngeal mask or an
endotracheal tube is used.70–72 Removal of a laryngeal mask airway in the awake state
marginally increases the risk of PRAE compared with removal during deep anesthesia
(RR 1.3 [1.1–1.5], P 5 .001).3 A recent study from our group reported that awake extu-
bation in high-risk children after adenotonsillectomy was associated with a higher inci-
dence of severe persistent coughing (60% vs 36%) and hoarse voice (48% vs 26%),
as well as more and longer episodes of oxygen desaturations.70–72 Although persistent
coughing is often seen as a minor problem, it can affect surgical hemostasis, with an
increased risk of postoperative bleeding, and can increase postoperative pain. On the
other side, extubation while deeply anesthetized moderately increased rates of airway
obstruction without increasing oxygen desaturations, because airway obstructions
were easily removed by simple airway maneuvers.72 Although deep extubation is
less likely to stimulate the airway, and may increase efficiency and operating room
turnover times, the setup of the PACU must enable close supervision by well-
trained PACU nurses of the children extubated deep and must incorporate staff
who are fully trained in performing simple airway maneuvers in case of airway obstruc-
tion.72 With such a setup, it is not surprising that against common belief, the level of
wakefulness in the PACU after pediatric anesthesia does not correlate with the occur-
rence of oxygen desaturation.73
In recent years, cuffed endotracheal tubes have increasingly been used also in
younger children, including term neonates.74 Cuffed endotracheal tubes are associ-
ated with lower rates of PRAE, even after correction for age, particularly if cuff pres-
sure has been continuously monitored.3,75 An increased cuff pressure correlates
with negative outcome, particularly with the incidence of sore throat.3,75
DRUGS
Most anesthetic drug-related PRAE are caused by the mechanisms of reduced respi-
ratory drive or impaired respiratory muscle function, leading to hypoventilation, atelec-
tasis, and hypoxia. Rarely, anesthetic drugs can lead to allergic or nonallergic
bronchoconstriction.
Neuromuscular Blocking Agents
Residual neuromuscular blockade has been found in nearly half of the patients who
received intraoperative neuromuscular blocking agents, even though the patient
was deemed appropriately reversed by the attending anesthesiologist.76–80 This is
not surprising, because neuromuscular monitoring is not standard in all institutions;
it is particularly rarely used in many private institutions.81 In addition, neuromuscular
monitoring in children is technically challenging and cannot completely exclude resid-
ual paralysis. For example, a tetanic stimulation in an awake premature baby leads to a
fade at 20 Hz; term neonates show fade on stimulation from 50 Hz onwards.82 Resid-
ual neuromuscular blockade is even found after a single intubation dose.83 Residual
neuromuscular blockade often leads to hypoventilation, respiratory fatigue, and
consequent hypoxia. Furthermore, infants show a fade without the administration of
muscle relaxants under nitrous oxide and methohexital anesthesia.84 To avoid residual
neuromuscular blockade, reversal agents are given in many cases. However, reversal
given too early is associated with the danger of recurarization, which can occur in the
PACU or on the ward. The incidence of hypoxia in the PACU is nearly doubled in chil-
dren who received neuromuscular blocking agents compared with those who did not.3
Against more traditional anesthetic teaching routinely using neuromuscular blockade,
it has been shown that endotracheal intubation can be performed equally well in most
children without neuromuscular blockade.85 Therefore, it is advisable not to use
neuromuscular blocking agents in children unless they are necessary for procedural
reasons.
Opioids
Most children admitted to the PACU have received opioids within their anesthesia
regimen. Children with obstructive sleep apnea as well as neonates and young infants
(<6 months) are particularly sensitive to opioids.86 The highest-risk groups for patients
after opioid administration are listed in Box 4. Particularly after major surgery, it is
Box 4
Risk factors for respiratory complications with opioid administration
Age younger than 6 months, particularly neonates

Cardiac disease
Underlying respiratory disease
Central/obstructive sleep apnea
Syndromes associated with airway obstruction
Hepatic/renal insufficiency
Neurodevelopmental disorders, global developmental delay
Concurrent administration of other sedative drugs (eg, benzodiazepines, clonidine,
gabapentin)
often a fine balance to have the children pain free but not oversedated with opioids. It
has been shown that reducing the dose of intraoperative morphine decreases the inci-
dence of PRAE after tonsillectomy, particularly apneas, airway obstruction, and oxy-
gen desaturations.87 It is important that postoperative agitation is not misdiagnosed
as pain, because this can falsely trigger further administration of opioids. If naloxone
is given, it is important to consider the potential for resedation once naloxone has worn
off. Therefore, the patients should remain in the PACU until the time naloxone is known
to have lost effect.
Accidental drug injection

A further source for complications in the PACU is the accidental postoperative injec-
tion of an anesthetic drug (neuromuscular blocking agents, opioids, or hypnotics).
Even small volumes of an anesthetic drug (particularly neuromuscular blocking
agents) in an insufficiently flushed drip can cause muscle relaxation or neuromuscular
blockade and can consequently lead to hypopnea or apnea or even cardiac arrest in
infants because of a potentially high dose per body weight. Strict departmental guide-
lines about postoperative flushing of line with sufficient fluid are therefore crucial in the
pediatric setting. In our institution, flushing of the line is part of the World Health Orga-
nization checklist at the end of surgery in the operating room. In addition, we routinely
also mention the flushing of the line as part of our standardized handover in the PACU,
which has decreased the number of incident reports filled out on the wards of white
(propofol) residues in the line.
PREVENTION AND TREATMENT OF RESPIRATORY COMPLICATIONS

Infrastructure and Organization
Because children have high oxygen demands, they are particularly vulnerable to
hypoxemia should a PRAE occur. However, many pediatric PACUs are solely staffed
by nurses, without an attending anesthesiologist in the unit. The availability of med-
ical backup in the PACU as well as the nurse/patient ratio varies between centers.
Therefore, in anticipation of potential PRAE, regular training of the staff in rapid
recognition and knowledge of the cause and treatment of PRAE in the PACU is
vital.21 For example, in our institution, we retrain our PACU nurses on a regular
basis with hands-on airway management (eg, airway maneuvers, holding the face
mask) in the operating room under the direct supervision of pediatric anesthesia
consultants.
Furthermore, the PACU should be close to the operating rooms to allow for rapid
and safe patient transport and fast response rates of the attending anesthesiologist
when their immediate presence is required in the PACU because of a complication.
Furthermore, an alarm system is of great benefit to allow for rapid backup in case
of an emergency in the PACU. Given the small hypoxia tolerance in young children,
time is vital. Each patient bed space should be well equipped, including compatible
patient monitoring (SpO2, CO2, heart rate, blood pressure), oxygen supply, and
suction. An emergency drug and airway cart should be readily available within the
PACU. A thorough, preferably standardized, handoff report from the anesthesia
team to the PACU team is of vital importance to make the PACU team aware of poten-
tial risk factors for complications. This handoff should include a check whether or not
the intravenous (IV) line of the patient was appropriately flushed and whether the
patient had received any drugs which could resedate or remuscle relax them. A
nurse/patient care ratio of 1:1 is the goal in the immediate postoperative period.
PACU staff must be well trained and competent in recognizing and treating respiratory
complications in children.
Bronchospasm
As soon as bronchospasm is suspected in the PACU, 100% oxygen should be de-
livered, and repeated doses of salbutamol or levalbuterol should be given, preferably
via mask and spacer, using a metered dose inhaler. If salbutamol/levalbuterol is insuf-
ficient to relieve the bronchospasm, IV ketamine, epinephrine, or magnesium should
be considered.
Laryngospasm
The key point in the treatment of laryngospasm is to start therapy as early as pos-
sible once laryngospasm is suspected, before the development of hypoxia. Initial
therapy includes jaw thrust and continuous positive airway pressure (CPAP) with
100% oxygen via a face mask. If this procedure is unsuccessful, 1 to 3 mg/kg of
IV propofol is administered; if oxygen saturation begins to decrease and other treat-
ment has failed, IV succinylcholine 1 to 2 mg/kg is the drug of choice to relieve laryng-
ospasm. If succinylcholine is contraindicated, atracurium or rocuronium are safe
alternatives. Most children recover from laryngospasm without any sequelae. How-
ever, some children are oxygen dependent for some time, particularly if they have un-
derlying lung disease (eg, respiratory tract infection, cystic fibrosis). Laryngospasm
can lead to atelectasis, loss of FRC, and retention of secretion, causing V/Q mismatch,
which resolves once the child is sufficiently awake to cough and by doing so reexpand
atelectatic lung segments.88 Strong inspiratory efforts against a closed glottis can
generate large negative intrapleural pressures, which can cause large fluid shifts
from the vascular system into the interstitium by causing a sudden increase in left
ventricular preload and afterload and consequently into the alveoli, leading to a nega-
tive pressure pulmonary edema.89,90 Negative pressure pulmonary edema usually
resolves quickly but may require the administration of high-flow oxygen, CPAP, and
even admission to the ICU/NICU.
Desaturation
All patients should receive supplemental oxygen in the immediate postoperative
period. This treatment also includes oxygen administration as a standard for all patient
transfers. In our institution, we provide all patients with oxygen either via a facemask or
via a laryngeal mask airway connected to a T-piece, allowing for manual ventilation or
the administration of CPAP if required. Other supplemental oxygen administration
options in the PACU include nasal cannula, simple face mask, or blow-by humidified
oxygen via 22-mm corrugated tubing. The exact method is determined by supple-
mental oxygen requirement and tolerance of the child for device chosen.
Anesthesia decreases pulmonary gas exchange, mainly because of FRC loss,
consequent airway closure, and atelectasis.27 This situation can be minimized by
performing a recruitment maneuver before removal of the airway device. Oxygen sup-
plementation can be ceased entirely when pulse oximetry readings are normal and
stable at or higher than preoperative levels with the patient breathing room air.
Because of their higher susceptibility to oxygen toxicity, the level of oxygen supple-
mentation necessary for appropriate oxygenation should be reviewed regularly in ne-
onates, particularly if born premature. An air oxygen blender is useful particularly in
this vulnerable population. For all patients, wakefulness does not correlate with the
risk for oxygen desaturations.73
Severe persistent coughing and airway obstruction

Severe persistent coughing normally is self-limiting once the stimulus is removed and
secretions have been mobilized. Airway obstruction in the PACU can easily be over-
come in most children with simple airway maneuvers such as jaw thrust and chin lift
and CPAP.72 If these maneuvers are not sufficient, oral or rarely nasal airways can
be used. In addition, it is advisable to recover all children in the lateral position,
because this improves airway patency compared with the supine position.91
Stridor
Stridor and postintubation croup used to have an incidence of around 1% in intubated
children,92 but this has been decreasing over time with the increasing use of noninva-
sive airway devices and the introduction of cuffed endotracheal tubes, which are asso-
ciated with lower rates of stridor compared with uncuffed endotracheal tubes.3
Treatment, if at all, may consist of cool humidified mist or nebulized racemic epineph-
rine, which results in vasoconstriction of the swollen airway mucosa. Clinicians need
to be aware of a potential rebound effect after nebulized racemic epinephrine, which
necessitates an observation for 4 hours after nebulizer treatment in order to avoid an
unobserved worsening of the respiratory symptoms. Furthermore, dexamethasone
has been described to be useful in patients after longer-term ventilation (>48 hours),93
whereas it has been controversial for postintubation croup after shorter intubation
periods.94,95
Perioperative improvement of patients at risk of PRAE

To improve patient management and minimize respiratory complications in the PACU,
it is crucial to start preventative measures as early as possible, even before the
patient’s admission. Prevention strategies are summarized in Box 5.
Therapy for asthma and BHR in general should be optimized by the treating physi-
cian with intensified inhaler therapy or in severe cases with oral corticosteroids before
elective procedures.38
Performing a procedure at a purely pediatric hospital compared with a mixed pop-
ulation hospital is associated with significantly lower morbidity and mortality.3,7,16
Furthermore, during anesthesia, preventative measures should be taken (eg, consul-
tant anesthesiologist, noninvasive airway management, and premedication with sal-
butamol/levalbuterol).3,18,19
Anesthesia induction for patients at risk of PRAE, particularly bronchospasm,
should include premedication with salbutamol/levalbuterol, IV induction, and mainte-
nance with propofol.3,18,19 In the PACU, close observation by staff trained to recognize
and immediately treat respiratory complications in children is vital to assure a safe
recovery.
Box 5
Prevention strategies for respiratory complications in the PACU
Patient
Preoperative optimization of children with BHR (if possible)
Age-appropriate fasting
Anesthesia
Premedication with salbutamol in children with BHR
Avoidance of premedication with midazolam; if needed, use clonidine
Noninvasive airway management
Prefer cuffed over uncuffed endotracheal tube
Propofol anesthesia
Regional anesthesia
Avoidance of desflurane
Appropriate opioid dosing
Careful flushing of lines
Monitoring of neuromuscular function after neuromuscular blocking agents
Consultant pediatric anesthesiologist
Pediatric hospital
PACU management
Oxygen administration during transport
Patient/nurse ratio in PACU 1:1
Continuous SaO2 monitoring
CO2 monitoring if possible
Careful flushing of lines
ACKNOWLEDGMENTS
I thank Professor Adrian Regli, Intensive Care Unit, Fremantle Hospital, Perth,
Australia for his valuable input into this article.
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M a j o r Su r g i c a l Pro c e d u re s i n
C h i l d ren wi t h C e re b r a l P a l s y
a,b, a,b
Mary C. Theroux, MD *, Sabina DiCindio, DO
KEYWORDS
Cerebral palsy Spine fusion Varus osteotomy Pelvic osteotomy
Baclofen pump Spasticity Coagulopathy
KEY POINTS
Cerebral palsy is the most common and most debilitating neurological disease in children.
Pediatric Anesthesiologist may expect to care for this population at an increasing
frequency.
Children with cerebral palsy have many co-morbid conditions which may result in
increased morbidity and even mortality in the peri-operative period.
This chapter describes the three most common major procedures that these children
undergo and discusses the anesthetic care in detail.
INTRODUCTION
There are 3 surgical procedures that patients with cerebral palsy (CP) undergo that
may be considered major procedures: femoral osteotomies combined with pelvic
osteotomies, spine fusion, and intrathecal baclofen pump implant for the treatment
of spasticity. Most patients with CP who undergo these procedures have spastic
quadriplegic CP, and they are often developmentally delayed.
Many complications are known to occur at a higher rate in this population, and some
may be avoided with prior awareness of the preoperative pathophysiology of the pa-
tient with CP. For example, awareness of suboptimal levels of clotting factors help
plan for major surgeries with large blood loss by optimizing factor levels in a timely
manner. Using information from trauma literature regarding transfusion and fluid
resuscitation and adapting it to major surgeries in patients with CP in whom massive
Funding Sources: None.

Conflict of Interest: None.
a
Department of Anesthesiology and Critical Care Medicine, Nemours/Alfred I. duPont Hospital
for Children, Post Office Box 269, Wilmington, DE 19899, USA; b Department of Pediatrics,
Jefferson Medical College, Thomas Jefferson University, Philadelphia, 111 S 11th Street, PA
19107, USA
* Corresponding author. Department of Anesthesiology and Critical Care Medicine,
Nemours/Alfred I. duPont Hospital for Children, Post Office Box 269, Wilmington, DE 19899.
E-mail address: mtheroux@nemours.org

64 Theroux & DiCindio
bleeding occurs will help decrease dilutional coagulopathy. Extubating patients

earlier, such as the day of surgery, may have beneficial effects, and may result in
decreased intensive care unit (ICU) and hospital days. Measures to decrease blood
loss, such as use of tranexamic acid (TXA), are increasingly employed to help with
an earlier extubation. Extensive lower extremity surgical procedures are often per-
formed in this patient population because of the nature of their frequent bilateral dis-
ease and the need to decrease multiple hospitalizations and expenses. In order to
provide optimal pain relief, the use of epidurals or caudal catheters using fluoroscopic
aid is warranted. Treating spasticity postoperatively is important and controls pain
more easily by preventing the cycle of pain leading to spasm and vice versa.
This article is organized into 2 major sections: (1) description of general risk associ-
ated with anesthesia and CP and (2) the 3 major surgical procedures and their specific
risks (derotational femoral osteotomies and reconstructive acetabular surgeries, scoli-
osis correction, and baclofen catheter and pump placement).
GENERAL RISK OF ANESTHESIA AND SURGERY
The general risk of anesthesia is complicated by CP1 and may be largely attributed to
abnormal muscle tone and nutritional status. Fig. 1 lists complications from a retro-
spective study examining 517 patients who underwent surgery and anesthesia at
Mayo Clinic and the percentage of patients who had each complication. Some com-
plications may be considered minor, but some may lead to major morbidity and mor-
tality if left unattended.
Hypothermia
Hypothermia, the etiology of which is poorly understood, is the most prevalent compli-
cation (55.1%) observed in children with CP under anesthesia.1 The global ischemic
injury sustained by the patient that led to the development of CP in early childhood
Fig. 1. Incidence of complications in patients with cerebral palsy. (From Wass CT, Warner ME,
Worrell GA, et al. Effect of general anesthesia in patients with cerebral palsy at the turn
of the new millennium: a population-based study evaluating perioperative outcome and
brief overview of anesthetic implications of this coexisting disease. Child Neurol
2012;27(7):861; with permission.)
Cerebral Palsy - Major Surgical Procedures 65
likely may have injured the hypothalamus, resulting in poor thermal regulation. A rela-
tive lack of adipose tissue protecting the body may also be a contributory factor to hy-
pothermia complications. Unless special attention is paid to prevent it, a patient with
spastic quadriplegic will likely sustain hypothermia in the operating room. At the au-
thors’ pediatric hospital, patients with CP scheduled for major surgeries are warmed
using a forced air warming gown (Arizant Healthcare, St. Paul, Minnesota) system in
the preoperative holding area, not only to minimize temperature decrease associated
with the relatively sparse hospital clothing, but also to create a more favorable base-
line temperature. When active warming, it is important to monitor temperature,
because patients with CP may easily sustain temperatures greater than normal due
to the inability to maintain normothermia when swings in ambient temperatures occur.
When patients arrive for the 2 most common major surgical procedures, spine fusion
for scoliosis and acetabulum/femur surgery for dislocated and subluxed hip joints, it is
important to prevent them from plunging into a deep hypothermia, which is frequently
sustained shortly after induction of anesthesia. Prewarming the patients while they
are in the preoperative area not only allows a better baseline temperature but also
facilitates line placement.
Hypotension
Hypotension that occurs in association with anesthesia and surgery in patients with
CP may be attributed to different etiologic factors: (1) increased sensitivity to anes-
thetic agents, (2) chronic underhydration, and (3) volume of blood loss of great magni-
tude in relation to estimated blood volume. Among volatile anesthetics, halothane and
sevoflurane have been studied in children with CP. Minimum alveolar concentration for
halothane is decreased (0.7) in children with CP and severe mental retardation, and a
further decrease (0.6) manifests in patients with CP who are on anticonvulsant medi-
cations, with normal children acquiring 0.9 in the same study.2 There is evidence for a
greater drop in bispectral (BIS) values in children with spastic quadriplegic CP with
sevoflurane when compared with neurologically normal children.3 Similarly, increased
respiratory depression and greater obtundation are observed with narcotic analgesics
in clinical practice, and greater titration of such medications is imperative in CP
patients.
Most patients with spastic quadriplegic CP who are in need of major surgical pro-
cedures are nonambulatory and are fed via gastrostomy tube or are given pureed
food by their caretaker. Children are given a prescribed amount of free water, typically
via their gastrostomy feeding tube, and do not follow normal physiologic feedback
initiated by thirst. Expect such children to be chronically underhydrated with higher
than expected hemoglobin due to relative hemoconcentraion. It is important not to
misjudge the degree of their underhydration and lack of clear, or any, urine upon Foley
catheter placement. Repeating hemoglobin and clotting studies after hydrating the
patient until free flow of urine is observed will provide values more representative of
their actual baseline.
Patients with CP thus may sustain hypotension more easily than otherwise normal
patients if induction of anesthesia is not given due consideration and special care.
Other contributing factors to perioperative hypotension in CP, especially quadriplegic
CP, include a propensity to greater blood loss during surgery, the etiology of which
includes a subnormal level of clotting factors. A detailed description of increased
bleeding and inadequate hemostatic ability in patients with CP follows later in this
article.
Excessive salivation caused by a disturbed coordination of orofacial and palatolin-
gual muscles is common and can be managed both pharmacologically, using
anticholinergic medication, and mechanically, with sufficient anticipation and suction-

ing in the perioperative arena.4 Oropharyngeal aspiration and silent aspiration in chil-
dren with CP are not only prevalent but also have significant association with
neurologic impairment, developmental delay, and aspiration-related lung disease.5
Salivary aspiration may contribute to, and often aggravate, preexisting chronic lung
disease and reactive airway disease in such patients.
A greater amount of blood loss has been recognized in patients with CP during spine
fusion surgery when compared with idiopathic scoliosis patients.6 A pilot study exam-
ining the etiology of increased bleeding in patients with CP showed clotting factor
levels7 (Table 1) that were lower than normal. Further study by the same investigators
comparing the thromboelastography findings during spine fusions in children with CP
and in children with idiopathic scoliosis found maximum amplitude of the thromboe-
lastograph significantly lower in patients with CP at early blood loss. The results
from this study provide insight into why patients with CP appear to lose a greater
amount of blood during surgery. Additionally, subnormal calcium and magnesium
levels were observed in patients with CP with early blood loss, which could further
explain increased bleeding, as calcium is an essential component of the hemostatic
mechanism.
Neuromuscular blocking agents are known to have altered sensitivity in patients
with spastic quadriplegic CP. A dose response study showed patients with CP have
an increased sensitivity to succinylcholine.8 Further scrutiny of the neuromuscular
junctions of the spastic quadriplegic CP patients has revealed an abnormal spread
of acetylcholine receptors in approximately 30% of patients studied (Fig. 2).9 Specif-
ically, the abnormality occurred in the spread of acetylcholine receptors, which
extended beyond the boundary of the neuromuscular junctions. Nonambulatory
patients with CP were found to have significantly greater numbers of abnormal neuro-
muscular junctions, as well as greater abnormality in the spread of acetylcholine
receptors.10
These abnormalities are further validated indirectly by the study of vecuronium, a
nondepolarizing neuromuscular blocking agent, which showed a decreased potency
of vecuronium in patients with CP.11 This study did not enroll patients who were on
seizure medications in order to avoid the confounding effect of anticonvulsants on
the results.12 Implications of these abnormalities may be twofold:
1. The paralytic effects of succinylcholine may not be clinically significant because of
the differences in the potency of the drug in patients with CP, while decreased
potency of vecuronium may be more clinically apparent.
2. Caution may need to be exercised if succinylcholine is used in patients with CP,
because some patients may harbor enough neuromuscular junctions with
abnormal acetylcholine receptors to lead to complications, such as hyperkalemia,
upon receiving succinylcholine.
To follow up on the findings of increased sensitivity to succinylcholine by CP pa-
tients, the investigative team embarked on research examining neuromuscular junc-
tions in this population. The incident was thought to be the result of succinylcholine
administration. Neuromuscular junctions are known to be up-regulated in patients
who are in a state of immobility; patients with CP, particularly those who have spastic
quadriplegic CP, are often bedridden and immobile.13–18
Topiramate is a relatively new anticonvulsant drug commonly used in patients with
CP. Other indications for the use of this drug are migraine and bipolar disease. An
adverse effect of topiramate is the development of closed angle glaucoma, which,
when it occurs, typically presents within the first year of treatment.19,20 Delayed onset
Table 1
Conventional clotting studies (PT/PTT) and factors II, VII, IX, X in 5 consecutive patients performed prior to induction of anesthesia and repeated at an
estimated blood loss of approximately 20% (of their estimated blood volume)
Patient Base PT BL25 PT Base PTT BL25 PTT Base II BL25 II Base VII BL25 VII Base IX BL25 IX Base X BL25 X
1 10 12 29 38 90 68 43 49 70 74 58 45
2 10 15 34 67 100 46 110 30 100 37 100 57
Cerebral Palsy - Major Surgical Procedures

3 12 15 28 43 85 48 64 12 100 52 100 22
4 13 14 39 48 90 55 70 70 37 52 60 39
5 13 16 30 46 100 46 80 64 74 29 57 57
Normal range for PT 5 9–11 min, normal range for PTT 5 23–38 min, and normal range for factor levels 5 50%–150% of normal.
No blood or blood products had been given during this period.
67
Fig. 2. (A-1) Normal neuromuscular junction first stained with a-bungarotoxin (red) to show
the spread of acetylcholine receptors (AchRs). (A-2) The same neuromuscular junction
stained with acetyl cholinesterase (green) to define the limits of the junction. (A-3) The
superimposed neuromuscular junction with both a-bungarotoxin and acetyl cholinesterase
staining. Red staining outside of the green indicates spread of AchRs outside the limits of
the neuromuscular junction. (B-1–B-3) The same staining methods of a neuromuscular junc-
tion from a patient with CP. Significant spread of AchRs outside of the limits of the neuro-
muscular junction is seen.
has also been reported.21 The proposed mechanism of closed angle glaucoma is
choroidal effusion and forward rotation of the iris–lens diaphragm.22 The effusion pla-
ces pressure on the vitreous body and causes anterior displacement and closure of
the angle. Conditions of surgery and anesthesia, especially those requiring prone posi-
tioning with large shifts in fluid status, may predispose patients on topiramate to devel-
oping acute closed angle glaucoma. The authors have seen such an incidence
of acute closed angle glaucoma in a patient with CP who had been on topiramate
for more than 1 year. After revision of her spine fusion, which lasted 4 hours, she devel-
oped closed angle glaucoma within the first 48 to 72 hours of recovery. Medical
management, and, finally, surgical intervention were necessary to adequately treat
her condition. Awareness, recognition, and treatment of closed angle glaucoma in pa-
tients who are on topiramate are necessary.
No discussion of CP is complete without a thorough review of spasticity, which is
the most functionally debilitating feature of CP.23 Cerebral palsy is associated with
spasticity in 75% to 85% of the patient population.24 Clinically, spasticity can present
as hyperactive reflexes, clonus, weakness, and discoordination. Some patients
benefit from their spasticity, as their stiffness aids with upright positioning and ambu-
lation.25–27 Other patients with spasticity have decreased range of motion, functional
impairment, pain, and deformities. For patients who do not benefit from their
increased muscle tone, the goals of spasticity therapy are to increase mobility and in-
dependence, to prevent or slow the development of contractures, to improve posi-
tioning, and to increase ease of care in those severely affected.26,27
Considering that environmental factors can aggravate spasms, it is important to
address any or all pertinent afflictions. These can include pain, fatigue, excitement,
cold, illness, sleep disturbance, immobility, and/or hormonal fluctuation.27,28 Physical
therapy and occupational therapy aim to maximize patient function and optimize results
of surgery. Therapy directed toward focal spasticity can be achieved with denervation
of neuronal input with phenol or Botulinum toxin injections. Orthopedic procedures
improve limb mobility and provide long-term efficacy. Selective dorsal rhizotomy
(SDR) is used to treat lower extremity spasms. In conjunction with postoperative reha-
bilitation, SDR has a favorable outcome; however, pediatric patients having SDR often
sustain lower extremity weakness. Increased spasticity because of pain often escalates
during postoperative care and pain management. Different modalities of treatment of
spasticity are discussed in the baclofen pump insertion section of this article.
SURGERY FOR SCOLIOSIS AND KYPHOSIS CORRECTION
The most commonly performed surgery for scoliosis and kyphosis correction in chil-
dren with CP involves primary instrumentation that fuses the spine from T1 to sacrum.
An occasional patient with mild CP may undergo a segmental spine fusion similar to an
idiopathic scoliosis correction. The discussion of scoliosis correction in this article
refers to the commonly performed spine fusion (T1 to sacrum) and instrumentation.
There are currently 2 instrumentations being used: (1) a precontoured rod known as
unit rod, which uses sublaminar wires to fix along the vertebral segments,29 and (2)
a modular system, or custom rod, which is contoured by the surgeon and employs
a double-rod system using screws with or without sublaminar wires to fix the rod at
vertebral segments (Fig. 3).
The quality of curve correction is different between the 2 systems. The unit rod pro-
vides superior correction, especially of pelvic obliquity, which has an impact on the
patient’s ability to sit (Fig. 4). However, unit rod instrumentation leads to greater blood
loss and longer ICU and hospital stay.30
Fig. 3. (A) Classic unit rod instrumentation, which is a double rod connected at the top that
has 2 pelvic legs drilled into the iliac bones. (B, C) Modular or custom rods, which may use
screws and or sublaminar wires (B) and may use the pelvic legs (C) or may not use the pelvic
legs (B).
A subpopulation of children with CP needs anterior spine release prior to posterior

spine fusion. For children with spastic quadriplegic CP who are severely developmen-
tally delayed, the anterior release is performed approximately 1 week prior to posterior
spine fusion.31 Occasionally, a child who is clinically judged to be healthier than the
average CP patient will have both anterior release and posterior spine fusion per-
formed on the same day. Flexibility is increased by anterior disc excision, allowing
greater correction with posterior instrumentation. Some surgeons prefer a thoraco-
scopic approach, particularly when the number of discs released is not large. This
approach requires one-lung ventilation, facilitating approach to the disc through the
scope, which otherwise can be difficult because of the movement of the lung. There
are studies, intended to benefit pediatric population, in piglets that examine one-
lung ventilation and interventions to reduce injury from one-lung ventilation.32–34
Indications for anterior spine release include scoliosis curve approaching 90 in a
growing child, a stiff curve where side bending to midline is difficult, or a kyphotic
curve that is stiff or is a significant impairment to sitting.
Anesthetic Management for Spine Fusion in Patients with CP
Spine fusion is the most extensive of the elective surgical procedures that patients
with CP undergo. A multidisciplinary approach is best when caring for these patients,
as most who need posterior spine fusion have the most debilitating kind of spastic
quadriplegic CP, with severe developmental delay and multisystem involvement. Pre-
operative workup should include neurology, pulmonology, and, less commonly car-
diac consultations. At our Institution we have, in the past, routinely performed
cardiac evaluations including an echocardiogram in patients with a scoliotic curve
Fig. 4. (A-1) Radiograph of the spine of the patient in (A-2). The same patient’s radiograph
of the spine is shown in (B-1), with the patient in a sitting position postoperatively following
spine fusion with unit rod instrumentation in (B-2). The obvious correction of the patient’s
pelvic obliquity is evident in the postoperative film. (Courtesy of Freeman Miller, MD,
Wilmington, DE.)
>900. However, a recent examination of our data has yielded little or no helpful find-
ings (manuscript in preparation). Therefore we no longer recommend cardiac evalua-
tion based on the degree of the scoliotic curve alone in our CP population. Note that
history of activity at school or ability to play sports is not of value, as most or all of such
patients are either physically inactive or only minimally active. Neurology consultation
is necessary for the consideration of seizure medications prior to and immediately
following spine fusion, during which the levels of seizure medications fall precipitously
and are often undetectable. A team dedicated to medically complex patients is ideal
and should be involved in care prior to surgery. Care should be continued postoper-
atively until the patient is discharged from the hospital.
Besides the general risk discussed earlier, spine fusion will require 2 large intrave-
nous lines, a central line, and an arterial line due to the anticipated blood loss.
Anesthetic agents used will largely be dictated by whether somatosensory and

motor-evoked potentials are being monitored during the spine fusion.35 Most patients
with CP will have neuromonitoring employed (Table 2), with the exception of an occa-
sional patient who will have such poorly recordable evoked potentials that monitoring
may be abandoned; in this case, a combination of volatile anesthetics, muscle relax-
ants, and narcotics is used. History of seizures, which was considered a relative
contraindication for neuromonitoring because of the possibility of provoking an
episode of seizure, is no longer considered a contraindication. In such situations,
the neurophysiology team often uses reduced-strength stimuli. When neuromonitoring
is planned, several anesthetics are recommended as part of the total intravenous
technique (note that a total intravenous technique is not practiced at all institutions,
and opinions vary among the neurophysiology teams as to the optimal anesthetic
techniques for neuromonitoring. It is not the intent of this article to cover this contro-
versial subject).
Recommended intravenous anesthetics for planned neuromonitoring include
Fentanyl, preferably continuous infusion or intermittent boluses; sufentanil, which
is often an ideal agent for idiopathic patients, might be too potent for the patient
with severe CP
Remifentanil infusion, which helps to decrease the amount of propofol
Ketamine infusion
Low-dose dexmedetomidine, no higher than 0.2 mg/kg/min (this dose has the
least influence on neuromonitoring)
Other considerations include
Optimizing the patient status by treating any preoperative treatable conditions,
such as reactive airway disease
Considering a prophylactic dose of methylprednisolone, 2 mg/kg up to 40 mg,
especially for anterior spine release and patients with reactive airway
disease32,36
Using simple measures, such as suctioning via endotracheal tube, before turning
the patient
Using procoagulants to reduce blood loss
Among procoagulants studied thus far, TXA has been shown to be more efficacious
in decreasing blood loss during spine surgery in patients with CP.37–41 TXA both re-
duces firbinolysis and reduces platelet aggregation.42 The dosage regime that the au-
thors currently use is a bolus of 50 mg/kg followed by 10 mg/kg/h infusion until skin
Table 2
Number and percentage of patients with CP- and non-CP-related neuromuscular scoliosis
(NMS) for whom monitorable somatosensory-evoked potentials (SSEP) and/or transcranial
electric motor$evoked potentials (TceMEP) could be recorded at baseline
Type of NMS SSEP TceMEP

Mild CP 4/4 (100%) 3/3(100%)
Moderate CP 12/12 (100%) 7/7(100%)
Severe CP 16/23 (70%) 9/10(90%)
No CP scoliosis 25/29 (86%) 25/29(86%)
From DiCindio S, Theroux M, Shah S, et al. Multimodality monitoring of transcranial electric motor
and somatosensory-evoked potentials during surgical correction of spinal deformity in patients
with cerebral palsy and other neuromuscular disorders. Spine 2003;28(16):1852; with permission.
closure.43 Fluid management during spine fusion needs to take into consideration the
suboptimal factor levels in patients with CP. Early use of fresh frozen plasma, cryopre-
cipitate, platelets, and red cells is most logical, or severe coagulopathy may result.
Given the expected blood loss of a one-to-three blood volume (sometimes more), pa-
tients may benefit from a management similar to patients undergoing major trauma.
Limiting crystalloids and transfusing plasma, platelets, and red cells have improved
patient outcomes in the trauma literature.44–49 the authors have found that patients
with CP undergoing spine surgery may benefit from a similar strategy of intraoperative
fluid management. The authors’ data from an ongoing study is indicative of greater
physiologic patient stability during both the intraoperative and postoperative periods
with this regime of fluid management. For institutions in which blood loss from spine
fusion is not of the same magnitude, it is logical to modify such trauma protocol-
based transfusion guidelines.
Postoperative management of these patients may frequently require mechanical
ventilation and ongoing fluid management including use of vasopressors. Patients
frequently undergo a systemic inflammatory response, which may be associated
with hypotension requiring use of vasopressors. Length of stay in the ICU is expected
to be 3 to 10 days, and the authors are currently examining factors that influence this
duration.30
DEROTATIONAL FEMORAL OSTEOTOMIES AND RECONSTRUCTIVE ACETABULAR

SURGERIES
Indications include subluxation and dislocation of the hip joints.
Pathophysiology
There is a high incidence of subluxation and dislocation of hip joints in patients with
spastic CP, especially in nonambulatory patients. Spasticity in these children allows
flexion and adduction to overpower extension and abduction, which, over a period
of time, results in subluxation or dislocation of the hip joints.50 These conditions are
painful, may cause decubitus ulcers, may interfere with perineal hygiene, and may
lead to imbalance while sitting. Operative treatment of these conditions is varus der-
otational osteotomy (VDRO) and pelvic osteotomy, and this may be combined with
soft tissue release as necessary. Revisions of such procedures may be necessary if
timing of the procedure is inaccurate, or insufficient attention is paid to the contrib-
uting factors, including spasticity of adductor muscles.51 Bilateral hip procedures
are almost always performed in this patient population.52,53 Given that each hip would
be subjected to a pelvic osteotomy as well as a femoral osteotomy, significant surgical
trauma, blood loss, and postoperative pain should be expected. Emphasis is placed
on adequate treatment of pain, which, unless treated optimally, will trigger spasms,
resulting in a vicious cycle of pain, spasm, pain. Detailed treatment of pain is dis-
cussed later in this article.
Surgical Procedure
Proximal femoral osteotomy and peri-ileal pelvic osteotomies are the most common
osteotomies performed for spastic disease of the hip joints in patients with CP. Prox-
imal shortening is performed to correct varus, derotation, or flexion extension. Blade
plates are inserted into the lateral aspect of the femoral shaft using screws (Fig. 5), and
the wound is packed. The peri-ileal pelvic osteotomy (referred to as pelvic osteotomy
from here on) is performed next, the indication for which is correction of posterior su-
perior acetabular dysplasia, the most common spastic hip disease. A second incision
Fig. 5. Radiograph of the pelvis showing the blade plates in the proximal femur, which are
fixed using screws. Acetabular osteotomy does not use instrumentation and therefore is not
distinguishable by radiograph. (Courtesy of Freeman Miller, MD, Wilmington, DE.)
is necessary and starts medial to the anterior superior iliac spine and extends laterally.
Reshaping of the acetabulum by wedge osteotomy is the main goal of this aspect of
the surgery.
Anesthetic Management of Bilateral Femur/Pelvic Procedures

Besides general risk, blood loss is often underestimated in pelvic osteotomies. A sig-
nificant amount of blood is lost on the drapes during drilling, and unlike spine fusion,
the surgical site is not as well suited for suctioning of blood. Expect hemoglobin to
drop 1 to 2 g postoperatively; consider this in deciding the need for transfusion during
the surgery. A good general rule is to consider transfusion if acetabular osteotomies
have been performed in addition to varus femoral osteotomies due to greater post
operative drop in their hemoglobin levels.
Factors important in postoperative pain management include
Spasticity and pain need to be treated simultaneously
For lower extremity osteotomies, consider a regional technique, which reduces
postoperative spasm54
When performing epidural anesthetics, use of fluoroscopy or ultrasound may be
necessary to aid in identifying midline structures due to kyphosis/scoliosis of the
spine
Documenting catheter tip position using iohexol (Omnipaque) is recommended
Benzodiazepines have remained the mainstay of treatment of spasticity in the
immediate postoperative period
Use of dexmedetomidine 0.5 to 1 mg/kg is useful as an adjuvant and is increas-
ingly employed intraoperatively or in the postoperative recovery period
Postoperative pain management of a spine fusion patient is largely determined
by whether the patient remains intubated
Use of agents such as fentanyl infusion will not be tolerated by a patient with CP
who has a natural airway
Minimizing opioids and taking advantage of adjuvant medications is
recommended
Adjuvants are intravenous acetaminophen, dexmedetomidine, and clonidine
patch (when patient is stable hemodynamically); ketorolac may be used after
discussion with the surgeon (unlike idiopathic spine fusion, where ketorolac is
commonly used for postoperative pain management, greater caution is exer-
cised when using ketorolac in CP patients for postoperative pain management;
due to the extensive nature of the surgical dissection, the surgeons are often
reluctant to the use of ketorolac in the immediate postoperative period for fear
of increased postoperative bleeding and may elect to wait till the first postoper-
ative day)
Patients who may have had prior spine fusion (T1 sacrum) may still be able to
have an epidural placed caudally (Fig. 6)
INTRATHECAL BACLOFEN PUMP INSERTION
Although treatment for spasm is initiated using oral medications with the goal to inhibit
excitatory or augment inhibitory neurotransmitters at the spinal cord,55,56 these drugs
have limited use because of adverse effects (Table 3). Another option for the treatment
of generalized spasticity is intrathecal baclofen (ITB), which requires a surgical
procedure.
Indications for ITB include when spasticity does not respond to oral medication or is
associated with adverse effects. ITB for cerebral spasticity was approved in 1996 by
the US Food and Drug Administration (FDA) for patients older than 4 years. It is asso-
ciated with fewer adverse effects than oral medications at same dosage.56 Lumbar
administration of baclofen results in one-fourth the concentration in the craniocervical
region.57 Tolerance to baclofen is not documented.58,59 Half-life of baclofen adminis-
tered intrathecally is 4 to 5 hours. Baclofen, 4-amine-3-(4-chlorphenyl)-butanoic
acid, is a muscle relaxant and antispasmodic drug. It is structurally similar to
Fig. 6. Caudal catheter and epidurogram using iohexol in a patient with CP who had a prior
spine fusion from T1 to sacrum using a unit rod. Patients with CP often lack adipose tissue
around the sacrococcygeal area, and bony landmarks are often felt more easily. However, in
the presence of a spine fusion, an epidurogram is recommended.
Table 3
Mechanism of action and adverse effects of commonly used oral agents
Oral Pharmacotherapy for Spasticity

Medication Mechanism of Action Adverse Effects
Benzodiazepine Binds GABA-a receptor and Sedation, ataxia, physical
increases GABA activity dependence, impaired memory
Alpha-2 adrenergic Binds alpha-2 receptors and Sedation, hypotension, nausea,
agonist hyperpolarizes neurons, vomiting, hepatitis
decreases excitatory
neurotransmitter release
Dantrolene Inhibits release of calcium at Weakness, nausea, vomiting,
sarcoplasmic reticulum hepatitis
Baclofen Binds GABA-b receptors, inhibits Sedation, ataxia, weakness,
release of excitatory hypotension
neurotransmitters in spinal cord
gamma-aminobutyric acid (GABA) and selective for GABAb receptors. GABAb recep-
tors are superficially located in the spinal cord in laminae 1 through 4. Binding of the
GABAb receptors inhibits monosynaptic and polysynaptic spinal reflexes by inhibiting
release of excitatory neurotransmitters presynaptically. Implanted pumps are used to
deliver continuous ITB. The pump weight, diameter, and size vary based on the model.
Reservoirs of different sizes can hold 10, 18, 20, or 40 mL of baclofen. Within the
implant, there is a peristaltic pump with a battery, which has a 3- to 7-year life span
and a telemetric control that allows for adjustments in dosing. Despite manufacturer’s
recommendations for use in patients over 4 years old, patient size is considered to be
a greater limitation to placement than age.60 The patient has to have enough distance
from the lowest rib superiorly, the iliac crest inferiorly, and the umbilicus medially to fit
the pump (Fig. 7). Prior to pump placement, a test dose of 25 to 100 mg of baclofen is
given by lumbar puncture. If bolus dosing results in a reduction by 1 of the Ashworth
score, a scale used for assessing spasticity, the patient is a candidate for pump
placement.28,60
Surgery for Baclofen Pump Insertion

The pump is placed with the patient under general anesthesia. The procedure itself
takes 1 to 1.5 hours. The surgeon creates a pocket in the anterior abdomen. This
pocket can be subfascial or subcutaneous. The intrathecal catheter is introduced
through a Touhy needle into the intrathecal space, tunneled around the flank, either
subcutaneously or under the fascia, and connected to the pump. The position of
the catheter is determined by the clinical goal. T8 to T10 levels allow for leg relaxation;
T3 to T6 levels allow for lower extremity and some upper extremity relaxation. C5–T5
placement is chosen for patients with severe upper extremity spasticity or opistho-
tonic posturing.61 A diaphragm located within the pump allows for reservoir refills
every 2 to 3 months. Drug dose escalation occurs more frequently within the first
2 years, with fewer adjustments in dosing being required subsequently.60
Significant complications associated with the ITB pump include
Drug delivery system (catheter breaks, dislodgements, and kinks with an inci-
dence of 5%–15%)
Infection, incidence of 5% to 46%61–64
Cerebrospinal fluid leakage, incidence of 2% to 8%62,65
Pocket seromas and/or hematoma
Fig. 7. Baclofen pump inserted into the right lower quadrant in a patient with cerebral palsy.
Figure on the left shows the pump in the location of the abdomen where it will be inserted.
(Circled A-C) indicates the reservoir, the connecting catheter exiting from the pump to attach
with the catheter placed intrathecally. Figure on the right is the X-Ray of the pump after
placement in the patient. (Courtesy of Freeman Miller, MD, Wilmington, DE.)
Medication-related adverse effects include

Constipation, incidence of 19% to 38%62
Nausea and vomiting, incidence of 11% to 14%
Headache, incidence of 11% to 12%
Increased oral secretions
Lower extremity deep vein thrombosis
Decubitus ulcers
Hypotonia
Somnolence
Drug titration alleviates most issues related to dosing.
Baclofen Overdose
There are many case reports related to baclofen overdose.62 This can be due to pump
malfunction, but it can also be associated with drug error. Mild overdoses can be
treated with physostigmine or flumazenil.66 Clinically, the authors have not seen
much efficacy with the use of either of these 2 drugs to reverse baclofen-related
obtunded state. A severe overdose of baclofen can lead to coma and flaccidity
requiring mechanical ventilation. At the authors’ institution, 3 episodes of overdose
occurred with ITB pump placement. This was determined when the patient did not
arouse from anesthesia, and careful review of the drugs suggested the most likely
source was an overdose of baclofen. Subsequently, the patients were admitted to
the ICU; one patient required assisted ventilation. All 3 patients had returned to base-
line within 24 to 36 hours.
Withdrawal from baclofen is felt to have greater consequence. The adverse effects
range from mild to severe. Mild withdrawal can present as increased spasticity, itch-
ing, and agitation. Severe withdrawal can present as psychosis, hyperthermia, dyski-
nesia, neuroleptic malignant syndrome, and, potentially, death.60,67 Withdrawal can
be treated with initiation of oral baclofen, benzodiazepines, supportive measures,
and surgical correction of the system malfunction. In protracted cases, temporary
placement of a subarachnoid catheter to administer intrathecal baclofen is warranted.
Many studies have demonstrated improvement in pain, comfort, and decreased
worsening of deformities with ITB.58,68 Functional and motor capabilities have also
shown improvement with ITB.69 Despite a significant risk of complications, ITB has
a high (81%) rate of caregiver satisfaction, and 87% of caregivers are willing to recom-
mend ITB therapy.70
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C h a l l e n g e s i n Pe d i a t r i c
N e u ro a n e s t h e s i a
Awake Craniotomy, Intraoperative Magnetic
Resonance Imaging, and Interventional
Neuroradiology
Craig D. McClain, MD, MPH*, Mary Landrigan-Ossar, MD, PhD
KEYWORDS
Pediatric Intraoperative magnetic resonance imaging Awake craniotomy
Neurointerventional Neuroendovascular Pediatric neuroanesthesia
KEY POINTS
There are many complexities to the care of children undergoing awake craniotomies.
The anesthesiologist must be prepared to deal with a variety of urgent and emergent intra-
operative scenarios.
When the techniques of cortical mapping are combined with an awake, responsive pa-
tient, optimal outcomes can be realized.
Intraoperative magnetic resonance imaging offers high-resolution intraoperative images
that can assess the extent of resection in pseudoreal time.
Angiography and embolization are frequent procedures performed in the neurointerven-
tional suite to address a variety of pediatric neurovascular lesions.
INTRODUCTION
Anesthesiologists involved in caring for children undergoing neurosurgical procedures

are required to have an intimate understanding of normal neurocognitive devel-
opment, the effects of anesthetics on the developing nervous system, the fundamental
differences between children and adults, and the implications of these surgical
approaches to children. Several surgical approaches such as image-guided proce-
dures and awake craniotomies add to the complex environment faced by the anesthe-
siologist. In addition, the neurointerventional suite has become increasingly used as
Disclosures: the authors have no disclosures to make.

Department of Anesthesiology, Perioperative and Pain Medicine, Boston Children’s Hospital,
Harvard Medical School, 300 Longwood Avenue, Bader 3, Boston, MA 02115, USA
E-mail address: craig.mcclain@childrens.harvard.edu

84 McClain & Landrigan-Ossar
children with a variety of neurovascular lesions present for often lengthy and compli-
cated procedures for definitive diagnosis or treatment. Planning and executing safe,
age-appropriate perioperative care in these environments is challenging. This article
offers some insight into the complexities of care of children undergoing awake crani-
otomies as well as procedures in intraoperative magnetic resonance imaging (iMRI)
suites and neurointerventional radiology.
AWAKE CRANIOTOMY
History of Awake Craniotomy
Evidence of craniotomy predates the invention of surgical anesthesia by several
millennia. There is evidence of trepanation (creating a hole through the skull and
dura) in human skulls unearthed in France from approximately 6500 BC.1 In addition,
it is clear that several pre-Columbian societies in Mesoamerica practiced trepanation,
most notably, the Incas.2,3 During the Middle Ages and Renaissance in western
Europe, trepanation was performed to alleviate headaches and seizures.4 Dutch
painter Hieronymus Bosch famously captured this practice in his painting, The Extrac-
tion of the Stone of Madness, from the late fifteenth century.
The modern use of awake craniotomy (AC) began in the second half of the nineteenth
century, when local anesthetics became widely available. With good local anesthesia,
Horsley was able to perform ACs.5 However, the modern understanding of the benefit
of AC began in 1951, when Wilder Penfield, the first director of the famous Montreal
Neurologic Institute, published his landmark monograph, Epilepsy and the Functional
Anatomy of the Human Brain.6 Penfield described the use of craniotomy performed
under local anesthesia only to facilitate resection of epileptogenic foci. Before resection,
Penfield stimulated various locations of the cortex and observed the responses in the
awake patient. This practice allowed him to generate cortical maps of motor and sensory
areas, which result in cortical homunculus.
The 1960s brought the advent of neuroleptic anesthetic techniques, which continued
to provide a responsive patient but offered some degree of analgesia and sedation in
order to tolerate prolonged awkward positions.7 A combination of drugs such as dro-
peridol and fentanyl were commonly used to facilitate a patient who was drowsy and
comfortable, yet still able to arouse to stimulation and follow commands. The downside
of prolonged use of dopaminergic drugs became apparent when the occurrence of side
effects, including extrapyramidal effects and dysphoria, was noted.
AC as a method of treating seizure foci and tumors became popular again in the
1990s and early 2000s, with the widespread use of shorter-acting hypnotic agents
and opioids, such as propofol and remifentanil.8,9 Current anesthetic techniques
use a wide range of agents. Dexmedetomidine, an a2 agonist with sedating and anal-
gesic properties, is a relatively newer drug that offers some distinct advantages over
other techniques using sedative hypnotics and opioids.10,11 One of the most advanta-
geous aspects of dexmedetomidine is its ability to offer mild analgesia and good seda-
tion without compromising the airway.
AC in Children
Equipment
No special equipment is needed for the performance of AC. The anesthesiologist
should have the operating room (OR) prepared for the same problems that may be
encountered during a craniotomy under general anesthesia. Invasive blood pressure
monitoring is useful. The anesthesiologist should be prepared to convert to a general
anesthetic if needed. Airway management while the patient is in head pins can be
Challenges in Pediatric Neuroanesthesia 85
particularly problematic. It can be lifesaving to have properly sized supraglottic airway

devices within easy reach. More advanced airway tools may be necessary to provide
definitive airway management.
The anesthesiologist must be prepared to deal with a variety of urgent and emergent
intraoperative scenarios. This strategy applies to any surgical case, but may be more
important for an AC. Seizures, which can occur during cortical mapping in an AC, must
be quickly and effectively controlled to prevent patient injury. Seizures are more
common in younger patients with frontal lobe lesions.12 Generalized tonic clonic
movements can be devastating to a patient who is fixed in head pins. Injuries that
may result can range from scalp lacerations to skull fractures and even cervical spine
injuries. Anesthesiologists should always have a heightened sense of concern with an
unrelaxed patient fixed in head pins (awake or under general anesthesia).
Indications
The benefits of having a responsive patient during surgery performed near eloquent
cortex are legion. Most commonly, AC is performed on patients with lesions located
near, adjacent to, or even within eloquent cortex. Intraoperative cortical mapping
can be used to identify areas that are dysfunctional as well as those cortical areas
that control important functions such as speech and motor movements. When the
techniques of cortical mapping are combined with an awake, responsive patient,
optimal outcomes can be realized. A prospective comparison in 201113 of AC versus
craniotomies performed under general anesthesia for resection of supratentorial
lesions found a statistically significant improvement in resection quality and better
neurologic outcome in the awake patients.
Certainly a useful technique in adults, AC in pediatric neurosurgical patients
presents the anesthesiologist with a tremendous challenge, because of the differ-
ences in level of cognitive development of children. The youngest patient reported
in the literature to have successfully undergone an AC is a 9-year-old boy, who under-
went resection of a glioblastoma in the left frontotemporal region using propofol seda-
tion.14 Despite this reported success, it is unlikely that many children younger than
10 years are emotionally mature enough to tolerate such a procedure.
Contraindications
Proper patient selection is probably the single most important factor in achieving an
optimal outcome for an AC. Relative contraindications include patient’s age (<11 or
12 years old) and the patient’s general level of emotional maturity. There may be
12-year-old patients who are candidates for an AC, whereas a particular 16-year-
old may not be amenable to such an approach. It is crucial to have thorough discus-
sions with both the patient and their parents before embarking on such an endeavor.
Further, similar conversations should occur with the neurosurgeon and neurologists
involved in order to determine the plan of cortical mapping and what the patient is
required to do.
Patient preparation
As noted earlier, proper patient selection and preparation are paramount. During pre-
operative conversations with the parents and child, the keen pediatric anesthesiolo-
gist is able to get a good assessment of the child’s emotional maturity and
consequent ability to tolerate the proposed procedure. The patient must be able to
calmly and coherently express their needs and concerns to the anesthesiologist,
and there needs to be a certain degree of trust.
Technique best practice

