Pediatric Protocols 1st Version 2024 - Collected (EHA - MAC)

Child Disability Protocol of EHA
0
Egyptian Clinical Practice Protocol

in
Child Disability
for
Egypt Healthcare Authority
First Edition
2024
Prepared By
Members of Child disability Committee
Of
Medical Advisory Council
Of
1
Executive Committee
1. Prof. Ehab Eid: (Head of committee) Professor of Public Health, Behavioral

and Disability Medicine, Head of Medical Studies Department, Faculty of
postgraduate Childhood studies, Ain Shams University
2. Prof. Nirvana Gamal El-Din: Head of Phoniatrics- ENT Department Faculty
of Medicine, Ain-Shams University
3. Prof. Maisa Nasr Farid: Professor of pediatrics, Faculty of postgraduate
Childhood studies, Ain Shams University
4. Prof. Samia Samy Aziz: Prof. of Child Mental Health, Faculty of
Postgraduate Childhood Studies, Ain Shams University
5. Prof. Ahmed Othman El-kahky: Professor of physiotherapy, Faculty of
postgraduate Childhood studies, Ain Shams University
6. Prof. Mostafa Ragab: Prof. of Child Mental Health, Faculty of postgraduate
Environmental & Research studies, Ain Shams University
7. Prof. Iman Sadek: Professor of Audiology- ENT Department Faculty of
Medicine, Ain-Shams University
8. Prof. Ahmed Moatasem: Professor of Ophthalmology, Faculty of Medicine-
Ain Shams University
9. Dr. Hala Adel Eraky: (Moderator) Pediatric Consultant, coordinator of
Medical Advisory Council of Egypt Healthcare Authority (EHA)
Intellectual Property Rights

All Intellectual Property Rights are reserved to EHA. No part of this
publication can be reproduced or transmitted in any form or by any means without
written permission from the EHA and authors.
2
Supervised & Revised By
➢ General Doctor/ Mourad Alfy Ramzy Tadros

• MD, FRCPCH(UK), MRCPI(Dublin)
• Consultant Paediatrician of Egyptian Military Medical Services.
• Professors of Paediatrics Military Medical Academy
• Head of Training Committee of Paediatrics of Egyptian Military Medical
Board
• Consultant Paediatrician of the Medical Advisory Council of Egypt Healthcare
Authority (EHA).
Reviewed By
1. Dr. Hala Adel: Pediatric Consultant, Moderator & coordinator of Medical

Advisory Council of Egypt Healthcare Authority (EHA)
2. Dr. Huda Karam: Pediatric Specialist, Moderator & coordinator of Medical

Cover Designed & Content Edited By
➢ Mr. Bassam Sayed: Technical Officer at Medical Advisory Council of Egypt

Healthcare Authority (EHA)
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PREFACE
Recently, there is an increasing need to provide programs with accurate

competency-based assessments to ensure the delivery of high-quality healthcare. The
aim of developing these Egyptian Clinical Practice Protocols in Child disability is to
unify and standardize the delivery of healthcare to all newborns at all health
facilities.
The current state of healthcare in which avoidable failures are abound. “We
train longer, specialize more, use ever-advancing technologies, and still we fail.” Part
of the problem, is that the ever-increasing complexity of medicine makes uniform
care delivery impractical or impossible. That is, unless there are protocols, checklists,
or care paths that are readily available to providers.
Standard textbooks, journals, and online resources currently available create
excellent repositories of detailed information about the etiology, pathogenesis,
clinical picture, diagnosis, and treatment of a condition. However, for a busy clinician
looking for the best way to manage a sick patient, a standardized path for effective
management of the patient may be impossible to discern. So, it would be a lot easier
if we all managed simple things in a uniform way using the best available evidence
and resources.
In child disability, busy clinicians have all felt the need for a concise, easy-to-
use resource at the bedside for evidence-based protocols, or consensus-driven care
paths where high-grade evidence is not available.
In this protocol, we offer comprehensive reviews of selected topics and
comprehensive advice about management approaches and procedures based on the
highest level of evidence available in each case. Our goal is to provide an
authoritative practical medical resource for neonatologists, pediatricians, and other
healthcare providers dealing with newborns after birth. This protocol is the product of
contributions from numerous neonatologists from all over Egypt.
Members of the Working Group

For Development of the Egyptian Clinical Practice Protocol
In Child Disability
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Table of Contents
Page
Title
Number
Executive Committee 2
Preface 4
Intellectual Developmental Disorder (IDD) 6
Working with Children with Neuro-Disability 19
Child Development Centers 20
Autism Spectrum Disorder 21
Diagnosis of Autism (ASD) 23
Musculoskeletal Disorders & Examination 24
Examination & Evaluation of Children with Neurological 29
Disorders
Hearing Assessment Flowchart (0-2yrs) 33
Hearing Assessment Flowchart (2-5yrs) 34
Speech Disorders 35
Delayed Language 36
Amblyopia 37
Congenital Cataract 38
Congenital Glaucoma 39
Congenital Ptosis 40
Retinopathy of Prematurity 41
The Bilaterally Blind Infant 42
Environmental Conditions for prevention of child 43
disability
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Intellectual Developmental Disorder (IDD)
Definition:
• Disability is extremely diverse. While some health conditions associated with

disability result in poor health and extensive health care needs, others do not.
However, all people with disability have the same general health care needs as
everyone else, and therefore need access to mainstream health care services.
• Levels of understanding and visibility have increased. And there have been
profound changes in public attitudes towards disability, captured and catalyzed by
national moments such as the Paralympic Games.
• Intellectual Disability (ID) (also known as Intellectual Developmental Disorder

(IDD), and previously Mental Retardation) is a disorder with onset during the
developmental period that includes both intellectual and adaptive functioning
deficits in 3 domains:
1. Conceptual
2. Social
3. Practical domains
• Intellectual disability is a heterogeneous condition with many different etiologies.

Two other diagnoses exist under the intellectual disability diagnostic category in
the DSM-5: Global Developmental Delay (GDD) and Unspecified Intellectual
Disability (UID).
Diagnostic Criteria:
• Intellectual disability is a disorder with onset during the developmental period that
includes both intellectual and adaptive functioning deficits in conceptual, social,
and practical domains. The following 3 criteria must be met:
Criterion A
• Deficits in intellectual functions, such as reasoning, problem solving, planning,
abstract thinking, judgment, academic learning, and learning from experience,
confirmed by both clinical assessment and individualized standardized intelligence
testing.
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Criterion B
• Deficits in adaptive functioning that result in failure to meet developmental and

sociocultural
• Standards for personal independence and social responsibility. Without ongoing
support, the adaptive deficits limit functioning in one or more activities of daily
life, such as communication, social participation, and independent living, across
multiple environments, such as home, school, work, and community.
Criterion C
• Onset of intellectual and adaptive deficits during the developmental period.
Pathophysiology:
• The etiology of ID/GDD is heterogeneous. The cause for ID and GDD can be
nongenetic/environmental or genetic. Nongenetic causes such as prenatal
infections, substance use like alcohol intake during pregnancy, and postnatal
meningoencephalitis account for only one-third of cases and the rest are of genetic
origin. The common causes of ID are also listed in the flowchart [Figure 1].
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Figure 1: Finnish Approach
Diagnosing Intellectual Disability and its Comorbidities:
• The diagnostic process of ID is similar to any other behavioral and mental

disorders but with subtle differences. The diagnostic process involves history
taking, observation including medical examination, intellectual and adaptive
behavioral assessment, identification of comorbid psychiatric disorders, and
need-based laboratory investigations for other medical conditions.
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I. History Taking:
• The purpose of eliciting the history is to establish that there is evidence for
deficits in both intellectual functioning and adaptive behaviors that have an
onset during the developmental period, to note possible etiology of ID, and to
identify comorbidities and response to interventions, if any. A useful and
comprehensive approach to assessment would include:
1. Noting chief complaints in chronological order with mode of onset,

duration, and precipitating event followed by
2. History of presenting illness and a detailed prenatal and perinatal history.
3. Developmental history in greater detail, particularly related to motor,
language, and communication; self-help skills; socioemotional skills;
cognition; and occupational skills/leisure-time activities;
4. Medical comorbidities and its treatments;
5. Psychiatric history including the details of onset, evolution, and current
status of behavioral and other psychopathological disturbances; and
treatment history.
6. This should be followed by a comprehensive family history including the
three- generation pedigree; consanguinity; family background; current
living arrangements; and details of potential stressors, coping and
adaptation by the family.
II. Physical Examination:
• Detailed physical examination helps to identify the etiology in most cases,

detect comorbid medical conditions, and also order appropriate investigations.
Physical examination in cases with ID consists of three parts which are as
follows: It must involve:
1. Routine systemic examination,
2. Anthropometric assessment, and
3. Observation of atypical morphological features suggestive of specific
genetic disorders.
• Anthropometry
This provides indication toward nutritional status and underlying medical or
genetic condition. The measures should include the following: height (length in
case of neonates and infants), arm span, upper segment, and lower segment
lengths, sitting height, weight, head circumference, chest circumference,
abdominal circumference, intercanthal and interpupillary distances, and palm
and foot lengths.
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• Dysmorphology examination
Dysmorphology is the observation, documentation, and study of birth defects
as well as syndromes. A thorough head-to-toe examination should be carried
out to identify minor physical anomalies (MPAs), which provide clues toward
etiological diagnosis, especially the genetic disorders (Table 1). It requires
keen observation and knowledge of normal versus abnormal morphology.
Table 1: Some common minor physical anomalies and other findings on
physical examination
Anatomical Region Features
Scalp hair Sparse, light colored, double whorl on scalp, easily breakable
Shape of skull Brachycephaly, scaphocephaly, trigonocephaly, oxycephaly, plagiocephaly
Facial appearance Coarse facies, elongated triangular, small
Eyes and periorbital Deeply set, promment eyes, microphthalmia, upslanting/downslanting palpebral
fissures, hypertelorism, epicanthal folds, strabismus,
structures ptosis, bushy eyebrows, synophrys, microcomea, comeal clouding, cataracts,
coloboma of iris, blue sclera, telangiectasia, etc.
Ears Low set, small, large, malformed, anteverted, posteriorly rotated, preauricular
tags, pits, cup shaped, etc.
Nose Depressed nasal bridge, short and stubby, beak shaped, bulbous tip, flaring or
hypoplastic nostrils, anteverted nares, etc.
Palate High arched, ridged palate, clefting, bifid uvula, etc.
Chin Prominent, retrognathia, micrognathia, etc.
Hands Broad hands, short hands, simian crease, Sidney line, spade shaped, etc.
Fingers Chinodactyly, brachydactyly, syndactyly, camptodacyly, arachnodactyly,
polydactyly, broad thumb, etc.
Chest Pectus excavatum, pectus carinatum, nipple anomalies, gynecomastia
Abdomen Protuberant, scaphoid, umbilical hernia, hepato-splenomegaly, ingamal hernia
Spine Kyphosis, scoliosis, spina bifida
External genitalia Micropenis, macro-orchidism, undescended testis, ambiguous genitalia,
hypospadias, absent secondary sexual characteristics, shawl
scrotum, etc.
Skin Dry and coarse, café-au-lait spots, abnormal pigmentation, hemangioma,
ichthyosis, absence of sweating
Feet Pes plans, pes cavus, valgus/varus anomaly, broad hallux, increased distance
between the 1" and 2 toes
Skeletal Exostoses, increase carrying angle, joint hypermobility
• Examination of major organ systems

A systematic examination of all the organ systems to rule out multiorgan
involvement and comorbid medical conditions has to be performed for overall
assessment and management. It is essential to be meticulous in observing and
documenting the findings of physical examination as many of the MPAs can be
easily missed.
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III. Behavioral Observation:

• The purpose of behavioral observation is to corroborate the clinical history regarding
intellectual functioning and behavioral repertoire. Therefore, it should start with:
1.Observation of general appearance,
2.Any oddities in behavior,
3.Attention span,
4.Receptive and expressive speech abilities, and
5.Social and interpersonal abilities.
• Any changes in behavior compared to previous period, should be carefully
recorded in each visit. If it is pervasive and indicative of a comorbid psychiatric
disorder, it has to be carefully considered. During clinical evaluation, a greater
reliance on onset and chronological evolution of symptoms, intensity, frequency,
context of occurrence of symptoms, and precipitating and relieving factors
elicited will help in uncovering the psychopathology.
• Clinicians may need to create child-friendly space with appropriate toys, picture
books, and art and craft materials. The setting should be safe, well lit, and
ventilated.
• Depending on the language development and conversational skills, verbal
interview can be conducted with simple, structured, clear, and concrete questions.
It is better to avoid leading questions. The examination may include the
following:
1.Basics: Behaviors suggesting sensory-motor impairments or physical health issues
2.Response to interview situation: Excited, fearful, tense, shy, inhibited, guarded,
uncooperative, or defiant
3.Alertness: Over-aroused, withdrawn
4.Attachment to parents and response to separation: Clinging, wanting to be carried
all the time, indifferent to separation
5.Sociability: Social orientation, approachability, social responsiveness, eye-to-eye
contact, reciprocal interactions, and awareness of social boundaries
6.Motor activity level: Fidgetiness, restlessness, hyperactivity, lethargy
7.Course of motor behaviors during interview or response to firm instructions: Quiet
initially, but restless later on; unresponsive to firm instructions
8.Impulse control: Snatching, spilling, falling, bumping, climbing, interfering, temper
tantrums; aggressive acts such as biting, throwing, beating, pulling hair, slapping
9.Attention and concentration: Goal directedness, task completion, distractibility
10.Speech, language, and communication: Verbal/nonverbal comprehension and
expression; vocabulary, articulation, and flow
11.Mood: Inhibited, excessively cheerful, whining and crying, irritable
12.Play behavior: Type of activity, duration, themes, etc .
13.Other inappropriate behaviors: Any excess behaviors that are inappropriate to the age
and sociocultural context
14.Impressions on current developmental attainment: Whether excess behaviors or skill
deficits are typical of a known psychiatric or developmental disorder?
15.Parent–child interactions: Quality of engagement with child; communication patterns;
degree and quality of control over the child; response to good and bad behaviors.
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Diagnosis of Comorbid Psychiatric Disorder:
• Some mental health, neurodevelopmental, medical and physical

conditions frequently co-occur in individuals with intellectual disability,
including Autism Spectrum Disorder, Cerebral Palsy, Epilepsy, Attention-
Deficit Hyperactivity, impulse control disorder, and depression and anxiety
disorders. Identifying and diagnosing co-occurring conditions can be
challenging, for example recognizing depression in an individual with
limited verbal ability an accurate diagnosis and treatment are important for a
healthy and fulfilling life for any individual.
Differential Diagnosis:
• A diagnosis of intellectual disability should not be presumed simply
because of a pre-existing genetic or medical condition. A differential
diagnosis includes:
1.Major and Mild Neurocognitive Disorders:
• Intellectual disability is categorized as a neurodevelopmental disorder and
is distinct from the neurocognitive disorders, which are characterized by a
loss of cognitive functioning. Major Neurocognitive disorder may co-occur
with intellectual disability (e.g. - an individual with Down syndrome who
develops Alzheimer's disease, or an individual with intellectual disability
who loses further cognitive capacity following a head injury). In such cases,
the diagnoses of intellectual disability and neurocognitive disorder may both
be given.
2. Communication Disorders and Specific Learning Disorder:
• These neurodevelopmental disorders are specific to the communication

and learning domains and do not show deficits in intellectual and adaptive
behaviour. They may co-occur with intellectual disability. Both diagnoses
are made if full criteria are met for intellectual disability and a
communication disorder or specific learning disorder.
3. Autism Spectrum Disorder:
• Intellectual disability is common among individuals with autism spectrum

disorder. Assessment of intellectual ability may be complicated by social-
communication and behaviour deficits inherent to autism spectrum disorder,
which may interfere with understanding and complying with test procedures.
4. Genetic disorders: such as Fragile X Syndrome (FXS)
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Overview of Assessments and Evaluation:

• Assessment is a process of collecting data for the purpose of making decisions.
Assessment provides us with baseline information for intervention, whereas the
evaluation is the assessment of outcome of an intervention. In clinical practice,
therefore, we need both assessment and evaluation methods.
Investigations:
• A comprehensive work up for intellectual disability includes assessing
intellectual capacity and adaptive functioning, identifying genetic, non-genetic,
and associated medical conditions (such as cerebral palsy and seizure
disorders). A prenatal/perinatal history, family pedigree, physical examination,
genetic evaluation (karyotype, chromosomal microarray, and/or genetic
syndrome tests), metabolic screening, and neuroimaging assessment can also
be important investigations.
• Malformations such as atrial septal defect in early infancy, single kidney,
holoprosencephaly, and mild hearing/visual impairment can be missed during
routine examination, which can be barriers for adequate management of ID. As
highlighted in the earlier sections, an array of etiological factors can result in
ID and at least some of them can be potentially treated. Hence, a bunch of
investigations are essential not only to identify the cause of ID, but also to
make sure the treatable causes have been investigated for [Table 2].
Table 2: Physical Investigations in Intellectual Disability
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Psychosocial Assessments:
• Persons with ID will be at a high risk for neglect and abuse. Adaptive behavior is
always impaired in people with ID, but the deficits are less evident in environments
where support systems are in place. Therefore, psychosocial assessments are very
important.
Assessment of Intellectual Functioning and Adaptive Behavior:
• Both ICD-10 and DSM-5 recognize the need for assessing the intellectual
functioning with standardized tools that yield intelligence quotients (IQs). When IQ
tests are not applicable because of young age (e.g., children below 3 years) or
associated sensory-motor issues and gross under stimulation, standardized
developmental scales (e.g., Developmental Screening Test and Bailey Scales for
Infants) can be used as applicable.
• Regarding the assessment of adaptive behavior, Vineland Social Maturity Scale
(VSMS) is the only standardized measure available at present. The VSMS yields
social quotient (SQ) and a profile of eight important domains of adaptive behavior.
Treatment:
• Once a diagnosis is made, help for individuals with ID is focused on looking at the
individual’s strengths and needs, and the supports he or she needs to function. Hence
formulating a treatment plan to address the following issues according to the severity
of ID:
1.Etiology/syndrome
2.Associated medical problems
3.Associated psychiatric problems
4.Family and psychosocial factors (e.g., awareness, attitude-overprotective, negligent,
hostile, favorable; expectations; consistency of parenting; quality of stimulation;
stressors in the family, family discard; caregivers’ burnout).
• Treatment needs A Multidisciplinary Team I.e. a collection of different

professionals, who:
✓ Meet regularly
✓ Allocate time to the pursuit of team’s objectives.
✓ Agree on explicit team’s objectives.
✓ Have adequate administrative & clinical coordination to support the team’s work.
✓ Respect skills & roles that are specific & unique to team individual members.
• Case Manager is any team member with:

✓ Appropriate interpersonal skills
✓ And broad background knowledge of the needs and requirements of the disabled
person.
➢ Role of the Case Manager:
✓ The main source of information.
✓ Feedback
✓ Simple coordination within a single agency.
✓ Coordination across agency boundaries.
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Medical Interventions:
• Medications, particularly antipsychotics, may be used to manage challenging

behavior such as aggression in individuals with intellectual disability. When
the behavior does not arise from an underlying mental illness, this is off-label
use and evidence of efficacy is very poor. Furthermore, these patients face
higher risks of drug-related side effects. It is also important to treat associated
medical problems along with therapies aimed at altering the pathophysiology
among children with ID. Specialists need to be consulted for appropriate
management to obtain maximal benefits. Few examples are treatment of
epilepsy with antiepileptic drugs, spasticity with antispasticity medications,
hearing impairment with hearing aids and cochlear implantation, sleep
problems with sedatives as well as sleep hygiene techniques, and so on.
• Some of the conditions which present with ID are nearly completely

preventable or to some extent reversible with appropriate management,
provided that it is treated early in the course. Examples of treatable disorders
are listed in Table 3, and such cases have to be referred to specialists
accordingly for further management.
Table 3: Summary of Medical Interventions
Genetic Counseling:
• Genetic counseling not only provides accurate information on the prognosis of

disorders and recurrence risks, but also helps in removing guilt and ongoing
recrimination in families.
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Management of Comorbid Behavioral and Psychiatric Disorders:
• Nearly 20%–80% of the ID population can have problematic behaviors ranging

from hyperactivity, temper tantrums, odd behaviors, to aggression. In principle,
the techniques should be least intrusive and culturally appropriate; therefore,
the behavioral management plan can be implemented through the following
three levels:
i. Restructuring the environment to control the antecedents and provide
ample opportunities for positive learning
ii. Differential reinforcement to strengthen the adaptive behaviors by
providing opportunities for reinforcement of adaptive behaviors
iii. Controlling inappropriate reinforcement of problematic behaviors.
• Psychiatric comorbidity not only presents itself more diffusely and atypically
in these children, but also it is often difficult to treat. Management may need a
multipronged approach usually involving pharmacological and psychosocial
interventions.
• As only a handful of medications have been licensed for use in children, often,
it is difficult to manage these disorders. This has to be discussed with parents
in detail and their expectations should be handled regarding the outcome of
such a treatment. Very few large systematic controlled trials are available in ID
group; however, the following is suggested:
➢ Begin with low dosage and increase it slowly
➢ Adequate trial time should be allowed before deeming failure of a
medication
➢ Outcome to be monitored at multiple settings (home, school)
➢ Rationalize medications when multiple medications are being used and
change one drug at a time Pediatric dosing schedules and guideline
should be followed.
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• There are few studies on medications in comorbid disorders in ID, namely,

methylphenidate in ADHD, or antipsychotics for schizophrenia. Risperidone
also is widely studied as symptomatic treatment for problematic behaviors such
as stereotypes and aggression [Table4]. Prescribing Guidelines is a good
source.
Table 4: Summary of Pharmacological Treatment Options
Nonpharmacological Management:
Child-Centric Interventions:
• Nonpharmacological interventions should be guided by life span and
functional approaches. Accordingly, the following general framework can be
adapted in regular clinical practice:
➢ Life span approach: In the initial 3 years, the focus should be on acquiring
sensory- motor skills, socio-communication skills, basic self-help skills, and
concepts. During 3–6 years of age, the focus can be on school readiness skills
and mastery of culturally appropriate adaptive behaviors. During 6–18 years of
age, the focus should be on the consolidation of academic and independent
personal skills that can lead to future vocational training, employment, and
adult independent living.
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➢ Functional approach: It is preferable that the tasks taught to the individual

enable him or her to function well in day-to-day tasks. Irrespective of the age
and sociocultural context, each individual first needs training in self-care (toilet
control, bathing, eating, dressing, and grooming), motor skills (especially, eye–
hand coordination skills), receptive and expressive language abilities, social
skills, and concepts in one set. Later, the children can be recommended for
academics or functional academics, finally leading to vocational training,
gainful occupation, and independent living skills.
➢ Making provisions for additional disabilities: the child may need aids and
appliances and appropriate therapeutic interventions. For example, adapted
furniture in cerebral palsy and hearing aids for hearing impairment
➢ Special focus on early intervention: Early identification, intervention is a top
priority.
➢ Referral and linkage: Appropriate services can be obtained from programs.
Family-Centered Interventions:
• Parents and families should be given proper information regarding the nature,
needs, and management of ID and its comorbidities in simple language devoid
of any technical terms. Siblings and other key family members can also be
involved in the program plan.
• Parents and families should be supported in finding right resources for health
care, therapy, education, and vocational and occupational needs.
• Ensure that parents and families are aware of the social provisions and
importance of disability certificate for the child to avail the same.
• Guardianship and National Trust Act must be compulsorily provided
• Making meaning of the condition and developing a sense of control are crucial
for optimum functioning of families. Various methods such as individual
counseling, group counseling, parent training programs, and self-help groups
can be used to achieve this.
• Parents and primary caregivers must be routinely screened for stress-related
disorders because there is ample evidence to suggest that syndromal depression
and anxiety are high among parents of children with ID.
In summary: ID is a developmental disorder that affects general intellectual

functioning and adaptive behaviors. It has no definite cause. Depending on the severity of
the condition and the underlying etiological processes, ID can also present with comorbid
conditions. It is important to identify the treatable conditions and treat the same. Special
attention should be paid to psychiatric and behavioral disorders, which are common in ID
and cause stigma, caregiver burden, and need for medication and segregation. Since ID
causes disability, appropriate measures should be taken to certify disability and guide the
families for appropriate support systems including the social benefits.
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Working with Children with Neuro-Disability
➢ 0-18 years
➢ Wide range of developmental difficulties / disabilities
➢ Holistic approach
➢ Partnership with parents
➢ Multidisciplinary working
➢ Interagency working
➢ Communication
Settings:
• Child Development Centres 0-5 years

• Mainstream School Health
• MLD Schools
• Complex Needs Schools
Referrals:
• Referrals from GP, nursery, educational psychology

• Referral centers for specialist developmental assessment
• Links with other agencies – education, social work
Children with Additional Needs:
• Ex – preterm
• Autism
• Down’s syndrome
• Early developmental impairment (“global developmental delay”)
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Child Development Centers
• It is composed mainly with a core team which is the child development team.
It is mainly composed of:
➢ Pediatrician,
➢ Occupational therapist,
➢ Physiotherapist,
➢ Clinical psychologist,
➢ Speech therapist,
➢ Social worker,
➢ And nurse
• Also, the team is joined or accessible to other services as mental health,
audiology, dietitian, education.
• The following diagram summarizes the main multidisciplinary team and all
other services that may be needed for the child with disability.
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Autism Spectrum Disorder

• Autism is a brain disorder that limits a person's ability to communicate and
relate to other people.
• It first appears in young children, who fall along a spectrum from mild to
severe. Some people can navigate their world, some have exceptional abilities,
while others struggle to speak.
• It is diagnosed according to DSM 5 or ICD 11
➢ The 3 defining areas of impairment (social deficits; communication deficits;
and restricted, repetitive behaviors and interest) were reduced to 2 domains
by combining social and communication to “social/communication deficits”
and retaining the behavioral impairment domain (RRB’s).
➢ Too difficult to separate social deficits from communication deficits
combine into one unit.
➢ Delays in language should be considered factors that influence symptoms
rather than define the disorder.
Signs of Autism:
• Before a child turns three, careful observers can see signs of autism. Some
children develop normally until 18-24 months old and then stop or lose skills.
Signs of an ASD can include:
➢ Repeated motions (rocking or spinning)
➢ Avoiding eye contact or physical touch
➢ Delays in learning to talk
➢ Repeating words or phrases (echolalia)
➢ Getting upset by minor changes
“It’s important to note that these signs can occur in children without ASDs, too”
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Early Warning Signs: First Year:
• Even young infants are very social, so it’s possible to detect signs of autism in
how babies interact with their world. At this age, a child with an ASD may:
➢ Not turn to a mother’s voice
➢ Not respond to his own name
➢ Not look people in the eye
➢ Have no babbling or pointing by age one
➢ Not smile or respond to social cues from others
Early Warning Signs: Year Two:
• The signs of autism are more noticeable in a child’s second year. While other
children are forming their first words and pointing to things they want, a child
with autism remains detached. Signs of autism include:
➢ No single words by 16 months
➢ No pretend games by 18 months
➢ No two-word phrases by age 2
➢ Loss of language skills
➢ No interest when adults point out objects, such as a plane flying
Other Signs and Symptoms:
• People with autism sometimes may have physical symptoms, including

digestive problems such as constipation and sleep problems.
• Children may have poor coordination of the large muscles used for running and
climbing, or the smaller muscles of the hand.
• About a third of people with autism also often have seizures.
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Diagnosis of Autism (ASD)
• ASD is diagnosed according to DSM 5 or ICD 11 criteria.

• Diagnosing ASD can be difficult since there is no medical test, like a blood
test, to diagnose the disorders.
• Doctors look at the child’s behavior and development to make a diagnosis.
• ASD can sometimes be detected at 18 months or younger. By age 2, a
diagnosis by an experienced professional can be considered very reliable.
• However, many children do not receive a final diagnosis until much older.
• This delay means that children with ASD might not get the early help they
need.
Early Screening for ASD:
• Many children aren’t diagnosed with an autism disorder until preschool or
even kindergarten, and may miss getting the help they need in the early years.
That's why guidelines call for screening all children at nine months old for
delays in basic skills. Special ASD checkups are needed at:
➢ 18 months
➢ 24 months
• As needed for children with worrisome behaviors or a family history of autism
Screening and Diagnostic tools for ASD:

Screening tools for ASD
• The Checklist for Autism in Toddlers (CHAT) for children 18-24 months of
age.
• The modified Checklist (M-CHAT) for children 16-30 month of age.
• The Social communication questionnaire (SCQ) for children 4 years and older.
Diagnostic tools for ASD
• Autism Diagnostic interview- Revised (ADI_R).
• Autism Diagnostic Observation Schedule (ADOS-G).
• Childhood Autism Rating Scale (CARS).
• Diagnostic Interview for Social and Communication Disorders (DISCD).
Diagnosis: Speech Problems:
• At regular checkups, the physician will check how the child responds to the mother’s
voice, smile, or other expressions. Is he cooing or babbling? Problems or delays in
speech call for a visit to a speech therapist.
• A hearing test may be needed, too.
• Most children with autism will eventually speak, but they do so later than others.
• Making conversation may be especially tough.
• Children with ASDs also may speak in a sing-song or robotic way.
23
Musculoskeletal Disorders & Examination
Basic Categories:
1. Hyperkinesia or dyskinesia, characterized by excessive movement.

2. Hypokinesia, bradykinesia or akinesia, characterized by slowness or a lack of
movement.
Ataxia:
• Ataxia describes a lack of coordination while performing voluntary
movements. It may appear as clumsiness, inaccuracy or instability:
A. Movements are not smooth, and may appear disjointed or jerky.
B. Associated tremor due to over-correction of inaccurate movements.
C. Past-pointing when an attempted reach overshoots the target.
D. Poor performance of regular, repeated movements, such as
handclapping.
E. When it affects mechanisms of walking, there will be instability
with a tendency to fall.
Examination:
• The first feature to observe about ataxia is where it occurs in the child's body.
It may affect only walking or arm and eye movements may be involved. It is
important to recognize if:
1. There are variations in the severity of the symptoms during the day.
2. There are variations in the severity of symptoms at mealtime.
3. Symptoms become worse when the child is tired, hungry or ill.
4. Whether particular types of foods that affect the symptoms.
Treatment:
1. Physical therapy to train and strengthen muscles to compensate.
2. Gait and balance training are essential.
3. Cane, crutches or walker is often beneficial.
4. Ddapted utensils and other tools may be helpful.
24
Bradykinesia (slow movement):
1. Bradykinesia essentially refers to a component of parkinsonism.

2. A child with bradykinesia has slow and painstaking movements of the affected
limbs.
3. If the whole body is affected, there may be an unnatural stillness or frozen
quality.
4. In some cases, there are reduced movements of the face leading to an
expressionless look referred as a “mask face”.
5. It may affect one limb, one side of the body, or the entire body.
6. Rigidity, refers to resistance to passive movement that may make
the limb feels like a “lead pipe”.
7. Rigidity, also affects the response to gravity, leading the child maintaining his
or her arm in a fixed posture while walking rather than swinging it loosely at
the side.
8. Cog wheeling, when rigidity and tremor are present at the same time.
Chorea:
1. Irregular, rapid, uncontrolled, involuntary, excessive movement that seems to
move randomly from one part of the body to another.
2. The affected child often appears restless and unable to sit still.
3. The jerky movements of the feet or hands are often similar to dancing or piano
playing.
4. When chorea is severe, the movements may cause motion of the arms or legs
that results in throwing whatever is in the hand or falling to the ground.
5. Walking may become bizarre, with inserted excessive postures and leg
movements.
6. Unlike parkinsonism, the movements of chorea, athetosis and choreoathetosis
occur by themselves, without conscious attempts at movement. In some cases,
attempts to move may make the symptoms worse.
7. Athetosis is a slow twisting movement.
8. Choreoathetosis is a movement of intermediate speed, between the quick,
flitting movements of chorea and the slow twisting movements of athetosis.
9. Ballism is a violent flinging of one or more limbs out from the body.
10. Choreoathetosis is the most common form in children.
11. These disorders may affect the hands, feet, trunk, neck and face. In the face,
they often lead to nose wrinkling, continual flitting eye movements and mouth or
tongue movements.
12. These disorders may be distinguished from tics, as tics tend to repeat the same
set of movements. In addition, the child often describes a “build-up” in the
need to make the tic, with a sense of release afterwards.
25
Dyskinesia:
Clinical Features and Classification:
1. Paroxysmal Kinesigenic Dyskinesia (PKD):
• The episodes of hyperkinetic movements are provoked by sudden voluntary
movement or unexpected stimuli (startle).
2. Paroxysmal Non-Kinesigenic Dyskinesia (PNKD):
• The attacks may occur spontaneously while at rest or out of a background of
normal motor activity, but may be exacerbated by alcohol or caffeine
consumption, stress, fatigue or other factors.
3. Paroxysmal Exertion-induced Dyskinesia (PED):
• A relatively rare form of paroxysmal dyskinesia has been described in which
episodes are induced by prolonged exertion.
4. Paroxysmal Hypnogenic Dyskinesia (PHD):
• A rare disease variant, characterized by transient attacks of involuntary
movements occurring during non-REM (NREM or non-rapid eye movement)
Sleep.
• In rare instances, episodes may be preceded by potentially painful sensations.
Paroxysmal dyskinesias may also be further categorized according to the
duration of the attacks. They may be described as “short-lasting” if episodes
are less than or equal to 5 minutes or “long-lasting” if attacks are longer than 5
minutes.
Dystonia:
1. A syndrome of sustained muscle contractions, frequently causing twisting and

repetitive movements, or abnormal postures”.
2. The muscle contractions related to dystonia may be quite rapid and not
sustained.
3. The movements may not be repetitive and not lead to fixed postures.
4. Usually occurs only during voluntary movement or with voluntary
maintenance of a posture of the limbs or body.
5. Characteristic postures that are frequently seen in dystonia include:
a. Spooning, d u r i n g w h i c h t h e f i n g e r s o f t h e h a n d a r e b e n t
backward with the wrist flexed.
b. Elbow and wrist flexion with the hand held near the body.
c. Foot in-turning or inversion at the ankle, which is frequently
pronounced with walking.
d. Extension of the great toe.
e. Turning of the neck or torticollis.
26
6. Focal dystonia: (only one body part is involved, such as a hand, foot or the
neck).
7. Segmental dystonia: (two contiguous parts are involved, such as the face and
neck).
8. Multifocal dystonia: (two noncontiguous parts of the body are involved, such
as the face and one leg).
9. Hemidystonia: (one half of the body is involved).
10. Generalized dystonia: (both legs, as well as one additional body part are
involved).
11. A dystonic posture of the right hand may occur while the left hand is
performing a rapid movement, or a dystonic posture of the foot may occur
during walking. The triggering movements may be very specific; for example,
walking forward may be a trigger, while walking backward may not be a
trigger.
Examination:
1. The child being evaluated for dystonia must be observed at rest, with
action of the parts of the body affected by dystonia, as well as actions
unrelated to the dystonia.
2. A child with foot dystonia must be observed while sitting, standing,
walking and performing tasks with the hands.
3. Mental distraction is also helpful; when possible, the evaluator may use
language or mathematical tasks to distract the child. These types of
distractions may help to determine the specific triggers for the dystonic
movements.
4. They may also assist in evaluating if other body parts are subtly affected
when provoked by attempted movement, stress or distraction.
5. It is important to test the child during the certain activities to observe
dystonia-obstructing movement or excessive movements. These activities
include:
a. Reaching movements of the arms.
b. Speaking.
c. Tongue movement.
27
Spasticity:
1. A velocity-dependent increase in resistance to passive movement of a limb.

2. Spasticity does not necessarily interfere with the child’s attempts at
voluntary movement. It is essentially a property of passive movement.
Therefore, spasticity is triggered by the interaction between the child and
the environment.
3. In children is most commonly due to Cerebral Palsy (CP) and there are sets
of spasticity syndromes or patterns that are well recognized. These includes:
i.Spastic diplegia (both legs involved greater than arms).
ii.Hemiplegia (involves an arm and a leg on the same side of the body).
iii.Double hemiplegia (both arms involved more than legs).
iv. iv. Tetraplegia (all four limbs involved usually severely).
Hereditary Spastic Paraplegia (HSP):
1. A group of genetic, degenerative disorders of the spinal cord.

2. Characterized by progressive weakness and stiffness of the legs. C- This
group of disorders is also sometimes referred to as:
a. Familial Spastic Paraparesis (FSP).
b. Familial Spastic Paraplegia (FSP).
c. Hereditary Spastic Paraparesis (HSP).
d. Strumpell-Lorraine Syndrome.
e. Strumpell's Disease
3. Primarily characterized by varying degrees of stiffness (rigidity) and
weakness of leg muscles and hip abductors, with associated gait
disturbances and increasing difficulties walking.
4. Symptoms may begin as early as infancy or early childhood to as late as the
eighth or ninth decade of life. In some kindreds, symptoms appear to occur
at a progressively younger age with
successive generations.
5. (HSP) that is characterized by progressive spasticity as an isolated finding
often described as uncomplicated or “pure” (HSP). In those patients’ initial
findings may include:
a. Rigidity and increased tone of certain leg muscles, including those of
the inner thigh, front and back of the thighs and of the calves.
b. Weakness of certain leg muscles, dorsi and planter flexors, hip flexor,
knee flexors.
c. Delayed walking, abnormal shuffling gait.
28
Examination & Evaluation of Children

with Neurological Disorders
1. Mental Status Examination:
a. Is the child awake, alert and responsive??
b. Does the child behave in an appropriate manner?
c. Are speech, language, reading and writing skills appropriate for the child's age?
d. Is judgment intact and memory for objects and numbers appropriate for the child’s
age?
2. Cranial Nerve Function:
a. Are eye, facial, mouth and tongue movements intact?
b. Is sensation on the face normal?
c. Are hearing and balance functions intact?
d. Are smell and taste normal?
3. Sensation:
a. Is the child able to feel light touch, temperature, pinprick and the position of joints
throughout the body?
b. Is the sensation the same on both sides of the body and the same in the face, arms
and legs?
4. Motor function:
a. Strength normal in all parts of the body?
b. Are there any areas of unusually reduced muscle bulk?
c. When relaxed, can the examiner move the limbs and neck easily?
d. Is there a change with the speed of movement or a “spastic catch”?
e. Is there a change when a distant part of the body is moved or when the child is
lying down, seated or standing?
f. Are there any abnormal postures of the limbs, trunk or face?
g. Are there excess involuntary movements such as choreoathetosis, myoclonus,
tremor or tics?
5. Coordination:
a. Can the child reach accurately to touch an object far from their body?
b. Are movements appropriately rapid?
c. Can the child manipulate objects with two hands and pick-up small objects
between the fingers?
d. Can the child perform rapidly alternating movements such as opening and closing
the hands or fingers?
6. Gait:
a. How does the child support his or her weight against gravity?
b. How does the child respond to a loss of balance?
c. Can the child stand and walk stably (depending on the child's age)?
d. Is it possible to walk on the toes or heels, to walk on a narrow line or to walk
backwards?
e. Is the child unsteady while standing with eyes closed?
f. Is there any unusual posturing of the arms, legs or face while walking or running?
29
Neurological Examination:
1. All 12 cranial nerves must be reviewed.

2. Sensory examination should include superficial touch and pain, deep pain,
position sense (large joints as well as small).
3. Vibration sense, two-point discrimination, hot and cold perception, and the
presence or absence of extinction to bilateral confrontation.
4. Cerebellar and coordination functions need careful review, as do the deep
tendon and pathological reflexes.
5. Communication skills are assessed during the neurological
examination either as part of or following a broad assessment of the optic
and auditory cranial nerves.
6. Speech assessment includes evaluating articulation as well as the content of
expression.
7. The listening (i.e., receptive) skill can be assessed by presenting concrete
instructions and abstract ideas of increasing complexity that require
responses by the patient. Similar performance requirements will help
assess reading and writing skills.
Musculoskeletal System:
1. A screening examination is useful in localizing abnormalities when the

disability problems are minor.
2. For conditions that may result in major disability, individual joint
examinations are necessary. Such examinations include:
a. Inspection: (the two sides of the body should be observed for
symmetry in contour and size and differences measured.
Atrophy, masses, swellings, and skin color changes must be noted).
b. Palpation: (the origin of a pain symptom may be localized by palpation
of the various anatomical structures about the joint. Palpation of masses
and swellings for consistency can allow to distinguish between bone
masses, edema, and joint effusions. To determine the presence of
muscle spasm).
c. Passive Range of Motion: (tests are performed by the examiner while
the patient is relaxed. When range of motion is limited, range limitation
is due to joint surface abnormality; joint fluid excess or loose bodies; or
capsule, ligament, or muscle contractures.
d. Stability: (assess whether a pathological condition of the bone, capsule,
or ligament is causing abnormal movement (subluxations or
dislocations). The joint should be moved under stress in the direction it
is not supposed to move by virtue of its contour, ligaments and capsule,
with the patient at rest).
30
e. Active Range of Motion: (tests should be performed prior to strength

tests in the event pain is a problem. Muscle tension and joint
compressions induced by an active movement are less stressful than in
a strength test. If pain is minimal in an active range of motion test, the
examiner can more easily proceed with a strength test. When active
range of motion is less than passive range of motion, the examiner must
decide between true weakness, hysterical weakness, joint stability or
pain as possible causes).
f. Muscle Strength:
i. GRADE 5: Normal strength, full range of motion against gravity and
against “full” resistance applied by the examiner.
ii. GRADE 4. Good strength, the muscle can move the joint it crosses
through a full range of motion against gravity with only “moderate”
resistance applied by the examiner.
iii. GRADE 3: Fair strength, the muscle can move the joint it crosses
through a full range of motion against gravity only.
iv.GRADE 2: Poor strength, the muscle can move the joint it crosses
through a full range of motion only if the pant is positioned so that the
force of gravity is not acting to resist the motion.
v. GRADE 1: Trace strength, muscle contraction can be seen or palpated
but strength is insufficient to produce motion even with gravity
eliminated.
vi.GRADE 0: Zero strength, complete paralysis. No visible or palpable
contraction.
vii. The key muscle grade with regard to disability assessment is grade 3.
Since any activity a patient may perform is done in a gravity field, if at
least grade 3 function is present. then the involved body part can be
used.
viii.For grades less than 3. external support may be necessary to make the
involved part useful to the patient.
ix.For conditions in which weakness is associated with spasticity, the
grading system is not as useful in predicting how much the patient
may get out of the muscle for the performance of his basic skill needs.
31
Functional Neuromuscular Examination:
1. The functional examination is the actual translation of the objective

neurological and musculoskeletal examinations into performance.
2. It defines at a given point in time the skill of the patient in the execution of
the activities of daily living.
3. It is the starting point from which improvement can occur through treatment
even if the objective neurological and musculoskeletal signs may not tie
alterable owing to the nature of the disease.
4. The functional examination confirms the skill status reported by the patient
in the history under Present Illness with regard to ambulation. transfers,
eating, dressing, and personal hygiene. The functions to be tested are as
follows:
a. Sitting Balance.
b. Transfers (abilities for turning from supine to prone and back, rising to a
sitting position, rising from sitting to standing, and moving from a bed or
low examining table to a chair).
c. Standing Balance (a necessary prerequisite for safe ambulation. Assessed
without support and, if balance is present, nudging from side to side should
then be done to assess the patient’s ability to recover.
d. Eating Skills (assessed by demonstration of hand-to- mouth abilities
utilizing various examining room objects or by means of actual
observation at mealtime).
e. Dressing Skills (assessed in the examining room if the examiner is present
at the time the patient removes the clothes prior to the examination and
puts them on at the conclusion).
f. Personal Hygiene Skills (motions necessary for face, perineal, and back
care can usually be mimicked in the examining room. Direct observation
of the specific task when actually performed may be necessary if personal
hygiene functions are significant disability problems.
g. Ambulation (walking should be observed if the patient has standing
balance. The patient should be essentially unclothed. Walking should be
inspected with and without street shoes, and from the front and back as
well as from the side. Abnormalities should be described in relation to the
phase of the gait at which they occur):
i. Cadence: Symmetrical? Asymmetrical? Consistent?
ii. Trunk. Fixed abnormal posture? Abnormal anterior, posterior, or
lateral movements?
iii. Arm Swing. Symmetrical?
iv. Pelvis.’ Fixed abnormal posture? Abnormal pelvic tilt or drop?
v. Base: Narrow? Broad?
vi. Stride Length: Short? Asymmetrical?
vii. Heel Strike and Push Off Present?
viii. Swing Phase: Knee flexion? Circumduction?
32
Hearing Assessment Flowchart (0-2yrs)
33
Hearing Assessment Flowchart (2-5yrs)
34
Speech Disorders
35
Delayed Language
36
Amblyopia
Diagnosis:
1. History:
➢ Eye problem in childhood such as misaligned eyes, patching or

muscle surgery?
2. Ocular examination to rule out an organic cause for the reduced vision.
3. Cover – uncover test to evaluate eye alignment.
4. Refraction: Cycloplegic in children too young to cooperate.
Treatment:
1. Patients younger than 10 years:
a. Appropriate spectacle correction

b. Patching: patch the eye with better corrected vision 2 to 6 hours /day
for a week per year of age with at least 1 hour of near activity.
c. Continue patching until the vision is equalized or show no
improvement after three cycles of patching.
2. Patient more than 10 years of age: atrial of Spectlacle correction, patching

and or may be atropine considered if not attempt previously.
3. Treatment of media opacity.
4. Treatment of anisometropic amblyopia: give the appropriate spectacle

correction at the youngest age possible (best if given before age 5).
37
Congenital Cataract
• Examination of the red reflex is an essential part of healthy baby/child visits in

nonverbal children.
• Infantile cataracts that are not extracted in the first 6-8 weeks of life may be
associated with irreversible visual loss and nystagmus.
Diagnosis:
1. History :
➢ Maternal illness or drud ingestion during pregency?
➢ Radiation exposure or trauma?
➢ Family history of congenital cataract.
2. Visual assessment of each eye alone.
3. Ocular examinations
4. Cycloplegic refraction.
5. B-scan US may be helpful when the fundus view is obscured.
6. Medical examination by pediatrician looking for associated abnormalities.
7. Red blood cell galactokinase (galactokinase level) with or without RBC
galactose -1- phosphate uridyl transferaseactivity to rule out galactosemia.
Treatment:
1. Referral to a pediatrician to treat any underlying disorder.

2. Treat associated ocular diseases.
3. Cataract extraction: usually within days to weeks of discovery to prevent
irreversible amblyopia …. Cataract extraction is performed in the following
condions:
a. Vision is obscured.
b. Cataract progression threatens the health of the eye .
4. After cataract extraction. treat amblyopia in children younger than 9 to 11

years.
38
Congenital Glaucoma
• When excess tearing is associated with photophobia (light aversion), corneal

enlargement and clouding, an immediate referral should be made for possible
congenital glaucoma
Diagnosis:
1. History:
➢ Other systemic abnormalities?
➢ Rubella infection during pregency?
➢ Birth trauma?
➢ family history of congenital glaucoma.
2. Ocular examination, including a visual acuity assessment of each eye
separately, apen light or portable slit lamp examination to detect corneal
enlargement and haziness, a dilated fundus examination is performed to
evaluate optic disc and retina.
3. IOP and pachymetry are performed, axial length is measured with us to
monitor the progression of the disease.
Treatment:
• Definitive treatment is usually surgical.
• Medical therapy is to temporizing measure before surgery.
Medical:
• Oral carbonic anhydrase inhibitor (e.g. acetazolamide, 10 to 15 mg / kg / day)
most effective often to clear cornea prior goniotomy.
• Topical carbonic anhydrase inhibitor (e.g brinzolamide) less effective.
Surgical:
• Goniotomy is procedure of choice.
• If the cornea is not clear, trabeculotomy is usually the preferred procedure.
Note:
▪ Amblyopia may be superimposed on glaucoma and should be treated by patching.
Follow Up:
1. Repeated examinations, under anaesthesia when needed, are necessary to
monitor corneal diameter, iop , cup / disc ratio , and axial length .
2. These patients must be followed throughout life to monitor for progression.
39
Congenital Ptosis
• Mechanical obstruction of vision can produce severe visual loss (derivational

amblyopia).
• Droopiness of Eyelid (ptosis) or Eyelid hemangioma can also cause visually
significant Astigmatism that can result in Refractive amblyopia
Diagnosis:
1. History:
➢ Age of onset?
➢ Duration? Family history?
➢ History of trauma or prior surgery?
➢ Any crossing of eyes?
2. Visual acuity for each eye separately, with correction to evaluate for
amblyopia.
3. Manifest and cycloplegic refraction checking for anisometropia.
4. Pupillary examination.
5. Ocular motility examination.
6. Measure interpalbral fissure distance, distance between corneal light
reflexand upper eyelid margin, levator function, postion and depth of upper
eyelid crease . check for bell phenomenon.
7. Slit-lamp examination looking for signs of corneal exposure.
8. Dilated fundus examination.
Treatment:
1. Observation if degree of ptosis mild, no evidence of amblyopia, and no
abnormal head positioning.
2. Simple congenital ptosis; if levator function is poor, consider frontalis
suspention, if levator function is moderate or normal, consider a levator
resection.
3. Macus gunn jaw winking: No treatment if mild, in general, the jaw winking
gets better around school age.
Follow Up:
1. If observing, patient should be reexamined every 3 to 12 months.
2. After surgery, patients should be monitored for undercorrection or
overcorrection and recurrence.
40
Retinopathy of Prematurity
• Very premature infants, <1500g or <32wks, are at risk for development of
retinopathy of prematurity.
Diagnosis:
1. Screening recommendations
a. Birth weight <1500g.
b. Gestional age <32wks.
2. Dilated retinal examination 4 weeks after birth.
Treatment:
1. Photocoagulation (laser therapy)
• Photocoagulation is the first line of defense against ROP. The setup is much
like a retinal exam, except your child will be given local or general anesthesia.
The ophthalmologist uses a diode laser mounted on the indirect ophthalmoscope
to make tiny “burns” in the periphery of the retina, to prevent further growth of
abnormal blood vessels.
• Your child's doctor will set follow-up exams — usually every one to two weeks
— to see how the eyes are responding to the laser treatment. If the ROP
continues to worsen, your child may need additional laser treatments or possibly
eye surgery.
2. Cryopexy (cryotherapy)
• Formerly the procedure of choice for treating ROP, cryopexy uses a penlike
instrument called a cryoprobe to freeze parts of the retina's periphery through
the outer wall of the eye. Though it's largely been replaced by laser therapy,
cryopexy is useful when the retina can't be fully seen (because of a hemorrhage,
for example).
• Because both photocoagulation and cryopexy destroy part of the retina's
periphery, your child may lose some of his side vision with these treatments.
However, the procedure aims to save his “central vision”—the most important
part of sight — which is necessary for things like reading and driving.
3. Eye surgery
• If your child's retinal becomes partly or completely detached — Stage 4 or 5 —
your doctor may refer him to a retinal surgeon for treatment, usually scleral
buckling or vitrectomy.
a. Scleral buckling involves placing a silicone band around the eye and
tightening it until the retina is close enough to the wall to reattach itself.
The band, called a scleral buckle, can be left in place to protect the eye for
months, or sometimes years.
b. Vitrectomy involves removing the vitreous (the gel-like substance that fills
the back of the eye) and replacing it with saline solution or oil. The scar
tissue on the retina can then be peeled back or cut away, allowing the
retina to flatten back down against the wall of the eye.
41
The Bilaterally Blind Infant
Diagnosis:
1. History:
➢ premature?
➢ Normal development and growth?
➢ Maternal infection, diabetes or drug use during pregensy ?
➢ Family history of eye disease?
2. Evaluate the infant ability to fixate on an object and follow it.
3. Pupillary examination.
4. Look carefully for nystagmus.
5. Fundus examination for optic nerve and retinal evaluation.
6. Cycloplegic refraction.
7. ERG.
8. Consider a CT or MRI of the brain.
Treatment:
1. Correct refractive errors and treat known or suspected amblyopia.

2. Parental counseling is necessary in all conditions.
3. Referral to educational services for the visually handicapted may be helpful.
4. Provide genetic counseling.
5. If neurological or endocrine abnormalities are found or suspected, the child
should be referred to a pediatrician for appropriate work up or management.
42
Environmental Conditions for prevention of child disability

There's increasing numbers of disabled newborn children that can be referred to many
factors that can be classified into two categories:
Genetic and/or Environmental
A) genetic factors which can be caused by abnormal gene that caused due to parents
inherited gene or exposure of the mother before, during or after labor such as
• Infection; German measels; Toxoplasmosis

• Premature baby
• Neonatal hypoxia
• Exposure to irradiation either to Ionizing such as x Ray or gamma Ray or one
neglected indoor source called Radon, non-ionizing radiation such as exposure
to electromagnetic I field that our life for a lot of electrical and electronics
Utensils.
• Food additive such as artificial sweeteners color flavor smells etc
• Junk food
• agricultural pollutants such as bisticids, fertilizer, herbicide, hormones,
Vermont..etc
• A lot of medications
Don't give medications to pregnant woman except if severely indicated
The best way is the prevented and genetic study and by genotherapy otherwise we
have to follow the rules of palliative regime of rehabilitation training reeducation
exercise.
43
44
Pediatric Endocrinology Protocol of EHA
0
Egyptian Clinical Practice Protocols

in
Pediatric Endocrinology
for
First Edition
2024
Prepared by
Working Group for Development of
in
Pediatric Endocrinology
for
1
Executive Committee
(Head of the Committee)
1. Prof. Mahmoud Abd Raboo Hussin El Helaly: Professor of Pediatric
Endocrinology and Diabetology Military Medical academy
(Members of the Committee)

(In the order of Alphabets)
2. Prof. Basma Abdelmoez Ali: Prof of Pediatrics, Pediatric Endocrinology and

Diabetology, Minia university
3. Prof. Hesham El Hefnawy: Prof of Pediatrics, Pediatric Endocrinology and
Diabetology, NIDE, Ex Dean of National Diabetes Institute, Head of National
Diabetes committee
4. Prof. Mona Attia: Prof of Pediatrics, Pediatric Endocrinology and Diabetology,
Cairo University
5. Prof. Mona Karem Amin: Associate Professor of Pediatrics, Pediatric
Endocrinology and Diabetology, Suez Canal University
6. Prof. Mona Mamdouh A. Hassan: Prof of Pediatrics, Pediatric Endocrinology
and Diabetology, Cairo University
7. Prof. Mona Salem: Prof of Pediatrics, Pediatric Endocrinology and Diabetology
Ain shams university, President of ESPED
8. Prof. Sameh Tawfik: Prof of Pediatrics, Pediatric Endocrinology and
Diabetology, Military Medical Academy
9. Prof. Shaymaa Elsayed Abdel Meguid: Associate Professor of Pediatrics,
Pediatric Endocrinology and Diabetology, Alexandria University
10.Prof. Shereen Abdelghaffar: Prof. Of Pediatrics, Pediatric Endocrinology and
Diabetology, Cairo University
11.Prof. Yasmine Ibrahim Elhenawy: Associate Professor of Pediatrics
Endocrinology and Diabetology, Ain Shams University
12.Dr. Dalia Abdel-Basser Elkherbawy: Consultant of pediatrics, Pediatric
Endocrinology and Diabetology in police hospitals
13.Dr. Ramy Saleh Morsy: Lecturer of Pediatrics, Pediatric Endocrinology and
Diabetology, Armed Forces College of Medicine
14.Dr. Mariam Nader: Assistant Lecturer of Pediatrics Pediatric Endocrinology and
Diabetology, Armed Forces College of Medicine (Moderator)
15.Dr. Veronia Philip: Pediatric Specialist & Pediatric Diabetology Specialist
2
Disclaimer
Protocols and guidelines outline the recommended or suggested clinical practice;

however, they cannot replace sound clinical judgment by appropriately trained and
licensed physicians.
The physician is ultimately responsible for management of individual patients
under their care.
All Intellectual Property Rights are reserved to EHA. No part of this publication
can be reproduced or transmitted in any form or by any means without written
permission from the EHA and authors.
3

• Head of Training Committee of Paediatrics of Egyptian Military Medical Board
Authority (EHA).
Reviewed By


Cover Designed & Edited By

4
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric
Endocrinology is to unify and standardize the delivery of healthcare to any child at all
health facilities.
Pediatric Endocrinology service is usually offered to children below 16 years of

age in Egypt.
The current status of healthcare in which avoidable failures are abound. “We
of the problem, is that the ever-increasing complexity of medicine makes uniform care
delivery impractical or impossible. That is, unless there are protocols, checklists, or
care paths that are readily available to providers.
Regarding Pediatric Endocrinology, busy clinicians have all felt the need for a
concise, easy-to-use resource at the bedside for evidence-based protocols, or
consensus-driven care paths.
comprehensive advice about management approaches based on the highest level of
evidence available in each case. Our goal is to provide an authoritative practical
medical resource for pediatricians.
We hope that such an approach will encourage clinicians to apply available

evidence to their practice and also track compliance with desired practices. We hope
that practicing pediatricians, fellows and practitioners will find this protocol useful in
delivering high-quality clinical care to their patients. We remain open to feedback and
suggestions about how to improve this resource and how to make it maximally useful
to those delivering care at the bedside in for patients in Pediatric Endocrinology.
For Development of the Egyptian Clinical Practice Guideline
In Pediatric Endocrinology
5
Table of Contents
Page
Title
Number
Preface 5
Abbreviations 7
Diabetes 8
Diabetic Ketoacidosis 12
Hypoglycemia 29
Precious Puberty 35
Disorder of Sex Determination (DSD) 40
Congenital Hypothyroidism (CH) 44
Protocol for Growth Hormone Treatment 49
Diagnosis & Management of Osteoporosis in Children 56
Appendix 60
6
Abbreviations
AMH Antimullerian hormone

AIS Androgen insensitivity syndrome
CAH Congenital adrenal hyperplasia
CAIS Complete Androgen insensitivity syndrome
DHT Dihydrotestosterone
GD Gonadal dysgenesis
hcG Human chorionic gonadotropin
PAIS Partial Androgen insensitivity syndrome
PMDS Persistent mullerian duct syndrome
T Testosterone
17 oHP 17 hydroxyprogesterone
11B oHD 11 beta hydroxysteroid dehydrogenase
11DF 11 Deoxycortisol and 11 Deoxycorticosterone
Δ4 Delta 4 Androstendione
7
Diabetes
When to suspect Diabetes?
➢ A child presenting with a classical history of increasing polyuria, polydipsia, and weight
loss over 2 to 6 weekspresents a straight forward diagnosis.
➢ Some children have a rapid onset of symptoms or late misdiagnosis present within days
in diabeticketoacidosis.
IF diagnosis of DKA is confirmed,

emergency referral to a tertiary
Hospital with ICU
Refer to DKA flowchart and algorithm
Start immediately Insulin therapy

➢ Insulin Dosage
Total daily dose (TDD) depends on age, pubertal status and initial presentation of the patient.
❖ During the partial remission phase, the total daily insulin dose is often <0.5 u/kg/d
❖ Prepubertal children (outside the partial remission phase) usually require 0.7-1.0 u/kg/d
❖ During puberty, requirements may rise substantially 1.2 - 2 u/kg/d
➢ Distribution of Insulin Dose
Basal-bolus regimen is the best and most physiologic method.
❖ In case of using insulin analogs: 50% of TDD basal and 50 % bolus

*In toddlers (start by 40% of TDD basal)
❖ In case of regular insulin: 40% of TDD basal and 60% bolus

ICR (Insulin: Carb. ratio): 500/TDD= grams of carbs. covered by 1 unit of rapid acting insulin
ICR: 450/TDD= grams of carbs. covered by 1 unit of REGULAR insulin
ISF (Insulin sensitivity factor) = 1700/TDD= mg/dl of BG (BG target for correction=180 mg/dl)
8
A multidisciplinary team approach is required to achieve target glycemic control
Diet
➢ Appropriate dietetic support to help optimize body weight and glycemic control
➢ Total daily energy intake distributed as follows:
❖ Carbohydrate 45% to 55% energy
❖ Fat 30% to 35% energy
(<10% saturated fat + trans fatty acids)
❖ Protein 15% to 20% energy
 Step 1: Calculate the caloric needs

 Step 2: Calculate the carbohydrates needs
Exercise
➢ An individualized blood glucose management plan should be developed for each patient
➢ This plan should specifically include the following:
❖ Discuss the type and amount of carbohydrate required for specific exercise.
❖ Discuss the percentage reductions in insulin before exercise.
❖ Discuss when best to exercise safely.
When to suspect Monogenic Diabetes

➢ Diabetes presenting before 6 months of age
➢ Family history of diabetes in one parent and other first-degree relatives of that affected parent
➢ Absence of autoantibodies ( if available)
➢ Preserved β-cell function, with low insulin requirements and detectable C-peptide over an extended
partial remission phase
When to suspect Type 2 Diabetes

➢ Overweight or obesity in an adolescent
➢ positive family history of type 2 diabetes
➢ Acanthosis Nigerians
➢ Undetectable auto antibodies ( if available)
➢ Persistent high fasting c- peptide ( 6 to 12 months after the onset)
9
 Processes of Diabetes Care
check log books
 Annual screening of vascular complications
10
References
1) Danne T, Phillip M, Buckingham BA, Jarosz-Chobot P, Saboo B, Urakami

T, Battelino T, Hanas R, Codner E. ISPAD Clinical Practice Consensus
Guidelines 2018: Insulin treatment in children and adolescents with
diabetes. Pediatr Diabetes. 2018 Oct;19 Suppl 27:115-135.
2) Smart CE, Annan F, Higgins LA, Jelleryd E, Lopez M, Acerini CL.