A variety of anesthetic approaches are currently used. There is no single best
approach. Each has its advantages and disadvantages. The individual anesthesiolo-
gist needs to have a clear understanding of what the surgical and neurophysiologic
needs are. The specific anesthetic technique may be adopted to best facilitate the
goals within the resource constraints (both human and physical) of the given
environment.
Essentially, the differences in technique boil down to the degree of anesthesia/
sedation used before and after cortical mapping. One approach is to perform the
entire procedure with the patient completely awake.15 This approach necessitates a
mature, motivated, and cooperative child, because several tasks need to be accom-
plished with an awake or minimally sedated patient, including line placement, infiltra-
tion of local anesthetic, placement of head pins, positioning, skull and dural opening,
and resection. This type of approach is well described in the adult literature. A variation
on this technique uses short-acting sedatives and analgesics, such as propofol and
fentanyl, titrated to induce unconsciousness but maintain spontaneous ventilation
for instillation of local anesthetics, insertion of monitoring catheters, placement of
head pins, and skull opening.9,16 Subsequently, patients can be allowed to awaken
to facilitate cortical mapping before definitive resection. After that, the patient may
then have sedatives and opioids reinstituted for the closure.
Another approach is the asleep-awake-asleep technique.17 This approach consists
of inducing general anesthesia and maintaining airway control with a supraglottic
device. General anesthesia is maintained for line placement, placement of head
pins, positioning, and skull and dural opening. The patient is then awakened, the
supraglottic airway is removed, and the surgeons then proceed with mapping and
resection. At the conclusion of the resection, general anesthesia is once again induced
and the supraglottic airway reinserted for closure of the dura, skull, and skin. Although
this technique offers the patient a stress-free procedure up to the point of functional
testing and cortical mapping, there are some disadvantages. Airway management
during emergence and induction while the patient is in head pins presents a greater
challenge. Should the patient cough or buck while immobilized, cervical spine injuries
or scalp lacerations can occur. In addition, brain swelling is a real concern in a patient
who is breathing spontaneously under general anesthesia with an inhalational anes-
thetic and possibly nitrous oxide.
Procedural steps
Line placement and placement of head pins in a child is the first challenge for the anes-
thesiologist. As noted earlier, short-acting, potent sedatives and analgesics such as
propofol and remifentanil may be useful to ensure patient cooperation with placement
of multiple intravenous (IV) lines, arterial lines, and a Foley catheter. These same
agents may also be useful for placement of head pins. Another useful adjunct for scalp
analgesia to facilitate placement of head pins is a scalp block.18 Dosing adjustments
of local anesthetic should be made to account for differing sizes of pediatric patients.
Positioning is best undertaken with an awake patient if at all possible. The advan-
tage to having an awake patient at this juncture is that the patient can communicate
what is most comfortable to them and give feedback as to how to optimize the posi-
tion. A comfortable position is crucial, because the patient needs to remain there for
several hours. It is common for patients to become anxious. Discomfort from awkward
positions only exacerbates this problem. An important aspect of optimal patient posi-
tioning is the creation of a tent or drape tunnel so that the patient does not feel covered
up and can see the anesthesiologist (Fig. 1).
Fig. 1. Pediatric patient during an AC. Note creation of tunnel or tent so that patient can
see anesthesiologist and communicate. Note also the head pins in place and the awkward
position that the patient is required to maintain for several hours.
Regardless of the chosen technique, it is most important that the anesthesiologist

themselves (or a trusted designee) remain in close visual contact and verbal commu-
nication with the patient at all times. Communication of every aspect of patient care in
the OR suite must be clear and age appropriate for the patient. It is the anesthesiolo-
gist’s job to decrease the patient’s stress. In this setting, that responsibility involves
letting the patient know who is in the room, what kinds of questions are being asked,
explaining what they may feel, explaining noises, getting feedback about level of
comfort, and distracting the patient to minimize anxiety. This is one of the most chal-
lenging aspects of an AC. It is useful to aggressively control traffic in the room, so that
there is not a constant parade of people of various specialties coming in and out and
inundating the room with multiple conversations. These things can be confusing and
anxiety provoking to a patient who cannot see where the voices and noises are coming
from and may feel like no one is talking to them.
If the patient is sedated during cranial and dural opening and initial exposure, it is
important for them to be awake enough to engage in neurologic testing by the team.
This testing may involve language skills, identifying pictures, memory tests, and so
forth. This is the crucial moment for creating the cortical map to help facilitate resection
of the lesion. If this part of the procedure cannot be accomplished effectively, the whole
point of performing the procedure on an awake patient is rendered moot.
After mapping and resection, the remaining surgical steps involve closure and
removing the head fixation device. This procedure can be performed using sedation
as needed. It is often a welcome break for the patient to be sedated at this point,
because they are often uncomfortable from awkward positions by this point of the
procedure.
Postprocedure care
Caring for patients who have undergone ACs in the postoperative period should have
little difference from postoperative care for pediatric patients who have had craniot-
omies performed under general anesthesia. Frequent neurologic assessments are
the most sensitive indicator of postoperative problems. Control of pain and hemody-
namic parameters is an important goal. The common complications after a craniotomy
performed under general anesthesia are similar to those for ACs: bleeding, cerebro-
spinal fluid (CSF) leaks, electrolyte disturbances, and postoperative emesis. If the pro-
cedure is performed to resect seizure foci, caregivers must be keenly aware of the risk
for postoperative seizures and have a plan for treatment.
Avoiding complications
Regardless of the technique chosen, it is important for the anesthesiologist to have
an in-depth discussion with the patient with respect to intraoperative needs and ex-
pectations. The preoperative period is the time to decide whether the patient is a
candidate for an AC. There are no randomized controlled trials comparing the safety
or effectiveness of the techniques just described.
Common complications during ACs include seizures, failure of adequate communi-
cation with the patient, and hemodynamic derangements, including tachycardia and
hypertension.12,19,20 These problems have been noted in larger series of adult ACs.
There are no such data for children. Despite this situation, anesthesiologists should
be prepared to immediately address such concerns in pediatric patients.
iMRI
History of iMRI
The development of iMRI represents a significant leap in the continued effort to
improve intraoperative navigation and the quality of resection of intracranial masses.21
iMRI was first used in the mid-1990s for adult intracranial procedures.22 However, its
success was soon exported to pediatric neurosurgical procedures.23 Coupled with a
frameless navigation system, iMRI offers state-of-the-art ability to localize lesions as
well as improve the quality and pseudoreal time assessment of resection during
neurosurgical procedures. iMRI suites are common, with an increasing number of
such suites being located in pediatric hospitals.24,25 Thus, it is becoming increasingly
important for pediatric anesthesiologists to be familiar with the unique considerations
of working in an iMRI suite.
Before the advent of iMRI, frame-based or frameless navigation systems were used
to aid in localization of intracranial lesions in children. Both types of navigation sys-
tems are predicated on layering a series of fixed points (often using either fiducials
or a face recognition system) over previously obtained imaging. Although these
systems were certainly advantageous, they had their limitations.
First, although these systems offer improved ability to localize lesions that may be
difficult to differentiate with the naked eye (such as in deep brain structures or near
eloquent cortex), they offer no opportunity to intraoperatively assess extent of resec-
tion. iMRI offers high-resolution intraoperative images, which can assess the extent of
resection in pseudoreal time. This technique may lead to improved patient outcomes
and decrease the need for unnecessary second operations in some situations.
Further, these types of navigation systems cannot account for the phenomenon of
brain shift, which occurs naturally during intracranial surgery.26 Brain shift describes
the movement of intracranial structures throughout the procedure. Brain shift leads
to decreased accuracy of navigation because of position changes, egress of CSF
from the cranium, and mass resection. The degree of brain shift can vary with resected
tissue type, patient position, CSF loss, size of craniotomy, hyperventilation, and
amount of tissue resected. As the duration of the surgery increases, so does the degree
of brain shift. This situation leads to the decreased accuracy of conventional intraoper-
ative navigation systems. The advantage that iMRI offers is that images obtained intra-
operatively can update the navigation systems and allow for continued precision.
Equipment
Much like any anesthetic performed to facilitate diagnostic MRI, anesthetics delivered
during procedures that use iMRI require a significant investment in special equip-
ment.27,28 Special MRI-conditional physiologic monitors are required, as are MRI-
conditional anesthesia machines and MRI-conditional infusion pumps. Depending on
the particular configuration of a given iMRI suite, it may be possible to use normal sur-
gical instruments, microscopes, drills, tables, and so forth (Fig. 2). However, in suites in
which there is either a movable patient and stationary magnet or a movable magnet
with a stationary patient, the patient still needs to have safe delivery of an anesthetic
during imaging sequences. This procedure necessitates the MRI-safe anesthesia
equipment during the maintenance phase of the anesthetic.
There are a limited number of manufacturers who produce such equipment. The
equipment itself tends to be more expensive and more delicate than standard physi-
ologic monitors, anesthesia machines, and infusion pumps. Also, there are certain
limitations to such equipment. Pulse oximeters are often more sensitive to motion arti-
fact and it can be difficult to obtain a consistent signal in a small child or cold digit.
Electrocardiographic (ECG) interpretation can be challenging, especially during
imaging, when the fluctuating magnetic fields can cause significant interference. ST
analysis can be profoundly unreliable. Core temperature monitoring is not nearly as
simple in an MRI environment. Some manufacturers have produced a temperature
probe, which can be covered with a disposable condom.
Fig. 2. A common iMRI setup. This system uses a movable magnet and stationary patient.
This is the system used at our institution.
There are also several pieces of essential equipment that do not have an MRI-safe
or conditional analogue. This equipment includes forced-air warming devices, nerve
stimulators, precordial Doppler probes, and fluid warmers. The lack of availability of
certain MRI-compatible equipment creates challenges in the iMRI environment. This
situation results in the anesthesiologist being responsible for accounting for several
items that must be removed from within the 5-Gauss line when magnet deployment
and imaging occur. The existence of a movable magnetic field creates unique chal-
lenges to the care team. The modern iMRI environment is not analogous to diagnostic
MRI, in which is a stationary field. Because of the movable field, iMRI is unlike any
other environment within which the anesthesiologist works.
Indications
The indications for a pediatric neurosurgical procedure using iMRI can be diverse,
depending on the capabilities of the magnet itself.29 Most commonly, iMRI is used
to help facilitate intracranial tumor resection. iMRI can be used to help localize small
masses, improve precision of other intraoperative navigation systems, and assess
extent of intraoperative resection in pseudoreal time. In addition, iMRI may be used
to help delineate the extent of cortical disconnection in major seizure surgery, such
as corpus callosotomy or functional hemispherectomy.
As imaging technology improves, the opportunities for iMRI to aid in pediatric neuro-
surgical procedures will expand. For example, there are new approaches to ablation of
deep brain lesions using stereotactic MRI-guided laser-induced thermal ablation.30,31
This technique requires multiple intraoperative images, with the ablation completed in
real time while imaging.
Contraindications
A large volume of literature champions the safety of iMRI for many different tumor
types and surgical approaches. However, there is little guidance for practitioners on
exclusion criteria for patients being operated on in an iMRI suite. It may be easiest
to break down the absolute and relative contraindications into some broad categories.
First, we can look at the patient characteristics that may prevent that child from even
entering the iMRI suite. Children who have certain implantable devices may be abso-
lutely excluded from a high-strength magnetic field environment. Examples of these
devices may include implanted cardiac devices (ICDs) (pacemakers and defibrilla-
tors).32,33 Although this remains generally the case, the prevalence of magnetic reso-
nance (MR)-compatible ICDs and pacemakers is becoming more common. Other
devices such as vagal nerve stimulators or certain types of programmable ventricular
shunt valves may be acceptable, depending on the field strength of the magnet.34 It is
crucial to always consult with the MR technologist or radiologist when there is a ques-
tion about the safety of implantable devices.
There are also some relative contraindications because of both the environment of
the room and the size of the bore of the magnet. It can be difficult to perform lengthy
surgical procedures on infants and small children in an iMRI suite for several reasons.
First, the room itself must be kept cold to provide an optimal magnetic field for imag-
ing. Thus, patients such as neonates under general anesthesia, who cannot effectively
self-regulate temperature, are at particular risk for hypothermia and its conse-
quences.35 In our suite, we prefer to avoid having such patients in the iMRI room, un-
less there is some compelling reason to use the magnet and it aids in optimizing the
child’s outcome. In addition, the MRI-conditional equipment itself can be more difficult
to use in small children, in our experience. Movement artifact is more common with
pulse oximetry and ECG. Because of these issues with small children, we prefer not
to care for children less than 10 kg or 1 year old, unless there is significant potential
benefit that would alter the risk/benefit ratio in favor of accepting the risks.
Some patients may be too large to safely place in the magnet intraoperatively. Mag-
net bores vary in size, and practitioners must be aware of the limitations of their partic-
ular magnet. Once the patient is under anesthesia and under surgical drapes, they are
not able to alert the care team to potential positioning problems within the magnet. In
order to maintain sterility during intraoperative imaging, the patient remains draped
and padded underneath. This situation further increases the footprint of the patient
(Fig. 3). It is useful to have a template for sizing the patient preoperatively to determine
if larger or obese patients are able to fit in the iMRI. Caregivers should take into ac-
count that the bulk from the drapes and padding is not accounted for in this situation.
Patient preparation
Specific patient preparation for procedures in an iMRI suite should be directed at
screening to ensure the appropriateness of the patient for a high-strength magnetic
field environment. Usually, the MR technician is considered the safety official.36 There-
fore, questions and concerns about the appropriateness of given implantable devices
for a given MRI should be directed to the MR technician. All implanted devices, such
as ventriculoperitoneal shunts, baclofen pumps, aneurysm clips, orthopedic hard-
ware, and so forth, must be noted and cleared by the safety officer. In addition to
the patient, all other people entering the room must also be cleared, including all
medical personnel and parents if it is planned that a parent is to be present during
the induction.
Aside from these considerations, the preparation of the patient for a procedure in an
iMRI suite should proceed similar to the preparation of a patient for the same proce-
dure in a conventional OR suite.
Technique best practice

Although the equipment that the anesthesiologist uses caring for the patient in an iMRI
suite may be different from a conventional OR, the basic approach and anesthetic
techniques should not be significantly different from similar procedures performed
in a conventional OR suite. For craniotomies, common techniques such as total IV
anesthesia or inhaled anesthesia and high-dose opioid are acceptable. No single
best anesthetic technique has been identified for craniotomies.37
Fig. 3. Patient being placed into movable 1.5-T iMRI. Note the degree of draping to pad and
protect the patient as well as maintain sterility.
Procedural steps
When caring for patients in an iMRI environment, practitioners must develop pro-
cesses that account for the different risk profile resulting from the movable magnetic
field presented to the patient and caregivers. These additional considerations include
accounting for necessary MRI-incompatible equipment used before placing the
patient in the high-strength magnetic field. Examples include IV needles, airway equip-
ment, manometers, flashlights, scissors, and so forth. Inadvertently leaving
MRI-incompatible equipment around the patient and subsequent placement in a
high-strength magnetic field can result in serious injury or even death to the patient
or caregivers if the object is ferromagnetic and becomes a missile. Even if the object
is not ferromagnetic, it may still present danger to the patient by being a potential
source of thermal injury. Some objects can also cause problems by interfering with
image quality by introducing interference.
Other necessary MRI-incompatible devices include forced-air warming devices and
nerve stimulators. These devices are certainly useful and necessary in modern prac-
tice, but no MRI-compatible version is commercially available. They can be used
safely before placement of the patient in the high-strength magnetic field. Thus, the
issue that arises has to do with the safe use of MRI-incompatible equipment in a
movable magnetic field environment.
One solution is to create a series of checklists. We have used such a system in our
practice with great success. When setting up our iMRI suite, we designed several
different checklists to be implemented at critical steps in the surgical procedure to ac-
count for potential hazards and try to minimize adverse events. The first checklist oc-
curs after induction but before draping the patient. This checklist is designed to ensure
that, after induction, line placement, and positioning, there are no unaccounted for
MRI-incompatible materials near the patient that would be hidden by the drapes
when it comes time to image. After the initial checklist and ensuring appropriate
counts of equipment and instruments, the surgical procedure occurs. Before deploy-
ing the movable magnet, another checklist is implemented. At this point, the nurses
ensure accurate counts of all instruments and sutures. The same process occurs
for the anesthesia provider. The anesthesiologist must ensure that the airway equip-
ment, all IV lines and wires, nerve stimulator, forced-air warmer, fluid warmer, and pre-
cordial Doppler are moved outside the 5-Gauss line. Once all equipment is accounted
for, the magnet is deployed and intraoperative imaging occurs. If repeat imaging is
required after further resection, the process is repeated.
Postprocedure care
Postoperative care of children who have undergone neurosurgical procedures using
iMRI is, in most ways, the same as for those undergoing similar procedures in a con-
ventional OR suite. One caveat is that in suites that take advantage of a high field
strength magnet (eg, 1.5 or 3 T), intraoperative images may obviate routine postoper-
ative MRI. This has certainly been the case at our institution, where we have essentially
eliminated the need for routine postoperative MRI evaluation of children who have un-
dergone craniotomy with iMRI. There remain instances of requests for postoperative
MRI, but these are universally because of some specific concern that would not be
evident on intraoperative images obtained at the end of the case. iMRI has been
shown to help in early diagnosis of some rare serious complications, such as intracra-
nial bleeding, before significant patient compromise.38 Avoidance of such routine
postoperative imaging is advantageous, especially in young children. In addition to
avoiding the logistic challenges of scheduling an MRI in busy centers, young children
may avoid a second anesthetic and the attendant risks.
Avoiding complications
Proper training, patient selection, and establishment of strong lines of communication
across disciplines optimize the environment to offer the safest, best possible outcome
to the patient. We began the development of our suite by using a multidisciplinary
approach involving all clinical departments involved in caring for patients in this envi-
ronment: anesthesiology, neurosurgery, radiology, and nursing. We have continued to
have regular meetings of a core group to ensure that this cross-disciplinary commu-
nication is maintained as this technology evolves. This strategy allows us a great
deal of flexibility to address concerns as they arise. These concerns can include prob-
lems with or updates to the iMRI system itself, issues with the anesthesia equipment,
advances in technology that affect the room, near misses, and the use of simulation
approaches to address rare but serious concerns related to the suite.
The use of iMRI is becoming increasingly common. Practitioners must be aware of
the unique considerations when caring for patients in this environment. Its proponents
tout the purported benefits of iMRI. Practitioners must recognize that there are also
some potential downsides as well. Delivering an anesthetic for a patient in diagnostic
MRI is challenging enough. The additional concerns of performing a surgical proce-
dure in a suite with a movable high-strength magnetic field demand a thoughtful
approach from the anesthesiologist.
NEUROINTERVENTIONAL PROCEDURES
It is becoming increasingly common for children with a variety of intracranial diseases

to require anesthesia for diagnostic imaging. In particular, children with some neuro-
vascular lesions require either isolated diagnostic imaging or therapeutic interventions
in the neurointerventional suite. Angiography and embolization are frequent proce-
dures performed in the neurointerventional suite to address a variety of pediatric neu-
rovascular lesions. This section describes the complex considerations of caring for
children with significant neurovascular disease out of the OR.
DIAGNOSTIC CEREBRAL ANGIOGRAPHY

Equipment
Specialized anesthesia equipment is not generally necessary in the interventional
radiology (IR) suite, unlike in MRI. Nonetheless, there are several considerations
worthy of comment. It is generally accepted that older anesthesia equipment is rele-
gated to the non-OR anesthesia (NORA) milieu.39,40 Closed-claims data have shown
that patients in the NORA environment are more likely to suffer more serious harm,
and inadequate monitoring is cited as a contributor.41 Anesthesia equipment in IR,
in which lengthy complex cases are performed on sicker patients, should be standard-
ized with that being used in the main OR. This strategy promotes safety not only by
allowing the use of up-to-date technology for complex patients but also by reducing
the chance of operator unfamiliarity with little-used devices.
Radiation safety in IR is another area of particular concern for anesthesiologists. As
IR anesthesia services increase, anesthesiologists will have increased exposure to ra-
diation. In the procedure room, anesthesiologists’ exposure to radiation is 3-fold
greater than that of radiologists on the opposite side of the procedure table, because
of scatter radiation.42 To reduce exposure, anesthesiologists should wear lead
aprons, preferably wrap-around, and protective eyewear. Portable lead shields should
be placed between the radiation source and the anesthesiologist. If feasible, the anes-
thesiologist should leave the room during angiography runs.43 Portable dosimeters
should be worn and monitored in compliance with local regulations. Because cerebral
angiography is generally performed with biplane imaging, the dose to the anesthesi-
ologist is increased, making these precautions even more necessary (Fig. 4).
Indications
Diagnostic cerebral angiography in pediatric patients is generally reserved for those
cases in which computed tomographic angiography or MR angiography provides
partial or questionable information and is the reference standard for diagnosis of neu-
rovascular pathology.44,45 This finding is borne out across several institutions, where
the most common indications are stroke (including moyamoya disease), hemorrhage,
and postoperative evaluation of cerebrovascular treatment.46,47
Patient Preparation
Because this procedure is often brief, little beyond routine preparation for general
anesthesia is required. Preoperative blood pressures are helpful in establishing a
baseline for comparison with intraoperative values. Parents may continue clear oral
fluids until 2 hours before the procedure in the hope that euvolemia contributes to
hemodynamic stability on induction of anesthesia. IV access should be sufficient for
adequate hydration, because the likelihood of significant blood loss is low.
Technique Best Practices and Procedure Steps

Once arterial access is accomplished (usually via a femoral artery), a catheter is
advanced over a guide wire with fluoroscopic guidance to the carotid or vertebral
arteries. Angiography is performed with apnea for the 10-second to 15-second angio-
graphic runs. Once imaging is complete, the arterial sheath is removed, and pressure
is held until hemostasis is achieved (15–20 minutes). Patients are kept flat in the recov-
ery area for several hours to assist with hemostasis.47
General endotracheal anesthesia is most commonly used in pediatric patients.48 A
more mature patient can successfully accomplish the procedure with anxiolysis. How-
ever, sedation beyond anxiolysis can be problematic, because the patient may
become disinhibited and not be able to comply with breath holding.
Fluid management during cerebral angiography is aimed at preserving normoten-
sion by restoring euvolemia after fasting. Euvolemia to slight hypervolemia is prefer-
able to reduce the chances of kidney damage in the setting of a contrast-induced
osmotic diuresis.49,50 Painful stimuli associated with this procedure are minimal
Fig. 4. Room setup for biplane imaging in cerebral angiography. Note radiation sources
both below the procedure table and immediately adjacent to the anesthesiologist.
once arterial access is established, and the need for long-acting opioids is low.
Muscle relaxation can be helpful in achieving apnea for angiography but is not
mandatory.
Postprocedure Care
One challenge for pediatric patients is the need for flat bed rest for 2 to 6 hours
after removal of the femoral sheath, to reduce the chances of postprocedural bleeding
or hematoma.51 Behavioral techniques such as reassurance and distraction can be
useful, and chemical adjuncts can help for a younger or less compliant child. Deep
extubation aided by longer-acting narcotics or an a2 agonist, such as clonidine, can
assist a child to sleep quietly in the recovery area.48,52
Avoiding Complications
Complication rates for cerebral angiography in the range of less than 0.4% have been
found in large pediatric series with experienced neuroradiologists.45,46,48 The most
common problem seen is bleeding or hematoma at the femoral puncture, and even
this is rare.53 Neurologic or vascular complications of catheterization are extremely
low in children, as are nephropathic consequences of contrast administration in
patients with no preexisting renal dysfunction.
The risk of acute allergic-like reactions when low-osmolality contrast is used is less
than 1%.54,55 These reactions usually occur within 1 hour of administration and range
from nausea, rash, and mild hemodynamic changes to severe reactions involving ur-
ticaria, bronchospasm, and hemodynamic collapse. Although similar to anaphylaxis,
their nature is still a matter of debate. Mild reactions are treated symptomatically
and are usually self-limited. Treatment of severe reactions is the same as the treatment
of anaphylaxis, with hemodynamic and airway support, antihistamines, steroids, and
epinephrine when indicated.55 In patients at high risk for a reaction (history of previous
reaction, asthma, or atopy), pretreatment with corticosteroids and antihistamines is
standard.
NEUROENDOVASCULAR INTERVENTIONS
Equipment
Equipment requirements and safety considerations for neurointerventional proce-
dures are similar to those required for diagnostic cerebral angiography.
Indications
Indications for neurointerventional procedures include embolization of intracerebral
vascular anomalies, such as arteriovenous malformations, arteriovenous fistulae,
and aneurysms, and targeted injection of intra-arterial chemotherapy for tumors
(Fig. 5).56–59
Patient Preparation
Because of the often lengthy nature of these procedures, meticulous patient posi-
tioning and padding are crucial, because it may be impossible to reposition a patient
once a procedure is under way. Good IV access should be obtained primarily for hy-
dration and drug administration, because the chance of blood transfusion is small. An
arterial line for blood pressure monitoring is usually required for close blood pressure
monitoring as well as regular assessment of activated clotting times (ACTs) if heparin
is administered.
Fig. 5. Angiography before (A) and after (B) embolization of right frontal lobe arteriove-
nous malformation in a 9-month-old male.
Technique Best Practices and Procedure Steps

All endovascular work is performed via catheters guided fluoroscopically to the vessel
of interest. Embolic agents such as coils or glue can be deployed or chemotherapeutic
drugs can then be injected. Once the procedure is complete, arterial access is discon-
tinued, and pressure is held at the puncture site. The patient must then lie flat for
several hours to assist hemostasis.
These long procedures are performed almost exclusively under general anesthesia in
pediatric patients. The requirements of an immobile patient and the need for frequent
periods of apnea make this the safest choice. Consistent muscle relaxation is a neces-
sity, because it would be catastrophic for a patient to move during a critical period.60,61
These procedures are not particularly painful, and aggressive pain management may
not be necessary. As in diagnostic angiography, euvolemia to slight hypervolemia
should be maintained to offset the diuretic effect of contrast.49 A continuous infusion
of heparinized saline is used in the guide catheter to prevent microemboli; this can
result in a significant amount of fluid being delivered to the patient via the femoral
sheath, which may not be recognized by the anesthesiologist.62 In addition to this infu-
sion, patients are often heparinized to an ACT of 250 to 300 during the procedure.56
Blood pressure parameters are generally agreed between the anesthesiologist and
neurointerventionalist, and close control of blood pressure is crucial when arteriove-
nous malformations and aneurysms are being treated. Deliberate hypotension has
been described, as has induced asystole to facilitate injection of glue or coil placement
into a high-flow lesion.61 These procedures have not been well described in pediatric
patients, and the technique of balloon-assisted glue embolization may make such
radical measures unnecessary.63
Hemodynamic changes can occur during neurointerventional procedures and
should be monitored closely to maintain stability. Intra-arterial embolization using
Onyx (ev3, Irvine, CA), a popular type of glue, has been reported to induce
bradycardia.64 When a high-flow lesion, which has already affected a patient’s hemo-
dynamics, is closed, it is not uncommon to observe immediate positive changes in the
patient’s condition.56
Postprocedure Care
It can be challenging to keep a young child still for several hours after a procedure, and
both chemical and behavioral assistance may be used as described earlier.
After embolization of an intracranial vascular malformation, close control of blood
pressure may be required to reduce the risk of postprocedure hemorrhage.65 This
requirement is particularly true of partial embolization, such as before a surgical resec-
tion. There is evidence for close blood pressure control after the procedure, but there
are few descriptions of how this is to be achieved.66 Our group has had success with a
low-dose dexmedetomidine infusion used after the embolization.
Avoiding Complications
The complications described for diagnostic angiography apply to interventional pro-
cedures as well. Although the most frightening complication for an anesthesiologist
to contemplate is frank rupture of an intracranial vessel, its incidence is estimated
at less than 0.5% of cases.47 Treatment of this complication involves immediate oc-
clusion of the perforated vessel and possible hematoma evacuation, with supportive
treatment as necessary by the anesthesiologist. Migration of embolic agents has been
described; both local flow into unintended vessels and distant glue embolization have
been described. One series described a rate of migration of approximately 3%, with
complications more likely to occur in more complex arteriovenous malformations or
in those with deep draining veins.67 A multispeciality team in the neurointerventional
suite who know how to handle a crisis is an invaluable asset should a complication
arise.68
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N e u ro m o n i t o r i n g f o r Sc o l i o s i s
S u r ge ry
Chris D. Glover, MD*, Nicholas P. Carling, MD
KEYWORDS
Anesthesia Pediatrics Scoliosis Evoked potentials Electromyography TIVA
Propofol
KEY POINTS
Somatosensory evoked potentials (SSEPs) are more sensitive to inhalation agents, with
decreases in amplitude and increases in latency, compared with intravenous agents,
such as propofol, ketamine, dexmedetomidine, and opioids.
Ketamine and etomidate may be used to augment SSEPs.
Motor evoked potentials (MEPs) are the modality of choice for monitoring motor tract
function, are easily abolished by inhalational agents, and negate the use of full neuromus-
cular blockade.
Patients with immature neural pathways or preexisting neuromuscular disease may have
abnormal baseline SSEP recordings.
Maintenance of adequate physiologic parameters for normal neuronal functioning is crit-
ical to intraoperative neuromonitoring (IONM) during scoliosis repair.
INTRODUCTION
The management of the pediatric patient presenting for scoliosis repair places many
demands on pediatric anesthesiologists. These procedures are fraught with compli-
cations and require strict attention to acid-base status, hemodynamic fluctuations,
coagulation, and temperature maintenance with constant neurologic monitoring to
assess for neurologic injury to the spinal cord and nerve roots. Neurologic injury
resulting in postoperative paralysis or sensory loss is an uncommon yet devastating
and unpredictable complication of spine surgery.1 The goal of IONM is to assess the
integrity of neural pathways that may become compromised during a procedure from
direct injury to the spinal cord or nerves during instrumentation, from excessive trac-
tion placed on the spinal cord, or from inadequate perfusion of the spinal cord. IONM
facilitates the identification of neural irritation or injury along a time frame that allows
Disclosures: No relevant financial disclosures.

Department of Pediatrics and Anesthesiology, Texas Children’s Hospital, Baylor College of
Medicine, 6621 Fannin Street, Suite A3300, Houston, TX 77030, USA
E-mail address: chris.glover@bcm.edu
Anesthesiology Clin - (2013) -–-

2 Glover & Carling
for corrective anesthetic and surgical interventions. IONM also aids in defining
the nature of the injury so that the surgical procedure may be completed while mini-
mizing the risk of further neurologic injury.2 In order to fully understand how anes-
thetic choices and management influence IONM during scoliosis surgery and how
this may affect neurologic outcomes, it is necessary to understand how the various
types of neurophysiologic monitors (SSEPs, MEPs, and electromyography [EMG])
provide an assessment of neuronal functioning, how individual anesthetic agents
can affect each type of neuromonitoring technique, and how physiologic parameters
can alter normal neuronal function. In doing so, it becomes evident that the anes-
thetic principles and considerations are similar for providing anesthetic care to
adult and pediatric patients for scoliosis repair and that the immature neural devel-
opment of young pediatric patients or those with preexisting neurologic deficits
may render neurophysiologic monitoring more unreliable and sensitive to anesthetic
techniques.3
BACKGROUND
Scoliosis is a multidimensional deformity of the thoracolumbar spine resulting from a

lateral and rotational deformity of the spine that occurs at an incidence of 1% to
2%.4 The degree of scoliosis is quantified by the Cobb angle, which is measured by
the intersection of perpendicular lines extending from lines along the vertebral body
at the superior and inferior margins of the spine deformity.
Scoliosis can be categorized as idiopathic, congenital, or neuromuscular. Idiopathic
scoliosis can be further subdivided based on age of onset (Table 1). Despite extensive
research, the cause and pathogenesis remain unknown, although leading hypotheses
center on a multifactorial origin.5,6 Adolescent idiopathic scoliosis is the most common
variant seen, with an incidence of 1% to 3% in children aged 10 to 16 years. The vast
majority of these patients can be managed with conservative therapy. Congenital
scoliosis, a defect noted at birth that occurs from vertebral or costal maldevelopment,
occurs in approximately 1 of every 1000 live births.7 Animal studies have postulated
that congenital scoliosis may be linked to maternal toxin exposure during fetal devel-
opment. The rate of disease progression is rapid in the first 5 years of life and again
during puberty, coinciding with stages of rapid spine growth. Neuromuscular scoliosis
is commonly associated with patient conditions listed in Table 1. Because severity of
symptoms is associated with progression of this disease, surgical correction is usually
undertaken when the Cobb angle is greater than 50 in those considered skeletally
mature and greater than 40 in those with skeletal immaturity to arrest progression.
Table 1
Scoliosis classification and associated conditions
Scoliosis Classification Associated Conditions

Idiopathic Infantile (0–3 y)
Juvenile (4–10 y)
Adolescent (>10 y)
Congenital Bony deformity
Neural tube defects
Neuromuscular Cerebral palsy
Poliomyelitis
Muscular dystrophy
Spinal muscular atrophy
Neurofibromatosis
ANATOMY OF THE SPINAL CORD AND PATTERNS OF INJURY
The blood supply of the spinal cord is organized segmentally both along the longi-
tudinal axis of the spinal cord as well as cross-sectionally. Longitudinally, paired pos-
terior spinal arteries supply the posterior third of the spinal cord whereas a single
anterior spinal artery supplies the anterior two-thirds of the spinal cord.8 Longitudi-
nally, the paired posterior arteries and the collateral circulation that exists from the
subclavian and intercostal arteries provide some redundancy in blood flow for the
posterior third of the cord, making the dorsal columns less likely to suffer ischemic
insult. Segmentally, sulcal arteries branch from the anterior spinal artery and pene-
trate into the spinal cord to supply the gray matter of the anterior horn.9 The blood
flow through the anterior spinal artery is not continuous because the collateral circu-
lation from iliac and intercostal arteries is widely variable. Watershed areas along the
thoracic spine can be attributed to this lack of collateral circulation. Because of this
flow variability along the anterior spinal artery, segmental medullary and radicular
arteries arising from the aorta facilitate perfusion for the lower thoracic and lumbar
spinal cord. The most significant of these medullary arteries is the artery of Adamkie-
wicz, which usually anastomoses with the anterior spinal artery between T8 and
L3, and is the primary source of blood supply for the lower two-thirds of the spinal
cord. As a result of this vascular anatomy, the thoracic spinal cord receives less over-
all blood supply than the cervical and lumbosacral regions, placing the thoracolumbar
area at increased risk for hypoperfusion when manipulation of the spinal column or
aorta occurs.10
Cerebral and spinal cord blood flow follow the same principles of autoregulation and
response to hypoxia, hypercarbia, and temperature. Spinal cord perfusion is depen-
dent on the arterial blood pressure minus the central venous pressure or the cerebro-
spinal fluid pressure, whichever of the latter two is higher.
Neurologic injury during spine surgery can occur from a multitude of causes and is
the most concerning complication associated with repair. Injury can involve nerve
roots as well as the spinal cord with a permanent deficit, such as quadriplegia, as
one catastrophic outcome. A previous combined analysis by the Scoliosis Research
Society and the EuroSpine in 1991 reported on 51,000 surgical cases and noted an
overall injury occurrence of 0.55%.11 Distraction of the spine accounts for the highest
risk of spinal cord injury. Direct trauma from surgical manipulation, damage to vascu-
lature with surgical exploration, and positional issues can also lead to spinal cord
ischemia. Patient conditions associated with a higher incidence of neurologic injury
include combined anterior and posterior repair, neuromuscular scoliosis, and signifi-
cant kyphosis.12–14 Other studies point to neurologic injury occurring at an incidence
of 0.5% to 1% of all cases. A 2011 analysis of data submitted to the Scoliosis.
Research Society puts the incidence of new neurologic deficit (NND) associated
with spine surgery at 1%, with revision cases having 40% higher incidence of neuro-
logic injury when compared to primary cases. Pediatric cases versus adult cases re-
ported an approximately 60% higher incidence of NND (1.32% vs 0.83%). Cases with
implants doubled the chance of developing a neurologic deficit in the perioperative
period. The cohort with the highest rate of NND’s at 2.5’ were pediatric patients under-
going revision with implants.15
Positioning injuries for scoliosis repair can range from isolated neuropathies along
the extremities to quadriplegia, with one study reporting a prevalence of ulnar neuro-
pathy at 6.2% with occurrence at a higher frequency related to prone positioning and
in those whose arms were abducted greater than 90 .16,17 The presentation of spinal
cord injury can be varied given the separate blood supply (discussed previously).
4 Glover & Carling
Selective insult to the posterior blood supply can result in sensory deficits with intact
motor function. Impaired anterior cord perfusion can result in flaccid paralysis with
impairment in temperature and pain (spinothalamic tracts) but intact proprioception
and sensation (dorsal columns) and is known as anterior spinal artery syndrome.18
Intraoperative neurophysiologic monitoring allows assessment of the integrity of the
spine through the surgical period with real-time feedback to allow for interventions if
needed, all with the goal of minimizing neurologic injury. All potentials are graded
on their respective amplitudes, latencies, and shape. With respect to injury, expected
neurophysiologic findings center on a decrease in amplitude potentials and increase in
latency caused by decreased impulse transmission from damaged axons. Isolated
latency changes are rare and are usually associated with hypothermia and/or hyper-
carbia. Significant findings requiring intervention include unilateral or bilateral ampli-
tude changes of greater than 50%.
The quest for appropriate spinal cord monitoring techniques dates back to the early
1960s when Harrington19 introduced instrumentation to allow for correction of spinal
column deformities. A retrospective analysis performed by the Scoliosis Research
Society in 1974 found that from 1965 to 1971, neurologic complications occurred at
a rate of 0.72%, with partial or irreversible injury occurring in 0.65% in this patient
cohort.13 This discussion is an overview of the commonly used intraoperative moni-
toring techniques used today; readers are referred to several excellent reviews and
studies cited in the References for more detailed information.1–3,21,24,26,32
WAKE-UP TEST
The wake-up test has historically been considered the first method to assess the func-
tional integrity of the motor tracts during spine surgery and remains the standard for
assessing global motor function. Developed by Stagnara and Vauzelle in 1973, anes-
thesia was reversed after implant placement and the patient was allowed to emerge
intraoperatively from anesthesia with assessment of motor function in the lower
extremities.20,21 A major limitation of this form of testing is that although it can localize
injury along the motor pathway, it can only do so for a single point in time.22 An anes-
thetic technique tailored for rapid emergence should be a part of the anesthetic plan in
those undergoing spinal fusion. A preoperative anesthetic consultation is imperative to
decrease anxiety, to inform the patient and family about the details of the wake-up
process, and to answer questions related to emergence, pain, and recall. Performance
of the wake-up test first entails removing the anesthetic from the patient. The oper-
ating room environment should be made conducive to wake-up with minimized noise
and activity. With indications of emergence, the anesthesiologist remains at the head
of the bed asking the patient to follow a set of commands, such as “move your hands”
or “move your feet,” with operating room personnel assessing the upper and lower
extremities. Once the patient has followed the indicated commands, the anesthetic
is then reintroduced.
The wake-up test is still performed today, although it occurs more commonly in the
face of changing neurophysiologic findings. There seems little debate that SSEP and
MEP changes likely correlate with compromised spinal cord function with much higher
sensitivity and specificity than the wake-up test.23 Risks associated with the wake-up
test include the potential for recall, increased surgical time, and potential for acci-
dental tracheal extubation. Risks can be further compounded by delay in wake-up,
resulting in a potential increase in time from diagnosis to treatment in those with actual
injury. Practically, the wake-up test may offer therapeutic benefit in patients with po-
tential spinal cord compromise because the hemodynamic changes associated with
an intraoperative wake-up (increase in blood pressure) would have a positive affect on

spinal cord perfusion.
SOMATOSENSORY EVOKED POTENTIALS
SSEP monitoring became widely adopted in the 1980s and is currently the mainstay
for intraoperative monitoring during scoliosis repair (Fig. 1). Tamaki and Yamane24
and Nash and colleagues25 first reported its use in the late 1970s. SSEPs monitor
the integrity of the dorsal column-medial lemniscus pathway, which mediates pro-
prioception, vibration, and tactile discrimination. The dorsal column medial lemniscus
pathway comprises afferent axons from the periphery, which ascend via the dorsal
columns and synapse at the lower medulla, where they cross the midline and form
the medial lemniscus. Second- and third-order neurons project from the thalamus
to the primary sensory cortex. Pain and temperature are not mediated by this process
and are instead mediated through the spinothalamic system. SSEPs involve
Fig. 1. SSEP recording. This recording was taken from the left side (blue tracings) and right
side (red tracings) with control (green tracings). The total time of this trace is exhibited in
the second line of each waveform and in this example is 100 ms. The abbreviations Cp3,
Cpz, Cv, and L Pop refer to active electrode positions whereas C and Fz are the reference
electrodes. 216/0 Refers to the average of 216 waveforms over the rejected waveforms dur-
ing the time period measured (100 ms). The various voltages listed reference the sensitivity
of the waveform. These numbers listed above are the latency associated with the examina-
tion whereas the numbers listed in parenthesis are the amplitudes.
6 Glover & Carling
stimulation of the peripheral nerve at fixed intervals distal to the surgical site, leading to
signal propagation from the periphery to the primary sensory cortex. These cortical
and subcortical signals are then recorded via scalp electrodes. The amplitude and
latency of the responses are measured and then averaged with a comparison to base-
line recordings to assess the potential for neurologic injury.20 Changes are considered
significant if the amplitude is decreased by more than 50% and/or the latency is
increased by 10%.26
In addition, testing at the level of the brachial plexus can give insight into potential
limb ischemia or nerve compression due to patient positioning, stretch injury to
nerves, or during surgical manipulation. Any reduction of 50% in amplitude and/or a
10% increase in latency should cause personnel to investigate for potential neurologic
defect.20,26 Anesthetic agents have been noted to affect SSEPs (Table 2).27,28
Regarding safety and efficacy, a large multicenter study by Nuwer evaluated the
efficacy of SSEP monitoring in diagnosing neurologic injury and found a statistically
significant reduction in the total number of neurologic deficits (0.55% v 0.72%). He
further pointed out that definite neurologic injury in the face of stable SSEPs occurred
at a rate of just 0.063%. Although SSEP specificity in the detection of neurologic de-
fects approaches 99%, a major limitation of SSEP monitoring is that this modality can
only monitor the ascending dorsal columns. Specific patient conditions, such as
neuromuscular scoliosis, cerebral palsy, and Down syndrome, have all been moni-
tored reliably.
No information should be inferred on the integrity of the motor tracts or nerve roots
from SSEP monitoring. Multiple reports of motor paresis after procedures with un-
changed intraoperative SSEPs contributed to the search for other modalities to allow
for improved intraoperative monitoring of the motor tracts of the spine.23,29–32
MOTOR EVOKED POTENTIALS
Mertin and Morton33 revolutionized spinal cord monitoring in 1980 by demonstrating

that single-pulse voltage applied transcranially could result in contralateral
motor activity, marking the first time integrity of the corticospinal tract could be
assessed. Translating these findings to the operating room was difficult given the
Table 2
Anesthetic agents and somatosensory evoked potential effects
Anesthetic Agents Amplitude Latency

Volatile agents YY [[
Isoflurane
Desflurane
Sevoflurane
Barbiturates Y [
N2O Y 4
Midazolam Y 4
Propofol 4 4
Dexmedetomidine 4 4
Opioids 4 4
Etomidate [ 4
Ketamine [[ 4
Symbols: Y, decrease; [, increase; 4, no change.

exquisite sensitivity of this single-pulse technique to volatile anesthetics.34 This

difficulty remained until introduction of multiphase techniques in the mid-1990s.
Incorporation of propofol into anesthesia practice was also occurring over this
period.35,36
Currently, transcranial stimulation can occur via magnetic pulse or via electrical
energy (Fig. 2). The multipulse technique relies on a train of 5 to 7 short successive
electrical pulses applied over the scalp, causing pyramidal cell activation and summa-
tion at the anterior horn, resulting in alpha motor neuron firing of skeletal muscle.36
Transcranial MEPs (TcMEPs) can be recorded at multiple levels. Direct (D) waves
are recorded through epidural electrodes.37 This recording of D waves is not routinely
used because electrodes need to be placed into the epidural space. TcMEPs are
recorded more commonly as compound muscle action potentials (cMAPs) via surface
electrodes or subdermal needles placed in peripheral muscles.38 Monitoring
commonly occurs in adductor pollicus, adductor hallucis, and tibialis anterior. The
control cMAP is taken in the upper extremity for comparison to the lower extremity
cMAP. Determining which TcMEP changes are significant remains difficult because
of the large variability seen in the response to stimulation under anesthesia.39 The
Fig. 2. TcMEP—exhibits a TcMEP tracing and associated change on the left tibial electrode
(L tib) only signified by the arrow. Sensitivity of the waveform noted to be 35 mV over an
examination time of 100 ms. The terminology, R Ext – R ext, refers to the active electrode
versus the reference. TcMEP to baseline with intervention as noted by the triangle along
the right side of the body. Upper panel is L side tracings, Lower panel is R side tracings.
8 Glover & Carling
most common methods for evaluation are using criteria similar to SSEP monitoring,
where a threshold decrease signals potential injury, or evaluating TcMEP as all-or-
none method.
Monitoring TcMEPs has several advantages. TcMEPs are exquisitely sensitive to
spinal cord impairment and are able to detect spinal cord impairment an average of
5 minutes before SSEPs in a study by Schwartz.23 TcMEPs are also sensitive to blood
pressure changes given the blood supply to the anterior spinal cord. A major limitation
with this monitoring modality is cMAPs’ exquisite sensitivity to volatile anesthetics.40
Other limitations include avoidance or limitation in the use of nondepolarizing muscle
relaxants as well as the need for intermittent testing because patient movement makes
operating conditions less than ideal.41,42
ELECTROMYOGRAPHY
Nerve root injuries are some of the most common neurologic deficits seen after scoli-
osis surgery, accounting for 65% of all NNDs.11 SSEPs do not have the specificity or
sensitivity to identify individual nerve root injury because they assess multiple nerve
roots simultaneously. EMG assesses for potential nerve injury by electrical stimulation
along the pedicle track or screw with placement of recording needle electrodes in spe-
cific muscles innervated by nerve roots (Table 3). A normal EMG has low-amplitude,
high-frequency activity. EMG can be classified as free-running or triggered EMG.
Free-running and spontaneous EMGs are passive continuous EMGs and primarily
used to map and assess nerve root function. Trauma to nerve roots causes depolar-
ization with a subsequent muscle action potential in the muscles monitored. This sus-
tained “burst” on the EMG is an asynchronous wave and can imply use of irrigation,
contact of the nerve root, abrupt traction, and/or stretch injury. Long and sustained
bursts imply nerve root irritation and potential risk for injury with the need for prompt
action by the operative team (increasing blood pressure, release of distraction, and
removal of hardware).43
Triggered EMG or stimulus-evoked EMG is primarily used to assess pedicle screw
placement and cortical integrity of the vertebra. This is based on the principle that the
conduction of an electrical stimulus between bone and soft tissue is relatively high.
With cortical perforation, the resistance to the electrical stimulus drops significantly,
resulting in cMAPs seen at very low voltage. Triggered cMAPS with unusually low
voltage on EMG imply incorrect pedicle screw placement and the need for re-
evaluation by a surgeon.44,45 Pedicle screw malposition occurs in approximately
5% to 15% of cases.46 In a large retrospective analysis of 1078 patients, Raynor
and colleagues47 found threshold levels less than 2.8 mA were 100% specific for
cortical breech with sensitivity of 8.4%. Specificity decreased to 99% in those where
the threshold was less than 4 mA but the sensitivity increased 4-fold. Current
Table 3
Electromyography nerve roots and corresponding muscles monitored
Nerve Root Muscles Monitored

C8-T1 Adductor pollicis
T2-T6 Intercostals
T6-T12 Rectus abdominus
L3-L4 Vastus lateralis
L4-L5 Anterior tibialis
S1-S2 Gastrocnemius
recommendations include the use of EMG in conjunction with radiography and palpa-
tion for optimized pedicle screw placement.
Regarding anesthetic agents, EMG is resistant to their effects and, as such, there
are few limitations to maintain adequate monitoring conditions besides limiting or
avoiding neuromuscular blocking agents.
ANESTHETIC EFFECTS ON NEUROPHYSIOLOGIC MONITORING
Neurophysiology and its use in scoliosis repair provide multiple challenges for anesthe-
siologists attempting to ensure patient comfort and safety while providing an anesthetic
that minimally affects monitoring techniques. The impact of anesthetics on neurophys-
iologic recordings cannot be overstated. All anesthetics depress synaptic activity and
axonal conduction in a dose-dependent manner with prominent alterations seen in corti-
cally generated responses.48 The difference in the severity of the decreased amplitude
and increased latency seen from anesthetics relate to an individual agent’s lipid solubi-
lity, which has traditionally been considered a gauge of an anesthetic’s potency. Gener-
ally speaking, increasing lipid solubility resulted in increased cortical depression.28
The neurophysiologic effects of the commonly used volatile anesthetics are summa-
rized as follows. Isoflurane, sevoflurane, and desflurane all produce an initial excitation
with increased alpha wave activity. With increased exposure, slowing occurs with
eventual burst suppression noted. All halogenated inhalational agents produce
dose-dependent decrease in amplitude and increase in latency for SSEPs with cortical
responses affected to a larger degree than subcortical and peripheral nerve re-
sponses.41 Although isoflurane is most potent given its lipophilicity, studies with sevo-
flurane and desflurane suggest similar effects on EEG and potential recordings. Doses
up to 0.5 minimum alveolar concentration (MAC) can be used if subcortical responses
are adequate, whereas the use of cortical SSEP recordings restricts use of these an-
esthetics.41 With increasing concentrations of halogenated agents, a prominent effect
on the anterior horn is noted with cMAP responses being eliminated.49 Concentrations
as low as 0.2 MAC largely abolish TcMEPs, relegating these agents suboptimal for use
in cases where IONM is used.40,49,50
Nitrous oxide (N2O) causes profound reduction in amplitude with increased latency
in all neurophysiologic monitoring with suppression of cortical responses that mimic
halogenated agents. Given its synergistic effects on SSEPs when combined with vol-
atile anesthetics, use of this insoluble agent should be limited, although techniques
with N2O and opioids have been described.35,51
Intravenous opioids produce minimal depression of cortical SSEPs and TcMEP
recordings. Studies have shown mild amplitude decreases and latency increases
with opioids thought secondary to the action at the m receptor via G protein–medi-
ated activity, resulting in depressed electrical excitability.41,52 Considering their min-
imal neurophysiologic effects and superior analgesic properties, an opioid-based
anesthetic for scoliosis cases requiring monitoring seems beneficial.
Ketamine, via its N-methyl-D-aspartate receptor inhibition, and etomidate, via its
g-aminobutyric acid A (GABAA) receptor inhibition, differ from halogenated agents in
that they cause increases in cortical amplitudes of SSEP and MEP, making them
agents of choice when monitoring responses to stimulation are difficult.53,54 Ketamine
provides superb analgesia and hypnosis, but its use must be weighed against poten-
tial dissociative effects and its effects on patients with intracranial pathology. Etomi-
date can be used as a constant infusion to enhance SSEP cortical recordings, but
lack of analgesia, potential for enhanced seizure activity, and adrenal suppression
are factors to consider with its use.55
10 Glover & Carling
Benzodiazepines and midazolam, in particular, can be used for cortical SSEP

monitoring because only mild effects are seen when used at induction doses.56 These
agents also seem to have minimal effect on subcortical and peripheral responses. Use
of benzodiazepines in TcMEP monitoring results in significant depression of motor
potentials, necessitating caution if midazolam is used for induction.56,57
Propofol does not result in amplitude enhancement. This agent produces amplitude
depression on induction with isoelectric EEGs seen in those given large doses. This is
transient given propofol’s rapid metabolism. This rapid metabolism makes propofol an
excellent agent for total intravenous anesthesia (TIVA) and for rapid titration of anes-
thetic depth, thereby minimally effecting evoked potentials.50
Dexmedetomidine is a specific a2-receptor agonist that provides anxiolysis and
analgesia without depression of respiration. At clinically relevant doses, there is little
effect on neurophysiologic monitoring.58–60 This ability to minimally affect IONM in
combination with its MAC-sparing ability for volatile agents makes dexmedetomidine
an appealing adjunct when cases require IONM.61,62 There are 2 reported cases of
significant impairment on neurophysiologic monitoring because of dexmedetomi-
dine’s effect on TcMEP, but further analysis of the study revealed dosing well above
the clinical recommendations.63–65
NEUROPHYSIOLOGIC CONSIDERATIONS FOR SPECIAL POPULATIONS
In neuromuscular scoliosis and associated conditions, such as cerebral palsy and

Down syndrome, IONM is still possible although there is debate about its utility and
reliability in patients with these conditions. SSEP monitoring has been successfully
accomplished in this patient population with rates approaching 85% to 95%, but
failure rates with TcMEP monitoring in those with cerebral palsy ranged from
40% to 60% based on the severity of their cerebral palsy.66–69 Congenital scoliosis oc-
curs at a time when a still developing nervous system may be encountered, potentially
rendering IONM less reliable. Recent prospective data, however, document reliable
and successful IONM in infants and young children using a TIVA technique.70,71
When encountering scoliosis patients who fall outside the common diagnosis of idio-
pathic scoliosis, addition of ketamine and/or etomidate to the anesthetic plan should
be considered to assist neurophysiologic monitoring.
SUMMARY
The intraoperative management of patients presenting for scoliosis repair presents

many challenges for anesthesiologists. Along with normal intraoperative and perioper-
ative concerns for a procedure that involves hemodynamic fluctuations, potentially
large intraoperative blood losses, and long operating times in the prone position, there
is the added challenge of providing an anesthetic regimen that permits neurophysio-
logic monitoring to assess for intraoperative neurologic compromise. Commonly used
anesthetic techniques for scoliosis repair include combinations of opioid with propofol
infusions to allow for SSEP and TcMEP monitoring. If volatile agents are administered,
they should be used in low concentrations with communication to the neurophysiolo-
gist. Patients in whom there may be difficulty obtaining reliable intraoperative signals
because of preexisting neurologic deficits or because of immature neurologic devel-
opment may require the use of etomidate or ketamine infusions to improve SSEP am-
plitudes. Anesthesiologists taking care of these patients must have a comprehensive
understanding of the effects of anesthetic agents on monitoring techniques, including
SSEPs, TcMEPs, EMG, and the intraoperative wake-up test. Appropriate anesthetic
regimens should allow for rapid emergence in case of the need to wake a patient
intraoperatively to assess neurologic function and should therefore use anesthetic

agents that are known to have minimal effects on the monitoring technique used.
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are well maintained in patients given dexmedetomidine during spine surgery.
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B r a i n Mo n i t o r i n g i n C h i l d ren
Michael Sury, MB, BS, FRCA, PhD
KEYWORDS
Near infrared spectroscopy Electroencephalography Bispectral Index
Amplitude-integrated electroencephalography Oxygen Cerebral function
Cardiopulmonary bypass
KEY POINTS
Electroencephalography (EEG) monitors are potential surrogate markers of conscious
level and may detect effect of anesthesia on the cerebral cortex.
Near infrared spectroscopy (NIRS) estimates cerebral oxygenation, which is affected by
the balance between oxygen supply and demand.
There is only weak evidence to support routine use of EEG or NIRS monitors to improve
patient outcome.
INTRODUCTION
An anesthetist tries to keep a patient both alive and asleep during surgery. Monitoring
is important to ensure that these objectives are met. Current practice is to prioritize the
monitoring to ensure that anesthesia interventions maintain vital functions, such as
arterial oxygen saturation, end-tidal carbon dioxide concentration, heart rate, and
blood pressure. From these measurements, adequate oxygen delivery to the brain
and other vital organs can be inferred. The adequacy of anesthesia can be judged
by a combination of clinical observations of immobility and autonomic quiescence
and also by the estimation of the concentration of anesthesia drug in the brain. These
strategies are achievable and are standard, yet they may not be enough in some
circumstances, and their accuracy is not certain.
Measuring unconsciousness is an ideal. Efficacy of anesthesia depends to a large
extent on the concentration of anesthesia in the brain. Yet, this is not a simple concept.
First, there is uncertainty about the concentration in blood. The assumption about an
insoluble vapor achieving a steady state concentration in blood and therefore the brain
is not supported by data, although few data are available to strengthen or weaken our
assumptions. Data in adults measuring the washin and washout of 1% isoflurane show
that there are delays between expired breath and blood concentrations, and, more
importantly, there are wide limits of agreement within a patient group, which makes
Department of Anaesthesia, Great Ormond Street Hospital, Great Ormond Street, London
WC1N 3JH, UK
E-mail address: mike.sury@gosh.nhs.uk

116 Sury
the prediction of blood concentration, from expired breath analysis, weaker than ex-
pected.1 Similar variation exists between target and measured blood concentrations
of propofol.2
The effective dose is guided by minimal alveolar concentration (MAC). Because MAC
is a median value, it should be expected that some patients are not adequately anesthe-
tized, and that the dose needs to be increased. Conversely, some patients are exces-
sively anesthetized, perhaps with dangerous cardiovascular depression, and the dose
needs to be decreased. The measurement of MAC itself has many problems.3 Efficacy
of a chosen dose can, to a degree, be assumed from immobility, yet, movement itself
may be largely related to lack of suppression of the spinal cord rather than the brain.4
It may be assumed, from our understanding of MAC studies, that the dose required
to cause unconsciousness is lower than that required for immobility, which is reassur-
ing, but the use of muscle relaxants removes the usefulness of immobility.
The sum of these considerations is that anesthesiologists should not be 100% confi-
dent about the effects of a specified anesthesia dose on the brain. This dose is too
much for some patients and too little for others. This review examines monitoring de-
vices that may help to reduce this uncertainty in children. Moreover, it focuses on direct
brain monitoring rather than discussion of monitors of vital cardiorespiratory or auto-
nomic functions, which are important but are indirect monitors of brain function.
The usefulness of direct monitoring may be best shown in the scenario of uncer-
tainty about the adequacy of oxygen delivery to the brain. For example, hypotension
is a common phenomenon in anesthesia,5 and yet there is uncertainty about the lower
limit of blood pressure that ensures safe brain oxygenation. If hypotension is assumed
to be caused by cardiovascular depression by an excessive dose of anesthesia, what
is the dose that is compatible with both safe brain oxygenation and unconsciousness?
This problem may be one of the main causes for accidental awareness under anes-
thesia. Awareness in children6 is uncommon, but the ability to monitor the brain, which
helps to detect and prevent awareness, is a long-held aspiration for the specialty.
Brain monitoring for anesthesia needs to be simple, robust, and reliable. Monitors
that use noninvasive skin sensors, placed on the scalp, should have these qualities.
Monitors of the following are considered in this article:
Cerebral electrical activity
Cortical oxygenation
Monitors of blood flow are also important. Monitoring cardiac output and cerebral
blood flow is valuable but these topics not considered in this article because they
are not direct monitors of brain function. Moreover, they are not sufficiently developed,
as yet, to be practicable in small infants in a wide range of settings.
ELECTRICAL ACTIVITY
Electroencephalography
Before discussing processed electroencephalography (EEG), an understanding of the
raw EEG is essential. The EEG is believed to represent a composite of the postsyn-
aptic potentials of the cerebral cortex. The origin of this activity, whether it is from cen-
tral or peripheral parts of the brain, remains unclear, but there is evidence that thalamic
signals play a key role in the arousal of the cortex. The EEG is a complex random-
looking waveform and has many constituent oscillations of varying amplitude and
frequency.
Signals are detected from skin electrodes placed on the scalp. The signal amplitude
is smaller than the electrocardiogram (ECG) (microvolts compared with millivolts), and
therefore, the electrodes must have a secure contact on the skin so that the imped-
ance does not vary. The electromyogram (EMG) has oscillations of higher amplitude
than the EEG, and, because the EMG has wide frequency band, it can easily obscure
the EEG. Muscle activity is a problem and makes interpretation of the underlying EEG
uncertain, and electrical equipment (eg, diathermy) can cause large interference.
Frontal electrodes are favored for practical reasons, but the amplitude of oscillations
from centroparietal electrodes is larger. Three simple features of the EEG can be
visualized:
Steady oscillations
A complex waveform that seems to be continuous
Accidentals
Sudden short-lived oscillations often of higher amplitude (eg, epileptiform
activity)
Silence
Periods of inactivity may be continuous or intermittent. Intermittent silence
alternating with high-amplitude oscillations is called burst suppression
(perhaps more easily understood as bursts and suppressions)
Visualizing the EEG requires expertise, but it allows immediate recognition of small
and irregular changes. For example, d (<4 Hz), q (4–7 Hz), a (8–13 Hz), and b (15–30 Hz)
waves, can be identified on short samples. Some degree of processing, using Fourier
analysis principles, enables long samples (a few seconds) to be assessed, and the
amplitude of constituent frequencies can be estimated. Using both the visual expert
eye and Fourier analysis, changes in the EEG during anesthesia have been described.
In children older than 6 months, the awake EEG is low amplitude and irregular with a
waves on a background of fast oscillations (Table 1).
With anesthesia induction (eg, sevoflurane), the EEG becomes more regular. As
depth increases, the oscillations increase in amplitude. Lower-frequency, large-ampli-
tude oscillations become prominent. Deeper anesthesia causes burst suppression;
periods of silence become longer until there is no EEG activity. EEG changes during
sevoflurane washout and emergence are usually the same but in reverse. Propofol
and other vapor anesthetics are believed to have similar effects on the EEG. Ketamine
and nitrous oxide cause low-amplitude, high-frequency oscillations. Opioids, in clin-
ical doses, have an effect on the EEG that is probably indirect, in that they counter
the arousal activity related to pain.
The EEG of awake and naturally sleeping infants less than 6 months old is different
mainly in terms of lower amplitude and the presence of irregular periods of low activity
frequently seen before the age of 3 months, known as tracé alternant (Table 2).7,8 Few
researchers have investigated the effects of anesthesia on the EEG in young infants.9
There are 4 studies published on the effects of sevoflurane or isoflurane in infants and
small children. Constant and colleagues10 induced sevoflurane anesthesia in children
aged 2 to 12 years old. As the dose increased, the total spectral power increased,
especially in low-frequency bands, and 14-Hz to 30-Hz oscillations were common.
Emergence was studied by Davidson and colleagues8 (in infants, toddlers, and chil-
dren) and Lo and colleagues11 (in children aged 22 days to 3.6 years). Both studies
found that infants younger than 6 months have low EEG power during anesthesia,
but in older infants, there is appreciable power between 2 and 30 Hz. However, 1 study
reported that the power within the 2-Hz to 20-Hz range decreased,8 and in the other
study,11 power within the 8-Hz to 30-Hz range increased. A recent observation study
of sevoflurane washout in infants found that anesthesia was associated with appre-
ciable power between frequencies 5 and 20 Hz and that this decreased as sevoflurane
118 Sury
Table 1
EEG characteristics during wakefulness, natural sleep, and anesthesia after 6 months of age
State Dominant EEG Oscillations EMG

Alert wakefulness 30–50 Hz (low amplitude) High
Relaxed wakefulness 8–13 Hz Reduced
Non-REM sleep
Stage 1 2–3 s of 4–8 Hz and sharp waves over vertex Reduced
Stage 2 Sleep spindles appear 1–3/min Minimal
Up to 20% of epoch high-amplitude d waves
K complexes appear
Stage 3 20%–50% of epoch d waves Minimal
Stage 4 >50% of epoch d waves Minimal
REM sleep Irregular 30–50 Hz (low amplitude) Sporadic bursts
Sharp waves replaced by saw tooth waves at
2–5 Hz
Sedation through to Continuous oscillations of low amplitude and Minimal
light anesthesia mixed frequency
Progressing to higher amplitude (1–4 Hz) and
middle amplitude (8–16 Hz) (approximately)
oscillations
Anesthesia through Burst suppression (alternating periods of high- Minimal
to excessively deep amplitude mainly low-frequency oscillations
anesthesia with suppression), increasing length of
suppression until electrical silence
Abbreviation: REM, rapid eye movement.
washed out (Fig. 1).12 Moreover, the band power during anesthesia was age related,
and only infants older than 3 months had appreciable band power (Figs. 2 and 3).
Whether or not band power is useful enough to assess level of consciousness is not
known; nevertheless, it is possible that EEG power changes indicate that an anes-
thetic drug is having a pharmacologic effect on the brain, and this may be useful in
some circumstances. For example, in the development of target controlled infusion
pharmacokinetic models, the effect site concentration is assumed to peak based on
EEG changes.
Processed EEG
Given that the raw EEG may be difficult for nonneurophysiologists to interpret, there
has been, and continues to be, a demand for a simple EEG variable that is useful in
the assessment of conscious level. In addition, both the practical constraints of scalp
electrodes and the technical complexities of signal interference, filtration, and ampli-
fication have prevented widespread use of EEG monitors during anesthesia. Clinicians
need a robust monitor, easy to set up and reliable under the conditions of an operating
theater rather than an EEG laboratory.
Amplitude-integrated EEG
In the 1960s, the cerebral function monitor (CFM) was developed.13 It amplified and
filtered a single EEG channel to create a fast (within seconds) visual printout of the
trend of median and the range of the amplitude of a wide frequency band. The
band amplitude was represented on a logarithmic scale. The observer could see sim-
ple characteristics of the EEG, for example, the minimum amplitude, reflected the
Table 2
EEG characteristics of natural sleep in infants younger than 6 months
Gestation EEG
Maternal transabdominal Continuous low-amplitude irregular activity unrelated to body
recordings of fetal EEG movement
(from 12 wk)
24–27 wk Tracé discontinu
Bursts of high-amplitude slow waves lasting 2–6 s mainly
over the occipital cortex followed by depressed activity
lasting 4–8 s
28 wk REM-like
Bursts of low-amplitude high-frequency oscillations
32–36 wk Tracé discontinu becomes associated with quiet sleep
36 wk Tracé discontinu is replaced by tracé alternant
3-s to 8-s bursts of high-amplitude slow-frequency activity
interspersed with low-amplitude mixed-frequency
oscillations
Disappears by 48 wk
37 wk REM-like becomes more continuous and associated with eye
movements
Term–3 mo Active sleep (eyes closed)
Mixed irregular activity and EMG prominent
Quiet sleep
Single pattern of high-amplitude low-frequency
Awake (eyes open)
Low-amplitude, irregular activity
3–6 mo Non-REM and REM sleep develop gradually from 3 mo from
quiet sleep and active sleep, respectively
Sleep spindles
Appear by 4 wk of age
Become characteristic of non-REM sleep by 3 mo
K complexes appear by 6 mo
Fig. 1. EEG changes in infant older than 3 months during sevoflurane washout. EEG record-
ings from centroparietal channel. Top trace is during sevoflurane anesthesia after surgery
(end-tidal sevoflurane 2.5%). Bottom trace is 5 minutes later: note that the amplitude has
decreased. The arrow marks movement artifact at the point of awakening.
120 Sury
Fig. 2. Power spectrum of EEG during anesthesia in infants. EEG recordings and power spec-
trum density (PSD) taken during sevoflurane anesthesia after surgery from a centroparietal
channel in 2 infants: (A) aged 45 weeks and (B) aged 66 weeks (postmenstrual age). Note
that the older infant has appreciable power in frequency band 5 to 20 Hz, unlike the
younger infant.
presence of EEG suppression, and zero minimum amplitude coincident with a high
maximum amplitude indicated burst suppression. Epileptiform activity could also be
easily distinguished. The CFM algorithm used was restricted for commercial reasons,
and a monitor with a similar algorithm, known as the amplitude-integrated EEG
(aEEG), is now frequently used in neonatal intensive care14 and has been used in trials
as an important outcome variable to test the usefulness of hypothermic protection af-
ter hypoxic ischemic encephalopathy15 and to detect cortical suppression and
convulsion activity.16 Some neonatologists urge caution in its interpretation.17 aEEG
detection of cerebral ischemia during or after cardiopulmonary bypass (CPB) is
poor.18 Few studies have been undertaken to test its use in discerning depth of anes-
thesia in children, and results have not been promising.19
1000
100
P5-20 Hz
10
1
0 50 100 150 200 250 300 350 400 450 500
Age (PMA (weeks))
Fig. 3. Relationship between EEG power and age. Age is in weeks postmenstrual age.
P5-20 Hz is the EEG band power (mV2) between the frequencies 5 to 20 Hz recorded from
a centroparietal channel.
Spectral edge frequency

Spectral edge frequency (SEF) is the frequency at lower than which 90% (SEF90) of
the EEG power exists (or other specified % cutoff); it is a commonly studied variable
calculated from the frequency spectrum. Hayashi and colleagues20 studied SEF90 in
neonates and infants during sevoflurane concentrations between 0.5% and 2%. In
children aged 6 months to 2 years, SEF90 was inversely related to sevoflurane con-
centration, but this was less so in younger infants. In children younger than 3 months,
SEF90 was always low.
A common problem with processing EEG is that any simple variable may miss the
appearance of burst suppression. Consequently, as the concentration of anesthesia
increases, the EEG power (and SEF) first increases and then decreases as periods
of electrical silence dominate (Fig. 4).
Bispectral Index and other processed EEG

The Bispectral Index (BIS) (Covidien, Mansfield, MA), Entropy (E-Entropy, GE Health-
care, Milwaukee, WI), and Narcotrend (Narcotrend-Compact M, MonitorTechnik,
GmbH & Co, Bad Bramstedt, Germany) monitors are 3 examples of sophisticated pro-
cessed EEG monitors that rely on forehead electrodes. Each monitor has its algorithm to
process the EEG and create a score from 0 to 100, representing the extremes of coma
Fig. 4. Common relationship of EEG band power to concentration of anesthetic.