ISPAD Clinical Practice Consensus Guidelines 2018: Nutritional
management in children and adolescents with diabetes. Pediatr Diabetes.
2018 Oct;19 Suppl 27:136-154.
3) Donaghue KC, Marcovecchio ML, Wadwa RP, Chew EY, Wong TY,
Calliari LE, Zabeen B, Salem MA, Craig ME. ISPAD Clinical Practice
Consensus Guidelines 2018: Microvascular and macrovascular
complications in children and adolescents. Pediatr Diabetes. 2018 Oct;19
Suppl 27(Suppl 27):262-274.
4) DiMeglio LA, Acerini CL, Codner E, et al. ISPAD Clinical Practice

Consensus Guidelines 2018: Glycemic control targets and glucose
monitoring for children, adolescents, and young adults with diabetes.
Pediatr Diabetes. 2018;19(Suppl. 27):105–114.
5) Adolfsson P, Riddell MC, Taplin CE, et al. ISPAD Clinical Practice

Consensus Guidelines 2018: Exercise in children and adolescents with
diabetes. Pediatr Diabetes. 2018;19(Suppl. 27):205–226.
11
Diabetic Ketoacidosis
 Diagnosis of diabetic ketoacidosis (ISPAD, 2022)
➢ Clinically,patients may present with history of weight loss, secondary enuresis,
fatiguability and weakness, polydipsia/polyuria/polyphagia with sugar craving. They then
may develop nausea and vomiting (without diarrhea) and shortness of breath.
➢ The biochemical criteria for the diagnosis of DKA are:
✓ Hyperglycemia [BG >200 mg/dL]
✓ Venous pH < 7.3 or
✓ Bicarbonate < 18 mEq/L
✓ Ketonemia or moderate or large ketonuria. (ISPAD, 2022)
✓ If available, blood beta-hydroxybutyrate (BOHB) concentration should be
measured. A level ≥3 mmol/L is indicative of DKA.
 Severity of DKA (ISPAD, 2018)

✓ Mild DKA: venous pH<7.3 or bicarbonate <18
✓ Moderate DKA: venous pH<7.2 or bicarbonate <10
✓ Severe DKA: venous pH<7.1 or bicarbonate <5.
 Hyperglycemic Hyperosmolar State (HHS)

➢ Formerly called Hyperosmolar non-ketotic coma, it is a condition that may occur in young
T2DM.
➢ Some type 1 diabetic children and adolescents in DKA may also have some features of HHS
especially when high carbohydrate beverages have been consumed to combat dehydration
at the time of diagnosis.
➢ It may also occur in especially those with 6q24-related transient neonatal diabetes mellitus.
➢ Criteria of HHS are:
✓ Plasma glucose concentration > 600 mg/dL
✓ Arterial pH > 7.30; venous pH > 7.25
✓ Serum bicarbonate >18 mmol/L
✓ Small ketonuria, absent to small ketonemia
✓ Effective serum osmolality >320 mOsm/kg
✓ Obtundation, combativeness, or seizures (in almost half the patients).
 Causes of Morbidity and Mortality of DKA (Complications)

✓ Cerebral edema*
✓ Hypokalemia*
✓ Hypocalcemia, hypomagnesemia
✓ Severe hypophosphatemia
✓ Hyperchloremic acidosis*
✓ Hypoglycemia*
✓ Other central nervous system complications include dural sinus thrombosis, basilar
artery thrombosis, intracranial hemorrhage, cerebral infarction
✓ Venous thrombosis, pulmonary embolism
✓ Sepsis
✓ pulmonary edema, ARDS
✓ Rhabdomyolysis
✓ Acute kidney injury including renal failure
*= can also occur as complications of therapy.
12
key Recommendations
Grade/ Level
CPG Source Recommendation
of Evidence
Initial Assessment and Calculations
ISPAD 2018 Do the following: E

• Immediate measurement of blood glucose.
• blood or urine ketones.
• serum electrolytes.
• blood urea nitrogen and s.creatinine.
• venous blood gases.
• complete blood count.
• weigh the patient, measure height/ length to calculate surface area.
• Connect the patient to an ECG monitor and check T waves.
• Obtain appropriate specimens for cultures if there is evidence
of infection e.g. fever.
ISPAD 2018 Assess the severity of dehydration(table 1) by:
• Capillary refill time (normal capillary refill is ≤1.5-2 seconds).
• Skin turgor ('tenting' or inelastic skin) or other signs of E
dehydration.
• Pulse rate and volume (weak rapid pulse in shock).
• Hypotension is a late sign (blood pressure is maintained for a
long time by sympathetic tone, stress hormones and increased
osmotic pressure from marked hyperglycemia).
• Reduced conscious level (in shock).
ADA 2006 Estimation of the degree of dehydration in DKA is imprecise

(hyperosmolar dehydration) and may vary among examiners.
Assess the degree of severity of DKA to estimate the degree of
dehydration (e.g. severe dehydration in severe DKA).
Assess level of consciousness:

ISPAD 2018 Glasgow coma scale (GCS) assessment E
ISPAD 2018 (table 2) Examine
Peripheral pupillary
venous blood size
gases and be used for diagnosis of DKA
should E
reflexes
and its degree and for guiding management plan to decrease the
hazards of arterial sampling with no drawbacks on the outcome of
DKA.
ISPAD 2018 Calculate the following: E
• Anion gap = Na – (Cl + HCO3):
----normal is 12 ± 2 mmol/L
----In DKA the anion gap is typically 20-30 mmol/L
----an anion gap >35 mmol/L suggests concomitant lactic
acidosis (e.g. due to sepsis)
• Corrected sodium = measured Na + 2 ([plasma glucose –
100]/100)mg/dL
• Effective osmolality (mOsm/kg) = 2 (plasma Na) + (plasma glucose
mg/dl)/18
13
Grade/ Level
of Evidence
ISPAD 2018 • Suspect infection if the patient has fever and give antibiotics after
obtaining appropriate cultures. E
• Consider Sepsis if acidosis is not improving (lactic acidosis) after
revising fluid and insulin infusions.
ISPAD 2018 Indications for ICU admission: E
➢ Children in severe DKA (pH< 7.1, HCO3-< 5 mEq/L)
➢ Children at increased risk of cerebral oedema
(e.g., <5 years of age, severe acidosis, low pCO2, high blood
urea nitrogen).
Monitoring:
• Hourly heart rate, respiratory rate, capillary refill time and blood
pressure. E
• Hourly fluid input and output (or more frequently, with the
possibility of urinary catheterization when there is impaired
consciousness).
• Hourly GCS assessment, neurologic assessment
• Observe for warning signs of cerebral oedema, including headache,
irritability, inappropriate slowing of heart rate and rise of blood
ISPAD 2018 pressure, repeated vomiting, increased drowsiness, incontinence, E
specific nerve palsies, change in pupillary size or reaction.
• Hourly capillary blood glucose monitoring
• Do The Following Laboratory Measurements At 2 Hours And
Every 2-4 Hours (Or Hourly In Severe Cases Until Stabilization Of
The Patient)
O Venous Blood Gases
O S-Sodium, S-Potassium,
O Blood Urea Nitrogen, S-Creatinine
O S-Calcium, Magnesium, Phosphate.
Fluid Therapy
Initial Resuscitation Fluid:
ISPAD 2018
➢ If patient is not in shock, give initial bolus of A
0.9 % saline at 10 ml/kg over 30-60 minutes.
➢ If tissue perfusion is poor (capillary refill time more than 3 seconds),
give initial bolus more rapidly (e.g. over 15- 30 min) and a second
bolus may be given to achieve adequate tissue perfusion.
➢ In a shocked patient with weak peripheral pulses, the initial fluid
bolus is given at 20 ml/kg infused as quickly as possible
through a wide bore cannula. It can be repeated with re-
assessment of circulatory status after each bolus.
➢ After volume corrections, if a child in DKA is in hypotensive shock,
especially if septic, then consult a pediatric critical care specialist
to start inotropes.
➢ Blood glucose may drop 75-100 mg/dl/hour in this
initial rehydration phase.
Type of Fluid
➢ Use crystalloid, like normal saline, not colloid for initial volume E
expansion.
14
Grade/ Level
of Evidence
ISPAD 2018 Subsequent Deficit and Maintenance Fluid:
• Calculate the total fluid requirement by adding the estimated fluid A
deficit to the fluid maintenance requirements.
• Estimating Fluid Deficit: Assume 5-7% dehydration (6-10% in
infants) in moderate DKA.
• Assume 7-10% dehydration in severe DKA (˃10-15% in infants).
• In shocked patients, deficits may exceed 10% body weight. Use
Table 1
for estimating severity of dehydration.
• Aim to replace the estimated fluid over 24 to 48 hours.
• ISPAD table (3)of precalculated volumes of replacement and
maintenance fluids (provided in this document in implementation A
tools) can be used when 10% dehydration is assumed and the total
fluid replacement will be given over 48 hours. The fluid volume in
the table is calculated per 24 hours and per hour based on body
weight.
• For body weights >32 kg, the volumes have been adjusted so as not
to exceed twice the maintenance rate of fluid administration.
• I.V. fluids given in another hospital before assessment
should be subtracted from the calculations. A
• Do not add urine output to the calculation of replacement fluids.
15
ISPAD 2018 Type of subsequent fluid to use:

• Use 0.9% saline, 0.45 saline or a balanced salt solution (Ringer’s
lactate) with added potassium chloride for subsequent fluid A
replacement.
• Sodium should rise by 0.5 mmol/L for each 1 mmol/L decrease
in glucose concentration.
• If measured serum sodium concentration is low and does not rise
appropriately with the fall in plasma glucose level, increase the
sodium content of the fluid (e.g. use 0.675% saline which is 3/4
normal saline,
115.5 mmol sodium or higher sodium content fluid like 0.9%
normal saline).
• Both the failure of serum sodium to rise and a rapid ongoing rise
in serum sodium are risk factors for development of brain
edema.
Introducing Glucose to IV Fluid to avoid hypoglycemia:
• Introduce 5% glucose once blood glucose falls below 250-300
mg/dl or rate of drop of blood glucose exceeds 90 mg/ dl/hr. A
(e.g. use 250 ml glucose 10% and 250 ml 0.9% saline to get 5%
glucose
in 0.45% saline).
• Introduce 10% glucose once BG falls below 150 mg/dl or the
rate of hourly drop of BG exceeds 90 mg/dl/hr.
(e.g. use 200 ml of 25% glucose and 300 ml of 0.9% saline to
get 10% glucose in 0.45% saline).
Increase IV glucose concentration to 12.5% as needed (made by
adding 250 ml glucose 25% and 250 ml of 0.9% saline to give
12.5% glucose in 0.45% saline).
NB.: Glucose 10%= 10 gram glucose in 100 ml = 100 mg glucose in 1ml
Grade/ Level
of Evidence
ISPAD 2018 Acidosis and Bicarbonate therapy:
In general, DO NOT give bicarbonate as it may cause harm (increases C
risk of hypokalemia, worsen tissue oxygenation, may cause
paradoxical CNS acidosis and significantly increases the risk of
development of cerebral edema later).
Bicarbonate may be indicated if:
1. in severe acidosis (pH<6.9) with evidence of compromised
cardiac contractility
2. for treatment of life-threatening hyperkalaemia
If bicarbonate is indicated, carefully give 1-2 mmol/kg over 60 minutes.
16
Potassium Therapy: E
ISPAD 2018 A. Assessment of serum potassium:
• If immediate serum potassium measurements unavailable, an
ECG is an alternative.
➢ In ECG: T wave flattening and inversion, prominent U waves
indicate hypokalemia while tall peaked T waves indicate
hyperkalemia (figure3).
B. Potassium Replacement:
• Usually there is an average of 5 mEq/ kg (range 3-6 mEq/kg)
loss of potassium (lost in urine with polyuria). Potassium shifts
out of the cells in presence of acidosis and with lack of insulin.
• Unless the patient is in renal failure with poor urine output,
fluid should have added potassium.
• If initial s-K+ is below 3.5 mmol/L, start potassium replacement
at the time of initial fluid resuscitation.
• Do not start insulin therapy if the potassium level is at or below
2.5 mmol/L.
• If s-K+ is 2.5-3.5 mmol/L, start of insulin treatment may need to
be delayed or reduced.
• Note that only 20 mmol/L potassium can be used if fluid is
infused at ≥ 10 ml/kg/hour (e.g. during initial resuscitation)
because the maximum allowed rate of potassium infusion is 0.5
mmol/kg/hour.
• The maximum allowed concentration of potassium in a
peripheral IV line is 60 mmol/L. Make sure there is no
extravasation (potassium is a caustic).
• Monitor s-K+ hourly in this case.
• If hypokalemia persists despite a maximum rate of
potassium replacement, then the rate of insulin infusion
can be reduced.
• If s-K+ is 3.5-5 mEq/L, start potassium chloride at a rate 40
mmol/L fluid at the time of starting insulin after the initial fluid
resuscitation.
• Subsequent potassium replacement therapy should be based on
serum K+ measurements (do s-K+ 2 hours after starting
potassium then every 4 hours in this case).
• If initial s-K+ is above 5 mmol/L, wait until urine output is
established and s-K+ drops below 5 mmol/L to start potassium
replacement
17
Grade/ Level
of Evidence
Insulin Therapy: B
A. Timing of starting insulin

• Start I.V. insulin infusion 1–2 hours AFTER starting
fluid replacement therapy; i.e., after the patient has
received initial volume expansion.
• Do not give an IV bolus of insulin at the start of therapy because:
--- It may increase the risk of cerebral oedema
ISPAD 2018
--- It may precipitate shock by
rapidly decreasing osmotic
pressure.
--- It may exacerbate hypokalemia.
• In HHS start insulin once the drop of BG is less than 50
mg/dl/hour with fluids only.
B
ISPAD 2018 B. Insulin Route
• Route of administration: IV
• If a child or young person with DKA is using insulin pump
therapy, start intravenous insulin therapy and disconnect the
pump.
B
ISPAD 2018 C. Insulin dose
• Insulin therapy should begin with 0.1 U/kg/h [ dilute 50 units
regular (soluble) insulin in50mL normal saline, 1 unit=1mL]
• Start at 0.05 unit /kg /hour if
▪ the patient shows marked sensitivity to insulin as in:
---young children below age of 5 years,
---some known cases of diabetes who received a dose of
insulin prior to presentation in DKA
▪ less severe DKA (pH >7.1-7.2)
• The insulin dose may be decreased further provided that
metabolic acidosis continues to resolve.
(For example, in a child below 5 years and mild DKA, insulin
may drop from 0.05 unit/kg/h, to 0.03 unit/kg/h).
• Aim for a decrease in serum glucose of 35-90 mg/dl/hour after
insulin is started.
• Increase the rate of insulin infusion if the rate of drop of blood
glucose is less than 35 mg/dl/hour.
• The dose of insulin should usually remain at 0.05–0.1
unit/kg/h until resolution of DKA.
• Resolution of DKA takes longer than normalization of blood
sugar. So, increase glucose concentration in infused fluid (see
fluid section) to be able to maintain insulin infusion without
development of hypoglycemia until complete resolution of
DKA.
• In HHS, give insulin at a dose of 0.025-0.05 U/Kg/hour.
C
18
ISPAD 2018 D- Transition to subcutaneous Insulin: E

• Transition to subcutaneous therapy and stop intravenous therapy at
resolution of DKA which is WHEN ALL OF THE FOLLOWING occurs:
1.ketosis has resolved,
N.B. Absence of ketonuria (ketones in urine) should not be C
used as an endpoint for determining resolution of DKA.
Ketonuria characteristically continues for several hours after
serum β- hydroxybutyrate level returns to normal.
2.pH>7.30, bicarbonate >15 mmol/L and closure of the anion
gap.
3.Patient is fully conscious.
4.Patient can take oral fluids without nausea or vomiting.
• Shift may be more convenient before a meal time.
• Start subcutaneous insulin before stopping intravenous insulin:
---give short-acting regular insulin 30 min-1 hour before stopping IV insulin
(rapid-acting analogues should be injected 15-30 minutes before stopping IV
insulin).
---timing of intermediate- or long-acting insulin should be determined by
the individual patient’s SC insulin regimen. For example, for the patient
on a basal-bolus insulin regimen, the first dose of basal insulin may be
started in the evening and IV insulin stopped the next morning if DKA
has resolved by the morning.
• Do NOT use premixed insulin (to allow more flexibility of dosing
insulin rather than a fixed basal to mealtime insulin ratio).
ISPAD 2018 CerebralOedema (CE):
A-Diagnosis:
• SUSPECT, who is at high risk? E
- younger age, especially below 5 years.
- new onset diabetes or long duration of symptoms.
- severe acidosis.
- high BUN.
- severe hypocapnia.
- bicarbonate treatment for correction of acidosis.
- A poor rise in serum sodium concentration or an early fall in glucose-
corrected sodium during therapy.
- Giving IV insulin in the first hour of fluid treatment.
- Greater volumes of fluid in the first 4 hours of therapy.
In these cases, mannitol or hypertonic saline should be available at the bedside
with dose calculated,
• When does CE occur?
Usually within 12 hours after treatment is started but, uncommonly, may occur
before the start of treatment. E
• Clinical Diagnosis:
Use criteria in table (4) :
One diagnostic criterion, or two major criteria, or one major and two E
minor criteria have a sensitivity of 92%, a specificity of 96% and a false
positive rate of only 4% for the early recognition of DKA-related cerebral
oedema; early enough to allow for effective treatment.
• When to do cranial imaging?
Start treatment first as with any critically ill patient and do not delay until
imaging is done. C
The primary indications for imaging are focal neurologic deficit or suspicion for:
1. intracranial hemorrhage which requires emergency neurosurgery
2. cerebrovascular thrombosis which may require anticoagulation
In both cases the patient will clinically present with focal or severe
progressive headache or focal neurologic deficit.
-
19
Grade/ Level
of Evidence
ISPAD 2018 Treatment of CE:
A- If clinical diagnosis of CE is done, treat immediately.
Transfer patient to ICU. C
B- Give the most readily available one of the following:
• mannitol 20%, give 0.5–1 g/kg over 10–15 minutes. Effect
of mannitol is apparent after 15 minutes and lasts for 2
hours. It can be repeated after 30 minutes if necessary.
• hypertonic sodium chloride (3%), 2.5–5 ml/kg over 10–15
minutes. It can be used if mannitol is not available or in addition
to mannitol if there is no response to mannitol after 30 minutes.
C- Adjust rate of fluid infusion so as to avoid excessive fluids
that might increase cerebral edema while also maintaining a
normal blood pressure to avoid cerebral hypoperfusion.
D- Elevate the head of the bed to 30° and keep the head in
the midline position.
ISPAD 2018 Phosphate Replacement: E
• Severe hypophosphatemia is uncommon, but can have severe
consequences.
• Patients usually do not have symptoms until plasma
phosphate is <1 mg/dL (0.32 mmol/L).
• Clinically significant hypophosphatemia may occur if
intravenous therapy without food consumption is prolonged
beyond 24 hours.
• Prospective studies with limited statistical power have not
shown clinical benefit from phosphate replacement. Severe
hypophosphatemia associated with symptoms should be
treated.
• Administration of phosphate may induce hypocalcaemia.
Potassium phosphate salts may be safely used as an alternative to or C
combined with potassium chloride or acetate provided that careful
monitoring of serum calcium is performed to avoid hypocalcaemia
ISPAD 2018 Role Of Oral Fluid Therapy: E
1- In severe cases when patient is fully conscious, oral

fluids can typically be initiated after 24 hours of starting
therapy even though fluid replacement may be planned
for 24-48 hours. In this case oral fluid should be
subtracted form the daily calculated IV fluids.
2- In cases when IV fluids are not available, give Oral
Rehydrating Solution (ORS) small sips (or small volumes
through a syringe) as frequently as possible without
causing the child to vomit. If vomiting does not occur
after 12 hours, give ORS at a rate of 5 mL per kg body
weight per hour. This can be done till transfer to a place
where IV fluid is available.
20
Figure (1): Pathophysiology of diabetic ketoacidosis
Source:
▪ Pathophysiology of diabetic ketoacidosis. Copyright © 2006 American Diabetes

Association. From Diabetes Care, Vol. 29, 2006:1150-1159. Reprinted with
permission of The American Diabetes Association.
21
Figure (2): Algorithm for the management of diabetic ketoacidosis
Source:
▪ Pinhas-Hamiel O, Sperling M. Diabetic ketoacidosis. In: Hochberg Z, ed.
Practical Algorithms in Pediatric Endocrinology. 3rd, revised edition ed. Basel:
Karger; 2017:112-113.
22
Table (1): Estimating the degree of dehydration
Source:
▪ Rosenbloom AL. The Management of Diabetic Ketoacidosis in Children. Diabetes
Ther 2010. 1 (2): 103-120.
Table (2): Glasgow Coma Scale
Source:
Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale
Lancet 1974: 2: 81–4
Figure (3): ECG findings in hypo- and hyperkalemia
23
Table (3): An alternative example of fluid volumes for the subsequent phase
of rehydration
Source:
▪ Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State: A Consensus
Statement from the International Society for Pediatric and Adolescent Diabetes.
Pediatric Diabetes 2018; 19 (Suppl 27): 155-177.
24
Table (4): Determining Clinical cerebral edema risk
*One diagnostic criterion, or two major criteria, or one major and two minor criteria have a
sensitivity of 92%, a specificity of 96% and a false positive rate of only 4% for the early
recognition of DKA-related cerebral edema; early enough to allow for effective treatment
Source:
▪ Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral Edema in Childhood
Diabetic Ketoacidosis: Natural history, radiographic findings, and early identification.
Diabetes Care. 2004; 27 (7):1541-1546.
Table (5): General Sick Day Management Principles To prevent development

of DKA in diabetics during periods of illness (ISPAD, 2018)
1) More frequent BG and ketone (urine or blood) monitoring
2) DO NOT STOP INSULIN
3) Monitor and maintain hydration with adequate salt and water balance.
4) Treat the underlying precipitating illness
5) Sick day guidelines including insulin adjustment should be taught soon
after diagnosis and reviewed at least annually with patients and family
members with a goal of minimizing and/or avoiding DKA and similarly
minimizing and/or avoiding illness associated hypoglycemia.
25
26
27
References:
▪ Egyptian Pediatric Guidelines Committee National Pediatric

Endocrinology Guidelines Group.
28
Hypoglycemia
Diagnostic approach of hypoglycemia in infants and children
➢ In the presence of symptoms of hypoglycemia, check blood glucose (BG).
➢ The following targets are accepted for diagnosis of hypoglycemia: First 48

hours of life the target threshold BG for treatment should be 50 mg/dl ,
afterwards BG thresholds of 60 mg/dl.
➢ Symptoms of hypoglycemia are the result of both neuroglycopenic and

autonomic pathways. Autonomic symptoms, resulting from sympathetic
activation, includes tachycardia, anxiety, tremors, sweating and
nausea/vomiting. Decreased glucose availability to the central nervous system
results in neuroglycopenic symptoms such as headaches, lethargy, and motor/
sensory/visual disturbance.
29
30
31
Diagnostic algorithm to hypoglycemia
** Critical Sample (Refer to appendix)

 Blood glucose
 B-hydroxybutyrate
 Blood gas (PH)
 Insulin level
 C-Peptide
 Lactate
 Cortisol
When to refer for genetic consultation

➢ Non-ketotic hypoglycemia in absence of detectable/ increased insulin and C-peptide
levels and Insulin (µU/mL): glucose (mg/dL) >0.4
➢ ketotic hypoglycemia in absence of metabolic acidosis and with hepatomegaly.
➢ Ketotic hypoglycemia in the presence of metabolic acidosis with high levels of Lactate.
➢ Ketotic hypoglycemia in the presence of metabolic acidosis with low levels of
Lactate after exclusion of Adrenal insufficiency
Controlled Fasts
➢ In case patient did not have investigations carried out at the time of hypoglycemia,
controlled fast may be needed to help make a diagnosis.
➢ Fasting challenges should only be performed in specialized tertiary hospital.
➢ Excluding fatty acid oxidation defects is important before a fasting challenge.
➢ Patients’ age defines the suitable maximum duration of fasting:
✓ 18 h at 1–2 years
✓ 20 h at 2–7 years
✓ 24 h in children >7 years
➢ The fasting challenge is to be stopped at any time if glucose concentration is below 47
mg/dl.
Important clues during Diagnosing Hypoglycemia

➢ Timing of the episode of hypoglycaemia and its relation to food
➢ Micropenis, short stature, midline anomalies: suggest Hypopituitarism
➢ Skin hyperpigmentation: suggest Adrenal Insufficiency
➢ GIR > 12 mg/kg/min :suggest Hyperinsulinism
➢ Inherited metabolic disease
✓ Hepatosplenomegaly
✓ Cataract: Galactosemia
✓ Cardiac murmurs/ arrythmia: Fatty Acid Oxidation Disorders
✓ Hypotonia, inverted nipples: Congenital Disorders of Glycosylation
32
➢ Long-acting release (LAR) octreotide analogues needs long duration to achieve a steady
therapeutic state (lanreotide : 23–30 days – sandostatin: 3 months).
➢ They should be started together with octreotide.
Dose:
 Lanreotide (SC): starting dose is 30-60 mg/dl
 Sandostatin-LAR (IM) : the dose is equivalent to the cumulative 31-day subcutaneous
octreotide dose ( Dose of octreotide x 31).
➢ In case of refractoriness to DZX and when no mutation is identified you may consider
18-Fluoro- DOPA-Positron Emission Tomography (PET) to search for any focal forms.
33
References
1) https://www.piernetwork.org › hypoglycaemia
2) Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain
K, et al. Recommendations from the Pediatric Endocrine Society for
Evaluation and Management of Persistent Hypoglycemia in Neonates,
Infants, and Children. J Pediatr. 2015 Aug;167(2):238-45.
3) Casertano A, Rossi A, Fecarotta S, Rosanio FM, Moracas C, Di Candia F,

et al. An Overview of Hypoglycemia in Children Including a Comprehensive
Practical Diagnostic Flowchart for Clinical Use. Front Endocrinol
(Lausanne). 2021 Aug 2;12:684011. doi: 10.3389/fendo.2021.684011. PMID:
34408725; PMCID: PMC8366517.
4) Van der Steen I, van Albada ME, Mohnike K, Christesen HT, Empting S,
Salomon- Estebanez M, et al. A Multicenter Experience with Long-Acting
Somatostatin Analogues in Patients with Congenital Hyperinsulinism.
Horm Res Paediatr. 2018;89(2):82-89. doi: 10.1159/000485184. Epub 2017
Dec 14. PMID: 29241206.
5) Shah P, Rahman SA, McElroy S, Gilbert C, Morgan K, Hinchey L, et al. Use

of Long- Acting Somatostatin Analogue (Lanreotide) in an Adolescent with
Diazoxide- Responsive Congenital Hyperinsulinism and Its Psychological
Impact. Horm Res Paediatr. 2015;84(5):355-60. doi: 10.1159/000439131.
Epub 2015 Sep 17. PMID: 26375451.
34
Precious Puberty
Diagnostic Algorithm and clinical approach to Precious Puberty
When To Suspect?
➢ Precocious puberty is usually defined as onset of puberty before age 8 in

girls and before age 9 in boys.
35
36
37
History
➢ The onset and progression of secondary sexual characters (breast or

testicular development, and pubic and axillary hair).
➢ Current or previous therapies, including chemotherapy, radiation
therapy, or exogenous sex steroids
➢ Neurologic symptoms to exclude intracranial pathology.
➢ Family history with emphasis on pubertal timing, especially the mother’s

age of menarche and father’s age of reaching adult height.
Physical Examination
➢ Height, weight, and body mass index should be plotted on growth curves,
and the height velocity should be evaluated.
➢ Tanner staging (refer to appendix)
➢ Thorough system review (thyroid, abdomen, and neurologic system,

dysmorphic features or café au lait spots)
38
References
1) Misra, M., Radovick, S. (2018). Precocious Puberty. In: Radovick, S., Misra,
M. (eds) Pediatric Endocrinology. Springer, Cham.
https://doi.org/10.1007/978-3-319-73782-9_26.
2) Klein DA, Emerick JE, Sylvester JE, Vogt KS. Disorders of Puberty: An
Approach to Diagnosis and Management. Am Fam Physician. 2017 Nov
1;96(9):590-599. PMID: 29094880.
3) Gangat M, Radovick S. Precocious puberty. Minerva Pediatr. 2020

Dec;72(6):491-500. doi: 10.23736/S0026-4946.20.05970-8.
4) Emmanuel M, Bokor BR. Tanner Stages. 2021 Dec 15. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID:
29262142.
39
Disorder of Sex Determination (DSD)
When To Suspect? (At 1ry or 2ry care levels)
 Isolated micropenis (>2SD) or < 1.9cm.

 Perineal Hypospadius
 Bilateral undescended testes
 Unilateral undesceded testes with Hypospadius
 Bifid scrotum
 Asymmetry of labioscrotal folds
 Clitromegaly (>1cm)
 A combination of all those > 2
 External genitalia not going with karyotyping
40
41
Table 1: Disorders of Sex Development
Disorder Persistent
Disorder of Disorder of Disorder of Defects of Non- specific
of Leydig cell Mullerian
gonadal androgen androgen Mullerian disorder of Other
androgen defect Duct
development synthesis excess development undermasculimisation
action Syndrome
42
N.B:
 DSD is not that easy issue within the field of pediatric endocrinology. it requires
a multidisciplinary team approach in which the pediatric endocrinologist is the
team coach or the coordinator and the team players are (Pediatric surgeon -
urologist - psychologist - Gynecologist - Geneticist - Histo/pathologist ).
References
1) Practical algorithms in pediatric endocrinology / editor, Ze’ev Hochberg. –

2nd, rev. ed. p. ; cm.
2) European Society of Pediatric Endocrinology.
43
Congenital Hypothyroidism (CH)
➢ The most sensitive test for detecting primary CH is measurement of

thyrotropin (TSH)
➢ The European Society for Pediatrics Endocrinology (ESPE) recommend

that screening should take place 48–72hours after birth
➢ Classification is according to:
✓ Site of Abnormality: primary (thyroid), secondary (pituitary), and tertiary

(hypothalamus);
✓ Onset of Abnormality: congenital (prenatal) or acquired (postnatal);
✓ Severity: compensated hypothyroidism (thyroid axis jeopardized but

able to produce normal T4 levels); and decompensated
hypothyroidism (thyroid axis unable to maintain normal T4
levels).
44
45
46
 Treatment
➢ Should be started as soon as possible, not later than 2 weeks after birth or
immediately after confirmatory (serum) thyroid function testing in
neonates in whom CH is detected by a second routine screening test .
 Monitoring
➢ Measurement of serum fT4 and TSH concentrations should be before or

at least 4 hours after the last (daily) LT4 administration.
➢ Any reduction of the LT4 dose should not be based on a single higher than
normal fT4 concentration, unless TSH is suppressed (i.e., below the lower
limit of the reference interval) or there are signs of overtreatment (e.g.,
jitteriness or tachycardia) .
➢ The first clinical and biochemical follow-up evaluation should take place 1
to 2 weeks after the start of LT4 treatment.
➢ Subsequent (clinical and biochemical) evaluation should take place every

2 weeks until complete normalization of serum TSH is achieved; therafter,
the evaluation frequency can be lowered to once every 1 to 3 months until
the age of 12 months .
➢ Between the ages of 12 months and 3 years, the evaluation frequency can
be lowered to every 2 to 4 months; thereafter, evaluations should be
carried out every 3 to 6 months until growth is completed .
47
References
1) Van Trotsenburg P, Stoupa A, Léger J et al. Congenital Hypothyroidism: A

2020-2021 Consensus Guidelines Update-An ENDO-European Reference
Network Initiative Endorsed by the European Society for Pediatric
Endocrinology and the European Society for Endocrinology. Thyroid. 2021
Mar;31(3):387-419.
2) Grosse, S.D. and Van Vliet, G. (2011). Prevention of intellectual disability
through screening for congenital hypothyroidism: how much and at what
level? Arch. Dis. Child. 96: 374–379.
48
Protocol for Growth Hormone Treatment
 Indications
1. Short stature due to growth hormone deficiency (idiopathic or organic)
2. Turner Syndrome
3. Idiopathic short stature (ISS)
4. Chronic Kidney Disease (CKD)
5. Small for gestational age (SGA) with failure of catch-up growth by age of 4 years
6. Prader Willi Syndrome (after referral to higher committee of GH)
7. Noonan Syndrome (after referral to higher committee of GH)
 Diagnostic Criteria for GH deficiency (GHD)

1. Short stature (height <-2.25SD) that is inappropriate for the target centile range
(accepted difference between patient’s height SDS and target height SDS is up to 1.6)
2. Normal karyotype in girls for exclusion of TS
3. Bone age delay more than 2 SD
4. Normal thyroid functions. If abnormal, thyroid functions must be normalized
with treatment before performing GH provocation
5. Celiac screening
6. Subnormal GH response to 2 provocation tests. Peak GH < 7 ng/ml. Cortisol is to
be measured in the 60 minutes sample of an insulin tolerance test
7. One GH provocation test is sufficient for the following categories
a. Defined CNS pathology
b. History of irradiation
c. Multiple pituitary hormone deficiency (MPHD)
8. MRI Sella turcica to be done on individual basis
9. No provocation tests are needed for Turner Syndrome
 Exclusion Criteria
1. Skeletal dysplasia
2. Systemic diseases causing growth failure
3. Children under corticosteroid treatment
4. Males with a bone age ≥16 years and females with a bone age ≥ 14 years
5. Children with a known risk for malignancy, e.g., chromosomal abnormality such
as Down, Bloom and Fanconi syndromes or other chromosomal breakage
syndromes
6. Children who have extra cranial malignancies
7. Growth failure due to diabetes
8. IQ less than 60% i.e., profound mental delay
49
 Dosage
Growth hormone should be given daily 7 days /week
• Dose for GHD: 0.03 mg/kg/day or 0.09 IU/kg/day (0.025 – 0.035 mg/kg/day)). GH
should be given 7 days per week by subcutaneous injection. Results may worsen if
frequency is reduced.
• Dose for ISS: 0.04mg /kg/day or 0.12 IU/kg/day
• Dose for SGA: start with 0.035 and escalate to 0.05 mg/kg/day according to response
• Dose for CKD: 0.045-0.05 mg/kg per day
• Dose for PWS: 0.5 mg/m2/d with subsequent adjustments toward 1.0 mg/m2/d every
3–6 months according to clinical response and guided by maintenance of physiological
levels of IGF-I (not to exceed +2SD according to age and sex)
• Dose for Turner syndrome: 0.05 mg/kg/day
• Dose for Noonan syndrome: 0.03 – 0.06 mg/kg/day, start with lower dose
• IGF-I (not to exceed +2SD according to age and sex)
 Method of administration
Subcutaneous injection by
1. Regular syringe
2. Pen
 Response Criteria
1. Improvement of height SDS of at least 0.5 over 1 year
2. Increase of growth velocity of at least 2.5 cm above pre-treatment growth velocity
3. Check IGF1 level if no improvement in height SDS and /or subnormal growth velocity
4. In cases where the above criteria are not met, an increased dose of GH may be approved
to a maximum of 0.04 mg/ kg/day or 0.12 IU/kg/day.
5. IGF-I should not exceed +2SD according to age and sex
 Termination of Therapy
1. If response is inadequate after a 6 months’ period at the maximum dose, treatment
should cease.
2. No improvement of SDS after 1 year of treatment in prepubertal children.
3. GH treatment should be discontinued once growth velocity declines to ≤ 2.5 cm/year
(the bone age has reached 16 years in males and 14 years in females).
50
 Turner Syndrome
Girls with Turner Syndrome are candidates for therapy. Before start of therapy,
document:
1. Karyotype
2. Bone age
3. GH provocative test is not needed to be done
4. Plot on TS charts
Treatment of Turner syndrome

• GH: 0.05 mg/kg/day (0.15 IU/kg/day). GH should be given daily by subcutaneous injection.
Results may worsen if frequency is reduced. If available, we recommend serum IGF-1 level
should be checked once yearly to make sure that it DOES NOT exceed + 2 SD value.
• Estrogen replacement: Started at a chronological age of 13 years. The starting dose of depot
estradiol (Folone 5mg) IM is 0.2 mg; the dose is then increased at successive 6-month
intervals by 0.2 mg initially and by 0.5 mg after a dose of 1.0 mg is reached, to a maximum
of 3.0 mg monthly. Progestin is not prescribed until after 4 years of estradiol therapy unless
irregular menstrual bleeding occurs.
Response Criteria and Termination of Therapy for TS

• In girls with Turner Syndrome, the growth velocity should exceed that normally expected in
untreated Turner girls with reference to the Turner specific chart (at least 3 cm/year). Therapy
may be continued until a satisfactory height has been attained or until the growth rate falls to
≤ 2 cm/year (bone age is more than 14 years).
51
 Noonan Syndrome
• Growth hormone therapy can be considered if height is below 2.5 SD on standard growth
chart and after referral to the higher committee of GH for evaluation
 Chronic Kidney Disease (CKD)

Definition of CKD in children older than 2 years old
1. Kidney damage for at least 3 months with or without a decreased GFR
2. GFR of less than 60 mL/min/1.73 m2 for at least 3 months
➢ Stage 1: Kidney damage with a normal or increased GFR (>90 mL/min/1.73 m2)
➢ Stage 2: Mild reduction in the GFR (60 to 89 mL/min/1.73 m2)
➢ Stage 3: Moderate reduction in the GFR (30 to 59 mL/min/1.73 m2)
➢ Stage 4: Severe reduction in the GFR (15 to 29 mL/min/1.73 m2)
➢ Stage 5: Kidney failure (GFR <15 mL/min/1.73 m2 or dialysis)
The indications for GH therapy in CKD are

Persistent growth failure: height < -2 SDS and growth velocity below – 1 SD (25th %)
• In children older than 6 months, and have CKD stage 3–5 OR are on dialysis
• In children post kidney transplant 1 year after transplantation if spontaneous catch-up
growth does not occur and steroid-free immunosuppression is not a feasible option
• In children with CKD due to nephropathic cystinosis, GH therapy is considered at all
stages of CKD
• If height is above - 2 SD BUT growth velocity over at least 6 months is less than – 1 SD,
you may consider GH treatment once other potentially treatable risk/metabolic factors are
addressed AND through discussion with/referral to the higher committee of GH
• Severe rachitic manifestations should be evaluated before deciding on GH therapy
52
Work up before starting growth hormone in CKD patients

1. Clinical:
• Height (or length)
• Growth velocity over minimum of 6 months
• Mid parental height
• Body mass index
• Bone age
• Fundoscopic examination
• Tanner staging
• Document the type of primary renal disease, stage CKD, dialysis adequacy; if post renal
transplant, document dose of glucocorticoid
2. Laboratory:
• CBC (anaemia is defined as Hb < 11 g/dl in children 0.5 – 5 years, < 11.5 g/dl in 5-12
years, < 12 g/dl in 12-15 years, < 13 g/dl in males > 15 years, < 12 g/dl in females > 15
years)
• Serum creatinine, BUN
• eGFR (DTPA scan can be used for this purpose)
• Serum bicarbonate (Hco3 > 22)
• Calcium, phosphorus, total alkaline phosphatase
• Intact Parathyroid hormone (should be less than 500 pg/ml)
• 25(OH) vitamin D
• Serum albumin
• Fasting glucose, HbA1c
• Thyroid Function test
Follow up of a child with CKD on GH therapy

• Nutritional status
• Stage of puberty
• Serum glucose, electrolytes, creatinine, calcium phosphorus and parathyroid hormone
levels (intact PTH should be < 500 pg/ml)
• Serum IGF-1 level
• Bone age
• Fundus examination (raised intracranial pressure)
• Knee and hip imaging only if persistent hip or leg pain is present (avascular necrosis,
slipped capital femoral epiphysis)
• Nutritional status can be measured by clinical, anthropometric, and biochemical
parameters such as height, weight, BMI, and serum albumin and prealbumin
53
 Growth hormone safety

The main concerns include the following:
1. Skeletal abnormalities (slipped capital femoral epiphysis, avascular necrosis of
hip, scoliosis)
2. Progression of renal failure
3. Glucose intolerance
4. Hypothyroidism
5. Raised intracranial pressure
6. Hypertension
Existing clinical data have shown that rhGH therapy does not accelerate the residual renal
function loss in patients with CRF.
However, individual rises in the plasma creatinine concentrations have been observed. In
the absence of any other reason for a decrease in renal functions, rhGH therapy should
be revised.
 Idiopathic Short Stature

For children with a height SD <-3 and normal GH provocation test, if a growth velocity
calculated over a 6-month period is subnormal (<-1 SD), a trial of GH treatment for 6
months is started. If the child demonstrates a good response i.e., improvement of GV and
height SDS, then therapy is continued. If no improvement is documented after 6 months,
therapy is terminated.
N.B.
“Response and termination criteria are the same as in GHD patients (see above)”
 Prader Willi Syndrome

Child is to be referred to the higher committee of GH after genetic documentation of the
condition.
1. Determination of basal IGF-I level
2. Polysomnography (sleep study) should be performed before starting therapy
3. Evaluation of metabolic status if age ≥ 12 y and obesity: HbA1c, fasting insulin
and glucose; consider oral glucose tolerance test if family history of diabetes or
presence of acanthosis nigricans
4. Evaluation of cardiovascular risk profile: fasting total cholesterol, triglycerides,
LDL-cholesterol and HDL cholesterol
5. Assess for hepatic steatosis: AST and ALT levels
6. ACTH and cortisol levels at 8 am to exclude ACTH deficiency
7. Spine x-ray for scoliosis
8. ENT consultation for enlarged tonsils or adenoids
 Compliance
❖ Adherence to GH therapy is a major determinant of the response to GH therapy.
❖ Emphasis should be made on the importance of adherence to therapy at every
patient’s visit.
54
References
1) Maghnie M, Labarta J, Kledova E, et al. Short stature diagnosis and

referral. Front Endocrinol (Lusanne) 2018 Jan 11; 8: 374
2) Murray PG, Dattani MT, Clayton PE. Controversies in the diagnosis and
management of growth hormone deficiency in childhood and adolescence.
Arch Dis Child 2016; 101: 96–100
3) Drube J, Wan M, Bonthuis M, et al. Clinical practice recommendations for
growth hormone treatment in children with chronic kidney disease Nat Rev
Nephrol. 2019 Sep;15(9): 577-589
4) Grimberg A, DiVall S, A, Polychronakos et al. Guidelines for Growth
Hormone and Insulin-Like Growth Factor-I Treatment in Children and
Adolescents: Growth Hormone Deficiency, Idiopathic Short Stature, and
Primary Insulin-Like Growth Factor-I Deficiency. Horm Res Paediatr
2016; 86:361-397
5) Deal CL, Tony M, Waters MJ. Growth Hormone Research Society
Workshop Summary: Consensus Guidelines for Recombinant Human
Growth Hormone Therapy in Prader-Willi Syndrome. JCEM. 2013; 98(6):
E1072–E1087
6) Noonan J, Kappelgaard AM. The Efficacy and Safety of Growth Hormone
Therapy in Children with Noonan Syndrome: A Review of the Evidence
Horm Res Paediatr 2015; 83:157–166
7) Guidelines for the use of growth hormone in children with short stature. A
report by the Drug and Therapeutics Committee of the Lawson Wilkins
Pediatric Endocrine Society. J Pediatr 1995 Dec;127(6):857-67.
55
Diagnosis & Management of Osteoporosis in

Children
Figure (1)
▪ A proposed approach to the diagnosis of osteoporosis in children. After a careful diagnostic

pathway, children will typically fall into one of three categories: a. primary osteoporosis due to
a confirmed monogenic etiology, b. secondary osteoporosis due to an underlying medical
condition or its treatment which predisposes to an increased risk of fractures, or c. “fractures in
otherwise healthy children” (middle bottom). In cases of primary and secondary osteoporosis,
even a single, low-trauma fracture may be sufficient to diagnose the child with osteoporosis, even
if BMD Z-scores are normal. In the absence of a discrete etiology uncovered by the diagnostic
process (middle bottom), a more conservative definition of osteoporosis is proposed in order to
prevent children who were unfortunate during sports or play from being over-diagnosed with
osteoporosis.
56
Figure (2)
▪ This figure provides an approach to gauge whether a child has the capacity to undergo
spontaneous (medication-unassisted) recovery from osteoporosis, obviating the need for
osteoporosis drug therapy.
57
*Annual maximum initiation doses: pamidronate 4.5 to 9 mg/kg/year, every four months; zoledronic acid 0.05
to 0.1 mg/kg/year, every six months
**Annual maintenance doses: pamidronate 4.5 mg/kg/year, every four months; zoledronic acid 0.025 to 0.05
mg/kg/year, every six to 12 months
Figure (3)
▪ This figure provides an algorithm for the treatment of osteoporosis with intravenous
bisphosphonate therapy, the standard of care, including initiation doses (during the
stabilization phase) plus dose titration (during the maintenance phase).
58
▪ &A single, low-trauma vertebral fracture is a valid criterion for the

diagnosis of osteoporosis in children, even in the absence of a specific
diagnosis, and even in the absence of a BMD Z-score ≤ -2. In such cases,
it is imperative to distinguish a fracture from a normal variant (such as
anterior wedging due to physiological rounding of the vertebrae.
▪ For children with low-trauma long bone fractures and lack of an apparent
etiology (i.e. absence of secondary osteoporosis, of osteogenesis stigmata,
and congenital bone fragility genetic testing), a diagnosis of osteoporosis
may be best reserved for those with more frequent fractures.
▪ According to the 2013 ISCD Position Statement, a diagnosis of osteoporosis
in such cases reserved for children with two or more low-trauma long
bone fractures by 10 years of age or 3 or more low-trauma long bone
fractures by 19 years of age plus a BMD Z-score ≤ -2. This approach avoids
over-diagnosis of osteoporosis in a child with long bone fractures and
absence of an apparent cause who may have been unlucky during sports or
play. At the same time, the ISCD recognized that BMD Z-scores > -2 do not
preclude the possibility of skeletal fragility and increased fracture risk;
therefore, a degree of judgment is involved in the overall assessment of
children with a history of bone fragility absence of an apparent cause a
comprehensive work-up.
▪ *Annual maximum initiation doses: pamidronate 4.5 to 9 mg/kg/year, every
four months; zoledronic acid 0.05 to 0.1 mg/kg/year, every six months
▪ **Annual maintenance doses: pamidronate 4.5 mg/kg/year, every four
months; zoledronic acid 0.025 to 0.05 mg/kg/year, every six to 12 months
59
Appendix
Timely critical investigations

If sampling is difficult, the most important tests to collect at the time of hypoglycamia are:
A. Blood glucose
B. Ketone level (request B-hydroxybutyrate) ( if not available, check : urine for ketones)
C. Blood gas
D. Insulin level
E. C-Peptide
F. Cortisol
G. Lactate
H. 1st Urine passed
Precautions and preparation of critical sample
Common adverse events of drugs
 Diazoxide
• Common: Water and salt retention, hypertrichosis, loss of appetite, other rare complications
Rare: Cardiac failure, pulmonary hypertension, hyperuricaemia, blood dyscrasias (bone
marrow suppression, anaemia, eosinophilia), paradoxical hypoglycaemia.
 Octreotide
• Acute complication: Anorexia, nausea, abdominal discomfort, diarrhoea, drug induced
hepatitis, elevated liver enzymes, long QT syndrome, tachyphylaxis, necrotizing
enterocolitis.
• Long-term complections: Decreases intestinal motility, bile sludge and gallstone,
suppression of pituitary hormones (Growth hormone, TSH)
60
Tanner Staging
Orchidometer
Testicular Volume
61
62
Pediatric Genetic & Metabolic of EHA
0

in
Pediatric Genetic & Metabolic
for
First Edition
2024
Prepared by
Working Group for Development
of
in
Pediatric Genetic & Metabolic
for
1
Executive Committee
1. Prof. Iman Ahmed Ihsan: (Head of Committee) Professor of Pediatrics Chair of

the Pediatric department at AFCM, Former head of the pediatric department at
faculty of medicine Cairo university, Former head of the genetic unit at faculty of
medicine Cairo university.
2. Prof. Hala El- Gendy: Assistant Professor of Pediatrics, Head of the clinical
genetic unit- Pediatric department-Faculty of medicine, Cairo university.
3. Prof. Nahed AbdelKhalek: Genetic and metabolic Consultant, Children with
special needs general directorate MOHP.
4. Prof. Mohamed Abdel- Adl ElSawy: Professor of Pediatrics and clinical genetics-
Pediatric Department- Faculty of Medicine, Ain Shams University.
5. Dr. Hany Soliman Hassan: Consultant of Pediatrics & Clinical Genetics, Pediatric
Department, Faculty of Medicine, Cairo University.
6. Dr. Radwa Ezzat Amin: Lecturer of Pediatrics and Clinical Genetics- Faculty of
Medicine Cairo University.
7. Dr. Mariane Abd El Masseh Fahem: (Moderator of the Committee) Pediatric
Specialist
2
Disclaimer

under their care.
3

Authority (EHA).
Reviewed By



4
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric Genetic &
Metabolic is to unify and standardize the delivery of healthcare to any child at all health
facilities.
Pediatric Genetic & Metabolic service is usually offered to children below 16

years of age in Egypt.
Regarding Pediatric Genetic & Metabolic, busy clinicians have all felt the need
for a concise, easy-to-use resource at the bedside for evidence-based protocols, or

to those delivering care at the bedside in for patients in Pediatric Genetic & Metabolic.
In Pediatric Genetic & Metabolic
5
Table of Contents
Page
Title
Number
Preface 5
Down Syndrome (DS) 7
Fragile X Syndrome and Premutation Associated
28
Disorders
Turner Syndrome (TS) 37
SILVER–RUSSELL SYNDROME (SRS) 50
Achondroplasia 61
Marfan Syndrome (MFS) 74
Approach to the Patient with a Suspected Inherited
85
Disorder of Metabolism
112
Genetics Guidelines 181
Atlas 199
6
Down Syndrome (DS)
Recurrence Risk
• No evidence for increased prevalence of DS has been found in second- and third-
degree relatives of individuals with trisomy 21.
• A common question is that of the chance for DS for a couple in which one member
has a relative with DS of unknown karyotype.
Prenatal Testing
• Noninvasive prenatal screening (NIPS) or testing (NIPT) (also known as cell free fetal
DNA testing – cffDNA) is considered a highly accurate screening test for DS compared
with conventional combined first trimester screening.
• Ultrasounds in the first trimester are done at 11–14 weeks to detect nuchal
translucency, nasal bone abnormalities and ductal venous flow measurements.
• Ultrasounds in the second trimester detect soft biomarkers that do not in themselves
confirm a diagnosis but are seen more frequently in fetuses with an abnormality. Soft
biomarkers include echogenic intracardiac focus, ventriculomegaly, nuchal fold thickness
>6 mm, echogenic bowel, hypoplastic/absent nasal bone, shortened humerus, mild
pyelectasis, shortened femur, and aberrant right subclavian artery.
• Test strategy involving maternal age, a combination of first trimester nuchal translucency
and PAPPA, and second trimester total hCG, uE3, AFP and Inhibin A, significantly
outperformed other test combinations that involved only one serum marker or nuchal
translucency in the first trimester.
• Karyotyping using chromosome analysis is the gold standard test to confirm the diagnosis.
Chromosome analyses may be completed prenatally using amniocentesis or chorionic
villus sampling.
• The diagnosis of DS can also be made on interphase nuclei using fluorescence in situ
hybridization (FISH), microarrays, and quantitative fluorescent polymerase chain reaction
(QF PCR).
7
Manifestations, Evaluation, and Management
Growth and Feeding
Manifestations Evaluation Management

Feeding difficulties are due Using DS specific growth Encourage healthier feeding
to hypotonia, large tongue, charts for plotting measures. habits, advocating techniques
small oral cavity, dysphagia, For severe failure to thrive, a to reduce feeding problems
constipation, and hospitalization is often (like smaller feeds, keeping
gastrointestinal regurgitation needed to determine etiology the child upright for 30
They tend to breastfeed for a and to begin treatment. minutes post feeds, head
shorter time, have more Appropriate tests should be elevation during feeds), and
respiratory infections, and performed to diagnose promoting breastfeeding
develop nonnutritive oral common causes of growth GIT, endocrine referral as
sucking habits. failure, including needed.
hypothyroidism, growth
DS is associated with hormone deficiency, and It is helpful to tell parents that
increased risk for obesity. celiac disease. their child’s obesity may not
Failure to thrive: high output Video fluoroscopic swallow be not their fault, but changes
heart failure from congenital study and a barium swallow will need to be made in diet
heart disease is probably the with small bowel follow and activity for the long-term
most common cause. through to rule out a health of their child.
tracheoesophageal fistula and
Psychosocial failure to thrive gastroesophageal reflux,
(parental neglect or small bowel stenosis or
inadequate education) should duodenal stenosis associated
always be considered. with annular pancreas, and to
rule out other gut
malformations.
In obesity: evaluation of
diabetes (random blood
glucose, insulin level, Hb
A1C level), hypothyroidism
(TSH, free T4), sleep
disordered breathing and
pulmonary hypertension
8
Development and Behavior

The cognitive ability, as There is a growing need for a Current goals are maximizing
measured by standardized screening test for self-help skills and foster
intelligence tests, ranges from ASD/ADHD in children with independence. A major
profound intellectual DS at the age of 3 years and challenge is to find
disability to borderline. Still, before entering school. meaningful employment.
overall IQ is a poor measure Ensure that the child has been Growth hormone has been
of an individual’s spectrum of connected with the local shown to have no benefit for
abilities that may be highly agency providing early the growth of head
variable. intervention services. circumference or cognitive
Higher rates of hyperactivity, Research has shown that development.
impulsivity, tantrums, children with disabilities There is no benefit of
agitation, repetitive benefit significantly from supplements, hormones,
movements, and sensory early intervention. vitamins, growth and thyroid
dysregulation. Early signs of Alzheimer hormone, vitamins, 5-OH
Obsessive compulsive disease in high functioning tryptophan, glutamic acid,
behaviors among school aged individuals include a decline injection of fetal cells, and
children. in memory and verbal various “cocktail” mixtures to
They are frequently “self- capability, whereas others improve the motor and
talk” and have imaginary may show a decrease in social cognitive function of
friends. These behaviors are interaction, attention and individuals with DS.
not associated with increasing apathy. It is Currently there is no curative
behavioral, communication, important to rule out treatment for Alzheimer
or socialization problems, and hypothyroidism and disease.
should be considered adaptive depression in such cases. Early intervention services
and not pathological. Cholesterol values should be may be initially provided in
Autism spectrum disorder assessed. the child’s home, and later in
(ASD) and attention a clinic and/or school setting.
deficit/hyperactivity disorder Early behavioral intervention
(ADHD) are more prevalent. may be an important
Alzheimer Disease: they have preventive measure for some
a third copy of the amyloid children.
precursor protein (APP) gene Caution is needed in using
on chromosome 21 that is psychotropic medications in
linked to risk for Alzheimer DS. Those with congenital
disease. heart disease should be seen
It is now well established that by a cardiologist before
almost 100% of individuals starting a stimulant
with DS show the medication for ADHD or a
neuropathologic changes of neuroleptic for more serious
Alzheimer disease by the age behavior problems.
of 35–40 years. Weight gain is often a serious
complication of psychotropic
drugs in people with DS.
9
Family Adjustment
Management
Families of DS cope better and experience Explore parents’ knowledge about DS.
less stress than other disabilities. Some Clarify the potential social/support
studies have concluded that this “DS network available.
advantage” is due to the child based
characteristics, such as their prolonged eye A balanced perspective should be
contact, the tendency to use charm to avoid provided by an experienced individual,
tasks, societal awareness and available including information about positive
support networks. aspects of having a child with DS as well
as the challenges commonly encountered.
Mothers do better on coping/adaptation
than mothers of children with other types It is helpful to mention that caring for a
of intellectual disabilities. child with DS is generally not greatly
different from the care of other children.
Fathers’ stress focus more on financial However, some children may have health
burden, the potential impact on the broader complications that need to be addressed.
family, and the public perception and
attitude of society for accepting their Physicians should inform parents of their
children. suspicion for DS immediately, even if the
diagnosis has not been confirmed with
karyotyping. This way parents are prepared
psychologically in a stepwise manner.
10
Cardiovascular

Congenital heart disease Clinical examination and a There is now a consensus
occurs in 40–50% and is an mandatory should be a part favoring early surgical
important determinant of of routine newborn screening intervention.
survival. of babies with DS. Large VSD without
The most common is Infants with an abnormal obstruction to pulmonary
atrioventricular septal defect echocardiogram should be blood flow require surgical
(endocardial cushion defect), referred to a pediatric repair before 4 months of age
followed by atrial septal cardiologist. to avoid further
defect, ventricular septal Educate parents to recognize complications.
defect, patent ductus signs of heart failure such as Medical management and
arteriosus, coarctation of tachypnea, feeding proper nutrition should be
aorta, and tetralogy of Fallot. difficulties, and poor weight offered to those who are not
They have a higher gain. fit for surgery.
propensity for risk factors In older children and adults, Close monitoring and early
such as obesity and annual cardiac examinations follow up after surgery with
metabolic disturbances for may help in early diagnosis complete blood counts due to
developing coronary artery of acquired valvular diseases. more prolonged course of
disease, particularly postoperative
atherosclerosis. Despite this, thrombocytopenia than the
they have a lower incidence general population, and may
rate of coronary artery have an increased risk of
disease. post‐discharge syncope
Maternal smoking, lack of because of complete
folic acid/ multivitamin atrioventricular block.
supplementation, and
parental consanguinity are
potential factors for
congenital heart disease in
children with DS.
Increased risk of pulmonary
hypertension, even in the
absence of intracardiac
structural defects.
Obstructive sleep apnea is a
major contributing factor.
11
Endocrinologic

Hypothyroidism There is a need for Treatment of
Normal onset and chronology additional screening, in hypothyroidism with L-
of puberty, fewer differences addition to newborn thyroxin and continued
in hormonal levels than screening, especially in the monitoring of blood
previously thought. first year of life (before 6 levels. Some centers treat
months). Thyroid screening with low dose thyroxin in
Increased risk of using TSH and serum free the face of significantly
cryptorchidism. T4 is recommended to be elevated TSH and normal
Spermatogenesis is known to continued throughout the T4 levels.
be insufficient in males. lifespan of DS.
Counseling concerning
Female pubertal development When borderline thyroid interpersonal
appears to be normal. Normal functions, repeat the tests in
relationships,
ovaries with follicles at six weeks. If they are still appropriate social
various stages of maturation, abnormal, a referral to behavior, sexual activity,
and normal uterus. Age at endocrinologist. and situations that may
which menopause occurs
varies widely, but typically Any variation from normal place them at increased
occurs before the age of 40. physiological sexual risk for sexual abuse.
maturation is unexpected Success will generally
Potential contributors to and requires a standard require the
infertility may be hormonal evaluation for cause. understanding and
abnormalities, gonadal participation of parents.
malformations, and Women require standard
gynecological care. Encourage independence
psychological and social with personal hygiene
factors. and self-care.
12
Audiologic

Short ear lengths, the helix is Brainstem auditory evoked Treatment of acute and
often angulated and response (BAER) or chronic complications, which
overfolded, and the lobes are otoacoustic emission, may compromise hearing and
small to absent. according to the universal thereby interfere with speech
A small minority have newborn hearing screening and education. Treatment
congenitally malformed guidelines. Newborns should methods are standard.
stapes, and other ossicular have a follow‐up at 3 months They may benefit from
anomalies may be acquired. thereafter. classroom accommodations
Inner ear anomalies, In younger children, review for hearing loss by some
including malformed bone the risks associated with means of amplification and
islands of lateral semicircular serous otitis media. Follow‐ early interventions by an
canal, narrow internal up annually or every 6 experienced speech language
auditory canals, cochlear months. pathologist.
nerve canal stenoses, Refer to an otolaryngologist
semicircular canal for conducting ear
dehiscence, and enlarged examinations of children with
vestibular aqueducts. stenotic ear canals.
High risk for conductive For older, school-aged
hearing loss, although mixed children, make sure to
and pure sensorineural conduct annual audiologic
hearing loss may also occur. evaluations.
13
Ophthalmologic
Manifestations
Evaluation Management
By a pediatric ophthalmologist within the Refractive errors require early refraction
first six months of life. studies and prescription for glasses.
Ophthalmologists should be aware of the Strabismus may respond to eye patching or
possibility of pseudotumor cerebri if may require surgery and is treated in a
elevated optic disk. standard fashion.
Blepharitis usually will respond to lid
cleansing and topical antibiotics.
Cataract may require removal of the lens
and a prosthetic implant, and significant
keratoconus may be treated with
penetrating keratoplasty and a corneal
transplant.
Pseudotumor cerebri may respond to
weight loss and acetozolamide therapy.
14
Musculoskeletal

Hypotonia, and ligament Newborns: Evaluate hypotonia. Custom made foot insoles
laxity that leads to excessive Infancy–adulthood: Once every provide the additional
joint flexibility. There is a 2 years, evaluate for signs of physical support and could
delayed achievement of myelopathy. help prevent future surgical
motor milestones. For asymptomatic atlantoaxial
corrections when used as an
Scoliosis, neck instabilities, instability: Since radiographs early intervention to correct
hip anomalies (subluxa-tion, are not predictive of instability, gait abnormalities.
Perthes disease, slipped radiologic screening is not Obese DS and those who have
capital femoral epiphysis), recommended. autoimmune diseases may
patellofemoral joint Parents should be advised that require a higher
instability, genu valgum, participation in some sports, supplementation of vitamin D
hallux valgus, foot including contact sports such as to maintain normal levels.
deformities (pes planus, football, soccer and gymnastics,
Participation
places children at increased risk in high risk
metatarsus primus varus), activities should be
trigger finger, trigger thumb of spinal cord injury.
discouraged if there is
and arthritis/arthropathy Trampoline use should be evidence of chronic
precociously. avoided by children younger
instability.
than 6 years, and by older
Reduced bone density: high children unless under direct Complication rates for
risk of fractures with age. professional supervision. cervical surgery to repair
Occipitoatlantoaxial For symptomatic atlantoaxial atlantoaxial instability is
instability (10–30%), with instability: If a child has 82%.
neurological symptoms signs/symptoms of myelopathy,
occurring in 1%. plain cervical spine
radiography. If significant
abnormalities are seen in the
radiography, the child should be
immediately referred to
pediatric neurosurgery/pediatric
orthopedic surgery to further
manage the atlantoaxial
instability.
If standard radiographs raise
concern, MRI could be
considered. CT is not likely to
add useful information.
A medical history and physical
examination for joint complaints
and scoliosis.
15
Gastrointestinal

Large tongue, small oral Routine screening for celiac Malformations and functional
cavity, tracheoesophageal disease among children with gastrointestinal problems
fistula, dysphagia, DS. should be treated as in the
constipation, gastrointestinal After the age of one year, general population.
regurgitation, duodenal those on a gluten diet should Adequate response to chronic
atresia, annular pancreas, be evaluated for symptoms of constipation is generally
celiac disease, Hirschsprung celiac disease at each obtained with a standard
disease, pyloric stenosis, anal wellness visit. pediatric approach when not
atresia/ stenosis.
Symptomatic children need caused by a malformation or
Paucity of bile ducts is an assessment of TTG (IgA) Hirschsprung disease or
common. level and quantitative IgA. It hypothyroidism.
Helicobacter pylori infection is recommended that those Treatment for celiac disease
is common in adults. with abnormal laboratory is as for the general
Non‐immunity to Hepatitis A values be referred for population, with a gluten free
and B is high and specialty assessment. Small diet.
immunization against these is intestinal biopsy is typically
important. used to confirm the diagnosis.
Screening is recommended to
Celiac disease has a high be done at least every third
prevalence rate (up to 18.6%). year, and more frequently in
A known complication of those with a family medical
celiac disease among affected history of celiac disease.
individuals who do not follow Radiographic swallow studies
a gluten‐free diet or those may be needed for further
who do not seek appropriate evaluation to diagnose
evaluations is the risk of various neuroanatomical
developing intestinal defects.
lymphoma.
For severe chronic cases of
constipation, a rectal biopsy is
indicated for possible
Hirschsprung disease.
16
Sleep Disorders

Poor sleep may be associated At least once during the first Many symptomatic
with daytime drowsiness or a six months of life, discuss individuals with obstructive
decline in behavior. with parents symptoms of sleep apnea will respond
As many as 50% of children obstructive sleep apnea. adequately to tonsillectomy
may have sleep apnea A referral to a sleep specialist and adenoidectomy.
Obstructive sleep apnea may for further evaluation of a Continuous positive airway
increase the risk for possible sleep disorder should pressure may be the
pulmonary hypertension in be made if necessary. appropriate intervention for
susceptible individuals. It has been recommended that some.
Obesity is a risk factor for all children with DS should Very occasionally, more
sleep apnea. have a sleep study by the age involved surgery, such as
of 4 years old. enlargement of the midface,
may be required.
Dental

Delayed and asynchronous Early referral for regular Educate the parents about the
primary and secondary semiannual dental care is possible dental anomalies.
dentition. important both for repeated Instruction in dental hygiene,
There is also a high incidence instruction in dental hygiene Antibiotic prophylaxis
of aphthous ulcers, oral for the prevention of gum against subacute bacterial
candidiasis, and acute disease and the longer term endocarditis is required at the
ulcerative gingivitis. planning of possible
orthodontics. time of dental care for many
Prevalence of periodontal individuals with DS and
diseases in young adults is congenital heart disease.
about 35% with increasing
prevalence in the third and
fourth decades.
17
Dermatologic
Manifestations
18
Immunologic

More frequent infection rates, There is no recommendation Although response to
impaired immunity, for routine immunologic vaccinations may not be as
suboptimal immunologic evaluation. This should be effective in people with
response to vaccinations, and reserved for unusually severe Down syndrome, it is
higher rates of autoimmune problems and/ or evidence of recommended that they
diseases. frank immunodeficiency or follow a normal vaccination
More susceptible to infections autoimmune disease. schedule, including hepatitis
compared to the general Consult specialists and enable B, for which they are at
population, due to abnormal prompt treatment of significant risk to become
structural morphologies, infections and other factors chronic carriers.
comorbidities, developmental that lead to increased Children with confirmed
delays, and immunologic prevalence of infections in comorbidities should have
deficits. individuals with DS. respiratory syncytial virus
Increased prevalence of prophylaxis.
autoimmune diseases Influenza vaccine should be
affecting both endocrine and given annually.
non-endocrine systems. Children with chronic cardiac
These include Addison’s or respiratory diseases should
disease, allergic dermatitis, be given the 23‐valent
alopecia, celiac disease, pneumococcal
chronic autoimmune polysaccharide vaccine
hepatitis, diabetes mellitus (PPS23) at 2 years or older.
(type I more common than II),
hypo‐ and hyperthyroidism, The possible role of vitamin
autoimmune hemolytic A and zinc in normalizing
anemia, dermatomyositis, some aspects of the
multiple sclerosis, pernicious immunodeficiency in DS
anemia, polyarteritis nodosa, remains controversial. Based
primary sclerosing on clinical judgement, these
cholangitis, rheumatoid may be replaced if low.
arthritis, scleroderma,
Sjogren’s syndrome, and
SLE.
19
Neurologic

Neuromuscular hypotonia, Evaluation of seizures does Treatment of seizures does
epilepsy, intellectual not differ from that in the not differ from that in the
disability, cervical cord general population; EEG is general population.
compression, gait indicated if there is a Abnormal movements do not
abnormalities, suspicious history. usually require treatment,
cerebrovascular eventsMonitor for signs of although medication or other
leading to early strokes, sleepneurologic dysfunction toxicity should be ruled out.
disorder, and defects in visionincluding seizures. New focal
and hearing. weakness should be fully
Seizures occur more often investigated, as the cause may
than in the general population be treatable.
but are less frequent than
among those with other forms
of intellectual disabilities.
Seizure onset occurs most
commonly during infancy or
before age 12 years. Infantile
spasms are 8–10 times more
common than in the general
population.
Focal weakness may affect
about 1% of individuals with
DS.
Stereotypic movements are
common among DS.
20
Neoplasia

At younger ages, the overall risk For newborns: Obtain a Children with DS and
is relatively higher because of complete blood cell count. leukemia who are treated
the increased risk of leukemias.
In the adult population, the risk Infants with TMD or have not been found to have
is much lower because of the polycythemia should be greater risk of relapses or
significantly decreased referred to a pediatric mortality when compared
hematologist/oncologist. with typically developing
occurrence of solid tumors.
children with leukemias.
The increased risk for leukemia Parents of younger children
is present from the age of 1–10 with TMD should be They may have more side
years. It is about 20 times that in counseled regarding the risk effects due to chemotherapy
the general population. of leukemia and be made because they are more
Acute lymphoblastic leukemia aware of the suggestive sensitive to toxicity from
and acute non-lymphocytic symptoms. chemotherapy, particularly
leukemia like acute from methotrexate, because
No routine screening is of slower clearance.
megakaryocytic leukemia are
the most common leukemias indicated by current AAP
noted in childhood. guidelines.
Chronic myeloid and chronic The testes should be
lymphocytic leukemia are less examined periodically
common than expected. because of the higher rate of
Up to 10% of neonates may testicular germ cell tumors.
show a transient leukemoid
reaction, also referred to in the
literature as transient
myeloproliferaive disorder
(TMD).
In most cases, TMD regresses
spontaneously in three months.
The outcome for children who
present at less than 2 years of
age is significantly better than
for those who present later.
In contrast to leukemia, they are
largely protected from solid
tumors, with a significantly
lower risk of lung cancer, breast
cancer, and cervical cancer.
Testicular cancer is the only
solid tumor with an increased
standardized incidence rate, out
of all the solid tumors.
21
Craniofacial

Craniofacial morphologies Medical history and physical Surgical options such as
vary widely among ethnic andexamination should be partial glossectomy,
geographical groups across obtained to identify any internally rotating the lower
the world. potentially deleterious effects lip, neck and cheek
Breathe through the mouth, of a prominent tongue. liposuctions, augmenting the
exhibiting open bite and nasal bridge or midfacial
opened lips, with orofacial area, and repositioning
hypotonia epicanthal folds are available.
Relative macroglossia and There are claims that these

hypotonicity of the tongue procedures improve speech,
and muscles of the mouth breathing and/or
oropharynx contribute to aesthetics, reduce oral
difficulties in feeding, inflammation, chieliosis,
breathing, swallowing, and halitosis and dental problems.
speaking. While there are cases where
Hypotonia of the facial such procedures have been
muscles can result in chronic reported to boost self-
drooling, chapping, and confidence and increase the
cheilitis, which may play a emotional.
role in the increased rate of Due to controversy
upper respiratory infections surrounding plastic surgeries,
and periodontitis. it is important to discuss the
risk versus benefit ratio with
parents, based on each
individual, case by case.
22
Urologic

Anomalies reported include Standardized screening for If anomalies are detected
bladder extrophy, these anomalies with renal during screening, an
hypospadias, posterior ultrasound. evaluation by a nephrologist
urethral valves, micropenis, Physical examination of or urologist is indicated.
reflux, renal hypoplasia, males for cryptorchidism Treatment for anomalies,
elevated urinary and/or blood should occur at diagnosis, including undescended
uric acid, dysfunctional with follow up examination testes, is as for the general
voiding as a result of both in a standard manner if they population.
neurogenic and non- cannot be palpated.
neurogenic bladder, and
chronic renal failure. The testes should be palpated
yearly. Parents should be
Undescended testes occur taught how to do an
with increased frequency. If examination of the testes for
uncorrected, cryptorchidism detection of a mass.
can lead to infertility,
testicular cancer, hernias and
testicular torsion.
23
AAP recommendations for management of DS (Bull, 2011)
Table (1): American Academy of Pediatrics:

Health supervision for children with DS (Bull, 2011)
Prenatal Birth–1 mo 1 mo–1 y 1–5 y 5–13 y 13–21 y
Counseling regarding prenatal screening

test & imaging results
Plan for delivery
Referral to geneticist
Parent-to-parent contact, support groups,
current books and pamphlets
Physical exam for evidence of trisomy 21
Chromosomal analysis to confirm dx
Discuss risk of recurrence of Down
syndrome
Echocardiogram
Radiographic swallowing assessment if
marked hypotonia, slow feeding, choking
with feeds, recurrent or persistent
respiratory
sx, FTT
Eye exam for cataracts
Newborn hearing screen and follow-up
Hx and PE assessment for duodenal or
anorectal atresia
Reassure parents delayed and irregular
dental eruption, hypodontia are common
If constipation, evaluate for limited diet or Any visit
fluids, hypotonia,hypothyroidism, GI
malformation, Hirschsprung
CBC to R/O TMD, polycythemia
Hb annually; CRP & ferritin or CHr if Annually
possible risk iron deficiency or Hb <11 g.
Hemoglobin Annually
TSH (may be part of newborn screening) 6 and 12 Annually
mo
Discuss risk of respiratory infection
24
If cardiac surgery or hypotonic: evaluate

apnea, bradycardia, or oxygen
desaturation in car seat before discharge
Discuss complementary & alternative All health maint. visits
therapies
Discuss cervical spine positioning, All health maint. visits
especially for anesthesia or surgical or
radiologic procedures
Review signs and symptoms of myopathy All health maint. visits
If myopathic signs or symptoms: obtain
neutral position spine films and, if Any visit
normal, obtain flexion & extension films
& refer to pediatric neurosurgeon or
orthopedic surgeon with expertise in
evaluating and treating atlanto-axial
instability
Instruct to contact physician for change in
gait, change in use of arms or hands, Biennially
change in bowel or bladder function, neck
pain,
head tilt, torticollis, or new-onset
weakness
Advise risk of some contact sports, All health maint. visits
trampolines
Audiology evaluation at 6 mo
If normal hearing established, behavioral Every
audiogram and tympanometry until 6 mo
bilateral ear specific testing possible.
Refer
child with abnormal hearing to ot
If normal ear-specific hearing established, Annually
behavioral audiogram
Assess for obstructive sleep apnea Sx All health maint. visits
Sleep study by age 4 years
Ophthalmology referral to assess for
strabismus, cataracts, and
Nystagmus
Annually
Refer to pediatric ophthalmologist Every 2 Every 3 y
y
If congenital heart disease, monitor for All visits
signs & Sx of Congestive heart failure
Assess the emotional status of parents and All health maint. visits
intrafamilial relationships
25
Check for Sx of celiac disease; if Sx All health maint. visits

present, obtain tissue
transglutaminase IgA & quantitative IgA
Early intervention: physical, occupational, Health maint. visits
and speech therapy
At 30 months, discuss transition to
preschool and development of IEP
Discuss behavioral and social progress Health maint.
visits
Discuss self-help skills, ADHD, OCD, Health
maint.
wandering off, transition to middle school
visits
If chronic cardiac or pulmonary disease,
23-valent pneumococcal vaccine at age >2
y
Reassure regarding delayed and irregular
dental eruption
Establish optimal dietary and physical Health
maint.
exercise patterns
visits
Discuss dermatologic issues with parents
Discuss physical and psychosocial
changes though puberty, need for
gynecologic care in the pubescent female
Facilitate transition: guardianship, Health
financial planning, behavioral problems, maint.
school placement, vocational training, visits
independence with hygiene and self-care,
group homes, work settings
Discuss sexual development and Health
behaviors, contraception, sexually maint.
transmitted diseases, recurrence risk for visits
offspring
Do once at this age

Do if not done previously
Repeat at indicated intervals
Maint. indicates maintenance; dx, diagnosis; sx, symptoms; FTT, failure to thrive; Hx,
history; PE, physician examination; Gl, gastrointestinal; CBC, complete blood count; R/O,
rule out; Hb, hemoglobin; ot, occupational therapy; CHr, reticulocyte hemoglobin; IgA,
immunoglobulin A; IEP, Individualized Education Plan; ADHD, attention-
deficit/hyperactivity disorder; OCD, obsessive compulsive disorder.
26
References
▪ Carey, J. C. (2021). Cassidy and Allanson's management of genetic syndromes. Wiley-

Blackwell.
▪ Bull MJ (2011) Health Supervision for Children With Down Syndrome. Pediatrics
128(2):393–406.
27
Fragile X Syndrome and Premutation Associated

Disorders
Key Points:
The facial features including a long face, a high forehead, a high‐arched palate,
prognathism and prominent ears are key points for diagnosis.
The diagnosis of fragile X syndrome must be confirmed by DNA testing, which
includes both Southern blot and PCR. Cytogenetic testing is not adequate to make
the diagnosis.
Incidence
• Fragile X syndrome is the most common cause of inherited intellectual disability
and is second only to Down's syndrome as the most common genetic cause of
intellectual disability.
• The so called premutation, or small expansion of the CGG repeat, is relatively
common, having been identified in 1 in 130–259 females in the general population
and 1 in 250–813 males in the general population.
Etiology and Genetics

• Fragile X syndrome is caused by a trinucleotide repeat expansion of three bases
(cytosine, guanine, guanine), (CGG)n, that occurs in the fragile X mental
retardation 1 gene (FMR1) at Xq27.3
• A small expansion, or premutation, has approximately 55–200 CGG repeats and is
usually not associated with cognitive deficits. However, a larger expansion, greater
than 200 CGG repeats, the full mutation, is associated with fragile X syndrome
• The size of the CGG repeat expansion correlates with the risk of passing on a full
mutation from a mother to the next generation. There is a low likelihood (<1%) of
decrease (contraction) of the CGG repeat to the normal range.
• Males with the premutation will pass on the premutation to 100% of their daughters
but to none of their sons.
28
Abnormalities in Premutation Carriers

• Fragile X associated tremor/ataxia syndrome (FXTAS): The clinical features
include a progressive intention tremor, cerebellar ataxia, Parkinsonian features,
brain atrophy, and executive function deficits.
• Other neurological problems may also occur in individuals with the premutation,
including neuropathy, fibromyalgia, hypertension, autonomic dysfunction,
migraine headaches, hypothyroidism, anxiety, depression, and primary ovarian
insufficiency. Emotional problems may occur in some carriers, including anxiety
disorders, mood instability, and depression.
Diagnostic Testing
• The diagnosis of fragile X syndrome must be confirmed by DNA testing, which
includes both Southern blot and PCR. Cytogenetic testing is not adequate to make
the diagnosis.
• Once a proband with fragile X syndrome or premutation involvement has been
identified in a family, DNA testing of family members can be offered.
• DNA FMR1 testing should be considered in all individuals who present with
intellectual disability or autism spectrum disorders when the etiology for these
problems is not known. Individuals who present with just hyperactivity or ADHD
are not routinely tested for fragile X syndrome unless typical physical features,
cognitive deficits, or behavioral problems reminiscent of fragile X syndrome are
present or there is a family history of intellectual disability compatible with an X
linked inheritance pattern.
29
Manifestations, Evaluation and Management

Craniofacial
The facial features include a long face, a high forehead, a high On all visits, the The use of
arched palate, prognathism and prominent ears tympanic prophylactic
membranes should antibiotic therapy
(figure 1).
be visualized to and/or the insertion
Cleft palate occurs occasionally, but dental crowding and assess for infection of ventilation tubes
malocclusion are common. or persistent serous are recommended
The most common medical complication is recurrent otitis otitis media. for recurrent
media and a persistent conductive hearing loss. infections.
Referral to an
Transient hypogammaglobulinemia with IgG subclass otolaryngologist for On occasion,
deficiencies is occasionally reported, although this may be evaluation of parents request ear
secondary to the recurrent otitis and sinusitis. Recurrent ear recurrent otitis pinning surgery if
infections and recurrent sinusitis usually resolve by 5–6 years media. the pinnae are
of age. The rare instance of isolated IgG subclass Audiometric excessively large,
immunoglobulin deficiency usually also improves with time. evaluations and/or leading to social
problems.
Obstructive sleep apnea, and this may relate to facial tympanograms
structural changes, enlarged adenoids, connective tissue should be obtained If obstructive sleep
dysplasia, or hypotonia of facial and pharyngeal muscles. at the end of otitis apnea,
media treatment to adenoidectomy is
The facial features include a long face, a high forehead, a high assess hearing and considered.
arched palate, prognathism and prominent ears (figure 1). possible persistence Persistent sleep
Cleft palate occurs occasionally, but dental crowding and of middle ear fluid. apnea may require
malocclusion are common. the use of
A sleep study
continuous
The most common medical complication is recurrent otitis should be done if a positive airway
media and a persistent conductive hearing loss. history of nighttime
pressure with nasal
obstruction with
Transient hypogammaglobulinemia with IgG subclass snoring is obtained. prongs during
deficiencies is occasionally reported, although this may be sleep.
secondary to the recurrent otitis and sinusitis. Recurrent ear Yearly dental
infections and recurrent sinusitis usually resolve by 5–6 years evaluations should
of age. The rare instance of isolated IgG subclass be carried out.
immunoglobulin deficiency usually also improves with time.
Obstructive sleep apnea, and this may relate to facial
structural changes, enlarged adenoids, connective tissue
dysplasia, or hypotonia of facial and pharyngeal muscles.
Figure (1): Note the increased head circumference with prominent forehead, prognathism,
and big ears. adapted from Smith's recognizable patterns of human malformation. Elsevier, Inc.
30
Growth and Feeding

There may be a mild
overgrowth.
Normal to increased birth Evaluation and management of GERD as other population.
weight, and the head
circumference may be large at
the time of birth.
Feeding problems, GERD

Hypotonia and joint At the time of diagnosis: speech, Speech and language therapy,
hyperextensibility may interfere language and motor evaluation. physical therapy, and special
with achievement of normal motor education support by a special
A complete psychological
milestones. education teacher. Many of these
evaluation that includes IQ testing
programs are in an integrated
Tantrum behavior and is an essential part of the evaluation
setting with both developmentally
hyperactivity may begin in the of cognitive deficits.
disabled children and typically
second year. An evaluation for ASD that developing children. Whenever
Language delays and unusual includes standardized testing such possible, they should be
autistic like features such as hand as the ADOS is recommended in all incorporated in a mainstreamed
flapping, poor eye contact, social children after age 2 years to see if situation, because they model
anxiety, and self-injurious behaviorABA programming is needed. normal children very well.
including hand biting typically Children who are treated with Parents should become aware of
begin by the second or third year of psychotropic medication requirethe need to avoid excessive sensory
life. periodic physical assessment, stimulation whenever possible. The
Hyperactivity persists throughout including blood pressure and avoidance of large crowds and loud
childhood, attention problems and cardiac examination. noises or shielding the child from
impulsivity. Psychotic symptoms: Psychiatry stimuli, for example, by using
earphones so that the child can
Anxiety particularly social anxiety. referral. listen to a favorite tape or calming
Obsessive and compulsive music while shopping, can be
behavior helpful.
Psychosis or psychotic features The use of stimulant medication is

helpful for children > 5 years.
For treatment of anxiety, social phobia,
obsessive compulsive disorder,
depression, and aggression, the use of
an SSRI can be used.
The use of metformin can help to avoid
weight gain with the use of atypicals,
and metformin is also a very promising
targeted treatment, so it should be
started in childhood.
Atypical antipsychotic for psychosis
31
Neurologic

Seizures in early childhood may A careful medical history about The most commonly used
include generalized tonic clonic any seizure episodes. anticonvulsant is valproic acid.
seizures, staring spells or An EEG should be obtained if Carbamazepine has also been
absence seizures, partial motor seizures are suspected by used in the treatment of seizures.
seizures, and temporal lobe medical history. It should Newer anticonvulsants such as
seizures. include a waking and a sleep topiramate and lamotrigine may
be used as an adjunct.
Usually the seizures respond record.
Phenobarbital should be
well to anticonvulsant Neurological consultation can avoided, because it typically
medication. The seizures be obtained to guide the increases hyperactivity.
usually resolve by adolescence. evaluation or treatment of
The use of folic acid may
The fragile X associated seizures.
exacerbate a seizure disorder,
tremor/ataxia syndrome If focal symptoms: MRI of the and it is often avoided in
(FXTAS) brain should be done. individuals with seizures.
Evaluation for fragile X
associated tremor/ataxia
syndrome includes brain MRI
and neurological examination
and consultation.
Ophthalmologic

Strabismus and refractive errors, Referral to an ophthalmologist if Approaches are the same as
particularly hyperopia and found. those used in the general
astigmatism. If no abnormality is seen on population.
clinical examination, then a
routine assessment by an
ophthalmologist should occur
before 4 years of age.
32
Cardiovascular

The most common cardiac Auscultation of the heart should Hypertension can be initially
problem is mitral valve be carried out at all clinical visits treated with diuretics or low‐
prolapse. The presence of a murmur or a dose β‐blockers. Treatment
Mild dilation of the aortic root click requires an evaluation by a choices are the same as in the
cardiologist. general population.
has also been seen in adults.
ECG and an Echo, including Management of mitral valve
Hypertension
measurement of the aortic root prolapse is standard.
Sudden death secondary to an diameter.
Use of antibiotic prophylaxis is
arrhythmia is very rare.
Blood pressure should also be no longer required for mitral
monitored at all clinical visits, valve prolapse.
and this should be measured at Treatment of aortic root
least once a year in all adults. dilatation is usually not
required.
Genitourinary

Macroorchidism is the most Testicular volume can be Delays in toilet training can be
common genital anomaly in measured with an orchidometer helped by behavioral
males. to monitor size changes over interventions.
It is usually not associated with time. Treatment of enuresis
other complications, although Males should be assessed for the conservative measures and
the weight of the testicle in presence of a hernia. medications may be used, as
combination with connective Urinary tract infection should be other population.
tissue problems may predispose evaluated with a Macroorchidism will be
to inguinal hernias. cystourethrogram and renal maintained throughout adult life
Enuresis, dilation of the ureters ultrasound. and does not require
with reflux due to connective Referral to nephrology or intervention.
tissue dysplasia. urology is recommended for
recurrent urinary tract
infections, abnormalities in
renal structure, or reflux on the
cystourethrogram.
Hypertension should be
followed closely, if persistent
hypertension, a more detailed
evaluation, including studies of
the kidney is needed.
33
Musculoskeletal

Hyperlaxity or The regular physical The majority with joint
hyperextensibility due to examination should include an hyperextensibility do not require
connective tissue dysplasia. The assessment of joint treatment. Severe joint
joint hyperextensibility usually hyperextensibility in addition to hyperlaxity, particularly in
improves with age, perhaps asking for a history of joint association with hypotonia, may
related to ligament tightening dislocation or pain. require physical therapy
with time. intervention in early childhood.
All individuals should be
Flat feet, or pes planus. assessed clinically for scoliosis. Joint dislocations, however,
Joint dislocations, particularly If scoliosis is present, it should require an orthopedic evaluation
congenital hip dislocation be documented with baseline and follow‐up.
identified at birth, recurrent spine films and referral to an Recurrent joint dislocations may
patellar dislocation, or shoulder orthopedist. require surgery.
dislocation. Flat feet are frequently treated
Clubfoot deformity can be seen with a shoe insert or orthotic,
in 1–2%. which may improve shoe wear
and gait patterns.
Scoliosis is seen in less than
20%. Scoliosis should be treated as in
the general population.
34
Endocrine

Precocious puberty: The cause Signs of precocious puberty The use of a gonadotropin
is unknown, may be should be sought in the periodic agonist to block precocious
hypothalamic dysfunction and clinical examination and puberty may be necessary.
macroorchidism. endocrinology referral if The use of SSRIs is helpful for
present.
Women with the full mutation severe premenstrual syndrome
usually have a cognitive deficit, Questions regarding the and the depression associated
and on occasion this can lead to emotional status during or with menopause or postpartum
promiscuous sexual behavior. before menses with the states.
These individuals may require premutation or the full mutation The use of Depo Provera
more detailed counseling for should be addressed at each injections, monthly or every
birth control and may be unable clinical evaluation, including three months, for birth control
to reliably take medication such questions regarding anxiety, may be beneficial in women
as daily birth control pills depression, and mood lability. with a cognitive deficit who may
without supervision. forget to take daily pills.
Approximately 20% of women All females should be referred
with the premutation undergo for genetic counseling and a
premature menopause also discussion of reproductive
called fragile X‐associated alternatives, such as in vitro
primary ovarian insufficiency
fertilization and prenatal
(FXPOI), and this may occur as diagnosis techniques.
early as the 20s.
The risks for premature
Males and females with fragile menopause should be explained
X syndrome are fertile. to carriers of the premutation so
All women with the FMR1 that appropriate adjustments can
mutation should be offered be made in reproductive
prenatal diagnosis with planning.
pregnancies. In addition, both
women with the premutation
and women with the full
mutation are at higher risk for
emotional problems compared
with the general population,
particularly at times of
hormonal changes or estrogen
deficiency, such as menopause,
postpartum, and even during
their monthly periods. Some
women suffer from severe
premenstrual syndrome.
35
References
▪ Jones, K. L., Campo, M. del, & Jones, M. C. (2022). Smith's recognizable patterns of
human malformation. Elsevier, Inc.

Blackwell.
36
Turner Syndrome (TS)
Key Points:
The diagnosis of TS is made by chromosome analysis and consideration of clinical
manifestations.
TS should be considered in newborn with cystic hygroma and pedal edema.
Karyotype is indicated for any female with unexplained short stature especially if
puberty is delayed.
Incidence
• The livebirth occurrence is approximately 1:2000.
Diagnostic Criteria
• The diagnosis of TS is made by chromosome analysis and consideration of clinical
manifestations.
Diagnostic Testing
• The diagnosis of TS is made by obtaining a standard 20 cell karyotype. If this is
negative and there remains suspicion for the diagnosis, then further testing can be
performed by extended FISH analysis or by testing an additional tissue such as skin
or buccal cells. Different Types of chromosome abnormalities in Turner syndrome
are shown in (Table 1).
Table (1): Type and frequency of chromosome abnormalities in Turner syndrome

(adapted from Gravholt et al. 2017)
37
• Several karyotypes are not listed, including various unbalanced X‐autosome

translocations which are usually limited to single case reports. 46,XX,del(q24) is
not considered Turner syndrome, although premature ovarian failure is present.
46,X,idic(X)(q24) is not considered Turner syndrome .
• There is an approximate 1% risk for any individual with TS to have
gonadoblastoma, a risk which can be reduced by screening for the Y chromosome
material present in approximately 10% of individuals with TS.
• Increased mosaicism as well as masculinization can be associated with increased
risk for gonadoblastoma, which is approximately 10% overall in individuals with
Y material. Screening for cryptic Y material by PCR is recommended for those
with masculine features who have had normal female karyotype and FISH testing.
Table (2): Indications for chromosome analysis to diagnose Turner syndrome

(adapted from Gravholt et al. 2017)
1) Typically bicuspid aortic valve, coarctation, aortic stenosis (with/without

bicuspid aortic valve), mitral valve anomalies, and hypoplastic left heart
syndrome.
2) Downslanted palpebral fissures, epicanthal folds, low‐set anomalous pinnae,
micrognathia, narrow palate, short broad neck, and webbing.
3) Partial anomalous pulmonary venous return; atrial septal defect, secundum type;
and ventricular septal defects, muscular or membranous.
38

Growth and Feeding

Growth deficiency as short Growth should be monitored Girls who manifest growth
stature is a cardinal feature of carefully at each visit. deficiency should be offered the
TS. option of growth hormone.
Referral to a pediatric
Growth hormone therapy is now endocrinologist is The age of initiation and
offered to all girls with TS with recommended at the time of duration of treatment are key
growth deficiency. Referral to a diagnosis. factors in the effectiveness of
growth hormone therapy. It is
pediatric endocrinologist at the Growth decline in a girl already
recommended that this be
time of diagnosis is on growth hormone treatment
started no later than 12–13 years
recommended. should prompt consideration of
of age and possibly as early as
other causes for growth decline
4–6 years of age
such as celiac disease or feeding
problems. Individuals on growth hormone
are generally assessed by a
pediatric endocrinologist at 3–6
month intervals.
39
Puberty and Fertility

Ovarian insufficiency is due to Pubertal status should be • Begin estrogen therapy
the accelerated loss of oocytes in evaluated at each routine clinic around the age of 12 years in
fetal life and results in a greatly visit by physical exam. girls with elevated gonadotropin
reduced (“streak”) ovary. If there is no spontaneous breast levels and no puberty.
Unassisted pregnancies occur in development by age 12 years, • Hormone replacement
a small number who usually obtain serum gonadotropin therapy must continue during
have mosaicism, although a few levels (FSH and LH) to ensure adulthood, otherwise women
women with 45,X have become that they are elevated. with TS develop an even greater
pregnant. Continue to monitor pubertal risk for osteoporosis, an adverse
development after initiation of metabolic profile, and
The frequency of miscarriages is
cardiovascular disease than they
high, and various anomalies therapy.
have at baseline.
have been noted in live‐born Counseling should be provided
early about the reduced fertility, • Two years before pregnancy is
infants conceived by women
with TS. avoiding the terms ovarian contemplated, they should have
imaging of the thoracic aorta
The increased rate of aortic “failure” and infertility.
with transthoracic echo and
dissection and maternal death
MRA or CT angiography. Blood
must be discussed with the
pressure must be strictly
cardiologist.
controlled.
TS who does not have aortic
dilatation, hypertension,
bicuspid aortic valve,
coarctation, or previous surgery,
pregnancy can be contemplated
with the understanding that a
degree of risk for aortic
dissection remains.
Avoidance of obesity and
encouragement of
cardiovascular fitness should be
counseled.
Vaginal delivery is usually
acceptable in the absence of
aortic dilatation.
40
Cardiovascular

Congenital heart defects and All individuals with TS should Follow up with a cardiologist.
abnormalities of the aorta and have a baseline evaluation with Hypertension should be treated
peripheral arteries, but also transthoracic echocardiography
acquired problems such as early‐ aggressively, given the risk for
MRA or CT angiography.
onset systemic hypertension, aortic dissection.
ischemic heart disease and Coarctation in the newborn A healthy lifestyle should be
cerebrovascular disease. female is an independent marker encouraged.
of TS, and karyotype should be
Cardiomyopathy and serious strongly considered. All individuals with TS,
arrhythmias are extremely rare. especially those with existing
Blood pressure should be aortic dilatation and/or bicuspid
The well recognized pattern monitored at each clinic visit.
includes various levels of Ambulatory blood pressure aortic valve, should be taught
obstruction on the left side of the monitoring that if they have severe chest
is strongly pain, aortic dissection must be
heart. Most common is aortic encouraged.
coarctation, with or without a considered and an imaging
bicuspid valve, bicuspid valve A resting ECG should be done at study, such as MRA, must be
alone, and aortic stenosis and/or diagnosis. When QTc interval performed.
regurgitation. Other defects prolongation is present, 24 hour
include hypoplastic left heart,
Holter monitoring and exercise
testing should be performed.
mitral valve anomalies
(hypoplastic, prolapsed), atrial
septal defect and ventricular
septal defect.
The spectrum of vascular
anomalies includes elongation of
the transverse arch, aberrant right
subclavian artery, persistent left
superior vena cava, and partial
anomalous pulmonary venous
return. Congenital coronary
artery anomalies must also be
considered.
The most concerning
manifestation of the vasculopathy
of TS is aortic dissection and
aortic dilatation.
Systemic hypertension.
Ischemic heart disease and
atherosclerosis, risk factors
include hypertension, insulin
resistance, hyperlipidemia, and
estrogen deficiency.
41
Lymphatic System

Lymphedema is one of the Individuals with TS should be Although peripheral edema
hallmark features of TS. monitored for increasing and often resolves by age 2 years,
Central lymphedema manifests persistent lymphedema as well referral to a surgeon is
as early as the prenatal period as as possible skin and nail recommended for those with
a cystic hygroma (nuchal complications. For example, significant compromise of the
thickening on ultrasound) and in deeply‐set dysplastic toenails skin or nails.
the newborn period as distinct can become ingrown. Support stockings can be
webbing of the neck. The presence of central helpful, even for adolescents.
Peripheral lymphedema of the lymphedema (neck, Cellulitis should be avoided by
mediastinal) should prompt
hands and feet is also promoting good hygiene,
concern for left‐sided heart
characteristic of TS. moisturization, and avoidance
anomalies and further cardiac of skin trauma.
It is due to abnormal lymphatic evaluation.
formation from early in
embryonic development.

Most of TS have intellectual Neuropsychology evaluations as • Learning and performance
functioning within the normal a routine part of health challenges should be addressed
range. However, approximately maintenance and should be with academic and occupational
10% do have some degree of completed at important adjustments.
intellectual disability. transitional stages in education,
• Puberty should be initiated on
Even those with normal intellect career and personal milestones.
time and monitored, with any
can experience a variety of Annual developmental and impairment addressed to
cognitive challenges. behavioral screenings should be
optimize psychosocial and
About 25% will have ADHD and performed from diagnosis until psychosexual development.
about 50% of girls and women adulthood.
• Evidence‐based intervention
with TS have a math learning
should be adapted and initiated
disability, dyscalculia.
to treat psychosocial and
Difficulties with aspects of social cognitive issues experienced in
cognition as facial and emotional TS.
recognition. Their
neuropsychologic profile may • Referral to a psychiatrist, if
resemble autism spectrum specific diagnoses are
disorders. identified, such as anxiety,
depression, and attention deficit
Because of impairments in social hyperactivity.
cognition, they have lower self-
esteem, more subject to bullying
and develop fewer close
friendships.
42
Urologic

Congenital anomalies of the • All girls with TS should have The same as that for the general
urinary system are present in a renal ultrasound study population.
30–40% and are usually performed at the time of
asymptomatic. diagnosis.
Anomalies include horseshoe
kidney, either partially or
totally duplicated or absent
kidneys, and either multicystic
or ectopic kidneys.
A small number have secondary
morbidity, such as obstructive
uropathy, hypertension, chronic
renal failure and urinary tract
infections.
43
Endocrine

Thyroid disease: The most • Thyroid function tests should Girls and women with TS
prevalent autoimmune disorder be obtained yearly; regular should be counseled on a
in TS is thyroid disease, which screening for antithyroid healthy lifestyle and estrogen
occurs in approximately 25% antibodies does not alter replacement, including healthy
and manifests more often as management. nutrition and physical activity.
hypothyroidism due to • Hemoglobin A1c and fasting Estrogen replacement therapy
Hashimoto thyroiditis. plasma glucose should be should be initiated at 11–12
Diabetes: The incidence of both monitored annually beginning at years of age, reaching an adult
type 1 and type 2 diabetes is age 10. dose 2–3 years after initiation.
increased. • Those with at least one risk Progesterone should be added
Body composition: Obesity factor for cardiovascular disease after two years of estrogen
therapy or once breakthrough
Bone metabolism: The lifetime should have a fasting lipid bleeding ensues.
risk for fractures is increased. profile annually beginning at
This occurs even in those with age 18.
normal bone mineral density. • Quality of diet and vitamin and
Bone mineral density can be mineral intake should be
improved with estrogen ascertained.
replacement. • BMI should be reviewed with
each visit.
• Vitamin D levels should be
monitored via monitoring a
serum 25‐hydroxyvitamin D
beginning at 9–11 years of age
and repeated every 2–3 years.
• Bone densitometry scans
(DXA) should be used to
monitor bone density in those on
adult hormone replacement and
when considering discontinuing
this therapy.
Respiratory

Microstomia, micrognathia and • Individuals with signs and The same as that for the general
a generally small oropharynx symptoms of sleep apnea should population.
are risk factors for obstructive be referred for evaluation and a
sleep apnea. sleep study.
44
Gastrointestinal and Liver

Liver dysfunction, celiac Liver function tests should be The same as that for the general
disease and Inflammatory bowel obtained once a year beginning population.
disease. at age 10 years. Weight loss is advised for
(ALT, AST, GGT) are elevated Screening for celiac disease steatosis.
while bilirubin and coagulation using tissue transglutaminase
parameters are normal. There is IgA antibodies should begin at
a five‐fold risk of cirrhosis age 2–3 years and should be
compared to the normal repeated every two years
population, especially in those throughout adulthood.
with elevated liver function Liver Imaging with Doppler
tests, portal hypertension and ultrasound and MRI may be
esophageal varices. indicated for vascular
Non‐alcoholic liver disease with anomalies. Capsule endoscopy
steatosis, steatohepatitis, and may be needed in addition to
steatofibrosis, which are upper endoscopy and
probably related to metabolic colonoscopy.
disorders such as increased
adiposity.
In addition to liver
vasculopathy, there can be
gastrointestinal bleeding due to
intestinal telangiectases on the
serosal surface of the small
bowel. Bleeding generally
resolves with age, perhaps as the
result of estrogen
supplementation.
Ophthalmologic

Myopia or hyperopia, ptosis, Formal ophthalmology The same as that for the general
epicanthal folds and evaluation is recommended at population.
hypertelorism. 12–18 months of age or at the
time of diagnosis if it occurs
Strabismus and amblyopia.
later.
Red green color blindness as in
the male population.
45
Audiologic

Hearing loss and ear anomalies Formal audiology evaluation is Otitis media should be treated
are a common challenge, with recommended every five years. using antibiotics, myringotomy
the onset of hearing loss Surveillance is important and pressure equalizing tubes to
occurring from infancy through throughout the lifespan as this preserve normal hearing and
late adulthood. It is universally can affect development as well optimize speech development
present in those older than 50. and social skills.
as social interactions.
Structural ear anomalies, which Encourage the use of sound
can include protrusion of the amplification (hearing aids) and
ears, abnormal pinnae, low set classroom accommodation for
ears, and narrow external those with hearing loss, since
auditory canals. The most hearing loss can contribute to
common hearing issue is language‐based and social
sensorineural hearing loss. disabilities. Improvements in
Frequent otitis media leading to the design of hearing aids has
conductive hearing loss. increased acceptance.
Orthodontic

Retrognathia, high arched It is recommended that all girls Treatment should be tailored in
palate along with malocclusion with TS see a pediatric dental accordance with skeletal age
of the teeth can provide unique specialist by age 2 years, and an and growth.
challenges in orthodontic orthodontist no later than age 7 The timing of any orthodontic
treatment of girls with TS. years. treatment should take into
consideration growth promoting
therapies that may alter tooth
and jaw alignment.
Unnecessary tooth movement
should be minimized to avoid
root resorption and loss of
teeth.
46
Dermatologic

Increased number of Individuals with TS should be Management of skin nevi is the
melanocytic and sebaceous taught how to evaluate their nevi same as that for the general
nevi, hypertrophic scars for possible malignant changes. population.
(keloids), vitiligo, alopecia and Any attempt to treat existing
skin cancers, halo nevi, and scars should be viewed with
psoriasis. extreme care.
Dysplastic or hyperconvex nails
and long eyelashes.
Oncologic

Gonadoblastoma associated Karyotype should be reviewed If Y chromosome material is
with the presence of a Y to ensure that marker present, the individual should be
chromosome fragment. chromosomes have been referred to a surgeon for
identified and that no Y prophylactic removal of the
CNS tumors including
meningioma and schwannoma chromosome material is present. gonads.
compared to the general Screening for cryptic Y material There is no routine screening for
population. by PCR is recommended for other tumors, but a high index of
suspicion should be maintained
Neuroblastoma, non-Hodgkin those with masculine features
for tumors of the nervous
lymphoma, bladder cancer, and who have had normal female
karyotype and FISH testing. system.
eye cancer.
Immunologic
• Increased risk for autoimmune disorders including thyroiditis, celiac disease,
inflammatory bowel disease, and juvenile rheumatoid arthritis.
• Associations may also exist for type I diabetes, alopecia areata, acquired von
Willebrand’s disease, primary biliary cirrhosis, and uveitis.
47
Table (3): Recommendations for screening girls and women with Turner syndrome
(Gravholt et al. 2017).
• Individuals with a problem in one or more areas may be followed by more than one
specialist and be evaluated more frequently. The recommendations are for screening
only. A clinical suspicion of active disease should always lead to relevant
investigation.
48
References
▪ Gravholt, C. H., Andersen, N. H., Conway, G. S., Dekkers, O. M., Geffner, M. E., Klein,
K. O., Lin, A. E., Mauras, N., Quigley, C. A., Rubin, K., Sandberg, D. E., Sas, T.,
Silberbach, M., Söderström-Anttila, V., Stochholm, K., van Alfen-van derVelden, J. A.,
Woelfle, J., Backeljauw, P. F., & International Turner Syndrome Consensus Group
(2017).
▪ Clinical practice guidelines for the care of girls and women with Turner syndrome:
proceedings from the 2016 Cincinnati International Turner Syndrome Meeting.
▪ European journal of endocrinology, 177(3), G1–G70. https://doi.org/10.1530/EJE-17-

0430.

Blackwell.
49
SILVER–RUSSELL SYNDROME (SRS)
SRS should remain primarily a clinical diagnosis. Molecular testing is

useful for the confirmation and stratification of diagnosis in SRS. Lack of a
positive molecular result does not exclude the diagnosis of SRS.
An international consensus on diagnosis and management of SRS has
recommended that SRS remains first and foremost a clinical diagnosis.
Diagnostic Criteria
• SRS is currently a clinical diagnosis based on a combination of characteristic
features. Molecular testing can confirm the diagnosis in around 60% of patients.
Molecular testing enables stratification of patients with SRS into subgroups, which
can lead to more tailored management.
• International consensus guidelines recommend use of the Netchine–Harbison
clinical scoring system (NH-CSS). Clinical diagnosis is considered if a patient
scores at least four of six from these criteria (Table 1). If all molecular tests are
normal and differential diagnoses have been ruled out, patients scoring at least four
of six criteria, including both prominent forehead and relative macrocephaly should
be diagnosed as clinical Silver–Russell syndrome.
Table (1): | Netchine–Harbison clinical scoring system

Clinical criteria Definition
SGA (birth weight and/or birth length) ≤−2 SDS for gestational age
Postnatal growth failure Height at 24 ± 1 months ≤−2 SDS or height ≤−2 SDS
below mid-parental target height
Relative macrocephaly at birth Head circumference at birth ≥1.5 SDS above birth
weight and/or length SDS
Protruding forehead Forehead projecting beyond the facial plane on a side
view as a toddler (1–3 years)
Body asymmetry LLD of ≥0.5 cm or arm asymmetry or LLD <0.5 cm
with at least two other asymmetrical body parts (one
non-face)
Feeding difficulties and/or low BMI BMI ≤−2 SDS at 24 months or current use of a
feeding tube or cyproheptadine for appetite
stimulation
▪ LLD, leg length discrepancy; SDS, SD score; SGA, small for gestational age.
▪ The flow chart (Figure 1), based on the NH-CSS, should be adopted for the investigation
and diagnosis of SRS.
50
Table (2): Additional clinical features of Silver–Russell syndrome
Clinical feature Frequency % (total no. patients)

Triangular face 94 (164)
Fifth finger clinodactyly 75 (319)
Shoulder dimples 66 (61)
Micrognathia 62 (115)
Low muscle mass 56 (103)
Excessive sweating 54 (106)
Low-set and/or posteriorly rotated ears 49 (266)
Down-turned mouth 48 (176)
High pitched or squeaky voice 45 (26)
Prominent heels 44 (61)
Delayed closure of fontanelle 43 (47)
Male genital abnormalities 40 (85)
Speech delay 40 (189)
Irregular or crowded teeth 37 (195)
Motor delay 37 (254)
Syndactyly of toes 30 (264)
Hypoglycaemia 22 (103)
Scoliosis and/or kyphosis 18 (227)
▪ Studies have excluded 11p15 LOM and upd(7)mat in patients with intrauterine growth
retardation and postnatal growth retardation alone; some patients, particularly those
with upd(7)mat or children under 2 years, score 3/6 (see text for details).
▪ Arrange CNV analysis before other investigations if patient has notable unexplained
global developmental delay and/or intellectual disability and/or relative microcephaly.
▪ Insufficient evidence at present to determine relationship to SRS, with the exception of
tissue mosaicism for 11p15 LOM.
▪ Unless evidence of catch-up growth by 2 years. ¶Previously known as idiopathic SRS.
CNV, copy number variant; LOM, loss of methylation; NH-CSS, Netchine-Harbison
clinical scoring system; SRS, Silver–Russell syndrome.
51
Figure (1): Flow chart for investigation and diagnosis of SRS
52
Differential Diagnosis
• A correct diagnosis can have extremely important implications for management.

Response to GH treatment, if given, varies depending on the underlying syndromic
diagnosis.
• For instance, GH treatment is contraindicated in patients with chromosome
breakage disorders, such as Bloom syndrome, due to the associated risk of
malignancy.
• GH treatment in patients with SHORT syndrome has been reported to precipitate
insulin resistance and subsequent type 2 diabetes mellitus.
• An incorrect diagnosis of SRS leading to the recommendation of GH treatment
could, therefore, have adverse consequences in these patients.
53
Table (3): Differential diagnosis of Silver–Russell syndrome in patients with relative

microcephaly
Syndrome (OMIM number)
Meier–Gorlin
IGF1R
syndrome
Nijmegen mutation IGF1
Feature Bloom (#224690,
breakage MOPD II or
syndrome #61380,
syndrome (#210720) deletion mutation
(#210900) #613803,
(#251260) (#147370, (#147440)
#613804,
#612626)
#613805)
Birth weight Mean: −4.6 Mean: −1.6 Mean: −3.9 Mean: −3.8 –1.5 to −4.9 –2.5 to −4.5
SDS
Adult height • Male • Male Mean: 96 • Male patients: IGF1R 1 male
range (cm) patients: patients: 136–157 mutation:
128–164 161–172 1 female patient: 117
• Female patients: patient
• Female • Female 127–150 (140), 2
patients: patients: male
115–160 150–165 patients
(133 and
170)
Cognitive Usually At pre- Variable: 90% normal IQ, Variable: Severe ID
function normal school age none or occasionally mild normal
IQ normal mild ID or moderate ID (~50%),
or (majority), mild ID
borderline; occasionall (25%),
progressiv y severe ID moderate
e or severe
deteriorati ID (25%)
on to
moderate
ID
Facial Narrow Receding Prominent, Microtia, narrow, • IGF1R No
features face with forehead, long, broad beaked nose with mutation: consistent
underdevel prominent nose with low insertion of often features
oped malar mid-face, hypoplastic columella, small normal; reported
area and small tip, low mouth, triangular
mandible, mandible, insertion of retrognathia face,
fairly up-slanting columella, micrognat
prominent palpebral prominent hia.
nose, sun- fissures, eyes in
sensitive long nose infancy, • 15q26-
telangiecta and micrognathia qter
sia in philtrum, deletion:
malar large ears micrognathia
distribution
Other Patchy Severe, Mean OFC Patellar • IGF1R Sensorineural
features areas of progressive at birth −4.6 hypoplasia, mutation: deafness
hypopigme microcepha SDS, pulmonary pectus
54

Meier–Gorlin
IGF1R
syndrome
Nijmegen mutation IGF1
Feature Bloom (#224690,
breakage MOPD II or
syndrome #61380,
syndrome (#210720) deletion mutation
(#210900) #613803,
(#251260) (#147370, (#147440)
#613804,
#612626)
#613805)
nted and ly, progressive emphysema, excavatum,
hyperpigm immunodef microcephal cryptorchidism, 5th finger
ented skin, iciency, y, mammary clinodactyl
feeding cancer mesomelic hypoplasia (post- y, short
difficulties, predispositi limb pubertal 100%), fingers
high on, shortening, hypoplastic labiae
tumour risk chromosom progressive • 15q26-
(44% al metaphyseal qter
develop instability deletion:
cancer by and bone fifth finger
age 25 rearrangem dysplasia, clinodactyl
years), ents, café hip y, short
hypogonadi au lait dysplasia, fingers,
sm, type 2 spots, acanthosis talipes,
diabetes premature nigricans, congenital
mellitus, ovarian insulin heart
immunodef failure resistance, disease,
iciency, cryptorchidi renal
chromosom sm, anomalies
al intracranial
instability aneurysm,
with dental
increased anomalies,
frequency squeaky
of sister voice
chromatid
exchange
Inheritance • Autosomal Autosomal • Autosomal • Autosomal IGF1R • Autosomal
and recessive recessive recessive recessive mutation: recessive
molecular • Mutations Mutations • Mutations • Mutations in majority • Mutations
abnormality in RECQL3 in NBN in PCNT ORC1, autosomal in IGF1
• High High ORC4, ORC6, dominant;
prevalence prevalence CDT1, CDC6 compound
in in Slavic heterozygo
Ashkenazi population sity
Jewish reported in
population two
patients
▪ ID, intellectual disability; MOPD II, microcephalic osteodysplastic primordial dwarfism type II;
OFC, occipito-frontal circumference; SDS, SD score.
55
Table (4): Differential diagnosis of Silver–Russell syndrome in patients with relative

normocephaly or macrocephaly
3‐M syndrome Mulibrey nanism SHORT Floating IMAGe
Feature (#273750) (#253250) syndrome harbour syndrome
(#269880) syndrome (#614732)
(#136140)
Birth Mean: −3.1 Mean: −2.8 (range −4.0 to Mean: −3.3 Mean: −2.5 –2.0 to −4.0
0.5)
weight SDS
Adult 115–150 136–150 Mean: 154 • Female • 1 male patient:
height patients: 98– 160 • 1 female
156 • Male patient: 143
range (cm) patients: 106–
164
Cognitive Normal Mild motor and speech Normal Delayed Normal or mild
function delay only speech. ID
Intellect
variable:
normal to
significant ID
Facial Anteverted nares, Triangular face, frontal Micrognathia, high Triangular Frontal bossing,
features full lips, mid-face bossing broad forehead, face, deep-set low-set ears,
hypoplasia, long triangular-shaped eyes, long flat nasal
philtrum face, deep-set eyes, eyelashes, bridge, short
prominent nose, bulbous nose, nose
low-set posteriorly wide
rotated ears, columella,
hypoplastic nasal short
alae, facial philtrum, thin
lipodystrophy, thin lips
hair
Other Prominent heels Hepatomegaly, yellow Rieger anomaly, Delayed Congenital
features (also in upd(7)mat), spots on retina, dental delay, partial speech adrenal
short broad neck, progressive restrictive lipodystrophy, development hypoplasia,
pectus deformity, perimyocarditis, insulin transparent skin, with metaphyseal
short thorax, resistance, high pitched dimples on elbows expressive and/or
winged scapulae, voice, slender long and buttocks, language epiphyseal
hyperlordosis, hip bones with thick cortex herniae, fifth finger delay, dysplasia, male
dysplasia, subtle and narrow medullar clinodactyly, considerably genital
radiographic channels, shallow sella hyperextensible delayed bone anomalies
changes (slender turcica, increased joints, age, broad
long bones, tall tumour risk hypogonadism, fingertips
vertebral bodies) (particularly Wilms and high pitched voice,
ovarian stromal type 2 diabetes
tumours) mellitus,
nephrocalcinosis,
thin gracile bones
Inheritance • Autosomal • Autosomal recessive • • Autosomal • Autosomal Imprinted –
and recessive • Mutations in TRIM37 • dominant • dominant • maternally
Mutations in High prevalence in Mutations in Mutations in inherited
molecular CUL7, OBSL1, Finnish population PIK3R1 SRCAP mutations in
abnormality CCDC8 CDKN1C
▪ ID, intellectual disability, SDS, SD score.
56
Management
• These management recommendations apply to all patients clinically diagnosed with

SRS, both with and without a molecularly confirmed diagnosis. However,
identification of the underlying molecular subtype can guide treatment with regard
to specific risk factors. Management should involve a multidisciplinary approach
and close parental guidance. A practical checklist for use in routine clinical follow
up of these patients is proposed in (Table 5).
57
Table (5): Checklist for management of patients with Silver–Russell syndrome

At 0–2 2–10 10–18
Management issue
diagnosis years years years
General
Document molecular subtype R N/A N/A N/A
Provide support group information R N/A N/A N/A
Genetic counselling for parents R N/A N/A N/A
Feeding and Growth
Exclude feeding difficulties R R C C
Ensure nutritional repletion R R R R
Screen for gut dysmotility R R C C
Screen for oromotor or sensory issues R C C C
Avoid rapid postnatal and/or childhood weight gain R R R R
Measure head circumference R R R R
Measure and monitor linear growth R R R R
Calculate and monitor BMI R R R R
Screen for symptoms and/or signs of hypoglycaemia R R C C
Consider growth hormone treatment R C R R
Monitor IGF1 or IGFBP3 levels (more than yearly) R C R R
Monitor clinically (with or without biochemical testing)
R N/A R R
for insulin resistance
Adrenarche and Puberty
Monitor clinically for early adrenarche R R R N/A
Anticipate early bone age advancement R N/A R R
Consider treatment of early or rapid central puberty R N/A R C
Other Medical Issues
Monitor for symptoms of sleep disordered breathing R R R R
Orthodontic or dental R C R R
Ear, nose and throat R C C C
Neurodevelopment
Developmental assessment R R C C
Screen for myoclonus dystonia* R R R R
Speech and language evaluation R R R C
School progress R N/A C C
Monitor for speech, motor and cognitive difficulties R C R C
Psychosocial evaluation R N/A C C
Musculoskeletal
Limb length discrepancy or asymmetry R C C C
Scoliosis R C C C
Screen for hip dysplasia R R C C
▪ upd(7)mat only. C, consider assessment, depending on the clinical features of the
patient; N/A, not applicable; R, recommend assessment (unless N/A to age group).
58
Notes on Management:
➢ Goals of GH treatment are to improve body composition, psychomotor
development and appetite, to reduce the risk of hypoglycaemia, and to optimise
linear growth. Treat with GH as soon as possible; starting at age 2–4 years is
adequate for the majority of patients.
➢ Defer GH treatment until caloric deficits are addressed. Avoid GH stimulation
testing.
➢ Advocate a healthy diet and lifestyle in older children and young adults with
particular emphasis on protein calorie balance and regular exercise to avoid
disproportionate weight gain, particularly after discontinuation of GH treatment.
➢ Consider personalized treatment with GnRHa for at least 2 years in children with
evidence of central puberty (starting no later than age 12 years in girls and age
13 years in boys) to preserve adult height potential.
59
References:
▪ International Consensus Guidelines for diagnosis and management of Silver–Russell

syndrome can be found at: https://www.nature.com/articles/nrendo.2016.138
▪ Wakeling, E., Brioude, F., Lokulo-Sodipe, O. et al. Diagnosis and management of Silver–
Russell syndrome: first international consensus statement. Nat Rev Endocrinol 13, 105–
124 (2017). https://doi.org/10.1038/nrendo.2016.138
60
Achondroplasia
Key Points:
Well‐defined clinical and radiologic features allow for virtual certainty
of diagnosis in all infants with achondroplasia.
Incidence
• It is the most common and most readily recognizable type of the skeletal dysplasias.
• Birth prevalence around 1 in 25,000– 30,000.
Inheritance
• Although achondroplasia is an autosomal dominant single‐gene disorder, most
cases are sporadic.
Diagnostic Criteria
• Well‐defined clinical and radiologic features allow for virtual certainty of
diagnosis in all infants with achondroplasia.
• External physical characteristics include disproportionately short limbs,
particularly the proximal or rhizomelic (upper) segment of the arms; short fingers
often held in a typical “trident” configuration with fingers deviating distally;
moderately enlarged head; depressed nasal bridge; and modestly constricted chest
(Figure 1).
• In all infants in whom the diagnosis is suspected, radiographic assessment is
mandatory.
Figure (1): Adapted from: Carey, J. C. (2021). Cassidy and Allanson's management of
genetic syndromes. Wiley-Blackwell.
61
Prenatal Diagnosis
• Prenatal diagnosis of achondroplasia using ultrasonographic criteria can be
exceedingly difficult particularly because bone foreshortening is often not evident
until about 20–24 weeks of gestation.
• Other alternatives, including molecular diagnosis earlier in gestation, before
ultrasonographic manifestations are evident, are not generally applicable, because
of the predominance of sporadic occurrences.
• Prenatal testing by FGFR3 molecular analysis may be elected, principally in two
circumstances. First, when both parents have achondroplasia it can be used to
distinguish homozygous achondroplasia from other possible outcomes. Second,
when a sporadic short‐limbed dwarfing condition is discovered by ultrasound, the
presence or absence of achondroplasia as the cause of limb shortening can be
determined in this manner. This will now often be undertaken as part of a skeletal
dysplasia molecular panel.
Diagnostic Testing
• FGFR3 molecular testing reserved for those rare instances in which diagnosis
is in doubt, as the vast majority of affected individuals can be unequivocally
diagnosed on the basis of clinical and radiologic features.
• Hypochondroplasia: Compared to those who have achondroplasia, those
with hypochondroplasia have less height difference. They have less pronounced
midface features, and limbs are shorter than the trunk, but it is not as obvious as in
achondroplasia.
• Pseudoachondroplasia (PSACH): due to mutations in the COMP gene. All
patients have short stature, other characteristic features include rhizomelic short
arms and legs; a waddling walk, joint laxity. People with pseudoachondroplasia
have normal facial features, head size, and intelligence.
• Thanatophoric dysplasia: It is nearly always lethal, usually in the perinatal period.
Features include profound shortening of the limbs, marked macrocephaly, and
marked chest constriction. It has characteristic radiologic findings and usually die
from respiratory insufficiency as a result of either a constricted chest or central
apnea related to profound stenosis of the foramen magnum.
• SADDAN (Severe Achondroplasia with Developmental Delay and Acanthosis
Nigricans): Bony changes nearly as severe as those in thanatophoric dysplasia, plus
developmental retardation and acanthosis nigricans
62
Manifestations, Evaluation and Management:

Growth and Feeding

Moderate to marked Anthropometric measures • Currently there is no
disproportionate short stature should be obtained each visit effective treatment that will
and plotted on achondroplasia reverse the decremental
obesity
specific growth charts (attached growth found in
below). achondroplasia.
• Exceptional interventions,
Nutritional assessment
such as growth hormone
therapy or extended limb
lengthening is controversial
(may be elicited in some
families): referral to
orthopedic surgeon and
endocrinologist.
• Early parental counseling,
encouraging high‐volume,
low‐calorie food snacks, not
using food as reward, and
involvement in age‐
appropriate and safe
physical activities. Caloric
need and energy expenditure
are less in individuals with
achondroplasia. Typical
interventions to prevent or
treat obesity are usually
effective.
• Referral to nutritionist for
obesity management if
indicated.
• Bariatric surgery may be
needed: surgery referral.
63

Delayed motor development, Every child with achondroplasia • Standard interventions are used if
principally on the basis of who diverges significantly from delayed development is noted.
biophysical differences related to these published standards should
stature, disproportion, be referred for further assessment, Physiotherapy referral if needed.
macrocephaly, joint hypermobility, considering figure 2.
and hypotonia.
• Assessment for adaptive needs,
Number of children have particularly at early school age, is
language-related problems this is crucial.
most likely caused, at least in part,
by an extremely high frequency of
middle ear disease and either
persistent or fluctuating hearing
loss.
A small minority of children with
achondroplasia will be more
seriously delayed, demonstrate
significant learning disabilities,
and may have autism spectrum
disorders and/or a cognitive
disability.
Figure (2): Developmental milestones in infants and young children with

achondroplasia. (Reproduced from Ireland et al. 2012)
64
Neurologic

1) Hydrocephalus At the time of diagnosis, every • If features of increased
Nearly all children with child with achondroplasia intracranial pressure develop,
should have assessment of but subsequently no acute
achondroplasia are
ventricular size and volume of symptoms persist, and if
macrocephalic. It is important to extra axial fluid by CT or MRI. imaging shows preservation of
differentiate benign the subarachnoid space and lack
ventriculomegaly and clinically All children should have serial of evidence for periventricular
significant hydrocephalus. head circumference
parenchymal edema, the
measurements plotted on
physician, in consultation with
achondroplasia specific grids
a neurosurgeon, may elect a
every 1–2 months in the first
period of watchful waiting.
year of life and at each well
This compensated
child visit thereafter until
hydrocephalus (benign
around 5 years of age.
ventriculomegaly) is probably
Search for signs and symptoms of no consequence.
of acute increased intracranial
• In instances where
pressure + sudden increase in
the prominence of superficial symptomatic hydrocephalus has
veins over the scalp or eye unequivocally developed,
region (reflecting increased standard shunting is
ancillary blood flow bypassing appropriate. With appropriate
the pressure gradient at the intervention in those few
jugular foramina) acceleration requiring intervention,
of head growth. prognosis for hydrocephalus in
general should be favorable.
• A few children have been
treated by third
ventriculostomy.
• Decompression of a jugular
foramen has only rarely been
attempted.
65
Manifestation Evaluation Management

2) Cervicomedullary At the time of initial diagnosis: • Parents counselling about careful
Junction Constriction neck support, using a solid back
• Complete a
Every infant with achondroplasia stroller and an infant head and
neurological history.
has a small foramen magnum that neck pillow, and avoidance of
• Perform a careful umbrella strollers, automatic
causes risks for either apnea
associated death (sudden death) or neurological swings, doorway jumpers and so
high cervical myelopathy and examination on, which may precipitate
paralysis, disproportionate and Complete neuroimaging. This uncontrolled head movement
long persistent hypotonia, around a constricted foramen
can either be CT with thin cuts
weakness, hyperreflexia, magnum. Automatic swings in
and bone windows through the
asymmetric reflexes, and ankle which an infant is in a sitting or
foramen magnum or MRI near sitting position are
clonus are due to hypoxic injury or
[avoiding radiation exposure, particularly risky.
traumatic compression.
with better visualization, but no
direct measure of foramen • If there is evidence of cord
compression, then surgical
magnum size, absence of
decompression should be done
standards with which to
compare] • Certain physical activities should be
strongly discouraged, including full‐
Note that calvarial ultrasound
contact American football, full‐
cannot assess foraminal
contact ice hockey, rugby, downhill
structures and should be skiing, trampoline, dive rolls,
vaulting or other gymnastics in
abandoned as a screening tool
in assessing infants with which full body weight impact on the
achondroplasia. head or neck is likely, hanging
upside down from knees or feet,
Polysomnographic evaluation diving from diving boards, and
(sleep study) looking heading in soccer .
specifically for evidence of
central apnea.
If initial findings of the mentioned
assessment are reassuring, no
further investigations are needed.
However, the infant should
continue to have careful periodic
monitoring of neurological and
respiratory history and clinical
and neurological reexaminations
about every 6 months.
In infants with worrisome features
[persisting hypotonia, increased
reflexes or clonus in the legs,
foramen magnum measurements
below −1 SD for achondroplasia,
and central hypopneas, MRI
should be completed.
66
Respiratory

They have smaller than average • Marked tachypnea or failure to In obstructive apnea, refer to
thoraces that may result in thrive in infancy should alert the pulmonologist, with these
decreased effective lung clinician to the possibility of considerations:
volumes, decreased respiratory significant restrictive
In those with small chests,
reserve, and increased pulmonary disease. significant hypoxemia, and no
probability of chronic • Night time oximetry should be other identified cause of
hypoxemia. assessed as part of respiratory problems, transient
In untreated, secondary polysomnography. oxygen supplementation can be
difficulties related to cor effective.
• Persistent hypoxemia or
pulmonale might be life Intervention for obstructive
desaturations below 85%
threatening, apnea, is a stepwise approach.
require further assessment.
Tonsillectomy, adenoidectomy
Snoring, is a virtually uniform • Evaluation of oxygen and weight loss efforts in obese
feature and mostly not saturations by spot oximetry may be performed.
significant. during waking hours. If follow up polysomnography
Obstructive apnea is common • Parents should be taught to demonstrate persistent clinically
due to hypoplasia of the cranial monitor symptoms of significant obstruction then
base and midface. positive airway pressure
obstruction during sleep and
[continuous positive airway
should be questioned about at
pressure (CPAP) or bilevel
each visit. positive airway pressure
Physical assessment, of tonsillar (BiPAP)] is considered
(and, adenoidal) hypertrophy. Additional surgical intervention
When significant obstructive may occasionally be considered
apnea is demonstrated, should positive airway pressure
assessment for right ventricular be ineffective or not tolerated,
hypertrophy and pulmonary including uvulectomy and
hypertension should be carried modified
out. uvulopharyngopalatoplasty in
rare instances.
Finally, only in a small minority
will temporary tracheostomy be
needed.
67
Ears and Hearing

Middle ear dysfunction is as a Audiometric and Medical management and mostly
frequent complication that could tympanometric assessment the use of myringotomy and tube
interfere with normal language should be completed first at placement is encouraged.
acquisition. approximately 8–12 months of Some individuals may show
age and then every 6–12 months substantial speech and language
throughout preschool years and delay. In those instances, referral
should be completed less for speech and language therapy is
frequently in older children and indicated.
adults as well. Some individuals will have
persistent, sufficiently severe
hearing loss that amplification is
necessary.
Musculoskeletal

1) Kyphosis Transient non Clinical evaluation of spine With appropriate care, this is a
congenital at the every 6 months through the first preventable problem. The use of
thoracolumbar junction of 3 years of life, with particular the protocol summarized below
the spine is present in 90– (figure 3) should prevent virtually
emphasis on the severity of all clinically significant
95% of young infants. In persisting kyphosis when the thoracolumbar kyphosis; failures
most, it spontaneously child is placed prone. are rare and usually due to failed
resolves. However, about compliance.
10% of adults with
If the kyphosis is moderate or
achondroplasia have a Parents of infants should be
marked, then radiographic
fixed, angular kyphosis counseled against allowing
that can result in serious assessment of the thoracolumbar
unsupported sitting for at least the
neurological sequelae. spine. first 12 months of life, and to avoid
devices that cause disadvantageous
positioning such as soft infant
carriers, umbrella‐style strollers,
and canvas seats.
In infants and young children, if the

prone radiograph shows that there
is an irreversible curve of >30°, the
family should be referred to
orthopedic surgeon for the
consideration of bracing using a
thoracolumbosacral orthosis
(TLSO)
In those for whom such

anticipatory medical care has not
been provided, or in whom it has
failed, surgical intervention for
kyphosis may be needed.
68
Figure (3): Algorithm for the assessment and prevention of fixed angular kyphosis
(originally published in Pauli et al., 1997)
69

2) lumbosacral spinal stenosis Symptoms to be sought include Neurosurgery referral.
Stenosis of the entire spinal numbness, dysesthesias, Those with severe and/or
radicular pain, leg weakness,
canal, although problems related progressive spinal stenosis
clumsiness, changes in gait, or
to cervical spinal stenosis are of problems with bladder or bowel require urgent neurosurgical
greater concern in infants and continence. intervention through extended
young children, lumbosacral and wide posterior
spinal stenosis is more Examination should include laminectomy.
complete motor and sensory
commonly problematic in Decompression laminectomy
evaluation of the legs.
adolescents and adults. usually results in some
If abnormalities are discovered, improvement of symptoms and
and particularly if there is function, although perioperative
change in neurological findings complications are frequent with
over time, referral for only 50% of affected individuals
neurological and neurosurgical showing long term benefit.
assessment should be made. At
that time, neuroimaging (CT,
MRI) should help in the
assessment of the anatomic
severity, level, and associated
factors of the stenosis.

3) Knee Instability Historical and physical Parents of those with
determination of the severity of asymptomatic mild or moderate
Nearly all young children have
genu knee hyperextensibility knee instability should be
unstable knees
recurvatum. It is usually most A history of activity precipitated reassured that no intervention is
severe in the second year of life pain over the lateral or posterior needed.
and rarely requires intervention knee should be sought. In those in whom knee
but does contribute to the motor instability causes recurrent pain
delays seen in young children (most often seen after a day of
compared to their peers. physical activity), rest, warmth,
massage, and non-steroidal anti-
inflammatory medications can
be used.
When such knee pain is
associated with moderate or
severe varus deformity, it should
precipitate additional referral for
orthopedic surgical assessment.
70

4) Varus Deformity (bow leg) Examination should include For those with varus deformity
assessment of the child while of sufficient severity to be out
With appropriate management,
standing. Serial measurements of plumb and symptomatic, or
no long term sequelae should be
of unloaded and loaded in whom a marked knee thrust
anticipated. If untreated,
distances between the knees, has developed, surgery is
worsening pain, increasing
mid tibiae, and medial malleoli. indicated. Surgery in those who
disability, and secondary joint
are out of plumb but essentially
damage arise.
asymptomatic is elective.
5) Other Musculoskeletal • An assessment of the degree of • Physical therapy for lower
Complications hyperlordosis should be made, and abdominal muscle strengthening.
a history of coccyx pain should be
A discoid lateral meniscus may be • Surgical intervention for elbow
elicited.
another source of leg pain in this limitation generally is not
population. • Evaluation for joint indicated. Although humeral
hypermobility should be done, and lengthening is occasionally
With assumption of standing and
a history of subluxation or pain considered, it is rarely warranted;
walking, most children develop a
should be elicited. instead adaptive devices (such as
hyperlordosis of moderate or
bottom wipers) should be used as
severe degree. This is usually
needed.
asymptomatic. It may exacerbate
risk for lumbosacral spinal stenosis • Discomfort and fatigue of the
in adulthood wrists when doing fine motor
tasks, because of hypermobility,
The elbows are the one exception to
may be relieved by using a simple
the generalized joint
stabilizing brace, if this proves
hypermobility, limitation of
particularly problematic.
extension often develops in early
childhood
Dental

Structural abnormalities, In addition to routine pediatric Options can include palatal
midface hypoplasia and relative dental care, children with expansion or other early
mandibular overgrowth the apparent bite abnormalities management, traditional
palate is often narrow and should be referred for orthodontic manipulations.
anteriorly V-shaped. orthodontic assessment as early In instances of exceedingly
as 5–6 years of age.
The result is a high frequency severe midface hypoplasia:
of malocclusion and crowding surgical.
of the teeth.
71
Anesthetic Risks

Primary areas of concern Anesthesiologists should be Many pediatric surgeons elect
include cervical spinal stenosis made aware of the potential (appropriately) to admit young
and consequent risks related to risks and of the availability of children with achondroplasia for
extremes of positioning while the excellent review. an overnight stay even for
sedated or anesthetized; surgery that usually is done as a
obstructive apnea with or same day procedure because of
the risk of airway related
without cor pulmonale and
complications.
concomitant risks of post
sedation obstruction or post‐
extubation pulmonary edema;
reduced airway size and
possible restrictive lung disease
in young children.
Pregnancy

Women with achondroplasia Pre pregnancy counseling for Women should be counseled to
can continue pregnancies to prenatal diagnosis. anticipate a scheduled Cs
term. without a trial of labor.
Due to high risk of respiratory
Complications during compromise, baseline There is current controversy and
pregnancy are relatively pulmonary function studies may no consensus about appropriate
infrequent but may include risk provide a basis for monitoring anesthetic management –
for worsening of neurological respiratory status as the general, spinal, or epidural – for
symptoms related to increasing pregnancy progresses. Cs in these women.
hyperlordosis and maternal Careful follow‐up for this and
respiratory failure. other maternal complications is
Except for the small possibility essential.
of maternal respiratory failure
requiring early delivery,
successful pregnancies should
be anticipated.
Because of cephalopelvic
disproportion, all women with
achondroplasia need to have
delivery by Cs.
72
References
▪ Hoover-Fong JE, McGready J, Schulze KJ, Barnes H, Scott CI. 2007. Weight for age
charts for children with achondroplasia. Am J Med Genet Part A 143A:2227–2235.
▪ Hoover-Fong JE, Schulze KJ, McGready J, Barnes H, Scott CI. Age-appropriate body
mass index in children with achondroplasia: interpretation in relation to indexes of
height. Am J Clin Nutr. 2008 Aug;88(2):364-71. doi: 10.1093/ajcn/88.2.364. PMID:
18689372.
▪ Hunter AG, Hecht JT, Scott CI Jr. Standard weight for height curves in achondroplasia.
Am J Med Genet. 1996 Mar 29;62(3):255-61. doi: 10.1002/(SICI)1096-
8628(19960329)62:3<255::AID-AJMG10>3.0.CO;2-J. PMID: 8882783.

Blackwell.
▪ Ireland PJ, Johnson S, Donaghey S, Johnston L, Ware RS, Zankl A, Pacey V, Ault J,
Savarirayan R, Sillence D, Thompson E, Townshend S, McGill J (2012b) Medical
management of children with achondroplasia: evaluation of an Australasian cohort
aged 0‐5 years. J Paediatr Child Health 48:443–449.
▪ Pauli RM, Breed A, Horton VK, Glinski LP, Reiser CA (1997) Prevention of fixed,
angular kyphosis in achondroplasia. J Pediatr Orthop 17:726–733.
73
Marfan Syndrome (MFS)
Key Points:
The diagnosis of MFS is primarily based on clinical criteria.
Homocystinuria is an important differential diagnosis and should be excluded.
Diagnostic Criteria
• The diagnosis of MFS is primarily based on clinical criteria (Table 1).

• Individuals who may not meet diagnostic criteria because of young age, ethnicity,
or limited access to diagnostic imaging technology may still be at risk for serious
complications such as aneurysm and dissection of the ascending aorta.
• In these cases MFS diagnosis must be weighed on an individualized basis against
the necessity for clinical follow up to reduce the risk of serious complications.
74
Table (1): Diagnostic criteria for Marfan syndrome (revised 2010)

(Loeys et al. 2010)
75
Differential Diagnosis (AAP, 2013)
Table (2): Differential Diagnoses: Syndromes with Overlapping Features of MFS
76
Management
Table (3): Anticipatory guidance in MFS (AAP, 2013)
77

Growth and Feeding

Tall stature and long slender All individuals with MFS In prepubertal girls with
limbs and digits are cardinal should be measured at the initial excessively tall stature in
features of MFS. evaluation and periodically relationship to bone age, final
The growth spurt occurs at an thereafter during their growth adult height can be reduced by
earlier age in adolescents with period, noting height, arm span initiation of high dose estrogen
to height ratio, and upper to therapy that should be combined
MFS than in unaffected
adolescents (2.4 years earlier for lower body segment ratio. with progesterone to prevent
males and 2.2 years for Dolichostenomelia endometrial hyperplasia.
females). (disproportionately long limbs),
Although requests for growth
The majority of children and in the Ghent criteria, the ratio arrest are not often made for
(upper/lower segment) is
young adults affected with MFS boys, accelerated bone
have a weight below the 50th considered increased if it is maturation can be accomplished
centile and a reduction in the greater than 1.05.
by treatment with testosterone.
amount of subcutaneous fat, as
well as muscular hypoplasia.