122 Sury
and full wakefulness; the scores correlate with depth of sedation and anesthesia. The
BIS uses a combination of power in various frequency bands, phase synchronization
between common frequencies, EMG, and burst suppression.21–24 Entropy measures
the predictability (or the sinusoidal nature) of 2 wide EEG frequency bands: 0.8 to
30 Hz for state entropy and 0.8 to 47 Hz for response entropy25; the latter incorporates
the frontalis EMG.26 The Narcotrend algorithm has not been published.27 All have been
developed to produce scores that decrease with both decreasing conscious level (as
defined by a validated scale of behavior)28,29 and also with increasing doses of propofol
and concentrations of common inhalational agents.30–32 All monitors of EEG are poor
predictors of movement during surgery. This situation is not only because the monitor
takes at least 15 seconds to calculate a score but also because pain activates spinal
reflexes that remain present even in major brain damage.33 Also, a major consideration
is that an anesthesia drug can have an immobilizing effect at the spinal cord in addition
to cortical effects.4 For example, in a study, comparing the effects of equi-MAC doses of
halothane and sevoflurane, the BIS scores were higher during halothane,34 and this may
be because halothane has a greater immobilizing action at the spinal cord than sevoflur-
ane rather than because halothane has a different effect on the EEG and BIS.35–37
Evidence of usefulness in maintaining adequate depth of sedation or anesthesia A

BIS score of 40 to 60 is said to be compatible with absence of explicit recall. Large
trials have been conducted in adults. Myles and colleagues38 showed that adults
who could not receive high-dose anesthesia (eg, patients with cardiac disease, known
difficult intubation, obstetric emergencies) had a reduced chance of accidental aware-
ness if their anesthesia was directed by BIS. Avidan and colleagues39 showed that, in
protecting against awareness, BIS was equivalent to monitoring end-tidal anesthesia
vapor concentration (maintaining a level >0.7 MAC). More recent studies showed no
benefit of BIS in reducing awareness.40,41 Nevertheless a UK National Institute for
Health and Care Excellence technology evaluation42 recommended that BIS and
similar monitors may be helpful “for avoiding excessively light or deep anesthesia in
patients at high risk of adverse outcomes from general anesthesia” and should be
considered especially in total intravenous anesthesia (TIVA) techniques.
The distinction between explicit recall and awareness is important, and Russell has
shown that when the BIS (or the Narcotrend) monitor is tested with the isolated fore-
arm technique, neither monitor is able to distinguish between patients who can
communicate and those who cannot.43–45 Further studies may show that the cutoff
BIS score (and equivalent) may be important. BIS may (or may not) help to reduce
explicit recall, but it does not detect intraoperative awareness in patients who are
pain free. There are no studies showing the effect on the EEG of awareness during
painful surgery.
BIS can mislead. Changes may not be caused by anesthetic drugs. BIS can change
with ischemia,46 epileptiform activity,47 muscle relaxants,48 and hypoglycemia.49 Ke-
tamine50 and nitrous oxide51 tend to increase the BIS score and increase depth of
anesthesia.
BIS scores correlate with isoflurane concentration in children older than 1 year simi-
larly to adults.52 However, several studies have reported that BIS scores are less reli-
able in infants and small children.53–60 Given equi-MAC concentrations of sevoflurane,
BIS scores are slightly higher in infants than in children.56 In another study of sevoflur-
ane,61 the highest BIS scores tended to be in the youngest infants, and BIS increased
paradoxically when sevoflurane increased from 3% to 4%. Comparing 3-month-old
with 6-month-old infants with 7-month-old to 12-month-old infants, given equal doses
of sevoflurane, BIS scores were lower in the youngest infants.62 This situation may be
because there is a special feature of young infants or perhaps because the BIS algo-
rithm is not appropriate for their EEG. The unprocessed EEG needs to be seen to help
to explain these changes.
At the end of anesthesia, BIS correlates with conscious level poorly in infants59 and
in children.57 Infants who are not in pain (eg, who have an effective caudal local anes-
thetic block) need only very small concentrations of sevoflurane to keep BIS low.55
Davidson and colleagues58 measured BIS and Entropy in children having cardiac angi-
ography and found that the youngest patients had the widest variation of scores and
awakening occurred at lowest scores. In a study of children recovering after circum-
cision, infants often awoke spontaneously at low BIS scores.53
In a study of 60 children receiving anesthesia with propofol and remifentanil,63 EEG
variables were similarly predictive of awakening in children older than 1 year but were
least reliable in infants. The prediction of conscious level in a sedation technique using
propofol was poor, and this shows that BIS is not useful in directing the dose of pro-
pofol to achieve a certain level of sedation.64 Probably, the presence of pain is influ-
ential in the steadiness of the BIS score.
The Narcotrend was used successfully to predict recovery in children older than
1 year.65 Three other studies showed that Entropy and BIS are similar in monitoring
conscious level in children older than 1 year.26,58,59
Evidence of usefulness in avoiding excessive depth of anesthesia There are 2 studies

that support the concept that low BIS scores (perhaps related to excessive doses of
anesthesia), in adults, are associated with poor long-term outcomes.66,67 Whether
these findings are related directly to low BIS scores or perhaps the finding relates to
a vulnerable population has yet to be determined, but BIS and other monitors may pro-
tect vulnerable adults from long-term harm. In infants, studies of excessive depth may
be important in avoiding potential harm of neuroapoptosis, but this problem has been
shown only in young animals after heavy and prolonged anesthesia exposure, and the
EEG effects of deep anesthesia have not been studied.
Evoked Potentials
Auditory evoked potentials (AEP) are EEG signals provoked by a noise (a click) and
detected from EEG scalp electrodes. Noise causes a neural transmission through
the brainstem, the midbrain, and the cortex. Averaging the EEG over many clicks
removes background EEG; a typical accurate recording (used for assessment of hear-
ing deficit) may use 1024 clicks at 6 Hz and take 2 to 3 minutes to achieve. The AEP
waveform has characteristic peaks and troughs, which are time related to brainstem,
early cortical, and late cortical transmission.68,69 The brainstem component is resistant
to anesthesia, and the late cortical component disappears easily at low doses of anes-
thetic. However, the early cortical waveform is suppressed by anesthesia (peaks are
delayed) in a dose-dependent manner and is therefore useful as a depth monitor.68–70
The Alaris AEP monitor can estimate the shape of the AEP within 2 to 6 seconds by
autoregressive modeling.71 From the AEP waveform, an algorithm calculates an index
from 0 to 100 (representing deep coma and fully awake states, respectively).
This method is vulnerable to non-EEG interference; EMG, in particular, caused by
contraction of the posterior auricular muscle, is triggered by noise, and therefore,
the AEP is least reliable when muscle relaxants are not used.68 A study of children
older than 2 years found that AEP was as reliable as in adults,72 but ECG interference
is a problem in infants.73
EEG-evoked activity from pain may be detected in preterm infants whose back-
ground EEG is low amplitude.74
124 Sury
Learning points on EEG monitors
EEG monitors are potential surrogate markers of conscious level and may be rational
indicators of effect of anesthesia on the cerebral cortex
They can be misleading; ischemia and hypoglycemia cause EEG suppression
In respect of processed EEG and monitoring conscious level during anesthesia, monitoring
inhaled anesthetic vapor concentration is equally effective (or perhaps more so); EEG
monitors do not detect awareness shown by the isolated forearm technique
Processed EEG monitors may be useful in some situations, perhaps with TIVA, in which
monitoring blood level is not possible
BIS monitoring in children (not infants) is similar to adults (BIS monitoring is less reliable in
infants)
The EEG in young infants is irregular and low amplitude
aEEG is potentially useful as a simple monitor of seizure activity in intensive care
OXYGENATION MEASURED BY NEAR INFRARED SPECTROSCOPY

Validation
Near infrared spectroscopy (NIRS) measures and monitors nonpulsatile regional tis-
sue oxygenation (rSatHbO2) continuously. (rSatHbO2 is used throughout this article
to represent the % of saturated hemoglobin [Hb] relative to the total Hb assumed to
be present in the cerebral cortex and surrounding tissue.) Light is beamed from a fore-
head scalp sensor into underlying tissue, and the wavelength spectrum of light re-
flected back is measured and processed to estimate the amount of oxygenated Hb
in the cerebral cortex. Some monitors estimate the % of Hb saturated relative to
the total Hb, and others monitor the absolute amount of saturated Hb.75 Comparison
of these 2 types of monitors in adult patients showed that there were large differences
in rSatHbO2.76
NIRS also detects the redox state of cytochrome, which in theory is useful, except
that the contribution of this to the signal may be too small to be useful.77 All the tissue
components underlying the sensor make a contribution to the rSatHbO2 and have
different oxygen saturations. The venous and arterial blood, for example, make
different contributions to rSatHbO2, and the tissue itself, which consumes oxygen,
has an rSatHbO2 less than 100%. Various NIRS machines are calibrated to assume
that tissue has a fixed volume contribution of venous and arterial blood. Cerebral
vasoconstriction and dilatation, of capillaries, arteries, and veins, may have a large
influence on the rSatHbO2. Normal rSatHbO2 in noncyanotic infants breathing air is
approximately 70%, and this is reduced in cyanotic children to 40% to 60%.78 Inac-
tive cerebral tissue (perhaps as a result of cooling or irreversible cortical damage)
may have rSatHbO2 close to 100%, and excessively active cortical tissue (such as
in status epilepticus) may have low rSatHbO2, despite adequate oxygen supply.
Regional brain metabolic activity and blood flow are linked, and in neonates the ratio
is higher than in older infants, which means that neonates may be more vulnerable to
ischemia.79
The mixed venous saturation has been used to detect cerebral hypoxia and may
therefore help to validate rSatHbO2. In cyanotic children, some investigators have re-
ported a good correlation with rSatHbO280 and others have not.81,82 The use of jugular
venous saturation (SjvO2) should be more closely related to rSatHbO2, yet the evidence
does not support this idea. SjvO2 and rSatHbO2 were poorly correlated in 1 study in
children (except in infants),83 but others found that correlation was high.84–86 In a
comparison of both mixed venous and jugular bulb saturations, SjvO2 was found to
correlate with rSatHbO2 least.87
rSatHbO2 During Cardiac Surgery
Typically, CPB increases rSatHbO2 close to 100%, because cerebral oxygen demand
has been reduced by anesthesia and hypothermia.75,88,89 As brain circulation is inter-
rupted, rSatHbO2 falls to 70% of the baseline by approximately 20 to 40 minutes, and
then reperfusion should restore rSatHbO2 to normal (Fig. 5).88 In some neonates and
infants, long deep hypothermic cardiac arrest (DHCA) times delay the recovery of
rSatHbO2.90,91 Reduced rSatHbO2 may be caused by increased cerebral metabolism
as result of a metabolic debt.79
Kurth and colleagues92,93 studied the rSatHbO2 in a piglet model. Baseline rSatHbO2
was 68%, and rSatHbO2 was highly correlated with sagittal sinus oxygen saturation.
As oxygen levels were reduced, cerebral lactate levels began to increase at rSatHbO2
of 44%, major EEG change occurred at 37%, and brain adenosine triphosphate
decreased at 33%. Sakamoto and colleagues94,95 exposed piglets to DHCA and
showed that hypothermia slowed the reduction of rSatHbO2 during circulatory arrest
and that at 15 C animals could tolerate 25 minutes of cerebral circulatory arrest
without obvious neurologic harm.
In a study of neonates and infants having repair of aortic coarctation, rSatHbO2
decreased during aortic clamping and the decrease was greatest in neonates,
although this may have been related to the possible presence of collateral circulation
in older infants.96,97
Outcome After Cardiac Surgery
The incidence of severe brain damage after CPB surgery has decreased over the de-
cades, largely because of improvements in the management of CPB.98–100 The causes
of global delay and epilepsy seen after CPB may be related to ischemia and inflamma-
tion from emboli101 or from underlying congenital brain defects and genetic factors.102
The institution of low-flow CPB (either continuous or intermittent) during what would
otherwise be circulatory arrest has been shown, in randomized controlled trials, to
reduce early postoperative seizures103 and, at age 1 year, to improve neurologic
assessment scores.104
Fig. 5. Typical changes of rSatHbO2 during cardiac surgery. Schematized typical changes in
rSatHbO2 with time in an infant undergoing cardiac surgery under CPB and deep hypother-
mic cardiac arrest (DHCA). (Adapted from Andropoulos DB, Stayer SA, Diaz LK, et al. Neuro-
logical monitoring for congenital heart surgery. Anesth Analg 2004;99(5):1369; with
permission.)
126 Sury
With this background, the use of NIRS and transcranial Doppler assessment of
cerebral blood flow was begun, in 1 center, without a control group, and may have
improved outcome.105 Nevertheless, the potential of NIRS106 is uncertain and
debated. Many hospitals have decided to use NIRS as a standard monitor, yet, others
have not.106 The evidence for improved outcome is limited to small studies. In a study
of 26 children undergoing DHCA,88 3 patients, all with low rSatHbO2, had seizures or
prolonged coma. In a larger study of 250 patients, 41% had prolonged low rSatHbO2
(20% decrease from baseline) and 25% of these had prolonged coma, seizures, or
hemiparesis.105 Andropoulos and colleagues75 reported that approximately 90% of all
interventions to improve cerebral oxygenation during cardiac surgery are triggered by
low rSatHbO2 rather than EEG or other monitors. In another review, Hirsch and col-
leagues107 concluded that NIRS may contribute to multimodal monitoring of cerebral
perfusion and function, but evidence is lacking for its value as an isolated monitor. A
recent review in respect of adult cardiac surgery concluded that current evidence for
improved outcome using NIRS was low level.108
Notwithstanding all the debate, cerebral white matter changes, infarction, and hem-
orrhage are seen on magnetic resonance imaging scans in about a third of neonates
after CBP.109
Usefulness in Neonatal Intensive Care
NIRS is being used as trend monitor of cerebral oxygenation in neonatal intensive
care.110 Only small studies so far have tested the usefulness of NIRS; in a study of
18 preterm infants, of whom 9 died of cerebral deterioration, rSatHbO2 increased,
as a result of reduced cerebral oxygen consumption, in those with a poor outcome.111
Overview of the usefulness of cerebral oxygenation monitors
rSatHbO2 estimates cortical oxygenation and is affected by the balance between
oxygen supply and demand
Isolated readings should be interpreted after consideration of the clinical
circumstances
It may be useful as a trend monitor and for goal-directed management
It may be more useful in detection of cortical function when combined with other
monitors of EEG and blood flow
SUMMARY
Applying scalp sensors in the operating theater, intensive care, or resuscitation sce-
narios to detect and monitor brain function is achievable, practical, and affordable.
However, the clinician needs to understand that the modalities are complex and the
output of the monitor needs careful interpretation. The monitor itself may have tech-
nical problems, and a single reading must be considered with caution. These monitors
may have a use for monitoring trends in specific situations, but good evidence does
not yet support their widespread use. Nevertheless, research should continue to
investigate their role. Future techniques and treatments may show that these monitors
can monitor brain function and prevent harm.
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82:74–82.
89. Daubeney PE, Smith DC, Pilkington SN, et al. Cerebral oxygenation during pae-
diatric cardiac surgery: identification of vulnerable periods using near infrared
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90. Toet MC, Flinterman A, Laar I, et al. Cerebral oxygen saturation and electrical
brain activity before, during, and up to 36 hours after arterial switch procedure
in neonates without pre-existing brain damage: its relationship to neurodevelop-
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91. Greeley WJ, Bracey VA, Ungerleider RM, et al. Recovery of cerebral metabolism
and mitochondrial oxidation state is delayed after hypothermic circulatory
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92. Kurth CD, Levy WJ, McCann J. Near-infrared spectroscopy cerebral oxygen
saturation thresholds for hypoxia-ischemia in piglets. J Cereb Blood Flow Metab
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93. Kurth CD, McCann JC, Wu J, et al. Cerebral oxygen saturation-time threshold for
hypoxic-ischemic injury in piglets. Anesth Analg 2009;108(4):1268–77.
94. Sakamoto T, Zurakowski D, Duebener LF, et al. Combination of alpha-stat strat-
egy and hemodilution exacerbates neurologic injury in a survival piglet model
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95. Sakamoto T, Hatsuoka S, Stock UA, et al. Prediction of safe duration of hypother-
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97. Berens RJ, Stuth EA, Robertson FA, et al. Near infrared spectroscopy monitoring
during pediatric aortic coarctation repair. Paediatr Anaesth 2006;16(7):777–81.
98. Fallon P, Aparicio JM, Elliott MJ, et al. Incidence of neurological complications of
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99. Ferry PC. Neurologic sequelae of cardiac surgery in children. Am J Dis Child
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101. du Plessis AJ. Mechanisms of brain injury during infant cardiac surgery. Semin
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104. Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic
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117(2):333–9.
A n e s t h e t i c N e u ro t o x i c i t y
Erica P. Lin, MDa,*, Sulpicio G. Soriano, MD
b
,
Andreas W. Loepke, MD, PhDa
KEYWORDS
Anesthetics Anesthesia Neurodegeneration Neurotoxicity Infant
Learning impairment
KEY POINTS
All routinely used sedatives and anesthetics have been found to be neurotoxic in a wide
variety of animal species, including nonhuman primates.
The neurotoxic effects observed in animals include apoptotic neuronal cell death, dimin-
ished neuronal density, decreased neurogenesis and gliogenesis, alterations in dendritic
architecture, diminution of neurotrophic factors, mitochondrial degeneration, cytoskeletal
destabilization, abnormal reentry into the cell cycle, as well as learning and memory
impairment.
Several epidemiologic human studies have observed an association between anesthesia
exposure in patients younger than 3 to 4 years and subsequent learning disabilities and
language abnormalities, whereas others have not found this link.
It remains unresolved whether anesthetic exposure or other factors, such as the underly-
ing medical condition, surgery, inflammatory response, pain, physiologic abnormalities
during surgery, or other unknown factors, are causative for the observed abnormalities.
Additional animal and clinical research is urgently needed to identify the phenomenon’s un-
derlying mechanisms, to assess human applicability, and to devise mitigating strategies.
ANESTHESIA: WITHOUT SENSATION
Since its inception more than a century ago, anesthesia has become a mainstay of
modern medicine for its ability to render patients insensate to the trauma and stress
associated with surgery. Because millions of children across the world are anesthe-
tized annually for surgeries, painful procedures, and imaging studies,1 it has been
widely thought that once the anesthetic effects dissipate, the brain returns to its
Funding Sources. None.

Conflicts of Interest. None to disclose.
a
Department of Anesthesiology, Cincinnati Children’s Hospital Medical Center, University of
Cincinnati College of Medicine, 3333 Burnet Ave, MLC 2001, Cincinnati, OH 45229, USA;
b
Department of Anesthesiology, Perioperative, and Pain Medicine, Harvard Medical School,
Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115, USA
E-mail address: erica.lin@cchmc.org

134 Lin et al
baseline preanesthetic state. More recently, however, a growing body of work, largely
arising from laboratory research, has suggested that sedatives and anesthetics may
have long-lasting effects on the brain. Numerous animal studies have observed histo-
logic evidence for widespread apoptotic brain cell death (an inborn cell suicide pro-
gram) immediately following anesthetic exposure early in life. Several laboratory
studies have also demonstrated subsequent neurocognitive impairment. Although it
remains unknown whether the phenomenon’s mechanism parallels that of the anes-
thetic state, these findings have raised substantial disquiet within the anesthesia com-
munity, as well as among parents and government regulators, about the safety of
clinical pediatric anesthesia practice. Accordingly, this article provides an overview
of the currently available data from both animal experiments and human clinical
studies regarding the effects of sedatives and anesthetics on the developing brain.
HISTORICAL PEDIATRIC ANESTHESIA: NOCICEPTIVE RESPONSE OF THE IMMATURE

BRAIN TO SURGERY
Before the 1980s, general anesthetics were routinely withheld from critically ill neo-
nates to avoid hemodynamic deterioration and myocardial depression. Instead, peri-
operative drug regimens were oftentimes limited to muscle relaxants and nitrous
oxide,2 termed the Liverpool technique, because neonates were widely thought to
be incapable of perceiving or localizing pain. However, with the recognition that painful
stimulation can also lead to dramatic metabolic and endocrine responses in premature
infants,3 an analgesic component was introduced into neonatal anesthesia practice to
blunt the nociceptive response to surgery.4
Robinson and Gregory5 showed that fentanyl analgesia can be safely administered
in neonates and is effective in blunting response to surgical stimulation. A randomized
study in newborn patients undergoing ligation of a patent ductus arteriosus further
demonstrated that the addition of fentanyl to the minimalist, conventional approach
of nitrous oxide and paralytic blunted the hormonal response to surgery and improved
the postoperative outcome by decreasing circulatory and metabolic complications.4
Since then, the advent of modern analgesics and anesthetics, including the develop-
ment of volatile anesthetics with less myocardial depressant effects, combined with
better monitoring techniques has afforded critically ill infants the benefits of amnesia
and analgesia, while enabling surgeons to undertake more extensive and effective in-
terventions in one of the most vulnerable of patient populations. General anesthesia
for stressful procedures may even lead to immediate improvement in outcomes
because a small retrospective study noted that patients undergoing ward reduction
of gastroschisis without general anesthesia had a higher incidence of serious adverse
events, such as bowel ischemia, need for total parenteral nutrition, and unplanned
reoperation, compared with neonates receiving anesthesia for the same procedure.6
Moreover, untreated painful stimulation early in life has been demonstrated to be
associated with subsequent diminished cognition and motor function.7,8
Importantly, widespread neuronal cell death has been found following repetitive
painful stimulation in neonatal animals9 and resulted in adverse neurologic outcomes,
including altered pain processing, changes in behavioral and cognitive function that
increase vulnerability to stress- and anxiety-mediated disorders, and chronic pain
syndromes.10 Concomitant administration of a small dose of ketamine significantly
reduced pain-induced neuronal degeneration.9 Furthermore, preemptive morphine
analgesia administered in neonatal rats before an inflammatory injury facilitated recov-
ery from the insult and attenuated subsequent injury-induced hypoalgesia in adoles-
cence and adulthood.11
Taken together, both animal and human data suggest that pain-related stress
early in life is deleterious to nervous system development and that blunting this stress
pharmacologically may interrupt some of these degenerative effects.
DELETERIOUS EFFECTS OF ANESTHETIC EXPOSURE ON THE DEVELOPING BRAIN
Concerns regarding the potentially debilitating effects of general anesthesia on neuro-

logic function initially arose in the 1950s based on personality changes, such as
increased temper tantrums, night terrors, fear behaviors, and bed wetting, that were
observed especially in younger children following exposure to vinyl ether, cyclopro-
pane, or ethyl chloride for otolaryngologic surgery.12 Because these abnormalities
were partially alleviated by the timely administration of preoperative sedative medica-
tion before induction, it was thought that these behavioral abnormalities were more
psychological in nature than a representation of underlying structural defects. Several
decades later, animal studies investigating the potential occupational health hazards
for pregnant health care workers chronically exposed to low levels of anesthetic waste
gases observed delayed synaptogenesis and behavioral abnormalities in offspring
born to rats exposed to subclinical doses of halothane during their intrauterine life.13,14
Approximately 10 years ago, potentially deleterious effects of anesthetics on young
children garnered interest, first, in a ground-breaking study observing widespread
neuronal degeneration following repeated N-methyl-D-aspartate (NMDA) antagonist
exposure in neonatal rat pups15 and later in a sentinel article by Jevtovic-Todorovic
and colleagues16 focusing on the deleterious effects of a combination of the gamma-
aminobutyric acid (GABA)-agonist midazolam, the combined GABA-agonist and
NMDA-antagonist isoflurane, and the NMDA-antagonist nitrous oxide. Neonatal rats
exposed to doses sufficient to maintain a surgical depth of anesthesia experienced
both immediate brain cell loss and impaired long-term neurocognitive function. Subse-
quent studies by a variety of research groups have documented acute neuronal cell
loss, altered dendritic architecture, reduced synaptic density, decreased levels of neu-
rotrophic factors, mitochondrial degeneration, destabilization of the cytoskeleton, and
cell cycle abnormalities following exposure to all routinely used anesthetics and seda-
tives in several immature animal species, including chicks, mice, rats, guinea pigs,
swine, sheep, and rhesus monkeys (reviewed in17). Of these deleterious effects during
anesthetic exposure, the most obvious manifestation is widespread neuronal cell death.
APOPTOTIC NEURONAL CELL DEATH: PHYSIOLOGIC AND PATHOLOGIC
Brain architecture is not static, and both expanding and regressing processes are in-
tegral to proper brain development. In utero and postnatally during infancy, the human
brain undergoes rapid growth. The resulting overabundance of neurons and neuronal
connections is followed by neuronal cell death and synaptic regression, resulting in
less than half the neurons generated during development actually surviving into adult-
hood.18 This naturally occurring, cellular suicide process of programed cell death,
termed apoptosis, is required for normal central nervous system structure and func-
tion; disruptions to this process can result in brain malformation and intrauterine
demise.19 Across species, apoptotic cell death is characteristic of normal tissue turn-
over, embryonic cell death, and metamorphosis. Cells that are either functionally
redundant or potentially detrimental are eliminated. For example, apoptosis is respon-
sible for the embryonal cell death of interdigital mesenchymal tissue separating the
digits of hands and feet as well as the ablation of tail tissue as part of tadpole meta-
morphosis in amphibians. In contrast to the other main cell death process, necrosis,
apoptosis represents an active, energy-consuming process. This built-in cell death
136 Lin et al
program involves cascades of caspases, which are specialized enzymes that break
down cells by chromatin aggregation, nuclear and cytoplasmic condensation, decon-
struction of cellular debris into apoptotic bodies, and removal of this material without
the need for an extensive inflammatory response.20
Physiologic apoptotic cell death also occurs in the developing brain, but its distribu-
tion is not uniform across all regions because it is regulated by the age and matura-
tional stage of the neurons. Specifically, 2 main waves of natural apoptosis take
place: one involving progenitor cells occurs during early embryonic development
and another, later apoptotic surge affects early postmitotic neurons.21 The former
wave of neuronal elimination is thought to regulate the neuronal precursor pool size,
whereas the latter adjusts the size of neuronal populations to their functional target
fields.22 Furthermore, it also fine tunes the neuronal wiring of developing networks
by eliminating neurons with erroneous or inadequate projections and selectively
removing long axon collaterals.23 Throughout this process, the development of neigh-
boring cells is largely unaffected.
Given the central role of physiologic apoptosis in the immature brain, cell death trig-
gered by pathologic insults during development, such as hypoxia and ischemia, may
also heavily depend on this process and manifest with mixed characteristics of both
apoptosis and necrosis.22 As an example, although early hypoxic-ischemic injury in
the striatum and cortex of neonatal rats seems necrotic, later injury in the thalamus,
white matter tracts, and synaptic terminal fields remote from the primary injury is
more consistent with apoptosis, suggesting that neuronal death outside of the imme-
diate infarct area may heavily depend on apoptotic pathways.24
APOPTOSIS: TRIGGERED BY ANESTHETICS
A widespread and dramatic increase in neuronal cell death has been observed imme-
diately following anesthetic exposure in a wide variety of animal species when
compared with unanesthetized littermates. The cell death pathway has been delin-
eated as using both intrinsic and extrinsic apoptotic pathways.25 The final step of
this process involves activated caspase 3, which has been repeatedly used as a
marker in laboratory studies to assess and quantify anesthesia-induced neuroapopto-
sis. Caspase 3 expression is dose- and exposure-time dependent and has been
observed as early as 1 hour into an isoflurane anesthetic exposure.26 All commonly
clinically used anesthetics and sedatives, such as ketamine, desflurane, enflurane,
halothane, isoflurane, sevoflurane, xenon, diazepam, midazolam, chloral hydrate,
pentobarbital, and propofol, have been found in either in vivo or in vitro experiments
to dramatically increase neuroapoptosis. These observations have been made in
such diverse species as nematodes, chicks, mice, rats, guinea pigs, piglets, and rhe-
sus monkeys. Neurotoxic effects are amplified when several sedatives and anes-
thetics acting by different mechanism are combined in that midazolam and nitrous
oxide by themselves do not seem to trigger neuroapoptosis but dramatically increase
neuroapoptosis when administered in combination with isoflurane.16 Even though of
great concern, given the inability to directly assess human brain histology immediately
following exposure, it remains unclear whether similar neurodegeneration occurs in
infants and children undergoing anesthesia.
LONG-TERM BRAIN CELL VIABILITY AND NEUROLOGIC FUNCTION FOLLOWING

ANESTHESIA IN ANIMALS
Even in animals, whereby brain injury can be assessed histologically, it remains

unclear whether neuronal elimination early in life leads to permanent cell loss and
dysfunction or can be compensated for by the developing brain’s capacity for repair.
Only a few studies have examined neonatal neuroapoptosis and adult neuronal den-
sity and function. In a neonatal rat model, a 6-hour exposure to midazolam, isoflurane,
and nitrous oxide early in life dramatically increased neuroapoptosis immediately
following the exposure and led to impaired learning in the Morris water maze in young
adulthood and older age16 as well as decreased adult neuronal density in brain regions
affected by neonatal neuroapoptosis.27 In the same animals, however, other tests of
behavior and learning, such as acoustic startle response, sensorimotor tests, sponta-
neous locomotor behavior, and learning and memory in the radial arms maze, were
unaffected, making it unclear which specific neurocognitive domains are affected
long-term by neonatal anesthetic exposure. Although another study in neonatal
mice also demonstrated dramatically increased apoptotic cellular degeneration in
several brain regions immediately following a 6-hour isoflurane exposure, subsequent
neuronal density in the corresponding brain regions was unaltered, and Morris water
maze learning and memory function remained intact into adulthood.28 Thus, it remains
unresolved whether differences in species or anesthetic regimen can lead to differen-
tial effects on the neurocognitive outcome. In a different study involving isoflurane
exposure in neonatal rats, neuronal apoptosis was observed after 2 hours of exposure.
However, long-term neurologic abnormalities only appeared after 4 hours of anes-
thesia exposure.29 Furthermore, in this same study, 4 hours of carbon dioxide–
induced hypercarbia induced substantial apoptotic cell death but did not result in
long-term deficits and actually improved spatial reference and working memory.29
Accordingly, this study calls into question the relationship between early neuronal
cell death and subsequent neurologic sequelae; it remains to be determined whether
there exists a threshold exposure time after which neurologic abnormalities occur.
Similar uncertainty exists regarding a possible threshold dose of intravenous anes-
thetic necessary to induce permanent neurologic damage. Exposure to 20 to
50 mg/kg/h of ketamine for 24 hours in newborn rhesus monkeys has been demon-
strated to lead to long-term impairment of memory tasks and motivation,30 but this
dosing far exceeds routine clinical regimens.
THE CLINICAL RELEVANCE OF EXPERIMENTAL CONDITIONS: CAN ANIMAL STUDIES BE

DIRECTLY TRANSLATED TO HUMANS?
The mounting evidence of neurotoxic effects following anesthetic exposure in animal

models is undeniable. However, it remains highly questionable whether these findings
can be directly translated from bench to bedside (or operating room). Anesthetic man-
agement in rodent models is vastly different when compared with clinical practice, in
particular the lack of continuous monitoring and airway management. The neonatal
animals’ diminutive size precludes continuous hemodynamic monitoring as well as
repeated blood measurements of acid-base status and glucose levels, both standard
practices in clinical anesthesia for human neonates. In small rodents, anesthetic expo-
sure can result in extensive hypercarbia, metabolic acidosis, and hypoglyce-
mia,28,29,31 derangements that would not be tolerated without acute intervention in
clinical practice and can lead to neurologic deficits.32
Most laboratory studies also do not include continuous stimulation of the central
nervous system by surgical stress and pain, which is frequently encountered during
human perioperative care. The effects of surgical anesthesia in children, in the face
of these noxious stimuli, may be different than prolonged unstimulated anesthetic
exposure in the animal laboratory. Animal studies attempting to address this question,
however, by introducing caustic injections or tail clamping as nociceptive stimuli have
138 Lin et al
provided conflicting results. One study showed increased neuroapoptosis following

isoflurane anesthesia exposure with painful stimulation.33 Another study noted that
a small anesthetic dose of ketamine alleviated the deleterious effects of painful stim-
ulation,9 whereas a separate report showed that concurrent noxious stimulus miti-
gated the expected neuroapoptosis associated with a large dose of ketamine.34
Finally, a study using isoflurane did not demonstrate any differences between stimu-
lated and unstimulated animals.35 Importantly, when factoring in long-term outcomes,
neonatal stress in animals has been found to obviate adult behavioral impairment
because of neonatally administered morphine.36
The anesthetic dose required to cause injury is also a point of controversy that limits
the immediate application of animal data to human practice. Unlike in pediatric anes-
thesia, clinical doses of volatile anesthetics for only a few hours can be lethal in a
significant percentage of small rodents.28,29 Furthermore, the doses of intravenous
agents necessary to generate neuronal injury far exceed those used in clinical prac-
tice, by a factor of 10 for ketamine and a factor of 20 to 30 for propofol, using
weight-based comparisons. Even when accounting for differential body size and
metabolic rates among species, doses in animal studies still remain higher than those
routinely clinically used.17 Accordingly, plasma concentrations of ketamine leading to
increased neuronal cell death in a nonhuman primate model were 5 to 10 times higher
than those measured in humans.37
It remains controversial whether the duration of anesthetic exposure should be
expressed as a fraction of the animal’s life expectancy or as an absolute number. If
applying the former strategy, exposure times in rodent models clearly represent a
much larger fraction of the animal’s life than that of a human’s. Although it is probably
an oversimplification to compare exposure times like dog years, it is undeniable that a
multi-hour anesthetic in rodents covers a much larger portion of the functionally impor-
tant brain growth spurt during the first 2 weeks of rodent life, compared with the equiv-
alent fraction of brain development that occurs over several years in humans. It would,
therefore, also be conceivable that brain damage caused in rodents cannot be
repaired in the relatively short remaining time of rapid brain development, thereby
becoming functionally relevant, whereas human brain function following a similar injury
may fully recover because of the substantially longer brain developmental period dur-
ing which repair mechanisms can occur. Alternatively, the much greater complexity of
human brain development and the higher level of brain function may render humans
more vulnerable to potential injury compared with lower animals, following similar
neurotoxic insults.
EFFECTS OF ANESTHETIC EXPOSURE ON SUBSEQUENT LEARNING AND BEHAVIOR IN

YOUNG CHILDREN
In light of the emerging experimental evidence that anesthetic exposure causes neuro-
degeneration across a wide variety of animal species and that anesthesia-induced
neuronal cell loss may be associated with subsequent neurologic abnormalities, the
possibility of this phenomenon also occurring in humans cannot be ignored. Because
it is impossible to examine brain tissue in healthy children, human studies have relied
on assessing neurologic function. However, these studies have thus far not been able
to produce any prospective data and are obviously hampered by the inability to
randomize young children to undergo painful procedures without anesthesia and
analgesia. Furthermore, exposure to anesthetic agents cannot be justified without a
surgical or diagnostic indication, rendering it difficult to distinguish the respective con-
tributions of the underlying condition, the surgical procedure, and anesthesia on the
neurologic outcome. Therefore, currently available human data rely heavily on postop-
erative behavioral studies, epidemiologic analyses, and studies into long-term neuro-
logic outcomes in children suffering from illnesses requiring the administration of
anesthetics and sedatives during surgery and intensive care.
It is widely known that surgery and anesthesia in young children can lead to pro-
longed behavioral changes (eg, attention seeking, crying, temper tantrums, sleep dis-
turbances, anxiety). These maladaptive behaviors usually occur early in the
postoperative course and decrease significantly during the first month.38 Predictors
for these behaviors have included younger age, severity of postoperative pain, previ-
ous negative experience with health care, and patient and parental anxiety.38–40
Although the precise mechanism underlying these behavioral changes is unknown,
it presumably involves psychological factors and not structural brain abnormalities
because the administration of preoperative benzodiazepines did not worsen postop-
erative maladaptive behaviors as would be expected for a cytotoxic cause, but instead
significantly ameliorated behavioral symptoms.41 However, these behavioral studies
heavily relied on parental reporting and did not include professional assessment or
long-term neurocognitive outcome evaluations, adding uncertainty to the permanent
sequelae of these abnormal behaviors.
Conversely, a patient population whose neurocognitive development has been fol-
lowed closely long-term with neurologic testing tools are neonates and infants who
have undergone palliative or corrective congenital heart surgery early in life, such as
children with hypoplastic left heart syndrome or transposition of the great arteries.
Neurocognitive impairment is well documented in these populations, and its underly-
ing cause is likely multifactorial.42 Many newborns with complex heart defects may
already present with abnormal brain structure and function preoperatively.43 Perioper-
ative diminution of oxygenation and cardiac output, compounded by intraoperative
techniques interfering with physiologic homeostasis, including nonpulsatile flow dur-
ing cardiopulmonary bypass, deep hypothermia, circulatory arrest, and regional cere-
bral perfusion, may all contribute to poor neurologic outcomes. In cohorts of patients
who underwent neonatal arterial switch operation, follow-up standardized testing at
12 months,44 preschool and school age,45–48 and adolescence49 have demonstrated
abnormalities in motor and cognitive development. These persistent neurologic ab-
normalities, despite improved surgical and supportive techniques, raise the possibility
that the repeated obligatory anesthetic exposures in many of these children may
contribute to poor outcomes. None of the aforementioned referenced studies, how-
ever, specified the anesthetic techniques used. A smaller study in 95 survivors of
neonatal cardiac surgery aiming to address these concerns found no effects of cumu-
lative anesthetic doses and exposure times on neurologic performance, adaptive
behavior, or vocabulary at 18 to 24 months.50 However, because of a switch in the
neurocognitive measuring tool during the study, the investigators were unable to
use their testing tool as a continuous variable, thereby significantly limiting the study’s
assessment of subtle neurologic abnormalities.
Other cohort studies involving critically ill neonates with necrotizing enterocolitis51,52
and patent ductus arteriosus53 have demonstrated that subsets of patients requiring
surgical intervention with anesthesia experienced significant growth delay and
adverse neurodevelopmental outcomes compared with their counterparts who were
managed with medical therapies alone. However, some of these results could be
skewed by selection bias because some of the extremely low-birth-weight study par-
ticipants requiring surgery seemed sicker and required higher inotropic support.51
In order to examine the long-term neurodevelopmental implications of pediatric
anesthetic exposure in comparably healthy children, several research groups have
140 Lin et al
conducted retrospective analyses of large-scale epidemiologic data. DiMaggio and

coworkers54 used the International Classification of Diseases, Ninth Revision (ICD-9)
procedural code for inguinal hernia repair to query the New York State Medicaid data-
base for patients who underwent general anesthesia for this procedure during the first
3 years of life (n 5 383), comparing them with an age-matched cohort of 5050 children
who had no history of hernia repair.54 After controlling for gender and birth-related
complications, children who underwent inguinal hernia repair who were younger
than 3 years were more than twice as likely to subsequently be diagnosed with a
developmental or behavioral disorder. To control for environmental confounders (eg,
home environment, parenting style, education system), a subsequent study by the
same group focused on a sibling birth cohort of 10,450 of whom 304 had surgery/
anesthesia before 3 years of age.55 Using both proportional hazards modeling and
pair-matched analysis, they found evidence linking surgery with anesthesia to a
poor neurodevelopmental outcome. A single exposure did not increase the risk of
behavioral/developmental abnormalities (hazard ratio [HR] 1.1 [95% confidence inter-
val (CI): 0.8, 1.4]). Two exposures increased the risk (HR 2.9 [95% CI: 2.5, 3.1]), and 3
or more anesthetics increased it even further (HR 4.0 [95% CI: 3.5, 4.5]).
To further correct for environmental and genetic confounders, Bartels and col-
leagues56 conducted a retrospective study in 1142 monozygotic twin pairs, demon-
strating that twin pairs in which one or both siblings were exposed to anesthesia
before 3 years of age had significantly lower educational achievement scores and
more cognitive problems than twins not exposed to anesthesia. Strikingly, however,
in discordant twins whereby one twin was exposed to anesthesia but not the other,
school performance was identical among siblings, suggesting no direct causal rela-
tionship between anesthesia exposure and later learning-related difficulties but
perhaps indicating a genetic component that increases both the need for surgery
and the risk for poor school performance.
In another set of studies, the Mayo Clinic anesthesia group used an existing birth
cohort in Olmstead County, Minnesota to perform several anesthesia-related epidemi-
ologic analyses. In a study of 5357 children, of whom 593 received general anesthesia
before 4 years of age, Wilder and colleagues57 used the subsequent development of
learning disabilities as the primary end point, defined as low performance on standard-
ized aptitude tests administered by the school district. Compared with those not
exposed to anesthesia, which consisted predominantly of halothane and nitrous ox-
ide, a singular exposure was not a significant risk factor for developing a learning
disability. Conversely, multiple anesthetic exposures incrementally increased this
risk, concomitant with an increased cumulative duration of anesthesia. However,
the principal use of the now-obsolete anesthetic halothane and the lack of pulse ox-
imetry monitoring in many of the children temper the direct applicability of these find-
ings to contemporary pediatric anesthesia.
Using the same cohort, the research group also examined anesthetic exposures
before the second birthday.58 Similar to the patients exposed up to their fourth
birthday, the risk for developing a learning disability did not increase following a single
anesthetic exposure in the younger children. However, after adjustment for health sta-
tus, multiple anesthetic exposures before the age of 2 years represented a significant
independent risk factor (HR 2.12 [95% CI: 1.26–3.54]).
In another study, the same group assessed the neurocognitive implications of a brief
anesthetic exposure even earlier in life, just before delivery by cesarean section.
School and health data from almost 5000 children delivered via vaginal delivery
were compared with data from approximately 200 neonates born via cesarean section
with general anesthesia (consisting primarily of sodium thiopental, halothane, and
nitrous oxide) and 300 neonates born via cesarean section with regional anesthesia.59
Children exposed to general or regional anesthesia for cesarean delivery were not at a
higher risk for developing learning disabilities when compared with their counterparts
who were vaginally delivered, suggesting that a brief peripartum anesthetic exposure
had no lasting impact on neurodevelopment. This finding was not entirely expected,
given that infants in the general-anesthesia group experienced lower birth weights,
lower gestational ages, lower Apgar scores, and their deliveries were more commonly
complicated by hemorrhage, eclampsia/preeclampsia, and emergent circumstances
than their peers delivered without anesthesia.
In a study involving Danish birth cohorts from 1986 to 1990, Hansen and co-
workers60 assessed the academic performance of 2689 children with a history of
inguinal hernia repair in infancy with that of a randomly selected, age-matched 5%
population sample.60 After an adjustment for known confounders, no difference in
test scores on a standardized, nationwide ninth grade general examination of aca-
demic achievement was observed between the previously exposed children and the
population sample. However, previously exposed children were more likely to not
sit for the examination, which could mean that they were either academically or other-
wise unable to do so.
Finally, using the Western Australian Pregnancy Cohort in Perth, Australia, Ing and
colleagues61 found an association between a single previous exposure to surgery with
anesthesia in infants and toddlers and deficits in abstract reasoning and language
development when measured at 10 years of age. Raven’s Colored Progressive
Matrices and Clinical Evaluation of Language (CELF) tests were used as measures
for abstract reasoning and language (receptive, expressive, and total language) devel-
opment, respectively. After an adjustment for confounders, any anesthetic exposure
to children younger than 3 years increased the risk ratio for disability to between 1.7
and 2.1. However, several other domains, such as tests of vocabulary, behavior,
and motor functions, were not affected by exposure.
In summary, the clinical evidence of anesthetic neurotoxicity in humans is not entirely
clear. Several retrospective studies have found an association between anesthetic
exposure early in life and abnormal subsequent neurocognitive function, whereas
others have not (Table 1). Rigorous prospective, randomized, placebo-controlled clin-
ical trials are unfeasible; retrospective studies are limited by multiple confounders, both
known and unknown. The currently available retrospective data in humans have relied
heavily on group-administered tests assessing school performance or the need for
remediating services. Moreover, several of the retrospective epidemiologic studies
collected data in an era before the anesthetic standard of care included continuous
pulse oximetry and when inhalational anesthetics with profound cardiovascular effects,
such as halothane, were commonly used.57 Knowing that the at-risk population of ne-
onates and infants has higher incidences of oxygen desaturations, hypercarbia, or
hypocarbia62 introduces physiologic instabilities related to surgery/anesthesia as po-
tential contributing factors for adverse neurologic outcomes.32,63 On the other hand,
most studies using validated neurocognitive testing tools have examined severely ill
patients with multiple confounders and have not described the used anesthetic or
sedative regimens. Study design and medical ethics preclude the separation of the
respective effects of the surgical procedure from those related only to the anesthetic
exposure. Surgery is commonly associated with neurohumoral and inflammatory re-
sponses, which have been found to influence neurocognitive outcomes. Moreover,
any congenital malformations or morbidities associated with the underlying disease
process requiring surgical intervention may also increase the risk of poor neurodeve-
lopmental performance regardless of surgery/anesthesia exposure.
142
Lin et al
Table 1
Clinical and epidemiologic studies into the effect of surgery with anesthesia early in life on subsequent neurologic function
Age During
Number of Age During Neurologic Neurologic Neurologic Sequelae
Study Design Study Group Control Group Patients Exposure Assessment Assessment Tools in Study Group Reference
Survey study General None, some 1027 3–12 y 3 and 30 d PHBQ Behavioral changes Stargatt
anesthesia sibling controls postanes- in 24% on day 3 et al,40
for general thesia after surgery, 16% 2006
surgery, ENT, on day 30,
gastroenter- including anxiety
ology, plastics and regression,
surgery, apathy or
orthopedics withdrawal, and
separation anxiety
Case series ASO None, comparison 30 Neonatal 12 mo BSID3, structural Diminished language Andropoulos
with normative assessment composite was et al,44
values with MRI within population 2012
norm, lower scores
correlated with
higher cumulative
midazolam dose
Case series ASO None, comparison 60 Neonatal 3–14 y Kiphard and Assessor not blinded: Hövels-
with normative Schilling Body increased Gürich45,46
values Coordination prevalence of
Test, Kaufman neurologic
Assessment impairment (27%),
Battery for speech impairment
Children, Oral (40%), motor
and Speech dysfunction,
Motor Control language
Test, Mayo Test impairment; no
of Speech and difference in
Oral Apraxia intelligence
Prospective, ASO with DHCA ASO with LF-CPB 155 Neonatal 1.0, 2.5, WISC 3, WIAT, Lower Full-Scale IQ, Bellinger
randomized or general 4.0, 8.0 y TRF, CBCL, Perceptual et al,47,49
trial population WCST, TOVA, Organization, and
Mayo Test for Freedom from
Apraxia of Distractibility scores,
Speech, WIAT Reading and
Goldman-Fristoe Mathematics
Test of Composites, Memory
Articulation Screening Index,
WCST, TOVA scores;
most differences were
<1 SD
Case series Congenital None, examined 95 Infant 18–24 mo BSID2 & 3 No evidence for Guerrra
heart surgery effect of 6 wk association between et al,50
cumulative doses dose and duration of
of anesthetics/ sedation/analgesia
sedatives adverse
neurodevelop-
mental outcomes
Case-control NEC requiring No NEC or NEC 115 26–27 wk 12 mo, 3 y, GMDS, SBIS No blinded assessor: Tobiansky
study laparotomy managed PCA, and 5 y higher incidence of et al,51
medically VLBW neurodevelop- 1995
mental impairment;
use of inotropes and
TPN dependence
Anesthetic Neurotoxicity
more prevalent after
laparotomy
Cohort study, Laparotomy Peritoneal drain 3725 Neonatal, 18–22 mo Neurologic Blinded assessor: higher Hintz
case-control placement ELBW examination, frequency of CP and et al,52
study BSID2 lower BSID 2; no 2005
difference between
medically treated
patients with or
without NEC
(continued on next page)
143
144
Lin et al
Table 1
(continued )
Age During
Cohort study, PDA ligation Indomethacin 340 84% 18 mo Neurologic Increase in cerebral Kabra
case-control treatment neonatal examination, palsy, cognitive delay, et al,53
study (25–29 wk BSID2 hearing loss, bilateral 2007
PCA), blindness
ELBW
Matched ICD-9 procedural Children in birth 5433 Younger n/a Diagnostic code Not individually DiMaggio
cohort code for cohort without than 3 y for unspecified specified, increased et al,54
study inguinal procedural code delay or hazard ratio for
hernia without for inguinal behavioral diagnosis following
preexisting hernia disorder, mental multiple exposures
developmental/ retardation,
behavioral autism, and
diagnosis language or
speech problems
Cohort study ICD-9 procedural Siblings in birth 10,450 Younger n/a Diagnostic code Not individually DiMaggio
codes for cohort without than 3 y for autism, specified, increased et al,55
anesthesia/ anesthesia/ unsocial and HR for diagnosis
surgery without surgery social conduct, following multiple
preexisting developmental exposures but not in
developmental/ delay, reading sibling pairs
behavioral and language discordant for
diagnosis disorders, exposure
attention deficit
and hyperkinetic
disorders
Cohort study Exposure to Other unexposed 1142 twin Younger 12 y CITO test assessing Lower educational Bartels
anesthesia monozygotic pairs than 3 y language, achievement scores et al,56
according to twin pairs or mathematics, and cognitive 2009
parent unexposed information problems compared
co-twin processing, and with unexposed twin
world pairs but no
orientation difference within co-
twins discordant for
exposure
Cohort study Any surgical Unanesthetized 5357 Younger Any learning Included Educational Wilder
procedure as members of the than 4 y disability standardized achievement >1.75 SD et al,57
identified by birth cohort before 19 y school aptitude deviations less than 2009
hospital and of age tests, WISC, predicted score more
county records and/or frequently observed
Woodcock following multiple
Johnson anesthetic exposures
but not single
exposure
Matched Any surgical Unanesthetized, 1050 Younger Any learning Included More frequent learning Flick et al,58
cohort procedure as matched than 2 y disability standardized disabilities and need 2011
study identified by members before 19 y school aptitude for individualized
hospital and of the birth of age tests, WISC, education program
county records cohort and/or for speech/language
Woodcock impairment in
Johnson children with
Anesthetic Neurotoxicity
multiple, but not
single exposures
145
146
Lin et al
Table 1
(continued )
Age During
Cohort study Birth by cesarean Birth by cesarean 5320 Neonatal Any learning Included Equal risk of developing Sprung
section with section with disability standardized learning disability in et al,59
general regional before 19 y school aptitude children born via 2009
anesthesia anesthesia or by of age tests, WISC, vaginal delivery or by
spontaneous and/or cesarean section with
vaginal delivery Woodcock general anesthesia
without any Johnson
anesthesia
Cohort study Inguinal hernia Unanesthetized, 17,264 Infancy 15–16 y Ninth grade No difference in scores, Hansen
repair age-matched school exit but exposed children et al,60
members of the examination less likely to sit for 2011
birth cohort examination
Cohort study Any anesthetic Unanesthetized 2868 Younger 10 y Individually Even single anesthetic Ing et al,61
exposure members of the than 3 y administered exposure associated 2012
birth cohort tests of with increased risk of
language language and
development abstract reasoning
(CELF) and deficits
cognition (CPM)
Abbreviations: ASO, arterial switch operation; BSID, Bayley Scales of Infant Development; CBCL, Achenbach Child Behavior Checklist Parental Assessment; CITO,
Centraal Instituut voor Toetsontwikkeling; CP, cerebral palsy; CPM, Colored Progressive Matrices; CTRS-R, Connor’s Teacher Rating Scale-Revised; DHCA, deep hy-
pothermic circulatory arrest; ELBW, extremely low birth weight (<1000 g); ENT, ears, nose, and throat; GMDS, Griffiths Mental Development Scales; LF-CPB, low
flow-cardiopulmonary bypass; MRI, magnetic resonance imaging; NEC, necrotizing enterocolitis; PCA, post-conceptual age; PDA, patent ductus arteriosus; PHBQ,
Vernon Post Hospitalization Behavior Questionnaire; SBIS, Stanford-Binet Intelligence Scales; TOVA, Test of Variables of Attention; TPN, total parenteral nutrition;
TRF, Teacher’s Report Form; VLBW, very low birth weight (1500 g); WCST, Wisconsin Card Sorting Test of problem solving; WIAT, Wechsler Individual Achievement
Test; WISC 3, Wechsler Intelligence Scale for Children, Third Edition.
Data from Refs.40,44–61
CHALLENGING STANDARD THERAPIES: THE UTILITY OF PROSPECTIVE RANDOMIZED

CONTROLLED TRIALS
Prospective randomized controlled trials remain the gold standard for determining
the efficacy and identifying complications associated with a specific intervention.
Certainly, prospective studies neutralize the confounding factors that are inherent to
retrospective analyses by precise stratification of the treatment groups. Furthermore,
this type of study not only determines the utility and consequences of a routine treat-
ment modality but can also uncover unexpected sequelae of the therapy.
The well-publicized line of investigation into the effect of routine dexamethasone
therapy for bronchopulmonary dysplasia in premature neonates highlights the useful-
ness of prospective randomized controlled trials. Much like the routine use of general
anesthetic for neonatal surgery, dexamethasone had been the standard treatment
regimen for the prevention of bronchopulmonary dysplasia in premature neonates
and led to decreased pulmonary-related morbidity and mortality. However, this prac-
tice was associated with increased incidences of gastrointestinal bleeding, hypergly-
cemia, hypertension, cardiomyopathy, and cerebral palsy. These observations fueled
a rigorous double-blind placebo-controlled trial in premature neonates requiring me-
chanical ventilation. The initial analysis of these patients at 2 years of age revealed
adverse effects on neuromotor function and somatic growth.64 A follow-up evaluation
of these children at school age demonstrated significant decrements in height, head
circumference, motor skills and coordination, visual-motor integration, and IQ scores
for the dexamethasone-treated group.65 These unexpected findings resulted in pub-
lished guidelines against the routine use of prophylactic dexamethasone in this setting
by the American Academy of Pediatrics (AAP).66 Subsequently, a 15-year follow-up
neurodevelopmental evaluation of a similar cohort resulted in no observed differences
between the treatment groups.67 Given these conflicting findings, the AAP reissued
a consensus statement confirming the link between high-dose dexamethasone
treatment and neurodevelopmental deficits and advocating studies of low-dose
dexamethasone.68
At present, there are several investigations into the effects of anesthetic exposure
early in life. The GAS study, which is an ongoing National Institute of Health–funded
prospective clinical study that compares regional and general anesthesia for effects
on neurodevelopmental outcome and apnea in infants, has recruited more than 700
infants randomized to either a general or spinal anesthetic for inguinal hernia surgery
in 7 countries.69 In a neonatal rat model comparing general and spinal anesthesia, pro-
longed exposure to isoflurane clearly increased neuroapoptosis, whereas a short
exposure to isoflurane or a bupivacaine spinal anesthetic did not.70 Given these find-
ings in the laboratory, the GAS study intends to examine the effect of a general anes-
thetic (sevoflurane) versus a spinal anesthetic (bupivacaine) on neurocognitive
performance at 2 and 5 years using a battery of individually administered neurocogni-
tive tests. Further analysis of the data collected from this international study will likely
demonstrate the effects of these different anesthetic techniques on other clinical and
technical variables. The GAS study has completed enrollment; but given the substan-
tial duration between exposure and testing, the initial results are not expected before
2017.
Another approach has been taken by the Pediatric Anesthesia and Neurodevelop-
mental Assessment study, a multicenter ambidirectional trial comparing the perfor-
mance of existing sibling cohorts discordant for anesthetic exposure for inguinal
hernia repair in children younger than 3 years in prospectively administered neurocog-
nitive function tests, including the developmental neuropsychological assessment tool
148 Lin et al
NEPSY-II, which assesses attention, executive function, language, learning, memory,

sensorimotor development, social perception, and visuospatial processing.71 This trial
is still enrolling children, and the initial results are anticipated in 2014.
A third study currently being performed, the Mayo Safety in Kids study, compares
the performance of children previously exposed to one or multiple anesthetics before
3 years of age to those never anesthetized using an extensive battery of neurocogni-
tive tests, including the operant test battery previously used by researchers at the Na-
tional Center for Toxicologic Research in nonhuman primates. This particular study
has just started enrolling and testing children, and preliminary results are not expected
before 2015.
IMMEDIATE LESSONS FROM ANIMAL STUDIES: ARE THERE ANY SAFE DRUGS OR
NONTOXIC EXPOSURE TIMES OR DOSES?
The expanding evidence for the neurotoxic effects of many commonly used anesthetic
agents in animals, the emerging epidemiologic evidence for a potential association
between exposures early in life and learning abnormalities, and the current dearth of
prospective studies addressing these concerns led to 2 clinically very important ques-
tions: do there exist any anesthetic drugs that the developing brain can be safely
exposed to and, if not, are there any differences in toxic potency among different an-
esthetics? The latter question has been recently addressed for several inhaled anes-
thetics, whereby equal anesthetic potency can be assessed as the minimum alveolar
concentration (MAC). Unfortunately, the findings have not been uniform. Liang and co-
workers72 observed that the relatively small dose of 0.75% isoflurane when adminis-
tered for 6 hours in 7-day-old mice caused greater neurodegeneration than an
exposure to 1.1% sevoflurane, although neither of these exposures altered subse-
quent memory and learning abilities in adult animals.72 Using higher doses of 7.4%,
1.5%, or 2.9% for desflurane, isoflurane, or sevoflurane, respectively, (all representing
0.6 MAC equivalents) for 6 hours in 7- to 8-day-old mice, Istaphanous and col-
leagues73 did not observe any differences among the 3 volatile agents. Conflicting re-
sults were reported by Kodama and colleagues74 who observed similar degrees of
neuroapoptosis in 6-day-old mice following 6 hours of 3% sevoflurane and 2% isoflur-
ane, compared with the higher neurotoxic effects of 8% desflurane, which led to
subsequent short-term memory impairment in addition to the long-term memory ab-
normalities that were observed in all exposed animals. Accordingly, these discrepant
findings are unable to guide clinical recommendations regarding the selection of one
particular inhaled anesthetic over another. However, the combined findings suggest
that the toxic potency may be more closely linked to anesthetic properties or related
functions, rather than the absolute concentration, because desflurane did not cause 4
times the degree of neuroapoptosis of isoflurane while being administered in 4 times
the dose. Moreover, although the sevoflurane concentration was generally higher than
the isoflurane concentration, none of the studies observed a higher degree of neuro-
toxicity when comparing the two agents. It remains to be determined whether differ-
ences between the studies may be explained by the methodological complexities
of quantifying the 3-dimensional cell death pattern and differential counting
methodologies.
Comparing the neuroapoptotic properties of injectable anesthetics with each other
or with inhaled anesthetics is even more difficult because in small animal studies
injectable anesthetics are frequently administered as intermittent boluses, and main-
tenance of the anesthetic state cannot be guaranteed. Moreover, even when admin-
istered by infusion, the equipotency of injectable drugs with inhaled anesthetics may
be difficult to prove. When the injectable anesthetic ketamine was administered for
5 hours in newborn rhesus monkeys, it elicited a 3.8-fold increase in neuroapoptosis
compared with control animals,75 whereas a 5-hour exposure to isoflurane raised the
neuronal degeneration to 12-fold that observed in controls.76 However, although both
animal groups were reported to be in a surgical stage of anesthesia, an exactly equi-
potent depth of anesthesia could not be verified.
Toxic effects have been demonstrated in newborn mice as early as 1 hour after
initiation of 2% isoflurane,26 suggesting that any potential nontoxic exposure time in
rodents may be brief. Longer exposures of 2 to 6 hours at 0.6 to 1.0 MAC of all
commonly used inhaled anesthetics have been found to cause neurodegenera-
tion.29,73 Several studies using injectable anesthetics have tried to determine a toxic
threshold for single-dose administration in developing animals. However, translation
of these data is complicated by the fact that the doses of these drugs needed to anes-
thetize small animals, such as mice and rats, are much larger than similar doses for
humans. When adjusting the drug doses administered to animals according to allome-
tric scaling techniques,77 single doses equivalent to greater than 6 or 7 mg/kg of pro-
pofol were found to lead to neuronal degeneration in newborn rats78 and mice,79
respectively. Only a single dose equivalent of less than a 2 mg/kg was found devoid
of immediate toxic effects in mice. Ketamine has been found neurotoxic in mice at
a dose equivalent of 3 mg/kg.79 By comparison, a single dose that would be akin to
up to 18 mg/kg in humans did not cause any acute neurodegeneration in rats.80 Simi-
larly, mice were more sensitive to a single dose of midazolam (1.1 mg/kg equivalent),81
whereas up to 2.1 mg/kg did not cause neuroapoptosis in neonatal rats.16 However,
most of these studies did not assess subsequent neurologic function; even in studies
that did, neurodegeneration has not consistently led to neurocognitive abnormalities.
In contrast to this growing body of evidence demonstrating toxic effects of all routinely
used general anesthetics and sedatives, the relatively mild sedative dexmedetomi-
dine, in limited studies, has been found to not cause neuroapoptosis and to potentially
protect from isoflurane-induced neurotoxicity.82
PERIOD OF VULNERABILITY: IS THERE A SAFE AGE FOR GENERAL ANESTHESIA?
Anesthetic neurotoxicity was initially described in very young animals, occurring

between 4 to 10 days of age in small rodents,25,73 around midgestation in guinea
pigs,83 and before 35 days of age in rhesus macaques.37 Using now-dated brain
developmental data, the corresponding maturational state of the human brain during
this peak of vulnerability was estimated to range from the third trimester to the first 3 to
4 years of life.84 However, more contemporary models using computational brain
developmental data have equated brain maturation in these animal models to prema-
ture humans during mid to late gestation.85,86
Although these previous findings would place the potentially vulnerable period to
anesthetic exposures for humans in utero, more recent animal studies have demon-
strated anesthesia-induced neuronal cell death to also occur in adult mice following
exposures to isoflurane or propofol.87,88 These novel findings may be explained by
recent observations that the age of the animal during exposure may be less relevant
to the phenomenon’s underlying mechanism than previously thought and that the
age of the neuron during exposure may be a better predictor for neurodegeneration.
In agreement with this hypothesis, dentate granule cells were recently found to be
particularly vulnerable to isoflurane-induced degeneration when exposed before
18 days of neuronal age.87 Complementary to these results, differential windows of
vulnerability have been observed for different brain regions, in line with the specific
150 Lin et al
region’s peak in neurogenesis.89 In brain regions with ongoing neurogenesis

throughout life, such as the dentate gyrus and olfactory bulb, vulnerability to the phe-
nomenon occurs throughout life, albeit to a reduced degree at an older age. This point
suggests that no safe period for anesthetic exposure may exist, but rather the brain
regions most susceptible to the toxic effects change depending on the age of most
of the neurons within each region and that the heightened vulnerability of neonatal an-
imals can be explained by their greater number of immature neurons. By extension,
these findings further suggest that anesthetic neurotoxicity may not only be relevant
for young children but also for adults undergoing anesthesia.
In summary, all currently routinely used anesthetics and sedatives acting as GABAA-
receptor agonists and/or NMDA-receptor antagonists have demonstrated deleterious
effects on neuronal survival, brain structure, and neurocognitive function. Several
epidemiologic studies have associated anesthetic exposures for surgery early in life
with subsequent learning abnormalities and language impairment. However, the rela-
tive contributions of surgery, pain, underlying medical conditions, and anesthetics to
this phenomenon are unknown. Although anesthetic toxicity peaks at a very early age
in animals, emerging research has found this process to extend into adulthood in brain
regions with ongoing neurogenesis, suggesting that the phenomenon targets neurons
of an immature state. Accordingly, no particular age can be designated as entirely safe
for anesthetic exposures. Because pediatric surgery frequently has to be performed at
an early age to save patients’ lives or to improve their quality of life, additional research
is urgently needed to clarify the phenomenon’s human applicability, to elucidate its
mechanism, and to devise mitigating strategies.
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T h e A n e s t h e t i c Ma n a g e m e n t
o f C h i l d ren wi t h Pu l m o n a r y
Hypertension in the C ardiac
Catheterization Laboratory
Mark D. Twite, MB BChir*, Robert H. Friesen, MD
KEYWORDS
Pulmonary hypertension Cardiac catheterization laboratory Anesthesia
Children
KEY POINTS
A new classification of pediatric pulmonary arterial hypertension (PAH) has been devel-
oped that incorporates abnormalities of lung growth and development as well as syn-
dromes frequently contributing to PAH.
Children with PAH will require cardiac catheterization to establish the diagnosis and
monitor the response to therapy.
Children receiving general anesthesia for cardiac catheterization are at significantly
increased risk of perioperative complications such as a pulmonary hypertensive crisis.
There is no one ideal anesthetic agent for children with PAH, and it is essential to under-
stand the different hemodynamic effects of anesthetic agents and adopt a balanced anes-
thetic technique for children with PAH.
INTRODUCTION
Pulmonary hypertension has many different causes, which all share the final common
pathway of elevated pulmonary arterial pressure (PAP). Pulmonary arterial hyper-
tension (PAH) is due to abnormalities in the pulmonary arterial vasculature. Pulmonary
venous hypertension is a result of left-sided heart disease, for example, pulmonary
vein stenosis or left-side valvar heart disease. The treatments of PAH and pulmonary
venous hypertension are different, so the distinction of one from the other is of obvious
clinical importance.1 This article focuses on PAH in children. PAH is a life-threatening
disease which, if undiagnosed, will eventually culminate in irreversible elevation of
Neither author has any financial disclosures to make.

Department of Anesthesiology, University of Colorado School of Medicine, CO, USA
* Corresponding author. Department of Anesthesiology B090, Children’s Hospital Colorado,
University of Colorado Anschutz Medical Campus, 13123 East 16th Avenue, Aurora, CO 80045.
E-mail address: Mark.Twite@childrenscolorado.org

158 Twite & Friesen
pulmonary vascular resistance (PVR), leading to right ventricular failure and death.2
Unfortunately, delays in diagnosis and treatment are not uncommon because of
nonspecific presenting symptoms, especially in young children, and the low incidence
of the disease.3 The estimated prevalence in adults is 15 to 50 cases per 1 million,
whereas in children it is less than 10 cases per 1 million.4,5
Children with suspected PAH require invasive hemodynamic assessment in the car-
diac catheterization laboratory to confirm the diagnosis of PAH and determine future
therapy. To tolerate the procedure, most of these children will need general anesthesia
provided by an anesthesiologist. It is essential, therefore, that the providing anesthe-
siologist understands the pathophysiology of PAH, which measurements are made in
the catheterization laboratory, how anesthetic medications may affect these measure-
ments, and how to manage a pulmonary hypertensive crisis.6–9 Children with PAH,
especially those with a new diagnosis who are not yet on any treatment, are at
increased risk of complications under anesthesia in the cardiac catheterization labo-
ratory. The cardiologist performing the procedure, the pediatric anesthesiologist, and
the catheterization laboratory support staff must effectively communicate to provide
safe perioperative care.
DEFINITION AND CLASSIFICATION
In normal, healthy individuals the mean pulmonary artery pressure (mPAP) at rest is
around 15 mm Hg, and is independent of age, ethnicity, and gender. During exercise,
mPAP increases and is dependent on the level of exertion and age. During mild exer-
cise, mPAP is 20 5 mm Hg in subjects younger than 50 years compared with 30
5 mm Hg in subjects older 50, which makes it difficult to define normal mPAP during
exercise; hence, the definition of PAH uses mPAP at rest.10 PAH is defined as mPAP
greater than 25 mm Hg at rest, with a normal pulmonary capillary wedge pressure
(15 mm Hg) and increased pulmonary vascular resistance index (PVRI) greater
than 3 Wood units per m2.11 The normal pulmonary capillary wedge pressure excludes
patients with pulmonary venous hypertension from left-sided heart disease. In patients
with suspected PAH, the initial investigation is usually a transthoracic echocardiogram
that can estimate the mPAP and diagnose any congenital cardiac lesions that may be
contributing to the PAH. Echocardiography may support the diagnosis of PAH with
qualitative images of elevated right ventricular pressure, such as right ventricular
hypertrophy and septal-wall flattening. Quantitative information may be obtained on
echocardiography if there is tricuspid regurgitation during systole. In this case, the
modified Bernoulli equation may be applied to estimate mPAP, with a tricuspid regur-
gitant velocity of greater than 2.8 m/s being highly indicative of PAH (Box 1).10,12
Transthoracic echocardiography is an attractive method to monitor children with
PAH, and possibly enable the cardiologist to lengthen the interval between cardiac
catheterizations that the child will require to monitor ongoing therapy. There are
many echocardiographic techniques in the research and validation phase. One tech-
nique is to monitor the right ventricular systolic to diastolic duration ratio, whereby an
increase has been shown to be associated with worse right ventricular function, exer-
cise capability, and survival.13 Another is to measure the degree of tricuspid annular
plane systolic excursion (TAPSE), which has been shown to reflect right ventricular
function and prognosis in PAH.14,15
In the absence of shunts, the pulmonary and systemic circulations receive the same
amount of blood flow per minute. PVR beyond the newborn period is more than
10-fold lower than resistance in the systemic circulation, and the pressure in the
venous bed draining the pulmonary arteries (pulmonary veins, left atrium) accounts
Anesthesia for Pulmonary Hypertension in the Cath Lab 159
Box 1
Estimating mPAP from systolic tricuspid regurgitant jet velocity on echocardiography
Modified Bernouilli equation:

sPAP 5 4v2 1 RAP
eg, sPAP 5 4 (2.82) 1 10 5 41 mm Hg
Converting sPAP to mPAP
mPAP 5 (0.61 sPAP) 1 2 mm Hg
eg, mPAP 5 (0.61 41) 1 2 5 27 mm Hg
Abbreviations: mPAP, mean pulmonary artery pressure; RAP, right atrial pressure; sPAP,
systolic pulmonary artery pressure; v, tricuspid regurgitation velocity using Doppler on
echocardiography.
for a much greater percentage of PAP (40%–60%) than the corresponding down-
stream venous pressure in the systemic circuit. Hence, pulmonary hypertension attrib-
utable to pulmonary venous hypertension from left-sided heart disease is the most
common form of pulmonary hypertension in adults but not in children.16
Three factors can lead to an increase in mPAP: increases in left atrial pressure (LAP),
cardiac output, or PVR. From these 3 parameters it is possible to consider 3 broad cat-
egories that cause elevated mPAP and pulmonary hypertension (Box 2).2 The original
classification of pulmonary hypertension was conceived at the 1998 World Health Or-
ganization (WHO) Symposium in Evian, and underwent subsequent revisions at sym-
posia in Venice and Dana Point. However, using this WHO classification system for
children has been problematic, as it often does not reflect the complex heterogeneity
of factors that contribute to pediatric PAH. For example, children who are commonly
evaluated for PAH may have been born prematurely and have chromosomal or genetic
anomalies. In addition, such children may have congenital heart defects and acquired
problems such as sleep-disordered breathing, chronic aspiration, and secondary lung
disease. As a result, the Pulmonary Vascular Research Institute Pediatric Taskforce
proposed a new classification of pediatric PAH at its meeting in Panama in 2011.
The classification comprises 10 categories based on clinical pediatric practice
(Box 3). The Panama classification includes an additional definition of pulmonary
Box 2
Deriving the potential causes of increased mPAP
Derived from Ohm’s Law:

PVR 5 DP/Flow
DP (TPG)5 mPAP LAP
PVR 5 (mPAP LAP)/CO
mPAP 5 LAP 1 (CO PVR)
eg, [ LAP: left-side heart dysfunction; [ CO: congenital heart disease with a large left-to-right
shunt; [ PVR: pulmonary parenchymal disease or thromboembolic disease
Abbreviations: DP, difference in pressure; CO, cardiac output; LAP, left atrial pressure; mPAP,
mean pulmonary artery pressure; PVR, pulmonary vascular resistance; TPG, transpulmonary
gradient.
160 Twite & Friesen
Box 3
The 10 categories of pediatric pulmonary hypertensive vascular disease
Category Description
1 Prenatal or developmental pulmonary hypertensive vascular disease

2 Perinatal pulmonary vascular maladaptation
3 Pediatric cardiovascular disease
4 Bronchopulmonary dysplasia
5 Isolated pediatric pulmonary hypertensive vascular disease
6 Multifactorial pulmonary hypertensive vascular disease in congenital
malformation syndromes
7 Pediatric lung disease
8 Pediatric thromboembolic disease
9 Pediatric hypobaric hypoxic exposure
10 Pediatric pulmonary vascular disease associated with other system disorders
Adapted from Cerro MJ, Abman S, Diaz G, et al. A consensus approach to the classification of
pediatric pulmonary hypertensive vascular disease: report from the PVRI Pediatric Taskforce,
Panama 2011. Pulm Circ 2011;1:288; with permission.
hypertension for children with univentricular circulations: following a cavopulmonary

anastomosis PAH is defined as a PVRI greater than 3 Wood units/m2 or a transpulmo-
nary gradient (mPAP LAP) greater than 6 mm Hg even if the mPAP is less than
25 mm Hg (Box 4).17,18
PATHOPHYSIOLOGY AND TREATMENT
The factors leading to an increase in mPAP may all eventually result in pulmonary
vascular remodeling and increased PVR. As the pulmonary vasculature remodels in
PAH, changes occur that may be reactive or fixed. Reactive changes will result in
vasodilation of the pulmonary vasculature to an exogenously administered pulmonary
vasodilator such as inhaled nitric oxide (iNO). Fixed changes are unreactive to such
pulmonary vasodilators. As the disease processes leading to PAH progress, the
cross-sectional area of the pulmonary vasculature exponentially decreases according
to Poiseuille’s Law, leading to increased PVR. Poiseuille’s Law states that the
Box 4
The modern definition of pulmonary arterial hypertension in children with biventricular and
palliated univentricular circulations
Biventricular Circulation
mPAP >25 mm Hg and PVRI >3 Wood units/m2
Positive vasodilator response, defined as a decrease in mPAP and PVRI by 20% with no
change in CO
Univentricular Circulation
Following palliation with a cavopulmonary anastomosis
PVRI >3 Wood units/m2 or TPG >6 mm Hg even if mPAP <25 mm Hg
Abbreviations: CO, cardiac output; mPAP, mean pulmonary artery pressure; PVRI, pulmonary
vascular resistance index; TPG, transpulmonary gradient.
resistance of a vessel is proportional to the fourth power of the radius. In other words,
as the pulmonary arterioles develop thickening of their walls and a smaller intraluminal
radius, the resistance will increase exponentially. A pulmonary hypertensive crisis is an
acute on chronic increase in PVR during the perioperative period resulting from an
acute increase in vascular tone of the reactive portion of the pulmonary vasculature.
Early recognition and appropriate management of a pulmonary hypertensive crisis
can be life-saving.
The current treatment strategies for PAH are aimed at the 3 pathologic processes.
Vasodilators treat reactive vasoconstriction, antiproliferative drugs attenuate vascular
remodeling, and anticoagulation may be used to treat and prevent thrombosis from
forming in narrowed vessels. Based on the understanding of abnormalities of the
vascular endothelium, 3 classes of drugs have been studied for the treatment of
PAH.19 The prostanoids epoprostenol (Flolan), treprostinil (Remodulin), and iloprost
(Ventavis) act via cyclic adenosine monophosphate in the smooth muscle cell to pro-
duce vasodilation, and may also have some antiproliferative effects. The nitric oxide
pathway acts via a cyclic guanosine monophosphate (cGMP) pathway in the smooth
muscle cell to produce vasodilation. This pathway may be stimulated directly with iNO,
or the breakdown of cGMP may be inhibited by phosphodiesterase type 5 inhibitors
such as sildenafil (Revatio) and tadalafil (Adcirca). Recently the US Food and Drug
Administration issued a warning against the use of sildenafil for pediatric PAH,
because of an apparent increase in mortality during long-term therapy.20 The endothe-
lin pathway acts via endothelin receptors, which are present on both the endothelial
and smooth muscle cells. The endothelin type 1 receptor has 2 further subtypes, A
and B. Bosentan (Tracleer) is a nonselective antagonist of both subtypes, whereas
ambrisentan (Letairis) is a selective type A antagonist. Both endothelin receptor antag-
onists require close monitoring of liver function tests. Whereas therapy for PAH in
adults is evidence-based, most therapy for PAH in children is extrapolated from the
adult data and is based on the experience of clinicians.18
CARDIAC CATHETERIZATION
Despite advances in noninvasive imaging techniques, cardiac catheterization with

vasodilator testing is necessary for the diagnosis, treatment stratification, and prog-
nosis of PAH in children.21 There are 3 objectives during the catheterization pro-
cedure: to obtain hemodynamic data, to test vasoreactivity, and to rule out any
associated disease states.
Accurate hemodynamic data are essential for the diagnosis and ongoing monitoring
of patients with PAH. End-hole or flow-directed catheters are used to obtain hemody-
namic data. Catheters with multiple side holes are used for angiography to prevent
myocardial staining during injection. During catheterization, baseline measures
include right atrial pressure, PAP, systemic arterial pressure, mixed venous and sys-
temic arterial saturation, cardiac output, and pulmonary artery occlusion pressure.
From these measures, important calculations can be made for pulmonary-to-
systemic flow ratio (Qp:Qs) (Box 5) and PVR (Box 6).22 It is important for the cardiol-
ogist performing the catheterization procedure to exclude intracardiac defects. It is
essential that the anesthesiologist maintain stability during these periods of measure-
ment and that the conditions under which they are made is clearly communicated.
Most cardiac catheterization laboratories will obtain baseline measurements in room
air followed by 70% to 100% oxygen, and then introduce an acute vasodilator such
as iNO 20 to 40 ppm. In a recent review of cardiac catheterization laboratory protocols
and hemodynamic data in pediatric patients with PAH, general anesthesia was found
162 Twite & Friesen
Box 5
Calculating Qp and Qs
Based on the Fick principle:

Qp:Qs 5 (Sat Ao Sat MV)/(Sat PV Sat PA)
Abbreviations: Qp, pulmonary blood flow; Qs, systemic blood flow; Sat Ao, aortic saturation;
Sat MV, mixed venous saturation; Sat PA, pulmonary artery saturation; Sat PV, pulmonary
vein saturation.
to lower systemic arterial pressure, but there was no difference between general anes-
thesia and procedural sedation regarding mPAP or PVRI. It also demonstrated that pe-
diatric patients with PAH demonstrate a higher incidence of PAH associated with
congenital heart disease and neonatal specific disorders in comparison with adults.
Pediatric PAH patients had baseline mPAP of less than 40 mm Hg but greater than
50% of their systemic blood pressure, illustrating the difficulty of applying adult criteria
to children with PAH.23
The degree to which mPAP and PVR can be decreased acutely by the administra-
tion of fast-acting, short-duration vasodilators reflects the extent to which vascular
smooth muscle constriction is contributing to the hypertensive state. The response
to vasodilators has important therapeutic implications in PAH, and almost all patients
will undergo a vasodilator trial during their initial cardiac catheterization. Intravenous
epoprostenol, intravenous adenosine, and iNO are commonly used for acute vasodi-
lator testing. The definition of a positive vasodilator response in adults is a reduction in
mPAP by at least 10 mm Hg, and this number must be lower than 40 mm Hg. The pe-
diatric definition of a positive response to vasodilators is a decrease in mPAP and PVRI
by 20% with no significant change or increase in cardiac index. Such responders are
likely to have a beneficial hemodynamic and clinical response to treatment with
calcium-channel blocking drugs. It is estimated that 70% to 90% of children with se-
vere PAH are nonresponders to acute vasodilator testing, and therefore require ther-
apy other than calcium-channel antagonists.18,24
A pediatric anesthesiologist should be present during the cardiac catheterization, as
anesthesia may pose a significant risk to the pediatric patient with PAH. Studies of
children with PAH have demonstrated a high incidence of perioperative cardiac arrest
and death. A benchmark estimate of the incidence of perioperative cardiac arrest in all
pediatric patients is 0.014%.25 By comparison, children with PAH experienced an
Box 6
Calculating PVR
Based on Ohm’s Law:
PVR 5 ðPin Pout Þ=Qp

5 ðmean PAP mean LAPÞ=Qp
PVR is measured in Wood units 5 mm Hg/L/min

or 80 Woods units 5 dyne/s/cm5 (metric units)
Abbreviations: LAP, left atrial pressure (equivalent to pulmonary artery occlusion pressure);
P, pressure; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; Qp, pulmonary
blood flow.
incidence of perioperative cardiac arrest of 1.6% associated with all types of proce-
dures and 10% associated with major surgical procedures, including cardiac sur-
gery.26 Preoperative PAH has been shown to be significantly associated with
perioperative death following pediatric open cardiac surgery.27 The presence of
PAH also adds significantly to perioperative risk in children undergoing cardiac cath-
eterization (Fig. 1). The incidence of cardiac arrest during pediatric cardiac catheter-
ization is reported to be 0.45%.28 This incidence increases dramatically when only
children with PAH undergoing cardiac catheterization are considered, with reports
of 0.8%,26 1.2%,29 and 5.7%.30 Such morbidity is directly associated with the severity
of PAH, with patients with suprasystemic PAH having a much greater incidence of ma-
jor complications than those with systemic or subsystemic PAH (Fig. 2).29
ANESTHETIC MANAGEMENT
Cardiac catheterization is rarely tolerated in the awake child. Pediatric anesthesiolo-

gists working in the cardiac catheterization laboratory needs to consider some of
the unique issues of their surrounding environment. The cardiac catheterization labo-
ratory may be in a remote location away from the main operating rooms, and as a
result there may be a delay in help arriving when it is called for. It is therefore essential
to work closely with the team in the laboratory, as they may offer the most immediate
help during an acute crisis.31 The position of the cameras in the catheterization labo-
ratory may hinder access to the patient, especially the airway, during a procedure.
Usually the anterior-posterior camera may be swung out of the way for a mask induc-
tion of the patient, but this may be more difficult to achieve rapidly during a case if
there is an airway problem. It is essential to have all necessary equipment and moni-
toring available. Standard intraoperative American Society of Anesthesiologists (ASA)
monitoring should be used, and consideration given for additional monitoring such as
a radial arterial line if the cardiologist performing the procedure does not plan to place
a femoral arterial line. There may also be frequent interruptions in the invasive pressure
wave form as catheters are changed in and out of the femoral arterial sheath, which
may again influence placement of a dedicated radial arterial line. Children should be
placed on a forced air-warming blanket, as the catheterization laboratory is usually
kept cool because everyone is wearing a lead apron to protect against the radiation
being used for taking images. Patient monitors such as pulse oximetry and
POCA Cath PAH
1.2
0.8
%
0.4
0
Cardiac Arrest Death
Fig. 1. Estimated incidence of perioperative cardiac arrest and death. Green bars, Perioper-
ative Cardiac Arrest Registry (POCA), all children; blue bars, children undergoing cardiac
catheterization (Cath); red bars, children with pulmonary arterial hypertension (PAH) under-
going cardiac catheterization. (Data from Refs.25,28,29)
164 Twite & Friesen
Procedures Complications
70
60
50
40
%
30
20
10
0
Sub-Systemic Systemic Supra-
Systemic
Fig. 2. Perioperative complications are directly related to severity of pulmonary hyperten-
sion. (Adapted from Carmosino MJ, Friesen RH, Doran A, et al. Perioperative complications
in children with pulmonary hypertension undergoing noncardiac surgery or cardiac cathe-
terization. Anesth Analg 2007;104:521–7; with permission.)
noninvasive blood-pressure cuff, in addition to peripheral vascular access, are gener-

ally best placed on an upper extremity, because the cardiologist will be accessing the
femoral vessels. Appropriate drugs to manage a pulmonary hypertensive crisis should
be readily available for each patient.32,33
The specific anesthetic technique and drugs chosen are probably less important
than the attention to careful titration and maintaining hemodynamic stability. The ideal
anesthetic drug for children with pulmonary hypertension would have pulmonary vas-
odilating effects, would not depress cardiac contractility, would maintain systemic
vascular resistance and cardiac output, and would be short lasting and easy to titrate.
Such an anesthetic agent, unfortunately, does not exist. Most anesthetics are associ-
ated with undesirable hemodynamic effects, depending on dosage and speed of
administration, by altering heart rate or rhythm, cardiac contractility, systemic vascular
resistance, or PVR (Table 1). The cardiovascular effects of anesthetic drugs pertinent
to a discussion of pulmonary hypertension are summarized here.
Volatile Anesthetics
Volatile anesthetics cause a dose-dependent depression of cardiac contractility and a
decrease in systemic vascular resistance (SVR),34,35 and attenuate hypoxic pulmonary
vasoconstriction during one-lung ventilation.36 The ratio of pulmonary blood flow (Qp)
Table 1
Hemodynamic effects of anesthetic drugs
Contractility MAP SVR PAP PVR

Volatile Z Z ZZ Z Z
Propofol Z Z ZZ Z Z
Ketamine 0 0 \ \0 \0
Etomidate 0 0 0 \ \
Dexmedetomidine 0 \ \ 0 0
Opioids 0 0 0 0 0
Benzodiazepines 0 0 0 0 0
Abbreviations: Z, decrease; \, increase; 0, no significant change; MAP, mean arterial pressure;

PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular
resistance.
to systemic blood flow (Qs) remains unchanged in children with cardiac septal defects
in response to halothane, sevoflurane, and isoflurane, so it is assumed that PVR has a
similar response to that of SVR.37
Nitrous Oxide
Nitrous oxide may increase PVR during prolonged use in adults, but probably has no
or little effect in children when it is used for a brief time to perform a mask induction of
anesthesia.38
Propofol
Propofol causes dose-dependent depression of cardiac contractility.39 In both adults
and children with cardiac disease, propofol is associated with a marked decrease in
SVR and mean arterial pressure (MAP), and a slight decrease in PVR and PAP.40,41
In adults with artificial hearts, propofol causes vasodilation of systemic resistance
and capacitance vessels, and a decrease in PAP.42
Ketamine
Whereas ketamine is supportive of hemodynamic stability and is frequently recom-
mended as an anesthetic of choice in patients with cardiovascular impairment or
instability, its use in patients with PAH is debated because of conflicting results
from various studies conducted under a variety of conditions.43 Study conditions
have been varied (spontaneous vs controlled ventilation, natural airway vs endotra-
cheal tube, room air vs added oxygen). A marked increase in PAP and PVR has
been observed in children with PAH breathing room air through the natural airway.44–46
On the other hand, no change in PAP or PVR has been observed in children with
PAH during controlled ventilation or while receiving a pulmonary vasodilator, such
as oxygen or sevoflurane.47,48
Etomidate
Etomidate is known to support systemic hemodynamics, but is associated with signif-
icant increases in both SVR and PVR. Despite the observed increase in PVR, etomi-
date is used as an anesthetic induction drug in patients with PAH because of its
support of cardiac contractility and SVR. Only one pediatric study has been per-
formed, which demonstrated a 28% increase in PVR.49
Dexmedetomidine
Dexmedetomidine is associated with acutely decreased heart rate and increased MAP
and SVR, followed over time by a decrease in MAP.50,51 These changes appear to be
dose dependent. Despite the early significant increase in SVR, a similar pulmonary
vasoconstrictor response was not observed in children with pulmonary
hypertension.52
Opioids
Opioids have minimal hemodynamic effects. PVR remains unchanged in response to
fentanyl.53 Pulmonary vascular responses to remifentanil are clinically insignificant in
adults with artificial hearts.54
Midazolam
Midazolam exerts clinically insignificant effects on the pulmonary vasculature of adults
with cardiac disease.55
166 Twite & Friesen
To minimize the undesired hemodynamic effects of a full anesthetic dose of a single

anesthetic drug, it is preferable to use a balanced anesthetic technique; that is, admin-
istration of subanesthetic doses of several anesthetics. Thus an adequate depth of
anesthesia can be achieved without marked hemodynamic changes. For most proce-
dures the authors use midazolam, fentanyl, or remifentanil, and low-concentration
sevoflurane or isoflurane. Dexmedetomidine can be added, especially when postop-
erative sedation is desirable, and high doses of fentanyl can be used if postoperative
tracheal extubation is not anticipated. Judicious use of propofol at low infusion rates
can be considered, and balancing propofol with ketamine may avoid the undesired
effects on SVR of each drug alone. Sometimes hypotension can be observed despite
a balanced technique, especially in children who are hypovolemic.
AIRWAY MANAGEMENT
Airway management techniques by the anesthesiologist are chosen as appropriate

for the surgical or catheterization procedure. Although case reports have described
pulmonary hypertensive crises in association with emergent tracheal intubation, the
reports are unclear as to whether intubation caused the pulmonary vascular response
or the patients were intubated because of impending cardiac arrest following pulmo-
nary hypertensive crisis. Tracheal suctioning is associated with a significant increase
in both PAP and PVR in children with pulmonary hypertension,56 but with adequate
topical and general anesthesia, the authors do not hesitate to intubate when indicated
for the type of procedure or condition of the patient. The authors are more inclined
to use tracheal intubation for long procedures, interventional cardiac catheterization
procedures, or unstable patients.
Alternatively, airway management with a face mask, laryngeal mask airway, or the
natural airway (with end-tidal CO2 monitoring via nasal cannulas) can be chosen
when indicated, and the authors often use these for shorter diagnostic catheterization
procedures in stable children. It should be remembered that hypoxia and hypercarbia
can be associated with a pulmonary hypertensive event, and that airway obstruction
or hypoventilation during cardiac catheterization are more likely to occur during seda-
tive techniques with a natural airway than during anesthesia with controlled ventila-
tion.57 Therefore, the anesthesiologist should consider all options for airway access
and ventilatory support.
PULMONARY HYPERTENSIVE CRISIS
Cardiac arrest in children with PAH is often immediately preceded by an acute pulmo-
nary hypertensive crisis, whereby an acute increase in PVR leads to right ventricular
failure and a decrease in cardiac output. The self-perpetuating cycle of biventricular
failure associated with a pulmonary hypertensive crisis is illustrated in Fig. 3. A pulmo-
nary hypertensive crisis can be triggered by several stimuli that directly affect PVR,
such as hypoxia,58,59 acidosis,60 noxious tracheal stimulation,56 or events that cause
ventricular dysfunction, such as inadequate coronary perfusion associated with sys-
temic hypotension (Box 7). Early studies by Rudolph and Yuan59 suggest that keeping
an arterial pH higher than 7.40 and an arterial oxygen pressure (PaO2) GREATER than
60 mmHg can avoid a severe increase in PVR (Fig. 4).
Treatment of a pulmonary hypertensive crisis is directed toward ameliorating the
stimulating event and stabilizing hemodynamics (Table 2). Early use of a systemic
vasoconstrictor, such as epinephrine, norepinephrine, or phenylephrine, or an inotrope,
such as epinephrine or dopamine, can improve coronary perfusion and cardiac func-
tion, and may avert cardiac arrest. A pulmonary vasodilator should be administered.
Fig. 3. Pathophysiologic changes during a pulmonary hypertensive crisis. HR, heart rate; LV,
left ventricular; PVR, pulmonary vascular resistance; RV, right ventricular.
Because hypotension can be associated with acute administration of an intravenous

vasodilator, it is preferable in an urgent setting to give pulmonary vasodilators by inha-
lation. This approach reduces the risk of systemic hypotension and coronary hypoper-
fusion by delivering the drug to the target pulmonary vasculature. iNO is the standard
for inhaled pulmonary vasodilators, but inhaled prostacyclin analogues may be as
effective. Once the cycle of increased PVR and decreased ventricular function begins,
however, cardiac arrest may be difficult to prevent. If cardiac arrest occurs, Pediatric
Advanced Life Support guidelines for cardiopulmonary resuscitation should be fol-
lowed.61 Cardiac arrest associated with pulmonary hypertensive crisis can be difficult
to treat, and emergent use of extracorporeal membrane oxygenation (ECMO) may be
necessary.62 If emergent ECMO is required, improved outcomes are associated with
shorter duration of cardiopulmonary resuscitation before ECMO, so an institutional
protocol that anticipates the need for emergent ECMO in these situations is desirable.63
In addition to the avoidance of triggering stimuli, the risk of intraoperative cardiac
arrest can be reduced by preoperative treatment with pulmonary vasodilator therapy.
The odds ratio for children with PAH to develop a major perioperative complication
was only 0.31 if they were chronically treated with a pulmonary vasodilator preopera-
tively.26 Although the authors often use prophylactic administration of iNO during the
Box 7
Triggering stimuli for perioperative pulmonary hypertensive crisis
Hypoxia
Acidosis
Hypercarbia
Agitation and pain
Tracheal suctioning
Hypotension
168 Twite & Friesen
Fig. 4. Pattern of pulmonary vascular responses to changes of pH and PaO2. The increases of
pulmonary vascular resistance (PVR) are expressed as a percentage of the level at pH 7.4 and
PaO2 100 mm Hg. The changes in PVR with changes in PaO2 have been related at different
levels of pH. (From Rudolph AM, Yuan S. Response of the pulmonary vasculature to hypoxia
and H1 ion concentration changes. J Clin Invest 1966;45:407; with permission.)
perioperative period for noncardiac surgical procedures, this is not usually done for
diagnostic cardiac catheterization procedures in children with PAH, in which hemody-
namic measurements under baseline conditions are measured.
When administration of a pulmonary vasodilator is indicated, the authors favor peri-
operative iNO over other pulmonary vasodilators for this purpose because it delivers
drug directly to the pulmonary vascular bed, thus avoiding the systemic hypotension
that can occur with acute intravenous administration of vasodilators. The authors
administer iNO from beginning of induction of anesthesia into the recovery period,
Table 2
Treatment of pulmonary hypertensive crisis
Treatment Rationale/Therapy
Administer 100% O2 [ PAO2 and PaO2 will Y PVR
Hyperventilate PVR is directly related to PaCO2
Exclude pneumothorax Optimize ventilation
Y Mean airway pressure Avoid Palv>Part
Correct metabolic acidosis PVR is directly related to H1 level
Administer pulmonary vasodilators iNO, magnesium
Analgesia Decrease sympathetic mediated [ PVR
Support cardiac output Phenylephrine, cautious volume, epinephrine
ECMO Support cardiac output and oxygenation
Abbreviations: ECMO, extracorporeal membrane oxygenation; iNO, inhaled nitric oxide; Palv, alve-
olar pressure; PAO2, alveolar oxygen pressure; PaO2, arterial oxygen pressure; Part, arterial pressure;
PVR, pulmonary vascular resistance.
when it can be administered by face mask or nasal cannulas.64 Other pulmonary va-
sodilators that can be effectively administered by inhalation may emerge as satisfac-
tory prophylactic perioperative drug therapy for children with pulmonary hypertension.
These agents include the prostacyclin analogues epoprostenol,65 iloprost,66 and tre-
prostinil,67 the phosphodiesterase inhibitor milrinone, and nitroglycerin.68
POSTANESTHESIA RECOVERY
Children with PAH are at increased risk of adverse events following anesthesia.69
Possible causes include increased pulmonary vascular tone, pulmonary hypertensive
crisis, pulmonary thromboembolism, cardiac arrhythmia, and fluid shifts. All precau-
tions should be taken to avoid hypoxemia, hypotension, and hypovolemia. Postoper-
ative control of pain should be effective. Any therapy to decrease PVR, such as iNO,
should be weaned with caution so as to avoid rebound increases in PVR.70 It may be
necessary to admit the child overnight to a unit where monitoring is available and
immediate medical response is possible.
SUMMARY
Children with PAH undergoing cardiac catheterization are at increased risk of periop-
erative complications. This risk is greatest for those with suprasystemic pulmonary ar-
tery pressures and those with PAH who are not yet on any therapy. Although there are
many factors that may contribute to the development of PAH, the final common
pathway is elevated PAP. All currently available anesthetic agents will have an effect
on the cardiovascular system. It is essential for the anesthesiologist to be aware of
these effects and how they may change the data being acquired by the cardiologist.
It is important to avoid factors that may trigger a pulmonary hypertensive crisis and, if
one does occur, it is essential to respond appropriately. The most immediate available
help in this situation may be the staff in the cardiac catheterization laboratory, making
good communication important.
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Anesthesia and Analgesia for
Pectus Excavatum Surgery
Jagroop Mavi, MD, David L. Moore, MD*
KEYWORDS
Pectus excavatum Nuss procedure Thoracic epidural Haller index
Chest wall deformities Multimodal analgesics
KEY POINTS
Special attention is needed during surgical dissection across the mediastinum due to
arrhythmias and potential viscus/vessel perforation.
Deep extubation is preferable for avoidance of coughing and straining on the endotracheal
tube, which can cause subcutaneous emphysema.
Pain tends to be worse with increased age, because patients with ossified ribcages
tolerate the procedure less.
Multimodal analgesic techniques work best including nonnarcotic analgesics, narcotics,
regional anesthesia, muscle relaxants, and anxiolytics.
Aggressive physical therapy, particularly ambulation, improves dynamic pain control and
may decrease chronic postoperative pain.
INTRODUCTION
Pectus deformities, mainly pectus excavatum, are the most common chest wall defor-
mity seen by pediatricians and family practitioners.1 Originally described by Ravitch in
1949, pectus repair was undertaken in the more severe instances to correct the exist-
ing deformity and to prevent its progression. It was believed at the time of surgical
correction that younger patients had a higher chance for attaining a normal appear-
ance with subsequent growth of the thoracic cage.2
These deformities are caused by defective growth of the sternum and surrounding
costal cartilages. Although criticized by some as a cosmetic repair, other evidence
supports surgical repair because of the increased likelihood of progressive cardiopul-
monary dysfunction over time.
Disclosures: There are no disclosures to declare. Neither author has any direct financial interests
in the subject matter or materials discussed in the article, or with a company making a
competing product. No financial support except departmental salary support for the authors.
Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue,
Cincinnati, OH 45229, USA
E-mail address: david.moore@cchmc.org

176 Mavi & Moore
After need for surgical repair has been established, the technique of choice for the
last couple of decades has been the Nuss procedure.3 This is a minimally invasive
technique in which rigid metal bars are placed transthoracically beneath the sternum
and costal cartilages for a period of time until permanent remodeling of the chest wall
has occurred. That length of time tends to be 2 years before bars are removed.
During anesthesia, the three areas of focus include (1) potential for considerable
blood loss, (2) potential for lethal arrhythmias, and (3) potential consequences of pneu-
mothoraces. Postoperative pain is considerable, making multimodal analgesia the
hallmark of postoperative pain control. Controversy exists regarding the best method
of controlling postoperative pain, whether the emphasis is placed on patient-
controlled analgesia (PCA) or regional anesthesia. Part of the answer may be found
by examining patient outcomes. However, measuring patient outcomes depends on
the identity of the enquirer. Surgeons, anesthesiologists, pain services, and hospital
administration may all have different end points. Surgeons may look at optimal correc-
tion of the deformity followed by a short length of stay. The anesthesia team may be
invested in a safe passage through anesthesia without complications. The pain service
may focus on optimal postoperative pain control, and the hospital administration may
be most concerned with cost and patient satisfaction scores.
EPIDEMIOLOGY
Pectus excavatum occurred in approximately 0.12% of patients in one autopsy se-

ries.4 Researchers investigated the prevalence of pectus excavatum in teenage public
school students in Brazil, and found it to be 1.275%.5 Of the congenital chest wall
deformities, between 3% and 4% fall under the umbrella of rare deformities (eg, pen-
talogy of Cantrell, Jeune syndrome, and Poland syndrome).6 Pectus excavatum and
pectus carinatum represent the remainder, with 90% of those being pectus
excavatum.1,6
Gender distribution favors males, noted in different studies from a 2:1 ratio up to
9:1.5,6 Although no genetic defect has specifically been discovered, positive family
histories, up to 65.5% in one study, make this predisposition likely.5
Depending on the surgeon, the type of operation, and the presence of connective
tissue disorders, recurrence occurs with unsatisfactory results thus requiring reoper-
ation in 2% to 37%,7 although most series claim recurrence rates of 2% to 10%.8
PATHOPHYSIOLOGY
The cause of pectus deformity is largely unknown. There are multiple hypotheses
regarding the origin. The current dominant theory to explain the development of these
two most common chest wall deformities is overgrowth of the costal cartilages.9
Collagen type II is one of the major structural components of rib cartilage, but results
of histologic and biochemical studies of costal cartilages in patients with pectus exca-
vatum remain inconclusive.9
CLINICAL PICTURE
Patients with pectus excavatum, or “funnel chest” as it is known, typically present for
repair during adolescence. There has been some discussion in the literature as to the
best timing for surgical repair. In the past, these defects were repaired at an earlier age
(4–6 years of age) using a Ravitch procedure,2 which removes three to four overgrown
cartilages and repositions the sternum.10 Even Nuss tended to repair these defects
prepubertally. His patients had an age range of 1 to 15 years old, with most in the
Pectus Excavatum Surgery 177
3- to 5-year range.3 This contrasts with more recent studies involving the Nuss proce-
dure, which have a mean age of between 13 and 23 years of age.8,11–13
Pectus repair can be problematic in very young children. Patients may be more
active following discharge and have a greater rate of sustaining unexpected trauma.3
Rib growth after early pectus correction can also be impaired in younger patients,
sometimes to the point of minimizing chest wall movement, also known as asphyxi-
ating thoracic chondrodystrophy.3
Repairs in older patients can be more difficult, with prolonged operating time and
more blood loss.3 The trend in current practice is to wait for patients to reach their mid-
dle teenage years to perform a pectus excavatum repair. This allows for the patients to
complete their teenage growth spurt and have a less likely chance of recurrence.
Nonetheless, older school-age children and younger teenagers with significant cardio-
respiratory compromise affecting their ability to participate in aerobic sports could
also be candidates for repair.
Patients with connective tissue disorders, such as Marfan syndrome and Ehlers-
Danlos syndrome, are noted to have a higher incidence of recurrence.7 Therefore,
one might consider waiting to correct these deformities. However, this subset of pa-
tients is at risk for aortic dilation and aortic valve insufficiency. Patients with normal
cardiac anatomy may have repair of their pectus excavatum on an elective basis,
but those in need of aortic arch repair may need to have their pectus repaired at the
time of open heart surgery, or deferred to a later date after cardiac repair.14 Thus,
the timing of surgery for patients with these connective tissues disorders must also
be carefully assessed.
Reasons for postpubertal repair include body image issues that become manifest
during puberty, recurrence of the defect, and progressive cardiopulmonary dysfunc-
tion. Patients may have dyspnea on exertion, shortness of breath, breathlessness, a
feeling of heaviness in the chest, air hunger, and exercise intolerance.14 These symp-
toms can be progressive, and may not be eminent until the patient or family notices
difficulties in “keeping up with their peers.”
Indications for surgery to correct a pectus excavatum include symptomatic
patients, which includes exercise intolerance, decreased endurance, and pain; body
image issues; Haller index greater than 3; caliper measurement depth greater than
2.5 cm; exercise-induced asthma; abnormal pulmonary function tests (PFTs); and
compression of the right atrium or right ventricle on echocardiogram.14
Currently, the work-up for pectus excavatum repair includes a history and physical
examination and frequently includes a computed tomography (CT) scan of the chest.
Since the early 1990s, CT scans have been used to evaluate patients with pectus de-
formities for surgery. CT scans more clearly document the severity of the deformity,
along with the degree of cardiac compression and displacement, the degree of lung
compression, and other unexpected problems.3 In patients with known cardiac
issues, a cardiac magnetic resonance imaging has been used. Additional work-up
may include echocardiography, caliper measurement of the depth of pectus deformity
(>2.5 cm),14 and PFTs. In general, most patients with significant pectus excavatum
have low normal or below normal PFTs. Both static and exercise PFTs are useful in
eliciting a physiologic effect of the pectus excavatum defect on the patient.
The Haller index is a measure of pectus excavatum severity using a CT scan mea-
surement. The CT is used to demonstrate the abnormal ratio between the patient’s
transverse diameter and their anterior-posterior diameter.10 An index of more than
three is considered a moderately severe or greater defect.10,14 The width of the chest
between the ribs at the lowest level of the pectus defect is measured in centimeters
and divided by the height of the chest from the anterior aspect of the spine to the
178 Mavi & Moore
back of the lowest part of the sternal defect. The quotient from this division is the Haller
index (Figs. 1 and 2).
An echocardiogram may be useful to perform because it may show the depressed
sternum compressing the right atrium and right ventricle, which may interfere with dia-
stolic filling of these structures. Significant compression of the right heart chambers by
the depressed sternum is an indication for surgical correction.14 Mitral valve prolapse
is also commonly seen in patients with pectus excavatum.
Patients with pectus excavatum should also be assessed for connective tissue
disorders. Less than 1% of patients with pectus excavatum may have an underlying
connective tissue disorder, such as Marfan syndrome, Ehlers-Danlos syndrome, or
Loeys-Dietz syndrome. If this class of disorders is suspected then further genetic,
cardiac, and ophthalmologic evaluations should be performed.14
Most pectus excavatum defects involve the lower end of the sternum with the
turning down of the sternum and inward turning of costal cartilages four through
seven. In regards to the Nuss procedure and surgical technique, two bars are more
effective than a single bar but may cause overcorrection in some patients. Those
with Marfan syndrome and other connective tissue diseases have soft bones and
therefore require two bars to distribute the pressures over a wider area.3
The advantages of the minimally invasive technique include no anterior chest wall
incision, no need to raise pectoralis muscle flaps, and no need to resect rib cartilages
or perform sternal osteotomy. Other advantages include short operating time, minimal
blood loss, early return to full activity, and excellent long-term cosmetic results.3 Dis-
advantages of the Nuss minimally invasive technique include greater postoperative
pain; longer inpatient length of stay; higher cost compared with other techniques;
and more involved methods of pain control, including regional anesthesia.13
ANESTHESIA MANAGEMENT
The anesthesia management of pectus excavatum repairs can be divided into three
main categories: (1) preoperative evaluation and preparation, (2) intraoperative man-
agement, and (3) postoperative analgesia.
Preoperatively, the degree of cardiac and pulmonary dysfunction is important to
assess. This information can be obtained from a thorough history and physical examina-
tion focusing on exercise tolerance and symptomatology. Further knowledge of the
cardiopulmonary insult can be obtained from the CT scan and Haller index,
Fig. 1. Anterior photo of preoperative pectus patient. Note the incisional scar from original
pectus repair at earlier age.
Fig. 2. Photo from more lateral aspect. Pectus deformity more noticeable from this aspect.
Note the “rolling” forward of the shoulders and kyphosis, which are not unusual for these
patients.
electrocardiogram, echocardiogram, and PFTs. Knowledge about cardiac compromise,