Cognitive development is Developmental milestone Physical therapy- Psychosocial
unaffected in MFS. achievement should be assessed counseling is important for
at each routine childhood family.
Motor development may be medical visit.
somewhat delayed by joint
hyperextensibility. If significant delays in cognitive
development occur, this is likely
The psychosocial impact of because of an unrelated cause
having a disorder that includes and should be evaluated as in the
increased risk for aortic general population.
complications and death is a
significant one.
78
Musculoskeletal

Although skeletal abnormalities Careful clinical evaluation for Physical therapy and orthopedic
may not be pronounced in the the above mentioned features. braces, as needed.
first few years of life, they are On clinical suspicion, kyphosis The treatment of scoliosis and
the key to early diagnosis. Tall and scoliosis should be kyphosis depends on the
stature with disproportionately evaluated by radiography to severity of the curvature and rate
long limbs, long narrow digits, a determine the degree of spinal of progression over time.
long and narrow face with deep curvature. Referral to an
set eyes, and a high, narrow Pediatric orthopedists will often
orthopedist for evaluation is
palate are often combined with treat even minor spinal
appropriate.
joint hypermobility, pectus curvatures with a brace to
deformities and scoliosis. prevent progression. In the most
seriously affected individuals
Dural ectasia is usually with curvatures exceeding 40°,
asymptomatic, but can also be spinal arthrodesis may be
associated with back pain. warranted to stop further
Joint laxity can be pronounced deformity, reduce back pain,
in young children and may lead and prevent a reduction in lung
to delayed gross motor function.
development. Joint dislocations Criteria for spinal surgery would
are rare occurrences. Joint
be the same as for individuals
hyperextensibility lessens with without MFS.
increasing age.
Pectus excavatum or carinatum
Mild contractures of elbows, need be repaired only in severe
knees, or toes may be present. cases to prevent cardiac or
Over time, pes planus and laxity pulmonary compromise, and
of ligaments and joints can lead preferably after growth has been
to painful joints and feet. completed. Surgical correction
Crowding of the teeth and of the pectus deformity before
malocclusion commonly occur elective cardiovascular surgery
because of narrow maxilla and is often recommended.
mandible. Pes planus may be treated with
Protrusio acetabuli. arch support. Surgical treatment
of foot deformities is rarely
successful.
79
Cardiovascular

Potentially life threatening and Cardiology evaluation is β Adrenergic blockade has been the
standard of care, it can help to prevent
must be monitored closely. recommended in every complications. Given the known side
Mitral valve prolapse and mitral individual suspected of having effects of β blockers, the decision to
regurgitation are the most MFS. treat children needs to be considered
carefully and on an individual basis.
common. Echocardiographic examination
When β blockers are contraindicated,
is the method of choice to
Dilatation of the ascending aorta the ACE inhibitor enalapril is effective
establish baseline aortic root in improving aortic distensibility and
increases with age. It is the most
dimensions and to assess mitral reducing aortic stiffness as well as in
common indication for reducing the increase in aortic root
valve prolapse or regurgitation.
cardiovascular surgery in dimension, than β blockers, which had
childhood, followed by mitral Progression of aortic root no effect on these parameters.
regurgitation. Aortic root diameter, diminished aortic wall Losartan inhibits the angiotensin II
dilatation generally progresses compliance, development of type 1 receptor and has been proposed
over a period of years. mitral and aortic valve as a new treatment for MFS.
regurgitation, and subacute Composite graft replacement may be
Secondary aortic regurgitation is necessary in childhood. Aortic root
dissection should be monitored
a common feature and adds to replacement surgery at an aortic
on a regular basis throughout
the hemodynamic stress. The diameter of >5.0 cm, or if the rate of
life. increase of the aortic root diameter
root of the pulmonary artery can
approaches 0.5–1.0 cm per year.
also be enlarged. The Annual cardiology evaluations Standard composite graft includes a
cardiovascular manifestations of are appropriate in most cases, mechanical valve that requires long
MFS are the major causes of but more frequent evaluations term anticoagulation therapy
premature death: mitral valve may be advisable if Valve sparing aortic root replacement
regurgitation with congestive disproportionate increases in are now considered an acceptable
alternative for individuals who do not
heart failure in severely affected aortic root size or changes in want anticoagulation, such as women
children, aortic aneurysm valvular function. of childbearing age. Valve sparing
rupture and dissection in adults. surgery is contraindicated in
individuals with severe aortic
insufficiency and abnormal aortic
valves.
Mitral valve repair may be needed
during childhood.
Physical activity supports motor
development and increases muscle
strength, but contact sports such as
football, basketball, hockey,
volleyball, boxing, and wrestling
should be avoided.
Heavy lifting and other isometric
exercise should also be avoided
because of the acute increase of
pressure on the ascending aorta. In
addition, sudden stops and prompt
changes in direction should be
avoided.
Non‐competitive aerobic activity such
as swimming, bicycling, hiking,
golfing, and general physical
conditioning are encouraged.
80
Ophthalmologic

The most characteristic ocular Annual eye examination. Visual Corrective lenses. Aphakic
manifestation of MFS is ectopia acuity, refraction, signs of correction may be needed in
lentis in 50–80% , usually cataract and glaucoma, cases of severely dislocated
bilateral and typically strabismus and fundoscopic lenses.
superotemporal. findings must be assessed at Amblyopia must be treated
Myopia, cataracts and open diagnosis and annually aggressively in a standard
thereafter in addition to slit lamp
angle glaucoma. fashion.
examination.
Retinal detachment is a leading The so called “presenile”
cause of visual loss in MFS. cataract of MFS is an indication
Retinal detachment is related to for lens extraction.
elongation of the globe and If symptoms and signs of a
frequently even occurs in retinal detachment as flashes,
younger individuals. Retinal floaters, visual field changes, or
detachment has an increased a “curtain or shadow” over their
incidence after intraocular visual field, they should see a
surgery. retinal specialist immediately.
Strabismus because ectopia
lentis as well as mechanical and
craniofacial factors contribute to
its development Exotropia
(outward deviation) is the most
common type of strabismus in
MFS.
The prognosis of ocular
involvement in MFS is excellent
with appropriate evaluations and
treatment.
81
Neurologic
Dural ectasia can result in low back Dural ectasia can be evaluated only Orthostatic headache resulting
pain or in leakage of spinal fluid by MRI or CT scan. from cerebrospinal fluid leakage is
and intractable orthostatic often transient. Treatment with bed
headaches when the tear does not rest, hydration, analgesics, and
heal spontaneously. These caffeine may be sufficient in most
symptoms are usually transient and cases, because the intracranial
benign. hypotension will subside in the
recumbent position. If leakage of
the spinal fluid persists, however,
treatment with corticosteroids or
epidural blood patches can be
effective.
Neurosurgical repair may be
considered with recurring or severe
complaints, if the location of the
leak can be identified and the area
can be approached with low risk.
Respiratory
Apical blebs and lung bullae that The medical history regarding There is no need to treat an apical
predispose to spontaneous manifestations in the respiratory bleb unless there is rupture.
pneumothorax. system should be explored at each
Spontaneous pneumothorax is
evaluation.
Present with acute dyspnea and treated by evacuation of the
chest pain because of intrapleural Apical blebs can be observed on intrapleural air and restoration of
air accumulation. Chest chest radiography, but do not the negative pleural pressure by
radiography is generally require special evaluation because insertion of a drainage chest tube.
conclusive. their presence is inconsequential
In individuals with MFS, there is an
unless their thin wall ruptures,
Pulmonary emphysema is a feature increased risk for repeated rupture
leading to spontaneous
of neonatal MFS. of an apical bleb. Therefore,
pneumothorax.
pleurodesis is recommended after
recurring pneumothorax.
Dermatologic
Inguinal as well as incisional The presence or absence of For striae, neither prevention nor
hernias and stretch marks. inguinal or femoral hernias should effective treatment is available.
be assessed at the first examination
The skin may be soft and thin in Hernias should be treated as in the
and throughout childhood because
appearance. When stretch marks general population. Prognosis after
they may be congenital and often
develop during the adolescent surgical hernia repair is good,
recur.
growth spurt, they are often although the underlying connective
distinctly pink. they develop on the Hernias manifest in at least 50% of tissue defect may lead to
shoulders, axilla, chest, lower back, affected individuals. recurrence.
hips, thighs, and dorsum of the
knee.
82
Pregnancy

Women with MFS have an To achieve a favorable outcome, If aortic root replacement surgery
increased risk of cardiovascular it is preferable to start becomes necessary before
complications during gestation cardiovascular evaluation and pregnancy, valve sparing
and labor. stabilization before pregnancy. procedures should be carried out, if
feasible, to eliminate the need for
The preconceptional aortic root anticoagulants that have adverse
diameter is the single most effects on the fetus.
important parameter that During pregnancy, the woman
determines the degree of safety should be monitored by a high risk
of undergoing pregnancy. obstetrician, and echocardiography
Serial echocardiography is should be performed every two to
three months.
highly recommended because of
the possibility of accelerating In pregnant women, β blocker
aortic root dilatation and aortic therapy can have adverse effects on
dissection, and every pregnancy the fetus, such as IUGR, and on the
should be treated as a high‐risk mother, such as hypoglycemia,
bradycardia, and apnea.
event.
Professional guidelines
recommend use of labetalol or
metoprolol, rather than atenolol
because of adverse fetal effects.
Pregnancy induced hypertension
poses an additional risk factor for
aortic dissection and must be
treated aggressively. Anti-
hypertensive medications such as
methyldopa, hydralazine and
labetalol have a good safety profile.
ACE inhibitors and angiotensin
receptor blockers (e.g. losartan)
have adverse effects on the fetus
and should be avoided, while
calcium channel blockers may be
dangerous in MFS.
The method of delivery should be
individualized. Overall, vaginal
delivery with epidural anesthesia is
preferred over cesarean section
except for women with obstetric
complications or with progressive
aortic dilatation (aortic diameter
>45 mm) and a very high risk of
dissection.
83
References
▪ Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB,
Hilhorst‐Hofstee Y, Jondeau G, Faivre L, Milewicz DM, et al (2010) The revised Ghent
nosology for the Marfan syndrome. J Med Genet 47:476–485.
▪ Tinkle, B. T., Saal, H. M., & Committee on genetics (2013). Health supervision for
children with Marfan syndrome. Pediatrics, 132(4), e1059–e1072.
▪ https://doi.org/10.1542/peds.2013-206.

Blackwell.
84

➢ When to suspect Inborn Errors of Metabolism (IEM)?

Maternal and Prenatal History
✓ Abortions after 3 months of pregnancy
✓ Prolonged hyperemesis
✓ Acute fatty liver of pregnancy
✓ Increased fetal movements (Seizures in utero)
Obstetric History
✓ Prolonged hyperemesis in pregnancy, acute fatty liver, hepatomegaly,
elevated liver enzymes with low platelets may indicate Fat Oxidation
disorders. Increased fetal movements or rhythmic movements (? Seizures in
utero).
Neonatal History
✓ Normal healthy neonate at birth
✓ Lethargy
✓ Poor feeding
✓ Vomiting
✓ Seizures
Later Presentations
✓ Growth delay
✓ Developmental delay
✓ Neuromuscular symptoms, such as seizures, muscle weakness, hypotonia,
myoclonus, muscle pain, strokes, or coma.
✓ Congenital brain malformation
✓ Autonomic symptoms
✓ Nonphysiologic jaundice
✓ Unusual odors in body fluids
✓ Change in urine color
✓ Organomegaly
✓ Eye changes
85
Initial Testing
✓ Glucose
✓ Electrolytes with calculation of anion gap
✓ Complete blood count and peripheral smear
✓ Liver enzyme tests
✓ Ammonia levels and lactate
✓ Serum amino acid levels
✓ Urinalysis
✓ Urine organic acids
✓ VLCFAs
• Electrolyte measurement detects metabolic acidosis and presence or absence of
an anion gap; metabolic acidosis may need to be corroborated by arterial blood gas
measurement. Non-anion gap acidosis occurs in inherited disorders of metabolism
that cause renal tubular damage (eg, galactosemia, tyrosinemia type I).
• Anion gap acidosis occurs in inherited disorders of metabolism in which
accumulation of titratable acids is typical, such as methylmalonic
acidemia and propionic acidemia; it can also be caused by lactic acidosis (eg, in
pyruvate decarboxylase deficiency or mitochondrial oxidative phosphorylation
defects).
• When the anion gap is elevated, lactate and pyruvate levels should be obtained. An
increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation
defects from disorders of pyruvate metabolism, in which the lactate:pyruvate ratio
remains normal.
• Liver tests detect hepatocellular damage, dysfunction, or both (eg, in untreated
galactosemia, hereditary fructose intolerance, or tyrosinemia type I).
• Ammonia levels are elevated in urea cycle defects, organic acidemias, and fatty acid
oxidation defects.
• Urinalysis detects ketonuria (present in some GSDs and many organic acidemias);
absence of ketones in the presence of hypoglycemia with or without acidosis
suggests a fatty acid oxidation defect or hyperinsulinism.
Specific and Confirmatory Testing

✓ Plasma or urine Chromatography
✓ Tandem mass spectrometry (TMS)
✓ Quantitative plasma amino acid tests
✓ Urine organic acid tests should include a urine acylglycine profile.
Confirmatory Testing
✓ Organ biopsy
✓ Enzyme studies
✓ Gene sequencing
86
Early Main Diagnostic and Differentiating Clinical Features

Storage Diseases
According to type of material
✓ Lipidosis
✓ Mucopolysaccharidosis
✓ Mucolipidoses
✓ Glycogen Storage
According to Site of Storage
✓ Lysosomal
✓ Peroxisomal
Lysosomal Storage Diseases

1. Lipidosis
2. Mucopolysaccharidosis
3. Mucolipidoses
4. Glycogen Storage Diseases (Type 2)
Peroxisomal Storage Diseases

Disorders 0f Peroxisomal
1. Enzyme Import
2. Single Enzyme
Lipidosis
Gray Matter (Starting with convulsions)
✓ GM1, GM2, GM3
White Matter (Long tract affection i.e. loss of acquired milestones)

✓ Metachromatic leukodystrophy
✓ Krabbe
✓ Farber
✓ Gaucher
✓ Niemann Pick
✓ Fabry
87
 Gray Matter
Gangliosidosis (GM3)
✓ Macroglossia (DD with Beckwith-Wiedemann Syndrome)
Gangliosidosis (GM1)
✓ Facial dysmorphism
Gangliosidosis (GM2) Cherry red macula in absence of macroglossia

and facial dysmorphism
✓ Sandhoff → Visceromegaly
✓ Tay Sachs → No Visceromegaly
 White Matter
Metachromatic leukodystrophy
✓ Loss of motor skills and sensations
✓ Loss of intellectual skills
✓ Stiffness; rigidity and paralysis
✓ Cerebellar ataxia
✓ Blindness and hearing loss
✓ Seizures; emotional and behavioral problems
❖ Types:
➢ Late infantile form: The most common form, starting around 2 years of
age or younger. Progressive loss of speech and muscle function rapidly.
➢ Juvenile form: The second most common for and starts between 3 and
16 years of age. Behavior and cognitive problems are the early signs.
Loss of ability to walk may occur.
➢ Adult form: Less common and starts after 16 years of age. Behavior
and psychiatric problems progress slowly. Psychotic symptoms such as
delusions and hallucinations may occur.
Krabbe
✓ Optic atrophy
Farber
✓ Subcutaneous granulomas
Gaucher
✓ Visceromegaly
Niemann Pick
✓ Visceromegaly
Fabry
✓ Adult onset; Cutaneous angiectasis; Renal and cardiac disease
88
Mucopolysacchridosis (MPS)
✓ Visceromegaly
✓ Dysostosis Multiplex
✓ Facial Dysmorphism
✓ Corneal Clouding
✓ Intellectual Disability (Id)
❖ Types:
➢ Type I: Hurler, Scheie, Hurler Scheie
➢ Type II: Hunter (XR and AR)
➢ Type III: Sanfilippo (A; B; C; and D)
➢ Type IV: Morquio (A and B)
➢ Type V: (no longer used) formerly Scheie
➢ Type VI: Maroteaux-Lamy
➢ Type VII: Sly (highly variable + dense inclusions in granulocytes)
 Hurler
✓ Visceromegaly
✓ Dysostosis multiplex
✓ Corneal clouding
 Hunter
✓ Visceromegaly
✓ Clear Cornea with retinal degeneration
 Scheie / Maroteaux-Lamy
✓ Visceromegaly
✓ Normal mentality
 Morquio
✓ Kyphosis or Scoliosis with Knock knees
✓ Normal Mentality
✓ DD: Kniest dysplasia [barrel shaped chest]; Dyggve-Melchior-Clausen
Syndrome [Pectus carinatum with sever lumber lordosis
 Maroteaux-Lamy
✓ Visceromegaly
89
✓ Hyperactivity
Radiological Findings
✓ Tongue like vertebrae (Beaking) mainly thoraco-lumber (DD
Achondroplasia beaking increased from down to up)
✓ Spatulated ribs
✓ Piprone shaped metacarpals
✓ Flared iliac bones
✓ Shallow acetabulum
✓ J. Shaped sella (type I and VII)
✓ Ovoid vertebral bodies (type III)
✓ Sever beaking of vertebrae (type IV)
✓ Aortic regurgitation (type IS and IV)
Laboratory Enzymes (Sulphatasis)

✓ Heparan sulphate (Increased in cases with ID)
✓ Dermatan sulphate
✓ Keratan sulphate
✓ Chondroitin sulphate
Enzyme Replacement Therapy (does not treat but stop progress; must
continue for life; if stopped rapid deterioration well happened rapidly;
expensive)
✓ Aldurazyme for Hurler and Hurler-Scheie form of MPS
✓ Elaprase for Hunter syndrome
✓ Vimizim for Mosque syndrome type A
✓ Naglazyme for Maroteaux-Lamy syndrome
Clinical Approach
✓ Lipidosis (neurological)
✓ Mps (visceral and skeletal)
✓ Mucolipidosis (visceral; skeletal; and neurological)
Mucolipidosis
✓ Type I
✓ Type II
✓ Type III
✓ Type IV
Type I:
✓ Life expectancy to adolescence
✓ Hypotonia; Macular red spot
90
Type III
✓ Life expectancy to adolescence
✓ Joint stiffness
Type II (I Cell)
✓ Early onset; early death
✓ Severe form; clear cornea
Type IV
✓ Early onset; early death
✓ Mild form; corneal opacities
Glycogen Storage Disease (GSD)

❖ All are hepatic presentation except Types II; V; VII
✓ Type II: Cardiac muscle affection
✓ Type V; VII: Skeletal muscle affection
❖ All are normal mentality except Type VIII
❖ All are autosomal recessive (AR) except IX (AR and XR)
❖ All are with no rachitic manifestations except Type XI
❖ All are with mild clinical presentation except Types IV and VIII are fatal in
childhood
❖ Types with mild clinical presentation (I; III; VI; IX and X)
❖ Type I; III; VI
✓ Hepatomegaly
✓ Hypoglycemia
✓ Hyperlipidemia
✓ Acidosis
“But Improve with Adolescence”
❖ Type IX; X: clinically benign, with only hepatomegaly and improve with
time
91
Peroxisomal Diseases
Type of Storage Diseases
1) Enzyme Import (Clinical approach)
a. Zellweger Syndrome
✓ Cerebro Hepato Renal manifestations (mainly)
✓ Hypotonia
✓ Stippled epiphysis
b. Rhizomelic Chondrodysplasia punctata
✓ Short limbed short stature
✓ Stippled epiphysis
c. Neonatal adrenoleukodystrophy
✓ Adrenal insufficiency
✓ Cerebral demyelination
d. Infantile Refsum
✓ Retinal pigmentation
✓ Deafness
✓ Ataxia
✓ Phytanic acid in urine is high
2) Single Enzyme (Clinical and Laboratory approach)
✓ X-linked adrenoleukodystrophy
✓ Acyl CoA oxidase deficiency
✓ Bifunctional enzyme deficiency
✓ Peroxisomal thiolase deficiency
✓ Classic Refsum disease
✓ 2-Methylacyl CoA racemase deficiency
✓ DHAP acyltransferase deficiency
✓ Alkyl-DHAP synthase deficiency
✓ Glutaric aciduria type III
✓ Hyperoxaluria type I
✓ Mevalonic aciduria
✓ Acatalasemia
Clinical and Laboratory approach well include

1) VLCFAS
2) EMS (Extended Metabolic Screen)
3) PH with Ammonia
4) PH with Anion Gap
5) Others:
a. Ketosis
b. Lactic acidosis
c. Hypoglycemia
92
VLCFAs (Very Long Chain Fatty Acids)

1) Defects of single peroxisomal enzyme
✓ X-linked adrenoleukodystrophy
✓ Classic Refsum disease
✓ Glutaric aciduria type III
✓ Hyperoxaluria type I
✓ Mevalonic aciduria
2) Defects of single peroxisomal enzyme

✓ Acyl CoA oxidase deficiency
✓ Bifunctional enzyme deficiency
✓ Peroxisomal thiolase deficiency
✓ 2-Methylacyl CoA racemase deficiency
✓ DHAP acyltransferase deficiency
✓ Alkyl-DHAP synthase deficiency
✓ Acatalasemia
93
1) Defects of single peroxisomal enzyme:
a. X-linked adrenoleukodystrophy: late onset

i.Adrenal insufficiency
ii.Cerebral demyelination
b. Classic Adult Refsum: late onset
i. Retinal pigmentation
ii. Deafness
iii. Ataxia
iv. Increased phytanic acid in urine
c. Glutaric aciduria type III
i. No specific phenotype
ii. Symptoms vary
iii. Some individuals remain symptoms free
iv. Defective breakdown of lysine; hydroxy-lysine and tryptophan
d. DD with Glutaric acidemia II: not peroxisomal
Onset
i. Infancy and early childhood
ii. Adulthood: muscle weakness may be the first sign
Clinical
i. Sudden metabolic crisis (Acidosis with Hypoglycemia)
ii. Life threatening that may be triggered by common childhood illnesses and other stresses
e. Hyperoxaluria type I
i. Early Diagnosis is Macrocephaly at birth
ii. Accumulated oxalate combined with Ca and is deposited in the kidneys and urinary tract →
Stones
iii. Inability to break down LYSINE; HYDROXYLYSINE and TRYPTOPHAN due to
defective mitochondrial enzyme
iv. Treatment through low Lysine diet and oral Carnitine
f. DD with Glutaric acidemia I
i. Macrocephaly at birth; Autosomal recessive
ii. Bleeding in Brain (Basal ganglia); Eyes (Retinal)
iii. Inability to break down LYSINE; HYDROXYLYSINE and TRYPTOPHAN, thus decrease
energy production
iv. Treatment through low Protein diet (especially Lysine and Tryptophan) and oral Carnitine
g. Mevalonic aciduria
i. Recurrent episodes of fever during infancy
ii. Defective cholesterol biosynthesis
iii. Skin rashes
iv. Arthralgia
v. Psychomotor retardation
vi. Cerebellar ataxia
vii. Hepatosplenomegaly
viii. Lymphadenopathy
ix. Short stature
94
EMS (Extended Metabolic Screen approach)

Selected Inborn Errors of Amino Acid Metabolism
 Cystinosis: Growth failure with Rachitic manifestations and Renal colic (stones) →
renal failure
 Histidinemia: Impaired speech
 Homocystinuria: Tall stature; Lens dislocation (Downward and nasal) and ID (DD
with Marfan)
 Hartnup Disease: Skin rash; cerebellar ataxia with pyramidal tract affection
 Blue Diaper Syndrome: Hypercalcemia with nephrocalcinosis
 Alkaptonuria: Black (urine and cartilage); Blue (ears; nose; sclera and cheeks);
Arthritis.
 Tyrosinemia: Affected liver functions; Hepatic cirrhosis (late) and
Hypophosphatemic rickets
 Phenylketonuria (PKU): Diagnosed in National Screening Program
Late Clinical Manifestations
✓ Severe brain damage with ID
✓ Seizures
✓ Spasticity
Variants
✓ PKU
✓ BH4 sensitive PKU
✓ Mild hyperphenylalalaninaemia < 900
Diagnosis
✓ Increased Phenylalanine (EMS is an accurate diagnosis)
✓ Decreased Tyrosine
✓ More than 900 mutations
DD
✓ BH4 cofactor deficiency
Management
✓ PKU: requires diet restriction (differences in disease severity /
phenylalanine tolerance)
✓ BH4 sensitive PKU: requires (BH4 supplementation) well reduce
phenylalanine levels in many patients with mild PKU due to
enhancement of residual activity
✓ Mild hyperphenylalalaninaemia does not require diet therapy
95
Clinical + EMS + PH + Ammonia

Hyperammonemia
It is an emergency situation needs to be treated immediately to prevent
irreversible neurological damage.
After exclusion of sepsis, ammonia should be measured in all neonates with
lethargy, encephalopathy and coma.
• Ammonia level is more than 100 μmol/l in absence of clear cause requires
investigations and treatment sodium benzoate and sodium phenylbutyrate.
• Ammonia level more than 300 μmol/l and failing to respond to sodium benzoate
and sodium phenylbutyrate, we should move to urgent dialysis and (Trial for
treatment by carbamyl phosphate synthetase).
• But if more than 1000 μmol/l, urgent dialysis and deferential diagnosis (Urea Cycle
Defects [UCDs], Organic Acidemia [OAs], Fat Acid Oxidation defects [FAOs],
Liver failure/impairment), for specific treatment of each disorder.
PH
Levels well differentiate (Respiratory alkalosis → UCDs; Metabolic
acidosis → OAs, FAOs and liver failure)
PH → Respiratory alkalosis
 Urea Cycle defects (UCDs)

• UCDs present mainly with high ammonia levels (more than 1000 μmol/L),
respiratory alkalosis, and increased liver functions (transaminases). Amino acid
in plasma (decreased arginine), Amino acid in urine (increased arginine).
• Amino acid (AA) in plasma with increased glutamine and decreased arginine
indicates either Citrullinemia or Argininemia.
• Amino acid in urine with increased arginine indicates Argininosuccinic
aciduria.
• CPS (Carbamyl Phosphatase Synthetase deficiency):
✓ CPS are 2 types, one AR and other mitochondrial inheritance. Show elevated
plasma ornithine and glutamine, decreased citrulline and arginine with normal
urinary orotic acid.
• OTC (Ornithine Transcarbamylase deficiency) (XR) show elevated plasma
ornithine and glutamine, decreased citrulline and arginine with markedly
increased urinary orotic acid.
96
PH → Metabolic acidosis
A. Organic Acidemia (OAs)

Disruption Of Normal Metabolism of Amino Acids Particularly
Valine; Leucine; Isoleucine; Lysine; Hydroxylysine; Tryptophane;
Carbohydrates and Fatty Acids.
1. Valine; Leucine; Isoleucine
✓ Msud
✓ Methylmalonic Acidemia
✓ Methylmalonic Acidemia With Hc
✓ Propionic Acidemia
✓ Isovaleric Acidemia
2. Lysine; Hydroxylysine; Tryptophane
✓ Glutaric Acidemia Type I
✓ Glutaric Acidemia Type Ii
✓ Glutaric Aciduria Type Iii
✓ Hyperoxaluria Type I
3. Tyrosine
✓ Alkaptonuria
4. Defective Cholesterol Biosynthesis (Mevalonic Aciduria)
Laboratory
✓ ⇧ Organic acid in URINE
✓ ⇧ Ketones
✓ ⇧ Lactate
✓ ⇧ Glycine in plasma
✓ Liver function ⇧ Transaminases
B. Fatty Acid Oxidation defects (FAOs)

• Fatty acid oxidation defects presents with high levels of Ammonia
(more than 1000 μmol/L) and Metabolic acidosis. Hypoketotic
hypoglycemia with normal amino acid in plasma and urine.
Increased liver transaminases, lactate and acyl carnitines (TMS).
Defective clotting mechanism.
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Clinical + EMS + PH + Anion Gap

Anion gap (AG)
• Anion gap is a measure of acid base balance
• The body maintains balance by releasing CO2 by the lungs (acid) or by the
kidneys (base)
• Cations are positive (Base)
• Anions are negative (Acid)
• To calculate anion gap = (Na+ + K+) – (HCO3- + Cl-)
• Normal AG in blood (8 – 12 mEq/L with potassium, 12 – 16 mEq/L without
potassium)
• Normal AG in urine (0 – 10 mEq/L)
• Normal AG with metabolic acidosis, is called hyperchloremic acidosis
because the kidneys reabsorb chloride instead of bicarbonate.
High AG with Acidosis

➢ Causes
✓ Keto Acidosis
✓ Lactic acidosis
✓ Renal failure
➢ Signs and symptoms
✓ Nausea and vomiting
✓ Malaise
✓ Cardiac dysfunction (hypotension; shock; arrhythmia)
Normal AG with Metabolic Acidosis

➢ Causes
✓ Renal bicarbonate losses (Renal tubular acidosis → ↑ Urine AA)
✓ GIT (Total Villus Atrophy → Gut biopsy)
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Metabolic Acidosis with High Anion Gap

1. Respiratory Chain Defects
✓ Ketotic hypoglycemia
✓ MRI brain (Basal ganglia and brain stem changes)
✓ Increased CSF Lactate
2. Pyruvate Disorders
✓ Increased Lactate and Pyruvate
✓ Decreased L/P ratio (normal value less than 30)
3. Organic Acidemia
✓ Increased urine organic acids
✓ Increased Ketones
✓ Increased Lactate
✓ Increased Ammonia
“Organic acidemia is due to disruption of normal amino acid metabolism

particularly Valine; Leucine; Isoleucine (MSUD)”
❖ Types:
1. MSUD
2. Methylmalonic Aciduria
3. Methylmalonic Aciduria with Homocystinuria (HC)
4. Glutaric Acidemia Type I
5. Glutaric Acidemia Type II
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Organic Aciduria
Defect in intermediary metabolic oxidation pathways of Amino acids;
Carbohydrates; Fatty acids.
Clinical + Lab. + Others
1. Ketosis
2. Lactic Acidosis
3. Hypoglycemia
 Ketosis in Neonates
❖ Mainly in Organic acidemia (as above)
 Lactic Acidosis
✓ Secondary to tissue hypoxia
✓ Fatty acid oxidation defects
✓ Respiratory chain disorders
✓ Pyruvate Disorders Organic acidemia
✓ Biotinidase deficiency
“Ketosis And Lactic Acidosis in Neonates Mainly in Organic Acidemias”

 Hypoglycaemia
A. Ketotic Hypoglycaemia
✓ Sepsis
✓ Respiratory chain disorders
✓ Hypopituitarism (may be associated with cholestatic jaundice)
✓ Adrenal insufficiency
B. Hypoketotic Hypoglycemia
✓ Fat oxidation defect
✓ Hyperinsulinism
✓ Liver failure
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❖ Arterial Blood Gases (Abg)

“O2 and CO2 within arteries opposed to levels in venous blood Normal PH and
Normal PaCO2 means normal ABG”
Acidosis and Alkalosis (Normal 7.4)

Acidosis
✓ ⇧ Acid Production
✓ ⇩ Bicarbonate
✓ ⇩ Ability of The Kidneys to Excrete Excess Acids
1. Metabolic Acidosis
✓ Gain of anions (-ve Charged) eg. Chloride; Bromide; Sulfate
✓ Loss of cations (+ve Charged) eg. Sodium; Iron; Ammonium
2. Respiratory Acidosis
Lungs cannot remove all of CO2 due to Diseases of:
✓ Airways
✓ Lung tissue
✓ Nerve and muscles that inflate and deflate the lungs
Alkalosis
✓ ⇩ Acid Prodution (Paco2) ⇨ Respiratory Alkalosis
✓ ⇧ Bicarbonate (Hco3) ⇨ Metabolic Alkalosis
✓ The Kidneys Excrete Excess Acids
1. Metabolic Alkalosis
✓ Hypochloremic → Prolonged vomiting
✓ Hypokalemic → Diuretics
✓ Compensated → Acid base balance near normal but bicarbonate and CO2
remain abnormal
2. Respiratory Alkalosis
Low Blood Co2 Due To:
✓ Fever
✓ Lack of O2
✓ Liver disease
✓ Lung diseases with hyperventilation
✓ High altitude
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Acidosis and Alkalosis

✓ ⇩ Ph And ⇩ Paco2 ⇨ Metabolic Acidosis
✓ ⇩ Ph And ⇧ Paco2 ⇨ Respiratory Acidosis
✓ ⇧ Ph And ⇧ Paco2 ⇨ Metabolic Alkalosis (Partial Compensated)
✓ ⇧ Ph And ⇩ Paco2 ⇨ Respiratory Alkalosis (If Mild ⇧ Ph ⇨ Compensated Respiratory
Alkalosis)
Neonatal Seizures
Seizures
• Disruption of the electric communication between neurons in the brain.
Epilepsy
• Condition of the brain causing seizures.
• Someone is said to have epilepsy if two or more unprovoked seizures
separated by 24 hours or one seizure with a high risk for more
DD from Jitteriness:
1. No abnormality of gaze or eye movement
2. Brought out by stimulation
3. Associated with
✓ Hypocalcemia; Hypoglycemia
✓ Infant of diabetic mother
✓ Hypoxic ischemic encephalopathy
4. N.B:
▪ Sodium valproate must be avoided when IEM is suspected causing
severe electrolyte disturbance.
We should suspect
• Biotinidase deficiency → treated with 10mg biotin/daily [VIT H]
• Pyridoxine deficiency → treated with Alpha amino adipic semi aldehyde
+ VIT B6
• Purine Disorders (Purine in urine by dipstick test) (Uric acid; Xanthine;
Hypoxanthine; Adenine; Guanine; Caffeine and Theobromine)
• Sulphite Oxidase deficiency (Molybdenum cofactor deficiency) →
decreased Sulphite (dipstick in fresh urine)
• Peroxisomal Disorders → measurement of VLCFAs
• 3₋phosphoglycerate dehydrogenase deficiency → decreased serine in
CSF
• Non Ketotic Hyperglycinemia (NKH) → increased glycine (CSF /
PLASMA) RATIO > 0.09 → treatment with dextromethorphan and
sodium benzoate
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Management
I- Adequate ventilation and perfusion
II- Correct IEM
✓ 10% Glucose
✓ 10% Calcium Gluconate
✓ Magnesium Sulfate 25 – 250 Mg/Kg/Dose Iv/Im
III- Anticonvulsant therapy
✓ Phenobarbital 20 mg/kg
✓ Lorazepan 0.05 – 0.10 mg/kg IV
✓ Phenytoin 20 mg/kg IV (diluted in 0.9% Saline)
IV- Vitamins and others (improves with no harm if not indicated)
✓ Vitamin B group (Thiamin [Vit. B1]; Riboflavin [Vit. B2]; Pyridoxine
[Vit. B6]; Cobalamin [Vit. B12])
✓ Calcium and Vitamin D
✓ Biotin (Vit H)
✓ Folate
Duration of Treatment
A. Stoppage of Phenobarbital
✓ Neurological Normal; EEG Normal
✓ Neurological Abnormal; EEG Normal
B. No Stoppage
✓ Neurological Abnormal; EEG Abnormal
N.B:
▪ This must be considered before discharge and frequently after discharge on
Phenobarbital.
▪ Stop Phenytoin if IV therapy is stopped.
Sever Hypotonia
✓ NKH (Non Ketotic Hyperglycinemia)
✓ Sulphite Oxidase deficiency
Encephalopathy
✓ MSUD
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Management of IEM
• Stop feeds
• Promote anabolism
A. 10% Dextrose + appropriate electrolyte additives at maintenance rates
B. 5% dextrose for congenital lactic acidosis +/- insulin infusion if hyperglycemia
develops
• Correct electrolyte imbalance (proper hydration and treatment of sepsis)
• Elimination Of Toxic Metabolites
1. Sodium Benzoate → Ammonia
2. Sodium Phenylbutyrate → Ammonia
3. Carnitine → Organic Acids
4. ⇩ Glycine → Nkh
5. Dialysis To Eliminate Ammonia; Organic Acids; Leucine(Msud); Lactate
• Vitamins And Minerals especially with convulsions (B1; B6; B12; Riboflavin);
Calcium; Vit D; Biotin; Folate.
• Transport Of Neonates With Suspected IEM
✓ Airway (Patent)
✓ Breathing (Clinically And With Abg)
✓ Circulation (Bp And Perfusion)
✓ Enviroment (Adjust Incubator And Iv Lines)
✓ Drugs
➢ Sedation
➢ IV antibiotics
➢ IV dextrose +/- insulin (for hypoglycemic babies)
➢ Surfactant as required
➢ Inotropes as required
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Galactosemia
Galactose-1-Phosphate Uridyl Transferase Deficiency (Type I)
• This deficiency causes classic (Type I) galactosemia. Infants become
anorectic and jaundiced within a few days or weeks of consuming breast
milk or lactose-containing formula. Vomiting, hepatomegaly, poor growth,
lethargy, diarrhea, and septicemia (usually E. coli) develop, as does renal
dysfunction (eg, proteinuria, aminoaciduria, Fanconi syndrome), leading
to metabolic acidosis and edema. Hemolytic anemia may also occur.
Galactokinase deficiency (Type II)
• Patients develop cataracts from production of galactitol, which osmotically
damages lens fibers; idiopathic intracranial hypertension (pseudotumor
cerebri) is rare.
Uridine diphosphate galactose 4-epimerase deficiency (Type III)
• There are benign and severe phenotypes.
• Without treatment, children remain short and develop cognitive, speech,
gait, and balance deficits in adolescence; many also have cataracts,
osteomalacia (caused by hypercalciuria), and premature ovarian failure.
➢ Diagnosis
▪ Galactosemia is suggested clinically and supported by elevated galactose
levels and the presence of reducing substances other than glucose (eg,
galactose, galactose 1-phosphate) in the urine; it is confirmed by DNA
analysis or enzyme analysis of red blood cells, hepatic tissue, or both. All
Neonates at risk require routine neonatal screening for galactose-1-
phosphate uridyl transferase deficiency.
➢ Treatment
▪ Elimination of all sources of galactose in the diet, most notably lactose (a
source of galactose), which is present in breast milk, all dairy products,
including milk-based infant formulas, and is a sweetener used in many
foods. A lactose-free diet prevents acute toxicity and reverses some
manifestations (e.g., cataracts) but may not prevent neurocognitive
deficits.
▪ Supplemental calcium and vitamins.
▪ For patients with epimerase deficiency, some galactose intake is critical
to ensure a supply of uridine-5′-diphosphate-galactose (UDP-galactose)
for various metabolic processes.
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Phenylketonuria (PKU)
• The primary cause is deficient phenylalanine hydroxylase activity.
• Untreated PKU has severe intellectual disability. Extreme hyperactivity, gait
disturbance, and psychoses. Children also tend to have a lighter skin, hair, and
eye color than unaffected family members, and some may develop a rash
similar to infantile eczema.
➢ Diagnosis
▪ Is by National Routine Neonatal Screening detecting high
phenylalanine levels. Abnormal results are confirmed by directly
measuring phenylalanine levels (high), plasma tyrosine (low), and BH4
loading test.
▪ Children in families with a positive family history can be diagnosed
prenatally by using direct mutation studies after amniocentesis.
➢ Treatment of PKU
▪ Treatment of phenylketonuria is lifelong dietary phenylalanine restriction.
All natural protein contains about 4% phenylalanine.
▪ Therefore dietary staples include:
✓ Breast milk / low phenylalanine formula according to infant's needs for
protein and energy.
✓ Low-protein natural foods (eg, fruits, vegetables, certain cereals)
✓ Protein hydrolysates treated to remove phenylalanine
✓ Phenylalanine-free elemental amino acid mixtures
✓ Tyrosine supplementation, an essential amino acid in patients with PKU.
✓ Sapropterin "Kuvan" should be given for all patients with phenylalanine
hydroxylase deficiency as a trial to determine its benefit.
N.B:
▪ Frequent monitoring of plasma phenylalanine levels is required; recommended
targets for all children are between 2 mg/dL and 6 mg/dL (120 to 360
micromol/L).
▪ Dietary planning and management need to be initiated in women of
childbearing age before pregnancy to ensure a good outcome for the child.
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Tetrahydrobiopterin
• Phenylalanine can also accumulate if Dihydrobiopterin (BH4) is not
synthesized because of deficiencies of dihydrobiopterin synthase or not
regenerated because of deficiencies of dihydropteridine reductase.
• BH4 deficiency alters synthesis of neurotransmitters, causing neurologic
symptoms independently of phenylalanine accumulation, because BH4 is also
a cofactor for tyrosine hydroxylase, which is involved in the synthesis
of dopamine and serotonin.
➢ Diagnosis
▪ Elevated concentrations of biopterin or neopterin in urine, blood,
cerebrospinal fluid, or all 3.
▪ Genetic testing also can be used.
N.B:
▪ Recognition is important, and the urine biopterin profile should be determined
routinely at initial diagnosis because standard PKU treatment does not prevent
neurologic damage.
➢ Treatment
▪ Goals and approach are the same as those for PKU.
▪ Tetrahydrobiopterin 1 to 15 mg/kg orally 3 times a day.
▪ Levodopa, carbidopa, and 5-OH tryptophan.
▪ Folinic acid 10 to 20 mg orally once a day in cases of dihydropteridine
reductase deficiency.
▪ Sapropterin "Kuvan" begin with 1-5 mg, may increase up to 15 mg
according to the patient response.
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Gaucher Disease (Gaucher's Disease)

• Gaucher’s disease is the most common lysosomal storage disorder.
Type 1
▪ Gaucher’s disease (nonneuronopathic) is most common (90% of all
patients), typically presents with hepatosplenomegaly, pancytopenia, and
destructive bone disease.
Types 2 and 3
▪ Gaucher’s disease (acute and subacute neuronopathic) presents with
strabismus, bulbar signs, progressive cognitive deterioration, and
myoclonic seizures.
➢ Diagnosis
▪ Enzyme analysis.
▪ DNA analysis and mutation analysis to distinguish the deferent types.
▪ WES (NGS) for Prenatal and Carrier detection.
➢ Treatment
▪ Types I and III: Enzyme replacement with glucocerebrosidase; there is no
treatment for type II.
▪ Sometimes miglustat, eliglustat, splenectomy, or stem cell or bone
marrow transplantation
✓ Miglustat (100 mg orally 3 times a day), a glucosylceramide synthase
inhibitor, reduces glucocerebroside concentration (the substrate for
glucocerebrosidase) and is an alternative for patients unable to receive
enzyme replacement.
✓ Eliglustat (84 mg orally once a day or 2 times a day), another
glucosylceramide synthase inhibitor, also reduces glucocerebroside
concentration.
✓ Splenectomy may be helpful for patients with anemia, leukopenia, or
thrombocytopenia or when spleen size causes discomfort. Patients with
anemia may also need blood transfusions.
✓ Bone marrow transplantation or stem cell transplantation provides a
definitive cure but is considered a last resort because of substantial
morbidity and mortality.
N.B:
▪ Patients receiving enzyme replacement require routine hemoglobin and platelet
monitoring, routine assessment of spleen and liver volume by CT or MRI, and
routine assessment of bone disease by skeletal survey, dual-energy x-ray
absorptiometry scanning, or MRI.
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Ornithine Transcarbamylase (OTC) Deficiency

• OTC deficiency is the most common urea cycle disorder. X-linked recessive
(XR).
➢ Clinical features
▪ In males, recurrent vomiting, irritability, lethargy, hyperammonemia,
progressive encephalopathy, spasticity, coma, seizures and death.
▪ Heterozygous females, may present with symptoms such as mild, growth
delay, short stature, notable avoidance of dietary protein and postpartum
hyperammonemia.
➢ Diagnosis
▪ Serum and Urinary amino acid profiles (Thin layer chromatography),
elevated ornithine and glutamine, decreased citrulline and arginine with
markedly increased orotate.
▪ TMS
▪ DNA analysis (confirmatory)
▪ WES (NGS) for Prenatal and Carrier detection in females.
➢ Treatment
▪ Dietary protein restriction
▪ Arginine or citrulline supplementation
▪ Sodium benzoate, sodium phenylacetate
▪ Liver transplantation (curative)
▪ Hemodialysis for emergent hyperammonemia
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Methylmalonic Acidemia (Mma)

• This disorder is caused by deficiency of methylmalonyl CoA mutase, which
converts methylmalonyl CoA (a product of the propionyl CoA carboxylation)
into succinyl CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a
cofactor; its deficiency also may cause methylmalonic acidemia.
➢ Clinical features
▪ Hypotonia, vomiting, lethargy, coma, ketoacidosis, hypoglycemia,
hyperammonemia, bone marrow suppression, growth delay, intellectual
disability, and physical disability
➢ Diagnosis:
▪ TMS show elevated plasma glycine
▪ Urinary organic acid for increased urine methylmalonate, 3-
hydroxypropionate, methylcitrate, and tiglylglycine
▪ DNA analysis and mutation analysis to distinguish the deferent types.
▪ WES (NGS) for Prenatal and Carrier detection.
➢ Treatment
▪ During acute episodes, high-dose glucose, aggressive fluid resuscitation,
and protein restriction
▪ Close monitoring for stroke, renal failure, and acute pancreatitis
▪ For extreme hyperammonemia, may need hemodialysis or peritoneal
dialysis
▪ For long-term management, controlled intake of threonine, valine,
isoleucine, and methionine; carnitine supplementation; vitamin B12 for
patients with mut- type
▪ Intermittent courses of antibiotics considered for reduction of propionic
acid load from intestinal bacteria
▪ Emergency plan for acute illness, which may provoke a metabolic crisis
110
Medium-Chain Acyl-Coa Dehydrogenase Deficiency (MCADD)

• This deficiency is the most common defect in the beta-oxidation cycle.
➢ Clinical features:
▪ Episodic hypoketotic hypoglycemia after fasting, vomiting,
hepatomegaly, lethargy, coma, acidosis, sudden infant death syndrome,
Reye-like syndrome.
▪ During attacks, patients have hypoglycemia, hyperammonemia, and
unexpectedly low urinary and serum ketones.
▪ Metabolic acidosis is often present but may be a late manifestation.
➢ Diagnosis:
▪ TMS show elevated saturated and unsaturated C8–C10 acylcarnitine
esters
▪ Elevated urinary C6–C10 dicarboxylic acids, suberylglycine, and
hexanoylglycine; low free carnitine
▪ DNA testing can confirm most cases.
➢ Treatment
▪ Of acute attacks is with 10% dextrose iv at 1.5 times the fluid maintenance
rate; also advocate carnitine during acute episodes.
➢ Prevention
▪ Is a low-fat, high-carbohydrate diet and avoidance of prolonged fasting.
Cornstarch therapy is often used to provide a margin of safety during
overnight fasting.
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➢ When to suspect Inborn Errors of Metabolism (IEM)?

Maternal and Prenatal History
✓ Abortions after 3 months of pregnancy
✓ Prolonged hyperemesis
✓ Acute fatty liver of pregnancy
✓ Increased fetal movements (Seizures in utero)
Neonatal History
✓ Normal healthy neonate at birth
✓ Lethargy
✓ Poor feeding
✓ Vomiting
✓ Seizures
Later Presentations
✓ Growth delay
✓ Developmental delay
✓ Neuromuscular symptoms, such as seizures, muscle weakness, hypotonia,
myoclonus, muscle pain, strokes, or coma.
✓ Congenital brain malformation
✓ Autonomic symptoms
✓ Nonphysiologic jaundice
✓ Unusual odors in body fluids
✓ Change in urine color
✓ Organomegaly
✓ Eye changes
Initial Testing
✓ Glucose
✓ Electrolytes with calculation of anion gap
✓ Complete blood count and peripheral smear
✓ Liver tests
✓ Ammonia levels
✓ Serum amino acid levels
✓ Urinalysis
✓ Urine organic acids
112
• Electrolyte measurement detects metabolic acidosis and presence or

absence of an anion gap; metabolic acidosis may need to be corroborated
by arterial blood gas measurement. Non-anion gap acidosis occurs in
inherited disorders of metabolism that cause renal tubular damage
(eg, galactosemia, tyrosinemia type I). Anion gap acidosis occurs in
inherited disorders of metabolism in which accumulation of titratable acids
is typical, such as methylmalonic acidemia and propionic acidemia; it can
also be caused by lactic acidosis (eg, in pyruvate decarboxylase deficiency
or mitochondrial oxidative phosphorylation defects). When the anion gap
is elevated, lactate and pyruvate levels should be obtained. An increase in
the lactate:pyruvate ratio distinguishes oxidative phosphorylation defects
from disorders of pyruvate metabolism, in which the lactate:pyruvate ratio
remains normal.
• Liver tests detect hepatocellular damage, dysfunction, or both (eg, in
untreated galactosemia, hereditary fructose intolerance, or tyrosinemia
type I).
• Ammonia levels are elevated in urea cycle defects, organic acidemias, and
fatty acid oxidation defects.
• Urinalysis detects ketonuria (present in some GSDs and many organic
acidemias); absence of ketones in the presence of hypoglycemia with or
without acidosis suggests a fatty acid oxidation defect or hyperinsulinism.
Clinical Calculator
Anion Gap
113
Specific And Confirmatory Testing

✓ Tandem mass spectrometry (TMS) and chromatography
✓ Quantitative plasma amino acid tests
✓ Urine organic acid tests should include a urine acylglycine profile.
Confirmatory Testing
✓ Organ biopsy
✓ Enzyme studies
✓ Gene sequencing
Mitochondrial Oxidative Phosphorylation Disorders
Impairment of oxidative phosphorylation often, but not always,

causes lactic acidosis, particularly affecting the central nervous system, retina,
and muscle.
The most common clinical manifestations are:
✓ Seizures
✓ Hypotonia
✓ Ophthalmoplegia
✓ Strokelike episodes
✓ Muscle weakness
✓ Severe constipation
✓ Cardiomyopathy
Pearls & Pitfalls

• Increase in the lactate:pyruvate ratio distinguishes oxidative phosphorylation
defects from other genetic causes of lactic acidosis.
Leber Hereditary Optic Neuropathy (LHON)

• LHON is characterized by acute or subacute bilateral central vision loss caused by
retinal degeneration.
• Onset usually occurs in the patient’s 20s or 30s but can occur from childhood to
adulthood.
• Male:female ratio is 4:1.
• Many mitochondrial DNA mutations have been defined, but 3 common ones
account for 90% of cases.
• LHON pedigrees usually show a pattern of maternal inheritance typical of
mitochondrial disorders that involve mutations of mtDNA.
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Mitochondrial Encephalomyopathy, Lactic Acidosis, and Strokelike Episodes

(MELAS)
• Mutations in the mitochondrial tRNAleu gene cause this progressive
neurodegenerative disease characterized by repeated episodes of “chemical
(metabolic) strokes,” myopathy, and lactic acidosis.
• In many cases, cells contain both wild-type and mutant mitochondrial DNA
(heteroplasmy); thus, expression is variable.
Myoclonic Epilepsy with Ragged-Red Fibers (MERRF)

• This progressive disorder is characterized by uncontrolled muscle contractions
(myoclonic seizures), dementia, ataxia, and myopathy, which shows ragged-red
fibers (indicating mitochondrial proliferation) with specialized stains when
biopsied.
• Mutations are in the mitochondrial tRNAlys gene. Heteroplasmy is common; thus,
expression is variable.
Kearns-Sayre Syndrome and Chronic Progressive External Ophthalmoplegia

(CPEO)
• These disorders are characterized by ophthalmoplegia, ptosis, atypical retinitis
pigmentosa, ragged-red fiber myopathy, ataxia, deafness, and cardiomyopathy
typically occurring before age 20 years.
• Kearns-Sayre syndrome is caused by a large contiguous deletion in mtDNA that
results in the loss of genes important for mitochondrial protein formation and
oxidative phosphorylation.
• CPEO can result from mutations in one of several different nuclear genes that are
critical for the production and maintenance of mtDNA and result in the deletion of
large segments of mtDNA in muscle cells. Less common causes involve point
mutations in mtDNA genes that provide instructions for making molecules called
transfer RNAs.
115
Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP)

• NARP is a progressive condition characterized by sensory neuropathy (with
numbness, tingling or pain in the extremities), muscle weakness, ataxia, vision loss
caused by retinal deterioration (retinitis pigmentosa), cognitive decline, seizures,
hearing loss, and cardiac conduction defects. The disorder can begin in childhood
or early adulthood.
• NARP results from mutations in the ATP6 gene contained in mtDNA. ATP6
mutations alter the structure or function of adenosine triphosphate (ATP) synthase,
reducing the ability of mitochondria to make ATP.
Leigh Disease (Subacute Necrotizing Encephalopathy)

• Leigh disease is a severe neurologic disorder that usually manifests in the first year
of life. It is characterized by progressive swallowing problems, poor weight gain,
hypotonia, weakness, ataxia, ophthalmoplegia, nystagmus, and optic atrophy along
with lactic acidosis. Patients typically die within 2 to 3 years, usually due to
respiratory failure.
• Imaging studies show degenerative lesions in the basal ganglia, cerebellum, and
brain stem.
• Leigh disease results from mutations in one of more than 75 different nuclear or
mtDNA genes involved in energy production in mitochondria.
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

• MNGIE is a very rare disorder characterized by degeneration of the muscles of the
gastrointestinal (GI) tract, leading to poor motility of the GI tract and causing
numerous GI symptoms. Additionally, weakness of the eye muscles as well as loss
of sensation and weakness of the extremities due to degeneration of the peripheral
nerves also occur. Onset is variable but usually before 20 years of age.
• MNGIE is caused by mutations in the TYMP gene, which encodes thymidine
phosphorylase with secondary changes in mtDNA. Inheritance is autosomal
recessive; males and females are equally affected.
• Treatment is focused on management of symptoms. Long-term prognosis is poor,
with mean age of death in the late 30s.
116
Peroxisomal Disorders
There are 2 types of peroxisomal disorders:
✓ Those with defective peroxisome formation
✓ Those with defects in single peroxisomal enzymes
X-Linked Adrenoleukodystrophy
• Is the most common peroxisomal disorder (incidence 1/17,000 births); all others
are autosomal recessive, with a combined incidence of about 1/50,000 births.
Peroxisome Biogenesis and Very Long-Chain Fatty Acid Metabolism Disorders
117
118
Zellweger Syndrome (ZS), Neonatal Adrenoleukodystrophy, and Infantile

Refsum Disease (IRD)
• These disorders are 3 expressions of a disease continuum, from most (ZS) to least
(IRD) severe. The responsible genetic defect occurs in 1 of at least 12 genes
involved in peroxisomal formation or protein import (the PEX gene family).
• Manifestations include facial dysmorphism, central nervous system
malformations, demyelination, neonatal seizures, hypotonia, hepatomegaly, cystic
kidneys, short limbs with stippled epiphyses (chondrodysplasia punctata), cataracts,
retinopathy, hearing deficit, psychomotor delay, and peripheral neuropathy.
• Diagnosis is suspected when elevated blood levels of VLCFA, phytanic acid, bile
acid intermediates, and pipecolic acid are detected and is confirmed by genetic
testing.
• There is currently no specific treatment for these disorders.
• Management is mainly symptomatic.
119
Rhizomelic Chondrodysplasia Punctata

• This defect of peroxisomal biogenesis is caused by PEX7 gene mutations and
characterized by skeletal changes that include midface hypoplasia, strikingly short
proximal limbs, frontal bossing, small nares, cataracts, ichthyosis, and profound
psychomotor retardation. Vertebral clefts are also common.
• Diagnosis of rhizomelic chondrodysplasia punctata is suspected by x-ray findings,
elevation of serum phytanic acid, and low red blood cell plasmalogen levels;
VLCFA levels are normal. Confirmation is by genetic testing.
• There is no specific treatment for rhizomelic chondrodysplasia punctata.
120
X-Linked Adrenoleukodystrophy
• This disorder is caused by deficiency of the peroxisomal membrane transporter
ALDP, which is coded for by the gene ABCD1. This is an X-linked gene and thus
the disorder manifests primarily in males. Currently, > 900 mutations have been
identified (see ALD Info).
• The cerebral form affects 40% of patients. Onset occurs between age 4 years and 8
years, and symptoms of attention deficit progress over time to severe behavioral
problems, dementia, and vision, hearing, and motor deficits, causing total disability
and death 2 to 3 years after diagnosis. Milder adolescent and adult forms have also
been described.
• About 45% of patients have a milder form called adrenomyeloneuropathy (AMN);
onset occurs in the 20s or 30s, with progressive paraparesis, and sphincter and
sexual disturbance. About one third of these patients also develop cerebral
symptoms.
• Patients with any form may also develop adrenal insufficiency; about 15% have
isolated Addison disease without neurologic involvement.
• Diagnosis of X-linked adrenoleukodystrophy is suspected by isolated elevation of
VLCFA and confirmed by gene sequencing.
• Bone marrow or stem cell transplantation may help stabilize symptoms in some
cases. Adrenal steroid replacement is needed for patients with adrenal insufficiency.
Dietary supplement with a 4:1 mixture of glyceryl trioleate and glyceryl trierucate
(Lorenzo’s oil) can normalize plasma VLCFA levels but does not appear to stop
neurologic degeneration in symptomatic patients. However, if given to boys before
symptom onset, it may slow disease progression; the exact benefit has not been
determined.
Classic Refsum Disease

• Genetic deficiency of a single peroxisomal enzyme, phytanoyl-CoA hydroxylase,
which catalyzes metabolism of phytanic acid (a common dietary plant component),
causes phytanic acid accumulation.
• Clinical manifestations include progressive peripheral neuropathy, impaired vision
caused by retinitis pigmentosa, hearing deficit, anosmia, cardiomyopathy and
conduction defects, and ichthyosis. Onset is usually in the 20s.
• Diagnosis of Refsum disease is confirmed by elevation of serum phytanic acid and
decreased levels of pristanic acid (phytanic acid elevation is accompanied by
pristanic acid elevation in several other peroxisomal disorders).
• Treatment of Refsum disease is dietary restriction of phytanic acid (< 10 mg/day),
which can be effective in preventing or delaying symptoms when started before
symptom onset.
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Overview of Amino Acid and Organic Acid Metabolism Disorders

• The kidneys actively reabsorb significant amounts of amino acids. Defects of amino acid
transport in the renal tubule include cystinuria and Hartnup disease, which are discussed
elsewhere.
• Amino acid and organic acid metabolism disorders include:
✓ Branched-chain amino acid disorders
✓ Methionine metabolism disorders
✓ Phenylketonuria
✓ Tyrosine metabolism disorders
✓ Urea cycle disorders
• In addition, there are a number of other disorders of amino acid and organic acid
metabolism, including those involving beta- and gamma-amino acids, the gamma-
glutamyl cycle, glycine, histidine, lysine, proline and hydroxyproline, and
miscellaneous other amino acid disorders.
Beta-Amino Acid and Gamma-Amino Acid Disorders
122
Gamma-Glutamyl Cycle Disorders
Glycine Metabolism Disorders
Histidine Metabolism Disorders
Lysine Metabolism Disorders
123
Proline and Hydroxyproline Metabolism Disorders
Miscellaneous Amino Acid and Organic Acid Metabolism Disorders
124
Branched-Chain Amino Acid Metabolism Disorders
• Valine, leucine, and isoleucine are branched-chain amino acids; deficiency of

enzymes involved in their metabolism leads to accumulation of organic acids with
severe metabolic acidosis.
• There are numerous disorders of branched-chain amino acid metabolism (see
the table) as well as many other amino acid and organic acid metabolism
disorders.
Branched-Chain Amino Acid* Metabolism Disorders
125
126
127
Maple Syrup Urine Disease

• This is a group of autosomal recessive disorders caused by deficiency of one or
more subunits of a dehydrogenase active in the 2nd step of branched-chain amino
acid catabolism. Although quite rare, incidence is significant (perhaps 1/200
births) in Mennonite populations.
• Clinical manifestations include body fluid odor that smells like maple syrup
(particularly strong in cerumen) and overwhelming illness in the first days of life,
beginning with vomiting and lethargy, and progressing to seizures, coma, and
death if untreated. Patients with milder forms of the disease may manifest
symptoms only during stress (eg, infection, surgery).
• Biochemical findings are profound ketonemia and acidemia. Diagnosis of maple
syrup urine disease is by finding elevated plasma levels of branched-chain amino
acids (particularly leucine) and confirmed by genetic testing.
• Treatment of maple syrup urine disease with peritoneal dialysis or hemodialysis
may be required, along with IV hydration and nutrition (including protein
restriction and high-dose dextrose). Patients should be closely monitored for
cerebral edema and acute pancreatitis.
• Long-term management is restriction of dietary branched-chain amino acids;
however, small amounts are required for normal metabolic function. Thiamin is a
cofactor for the decarboxylation, and some patients respond favorably to high-
dose thiamin (up to 200 mg orally once a day). An emergency plan for how to
manage acute illness, which may provoke a metabolic crisis, should be in place.
Liver transplantation is curative.
128
Isovaleric Acidemia
• The 3rd step of leucine metabolism is the conversion of isovaleryl CoA to 3-
methylcrotonyl CoA, a dehydrogenation step. Deficiency of this dehydrogenase
results in isovaleric acidemia, also known as “sweaty feet” syndrome, because
accumulated isovaleric acid emits an odor that smells like sweat.
• Clinical manifestations of the acute form occur in the first few days of life with poor
feeding, vomiting, and respiratory distress as infants develop profound anion gap
metabolic acidosis, hypoglycemia, and hyperammonemia. Bone marrow
suppression often occurs. A chronic intermittent form may not manifest for several
months or years.
• Diagnosis of isovaleric acidemia is made by detecting elevated levels of isovaleric
acid and its metabolites in blood or urine.
• Acute treatment of isovaleric acidemia is with IV hydration and nutrition (including
high-dose dextrose) and measures to increase renal isovaleric acid excretion by
conjugation with glycine. If these measures are insufficient, exchange transfusion
and peritoneal dialysis may be needed. Long-term treatment is with dietary leucine
restriction and continuation of glycine and carnitine supplements. Prognosis is
excellent with treatment.
Propionic Acidemia
• Deficiency of propionyl CoA carboxylase, the enzyme responsible for metabolizing
propionic acid to methylmalonate, causes propionic acid accumulation.
• Illness begins in the first days or weeks of life with poor feeding, vomiting, and
respiratory distress due to profound anion gap metabolic acidosis, hypoglycemia,
and hyperammonemia. Seizures may occur, and bone marrow suppression is
common. Physiologic stresses may trigger recurrent attacks. Survivors may
have tubular nephropathies, intellectual disability, and neurologic abnormalities.
Propionic acidemia can also be seen as part of multiple carboxylase deficiency,
biotin deficiency, or biotinidase deficiency.
129
• Diagnosis of propionic acidemia is suggested by elevated levels of propionic acid

metabolites, including methylcitrate and tiglate and their glycine conjugates in
blood and urine, and confirmed by measuring propionyl CoA carboxylase activity
in white blood cells or cultured fibroblasts and/or genetic testing.
• Acute treatment of propionic acidemia is with IV hydration (including high-dose
dextrose), nutrition, and protein restriction; carnitine may be helpful. If these
measures are insufficient, peritoneal dialysis or hemodialysis may be needed. Long-
term propionic acidemia treatment is dietary restriction of precursor amino acids
and odd-chain fatty acids and possibly continuation of carnitine supplementation.
A few patients respond to high-dose biotin because it is a cofactor for propionyl
CoA and other carboxylases. Intermittent courses of antibiotics should be
considered for reducing a propionic acid load resulting from intestinal bacteria. An
emergency plan for how to manage acute illness, which may provoke a metabolic
crisis, should be in place.
Methylmalonic Acidemia
• This disorder is caused by deficiency of methylmalonyl CoA mutase, which
converts methylmalonyl CoA (a product of the propionyl CoA carboxylation) into
succinyl CoA. Adenosylcobalamin, a metabolite of vitamin B12, is a cofactor; its
deficiency also may cause methylmalonic acidemia (and
also homocystinuria and megaloblastic anemia). Methylmalonic acid
accumulates. Age of onset, clinical manifestations, and treatment are similar to
those of propionic acidemia except that cobalamin, instead of biotin, may be
helpful for some patients.
130
Methionine Metabolism Disorders

• A number of defects in methionine metabolism lead to accumulation of
homocysteine (and its dimer, homocystine) with adverse effects including
thrombotic tendency, lens dislocation, and central nervous system and skeletal
abnormalities.
• Homocysteine is an intermediate in methionine metabolism; it is either
remethylated to regenerate methionine or combined with serine in a series of
transsulfuration reactions to form cystathionine and then cysteine. Cysteine is then
metabolized to sulfite, taurine, and glutathione. Various defects in remethylation or
transsulfuration can cause homocysteine to accumulate, resulting in disease.
• The first step in methionine metabolism is its conversion to adenosylmethionine;
this conversion requires the enzyme methionine adenosyltransferase. Deficiency of
this enzyme results in methionine elevation, which is not clinically significant
except that it causes false-positive neonatal screening results for homocystinuria.
Methionine and Sulfur Metabolism Disorders
131
Classic Homocystinuria
• This disorder is caused by an autosomal recessive deficiency of cystathionine
beta-synthase, which catalyzes cystathionine formation from homocysteine and
serine. Homocysteine accumulates and dimerizes to form the disulfide
homocystine, which is excreted in the urine. Because remethylation is intact, some
of the additional homocysteine is converted to methionine, which accumulates in
the blood. Excess homocysteine predisposes to thrombosis and has adverse effects
on connective tissue (perhaps involving fibrillin), particularly the eyes and
skeleton; adverse neurologic effects may be due to thrombosis or a direct effect.
• Arterial and venous thromboembolic phenomena can occur at any age. Many
patients develop ectopia lentis (lens subluxation), intellectual disability, and
osteoporosis. Patients can have a marfanoid habitus even though they are not
usually tall.
• Diagnosis of classic homocystinuria is by neonatal screening for elevated serum
methionine; elevated total plasma homocysteine levels and/or DNA testing are
confirmatory. Enzymatic assay in skin fibroblasts can also be done.
• Treatment of classic homocystinuria is a low-methionine diet and L-cysteine
supplementation combined with high-dose pyridoxine (a cystathionine
synthetase cofactor) 100 to 500 mg orally once a day. Because about half of
patients respond to high-dose pyridoxine alone, some clinicians do not restrict
methionine intake in these patients. Betaine (trimethylglycine), which enhances
remethylation, can also help lower homocysteine. Betaine dosage is usually
started at 100 to 125 mg/kg orally 2 times a day and titrated based on homocysteine
levels; requirements vary widely, sometimes ≥ 9 g/day is needed. Folate 1 to 5 mg
orally once a day is also given. With early treatment, intellectual outcome is
normal or near normal. Vitamin C, 100 mg orally once a day, may also be given
to help prevent thromboembolism.
132
Other Forms of Homocystinuria

• Various defects in the remethylation process can result in homocystinuria. Defects
include deficiencies of methionine synthase (MS) and MS reductase (MSR),
delivery of methylcobalamin and adenosylcobalamin, and deficiency of
methylenetetrahydrofolate reductase (MTHFR, which is required to generate the 5-
methyltetrahydrofolate needed for the MS reaction). Because there is no methionine
elevation in these forms of homocystinuria, they are not detected by neonatal
screening.
• Clinical manifestations are similar to other forms of homocystinuria. In addition,
MS and MSR deficiencies are accompanied by neurologic deficits
and megaloblastic anemia. Clinical manifestation of MTHFR deficiency is
variable, including intellectual disability, psychosis, weakness, ataxia, and
spasticity.
• Diagnosis of MS and MSR deficiencies is suggested by homocystinuria and
megaloblastic anemia and confirmed by DNA testing. Patients with cobalamin
defects have megaloblastic anemia and methylmalonic acidemia. MTHFR
deficiency is diagnosed by DNA testing.
• Treatment is by replacement of hydroxycobalamin 1 mg IM once a day (for patients
with MS, MSR, and cobalamin defects) and folate in supplementation similar to
characteristic homocystinuria.
133
Cystathioninuria
• This disorder is caused by deficiency of cystathionase, which converts cystathionine
to cysteine. Cystathionine accumulation results in increased urinary excretion but
no clinical symptoms.
Sulfite Oxidase Deficiency

• Sulfite oxidase converts sulfite to sulfate in the last step of cysteine and methionine
degradation; it requires a molybdenum cofactor. Deficiency of either the enzyme or
the cofactor causes similar disease; inheritance for both is autosomal recessive.
• In its most severe form, clinical manifestations appear in neonates and include
seizures, hypotonia, and myoclonus, progressing to early death. Patients with milder
forms may present similarly to cerebral palsy and may have choreiform
movements.
• Diagnosis of sulfite oxidase deficiency is suggested by elevated urinary sulfite and
confirmed by measuring enzyme levels in fibroblasts and cofactor levels in liver
biopsy specimens and/or genetic testing. Treatment of sulfite oxidase deficiency is
supportive.
134
Phenylketonuria (PKU)
• Phenylketonuria is a disorder of amino acid metabolism that causes a clinical
syndrome of intellectual disability with cognitive and behavioral abnormalities
caused by elevated serum phenylalanine.
• The primary cause is deficient phenylalanine hydroxylase activity.
• Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine
levels. Treatment is lifelong dietary phenylalanine restriction.
• Prognosis is excellent with treatment.
Variant Forms
• Although nearly all cases (98 to 99%) of PKU result from phenylalanine
hydroxylase deficiency, phenylalanine can also accumulate if BH4 is not
synthesized because of deficiencies of dihydrobiopterin synthase or not regenerated
because of deficiencies of dihydropteridine reductase.
• Additionally, because BH4 is also a cofactor for tyrosine hydroxylase, which is
involved in the synthesis of dopamine and serotonin, BH4 deficiency alters
synthesis of neurotransmitters, causing neurologic symptoms independently of
phenylalanine accumulation.
Symptoms and Signs of PKU

• Most children with phenylketonuria are normal at birth but develop symptoms and
signs slowly over several months as phenylalanine accumulates.
• The hallmark of untreated PKU is severe intellectual disability.
• Children also manifest extreme hyperactivity, gait disturbance, and psychoses and
often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a
breakdown product of phenylalanine) in urine and sweat.
• Children also tend to have a lighter skin, hair, and eye color than unaffected family
members, and some may develop a rash similar to infantile eczema.
135
Diagnosis of PKU
✓ Routine neonatal screening
✓ Phenylalanine levels
• BH4 deficiency is distinguished from other forms of PKU by elevated

concentrations of biopterin or neopterin in urine, blood, cerebrospinal fluid, or all
3; genetic testing also can be used. Recognition is important, and the urine biopterin
profile should be determined routinely at initial diagnosis because standard PKU
treatment does not prevent neurologic damage.
• Children in families with a positive family history can be diagnosed prenatally by
using direct mutation studies after chorionic villus sampling or amniocentesis.
Prognosis for PKU

• Adequate treatment begun in the first days of life prevents the severe manifestations
of the disease. However, mild cognitive deficits and mental health issues may still
occur even with even with good dietary control. Treatment begun after 2 to 3 years
may be effective only in controlling the extreme hyperactivity and intractable
seizures.
• Children born to mothers with poorly controlled PKU (ie, they have high
phenylalanine levels) during pregnancy are at high risk of microcephaly and
developmental deficit.
136
Treatment of PKU
✓ Dietary phenylalanine restriction
✓ Formula feeding (PKU Neutri 1; PKU Neutri 2; PKU Neutri 3).
• Treatment of phenylketonuria is lifelong dietary phenylalanine restriction. All

natural protein contains about 4% phenylalanine. Therefore dietary staples include
✓ Low-protein natural foods (eg, fruits, vegetables, certain cereals)
✓ Protein hydrolysates treated to remove phenylalanine
✓ Phenylalanine-free elemental amino acid mixtures
✓ Multivitamin and Mineral supplementation
• Frequent monitoring of plasma phenylalanine levels is required; recommended

targets for all children are between 2 mg/dL and 6 mg/dL (120 to 360 micromol/L).
Dietary planning and management need to be initiated in women of childbearing
age before pregnancy to ensure a good outcome for the child. Tyrosine
supplementation is increasingly used because it is an essential amino acid in patients
with PKU. In addition, all patients with phenylalanine hydroxylase deficiency
should be given a trial of sapropterin to determine benefit.
• For those with BH4 deficiency, treatment also includes tetrahydrobiopterin 1 to 5
mg/kg orally 3 times a day; levodopa, carbidopa, and 5-OH tryptophan; and folinic
acid 10 to 20 mg orally once a day in cases of dihydropteridine reductase deficiency.
However, treatment goals and approach are the same as those for PKU.
Key Points
• PKU is caused by one of several gene mutations that result in deficiency or absence
of phenylalanine hydroxylase so that dietary phenylalanine accumulates; the brain
is the main organ affected, possibly because of disturbance of myelination.
• PKU causes a clinical syndrome of intellectual disability with cognitive and
behavioral abnormalities; if untreated, the intellectual disability is severe.
• In the US and many developed countries, all neonates are screened for
phenylketonuria 24 to 48 hours after birth with one of several blood tests; abnormal
results are confirmed by directly measuring phenylalanine levels.
• Treatment is lifelong dietary phenylalanine restriction; adequate treatment begun in
the first days of life prevents many manifestations of the disease.
• Although prognosis is excellent with treatment, frequent monitoring of plasma
phenylalanine levels is required; recommended targets are between 2 mg/dL and 6
mg/dL (120 to 360 micromol/L) for all children.
137
Tyrosine Metabolism Disorders
• Tyrosine is an amino acid that is a precursor of several neurotransmitters

(eg, dopamine, norepinephrine, epinephrine), hormones (eg, thyroxine), and
melanin; deficiencies of enzymes involved in its metabolism lead to a variety of
syndromes.
• There are numerous disorders of phenylalanine and tyrosine metabolism (see
the table).
Phenylalanine and Tyrosine Metabolism Disorders
138
Transient tyrosinemia of the newborn

• Transient immaturity of metabolic enzymes, particularly 4-hydroxyphenylpyruvic
acid dioxygenase, sometimes leads to elevated plasma tyrosine levels (usually in
premature infants, particularly those receiving high-protein diets); metabolites may
show up on routine neonatal screening for phenylketonuria (PKU).
• Most infants are asymptomatic, but some have lethargy and poor feeding.
• Tyrosinemia is distinguished from PKU by elevated plasma tyrosine levels.
• Most cases resolve spontaneously. Symptomatic patients should have dietary
tyrosine restriction (2 g/kg/day) and be given vitamin C 200 to 400 mg orally once
a day.
Tyrosinemia type I
• This disorder is an autosomal recessive condition caused by deficiency of
fumarylacetoacetate hydroxylase, an enzyme important for tyrosine metabolism.
• Disease may manifest as fulminant liver failure in the neonatal period or as
indolent subclinical hepatitis, painful peripheral neuropathy, and renal tubular
disorders (eg, normal anion gap metabolic
acidosis, hypophosphatemia, vitamin D–resistant rickets) in older infants and
children. Children who do not die of associated liver failure in infancy have a
significant risk of developing liver cancer.
• Diagnosis of tyrosinemia type I is suggested by elevated plasma levels of tyrosine;
it is confirmed by genetic testing or a high level of succinylacetone in plasma or
urine and by low fumarylacetoacetate hydroxylase activity in blood cells or liver
biopsy specimens. Treatment with nitisinone (NTBC) is effective in acute
episodes and slows progression.
• A diet low in phenylalanine and tyrosine is recommended. Liver transplantation is
effective.
139
Tyrosinemia type II
• This rare autosomal recessive disorder is caused by tyrosine transaminase
deficiency.
• Accumulation of tyrosine causes cutaneous and corneal ulcers. Secondary
elevation of phenylalanine, though mild, may cause neuropsychiatric
abnormalities if not treated.
• Diagnosis of tyrosinemia type II is by elevation of tyrosine in plasma, absence of
succinylacetone in plasma or urine, and genetic testing; measurement of decreased
enzyme activity in liver biopsy is usually not needed.
• This disorder is easily treated with mild to moderate restriction of dietary
phenylalanine and tyrosine.
Alkaptonuria
• This rare autosomal recessive disorder is caused by homogentisic acid oxidase
deficiency; homogentisic acid oxidation products accumulate in and darken skin,
and crystals precipitate in joints.
• The condition is usually diagnosed in adults and causes dark skin pigmentation
(ochronosis) and arthritis. Urine turns dark when exposed to air because of
oxidation products of homogentisic acid. Diagnosis of alkaptonuria is by finding
elevated urinary levels of homogentisic acid (> 4 to 8 g/24 hours).
• There is no effective treatment for alkaptonuria, but ascorbic acid 1 g orally once
a day may diminish pigment deposition by increasing renal excretion of
homogentisic acid.
Oculocutaneous Albinism
• Tyrosinase deficiency results in absence of skin and retinal pigmentation, causing a
much increased risk of skin cancer and considerable vision loss. Nystagmus is often
present, and photophobia is common.
140
Urea Cycle Disorders
• Urea cycle disorders are characterized by hyperammonemia under catabolic or

protein-loading conditions.
• There are many types of urea cycle and related disorders (see the table) as well as
many other amino acid and organic acid metabolism disorders.
• Primary urea cycle disorders (UCDs) include carbamoyl phosphate synthase (CPS)
deficiency, ornithine transcarbamylase (OTC) deficiency, argininosuccinate
synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency
(argininosuccinic aciduria), arginase deficiency (argininemia), and N-
acetylglutamate synthetase (NAGS) deficiency. The more “proximal” the enzyme
deficiency is, the more severe the hyperammonemia; thus, disease severity in
descending order is NAGS deficiency, CPS deficiency, OTC deficiency,
citrullinemia, argininosuccinic aciduria, and argininemia.
• Inheritance for all UCDs is autosomal recessive, except for OTC deficiency, which
is X-linked.
141
Urea Cycle and Related Disorders
142
Symptoms and Signs of Urea Cycle Disorders

• Clinical manifestations range from mild (eg, failure to thrive, intellectual disability,
episodic hyperammonemia) to severe (eg, altered mental status, coma, death).
Manifestations in female carriers of OTC deficiency range from growth failure,
developmental delay, psychiatric abnormalities, and episodic (especially
postpartum) hyperammonemia to a phenotype similar to that of affected males (ie,
recurrent vomiting, irritability, lethargy, hyperammonemic coma, cerebral edema,
spasticity, intellectual disability, seizures, death).
Diagnosis of Urea Cycle Disorders
Serum amino acid profiles
• Diagnosis of urea cycle disorders is based on amino acid profiles. For example,
elevated ornithine indicates CPS deficiency or OTC deficiency, whereas elevated
citrulline indicates citrullinemia. To distinguish between CPS deficiency and OTC
deficiency, orotic acid measurement is helpful because accumulation of carbamoyl
phosphate in OTC deficiency results in its alternative metabolism to orotic acid.
Genetic testing can confirm the diagnosis.
Treatment of Urea Cycle Disorders
✓ Dietary protein restriction
✓ Arginine or citrulline supplementation
✓ Sodium phenylbutyrate
✓ Possible liver transplantation
• Treatment of urea cycle disorders is dietary protein restriction that still provides
adequate amino acids for growth, development, and normal protein turnover.
• Arginine has become a staple of treatment. It supplies adequate urea cycle
intermediates to encourage the incorporation of more nitrogen moieties into urea
cycle intermediates, each of which is readily excretable. Arginine is also a positive
regulator of acetylglutamate synthesis. Recent studies suggest that oral citrulline is
more effective than arginine in patients with OTC deficiency.
• Additional treatment is with sodium benzoate, phenylbutyrate, or phenylacetate,
which by conjugating glycine (sodium benzoate) and glutamine (phenylbutyrate
and phenylacetate) provides a “nitrogen sink.”
• Despite these therapeutic advances, many UCDs remain difficult to treat, and liver
transplantation is eventually required for many patients. Timing of liver
transplantation is critical. Optimally, the infant should grow to an age when
transplantation is less risky (> 1 year), but it is important to not wait so long as to
allow an intercurrent episode of hyperammonemia (often associated with illness) to
cause irreparable harm to the central nervous system.
143
Overview of Carbohydrate Metabolism Disorders

• Carbohydrate metabolism disorders are errors of metabolism that affect the
catabolism and anabolism of carbohydrates.
• The inability to effectively use metabolites of carbohydrates accounts for the
majority of these disorders.
• These disorders include:
✓ Fructose metabolism disorders
✓ Galactosemia
✓ Glycogen storage diseases
✓ Pyruvate metabolism disorders
✓ Other carbohydrate metabolism disorders
Fructose Metabolism Disorders

• Deficiency of enzymes that metabolize fructose may be asymptomatic or cause
hypoglycemia.
• Fructose is a monosaccharide that is present in high concentrations in fruit and
honey and is a constituent of sucrose and sorbitol.
• Fructose metabolism disorders are one of the many carbohydrate metabolism
disorders.
Fructose 1-phosphate aldolase (aldolase B) deficiency
➢ This deficiency causes the clinical syndrome of hereditary fructose intolerance.
Inheritance is autosomal recessive; incidence is estimated at 1/20,000 births. Infants
are healthy until they ingest fructose; fructose 1-phosphate then accumulates, causing
hypoglycemia, nausea and vomiting, abdominal pain, sweating, tremors, confusion,
lethargy, seizures, and coma. Prolonged ingestion may cause cirrhosis, mental
deterioration, and proximal renal tubular acidosis with urinary loss of phosphate and
glucose.
➢ Diagnosis of fructose 1-phosphate aldolase deficiency is suggested by symptoms in
relation to recent fructose intake and is confirmed by DNA analysis. Previous
confirmatory testing used liver biopsy or induction of hypoglycemia by fructose
infusion 200 mg/kg IV.
➢ Diagnosis and identification of heterozygous carriers of the mutated gene can also be
made by direct DNA analysis.
➢ Short-term treatment of fructose 1-phosphate aldolase deficiency is glucose for
hypoglycemia; long-term treatment is exclusion of dietary fructose, sucrose, and
sorbitol. Many patients develop a natural aversion to fructose-containing food.
Prognosis is excellent with treatment.
144
Fructokinase deficiency
➢ This deficiency causes benign elevation of blood and urine fructose levels (benign
fructosuria). Inheritance is autosomal recessive; incidence is about 1/130,000 births.
➢ The condition is asymptomatic and diagnosed accidentally when a non-glucose
reducing substance is detected in urine.
Deficiency of fructose-1,6-biphosphatase
➢ This deficiency compromises gluconeogenesis and results in fasting hypoglycemia,
ketosis, and metabolic acidosis.
➢ This deficiency can be fatal in neonates. Inheritance is autosomal recessive;
incidence is unknown. Febrile illness can trigger episodes.
➢ Acute treatment of fructose-1,6-biphosphatase deficiency is oral or IV glucose.
Tolerance to fasting generally increases with age.
Galactosemia
• Galactosemia is a carbohydrate metabolism disorder caused by inherited
deficiencies in enzymes that convert galactose to glucose.
• Symptoms and signs include hepatic and renal dysfunction, cognitive deficits,
cataracts, and premature ovarian failure.
• Diagnosis is by enzyme analysis of red blood cells and DNA analysis.
• Treatment is dietary elimination of galactose.
• Physical prognosis is good with treatment, but cognitive and performance
parameters are often subnormal.
• Galactose is present in dairy products, fruits, and vegetables.
• Autosomal recessive enzyme deficiencies cause 3 clinical syndromes.
Galactose-1-phosphate uridyl transferase deficiency

➢ Infants become anorectic and jaundiced within a few days or weeks of consuming
breast milk or lactose-containing formula. Vomiting, hepatomegaly, poor growth,
lethargy, diarrhea, and septicemia (usually Escherichia coli) develop, as does renal
dysfunction (eg, proteinuria, aminoaciduria, Fanconi syndrome), leading
to metabolic acidosis and edema. Hemolytic anemia may also occur.
➢ Without treatment, children remain short and develop cognitive, speech, gait, and
balance deficits in adolescence; many also have cataracts, osteomalacia (caused by
hypercalciuria), and premature ovarian failure. Patients with the Duarte variant have
a much milder phenotype.
Galactokinase deficiency
➢ Patients develop cataracts from production of galactitol, which osmotically damages
lens fibers; idiopathic intracranial hypertension (pseudotumor cerebri) is rare.
Incidence is 1/40,000 births.
145
Uridine diphosphate galactose 4-epimerase deficiency

➢ There are benign and severe phenotypes. Incidence of the benign form is 1/23,000
births in Japan; no incidence data are available for the more severe form. The benign
form is restricted to red and white blood cells and causes no clinical abnormalities.
The severe form causes a syndrome indistinguishable from classic galactosemia,
although sometimes with hearing loss.
 Diagnosis of Galactosemia
✓ Galactose levels
✓ Enzyme analysis
• Diagnosis of galactosemia is suggested clinically and supported by elevated

galactose levels and the presence of reducing substances other than glucose (eg,
galactose, galactose 1-phosphate) in the urine; it is confirmed by DNA analysis or
enzyme analysis of red blood cells, hepatic tissue, or both. All states require
routine neonatal screening for galactose-1-phosphate uridyl transferase
deficiency.
 Treatment of Galactosemia
✓ Dietary galactose restriction
• Treatment of galactosemia is elimination of all sources of galactose in the diet, most

notably lactose (a source of galactose), which is present in breast milk, all dairy
products, including milk-based infant formulas, and is a sweetener used in many
foods. A lactose-free diet prevents acute toxicity and reverses some manifestations
(eg, cataracts) but may not prevent neurocognitive deficits. Many patients require
supplemental calcium and vitamins. For patients with epimerase deficiency, some
galactose intake is critical to ensure a supply of uridine-5′-diphosphate-galactose
(UDP-galactose) for various metabolic processes.
146
Glycogen Storage Diseases

• Glycogen storage diseases are carbohydrate metabolism disorders. There are
many numbered and named types, all of which are caused by deficiencies of
enzymes involved in glycogen synthesis or breakdown; the deficiencies may occur
in the liver or muscles and cause hypoglycemia or deposition of abnormal amounts
or types of glycogen (or its intermediate metabolites) in tissues.
• Inheritance for glycogen storage diseases (GSDs) is autosomal recessive except
for GSD type VIII/IX, which is X-linked. Incidence is estimated at about 1/25,000
births, which may be an underestimate because milder subclinical forms may be
undiagnosed. For a more complete listing of glycogen storage diseases, see
table Glycogen Storage Diseases and Disorders of Gluconeogenesis.
• Age of onset, clinical manifestations, and severity vary by type, but symptoms and
signs are most commonly those of hypoglycemia and myopathy.
• Diagnosis of glycogen storage diseases is suspected by history, examination, and
detection of glycogen and intermediate metabolites in tissues by MRI or biopsy.
Diagnosis is confirmed by DNA analysis or less commonly by detecting a
significant decrease of enzyme activity in liver (types I, III, VI, and VIII/IX),
muscle (types IIb, III, VII, and VIII/IX), skin fibroblasts (types IIa and IV), or red
blood cells (type VII) or by lack of an increase in venous lactate with forearm
activity/ischemia (types V and VII). GSD II (Pompe disease) is now part of the
newborn screening panel in many states in the US.
• Prognosis for and treatment of glycogen storage diseases vary by type, but
treatment typically includes dietary supplementation with cornstarch to provide a
sustained source of glucose for the hepatic forms of GSD and exercise avoidance
for the muscle forms.
• Defects in glycolysis (rare) may cause syndromes similar to GSDs. Deficiencies
of phosphoglycerate kinase, phosphoglycerate mutase, and lactate dehydrogenase
mimic the myopathies of GSD types V and VII; deficiencies of glucose transport
protein 2 (Fanconi-Bickel syndrome) mimic the hepatopathy of other GSD types
(eg, I, III, IV, VI).
147
148
Pyruvate Metabolism Disorders

• Inability to metabolize pyruvate causes lactic acidosis and a variety of central
nervous system abnormalities.
• Pyruvate is an important substrate in carbohydrate metabolism. Pyruvate
metabolism disorders are included among the carbohydrate metabolism
disorders.
Pyruvate dehydrogenase deficiency
➢ Pyruvate dehydrogenase is a multi-enzyme complex responsible for the generation
of acetyl CoA from pyruvate for the Krebs cycle. Deficiency results in elevation of
pyruvate and thus elevation of lactic acid levels. Inheritance is X-linked or autosomal
recessive.
➢ Clinical manifestations vary in severity but include lactic acidosis and central
nervous system malformations and other postnatal changes, including cystic lesions
of the cerebral cortex, brain stem, and basal ganglia; ataxia; and psychomotor
retardation.
➢ Diagnosis of pyruvate dehydrogenase deficiency is confirmed by enzyme analysis of
skin fibroblasts, DNA testing, or both.
➢ There is no clearly effective treatment for pyruvate dehydrogenase deficiency,
although a low-carbohydrate or ketogenic diet and dietary thiamin supplementation
have been beneficial for some patients.
Pyruvate carboxylase deficiency
➢ Pyruvate carboxylase is an enzyme important for gluconeogenesis from pyruvate and
alanine generated in muscle. Deficiency may be primary, or secondary to deficiency
of holocarboxylase synthetase, biotin, or biotinidase; inheritance for both
is autosomal recessive, and both result in lactic acidosis.
➢ Primary deficiency incidence is < 1/250,000 births but may be higher in certain
American Indian populations. Psychomotor retardation with seizures and spasticity
are the major clinical manifestations. Laboratory abnormalities include
hyperammonemia; lactic acidosis; ketoacidosis; elevated levels of plasma lysine,
citrulline, alanine, and proline; and increased excretion of alpha-ketoglutarate.
➢ Secondary deficiency is clinically similar, with failure to thrive, seizures, and other
organic aciduria.
➢ Diagnosis of pyruvate carboxylase deficiency is confirmed by enzyme analysis of
cultured skin fibroblasts or DNA analysis.
➢ There is no effective treatment for pyruvate carboxylase deficiency, but some
patients with primary deficiency and all those with secondary deficiencies should be
given biotin supplementation 5 to 20 mg orally once a day.
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Other Carbohydrate Metabolism Disorders

Phosphoenolpyruvate carboxykinase deficiency
• Impairs gluconeogenesis and results in symptoms and signs similar to the hepatic
forms of glycogen storage disease but without hepatic glycogen accumulation.
Other deficiencies
• Include those of glycolytic enzymes or enzymes in the pentose phosphate pathway.

Common examples are pyruvate kinase deficiency (see glycolytic pathway
defects) and glucose-6-phosphate dehydrogenase (g6pd) deficiency, both of
which may result in hemolytic anemia.
• Wernicke-korsakoff syndrome is caused by a partial deficiency of transketolase,
which is an enzyme for the pentose phosphate pathway that requires thiamin as a
cofactor.
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Overview of Fatty Acid and Glycerol Metabolism Disorders
• Fatty acids are the preferred energy source for the heart and an important energy
source for skeletal muscle during prolonged exertion.
• Also, during fasting, the bulk of the body’s energy needs must be supplied by fat
metabolism. Using fat as an energy source requires catabolizing adipose tissue into
free fatty acid and glycerol.
• The free fatty acid is metabolized in the liver and peripheral tissue via beta-
oxidation into acetyl CoA; the glycerol is used by the liver for triglyceride synthesis
or for gluconeogenesis.
• Carnitine is required for long-chain fatty acid oxidation.
• Carnitine deficiencies can be primary or secondary.
• Secondary carnitine deficiency is a secondary biochemical feature of many organic
acidemias and fatty acid oxidation defects.
• There are a number of other disorders of fatty acid and glycerol metabolism,
including those involving:
✓ Fatty acid transport and mitochondrial oxidation

✓ Glycerol
✓ Ketones
✓ Peroxisome biogenesis and very long-chain fatty acids
✓ Other disorders of fat metabolism
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Beta-Oxidation Cycle Disorders

• In these processes, there are numerous inherited defects, which typically manifest
during fasting with hypoglycemia and metabolic acidosis; some cause
cardiomyopathy and muscle weakness.
• Acetyl CoA is generated from fatty acids through repeated beta-oxidation cycles.
Sets of 4 enzymes (an acyl dehydrogenase, a hydratase, a hydroxyacyl
dehydrogenase, and a lyase) specific for different chain lengths (very long chain,
long chain, medium chain, and short chain) are required to catabolize fatty acids
completely. Inheritance for all fatty acid oxidation defects is autosomal recessive.
152
Fatty Acid Transport and Mitochondrial Oxidation Disorders
153
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)

• This deficiency is the most common defect in the beta-oxidation cycle.
• Clinical manifestations typically begin after 2 to 3 months of age and usually follow
fasting (as little as 12 hours). Patients have vomiting and lethargy that may progress
rapidly to seizures, coma, and sometimes death (which can also appear as sudden
infant death syndrome). During attacks, patients have hypoglycemia,
hyperammonemia, and unexpectedly low urinary and serum ketones. Metabolic
acidosis is often present but may be a late manifestation.
• Diagnosis of MCADD is by detecting medium-chain fatty acid conjugates of
carnitine in plasma or glycine in urine or by detecting enzyme deficiency in cultured
fibroblasts; however, DNA testing can confirm most cases. MCADD is now
included in routine neonatal screening in all states in the US.
• Treatment of acute attacks is with 10% dextrose IV at 1.5 times the fluid
maintenance rate (see Maintenance requirements); some clinicians also advocate
carnitine supplementation during acute episodes. Prevention is a low-fat, high-
carbohydrate diet and avoidance of prolonged fasting. Cornstarch therapy is often
used to provide a margin of safety during overnight fasting.
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD)
• This deficiency is the 2nd most common fatty acid oxidation defect. It shares many
features of MCADD, but patients may also have cardiomyopathy; rhabdomyolysis,
massive creatine kinase elevations, and myoglobinuria with muscle exertion;
peripheral neuropathy; and abnormal liver function. Mothers with an LCHADD
fetus often have HELLP syndrome (hemolysis, elevated liver enzymes, and low
platelet count) during pregnancy.
• Diagnosis of LCHADD is based on the presence of excess long-chain hydroxy acids
on organic acid analysis and on the presence of their carnitine conjugates in an
acylcarnitine profile or glycine conjugates in an acylglycine profile. LCHADD can
be confirmed by enzyme study in skin fibroblasts or by genetic testing. LCHADD
is now included in routine neonatal screening in all states in the US.
• Treatment during acute exacerbations includes hydration, high-dose glucose, bed
rest, urine alkalinization, and carnitine supplementation. Long-term treatment
includes a high-carbohydrate diet, medium-chain triglyceride supplementation, and
avoidance of fasting and strenuous exercise.
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Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)

• This deficiency is similar to LCHADD but is commonly associated with significant
cardiomyopathy.
Glutaric acidemia type II

• A defect in the transfer of electrons from the coenzyme of fatty acyl dehydrogenases
to the electronic transport chain affects reactions involving fatty acids of all chain
lengths (multiple acyl-coA dehydrogenase deficiency); oxidation of several amino
acids is also affected.
• Clinical manifestations thus include fasting hypoglycemia, severe metabolic
acidosis, and hyperammonemia.
• Diagnosis of glutaric acidemia type II is by increased ethylmalonic, glutaric, 2- and
3-hydroxyglutaric, and other dicarboxylic acids in organic acid analysis, and
glutaryl and isovaleryl and other acylcarnitines in tandem mass spectrometry
studies. DNA analysis can be confirmatory.
• Treatment of glutaric acidemia type II is similar to that for MCADD, except that
riboflavin may be effective in some patients.
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Glycerol Metabolism Disorders

• Glycerol is converted to glycerol-3-phosphate by the hepatic enzyme glycerol
kinase; deficiency results in episodic vomiting, lethargy, and hypotonia.
• Glycerol metabolism disorders (see the table) are among the fatty acid and
glycerol metabolism disorders.
• Glycerol kinase deficiency is X-linked; many patients with this deficiency also
have a chromosomal deletion that extends beyond the glycerol kinase gene into the
contiguous gene region, which contains the genes for congenital adrenal hypoplasia
and Duchenne muscular dystrophy. Thus, patients with glycerol kinase deficiency
may have one or more of these disease entities.
• Symptoms of glycerol metabolism disorders begin at any age and are usually
accompanied by acidosis, hypoglycemia, and elevated blood and urine levels of
glycerol.
• Diagnosis of glycerol metabolism disorders is by detecting an elevated level of
glycerol in serum and urine and is confirmed by DNA analysis.
• Glycerol metabolism disorder treatment is with a low-fat diet, but glucocorticoid
replacement is critical for patients with adrenal hypoplasia.
Glycerol Metabolism Disorders
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Overview of Lysosomal Storage Disorders
• Because there are numerous specific deficiencies, storage diseases are usually
grouped biochemically by the accumulated metabolite.
• Subgroups include:
✓ Mucopolysaccharidoses
✓ Sphingolipidoses (lipidoses)
✓ Mucolipidoses
• The most important are the mucopolysaccharidoses and sphingolipidoses.

• Type 2 glycogenosis is a lysosomal storage disorder, but most glycogenoses are not.
• Because reticuloendothelial cells (eg, in the spleen) are rich in lysosomes,
reticuloendothelial tissues are involved in a number of lysosomal storage disorders,
but, generally, tissues richest in the substrate are most affected.
• Thus the brain, which is rich in gangliosides, is particularly affected by
gangliosidoses, whereas mucopolysaccharidoses affect many tissues because
mucopolysaccharides are present throughout the body.
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Mucopolysaccharidoses (MPS)
• MPS are inherited deficiencies of enzymes involved in glycosaminoglycan
breakdown. Glycosaminoglycans (previously termed mucopolysaccharides) are
polysaccharides abundant on cell surfaces and in extracellular matrix and structures.
Enzyme deficiencies that prevent glycosaminoglycan breakdown cause
accumulation of glycosaminoglycan fragments in lysosomes and cause extensive
bone, soft tissue, and central nervous system changes. Inheritance is
usually autosomal recessive (except for MPS type II).
• Age at presentation, clinical manifestations, and severity vary by type (see
table Mucopolysaccharidosis (MPS)).
• Common manifestations include coarse facial features, neurodevelopmental delays
and regression, joint contractures, organomegaly, stiff hair, progressive respiratory
insufficiency (caused by airway obstruction and sleep apnea), cardiac valvular
disease, skeletal changes, and cervical vertebral subluxation.
• Diagnosis of mucopolysaccharidoses is suggested by history, physical examination,
bone abnormalities (eg, dysostosis multiplex) found during skeletal survey, and
elevated total and fractionated urinary glycosaminoglycans. Diagnosis is confirmed
by DNA analysis and/or enzyme analysis of cultured fibroblasts (prenatal) or
peripheral white blood cells (postnatal). Additional testing is required to monitor
organ-specific changes (eg, echocardiography for valvular disease, audiometry for
hearing changes).
• Treatment of mucopolysaccharidosis type I is enzyme replacement
with laronidase, which effectively halts progression and reverses all non-central
nervous system complications of the disease. Hematopoietic stem cell (HSC)
transplantation has also been used. The combination of enzyme replacement and
HSC transplantation is under study. For patients with MPS type IV-A (Morquio A
syndrome), enzyme replacement with elosulfase alfa may improve functional
status, including mobility.
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Mucopolysaccharidosis (MPS)
159
Sphingolipidoses
• Sphingolipids are normal lipid components of cell membranes; they accumulate in
lysosomes and cause extensive neuronal, bone, and other changes when enzyme
deficiencies prevent their breakdown. Although incidence is low, carrier rate of
some forms is high.
• There are many types of sphingolipidosis; the most common sphingolipidosis is
✓ Gaucher disease
• Others sphingolipidosis include
✓ Cholesteryl ester storage disease

✓ Fabry disease
✓ Krabbe disease
✓ Metachromatic leukodystrophy
✓ Niemann-Pick disease
✓ Sandhoff disease
✓ Tay-Sachs disease
✓ Wolman disease
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Some Sphingolipidoses
161
162
Mucolipidoses and other lysosomal disorders

• In addition to mucolipidoses, there are many other lysosomal disorders including
✓ Other lipidoses
✓ Oligosaccharidosis and related disorders
✓ Lysosomal transport defects
✓ Other lysosomal disorders
Mucolipidosis (ML)
Other Lipidoses
163
Oligosaccharidosis and Related Disorders
164
165
Lysosomal Transport Defects
Other Lysosomal Disorders
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Cholesteryl Ester Storage Disease and Wolman Disease (Wolman's Disease)

➢ Cholesteryl ester storage disease and Wolman disease are sphingolipidoses, an
inherited disorder of metabolism, caused by lysosomal acid lipase deficiency
resulting in hyperlipidemia and hepatomegaly.
➢ These diseases are rare, autosomal recessive disorders that result in accumulation of
cholesteryl esters and triglycerides, mainly in lysosomes of histiocytes, resulting in
foam cells in the liver, spleen, lymph nodes, and other tissues. Serum low-density
lipoprotein (LDL) is usually elevated.
➢ Wolman disease is the more severe form, manifesting in the first weeks of life with
poor feeding, vomiting, and abdominal distention secondary to hepatosplenomegaly;
infants usually die within 6 months if untreated.
➢ Cholesteryl ester storage disease is less severe and may not manifest until later in
life, even adulthood, at which time hepatomegaly may be detected; premature
atherosclerosis, often severe, may develop.
➢ Diagnosis is based on clinical features and DNA analysis and/or detection of acid
lipase deficiency in liver biopsy specimens or cultured skin fibroblasts, lymphocytes,
or other tissues. Prenatal diagnosis is based on the absence of acid lipase activity in
cultured chorionic villi.
Fabry Disease (Fabry's Disease; Angiokeratoma Corporis Diffusum)
➢ Fabry disease is a sphingolipidosis, an inherited disorder of metabolism, caused by

deficiency of alpha-galactosidase A, which causes angiokeratomas, acroparesthesias,
corneal opacities, recurrent febrile episodes, and renal or heart failure.
➢ Fabry disease is an X-linked deficiency of the lysosomal enzyme alpha-
galactosidase A, which is needed for normal trihexosylceramide catabolism.
Glycolipid (globotriaosylceramide) accumulates in many tissues (eg, vascular
endothelium, lymph vessels, heart, kidney).
➢ Diagnosis in males is clinical, based on appearance of typical skin lesions
(angiokeratomas) over the lower trunk and by characteristic features of peripheral
neuropathy (causing recurrent burning pain in the extremities), corneal opacities, and
recurrent febrile episodes. Death results from renal failure or cardiac or cerebral
complications of hypertension or other vascular disease. Heterozygous females are
usually asymptomatic but may have an attenuated form of disease often characterized
by corneal opacities.
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Angiokeratomas in Fabry Disease
➢ Diagnosis of Fabry disease is by DNA analysis and/or assay of galactosidase

activity—prenatally in amniocytes or chorionic villi and postnatally in serum or
white blood cells.
➢ Treatment of Fabry disease is enzyme replacement with recombinant alpha-
galactosidase A (agalsidase beta) combined with supportive measures for fever and
pain. Kidney transplantation is effective for treating renal failure.
Gaucher Disease (Gaucher's Disease)

➢ Gaucher disease is a sphingolipidosis, an inherited disorder of metabolism, resulting
from glucocerebrosidase deficiency, causing deposition of glucocerebroside and
related compounds. Symptoms and signs vary by type but are most commonly
hepatosplenomegaly or central nervous system changes. Diagnosis is by DNA
analysis and/or enzyme analysis of white blood cells. Treatment is enzyme
replacement with glucocerebrosidase.
➢ Glucocerebrosidase normally hydrolyzes glucocerebroside to glucose and ceramide.
Genetic defects of the enzyme cause glucocerebroside accumulation in tissue
macrophages through phagocytosis, forming Gaucher cells. Accumulation of
Gaucher cells in the perivascular spaces in the brain causes gliosis in the
neuronopathic forms.
➢ There are 3 types of Gaucher disease, which vary in epidemiology, enzyme
activity, and manifestations.
1) Type I Gaucher disease

 Type I (nonneuronopathic) is most common (90% of all patients). Residual
enzyme activity is highest. Ashkenazi Jews are at greatest risk; 1/12 is a carrier.
Onset ranges from childhood to adulthood.
 Symptoms and signs of type I Gaucher disease include splenohepatomegaly,
bone disease (eg, osteopenia, pain crises, osteolytic lesions with fractures),
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growth failure, delayed puberty, ecchymoses, and pingueculae. Epistaxis and

ecchymoses resulting from thrombocytopenia are common.
 X-rays show flaring of the ends of the long bones (Erlenmeyer flask deformity)
and cortical thinning.
2) Type II Gaucher disease
 Type II (acute neuronopathic) is rarest, and residual enzyme activity in this type
is lowest. Onset occurs during infancy.
 Symptoms and signs of type II Gaucher disease are progressive neurologic
deterioration (eg, rigidity, seizures) and death by age 2 years.
3) Type III Gaucher disease
 Type III (subacute neuronopathic) falls between types I and II in incidence,
enzyme activity, and clinical severity. Onset occurs at any time during
childhood.
 Clinical manifestations vary by subtype and include progressive dementia and
ataxia (IIIa), bone and visceral involvement (IIIb), and supranuclear palsies with
corneal opacities (IIIc). Patients who survive to adolescence may live for many
years.
 Diagnosis of Gaucher Disease
✓ Enzyme analysis
• Diagnosis of Gaucher disease is by DNA analysis and/or enzyme analysis of white
blood cells. Carriers are detected, and types are distinguished by mutation analysis.
Although biopsy is unnecessary, Gaucher cells—lipid-laden tissue macrophages in
the liver, spleen, lymph nodes, bone marrow, or brain that have a wrinkled tissue-
paper appearance—are diagnostic.
 Treatment of Gaucher Disease
✓ Types I and III: Enzyme replacement with glucocerebrosidase
✓ Sometimes miglustat, eliglustat, splenectomy, or stem cell or bone marrow
transplantation
• Enzyme replacement with IV glucocerebrosidase is effective in types I and III;
there is no treatment for type II. The enzyme is modified for efficient delivery to
lysosomes. Patients receiving enzyme replacement require routine hemoglobin and
platelet monitoring, routine assessment of spleen and liver volume by CT or MRI,
and routine assessment of bone disease by skeletal survey, dual-energy x-ray
absorptiometry scanning, or MRI.
• Miglustat (100 mg orally 3 times a day), a glucosylceramide synthase inhibitor,
reduces glucocerebroside concentration (the substrate for glucocerebrosidase) and
is an alternative for patients unable to receive enzyme replacement.
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• Eliglustat (84 mg orally once a day or 2 times a day), another glucosylceramide

synthase inhibitor, also reduces glucocerebroside concentration.
• Splenectomy may be helpful for patients with anemia, leukopenia, or
thrombocytopenia or when spleen size causes discomfort. Patients with anemia
may also need blood transfusions.
• Bone marrow transplantation or stem cell transplantation provides a definitive cure
but is considered a last resort because of substantial morbidity and mortality.
 Key Points
• Gaucher disease is a sphingolipidosis resulting from glucocerebrosidase
deficiency, causing deposition of glucocerebroside.
• There are 3 types, which vary in epidemiology, enzyme activity, and
manifestations.
• Symptoms and signs vary by type but are most commonly hepatosplenomegaly or
central nervous system changes.
• Diagnosis of Gaucher disease is by DNA analysis and/or enzyme analysis of white
blood cells; carriers are detected, and types are distinguished by mutation analysis.
• Treatment for types I and III include enzyme replacement with glucocerebrosidase,
and sometimes miglustat, eliglustat, splenectomy, or stem cell or bone marrow
transplantation; there is no treatment for type II.
Krabbe Disease (Krabbe's Disease; Galactosylceramide Lipidosis; Globoid

Cell Leukodystrophy)
➢ Krabbe disease is a sphingolipidosis, an inherited disorder of metabolism, that

causes intellectual disability, paralysis, blindness, deafness, and pseudobulbar palsy,
progressing to death.
➢ Krabbe disease is caused by an autosomal recessive galactocerebroside beta-
galactosidase deficiency. There are 4 forms: infantile, late infantile, juvenile, and
adult.
➢ It affects infants and is characterized by intellectual disability, paralysis, blindness,
deafness, and pseudobulbar palsy, progressing to death.
➢ Diagnosis of Krabbe disease is by DNA analysis and/or detecting enzyme deficiency
in white blood cells or cultured skin fibroblasts. (Also see testing for suspected
inherited disorders of metabolism.)
➢ Because bone marrow or stem cell transplantation prolongs life span and improves
functional abilities of children who have the infantile or late infantile form, prenatal
testing or neonatal screening is sometimes done.
➢ Treatment of Krabbe disease is supportive.
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Metachromatic Leukodystrophy (Sulfatide Lipidosis)
➢ Metachromatic leukodystrophy is a sphingolipidosis, an inherited disorder of

metabolism, caused by arylsulfatase A deficiency. There are several forms, the most
severe of which causes progressive paralysis and dementia resulting in death by age
10 years.
➢ In metachromatic leukodystrophy, arylsulfatase A deficiency causes metachromatic
lipids to accumulate in the white matter of the central nervous system, peripheral
nerves, kidney, spleen, and other visceral organs; accumulation in the nervous system
causes central and peripheral demyelination. Numerous mutations exist; patients vary
in age at onset and speed of progression.
➢ The infantile form is characterized by progressive paralysis and dementia usually
beginning before age 4 years and resulting in death about 5 years after onset of
symptoms.
➢ The juvenile form manifests between 4 years and 16 years of age with gait
disturbance, intellectual impairment, and findings of peripheral neuropathy. Contrary
to the infantile form, deep tendon reflexes are usually brisk.
➢ There is also a milder adult form.
➢ Diagnosis of metachromatic leukodystrophy is suggested clinically and by findings
of decreased nerve conduction velocity; it is confirmed by DNA analysis and/or
detecting enzyme deficiency in white blood cells or cultured skin fibroblasts.
➢ There is currently no effective treatment for metachromatic leukodystrophy in
patients with advanced symptoms. Bone marrow or stem cell transplantation may
stabilize neurocognitive function in mildly symptomatic forms of the disease. Several
other therapeutic options are currently being investigated, primarily in late infantile
forms of the disease, including gene therapy, enzyme replacement therapy, substrate
reduction therapy, and, potentially, enzyme enhancement therapy.
Niemann-Pick Disease
➢ Niemann-Pick disease is a sphingolipidosis, an inherited disorder of metabolism,

caused by deficient sphingomyelinase activity, resulting in accumulation of
sphingomyelin (ceramide phosphorylcholine) in reticuloendothelial cells. Diagnosis
is by DNA analysis and/or enzyme analysis of white blood cells. Bone marrow
transplantation, stem cell transplantation, and enzyme replacement may be treatment
options.
➢ Niemann-Pick disease inheritance is autosomal recessive and appears most often in
Ashkenazi Jews; 2 types, A and B, exist. Type C Niemann-Pick disease is an
unrelated enzymatic defect involving abnormal cholesterol storage.
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➢ Children with type A have < 5% of normal sphingomyelinase activity. The disease is
characterized by hepatosplenomegaly, failure to thrive, and rapidly progressive
neurodegeneration. Death occurs by age 2 or 3 years.
➢ Patients with type B have sphingomyelinase activity within 5 to 10% of normal. Type
B is more variable clinically than type A. Hepatosplenomegaly and lymphadenopathy
may occur. Pancytopenia is common. Most patients with type B have little or no
neurologic involvement and survive into adulthood; they may be clinically
indistinguishable from those with type I Gaucher disease. In severe cases of type
B, progressive pulmonary infiltrates cause major complications.
 Diagnosis of Niemann-Pick Disease
✓ Prenatal screening
✓ White blood cell sphingomyelinase assay
• Both types are usually suspected by history and examination, most notably
hepatosplenomegaly. Diagnosis of Niemann-Pick disease can be confirmed by
DNA analysis and/or sphingomyelinase assay on white blood cells and can be made
prenatally by using amniocentesis or chorionic villus sampling. DNA tests also can
be done to diagnose carriers.
 Treatment of Niemann-Pick Disease
✓ Possible bone marrow transplantation, stem cell transplantation, and enzyme

replacement
• Bone marrow transplantation, stem cell transplantation, and enzyme replacement
are under investigation as potential treatment options.
Tay - Sachs disease and Sandhoff Disease

➢ Tay-Sachs disease and Sandhoff disease are sphingolipidoses, inherited disorders of
metabolism, caused by hexosaminidase deficiency that causes severe neurologic
symptoms and early death.
➢ Gangliosides are complex sphingolipids present in the brain. There are 2 major
forms, GM1 and GM2, both of which may be involved in lysosomal storage
disorders. There are 2 main types of GM2 gangliosidosis, each of which can be
caused by numerous different mutations.
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❖ Tay-Sachs disease
 Deficiency of hexosaminidase A results in accumulation of GM2 in the brain.
Inheritance is autosomal recessive; the most common mutations are carried by
1/27 normal adults of Eastern European (Ashkenazi) Jewish origin, although
other mutations cluster in some French-Canadian and Cajun populations.
 Children with Tay-Sachs disease start missing developmental milestones after
age 6 months and develop progressive cognitive and motor deterioration
resulting in seizures, intellectual disability, paralysis, and death by age 5 years.
A cherry-red macular spot is common.
 All patients with Tay-Sachs disease have a cherry-red spot, easily observable by
a physician using an ophthalmoscope, in the back of their eyes.
 Diagnosis of Tay-Sachs disease is clinical and can be confirmed by DNA
analysis and/or enzyme assay. (Also see testing for suspected inherited
disorders of metabolism.)
 In the absence of effective treatment, management is focused on screening adults
of childbearing age in high-risk populations to identify carriers (by way of
enzyme activity and mutation testing) combined with genetic counseling.
❖ Sandhoff disease
 There is a combined hexosaminidase A and B deficiency.
 Clinical manifestations include progressive cerebral degeneration beginning at
6 months, accompanied by blindness, cherry-red macular spot, and hyperacusis.
It is almost indistinguishable from Tay-Sachs disease in course, diagnosis, and
management, except that there is visceral involvement (hepatomegaly and bone
change) and no ethnic association.
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Overview of Purine and Pyrimidine Metabolism Disorders

• Purines are key components of cellular energy systems (eg, ATP, NAD), signaling
(eg, GTP, cAMP, cGMP), and, along with pyrimidines, RNA and DNA production.
• Purines and pyrimidines may be synthesized de novo or recycled by a salvage
pathway from normal catabolism.
• The end product of complete catabolism of purines is uric acid; catabolism of
pyrimidines produces citric acid cycle intermediates.
• Purine metabolism disorders (see the table) are categorized as:
✓ Purine catabolism disorders

✓ Purine nucleotide synthesis disorders
✓ Purine salvage disorders
• There are a number of pyrimidine metabolism disorders.
Purine Metabolism Disorders
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Purine Catabolism Disorders

• Purines and pyrimidines may be synthesized de novo or recycled by a salvage
pathway from normal catabolism.
• The end product of complete catabolism of purines is uric acid.
• In addition to purine catabolism disorders, purine metabolism disorders (see also
table Purine Metabolism Disorders) include:
• Diagnosis is suspected clinically and typically confirmed by DNA analysis.
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Myoadenylate deaminase deficiency (or muscle adenosine monophosphate

deaminase deficiency)
➢ The enzyme myoadenylate deaminase converts AMP to inosine and ammonia.
Deficiency may be asymptomatic or it may cause exercise-induced myalgias or
cramping; expression seems to be variable because, despite the high frequency of the
mutant allele (10 to 14%), the frequency of the muscle phenotype is quite low in
patients homozygous for the mutant allele. When symptomatic patients exercise, they
do not accumulate ammonia or inosine monophosphate as do unaffected people; this
is how the disorder is diagnosed.
➢ Treatment of myoadenylate deaminase deficiency is exercise modulation as
appropriate.
Adenosine deaminase deficiency
➢ Adenosine deaminase converts adenosine and deoxyadenosine to inosine and
deoxyinosine, which are further broken down and excreted.
➢ Enzyme deficiency (from 1 of > 60 known mutations) results in accumulation
of adenosine, which is converted to its ribonucleotide and deoxyribonucleotide
(dATP) forms by cellular kinases.
➢ The dATP increase results in inhibition of ribonucleotide reductase and
underproduction of other deoxyribonucleotides.
➢ DNA replication is compromised as a result. Immune cells are especially sensitive to
this defect; adenosine deaminase deficiency causes one form of severe combined
immunodeficiency.
➢ Diagnosis of adenosine deaminase deficiency is by DNA analysis.
➢ Treatment of adenosine deaminase deficiency is by bone marrow or stem cell
transplantation and enzyme replacement therapy.
Purine nucleoside phosphorylase deficiency

➢ This rare, autosomal recessive deficiency is characterized by immunodeficiency
with severe T-cell dysfunction and often neurologic symptoms. Manifestations are
lymphopenia, thymic deficiency, recurrent infections, and hypouricemia. Many
patients have developmental delay, ataxia, or spasticity.
➢ Diagnosis of purine nucleoside phosphorylase deficiency is by DNA analysis.
➢ Treatment of purine nucleoside phosphorylase deficiency is with bone marrow or
stem cell transplantation.
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Xanthine oxidase deficiency

➢ Xanthine oxidase is the enzyme that catalyzes uric acid production from xanthine
and hypoxanthine. Deficiency causes buildup of xanthine, which may precipitate in
the urine, causing symptomatic stones with hematuria, urinary colic, and urinary tract
infections.
➢ Diagnosis of xanthine oxidase deficiency is by DNA analysis. Enzyme determination
requires liver or intestinal mucosal biopsy and is rarely indicated.
➢ Treatment of xanthine oxidase deficiency is high fluid intake to minimize likelihood
of stone formation and allopurinol in some patients.
Purine Nucleotide Synthesis Disorders

• Purines may be synthesized de novo or recycled by a salvage pathway from normal
catabolism.
• In addition to purine nucleotide synthesis disorders, purine metabolism disorders
include:
Phosphoribosylpyrophosphate synthetase superactivity

➢ This X-linked recessive disorder causes purine overproduction. Excess purine is
degraded, resulting in hyperuricemia and gout and neurologic and developmental
abnormalities.
➢ Diagnosis of phosphoribosylpyrophosphate synthetase superactivity is by DNA
analysis.
➢ Phosphoribosylpyrophosphate synthetase superactivity treatment is
with allopurinol and a low-purine diet.
Adenylosuccinase deficiency
➢ This autosomal recessive disorder causes profound intellectual disability, autistic

behavior, and seizures.
➢ Diagnosis of adenylosuccinase deficiency is by DNA analysis.
➢ There is no effective treatment for adenylosuccinase deficiency.
177
Purine Salvage Disorders

• Purines may be synthesized de novo or recycled by a salvage pathway from normal
catabolism.
• In addition to purine salvage disorders, purine metabolism disorders include
Lesch-Nyhan syndrome
➢ This is a rare, X-linked recessive disorder caused by deficiency of hypoxanthine-
guanine phosphoribosyl transferase (HPRT); degree of deficiency (and hence
manifestations) vary with the specific mutation. HPRT deficiency results in failure
of the salvage pathway for hypoxanthine and guanine. These purines are instead
degraded to uric acid. Additionally, a decrease in inositol monophosphate and
guanosyl monophosphate leads to an increase in conversion of 5-phosphoribosyl-1-
pyrophosphate (PRPP) to 5-phosphoribosylamine, which further exacerbates uric
acid overproduction. Hyperuricemia predisposes to gout and its complications.
Patients also have a number of cognitive and behavioral dysfunctions, etiology of
which is unclear; they do not seem related to uric acid.
➢ The disease usually manifests between 3 months and 12 months of age with the
appearance of orange sandy precipitate (xanthine) in the urine; it progresses to central
nervous system involvement with intellectual disability, spastic cerebral palsy,
involuntary movements, and self-mutilating behavior (particularly biting). Later,
chronic hyperuricemia causes symptoms of gout (eg, urolithiasis, nephropathy, gouty
arthritis, tophi).
➢ Diagnosis of Lesch-Nyhan syndrome is suggested by the combination of dystonia,
intellectual disability, and self-mutilation. Serum uric acid levels are usually
elevated, but confirmation by DNA analysis is done.
➢ Central nervous system dysfunction has no known treatment; management is
supportive. Self-mutilation may require physical restraint, dental extraction, and
sometimes drug therapy; a variety of drugs has been used. Hyperuricemia is treated
with a low-purine diet (eg, avoiding organ meats, beans, sardines) and allopurinol,
a xanthine oxidase inhibitor (the last enzyme in the purine catabolic
pathway). Allopurinol prevents conversion of accumulated hypoxanthine to uric
acid; because hypoxanthine is highly soluble, it is excreted.
178
Adenine phosphoribosyltransferase deficiency

➢ This is a rare autosomal recessive disorder that results in the inability to salvage
adenine for purine synthesis. Accumulated adenine is oxidized to 2,8-
dihyroxyadenine, which precipitates in the urinary tract, causing problems similar to
those of uric acid nephropathy (eg, renal colic, frequent infections, and, if diagnosed
late, renal failure). Onset can occur at any age.
➢ Diagnosis of adenine phosphoribosyltransferase deficiency is by detecting elevated
levels of 2,8-dihyroxyadenine, 8-hyroxyadenine, and adenine in urine and confirmed
by DNA analysis; serum uric acid is normal.
➢ Treatment of adenine phosphoribosyltransferase deficiency is with dietary purine
restriction, high fluid intake, and avoidance of urine alkalinization.
➢ Allopurinol can prevent oxidation of adenine; renal transplantation may be needed
for end-stage renal disease.
Pyrimidine Metabolism Disorders

• Pyrimidines may be synthesized de novo or recycled by a salvage pathway from
normal catabolism. The catabolism of pyrimidines produces citric acid cycle
intermediates. There are several disorders of pyrimidine metabolism (see
the table).
Pyrimidine Metabolism Disorders
179
Uridine monophosphate synthase deficiency (hereditary orotic aciduria)

➢ Uridine monophosphate is the enzyme that catalyzes orotate
phosphoribosyltransferase and orotidine-5′-monophosphate decarboxylase reactions.
With deficiency, orotic acid accumulates, causing clinical manifestations of
megaloblastic anemia, orotic crystalluria and nephropathy, cardiac malformations,
strabismus, and recurrent infections.
➢ Diagnosis of uridine monophosphate synthase deficiency is by DNA analysis and/or
enzyme assay in a variety of tissues.
➢ Treatment of uridine monophosphate synthase deficiency is with oral uridine
supplementation.
Drugs Mentioned in This Article
Drug Name Select Trade

Arginine R-Gene 10
Adenosine Adenocard
Heparin No Brand Name
Allopurinol Zyloprim
Probenecid Probalan
Dextromethorphan Delsym
Laronidase Aldurazyme
Betaine Cystadane
Miglustat Zavesca
Eliglustat Cerdelga
Sapropterin Kuvan
Levodopa Inbrija
Carbidopa Lodosyn
180
Genetics Guidelines
Primary Care Centers

1st. visit of the child after birth (newborn)
• Normal looking child
• Abnormal looking:
o Single congenital anomaly
▪ Deformation
▪ Malformation
▪ Disruption
▪ Dysplasia
o Multiple anomalies
▪ Chromosomal abnormalities
▪ Syndrome
▪ Association
▪ Sequence
Aiming for:
 Prevention and risk of recurrence
 Early detection
o Early management
o Prevention of complication's
 Rehabilitation
Before asking for laboratory test we should ask for:

 Provisional diagnosis
 Deferential diagnosis
 What is the Benefit for the Patients?
181
Chromosomal autosomal abnormalities (diagnosed by Chromosomal study

and rearrangement [Karyotyping])
1. Facial dysmorphism
a. Upward slanting of palpebral fissures: Trisomy
b. Downward slanting of palpebral fissures: Monosomy
2. Intellectual disability (eye contact, reaction, IQ)
3. Dating since birth
4. Repeated fetal losses (early trimester abortions)
• Down syndrome (Trisomy 21):Hypotonia, flat face, Brachycephaly,
Upslanting palpebral fissures, small ears, ID (Intellectual disability).
• Trisomy 13 syndrome: Microcephaly, ID, midline defects (cleft lip, cleft
palate, or both, coloboma of the iris, holoprosencephaly, skin defects of posterior
scalp), polydactyly.
• Trisomy 18 syndrome: Hypertonia, clenched hands, ID, low birth weight,
prominent occiput, rocker-bottom feet.
• Trisomy 8 syndrome: Thick lips, deep-set eyes, prominent ears, camptodactyly.
Partial deletion and microdeletions diagnosed by high resolution Karyotyping

and better Microarray (Array CGH)
• Deletion 4p* syndrome: Microcephaly; wide bridge of nose, high forehead,

prominent glabella "Greek warrior helmet", downward slanting of the palpebral
fissures, ID.
• Deletion 5p* syndrome (Cri du Chat syndrome): Cat-like cry in
infancy, ID, microcephaly, downward slant of the palpebral fissures.
• Deletion 9p* syndrome: Craniostenosis with trigonocephaly, upslanting
palpebral fissures, and hypoplastic supraorbital ridges.
• Deletion 13q syndrome (Long arm 13 deletion syndrome, 13q- syndrome):
Microcephaly with high nasal bridge, eye defects, and thumb hypoplasia.
• Deletion 18q syndrome (Long arm 18 deletion syndrome): Midfacial
hypoplasia, prominent antihelix (DD of Far-X).
• DiGeorge syndrome (22q11.2 microdeletion syndrome, Velo-Cardio-Facial
syndrome): Velopharyngeal incompetence, prominent nose with squared nasal
root, cardiac defects (VSD, right aortic arch, F4), brain anomalies, renal
anomalies.
• 11p13 microdeletion: Wilms tumor, aniridia, ambiguous genitalia, mental and
growth retardation.
• 11p14 microdeletion: Retinoblastoma.
182
Sex Chromosomal abnormalities (diagnosed by Karyotyping)
• Turner syndrome (45 X syndrome): Presenting as abortion, short female with

congenital lymphedema of hand and foot, neck webbing, broad chest, wide
spaced nipples, cubitus valgus (we should ask for silent Y detection to do
gonadectomy to avoid gonadal tumor and Echocardiography to exclude aortic
coarctation).
• D.D. Noonan syndrome (no chromosomal abnormality): Neck webbing;
moderate short stature, pectus excavatum, cryptorchidism, pulmonary stenosis,
prescribed in males and females, Intellectual disability.
• Klinefelter syndrome (XXY syndrome): Tall stature, hypogenitalism,
hypogonadism (small penis and testis), gynecomastia (If karyotyping result was
46, XX i.e. sex reversal syndrome because HY antigen translocated on one of
the X chromosomes and the patient is phenotypically like Klinefelter syndrome
with gonadal dysgenesis).
• XYY syndrome: Normal mentality, normal fertility, aberrant behavior
(antisocial criminal behavior)
• XXX syndrome: Tall stature (hyracoid habitus), long limbs, MR, reduced
fertility, irregular menses; most cases were mosaic (with normal mentality and
fertility).
• Mixed gonadal dysgenesis (45X/46, XY): Highly variable, ranging from partial
virilization and ambiguous genitalia at birth with completely male or female
phenotype.
• Fragile X syndrome (diagnosed by PCR): Intellectual disability, autistic
behavior, craniofacial dysmorphism (prominent forehead, elongated face,
prognathism, large ears, anteverted lips).
❖ If the with dysmorphic features and normal chromosomal study, normal array CGH,
we have to suspect other syndromes with single gene disorder, environmental agents,
spectra of defects, miscellaneous associations and proceed to other investigations.
❖ Some syndromes are diagnosed by phenotypic features so no need to ask for specific
diagnostic test such as Whole Exome Sequencing (WES, NGS) unless there is specific
treatment for such type or subtype of the syndrome.
❖ Phenotypic features in some skeletal dysplasia (Achondroplasia) may be enough, If
there doubts proceed to skeletal survey and C.T or MRI if needed and helps in
management.
❖ New Guidelines for the diagnosis of Dysmorphic Features not likely major
chromosomal abnormalities recommends asking for Array CGH to diagnose minor
chromosomal abnormalities with unclear phenotypic diagnosis.
183
Macrocephaly
• Familial macrocephaly: normal child, most of the family members with large
skull.
• Hydrocephalus: Rapid head growth with increased CSF; sunset eyes.
• Macrocephaly with early over growth
o Sotos syndrome (Cerebral gigantism syndrome): Large size of prenatal onset more
in length than in weight, large hands and feet, poor coordination.
o Weaver syndrome: Macrosomia with accelerated skeletal maturation, camptodactyly,
large bifrontal diameter, ocular hypertelorism, large ears.
o Beckwith-Wiedemann syndrome (Exomphalos-Macroglossia-Gigantism
syndrome): Macroglossia, Omphalocele, Macrosomia, Ear creases.
Microcephaly
• Autosomal recessive microcephaly: sloping forehead, learning disability, runs in
families.
• Microcephaly due to Chromosomal abnormalities.
• Syndromes with Microcephaly:
o Cornelia de Lange syndrome: Microcephaly, synophrys, micromelia, intellectual
disability.
• Craniosynostosis syndromes (Premature fusion of one or more of the sutures):
o Crouzon syndrome (Craniofacial Dysostosis): Shallow orbits (proptosis), maxillary
hypoplasia, and premature craniosynostosis.
o Apert syndrome (Acrocephalosyndactyly type 1): Irregular craniosynostosis,
midfacial hypoplasia, syndactyly, broad distal phalanx of thumb and big toe.
o Carpenter syndrome: Acrocephaly, polydactyly and syndactyly of the feet, broad
bifid thumbs, Sever intellectual disability, autosomal recessive.
o Pfeifer syndrome: Brachycephaly, preaxial polydactyly, partial syndactyly, broad
thumbs and toes.
o Curry-Jones syndrome: Craniosynostosis, polysyndactyly, agenesis of the corpus
callosum, patchy skin findings.
• Holoprosencephaly sequence: Primary defect in prechordal mesoderm.
Microcephaly, severe mental retardation, seizures, Hypotelorism, cleft lip and
palate, absent philtrum, microphthalmia, retinal defect.
184
Neural tube defect

❖ Multifactorial, increased risk of recurrence with increase in severity and prevented
by folic acid intake 3 months before pregnancy to be continued for the first 3 months
of pregnancy
• Anencephaly (Absence of a major portion of the brain, skull, and scalp. lethal,
usually still birth or abortion)
• Iniencephaly (Rare complex neural tube defect involving the occiput and inion,
resulting in extreme retroflexion of the head, combined with occipital
encephalocele or rachisciasis of the cervical or thoracic spine)
• Encephalocele (Sac-like protrusion or projection of the brain and the membranes
that cover it through an opening in the skull)
• Meningocele, Meningomyelocele (A sac that pushes through the gap in the spin.
Follow up for the child as he may develop hydrocephalus [Arnold chiari
syndrome])
o Meningomyelocele, Anencephaly, Iniencephaly sequence: Primary defect in neural
tube closure. Anencephaly due defect in closure at the anterior portion of the neural
groove. Defects in closure at the mid or caudal neural groove can give rise to
meningomyelocele. Defects in closure in the cervical and upper region can culminate in
the iniencephaly (retroflexion of the upper spine with short neck and trunk. Cervical and
upper thoracic vertebral anomalies. Defects of thoracic cage, anterior spina bifida)
• Spina bifida occulta (Dimple, Patch of hair, or a red mark at the base of the spine)
o Occult spinal dysraphism sequence (Tethered cord malformation sequence):
Tufts of hair, skin tags, dimples, lipomata and aplasia cutis at the region of L2-L3. Sacral
and vertebral anomalies. Evaluation and early management should be done to prevent
neuromuscular lower limb or urologic problems. Roentgenograms of the spine,
ultrasound to detect normal movement of the spine with respiration followed by
magnetic resonance imaging in questionable cases.
185
Tall Stature
• Familial: Normal tall stature in the family.
• Marfan syndrome (single gene): Arachnodactyly (positive thumb singe) with
hyperextensibility, lens subluxation (upward and lateral), aortic dilatation.
• Homocystinuria: lens dislocation downward and nasal, increased homocystine in
extended metabolic screen (for DD).
• Klinefelter syndrome
• XYY syndrome
• XXX syndrome
Limb Anomalies as Major feature
• Polydactyly (Postaxial i.e. near little finger, Preaxial i.e. near thumb finger)
o Familial polydactyly (Autosomal dominant, isolated with no other abnormalities)
o Syndromes
• Split hand (ectrodactyly)
o Split-Hand/Foot with Long Bone deficiency (SHFLD): Split hand/Split foot, absent
of long bones of arms and legs.
• Brachydactyly (Short square hand)
o Cartilage-hair-hypoplasia (short square hands, Short limbed, sparse hair, diminished
cellular immunity).
• Thumb dysplasia
o Holt Oram syndrome (hand anomaly and heart defects)
• Big thumb (Rubinstein-Taybi syndrome [broad thumb syndrome])
o Oral-Facial-Digital syndrome
❖ Type I (X-linked dominant): Oral frenula and clefts, hypoplasia of alae nasi, digital
asymmetry and syndactyly.
❖ Type II (Mohr syndrome) AR: Cleft tongue, conductive hearing loss, partial
reduplication of hallux, postaxial polydactyly.
o Ellis-van Creveld syndrome (Chondroectodermal dysplasia): Neonatal teeth, oral
frenula, narrow elongated trunk, short distal extremities, polysyndactyly, nail
hypoplasia.
o Radial aplasia-Thrombocytopenia syndrome (TAR syndrome): Thrombocytopenia
with absent or hypoplasia of megakaryocytes, bilateral absent radius with ulnar
abnormalities.
186
o Holt-Oram syndrome (Cardiac-Limb syndrome): Upper limb defects (hypoplasia of

ulna, thumbs may be absent, hypoplastic, triphalangeal or bifid, phocomelia between
thumb and index finger), Cardiac anomaly, Narrow shoulders.
o Fanconi pancytopenia syndrome: Radial hypoplasia, hyperpigmentation,
pancytopenia, liable to malignancy.
o Wiskott-Aldrich syndrome (Eczema-Thrombocytopenia-Immunodeficiency
syndrome): Eczema, thrombocytopenia (low platelet count), immune deficiency and
bloody diarrhea, increase risk of malignancy.
• Familial Thrombocytopenia: increased IgA with Nephritis but not with limb
anomaly.
o Levy-Hollister syndrome (Lacrimo-Auriculo-Dento-Digital syndrome):
Nasolacrimal duct obstruction, simple cup-shaped ears with short helix and
underdeveloped antihelix, hypodontia with enamel hypoplasia, digital abnormalities
with absent radius.
o Diamond-Blackfan anemia (AASE syndrome): Triphalangeal thumb with mild radial
hypoplasia, hypoplastic anemia that tends to improve with age.
o Poland sequence: Unilateral defect of pectoralis muscle, hypoplasia of the upper limbs
distally with varying degrees of syndactyly.
o Ulnar-Mammary syndrome: Ulnar ray defects, Absent/hypoplasia of breast
development, diminished/absent axillary hair and perspiration.
o Child Syndrome (Child is an acronym for Congenital Hemidyspalsia with
Ichthyosiform erythroderma and Limb Defects): Unilateral hypomelia and skin
hypoplasia "ichthysiform nevus" or "inflammatory epidermal nevus", cardiac defects.
o Adams-Oliver syndrome: Aplasia cutis congenita of the scalp with or without
underlying defect of bone, terminal transverse defects of limbs.
o Popliteal Pterygium syndrome (Facio-Genito-Popliteal syndrome): Popliteal web,
cleft palate, lower lip pits.
o Escobar syndrome (Multiple Pterygium syndrome): Multiple pterygia,
camptodactyly, syndactyly.
o Femoral Hypoplasia-Unusual Facies syndrome (Femoral-facial syndrome):
Femoral hypoplasia, short nose, cleft palate.
o Amnion ruptures sequence (Amniotic bands disruption complex): Variable limb
anomalies (Pseudosyndactyly, amputation of fingers by amniotic strands. Bands
constricting ankle). Annular constrictions, intrauterine amputations and umbilical cord
constriction.
o VACTERL association: VACTERL is an acronym that stands for Vertebral, Anal,
Cardiac, Tracheal, Esophageal, Renal and Limb anomalies. Vertebral anomalies.
Cardiac defects. Anal atresia with or without fistula. Tracheoesophageal fistula with
esophageal atresia. Renal anomaly. Radial dysplasia, including thumb or radial
hypoplasia, preaxial polydactyly, syndactyly. Single umbilical artery.
187
Hearing loss (Deafness)