arrhythmias, and pectus recurrence can only help to increase situational awareness.
Preparation before the case is essential, and the need to be prepared for potentially
large blood loss is foremost. Type and screening of the patient’s blood is necessary to
receive emergency blood products in case of catastrophe. It is mandatory to receive
confirmation of potential blood products in the operating room before proceeding with
surgery.
Decisions concerning methods of postoperative pain control need to be made and
addressed preoperatively. Typically, a postoperative pain service manages the pa-
tient’s pain after the procedure. The pain service confers with surgery and anesthesia
about the type of regional anesthesia and type of narcotic. Regional anesthesia in-
cludes anesthesia-driven blocks, such as thoracic epidural and paravertebral blocks;
and surgeon-driven blocks, such as intercostal nerve blocks, wound catheter place-
ment, and local infiltration. Anesthesia-driven blocks need to be placed preoperatively
and many choose to do awake thoracic blocks when possible. The practitioner cannot
use the lateral decubitus position after surgery for fear of dislodging the newly placed
pectus bar.
Because this surgery is extremely painful, another important preoperative consid-
eration, preferably days to weeks preoperatively, is to alleviate anxiety among the
patient and family, and manage expectations about the surgery. A chief method of
diminishing anxiety and creating reasonable expectations is through education. Par-
ents and patients, if possible, are expected to attend a mandatory educational class
about the surgery and hospital course, or view a simulcast of the class. This helps to
create more appropriate expectations and assuage anxiety. Once the preoperative
evaluation and preparations are complete, the patient is ready for the operating
room.
Intraoperative management is often as follows. The patient is brought into the oper-
ating room, and after placement of monitors, a peripheral intravenous (IV) line is placed
with the aid of nitrous sedation. After securing IV access, the patient is lightly sedated
and assisted to the sitting position in preparation for placement of regional anesthesia,
which frequently consists of a thoracic epidural.
Compliance with inserting the epidural catheter awake may be difficult in more
immature teenagers and young children. Typically, this is attempted in adults and
teenagers, or uncommonly in less anxious children. After local anesthetic is infiltrated
subcutaneously, an 18-G Tuohy needle is inserted between the spinous processes of
180 Mavi & Moore
T5-6 or T6-7, and the epidural space noted by loss of resistance to air or preservative-
free saline. Placement of the epidural at higher intervertebral spaces has been noted
postoperatively to have a higher rate of failed block; higher rate of Horner syndrome;
and higher rate of upper extremity issues, such as weak grip and numbness. Weak
grip and numbness, although confirmatory for success of block, may cause distress
for the patient and necessitate changes in rate and concentration of epidural solution.
The catheter is advanced 3 to 4 cm into the epidural space and secured in place.
Further advancement has been noted to result in one-sided and failed blocks. A
test dose is administered, and once confirmed negative a sterile dressing is placed
around the catheter and the patient is returned to a supine position. If there are prob-
lems placing the regional anesthetic in the seated patient because of compliance or
positioning issues, it may be more advantageous to induce anesthesia, secure the
airway, and then place the epidural in the lateral decubitus position.
In regards to further access and monitoring, a second, preferably large-bore periph-
eral intravenous line (PIV) is placed in preparation for possible rapid fluid or blood
administration. An arterial line is not required unless the patient has significant cardiac
or pulmonary derangements requiring continuous blood pressure monitoring or
frequent blood gas measurements.
The patient is initially placed in a supine position; however, because the surgeon
needs to enter and exit through the midthorax by way of the anterior to midaxillary
line, the patient’s arms must be placed in anatomic position, palm out, at right angles
above their head. To minimize traction injuries of the upper extremity, padding is
important, as is keeping the patient’s joints at right angles.
There are some major anesthetic concerns intraoperatively, particularly injury to the
heart and other mediastinal structures, that have been described with this procedure.
This complication can happen at the time of bar placement or later, when the bar is
removed. With placement, use of bilateral thoracoscopy aids in the careful dissection
around the lungs, mediastinum, and pericardium to pass to the contralateral pleural
space.15 Mediastinal dissection is typically the time when arrhythmias can be an issue.
Usually, the volume of the pulse oximetry monitor is increased to help the surgeons
recognize moments that the dissection may be imperiling the patient. Auditory cues
and heightened focus of the electrocardiogram at this time are expected.
After the bar (or bars) is in place and secured, management of the iatrogenic bilateral
pneumothoraces is important. Typically, temporary suctioning of the pleural spaces
along with a Valsalva maneuver is used to alleviate the pneumothorax on either
side. An intraoperative chest radiograph is used to confirm this.
Avoidance of coughing or straining is preferable to circumvent the development of
subcutaneous emphysema, created by forcible expulsion of residual pneumothorax.
Obviating this can be achieved by deep extubation or significant narcotics to avoid
straining on the endotracheal tube.
Intraoperative mortality from exsanguination caused by cardiac or vascular injury
has been described, and although rare, heightened vigilance, adequate IV access,
and availability of packed red blood cells are important. When these patients return
for pectus bar removal after several years, occasionally the bar has become adherent
to the lung or pericardium resulting in a severe, sudden, and catastrophic rupture of a
major vessel or heart chamber on removal.16 It is important to be prepared and estab-
lish ample IV access to massively resuscitate and transfuse fluids to these patients
should a catastrophe occur.
Other common risks postoperatively include bar displacement, residual pneumo-
thorax, and infection; however, cardiac injury, sternal erosion, arterial pseudoaneur-
ysm, and persistent cardiac arrhythmias are also possible.
Patients undergoing thoracic surgery experience a great amount of postoperative

pain, particularly in the older subset because the ribcage has become more rigid and
ossified. This may be caused by surgical retraction and dissection of intercostal mus-
cles, and conformational change of an ossified ribcage. These patients have been
shown to have better pain control and improved postsurgical ventilation and pulmonary
toilet with epidural analgesia.17–20 However, there are studies that show similar pain con-
trol between thoracic epidural and PCA.21–24 Whichever approach to postoperative pain
is chosen, the regimen for pectus excavatum repairs requires a multimodal approach.
Patients and families should be educated preoperatively in regards to the high de-
gree of postoperative pain expected despite being a minimally invasive approach.
Classic studies have demonstrated that the knowledgeable patient requires less anal-
gesia in the postoperative period, and at the same time experiences less pain than the
less informed patient.25 The transition from an epidural to oral pain medication can
also be challenging and often requires dosing or medication adjustments to establish
an optimal regimen. Aggressive physical therapy, particularly ambulation, improves
dynamic pain control and may decrease chronic postoperative pain.25 It is vital for
the patient’s care team to encourage movement up to the chair and ambulation
even before the epidural has been removed.
Patients who have had previous repair of their pectus excavatum with either a modi-
fied Ravitch procedure or a Nuss procedure may present with recurrent disease. For
patients with recurrent pectus excavatum it is important to know if the patient is having
recurrent symptoms. Patients often may present with pain associated with their recur-
rence, and a return to their original pulmonary symptomatology. Patients with chronic
pain as the only feature of their recurrence may continue to have pain after repair.14
There are numerous protocols established to manage postoperative pain control
after pectus excavatum repairs. Institutions use either a PCA or regional anesthesia,
either a thoracic epidural or paravertebral blocks as the main method of controlling im-
mediate postoperative pain.
One such protocol that has been used effectively begins with the placement of a
thoracic epidural in the T5-6 or T6-7 interspace followed by a loading dose of local
anesthetic (0.2% ropivacaine) up to 10 mL based on weight, given in an incremental
fashion. When the loading dose is complete, an epidural infusion is started consisting
of local anesthetic plus clonidine. For the local anesthetic in this mixture a higher con-
centration is often used (eg, 0.15% ropivicaine). The epidural is run until postoperative
Day 3 for all pectus repairs.
The multimodal approach to pain management is used and has been shown to be
most effective. Intermittent IV narcotics are available to the patient as needed; howev-
er, some patients may need a PCA to supplement the epidural analgesia. Other
supplemental medications include methocarbamol (Robaxin), 15 mg/kg IV, with a
maximum dose of 1000 mg every 8 hours for 3 days followed by transition to oral
Robaxin. Diazepam (Valium), 0.05 mg/kg IV every 4 hours as needed, is very effective
in the treatment of muscle spasms and postoperative anxiety, and ketorolac (Toradol),
0.5 mg/kg IV with a maximum of 30 mg every 6 hours for 2 days started on postoper-
ative Day 1, is a useful anti-inflammatory agent. IV acetaminophen every 6 hours is
started intraoperatively and continued for up to 3 days postoperatively, then transi-
tioned to the oral form as needed.
As the patient begins oral intake, they also begin to be transitioned to oral pain med-
ications. Oxycodone (Oxycontin), 10 mg twice daily, is started on the first postopera-
tive day. This can be titrated upward if needed. Oxycodone, 0.1 to 0.2 mg/kg every
4 hours, is started on the second postoperative day in the morning. The urinary cath-
eter is also removed approximately 4 hours after epidural removal.
182 Mavi & Moore
All medications are switched to the oral route, and doses and frequency are
adjusted as needed to provide optimal patient comfort. The intermitted IV narcotic
is kept available for breakthrough pain after epidural removal, because this is a tran-
sition when pain scores often increase by one to two points until an optimal oral pain
medication regimen has been achieved. Pain medications are continued for 2 weeks
postoperatively; older patients may need pain medication coverage for longer. Pa-
tients older than the age of 17 years may require narcotic pain medications longer
than 2 weeks postoperatively, and patients with excessive pain issues during
Box 1
Cincinnati Children’s Hospital pectus excavatum postoperative pain protocol
Preoperative preparation
Manage expectations: despite “minimally invasive” still quite painful
Pain plan: agree and consent for regional anesthesia if agreed on
Day of surgery (POD#0)
Epidural placement (T5-7) by anesthesia/pain team
Epidural solution: ropivacaine, 0.15%–0.2% with clonidine, 1 mg/mL
IV acetaminophen (Ofirmev), 15 mg/kg IV (Max 1000 mg) every 6 hours ATC 3 days
IV methocarbamol (Robaxin), 15 mg/kg IV (Max 1000 mg) every 8 hours ATC 3 days
IV diazepam (Valium), 0.05 mg/kg IV every 4–6 hours prn for spasm
IV opioids, if needed, prn or PCA
Postoperative Day 1 (POD#1)
Continue epidural analgesia, IV acetaminophen, IV methocarbamol, IV diazepam prn
Start IV ketorolac (Toradol), 0.5 mg/kg up to 15 mg IV every 6 hours ATC
Start oxycontin, 10 or 20 mg PO every 12 hours; if needed, make every 8 hours
Start oxycodone, 0.1–0.2 mg/kg PO every 4 hours; schedule as ATC, but may be held for
parent-patient refusal, respiratory depression, oversedation (Ramsey 4 to 6)
Continue epidural analgesia, IV acetaminophen, IV/PO methocarbamol, IV/PO diazepam as
needed
Place order in electronic records to stop epidural at 6 AM on POD#3
Stop epidural at 6 AM and remove on morning pain rounds
Discontinue urinary catheter 4 hours after stopping epidural (w10 AM)
Once epidural is out: continue oxycontin/oxycodone, PO acetaminophen every 6 hours
(maximum, 75 mg/kg/d), PO methocarbamol ATC and/or PO diazepam as needed
Start PO ibuprofen (10 mg/kg/dose, up to 3 times per day)
Keep on service and help manage postepidural pain control
If 17 years1, history of chronic pain, or prolonged need for oral narcotics >2 weeks, have
patient follow up in chronic pain clinic to assist in titration off of narcotics
Abbreviations: ATC, around the clock; IV, intravenous; PO, per os (oral); POD, postoperative
day.
hospitalization are followed by the chronic pain service until successfully transitioned
off pain medications (Box 1).
Problems that can be encountered with thoracic epidural analgesia include hypo-
tension, failed epidural, one-sided epidural, upper extremity weakness or tingling,
Horner syndrome, inadequate dermatomal coverage requiring a higher epidural
rate, and in rare but serious cases an epidural hematoma or an epidural abscess.
The epidural site should be checked multiple times daily by the pain management
team and nursing staff to assess for signs of infection at the site or dislodgement of
the epidural catheter. Fever is also important to follow up, because this can be a
sign of epidural infection. Typically, sustained high fever is an indication for epidural
removal.
Other forms of regional anesthesia have been described in lieu of placing a thoracic
epidural and have been successful in treating postoperative pain control. These
include bilateral intercostal nerve blocks, bilateral paravertebral catheters, and wound
catheter infusions.
In conclusion, pectus excavatum repairs are a common type of congenital chest
wall deformity, and although minimally invasive are categorized as extremely painful
procedures. Preoperative evaluation should focus on patient symptoms, cardiopul-
monary examination, and radiologic evidence of the magnitude of the defect. Prepa-
ration should include patient-parent education, readiness of donor blood products,
and establishment of a postoperative pain management plan. Intraoperative vigilance
is extremely important during bar placement and dissection because this could be a
time of catastrophic events. Postoperatively, thoracic epidurals are the superior
form of postoperative pain control, in addition to use of supplemental medications
as part of a multimodal analgesic technique.
REFERENCES
1. Ravitch MM. Congenital Deformities of the Chest Wall and their Operative Correc-
tion. Philadelphia: W.B. Saunders Company; 1977.
2. Ravitch MM. The operative treatment of pectus excavatum. Ann Surg 1949;129:
429.
3. Nuss D, Kelly RE Jr, Croitoru DP, et al. A 10-year review of a minimally inva-
sive technique for the correction of pectus excavatum. J Pediatr Surg 1998;
33(1):545.
4. Kelly RE Jr, Lawson ML, Paidas CN, et al. Pectus excavatum in a 112-year au-
topsy series: anatomic findings and the effect on survival. J Pediatr Surg 2005;
40:1275.
5. Westphal FL, Lima LC, Lima Neto JC, et al. Prevalence of pectus carinatum and
pectus excavatum in students in the city of Manaus, Brazil. J Bras Pneumol 2009;
35:221.
6. Brochhausen C, Turial S, Muller FK, et al. Pectus excavatum: history, hypotheses
and treatment options. Interact Cardiovasc Thorac Surg 2012;14:801.
7. Ellis D, Snyder C, Mann C. The ‘redo’ chest wall deformity correction. J Pediatr
Surg 1997;32:5.
8. Redlinger RE Jr, Kelly RE Jr, Nuss D, et al. One hundred patients with recurrent
pectus excavatum repaired via the minimally invasive Nuss technique–effective
in most regardless of initial operative approach. J Pediatr Surg 2011;46:1177.
9. Fokin AA, Steuerwald NM, Ahrens WA, et al. Anatomical, histologic, and genetic
characteristics of congenital chest wall deformities. Semin Thorac Cardiovasc
Surg 2009;21:44.
184 Mavi & Moore
10. Haller JA Jr, Scherer LR, Turner CS, et al. Evolving management of pectus exca-
vatum based on a single institutional experience of 664 patients. Ann Surg 1989;
209:578.
11. Barua A, Rao VP, Barua B, et al. Patient satisfaction following minimally invasive
repair of pectus excavatum: single surgeon experience. J Surg Tech Case Rep
2012;4:86.
12. Croitoru DP, Kelly RE Jr, Goretsky MJ, et al. The minimally invasive Nuss tech-
nique for recurrent or failed pectus excavatum repair in 50 patients. J Pediatr
Surg 2005;40:181.
13. Antonoff MB, Erickson AE, Hess DJ, et al. When patients choose: comparison of
Nuss, Ravitch, and Leonard procedures for primary repair of pectus excavatum.
J Pediatr Surg 2009;44:1113.
14. Colombani PM. Preoperative assessment of chest wall deformities. Semin Thorac
Cardiovasc Surg 2009;21:58.
15. Guo L, Mei J, Ding F, et al. Modified Nuss procedure in the treatment of recurrent
pectus excavatum after open repair. Interact Cardiovasc Thorac Surg 2013;17:258.
16. Cote CJ. A Practice of Anesthesia for Infants and Children. 5th edition. Philadel-
phia: W.B. Saunders Company; 2009.
17. McBride WJ, Dicker R, Abajian JC, et al. Continuous thoracic epidural infusions
for postoperative analgesia after pectus deformity repair. J Pediatr Surg 1996;
31:105.
18. Kavanagh BP, Katz J, Sandler AN. Pain control after thoracic surgery. A review of
current techniques. Anesthesiology 1994;81:737.
19. Soliman IE, Apuya JS, Fertal KM, et al. Intravenous versus epidural analgesia
after surgical repair of pectus excavatum. Am J Ther 2009;16:398.
20. Weber T, Matzl J, Rokitansky A, et al. Superior postoperative pain relief with
thoracic epidural analgesia versus intravenous patient-controlled analgesia
after minimally invasive pectus excavatum repair. J Thorac Cardiovasc Surg
2007;134:865.
21. Gasior AC, Weesner KA, Knott EM, et al. Long-term patient perception of pain
control experience after participating in a trial between patient-controlled anal-
gesia and epidural after pectus excavatum repair with bar placement. J Surg
Res 2013;185(1):12–4.
22. Butkovic D, Kralik S, Matolic M, et al. Postoperative analgesia with intravenous
fentanyl PCA vs epidural block after thoracoscopic pectus excavatum repair in
children. Br J Anaesth 2007;98:677.
23. St Peter SD, Weesner KA, Sharp RJ, et al. Is epidural anesthesia truly the best
pain management strategy after minimally invasive pectus excavatum repair?
J Pediatr Surg 2008;43:79.
24. St Peter SD, Weesner KA, Weissend EE, et al. Epidural vs patient-controlled anal-
gesia for postoperative pain after pectus excavatum repair: a prospective, ran-
domized trial. J Pediatr Surg 2012;47:148.
25. Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J
Surg 2002;183:630.
A n e s t h e s i a f o r th e C h i l d w i t h
Cancer
Gregory J. Latham, MD
KEYWORDS
Cancer Oncology Pediatric Anesthesia Anterior mediastinal mass
Anthracycline-induced cardiotoxicity
KEY POINTS
At present, there are insufficient data regarding the immunomodulatory effects of anes-
thetic drugs and techniques to support altering the anesthetic plan in adults, let alone
children, with cancer undergoing surgery.
The presence of a clinically significant anterior mediastinal mass is common in children
newly diagnosed with lymphoma, as well as leukemia, neuroblastoma, and germ cell
tumors.
Goals for safe provision of anesthesia care in children with anterior mediastinal mass
include a meticulous preoperative assessment; discussion with the oncologist, radiolo-
gist, and surgeon about whether the procedure is required before treatment of the
mass; and cautious administration of anesthesia.
Treatment-related cardiopulmonary toxicity is common in the acute and chronic settings
of childhood cancer; however, most toxicity is subclinical or mild, and thus such children
tend to tolerate anesthesia, at least for outpatient procedures, as well as their healthy
peers.
Because cancer and its treatment can affect every organ system of the body, a systems-
based approach to the preoperative assessment is a helpful way to ensure a thorough
investigation of each potential comorbidity that could affect safe anesthetic management
of the child.
INTRODUCTION
Cancer is the second and fourth most common cause of death in children younger
than 15 and 20 years of age, respectively.1,2 More than 23,000 children were newly
diagnosed with cancer in the United States in 2009,3 and the number of Americans
living with or having survived childhood cancer in 2006 was nearly 260,000.4 However,
survival from childhood cancer has improved dramatically over the last several
Disclosures: None.
Department of Anesthesiology and Pain Medicine, Seattle Children’s Hospital, University of
Washington School of Medicine, 4800 Sand Point Way Northeast, MB.11.500.3, Seattle, WA
98105, USA
E-mail address: gregory.latham@seattlechildrens.org

186 Latham
decades, with average 5-year survival rates exceeding 80%.4,5 This increased survival
entails various long-term sequelae of cancer and its therapy in children with ongoing or
remissive cancer. In one report, 62% of survivors of childhood cancer reported at least
one chronic health condition from cancer, and 28% of patients reported a severe or
life-threatening condition.5 Long-term chronic health conditions can affect nearly
every organ system and be pertinent to the anesthetic plan.
The most common cancers in children are different than in adults, and the incidence
of specific cancers in children varies not only from those in adults but also between
different childhood age groups (Table 1). The most common malignancies in children
include leukemia, lymphoma, brain tumors, and solid tumors of soft tissue and bone.3
Other tumors are specific to childhood, including neuroblastoma, retinoblastoma,
medulloblastoma, and Wilms tumor.
POTENTIAL COMPLICATIONS OF ANESTHESIA IN THE PEDIATRIC PATIENT WITH

CANCER
Children with cancer undergo many surgeries and procedures that require anesthesia
during acute phases of the disease, years into remission, or terminal stages of the dis-
ease. Inherent to a safe anesthetic plan is consideration of the direct effects of tumor,
toxic effects of chemotherapy and radiation therapy, the specifics of the surgical pro-
cedure, drug-drug interactions with chemotherapy agents, pain syndromes, and psy-
chological status of the child. However, reports have shown that outpatient anesthetic
management of children for radiotherapy, lumbar puncture, and bone marrow aspira-
tion is safe, with a complication rate comparable with similar studies of propofol-
based anesthesia in children without cancer.6,7 However, children with cancer can
be very ill, and potential issues arising during anesthetic management include sepsis,
multiorgan failure, respiratory insufficiency, thromboembolism, coagulopathy, tumor
lysis syndrome, and cardiopulmonary collapse.8 Therefore, it is imperative for the
Table 1
Incidence of pediatric cancer by age
Incidence by Age Group (%)

Type of Cancer 0–4 y 5–9 y 10–14 y 15–19 y 0–19 y
Leukemias 36.1 33.4 21.8 12.4 25.2
Central nervous system tumors 16.6 27.7 19.6 9.5 16.7
Lymphomas 3.9 12.9 20.6 25.1 15.5
Carcinomas and other malignant epithelial 0.9 2.5 8.9 20.9 9.2
tumors
Soft tissue sarcomas 5.6 7.5 9.1 8.0 7.4
Germ cell, trophoblastic, and other gonadal 3.3 2.0 5.3 13.9 7.0
tumors
Malignant bone tumors 0.6 4.6 11.3 7.7 5.6
Sympathetic nervous system tumors 14.3 2.7 1.2 0.5 5.4
Renal tumors 9.7 5.4 1.1 0.6 4.4
Retinoblastoma 6.3 0.5 0.1 0.0 2.1
Hepatic tumors 2.2 0.4 0.6 0.6 1.1
Other and unspecified malignant neoplasms 0.5 0.3 0.6 0.8 0.6
From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient–part 1:
a review of antitumor therapy. Paediatr Anaesth 2010;20(4):296; with permission.
anesthesiologist caring for these children to have an understanding of the multiple

effects of the tumor, toxicities of therapy, significant coexisting illnesses, and psycho-
social vulnerabilities to best formulate an anesthetic plan that is appropriate for the pa-
tient and type of procedure.
EFFECTS OF ANESTHETIC AGENTS ON PERIOPERATIVE IMMUNOMODULATION
Although this is a new area of research, there has been large increase of data over
the past decade reporting the impact of multiple perioperative factors on immunomo-
dulation in the patient who has cancer. All of the research thus far has been in tissue
cultures or retrospective studies in adults9 and may or may not be applicable to the
common childhood cancers. These data should therefore be interpreted with caution
regarding clinical applicability in children.
The host immune system combats progression, spread, and recurrence of cancer.
Surgical stress and perhaps some anesthetic agents can suppress the host immune
response or directly augment the cancer cells (proliferation, migration, and invasion)
and theoretically allow spread or recurrence of cancer.9,10 Most, but not all, research
has shown an association with ketamine, sevoflurane, isoflurane, desflurane, and opi-
ates (predominantly morphine) and harmful immunosuppression or cancer cell
augmentation. Propofol has shown mixed results but may prove to be superior
compared with volatile anesthetics.9,10 Nitrous oxide, although shown in vitro to
reduce natural killer cell activity, has not been shown in a retrospective adult study
to affect cancer recurrence.9 In addition, regional anesthesia was shown in some
but not all studies to lessen immunosuppression during surgery and potentially reduce
cancer recurrence in adults, but this prior finding in animal and retrospective data was
not confirmed in a more recent prospective trial.11 Other perioperative factors, such as
hypotension, hypothermia, hypoglycemia or hyperglycemia, and blood transfusion are
also being investigated.9
At present, there is insufficient evidence to support altering the anesthetic plan in
adults, let alone children, with cancer undergoing surgery because of any concern
about immunomodulation.
A SYSTEMS-BASED APPROACH TO THE TOXICITY OF CANCER AND ANTITUMOR

THERAPY
Background
Most childhood cancers are treated by cooperative clinical trial protocols, which may
include chemotherapy, radiation therapy, biologic modifiers, and hematopoietic stem
cell transplant (HCST). Surgical resection of tumor is warranted with certain types of
cancers. Although each of these therapies is designed to eradicate tumor, the effect
on healthy tissue is rarely avoidable or benign.
Conventional chemotherapy drugs are designed to be cytotoxic to rapidly dividing
cells by various mechanisms. These agents have been the mainstay of cancer treat-
ment in children for decades and have led to remarkable cure rates. However, the
toxicity of these agents to healthy tissues can reduce the child’s quality of life and
cause long-term morbidity and mortality.12,13 Bone marrow suppression, immunosup-
pression, myocardial and pulmonary toxicity, and dysfunction of nearly every other or-
gan system are possible. Specific toxicities of chemotherapeutics that are especially
pertinent to anesthesia are discussed later, but, as a point of reference, Table 2 pro-
vides an organized list of traditional chemotherapy agents by category, and Table 3
provides a list of traditional chemotherapeutic agents, molecularly targeted agents,
and adjuvant medications used in children, with their corresponding toxicities.
188
Latham
Table 2
Traditional chemotherapeutic agents by class
Alkylating Agents Antimetabolites Natural Products Miscellaneous Hormonal Agents

Nitrogen mustards Folic acid analogues Vinca alkaloids Anthracenedione Antiestrogens
Mechlorethamine Methotrexate Vinblastine Mitoxantrone Estrogens
Cyclophosphamide Pyrimidine analogues Vincristine Substituted urea Aromatase inhibitors
Ifosfamide Fluorouracil Vinorelbine Hydroxyurea GNRH analogues
Melphalan Cytarabine Vindesine Methylhydrazine derivative Antiandrogens
Chlorambucil Gemcitabine Epipodophyllotoxins Procarbazine
Ethylenimines Purine analogues Etoposide Adrenocortical suppressants
Thiotepa 6-Mercaptopurine Teniposide Mitotane
Alkyl sulfonates 6-Thioguanine Enzymes Aminoglutethimide
Busulfan Pentostatin L-Asparaginase Estradiol–mustard ester
Nitrosoureas Cladribine Antibiotics Estramustine
Carmustine Fludarabine Actinomycin D
Lomustine Clofarabine Daunorubicin
Streptozotocin Dactinomycin
Platinum complexes Doxorubicin
Cisplatin Idarubicin
Carboplatin Bleomycin
Oxaliplatin Mitomycin
Triazenes Plicamycin
Dacarbazine Camptothecin analogues
Topotecan
Irinotecan
Taxanes
Paclitaxel
Docetaxel
Abbreviation: GNRH, gonadotropin-releasing hormone.

From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient–part 1: a review of antitumor therapy. Paediatr Anaesth
2010;20(4):298; with permission.
Although advances in radiation therapy have reduced the morbidity of this therapy,
toxicity to healthy tissues occurs. The susceptibility of normal tissues to radiation ther-
apy depends on the total and fractional dose received, the sensitivity of the tissue to
the dose of radiation, the volume of tissue irradiated, and time course of treatment.14
Concurrent treatment with chemotherapeutics also affects toxicity by causing additive
tissue damage.15 Table 4 lists late effects of radiation therapy that may be present in
children with or having survived cancer.
Anterior Mediastinal Mass

Effect of tumor and its treatment
Most children with Hodgkin or non-Hodgkin lymphoma have mediastinal involvement
at diagnosis, and half have respiratory symptoms.16 Other tumors that may present
with an anterior mediastinal mass (AMM), albeit much less commonly, include neuro-
blastoma, germ cell tumors, and acute lymphoblastic leukemia.17,18
Anesthetic considerations
The risk of cardiopulmonary collapse under anesthesia is ever present in children with a
clinically significant AMM. Although the definitive treatment of an AMM is antitumor ther-
apy, some children may require an anesthetic at presentation. The anesthesiologist, in
conjunction with the surgeon and oncologist, must weigh the pros and cons of proceed-
ing with an anesthetic in the setting of symptomatic AMM. Three choices are possible:
Perform the procedure with local anesthetic if possible
Administer general anesthesia
Pretreat the child with chest irradiation or corticosteroids to reduce the mass size
Pretreatment is controversial because of its potential to alter the tumor cell histology
if biopsy is required for diagnosis, but a recent study has shown that a histologic diag-
nosis is still possible in 95% of children treated with up to 5 days of corticosteroids.19
Caution should be practiced in the management of any child with an AMM, but
certain clinical findings more strongly predict cardiopulmonary compromise under
anesthesia, as listed in Box 1. Before surgery, the anesthesiologist should review im-
aging of the chest to gain an understanding of the exact nature and location of
obstruction to airways and vascular structures and should have a plan for reposition-
ing the patient should collapse of these structures occur.
Unless an awake fiberoptic intubation is chosen, induction of anesthesia is classi-
cally performed gradually with intravenous or inhalational agents, maintaining sponta-
neous ventilation through the time of intubation.19–21 Maintenance of spontaneous
ventilation and avoidance of paralysis throughout the procedure is prudent to avoid
cardiac collapse or collapse of the airway beyond the tip of the endotracheal tube.
Cardiopulmonary collapse can occur rapidly, and treatment must begin immedi-
ately; therefore, a plan for resuscitation and the appropriate equipment should be
ready at the start of the case. Initial resuscitation of airway compromise includes20:
Increase the inspired oxygen
Apply continuous positive airway pressure
Reposition the child into the appropriate lateral or even prone position
If these maneuvers fail to rescue airway collapse, ventilation through a rigid bron-
choscope may be required22
If cardiac collapse occurs20
Administer a fluid bolus
Reposition the patient into the appropriate lateral or even prone position
190
Latham
Table 3
Organ toxicity of chemotherapeutic agents
Pulmonary Gastrointestinal
Drug Myelotoxicity Cardiotoxicity Toxicity Nephrotoxicity Hepatotoxicity Toxicity Neurotoxicity Other
Alemtuzumab 11 — — — — 1 (N/V/D/M) —
Altretamine 11 — — — 1 (LFT[) 11 (N/V) 1
Arsenic trioxide 1 (leukocy- 11 1 (effusion) — — 1 (N/V/D) 1/ Differentiation
tosis) (prolonged syndrome
QT interval)
Asparaginase 1 (bleeding) — — — 1 (LFT[) 1 (pancreatitis) — Coagulopathy
5-Azacitidine 111 — — — 1 (LFT[) 1 (N/V/D) —
Bevacizumab — 11 — 1 (nephrotic — 1 (N/V/D/M) 1 (asthenia)
(HTN, CHF) syndrome)
Bleomycin — — 111 1 1 1/ —
Bortezomib 1/ — — — — 1 (N/V/D) 1 Fever common
Busulfan 111 — 11 — 11 1 (N/V) 1 (seizures) Electrolyte
(LFT[, VOD) abnormalities
Capecitabine 11 1 (in adults) — — 1 (LFT[) 11 (D/M) 11
Carboplatin 111 — — 1 — 11 11
Carmustine 111 — 111 1 1 (LFT[) 1 (N/V) —
Cetuximab — — 1 (rare) — — — — Rash,
hypomagne-
semia
Chlorambucil 111 — 11 (rare) — — — 11 (rare)
Cisplatin — — — 111 — 11 (N/V) 11 SIADH
Cladribine 111 — — 1 (at high — — 1 (at high Tumor
doses) doses) lysis syndrome
Clofarabine 111 — — 1 (rare) 11 (LFT[) 11 (N/V) —
Cyclophos- 111 11 (at high — 11 — — — SIADH
phamide doses) (hemorrhagic
cystitis)
Cytarabine 111 — 11 (at high — 1 (LFT[) 111 11 Ara-C syndrome
doses) (pancreatitis)
Dacarbazine 111 — — — — 11 (N/V) 11 (rare)
Dactinomycin-D 111 — — — 11 111 (N/V/D/M) —
(LFT[, VOD)
Darbepoetin — 1 (HTN) — — — — —
alfa
Dasatinib 111 11 — — — 11 (N/V/D) — Bleeding
(arrhythmias) disorders
Daunorubicin 111 111 — — — — — Skin disorders
Decitabine 111 — 1 (cough, — 1 (LFT[) 11 (N/V/D) —
edema)
Denileukin — 11 (Vascular — 1 (rare) 1 (rare) — 1 (rare)
diftitox leak
syndrome)
Anesthesia for the Child with Cancer

Dexamethasone 1 (leukocy- — — — — — — Adrenal
tosis) suppression
Docetaxel 111 — — — 1 (LFT[) — 1 Fluid retention
(uncommon)
Doxorubicin 111 111 — — — — — Skin disorders
Epirubicin 111 111 — — — — — Skin rash
Erlotinib — — 111 (ILD; — 1 (LFT[) 1 (D) —
rare)
Erythropoietin — 1 (HTN) — — — — —
Estramustine — 111 — — — 111 (N/V) —
(very rare)
191
192
Latham
Table 3
(continued )
Etoposide 111 — — — 1 (rare) 1 (N/V) 1 (rare)
Filgrastim — — — — — — — Bone pain
Floxuridine 11 11 (rare) — — 111 11 (ulcers) 1 (rare)
Fludarabine 111 — — — — — 111 Autoimmune
(uncommon) hemolytic
anemia
5-Fluorouracil 111 11 (rare) — — — 111 (D/M) 111
(uncommon)
Gefitinib — 1 (HTN) 111 (ILD; — 1 (LFT[) — — Rash
rare)
Gemcitabine 111 — 111 (ILD; 1 (hematuria) 1 (LFT[) 1 (N/V) 1 (rare)
rare)
Gemtuzumab 111 — — — 11 — —
ozogamicin (LFT[, VOD)
Hydroxyurea 111 — — — — — — Skin disorders
Ibritumomab 111 — — — — — 1 (asthenia) Infusion
tiuxetan reactions
Idarubicin 111 111 — — 1 (LFT[) 1 (N/V/D/M) — Skin disorders
Ifosfamide 111 — 111 111 1 (LFT[) 111 (N/V) 11 SIADH
(uncommon) (hemorrhagic
cystitis;
Fanconi-like
syndrome)
Imatinib 1 — — — 1 (LFT[) 1 (D) —
mesylate
Interferon- 11 11 (rare) — — 1 (LFT[) — — Autoimmune
alpha symptoms
Interleukin-2 1 11 (vascular — — 1 (LFT[) — 1
leak
syndrome)
Irinotecan 111 — — — 1 (LFT[) 11 (D) 1 (asthenia) Electrolyte
abnormalities
Lapatinib 1 — — — 1 (LFT[) 11 (N/V/D) —
Lenalidomide 11 — — — — 1 (D) — Thrombosis
Leucovorin — — — — — 1 (N/V) — Rash
Lomustine 111 — 111 111 — 1 (N/V) —
(uncommon) (uncommon)
Mechloretha- 111 — — — 11 111 (N/V) 1 (rare)
mine
Melphalan 111 — 11 (rare) — — 1 (N/V/D/M) — SIADH (rare)
Mercapto- 111 — — — 1 (LFT[) 1 (N/V/D/M) — Skin disorders
purine
Mesna — — — — — 1 (N/V) — Rash, arthralgias

Methotrexate 111 — 111 11 — 11 (M/D) 11 (at high
(uncommon) doses)
Mitomycin C 111 — 111 (rare) 111 (HUS – 111 1 (N/V/M) —
rare) (VOD – rare)
Mitoxantrone 111 111 — — 1 (LFT[) 1 (N/V/D/M) —
Nelarabine 111 — 1 (uncommon) — — 1 (N/V/D) 111 Edema
(common)
Oprelvekin — 111 111 (pleural — — 1 (N/V/D/M) 1 Edema
effusions,
dyspnea)
Oxaliplatin 11 — 111 (rare) 111 (rare) 111 11 (N/V/D) 111 Hypersensitivity
(VOD – rare) (common) reactions
193
194
Latham
Table 3
(continued )
Paclitaxel 111 1 (arrhythmia) — — 1 (LFT[) 1 (N/V/D/M) 111 Arthralgias
(common)
Panitumumab — — 111 (rare) — — 1 (N/V/D) — Infusion
reactions
Pegaspara- — — — — 111 — — Thrombosis,
ginase (pancreatitis – glucose
uncommon) intolerance
Pegfilgrastim — — — — 1 (LFT[) — — Bone pain
Pemetrexed 111 — — — — 11 (N/V/D/M) 1
Pentostatin 111 1 (rare) — — 1 (LFT[) 1 (N/V) 1 Hypersensitivity
reactions
Prednisone 1 (leukocy- — — — — — — Adrenal
tosis) suppression
Procarbazine 111 — 111 — — 1 (N/V) 11 Hypersensitivity
(ILD; rare) reactions
Rituximab 1 1 (rare) — — — — 1 Infusion
reactions,
tumor lysis
syndrome
Sargramostim — 1 (arrhyth- — — 1 (LFT[) — — Bone pain,
mias – infusion
uncommon) reactions
Sorafenib 1 11 (adults – — — 1 (LFT[) 1 (N/V/D) 1 Skin disorders
rare)
Streptozocin 1 — — 111 1 (LFT[) 111 (N/V) — Glucose
(azotemia) imbalance
Sunitinib 111 1 (HTN, — — 1 (LFT[) 11 (N/V/D/M) — Bleeding
YLVEF) disorder
Temozolomide 111 — — — 1 (LFT[) 11 (N/V/D) —
Teniposide 111 — — — — 1 (N/V/M) 1 Hypersensitivity
reaction
Thalidomide — — — — — 1 111 Thrombosis,
teratogenesis
Thioguanine 111 — — 1 (rare) 111 (VOD) 111 (D/M) 1 (rare)
Thiotepa 111 — — — — 1 (N/V) —
Topotecan 111 — — 1 (hematuria) 1 (LFT[) 11 (N/V/D) —
Tositumomab 111 — — — — 1 (N/V) — Infusion
reactions
Trastuzumab — 11 (CHF) 1 (rare) — — 1 (N/V/D) — Infusion
reactions
Tretinoin 111 111 (RAS) 111 (RAS) 1 (rare) 1 (LFT[) 1 (N/V) 1 (common), RAS
(all-trans (leukocy- 111 (rare)
retinoic acid) tosis)
Vinblastine 111 11 (rare) 111 (rare) — — 11 (N/V/D/M) 1 (common), SIADH (rare)

111 (rare)
Vincristine 11 11 (rare) 111 (rare) — — 11 (N/V/D/M) 111 SIADH (rare)
Vinorelbine 111 — — — 1 (LFT[) 11 (N/V/D/M) 1 SIADH (rare)
Vorinostat 1 — — — — 11 (N/V) 1 (uncommon) Thrombosis
(rare)
Note: data are from pediatric studies whenever possible, but, when pediatric data were incomplete or absent, adult data were included.
Abbreviations: 1, mild toxicity; 11, moderate toxicity; 111, severe toxicity or dose-limiting toxicity; Ara-C, arabinofuranosyl cytidine or cytarabine; CHF,
congestive heart failure; D, diarrhea; HTN, hypertension; ILD, interstitial lung disease; LFT, liver function test; M, mucositis; N, nausea; RAS, retinoic acid syndrome;
SIADH, syndrome of inappropriate antidiuretic hormone; V, vomiting; VOD, veno-occlusive disease.
From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient–part 1: a review of antitumor therapy. Paediatr Anaesth
2010;20(4):299–301; with permission.
195
196 Latham
Table 4
Late effects of radiation therapy
Radiation Field Late Effects Risk Factors (if known)

Cranial Neurocognitive deficits >18 Gy, IV/IT methotrexate
Leukoencephalopathy >18 Gy with IT methotrexate
Growth hormone deficiency >18 Gy
Panhypopituitarism >40 Gy
Large vessel stroke >60 Gy
Second cancers Variable
Dental problems >10 Gy
Cataracts >2–8 Gy single dose, 10–15 Gy
fractionated dose
Ototoxicity >35–50 Gy
Chest Cardiac disease:
Coronary artery disease >30 Gy
Cardiomyopathy >35 Gy, >25 Gy with anthracyclines
Valvular disease >40 Gy
Pericardial disease >35 Gy
Arrhythmias —
Thyroid disease:
Hypothyroidism >20 Gy local, >7.5 Gy TBI
Hyperthyroidism >20 Gy local, >7.5 Gy TBI
Thyroid nodules/cancer Any dose
Pulmonary disease:
Pulmonary fibrosis >15–20 Gy
Restrictive lung disease —
Obstructive lung disease —
Abdomen/pelvis Chronic enteritis >40 Gy
Gastrointestinal malignancy —
Hepatic fibrosis/cirrhosis >30 Gy
Renal insufficiency >20 Gy
Bladder disease:
Fibrosis >30 Gy before puberty, >50 after
puberty
Hemorrhagic cystitis Enhances cyclophosphamide and
ifosfamide effect
Cancer —
Gonadal dysfunction:
Ovarian failure 4–12 Gy
Testicular failure >1–6 Gy
Any radiation Skin cancer —
Musculoskeletal changes:
Bone length discrepancy >20 Gy
Pathologic fractures >40 Gy
Total body irradiation All the effects listed earlier —
Abbreviations: Gy, gray; IT, intrathecal; IV, intravenous; TBI, total body irradiation.
From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient–
part 1: a review of antitumor therapy. Paediatr Anaesth 2010;20(4):302; with permission.
If these measures fail, immediate sternotomy and elevation of the mass may be
life saving
Immediate availability of cardiopulmonary bypass or extracorporeal membrane
oxygenation has been described, but the usefulness of these measures as first-line
Box 1
Strongest risk factors for acute perioperative cardiac or respiratory complications in patients
with an AMM
Clinical signs and symptoms:

Orthopnea
Upper body edema (signs of SVCS)
Stridor
Wheeze
Diagnostic imaging findings:
Tracheal, bronchial, or carinal compression
Great vessel compression, SVC obstruction
Pulmonary artery outflow obstruction
Ventricular dysfunction
Pericardial effusion
Abbreviations: SVC, superior vena cava; SVCS, superior vena cava syndrome.
From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology
patient–part 2: systems-based approach to anesthesia. Paediatr Anaesth 2010;20(5):397; with
permission.
therapy is questionable because of the degree of global hypoxia that ensues before
successful cannulation in many cases.19
Oral Cavity and Airway

Primary tumors of the airway are uncommon in children, and most are benign.23 How-
ever, the impact of chemotherapy and radiation therapy to the airway is common.
Mucositis and xerostomia can develop as soon as a week after beginning treatment
with many different chemotherapy drugs and as soon as 2 to 4 weeks after radiation
to the head and neck.24,25 Mucositis and more significant ulcerative lesions may occur
as part of graft-versus-host disease (GVHD) after hematopoietic stem cell transplant
(HSCT). In addition, chronic fibrosis and distortion of the airway is possible after irra-
diation of the head and neck.26
High-dose chemotherapy or total body irradiation (TBI) for HSCT can lead to muco-
sitis that threatens the airway from pseudomembrane formation, supraglottic edema,
bleeding, and aspiration of blood and secretions.27,28 Up to 30% of children who
receive HSCT may have a difficult airway.28 Past irradiation of the neck has been re-
ported to cause difficult airway management, including poor laryngeal mask airway
seating and the requirement for a smaller endotracheal tube.26,29
Cardiovascular System
The primary cardiac manifestations of the tumor include AMM and pericardial effusion.
Primary tumors of the heart are uncommon and are usually benign.30
The anthracycline drugs (doxorubicin, daunorubicin, idarubicin, and epirubicin) are
perhaps the most cardiotoxic used in pediatric oncology; however, other drugs are
also cardiotoxic. Mitoxantrone should be considered in the same risk stratification
198 Latham
as anthracyclines.31 Cyclophosphamide, fluorouracil, vinca alkaloids, cytarabine, cla-

dribine, asparaginase, paclitaxel, trastuzumab, etoposide, teniposide, and pentostatin
have also been reported to cause cardiotoxicity.32,33
The effects of chest irradiation on the heart can be significant, and its effects are ad-
ditive with any administered cardiotoxic chemotherapeutics.34 It is likely that current
dosing protocols using less than 25 to 30 Gy cumulative doses minimize long-term
cardiac risk.35
Symptomatic heart failure after anthracycline therapy is uncommon during the child-
hood years. In one study, echocardiography did not show a significant reduction in
cardiac index during anesthesia for central line placement in children treated with
anthracyclines versus those who had not.36 However, the impact during major surgery
is unknown. In general, if a child has diminished cardiac function shown by echocar-
diography, caution should be exercised during the administration of anesthetics with
negative inotropic properties, because cardiac failure or arrhythmias can develop at
any time after anthracycline therapy.
Unlike anthracyclines, radiation-induced cardiotoxicity can affect any component of
the heart, causing pericardial effusions, pericarditis, cardiomyopathy, valvular fibrosis,
conduction disturbances, and coronary artery disease.34,37 Current irradiation proto-
cols use careful blocking and cumulative doses less than 25 to 30 Gy, which seemingly
limits the short-term risk of heart disease, but clinically evident, long-term toxicity has
been reported at these dosing limits.34
Children receiving anthracycline treatment or chest irradiation usually have routine
cardiac evaluations. In general, a recent echocardiogram should be available if a pa-
tient has received anthracycline therapy or chest radiotherapy and any of the following
conditions are met38:
The cumulative dose of anthracycline was greater than 240 mg/m2
Any dose of anthracycline was received during infancy
Chest irradiation was greater than 40 Gy (or >30 Gy with concomitant anthracy-
cline treatment)
These data are unknown
Pulmonary System
Primary lung tumors in children are rare, and metastases to the lung are uncommon.39
Most tumor-related causes of respiratory compromise in the acute setting are there-
fore indirect effects and include pleural effusion, infiltrate, pulmonary embolus,
chylous effusion from obstructed lymphatics, AMM, and hyperleukocytosis-induced
pulmonary leukostasis.40
Although bleomycin may be the best known and have the highest incidence, many
chemotherapeutic agents can cause significant acute and chronic lung toxicity
(Table 5). Acute chemotherapy-induced lung toxicity in children may manifest as
pneumonitis, pulmonary fibrosis, or noncardiogenic pulmonary edema, all of which
can occur after the first dose or months later.41,42 Pneumonitis has an insidious onset,
presenting with nonproductive cough, progressive dyspnea, and rales. Many cases of
pneumonitis are subclinical and resolve with cessation of the causative chemothera-
peutic, but the course may be irreversible once radiologic changes are evident.41,43,44
Chemotherapy-induced lung fibrosis in children has a high incidence of onset
acutely during treatment, but fibrosis is also the hallmark of late chemotherapy-
induced pulmonary toxicity, with an onset of months to years after treatment.41,45
Table 5
Chemotherapy agents and pulmonary toxicity
Incidence Cumulative
Drug (%) Onset Dose Disorders
Bleomycin Adults: Early Unknown; Interstitial
Up to 46 (pneumonitis) probably pneumonitis;
to late (fibrosis) >400 U/m2 pulmonary fibrosis
Busulfan Adults: 6 Usually late Unknown in Diffuse interstitial
(range, children fibrosis;
2.5–43) bronchopulmonary
dysplasia; obstructive
bronchiolitis
Carmustine Up to 53 Early to late 600 mg/m2 Pulmonary fibrosis
Cyclophosphamide Unknown Early to late Unknown Interstitial
pneumonitis
Lomustine Adults: Early to late Unknown Interstitial
up to 63 pneumonitis
Methotrexate 2–33 Early (usually) Unknown Acute pneumonitis,
to late BOOP, pulmonary
fibrosis
Mitomycin Adults: Early Unknown: Pulmonary fibrosis
rare (1.8) probably
>15 mg/m2
Vincristine Adults: 4 Early Unknown ARDS when
combined
with mitomycin
Abbreviations: ARDS, acute respiratory distress syndrome; BOOP, bronchiolitis obliterans with
organizing pneumonia.
From Latham GJ, Greenberg RS. Anesthetic considerations for the pediatric oncology patient–
part 2: systems-based approach to anesthesia. Paediatr Anaesth 2010;20(5):401; with
permission.
Although most cases are subclinical, severe morbidity and mortality are possible.45
Bleomycin is the most commonly causative agent of chronic lung toxicity, but others
have been implicated (see Table 5). Studies of bleomycin-induced pneumonitis in chil-
dren are scant, but adult studies have reported the incidence to be up 46%, with a
mortality of 3%.46,47
Radiation-induced pulmonary disease also occurs as a progression from interstitial
pneumonitis in the acute phase to pulmonary fibrosis in the late phase,45 and signs
and symptoms are similar to those described earlier. Pulmonary dysfunction after
HSCT is likely caused by the combination of aggressive chemotherapy, TBI, and
chronic GVHD.35 Almost 25% of posttransplant children show decrements in pulmo-
nary function testing, but fewer have clinical symptoms.48,49
Bleomycin-induced pulmonary fibrosis can lead to severe restrictive lung disease.
Although data are conflicting, most human and animal data suggest that high concen-
trations of inspired oxygen during or after recent bleomycin therapy might exacerbate
pulmonary toxicity and lead to postoperative respiratory distress.50–53 Despite a lack
of definitive data, it is reasonable to recommend adjustment of intraoperative inspired
oxygen concentrations to the lowest possible level during and after bleomycin
200 Latham
therapy, as well as judicious use of intraoperative and postoperative fluid administra-

tion.54 In summary, the anesthesiologist must assess the presence of symptomatic
pulmonary dysfunction as well as consider the possibility of occult respiratory
compromise in the pediatric oncology patient.54 Overall, 6% of children treated with
chemotherapy alone, 20% treated with both chemotherapy and radiation therapy,
and 25% after HSCT have symptoms of pulmonary dysfunction or significantly
abnormal pulmonary function tests.38
Renal System
Wilms tumor represents most of the primary renal tumors in children, followed by clear
cell sarcoma of the kidney, malignant rhabdoid tumor, congenital mesoblastic neph-
roma, and renal cell carcinoma.55,56 Nonrenal tumors, typically neuroblastoma, can
infiltrate the kidneys or obstruct the urinary tract and renal vasculature, causing acute
renal failure (ARF).57
Almost all chemotherapy agents can cause nephrotoxicity in high enough doses.
Cisplatin, carboplatin, and ifosfamide are the most commonly implicated, but lomus-
tine, carmustine, cyclophosphamide, and high-dose methotrexate are occasionally
nephrotoxic.57,58 Ifosfamide causes chronic glomerular toxicity in up to 30% of pa-
tients and subclinical toxicity in up to 90%, but progressive chronic renal failure is un-
common.59 Fanconi syndrome is of particular concern with ifosfamide and may
present up to 18 months after therapy.59 Cisplatin can produce cumulative nephrotox-
icity and hypomagnesemia in children, but lower doses and careful medical manage-
ment have minimized the incidence of this toxicity in recent years.60 High-dose
methotrexate can lead to severe ARF in 2% of children and represents the need for
emergent treatment.61 Many other supportive drugs used in children with cancer
may lead to nephrotoxicity, including amphotericin B, acyclovir, aminoglycosides,
and diuretics.57 The syndrome of inappropriate antidiuretic hormone (SIADH) can be
caused by multiple chemotherapeutics as well.
Exposure of one or both kidneys to radiation is common with abdominal irradiation
and with TBI before HSCT. Cumulative doses of radiation that cause nephrotoxicity in
children are not well known. However, radiation nephritis presents with azotemia, pro-
teinuria, anemia, and hypertension.62
Renal toxicity is common after HSCT. The incidence of ARF in children has been re-
ported to be 20% to 40% after HSCT.63,64 The incidence of chronic renal impairment
has been reported to range from 18% to 54% after HSCT.65,66
As with any child with renal impairment, the impact of existing hypertension, electro-
lyte imbalances, anemia, coagulation, fluid status, need for dialysis, and pharmacoki-
netics of anesthetic agents must be considered. Nonsteroidal antiinflammatory drugs
should be administered with caution, especially in the dehydrated state. Laparotomy
for resection of Wilms tumor can result in significant bleeding if the tumor invades
the renal vasculature. Cardiopulmonary bypass is rarely required to enable resection
of tumor that extends to the right atrium.
Hepatic System
Primary liver tumors are rare in children, accounting for 1% of childhood cancers.
Hepatoblastoma is most common, followed by sarcomas, germ cell tumors, and
rhabdoid tumors. In late adolescence, the incidence of hepatocellular carcinoma
increases.67,68 In young children, up to 20% of liver tumors are associated with a

genetic syndrome, such as Beckwith-Wiedemann syndrome, that could further affect
anesthetic management.68
Although many chemotherapeutic agents can cause acute hepatotoxicity that leads
to liver function abnormalities, the progression to chronic liver disease in childhood is
uncommon. These acute toxicities occur over hours to weeks after a chemothera-
peutic dose and are usually reversible. Methotrexate, actinomycin D, 6-mercaptopu-
rine, and 6-thioguanine have been most commonly implicated in childhood acute
hepatotoxicity.54
Acute radiation-induced hepatotoxicity in children is typically mild and self-
limited.35 The exception is potential development of sinusoidal obstruction syndrome
(SOS) after HSCT. SOS can occur days to years after HSCT, and the reported inci-
dence is 11% to 27% after HSCT, with a mortality of 19% to 50%.69,70 SOS is hall-
marked by portal hypertension, liver failure, and failure of other organ systems,
especially the kidneys, lungs, and heart.71 Chronic hepatic fibrosis is possible after
abdominal irradiation, but the lower doses in current use (<30–40 Gy) or focal irradia-
tion of just portions of the liver likely limit the risk.35
As for any patient with liver dysfunction, the presence of impaired hepatic biotransfor-
mation of drugs and diminished synthetic function of coagulation factors and other
proteins must be considered during perioperative management. Furthermore, the
risk of exacerbation of hepatocellular damage during anesthesia and surgery must
be considered.54
Gastrointestinal System
Primary tumors of the gastrointestinal (GI) tract are rare in children. However, intra-
abdominal tumors can cause intestinal obstruction, intussusception, erosive per-
foration and intra-abdominal hemorrhage, biliary obstruction (rare), and massive
hepatomegaly (from end-stage neuroblastoma).54,72
Most children undergoing chemotherapy experience episodes of nausea and vom-
iting. Other GI toxicities of chemotherapeutics include diarrhea, mucositis, neutro-
penic enterocolitis, and stomatitis, all of which can lead to anorexia, malnutrition,
and dehydration.73
The rapidly regenerating tissues of the GI tract are sensitive to irradiation, manifest-
ing as inflammation and edema. These changes are usually transient.74 Chronic GI
toxicity is typically not seen with the radiation doses of less than 20 to 30 Gy that
are currently used.35,74
Whether a child presents for general anesthesia during active cytotoxic therapy or well
after its completion, the risk of delayed gastric emptying and aspiration during induc-
tion of anesthesia must be considered. Preoperative use of opiates for pain manage-
ment may further exacerbate slowing of GI motility. The presence of vomiting,
mucositis, enteritis, or bowel obstruction can cause malnutrition, vitamin K deficiency,
electrolyte imbalances, and dehydration.54
Central Nervous System
The most common intracranial tumors in children are astrocytomas, ependymomas,
primitive neuroectodermal tumors, and gliomas.2 The direct effect of brain tumors is
202 Latham
variable, depending on type, location, and patient age. Symptoms especially can be
nonspecific in young children, including irritability, lethargy, macrocephaly, and vom-
iting. Acute neurologic deterioration at presentation is possible, including increased
intracranial pressure, herniation, seizures, stroke, tumor lysis syndrome, and leukemic
meningitis.18 Primary tumors of the spine are uncommon in children, and spinal cord
compression is a rare but potentially severe surgical emergency.75
Chemotherapeutics most commonly implicated in neurotoxicity are the platinum
agents (cisplatin, carboplatin, oxaliplatin), L-asparaginase, ifosfamide, methotrexate,
cytarabine, etoposide, vincristine, and cyclosporin A.76,77 Acute toxicity, which is often
reversible, can include altered mental status, seizures, cerebral infarctions, encepha-
lopathy, ototoxicity, and peripheral nerve dysfunction.54
Small doses of brain irradiation (>18 Gy) have been shown to cause neurocognitive
changes and leukoencephalopathy, but doses greater than 50 Gy are required to
cause severe focal tissue destruction.74
Most pediatric brain tumors require surgical resection. Neurologic deterioration on
presentation to the operating room is common, and the anesthesiologist must be
prepared to manage alterations in intracranial pressure, risk of aspiration, seizures,
impact of antiseizure medications on metabolism of other drugs, and postoperative
neurologic assessment.
Endocrine System
Primary endocrine tumors are rare in children, accounting for less than 5% of child-
hood cancers.3 Most childhood endocrine tumors are gonadal germ cell tumors
(40%–45%; testicular, ovarian, and extragonadal tumors), followed by thyroid tumors
(30%; adenomas and carcinomas) and pituitary tumors (20%; craniopharyngiomas
and pituitary adenomas).54,78 Other endocrine tumors are rare.
Glucocorticoids are an important component of many cancer treatment protocols,
and thus adrenal suppression is common. Other traditional chemotherapeutics do not
have strong associations with endocrine dysfunction.
However, radiation to the pituitary and hypothalamus can cause significant chronic
neuroendocrine dysfunction. Growth hormone and gonadotropin deficiency can occur
after radiation therapy that exposes the hypothalamic-pituitary region to cumulative
doses as low as 18 to 20 Gy, and the risk of panhypopituitarism increases after doses
in excess of 35 to 40 Gy.79 Hypothyroidism is also common (11%–50% of childhood can-
cer survivors) after doses of 20 Gy, and onset is typically 2 to 4.5 years after therapy.80
Treatment of children with exogenous corticosteroid therapy can lead to a measurable
inability to mount an appropriate stress response for up to a year.81 Although the need
for and benefit of stress dose therapy during anesthesia has been debated, the anes-
thesiologist should ascertain a history of recent corticosteroid therapy. Because the
stress response in children with cancer has been shown to be unpredictable, it has
been recommended that stress dose steroids be administered during stressful condi-
tions in the first 1 to 2 months after cessation of glucocorticoids.82
Pheochromocytomas are rare in children, and review of the anesthetic management
of these children is beyond the scope of this article and well reviewed elsewhere.83
However, other childhood tumors can be catecholamine secreting (eg, neuroblas-
toma, ganglioneuroma) or can cause significant hypertension secondary to renal
artery compression (eg, neuroblastoma, Wilms tumor).
Hematologic System
Myelosuppression, which manifests with various degrees of anemia, thrombocyto-
penia, and neutropenia, is a common direct effect of cancer in children. Anemia is
common at diagnosis with neuroblastoma, rhabdomyosarcoma, Hodgkin disease,
Ewing sarcoma, or osteosarcoma and with 80% of children with acute lymphoblastic
leukemia (ALL).84,85 Thrombocytopenia is a frequent finding at diagnosis of acute leu-
kemia or solid tumors with marrow infiltration.86 Neutropenia is usual in children with
ALL. In acute myelogenous leukemia (AML), hyperleukocytosis (>100,000/mm3) is
present in 20% of patients at diagnosis.87 Hyperleukocytosis, especially when greater
than 200,000/mm3 in children, increases blood viscosity and can result in the poten-
tially fatal condition of leukostasis.87
Radiation therapy and most chemotherapy agents have the ability to cause acute
myelosuppression.54 Radiation therapy typically does not cause complete myelosup-
pression unless large volumes or marrow are irradiated, as is the goal with HSCT pre-
conditioning TBI.
Chemotherapy-induced myelosuppression is the most common dose-limiting
toxicity of cancer treatment.12 Leukopenia especially leads to significant morbidity
and mortality and is the component of pancytopenia that typically results in dose
limitations during treatment. Although use of erythropoietin or recombinant human
granulocyte/macrophage colony-stimulating factor for anemia and neutropenia,
respectively, is sometimes used in children, the mainstay of treatment is cessation
or lowering of cytotoxic treatment and blood transfusions.54
Myeloablative preparative regiments for HSCT, by design, cause nearly complete
destruction of the host hematopoietic stem cells. Engraftment and hematopoietic re-
covery occur during the first month after transplantation. This recovery follows a pre-
dictable pattern: granulocytes recover first, followed by platelets, lymphocytes, and
then erythrocytes. During this period of recovery, the patient is susceptible to infec-
tions, bleeding, and symptoms of anemia.54
Neutropenic patients are prone to sepsis, a possibility that must be considered before
an anesthetic. Infection precautions are necessary with neutropenic patients,
including aseptic technique during invasive procedures, avoidance of drugs or tem-
perature probes per rectum, and protective isolation of the patient.
When considering the perioperative need for red cell transfusion in children with
cancer, several factors should be considered. The assessment should include the
overall clinical condition of the patient, signs and symptoms of anemia, the patient’s
ability to tolerate the decreased red cell volume and oxygen carrying capacity, the
presence of cardiopulmonary dysfunction, the stress and anticipated blood loss of
the surgical procedure, the risk of increased intraoperative hemorrhage caused by a
bleeding disorder, and the ability of the patient to tolerate a volume load. Thus, sound
clinical judgment and attention to the greater clinical context is warranted in each
case.54
Although the benefit of transfusion with leukoreduced red cells remains largely un-
tested in pediatric oncology patients, its use is widespread and currently recommen-
ded based on some promising prospective study results.88 Use of irradiated red cells
is also recommended to avoid the potentially fatal transfusion-associated GVHD in
these immunocompromised patients. Caution must be exercised when transfusing
red cells to a patient with hyperleukocytosis because hyperviscosity and leukostasis
can occur.89
204 Latham
No specific criteria exist for platelet transfusion triggers in children. According to

the American Society of Clinical Oncology guideline, a platelet count of 40,000 to
50,000/mL is sufficient before major invasive procedures in patients without concur-
rent coagulopathies. For minor procedures such as bone marrow biopsies, a platelet
count of 20,000/mL is sufficient, but counts of more than 100,000/mL should be pre-
sent before neurosurgical procedures are performed.90 A platelet count of 10,000/mL
seems to be sufficient for lumbar punctures in children, and even when counts are less
than 10,000/mL, data are insufficient to recommend for or against prophylactic
platelet transfusion before lumbar puncture to avoid epidural hematoma.91
Histocompatible platelets should be use in alloimmunized patients, and use of leu-
koreduced platelets is recommended in those who have had or will have multiple
platelet transfusions to reduce subsequent alloimmunization.90 If intraoperative
bleeding continues despite appropriate platelet transfusion and documented counts,
other disorders of hemostasis should be considered, as discussed later.
Children who have recently received HSCT and who require blood transfusion pre-
sent a unique challenge in determining the appropriate ABO and lesser antigen
compatibility for transfusion. Discussion with the patient’s hematologist-oncologist
and blood bank is warranted to ensure appropriate management.
Coagulation System
Bleeding disorders caused by the cancer itself are usually multifactorial in cause,
including thrombocytopenia, clotting factor deficiencies, circulating anticoagulants,
and defects in vascular integrity.
Coagulopathy at the time of diagnosis is common in some types of childhood tu-
mors, especially ALL and AML. Significant disseminated intravascular coagulation
can be found at presentation in children with acute promyelocytic leukemia and less
commonly with acute monocytic leukemia and T-cell ALL.92 Children may develop ac-
quired bleeding disorders, including lupus anticoagulant syndrome, acquired von Wil-
lebrand syndrome (in up to 8% of children at diagnosis of Wilms tumor), and inhibitors
to factor VIII (acquired hemophilia).92,93
Treatment-related causes of bleeding are typically multifactorial, including thrombo-
cytopenia caused by cytoreductive chemotherapy and radiotherapy, vitamin K defi-
ciency, hepatic dysfunction, disseminated intravascular coagulation, and infection.
The rate of hemorrhagic death in children with cancer is unknown, but it is most
commonly reported in children with ALL and AML.92
Venous thromboembolism (VTE) is rare in the general pediatric population but is
probably more common in children with cancer, especially given the frequent use of
long-term indwelling vascular access. The overall incidence of VTE in children with can-
cer is 8%, a number that likely underreports asymptomatic VTEs, and the incidence is
much higher in children with sarcoma or any of the hematologic malignancies.94
In the child with a bleeding diathesis, the anesthesiologist may be required to
transfuse fresh frozen plasma (FFP), cryoprecipitate, or factor concentrates. FFP is
warranted if the child has documented prolongation of prothrombin or partial throm-
boplastin time or has surgical bleeding despite normal platelet levels and function.95
However, FFP is ineffective for reversing the coagulation factor deficiencies induced
by L-asparaginase.96 FFP should be ABO-compatible and leukoreduced.86 Transfu-
sion of cryoprecipitate and factor concentrates should be guided by laboratory values
and possibly in discussion with a hematologist.
Children with ongoing thrombosis may be on chronic anticoagulation, which may be

required to be stopped or reversed before surgery. Perioperative consideration of the
balance between the risk of thrombosis and anticoagulation-induced bleeding should
be discussed with the child’s hematologist-oncologist.54
OTHER CONSIDERATIONS IN THE CHILD WITH CANCER

Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is an uncommon but potentially lethal oncologic emer-
gency. TLS is the acute destruction of tumor cells and the subsequent release of
cellular components sufficient to overcome the excretory capacity of the body.
Resultant ARF can lead to additional organ failure and death. TLS is most common
with the hematologic malignancies, especially ALL and Burkitt lymphoma, but can
occur with nonhematologic tumors that have a high proliferative rate, large tumor
burden, or high sensitivity to cytotoxic therapy.97 Although TLS can occur sponta-
neously, especially in children with AML, it most often occurs early in the disease
after induction of chemotherapy or during radiation therapy, fever, surgery, or anes-
thesia.97 Several reports exist of TLS occurring in children under anesthesia,
including 1 fatality.98
Children at risk of TLS should receive adequate perioperative hydration to lessen
the impact of TLS. Children at high risk should receive aggressive preoperative pro-
phylaxis with hydration, rasburicase, and allopurinol. With such patients, the perioper-
ative plan should be discussed with the child’s oncologist before the day of surgery.99
Dexamethasone is a known trigger of TLS, and the child’s oncologist should be
consulted before giving intraoperative corticosteroids to a child at risk of TLS.98
Retinoic Acid Syndrome

Retinoic acid syndrome (RAS) is seen in 2% to 27% of patients with acute promyelo-
cytic leukemia who receive induction therapy with all-trans retinoic acid (ATRA). RAS is
fatal in 2% of those who develop it. Primary symptoms are respiratory distress and fe-
ver, but weight gain, pulmonary infiltrates, pleural and pericardial effusions, hypoten-
sion, cardiac failure, and ARF can occur.100,101
Neurocognitive and Psychiatric Changes

Neurocognitive changes are common and continue years after cancer therapy. All
components of neurocognitive testing can be abnormal, including executive function
and academic achievement.102 Although the cause is likely multifactorial, intrathecal
methotrexate and cranial irradiation seem to lead to the greatest deficits, and thus sur-
vivors of central nervous system tumors, head and neck sarcomas, and ALL are at
greatest risk.103
The response of the child to the diagnosis of cancer and its initial treatment depends
on many factors, including the age of the patient, preexisting psychological dysfunc-
tion, and support from family and friends. Preschool and young school-aged children
are very affected by parental separation, body boundaries, fears of disfigurement, and
anticipation of painful procedures during their hospitalization. The coping mechanism
at this age is varied, including anxiety, panic, regression, psychosomatic complaints,
or stoic acceptance. Children at this age deserve, and often need, an honest discus-
sion of the upcoming procedure to allow them a greater sense of control and under-
standing of their medical management. However, special preparations are frequently
helpful, including role-playing or desensitization of the operating room environment,
mask induction, and so forth.38
206 Latham
Adolescents diagnosed with or undergoing treatment with cancer are profoundly

affected by the impact of their diagnosis. Caught in the transition from childhood to
attaining greater independence in life, reliance on and compliance with the medical treat-
ments are often difficult for the adolescent. To the greatest extent possible, these chil-
dren should be given the opportunity to regain control and be active participants in
their care, including cosigning of consents (assent), informed discussion of the proce-
dure and risks, and discussion of the expected effects of the anesthetic and procedure.38
Pain
Children with cancer live with significant pain. In a survey of 160 children 10 to 18 years
old undergoing cancer treatment, 87% of the inpatients and 75% of the outpatients
rated their pain as moderate to severe.104 Although antitumor therapy–related pain
is the most common cause of pain in children with cancer, children reported in a sur-
vey that the single greatest painful episode during their cancer treatment was a med-
ical procedure or surgery. The only variable that led to reduced pain scores from
painful medical procedures was the use of general anesthesia during lumbar punc-
tures and bone marrow biopsies.38,105
Therefore, anesthesiologists who care for these children likely have a key role in be-
ing able to reduce what has been reported as the most severe pain during cancer
treatment. Several general anesthetic techniques can be administered for these brief
but painful procedures. Although mask anesthesia with or without intravenous access
can be used, these children usually have central access. Therefore, total intravenous
anesthetic techniques with supplemental oxygen are commonly used for lumbar
punctures and bone marrow biopsies, including propofol, propofol and ketamine, pro-
pofol and opiate (fentanyl, alfentanil, or remifentanil), or midazolam and ketamine.38
Children with cancer who experience chronic pain benefit from a multimodal
approach to perioperative analgesia. Opioid tolerance must be assessed and appro-
priately managed when providing perioperative opiates. Regional anesthesia can be
advantageous, but additional risks exist in children with cancer. The primary concern
is the presence of an inherent coagulopathy or therapeutic anticoagulation and the
risk of bleeding with a regional procedure, especially an epidural hematoma.
Chemotherapy-induced neuropathy may be considered a relative contraindication
to regional anesthesia. Therefore, a preoperative neurologic evaluation and special
discussion of potential risks and benefits of regional anesthesia are warranted.106
Overall, discussion between anesthesia, oncology, surgery, and pain service pro-
viders is recommended to formulate the optimal perioperative analgesic plan for chil-
dren with cancer undergoing major surgery.
PREOPERATIVE LABORATORY EVALUATION
As is true for children without cancer, there is insufficient evidence to recommend any
routine preoperative laboratory testing in children with cancer. The decision to obtain
tests should be guided by the history, physical examination, concurrent illnesses,
known abnormalities, and whether such testing will augment safe perioperative man-
agement of the child.
Evidence-based guidelines are not available to guide the decision of whether a
complete blood count is needed or how recent a test is needed before surgery in
children. Determination of the need for a complete blood count should include the
condition of the patient, presence of comorbidities, proposed surgical procedure
and potential blood loss, potential thrombocytopenia, attendant risk of prolonged
bleeding, and known or suspected anemia.38
Children at risk for anemia include38:

New diagnosis of leukemia (50%–80% incidence) or lymphoma
Recent chemotherapy, radiation therapy, or HSCT
Children with cancer and age less than 6 months
Children at risk for hyperleukocytosis include any new diagnosis of leukemia
(>20% incidence)
Children at risk for leukopenia and neutropenia include any child receiving
aggressive chemotherapy or irradiation
Children at risk for thrombocytopenia include38:
New diagnosis of leukemia
Any child receiving aggressive chemotherapy or irradiation
Disseminated intravascular coagulation
Splenomegaly
The need for preoperative coagulation testing is not well defined in this patient pop-
ulation. If the platelet count is sufficient for the type of surgery and there is no clinical
evidence of bleeding, then testing is probably not required. Testing may be considered
for children with conditions that are known to cause a coagulopathy, including38:
Sepsis
Vitamin K deficiency or malnutrition
Hyperleukocytosis
L-Asparaginase treatment
Diagnosis of T-cell acute lymphoblastic leukemia, myelomonocytic leukemia, or
acute promyelocytic leukemia
Electrolyte testing should also be driven by the history and physical examination.
Conditions that can lead to electrolyte derangements include38:
SIADH
Hypercalcemia (bone tumors and neuroblastoma)
Intracranial disorder with altered level of consciousness
Dehydration or malnutrition
Aggressive hydration
Renal dysfunction
Recent TLS (hyperkalemia, hyperphosphatemia, hypocalcemia)
SUMMARY
Childhood cancers pose a wide array of challenges for the anesthesiologist caring for
children. The unique interplay among the direct effects of the tumor, complex pharma-
cologic management, and potentially extensive physiologic derangements mandates
a firm knowledge of each of these components to best formulate an anesthetic plan
that is appropriate for the individual patient and type of procedure. The considerations
described in this article also provide many opportunities for collaboration between the
anesthesiologist, oncologist, and surgeon to optimize perioperative outcomes for chil-
dren with these disorders.
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Anesthesia for Craniofacial
S u r g e r y in In f a n c y
Paul A. Stricker, MD*, John E. Fiadjoe, MD
KEYWORDS
Craniofacial surgery Craniosynostosis Pediatrics Transfusion Endoscopic
KEY POINTS
Complex cranial vault reconstruction remains a significant challenge for anesthetic
management.
Primary concerns include blood loss and its management.
Evolution of procedures to treat craniosynostosis has resulted in improvements in periop-
erative morbidity with less blood loss and shorter operations and length of hospital stays.
An understanding of the procedures performed to treat craniosynostosis is necessary to
provide optimal anesthetic management.
INTRODUCTION
Craniosynostosis is a disorder of skull development that occurs as a result of the pre-

mature fusion of one or more cranial sutures, occurring with an incidence of approx-
imately 1 in 2000 live births. The observed deformity relates to which sutures are
affected, with characteristic deformities associated with specific suture involvement
(Fig. 1). Although the relationship between craniofacial dysmorphism and fusion of
the cranial sutures was observed earlier, Virchow (1851)1 was the first to formally
describe many of the more common specific abnormalities, and in particular, he
was the first to describe the arrest of skull growth that occurs in a direction perpendic-
ular to the affected suture.
Craniosynostosis most commonly presents as an isolated abnormality but can pre-
sent as a component of an identified syndrome or genetic disorder (15%–40% of
cases (Table 1)). Ongoing research will likely reveal genetic causes of cases currently
thought to be isolated or idiopathic. In most infants, the abnormality is congenital and
diagnosed within the first few months of life, whereas some infants may present later.
The diagnosis is most commonly made based on the phenotype of skull deformation.
Department of Anesthesiology and Critical Care, Children’s Hospital of Philadelphia and the
Perelman School of Medicine at the University of Pennsylvania, 34th Street and Civic Center
Boulevard, Philadelphia, PA 19104, USA
E-mail address: strickerp@email.chop.edu

216 Stricker & Fiadjoe
Fig. 1. Depictions of characteristic skull deformities associated with different forms of cra-
niosynostosis. (A) Plagiocephaly caused by unicoronal synostosis (approximately 20%–25%
of craniosynostosis). (B) Trigonocephaly caused by metopic synostosis accounts (approxi-
mately 5%–15% of craniosynostosis). (C) Scaphocephaly caused by sagittal synostosis, the
most common form of nonsyndromic craniosynostosis (40%–55% of synostosis). (D) Bicoro-
nal synostosis is less common and more likely associated with syndromic craniosynostosis.
(From Seruya M, Magge S, Keating R. Diagnosis and surgical options for craniosynostosis.
In: Ellenbogen RG, Abdulrauf S, Sekhar L, editors. Principles of neurologic surgery. 3rd edi-
tion. St Louis (MO): Saunders; 2012. p. 138; with permission.)
Subsequent CT scanning and 3-D reconstruction allow for accurate diagnosis of spe-
cific suture involvement and can be used for surgical planning (Fig. 2). Untreated cra-
niosynostosis can lead to elevated intracranial pressure (ICP) and disturbances in
intellectual and neurologic development. Syndromic craniosynostosis is more
commonly associated with multiple suture involvement and is also more often associ-
ated with increased ICP. Children with syndromic craniosynostosis also require mul-
tiple operations throughout infancy and childhood.
From both a cosmetic and neurodevelopmental perspective, optimal outcomes are
achieved when these procedures are performed before a year of age, and earlier sur-
gical intervention may translate to a less extensive operation. Surgical treatment of
craniofacial dysmorphism associated with craniosynostosis was principally pioneered
by Dr Paul Tessier. Dr Tessier presented his initial work in 1967 and went on to train
the first generation of craniomaxillofacial surgeons. As a result, Dr Tessier is widely
regarded as the father of modern craniofacial surgery. The development of these sur-
gical techniques has led to dramatic improvements in cosmetic, neurodevelopmental,
and psychosocial outcomes in children afflicted by these conditions.2,3
Table 1
Selected craniosysnostosis syndromes
Genetic Mutation
Disorder Locus Inheritance Pattern Incidence Associated Features
Apert syndrome FGFR2 Most cases sporadic de novo w1 in 65,000 Midface hypoplasia, maxillary retrusion,
(acrocephalosyndactyly) (chromosome 10) mutations, autosomal dominant, proptosis, hypertelorism, syndactly, cleft
affects males/females equally palate. Can be associated with intellectual
disability but intelligence can be normal.
Crouzon syndrome FGFR2 Autosomal dominant, de novo w1 in 60,000 Midface hypoplasia, maxillary retrusion,
(chromosome 10) mutations, affects proptosis, hypertelorism, strabismus, beaked
males/females equally nose, often normal intelligence.
Pfeiffer syndrome FGFR 1 Autosomal dominant, de w1 in 100,000 Midface hypoplasia, maxillary retrusion,
(chromosome 8), novo mutations, affects nasopharyngeal stenosis, proptosis,
Anesthesia for Craniofacial Surgery in Infancy

FGFR2 males/females equally hypertelorism, strabismus, beaked nose,
(chromosome 10) hearing loss, partial syndacylty, cartilaginous
tracheal sleeve, broad thumbs and great toes,
often normal intelligence.
Saethre-Chotzen syndrome TWIST Majority familial autosomal w1 in 25,000– Short stature, hypertelorism, facial asymmetry,
(acrocephalosyndacytly (chromosome 7) dominant, de novo mutations 50,000 hearing loss, low frontal hairline, ptosis, mild
type III) possible, phenotype can be partial syndactyly, usually normal intelligence.
mild, affects males/females
equally
Muenke syndrome FGFR3 Autosomal dominant, 61% w0.8–1 in Unicoronal or bicoronal synsostosis, ptosis,
(FGFR3-related (chromosome 4) de novo mutations, affects 10,000 hypertelorism, high-arched palate, facial
craniosynostosis) males/females equally asymmetry, abnormalities of phalanges
without syndactyly, developmental delay in
approximately one-third of cases.
Data from Refs.77–83
217
Fig. 2. (A) Preoperative 3-D CT reconstruction image from an infant with right unicoronal
synostosis. Note ipsilateral orbital retrusion and contralateral frontal bossing. (B) Preopera-
tive 3-D CT reconstruction image of an infant with metopic synostosis.
Together with the development of these extensive procedures have come sig-
nificant challenges for anesthetic management. Early reports revealed major peri-
operative complications, including massive hemorrhage, airway complications,
infection, and death.4–6 These morbidities persist in the current era (although at lower
rates), with complications relating to massive blood loss of greatest concern to
anesthesiologists.7–11
The psychosocial implications of untreated craniosynostosis are tremendous.
Throughout history, and even today, children with significant craniofacial deformities
have been ostracized and excluded from society. Consequently, normalization of skull
shape, although “cosmetic,” has a tremendous and lasting impact on a child. This
review explores some of the current procedures performed in this population and
approaches to anesthetic management.
CURRENT SURGICAL APPROACHES TO CRANIOSYNOSTOSIS
As with any complex procedure, a firm understanding of the surgical procedure per-
formed is necessary to provide optimal anesthetic management. A description of
the most common procedure types follows, with attention to elements relevant to
anesthesiologists.
Open Strip Craniectomy and the Modified Pi Procedure

Craniectomy to treat craniosynostosis was described as early as 1890 and 1892 by
Lannelongue and Lane.12–14 Simple strip craniectomies in which the cranial stenotic
suture is excised alone do not result in good cosmetic outcomes and are rarely per-
formed. Instead, for the most common deformity of isolated sagittal synostosis, the
modified pi procedure or a variant thereof is performed (Fig. 3).15 Although traditional
anesthetic management of intracranial procedures involves invasive arterial pressure
Fig. 3. Modified pi procedure. This procedure involves a scalp incision with exposure of the
stenotic suture and adjacent calvarium. (A) Shows the exposed cranial vault with the areas
of bone to be excised adjacent to the stenotic suture marked with methylene blue. (B)
Shows the bone that has been removed (note the resemblance to the Greek letter pi). (C)
Shows the cranium after these osteotomies. (From Seruya M, Magge S, Keating R. Diagnosis
and surgical options for craniosynostosis. In: Ellenbogen RG, Abdulrauf S, Sekhar L, editors.
Principles of neurologic surgery. 3rd edition. St Louis (MO): Saunders; 2012. p. 149; with
permission.)
monitoring, some anesthesiologists manage these cases without an arterial cath-

eter.16 Adequate venous access is vital; 22-gauge or larger catheters are preferred
for blood administration. Careful attention must be paid to proper positioning of these
small infants. Other concerns relevant to children in this age group should be
addressed, including selection of the appropriate endotracheal tube size and attention
to blood glucose levels. Small size and blood volume coupled with the timing of these
operations at the physiologic hemoglobin nadir puts these infants at high risk of
needing transfusion, and most are transfused.
Endoscopic Strip Craniectomy and Postoperative Helmet Therapy

In 1996–1998, Jimenez and Barone14 described the novel approach of excision of the
stenotic sagittal suture followed by parietal barrel-stave osteotomies through two
small incisions using an endoscope. For sagittal synostosis, a small incision is
made over the anterior fontanelle and over the lambdoid. The scalp is then dissected
off the cranium in a subgaleal plane over the stenotic suture and extended parietally.
Under endoscopic visualization, the dura is dissected off the underside of the cranium
over the same area. The stenotic suture is then excised using bone cutting scissors,
followed by performance of parietal barrel stave osteotomies. The incisions are then
closed and the child is fitted postoperatively for a cranial molding helmet.
The principal advantage of the endoscopic approach is the use of smaller incisions
and minimization of blood loss, often allowing for transfusion to be avoided.17 In addi-
tion, shorter hospital stays are realized, with many infants discharged on the first post-
operative day.18 Most importantly, satisfactory cosmetic results compared with
traditional modified pi procedure are achieved.
After endoscopic surgery, infants wear cranial molding orthotics (helmets) for
approximately 6 months to promote normalization of skull shape with subsequent brain
growth and skull development (Fig. 4). These endoscopic procedures are most often
performed to treat isolated sagittal synostosis in infants under 6 months but they can
also be performed in infants with other suture involvement.19 Although blood loss is
typically minimal and transfusion can often be avoided, there is potential for inadvertent
dural venous sinus entry or emissary vein disruption and significant hemorrhage. These
children should, therefore, have preoperative laboratory testing that includes a hemo-
globin/hematocrit measurement and a specimen for blood typing and cross-matching.
Fig. 4. Infant wearing a custom cranial molding helmet after endoscopic strip craniectomy.
(From Kaufman BA, Muszynski CA, Matthews A, et al. The circle of sagittal synostosis sur-
gery. Semin Pediatr Neurol 2004;11:243–8; with permission.)
Preparation for hemorrhage should include two peripheral intravenous catheters, and
packed red blood cells (PRBCs) should be immediately available.
Spring-Mediated Cranioplasty
Although endoscopic strip craniectomy has the benefits of very low transfusion rates,
small incisions, and short hospital stays, the principal drawback is the need for
months of postoperative helmet therapy. In the mid-1980s, the concept of using
springs to promote skull expansion was developed in an animal model20 and later
applied to infants with isolated sagittal synostosis by Lauritzen and colleagues in
1998.21 Subsequent reports on larger series of children revealed good surgical results
with low perioperative morbidity.22,23 These procedures involve a scalp incision fol-
lowed by surgical exposure of the length of the involved suture followed by simple
strip craniectomy. Springs calibrated to deliver a specific force are then inserted be-
tween the cut edges of bone (Fig. 5) or into drill holes lateral to the osteotomy and the
incision is closed. The forces applied by the springs result in cranial expansion
perpendicular to the excised suture and normalization of skull shape with subsequent
growth.
Similar to endoscopic strip craniectomy, spring-mediated cranioplasties are most
commonly performed for isolated sagittal synostosis, and often can be done without
the need for transfusion. Patients are ideally under 6 months of age. These children
return for a second operation approximately 6 months after the initial surgery to
have the springs removed. The need for a second operation is the principal disadvan-
tage of this procedure. Anesthetic management is similar to that for endoscopic strip
craniectomy. These infants can often be discharged home on postoperative day 1.
Similar to endoscopic procedures, shorter hospital stays and shorter operating times,
together with less intraoperative blood loss and very low transfusion rates, have been
reported.24
Fig. 5. Spring-mediated cranioplasty. (A) View showing surgical exposure and cranium after
strip craniectomy of sagittal suture. (B) View of springs in place with excised cranial bone
strip beneath springs. (C) Patient prepped at follow-up operation for spring removal.
Note normal skull shape with correction of scaphocephaly.
Complex Cranial Vault Reconstruction

Infants with nonsagittal synostosis, infants with sagittal synostosis with a late presen-
tation, and infants with syndromic craniosynostosis all have significant cranial vault
deformities for which optimal surgical results are achieved with complex cranial vault
reconstruction. These procedures are typically performed in older infants between 6
and 12 months of age. Some children who previously underwent treatment of sagittal
synostosis may have residual cranial deformity that requires a subsequent operation.
Children with syndromic craniosynostosis usually require multiple operations as they
grow. In addition to concerns about the effects of untreated craniosynostosis and
elevated ICP, complete reossification of the cranial vault defects that are created
during these procedures is more likely the younger the child is at the time of operation;
the potential for residual postoperative bony defects increases as the age of the child
increases after 1 year of age (Fig. 6). Complex cranial reconstructions include total
calvarial reconstruction, fronto-orbital advancement, and posterior cranial vault
reconstruction.
Total calvarial reconstruction

At some centers, total calvarial reconstructions are performed. For this procedure, in-
fants are typically placed in the modified prone or sphinx position, where the child is
prone but with the head and neck extended. As its name suggests, it is an extensive
procedure and its association with problematic complications has led the approach to
be abandoned at many centers in favor of sequential operations separated by an in-
terval of several months (eg, fronto-orbital advancement followed by posterior cranial
vault reconstruction). Complications include massive hemorrhage and venous air
embolism from the elevated head position. The sphinx position may also cause
venous outflow obstruction that promotes both edema and bleeding.
Fronto-orbital advancement and reconstruction

Fronto-orbital advancement and reconstruction are performed for infants with
metopic, unicoronal, bicoronal, and multiple-suture craniosynostosis. These proce-
dures are done in the supine position and involve a wide bicoronal incision followed
by a frontal craniotomy and removal of the orbital bandeau (Figs. 7 and 8). The excised
bones are then cut, shaped, repositioned, bent, and replaced using wires or reabsorb-
able plates and screws to achieve the desired result depending on the preoperative
deformity (Fig. 9).
Fig. 6. Preoperative 3-D CT reconstruction showing residual bony defects in the skull in a
child with syndromic craniosynostosis who has undergone prior craniofacial surgery. A ven-
triculoperitoneal shunt is also present.
Epinephrine solutions (with or without local anesthetic) are often infiltrated in the
scalp to promote hemostasis. Other techniques include application of scalp clips
and temporary locking scalp sutures that are placed anterior and posterior to the inci-
sion that have a tourniquet effect on the scalp. Although bleeding can occur during
scalp dissection and exposure of the calvarium (particularly if the dissection is in
the subperiosteal plane rather than subgaleal plane), the period of greatest risk for
bleeding (and air embolism) is during the frontal craniotomy and during the osteoto-
mies for removal of the orbital bandeau. Once the osteotomies have been completed
and hemostasis obtained, the potential for catastrophic hemorrhage generally
subsides.
Fig. 7. Bicoronal scalp incision for fronto-orbital advancement. The incision is made zigzag
rather than straight so the scar is later hidden by hair.
Fig. 8. Intraoperative view after scalp dissection and exposure of the calvarium in the same
infant in Fig. 7 with metopic synostosis. The prominent metopic ridge can be seen between
the surgeon’s fingers.
When a surgeon is operating near the orbits, the oculocardiac reflex may be trig-
gered and bradycardia observed. This usually requires no treatment because there
are typically no worrisome invasive blood pressure changes. If necessary, simply hav-
ing the surgeon release pressure stops the reflex. Occasionally, the reflex is problem-
atic and an anticholinergic may be administered to allow the surgeon to continue
operating in this area.
Posterior cranial vault reconstruction

Posterior cranial vault reconstructions are performed in infants with late presentation
sagittal synostosis, children with residual deformity from sagittal synostosis treated in
Fig. 9. Postoperative 3-D CT reconstruction after fronto-orbital advancement in an infant

with metopic synostosis. The reconstructed cranial bones from the bifrontal craniotomy
are labeled A and the reconstructed orbital bandeau is labeled B.
early infancy, and children with syndromic craniosynostosis. These procedures are
done in the prone position, and a bicoronal incision is made as in fronto-orbital
advancements. After scalp dissection for cranial exposure, a neurosurgeon removes
a posterior cranial bone flap. Barrel stave osteotomies are performed laterally and
inferiorly along the edges of the craniotomy to allow for release and expansion of
the cranial vault. The bone flap is then cut, shaped, repositioned, and replaced and
anchored with wires or reabsorbable plates and screws. Concerns for anesthesiolo-
gists are similar to those for fronto-orbital advancement, with additional concerns
related to prone positioning.
PREOPERATIVE PREPARATION
In addition to surgical planning, infants and children undergoing these procedures

require a thorough medical evaluation as well as laboratory testing prior to surgery.
Most infants presenting with nonsyndromic forms of craniosynostosis are otherwise
healthy and require little preoperative preparation beyond appropriate laboratory
testing. Preoperative laboratory testing for all children should include a complete
blood cell count (hemoglobin, hematocrit, and platelet count) and a specimen for
type and screen (at a minimum); in most cases, in particular, open procedures,
cross-matching of blood is necessary.
Even those procedures associated with low rates of transfusion carry a risk of unan-
ticipated hemorrhage, and appropriate preparation is warranted. This is especially true
of younger infants undergoing these procedures, who are able to tolerate only small
volumes of blood loss. A coagulation profile is routinely ordered at many centers (pro-
thrombin time [PT]/international normalized ratio [INR], partial thromboplastin time
[PTT]). The cost-effectiveness and value of preoperative coagulation testing can be
questioned. One argument in favor of such testing is that these infants have little his-
tory for identifying a bleeding tendency.
Infants with syndromic craniosynostosis may have associated abnormalities that
affect the perioperative period. For example, midface hypoplasia and retrusion
may cause obstructive sleep apnea and postoperative airway obstruction such
that postoperative tracheal intubation and mechanical ventilation may be indicated.
Children with severe airway obstruction may require or may present with a
tracheostomy.
SPECIFIC INTRAOPERATIVE CONCERNS

Hemorrhage
The most recent report from the Pediatric Perioperative Cardiac Arrest Registry demon-
strated the most common cardiovascular cause of cardiac arrest in children was hypo-
volemia, often from hemorrhage during procedures involving a craniotomy.25 Complex
cranial vault reconstructions involve large scalp incisions followed by large craniot-
omies. Large surgical areas and cranial bone cuts result in large surface areas for
bleeding to occur. Infants undergoing open cranial remodeling procedures commonly
sustain blood losses in excess of the circulating blood volume,11,26,27 and blood losses
up to 5 times the circulating blood volume have been described.27 In addition to steady
blood loss that occurs during the procedure, precipitous hemorrhage can also occur
with inadvertent dural venous sinus tears or disruption of large emissary veins.
Venous Air Embolism
Having a surgical incision, in particular, cut edges of the cranial table at a level above
the heart, creates a risk of venous air embolism. The incidence of venous air embolism
during these cases is high (83%); however, a vast majority of these episodes are clin-
ically silent (Doppler tone changes only) and not associated with hemodynamic
compromise.28 Venous air embolism can also occur during endoscopic procedures;
however, the incidence seems much lower (8%) and is infrequently associated with
hemodynamic instability.29
Intracranial Hypertension
Children may present with evidence of elevated ICP, diagnosed by ophthalmic exam-
ination or CT scan or inferred from nonspecific findings, such as headaches in older
children. Elevated ICP is common in syndromic craniosynostosis with multiple suture
involvement (47%). Increased ICP may be also present in as many as 14% of infants
with isolated single-suture synostosis.30 Despite these incidence rates, a majority of
these children present as outpatients and, in the absence of overt symptoms, an
inhaled induction of anesthesia can usually be performed while other principles of
management of ICP are otherwise adhered to.
Hypothermia
Intraoperatively, the large surface area of an infant’s head coupled with its high perfu-
sion, together with anesthetic effects and administration of large volumes of cool intra-
venous fluids, can result in hypothermia. With the proper measures in place,
hypothermia can be prevented, but it requires attention by the team. Active warming
techniques include forced air convection blankets, circulating warm water mattresses,
overhead radiant lights, and fluid warmers. Even mild hypothermia (less than 36 C) im-
pairs coagulation enzyme function and is associated with increased bleeding and
transfusion31; therefore, it is imperative that management be directed to prevent it.
Positioning and Eye Protection
Many craniofacial procedures are lengthy and careful attention to proper patient posi-
tioning is important. During cranial vault reconstruction procedures in the supine po-
sition, surgeons may prefer that the eyes not be taped closed because the eyes are
within the surgical field. Ophthalmic ointment should be applied and careful attention
paid to the vulnerable eyes by all members of the team. Ophthalmic ointment should
be periodically reapplied. Children with syndromic forms of craniosynostosis can have
proptosis so severe that full eyelid closure is difficult. In these cases, the surgeons may
perform tarsorrhaphies. Infants undergoing procedures in the prone position are
placed in a horseshoe headrest. The head must be positioned and the headrest
configured to ensure there is no pressure on the orbits or other pressure points. Satis-
factory positioning should be periodically reassessed throughout the operation.
INTRAOPERATIVE MANAGEMENT
Induction, Airway Management, and Anesthetic Maintenance
An inhaled induction of anesthesia is most commonly performed. Children with signs
or symptoms of significant ICP elevation may benefit from an intravenous anesthetic
induction. Administration of a muscle relaxant facilitates laryngoscopy, tracheal intu-
bation, and vascular access and prevents coughing and movement during positioning.
Orotracheal intubation using a standard tracheal tube is preferred. Some anesthesiol-
ogists place a nasotracheal tube for infants in the prone position because they think it
is more secure. Although an oral RAE tube can be placed, the preformed bend can
make intraoperative tracheal suctioning difficult, and selecting the proper tube for
both length (location of the preformed bend) and diameter may be particularly chal-
lenging in younger infants. In general, RAE tubes are unnecessary and not worth the
extra trouble. Anesthesia is typically maintained with an inhaled anesthetic in air and
oxygen. Because of the risk of venous air embolism, nitrous oxide is avoided as is
spontaneous/negative pressure ventilation. Opioids are administered by bolus or by
infusion; some anesthesiologists supplement the anesthetic with a dexmedetomidine
infusion.
Peripheral Venous Access

All infants should have at least 2 peripheral intravenous lines when possible, preferably
22 gauge or larger. Blood products should be administered through large bore periph-
eral intravenous lines rather than through a central line, because peripheral adminis-
tration allows potentially high potassium content as well as citrate to mix and be
diluted before it returns to the heart.
Arterial Catheter
Invasive arterial pressure monitoring is generally recommended for intracranial proce-
dures because it allows for the immediate detection of hypotension and for frequent
blood sampling. An arterial catheter also allows for postoperative blood sampling.
Central Venous Catheter

Some centers routinely insert central venous catheters for children undergoing com-
plex cranial vault reconstruction procedures to measure central venous pressure to
guide fluid and transfusion management, whereas most reserve their use in these pro-
cedures for children in whom adequate peripheral access is difficult to obtain.16
Precordial Doppler
A precordial Doppler can be used for the detection of venous air embolism. This
monitor is a simple and effective noninvasive monitor for air embolus detection.
Because this monitor is so sensitive and because most episodes are clinically silent,
however, the majority of anesthesiologists do not use a precordial Doppler.16,28
MANAGEMENT OF MASSIVE HEMORRHAGE
Complications of massive hemorrhage not only relate to the immediate concerns of

hypovolemia but also the sequelae of imperfect replacement with crystalloids, col-
loids, and blood components. These sequelae include metabolic acidosis, dilutional
coagulopathy, thrombocytopenia, hyperkalemia (from high potassium content of
stored PRBCs), hypocalcemia (citrate toxicity), and hypothermia.
Rapid administration of PRBCs with prolonged storage, particularly in the setting of
hypovolemia, can result in hyperkalemic cardiac arrest.25,32 The potassium concen-
tration in a unit of PRBCs increases in a linear fashion with time. Irradiation of blood
drastically accelerates the transmembrane leakage of potassium from stored red
blood cells.33 In a recent advisory statement the Wake up Safe group recommends
using PRBCs less than 7 days from collection or PRBCs that have been washed
and resuspended in saline to minimize the risk of hyperkalemia in scenarios where
massive hemorrhage is antcipated.34
When blood loss is replaced with crystalloid and PRBCs, coagulopathy resulting
from dilution of soluble clotting factors develops after approximately 1.2 blood vol-
umes have been lost, and fresh frozen plasma (FFP) transfusion is indicated.35 In a
recent assessment of the authors’ practice, where median and average blood losses
have been in excess of a blood volume, replacement with crystalloid and PRBCs was
associated with a high incidence (24%) of postoperative dilutional coagulopathy.11
Over that time period, intraoperative FFP was administered once coagulopathy was
identified either by laboratory or clinical evidence, consistent with current American
Society of Anesthesiologists practice guidelines.11 In response to the findings in this
review, the authors implemented a practice in which FFP is administered prophylac-
tically together with PRBCs in a 1:1 ratio (1 unit of FFP:1 unit of PRBCs). Implemen-
tation of this practice resulted in near elimination of postoperative dilutional
coagulopathy.36 The number of blood donor exposures was minimized by using
FFP from the same blood donors from whom the PRBC units were obtained.
Another option for blood loss replacement is whole blood. Replacement with whole
blood provides coagulation proteins in addition to red blood cells. Beyond the
simplicity of replacing blood loss with whole blood, whole blood has the advantage
of replacing red blood cell loss and coagulation factors without the need for additional
blood donor exposures that would be required using traditional component therapy.
Also, refrigerated whole blood contains platelets. Although platelets contained in
refrigerated whole blood are cleared rapidly from the circulation after transfusion,
they have intact coagulation function as assessed by in vitro testing and may be
able to participate in coagulation after transfusion.37 Refrigerated whole blood retains
coagulation activity, as measured in vitro testing, within normal limits for up to 14 days
of storage.38 Unfortunately, the availability of whole blood is often limited.
Another technique to be considered in the setting of replacement of significant
blood loss is administration of fibrinogen concentrate. In a variety of settings,
decreased perioperative blood loss has been correlated with higher fibrinogen
levels.39,40 Haas and colleagues41 demonstrated that fibrinogen replacement using
fibrinogen concentrate was effective in maintaining normal hemostatic function in in-
fants undergoing craniofacial surgery, without the need for FFP transfusion. Fibrin-
ogen concentrate is a lyophilized, purified, pasteurized product that has several
advantages, including pathogen inactivation and elimination of infectious disease
transmission risk, ability to be stored for prolonged periods before reconstitution
and administration, and the ability for precise dosing. High cost may be a disadvan-
tage, although preventing transfusion of other hemostatic blood products may
outweigh this.
The off-label use of recombinant activated factor VII has been described as a
rescue measure in a variety of settings with massive hemorrhage, including cranio-
facial surgery.42 Acidosis, hypothermia, thrombocytopenia, and hypofibrinogenemia
all impair the efficacy of recombinant factor VIIa and should be corrected to maxi-
mize efficacy. Off-label use of recombinant activated factor VII has been associated
with significant thrombotic complications; therefore, its use should be reserved for
life-threatening situations in which all other methods of achieving hemostasis have
failed.
ASSESSMENT OF INTRAVASCULAR VOLUME STATUS
One of the greatest challenges of complex cranial vault reconstruction and open cra-
niectomy procedures is the accurate identification of blood loss and its timely replace-
ment. It is often impossible to accurately estimate ongoing losses because blood
seeps into and underneath surgical drapes, mixes with irrigation fluid, or is otherwise
difficult to account for in surgical sponges (Fig. 10).
Intravascular volume status is assessed most commonly through invasive arterial
pressure measurement in combination with invasive arterial pressure waveform
assessment. There is a body of evidence supporting the efficacy of using changes
in variability in pulse pressure/systolic pressure with positive pressure ventilation
Fig. 10. Intraoperative photographs from the right (A) and left (B) sides of the same infant
showing blood loss soaked into drapes. Accurate quantification of losses is not possible.
as a tool to direct fluid management in adults. There are conflicting data, however,
supporting the applicability of this technique to infants and children.43 Qualitative
waveform assessment has traditionally been done; more recently, software and
equipment have become available that can perform continuous automated quantita-
tive measurement of these parameters. The utility of these devices in infants remains
largely unexplored.
Some anesthesiologists use central venous pressure monitoring in addition to these
methods (discussed previously) for guiding fluid and transfusion therapy. In adults,
central venous pressure performs poorly compared with other measures for predicting
fluid responsiveness.44 The authors’ results showed that the implementation of central
venous pressure monitoring in infants undergoing complex craniofacial reconstruction
was not associated with a reduction in the incidence or duration of hypotension.45 The
authors also found that changes in heart rate (tachycardia) are not a valuable indicator
of hypovolemia in infants undergoing complex craniofacial surgery.46
Ultimately, constant vigilance remains the best tool for successful assessment of
intravascular volume status and prevention of hypovolemia, and in practice all avail-
able clinical data are combined to guide fluid administration. This includes direct
observation of the surgical field and directing close attention to the invasive blood
pressure and waveform, central venous pressure (if monitored), response to fluid chal-
lenges, urine output, hemoglobin measurements, and blood gas assessments.
STRATEGIES FOR MINIMIZATION OF BLOOD LOSS AND TRANSFUSION
Although anesthesiologists have made notable efforts to reduce blood loss and trans-
fusion, overall the reductions achieved with these approaches are modest. The great-
est reductions have resulted from innovations in surgical technique (eg, endoscopic
strip craniectomy and spring-mediated cranioplasty). A wide variety of nonsurgical
techniques to minimize blood loss and transfusion in this population have been stud-
ied, including antifibrinolytic administration,47–49 cell salvage,27,50–53 acute normovo-
lemic hemodilution,54,55 preoperative erythropoietin,55–58 reinfusion of shed blood,27
administration of fibrinogen concentrates,41 and prophylactic administration of
FFP.59 Each of these carries its own risks, evidence of efficacy, and costs.
When transfusion minimization strategies are considered, it is important to evaluate
what the achieved reduction means in terms of patient risk. One of the key multipliers
of transfusion risk is the number of unique blood donor exposures. Each additional
blood donor exposure from a new unit of PRBCs results in additive risks for infectious
disease transmission and alloimmunization. For this reason, if the volume of transfu-
sion is reduced from 200 mL to 100 mL, there is no benefit for a patient because
the number of blood donor exposures has not been reduced.
Transfusion Protocols
Implementation of standardized transfusion protocols is a simple, inexpensive, and
effective strategy to safely minimize transfusion. Moreover, there is a body of scientific
evidence demonstrating efficacy. Standardized transfusion thresholds have been
shown to reduce red blood cell transfusion without an increased incidence of adverse
events in adult patients without cardiac disease,60 in critically ill children,61 and in
pediatric postoperative patients.62,63 The use of transfusion protocols has been rec-
ommended in pediatric craniofacial surgery.64,65 At the authors’ institution, the imple-
mentation of a postoperative transfusion protocol for both hemostatic blood products
(FFP, platelets, and cryoprecipitate) and PRBCs (Box 1) resulted in a 60% overall
reduction in postoperative transfusion.66 For these reasons, transfusion protocols
should be a first-line approach to safe transfusion minimization in this population.
Administration of Antifibrinolytic Agents

The antifibrinolytic drug, tranexamic acid, has been shown effective in reducing blood
loss and perioperative transfusion in children undergoing craniofacial surgery.18,48
There are also data demonstrating the efficacy of aprotinin47; however, this drug is
no longer available. Efficacy data in this population are currently not available for ami-
nocaproic acid (another antifibrinolytic with the same mechanism of action as tranexa-
mic acid), although there are data in adults suggesting comparable efficacy of the two
drugs.67–71
Administration of antifibrinolytics is an attractive strategy because they are simple to
administer, inexpensive, and there seems to be a low incidence of adverse events. The
results of one study showed that tranexamic acid was efficacious despite the lack of a
measurable difference in fibrinolytic activity on thromboelastography.49
Cell Salvage
Intraoperative cell salvage is a technique that may allow for reduction of transfusion in
infant craniofacial surgery. There is one randomized trial supporting the efficacy of cell
Box 1
Postoperative transfusion protocol used at the Children’s Hospital of Philadelphia
Indications for hemostatic blood product transfusion:

Platelet count <100,000
Fibrinogen <100 mg/dL
PT >18.7
PTT >45.7
INR >1.5
Indications for PRBC transfusion:
Hemoglobin <7.5 g/dL
Hemodynamic instability with ongoing blood loss
saver in combination with preoperative erythropoietin in children undergoing cranial

vault reconstruction.72 Other published evidence includes mostly retrospective
data.27,52,53,65,73
Implementation of cell salvage may require changes in draping and attention to
technique to maximize blood recovery. Special cell salvage machines are available
that can be used in infants. These machines require small initial volumes for process-
ing and are subsequently able to process blood as it is recovered. The principal draw-
backs of cell salvage are the equipment costs and the attention (and possibly
additional personnel) needed to operate the machine.
Administration of Preoperative Erythropoietin and Acute Preoperative Normovolemic

Hemodilution
The use of preoperative recombinant erythropoietin has been described as part of a
strategy to minimize transfusion in pediatric craniofacial surgery55–57; however, its cur-
rent use seems infrequent and limited to select patients.16 When administered, this
technique is often combined with acute preoperative normovolemic hemodilution
and other techniques to maximize efficacy. An evaluation of acute preoperative nor-
movolemic hemodilution using a mathematical model suggests that the blood savings
achieved with this method alone are modest at best.74
High cost and the need for multiple preoperative visits for injections and hemoglobin
surveillance are significant drawbacks of this therapy. Moreover, recent adult data
showing associations of recombinant erythropoietin with increased risk for stroke, hy-
pertension, vascular access thrombosis, and probably increased risk for death,
serious cardiovascular events, and end-stage renal disease75 have led the Food
and Drug Administration to apply a black box warning to these drugs in the United
States. For these reasons, use in pediatric craniofacial surgery remains limited.
Transfusion-free Perioperative Course in Infants Undergoing Complex Cranial

Reconstruction
Despite the literature replete with descriptions of significant bleeding and transfusion,
low transfusion rates in children undergoing complex cranial vault reconstruction are
possible. One group was able to achieve low transfusion rates in using simple surgical
techniques for achieving intraoperative hemostasis and accepting a low postoperative
hemoglobin value (7.0 g/dL).64 Another group has achieved low transfusion rates using
preoperative erythropoietin combined with preoperative autologous donation, intrao-
perative hemodilution, and cell salvage.50 A recent practice survey corroborates these
reports, with some centers self-reporting achieving a transfusion-free perioperative
course in some of these children.16
POSTOPERATIVE CARE
At the authors’ hospital, all children who have had a craniotomy as part of their proce-
dure are admitted to the ICU postoperatively. The duration of ICU stay varies between
institutions, but in many cases these children can be transferred to the general ward
on postoperative day 1. At some centers, children are admitted to the general ward
after endoscopic procedures and spring-mediated cranioplasties.
Postoperative pain is usually not severe, and intermittent opioids together with
acetaminophen provide satisfactory postoperative analgesia. Nearly all infants are
extubated in the operating room at the completion of surgery. Infants who may
require postoperative intubation and mechanical ventilation include infants in the
prone position for lengthy procedures with significant facial swelling and infants
with syndromic craniosynostosis who have significant preoperative obstructive sleep

apnea.
As discussed previously, transfusion protocols should be in place to guide transfu-
sion therapy in the postoperative period. Postoperative hyponatremia is common
(31% in one study) although direct complications from hyponatremia seem uncom-
mon.76 Other postoperative concerns include cerebrospinal fluid leaks and infection.84
SUMMARY
Normalization of skull shape from craniofacial surgery in infancy has a major and last-
ing impact on the life of a child. These operations involve risks, with the potential for
major intraoperative hemorrhage the primary concern for anesthesiologists. Optimal
anesthetic management involves preparation for blood loss replacement, proper posi-
tioning, and attention to the fundamentals of anesthetic management of infants.
Various methods have been used to reduce the amount of blood transfused in this
population. Simple techniques, such as meticulous surgical attention to hemostasis,
administration of antifibrinolytic agents, and implementation of transfusion thresholds,
are probably the most cost-effective ways to safely minimize transfusion require-
ments. The greatest reductions in both perioperative transfusion and morbidity have
been achieved through innovations in surgical techniques, such as with the develop-
ment of endoscopic strip craniectomy and spring-mediated cranioplasty procedures.
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P e d i a t r i c O b s t r u c t i v e Sl e e p A p n e a
a,b, a
Deborah A. Schwengel, MD *, Nicholas M. Dalesio, MD ,
Tracey L. Stierer, MDc,d
KEYWORDS
Obstructive sleep apnea OSAS Pediatric Adenotonsillectomy
KEY POINTS
Obstructive sleep apnea syndrome (OSAS) is a disorder of airway obstruction with multi-
system implications and associated complications.
OSAS affects children from infancy to adulthood and is responsible for behavioral, cogni-
tive, and growth impairment as well as cardiovascular and perioperative respiratory
morbidity and mortality.
OSAS is associated commonly with comorbid conditions, including obesity and asthma.
Adenotonsillectomy is the most commonly used treatment option for OSAS in childhood,
but efforts are underway to identify medical treatment options.
INTRODUCTION
Obstructive sleep apnea (OSA) is a public health problem that affects approximately
1% to 6% of all children,1,2 up to 59% of obese children,3–5 2% to 24% of adults,
and 70% of bariatric surgery patients.6 The incidence increases with age; the disorder
is responsible for billions of dollars of direct and indirect health care costs7 in the form
of motor vehicle crashes; medical conditions, including cardiovascular disease, meta-
bolic syndrome, diabetes, and cerebrovascular disease; as well as perioperative
morbidity and mortality. The presence of OSA syndrome (OSAS) also has implications
for job and school performance and has been associated with potentially life-long
cognitive impairment as well as sudden death. Treatment programs for those identi-
fied with OSAS may improve functional outcomes, reduce health care costs, and
contribute to longevity.7,8
a
Division of Pediatric Anesthesiology, Department of Anesthesiology and Critical Care
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA; b Department
of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA;
c
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD, USA; d Department of Otolaryngology-Head and Neck Surgery,
Johns Hopkins University School of Medicine, 601 N. Caroline Street, 6th Floor, Baltimore,
MD 21287, USA
* Corresponding author. Bloomberg 6222, 1800 Orleans Street, Baltimore, MD 21287-4904.
E-mail address: dschwen1@jhmi.edu

238 Schwengel et al
Once thought to be an isolated disorder of pharyngeal muscular mechanical

dysfunction leading to partial or complete intermittent airway obstruction, we now
know that OSAS is much more complicated and should be thought of as a syndrome
with multisystem implications including the central nervous, cardiovascular, meta-
bolic, and immune systems. Although some of its potential causative mechanisms
are understood, the inciting cause is often unclear. Newer information about the impli-
cations of sleep hygiene and inflammation are especially relevant to the obesity
phenotype in OSA but does not delineate which comes first, hence, the chicken versus
the egg phenomenon. OSAS, also known as sleep apnea hypopnea syndrome, is char-
acterized by symptoms such as snoring, frequent nighttime awakenings, daytime
sleepiness, irritability, and depression in adults and behavioral disorders and poor
school performance in children. Sobering is the evidence of long-term and possibly
permanent cognitive impairment in patients of all ages, but particularly in younger
pediatric patients and older adult patients; they may demonstrate deficits in executive
function and lower IQ scores.9 Because the sequelae of OSAS are thought to be a
function of recurrent hypoxic injury and chronic sleep deprivation, prompt treatment
of the disorder seems imperative. The recommended treatment modalities differ by
age, cause, and comorbid conditions.
There are typically 4 main phenotypes that characterize OSAS, shown in Fig. 1.
Although some patients may have contributions of more than one cause, it has
become abundantly clear that the obesity phenotype now exceeds the other pheno-
types fourfold.10
As anesthesiologists, we are challenged with recognizing the patients at risk of peri-
operative complications of OSAS. Perioperative morbidity and mortality in patients
with OSAS have been well described,11–14 although evidence of an association with
the severity of disease and specific adverse events is lacking. The presence of a
known diagnosis of OSAS carries implications for the anesthetic technique and dispo-
sition planning; however, the decision dialogue is hampered by inconsistencies in atti-
tude regarding the need for formal testing and postoperative monitoring requirements.
The minority of patients presenting for otolaryngologic and general surgical proce-
dures have undergone polysomnography (PSG), the gold standard diagnostic test.
Expensive, inconvenient, and not universally available, PSG is infrequently performed
Fig. 1. The 4 phenotypes of OSAS.

in children unless required by the surgeon before intervention for surgical treatment of
OSAS. In addition, testing algorithms and interpretation of the resulting data are not
consistent among all facilities. Furthermore, pediatric patients may present a chal-
lenge to some sleep centers that routinely test adult patients because these facilities
may not be set up to accommodate children. Although pediatric OSAS has tradition-
ally been considered to be a disorder predominately affecting preschool to early
school-aged children, the age range of patients with the syndrome extends from in-
fancy to young adulthood. Three distinct groups of patients exist based on age: infants
younger than 2 years, children aged between 2 and 8 years, and children older than
8 years or those with disease characteristics that more closely resemble those of adult
patients with OSAS. There is some crossover in age ranges between the groups; the
characteristics of patients in the groups are shown in Table 1.
The goals of this article are to review the diagnostic criteria, sleep science, patho-
physiology, treatment, and perioperative management of children with OSAS.
DIAGNOSIS
The early identification and diagnosis of infants or children with OSAS is challenging at
best. Focused surveillance and clear communication between the patients’ caregivers
and health care providers are required to distinguish patients who might be at risk for a
sleep-related breathing disorder from patients with primary snoring. Recently pub-
lished guidelines recommend the screening of every child for snoring and sleep
Table 1
Characteristics of 3 different types of pediatric OSAS
Infants Children Teens

Age range (y) 0–2 2–8 8–21
Description Congenital, craniofacial, Lymphoid hypertrophy Teen or obese
or prematurity dominance children with
features similar
to adult OSA
Prevailing causes Congenital, Enlarged tonsils and/or Obesity, genetic,
(comorbid craniofacial121 genetic, adenoids, genetic, craniofacial
conditions may neuromuscular, craniofacial
exacerbate all prematurity
groups)
Presentation Snoring, failure to Snoring, small, normal Snoring, daytime
thrive, recurrent or overweight for somnolence,
respiratory infections, age, behavioral impaired school
developmental delay122 problems, impaired performance,
school performance, hypertension,
enuresis males >females,
increasing age,
African American
Treatment Observation, AT AT, CPAP, weight loss
adenoidectomy, AT,
CPAP, other medical
management,
tracheotomy,
other craniofacial
surgeries114–116,123
Abbreviations: AT, adenotonsillectomy; CPAP, continuous positive airway pressure.

240 Schwengel et al
apnea–related signs and symptoms.15 Unfortunately, compliance with these guide-

lines is poor in both primary care settings and in preoperative otolaryngologic and non-
otolaryngologic populations.16 Suspicion for OSAS may be high in children with
predisposing or associated conditions, such as those listed in Box 1, or in infants
with severe forms of the disease who may present after witnessed episodes of apnea,
cyanosis, or failure to thrive. In addition, unlike adults with OSAS who may exhibit day-
time somnolence, children with OSAS are more likely to present with behavioral and
cognitive disorders, including hyperactivity, attention-deficit disorder, poor school
performance, and nocturnal enuresis. Frequently, these children are found to be
mouth breathers and assume bizarre positions during sleep, optimizing their airway
patency by hyperextending their neck. Additional physical characteristics that may
lead the primary care provider to suspect sleep-disordered breathing include maxillo-
facial abnormalities, such as retrognathia, high-arched palate, narrow intermolar
distance, and adenotonsillar hypertrophy.
Overnight PSG performed in a laboratory is the gold standard for the diagnosis of
OSAS in pediatric as well as adult patients. However, the test is expensive, time
consuming, and labor intensive. Furthermore, it is neither possible nor pragmatic to
refer every child in whom there is concern for OSAS for a PSG. Over the last quarter
of a century, multiple questionnaires have been developed and studied in order to find
an easy-to-use tool to screen for pediatric OSAS. These questionnaires exhibit varying
degrees of performance depending on the population to which they are administered,
and they tend to be relatively sensitive but not very specific. In a systematic literature
review, Brietzke and colleagues17 identified 12 articles that evaluated the ability of a
clinical history and physical examination to accurately identify patients with OSAS.
They concluded, based on the existing evidence, that history and clinical evaluation
were inadequate to accurately diagnose OSAS when compared with PSG. Some
individuals use overnight oximetry as a screening tool for OSAS based on the depth
and duration of desaturation. Oximetry is a simple and available resource, but it
does not qualify as a diagnostic tool. Compared with PSG, it has limited sensitivity
and specificity. It can identify some children with significant nocturnal hypoxemia,
but a negative result requires PSG; there is poor positive predictive value with the
occurrence of postoperative respiratory complications.15,18,19
The various physiologic parameters of the pediatric PSG are similar to those
measured in adult patients; however, in accordance with the American Academy
of Sleep Medicine (AASM), the scoring criteria are specific for infants and
children. A full montage pediatric PSG recording includes the parameters shown in
Table 2.
According to the 2012 AASM scoring manual, the criteria for events during sleep for
infants and children can be used for children who are less than 18 years of age, but
individual sleep specialists can choose to score children who are 13 years of age
or older using adult criteria. Table 3 shows pediatric scoring rules for apnea and hypo-
pnea. The severity of OSAS can be categorized by the apnea/hypopnea index (AHI)
as shown in Table 4.
Test-retest validity exists for PSG as a diagnostic tool for OSAS.20 However, linking
the diagnosis and severity grading of OSAS to perioperative outcomes is an important
research question. Previous studies have shown increased postoperative respiratory
morbidity in patients having 10 or more obstructive events each hour, and a high
baseline AHI is linked to persistent OSAS following adenotonsillectomy (AT).21–24
Few pediatric patients come to surgery having had a PSG, thus necessitating addi-
tional investigation to determine which patients are at the highest risk of perioperative
morbidity and mortality.
Box 1
Some congenital and medical conditions associated with OSAS
Maxillofacial associations
Apert
Crouzon
Pfeiffer
Pierre-Robin
Treacher Collins
Goldenhar (hemifacial microsomia)
Choanal atresia/stenosis
Hallermann–Streiff syndrome
Klippel–Feil syndrome
Osteopetrosis
Sickle cell disease
Cleft syndromes
Soft tissue associations
Obesity
Cystic hygroma
Papillomatosis (oropharyngeal)
Prader–Willi syndrome
Mucopolysaccharidosis
Beckwith–Wiedemann syndrome
Pharyngeal flap surgery
Down syndrome
Cleft syndromes
Neuromuscular associations
Cerebral palsy
Hypothyroidism
Achondroplasia
Patients with cleft palate after repair
Down syndrome
Inflammatory associations
Asthma47
Metabolic syndrome
Sickle cell disease125
Data from Refs.47,65–69,72,121,124,125

242 Schwengel et al
Table 2
Recommended monitoring parameters of PSG
Device Purpose
Oronasal thermistor Detection of apnea/hypopnea
Nasal pressure transducer Detection of airflow/hypopnea
Capnometry (optional) Detection of hypercarbia
Thoracoabdominal respiratory Detection of chest/abdominal wall activity
plethysmography
Electroencephalography Determination of sleep stage, arousal,
identification of seizure activity
Pulse oximeter Detection of oxyhemoglobin desaturation
Cutaneous carbon dioxide detector Diagnosis of hypercarbia
(optional)
Electrocardiogram Detection of dysrhythmia
Electromyography (chin & legs) Identification of REM sleep and leg
movement disorders
Electrooculogram Identification of stage of sleep
Video To ascertain activity and body position
Acoustic sensor/microphone (optional) Documentation of snoring/airflow
PEDIATRIC AIRWAY PHYSIOLOGY
The upper airway is a vital component of the respiratory system, compromised of

highly complex neurologic, muscular, and boney structures that interact to maintain
a patent conduit to the lungs. As in adults, the upper airway of children follows
the concepts of a Starling resistor model (explained below), although neuromechan-
ical control and airway response mechanisms differ slightly in children. Alterations in
consciousness, as seen in stages of sleep and anesthesia, in addition to anatomic,
genetic, and neuromuscular factors can predispose patients to airway obstruction
or complete occlusion. Other causes for airway collapse during sleep include inflam-
matory responses, both systemic and local within the upper airway. In the following,
the authors describe the upper airway physiology and the causes of OSA as it per-
tains to children.
The upper airway has been described as a simple collapsible tube or Starling
resistor, despite the intricate multisystem involvement for patency regulation.25,26
Table 3
The apnea/hypopnea index score is the average of apneic and hypopneic episodes per hour
Terminology Definition
Apnea Any 1 of the following can apply:
90% decrease in airflow that lasts 2 breaths caused by obstruction
>20 s associated with an arousal
>3% oxygen desaturation with no respiratory effort (central apnea)
Hypopnea All of the following must apply:
Nasal pressure decrease of >30% of baselines
Duration of >30% decrease in signal lasts for >2 breaths
>3% oxygen desaturation from baseline
Table 4
Definition criteria for mild, moderate, and severe OSAS
Oxygen Saturation
Severity AHI Score Descriptors Nadir (%)
Mild 1–5 SpO2 <90% for 2%–5 % of sleep time >92
Moderate 5–9 SpO2 <90% for 5%–10% of total sleep time —
Severe 10 SpO2 <90% for >10% of total sleep time <80
Children with OSAS often have carbon dioxide retention. The peak values for end-tidal carbon di-
oxide concentration in the expired air (ETCO2) and the percent of time spent with ETCO2 of more
than 50 mm Hg may be good markers to determine the severity of patients’ sleep-disordered
breathing. Postoperative admission is recommended for patients with a peak ETCO2 of more
than 60 mm Hg.15
The Starling resistor model can be described as having rigid proximal and distal ends
with a collapsible region in between. This collapsible region is exposed to surrounding
tissue pressures, leading to collapse at high pressures. The term used for the point at
which the pharynx collapses is called the critical pressure (PCRIT). For the collapsible
segment to remain open, both the upstream and the downstream pressures must
be higher than the PCRIT. To create complete occlusion, the pressure upstream and
downstream to the collapsible segment must be lower than the PCRIT, as seen with
inspiratory airflow limitation (ie, caused by adenotonsillar hypertrophy). Flow-limited
(hypopneic) breathing, however, maintains some airflow through the collapsible
segment. During inspiratory flow limitation, airflow reaches a maximal level during
inspiration as long as upstream pressures remain higher than the PCRIT. This pattern
occurs during severe snoring whereby airflow oscillates during the closing and
reopening of the upper airway.
PATHOPHYSIOLOGY OF PEDIATRIC SLEEP APNEA
The pathophysiology of pediatric OSAS is usually different than that of adults. OSAS in
the adult population is frequently associated with obesity and an increased mechan-
ical load to the airway. Children have airways that are resistant to collapse, with those
suffering from OSAS manifesting predominantly with hypopneic breathing as opposed
to frank apnea. They have few apneic events during flow-limited breathing and have
increased arousal threshold compared with children without OSAS. Unlike in adults,
apneic events (when they do occur) are sleep-stage specific, occurring predominantly
during rapid-eye-movement (REM) sleep. In addition to hypoxemia, hypercarbia is a
dominant characteristic in children with OSA caused by prolonged hypoventilation
and is uncommonly seen in adult patients with OSA.
Anatomic Obstruction
Adenotonsillar hypertrophy is a predominant characteristic of airway obstruction in
pediatric OSAS. As normal children age, adenotonsillar tissue enlarges at a faster
rate than other airway structures. Adenotonsillar tissues are largest in relation to the
underlying airway between 3 and 6 years of age, which is the age range at which
the OSAS incidence peaks in children.27,28 During anesthesia, it has been shown
that the location of airway obstruction in children with OSAS occurs at the level of
the tonsils and adenoids compared with airways of normal children that collapse at
the level of the soft palate.29 Adenotonsillar size, however, does not directly correlate
to the severity of OSAS. Other anatomic abnormalities, such as those associated with
244 Schwengel et al
craniofacial disorders, physically obstruct the upper airway. As many as 50% of

patients with craniofacial abnormalities also suffer from OSAS. Many of these morpho-
metric variations decrease the physical space within the posterior oropharynx, the site
that is most associated with obstructive breathing.30,31 However, not all children with
anatomic airway obstruction develop OSAS, indicating that other factors must be
necessary to acquire sleep-disordered breathing.
Neuromechanical Dysfunction
Neuromechanical control of the upper airway plays a vital role in maintaining airway
patency. Mechanoreceptors and chemoreceptors, in addition to central neurologic
centers, control the ventilatory drive and airway patency muscles (genioglossus,
intrinsic palatal, posterior cricoarytenoid, and pharyngeal constrictor muscles). Output
from these neuromuscular centers is influenced by changes in airway pressure,
airflow, carbon dioxide, and oxygen tensions. Normal children have been found to
have less collapsible airways during sleep, despite anatomically smaller airway struc-
tures. Upper airway muscular tone is partially preserved, maintaining patency despite
increases in subatmospheric pressure.31 Airway pressure responses can be
measured by determining patients’ PCRIT, which is performed by intermittent negative
pressure drops induced via a nasal mask or face mask. Children with OSAS have been
found to have higher PCRIT values when compared with children without OSAS. After
AT, however, PCRIT values of patients with OSAS do not return to that of controls.
These results suggest dysfunction in the neuromuscular response to changes in
airway pressures in patients with OSAS despite the removal of an anatomic airway
obstruction.32 Responses to carbon dioxide and oxygen are predominantly un-
changed in children with OSAS. In normal children, muscular tone of the airway can
increase when exposed to hypercarbic and hypoxic environments. The administration
of carbon dioxide increases airflow by decreasing upper airway resistance; the
response remains intact in children with OSAS compared with controls, suggesting
that some neuromechanical pathways continue to be active and resist airway
collapse.33,34 But patients with OSAS have a decreased arousal threshold when
exposed to hypercarbia; only approximately one-third of patients have a cortical
arousal after an obstructive apnea during REM sleep.33,35 By not awakening during
obstructive breathing, patients continue prolonged hypopneic breathing and increase
their exposure to hypoxia and hypercarbia. Nevertheless, carbon dioxide levels have
been shown to be different in children with OSA during wakefulness and under anes-
thesia. In awake and anesthetized patients, a direct correlation to OSAS severity and
resting carbon dioxide concentration has been shown.36,37 It is postulated that insuf-
ficient gas exchange explains the signs and symptoms of inattentiveness, enuresis,
and opioid sensitivity that are common in children with OSAS.
Anatomic and Neuromuscular Dysfunction

Disease processes, such as Down syndrome and obesity, contribute to upper airway
obstruction via a multitude of physiologic changes. Patients with Down syndrome are
at risk of airway obstruction because of their many predisposing physical characteris-
tics, including midface hypoplasia, glossoptosis, small upper airways, mandibular
hypoplasia, and obesity. In addition, these patients suffer from generalized hypotonia
that leads to neuromuscular dysfunction, predisposing patients to airway collapse.
Obesity increases PCRIT, primarily through an increased anatomic load on the pharyn-
geal airway structures. Neurohumoral defects are also noted in obese patients
with OSAS. Leptin, a satiety factor produced by adipose tissue, alters ventilatory
responses and regulates body fat composition. Resistance to leptin has been shown
in patients with OSAS.38
Genetic Causes
Genetics and inflammation also play important roles in the pathophysiology of pediat-
ric OSAS. Children of African American decent are thought to be at a greater risk for
OSAS than the Caucasian or Hispanic pediatric population.39 Although family cohort
studies demonstrate the role of genetics in OSAS, it is unclear whether ventilatory
drive, anatomic features, or both are the sources of dysfunction. Research identifying
genetic causes of children with OSAS is currently in its infancy; however, studies have
identified genetic polymorphisms associated with the disorder.40 The Apolipoprotein E
(ApoE)-e4 allele of the ApoE gene alters membrane stability and has been associated
with children with OSAS who manifest with decreased neurocognitive performance.41
Children with excessive daytime sleepiness are more likely to have single nucleotide
polymorphisms in the tumor necrosis factor (TNF)-alpha–308G gene, where TNF-
alpha is an important proinflammatory cytokine and enhancer of slow-wave sleep. Ge-
netic variations in the reduced form of nicotinamide adenine dinucleotide phosphate
oxidase complex, an enzyme active in oxidative stress linked to stroke, hypertension,
and heart disease, have been linked to children with OSAS who have cognitive
dysfunction.42 Although genetic polymorphisms have been linked to OSAS, the com-
plex interplay between genic variations leading to phenotypic characteristics has yet
to be described.
Inflammation
Inflammation, both local and systemic, has been associated with OSAS. Adenotonsil-
lar hypertrophy is a common predisposing factor for OSAS; however, the cause of the
lymphoid tissue enlargement is unknown. Some hypothesize that environmental or ge-
netic factors initiate an inflammatory response leading to tonsillar hypertrophy,
whereas others think enlarged adenotonsillar tissue triggers an inflammatory
response. Regardless, there is ample evidence to show that inflammatory markers
are associated with pediatric OSAS.43–46 Glucocorticoid receptor and leukotriene
expression have been reported in the adenotonsillar tissue of children with OSAS,
likely playing a role in hypertrophy of the lymphoid tissue. Chronic upper airway inflam-
matory disorders, including sinusitis, allergic rhinitis, and asthma, coexist in patients
with OSAS, with increased production of proinflammatory cytokines, such as inter-
leukin (IL)-6, IL-1alpha, and TNF-alpha.40 Asthma is commonly associated with
OSAS and is thought to perpetuate a positive feedback loop of inflammation, nasal
obstruction, and airway collapse (Fig. 2).47 From this inflammatory response, urinary
biomarker concentrations, including cysteinyl leukotrienes and lipocalin-type prosta-
glandin D synthase, have been found to correlate to the severity of sleep-disordered
breathing in children. This finding suggests a possible role for the assessment of the
severity of OSAS through the measurement of urinary inflammatory markers.45,48,49
Sleep and Anesthesia

Sleep and anesthesia share similar neurophysiologic pathways; however, there are
distinct characteristics that separate the two states. Sleep is a natural state of uncon-
sciousness that is governed by homeostatic drive and circadian patterns, consisting of
various stages of brain activity. Anesthesia is a drug-induced state of fairly constant
brain activity, with arousal only after the drug has been eliminated.
Anesthesia and sleep both decrease ventilatory drive and neuromuscular activity of
airway patency musculature. Patients do not obstruct during periods of wakefulness,
246 Schwengel et al
Fig. 2. Interrelationship between asthma and sleep apnea. GER, gastroesophageal reflux.
(From Alkhalil M, Schulman E, Getsy J. Obstructive sleep apnea syndrome and asthma:
what are the links? J Clin Sleep Med 2009;5(1):72; with permission.)
suggesting decreases in consciousness increase the propensity for airway collapse.

Children with OSAS have increased Electromyogram, genioglossus muscle (EMGGG)
activity during wakefulness as well as a greater decrease in EMGGG activity at the
onset of sleep compared with normal children. This fact suggests that airway patency
is more dependent on neuromuscular control of pharyngeal dilator muscles in OSAS
children, reinforced by studies showing a greater decrease in airway diameter
compared with controls after local anesthetic is applied to the airway.50,51 With
increasing concentrations of anesthetic agents, such as propofol, benzodiazepines,
and inhalational anesthetics, the pediatric airway decreases in cross-sectional
area.52–56 Children with OSAS are more sensitive than normal children to these agents,
having airway collapse at higher airway pressures.57 Analgesic medications produce a
decrease in ventilatory and pharyngeal neuromotor drive to the upper airway. In addi-
tion to these effects, opioid sensitivity has been observed in children with severe
OSAS thought to be secondary to the upregulation of opioid receptors in the brain-
stem from recurrent hypoxic episodes.58–60 In contrast, dexmedetomidine, a centrally
acting alpha-2 agonist, has sedative properties that work directly at the locus coeru-
leus, or sleep center. The sedation produced by dexmedetomidine is similar to natural
non-REM sleep, does not produce significant respiratory depression, and is associ-
ated with fewer oxygen desaturation episodes when compared with propofol or mid-
azolam, which exert their effects primarily by GABAergic mechanisms. These
beneficial effects related to the preservation of the respiratory drive are more pro-
nounced in children with severe OSAS.61,62
TREATMENT
AT remains the mainstay of treatment of OSAS in children. In a national trial of 464 chil-
dren with OSAS, patients were randomized to tonsillectomy versus watchful waiting.
The primary outcome of the study was to detect differences in cognition. There were
no differences in executive function or attention between the groups; however, there

were reduced symptoms of OSAS and improved AHI, behavior, and quality of life, thus
providing evidence of the beneficial effects of AT.63 Infants, obese children, syndromic
children, and those with severe OSAS should be considered at risk for treatment fail-
ure or incomplete response to tonsillectomy. Nevertheless, AT may provide some
relief by decreasing severity and can be offered in conjunction with other therapies,
such as various forms of positive airway pressure (PAP) and control of comorbidities,
such as asthma. Children with mild OSAS or children with mild residual OSAS
following AT may be considered candidates for a 6-week trial of inhaled steroids.64
Some children with OSAS have maxillofacial abnormalities that may be treatable
with orthodontic therapies. Orofacial narrowing, malocclusion, and mandibular retro-
gnathia are abnormalities associated with OSAS.65,66
All patients with craniofacial syndromes should be suspected of having OSAS. Chil-
dren with cleft syndromes have a high prevalence of OSAS and should be assessed
with PSG.67–69 Children with abnormalities of anatomy or muscle tone may require
therapies, including craniofacial or pharyngeal surgeries or potentially tracheostomy.
Tissue-reduction surgeries have been used in patients with obstructive tissues other
than the tonsils and adenoids to create more room in the oropharyngeal or nasopha-
ryngeal spaces. Craniofacial surgeries may include mandibular or maxillary advance-
ment procedures. Although they are more invasive procedures with longer recovery
times, these surgical interventions may be considered to improve OSAS in patients
with disorders shown in Box 1, especially if AT has already been tried and some
degree of OSAS persists.70–72
Teens and older children with OSAS may share phenotypic features of adult OSAS
and, therefore, may benefit from treatments similar to those offered to adult patients.
In 2009, a task force designated by the AASM developed evidence-based clinical
guidelines for the long-term management of adults with OSAS.73 The treatment of pa-
tients with a diagnosis of OSAS requires a multidisciplinary approach and robust
patient/care-giver education with regard to physiology and treatment options. Once
the severity of disease has been established, there are behavioral, surgical, dental,
and medical treatment options. However, continuous PAP (CPAP) is the treatment
of choice for patients with moderate to severe disease. Although CPAP therapy has
been shown to be highly effective in the treatment of OSAS, adult compliance with
the use of the device has been reported to be very poor.74
Secondary behavioral treatments include weight-loss counseling, position therapy
or side sleeping, avoidance of factors that worsen the disease, use of oral dental de-
vices, and practice of proper sleep hygiene. Surgical options include single and multi-
level procedures, such as tracheostomy, maxillomandibular advancement,
uvulopalatopharyngoplasty, radiofrequency ablation, palatal implants, or a combina-
tion of these options, all of which are outside of the scope of this article. However,
in pediatric populations, as well as adults, success rates and potential complications
should be discussed during contemplation of the surgical treatment of OSAS. Obese
patients may be treated with AT but have a higher chance of residual disease. In a
meta-analysis, Costa and Mitchell75 reported that 88% of obese patients were not
cured by AT, although their OSAS was significantly improved.
PERIOPERATIVE MANAGEMENT
Preoperative Management, Assessment, and Disposition Planning
Preoperative assessment of patients should be done with disposition planning in
mind. Doing so permits the full discussion of plans and risks with patients, their
248 Schwengel et al
parents, surgeons, and nurses. Pediatric patients with OSAS commonly present for
AT, adenoidectomy, or tonsillectomy but certainly may undergo other types of sur-
geries. The suggestion of sleep-disordered breathing is obvious in AT patients but
may go unrecognized in patients having nonotolaryngologic surgeries. Unfortunately,
a minority of patients receive PSG testing preoperatively, even in the AT population.76
As a result, the anesthesiologist must screen patients for OSAS and consider whether
it is safe to discharge them to an unmonitored setting after surgery, particularly if opi-
oids will be used for pain management. Consequently, it is incumbent on the anes-
thesia provider to preoperatively screen all surgical patients for signs and
symptoms of obstructive sleep apnea. The problem is that even extensively developed
OSAS screening questionnaires have variable specificity, sensitivity, and/or negative
predictive value depending on the population being studied; most surveys are too
long to be useful on the morning of surgery.77–79 Although the literature is clear that
this type of evidence of OSAS is imprecise and such tools have not been studied
for the purpose of determining perioperative risk, their use raises awareness. Snoring
is a nonspecific sign but is often used as a starting question. The questions listed in
Fig. 3 scored with a Likert scale have been recently shown to have some validity as
components of a short questionnaire for primary care providers; a score of 2.72 or
more indicated a high risk for the presence of OSAS.80 No matter the tool used, it is
imperative that surgeons and anesthesiologists communicate effectively about the
safety of discharge and discuss whether postoperative monitoring is needed. Postop-
erative respiratory complications have been reported extensively in pediatric AT pa-
tients and may occur in as many as 36% of these patients, particularly those with
severe OSAS, younger age (aged <3 years), and medical comorbidities.81–86 Although
critical complications are not common, adverse events may be severe, including death
and permanent neurologic injury.11–14,87
The preoperative physical examination should include all of the elements of a stan-
dard preoperative assessment but should also include any notable facial features of
the child and their overall body habitus. Guilleminault and colleagues66 have reported
on the contributions of facial development and interaction of long, narrow facial fea-
tures, high-arched palate, and retromandibular positioning as risk features of OSAS,
especially in conjunction with enlarged tonsils. Mouth breathing, poor handling of
oral secretions, reduced muscle tone, and a large tongue, such as in patients with
Down syndrome, are other physical features suggestive of risk. The Mallampati score
has not consistently been shown to be predictive of OSAS in adult patients88 and has
not been well studied in pediatric patients.
Preoperative laboratory tests or imaging should be considered in the context of the
surgical procedure, the known severity of OSAS, and comorbidities. Patients with
severe OSAS are at risk of cardiovascular complications of their disease, and obese
patients have an increased risk of metabolic syndrome. Multiple studies have shown
that children without clinical evidence of cardiovascular effects of OSAS may have
echocardiographic evidence of wall motion abnormalities, diastolic dysfunction, ven-
tricular hypertrophy, or elevated pulmonary artery pressures; in most children, these
findings reverse with effective treatment.89 Severe and long-standing OSAS can
lead to cor pulmonale or cardiac failure. Therefore, an echocardiogram is recommen-
ded if a child with severe OSAS is suspected to have cardiac involvement as indicated
by systemic hypertension; right ventricular dysfunction; or frequent, severe desatura-
tions (<70%).72 Chest radiographs, electrocardiograms, and blood gases are not
recommended.
The metabolic syndrome can occur in normal patients but is most common in
patients with obesity and/or OSAS, and the likelihood of its presence increases as
Fig. 3. A short screening tool using severity discrimination scores. (Data from Spruyt K, Go-
zal D. Screening of pediatric sleep-disordered breathing: a proposed unbiased discriminative
set of questions using clinical severity scales. Chest 2012;142(6):1508–15; and Kadmon G,
Shapiro CM, Chung SA, et al. Validation of a pediatric obstructive sleep apnea screening
tool. Int J Pediatr Otorhinolaryngol 2013;77(9):1461–4.)
the severity of OSAS increases; up to 10% of children and 20% of adults have been
estimated to be affected.90 Women with polycystic ovary syndrome are at particular
risk.91 There is also evidence that daytime somnolence is a sign that especially indi-
cates the inflammatory pathophysiology involved in the metabolic syndrome, obesity,
and OSAS.91 Metabolic syndrome is characterized by metabolically active visceral fat
(typically in patients with central obesity), fatty liver, insulin resistance, hypertension,
250 Schwengel et al
and dyslipidemia. These derangements, especially in association with each other, are
thought to be associated with increased morbidity in the form of cardiovascular and
neurovascular pathological conditions and/or mortality.91,92 Specific perioperative
risk data are scarce, and the current recommendations only support the management
of the individual metabolic and cardiovascular derangements, such as glucose con-
trol and blood pressure control. There are some data to suggest that statin therapies
may reduce the perioperative risk.93 It is, therefore, prudent to consider obtaining lipid
and hepatic panels in addition to serum glucose in patients at risk for metabolic
syndrome.
Consideration should also be given to providing a referral to a pulmonologist for pa-
tients with severe OSAS. Children with signs of cardiovascular complications or likely
persistence of OSAS following surgery (Box 2) should be referred for consideration of
perioperative PAP therapies (CPAP or bilevel PAP [BiPAP]). Although data suggests
that perioperative CPAP therapy may reduce postoperative adverse outcomes, inves-
tigations examining the utility of preoperative CPAP therapy in newly diagnosed pa-
tients with OSAS have been inconclusive.94 Table 5 summarizes the preoperative
testing options.
ANESTHETIC TECHNIQUES
There is little evidence to support the benefit of any single anesthetic technique for pa-
tients with OSAS. Most anesthetic agents reduce pharyngeal tone, diminish the venti-
latory response to carbon dioxide,95 and impair or abolish patients’ ability to rescue
Box 2
Risk of persistent OSAS following tonsillectomy
Genetic or congenitally related

Family history of OSAS
Genetic or chromosomal disorders
Neuromuscular disorders
Nasal or maxillofacial disorders
Age <2 years
Comorbidity related
Obesity
Asthma
History of prematurity
Infiltrative soft tissue disorders of the airway
Upper respiratory infection within 4 weeks of surgery
Severity related
Severe OSA
Systemic hypertension
Cor pulmonale
Growth impairment caused by chronic obstructed breathing
Data from Refs.15,72,105,126,127

Table 5
Preoperative testing for patients with known or suspected OSAS
Test Indication
PSG To diagnose OSAS and determine severity
Echocardiography To establish evidence of cardiovascular risk, any of the following
are present:
Systemic hypertension
Evidence of right ventricular dysfunction
Frequent, severe oxygen desaturation (<70%)
Blood chemistries: liver If suspected metabolic syndrome
function tests, lipid
panel, glucose
Other As dictated by the surgical procedure or presence of comorbidities
themselves from obstructive apnea during sleep. One exception is dexmedetomidine,

which does not produce significant respiratory depression and may be particularly
useful in children with severe OSAS.61,62 Historically used as a staple for postoperative
analgesia, opioids have been shown to produce more profound respiratory depres-
sion in children, with smaller doses in patients with severe OSAS.37,60,96 Regional
anesthesia or other opioid-sparing management plans may be helpful; but pure
regional techniques are often not possible in pediatric patients or appropriate for
some surgical procedures, including AT. If opioids are necessary for pain manage-
ment, they should be administered judiciously and patients monitored appropriately
for complications. Sedatives should likewise be used with caution and with an appro-
priate monitoring plan.
Nonsteroidal antiinflammatory agents (NSAIDS), acetaminophen, and adjuvant pain
medications have been used to treat postoperative pain in patients for AT surgery and
other surgeries. However, there continues to be a debate about whether NSAIDS can
be safely used in AT surgery because of the risk of post-tonsillar hemorrhage (PTH). It
is clear that aspirin and aspirin-containing products should not be used in the periop-
erative care of tonsillectomy patients,97 and it is prudent to avoid ketorolac until hemo-
stasis is achieved. Ibuprofen products have been used extensively for postoperative
care, and a recent meta-analysis suggests no increased risk of PTH and no significant
differences between individual nonaspirin NSAIDS.98
Dexamethasone, well known to reduce nausea and vomiting, may have a role in the
effective treatment of postoperative pain. Raghavendran and colleagues99 have re-
ported the management of pain in tonsillectomy patients with severe OSAS using a
dose of 0.3 mg/kg of dexamethasone (maximum of 10 mg). In 2008, dexamethasone
was implicated as a cause of increased PTH in doses of 0.5 mg/kg or greater.100 More
recently, observations of dexamethasone use have not been linked to bleeding101; a
meta-analysis of dexamethasone use in AT did not show an overall association with
PTH, but it could not exclude the possibility of a bleeding association with specific
doses. Studies comparing doses of 0.4 to 0.6 mg/kg with placebo did demonstrate
increased odds of bleeding.102 Consequently, it may be prudent to avoid high doses
of dexamethasone; high doses are not needed to reduce vomiting.103 A dose-finding
study of the effects of dexamethasone related to analgesic effect is needed.
Airway management has the potential for difficulty in cases of craniofacial narrowing
or anomalies, especially with the addition of soft tissue enlargement. Studies both
support and refute the prediction of difficult airway management in patients with
OSAS. Preparations should be made for difficulties with mask ventilation or
252 Schwengel et al
endotracheal intubation. Helpful mask ventilation strategies include elevation of the

head of the bed, lateral positioning, jaw thrust maneuver, CPAP, and oral or nasal
airway placement.104 When an inhalational induction is performed, care must be
used to avoid placing an airway while patients still react to stimulation or laryngo-
spasm may occur. Persistent respiratory efforts against an obstructed airway from lar-
yngospasm or pharyngeal airway obstruction can result in negative pressure
pulmonary edema.72,105 In patients with a high risk of airway obstruction during induc-
tion, intravenous induction may be considered to facilitate rapid instrumentation of the
airway. This induction may be done for patients with documented or suspected severe
OSAS. Most patients presenting for AT with enlarged tonsils but no craniofacial de-
fects have airways that can usually easily be managed with an oral airway, and endo-
tracheal intubation is generally straightforward.
The laryngeal mask airway (LMA) is preferred by some anesthesiologists during
AT surgeries but must be accepted by the operating surgeon. Lalwani and col-
leagues106 reported that the use of LMA in AT is associated with a higher incidence
of airway obstruction on insertion or when the gag is placed by the surgeon. The overall
complication rate in the LMA group was 14.2% versus 7.7% in the endotracheal tube
group, but the total case time was less in the LMA group. LMA failure was 6.8% and was
associated with younger patients, controlled ventilation, and the surgeon. The LMA
may also be used as an adjunct to the management of a difficult airway.
On completion of the anesthetic in patients with OSAS, it is the opinion of these au-
thors that patients should be allowed to emerge from general anesthesia before extu-
bation of the airway because of the lingering effect of anesthetics on the airway muscle
tone. In addition, regular respiratory effort and adequate strength should be demon-
strated. However, the authors do acknowledge that some anesthesiologists choose
to extubate the trachea when patients are still deeply anesthetized and breathing
spontaneously.
POSTOPERATIVE MANAGEMENT
Opioids remain a major treatment option for perioperative pain management; but pa-
tients with documented or suspected severe OSAS are at an increased risk of postop-
erative respiratory complications, and their opioid doses should be reduced.99 These
patients have central alteration of their opioid receptors associated with severe inter-
mitted nocturnal hypoxemia; this change leads to vulnerability of these patients when
opioids are administered in the perioperative period.60,96 The options are, therefore, to
monitor postoperatively, discharge without opioid therapy, or discharge with opioid
therapy and the knowledge of mild or moderate OSAS severity. Codeine, hydroco-
done, and oxycodone liquid formulations are available for pediatric patients. Some
drugs are typically dispensed as combination drugs with acetaminophen, although
single-drug formulations are available. Combination drugs do not allow the flexibility
of dosing that is necessary to avoid toxicity of either of the drug components and,
therefore, should generally not be used. Codeine should be avoided because of the
genetic heterogeneity associated with its metabolism. Codeine is a prodrug metabo-
lized by the cytochrome P450 CYP2D system to morphine, the active drug. Both slow
and ultrarapid metabolizers exist in the population; slow metabolizers have little to no
pain relief, and ultrarapid metabolizers may experience unpredictable toxic morphine
levels. This toxicity has been implicated as the cause of death in several children
treated postoperatively with codeine.107 In 2013, the Federal Drug Administration
issued a warning with regard to the hazard of the use of codeine in children. Oxy-
codone, hydrocodone, and tramadol are also metabolized by the CYP2D system;
caution is also required with their use, particularly in AT patients with severe OSAS.
Around-the-clock dosing with opioids in the perioperative outpatient setting is extremely
dangerous. Many deaths related to opioids are reported in children; 18% of deaths and
5% of hypoxic brain injuries have been related to opioids.107 The Cincinnati Children’s
Hospital has adopted a nonopioid analgesic regimen in their tonsillectomy patients. The
protocol is for use in patients younger than 6 years and includes around-the-clock
acetaminophen (maximum 75 mg/kg/d), dexamethasone once a day for 3 days, and
ibuprofen as needed beginning on day 2 and limited to 2 doses per day.107
The American Society of Anesthesiology’s guidelines recommends that patients at
risk for OSAS remain in the postanesthesia care unit (PACU) 3 hours longer than their
non-OSA counterparts; if patients exhibit any signs of obstruction, their stay should be
extended for an additional 7 hours.108 This recommendation is a consensus of opinion
statement, not based on evidence; but it has been demonstrated that patients may
experience morbidity many hours after PACU discharge even when the PACU stay
has been uncomplicated.85,109,110
Protocols between institutions vary widely with regard to the admission of patients
following AT, and no consensus exists about which patients should be admitted to an
intensive care unit (ICU).111,112 Nevertheless, there is evidence that patients with
documented or suspected severe OSAS should be kept overnight. Children younger
than 3 years78,113 and those with comorbidities should be admitted, and children
requiring opioids for pain management should be considered for admission.11 More
specific perioperative guidelines are lacking, and it must be stated that being older
than 3 years is not evidence of safety for discharge. Fatal respiratory events following
tonsillectomy occur with twice the occurrence rate in children than adults, and the
younger children have greater risk.87,99 Infants with OSAS are a special group of pa-
tients who are more likely to have craniofacial disorders, neuromuscular disorders, or
prematurity. In addition, they are less likely to be effectively treated by AT and are
more likely to warrant ICU admissions for oxygen and/or CPAP administration.114–116
A proposed algorithm of disposition planning is shown in Fig. 4.
Fig. 4. Disposition planning algorithm.

254 Schwengel et al
The duration of stay in the hospital if admitted depends on the surgical procedure
but also on the risk of postoperative respiratory complications. The effects of anes-
thetics and pain medications continue into the postoperative period and may be
complicated by the physiologic effects of surgical stress and pain. Postoperative
sleep disruption and REM rebound may make patients with OSAS vulnerable to
respiratory complications for several days.117,118
SUMMARY
OSAS is a multisystem disorder with a complex of inciting factors that lead to a

pathophysiology that is still not completely understood. It is clear that OSAS is not
purely a mechanical disorder that can always be cured by removing the tonsils. In chil-
dren, normal growth and lymphoidal hypertrophy mismatch is often implicated as
causative; but maxillofacial, neuromuscular, and genetic factors are involved too.
Obese children may have large tonsils and adenoids but clearly have contributing
fat pads and inflammatory factors. Tonsillectomy is still the most common treatment
in children with OSAS; but more often, we are recognizing residual disease after AT. As
the understanding of OSAS improves, medical treatments may become more promi-
nent, especially in children with a risk of residual disease after AT. Pharmacologic ther-
apies are being explored and may add significantly to the resolution of inflammation
and metabolic syndrome.119,120 Treatment should be pursued for children with
OSAS; permanent cognitive impairment and cardiovascular and neurovascular dis-
ease are possible consequences of no treatment.
Perioperative management of children with OSAS remains controversial and chal-
lenging because many patients come to surgery without an assessment of disease
severity, leaving the anesthesiologist to wonder if it is safe to discharge patients to
an unmonitored environment. This situation is especially challenging if opioids are
needed for pain management. Mortality and respiratory morbidity in the perioperative
period is a concerning risk. All anesthesiologists should screen patients for OSAS.
Although questionnaires and screening tools are not perfect, they may be all that is
available on the day of surgery. The authors recommend the routine use of a preoper-
ative screening tool on all patients presenting for surgery or procedural sedation. Pa-
tients with known or suspected significant OSAS, comorbidities, young age, or obesity
should be considered for postoperative monitoring with continuous pulse oximetry or
possibly in an ICU setting for at least one night and perhaps longer.
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98. Riggin L, Ramakrishna J, Sommer DD, et al. A 2013 updated systematic review
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99. Raghavendran S, Bagry H, Detheux G, et al. An anesthetic manage-
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100. Czarnetzki C, Elia N, Lysakowski C, et al. Dexamethasone and risk of nausea
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103. Kim MS, Cote CJ, Cristoloveanu C, et al. There is no dose-escalation response
to dexamethasone (0.0625-1.0 mg/kg) in pediatric tonsillectomy or adenotonsil-
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107. Subramanyam R, Varughese A, Willging JP, et al. Future of pediatric tonsillec-
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Ultrasound for Regional
A n e s t h e s i a i n C h i l d ren
Santhanam Suresh, MD*, Amod Sawardekar, MD, Ravi Shah, MD
KEYWORDS
Peripheral nerve blockade Pediatric regional anesthesia Peripheral nerve catheter
Nerve stimulation Ultrasound-guided regional anesthesia
KEY POINTS
The use of ultrasonography has expanded the application of pediatric regional anesthesia.
One can visualize the needle advancement and injection of local anesthetic with
ultrasonography.
Ultrasonography can aid in the placement of peripheral nerve catheters to provide pro-
longed analgesia.
INTRODUCTION
Advances in ultrasonography have expanded the scope of regional anesthesia prac-

tice in pediatrics. Ultrasound guidance improves the ease and safety of peripheral
nerve blockade in children. It is well recognized that regional anesthesia is commonly
performed in anesthetized or sedated children, contrary to adult practice.1,2 Recent
large pediatric databases (Pediatric Regional Anesthesia Network [PRAN]) elucidates
the safety and efficacy of regional anesthesia in children.3 This article is devoted to the
use of ultrasound-guided pediatric regional anesthesia with its applications, tech-
niques, and potential complications (Table 1).
UPPER EXTREMITY BLOCKS
Blockade of the brachial plexus can be completed at various locations and is appli-
cable to children undergoing surgical procedures on the upper extremity. The brachial
plexus can be blocked at the axillary, infraclavicular, interscalene, and supraclavicular
locations. The supraclavicular brachial plexus block is the most common upper ex-
tremity block performed in children, but the increasing use of ultrasound guidance
Disclosures: None (S. Suresh, A. Sawardekar & R. Shah).

Department of Pediatric Anesthesiology, Ann & Robert H. Lurie Children’s Hospital of Chicago,
Feinberg School of Medicine, Northwestern University, 225 East Chicago Avenue, Box 19,
Chicago, IL 60611, USA
E-mail address: ssuresh@luriechildrens.org

264 Suresh et al
Table 1
Common peripheral nerve blocks in children
Block Indications Dosing

Upper extremity
Axillary Surgery of the elbow, forearm, or 0.2–0.4 mL/kg 0.25%
hand bupivacaine or 0.2%
ropivacaine
Interscalene Shoulder surgery, catheter placement 0.2–0.4 mL/kg 0.25%
for postoperative pain control bupivacaine or 0.2%
ropivacaine
Supraclavicular Most upper extremity procedures 0.2–0.4 mL/kg 0.25%
bupivacaine or 0.2%
ropivacaine
Infraclavicular Most upper extremity procedures, 0.2–0.3 mL/kg 0.25%
catheter placement bupivacaine or 0.2%
ropivacaine
Lower extremity
Lumbar plexus Surgery on the hip, knee, or foot 0.2–0.3 mL/kg 0.25%
bupivacaine or 0.2%
ropivacaine
Femoral Surgery on the thigh or knee (eg, knee 0.2–0.3 mL/kg 0.25%
arthroscopy) bupivacaine or 0.2%
ropivacaine
Saphenous Surgery on the knee, foot, or the 0.1–0.2 mL/kg 0.25%
medial aspect of the leg below the bupivacaine or 0.2%
knee ropivacaine
Sciatic Surgical procedures on the foot and 0.15–0.3 mL/kg 0.25%
ankle, knee surgery (in addition to bupivacaine or 0.2%
the femoral nerve block) ropivacaine
Truncal
Transversus abdominis Surgery on the abdominal wall, 0.1–0.2 mL/kg 0.25%
plane block, rectus chronic neuropathic abdominal bupivacaine or 0.2%
sheath wall pain, laparoscopic procedures, ropivacaine
umbilical hernia repair
Ilioinguinal/ Hernia repair, groin surgery 0.075–0.2 mL/kg 0.25%
iliohypogastric bupivacaine or 0.2%
ropivacaine
when performing regional anesthesia allows the practitioner to perform brachial

plexus blockade at any location safely and effectively (Santhanam Suresh MD, Per-
sonal communication). Ultrasound guidance allows the clinician to better recognize
brachial plexus anatomy and improves the localization of adjacent structures during
needle placement.
AXILLARY BLOCK
Anatomy and Indications
The axillary approach to the brachial plexus provides analgesia to the elbow, forearm,
and hand. A single needle insertion at this location facilitates the blockade of the
radial, median, and ulnar nerves. Although anatomic variations may exist, the radial
nerve commonly lies posterior to the axillary artery, and the ulnar nerve is anterior
Fig. 1. Ultrasound image of the axillary neurovascular sheath. AA, axillary artery; MN,
median nerve; RN, radial nerve; UN, ulnar nerve.
and inferior to the artery (Fig. 1). The median nerve is usually located anterior and su-
perior to the axillary artery.4 It is important to note that the musculocutaneous nerve is
situated outside of the axillary neurovascular sheath. Specifically, it lies between the
biceps brachii and coracobrachialis muscles and is often blocked separately from
the radial, median, and ulnar nerves.
Technique
Ultrasound-guided axillary blocks in children are not well described in the literature,
but the techniques used in adults can be applied in children.5,6 An in-plane technique
is used with the ultrasound probe placed transverse to the humerus (Fig. 2).7 Multiple
injections with needle repositioning allow for the circumferential spread of local anes-
thetic around each nerve.8,9 Careful ultrasound-guided needle advancement should
be completed because of the superficial depth of the axillary sheath.
Complications
Complications include neural injury, intravascular injection, hematoma, infection at the
site of skin puncture, and skin tenderness. The use of ultrasound guidance to facilitate
the needle advancement may help to reduce inadvertent intravascular puncture or in-
jection and nerve damage.
Fig. 2. Probe placement for axillary block.

266 Suresh et al
INTERSCALENE APPROACH
Analgesia to the shoulder and proximal humerus is accomplished by blocking the
brachial plexus at the interscalene groove. At this location, the trunks and roots of
brachial plexus are posterior to the sternocleidomastoid muscle and lie between the
anterior and middle scalene muscles (Fig. 3). Using this approach, the C5, C6, and
C7 nerve roots are visualized between the anterior and middle scalene muscles.
Technique
The ultrasound probe is placed in the transverse oblique plane at the level of the
cricoid cartilage at the lateral border of the sternocleidomastoid muscle (Fig. 4).
Deep to the sternocleidomastoid muscle and lateral to the subclavian artery are the
anterior and medial scalene muscles, which make up the interscalene groove. Con-
tained within this groove are the hyperechoic structures that compose the neurovas-
cular bundle of the C5, C6, and C7 nerve roots.10 Although nerve stimulation may be
used to deliver local anesthetic solution to the brachial plexus at this level, ultrasound
guidance may decrease the required total volume of the local anesthetic.11
Complications
Successful interscalene block is accompanied by hemidiaphragmatic paralysis, recur-
rent laryngeal nerve block, and Horner syndrome; such associated side effects should
not be mistaken for complications.11,12 Ultrasound use may decrease the total local
anesthetic needed for successful interscalene block.13,14 The interscalene block
should be used with caution in the pediatric population because of the potential risks
of pneumothorax, vertebral artery injection, and intrathecal injection.15,16
SUPRACLAVICULAR APPROACH
The supraclavicular block provides analgesia to the upper arm and elbow. This block
is the most common upper extremity block as recorded in the PRAN database. A sim-
ple test to check the viability of the median, radial, and ulnar nerve can be performed
before the placement of this block, particularly in children who may have a compro-
mised nerve as in elbow fractures. The trunks and divisions of the brachial plexus
Fig. 3. Ultrasound image of the brachial plexus showing the nerve roots (C5, C6, C7). ASM,
anterior scalene muscle; MSM, middle scalene muscle; SCM, sternocleidomastoid muscle.
Fig. 4. Probe placement and needle insertion for interscalene block.
can be blocked at this site and are located lateral and superficial to the subclavian ar-
tery (Fig. 5). A simple test to check the viability of the median, radial, and ulnar nerve
can be performed before the placement of this block, particularly in children who may
have a compromised nerve as in elbow fractures (Thumbs Up- Radial nerve; Pincer
grip of index and thumb: Median nerve; Scissoring of fingers: Ulnar nerve). The first
rib is located just posterior and medial to the brachial plexus, and deep to that is
the pleura.
Technique
Although few techniques have been described for pediatric patients,10 the ultrasound
probe is commonly positioned in the coronal-oblique plane, just superior to the upper
border of the midclavicle. The subclavian artery is identified as a hypoechoic and pul-
satile structure that lies adjacent to the brachial plexus. An in-plane approach is used
to guide the needle medially toward the brachial plexus, just superior and lateral to the
subclavian artery (Fig. 6). Directing the needle in a lateral-to-medial fashion decreases
injury to vascular structures and minimizes the risk of intraneural injection.6
Complications
Complications include pneumothorax, hematoma, infection, hematoma, and intravas-
cular injection. The potential for pneumothorax is present because of the lung
Fig. 5. Supraclavicular fossa as seen on the ultrasound. Note the proximity of the brachial
plexus to the subclavian artery (SA).
268 Suresh et al
Fig. 6. Probe placement and in-plane needle insertion for the supraclavicular block.
parenchyma’s location just medial to the first rib. Direct visualization of the tip and
shaft of the needle with ultrasonography may help avoid this complication.
INFRACLAVICULAR APPROACH
The infraclavicular block, like the supraclavicular block, is used to provide analgesia
for the upper arm and elbow.3 This approach to the brachial plexus allows for
blockade at the level of the cords. The cords of the plexus are located medial and infe-
rior to the coracoid process. The axillary artery and vein are deep to the cords. The
pectoralis major and minor lie superficial to the brachial plexus. The lateral cord of
the plexus is seen on ultrasound as a hyperechoic structure, and the posterior cord
is positioned deep to the axillary artery. The medial cord can be difficult to identify
because of its anatomic location between the axillary artery and vein (Fig. 7).15 This
site can also be used to place catheters for prolonged analgesia in children.16,17
Fig. 7. Ultrasound image of the infraclavicular block; at this location, the medial (MC), pos-
terior (PC), and lateral (LC) cords are seen around the axillary artery (AA).
Technique
A lateral approach is described to complete the ultrasound-guided infraclavicular
block in pediatrics.6 The ultrasound probe is positioned below the clavicle in a trans-
verse orientation to identify the brachial plexus. The needle is inserted inferior to the
probe and advanced using an out-of-plane technique.18 The needle is directed later-
ally to the cords of the brachial plexus, avoiding vascular structures as local anesthetic
is deposited into the deep portion of the neurovascular sheath. Alternatively, De José
Marı́a and colleagues15 positioned the probe parallel to the clavicle in a parasagittal
plane and directed the needle in a cephalad direction toward the brachial plexus.
Complications
Infraclavicular block confers similar risks to that of the supraclavicular block, including
the risk of a pneumothorax.19 The close proximity of the cervical pleura should be
noted. Additionally, the location of the axillary artery and vein make vascular puncture
possible.
TRUNCAL BLOCKS
The use of ultrasonography has increased the use of truncal blocks in pediatrics. The
emerging role of minimally invasive surgical techniques in children has expanded the
spectrum of patients that benefit from the completion of these blocks. Ultrasound-
guided techniques have increased the success rate as well as the safety of truncal
blocks.
TRANSVERSUS ABDOMINIS PLANE BLOCK

The transversus abdominis plane (TAP) block provides analgesia to the anterior
abdominal wall. It is important to note that the TAP block provides effective postoper-
ative pain control but not surgical analgesia.20 This block is commonly used for lapa-
roscopic procedures to provide analgesia for port placement sites as well as for larger
abdominal incisions.21 Three muscle layers are identified lateral to the rectus abdom-
inis: the external oblique, internal oblique, and the transversus abdominis (Fig. 8). The
TAP lies between the internal oblique and transversus abdominis muscles. It is within
this plane that the thoracolumbar nerve roots (T8–L1) traverse. These nerves deliver
Fig. 8. Anatomy of the TAP block with the ultrasound.

270 Suresh et al
sensory innervation to the skin and muscles of the anterior abdominal wall.21 A cath-
eter can be placed in the TAP to provide continuous analgesia in patients where the
neuraxial technique is avoided.22,23
Technique
An in-plane approach is used with ultrasound guidance to advance the needle into the
TAP where local anesthetic is delivered.20,23 The ultrasound probe is positioned adja-
cent to the umbilicus and moved laterally, away from the rectus abdominis, until the 3
muscle layers of the abdominal wall are visualized (Fig. 9).24,25 The needle is advanced
using an in-plane technique starting from either the lateral or medial side. Injection of
local anesthetic creates an elliptical pocket of local anesthetic in the TAP.
Complications
Potential complications include infection, peritoneal and/or bowel puncture, and intra-
vascular injection.
ILIOINGUINAL/ILIOHYPOGASTRIC NERVE BLOCK

The ilioinguinal/iliohypogastric (IL/IH) nerves provide sensation to the inguinal area and
the anterior scrotum and originate from T12 and L1 of the thoracolumbar plexus.20 The
IL/IH nerves are blocked medial to the anterior superior iliac spine as they travel across
the internal oblique aponeurosis. Successful blockade of the IL/IH nerves provides
equivalent relief to caudal blocks for inguinal surgery with the benefit of increased
duration of analgesia.26,27
Technique
The ultrasound probe is placed medial to the anterior superior iliac spine, in line with
the umbilicus (Fig. 10). Three abdominal muscle layers are identified by ultrasonogra-
phy (internal oblique, external oblique, and transversus abdominis). At this level, the
external oblique muscle layer can be aponeurotic and only 2 muscle layers may be
recognized.28 The IL/IH nerves appear as ovular structures between the internal obli-
que and transverse abdominal muscles (Fig. 11). The needle is inserted in-plane and
advanced to the IL/IH nerves to deposit the local anesthetic. The use of ultrasound
guidance has been demonstrated to reduce the volume of local anesthetic needed
to produce analgesia.29,30
Fig. 9. Probe placement for the TAP block.

Fig. 10. Probe placement for the IL/IH block. The probe is placed between the anterior
superior iliac spine and the umbilicus.
Complications
The IL/IH nerve block can rarely cause injection-site infection, intravascular injection,
bowel puncture, pelvic hematoma, and femoral nerve palsy.
RECTUS SHEATH BLOCK

The rectus sheath block provides analgesia to the anterior abdominal wall along the
midline. At this location, the rectus abdominis muscle lies on the anterior abdominal
wall and is separated by the linea alba (Fig. 12). The thoracolumbar nerves (T7–T11)
lie posterior to the rectus abdominis muscle just above the posterior sheath. The
rectus sheath block is commonly used to provide postoperative pain relief for umbil-
ical hernia and single-incision laparoscopic surgery.31
Technique
The ultrasound probe is placed lateral to the umbilicus so the rectus abdominis muscle
is identified as the only muscle layer (Fig. 13). The posterior sheath lies just below the
rectus abdominis and above the peritoneum (see Fig. 12). Using an in-plane tech-
nique, the needle is advanced in a lateral-to-medial direction to deposit local anes-
thetic between the rectus abdominis muscle and its posterior sheath.32 Careful
Fig. 11. IL/IH as seen on the ultrasound.

272 Suresh et al
Fig. 12. Ultrasound image of the rectus sheath block. Local anesthetic should be deposited
between the rectus abdominis muscle (RA) and Posterior Rectus Sheath (PS).
attention should be made to avoid injection of the local anesthetic in between the 2
layers of the posterior rectus sheath because this will result in block failure.
Complications
Complications include infection, intravascular injection, and bowel puncture.
LOWER EXTREMITY BLOCKS

Femoral Nerve Block
Anatomy and indications
The femoral nerve provides innervation to the anterior thigh and the knee. It originates
from the L2, L3, and L4 nerve roots and is commonly blocked in pediatrics for surgical
interventions in the knee. The femoral nerve is anatomically lateral to the femoral artery
and vein. This neurovascular bundle is easily seen with ultrasonography when the
probe is placed in the inguinal crease (Fig. 14).33 In addition to a single-shot technique,
a catheter can be safely placed to provide extended analgesia.34,35
Technique
With the patient in the supine position, the femoral nerve, artery, and vein are located
within the inguinal crease. Once the probe is placed in the inguinal crease, the femoral
artery is identified as a pulsatile structure. Lateral to this, the femoral nerve is identified
Fig. 13. The ultrasound probe is placed lateral to the umbilicus for the rectus sheath block.
Fig. 14. Probe placement for the femoral nerve block.
and the femoral vein is visualized just medial to the artery as a collapsible vessel
(Fig. 15). An in-plane or out-of-plane approach can be used to guide the needle to
the lateral portion of the femoral nerve and circumferentially surround it with local
anesthetic.34,36 Careful visualization of the needle with advancement will avoid inad-
vertent vascular puncture of the femoral vessels.
Complications
Complications include infection, nerve injury, and hematoma formation caused by the
femoral nerve’s juxtaposition to the vein and artery.
Saphenous Nerve Block

The saphenous nerve provides innervation to the knee and the medial portion of the
leg below the knee. It is a branch of the femoral nerve and travels within the adductor
canal and runs adjacent to the sartorius muscle before continuing to the medial aspect
of the knee (Fig. 16). It can be blocked proximally to provide sensory analgesia to the
anterior knee or can be blocked more distally to provide analgesia solely to the medial
aspect of the lower extremity.36
Fig. 15. Ultrasound image of the femoral nerve.