❖ Deafness or hearing defects should be suspected in such syndromes to prevent
intellectual disability or renal failure.
• Waardenburg syndrome: Deafness, heterochromia iridis, partial albinism
(hypopigmented fundus, white eye lashes, eyebrows and forelock).
• Oral-Facial-Digital syndrome, Type II (Mohr syndrome)
• Pendred syndrome: Neck swelling (Thyroid swelling), deafness.
• Stickler-Marshal syndrome (Hereditary Arthro-Ophthalmopathy): Myopia,
flat facies, spondyloepiphyseal dysplasia, deafness.
• Leopard syndrome: Skin rash, genital abnormalities, deafness.
• Goldenhar syndrome (Oculo-Auriculo-Vertebral Spectrum) (First and second
branchial arch syndrome, Hemifacial Micromelia): Notch in upper eye lid with
epibulbar lipodermoid, hypoplasia of the mandible (micrognathia), vertebral
anomalies commonly cervical, microtia, variable deafness.
• Treacher Collins syndrome (Mandibulofacial dysostosis): Mandibular
hypoplasia with downslanting palpebral fissures, defects of lower eye lid,
malformed external ear, conductive hearing loss.
• Klippel-Feil sequence: Short neck (cervical spine fusion + segmentation errors),
cardiac defects, deafness either conductive or sensorineural.
• Cevico-Oculo-Acoustic syndrome (Wildervank syndrome): Klippel-Feil
anomaly, abducens paralysis with retracted globes, sensorineural deafness.
EYE Anomalies
• Anophthalmia may be isolated with normal mentality
• Microphthalmia
o Lenz Microphthalmia syndrome: Microphthalmia, growth retardation, ear anomalies.
o Lowe syndrome (Oculocerbrorenal syndrome, OCRL): Microphthalmia, cataract
(neonatal), kidney problems (develops from the first year), brain anomalies with
intellectual disabilities.
o Oculodentodigital syndrome (Oculodentodigital dysplasia): Microphthalmia,
enamel hypoplasia, camptodactyly of fifth finger.
o Oculo-Facio-Cardio-Dental syndrome: Microphthalmia, congenital cataract, septated
nasal cartilage, septal cardiac defects, delayed primary dentition, radiculomegaly
(increased size of tooth root).
188
Obesity
• Bardet-Biedl syndrome (Laurence-Moon-Biedl syndrome): Obesity, red-cone
dystrophy (retinitis pigmentosa), postaxial polydactyly, intellectual disability,
hypogenitalism.
• Prader-Willi syndrome: Obesity, hypotonia, small hands and feet,
hypogenitalism, intellectual disability.
o Methylation analysis (fluorescent in situ hybridization [FISH]), can detect
microdeletion in chromosome 15q11.2-q13 (paternal origin).
o Growth hormone (GH) therapy results in significant improvement for obesity, growth
and physical function.
o 15q11.2 microdeletion and microduplication: Dysmorphic features, increased risk of
congenital malformations, intellectual disabilities, autism spectrum disorders, epilepsy.
Hemangioma and Hemihypertrophy

• Sturge-Weber syndrome: Flat facial hemangioma (at the distribution of
trigeminal nerve), meningeal calcifications and hemangiomata with seizures,
intracranial calcification.
• Klippel-Trenaunay syndrome: Asymmetric limb hypertrophy (contralateral),
hemangioma, vascular malformation, venous varicosities.
• Parkes Weber syndrome (Capillary malformation-arteriovenous
malformation syndrome [CV-AVM], RASA1 related disorders):
Arteriovenous (AV) malformations (AVMs) and fistulas (AVFs), capillary,
lymphatic, venous malformations and Segmental overgrowth.
• Beckwith-Wiedemann syndrome (Exomphalos-Macroglossia-Gigantism
syndrome): Macroglossia, omphalocele, macrosomia, ear pits and creases.
189
Connective Tissue Disorders

• Cutis laxa: Redundant skin (skin too large for the body), no skin fragility, no skin
bruisibility, no hyperextensible joints.
• Geroderma Osteodysplastica (Walt Disney dwarfism): cutis laxa (lax, wrinkled
skin), long hands, short lower limb, sever osteoporosis.
• Ehlers-Danlos syndrome: Hyperextensibility of joints, Skin Fragility,
Bruisibility:
o Type 3: Benign familial hypermobility.
o Type 4: Ecchymotic or arterial (arterial aneurysms, dissection or rupture).
o Type 5: Muscle hemorrhage.
o Type 6: Ocular fragility and keratoconus.
o Type 7: Arthrochalasis multiplex congenita.
o Type 8: Periodontal form.
o Type 1: Gravis (Fragility, bruisibility, hypermobility).
o Type 2: Mitis (Fragility, bruisibility, hypermobility).
• Osteogenesis imperfecta: Fragile bone (repeated fractures), blue sclera,
hyperextensibility, presenile deafness.
• Fibrodysplasia ossificans progressiva syndrome: Short hallux, fibrous dysplasia
leading to ossification in muscles and subcutaneous tissues.
• Myhre syndrome: Progressive thickness of the skin and serosa's, muscle
hypertrophy, joint limitations, cardiovascular abnormalities.
190
SKIN
• Ectodermal dysplasia {1. Trichodysplasia (hair dysplasia), 2. Dental dysplasia, 3.
Onychodysplasia (nail dysplasia), 4. Dyshidrosis (sweat gland dysplasia)}:
o Hypohidrotic (Anhidrotic) type: Sever form, most common (1-2-3-4 defects)
o Hydrotic type: (1-2-3 defects)
• Ectrodactyly-Ectodermal dysplasia-Clefting syndrome (EEC syndrome):
Ectrodactyly, ectodermal dysplasia, cleft soft palate.
• TP-63 Related Ectodermal dysplasia (Aka Hay Wells syndrome): Ectodermal
dysplasia, cleft lip/palate, ankyloblepharon.
• Ichthyosis: Scaly; Dry and Erythematous skin (Hyperkeratosis of stratum
corneum; Underdevelopment of stratum granulosum; Increased epidermal
turnover; Normal dermis)
o Lamellar ichthyosis AR: Collodion-like skin.
o Ichthyosis vulgaris X-L: Dry, fish-scale skin.
o Sjögren-Larsson syndrome: Ichthyosis, intellectual disability, spasticity, retinitis
pigmentosa.
• Epidermolysis bullosa: Very fragile skin. Vesicles and bullae of the skin and
occasionally the mucous membrane. Generalized or localized. Precipitated with or
without trauma. Congenital or later (AR – AD). Lethal or not.
• Goltz syndrome (Focal Dermal hypoplasia): Poikiloderma with focal dermal
hypoplasia, syndactyly, dental anomalies.
• Tuberous Sclerosis syndrome: Hamartomatous skin nodules, seizures,
phakomata (small grayish white tumor seen microscopically in the retina), should
exclude cranial calcifications.
• Neurofibromatosis syndrome: Café au lait skin spots (regular edges, more than
8) and freckles, multiple neurofibromata, deafness in some cases.
• Mccune-Albright syndrome: Irregular large skin pigmentation, polyostotic
fibrous dysplasia, sexual precocity.
• Incontinentia pigmenti syndrome: Irregular pigmented skin lesions with or
without dental anomaly, patchy alopecia.
191
• Increased sister chromatid exchange with skin manifestations

o Xeroderma Pigmentosa: Atrophic and pigmentary skin changes, undue sunlight
sensitivity, increased sister chromatid exchange, actinic skin tumors.
o De Sanctis-Cacchione syndrome: Xeroderma Pigmentosa, progressive neurologic
deterioration, growth deficiency, microcephaly and hypogonadism.
o Ataxia-Telangiectasia: Ataxia (cerebellar deterioration), oculocutaneous
telangiectasia, immunodeficiency, increased sister chromatid exchange.
o Bloom syndrome: Shot stature, malar hypoplasia, telangiectatic erythema of the face,
increased sister chromatid exchange (liable to malignancy).
• Premature senility with skin manifestations
o Cockayne syndrome: Postnatal growth failure, senile-like changes begin in infancy,
sunken eyes, retinal degeneration and impaired hearing, progressive neurologic
dysfunction, photosensitivity of thin skin.
o Werner syndrome (Adult progeria): Hyperkeratosis, subcutaneous calcifications, late
postnatal short stature with absence of growth spurt, early graying and whitening with
premature loss of scalp hair, develop disorders of aging early in life.
o Rothmund-Thomson syndrome: Development of poikiloderma (marbled skin),
cataract with or without other ectodermal dysplasia.
o Progeria syndrome: Early aging with alopecia, atrophy of subcutaneous fat, skeletal
hypoplasia and dysplasia.
• Altered skin manifestations, Melanomata
o Linear sebaceous nevus sequence: Midfacial nevus sebaceous, seizures, mental
deficiency.
o Hypomelanosis of Ito (Incontinentia Pigmentosa Achromians): Intellectual
disability, autistic behavior, seizures. Macrocephaly. Malformed auricles, iridal
heterochromia, abnormal retinal pigmentation. Central precocious puberty. Nevus of
Ota, angiomatous nevi, ichthyosis.
192
Bone Defects
• Cleidocranial dysplasia: Absent clavicle; late ossification of cranial sutures;
delayed eruption of teeth.
• Osteopetrosis: Dense, thick, fragile bone; secondary pancytopenia; cranial nerve
compression.
• Pyknodysostosis: osteosclerosis; short distal phalanges; delayed closure of
fontanels; dysplastic clavicle.
• Nail-Patella syndrome (Hereditary osteo-onychodysplasia): Nail dysplasia;
patella hypoplasia; iliac spurs.
• Femoral Hypoplasia-Unusual Facies syndrome (Femoral-Facial syndrome):
Femoral hypoplasia, short nose, cleft palate.
• Diabetic embryopathy: Sacral agenesis; limb anomalies.
Facial Defects
• Smith-Lemli-Opitz syndrome: Anteverted nostrils, Squint, Ptosis of eyelids,
Moderate short stature, Syndactyly of second and third toes, Hypospadias and
cryptorchidism in males.
• Mobius sequence: Sixth and seventh cranial nerve palsy, Micrognathia, Hearing
loss, cleft palate.
• Blepharophimosis-Ptosis-Epicanthus inversus syndrome: Inner canthal fold,
lateral displacement of inner canthi, ptosis.
• Oculocerebrofacial syndrome (Kaufman syndrome): Short upslanting palpebral
fissures, Blepharophimosis, micrognathia.
• Robin sequence (Pierre Robin syndrome): Sever micrognathia, Glossoptosis,
cleft soft palate; Primary defect due to early mandibular hypoplasia.
• Frontonasal dysplasia sequence (Median cleft face syndrome): Cranium
bifidum occultum, median facial cleft, ocular hypertelorism.
• Fraser syndrome: Cryptophthalmos (absence of the palpebral fissure but usually
includes varying absence of eyelashes and eyebrows and defects of the eye,
especially the anterior part), cutaneous syndactyly, genital anomalies.
• CHARGE syndrome: Acronym refers to, Coloboma of eyes, Heart defects,
Atresia choanae, Retarded growth and development and/or CNS anomalies, Genital
anomalies and hypogonadism, and Ear anomalies and deafness.
• Mandibulofacial dysostosis with microcephaly: Microcephaly, Midface
hypoplasia, ear anomalies.
193
Facial-Limb Defects
• Angelman syndrome (Happy Puppet syndrome): "Puppet-like" gait (ataxia and Jerky
arm movements), paroxysms of laughter, Characteristic facies (Microbrachycephaly,
blond hair, pale blue eyes, large mouth with tongue protrusion).
o Loss of function of the UBE3A gene located on chromosome 15q11-q13 expressed
from maternal chromosome only results for this disorder.
o 15q11.1q11.3 duplications and triplications is the most frequent benign
supernumerary marker chromosome which does not contain Prader-Willi/Angelman
syndrome (PWS/AS). Large 15q marker containing PWS/AS region results in
intellectual disability, seizures, and autism spectrum disorders, schizophrenia,
strabismus and dysmorphic features.
• Miller syndrome (Postaxial acrofacial dysostosis syndrome) (Treacher Collins-like
face syndrome): Malar hypoplasia, eyelids coloboma and ectropion, micrognathia, cleft
lip and/or cleft palate, hypoplastic cup-shaped ears; limb deficiency especially postaxial.
• Nager syndrome (Nager Acrofacial dysostosis syndrome): Radial limb hypoplasia,
Malar hypoplasia, Ear defects.
• Townes-Brocks syndrome: Thumb anomalies, Auricular anomalies, Ana anomalies.
• Laurin-Sandrow syndrome: Flat nose with grooved columella, complete
Polysyndactyly of fingers (cup-shaped hands), polydactyly of toes (Mirror image feet)
with talipes equinovarus.
• Oral-Facial-Digital syndrome (OFD syndrome, Type I): Oral frenula and clefts,
hypoplasia of alae nasi, digital asymmetry.
• Mohr syndrome (OFD syndrome, Type II): Cleft tongue, conductive deafness, Partial
reduplication of hallux.
• Coffin-Lowry syndrome: Downslanting palpebral fissures, bulbous nose, tapering
fingers.
• F G syndrome (Opitz-Kaveggia syndrome): Imperforate anus, hypotonia, prominent
forehead.
• Catel-Manzke syndrome (Palatodigital syndrome, Type Catel-Manzke):
Micrognathia, cleft palate (Robin sequence), hyperphalangy of index finger.
• Langer-Giedion syndrome (Tricho-Rhino-Phalangeal syndrome, Type II): Multiple
exostoses, bulbous nose with peculiar facies, loose redundant skin in infancy.
• Tricho-Rhino-Phalangeal syndrome, Type I: Bulbous nose, sparse hair, epiphyseal
coning.
• Roberts syndrome (Roberts-SC Phocomelia syndrome): Some degree of phocomelia
(more sever in the upper limb), midfacial defects, severe growth deficiency,
Cryptorchidism.
194
Short Stature
1) Proportionate
a. Normal Variation
1. Familial
2. Constitutional (short child, normal adult, normal bone age)
b. Nutritional
1. Chronic Mixed Malnutrtion (unstable hemoglobin)
c. Systemic chronic disease
1. Cardiac
2. Renal
3. Hepatic
4. GIT (Celiac disease)
d. Endocrine Causes
1. Growth hormone deficiency (normal birth weight)
2. Hypothyroidism
3. Pseudohypoparathyroidism (hypocalcemia)
4. Precocious puberty
5. Cushing’s
e. Intrauterine growth retardation
1. Cornelia de Lange syndrome (short stature, synophrys, thin downturning
upper lip, micromelia [D.D 13q- syndrome])
2. Russell Silver Syndrome (prenatal short stature, hemihypertrophy,
clinodactyly)
3. Seckel dwarfism (sever short stature, microcephaly, prominent nose)
4. Teratogenic (TORCH, smoking)
5. Placental insufficiency (short stature with hypospadias)
f. Chromosomal abnormalities (Turner syndrome, Down syndrome)
g. Short Stature with Skin Manifestations & Premature Senility
1. Cockayne syndrome (Senile-like changes, sunken eyes, retinal degeneration,
photosensitivity of thin skin)
2. Werner Syndrome (Adult progeria) (hyperkeratosis, no growth spurt)
3. Rothmund Thomson Syndrome (marbled skin and telangiectasia)
4. Bloom (malar hypoplasia, telangiectasia)
5. Progeria (Alopecia, atrophy of subcutaneous fat, skeletal hypoplasia and
dysplasia)
195
2) Non-Proportionate
a. Short limbed (Acromelic [near the fingers], Mesomelic [in-between],

Rhizomelic [near the trunk]).
1. Acromesomelic dysplasia (Acromelic and Mesomelic micromelia more on the
upper limbs than lower limbs, large big toes, large head)
2. Achondroplasia (Macrocephaly, short limbs, depressed nasal bridge, mild
hypotonia)
3. Pseudo achondroplasia (Normal skull, short limbs)
4. Achondrogenesis
i. Type I (soft skull, very short limbs, incomplete ossification, Hydropic)
ii. Type II (Large skull, extremely short stature)
iii. Type III non-lethal (Sever hypomelia, polydactyly)
5. Chondrodysplasia Punctata (Stapling of the epiphysis)
6. Diastrophic dysplasia (Short abducted thumb, soft cystic ear, talipes equinovarus)
7. Cartilage-hair Hypoplasia (Sparse hair, short square hands, lymphopenia, renal
abnormalities)
8. Femoral Hypoplasia with unusual facies (Short bowed femur with dysmorphic
facies)
9. Metaphyseal chondrodysplasia, malabsorption and neutropenia syndrome
10. Hereditary Arthro-Ophthalmopathy (Stickler-Marshall Syndrome) (Short
stature, deafness, myopia)
11. Osteogenesis Imperfecta
i. Type I (AD) (Fragile bone, blue sclera, hyperextensibility, deafness)
ii. Type II (AR) (Lethal, multiple fractures, soft skull)
iii. Type III (AR) (Neonatal death, multiple fractures)
iv. Type IV (Repeated fractures, blue sclera, bone deformity)
b. Short limbed, Short ribs
1. Thanatophoric dysplasia (Cloverleaf skull)
2. Short-rib polydactyly type 1 (Small pelvis, cardiac defects)
3. Short-rib polydactyly type 2 (Ambiguous genitalia, polysyndactyly)
4. Campomelic dysplasia (Bowed tibia, hypoplastic scapulae, ambiguous genitalia,
flat facies)
5. Asphyxiating thoracic dysplasia (Lung hypoplasia, micromelia, hypoplastic iliac
wings)
c. Short trunked
1. Mucopolysaccharidosis
2. Kniest dysplasia (Barrel shaped chest)
3. Clausen syndrome (Pectus carinatum, sever lumber lordosis)
d. Short trunked, short ribs (Costo-vertebral Segmentation Anomaly)
1. Spondylo-Costal dwarfism
196
DSD (Differences in Sex Development)

Sex Assignment
Actual Anatomy:
• Normal genitalia
• Abnormal genitalia
o Hypogenitalism (normal anatomy):
▪ Prader Willi syndrome (Hypotonia, MR, Obesity, Small hands and feet)
▪ Pure XX Gonadal Dysgenesis
o Intersex (DSD):
▪ True: diagnosed by detection of both gonads (testicular and ovarian tissues):
✓ Bilateral True-hermaphroditism
✓ Unilateral Hermaphroditism
✓ Alternating (one side testicle and ovary on the other side)
Chromosomal pattern:
 50% XX
 30% XY
 20% mixed XX,XY
▪ Pseudo:
• Female Pseudo hermaphroditism
o Excessive virilization
▪ Maternal: exclude ovarian virilizing tumor of the mother or drug intake.
▪ Fetal: Congenital adrenal hyperplasia (Male with bilateral anorchia
phenotype; 46, XX genotype).
o Undetermined origin (associated with other anomalies)
▪ Male Pseudo hermaphroditism (Defective Virilization)
➢ Defect in Testicular Differentiation
▪ Absent HY antigen (Campomelic dysplasia)
▪ Target Tissue Resistance: (Swyer syndrome) Pure XY gonadal
dysgenesis
▪ Embryonic Testicular Regression Syndrome (absence of testicles at
late embryonic period, child with minimal virilization)
▪ Bilateral Anorchia (absence of testicles at early embryonic period,
child with less minimal virilization)
➢ Leydig Cell Aplasia or Hypoplasia (decreased or lack of production
of sex steroids by the gonads despite high circulating levels of
gonadotropins)
➢ DYSHORMONOGENESIS
➢ MIF
▪ Uterine hernia syndrome
➢ Defect in Androgen Action
▪ Complete Testicular Feminization (complete female phenotype with
small penis)
▪ Partial Testicular Feminization
▪ 5-α Reductase Deficiency (more likely male phenotype with male
sexual desire)
197
Refer to Multidisciplinary Team

 Endocrine
 Genetics
 Urology
 Psychology/Psychiatry
 Religious Counseling
 Gynecologist
Sex Assignment
 Nonfunctioning female better than non-functioning male
 Actual Anatomy
 Available surgical intervention
 Functional Endocrinology
 Chromosoml Pattern
198
Atlas
199
200
201
202
203
204
205
206
207
208
209
210
211
Myotonic Dystrophy Congenital

Myotonic Dystrophy
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
Annex
Boys
253
254
255
256
257
258
259
260
Girls
261
262
263
264
265
266
267
268
269
Pediatric Gastroenterology Protocol of EHA
0
Egyptian Clinical Practice Guidelines

in
Pediatric Gastroenterology
for
First Edition
2024
Prepared By
in
Pediatric Gastroenterology
for
1
Executive Committee
1. Prof. Ayman Emil : (Head of the Committee) Professor Of Pediatrics And

Pediatric Gastroenterology, Head Of Pediatric Endoscopy Unit At Cairo
University.
2. Prof. Ahmad Hamdy : Professor of pediatrics and pediatric Gastroenterology Ain
Shams university.
3. Prof. Ahmad Foad : Professor Of Pediatrics And Pediatric Gastroenterology
Alexandria University.
4. Prof. Gehan Bepers : Professor Of Pediatrics And Pediatric Gastroenterology
Minia University.
5. Prof. Hatem Hussein : Professor Of Pediatrics And Pediatric Gastroenterology
Zagazig University.
6. Prof. Mohamed Ezz Elregal : Professor Of Pediatrics And Pediatric
Gastroenterology Mansoura University.
7. Prof. Naglaa Abou Faddan : Professor Of Pediatrics And Pediatric
Gastroenterology Assiut University.
8. Dr. Marian Abd El -Messiah : Pediatric Specialist, Coordinator Of
Gastroenterology Committee
All Intellectual Property Rights are reserved to EHA. No part of this publication can
be reproduced or transmitted in any form or by any means without written permission
from the EHA and authors.
2

Board
Authority (EHA).
Reviewed By



3
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Gastroenterology is
to unify and standardize the delivery of healthcare to all newborns at all health
facilities.
The current state of healthcare in which avoidable failures are abound. “We
excellent repositories of detailed information about the etiology, pathogenesis,
clinical picture, diagnosis, and treatment of a condition. However, for a busy clinician
looking for the best way to manage a sick patient, a standardized path for effective
management of the patient may be impossible to discern. So, it would be a lot easier
if we all managed simple things in a uniform way using the best available evidence
and resources.
In Gastroenterology, busy clinicians have all felt the need for a concise, easy-
to-use resource at the bedside for evidence-based protocols, or consensus-driven care
paths where high-grade evidence is not available.
highest level of evidence available in each case. Our goal is to provide an
authoritative practical medical resource for neonatologists, pediatricians, and other
healthcare providers dealing with newborns after birth. This protocol is the product of

that practicing neonatologists, fellows and nurse practitioners will find this protocol
useful in delivering high-quality clinical care to their patients. We remain open to
feedback and suggestions about how to improve this resource and how to make it
maximally useful to those delivering care at the bedside in gastroenterology.
In Pediatric Gastroenterology
4
Table of Contents
Page
Title
Number
Preface 4
Protocol for Management of Acute Diarrheal illness 6
‫عالج النزالت المعوية في المنزل‬ 11
Protocol for Management of H.pylori Related Diseases 12
Principles of Management of Constipation 13
Protocol for Management of Suspected Celiac Disease 16
Protocol for Management of Ingested Foreign Body 17
Protocol for Management of GI Bleeding 21
5
Protocol for Management of Acute Diarrheal illness
Figure (1) Management of a Case of Age
AGE = Acute gastroenteritis

PDS = Pediatric dehydration scale
ORS = Oral rehydration salts solution
6
Figure (2) Home Management of a Case of Age

7
Figure (3) Hospital Management of a Case of Age

IV= Intravenous
Na= Sodium
NG= Nasogastric
8
Table (1) Pediatric Dehydration Scale (PDS) for Children
Characteristics 0 1 2
Thirsty, restless or Drowsy, limp, cold
General Appearance Normal lethargic but irritable
or sweaty ±comatose
when touched
Eyes Normal Slightly sunken Extremely sunken
Mucous Membranes
Moist Sticky Dry
(tongue)
Goes back
Skin Turgor Delayed (<2sec) Very delayed (>2sec)
immediately
A score of 0 represents no dehydration; a score of 1 to 4, some dehydration; and a score of 5

to 8 moderate/severe dehydration.
Table (2) Indications for Hospitalization

Indications for Hospitalization:
✓ Shock
✓ Severe dehydration (>9% of body weight)
✓ Neurological abnormalities (lethargy, seizures, etc)
✓ Intractable or bilious vomiting
✓ Failure of oral rehydration
✓ Suspected surgical condition
✓ Conditions for a safe follow-up and home management are not met
✓ Complicated Age (electrolyte imbalance, DIC)
Table (3) Indications for Discharge

Indications for Discharge:
✓ Sufficient rehydration is achieved as indicated by weight gain and/or clinical status

✓ IV fluids are no longer required
✓ Oral intake equals or exceeds losses
✓ Medical follow-up is available via telephone or office visit
9
Table (4) Indications for IV Rehydration
Indications for IV Rehydration:
✓ Shock
✓ Dehydration with altered level of consciousness or severe acidosis
✓ Worsening of dehydration or lack of improvement despite oral or enteral rehydration therapy
✓ Persistent vomiting despite appropriate fluid administration orally or via an NG tube (Nasogastric)
✓ Severe abdominal distension and ileus
Table (5) Holliday–Segar Method to Calculate Maintenance Fluid
Child’s Weight Baseline Daily Fluid Requirement

(Kilogram) (Milliliter / Kilogram)
1–10 kg 100 ml/kg
10–20 kg 1000 ml + 50 ml/kg for each kg >10 kg
>20 kg 1500 ml + 20 ml/kg for each kg >20 kg
Table (6) Signs of Shock
Signs of Compensated Shock:

✓ Tachycardia
✓ Cool extremities
✓ Prolonged capillary refill (despite warm ambient temperature)
✓ Weak peripheral pulses compared with central pulses
✓ Normal blood pressure
Signs of Decompensated Shock:
✓ In addition to the above, these signs include:
✓ Depressed mental status
✓ Decreased urine output
✓ Metabolic acidosis
✓ Tachypnea
✓ Weak central pulses
Signs of decompensated shock include the signs listed above plus hypotension. In the absence of
blood pressure measurement, decompensated shock is indicated by the non- detectable distal pulses
with weak central pulses in an infant or child with other signs and symptoms consistent with
inadequate tissue oxygen delivery.
10
‫‪Pediatric Gastroenterology Protocol of EHA‬‬
‫عالج النزالت المعوية في المنزل‬

‫‪ .1‬محلول معالجة الجفاف‪:‬‬
‫• طريقة اإلعداد‪:‬‬
‫✓ يتم إضافة محتويات الكيس على ‪ 200‬سم ماء في كوب نظيف‪.‬‬
‫✓ يتم إعطاء المحلول لألطفال باستخدام ملعقة صغيرة نظيفة) لألطفال اقل من عامين( او عن طريق اخذ رشفات مباشرة من‬
‫الكوب‪.‬‬
‫✓ األطفال اقل من ‪ 6‬أشهر يمكن إعطائهم المحلول عن طريق حقنة منزوعة السن ويتم تقطير المحلول في فم الطفل) ال يتم‬
‫إعطاء المحلول في زجاجات الرضاعة( ‪.‬‬
‫• الجرعة المناسبة‪:‬‬
‫✓ يتم إعطاء الطفل ‪ 10 - 5‬مل )‪ 2 - 1‬ملعقة صغيرة( لكل كيلوجرام من وزن الطفل بعد كل حركة إسهال‪.‬‬
‫• طريقة إعطاء محلول معالجة الجفاف‪:‬‬
‫✓ يتم إعطاء ملعقة صغيرة أو رشفة من الكوب للطفل كل ‪ 2 - 1‬دقيقة‪.‬‬
‫✓ إذا حدث قيء يتم االنتظار لمدة ‪ 10‬دقائق ثم نعيد إعطاء المحلول للطفل ببطء أكثر) ملعقة صغيرة او رشفة من الكوب للطفل‬
‫كل ‪ 3 - 2‬دقيقة( ‪.‬‬
‫‪ .2‬تغذية الطفل‪:‬‬
‫✓ ال يجب إيقاف التغذية للطفل سواء كانت رضاعة طبيعية أو صناعية أو غذاء اعتيادي‪.‬‬
‫✓ يجب اإلكثار من إعطاء السوائل للطفل قدر المستطاع إلى حين توقف اإلسهال‪.‬‬
‫✓ السوائل التي ال يجب إعطائها للطفل هي‪:‬‬
‫‪ ‬المشروبات الغازية‬
‫‪ ‬العصائر التجارية المعلبة‬
‫‪ ‬المشروبات المحالة بالسكر‬
‫‪ ‬المشروبات التي تحتوي على مادة الكافيين‬
‫‪ .3‬الزنك‪:‬‬
‫✓ يتم إعطاء شراب الزنك لألطفال الذين يعانون من النزالت المعوية لمدة ‪ 14‬يوما وتكون الجرعة‪:‬‬
‫‪ ‬مجم يوميا لألطفال أقل من ‪ 6‬أشهر‪.‬‬
‫‪ ‬مجم يوميا لألطفال أكبر من ‪ 6‬أشهر‪.‬‬
‫‪ .4‬البروبيوتيك‬
‫❖ يجب زيارة الطبيب في الحاالت اآلتية‪:‬‬
‫✓ القيء المستمر‬
‫✓ قيام الطفل بتمرير العديد من البراز المائي‬
‫✓ ارتفاع درجة الحرا ة‬
‫✓ األكل أو الشرب القليل‬
‫✓ العطش الشديد‬
‫✓ وجود دم بالبراز‬
‫✓ عدم تحسن الطفل خالل ‪ 3‬أيام‪.‬‬
‫‪11‬‬
Protocol for Management of H.pylori Related Diseases
• Alarm signs include persistent right upper or right lower quadrant pain, dysphagia,
odynophagia, persistent vomiting, gastrointestinal blood loss, involuntary weight
loss, deceleration of linear growth, delayed puberty, unexplained fever, and a family
history (Jones NL et al., 2017)
• Refractoriness to oral iron is defined as failure to respond to treatment at a dose of
at least 100 mg of elemental iron per day after 4 to 6 weeks of therapy (Hershko C
and Camaschella C.2014)
• Chronic ITP is defined by ITP persistence beyond 12 months, with spontaneous
recovery occurring in less than 10% of adults (William B and Mitchell MD, 2019)
• Functional bowel disorders are heterogeneous group of disorder, the most
prevalent of which is irritable bowel syndrome (IBS) and functional abdominal pain
(FAP) syndrome. FAP characterized by frequent or continuous abdominal pain
associated with a degree of loss of daily activity, in the absence in change in bowel
habits (Farmer AD and Aziz Q.2014)
12
Principles of Management of Constipation

Infrequent passage of stool for whatever reason often leads to constipation and faecal
impaction with secondary problems of faecal soiling, anorexia, abdominal pain,
behavioral problems and low self-esteem. The management of constipation involves:
1. Education and explanation.

2. High fibre diet and high fluid intake (consider dietician review during
admission).
3. Retraining children to sit regularly on the toilet after meals.
4. Laxative medications to soften the stool (e.g. Lactulose) and increase stool
expulsion (e.g. Senokot® - Note: non-formulary at Auckland DHB - suggest
use docusate / senna combination). Other options include MgOH 8%, or
movicol.
5. Faecal disimpaction (e.g. colonic lavage or phosphate enema). Note the former
should be used with caution under the age of 1 year and the latter is
contraindicated under the age of 3 years.
Faecal Disimpaction:
• Some consultants will recommend a trial of Picoprep (sodium picosulphate) at home in
order to try and prevent an admission to hospital for Klean-Prep™ (if available )
Picoprep Dose
<2 yr olds ¼ sachet BD for 2/7 or 0.25mg\kg Max 5mg
2-4 yr olds ½ sachet BD for 2/7 or 2.5mg -5mg
>4 yrs 1 sachet BD for 2/7 or 5mg-10mg
• This is may prevent an admission. Adequate fluid intake during treatment is very
important. Restarting laxatives after treatment course is vital, this treatment should only
be instituted by an authorizing consultant and the caregivers have the ability to phone for
advice if required.
• Lactulose 2gm\kg\day in 1-2 doses.
• Movicol has also been used as a disimpaction agent in the outpatient setting. (if
available) The dose for this is 1-1.5g/kg/day for 3 days (1 packet of movicol contains
13g). The limitation of this treatment is the volume of fluid (125mL/packet) to be used.
Special authority required.
13
Colonic lavage (age > 1 year):
• Poor response to outpatient therapy may necessitate an admission in selected cases

for colonic washouts. Large volumes (5-10L) of a balanced electrolyte solution,
Klean-Prep™ (if available), is given orally to 'dissolve' the faecal lump.
• Most children will require a nasogastric tube to achieve the desired intake per hour.
Involve the Play Therapists. Oral Midazolam 0.5mg/kg to a maximum of 15mg
may be required. Abdominal x-rays are at the discretion of the admitting
consultant. All patients should be seen and assessed by a paediatric consultant
prior to admission. That individual is responsible for outpatient follow up
following discharge.
• Once the child is admitted to the ward, a large nasogastric tube should be inserted
and vital signs and weight recorded. Begin the nasogastric infusion at the lowest
rate and increase by 100ml/hour until the desired rate is reached or symptoms
develop. Most children need 10-40ml/kg/hr. Normal diet should continue if
tolerated.
• An input/output fluid balance chart is required, adequate fluid intake is required to
prevent dehydration and/or hypo/hypernatraemia, for young children (i.e. <24
months) daily electrolytes testing may be required.
Suggested Flow Rates for Klean-Prep™
Age (Years) Weight (kg) Initial (ml/hr) Maximum (ml/hr)
1-5 10-20 100 500
6-9 20-30 200 800
9-12 30-40 300 1000
Over 12 40+ 400 1200

• If symptoms develop (usually nausea &/or vomiting), reduce the flow rate to the
previous rate at which the child was asymptomatic. Metoclopramide may be given
to reduce nausea and reduce transit time. Discontinue at 8pm at night to allow rest
as'catharsis' may continue late into the evening. Restart at 6am.
Important: Success of treatment is judged by a clear effluent (SOMEONE NEEDS TO

LOOK IN THE PAN!). The commonest reason for failure of treatment is insufficient volume
of Klean-Prep™. Abdominal x-ray and rectal examination at the end of treatment are
unnecessary (frequently uninterpretable) if clear effluent is achieved.
14
Phosphate enemas (age > 3 years):
• Phosphate enemas can be used in the outpatient or Emergency Care setting to

disimpact the rectum, they should not be administered by parents and are contra-
indicated in children < 3 years, if there is no result they should not be repeated on
the same day, Dosage: 30-60mls. One to three enemas may be required, ideally 48
hours apart, refer to the Paediatric Nursing Service.
Discharge and Follow-up:
• A discharge plan should be discussed with the patient's primary paediatrician, with
outpatient follow-up needs arranged within one month.
• All children need to go home on laxative therapy, options include:
✓ Lactulose - 1-3ml/kg/day in two divided doses (softener only)

✓ Need to brush teeth after dose.
✓ Senokot - 1 tablet OD for <5 yrs, 2 tablets daily for > 5yrs. Not funded.
Stimulant laxative.
✓ Magnesium Hydroxide 8% - 1ml/kg/day in two divided doses. Advantage of
low dose for young children and palatability. Stool softener and stimulant. Has
been used in children under <18 months old with caution (usually
recommended for older children)
✓ Macrogol 3350 (Lax-Sachets/Molaxole/Movicol/etc) - 1g/kg/day. One packet
contains 13g. Not as well tolerated in children <4yrs because of palatability
(bitter) and volumes required for dilution (125mL/packet). Stool softener and
stimulant.
• For children with very difficult to manage constipation or significant behavioural

problems associated with this, referral to consult liaison may be indicated.
• Consideration and investigation where appropriate for organic disease (ie

hypothyroidism, spinal dysraphism, Hirschprung's disease etc) always required,
especially in difficult to treat constipation.
15
Protocol for Management of Suspected Celiac Disease
16
Protocol for Management of Ingested Foreign Body
History and Details Specific to Ingestion:

• Witnessed or Suspected? Are there concerns surrounding supervision or possible
NAI?
• Choking episode?
• Time of ingestion?
• Size and quantity (if width >2cm, length >5cm less likely to pass
pylorus/duodenum)?
• Does it have a sharp end?
• Last ate/drank?
• Any history of pain, vomiting and/or anorexia?
• Do family have similar object with them or know what it’s made from?
Hazardous objects include button batteries, multiple magnets, sharp objects

and objects larger than 5cm length or x2cm width- these warrant radiography
if emergent management not necessary.
17
Foreign Body Specifics:
Button battery suspected by history or confirmed on X-ray
Important recommendations for the surgical team removing button battery:

✓ Removal of an oesophageal button battery under general anaesthetic is a time
critical emergency.
✓ In theatre, as soon as the button battery is removed, it is recommended to gently
irrigate the oesophagus with 120-150ml of 0.25% acetic acid.
✓ This can be done using a luer-lock syringe attached to a 5 French suction catheter
introduced via the lumen of the oesophagoscope, Simultaneously, a rigid suction
can be used to continuously remove excess irrigant.
18
Magnets (single or multiple): suspected from history or confirmed on X-ray
Other hard objects: suspected from history or confirmed by X-ray (eg Lego®
coins, beads)
19
FBs Located in Ear or Nose:

Button Battery in Nose or Ear:
• Emergency removal in ED (or ORL referral if unable to retrieve)
• If successful removal in ED, ORL referral still required (to assess severity of burn)
• Even if removed - Keep NBM until ORL review
Other FBs in nose or ear (Eg: Single magnet, Lego®, coins, beads):
• Removal in ED (or ORL referral if unable to retrieve)
• If otitis externa present treat accordingly
Tips for Using the Handheld Metal Detector:

• May not be accurate in children >50kg (false negatives) or children with known
metallic implants (false positives)
• Very good at picking up coins- presence and absence of beep strongly corresponds
to presence/absence and location of coin.
• Less reliable with small metallic objects, button batteries etc- This means if it
beeps, you can be confident of position, but absence of beep should never be
interpreted as absence of a hazardous metallic object. In these situations, a prompt
positive metal detector result may be useful at triage to mobilise teams early, but
should not slow down the timeliness of your usual management.
• Can be useful in identifying location of aluminium objects (e.g. ringpulls), which
won’t show up on X-ray.
• Safe (no radiation) and will not adversely affect function of pacemakers, medical
devices or bank cards.
• Can be used to avoid serial X-rays in children who have a previously proven
ingested metallic object.
• To use the metal detector:
✓ Test it’s working against a metal object
✓ Remove stethoscope/metallic interference from near you and child
✓ Position child standing upright or lying flat on bed
✓ Sweep from nose to pubis, horizontally across hypocondrium and
posteriorly from occiput to sacrum
✓ If beep is more than 2cm below the Xiphisternum, indicates that
object is beyond gastro-oesophageal junction.
✓ If beep is at level of umbilicus or on right side of abdomen, indicates
that object is beyond the stomach.
20
Protocol for Management of GI Bleeding
• Tachycardia is an important sign of hypovolaemia in paediatric patients with blood

loss
• There are many causes of GI bleeding in children.
• Important factors that help determine aetiology and focus interventions include:
✓ Site of bleeding
✓ Age of onset
✓ Presence of abdominal pain
✓ Presence of diarrhoea
Site of Bleeding:
Non-GI mimics of GI blood loss:
• Epistaxis, maternal blood, dental work, haemoptysis Substances such as iron,

beetroot, spinach and blueberries can mimic melaena
Upper GI:
“mouth to the ligament of Treitz, the 2nd part of the duodenum”
Haematemesis (vomited blood)
✓ Bright red suggests active bleeding

✓ Altered blood - may be black (resembling coffee ground) suggests less active
bleeding
Upper GI blood loss may present as melaena
21
Haematemesis
Mallory-Weiss tear Repeated vomiting

Stigmata of chronic liver
Oesophageal varices disease or portal
Oesophagus hypertension
Oesophagitis Reflux symptoms
Including possible button
Foreign body
battery ingestion
H. pylori peptic ulcer
Stomach Non-steroidal anti-
Non-helicobacter gastritis
inflammatory use
H. pylori/peptic ulcer
Haemolytic uraemic
Elevated urea
syndrome
Henoch-Schoenlein purpura Rash
Cutaneous A-V
Small Intestine Arteriovenous malformation
malformations
Crohn's disease Weight loss, diarrhoea
Haemangioma Cutaneous haemangiomata
Intestinal necrosis
22
23
Lower GI:
"Distal to the Ligament of Treitz"
• Melaena (black, tarry odiferous stool) suggests blood proximal to ileo-caecal valve
• Haematochezia (bright red blood per rectum) generally indicates a colonic site of
bleeding. Occasionally red blood in the stool may originate from the small
intestine as a result of rapid gut transit.
24
History:
• Constipation (possible anal fissure)
• Diarrhoea (inflammatory bowel disease/ infectious causes Salmonella,

Campylobacter, Shigella, entero-invasive E.coli and Yersinia)
• Recent antibiotic exposure (clostridium difficile)
• In infants with a personal or family history of atopy or food allergy (breast and
formula fed) (allergic proctocolitis)
• Liver disease (oesophageal varices and vitamin K deficiency)
• Bleeding disorders
• Cystic fibrosis (oesophageal varices and vitamin K deficiency)
• Medication exposure NSAIDs (gastritis) and prior antibiotic exposure

(pseudomembranous colitis)
• Overseas travel (infectious)
• Family medical history (peptic ulcer disease, bleeding disorders, inflammatory

bowel disease, polyposis syndrome. Other sick contacts may indicate an infectious
cause)
25
Physical Examination:
Look for:
• Tachycardia
• Hypotension is a late and ominous sign in GI bleeding
• Orthostatic hypotension (a rise in the pulse rate by 20 beats per minute or a fall in
the systolic blood pressure of more than 10mmHg indicates significant volume
depletion, usually > 20%).
• Abdominal tenderness suggesting a surgical cause of pain, haemolytic uraemic

syndrome, gastric/ duodenal ulceration
• Anal fissure - constipation
• Anal skin tags suggesting Crohn's disease.
• "Haemorrhoids" are an uncommon in paediatric and adolescent patients. Anal skin

tags are a common mimic of "haemorrhoids". Presence of true anal varicosities
suggest portal hypertension.
• Stigmata of liver disease (hepatosplenomegaly, jaundice, cutaneous purpura, spider

naevi, clubbing, ascites)
• Cutaneous haemangiomata may indicate the presence of GI mucosal

haemangiomata.
• Pigmentation of the lips and buccal mucosa may suggest Peutz-Jeghers syndrome.
• Purpura on the buttocks and lower extremities are characteristic of Henoch
Schonlein Purpura.
26
Laboratory Tests:
• CBC --A recent bleed may not initially alter the haemoglobin or haematocrit . The
MCV can be low in chronic low-grade bleeding. Raised eosinophils may signify an
allergic colitis. Low platelets suggest hypersplenism or idiopathic
thrombocytopaenia.
• ESR/ CRP - may indicate inflammatory bowel disease or sepsis
• Coagulation profile to rule out a liver disease, bleeding disorder or disseminated

intravascular coagulopathy.
• Liver function tests if there are signs of portal hypertension or chronic liver
disease.
• Stool cultures and a C-difficile toxin assay if there are loose stools.
• Renal function tests

✓ A high urea may be a clue for haemolytic uraemic syndrome or may indicate
the presence of dehydration.
✓ A high urea may also be due to resorbed blood in the upper GI tract
• H.pylori stool antigen is not recommended as H.pylori is prevalent in the general

paediatric population and is not usually associated with morbidity. H.pylori
complications are diagnosed endoscopically.
27
Investigation:
Fibreoptic endoscopy and biopsy has increased the rate of positive diagnosis.
The yield decreases if endoscopy is delayed, so it is important that endoscopy
occurs promptly. Preparation of the patient is critically important. In emergency
situations where bleeding is severe, resuscitation of the patient is paramount.
Endoscopy should not be performed hastily if the patient is unstable.
Upper GI Bleeding
• Significant upper GI bleeding requires endoscopy for investigation.
• Contrast studies should not be the initial study to rule out oesophagitis, gastritis or
peptic ulcers because of the lack of sensitivity. Contrast studies may be indicated
in patients with dysphagia or odynophagia.
• Ultrasound should be requested if there is evidence of liver disease or

splenomegaly.
• Chest xray should be considered in cases of suspected upper GI bleeding to look

for an oesophageal foreign body.
Lower GI Bleeding
• Colonoscopy is the best test for significant lower GI bleeding. An exception is
suspected intussusception, where ultrasound should be requested (and if
confirmed, an enema for reduction).
Painless rectal bleeding
• A Meckel scan is the procedure of choice. CT angiography may also help localize
bleeding for AV malformations
Obscure bleeding in the GI tract
• Capsule endoscopy may provide a diagnosis in some cases.
28
Treatment:
1. If there is significant bleeding:
✓ Large bore IV lines
✓ Re-Establish blood volume (rapid infusion of 0.9% NaCl +- by red cells).
2. Acid suppression: Omeprazole (2mg/kg/day). Patients < 7 years should receive

q12hourly dosing.
3. Urgent referral to appropriate teams PICU/ Surgery/ General Paediatrics/

Gastroenterology
4. Significant GI bleeding requires admission for observation +/- ongoing

investigation and treatment.
5. Never discharge a patient with liver disease and GI bleeding unless discussed with
on-call Paediatric Gastroenterologist/Hepatologist.
29
30
Pediatric Hematology Protocol of EHA
0

in
Pediatric Hematology
for
First Edition
2024
Prepared by
of
in
Pediatric Hematology
for
1
Executive Committee
This protocol was written, reviewed and approved by the Pediatric Hematology
Committee of Egyptian Universities (in the order of Alphabets).
1. Prof. Ahmed Mansour, Professor of Pediatrics, Hematology, Pediatric

Oncology and Bone Marrow Transplant, Mansoura University
2. Prof. Alaa Al-Haddad Professor of Pediatric Oncology, Hematology and
Pediatric Bone Marrow Transplantation National Cancer Institute
3. Prof. Amal El-Bashlawy Professor of Pediatrics and Pediatric Hematology,
Cairo University
4. Prof. Amira Abdel Moneim Professor of Pediatrics, Hematology and Pediatric
Oncology, Ain Shams University
5. Prof. Azza Abdel-Gawad Tantawy Professor of Pediatrics, Hematology and
Pediatric Oncology, Ain Shams University (Head of the Committee)
6. Prof. Emad Obeid, Professor of Pediatric Oncology, Hematology and Pediatric
Bone Marrow Transplantation, National Cancer Institute
7. Prof. Huda Hassab, Professor of Pediatrics, Hematology, Pediatric Oncology
and Bone Marrow Transplantation, Alexandria University
8. Prof. Naglaa Shaheen, Consultant of Hematology at Children's Hospital of
Egypt and Health Insurance
9. Prof. Nayera Hazaa, Professor of Pediatrics, Hematology, Pediatric Oncology
and Bone Marrow Transplantation, Ain Shams University
10.Prof. Tamer Hassan Professor of Pediatrics, Hematology, Pediatric Oncology
and Bone Marrow Transplant, Zagazig University
11.Dr. Marian Abd El -Messiah, Pediatric Specialist, Coordinator of Hematology
Committee
2
Disclaimer

under their care.
3

Authority (EHA).
➢ Prof. Azza Abdel-Gawad Tantawy: Professor of Pediatrics, Hematology and

Pediatric Oncology, Ain Shams University (Head of the Committee)
Reviewed By



4
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric Hematology
is to unify and standardize the delivery of healthcare to any child at all health facilities.
Pediatric Hematology service is usually offered to children below 16 years of

age in Egypt.
Regarding Pediatric Hematology, busy clinicians have all felt the need for a

to those delivering care at the bedside in for patients in Pediatric Hematology.
In Pediatric Hematology
5
Table of Contents
Title Page Number

Preface 5
List of Figures 7
Approach to anemic infant and child 8
Approach to the child with hemolytic anemia 17
Immune hemolytic anemia 24
Diagnosis and Management of G6PD Deficiency 26
Guidelines for Management of Thalassemia 31
Severe Acquired Aplastic Anemia 49
Evaluation and Emergency Room Management of The 57
Bleeding Child
Hemophilia A and B 65
Immune Thrombocytopenia (ITP) 92
6
List of Figures
Title Page Number

Algorithm for management of child with low hemoglobin, low MCV
With normal leucocytes and platelets
11
Algorithm for management of child with low hemoglobin with

abnormal leucocytes and platelets
14
Diagnostic Algorithm to Child with Hemolytic Anemia 22
Flow chart for the diagnosis of hemoglobin disorders; steps in

carriers screening and disease diagnosis
31
Work Up for the diagnosis and differential diagnosis of

hemoglobin disorders
32
Clinical suspicion of Thalassemia at primary care 34
Thalassemia in the emergency department: special

considerations: With Consultation of Hematologist
35
Algorithm For Definite Treatment Of Severe And Very Severe

Acquried Aplastic Anemia < 18 Years Old
52
Algorithm for first-line screening in children with suspected

bleeding disorder
61
Algorithm for Management of Acute ITP 94
7
APPROACH TO ANEMIC INFANT AND CHILD
Is The Patient Anemic?

How Severe Is the Anemia?
➢ Ask For Complete Blood Picture
Anemia is defined as Hemoglobin level below the cut off values of hemoglobin
for age and sex.
The severity of anemia Is determined by hemoglobin level (table 1).
Pallor Is suggestive of anemia but is nonspecific.
Table 1 : Hemoglobin levels to diagnose anemia at sea level (g/l)

Anemia*
Population Non-anemia* Mild Moderate Severe
Children 6–59 110 or higher 100–109 70–99 Lower than 70
months of age

years of age

years of age
Non-pregnant 120 or higher 110–119 80–109 lower than 80

women (15 years
of age and above)
Men (15 years of 130 or higher 110–129 80–109 Lower than 80

age and above)
❖ a “Mild” is a misnomer: iron deficiency is already advanced by the time anemia is

detected. The deficiency even when no anemia is clinically apparent
Reference:
▪ WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of
severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health
Organization, 2011 (WHO/NMH/NHD/MNM/11.1)
(http://www.who.int/vmnis/indicators/haemoglobin, pdf, accessed 6/2/2022
8
Assessment of anemic infant and child
History
• Age and sex , history of previous transfusion , history of bleeding , other system
disease like renal or inflammatory disease.
• Medication history: past and current, particularly those that may cause hemolysis in
the instance of G6PD deficiency.
• Dietary history: iron intake (with particular attention to iron-rich foods, breast
feeding and cow’s milk intake), vitamin B12 intake, recent fava/broad bean
ingestion (may precipitate haemolysis in the case of G6PD deficiency).
• Family history: anemia, jaundice, gallstones or splenomegaly.
Examination
Clinical features suggestive of anemia:
✓ Pallor
✓ Pale conjunctivae
✓ Tachycardia
✓ Cardiac murmur
✓ Lethargy
✓ Listlessness
✓ Poor growth
✓ Poor concentration
✓ Weakness
✓ Shortness of breath
✓ Signs of cardiac failure
✓ Signs of haemolysis include jaundice, scleral icterus, splenomegaly and
dark urine
9
Management
Emergency management of severe anemia with pending heart failure
• It is important to quickly assess the patient’s clinical condition in patient with severe
anemia
• If the patient is severely pale and sick looking, breathless, has tachycardia, raised
jugular venous pressure (JVP) and tender hepatomegaly, it is suggestive of
congestive cardiac failure (CCF). Such a patient needs immediate attention and
prompt treatment including diuretics, restricted fluids, oxygen support and packed
cell transfusion
• Do not waste time in lengthy diagnostic tests and do as minimum tests as require.
• Immediately arrange for packed cell transfusion and remove blood for various tests
just before starting transfusion.
• If transfusion is not available in your facility immediately refer the patient under
oxygen support to nearest facility with available transfusion therapy
Investigations of anemia in infancy and childhood
• If anemia is suspected begin with a full blood examination including blood film
(FBC), and blood indices
• The initial management is based on the complete blood picture / blood film and the
Mean Corpuscular Volume (MCV)
Table 2 :Age-Specific Normative Red Blood Cell Values
Reference:
▪ Robertson J, Shilkofski N, eds. The Harriet Lane Handbook. 17th ed. Philadelphia, Pa.:
Mosby; 2005:337
10
Figure (1A) : Algorithm for management of child with low hemoglobin, low MCV
11
CONSULT
Figure 1B HEMATOLOGIST
REFER TO HEMATOLOGIST
Figure (1B) : Algorithm for management of child with low hemoglobin ,normal MCV
12
REFER TO
Figure 1C HEMATOLOGIST
CONSIDER B12 AND FOLATE CONSIDER BONE

THERAPY MARROW
DISORDER
Figure (1C) : Algorithm for management of child with low hemoglobin and increased
MCV With normal leucocytes and platelets
13
Go to figures 1
REFER TO HEMATOLOGIST
Figure (2): Algorithm for management of child with low hemoglobin with abnormal
leucocytes and platelets
14
Red Flags
(Consider Admission)
• Hb <60 g/L (including iron deficiency)

• Tachycardia, cardiac murmur or signs of cardiac failure.
• Features of hemolysis (dark urine, jaundice, scleral icterus).
• Associated reticulocytopenia.
• Presence of nucleated red blood cells on blood film.
• Associated thrombocytopenia or neutropenia may indicate malignancy
or an infiltrative disorder.
• Severe vitamin B12 or folate deficiency.
• Need for red cell transfusion: If the patient is compensated and stable
defer transfusion until a definitive diagnosis is made.
15
References:
1. Approach to the anemic child .Hastings C A , Torkildson J C , Agrawal A K
; in handbook of pediatric hematology and oncology children’s hospital and
research center Oakland ; Hastings C A , Torkildson J C, Agrawal A K
(editors); Wiley Blackwell publications , 3rd edition . chapter 1 , pages 1-14
, 2021.
2. B. Rosich del Cacho, Y. Mozo del Castillo . Anemia. Classification and
diagnosis Pediatr Integral 2021; XXV (5): 214 – 221.
3. Janus J, Moerschel SK. Evaluation of anemia in children. Am Fam
Physician. 2010;81(12):1468.
4. Mary Wang Iron Deficiency and Other Types of Anemia in Infants and
Children; Am Fam physician. 2016 Feb 15;93(4):270-278.
16
APPROACH TO THE CHILD WITH HEMOLYTIC ANEMIA
• Hemolytic anemia is defined as the destruction of red blood cells (RBCs) before
their normal 120-day life span.
• It includes many separate and diverse entities whose common clinical features can
aid in the identification of hemolysis.
• Hemolytic anemia exists on a spectrum from chronic to life-threatening, and
warrants consideration in all patients with unexplained normocytic or macrocytic
anemia.
• Premature destruction of RBCs can occur intravascularly or extra vascularly in the
reticuloendothelial system, although the latter is more common.
• The primary extravascular mechanism is sequestration and phagocytosis due to poor
RBC deformability (i.e., the inability to change shape enough to pass through the
spleen).
• Antibody-mediated hemolysis results in phagocytosis or complement-mediated
destruction, and can occur intravascularly or extra vascularly.
• The intravascular mechanisms include direct cellular destruction, fragmentation,
and oxidation.
• Direct cellular destruction is caused by toxins, trauma, or lysis. Fragmentation
hemolysis occurs when extrinsic factors produce shearing and rupture of RBCs.
Oxidative hemolysis occurs when the protective mechanisms of the cells are
overwhelmed.
• The etiologies of hemolysis are numerous as demonstrated in table (1).
17
Table 1: Differential Diagnosis of Hemolytic Anemia in Children
HEREDITARY HEMOLYTIC ANEMIAS

Enzymopathies
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Pyruvate kinase (PKLR) deficiency
Hemoglobin Disorders
• Thalassemias
• Sickle cell disease
• Unstable hemoglobin
• Congenital dyserythropoietic anemias
Membrane Defects
• Hereditary spherocytosis
• Hereditary elliptocytosis and pyro-poikilocytosis
ACQUIRED HEMOLYTIC ANEMIAS

Autoimmune Hemolytic Anemia (AIHA)
• Warm-reactive AIHA
• Cold agglutinin syndrome
• Paroxysmal cold hemoglobinuria (PCH)
• Drug-induced (very rare in children)
Alloimmune Hemolytic Anemia
• Neonatal alloimmune hemolysis
• Post-transfusion hemolysis
o Acute hemolytic reactions
o Delayed hemolytic reactions
Traumatic Hemolytic Anemia
• Macrovascular defects-prostheses (dysfunctional mechanical heart valve)
• Microvascular
o Typical and Atypical Hemolytic uremic syndrome
o Thrombotic thrombocytopenic purpura
o Disseminated intravascular coagulation
Hypersplenism
Hemolytic anemia due to toxic effects on the membrane
• Spur cell anemia in severe liver disease
• External toxins
• Animal or spider bites
• Metals
• Organic compounds
• Infection
Paroxysmal Nocturnal Hemoglobinuria
18
Clinical Presentation
• Hemolysis should be considered when a patient experiences acute jaundice or
hemoglobinuria in the presence of anemia. Symptoms of chronic hemolysis include
lymphadenopathy, hepatosplenomegaly, cholestasis, and choledocholithiasis. Other
nonspecific symptoms include fatigue, dyspnea, hypotension, and tachycardia.
Evaluation
• When hemolysis is suspected, the history should include known medical diagnoses,
medications, personal or family history of hemolytic anemia, and a complete review
of systems. Physical examination should focus on identifying associated conditions,
such as infections or malignancies (Table 2 and 3).
19
Table 2: Work Up of The Child with Hemolytic Anemia
History assessment for evidence of chronic hemolytic anemia and

possible precipitants of an acute event
• Family history
• History of newborn jaundice
• Gallstones
• Splenomegaly or splenectomy
• Episodes of dark urine and/or yellow skin/sclerae
• Anemia unresponsive to iron supplementation
• Medications
• Environmental exposures
• Ethnicity
• Dietary history
The physical exam should be complete, but focused on:
• Skin color (pallor, jaundice, and icteric sclerae)
• Facial bone changes (extramedullary hematopoiesis)
• Abdominal fullness and splenomegaly
The laboratory evaluation includes:
• Complete blood count, RBC indices, and reticulocyte count
• Peripheral blood smear (assess for fragmented forms or evidence of
inherited anemia with specific morphological abnormalities)
• Bilirubin, AST, lactate dehydrogenase (LDH)
• Coomb’s test, direct and indirect (to exclude antibody-mediated red
cell destruction)
• Urinalysis (for heme, bilirubin)
• Plasma haptoglobin
• Parvovirus PCR (if history is suspicious)
• Renal functions
Specific tests for diagnosis may include:
• Osmotic fragility
• Red cell enzyme defects mainly G6PD
• CD 55/59 if suspect PNH
• ADAMTS13 if suspected microangiopathic hemolytic anemia
20
Table 3: Initial Laboratory Tests for Hemolysis
Table 4: Diagnostic Clues for Hemolytic Anemia
21
Figure 1: Diagnostic Algorithm to Child with Hemolytic Anemia
22
References:
1. Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential

Diagnosis. Am Fam Physician. 2018 Sep 15;98(6):354-361.
2. Voulgaridou A, Kalfa TA. Autoimmune Hemolytic Anemia in the Pediatric

Setting. J Clin Med. 2021 Jan 9;10(2):216.
3. Noronha SA. Acquired and Congenital Hemolytic Anemia. Pediatr Rev.

2016 Jun;37(6):235-46.
23
IMMUNE HEMOLYTIC ANEMIA
Autoimmune Hemolytic Anemia
• AIHA is caused by autoantibody-mediated destruction. The hallmark of AIHA is a

positive DAT result (direct combs test)
• AIHA is organized into two primary subgroups based on binding temperatures,
referred to as cold and warm agglutinins.
• Many causes of AIHA are idiopathic; however, viral and bacterial infections,
autoimmune conditions, connective tissue disorder, lymphoproliferative
malignancies, blood transfusions, and transplantations have been associated with
AIHA.
Warm AIHA
• Warm AIHA is more common than cold AIHA and involves immunoglobulin G
(IgG) antibodies, usually to the Rh complex, that react with the RBC membrane at
normal body temperatures. The IgG-coated RBCs are then removed by
reticuloendothelial macrophages and sequestered in the spleen, sometimes leading
to splenomegaly. Treatment of warm AIHA typically includes the use of
glucocorticoids, management of the underlying condition, blood transfusion (if
necessary), and supportive care.
Cold AIHA
• Cold AIHA involves IgM antibodies (cold agglutinin titers) that react with
polysaccharide antigens on the RBC surface at low temperatures and then cause
lysis on rewarming by complement fixation and intravascular hemolysis.
Development of these antibodies is associated with infectious or malignant
processes. Mycoplasmal pneumonia and mononucleosis are the two most common
processes. Treatment of patients who have cold AIHA typically involves supportive
measures, avoidance of triggers, and underlying disease management.
24
References:
1. Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential

Diagnosis. Am Fam Physician. 2018 Sep 15;98(6):354-361.
2. Voulgaridou A, Kalfa TA. Autoimmune Hemolytic Anemia in the Pediatric

Setting. J Clin Med. 2021 Jan 9;10(2):216.
3. Noronha SA. Acquired and Congenital Hemolytic Anemia. Pediatr Rev.