274 Suresh et al
Fig. 16. Ultrasound image of the saphenous nerve (SN) adjacent to the sartorius muscle.
Technique
With patients in the supine position, the leg is abducted and laterally rotated as the
probe is placed on the medial aspect of the knee. The sartorius muscle is identified,
and juxtaposed to this is the saphenous nerve. The needle is directed using an in-
plane technique to the saphenous nerve, where the local anesthetic is deposited
(Fig. 17).
Complications
Complications include nerve injury, hematoma from arterial puncture, and infection.
Sciatic Nerve Block

The sciatic nerve provides innervation to the posterior thigh and the entire leg distal to
the knee (excluding the medial component). The sciatic nerve originates from the
Fig. 17. Probe placement for a saphenous nerve block proximal to the knee.
nerve roots of L4 to S3. From its origin, the nerve courses through and exits the pelvis
via the greater sciatic foramen and continues inferiorly to the gluteus maximus muscle.
The sciatic nerve continues to course through the posterior popliteal fossa where it
splits into the tibial and common peroneal nerves (Fig. 18). The sciatic nerve can be
blocked throughout its anatomic course at the subgluteal, anterior thigh, or popliteal
approaches in children.37,38 Continuous sciatic nerve blockade, as well as a single-
shot technique, can provide extended analgesia in children.39,40
Technique
The subgluteal approach to the sciatic nerve requires patients to lie in either the lateral
decubitus position, with the hip and knee flexed, or in the prone position. In these po-
sitions, the ultrasound probe is placed between the greater trochanter and the ischial
tuberosity. The gluteus maximus muscle is identified, and deep to this is the sciatic
nerve. An in-plane or out-of-plane technique can be used to advance the needle
with ultrasound guidance to the nerve.41,42 Local anesthetic is injected to circumferen-
tially surround the nerve in a single-shot technique, but a catheter can also be placed
to deliver continuous nerve blockade.43
The use of the ultrasound has facilitated the performance of an anterior approach to
the sciatic nerve blockade, during which patients may remain in the supine position.44
This technique allows for the completion of the sciatic nerve block in nonanesthetized
patients with lower extremity discomfort without moving them to the lateral or prone
position. While supine, the patients’ leg is abducted and laterally rotated and the probe
is placed inferior to the inguinal crease. The femur is identified, and the probe is moved
medially to reveal the sciatic nerve in its location deep and medial to the femur. The
nerve often lies deeper in larger patients, which can make this approach technically
challenging to complete in older children.
The sciatic nerve can also be blocked more distally in the popliteal fossa.45 Patients
are placed prone or can remain in the supine position, and the ultrasound probe is
placed in the popliteal crease (Fig. 19). The popliteal artery is visualized as a pulsatile
structure. Immediately adjacent to the artery is the tibial nerve. The tibial nerve can be
followed proximally to the junction with the common peroneal nerve, merging together
Fig. 18. Ultrasound image of the confluence of the common peroneal nerve (CP) and tibial
nerve (T) from the sciatic nerve.
276 Suresh et al
Fig. 19. Probe placement for the sciatic nerve block at the popliteal fossa while a patient is
supine.
to form the sciatic nerve. The sciatic nerve can be blocked here or the tibial and com-
mon peroneal nerves can be specifically targeted at this location.
Complications
Complications include infection at the site of skin puncture, hematoma from vessel
puncture, and local anesthetic toxicity.
Lumbar Plexus Block
The lumbar plexus originates from the nerve roots from T12 to L5. Its branches include
the femoral, genitofemoral, lateral femoral cutaneous, and obturator nerves. The lum-
bar plexus provides innervation to the lower abdomen and the upper leg and is located
within the psoas muscle deep to the paravertebral muscles. The lumbar plexus can be
blocked with the ipsilateral sciatic nerve to achieve complete analgesia to the lower
extremity.46
Technique
Patients are placed in the lateral decubitus position, and the iliac crest and spinous
processes are identified. The ultrasound probe is placed lateral to the midline, and
the L4 or L5 transverse processes are located. Deep to the transverse process are
the erector spinae and quadratus lumborum muscles. Beyond this, within the psoas
major muscle, is the lumbar plexus. Because of this anatomic location, the plexus is
often difficult to demarcate from the similar echogenicity to the muscle. Nerve stimu-
lation may be used in conjunction with ultrasonography to elicit twitches of the quad-
riceps muscles and confirm needle positioning near the plexus.
Complications
Complications include infection, hematoma, and retroperitoneal bleeding caused by
the location of the plexus.
SUMMARY
The use of ultrasonography has expanded the scope and applicability of regional
anesthesia in children, which is evidenced by the progressive increase in the use of
peripheral regional anesthesia in pediatric patients.47 Ultrasonography allows for
real-time visualization of needle advancement and local anesthetic spread. This
visualization may decrease the total volume of local anesthetic required to achieve
successful nerve blockade; however, additional data are needed to confer the benefits
and risks to patients. In addition, compared with nerve stimulation, the use of ultra-
sound does not require the avoidance of neuromuscular blockade. Nerve stimulation
continues to play a vital role in regional anesthesia,48 and available data demonstrate
the individual benefits of both the nerve stimulation and ultrasound-guided tech-
niques.49 Successful implementation of regional anesthesia in pediatrics is a vital
component in ensuring an optimal surgical experience for children.
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7. O’Donnell BD, Iohom G. An estimation of the minimum effective anesthetic vol-
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8. Diwan R, Lakshmi V, Shah T, et al. Continuous axillary block for upper limb sur-
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12. Fredrickson MJ. Ultrasound-assisted interscalene catheter placement in a child.
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16. Mariano ER, Ilfeld BM, Cheng GS, et al. Feasibility of ultrasound-guided periph-
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oping countries. Paediatr Anaesth 2008;18:598–601.
17. Ponde VC. Continuous infraclavicular brachial plexus block: a modified tech-
nique to better secure catheter position in infants and children. Anesth Analg
2008;106:94–6.
18. Diwan R, Raux O, Troncin R, et al. Continuous infraclavicular brachial plexus
block for acute pain management in children. Anesth Analg 2003;97:691–3.
19. Ilfeld BM, Morey TE, Enneking FK. Infraclavicular perineural local anesthetic infu-
sion: a comparison of three dosing regimens for postoperative analgesia. Anes-
thesiology 2004;100:395–402.
20. Suresh S, Chan VW. Ultrasound guided transversus abdominis plane block in
infants, children and adolescents: a simple procedural guidance for their perfor-
mance. Paediatr Anaesth 2009;19(1):296–9.
21. McDonnell JG, O’Donnell B, Curley G, et al. The analgesic efficacy of transversus
abdominis plane block after abdominal surgery: a prospective randomized
controlled trial. Anesth Analg 2007;104(1):193–7.
22. Visoiu M, Boretsky KR, Goyal G, et al. Postoperative analgesia via transversus
abdominis plane (TAP) catheter for small weight children - our initial experience.
23. Taylor L, Birmingham P, Yerkes E, et al. Children with spinal dysraphism: transversus
abdominis plane (TAP) catheters to the rescue! Paediatr Anaesth 2010;20:951–4.
24. Pak T, Mickelson J, Yerkes E, et al. Transverse abdominis plane block: a new
approach to the management of secondary hyperalgesia following major abdom-
inal surgery. Paediatr Anaesth 2009;19(1):54–6.
25. Fredrickson M, Seal P, Houghton J. Early experience with the transversus abdom-
inis plane block in children. Paediatr Anaesth 2008;18:891–2.
26. Jagannathan N, Sohn L, Sawardekar A, et al. Unilateral groin surgery in children:
will the addition of an ultrasound-guided ilioinguinal nerve block enhance the
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19(1):892–8.
27. Hannallah RS, Broadman LM, Belman AB, et al. Comparison of caudal and ilioin-
guinal/iliohypogastric nerve blocks for control of post-orchiopexy pain in pediatric
ambulatory surgery. Anesthesiology 1987;66:832–4.
28. Markham SJ, Tomlinson J, Hain WR. Ilioinguinal nerve block in children. A com-
parison with caudal block for intra and postoperative analgesia. Anaesthesia
1986;41:1098–103.
29. Willschke H, Marhofer P, Bösenberg A. Ultrasonography for ilioinguinal/iliohypo-
gastric nerve blocks in children. Br J Anaesth 2005;95(2):226–30.
30. Smith T, Moratin P, Wulf H. Smaller children have greater bupivacaine plasma
concentrations after ilioinguinal block. Br J Anaesth 1996;76:452–5.
31. Ferguson S, Thomas V, Lewis I. The rectus sheath block in paediatric anaes-
thesia: new indications for an old technique? Paediatr Anaesth 1996;6:463–6.
32. Willschke H, Bosenberg A, Marhofer P, et al. Ultrasonography-guided rectus
sheath block in paediatric anaesthesia: a new approach to an old technique.
Br J Anaesth 2006;97:244–9.
33. Oberndorfer U, Marhofer P, Bösenberg A, et al. Ultrasonographic guidance for
sciatic and femoral nerve blocks in children. Br J Anaesth 2007;98(6):797–801.
34. Casati A, Baciarello M, Di Cianni S, et al. Effects of ultrasound guidance on the
minimum effective anaesthetic volume required to block the femoral nerve. Br J
Anaesth 2007;98:823–7.
35. Johnson CM. Continuous femoral nerve blockade for analgesia in children with
femoral fractures. Anaesth Intensive Care 1994;22:281–3.
36. Simion C, Suresh S. Lower extremity peripheral nerve blocks in children. Tech
Reg Anesth Pain Manag 2007;11:222–8.
37. van Geffen GJ, Scheuer M, Muller A, et al. Ultrasound-guided bilateral continuous
sciatic nerve blocks with stimulating catheters for postoperative pain relief after
bilateral lower limb amputations. Anaesthesia 2006;61:1204–7.
38. van Geffen GJ, Gielen M. Ultrasound-guided subgluteal sciatic nerve blocks with
stimulating catheters in children: a descriptive study. Anesth Analg 2006;103:
328–33.
39. Ganesh A, Rose J, Wells L, et al. Continuous peripheral nerve blockade for inpa-
tient and outpatient postoperative analgesia in children. Anesth Analg 2007;
105(5):1234–42.
40. Ilfeld BM, Morey TE, Wang RD, et al. Continuous popliteal sciatic nerve block for
postoperative pain control at home. Anesthesiology 2002;97:959–65.
41. Chelly JE, Greger J, Casati A, et al. Continuous lateral sciatic blocks for acute
postoperative pain management after major ankle and foot surgery. Foot Ankle
Int 2002;23:749–52.
42. Dadure C, Bringuier S, Nicolas F, et al. Continuous epidural block versus contin-
uous popliteal nerve block for postoperative pain relief after major podiatric sur-
gery in children: a prospective comparative randomized study. Anesth Analg
2006;102:744–9.
43. Vas L. Continuous sciatic block for leg and foot surgery in 160 children. Paediatr
Anaesth 2005;15:971–8.
44. Tsui BC, Ozelsel TJ. Ultrasound-guided anterior sciatic nerve block using a lon-
gitudinal approach: “expanding the view”. Reg Anesth Pain Med 2008;33:275–6.
45. Schwemmer U, Markus CK, Greim CA, et al. Sonographic imaging of the sciatic
nerve and its division in the popliteal fossa in children. Paediatr Anaesth 2004;14:
1005–8.
46. Johr M. The right thing in the right place: lumbar plexus block in children. Anes-
thesiology 2005;102:865–6.
47. Tsui B, Suresh S. Ultrasound imaging for regional anesthesia in infants, children,
and adolescents: a review of current literature and its application in the practice
of extremity and trunk blocks. Anesthesiology 2010;112:473–92.
48. Klein S, Melton S, Grill W, et al. Peripheral nerve stimulation in regional anes-
thesia. Reg Anesth Pain Med 2012;37:383–92.
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ultrasound-guided regional anesthesia and pain medicine: executive summary.
Reg Anesth Pain Med 2010;35:S1–9.
Perspectives on Quality and
S a f e t y i n Pe d i a t r i c A n e s t h e s i a
David Buck, MD, MBA*, C. Dean Kurth, MD,
Anna Varughese, MD, MPH
KEYWORDS
Quality improvement Pediatric anesthesiology Safety analytics Measurement
Wake Up Safe
KEY POINTS
Organizational culture underlies every improvement strategy; without a strong culture, a
change, even if initially successful, is short lived.
Changing culture and improving quality require commitment of leadership, and leaders
must play an active and visible role to articulate the vision and create the proper
environment.
Quality-improvement (QI) projects require a consistent framework for improvement,
because the framework provides the structure for outlining a process, identifying prob-
lems, and testing, evaluating, and implementing changes.
Wake Up Safe is a patient safety organization composed of pediatric institutions, which
strives to use QI to make anesthesia care safer.
Root cause analysis (RCA) is a widely used methodology in safety analytics that is based
on a sequence of events model of safety.
INTRODUCTION
It is the professional responsibility of pediatric anesthesiologists to deliver care to the

best of their ability in the operating room.1 In reality, however, the factors that underlie
individual decisions and practices are more complex than simply “doing their best.”
They involve the systemic interactions of coordination of care, organizational culture,
communication between nursing and surgical teams, and practice guidelines.
Improving care requires an evolution in understanding how these systems interact
and deliberate testing of how changes affect their performance.
It is difficult to acknowledge that pediatric care is inadequate or, worse, harmful. Ac-
cording to the 2012 National Healthcare Quality Report,2 overall health care quality
Department of Anesthesiology, Cincinnati Children’s Hospital, 3333 Burnet Avenue, Cincinnati,

OH 45229, USA
E-mail address: David.Buck@cchmc.org

282 Buck et al
may be improving. Even so, as of 2009, Americans received only 70% of indicated
health care services needed for treating or preventing illness. Unfortunately, there is
no reason to believe similar deficiencies do not exist in pediatric anesthesia.
There are meaningful, systematic ways to increase the quality of care. Intermountain
Healthcare in Salt Lake City, Utah, was one of the first health care systems to pursue
clinical QI.3 Virginia Mason Medical center in Seattle, Washington, drove down waste
using Lean management principles.4 The common denominator in these organizations
is the use of a structured and systematic approach to QI and a culture that supports its
implementation.
At Cincinnati Children’s Hospital Medical Center (CCHMC), QI has become integral
to patient safety, patient and family satisfaction, efficiency, and cost. Its QI initiatives
continue to grow and mature as successes and failures are learned from. Key learning
areas in the QI journey have included a culture of improvement, institutional leader-
ship, QI training, and frameworks and tools for improvement.
THE CULTURE OF IMPROVEMENT
Organizational culture underlies every improvement strategy. Without a strong culture, a

change, even if initially successful, is short lived. It is not uncommon that an improve-
ment project, successful at one institution, fails when transplanted to a new environment.
The difference between success and failure may be differing organizational cultures.
Broadly, culture may be defined as “shared values and beliefs that interact with a
company’s people, organizational structures and control systems to produce behav-
ioral norms.”5 A culture of safety is one that encourages open discussion of mistakes,
transparency, and systems-based thinking as opposed to blaming individuals. At the
personal level, this means providers feel comfortable openly reporting and talking
about adverse events and near misses. At the organizational level, it means being
transparent about errors and shortcomings. Some organizations have gone so far
as to publish their adverse events and QI initiatives.
Organizational culture is complex and change is difficult. Poor leadership, perceived
lack of ownership, constraints of external stakeholders and professional allegiances,
and subcultural diversity all hinder culture change.6 Fortunately, there are several tools
and methods available to help navigate the complexity of measuring and implement-
ing a change in culture.
It is just as important to monitor safety culture, as it is to monitor clinical metrics.
Several surveys exist to measure safety culture at hospitals. For example, the
Agency for Healthcare Research and Quality (AHRQ) has developed and validated
a survey for hospitals on safety culture. Statements, such as the following, are
assessed on a scale of 1 to 5:
“People support one another in this unit.”
“Staff feel like their mistakes are held against them.”
“My supervisor/manager says a good word when he/she sees a job done accord-
ing to established patient safety procedures.”
The AHRQ also provides guidance on setting up the survey and analyzing the data.
Once a baseline is determined, repeating these surveys every 6 months is recommen-
ded until the goal is achieved and then yearly thereafter.7
Following baseline data, a first step may be to give employees and staff the tools to
discover current problems for themselves. A question often posed to employees is,
“How will the next patient be harmed?” It often takes years to bring about a measur-
able change in culture.
Quality and Safety in Pediatric Anesthesia 283
LEADERSHIP IN QUALITY IMPROVEMENT
Changing culture and improving quality require commitment of leadership. Leaders must
play an active and visible role to articulate the vision and create the proper environment.
This means creating a culture of continuous improvement; aligning QI projects with stra-
tegic objectives; providing appropriate incentives; and ensuring adequate resources,
such as time, administrative support, and information technology.
Some of the specific ways leadership promotes QI at CCHMC include
Development of a departmental quality scorecard
Presentation of data and goals on quality measures at quarterly staff meetings
Highlighting QI projects at clinical steering meetings
Participation in RCAs
Reviewing reported adverse events and near misses
Training new faculty and students on quality indicators and process improvement
Linking personal and department measures with financial incentives
Participation in organizational QI programs, both as mentors and as students8
Characteristics of Leadership
Certain kinds of leaders may be particularly effective at bringing about change. Man-
agement researcher Jim Collins examined more than 1400 companies looking for
attributes that led companies to achieve greatness. He discovered that a particular
kind of leadership, what he termed, level 5 leadership, is instrumental in organizational
transformation. A level 5 leader is one who paradoxically has both deep personal
humility and intense professional will. These leaders have exacting standards and
resolve to reach long-term goals. At the same time, they are able to put the organiza-
tion and greater purpose above seeking personal adulation.9
Taking on Leadership Roles as a Physician
The transition from practitioner to leader may be particularly difficult for physicians.
Physicians traditionally function as independent practitioners. In QI, however, they
may be asked to take on new roles as both team members and leaders. This transition
is often difficult and may require completely new skill sets than those taught in medical
school or residency.
A physician leader’s role requires balancing the goals of multiple stakeholders,
including the hospital, the department, and fellow colleagues. Negotiating these chal-
lenges requires an understanding of how the system functions as a whole. It also re-
quires interpersonal skills, such as proficiency in speaking and writing, open and
honest communication, negotiation, and motivation.
TRAINING IN LEADERSHIP AND QUALITY IMPROVEMENT
Leadership and QI training are shown to improve skills, knowledge, and even patient
care processes.10 Although there are not yet studies linking QI training to improved pa-
tient outcomes,10 it is reasonable to believe that these skills and knowledge sets trans-
late into better patient care. Many of these training programs create not only experts in
QI but also leaders and teachers, further extending their influence on health care.
QI training varies among industries and organizations. Internal training includes
formal hospital training programs, individual mentors, or informal on-the-job training.
The Advanced Training Program in Clinical Practice Improvement, developed by Inter-
mountain Healthcare, represents an example of an internally developed program. It
sought to bridge the gap between system improvement knowledge and professional
284 Buck et al
knowledge. Today, the program serves as an example for other institutions wishing to
create their own QI programs.3
External training includes professional degree programs, such as master of busi-
ness administration (MBA) and master of public health programs; online courses,
such as the Institute for Healthcare Improvement (IHI) Open School; and seminars
and workshops sponsored by consultants or professional societies. The IHI Open
School is an example of an online educational community. The Open School features
online courses, including a certificate program, forums, and a vast collection of multi-
media content. It is available at no charge to students in the health professions. As an
alternative to traditional MBA programs, many physicians are pursuing executive
MBAs. Executive MBAs are structured to allow professionals to enroll without leaving
their current job for the duration of the program. In addition, certain business schools
offer MBAs with a concentration in health care management.
A typical QI training program combines practical projects with knowledge-based
coursework. Studies have indicated this combination is more effective than providing
either option alone.10 Many programs emphasize testing small changes over time with
objective data through plan, do, study, act (PDSA) cycles and the Model For Improve-
ment. Other programs teach Six Sigma and Lean methodologies to improve efficiency
and smooth production flow.11 The trend in these programs is toward interdisciplinary
training, integrating people from different departments and backgrounds.
At CCHMC, an internal program, the Intermediate Improvement Science Series, has
been critical to the development of leaders in QI. Members from each department are
nominated to attend the course, which runs 6 months, with classes 2 days per month.
Over this period, attendees work with an improvement coach and their department
sponsor in formulating and managing an improvement project. The improvement proj-
ect is supported by workshops, seminars, and readings in the course. The classes are
multidisciplinary and students learn from each other as well as previous graduates.
Back in their own departments, students manage improvement projects and share
their knowledge with other department members.12,13
CHOOSING A FRAMEWORK FOR IMPROVEMENT
QI projects require a consistent framework for improvement. The framework provides the
structure for outlining a process; identifying problems; and testing, evaluating, and imple-
menting changes. Furthermore, it provides a tool to communicate the project to others.
Examples of popular frameworks include the IHI Model for Improvement, Toyota
Lean methodology, and GE Six Sigma. These frameworks share similar principles.
Their origins are often in industries entirely outside of health care. As an example,
the Virginia Mason Production System is a management methodology developed by
Virginia Mason Medical Center that originated from Lean methodology and the Toyota
Production System.4 Additionally, frameworks may be combined; for example, Lean
Six Sigma is a combination of Lean and Six Sigma.
THE MODEL FOR IMPROVEMENT
The Model for Improvement is a popular framework used at Cincinnati Children’s Hos-
pital (Fig. 1). It begins by asking 3 questions of change that help frame the improve-
ment project:
What are we trying to accomplish?
How will we know that a change is an improvement?
What changes can we make that will result in improvement?
Fig. 1. The Model for Improvement. (From Langley GJ, Moen RD, Nolan KM, et al. The
improvement guide: a practical approach to enhancing organizational performance. San
Francisco (CA): Jossey-Bass; 2009; with permission.)
These questions are evaluated by designing experiments known as small tests of

change, or PDSA cycles.14 Each cycle provides learning about the process, which
is used in planning the next cycle. Changes that are successful may be implemented
on a wider scale or expanded to other areas. Tests of change that are not successful
are modified through repeated cycles or discarded. Testing changes on a small scale
through PDSA cycles mitigates the risk of implementation of a bad process. As new
knowledge is gained through small tests, a theory of how the system functions is
formulated. This theory aids in developing and selecting future interventions and
applying them to new environments.
MEASURING QUALITY OF CARE IN PEDIATRIC ANESTHESIA

Defining Quality
In order to determine if a change is successful, appropriate quality measures must be
established and tracked over time. To determine these measures, it is necessary to
understand what defines quality care. The Institute of Medicine provides 6 aims of
health care. These aims state that health care should be
Safe—no patient should be harmed by health care
Effective—evidence-based treatment should be used when available
Patient centered—there should be a respectful approach to patient preferences,
needs, and values
286 Buck et al
Timely—delays should be reduced because these may affect satisfaction,

diagnosis, and treatment
Efficient—waste should be reduced or value increased
Equitable—the same care should be provided regardless of personal
characteristics.15–17
In pediatric anesthesia, it is helpful to imagine the ideal anesthetic experience for
children and their families. Some examples across the intraoperative process are
Preoperative process: timely, accurate history; thorough education; encourages
questions
Induction: no unnecessary anxiety or discomfort; appropriate parental
participation
Intraoperative experience: no serious adverse events
Postanesthesia care unit (PACU): pain managed and treated in a timely fashion
Postoperative course: no unexpected ICU or hospital admission.
Types of Measures
The categories of quality measures include outcome measures, process measures,
structural measures, and balancing measures. Ideally, a QI project has one measure
from each category, which is not always practical. For example, an outcome may
be so rare that measurement is problematic. A process measure, on the other hand,
may not correlate with outcomes, and should be based on evidence-based guidelines
when possible. Any change, especially in a complex system like health care, may
result in unintended consequences. Balancing measures look for unintended conse-
quences and can provide a more comprehensive understanding of the effects of a
change.
RUN CHARTS AND CONTROL CHARTS
After quality measures are determined, they are measured and tracked over time.
Baseline data should be collected prior to testing changes and all interventions within
the period of data collection should be noted.
Run charts and control charts are used to track data in QI. A run chart plots the var-
iable over time. The mean, or median, is included on the chart as a method of centering
the sample. In a control chart, upper and lower control limits are calculated to deter-
mine whether or not a process is stable, referred to as “in control.”
In Fig. 2, a control chart plots patient and family satisfaction with pain control in a
PACU. Most of the data are within the upper and lower control limits indicating this
process is in control.18
IMPROVEMENT TOOLS
Improvement tools, such as a key driver diagram, fishbone diagram, or process flow-
chart, may be applied within any framework to gain additional insight into a process.
Key Drivers
Key drivers are the driving elements behind an improvement project, and they are crit-
ical to understanding the theory behind improvement. Key drivers help develop future
interventions and apply successful interventions to new environments. They also help
others, perhaps in different organizations, apply the improvement to their unique
environment.
Fig. 2. A control chart for patient and family satisfaction with pain control in the PACU at
Cincinnati Children’s Hospital. (Courtesy of Department of Anesthesiology, Cincinnati Chil-
dren’s Hospital, Cincinnati, OH; with permission.)
Once the key drivers are identified, interventions are developed to target each key
driver. The key drivers may be thought of as the “how” and the interventions thought of
as the “what” of the improvement project. It may take multiple tests of change across
several key drivers before an improvement is realized.
An example of key drivers for improving patient and family satisfaction with pain in
the CCHMC PACU is listed in Fig. 3. The key drivers, such as “Parental Understanding
of Pain in the PACU,” are traditionally stated in the affirmative. They are specific
enough that interventions can be developed. For example, “Knowledge” is too broad
for a key driver. Several interventions are targeted at this key driver, including high-
lighting a “pain page” to parents in preoperative educational material and a preoper-
ative pain and delirium consultation.
Flowchart
A flowchart can also be used to gain better understanding of a process. A flowchart is
a graphic representation of how a process works. It should represent the current pro-
cess, not a goal or ideal process. A high-level flowchart consists of 6 to 12 steps and
helps give a balcony view of a process. A detailed flowchart examines the process and
its complexity at a much closer level and may contain many individual steps.19–21 The
flowchart presented in Fig. 4 is a high-level flowchart and represents the process used
at CCHMC to ensure children receive muscle relaxation during intubation when appro-
priate. This process was the result of a QI project at CCHMC to reduce serious airway
events and airway-related cardiac arrests in the operating room and PACU.
FAILURE MODES AND EFFECTS ANALYSIS
Failure modes and effects analysis (FMEA) is a proactive tool for preventing adverse
events. It examines a process to determine points of failure and identify potential
288 Buck et al
Fig. 3. Example key driver diagram for improving patient and family satisfaction in the
PACU and subsequent interventions. Abbreviations: LOR, Level of Reliability; SDS, Same
Day Surgery. (Courtesy of Department of Anesthesiology, Cincinnati Children’s Hospital,
Cincinnati, OH; with permission.)
Fig. 4. Example flowchart of a current process at CCHMC for giving muscle relaxants during
intubation. This process was developed to reduce serious airway events and airway cardiac
arrests in the operating room and PACU. (Courtesy of Department of Anesthesiology, Cincin-
nati Children’s Hospital, Cincinnati, OH; with permission.)
interventions. FMEAs work best when applied to smaller processes. Larger pro-
cesses may need to be subdivided. First, each step in the process is determined.
Each of these steps is then examined for potential failures. Failures may be priori-
tized based on likelihood of occurrence, likelihood of detection, and severity. Finally,
possible interventions for the failures in each step are determined.
Fig. 5 shows an example of an FMEA examining the process of an anesthesia
provider receiving narcotics from the pharmacy, administering them to a patient,
and discarding waste or returning unused vials. Parts of this process that could go
wrong are listed beneath each step, such as a dirty needle or syringe being used.
Possible interventions are listed above each step.22
A key driver diagram, flowchart, and FMEA are just a sample of tools used in QI
and safety analytics. The Quality and Safety Committee of the Society of Pediatric
Anesthesia (SPA) and Wake Up Safe are example organizations using these tools
as part of a larger framework, such as the Model for Improvement, or when
conducting RCA.
QUALITY AND SAFETY COMMITTEE OF THE SOCIETY OF PEDIATRIC ANESTHESIA
The Quality and Safety Committee of the SPA is composed of more than 40 members
representing the anesthesiology and pediatric anesthesiology departments of their
member institutions.
The group promotes QI and patient safety in pediatric anesthesia through initiatives,
such as a critical events checklist and an intraoperative handoff tool, both of which are
freely available on the SPA Web site (http://www.pedsanesthesia.org/).
Fig. 5. Example FMEA of the intraoperative administration of narcotics in a children’s hos-

pital. (Courtesy of Department of Anesthesiology, Cincinnati Children’s Hospital, Cincinnati,
OH; with permission.)
290 Buck et al
Critical Events Checklists

Certain intraoperative events, such as air embolism or malignant hyperthermia, occur
so infrequently that it is challenging for anesthesiologists to become proficient in their
management. Checklists have proved an effective tool to aid providers in these rare
situations. Studies in simulation have shown that checklists reduce the amount of
crucial steps that are missed in intraoperative emergencies.23
Expanding on the work done for adult event checklists, the Quality and Safety Com-
mittee developed checklists for 17 pediatric anesthesia emergencies. Each checklist
includes a brief summary of the problem and steps to take, including medications
when appropriate. The checklists were developed using research by the National
Aeronautics and Space Administration on checklist usability and were reviewed by hu-
man factors experts. Each checklist was then sent to a different organization for peer
review and, in some cases, was tested in simulation. Recently, the Children’s Hospital
of Philadelphia adapted these checklists for the creation of a mobile application that
includes a built-in timer, timestamps, and weight-based calculators.19,24,25
The checklists developed by the Quality and Safety Committee are
Air embolism
Anaphylaxis
Bradycardia
Cardiac arrest
Difficult airway
Fire: airway and operating room
Hyperkalemia
Hypertension
Hypotension
Hypoxia
Local anesthetic toxicity
Loss of evoked potentials
Malignant hyperthermia
Myocardial ischemia
Tachycardia
Transfusion and reactions
Trauma26
Intraoperative Handoff Tool
It is not uncommon for multiple providers to care for children across the anesthetic
course. The quality and reliability of handoffs between providers can, however, vary
substantially. In an attempt to standardize the handoff process between providers,
the Quality and Safety Committee developed an intraoperative handoff tool. The
tool consists of a checklist incorporating key elements of a patient’s intraoperative
course and background. The CCHMC has had success implementing a similar check-
list in operating rooms.
Categories in the intraoperative handoff tool include
Background information
History
Airway
Cardiac issues
Medications
Fluids
Monitors
WAKE UP SAFE
Wake Up Safe is a patient safety organization composed of pediatric institutions that

strives to use QI to make anesthesia care safer. It was established with the help of the
SPA, and it currently consists of 19 pediatric institutions. The goals of the organization
are to embed QI and safety analytics into pediatric anesthesia departments and insti-
tutions to decrease serious adverse events in children undergoing anesthesia.27
Wake Up Safe is unique in that its work encompasses all adverse events. An adverse
event results in significant harm to a patient. In contrast to a serious safety event, however,
which also results in harm, an adverse event does not imply that an error has occurred.
This allows a broader and more accurate investigation of harm in pediatric anesthesia.
In addition, Wake Up Safe investigates precursor events and near misses. Precursor
events are those that have reached a patient but caused little or no harm. Near misses
are events that did not reach a patient but would have caused harm if they did.
Wake Up Safe also differentiates itself from other patient safety groups by embed-
ding organizations with capability in safety analytics and QI. QI capability is encour-
aged through education and the use of high-reliability processes, such as checklists,
standardization, information technology, and automation.28
Data obtained from Wake Up Safe have offered insight into adverse safety events
occurring in pediatric anesthesia. Since data collection began in July 2010, an average
of 1.4 serious adverse events per 1000 anesthetics have been reported. Although it is
possible that these numbers are affected by under-reporting or over-reporting, this
rate corresponds closely to other rates in the literature.28
Respiratory events were the most common serious adverse event and often arose
from complete airway obstruction treated successfully before progressing to cardiac
arrest. The next most common events in decreasing order were cardiac arrest, care
escalation, and cardiovascular events. In total these categories comprised 76% of
all reported events. Care escalation was defined as events that did not lead to serious
temporary or long-term harm but required additional treatment and resources, such as
unplanned admission to a hospital or ICU. Care escalation events arose from medica-
tion errors (65%), equipment dysfunction (24%), blood reactions (9%), malignant
hyperthermia (1%), and operating room fire (1%).28
In addition, serious adverse events have prompted Wake Up Safe to publish advi-
sories to the pediatric anesthesia community:
An advisory on hyperkalemic cardiac arrest was published after 4 cases of
significant cardiovascular changes after large-volume intraoperative red blood
cell transfusion.
An advisory on preventing wrong-sided procedures was published after 5 such
cases were reported to the organization.
Finally, an advisory on decreasing the risk of intravenous medication errors was
published after 23 adverse events, which were related to medication errors,
including administering the incorrect drug, administering the incorrect dose,
administering via an incorrect route, and omitting a medication, or the result of
a medication reaction.
Further information and recommendations regarding these advisories can be found
on the Wake Up Safe Web site (http://wakeupsafe.org/findings.iphtml).
SAFETY ANALYTICS
RCA, a widely used methodology in safety analytics, is based on a sequence of events

model of safety. It looks in a linear fashion to find the most proximate error. This makes
292 Buck et al
it a practical approach to adverse events and one adopted by Wake Up Safe. An RCA
should be performed after an adverse event, a precursor event, or a near miss that has
potential to seriously harm a patient.
After an event has occurred, a fact-finding team interviews those directly involved.
This team, however, should be objective and not directly involved in the event. It may
also be beneficial to interview others, such as a supervisor or colleague, to understand
circumstances surrounding the event. Was there a particularly high volume that day?
Was staff moved to an area they were unfamiliar with? Are they aware of existing pro-
tocols, and are they typically followed? Wake Up Safe institutions uses 3 anesthesiol-
ogists trained in safety analytics to conduct an RCA on all serious adverse events.
Similar to the fact-finding team, an RCA team is composed of members familiar with
patient safety and not directly involved in the case. Members often include represen-
tatives from medical, legal, nursing, and administration. The team constructs a
sequence of events from the gathered facts. For comparison, they may also establish
a sequence of events of the way the process normally runs at the hospital. Flowcharts
are often used to map these sequences. The team also reviews applicable policies
and guidelines of the hospital.
After analysis of gathered information, the team works to establish proximate and
contributing causes. The proximate cause is the cause that, when removed, would
most likely have prevented the adverse event from occurring. Contributing factors
are those that, if removed, would have lessened the probability of the event or less-
ened its severity.
Once proximate and contributing causes are established, an action plan is created
to reduce the likelihood of a similar adverse event occurring. Interventions are devel-
oped for each proximate cause. The goal is to insert technologies or processes into
the system to prevent the error from occurring again. The objective is not to point
blame at individuals.
A specific, measurable, achievable, relevant, and timely (SMART) aim should be
established for each intervention, similar to when implementing a change in a PDSA
cycle. Individuals responsible for the interventions should be identified, and measures
of successful implementation should be tracked.
SPREADING CHANGE AND INNOVATION
A test of change, even after it has proved effective, still requires implementation and
dissemination for improvement to occur in the system of care. The spread of a change
usually proves more difficult than the test. Health care is notoriously slow to adopt
changes, even those that are evidence based.
Understanding the life cycle of innovation helps spread change through a depart-
ment, an organization, or even a health care system. Everett M. Rogers29 describes
5 groups of individuals in the adoption of an innovation. Communication and personal
connections are critical for the flow of innovation between groups.
Innovators are the first group to accept the innovation. They are often more
adventurous and tolerant of risk.
Early adopters are the next group to adopt the innovation. Unlike innovators, this
group is socially well connected and thought of as thought leaders.
The early majority are more risk adverse. They rely on familiarity and personal
connections, including looking to early adopters.
The late majority wait until an innovation has become the status quo.
Laggards are the last group to accept an innovation. They are traditionalists who
have skepticism for anything that is not tried and true.29
An often-cited phrase in QI is that not all change leads to improvement, but all
improvement requires change. A systematic approach to change, such as that
outlined in the Model for Improvement, increases the odds of success, minimizes
risk, reduces time, and ultimately spreads innovation. The authors firmly believe these
approaches have successfully increased quality of care for children at CCHMC. The
spread of these tools and the open sharing of successes and failures will further the
improvement of pediatric anesthesiology.
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I ndex
Note: Page numbers of article titles are in boldface type.
A
Acetabular surgery, reconstructive, in children with cerebral palsy, 73–75
Adenotonsillar hypertrophy, pediatric obstructive sleep apnea due to, 243–244
Adenotonsillectomy, for treatment of pediatric obstructive sleep apnea, 246–254
anesthetic techniques, 250–252
perioperative management, 247–250
postoperative management, 252–254
perioperative respiratory adverse events in children after, 51–52
Airway, anesthetic considerations in children with tumors of, 197
difficult, managing during pediatric anesthesia and sedation outside the OR, 38–39
physiology of, pediatric, 242–243
Analgesia, for pes excavatum surgery, 175–184
Anatomic dysfunction, pediatric obstructive sleep apnea due to, 244–245
Anesthesia. See also Pediatric anesthesiology.
and sedation outside the operating room, 25–43
anesthesia versus sedation, 26–27
goals of, 26
patient preparation, 27–28
specific extramural sites and best practices, 28–38
mobile sedation, 38
procedure suite, 34–38
radiology, 28–34
specific issues, 38
cardiopulmonary resuscitation, 39
difficult airway, 38–39
postprocedure care, 39
quality improvement and outcome, 40–41
risks and complications, 39–40
Anesthesiology, in children. See Pediatric anesthesiology.
Anesthetics, neurotoxicity of, 133–155
anesthesia without sensation, 133–134
animals models of, 136–137
immediate lessons from, 148–149
translation to humans, 137–138
apoptosis triggered by anesthetics, 136
apoptotic neuronal cell death, 135–136
effects on learning and behavior in young children, 138–146
historical perspective, 134–135
deleterious effects of anesthetics on developing brain, 135
nociceptive response of immature brain to surgery, 134–135

http://dx.doi.org/10.1016/S1932-2275(13)00114-6 anesthesiology.theclinics.com
1932-2275/14/$ – see front matter ª 2014 Elsevier Inc. All rights reserved.
296 Index
Anesthetics (continued )
period of vulnerability, 149–150
utility of prospective randomized trials, 147–148
perioperative respiratory adverse events in children due to, 52–53
accidental drug injection, 53
neuromuscular blocking agents, 52
opioids, 52–53
Angiography, diagnostic cerebral, challenges in pediatric, 93–95
avoiding complications, 95
equipment, 93–94
indications, 94
patient preparation, 94
technique, 94–95
Animal studies, of anesthetic neurotoxicity, 136–137
immediate lessons learned, 148–149
Anterior mediastinal mass, anesthetic considerations in children with, 189, 196–197
Anxiety, preoperative, in children, 1–23
factors contributing to, 2–4
age, 2–3
gender, 3
previous hospital experience, 3–4
temperament and ethnicity, 3
type of anesthesia, 4
type of surgery, 4
framework, 2
interventions, 4–11
additional nonpharmacologic strategies, 10–11
parental presence at induction of anesthesia, 5–6
perioperative dialogue, 6
pharmacologic anxiolysis, 8–10
preoperative preparation programs, 6–8
Anxiolysis, pharmacologic, 6–10
midazolam, 8–9
other agents, 9–10
Apnea. See Obstructive sleep apnea syndrome.
Apoptosis, triggered by anesthetics, 135
Awake craniotomy, 84–88
history of, 84
in children, 84–88
contraindications, 85
equipment, 84–85
indications, 85
postprocedural care, 87–88
procedural steps, 86–87
technique best practice, 86
Axillary block, in children, 264–265
Index 297
B
Baclofen, intrathecal pump insertion, 75–78
overdose, 77–78
surgical procedure, 76–77
Behavior, effects of anesthetic exposure in young children on, 138–146
Brain development, effects of anesthesia on, 135
Brain monitoring. See also Neuromonitoring.
electrical activity, 116–124
electroencephalography, 116–123
evoked potentials, 123–124
oxygenation measured by near infrared spectroscopy, 124–126
Bronchospasm, management of, in pediatric PACU, 54
C
Cancer, anesthesia for children with, 185–213
effects of anesthetics on perioperative immunomodulation, 187
other considerations in, 205–206
neurocognitive and psychiatric changes, 205–206
pain, 206
retinoic acid syndrome, 205
tumor lysis syndrome, 205
potential complications of, 186–187
preoperative laboratory evaluation, 206–207
systems-based approach to toxicity of cancer and antitumor therapy, 187–205
Cardiac catheterization laboratory, anesthesia for children with pulmonary hypertension in,
157–173
airway management, 166
anesthetic management, 163–166
cardiac catheterization, 161–163
definition and classification, 158–160
pathophysiology and treatment, 160–161
postanesthesia recovery, 169
pulmonary hypertensive crisis, 166–169
Cardiac surgery, in children, near infrared spectroscopy monitoring of oxygenation in, 125–126
during, 125
outcome after, 125–126
Cardiopulmonary resuscitation, during pediatric anesthesia and sedation outside the OR, 39
Cardiovascular system, anesthetic considerations in children with tumors of, 197–198
Central nervous system, anesthetic considerations in children with tumors of, 201–202
Cerebral angiography. See Angiography, cerebral.
Cerebral function. See Brain monitoring and Neuromonitoring.
Cerebral palsy, anesthesiology for major surgery in children with, 63–81
for derotational osteotomies and reconstructive acetabular surgeries, 73–75
pathophysiology, 73
for scoliosis and kyphosis correction, 69–73
for spine fusion, 70–73
298 Index
Cerebral (continued )
general risks of anesthesia and surgery in, 64–69
hypotension, 65–69
intrathecal baclofen pump insertion, 75–78
baclofen overdose, 77–78
Chest wall deformities, pectus excavatum surgery, 175–184
Clonidine, preoperative, for anxiolysis in children, 8–9
Coagulation system, anesthetic considerations in children with tumors of, 204–205
Computed tomography, pediatric anesthesia and sedation in the radiology suite, 29–30
Control charts, in quality improvement, 286
Coughing, severe persistent, in pediatric PACU, 54–55
Craniofacial surgery, craniosynostosis, anesthesia for surgery in infancy, 215–235
assessment of intravascular volume status, 227–228
current surgical approaches to craniosynostosis, 218–224
complex cranial vault reconstruction, 221–224
endoscopic strip craniectomy and postoperative helmet therapy, 219–220
open strip craniectomy and modified Pi procedure, 218–219
spring-mediated cranioplasty, 220
intraoperative management, 225–226
management of massive hemorrhage, 226–227
postoperative care, 230–231
preoperative preparation, 224
specific intraoperative concerns, 224–225
hemorrhage, 224
hypothermia, 225
intracranial hypertension, 225
positioning and eye protection, 225
venous air embolism, 224–225
strategies for minimization of blood loss and transfusion, 228–230
antifibrinolytic agents, 229
cell salvage, 229–230
preoperative erythropoietin, 230
transfusion protocols, 229
transfusion-free perioperative course, 230
Craniosynostosis. See Craniofacial surgery.
Craniotomy, awake. See Awake craniotomy.
D
Delirium. See Emergence delirium.
Desaturation, management of, in pediatric PACU, 54–55
Development, of brain, effects of anesthesia on, 135
Dexmedetomidine, preoperative, for anxiolysis in children, 9
Dialogue, perioperative, to reduce anxiety in children, 8
E
Electrical activity, brain monitoring in children, 116–124
Index 299
Electroencephalography, during surgery in children, 116–123

processed, 118–123
Electromyography, in neuromonitoring for scoliosis surgery, 108–109
Emergence delirium, in children, 1–23
assessment tools, 11–12
causative factors, 12–14
age, 12
anesthetic technique, 13
pain, 13–14
preoperative anxiety and temperament, 12–13
definition and incidence, 11
prevention and treatment, 14–15
Endocrine system, anesthetic considerations in children with tumors of, 202
Endoscopic procedures, strip craniectomy for craniosynostosis in infancy, 219–220
Evoked potentials, brain monitoring during surgery in children, 123–124
External beam radiation therapy, pediatric anesthesia and sedation in the radiology suite,
33–34
F
Failure models and effects analysis, in quality improvement, 287–289
Femoral nerve block, in children, 272–273
Femoral osteotomy, derotational, in children with cerebral palsy, 73–75
G
Gastrointestinal system, anesthetic considerations in children with tumors of, 201
Genetic causes, of pediatric obstructive sleep apnea, 245
H
Hematologic system, anesthetic considerations in children with tumors of, 203–204
Hepatic system, anesthetic considerations in children with tumors of, 200–201
Hypertension, pulmonary. See Pulmonary arterial hypertension.
Hypotension, risk during major surgery in children with cerebral palsy, 65–69
Hypothermia, risk during major surgery in children with cerebral palsy, 64–65
I
Ilioinguinal/iliohypogastric nerve block, in children, 270–271
Immunomodulation, perioperative, in children with cancer, effects of anesthetics on, 187
Improvement. See Quality improvement.
Infants, anesthesia for craniofacial surgery in, 215–235
Inflammation, pediatric obstructive sleep apnea due to, 245
Infraclavicular approach, for regional anesthesia in children, 268–269
Interscalene approach, for regional anesthesia in children, 266
Interventional radiology, pediatric anesthesia and sedation in the radiology suite,
31–32
Intraoperative magnetic resonance imaging
history of, 88
contraindications, 90–91
300 Index
Intraoperative (continued )
equipment, 88–90
indications, 90
postprocedural care, 92
procedural steps, 92
Intraoperative neuromonitoring. See Neuromonitoring.
K
Ketamine, preoperative, for anxiolysis in children, 9
Kyphosis, surgery for, in children with cerebral palsy, 69–73
L
Laryngospasm, management of, in pediatric PACU, 54
Leadership, in quality improvement, 283
training in, 283–284
Learning impairment, effects of anesthetic exposure in young children on,
138–146
Lower extremity blocks, in children, 272–276
femoral nerve block, 272–273
lumbar plexus block, 276
saphenous nerve block, 273–274
sciatic nerve block, 274–276
Lumbar plexus block, in children, 276
M
Magnetic resonance imaging, intraoperative, 88–93
history of, 88
contraindications, 90–91
equipment, 88–90
indications, 90
postprocedural care, 92
procedural steps, 92
pediatric anesthesia and sedation in the radiology suite, 30–31
Mediastinal mass, anterior, anesthetic considerations in children with, 189, 196–197
Midazolam, preoperative, for anxiolysis in children, 8–9
Mobile sedation, pediatric, 38
Motor-evoked potentials, in neuromonitoring for scoliosis surgery, 106–108
Multimodal analgesia, for pes excavatum surgery, 175–184
N
Near infrared spectroscopy, to measure oxygenation during surgery in children, 124–126
during cardiac surgery, 125
Index 301
in neonatal intensive care unit, 126

outcome after cardiac surgery, 125–126
validation, 124–125
Neonatal intensive care unit, near infrared spectroscopy use in, 126
Nerve blocks. See Regional anesthesia.
Neuroanesthesia, challenges in pediatric, 83–100
awake craniotomy, 84–88
diagnostic cerebral angiography, 93–95
intraoperative magnetic resonance imaging, 88–93
neuroendovascular interventions, 95–97
Neurocognitive changes, in children with cancer, 205–206
Neuroendovascular interventions, pediatric, challenges in, 95–97
equipment, 95
indications, 95
technique, 96
Neuromonitoring, for scoliosis surgery, 101–114
anatomy of spinal cord and patterns of injury, 103–104
anesthetic effects on, 109–110
background, 102
electromyography, 108–109
in special populations, 110
motor evoked potentials, 106–108
somatosensory evoked potentials, 105–106
wake-up test, 104–105
Neuromuscular blocking agents, perioperative respiratory adverse events in children due
to, 52
Neuromuscular dysfunction, pediatric obstructive sleep apnea due to, 244–245
Neurotoxicity, of anesthetics, 133–155
Nuclear medicine, pediatric anesthesia and sedation in the radiology suite, 32–33
O
Obstructive sleep apnea syndrome, pediatric, 237–261
adenotonsillectomy for treatment of, 246–254
302 Index
Obstructive (continued )
airway physiology in children, 242–243
diagnosis of, 239–242
pathophysiology of, 243–246
Oncology, anesthesia for children with cancer, 185–213
Operating room, pediatric anesthesia and sedation outside the, 25–43
Opioids, perioperative respiratory adverse events in children due to, 52–53
Oral cavity, anesthetic considerations in children with tumors of, 197
Osteotomies, derotational femoral, in children with cerebral palsy, 73–75
Oxygenation, monitoring during surgery in children, 124–126
P
Pain, in children with cancer, 205–206
Parental presence, at induction of anesthesia in children, 5–6
Pectus excavatum surgery, anesthesia and analgesia for, 175–184
anesthesia management, 178–183
clinical picture, 176–178
epidemiology, 176
pathophysiology, 176
Pediatric anesthesiology, 1–294
anesthesia and sedation outside the operating room, 25–43
anesthesia versus sedation, 26–27
goals of, 26
patient preparation, 27–28
specific extramural sites and best practices, 28–38
mobile sedation, 38
procedure suite, 34–38
radiology, 28–34
specific issues, 38
cardiopulmonary resuscitation, 39
difficult airway, 38–39
quality improvement and outcome, 40–41
risks and complications, 39–40
brain monitoring, 115–132
electrical activity, 116–124
oxygenation measured by near infrared spectroscopy, 124–126
challenges in, 83–100
awake craniotomy, 84–88
diagnostic cerebral angiography, 93–95
intraoperative magnetic resonance imaging, 88–93
neurovascular interventions, 95–97
Index 303
for children with cancer, 185–213

for craniosynostosis surgery in infancy, 215–235
assessment of intravascular volume status, 227–228
current surgical approaches to craniosynostosis, 218–224
intraoperative management, 225–226
management of massive hemorrhage, 226–227
postoperative care, 230–231
preoperative preparation, 224
specific intraoperative concerns, 224–225
strategies for minimization of blood loss and transfusion, 228–230
for major surgery in children with cerebral palsy, 63–81
general risks of anesthesia and surgery, 64–69
intrathecal Baclofen pump insertion, 75–78
for pectus excavatum surgery, 175–184
anesthesia management, 178–183
clinical picture, 176–178
epidemiology, 176
pathophysiology, 176
neuromonitoring for scoliosis surgery, 101–114
background, 102
neurotoxicity, 133–155
obstructive sleep apnea, 237–261
adenotonsillectomy for treatment of, 246–254
304 Index
Pediatric (continued )
airway physiology in children, 242–243
diagnosis, 239–242
pathophysiology of, 243–246
preoperative anxiety and emergence delirium, 1–23
pulmonary hypertension in the cardiac catheterization laboratory, 157–173
quality and safety in, 281–294
choosing a framework for improvement, 284–285
culture of improvement, 282
failure modes and effects analysis, 287–289
improvement tools, 286–287
leadership in quality improvement, 283
measuring quality of care in, 285–286
Quality and Safety Committee of Society of Pediatric Anesthesia, 289–291
run charts and control charts, 286
safety analytics, 291–292
spreading change and innovation, 292–293
Wake Up Safe, 291
respiratory complications in the PACU, 45–61
after adenotonsillectomy, 51–52
definitions and signs of, 46
drug-related, 52–53
incidence of, 46–47
prevention and treatment of, 53–56
severity and outcome of, 47–51
ultrasound guidance for regional anesthesia, 263–279
axillary blocks, 264–266
ilioinguinal/iliohypogastric nerve block, 270–271
infraclavicular approach, 268–269
interscalene approach, 266
lower extremity blocks, 272–276
rectus sheath block, 271–272
supraclavicular approach, 266–268
transversus abdominis plane block, 269–270
truncal blocks, 269
upper extremity blocks, 263–264
Perioperative dialogue, to reduce anxiety in children, 8
Perioperative respiratory adverse events. See Respiratory complications.
Index 305
Peripheral nerve catheters, ultrasound guidance for placement of, 263–279

Postanesthesia Care Unit (PACU), pediatric, respiratory complications in, 45–61
Preoperative anxiety. See Anxiety, preoperative.
Procedure suite, pediatric anesthesia and sedation in, 34–38
bone marrow/lumbar puncture, 36–38
bronchoscopy, 36
mobile sedation, 38
upper esophagogastroduodenoscopy, 35–36
Psychiatric changes, in children with cancer, 205–206
Pulmonary arterial hypertension, anesthesia in cardiac catheterization laboratory for
children with, 157–173
Pulmonary system, anesthetic considerations in children with tumors of, 198–200
Q
Quality improvement, in pediatric anesthesiology, 281–294
choosing a framework for, 284–285
for anesthesia and sedation outside the OR, 40–41
leadership in, 283
Wake Up Safe, 291
R
Radiation therapy, pediatric anesthesia and sedation in the radiology suite, 33–34
Radiology suite, pediatric anesthesia and sedation in, 28–34
computed tomography, 29–30
external beam radiation therapy, 33–34
interventional radiology, 31–32
magnetic resonance imaging, 30–31
306 Index
Radiology (continued )
nuclear medicine, 32–33
Rectus sheath block, in children, 271–272
Regional anesthesia, in children, ultrasound guidance for, 263–279
truncal blocks, 269
Remote anesthesia sites, pediatric, 25–43
Renal system, anesthetic considerations in children with tumors of, 200
Respiratory complications, in the pediatric PACU, 45–61
bronchospasm, 54
coughing, severe persistent, 55
desaturation, 54–55
laryngospasm, 54
stridor, 55
Retinoic acid syndrome, in children with cancer, 205
Risk factors, for respiratory complications in the pediatric PACU, 47–51
Run charts, in quality improvement, 286
S
Safety, and quality in pediatric anesthesiology, 281–294
choosing a framework for improvement, 284–285
leadership in quality improvement, 283
Wake Up Safe, 291
Index 307
Saphenous nerve block, in children, 273–274

Sciatic nerve block, in children, 274–276
Scoliosis surgery, in children with cerebral palsy, 69–73
neuromonitoring for, 101–114
background, 102
Sedation, pediatric, and anesthesia outside the operating room, 25–43
versus anesthesia, 26–27
Skull deformities. See Craniosynostosis.
Sleep, anesthesia and, 245–246
Sleep apnea. See Obstructive sleep apnea syndrome.
Society of Pediatric Anesthesia, Quality and Safety Committee of, 289–290
critical events checklists, 290
intraoperative handoff tool, 290
Somatosensory revoked potentials, in neuromonitoring for scoliosis surgery, 105–106
Spasticity, in children with cerebral palsy, intrathecal baclofen pump insertion for, 75–78
overdose, 77–78
Spectroscopy, near infrared. See Near infrared spectroscopy.
Spin fusion surgery, in children with cerebral palsy, 69–73
Spinal cord, anatomy of, and patterns of injury in children, 103–104
Stridor, management of, in pediatric PACU, 55
Supraclavicular approach, for regional anesthesia in children, 266–268
Surgical procedures, adenotonsillectomy for pediatric obstructive sleep apnea, 246–254
current approaches to craniosynostosis in infancy, 218–224
complex cranial vault reconstruction, 221–224
endoscopic strip craniectomy and postoperative helmet therapy, 219–220
open strip craniectomy and modified Pi procedure, 218–219
spring-mediated cranioplasty, 220
for pectus excavatum, 175–184
for scoliosis surgery, 101–114
major, in children with cerebral palsy, 63–81
general risks of anesthesia and surgery, 64–69
intrathecal Baclofen pump insertion, 75–78
T
Tonsillectomy. See Adenotonsillectomy.
Toxicity, of cancer and antitumor therapy, anesthetic considerations in, 187–205
anterior mediastinal mass, 189, 196–197
308 Index
Toxicity (continued )
background, 187–189
cardiovascular system, 197–198
central nervous system, 201–202
coagulation system, 204–205
endocrine system, 202
gastrointestinal system, 201
hematologic system, 203–204
hepatic system, 200–201
oral cavity and airway, 197
pulmonary system, 198–200
renal system, 200
Transfusions, for craniofacial surgery in infancy, 229–230
Transversus abdominis plane block, in children, 269–270
Truncal blocks, n children, 269
Tumor lysis syndrome, in children with cancer, 205
U
Ultrasound guidance, for regional anesthesia in children, 263–279
truncal blocks, 269
Upper extremity blocks, in children, 263–264
W
Wake Up Safe, 291
Wake-up test, after spinal surgery in children, 104

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Pediatric Anesthesiology

LEE A. FLEISHER, MD, FACC, FAHA

ALAN JAY SCHWARTZ, MD, MSEd

DEAN B. ANDROPOULOS, MD, MHCM

ANDREW DAVIDSON, MBBS, MD, FANZCA

DAVID BUCK, MD, MBA

MARY LANDRIGAN-OSSAR, MD, PhD

JERROLD LERMAN, MD, FRCPC, FANZCA

ERICA P. LIN, MD, FAAP

ANDREAS W. LOEPKE, MD, PhD, FAAP

CRAIG D. MCCLAIN, MD, MPH

SULPICIO G. SORIANO, MD, FAAP

SANTHANAM SURESH, MD, FAAP

MICHAEL SURY, MB, BS, FRCA, PhD

MARK D. TWITE, MB BChir

ANNA VARUGHESE, MD, MPH

BRITTA S. VON UNGERN-STERNBERG, MD, PhD, DEAA, FANZCA

Pediatric anesthesiology presents clinicians with recurring management issues that

Alan Jay Schwartz, MD, MSEd

Anesthesiology Clin 32 (2014) xiii–xiv

Dean B. Andropoulos, MD, MHCM

FORTHCOMING ISSUES RECENT ISSUES

NOW AVAILABLE FOR YOUR iPhone and iPad

Preoperative Anxiety Management, Emergence Delirium, and

Anesthesia and Sedation Outside the Operating Room 25

Respiratory Complications in the Pediatric Postanesthesia Care Unit 45

Major Surgical Procedures in Children with Cerebral Palsy 63

combined with pelvic osteotomies, spine fusion, and intrathecal baclofen

Challenges in Pediatric Neuroanesthesia: Awake Craniotomy, Intraoperative

Neuromonitoring for Scoliosis Surgery 101

Brain Monitoring in Children 115

Anesthetic Neurotoxicity 133

neuronal cell death and subsequent learning and memory impairment.

The Anesthetic Management of Children with Pulmonary Hypertension in the

Anesthesia and Analgesia for Pectus Excavatum Surgery 175

Anesthesia for the Child with Cancer 185

Anesthesia for Craniofacial Surgery in Infancy 215

Pediatric Obstructive Sleep Apnea 237

Ultrasound for Regional Anesthesia in Children 263

Perspectives on Quality and Safety in Pediatric Anesthesia 281

Anesthesiology Clin 32 (2014) 1–23

Factors that Contribute to Preoperative Anxiety

Temperament and ethnicity

Previous hospital experience

PREOPERATIVE PREPARATION PROGRAMS

Preoperative preparation programs to decrease preoperative anxiety have had mixed

The perioperative dialogue is a holistic intervention aimed at reducing perioperative

anterograde amnesia.60 Midazolam has been shown to confer anterograde amnesia in

Other Pharmacologic Agents

confounding factors such as the effects of clonidine on postoperative nausea and

ADDITIONAL NONPHARMACOLOGIC STRATEGIES

Several nonpharmacologic strategies have been found to be effective for anxiolysis in

cooperation compared with controls.80–82 Certain provider behaviors have been

Preoperative anxiety and temperament

decreased 3- to 4-fold when ketorolac was administered intraoperatively.111 Similarly,

PREVENTION AND TREATMENT OF ED

1. Schwartz BH, Albino JE, Tedesco LA. Effects of psychological preparation on

37. Litman RS, Berger AA, Chhibber A. An evaluation of preoperative anxiety in a

117. Constant I, Dubois MC, Piat V, et al. Changes in electroencephalogram and

CT uses ionizing radiation

One of the most commonly used imaging tools

Patients require complete immobility

Many healthy children can be deeply sedated

Failed procedures resulting from inadequate or problematic anesthesia or

Inversely correlated to gestational age

Lung disease with airway inflammation (eg, asthma, cystic fibrosis)

Age younger than 6 months, particularly neonates