2016 Jun;37(6):235-46.
25
DIAGNOSIS AND MANAGEMENT OF G6PD DEFICIENCY
• Glucose-6-phosphate dehydrogenase deficiency, the most common enzyme

deficiency worldwide, causes a spectrum of disease including neonatal
hyperbilirubinemia, acute hemolysis, and rarely chronic hemolysis. Persons with
this condition also may be asymptomatic. This is X-linked inherited disorder .
Males are more commonly affected although carrier females can occasionally be
symptomatic.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency increases the vulnerability
of erythrocytes to oxidative stress in the form of an infection, oxidative drug, or
fava beans
• Different gene mutations cause different levels of enzyme deficiency, with classes
assigned to various degrees of deficiency and disease manifestation. Acute
hemolysis is self-limited, but in rare instances it can be severe enough to warrant a
blood transfusion. Neonatal hyperbilirubinemia may require treatment with
phototherapy or exchange transfusion to prevent kernicterus. The variant that
causes chronic hemolysis is rare .
There is no cure for G6PD deficiency, and it is a lifelong condition. However, most
people with G6PD deficiency have a completely normal life as long as they avoid
the triggers.
G6PD Deficiency is rarely fatal as acute hemolysis can lead to anemic heart failure
and renal tubular injury and renal impairment related to severe hemolysis.
Three Clinical Phenotypes

1) Neonatal Hyperbilirubinemia
2) Acute Hemolysis
3) Rarely chronic non spherocytic hemolytic anemia
26
Acute Hemolysis in G6PD-Deficient Patients
• Acute hemolysis is caused by infection, ingestion of fava beans, or exposure to an

oxidative drug.
• Hemolysis occurs after exposure to the stressor but does not continue despite
continued infection or ingestion. This is thought to be a result of older erythrocytes
having the greatest enzyme deficiency and undergoing hemolysis first. Once the
population of deficient erythrocytes has been hemolyzed, younger erythrocytes and
reticulocytes that typically have higher levels of enzyme activity are able to sustain
the oxidative damage without hemolysis. Clinically, acute hemolysis can cause
back or abdominal pain and jaundice secondary to a rise in unconjugated bilirubin
(Table 1).
• Jaundice, in the setting of normal liver function, typically does not occur until
greater than 50 percent of the erythrocytes have been hemolyzed.
• Medications that should be avoided in patients with G6PD deficiency are listed in
Table 2, and drugs that can be used safely in these patients are listed in table 3.
• Hemolysis typically occurs 24 to 72 hours after exposure to oxidant stressor, with
resolution within four to seven days. Infection is the most common cause of acute
hemolysis in G6PD- deficient persons.
• Oxidative drugs ingested by a woman who is breast-feeding may be transmitted in
breast milk and can cause acute hemolysis in a G6PD-deficient child
Table 1: Symptoms and laboratory Evaluation in Patients with G6PD

and Acute Hemolysis
SIGNS /SYMPTOMS
27
Tests for G6PD deficiency include the following:

1) Semi-quantitative tests -The fluorescent spot test (not reliable in females)
2) Quantitative tests (spectrophotometric) - the criterion standard.
Table 2: Drugs to Be Avoided by G6PD - Deficient Patients
Table 3: Drugs to Be Used With Caution in Therapeutic Doses for Patients With G6PD
Deficiency (Without Nonspherocytic Hemolytic Anemia)
28
Treatment of Acute Hemolysis in G6PD-Deficient Patients

The usual treatment for hemolytic anemia in G6PD-deficient
patients is supportive care plus removal and avoidance of further
triggers
In severe hemolysis, blood transfusions may be required;
hemodialysis may be needed if acute kidney injury occurs.
Acute hemolytic anemia will prompt testing for G6PD
deficiency, which should be done by a quantitative test. A result
below 80% of the lower limit of normal must be regarded as
G6PD deficient.
Sometimes, during or immediately after a hemolytic attack, G6PD activity
from a G6PD-deficient patient may be within the “normal range” (as a
result of both destruction of the oldest cells and reticulocytosis). In such
cases, the test must be repeated after 6-8 weeks
Neonatal Hyperbilirubinemia in G6PD deficiency

• The prevalence of neonatal hyperbilirubinemia is twice that of the general
population in males who carry the defective gene and in homozygous females. It
rarely occurs in heterozygous females.
• The mechanism by which G6PD deficiency causes neonatal hyperbilirubinemia is
not completely understood. Although hemolysis may be observed in neonates who
have G6PD deficiency and are jaundiced, other mechanisms play a more important
role in the development of hyperbilirubinemia. Hyperbilirubinemia is likely
secondary to impairment of bilirubin conjugation and clearance by the liver leading
to indirect hyperbilirubinemia.
G6PD deficiency should be considered in neonates who develop

hyperbilirubinemia within 1-3 days after birth, a history of jaundice in a
sibling, bilirubin levels greater than the 95th percentile
Management
G6PD deficiency can lead to an increased risk and earlier onset of indirect
hyperbilirubinemia, which may require phototherapy or exchange
transfusion, and can be complicated by kernicterus if not properly managed
29
References:
1. Frank JE. Diagnosis and management of G6PD deficiency. Am Fam

Physician. 2005 Oct 1;72(7):1277-82.
2. Luzzatto L, Ally M, Notaro R. Glucose-6-phosphate dehydrogenase

deficiency. Blood. 2020 Sep 10;136(11):1225-1240.
3. Bubp J, Jen M, Matuszewski K. Caring for Glucose-6-Phosphate

Dehydrogenase (G6PD)-Deficient Patients: Implications for Pharmacy. P T.
2015 Sep;40(9):572-4.
4. Christensen RD, Yaish HM, Wiedmeier SE, Reading NS, Pysher TJ, Palmer
CA, Prchal JT. Neonatal death suspected to be from sepsis was found to be
kernicterus with G6PD deficiency. Pediatrics. 2013 Dec;132(6):e1694-8.
30
Guidelines for Management of Thalassemia
The term ‘thalassemia’ refers to a group of blood diseases

characterized by decreased or absent synthesis of one or more of the normal
globin chains. According to the chain whose synthesis is impaired, the
thalassaemias are called α, β.
Full Medical CBC

Then use an automated blood cell counter
&
Family History
• Hb
• MCH < 27 PG
• MCV < 78 FL • Iron Studies
Basic Hematology • Microcytosis S. ferritin,
hypochromia
anisopoikilocytosis
Normal Or Increased Decreased
• Electrophoresis
HPLC
Hemoglobin Pattern • Hemoglobin A, Consider Iron
A2, F, H Deficiency
• Hemoglobin
Variants
Molecular Confirmation
If Needed in
Doubtful Cases
Figure (1): Flow chart for the diagnosis of hemoglobin disorders; steps in carriers
screening and disease diagnosis MCH: Mean corpuscular Hb, F: Fetal hemoglobin,
MCV: mean cell volume.
31
Patient presents with pallor, jaundice, anorexia

± poor weight gain
• Physical examination (pale conjunctiva, ± yellow sclera, ±

splenomegaly ± Mongoloid face)
• Consanguinity
• Family history of similar condition
• Family History of splenectomy
• Complete blood count and examination of peripheral blood smear
• Iron profile
• Hemoglobin Electrophoresis
Differential diagnosis:
• Iron deficiency anemia
• Anemia of chronic disease
• Thalassemia minor
• Beta-thalassemia major
• Thalassemia Intermedia
• Other rare chronic anemias
Figure (2): Work Up for the diagnosis and differential diagnosis of hemoglobin
disorders
32
Table 1: Clinical phenotypes of thalassemia.
Clinical Severity Phenotype
• Asymptomatic
Silent carrier
• No hematological abnormalities
• Borderline asymptomatic anemia

Trait/minor
• Microcytosis and hypochromia
• Late presentation > 2 years

• Mild-moderate anemia
Intermedia • Mostly Transfusion-independent
• Clinical severity is variable and
ranges between minor to major
• Early presentation < 2 years

Major • Severe anemia
• Transfusion-dependent
33
Child with Symptoms of Anaemia
Family
Physician
Work-up Role of family physician after diagnosis
• Full medical and family history • Liaison with specialized team Confirmed
• Assessment of clinical symptoms • Patient support and information
• Anemia differential diagnosis • Compliance
• Primary laboratory tests • Monitoring treatment, prognosis and
complications as described by the
hematologist Hb Types
&
DNA Analysis
Findings:
• Hypochromic microcytic anemia

• Normal or excess iron status
Suspected
Reference to hematologist or thalassemia center
Figure 3 :Clinical suspicion of Thalassemia at primary care
34
Figure 4 : Thalassemia in the emergency department: special considerations:

With Consultation of Hematologist
Reference:
▪ Saliba, A.N., Atoui, A., Labban, M. et al. Thalassemia in the emergency department:
special considerations for a rare disease. Ann Hematol 99, 1967–1977 (2020).
https://doi.org/10.1007/s00277-020-04164-6
35
Criteria for initiating transfusion therapy (Decision by the Hematologist)
➢ For deciding whom to transfuse, the following should be included in the

investigations:
✓ Confirmed diagnosis of thalassemia by clinical and laboratory criteria:

• Hemoglobin level (Hb) <7 g/dI on 2 occasions, > 2 weeks
apart(excluding all other contributory causes such as infections)
AND/OR
➢ Clinical criteria irrespective of hemoglobin level:
• Significant symptoms of anemia

• Poor growth / failure to thrive
• Complications from excessive intramedullary hematopoiesis such
as pathological fractures and facial changes
• Clinically significant extra medullary hematopoiesis
Transfusion thresholds and frequency decided by hematologist
• The recommended treatment for transfusion dependent thalassemia is lifelong

regular blood transfusions, usually administered every two or five weeks to
maintain the pre transfusion Hb level 9 g/dL.
• This transfusion regimen promotes normal growth, allows normal physical
activities, adequately suppresses bone marrow activity in most patients, and
minimizes transfusional iron accumulation .
• A higher target pre-transfusion hemoglobin level may be appropriate for patients
with heart disease, clinically significant extramedullary hematopoiesis or other
medical conditions according to pediatric hematology consultant decision.
36
Important considerations in Transfusion therapy

• Observation for adverse events, management & reporting are key to the safety of
blood transfusion.
• Before first transfusion perform extended red cell antigen typing of patients at least
for d,c,e,E.e, and kell red cell phenotype.
• At each transfusion give ABO, Rh(D) compatible blood. Choosing units,
compatible units for ABO, Cc, Ee, kell antigen is highly recommended.
• Use leucodepleted packed red cells. Blood bank pre-transfusion filtration is
acceptable & Bedside filtration.
• Use washed red cells for patients who have severe allergic reactions.
• Keep a record of red cell antibodies, transfusion reactions and annual transfusion
requirements for each patient.
Treatment of Iron Overload

➢ Goals of iron chelation therapy:
• The primary goal of chelation therapy is to maintain safe levels of body iron at
all times.
• Once a patient is overloaded, it may take months or years to reduce body storage
of iron to safe levels, even with the most intensive treatment.
• Chelation must therefore begin in ß thalassemia major soon after 10
transfusions or when serum ferritin equals or more than 1000 microgm/L
• Chelation must begin in ß intermedia even if non transfused when serum ferritin
equals or more than 800 microgm/L
• 24 hours chelation coverage is the ideal, especially in heavily iron loaded
patients, to minimize the toxic (labile) iron pools responsible for causing
tissue damage.
• Compliance with chelation therapy determines prognosis
• Drugs used for iron chelation include desferasirox , deferiprone and
desferoxamine
37
Desferasirox (JADENU)
90, 180, 360 mg tablets
Table 2 :The desferasirox dose is based on serum ferritin level

S. ferritin level Dose
Monitoring Tests
(microgram/L) (mg/kg/day)
7-14 CBC/month
NTDT > 800
mg/kg/day S. creatinine/month
1000 – 1500 21 mg/kg/day Urine for proteinuria/month
24.5 mg/kg/dayLiver transaminases/ month
1500 -2500
S. bilirubin (when needed)
> 2500 28 mg/kg/day S. ferritin / 3 months
TDT Echocardiography / year
7-10 Ophthalmologic / audiological
< 500
mg/kg/day testing / year (when
required)
• Dose: Once daily on empty stomach or with light meal or apple juice in a fixed time.
• Dose adjustment: Every 3-6 months based on S. ferritin in step of 7 mg/kg.
38
Table 3 :Desferasirox (Jadenu) Adverse events and management
Adverse Event Management Strategy

Gastrointestinal disturbance • Take tab in evening rather than morning.
(mild-mod diarrhea, abdominal pain, • Avoid solid food for the first few hours.
nausea, vomiting). • Avoid Non steroidal Anti-inflammatory drugs
and aspirin
• If necessary → reduce dose to →
7 mg/kg/day →
Titrate in weekly 7 mg/kg/day increments after
resolution to return to previous dose.
Rash: (mild-moderate). • Resolve spontaneously without discontinuation
or adjustment.
Rash: (severe) • Interruption.
• Reintroduce after rash resolve at lower dose.
• Titrate gradually to previous dose.
Increase in serum liver transaminases
(> 4 normal range): • Reintroduce at a lower dose with gradual titration
(Search for cause hepatitis/cirrhosis). until previous dose
• Transient and non-progressive • Interruption
• Persistent and progressive
Increase in serum creatinine:

• Non progressive rise (> 33% above • Consider reducing dose by 7 mg/kg/day.
baseline at 2 consecutive
measurements)
• Progressive rise (S. creatinine > 2
times the age-appropriate upper • Interrupt.
limit of normal)
Cytopenia (unexplained) • Interruption
39
Deferiprone
Kelfer: (Cap. 500 mg)
Ferriprox: (Syrup 1 ml = 100 mg)
(Tablets: 500 mg)
Table 4 : Dose of deferiprone based on serum ferritin level in TDT
S. ferritin level Dose

Monitoring Tests
(microgram/L) (mg/kg/day)
CBC / week (1st month)
CBC/month
S. creatinine/month
Urine for proteinuria/month
Liver transaminases/ month
75 mg/kg/day S. bilirubin / month (when
TDT > 1000 ug/L (in 3 divided doses) needed)
after meals
S. ferritin / 3 months
Echocardiography / year
Ophthalmological /
audiological testing / year
(when needed)
40
Table 5 : Deferiprone adverse events and management
Adverse Event Management Strategy

Liver transaminase (> 4 times
upper normal level) • Continue by same dose
• Transient and non-progressive
• Stop the drug.
• Persistent and progressive
Severe neutropenia, • CBC / week
agranulocytosis ANC < 0.5 x 109/L • Stop drug and not reintroduced
• Stop drug (if joint symptoms
continue despite a reduction in
Arthropathy
deferiprone dose and are not
controlled by NSAI
41
Desferrioxamine
Desferal
Standard dose
• 20-40 mg/kg for children.
• 50-60 mg/kg for adult.
• Slow S.C. infusion over-8-12 hours/ at least 5-6 times a week using an infusion
pump.
• Should started after the first 10-20 transfusion or when serum ferritin level rises
above 800 (NTDT) -1000 (TDT) ug/l.
• Recommended to stop administration of desferal in any one with an unexplained
fever, until the cause has been identified and effective antibiotic treatment begun.
• Monitoring schedule:
✓ CBC/month
✓ S. creatinine/month
✓ Urine for proteinuria/month
✓ Liver transaminases/ month
✓ S. bilirubin (when needed)
✓ S. ferritin / 3 months
✓ Echocardiography / year
✓ Ophthalmologic / audiological testing / year
• If chelation therapy begins before 3 years of age, careful monitoring of growth and
bone development is advised.
Intensive therapy of desferal (50-60 mg/kg / 24 hour / day) 6-7 day/week
➢ INDICATIONS (Decided by consultant hematologist)
• Severe iron overload with persistently very high ferritin values.
• Significant cardiac disease (dysrhythmias / falling of left ventricular function).
• Evidence of very severe heart iron loading (MRI T2*<6 ms).
• Prior to bone marrow transplantation.
42
Combined Therapy
Desferrioxamine and Deferiprone
Indications
➢ Decided by consultant hematologist
1. When monotherapy with desferrioxamine or deferiprone has failed to
control iron overload.
2. Combination can control iron overload in the liver and heart.
Desferrioxamine 40-50 mg/kg/day [5 day/week]

+
Deferiprone 75 mg/kg/day [7 day/week]
If Iron load too high or increasing – rescue therapy to achieve negative iron
balance
➢ Decided by consultant hematologist
1. Increasing the daily dose of chelation (within recommended dose)
2. Increasing the frequency of the chelator (within recommended protocol)
3. Switching chelator regimen
4. Rotating or combining chelators
5. DFO ( desferoxamine) monotherapy is effective at producing negative iron
balance if it is given in sufficient doses and sufficient frequency, but adherence
is often a problem.
6. Dose escalation of deferasirox (DFX) is effective in producing negative iron
balance .Doses up to 28 mg/kg are effective in patients with high liver iron
content or serum ferritin
7. DFP ( deferiprone) monotherapy is likely to achieve iron balance at 75 mg/kg
in only about one third of patients, with average transfusion rates. It may be
increased up to 100 mg/kg with close monitoring. DFO is often added.
8. Rotation of individual monotherapies (sequential chelation) can be helpful
in managing individual patients, often for reasons of adherence as much as
for specific complications.
9. True ‘combination therapy’ (where two chelators are combined with some
degree of overlap pharmacologically) can be useful when monotherapy is
inadequate, either to control iron balance or to control iron distribution,
particularly in the heart.
43
Other important medical therapy in thalassemia

a) Vitamin supplementations
1. Folic a 1-5 mg/day
2. Vitamin D:
✓ For < 4 years old children: 1400 IU vit D daily
✓ For > 4 years old children: 2800 IU vit D daily
With such doses no need to assess vit D level except if there is clinical
evidence of vit D deficiency.
3. Vit B complex
4. Calcium
5. Zinc 10-15 mg/day: Starting from age 2 years.
6. L-Carnitine: 30-50 mg/kg/day 5 days a week
44
b) Hydroxyurea: (Should be prescribed by Hematology Consultant)

➢ Not indicated in transfusion dependent thalassemia
➢ Indications of use in non-transfusion dependent thalassemia intermedia
✓ Patients for which a transfusion course is required but are alloimmunized
✓ Pulmonary hypertension
✓ Extramedullary hematopoietic pseudotumor
✓ Leg ulcers
Dose:
Starting dose of 10 mg/kg/day with dose escalation by 3-5 mg/kg/day every 8 weeks
to the maximal tolerated dose, but not exceeding 20 mg/kg/day.
Response:
• Should be evaluated after 3 and 6 months of therapy
• Response defined as a total hemoglobin level increase of >1 g/dl at 6 months
• The drug should be discontinued in patients not showing response.
• Patients showing response should be re-evaluated every 6 months.
Other response parameters: that could be evaluated as indicated:
✓ Improvement in growth measures

✓ Improvement in functional status and exercise tolerance
✓ Improvement in quality of life
✓ Improvement in clinical morbidities (pulmonary hypertension,
extramedullary hematopoietic pseudotumor, leg ulcers)
Monitoring:
✓ Complete blood counts, every two weeks for the first three months then
monthly
✓ Hepatic and renal function studies, every two weeks for the first three
months then monthly
✓ History and physical examination evaluating for gastrointestinal,
neurologic, or dermatologic side-effects, monthly
Contraindications:
not used in pregnant women and in hepatic or renal dysfunction
45
c) Allogeneic Stem Cell Transplantation

Indication:
➢ Transfusion Dependent Thalassemia with HLA matched sibling donor and the
patient should be in good performance status
d) Luspatercept
ONLY PRESCRIBED AND FOLLOWED AND MONITORED BY CONSULTANT

HEMATOLOGIST IN SPECIALIZED HEMATOLOGY CENTERS
➢ Luspatercept (Reblozyl) is the most recently approved agent (in the United
States and Europe) and by the Egyptian Ministry of Health for the treatment of
adults (aged 18 years or more) with transfusion-dependent β-thalassemia given
subcutaneous every 3 weeks at a dose of 1mg/kg/dose, It increases hemoglobin
and reduces transfusion requirements in TDT by reducing ineffective
erythropoiesis
e) Splenectomy
Indications:
➢ Huge spleen causing dragging pain

➢ Hypersplenism
Precautions:
➢ Preoperative Vaccination
• Whenever splenectomy is indicated, patients should receive the following

vaccines 2 weeks prior to splenectomy
✓ Pneumococcal 23-valent polysaccharide vaccine and repeated three to five
years later
✓ Hemophilus influenzae vaccine
✓ Meningococcal polysaccharide vaccine
• Patients who underwent splenectomy without being given the vaccines may
still benefit from vaccination post splenectomy
• Influenza vaccine, annually is recommended
46
➢ Post operative
• Long-acting Penicillin for 5 years post-operative in children or till patient is 16

yrs. old.
• Monitor for risk of thrombosis including post operative platelet count and start
Aspirin 3-5 mg/kg daily if thrombocytosis.
• Post-splenectomy sepsis remains a risk in all splenectomized thalassemia

patients. Therefore, febrile splenectomized patients should undergo rapid
evaluation and treatment.
47
References:
1. Thalassemia International Federation, 2021 Guidelines for the management of
transfusion dependent thalassemia , 4th edition version 2.
2. Thalassemia International Federation, Guidelines for the management of non

transfusion dependent thalassemia , 2018.
3. Saliba, A.N., Atoui, A., Labban, M. et al. Thalassemia in the emergency

department: special considerations for a rare disease. Ann Hematol 99, 1967–
1977 (2020).
4. Amal EL Beshlawy, Azza Tantawy and Naglaa Shaheen. Guidelines of Clinical
Management of Iron Overload in Thalassemia. 2013.
48
SEVERE ACQUIRED APLASTIC ANEMIA
Definition
Acquired Aplastic anemia (AA) is a Bone Marrow Failure Disorder
characterized by Pancytopenia and Hypocellular bone marrow (a very limited number
of hematopoietic stem cells) due to an immune-mediated attack on the bone marrow.
Associated with high mortality rates if left untreated and no single test provides
a diagnosis of AA; diagnosis is a process of excluding other bone marrow failure
conditions.
Classification
Classification Criteria
Non-Severe Hypocellular bone marrow with peripheral blood values not meeting the
(Moderate) criteria for severe or very severe aplastic anemia.
Bone marrow cellularity equal to 25% of the normal control, or 25-50% of

the normal control with <30% residual hematopoietic stem cells (HSCs).
AND
Severe Two of the following peripheral blood criteria:
• Neutrophil count: <0.5×10⁹/L.
• Platelet count: <20×10⁹/L.
• Reticulocyte count: <20×10⁹ /L.
Very Severe Severe aplastic anemia with neutrophil count <0.2x10⁹/L.
49
Diagnostic evaluation of a patient with suspected acquired aplastic anemia

A variety of testing modalities and detailed personal/family history and exposure
history are required both in initial screening evaluation and for exclusion of alternative
diagnoses.
Initial screening evaluation
CBC with differential, peripheral blood smear, reticulocyte
Peripheral blood count Complete metabolic panel, LDH, haptoglobin,
coagulation parameters
Bone marrow aspirate and biopsy
Bone marrow aspirate Metaphase cytogenetics and FISH panel for MDS-associated
and biopsy with
ancillary studies chromosomal abnormalities of chromosomes 5, 7, 8, 20
± Molecular studies
Exclusion of alternative diagnoses
Infectious HIV, Hepatitis B/C, parvovirus B19 PCR, EBV, CMV,

bacterial, fungal (± mycobacterial testing)
Detailed family history focusing on cytopenias, congenital
abnormalities, cancers and lung and liver pathology
Inherited bone marrow Chromosomal breakage testing for Fanconi anemia
failure Lymphocyte telomere length for Dyskeratosis congenita
Additional syndrome-specific testing if personal or family
history are suggestive of specific disorders (IBMF, HLH)
Lymphoproliferative Flow cytometry and T-cell receptor rearrangement testing for

clonal LGL expansion
Detailed drug and occupational exposure history, with
Medication or toxin- attention to excessive alcohol intake, antibiotics, prior
related cytotoxic chemotherapeutic agents, and immune-activating
agents (e.g. interferon and checkpoint blockade inhibitors)
Nutritional Vitamin B12, folate, copper, iron studies, ferritin
Rheumatologic Antinuclear antibody, rheumatoid factor, erythrocyte

sedimentation rate, C- reactive protein
Others (rare) Exclude other rare etiologies of pancytopenia with a

hypocellular marrow: e.g. graft-versus-host disease, HLH
Reference:
▪ Peslak SA, et al . Diagnosis and Treatment of Aplastic Anemia. Curr Treat Options Oncol.
2017 Nov 16;18(12):70.
50
• Once the diagnostic evaluation is complete, treatment is guided by the AA severity

• For pediatric patients with severe aplastic anemia (SAA) or very severe aplastic
anemia (VSAA), a transplant evaluation should be rapidly initiated
• A referral to a tertiary center that specializes in the care of AA patients should be
strongly considered.
• Supportive care is mandatory
• Oral cyclosporine with or without elthrombopag has to be started in severe and very
severe AA till the workup and evaluation for donors is completed.
51
Algorithm For Definite Treatment Of Severe And Very Severe Acquried Aplastic
Anemia < 18 Years Old
Reference:
▪ Modified from Scheinberg P. Acquired severe aplastic anaemia: how medical therapy
evolved in the 20th and 21st centuries. Br J Haematol. 2021 Sep;194(6):954-969
52
Non-Transplant Therapy in Severe and Very Severe Aplastic Anemia
Immunosuppressive Therapy
• For young patients without matched sibling donor (MSD), immunosuppression with
anti-thymocyte globulin (ATG) and cyclosporine A (CsA) combined with
eltrombopag is the recommended frontline therapy, offering outcomes comparable
to allogeneic BMT
• Horse ATG is the recommended ATG source, based on a randomized-controlled
trial of 120 patients showing a superior overall response (68% compared to 37%)
and OS (96% compared to 76%) for horse ATG-based IST compared to rabbit ATG-
based IST
Cyclosporine
• CSA dose is 5mg/kg/day from d1 to day 365, adjusted to maintain the trough level
at 150-250 ng/ml (watching for toxicities mainly renal insufficiency and
hypertension) .
• Then tailoring the dose by 5-10%/month up to +24 months(watch for dropping
blood counts while reducing CSA).Maintain for longer if no CR has been achieved.
53
Eltrombopag In Severe and Very Severe Acquired Aplastic Anemia
Revolade (Eltrombopag)
Indication:
• For the first-line, treatment of acquired severe aplastic anemia (SAA) in
combination with standard immunosuppressive therapy in adult and Pediatric
patients aged 2 years and over who are unsuitable for hematopoietic stem cell
transplantation at the time of diagnosis.
• For the treatment of Cytopenias in adult patients with acquired severe aplastic
anemia (SAA) who are either treatment-refractory or who have undergone
considerable prior therapy and who are not eligible for a hematopoietic stem cell
transplant at the time of indication.
54
Eltrombopag(Revolade) In Frontline Therapy
Starting Dose:
• Recommended Initial Revolade Dose Regimen in the First-Line Treatment of
Severe Aplastic Anemia:
Age Dose Regimen

Patients 12 Years and Older 150 mg once daily for 6 months
Pediatric Patients 6 to 11 Years 75 mg once daily for 6 months
Pediatric Patients 2 to 5 Years 2.5 mg/kg once daily for 6 month
• If baseline ALT or AST levels are > 6x ULN, do not initiate Revolade until
transaminase levels are <5xULN.
• Dose Adjustments of Revolade for Elevated Platelet Counts in the First-line
Treatment of Severe Aplastic Anemia:
Platelet Count Results Dose Adjustment or Response

- Decrease the daily dose by 25 mg every 2 weeks
to lowest dose that maintains platelet count ≥ 50
>200 x 10⁹/L to ≤400 x 10⁹/L x 10⁹/L.
-In pediatric patients under 12 years of age,
decrease the dose by 12.5 mg,
Discontinue Revolade for one week. Once the
platelet count is<200 x 10⁹/L, reinitiate Revolade
>400 x 10⁹/L
at a daily dose reduced by 25 mg (or 12.5 mg in
pediatric patients under 12 years of age).
55
Eltrombopag(Revolade) In Refractory Severe And Very Severe Aplastic Anemia
• Use the lowest dose of Revolade to achieve and maintain a hematologic response.
• Dose adjustments are based upon the platelet count. Hematologic response requires
dose titration, generally up to 150 mg (Maximum Dose), and may take up to 16
weeks after starting Revolade
• Initial Dose Regimen:
✓ Initiate Revolade at a dose of 50 mg once daily.

• Monitoring and Dose Adjustment:
✓ Dose Adjustments of Revolade in Patients with Refractory Severe

Aplastic Anemia:
Platelet Count Dose Adjustment
<50,000/μl following at least 2 weeks Increase daily dose by 25 mg to a

of treatment maximum dose of 150 mg/day
Reduce the daily dose by 50 mg. Wait

≥100,000/μl to ≤200,000/µl at any
two weeks to assess the effects of this
point during treatment
and any subsequent dose adjustments.
Stop Revolade for at least one week.
At a platelet count of <150,000/μl
>200,000/ μl
reinitiate therapy at a dose reduced by 50
mg.
Discontinue Revolade. Reinitiate
>200,000/μl after 2 weeks of treatment therapy with 25 mg or the next lower
at the lowest dosage of Revolade dose once the platelet count is
<50,000/μl.
56
Discontinuation of Revolade is indicated if:

• No hematological response after 16 weeks of therapy of full dose eltrombopag
• New cytogenetic abnormalities are detected
• Excessive platelet count responses
• Important liver test abnormalities developed
Supportive Care
• Throughout the diagnostic and treatment process, patients must be provided
aggressive supportive care
• Generally, restrictive transfusion targets (hemoglobin > 7 g/dL, platelets > 10,000
cells/μL) are preferred, especially in potential transplant candidates, given the risk
of alloimmunization and transfusional iron overload
• Prophylactic platelet transfusions should be given when the platelet count is <10 ·
109/l (or <20 X109/l in the presence of fever).
• Irradiated blood products should be used to prevent transfusion-associated graft-
versus-host disease (GVHD) and specially in candidates of BMT.
• Antifungal prophylaxis with voriconazole or posaconazole should be used in
patients with severe neutropenia (absolute neutrophil count < 500 cells/μL) .
Intravenous amphotericin should be introduced into the febrile neutropenia regimen
early if fevers persist despite broad spectrum antibiotics.
• Pneumocystis jirovecii pneumonia (PJP) prophylaxis should be used during the
period of lymphopenia following immunosuppressive therapy, ideally selecting an
alternative to trimethoprim-sulfamethoxazole because of its myelosuppressive
effects.
• Routine G-CSF use outside of episodes of febrile neutropenia remains controversial
• Iron chelation therapy should be considered when the serum ferritin is >1000 ng/ml.
• The benefits and risks of vaccines in AA also remain controversial due to the risk
of immune activation, with some AA guidelines recommending against
vaccinations outside of the post-transplant setting
57
References:
1. Marsh JC, Ball SE, Cavenagh J, et al; British Committee for Standards in
Haematology. Guidelines for the diagnosis and management of aplastic
anaemia. Br J Haematol. 2009 Oct;147(1):43-70.
2. Peslak SA, Olson T, Babushok DV. Diagnosis and Treatment of Aplastic

Anemia. Curr Treat Options Oncol. 2017 Nov 16;18(12):70.
3. Scheinberg P. Acquired severe aplastic anaemia: how medical therapy

evolved in the 20th and 21st centuries. Br J Haematol. 2021 Sep;194(6):954-
969
58
EVALUATION AND EMERGENCY ROOM MANAGEMENT OF

THE BLEEDING CHILD
Bleeding in a child can be a diagnostic challenge because of the wide range

of possible causes, but making a specific diagnosis is clinically important in order
to provide appropriate therapy.
Emergency Initial Critical Points to assess when faced with a child who is
actively bleeding or by history has experienced a major hemorrhage
1) Is the patient continuing to bleed?

2) Is the patient hemodynamically stable?
Patients who are actively bleeding or have occult bleeding and are
hemodynamically unstable require rapid initiation of vascular re‐ expansion and
efforts directed at controlling the bleeding.
59
3) The third critical question is whether the child presenting with

bleeding having a bleeding disorder
a. History
• Age , gender ,family history , previous bleeding, previous surgery , drug intake , the
nature of the bleeding should be explored with particular attention to location,
duration, frequency, and the measures necessary to stop it.
b. Examination
• In addition to the routine examination, the skin should be scrutinized carefully for
petechiae, purpura, and venous telangiectasias. The joints should be examined for
swelling or chronic changes such as contractures or distorted appearance with
asymmetry related to repeated bleeding episodes. Mucosal surfaces, such as the
gingiva and nares, should be examined for bleeding.
c. Assess Severity of bleeding by scoring system
d. Initial Laboratory Evaluation
• The purpose is to screen for the presence of a bleeding disorder, categorize the
disorder as primary or secondary, and direct further evaluation. Appropriate
screening tests include a CBC, peripheral blood smear (PBS), prothrombin time
(PT), and activated partial thromboplastin time (APTT, hereafter PTT) and
fibrinogen/D-dimers if DIC is suspected Interpretation of lab results refer to
algorithm in figure (1).
60
History and physical examination suggestive of

underlying bleeding disorder
Petechiae, ecchymoses, mucosal bleeding, or other Soft tissue, muscle, joint bleeding, or other
symptoms suggestive of a platelet disorder symptoms suggestive of a coagulopathy
Platelet Count PT/APTT
Low Normal Normal Abnormal
⚫ Immune
• Platelet function defect
thrombocytopenia
• VWD
⚫ Marrow failure • Factor XIII deficiency
syndromes • Drugs
⚫ Malignancies
⚫ Congenital platelet
disorders
⚫ Platelet consumption/
sequestration
⚫ DIC (PT/APTT will also PT Normal PT PT
be prolonged)
APTT APTT Normal APTT
⚫ Multiple factor ⚫ Haemophilia⚫⚫ ⚫ Factor VII deficiency

deficiencies ⚫ Other factor ⚫ Vitamin K deficiency
⚫ Common pathway deficiency ⚫ Liver disease
factor deficiencies⚫ ⚫ VWD ⚫ Warfarin
⚫ DIC
Figure (1): Algorithm for first-line screening in children with suspected bleeding
disorder
⚫Factor I,II,V,X deficiency
⚫⚫Factor VIII,IX,XI deficiency
61
e. Management
Indications of Therapeutic Platelet Transfusions

 ITP with major and/or dangerous bleeding (e.g., severe intestinal, intracranial or
intraocular haemorrhage)
 Acute disseminated intravascular coagulation with major bleeding and platelet count
<50×106/µL
 Platelet function defects (congenital or acquired) with active bleeding
 Surgical patient with active bleeding and platelet count <50-100×106/µL
➢ Initial emergency management

“Managed by GP/Pediatritian/hematologist”
• Initial Stabilization
• Vitals should be recorded in a bleeding child as the bleeds may be substantial
and life threatening.
• Stabilization of airway, breathing and circulation is the priority in any child
in a decompensated state.
• The severity of bleeds governs the speed/extent of investigations versus
administration of treatment. e.g., a coagulation disorder with intracranial
bleed will require urgent action vs. a patient with hemarthrosis.
➢ Specific management
• This is directed towards the underlying etiology -Please revise specific
protocols
➢ Severe undiagnosed coagulation disorder
“Managed by GP/Pediaritian/Hematologist”
• In the setting of severe hemorrhage occurring in an undiagnosed coagulation

disorder, fresh frozen plasma (FFP) should be administered, as it contains all
the clotting factors.
• The average concentration of factor in FFP is 1 unit/ml; the typical dose is 15
ml/kg
62
➢ Bleeding in platelet disorders [managed by hematologist]

• Platelets are transfused to control bleeding in quantitative or qualitative
platelet disorders. Platelets are available as random donor platelets (RDP) or
as single donor apheresis platelets (SDAP). Both are effective. SDP has
particular indications mainly alloimmunized patients and potential
polytransfused patients or preparing for BMT. Transfusion trigger in a
thrombocytopenic patient depends not only on the platelet count, but also on
its etiology and the clinical condition of the patient. Platelet transfusion is
futile and not indicated in majority of patients with immune
thrombocytopenia (ITP) as the transfused platelets are quickly destroyed due
to circulating antibodies.
➢ Vitamin k deficiency [managed by GP/Pediaritian/Hematologist]

• Bleeding Infants with vitamin K deficiency should receive 250–300 μg/kg
(maximum 10 mg) of i.v vitamin K without any delay. FFP (10– 15 ml/kg)
is indicated if urgent control of bleeding is desired in case of life threatening
hemorrhage
➢ Antifibrinolytic therapy
“Managed by GP/Pediatritian/Hematologist”
• Given as adjuvant for control of bleeding from mucosal surfaces, particularly

epistaxis, gum bleeding and menorrhagia in platelet or coagulation disorders.
• Tranexamic acid dose of 10-20 mg/kg q 6–8h oral or 10mg/kg q 6–8h
intravenous (maximum dose of 1 gm/dose)
• Antifibrinolytic therapy is contraindicated in hematuria.
➢ Recombinant factor VIIa
“Managed by GP/ Pediatritian /Hematologist”
• The EMA approved indications recombinant factor 7 include treatment of

bleeding in children with hemophilia with inhibitors and congenital factor
VII deficiency and in bleeding in platelet function defects (e.g., Glanzmann's
thrombasthenia), which is not responsive to platelet concentrates.
• Standard dose is 90 μg/kg 2–3 h, till the cessation of bleeding.
“If the patient is known to have a specific coagulation or bleeding
disorder Contact the Haematologist” to follow specific disease protocol”
63
References:
1. Blanchette VS, Breakey VR, Revel-Vilk S (eds): SickKids Handbook of

Pediatric Thrombosis and Hemostasis.Basel, Karger, 2013, pp 14–22 (DOI:
10.1159/000346914).
2. Bansal D, Oberoi S, Marwaha RK, Singhi SC. Approach to a child with

bleeding in the emergency room. Indian J Pediatr. 2013 May;80(5):411-20.
3. Shin T. S. and Mei J. Haemophilia and Other Bleeding Disorders in

Children.Mims Pharmacy2018.
64
Hemophilia A and B
Background
• Hemophilia is an X-linked bleeding disorder affecting 1 in 6,000–10,000 males and

less than 1 in 300,000 females
• Hemophilia A is clotting Factor VIII (8) deficiency
• Hemophilia B is clotting Factor IX (9) deficiency
• Approximately 80% of hemophilia patients have hemophilia A and 20% have
hemophilia B.
Management of acute bleeding in hemophilia patient
Assessment
➢ History
• Elicit a detailed description of site and mechanism of injury. Internal and joint
injuries are often missed
• Determine the type of hemophilia (Factor VIII or IX); the child's clotting factor
treatment plan and if there are Factor VIII/IX inhibitors
• Check if the child is on a prophylaxis program and when the most recent dose of
factor(s) or non factor therapy was administered
➢ Examination
• Assess the site and extent of bleeding
• Assess the impact on function
• Major or suspected bleeding in the head, neck, chest, gastrointestinal tract and
abdomen and/or pelvis should be treated with clotting factor immediately, before a
full assessment is complete
65
Table 1: Assessment of severity of hemophilia
Concentration of
Severity Clotting Factor Typical Bleeding Picture
(%)
Frequent bleed episodes are common;

Severe <1 predominantly into joints & muscles. Bleeding
can occur spontaneously or after a minor injury
Can bleed after a minor injury. May have

Moderate 1–5 bleeding into joints. Severe bleeds occur with
moderate trauma, surgery & invasive procedures
Bleeding occurs with major traumas such as surgery

Mild >5–40
& invasive procedures
Management
❖ Key Points in Management
1. Assessment and investigation should not delay factor replacement.

2. If there is ongoing bleeding after adequate factor replacement, consider
that the patient has developed a factor inhibitor and treat accordingly.
3. All children with hemophilia and bleeding should be discussed with a
hemophilia treatment center.
4. A hemophilia treatment plan should be made, in consultation with a
Hematologist, before performing any procedure (eg lumbar puncture).
66
➢ Investigations
• Clotting factor replacement should not be delayed by investigation
• Imaging of the site of suspected bleeding is dependent on the site and mechanism of
injury (trauma)
• Routine coagulation studies are not required if known hemophilia diagnosis
• If surgery is planned or inadequate response to CFC (by observation or history) the
assessment of inhibitors is required
➢ Treatment
• Most bleeds will require factor replacement with the exception of minor soft tissue
injuries and bruising that does not impact on function or mobility
• Prompt clotting factor replacement reduces the pain and long-term consequences of
bleeding
• Invasive procedures such as arterial puncture and lumbar puncture must only be
performed after clotting factor replacement
• Do not give IM injections
I. Clotting factor replacement

➢ Do not delay clotting factor replacement when indicated especially in severe or life-
threatening bleeding.
➢ Recombinant clotting factor concentrates or plasma derived clotting factor
concentrates are recommended; whatever product is available in emergency
situation as long as the patient is known inhibitor negative patient
➢ The dose and protocol of CFR depend on the site of bleeding (tables 2,3)
✓ Doses should be rounded up to use whole vials
✓ The presence of a new inhibitor should be suspected in any child who fails to
respond clinically to adequate factor replacement, particularly if the child has
been previously responsive
✓ If the child has factor inhibitors (proven or suspected), a special product is
required to ’bypass’ the inhibitor to initiate clotting ie a bypassing agent
✓ As clotting factor concentrates are not routinely available in all hospitals, children
in regional or rural areas should have advanced care plans and ready access to
blood products
✓ Whilst it is recommended that children maintain treatment with their established
brand of FVIII product, in an emergency situation administration of any brand of
FVIII is acceptable.
67
II. General measures: joint and muscle bleeds
➢ For muscle and joint bleeds P.R.I.C.E will limit bleeding and reduce pain. Initiate
on arrival
✓ P = Protection (immobilise the affected area in a position of comfort eg

splint/slings/crutches)
✓ R = Rest
✓ I = Ice (apply a cold pack to reduce bleeding and pain)
✓ C = Compression bandage (gentle)
✓ E = Elevation
III. Venous Access
➢ Children with haemophilia are at risk of venepuncture related bleeding. Treat

veins with care, apply pressure for at least 3 minutes post venepuncture
➢ In general, IV cannulas are not left in situ on discharge unless discussed with
specialist
IV. Analgesia
➢ Do not use products containing aspirin or NSAIDS (eg ibuprofen, diclofenac) as

they may worsen bleeding
➢ Paracetamol may be sufficient.
➢ Splinting and immobilization is an effective adjunct for reducing pain
“Consider consultation with local paediatric team and haemophilia treatment

centre when assessing any child with haemophilia with bleeding episodes”
Monitoring of response
➢ Clinical assessment of bleeding
➢ Factor 8/9 assay recovery or by PTT follow up
➢ If inadequate response inspite of adequate F8/9 therapy, test for inhibitors
is mandatory
68
Consider transfer when

➢ Child requiring care beyond the level of comfort of the local hospital or
treating medical team
➢ Assessing any child with any of:
✓ Suspected intracranial haemorrhage

✓ Bleeding into neck/throat
✓ Forearm/calf bleed at risk of compartment syndrome
✓ Bleeding into hip or inguinal area (due to risk of iliopsoas haemorrhage)
✓ Undiagnosed abdominal pain
✓ Persistent hematuria
✓ Bleeding causing severe pain
Consider discharge when

➢ No active bleeding
➢ Appropriate follow-up is arranged
➢ Patients are provided with a Hemophilia Centre Treatment Card (for their
management plan)
69
Table 2 Dose and duration of CFC in bleeding in hemophilia A

Hemophilia A
Dose of Factor 8
Desired level
Type of Hemorrhage In severe/moderate Duration (days)
(IU dL-1)
HA
Joint
1-2, May be longer if response is
40-60 20-30 units/kg/12 hrs
inadequate
Superficial muscle/no N-V compromise (except iliopsoas)
40-60 20-30 units/kg/12 hrs 2-3, Sometimes longer if response
is inadequate
Iliopsoas and deep muscle with NV injury, or substantial blood loss
Initial 80-100 40-50 U/kg every 8-12 hours 1-2
3-5, sometimes longer as
Maintenance 30-60 15-30 units/kg/8-12 hrs secondary prophylaxis during
physiotherapy
CNS/Head
Maintenance 50 25 units/kg/8-12 hrs 8-21
Throat and Neck

Gastrointestinal Hemorrhage
Initial 80-100 40-50 U/kg every 8-12 hours
7-14
Maintenance 50 25 units/kg/8-12 hrs
Renal
50 25 units/kg/8-12 hrs 3-5
Deep laceration
50 25 units/kg/8-12 hrs 5-7
Surgery (Major)
80-100 40-50 U/kg
Pre-op 1-3
60-80 30-40 U/kg/8-12 hrs
40-60 20-30 U/kg/8-12 hrs 4-6
Post-op
30-50 15-25 U/kg/12 hrs 7-14
Surgery (Minor)
Pre-op 50-80 25-40 U/kg 1-5, depending on type of
Post-op 30-80 15-40 U/kg/8-12 hrs procedure
Reference:
▪ Srivastava A, et al; Haemophilia. 2013 Jan;19(1):e1-47
70
Table 3 Dose and duration of CFC in bleeding in hemophilia B

Hemophilia B
Dose of Factor 9
Desired level
Type of Hemorrhage In severe/moderate Duration (days)
(IU dL-1)
HB
Joint
1-2, May be longer if response is
40-60 40-60 units/kg/24 hrs
inadequate
Superficial muscle/no N-V compromise (except iliopsoas)
40-60 40-60 units/kg/24 hrs 2-3, Sometimes longer if response
is inadequate
Iliopsoas and deep muscle with NV injury, or substantial blood loss
3-5, sometimes longer as
Maintenance 30-60 30-60 units/kg/12-24 hrs secondary prophylaxis during
physiotherapy
CNS/Head
Throat and Neck

Gastrointestinal Hemorrhage
Initial 60-80 60-80 U/kg every 8-24 hours
7-14
Maintenance 30 30 units/kg/12-24 hrs
Renal
40 40 units/kg/12-24 hrs 3-5
Deep laceration
40 40 units/kg/12-24 hrs 5-7
Surgery (Major)
60-80 60-80 U/kg
Pre-op 1-3
40-60 40-60 U/kg/12-24 hrs
30-50 30-50 U/kg/12-24 hrs 4-6
Post-op
30-50 20-40 U/kg/12-24 hrs 7-14
Surgery (Minor)
Pre-op 50-80 50-80 U/kg 1-5, depending on type of
Post-op 30-80 30-80 U/kg/12-24 hrs procedure
Reference:
▪ Srivastava A, et al; Haemophilia. 2013 Jan;19(1):e1-47
71
Management of Acute Bleeding in Hemophilia Patient with Inhibitors
• The development of an inhibitor, an antibody that inactivates the coagulant function

of replacement factor, is one of the most serious complications of hemophilia
treatment. FVIII inhibitors develop in 20–30% of boys with severe hemophilia A,
whereas FIX inhibitors develop in 3–5% with severe hemophilia B. These usually
develop within the first 50 exposures to factor replacement.
• Acute bleeding in patients with low‐titer inhibitors (<5 BU) can be managed by
using larger doses of factor replacement
• Acute bleeding in patients with high titer inhibitors (≥5 BU) require the use of
alternative hemostatic agents (Bypassing agents) which include recombinant factor
VIIa (rFVIIa; NovoSeven) and activated prothrombin complex concentrates (pd‐
aPCC; FEIBA)
72
A high-responding inhibitor is applied if the inhibitor titre is greater than 5 BU at any time
73
Treatment of Breakthrough Bleedings If Patient on Emicizumab
1) In inhibitor positive patients

2) In inhibitor negative patient
In Hemophilia A With Inhibitors Receiving Emicizumab (WFH 2020 Guidelines)

❖ The WFH recommends:
➢ Low-responding inhibitors : clotting factor replacement therapy including

FVIII
➢ High-responding FVIII inhibitors: rFVIIa preferred over aPCC due to the
risk of thrombotic microangiopathy
• Bleeding episodes should not be treated with aPCC unless no other option is
available
• The cumulative dose of aPCC should not exceed 100 U/kg/day
• The use of aPCC at dose higher than 100 U/kg/day for more than 24 hours was
associated with thrombotic microangiopathy and thrombotic events
“Thrombotic risks may last for up to 6 months after stoppage of emicizumab

during which plasma levels of emicizumab may persist”
Remark:
❖ Caution is urged when rFVIIa is used in patients receiving emicizumab who
have risk factors for thrombosis (e.g., past venous thromboembolism, obesity,
smoking, chronic infection, inflammation) due to the risk of acute non-STE
myocardial infarction and pulmonary embolism.
74
In Hemophilia A With Inhibitors Receiving Emicizumab (UKHCDO 2020

Guidelines)
❖ UKHCDO : UK Hemophilia Center Doctor Organization
1) First-line treatment of bleeds should be with rFVIIa

➢ The initial dose of rFVIIa should not exceed 90 μg/kg
➢ Doses of 45 μg/kg every 4 h may be efficacious for some bleeds
➢ If lower doses or frequencies of rFVIIa do not result in adequate
haemostasis, rFVIIa should be increased to 90 μg/kg every 2 h before it is
assumed to have failed
2) Human FVIII may be a treatment option if the bleed does not resolve with
rFVIIa and inhibitor titres are low
3) If a severe bleed does not respond to rFVIIa and other treatment options are
not available:
➢ aPCC may be administered at an initial dose of ≤50 U/kg (25 U/kg may be
efficacious for some bleeds)
➢ If a second dose of aPCC is required, the patient should be admitted to
hospital for TMA surveillance
➢ A second dose of 25‐50 U/kg may be considered on Day 1 if necessary
➢ The cumulative dose of aPCC should not exceed 100 U/kg/day
In Hemophilia A Without Inhibitors Receiving Emicizumab (UKHCDO 2020

Guidelines)
❖ UKHCDO : UK Hemophilia Center Doctor Organization
1) Breakthrough bleeds should be treated with the lowest FVIII dose expected
to achieve haemostasis; this may be lower than the patients’ prior FVIII dose.
2) Co-exposure to emicizumab and FVIII was not reported with any unexpected
safety events, serious adverse events, thrombotic events, or thrombotic
microangiopathy (TMA).
75
Prophylaxis for children with Haemophilia A and B
➢ What is the aim of prophylaxis in the management of a person with haemophilia

(PWH)?
 The primary goal of haemophilia care is to prevent bleeding and preserve

musculoskeletal function : this is usually achieved by prophylaxis, because
outcome measures will clearly differ depending on the joint health status at onset
of prophylaxis , prophylaxis protocols are classified as primary, secondary and
tertiary.
❖ Primary prophylaxis
• Commences in early childhood at the latest before the second joint bleed or the
age of 3 years, in the absence of documented joint disease, with the aim that the
child reaches maturity with normal joints .
❖ Secondary prophylaxis
• Commences after two or more joint bleeds, but before the onset of proven joint
disease. It is likely that these bleeds have caused subclinical but established,
irreversible joint disease.
• Prophylaxis aims to limit the consequence of this damage by preventing further
bleeding, maximizing function long-term.
❖ Tertiary prophylaxis
• Commences after the onset of clinically/radiologically apparent joint disease and

aims to slow down progression of joint disease, reducing pain and maintaining
quality of life. It cannot, however, reverse established joint disease.
76
➢ Who should receive primary prophylaxis? When to start?
• All patients with severe hemophilia A and B disease (factor 8 or 9 level <1 IU/dl)
and all moderate hemophilia A or B with severe phenotype.
• Given after the first joint bleed in children aged two or more years.
➢ Who should receive secondary prophylaxis?
and all moderate hemophilia A or B with severe phenotype, if not on primary
prophylaxis.
• Given after the second or more joint bleeds in children aged two or more years in
the absence of osteochondral joint disease.
➢ Who should receive tertiary prophylaxis?
and all moderate hemophilia A or B with severe phenotype, if not on 1ry/2ry
prophylaxis.
• Given in the presence of one or more osteochondral joint disease who is
experiencing ongoing bleeding.
❖ Important Note:
“Prophylaxis should be started regardless of age and continued for life

following completion of treatment for a spontaneous intracranial bleed or other
life threatening hemorrhage, if not already established”
77
Choice of Product for Hemophilia Prophylaxis
1) Factor replacement or non-factor replacement

• All severe hemophilia A patients and phenotypically severe moderate
hemophilia A with factor 8 inhibitors should receive non-factor replacement
therapy prophylaxis (Emicizumab, HemLibra).
• All severe hemophilia A patients and phenotypically severe moderate
hemophilia A without factor 8 inhibitors should receive factor 8 prophylaxis
therapy with exceptions as below.
• Non-factor replacement therapy prophylaxis (Emicizumab, HemLibra) is
indicated in severe hemophilia A patients and phenotypically severe
moderate hemophilia A without factor 8 inhibitors in the following
conditions
a. After life threatening hemorrhage
b. After major surgery
c. In the presence of documented difficult venous access
d. As primary prophylaxis and early secondary prophylaxis in children more
than one year old and no target joint
• All severe hemophilia B patients and phenotypically severe moderate

hemophilia B without factor 9 inhibitors should receive factor 9 prophylaxis
therapy.
2) Plasma Derived or recombinant Factor 8 or Factor 9

• The European Hematology Agency [ EMA] concluded that there was no
clear evidence of a difference in the incidence of inhibitor development
between Plasma Derived and Recombinant FVIII products.
• The risk of transfusion-transmitted infection with Plasma Derived products
is low, but cannot be excluded, and should be taken into consideration when
selecting a product.
78
3) Switch of Factor Replacement Products

• It is preferrable to be maintained on prophylaxis with the same factor
replacement product especially in newly diagnosed hemophilia in the first
150 exposure days who are inhibitor negative.
• Switching between factor replacement products for prophylaxis may be
performed in patients with more than 150 exposure days and no prior
inhibitor. In this group of patients switching is not associated with increased
risk of development of inhibitors.
“Whilst it is recommended that children maintain treatment with their

established brand of FVIII product, in an emergency situation administration of
any brand of Factor 8 or 9 is acceptable”
4) Standard Half Life or Extended Half Life Factor 8 or 9 Products

• At present time the MOH supports Standard half-life factor 8 or 9 products
for prophylaxis in hemophilia A/B patients without inhibitors
• Extended half-life products have the potential of decreasing frequency of
administration and hence possibly increase patient compliance however not
available at present time
79
➢ How to start factor 8 or 9 prophylaxis in children?
• Factor 8 prophylaxis is given at dose of 25–40 u/kg twice per week, while Factor
9 prophylaxis is given at dose of 40-50 u/kg once per week with follow up of
breakthrough bleeds with dose and frequency adjustment and individualization
to control the bleeding pattern.
➢ How to start Emicizumab prophylaxis in hemophilia A children when indicated?
• Emicizumab is started at loading dose of weekly 3 mg/kg subcutaneous for 4

doses then the patient is maintained on either protocol of 1.5 mg/kg weekly or
protocol of 3 mg/kg every 2 weeks depending on treating physician decision
➢ How long should prophylactic therapy continue?
• Prophylaxis throughout childhood should result in the individual having normal

musculoskeletal function and the goal of haemophilia care in adults should be to
maintain that function by preventing bleeding. The standard of care should be to
continue life-long.
80
Monitoring for Adverse events
1) Screening and Monitoring for Inhibitors

• Inhibitors are IgG alloantibodies to exogenous clotting factor VIII (FVIII) or
factor IX (FIX) that neutralize the function of infused CFCs.
• Inhibitors are detected and measured by the Bethesda assay or Nijmegen-
modified Bethesda assay. Inhibitors are positive when Bethesda titer >0.6 BU for
FVIII and ≥0.3 BU for FIX. Testing is critical to detect inhibitors early to ensure
appropriate treatment.
There are 2 levels of inhibitors, based on the titers observed:
Low-responding inhibitor High-responding inhibitor
<5.0 BU, typically transient ≥5.0 BU, typically persistent
Screening and Monitoring for Inhibitors
✓ After initial factor exposure, every 6-12 months and then annually
✓ Failure to respond to adequate CFC replacement therapy
✓ After intensive CFC exposure, e.g., daily exposure for more than 5 days and
within 4 weeks of the last infusion
✓ Before major surgery and if suboptimal post operative response to CFC therapy
✓ Poor clinical response to CFC replacement therapy
2) Adverse Effects Associated with Emicizumab

• Thrombotic events have been reported with emicizumab use including
thrombotic microangiopathy and venous thrombosis, when activated
prothrombin complex concentrate is co-administered at a dose >100 u/kg for >24
hours with emicizumab.
• No thrombotic events have been reported in association of emicizumab with
FVIII replacement in inhibitor negative patients.
81
Assessment of clinical efficacy of a prophylaxis regimen
1. Bleeding rates
• Bleeding episodes should be reported and reviewed promptly by treating
physician in order to review the prophylactic regimen [ drug,dose and
frequency] and address musculoskeletal factors ,adherence and psycho-social
factors.
Recommendation:
❖ The nature and frequency of breakthrough bleeding should be carefully documented
and monitored. Any suspected bleeds on a prophylactic regimen should prompt a
clinical review.
❖ Adherence to prescribed prophylaxis should be recorded contemporaneously, with
systems in place for the clinical team to be alerted to changes in bleeding frequency.
2. Impact of haemophilia and treatment on daily life

• The impact of haemophilia and prophylaxis on daily life can be assessed by
direct questioning.
Recommendation:
❖ The acceptability of a prophylactic regimen should be discussed with the individual,
considering the impact of both haemophilia and prophylaxis on their quality of life,
performance of daily activities and physical activity levels.
3. Musculoskeletal health
• The role of the specialist haemophilia physiotherapist is to minimise the
likelihood of bleeds by maximising strength and biomechanics through
exercise, advice and prehabilitation.
• However, as children can develop arthropathy with no history of clinically
overt joint bleeding, regular assessment of joint function is essential and can
be done using targeted questioning (see above), physical examination and
imaging.
82
3).a Physical Examination and Joint Scoring
• Systematic musculoskeletal examination can reveal changes in gait, joints and

muscles/ligaments/tendons due to arthropathy or maladaptive changes due to previous
bleeds. This can inform rehabilitative regimens to improve joint function, reducing the
likelihood of further bleeds and may also signal the need for an alteration in prophylaxis.
This examination should be carried out by a physiotherapist skilled in musculoskeletal
examination and with a good understanding of developmental norms.
• Scoring using the Hemophilia Joint Health Score [ HJHS ] . A deterioration in an
individual's joint score should prompt a review of bleeding and the prophylaxis regimen.
Recommendation:
❖ Patients with hemophilia receiving prophylaxis should undergo annual, detailed
musculoskeletal assessment by an appropriately trained physiotherapist using a
validated objective scoring system.
3).b Joint Imaging
• Plain radiography, while cheap and relatively quick, is insensitive to early

arthropathy and current interest is focussed on MRI and ultrasonography
(USS).
• MRI scoring is more sensitive to early arthropathic lesions than clinical or X-
ray scores, but is time-consuming and expensive.
• There are no longitudinal data showing the predictive value of early MRI
changes or how MRI might aid the clinician in monitoring prophylaxis. In
addition, young children may require general anaesthesia in order to acquire
the imaging.
• Ultrasonography helps to establish the diagnosis of acute haemarthrosis,
ultrasonography can detect joint effusions, synovial hypertrophy and
osteochondral changes of developing arthropathy. It can be delivered cheaply
and simply in the clinic using a limited scanning protocol and has good inter-
user consistency, but at present the clinical relevance of early ultrasound
changes has not been established.
Recommendation:
❖ Radiological imaging should not be used to assess efficacy of prophylaxis: plain
radiographs are insufficiently sensitive and neither MRI nor ultrasonography
changes have yet been shown to be predictive of long-term joint function.
83
84
Fish Score
Functional Independence Score for patients with Hemophilia
• This score was developed to measure the functional independence of people with
hemophilia.
• FISH is based on observing the performance of daily life activities i8 tasks in n 3
categories
• The activities are graded from 1 to 4, according to the assistance required to
perform the tasks.
• The scores achieved in each task are summed giving a total from 8 to 32 points
with 32 indicating the highest level of functional independence.
Levels Of Function and Their Scores
1. The subject is unable to perform the activity, or needs complete assistance to

perform the activity.
2. The subject needs partial assistance/ aids/ modified instruments/ modified

environment to perform the activity.
3. The subject is able to perform the activity without aids or assistance, but with
slight discomfort. He is unable to perform the activity like his healthy peers.
4. The subject is able to perform the activity without any difficulty like other
healthy peers.
85
86
Synovectomy
Synovectomy should be considered if chronic synovitis persists with frequent

recurrent bleeding and cannot be controlled by other means.
The decision of synovectomy is the hematology consultant decision and done in

hemophilia expert center.
Recommendations:
❖ Non-surgical synovectomy, guided by ultrasound, is the procedure of choice.
❖ Chemical synovectomy should be used when appropriate and available.
Rifampicin is highly effective and has few side effects; it can be used in an
outpatient setting when preceded and followed by factor infusion, analgesics and
bed rest.
Immune Tolerance Induction
In hemophilia A and hemophilia B patients with inhibitors , Immune tolerance

induction (ITI) involves administration of factor VIII or factor IX in increased doses so
that the individual's immune system learns to tolerate the factor VIII/factor IX and
ceases to produce inhibitors.
The cost of a full course of treatment is considerable because the amounts of

factor VIII or IX used in ITI are relatively large. If successful, however, ITI reduces the
risk of bleeds, joint damage and other complications.
The decision of immune tolerance induction and the protocol used is the
hemophilia consultant decision and done in hemophilia expert center
87
Dental Care in Hemophilia
General Measures
• Good oral hygiene for people with hemoplilia should be encouraged to prevent
the need for dental work and oral diseases such as gingivitis, dental caries and
periodontal disease, which may cause serious gum bleeding. Teeth should be
brushed at least twice daily for plaque control, using a soft or medium textured
toothbrush and fluoridated toothpaste.
Dental Surgery and Invasive Procedures

• Before any dental surgery or other invasive procedure within the oral cavity,
hemostasis management should be individually planned with advice from a
hematologist.
• Systemic and/or topical antifibrinolytics (tranexamic acid or epsilon-
aminocaproic acid) are effective as adjuvant treatment in the management of
dental interventions pre- and postoperatively to reduce the need for factor
replacement therapy. Antibiotics should be prescribed only if clinically indicated
for management of infection. Antibiotic prophylaxis should be administered to
patients with prosthetic joint replacement.
• Any swelling, difficulty swallowing (dysphagia), hoarseness or prolonged
bleeding after dental surgery must be reported to the dentist/hematologist
immediately.
• For many dental procedures, adequate local anesthesia is necessary, and most
dental injections can be delivered safely. High-risk intramuscular oral injections
may require systemic hemostatic measures. These measures should be
established preoperatively with the advice of a hematologist. Low-risk routes of
delivery such as intraligamentary single tooth anesthesia or buccal infiltration
injections are effective alternatives to inferior alveolar nerve block.
88
Guidelines for people with moderate-to-severe hemophilia requiring

outpatient/inpatient surgical dental treatment
Recommendations:
❖ Good oral hygiene should be encouraged in people with hemophilia.
❖ Hemostasis management (including systemic and/or topical antifibrinolytics) should
be individually planned with advice from a hematologist before any dental work is
undertaken.
❖ Patients with prosthetic joint replacement need antibiotic prophylaxis.
❖ Any problems after dental surgery (swelling, difficulty swallowing, hoarseness,
prolonged bleeding) must be reported immediately.
❖ Most dental injections can be delivered safely in people with hemophilia.
89
References:
1. Collins, PW, et al. Haemophilia. 2018; 24: 344– 347.
2. Escuriola‐Ettingshausen, C, et al. Haemophilia. 2020; 00: 000– 000.
3. Hoffmann‐La Roche Ltd. HAVEN 3 protocol v3.
4. Mokhtar, G et al . The Journal of Haemophilia Practice, vol.5, no.1, 2018,

pp.83-92
5. Mahlangu J, et al. NEJM 2018;379:811–822.
6. Srivastava A, et al. Haemophilia. 2020 Aug;26 Suppl 6:1‐158.
7. Tarawah AM, et al. J Appl Hematol 2011;2:171-8.
90
IMMUNE THROMBOCYTOPENIA ( ITP)
Definition
Immune-mediated disorder characterized by isolated thrombocytopenia
(PLT <100 x 109 /L) with absence of any obvious underlying cause of the
thrombocytopenia.
Classification
Newly Diagnosed ITP

Clinical Workup:
✓ Complete Patient History.
✓ Physical Examination (Including Bleeding Score).
“Exclude other thrombocytopenia associated disease and assess bleeding score”
Lab Workup:
✓ Complete Blood Count (CBC).
✓ Blood Film.
✓ Reticulocyte Count.
✓ ±Coomb's Test.
✓ Age ≥ 10 years do ANAbs and anti DNA Abs
✓ Bone marrow examination is necessary if atypical features like
organomegaly , bicytopenia or pancytopenia, abnormal blood film , bone
aches …
91
Table 1 : Bleeding Score

The Buchannan Score
Severity of Bleeding Symptoms

Few petechiae (≤100 total) and/or ≤5 small bruises
Grade I Minor/ Minimal
(≤3 cm in diameter)
Many petechiae (>100 total) and/or >5 large
Grade II Mild
bruises (>3 cm in diameter)
Mucosal bleeding that does not require immediate
Grade III Moderate medical attention (eg, brief epistaxis, intermittent
gum bleeding, menorrhagia)
Mucosal bleeding or suspected internal
hemorrhage that requires immediate medical
Grade IV Severe attention but that is not life-threatening (eg, GI
bleeding, severe prolonged epistaxis, muscle or
joint hemorrhage)
Documented intracranial hemorrhage or life-
Grade V Life-threatening
threatening or fatal hemorrhage in any site
92
Table 2: Management of Acute ITP
Clinical Situation Therapy Options

- Platelets Count < 30 x 10 ⁹ /L ➢ Oral Corticosteroids:
- Bleeding Manifestation Score: 3,4 - Prednisolone: 2-4 mg/kg for 5-7 days
(Maximum dose of 80mg/day).
OR
-Dexamethasone: 0.6 mg/kg for 4 days
(Maximum dose of 40mg/day).
➢ ± IVIG
- Life Threatening Bleeding ➢ IVIG:
Bleeding score 5 1 gm/kg/day for 2 days
(Maximum Dose of 2gm/kg).
+
➢ Methyl Prednisolone
20 mg/kg/day for 3-4 days
(Maximum Dose of 1gm/day).
±
➢ With or without Platelets Transfusion
according to bleeding severity
- Follow up: CBC Twice/Week.
93
Assess the severity of patient's bleeding symptoms

(Refer to Table 1)
Severe bleeding symptoms Non severe bleeding symptoms

Grade IV/V (Grade I to III)
Is bleeding potentially
life-threatening?
Yes No
Treatment includes ALL of Is the patient at moderate to high risk of

Treatment includes either
the following: or severe bleeding complications based on
one or more of the following?
⚫ PLT transfusions both of the following:
⚫ IV methylprednisolone for 3 to 4 ⚫ IVIG or IV anti-D
days ⚫ Head trauma without ICH
⚫ IV methylprednisolone ⚫ Severe unexplained headache
⚫ IVIG
⚫ Planned surgery or procedure that is
likely to induce blood loss
⚫ Grade III bleeding symptoms
⚫ PLT <30,000/microL PLUS any of the
following risk factors:
-Use of antiplatelet or anticoagulant
medications (eg, NSAIDs, heparin)
-Concomitant bleeding disorder (eg, van
Willebrand disease)
-Very active lifestyle subjecting the patient
to frequent trauma (that cannot be
controlled with activity restriction)
-Close follow up and/or other required
parental supervision cannot be assured
and/or access to medical care is limited
Yes No
Is a rapid increase in
Pharmacologic therapy is
platelet count desired? (eg, generally not indicated
urgent surgery, head
trauma) Most patients are managed
with watchful waiting
Treat with IVIG
Yes
± oral steroid No Treat with oral
glucocorticoids
Algorithm for Management of Acute ITP
94
Pediatric Persistent and Chronic ITP

Criteria
Age less than 18 years
Platelet count less than 100,000/cmm
Persistent: ITP for 3 Months or More
Chronic: ITP For 12 Months or More
Lab Workup
✓ ANA/C3/Anti DNA (Especially for females 10 years of age or older to revise
diagnosis if needed)
✓ ±Bone Marrow Aspiration (BMA).
✓ ±Immunoglobulin Profile (If any abnormalities, please consult
Immunologist).
✓ Hepatitis Markers for patients with HCV. If suspected
THE GOALS IN THE MANAGEMENT OF PERSISTENT AND CHRONIC ITP

1. The goal of treatment in children with chronic/persistent ITP is to achieve a
hemostatic platelet count: minimize risk of bleeding regardless of the platelet
count
2. Treatment should be always tailored to the individual patient
3. Avoid splenectomy and drug toxicity
Second Line (2nd line) option:

Thrombopoeitin Receptor Agonist (TPO-RA)
 Goal of treatment: Safe hemostatic platelet count.
Response Measures Failure Measures

Clinical: No Bleeding, No hemostatic achievement for > 2 months
Lab: Hemostatic or doubling on maximum dose according to age
initial platelet count
Two thrombopoietin receptor agonists are approved for pediatric use

1. Eltrombopag (revolade)
2. Romiplostim (N-Plate)
95
Eltrombopag (revolade)
Indication
• For the treatment of Pediatric patients (aged 1 year and older) with immune
(idiopathic) thrombocytopenia (ITP) lasting at least 3 months from diagnosis and a
significant tendency to bleed who have not responded to an established treatment
(e.g. IVIG, corticosteroids) or become a Steroid dependent.
Starting Dose
o Pediatric patients aged 1 to 5 years:
✓ Start with 25mg/day.
✓ Assess the response after 2 weeks.
✓ No data are available on patients in this age group with hepatic impairment.
o Pediatric patients aged 6 to 17 years:
✓ Start with 50mg/day.
✓ Assess the response after 2 weeks
✓ For patients with hepatic impairment the starting dose should be reduced
to 25 mg.
Dose Adjustment of Revolade
Platelet Count Dose Adjustment

- Aged 1-5 years: Increase daily dose by 30%.
<50,000/μl after a minimum of 2
- Aged 6 to 17 years: Increase daily dose by 25 mg,
weeks' treatment up to a maximum dose of 75mg/day.
≥50,000/μL to <200,000/μl Maintain the dose
- Aged 1-5 years: Reduce daily dose by 30%.
≥200,000/μL to <400,000/μl - Aged 6 to 17 years: Reduce the daily dose by 25 mg.
- Aged 1-5 years: Stop Revolade (Until the patients
reach a platelet count of <150,000/μl, reinitiate
therapy at a reduced daily dose).
>400,000/ μl - Aged 6 to 17 years: Stop Revolade (Until the
patients reach a platelet count of <150,000/pl,
reinitiate therapy at a reduced daily dose).
96
Revolade follow Up
• The standard dose adjustment, either decrease or increase, would be 25 mg once
daily.
• After any Revolade dose adjustment, platelet counts should be monitored at least
weekly for 2 to3 weeks.
• To see the effect of any dose adjustment on the patient's platelet response prior to
considering another dose increase one should wait for at least 2 weeks.
Discontinuation
• Treatment with Revolade should be discontinued if the platelet count does not
increase to a level sufficient to avoid clinically important bleeding after 4 weeks of
Revolade therapy at 75 mg once daily as a maximum dose.
Special Populations
• Renal impairment: Caution and close monitoring are required for the use of
Revolade in patients with renal impairment due to the absence of clinical
experience.
• Hepatic Impairment: Caution, close monitoring, starting dose 25 mg once daily (For
patients with a Child Pugh score ≥5 the starting dose should be reduced to 25 mg
Revolade daily).
• Hepatotoxicity: Discontinuation if ALT is >3 x ULN in patients with normal liver
function, or ≥3 x baseline whichever is the lower.
• Thrombotic/thromboembolic complications: Cautious use in patients with risk
factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency,
antiphospholipid syndrome).
• Grade 4 neutropenia (<500/µl) and blood count monitoring for Pediatric ITP
patients must be performed (as well as additional blood counts in the event of fever).
Method of Administration
• Revolade should be taken at least two hours before or at least four hours after
products such as antacids, dairy products or mineral supplements containing
polyvalent cations (e.g. aluminium, calcium, iron, magnesium, selenium and zinc).
• Revolade may be taken with food that does not contain calcium or that only contains
a small amount of calcium (<50 mg).
97
Romiplostim (N-Plate)
Therapeutic indications inPediatrics

➢ Treatment of chronic primary immune thrombocytopenia (ITP) in paediatric
patients one year of age and older who have significant bleed and are
refractory to other treatments (e.g. corticosteroids, immunoglobulins) or are
steroid dependent
➢ Chronic ITP not responsive to eltrombobag
➢ Chronic ITP developed serious adverse event to eltrombobag
➢ Chronic ITP who cannot tolerate oral therapy
➢ Comatosed chronic ITP patient
Method of administration
➢ Treatment should remain under the supervision of a physician who is
experienced in the treatment of haematological diseases.
➢ N-plate should be administered once weekly as a subcutaneous injection.
➢ Self-administration of N-plate is not allowed for paediatric patients.
Initial dose
➢ The initial dose of romiplostim is 1 mcg/kg based on actual body weight.
o Starting Dose:
✓ 2-3 mcg/kg/week.
✓ Subcutaneous injection, lyophilized powder for reconstitution.
o Dose Adjustment of Nplate:
✓ To increase dose by 1-2 mcg/kg/week every 2 weeks until reaching maximum dose.
✓ Maximum dose: 10 mcg/kg/week.
Dose Adjustment
➢ The patient actual body weight at initiation of therapy should be used to calculate
dose. In paediatric patients, future dose adjustments are based on changes in
platelet counts and changes in body weight. Reassessment of body weight is
recommended every 12 weeks.
➢ The once weekly dose of romiplostim should be increased by increments of 1-2
mcg/kg until the patient achieves a platelet count ≥ 50 × 109/L. Platelet counts
should be assessed weekly until a stable platelet count (≥ 50 × 109/L for at least 4
weeks without dose adjustment) has been achieved. Platelet counts should be
assessed monthly thereafter and appropriate dose adjustments made as per the dose
adjustment table below in order to maintain platelet counts within the
recommended range. A maximum once weekly dose of 10 mcg/kg should not be
exceeded.
98
➢ Adjust the dose as follows:

Platelet count (x 109/1) Action
<50 Increase once weekly dose by 1 µg/kg
> 150 for two consecutive weeks Decrease once weekly dose by 1 µg/kg
Do not administer, continue to assess the
platelet count weekly
> 250
After the platelet count has fallen to
< 150 x 109/1, resume dosing with once weekly
dose reduced by 1 µg/kg
Treatment discontinuation
➢ Treatment with romiplostim should be discontinued if the platelet count does not
increase to a level sufficient to avoid clinically important bleeding after four
weeks of romiplostim therapy at the highest weekly dose of 10 mcg/kg.
Use in Special population

➢ Patients with hepatic impairment : not be used in moderate to severe hepatic
impairment
➢ Patients with renal impairment : Nplate should be used with caution
Adverse events reported include

➢ Reoccurrence of thrombocytopenia and bleeding after cessation of treatment
➢ Increased bone marrow reticulin so follow CBC and film
➢ Thrombotic/thromboembolic complications so not used in patient at TED risk
like APLS or SLE
➢ Progression of existing Myelodysplastic Syndromes (MDS)
99
Third Line (3rd line) option:

Mycophenolate Mofetil (MMF)
 Use:
o To use Mycophenolate alone or with small dose of steroids.
 Dose:
o Dose of mycophenolate moftil (Cellcept) Orally 600MG/M2/12 hours
Fourth Line (4th line) option:

Rituximab
 Use:
o After failure of: 1st, 2nd and 3rd line options

o Pre-medications: Antihistaminic & Steroids should be used.
o Immunoglobulin Assay should be done before treatment initiation. Exclude
immune deficiency
 Dose:
o 375 mg/m²/week for 4 weeks. +/- Pulse Steroid
Fifth Line (5th line) option:

Splenectomy
“RARELY INDICATED IN CHILDREN

1st exclude 1ry immune deficiency and 2ry ITP”
 Use:
o Failure of other treatment option after > 12 months.

o Chronic resistant ITP with life threatening bleeding.
o Age of >5 years.
100
References:
1. https://www.ema.europa.eu/en
2. https://www.hematology.org/
3. https://www.uptodate.com/contents/image?imageKey=PEDS/115184
4. Bradbury CA, Pell J, Hill Q, et al. Mycophenolate Mofetil for First-Line

Treatment of Immune Thrombocytopenia. N Engl J Med. 2021 Sep
2;385(10):885-895.
101
102
Pediatric Hepatology Protocol Of EHA
0
Pediatric Hepatology Protocols Of EHA

in
Pediatric Hepatology
for
First Edition
2024
Prepared by
in
Pediatric Hepatology
for
1
Executive committee

1. Prof. Hanaa El-Karaksy: Emeritus Prof. of Pediatrics and Pediatric Hepatology,
Cairo University (Head)
2. Prof. Sawsan Okasha: Prof. of Pediatrics and Head of Pediatric Hepatology Unit,
Cairo University
3. Prof. Lerine Bahy El-Deen: Prof. of Pediatrics and Head of Pediatric Hepatology
Unit, Ain Shams University
4. Prof. Hesham Fathey El-Sayed: Emeritus Prof. of Pediatrics and Clinical
Epidemiology, Suez Canal University
5. Prof. Mona El-Raziky: Prof. of Pediatrics and Pediatric Hepatology, Cairo
University
6. Prof. Manal El-Hawary: Prof. of Pediatrics and Pediatric Hepatology, Fayoum
University
7. Prof. Ahmad Sira: Prof. of Pediatric Hepatology, Gastroenterology and Nutrition,
National Liver Institute, Menoufeya University
8. Prof. Mona Fahmy: Emeritus Professor of Pediatrics, Research Institute of
Ophthalmology
9. Associate Prof. Ashraf Radwan: Associate Prof. of Pediatrics and Pediatric
Hepatology, Sohag University
10. Dr. Mona Ghoneim: Consultant Hepatology, Gastroenterology, Egypt healthcare
authority
11. Dr. Hanan Fouad: Lecturer of Pediatrics and Pediatric Hepatology, Helwan
University
12. Dr. Yasmeen Touson: Lecturer of Public Health and Community Medicine, Cairo
University
13. Dr. Mariam Nader: Assistant Lecturer of Pediatrics, Armed Forces college of
Medicine (Moderator)
2
Disclaimer
Protocols and guidelines outline the recommended or suggested clinical

practice; however, they cannot replace sound clinical judgment by appropriately
trained and licensed physicians.
under their care.
3
• MD, FRCPCH (UK), MRCPI (Dublin)

• Consultant Paediatrician of Egyptian Military Medical Services
• Professor of Paediatrics Military Medical Academy
Authority (EHA)
Reviewed By
1. Dr. Hala Adel: Pediatric Consultant, Moderator & Coordinator of Medical

2. Dr. Huda Karam: Pediatric Specialist, Moderator & Coordinator of Medical

4
PREFACE

competency-based assessments to ensure the delivery of high-quality healthcare.
The aim of developing these Egyptian Clinical Practice Protocols in Pediatric
Hepatology is to unify and standardize the delivery of health care to all pediatric
patients with liver diseases at all heath facilities.
The Egyptian Clinical Practice Protocols in Pediatric Hepatology are developed
to enable health care providers, especially on the primary care level, to apply
stepwise diagnosis and management of pediatric liver diseases/disorders. By
applying these protocols, healthcare providers will be able to (a) recognize
common clinical presentations of pediatric liver disease/disorders, (b) identify and
implement emergency interventions required for urgent cases (e.g., upper
gastrointestinal bleeding), (c) pinpoint the cases that need urgent referral to
secondary and tertiary care without delay (e.g., biliary atresia cases) and (d)
distinguish neonatal jaundice secondary to hepatic disease (direct
hyperbilirubinemia) from the huge volume of newborns with physiological jaundice
and direct them to proper medical care.
These Egyptian Clinical Practice Protocols in Pediatric Hepatology are dynamic
tools, reflecting the current state of literature and practice, in the field of Pediatric
Hepatology, at the time they were produced and are amenable to periodic revisions.
Most of the content herein is based on the most recent literature, including the latest
Practice Protocols produced by respectable societies in the field of Pediatric
Hepatology: European, North American and British Societies of Pediatric
Gastroenterology, Hepatology and Nutrition (ESPGHAN, NASPGHAN,
BSPGHAN). All flowcharts/algorithms were produced with 100% agreement of all
members of the Working Group for Development of Egyptian Clinical Practice
Protocols in Pediatric Hepatology for Egypt healthcare authority.
As a start, four subjects were agreed upon to be developed in the form of
flowcharts/algorithms for diagnosis and management including: direct
hyperbilirubinemia in neonates and infants, acute hepatitis, chronic liver diseases
and upper gastrointestinal bleeding in the pediatric age group.
5
Knowing the large number of patients, the practitioner can face, and the
importance of initial management of children with hepatic diseases using a clear
strategy, these protocols were meticulously and scientifically prepared in order to
provide proper and sound management, saving time and resources. Each algorithm
contains a stepwise approach according to the level of medical care. It was with
100% agreement of all members that the protocols were developed using color
coding: green for primary care, yellow for secondary care and red for tertiary care.
For more details about each algorithm, the users are asked to refer to the matched-
numbered text on the corresponding page.
These Egyptian Clinical Practice Protocols in Pediatric Hepatology were
produced by the joint efforts of a group of consultants in Pediatrics, Pediatric
Hepatology, Epidemiology and Egypt healthcare authority. The working group was
initially divided in 4 subgroups each working on one of the chosen subjects,
followed by an extended discussion of each subject attended by all members until
the final version was approved. All these efforts were offered voluntarily extending
over a period of three months of meticulous work, including over thirty hours of
online meetings for discussions by all group members.
Expected tasks post-production of these Egyptian Clinical Practice protocols in
Pediatric Hepatology include: (a) training of primary care physicians to use these
protocols, (b) evaluation of the feedback from end users, both physicians and
patients, (c) revision of the protocols on annual basis and (d) establishment of an
accurate database of liver diseases in the pediatric population and registry of
various diseases on a national level.
Ultimately, we hope that, soon enough, health authorities will be convinced with
the increasing needs for including pediatric patients with rare liver diseases under
the umbrella of Egypt healthcare authority, as they cumulatively constitute a
considerable health problem.
For Development of the Egyptian Clinical Practice Protocols
In Pediatric Hepatology
6
Table of Contents
Page
Title
Number
Preface 5
List of Figures 8
List of Abbreviations 9
Key Points in Neonatal Cholestasis 13
Biliary Atresia 15
Child with a Picture of Acute Hepatitis 19
Key points in Chronic Liver Disease in Pediatrics 24
Infants Born to HBV or HCV Positive Mothers 29
Key Points in Upper Gastrointestinal Bleeding 32
7
List of Figures
Page
Title
Number
Figure (1): Flow chart diagnosis of biliary atresia & non-
12
biliary cholestasis
Figure (2): Stool color cards 16
Figure (3): An approach to a child with a picture of acute
18
hepatitis
Figure (4): Flowchart for chronic liver disease in Children 23
Figure (5): Emergency management of active upper
31
gastrointestinal bleeding
8
List of Abbreviations
ABG Arterial Blood Gases
ALT Alanine Aminotransferase
ALP Alkaline Phosphatase
ANA Antinuclear Antibodies
AST Aspartate Aminotransferase
BA Biliary Atresia
BASM Biliary Atresia Splenic Malformation
BP Blood Pressure
CBC Complete Blood Count
CBD Common Bile Duct
CMV Cytomegalovirus
CPK Creatine Phosphokinase
DNA Deoxyribonucleic Acid
EBV Epstein-Barr Virus
ERCP Endoscopic Retrograde Cholangiopancreatography
EUS Endoscopic Ultrasonography
9
fT4 Thyroxine
GCS Glasgow Coma Scale
GGT Gamma Glutamyl Transferase
HAV Hepatitis A Virus
HAV IgM Hepatitis A Virus Immunoglobulin M
Hb Hemoglobin
HBcAb Hepatitis B Core Antibody
HBsAg Hepatitis B Surface Antigen
HCVAb Hepatitis C Virus Antibody
HCV RNA Hepatitis C Virus Ribonucleic Acid
IG Immunoglobulin
IgG Immunoglobulin G
IM Intramuscular
INR International Normalized Ratio
IV Intravenous
LFT Liver Function Tests
LKMA Liver-Kidney Microsomal Antibodies
NAFLD Non-Alcoholic Fatty Liver Disease
10
MRCP Magnetic Resonance Cholangiopancreatography
NICU Neonatal Intensive Care Unit
NPO Nothing Per Oral
p-ANCA Perinuclear Antineutrophil Cytoplasmic Antibody
PCR Polymerase Chain Reaction
PPI Proton Pump Inhibitors
PT Prothrombin Time
PTT Partial Thromboplastin Time
RBCs Red Blood Cells
RBS Random Blood Sugar
RR Respiratory Rate
SMA Smooth Muscle Antibodies
TSH Thyroid Stimulating Hormone
tTG Tissue Transglutaminase
UTI Urinary Tract Infection
11
Figure (1): Flow chart diagnosis of biliary atresia & non-biliary cholestasis
12
Key Points in Neonatal Cholestasis
1- All Infants Who Are Jaundiced:

● At 14 days of life (> 37 weeks gestation or artificially fed babies), or
● At 21 days (< 37 weeks gestation or breastfed babies), or
● Any newborn from day1 with jaundice, dark colored urine, and/or pale stools
Should be promptly investigated for conjugated hyperbilirubinemia
2- Vitamin K (5 mg IM):
● Should be given to all cholestatic babies to correct coagulopathy and prevent
bleeding (most serious is intracranial hemorrhage).
3- Conjugated Hyperbilirubinemia
● Is defined as a direct (conjugated) serum bilirubin level > 1 mg/dl or > 15% of
total serum bilirubin.
4- History & Examination:
● Onset of jaundice, NICU admission, medications received, parenteral nutrition,
results of newborn screening tests
● Prenatal history: maternal infections, medication, maternal illness
● Family history: consanguinity, similar condition in siblings or family
● Color of urine (deep yellow). Examine the diaper for urine color (colorless in
healthy newborn)
● Color of stools (using Stool Color Cards: Figure 2). Examine the stool color
yourself.
● Pale stools to investigate for biliary atresia (BA)
● Pale/sick appearance: lethargy, irritability (infections or metabolic disease)
● Failure to thrive, small for gestational age (congenital infections, metabolic
diseases)
NB: Infants with BA typically appear well with adequate growth at presentation.
● Dysmorphic features, eye and hearing abnormalities (Alagille syndrome,

metabolic disease, congenital infections)
● Cardiac anomalies: congenital infections, BASM syndrome, Alagille syndrome
● Abdominal examination: Firm hepatomegaly is suspicious of BA;
hepatosplenomegaly may be present in storage or hemolytic diseases.
● Hypoplastic male genitalia may be present in panhypopituitarism.
13
5- Imaging: Fasting abdominal ultrasound:
● To detect surgical causes of cholestatic jaundice (BA, choledochal cyst), assess

liver size and echogenicity, splenic size, ascites, renal size and echogenicity,
patency of portal and hepatic vessels.
NB: HIDA scan is not specific and can hardly distinguish BA from other
causes of cholestatic jaundice. It is NOT recommended in the workup of neonatal
cholestasis.
6- Laboratory test:
● Liver Function Tests (LFT): total and direct serum bilirubin, ALT, AST, ALP,
GGT, serum albumin, PT, INR, should all be done simultaneously. LFT may
point to some etiologies (normal GGT cholestasis) however, they are non-
specific.
● If INR is still impaired after vitamin K administration: Refer to Tertiary care for
diagnosis and management of liver cell failure.
● Complete blood count: look for cytopenias.
● Blood & urine cultures
● DO NOT TEST for viral hepatitis A, B, and C markers unless there is a clear
history of exposure.
● RBS: Hypoglycemia should be prevented by adequate feeding or iv fluids in
critically ill.
7- Treat neonatal sepsis or UTI by appropriate antibiotics.
8- Special targeted tests according to suspected etiologies to be discussed with

Pediatric Hepatologist:
● TSH, FT4, early morning cortisol level
● Serum ammonia and lactate
● TORCH screening especially CMV DNA by PCR
● Reducing substances in urine and galactose-1-P-uridyl transferase
● Succinyl acetone in urine or blood
● Tandem mass spectrometry
● Plasma and urine organic acids
● Serum bile acids
● Sweat chloride test
● Echocardiography for cardiac anomalies
● Spine X-ray for vertebral anomalies
● Fundus and/or slit lamp examination
● Liver biopsy
● Genetic testing: targeted gene panels, whole exome sequencing.
14
Biliary Atresia
● BA is the most common cause of cholestatic jaundice affecting up to 40% of infants.
● It is crucial to diagnose BA early enough for optimal management.
● Initial good general condition and proper weight gain of these infants is certainly
MISLEADING and leads to late diagnosis and referral to specialized centers.
● LFT are non-specific.
● Fasting (for 4 hours) abdominal ultrasound will help identify BA:
➢ Absent, atrophic, irregular morphology gall bladder,
➢ Abdominal heterotaxy (situs inversus, meso-position of liver),
➢ Polysplenia. asplenia
● Liver biopsy is the mainstay for diagnosis with an accuracy of up to 90%.
▪ Histopathological characteristics confirming BA include:
➢ Bile duct proliferation,
➢ Portal fibrosis and edema,
➢ Bile plugs formation,
➢ Absence of sinusoidal fibrosis.
15
Figure (2): Stool color cards
16
References:
1- Beattie M, Dhawan A, Puntis J, Batra Akshay, Kyrana E. Neonatal jaundice. In:

Pediatric Gastroenterology, Hepatology and Nutrition, 2nd edition, 2018; 53, p
446.
2- Chen S-M, Chang M-H, Du J-C, Lin C-C, Chen A-C, Lee H-C, Lau B-H, Yang
Y-J, Wu T-C, Chu C-H, Lai M-W, Chen H-L. Screening for biliary atresia by
infant stool color card in Taiwan. Pediatrics 2006; 117: 1147-54.
3- Fawaz R, Baumann U, Ekong U, Fischler B, Hadzic N, Mack CL, McLin
VA, Molleston JP, Neimark E, Ng VL, Karpen SJ. Guideline for the
Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the
North American Society for Pediatric Gastroenterology, Hepatology, and
Nutrition and the European Society for Pediatric Gastroenterology, Hepatology,
and Nutrition. JPGN 2017; 64:154–68.
4- Makin E and Davenport M. Biliary atresia and other causes of surgical jaundice
in infancy. In Kelly D. (ed.), Diseases of the Liver and Biliary System in
Children, 4th edition 2017; 25, p 415.
5- Mittal V , Saxena AK, Sodhi KS, Thapa BR, Rao KLN, Das A, Khandelwal
N. Role of abdominal sonography in the preoperative diagnosis of extrahepatic
biliary atresia in infants younger than 90 days. Am J Roentgenol 2011;196:
W438–45.
6- Moyer V, Freese DK, Whitington PF, Olson AD, Brewer F, Colletti RB,
Heyman MB, North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition. Guideline for the evaluation of cholestatic jaundice in
infants: recommendations of the North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition. JPGN 2004; 39:115–28.
7- Russo P, Magee JC, Boitnott J, Bove KE, Raghunathan T, Finegold M, Haas
J, Jaffe R, Kim GE, Magid M, Melin-Aldana H, White F, Whitington
PF, Sokol RJ, Biliary Atresia Research Consortium. Design and validation of
the biliary atresia research consortium histologic assessment system for
cholestasis in infancy. Clin Gastroenterol Hepatol 2011; 9:357-62.
8- Sturm E and Hartleif S. Practical approach to the jaundiced infant. In: D’Antiga
L (ed.) Pediatric Hepatology and Liver Transplantation 2019; 6, p 99.
17
Figure (3): An approach to a child with a picture of acute hepatitis
18
Child with a Picture of Acute Hepatitis
1. Picture of Acute Hepatitis:

● Acute onset of jaundice, dark urine and pale stools for <15-day duration.
2. History:
● Acute hepatitis is usually preceded by history of prodromal symptoms for few days,
i.e., anorexia, nausea, malaise, diarrhea, vomiting and fever. History of contact to a
jaundiced case or drug intake. Examination: mild to moderate tender hepatomegaly,
and occasionally splenomegaly and elevated ALT >100 IU/mL.
N.B:
➢ The degree of elevation of transaminases does not correlate with the severity
of the illness.
➢ Rarely patient may present with extrahepatic manifestations accompanying
the acute illness, e.g., hydrops of the gall bladder (acalculous cholecystitis),
autoimmune hemolytic anemia, aplastic anemia, acute reactive arthritis, or
acute pancreatitis. Refer to a tertiary hospital.
3. Acute Hemolytic Crisis:

● Manifested by acute onset of jaundice, with the following criteria:
➢ Hemoglobin in urine
➢ Anemia
➢ Indirect hyperbilirubinemia with normal ALT.
“Refer to a secondary hospital for evaluation and possible blood transfusion”
19
4. Management of HAV Infection is Mainly Supportive:
Do Do Not
✓ Advise rest according to child

tolerance.
 Restrict protein.
✓ Adequate hydration.
 Add extra sugar or carbohydrates
✓ Nutritional support: balanced diet.
✓ Antiemetic (Ondansetron) and
antipyretic (Paracetamol within the
recommended daily doses).  Give herbal remedies
✓ Proper hand hygiene of cases and
caregivers
✓ Bathroom hygiene: disinfect, using
house bleach, all objects touched by hands.
✓ Absence from child care or school: for
at least 1 week of onset of symptoms if the
child is toilet trained, 2 weeks if not trained  Give vitamins unless indicated.
or having diarrhea and > 2 weeks if the
child general condition is not back to
normal.
How to prevent transmission of infection among household members?
● Post-exposure immune prophylaxis within 14 days of exposure:

➢ Active immunization with HAV vaccine for those above 12 months of age.
➢ Passive immunization using immunoglobulin: in a dose of 0.1 mL/kg IM for
infants younger than 12 months old, and in whom vaccine is contraindicated.
➢ HAV vaccine and immunoglobulin: in immunocompromised, and those with

chronic liver disease.
20
5. Follow-up:
● Clinical assessment and investigations biweekly in the first month then, monthly till
normalization. If no normalization till 6 months refer to tertiary care. If confirmed
acute HBV or HCV refer to tertiary care even after normalization of ALT.
6. Fulminant Hepatic Failure:

● INR ≥1.5 not corrected by vitamin K in the presence of clinical encephalopathy or
INR ≥ 2.0 regardless of the presence or absence of clinical encephalopathy. Give
IV/IM vitamin K before referral for hospitalization.
7. Cholestatic Form:
● Pruritus, pale stools, fatigue, and weight loss.
8. Obstructive Lesions:
● By ultrasound including common bile duct stone, choledochal cyst.
9. Investigations for Chronic Diseases:
● Presented by acute hepatitis as autoimmune hepatitis or Wilson disease (Refer to

chapter on chronic liver disease).
21
References:
1- Abdel-Hady M and Tong C. Viral Hepatitis. In: Diseases of the Liver and
Biliary System in Children, Kelly D (ed.), 4th ed, 2017; pp 191-210.
2- Alonso E and Squires R. Acute Liver Failure. In: Diseases of the Liver and
Biliary System in Children, Kelly D (ed.), 4th ed., 2017; pp 27-287.
3- Chu J and Arnon R. Infections. In: Walker's Pediatric Gastrointestinal Disease:
Physiology, Diagnosis, Management. Kleinman R, Goulet O, Mieli-Vergani G,
Sanderson IR, Sherman PM, Shneider BL (eds.), 6th ed., 2018; pp 3258-3464.
4- Shanmugam NP, Dhawan A. Acute Liver Failure in Children. In: Textbook of
Pediatric Gastroenterology, Hepatology and Nutrition. Guandalini S, Dhawan
A, Branski D (eds.), 2016; pp 995-1005.
5- Nelson NP. Updated Dosing Instructions for Immune Globulin (Human)
GamaSTAN S/D for Hepatitis A Virus Prophylaxis. MMWR Morb Mortal
Wkly Rep 2017;66: pp 959–960.
22
Figure (4): Flowchart for chronic liver disease in Children
23
Key points in Chronic Liver Disease in Pediatrics
1. Definition:
Chronic liver disease is defined as ongoing liver injury for at least 6 months.
However, it is unwise to wait for 6 months before investigating a possible cause of
liver damage, as some hepatopathies, such as autoimmune liver disease or Wilson’s
disease, can become rapidly life-threatening without appropriate treatment.
2. Clinical Presentations (Signs and Symptoms):
● Jaundice and/or hepatomegaly, hepatosplenomegaly, splenomegaly, ascites.

● Associated symptoms may include bleeding tendency, lower limb edema, pruritus,
and disturbed conscious level.
● Non-specific clinical symptoms may include anorexia, fatigue, nausea, vomiting, or
abdominal pain.
● Hematemesis secondary to variceal bleeding may be the first symptom in a child
with chronic liver disease or with portal vein thrombosis.
● Faltering growth/growth failure, with weight and height percentiles below the
average for age or muscle wasting indicates chronic liver disease early in life.
Presence of ascites and organomegaly may mask decreased weight percentiles.
● A child with chronic liver disease may be asymptomatic with only incidental finding
of elevated transaminases.
● The presence of doll facies, increased appetite, night sweating, and or convulsions
may suggest the possibility of glycogen storage disease.
● Overweight/obesity with high BMI in an older child may suggest the possibility of
nonalcoholic fatty liver disease.
24
3. History Taking:
Ask About:
● Consanguinity, draw a family pedigree. Ask about family history of chronic liver
disease. Family history of auto immune disorders like SLE may suggest the
possibility of autoimmune hepatitis.
● Risk factor of viral hepatitis like history of blood transfusion or operations.
● Drug intake, such as antiepileptics, and non-steroidal anti-inflammatory drugs.
● Family history of gall bladder stones, cholestasis of pregnancy, or history of
cholestasis of infancy that resolved or improved partially that may suggest the
possibility of PFIC3.
● Cardiac symptoms suggestive of right sided heart failure with congestive
hepatomegaly.
● Poorly controlled type 1 diabetes mellitus for the possibility of glycogenic
hepatopathy.
Pitfalls in the Diagnosis of Chronic Liver Disease:
• Splenomegaly with non-palpable liver is met with in cases of:

✓ Liver cirrhosis in which there is shrunken liver associated with portal
hypertension.
OR
✓ Portal vein thrombosis in which there is pre-hepatic portal hypertension with
normal liver size and normal liver function tests.
• Do not miss to palpate the left lobe of the liver, in case of cirrhotic shrunken
liver, left lobe is felt firm in mid line. If normal liver as in case of portal vein
obstruction, left lobe is soft, not felt and even only detected by light percussion.
• Don’t miss percussion of the upper border of the liver, to assess the liver size
(to exclude ptosed liver).
25
4. Interpretation of Liver Function Tests:

• 8 Tests to be done at the same setting:
A. Total and direct serum bilirubin:
• Test for secretory functions of the liver. Only conjugated (direct) bilirubin
passes in urine. Dark urine or urine analysis positive for bilirubin indicates
direct hyperbilirubinemia.
B. AST and ALT: detect liver injury.
• Although elevated AST&ALT reflect hepatocyte injury, they do not

always reflect the degree of liver injury.
• Isolated elevation of AST &ALT within a completely normal panel of liver
functions may indicate muscle origin. Assess for Gower sign and
pseudohypertrophy of calf muscles & ask for CPK.
• Difficult sampling may cause some rise of AST.
C. GGT and ALP: detect impaired bile flow or biliary dysfunction.
• GGT is not produced from bone tissue, so it confirms the hepatic origin of
raised ALP in a growing child.
• Reference for GGT is age related, with higher levels in neonates (up to 385
IU/L), to reach less than 75 IU/L in 4 months of age.
D. Albumin and PT &INR: test the synthetic functions of the liver.
• In decompensated chronic liver disease, abnormal hepatic synthetic

function is denoted by hypoalbuminemia and a prolonged prothrombin
time & international normalized ratio (INR)
• High INR may reflect vitamin K deficiency. Administer vitamin K and
assess the response on the next day. Prolonged INR after vitamin K (10 mg
IM or IV) administration indicates significant hepatic dysfunction, either
acute or chronic.
E. Serum ammonia:
• Test the detoxifying function if liver cell failure is suspected.
26
5. Viral Markers:
• HBsAg:
Indicates chronic hepatitis B infection, associated with positive anti HBc.
• Anti HBc (isolated):
Indicates exposure to HBV infection.
• Anti HBc IgM:
Is positive in acute HBV infection and with reactivation.
• HCV Ab (isolated):
Indicates previous exposure to HCV.
• HCV RNA:
Indicates active infection.
• Anti EBV VCA IgM &Anti CMV IgM:
Are performed if the disease duration is less than 6 months.
6. Parenchymal /Diffuse Liver Disease:

• Bright liver by US: mostly excess glycogen or fat.
➢ Glycogen storage disease is suggested if bright liver is associated with short
stature, doll like facies, hypotonia with delayed motor milestones. Check for
hypoglycemia in the form irritability, excessive sweating or convulsions.
➢ In an older child with BMI ≥85th percentile, consider NAFLD. In absence of
red flag signs (chronic fatigue, GI bleeding, jaundice, splenomegaly, firm liver
on examination, enlarged left lobe of the liver, low platelets, low white blood
cell count, elevated direct bilirubin, prolonged INR, long history of elevated
liver enzymes >2 years), council for diet and exercise. Repeat liver functions
after 10% reduction of body weight.
➢ If positive red flag signs from the start OR persistent raised transaminases after
weight reduction REFER to pediatric hepatologist for further testing.
➢ Bright liver with normal BMI: Do TSH & freeT4 and check for HbA1C, if
normal, REFER to pediatric hepatologist for lysosomal acid lipase (LAL) in
leucocytes or cultured fibroblasts/or genetic study for diagnosis of cholesteryl
ester storage disease.
27
7. Vascular Abnormality by US:

• If portal vein thrombosis or attenuated hepatic veins (Budd Chiari disease),
test for thrombophilia
• If congested hepatic veins, check neck veins and do echocardiography to
exclude right sided heart failure and pericardial disease then REFER to
cardiologist.
• Further studies including Doppler study, Triphasic CT and/or CT
angiography may be needed.
8. Biliary Abnormalities:
• For gall bladder stones, do hemolytic profile & lipid profile & REFER to
pediatric hepatologist to assess need for surgery.
• Choledochal cyst REFER to pediatric surgery.
• Intrahepatic biliary radicles dilation is suggestive of Caroli disease.
• CBD dilation may be due to CBD stricture, stone or pancreatic mass.
• In cases with intrahepatic biliary radicles, CBD dilation or choledochal
cyst further investigations may include MRCP &/or ERCP (therapeutic) or
EUS (especially for pancreatic lesions).
9. Unremarkable US Findings:
• In a child with chronic liver disease ultrasonography may appear normal.
10. Wilson Disease:

• Diagnostic tests include: low serum ceruloplasmin <20 mg/dl, 24-hr urine
copper excretion >40 µg/24hrs, Kayser-Fleischer rings by slit-lamp
examination (by a skilled ophthalmologist), molecular testing (for common
mutation or whole exome sequencing) or liver biopsy for copper content
(>250μg/g dry weight).
11. Autoimmune Hepatitis:

• Is diagnosed after exclusion of other causes of chronic liver disease in presence
of high immunoglobulin G together with positive autoantibodies (ANA and/or
SMA [titre≥1/20] in type1, anti LKM-1 [titre≥1/10] in type 2). Positive p-ANCA
is detected in type 1 when associated with sclerosing cholangitis. Liver biopsy
shows piece meal necrosis/interface hepatitis.
28
Infants Born to HBV or HCV Positive Mothers
Infants Born to HBsAg +ve Mothers:

• Should receive 0.5 cc of HBIG IM within 12 hours of birth (and maximum
within 48 hours), in addition to zero dose of hepatitis B vaccine in a
separate thigh. Then continue the regular vaccination schedule.
Asymptomatic Infants Born to HCV +ve Mothers:

• Can be screened for HCV using HCV Ab after 18 months of age. If
positive, wait till age of available treatment (3 years) BUT don’t forget to
teach the family about precautions to prevent horizontal transmission
within the family. At 3 years of age, ask for quantitative HCV RNA by
PCR and refer for treatment if positive.
Mothers Positive for Either HBV or HCV:
• Should be encouraged to breast feed.
Any Case with HBV or HCV, Family Screening is Mandatory
29
References:
1- EASL Clinical Practice Protocols: Wilson’s disease: Journal of Hepatology

2012; 56: 671–685.
2- Kelly D. The Child with Chronic Liver Disease. In: Atlas of Pediatric
Hepatology Kelly D. (ed.), 1st edition 2018; 7:71.
3- Lee WS and Kelly D.A. Useful investigations in the assessment of liver
disease. In: Diseases of the Liver and Biliary System in Children, Kelly D.
(ed.), 4th edition 2017; 5: 41.
4- Mieli-Vergani G, Vergani D. Autoimmune liver disease. In: Diseases of the
Liver and Biliary System in Children, Kelly D. (ed.), 4 th edition 2017; 11,
p155.
5- Muller T and Tanner S. Disorders of Copper Metabolism. In: Diseases of the
Liver and Biliary System in Children, Kelly D. (ed.), 4th edition 2017; 20: 329.
6- Sokollik C, McLin VA, Vergani D, Beretta-Piccoli BT, Mieli-Vergani G.
Juvenile Autoimmune hepatitis: A comprehensive review. J Autoimmun 2018;
95: 69–76.
7- Vajro P, Maddaluno S, and Veropalumbo C. Persistent hypertransaminasemia
in asymptomatic children: A stepwise approach. WJG 2013;19: 2740-2751.
8- Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, Mouzaki M,
Sathya P, Schwimmer JB, Sundaram SS, Stavra A. Xanthakos SA.
NASPGHAN Clinical practice guideline for the diagnosis and treatment of
nonalcoholic fatty liver disease in children: Recommendations from the Expert
Committee on NAFLD (ECON) and the North American Society of Pediatric
Gastroenterology, Hepatology and Nutrition (NASPGHAN). JPGN 2017; 64:
319–334.
30
Figure (5): Emergency management of active upper gastrointestinal bleeding
31
Key Points in Upper Gastrointestinal Bleeding
1. Active UGIB:
• Is defined as either hematemesis, coffee-ground vomitus, melena, or
bleeding per rectum with hemodynamic instability.
2. IV Fluids:
• Should be given according to hemodynamic status; shock, deficit, or
maintenance.
Symptoms of Hypovolemic Shock:
Tachycardia, Tachypnea, Hypotension, changed state of consciousness
(irritability, confusion, unconsciousness), cool clammy skin, and low urine
output.
Shock Therapy:
20 ml/kg normal saline 0.9% and could be repeated up to 3 times till the
patient is hemodynamically stable.
Maintenance Fluids:
Give 2/3 of calculated maintenance IV fluids. Maintenance fluid
calculation; first 10 kg of body weight: 100 ml/kg. Second 10 kg of body
weight: 50 ml/kg. Third 10 kg of body weight and more: 25 ml/kg.
3. Propranolol:
• Stop propranolol during active bleeding if the patient was maintained on it.
32
4. Lab:
• ABG, RBS, CBC, kidney function (urea and creatinine), liver function
tests (total and direct bilirubin, total protein, albumin, ALT, AST, ALP,
GGT), electrolytes, PT, PTT, fibrinogen (if available), and blood cultures
5. PPI (IV):
• Omeprazole (1 mg/kg daily); Esomeprazole (0-1 month: 0.5mg/kg OD; 1-
11 months: 1mg/kg OD; 1-11 years and <20 kg: 10mg OD; 1-11 years and
> 20kg 10-20mg OD; 12 years and above: 40mg OD.
6. Octreotide Dose:
• Stat dose: 1microgram/kg IV over 5 minutes (maximum 50 microgram)
followed by Infusion at 1-3 µg /kg /hr. (max 50 µg /hour). Continue for 24
h after bleeding is controlled. Do not stop suddenly.
7. Vitamin K:
• 300microgram/kg as slow IV injection (max 10mg)
8. Intravenous Antibiotics:
• A third-generation cephalosporin or piperacillin/tazobactam depending on
local guideline.
9. Platelet Transfusion:
• When platelets <50×103/µl, and plasma transfusion when PT and
PTT>1.5 normal.
33
10. Ryle (Nasogastric Tube):

• Do gastric lavage with cold saline to remove blood from the stomach.
11. Inform the Target Tertiary Referral Center
• About the details of the case with the hemodynamic status at presentation
and after resuscitation. For those presenting with hemodynamic instability
a notification about the case should be given to the surgical and
radiological departments within the referral center.
12. When to Refer:

• If you don’t have feasibility to do upper endoscopy, Please Don’t Refer
Except After hemodynamic stabilization.
13. Secondary Prophylaxis:

• Propranolol; dose: 0.5-1 mg/kg/12 hr. orally.
14. Decision for Use of Balloon Tamponade:
• Will depend on the findings and actions in the first endoscopy.

endotracheal intubation should be used with balloon tamponade for the risk
of aspiration.
15. Re-endoscopy:
• Will be done when initial endoscopy was considered suboptimal. However,

when bleeding is severe, radiologic intervention or surgery are indicated.
34
References:
1- Beattie M, Dhawan A, Puntis J, Batra A, Kyrana E. Portal hypertention In:

Pediatric Gastroenterology, Hepatology, and Nutrition, Beattie M, Dhawan A,
Puntis J, Batra A, Kyrana E (eds.), Second ed., 2018:619-28.
2- BSPGHAN: Assessment and management of oesophageal varices in children
V2 September 2021. https://bspghan.org.uk/hepatology-protocols
3- Di Giorgio A, D’Antiga L. Portal hypertension in children. In: Textbook of
Pediatric Gastroenterology, Hepatology and Nutrition. Guandalini S, Dhawan
A, Branski D (eds.), 2016;791-817.
4- Di Giorgio A, D’Antiga L. Portal hypertension. In: Pediatric Hepatology and
Liver Transplantation. D’Antiga L (ed.), 2019; 299-327.
5- Ebel NH, Horslen SP. Complications and management of chronic liver disease.
In: Diseases of the Liver and Biliary System in Children. Kelly DA (ed.), 2017;
343-68.
6- Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J
Gastroenterol 2012; 107:345-60.
7- McDiarmid SV. End-stage liver disease. In: Walker’s Pediatric Gastrointestinal
Disease, Pathophysiology • Diagnosis •Management. Kleinman RE, Goulet O-
J, Mieli-Vergani G, Sanderson IR, Sherman PM, Shneider BL (eds.), 2018;
4396-475.
8- Shanmugam N. Management of acute portal hypertensive bleed. In: Pediatric
Liver Intensive Care. Shanmugam N, Dhawan A (eds), 2019; 53-7.
9- Tringali A, Thomson M, Dumonceau JM, Tavares M, Tabbers MM, Furlano R,
Spaander M, Hassan C , Tzvinikos C, Ijsselstijn H, Viala J , Dall'Oglio
L , Benninga M , Orel R, Vandenplas Y , Keil R, Romano C, Brownstone E,
Hlava S , Gerner P , Dolak W , Landi R , Huber WD , Everett
S , Vecsei A, Aabakken L , Amil-Dias J , Zambelli A. Pediatric gastrointestinal
endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and
European Society for Paediatric Gastroenterology Hepatology and Nutrition
(ESPGHAN) Guideline Executive summary. Endoscopy 2017; 49:83-91
10- Tsoi KK, Ma TK, Sung JJ. Endoscopy for upper gastrointestinal bleeding: how
urgent is it? Nat Rev Gastroenterol Hepatol 2009; 6:463-9
35
36
Pediatric IEI Protocol of EHA
0

in
Pediatric Inborn Errors of Immunity (IEI)
For
First Edition
2024
Prepared By
in
Pediatric Inborn Errors of Immunity
for
1
Executive Committee
1. Prof. Aisha M.Elmarsafy: Emeritus Professor of Pediatrics and founder of PID

center, Cairo University
2. Prof. Shereen Reda: Professor of Pediatrics, Pediatric Department, Faculty of
Medicine, Ain Shams University.
3. Prof. Nermeeen M.Galal: MD-FRCPCH, Professor of Pediatrics, Head of PID
center, Cairo University.
4. Prof. Mohamed Almalky: Professor of Pediatrics, Head of PID unit, Zagazig
University
5. Prof. Nesrine Radwan: Assistant Professor of Pediatrics, Children’s Hospital,
Faculty of Medicine, Ain Shams University.
6. Prof. Ali Sobh: Assistant Professor of Pediatrics, Mansoura University
Children’s Hospital,Faculty of Medicine, Mansoura University.
7. Dr.Walaa Shoman: Lecturer of Pediatrics, Faculty of Medicine, Alexandria
University.
8. Dr. Naglaa Samy Mohamed Osman: Lecturer of Pediatrics, Director of the Unit
of Allergy, Immunology and Rheumatology, Assiut University.
9. Dr. Shaimaa Refaat: Pediatric and neonatology specialist, MD researcher in
Pediatric rheumatology; Ministry of health. (Moderator)
All Intellectual Property Rights are reserved to EHA. No part of this publication can
be reproduced or transmitted in any form or by any means without written permission
from the EHA and authors.
2

Board
Authority (EHA).
Reviewed By



3
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Primary
Immunodeficiency Disorders is to unify and standardize the delivery of healthcare to
any child at all health facilities.
Primary Immunodeficiency Disorders (PIDS) also known as Inborn Errors of

Immunity (IEI) constitute over 450 different disorders with complex diagnostic and
therapeutic pathways. The main focus of the guidelines is helping clinicians when to
suspect PID disorders and advising care steps till urgent referral to a specialized
center is feasible.
In disorders of Inborn Errors of Immunity, busy clinicians have all felt the need
for a concise, easy-to-use bedside resource & evidence-based protocols, or

that practicing pediatricians, fellows and nurse practitioners will find this protocol
useful in delivering high-quality clinical care to their patients. We remain open to
feedback and suggestions about how to improve this resource and how to make it
maximally useful to those delivering care at the bedside in for patients with primary
Immunodeficiency disorders.
In Pediatric Inborn Errors of Immunity
4
Table of Contents
Page
Title
Number
Preface 4
When to suspect Inborn Errors of Immunity (IEI) in 6
Primary Health Care:
Inborn Errors of Immunity (IEI) 11
Cellular/Combined Immunodeficiency Disorders (CID)
Predominantly Antibody Disorders 14
Defects in Innate Immunity 17
Disorders of the Phagocytes 20
Diseases of Immune Dysregulation 23
Complement Disorders 26
Hereditary Angioedema (HAE) 28
Immunodeficiency with Syndromic Features 31
5
When to suspect Inborn Errors of Immunity (IEI) in

Primary Health Care:
-Family History:
Consanguinity
Sibling death (unexplained or caused by similar condition)
Only male affection (X-linked disorders)
Similar conditions or manifestations among sibs/ cousins
Repeated abortions
-Vaccination History:
Complications to BCG vaccine
Complications to Polio vaccine or Acute Flaccid Paralysis (AFP)
The 10 Warning Signs of IEI (2 positive signs warrant screening):

≥ Four new ear infections within 1 year.
≥ Two serious sinus infections within 1 year.
≥ Two pneumonias within 1 year (documented).
≥ Two deep-seated infections such as sepsis, meningitis or cellulitis.
Failure to thrive of an infant (unexplained by other causes).
Recurrent, deep skin or organ abscesses.
Persistent thrush in mouth or elsewhere on skin, after age 1.
≥ Two months on antibiotics with little effect.
Need for IV antibiotics to clear infections.
A family history of primary immune deficiency.
6
Specific warning signs for the neonatal period-first six months:

1. Severe/persistent/unusual /recurrent infections
2. Family history: Primary immune deficiency – early deaths due to infections
3. Adverse reactions to BCG or other live vaccines as Polio vaccine
4. Autoimmune/Autoinflammatory/Long lasting Fever
5. Extensive skin lesions (Erythroderma, atopy, petechiae, pustular or nodular)
6. Chronic diarrhea – failure to thrive –Early onset IBD
7. Congenital heart anomaly ± hypocalcemia
8. Delayed umbilical cord separation (>30d)
9. Absence of thymic shadow
10. Persistent alterations of WBCs: lymphopenia – cytopenia – leukocytosis-
thrombocytopenia
When to suspect IEI-general:

• Family history considerations:
o Consanguinity
o Individuals with similar diseases
o Individuals with recurrent infections or who were hospitalized for
infections
o Unexplained deaths
o Individuals with autoimmune disease/malignancy/bone marrow
transplant
• Failure to gain weight or grow normally (failure to thrive) unexplained
• Need for intravenous antibiotics and/or hospitalization to clear infections
• Six or more ear or respiratory tract infections within one year
• Two or more serious sinus infections or pneumonias within one year
• Four or more new ear infections within one year
• Two or more episodes of sepsis or meningitis in a lifetime
• Recurrent or resistant oral or cutaneous candidiasis
7
• Recurrent deep skin or organ abscesses

• Infection caused by an unusual microbial organism and/or in an unusual
location
• Complications from a live vaccine (eg, rotavirus, varicella, and Bacillus
Calmette-Guérin [BCG] vaccines)
• Chronic diarrhea
• Non-healing wounds
• Extensive skin lesions
• Persistent lymphopenia (a count of <1500 cells/uL in patients over five years
and <2500 cells/uL in younger children)
• Unexplained autoimmunity or fevers
• Granulomas or lymphoproliferation (unexplained)
• Malignancy in infancy
• Features typical of syndromic PIDs (eg, cartilage-hair hypoplasia, Chediak-
Higashi syndrome, ataxia-telangiectasia)
When to suspect IEI subspecialty version:
Pulmonology:
• Recurrent Pneumoniae, otitis, and sinusitis by encapsulated bacteria
• Lung abscess
• Pneumocystis jeroveci pneumonia
• Infections by atypical mycobacteria (including BCG), disseminated TB
• Interstitial pneumonia
Allergy:
• Difficult to control asthma
• Recurrent or complicated sinusitis
• Recurrent or complicated otitis media
• Severe eczema
• Recurrent angioedema
8
Cardiology:
➢ Congenital heart defects with hypocalcemia
Dermatology:
• Severe eczema
• Partial albinism
• Warts
• Molluscum contagiosum, recurrent
• Ectodermal dysplasia
• Severe periodontal disease
• Retained primary teeth
• Chronic mucocutaneous candidiasis
Endocrinology:
• Neonatal diabetes
• Neonatal tetany
• Hypothyroidism, hypoparathyroidism,
• adrenal insufficiency
Gastroenterology:
• Chronic diarrhea
• Difficult to treat Giardiasis
• Autoimmune colitis
• Esophageal candidiasis
• Hepatic abscess
• Celiac disease
• Inflammatory bowel disease
Hematology:
• Thrombocytopenia with microplatelets
• Autoimmune cytopenias
• Neutropenia
• Lymphoproliferation
• Hemophagocytic lymphohistiocytosis
• Marked leukocytosis
9
Neonatology:
• Erythroderma
• Omphalitis, delayed cord separation >40 days
• Neonatal tetany
• Neonatal diabetes
• Typical facies of DiGeorge syndrome
Neurology:
• Ataxia
• Meningoencephalitis by Neisseria sp
• Herpes simplex encephalitis
• Microcephaly
When Not to Refer or think of primary immunodeficiency:

1. Recurrent URTI, viral infections without bacterial complications
2. Recurrent septic spots /boils in absence of other infections
3. Recurrent tonsillitis
4. Recurrent regular fevers other than Autoinflammatory disorders.
5. Recurrent central line sepsis
6. Urinary tract infections
10
Inborn Errors of Immunity (IEI)

Cellular/Combined Immunodeficiency Disorders (CID)
Consider SCID or CID if Patients have:
• Appear ill
• Have facial dysmorphia (DiGeorge syndrome) or ectodermal dysplasia
(NEMO)
• Fail to thrive
• Have congenital heart disease (heart murmur at birth, cyanosis, DiGeorge
syndrome)
• Have skin changes
• Severe diaper rash or oral candidiasis (thrush)
• Eczema as in Wiskott-Aldrich syndrome or Graft versus Host Disease (GVHD)
• Red rash as in GVHD, Omenn’s syndrome or atypical complete DiGeorge
syndrome
• Petechiae in Wiskott-Aldrich syndrome
• Absence of nails, hair or sweating (NEMO)
• Cutaneous viral infections
• Thin hair or reduced sweating (NEMO)
• Have chronic intractable diarrhea
• Develop intractable viral infections due to respiratory syncitial virus (RSV),
parainfluenza, cytomegalovirus (CMV), Epstein Barr Virus (EBV), or
adenovirus
• Have adverse reactions after live vaccines BCG (BCGosis) or Oral polio (AFP)
• Have neurological findings such as ataxia or tetany of the newborn (DiGeorge
syndrome)
If the patient has one or more of the previous manifestations:
1. The Physician should order a CBC with differential counts

2. If Neutropenic or Leukopenic (according to age) → Refer to Immunologist (for
1ry health care physicians)
11
For 2ry health care physicians:

Do
1. CD3, CD4, CD8, CD19, CD56,16 and according to defect SCID is
divided to:
T-, B+, NK+
T-, B-, NK+
T-, B-, NK-
T-, B+NK+
2. IgG, IgM, IgA, IgE.
Medications:
1. Confirmed cases of SCID should be referred immediately to an immunologist
to prepare for HSCT
2. Confirmed cases should begin prophylactic anti Pneumocystis jirovecii
pneumonia (PJP) in the form of TMX, prophylactic antifungals and appropriate
antimicrobials according to the condition.
3. IVIG monthly
4. Patients should not receive live vaccines (OPV or BCG)
5. Only irradiated blood is transfused in case of emergency for fear of GVHD.
➢ Vaccination:
Patients with SCID should not be given BCG, oral polio, yellow fever, live
attenuated influenza, or typhoid fever vaccines, but family members and other
close contacts, with the exception of oral polio vaccine, may receive other
standard vaccines because transmission to an immune deficient patient is most
unlikely.
12
Consider Bone Marrow failure if Patients have:

1. Anemia with reticulocytopenia
2. Purpuric eruption
3. Recurrent infections with leukopenia
➢ The Physician should order a CBC → if Bicytopenia or pancytopenia → refer to

hematologist/immunologist (BM failure syndromes may be a part of combined
Immunodeficiency.
13
Predominantly Antibody Disorders
Antibody deficiencies are a group of primary immune deficiencies caused by

defects in B-cell development, activation, or antibody synthesis.
The most common antibody disorders include:

• X-linked and autosomal recessive Agammaglobulinemia (XLA)
• Common variable immunodeficiency (CVID)
• Immunoglobulin class-switch defect as Hyper IgM
• Transient hypogammaglobulinemia of infancy
• Selective IgA deficiency
When to suspect predominately antibody deficiency disorders?

Presentation usually starts at the age of 6 months by recurrent, severe, unusual
persistent bacterial, protozoal infections and less commonly with viral infections.
• Recurrent sinopulmonary infections (pneumonia, sinusitis, discharging otitis
media) and may be complicated by bronchiectasis and deafness.
• Prolonged use of antibiotics to clear infection.
• Enteroviral meningoencephalitis. (More with XLA).
• GIT infections, chronic diarrhea or malabsorption. (More with CVID, X-linked
agammaglobulinemia or X-linked Hyper IgM, due to infection with parasites,
e.g., Giardia lamblia or Cryptosporidium.)
• Recurrent cutaneous infections.
• Lymphoreticular malignancy and autoimmune manifestation mainly
autoimmune cytopenia and thrombocytopenia. (more with CVID)
• Rheumatic conditions as arthritis. (more with XLA)
Useful Physical Examination Findings:

• Absence or reduced size of tonsils and lymph nodes in X-linked and AR
agammaglobulinemia and in X-linked Hyper IgM syndrome.
• Enlarged lymph nodes and splenomegaly in CVID and AR Hyper IgM
syndrome.
• Scarred tympanic membranes.
• Rales and rhonchi in lungs, clubbing of the finger suggestive of bronchiectasis.
• Granulomatous lesions in the skin, liver, spleen and lungs (more with CVID
and may be misdiagnosed as sarcoidosis)
14
Useful Diagnostic Screening Tests:
1. Complete blood count with differential white blood cell count (manual
differential count is recommended)
It is very important to assess absolute count of neutrophils, lymphocytes and
platelets to rule out other types of pediatric immunodeficiency.
2. Quantitative serum immunoglobulin (IgG, IgA, IgM and IgE) levels
The assay results should be evaluated in the context of the tested patient’s age
and clinical findings
• If hypogammaglobulinemia exists (low IgG ±IgM and/or IgA), rule out
secondary causes as drug history, lymphoma, myeloma (bone marrow),
Igs loss (not IgM) in urine, GIT or skin.
• If no secondary cause is detected, think of predominately antibody
deficiency.
3. Enumeration of B cell {CD19} by flow cytometry
• If it is very low (<1%), it is more with agammaglobulinemia.
• If it is more than 1%, it is more with CVID phenotypes.
4. Blood Lymphocyte T Subpopulations by flow cytometry need to be checked
• T lymphocytes (CD3, CD4, and CD8)
Based on the previous investigations we can summarize:
• Severe reduction in all serum immunoglobulin isotypes (<2SD) with

profoundly decreased or absent B cells, it is a case of agammaglobulinemia
• Severe reduction in at least 2 serum immunoglobulin isotypes with normal or
low number of B cells, it is a CVID phenotype (further testing of naïve B cells
and class switched memory B cells are recommended)
• Severe reduction in serum IgG and IgA with normal/elevated IgM and normal
numbers of B cells, it is a case of hyper IgM (further testing of CD40 and
CD40L are recommended)
• When these screening tests are not conclusive and the clinical suspicion of an
antibody deficiency is strong, molecular genetic testing is recommended.
15
Management and Monitoring:
• With the exceptions of selective IgA deficiency and transient

hypogammaglobulinemia of infancy, patients with an identified antibody
deficiency disorder are treated at regular intervals throughout life with
replacement immunoglobulins, administered intravenously at intervals of 2-4
weeks at a dose of 700 mg/kg body weight. Trough (pre-dose) blood levels of
IgG should be at least at or above the lower range of normal for age-adjusted
IgG levels and it should be evaluated more frequently initially and at least once
a year after that. Patients should be premedicated and vigilantly monitored for
potential adverse events of IVIG transfusion.
• Ig replacement is a preventive therapy so, when a patient develops an infection,
this should be treated aggressively with appropriate antibiotics and if infections
are still recurrent, prophylactic antibiotic should be prescribed.
• Hematopoietic stem cell transplantation (HSCT) is the curative option for
many defects.
Vaccination:
• Patients with severe antibody deficiency (X-linked agammaglobulinemia,

CVID) should not be given oral polio, yellow fever, live attenuated influenza,
or typhoid fever vaccines, but family members and other close contacts, with
the EXCEPTION of oral polio vaccine, may receive other standard vaccines
because transmission to an immune deficient patient is most unlikely. Caution
is needed with BCG and rota vaccine as the level of T cell immunity is variable
especially with CVID. Patient may not necessarily mount an immune response.
Genetic counseling:
• Patients with absent B cells and agammaglobulinemia and most cases of the
Hyper IgM syndrome can follow either an X-linked recessive or an autosomal
recessive inheritance pattern.
• Gene identification along with an accurate family history help determine the
pattern of inheritance in the family, risks for family members who could be
affected, as well as identification of at-risk carrier females of X-linked
disorders.
16
Defects in Innate Immunity
Defects of the innate immune system can be classified into:
A. Bacterial and Parasitic Infections:

1. Predisposition to invasive bacterial infections (pyogens)
When to Suspect: Patients with defects in (Toll like receptor) TLR signaling
suffer from invasive bacterial infections such as meningitis, sepsis, arthritis,
osteomyelitis, and abscesses, often in the absence of fever. The predominant
pathogens include S. pneumoniae, Staphylococcus aureus, and Pseudomonas
aeruginosa.
2. Predisposition to parasitic and fungal infections:
i.Mucocutaneous candidiasis
When to Suspect: Unusually severe or persistent candidal infections can
represent a defect in mucosal immunity. Examples of this category include
STAT1 gain of function, IL-17F deficiency, and IL-17RA deficiency.
ii.Invasive fungal diseases

When to Suspect: Patients have a unique predilection to invasive fungal
infections, particularly of the central nervous system (eg, CARD9 deficiency).
iii.Parasitic infections
When to Suspect: Certain pathogenic variants can increase susceptibility to
fungal infections such as trypanosomiasis.
3. Others – These disorders include forms of isolated congenial asplenia, acute

necrotizing encephalopathy, osteopetrosis, and hidradenitis suppurativa
17
B. Mendelian susceptibility to mycobacterial disease (MSMD) and viral

infection:
1. MSMD
When to Suspect: Disseminated Bacillus Calmette-Guérin [BCG] and

mycobacteria infections.
2. Epidermodysplasia verruciformis (HPV); Patients suffer from recurrent

cutaneous warts from human papillomavirus (HPV).
Examples include: Warts, hypogammaglobulinemia, infections, and
myelokathexis (WHIM) syndrome
3. Predisposition to severe viral infection
When to Suspect: Severe recurrent viral infections such as influenza or herpes

viral infections.
4. Herpes simplex encephalitis (HSE)
When to Suspect: Patients develop HSE during primary infection with herpes
simplex virus type 1 (HSV1).
Diagnosis and Referral

• Patients with innate immune defects are usually suspected when they have
unusual severe infections as mentioned in different groups.
• The initial evaluation of all patients suffering from recurrent infections
begins with a detailed history of past infections, including frequency and
severity, the specific sites of infections, and review of any available culture
data to identify causative organisms. Family history and consanguinity is
essential in all IEI.
• Physical exam findings can provide important clues to possible immune
disorders (mucocutaneous candidiasis, multiple warts).
• Immune evaluation is mostly normal in most conditions and diagnosis is
confirmed by functional and molecular studies
• When you suspect a case according to described phenotypes with normal
basic immune evaluation (CBC, Immunoglobulin levels, lymphocyte
subsets refer immediately to an immunologist.
18
Treatment:
1. Aggressive treatment with antibiotic, antivirals or antimycobacterial when

required
2. Cytokine therapy with IFN-gamma is an additional treatment option for some
defects.
3. Hematopoietic stem cell transplantation (HSCT) is an increasingly successful
option for many defects
Vaccination:
In patients with defects in innate immunity, the specific susceptibilities seen with
each disorder should guide vaccine use. Examples are given below:
1. Patients who have increased susceptibility to mycobacterial infections should

not be given the BCG vaccine.
2. Patients with innate immune defects associated with severe viral infections
(e.g., in type 1 interferon signalling) should not receive live viral vaccines.
Genetic Counseling:
• Genetic defects associated with innate immune defects may be inherited as

X-linked, autosomal recessive or autosomal dominant.
• A detailed family history is very helpful to determine the inheritance pattern.
Importantly, not every individual carrying mutations associated with innate
immune defects will manifest the disease, so genetic testing is critical for
accurate genetic counseling.
• Prenatal diagnosis or even Pregestational diagnosis is available at specialized
centers.
19
Disorders of the Phagocytes
• Phagocytes are the immune cells responsible for the final killing process of the
organism.
• Phagocytes include Neutrophils, Monocytes, and Tissue Macrophages.
• Disorders of phagocytes according to the latest International Union of
Immunological Societies (IUIS) classification 2019 include:
I) Disorders of phagocytes' number

II) Disorders of phagocytes' function
I. Disorders of phagocytes' number:
These are disorders associated with neutropenia they are subclassified into two main
groups:
a. Neutropenia with syndromic features: In these disorders’ special

characteristic features and/or specific associated clinical manifestations
accompany the neutropenia. these associated manifestations help significantly
to identify the specific disease. Examples of these disorders are included in
table 1.
b. Neutropenia with no syndromic features: In these disorders, only the

manifestation related to neutropenia is present, no otherwise special features.
Examples of these disorders are included in table 1.
II. Disorders of phagocytes’ function:
In these disorders, there is a normal or increased number of phagocytes with impaired

function at different levels of the organism killing process. This group includes:
Phagocyte dysfunction with a syndrome associated: Cystic fibrosis, Leucocyte

adhesion defects.
Phagocyte dysfunction without a syndrome associated: chronic granulomatous

disease.
20
Clinical features and when to suspect:

Phagocytic disorders share some common features and are in general characterized
by:
✓ Recurrent skin and deep organ abscesses

✓ Gingival infection and periodontitis
✓ Suppurative lymphadenitis and osteomyelitis
✓ Episodic unexplained fever
✓ Skin ulceration without abscess formation.
✓ Infection with specific organisms such as Aspergillus, Pseudomonas, and other
catalase-positive organisms
✓ Special features related to each specific disease: as delayed separation of the
umbilical cord in Leucocyte adhesion defects.
✓ Family history of sibling death with recurrent infection.
Laboratory Testing:
First-Line Investigation:
To be done by the pediatrician who first examines the suspected case:
• CBC with differential WBCs counts and film: to confirm or exclude

neutropenia (according to age) and confirm the presence of a normal or
increased number of phagocytes. To confirm normal lymphocytic count and
platelets.
• Organism identification using, gram stain, Ziel Nelsen, fungal smear, culture,
and sensitivity from sites of abscess at time of drainage and before initiation of
antimicrobial therapy.
Second-Line Investigations:
To be requested and interpreted by Pediatric Immunology specialist and /or
consultant in a qualified Immunology lab:
1. Dihydrohodamine assay (DHR test) for diagnosis of chronic granulomatous

disease (CGD) followed by protein assay by flow cytometry.
2. Flow cytometry of CD 11/ 18 for diagnosis of leucocyte adhesion defect
(LAD)
3. Bone marrow examination: for examination of neutrophils granules for
syndromic disorders and arrest of myelocyte maturation in neutropenia.
4. Molecular diagnosis as a final confirmatory step and for genetic counselling.
21
Vaccination:
All vaccines are allowed in children with phagocytic disorders Except BCG vaccine
and live salmonella vaccine
Management:
First-Line Treatment:
1. Treatment of acute infection by antibiotic & antifungul agents according to

culture & sensitivity results.
2. Prophylactic antibiotics: trimethoprim-sulfamethoxazole or Cephalexin if the
child is allergic to sulfa.
3. Prophylactic antifungal: itraconazole in chronic granulomatous disease
Second-Line Treatment:
To be decided by Pediatric immunology specialist and /or consultant in a qualified
immunology unit:
1. Interferon-gamma Treatment for CGD patients

2. Hematopoietic stem cell transplantation (HSCT) from a matched related
donor.
22
Diseases of Immune Dysregulation
This category of immunodeficiencies is characterized by defects in self-

tolerance resulting in autoimmune disease with or without recurrent infections.
This group is categorized as class IV in the most recent International Union of
Immunological Societies (IUIS) classification of IEI, and further subclassified into
two main subgroups:
1) Hemophagocytic lymphohistiocytosis (HLH) and Epstein-Barr virus

(EBV) susceptibility. HLH may be primary or secondary.
2) Syndromes with autoimmunity and others:
✓ Regulatory T cell (Treg) defects (eg, IPEX)
✓ Autoimmunity with or without lymphoproliferation
✓ Immune dysregulation with colitis
When to Suspect?
This category is often the most difficult to define clinically and to diagnose but
important clinical clues that a patient with autoimmunity may have an underlying IEI
are:
• Age of presentation younger than usual for autoimmune disorders
• Autoimmunity affecting multiple organs or systems
• Allergy may present
• Lymphoproliferation (hepatosplenomegaly, lymphadenopathy or both)
3) If the patient has an acute or fulminant presentation with high fever, toxic
appearance, and signs of lymphoproliferation; HLH needs to be ruled out.
N.B: If the presentation is subacute or chronic, with features of recurrent infections

and pigmentary abnormalities, mostly one of syndromic HLH Chediak-higashi
syndrome (CHS) or Griscelli syndrome (GS)
4) If lymphoproliferation and autoimmune disease are prominent in the
Presentation, this suggests Autoimmune Lymphoproliferative Syndrome
(ALPS) or ALPS-Like disorders
5) Presence of any these features: (1) polyendocrine autoimmunity; (2)
chronic mucocutaneous candidiasis CMC; or (3) multiple food and/or
environmental allergies; indicates possible Autoimmune
Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED),
Immune Dysregulation, Poly endocrinopathy, Enteropathy linked
Syndrome (IPEX) or other Regulatory T cells (Treg) defect.
23
6) Presence of bloody diarrhea and manifestations of IBD (especially very

early onset type less than 6 years), highly suggestive of monogenic
immune disorders associated with Colitis like IL-10 and IL-10R defects
When to Refer?
• Care for Patients with Immune Dysregulation needs to be coordinated through
a Multidisciplenary team (MDT) including general pediatricians,
hematologists, rheumatologists and gastroenterologists.
• When a patient's presentation or clinical course raises the possibility of an
underlying IEI, initial testing can be performed by general Pediatrician (CBC,
Immunoglobulin levels, Autoantibodies, Inflammatory markers)
• Definitive diagnosis of an IEI usually requires the input of a specialist, since
more advanced immunologic tests require varying degrees of expertise to
perform and interpret, may not be widely available, and are often costly.
Management:
1. Treatment must be initiated by a specialist and expert in IEI
2. Treatment is multidisciplinary with other specialties like hematology,
gastroenterology according to manifestations
3. Most autoimmune diseases in patients with an IEI are managed with the same
therapies that are used in patients without IEI.
4. Targeted therapies: With the advent of next-generation sequencing tools as
part of the routine clinical diagnostic repertoire, a genetic diagnosis can be
made in more and more IEI patients over time. This enables the identification
and use of a drug that specifically targets the impaired pathway.
5. Transplantation and gene therapy: Ultimately, allogeneic hematopoietic
stem cell transplantation may be curative in certain severe monogenetic IEI
with autoimmunity.
Vaccinations:
• Patients with immune dysregulation usually receive immunosuppressive
therapy.
• Vaccination should be determined by immunologists according to cost, benefit
and level of immunosuppression
24
Suspected Immune Dysregulation
Acute presentation, High

fever, Hepatosplenomegaly
and or lymphadenopathy
No Yes
Autoimmunity, HLH ,
Lymphadenopath Polyendocrinopathy, Recurrent
and /or allergy, CMCD
Very early onset IBD Infection, accelarated
Hepatosplenomegaly hypopigmentation phase CHS, GS
Immune
ALPS, ALPS-Related Apeced, IPEX, other
Dysregulation with
Disorders Treg
Colitis
Genetic Counselling:
• Genetic defects associated with immune dysregulation may be inherited as
X-linked, autosomal recessive or autosomal dominant.
• A detailed family history is very helpful to determine the inheritance pattern.
Importantly, not every individual carrying mutations associated with immune
dysregulation will manifest the disease, so genetic testing is critical for
accurate genetic counseling.
• Prenatal diagnosis or even Pregestational diagnosis is available at specialized
centers.
25
Complement Disorders
Complement is the term used to describe a group of serum proteins that are
critically important in our defense against infection. There are deficiencies of each of
the individual components of complement.
When to Suspect Complement Defects?
• Recurrent episodes of bacteremia, meningitis or systemic Neisserial (either N.

meningitidis or N. gonorrhea) infections. (A single systemic Neisserial
infection warrants testing of the complement system).
• Recurrent Neisserial infections suggest C5-9 or properdin deficiencies.
• Recurrent Pneumococcal disease (otitis media, pneumonia or bacteremia)
suggest C1q, C1r/s, C4 or C2 deficiencies.
• Autoimmune diseases as systemic lupus erythematosus (SLE) are much more
common than infections as a manifestation of early complement component
deficiencies. (particularly with deficiencies of C1q, C1r/s, C2, or C4)
• C3 deficiency is very rare but is characterized by recurrent serious bacterial
infections, such as pneumonia or bacteremia, and development of
membranoproliferative glomerulonephritis.
• Recurrent episodes of angioedema unresponsive to antihistamines or
epinephrine abdominal pain, vomiting and laryngeal edema may suggest
hereditary angioedema due to a deficiency of C1 esterase inhibitor.
Useful Diagnostic Screening Tests:
1. The total serum classic hemolytic complement (CH50) is a broad screening

test.
2. If the CH50 is undetectable, the patient likely has a deficiency in a complement
component, however, if the CH50 is just low, it is more likely that the
specimen was not handled properly (stored or shipped at -70ºC) or that the
patient has an autoimmune disease.
3. The alternative hemolytic complement (AH50) test is used to screen the
alternative pathway.
4. Direct measurement of individual serum complements proteins, such as C3 and
C4, can also be performed.
5. Repeated finding of decreased quantities of C1 esterase inhibitor protein or
activity and reduced levels of C4 support the diagnosis of hereditary
angioedema.
26
Management and Monitoring:
✓ Antibiotic prophylaxis may be helpful for any person diagnosed with a C5

through C9 deficiency.
✓ Early recognition of fevers and prompt evaluation (including blood cultures) is
very important.
✓ Patients with hereditary angioedema need regular C1 esterase inhibitor
replacement (both plasma derived and recombinant products are available), and
if not available fresh frozen plasma can be used during attack.
✓ Vaccination: Meningococcal and Pneumococcal vaccines are recommended in
patients with complement defects
✓ Genetic counseling:
➢ Hereditary angioedema is inherited in an autosomal dominant pattern so
family history is important in the evaluation of angioedema. Genetic testing
is available for C1 Esterase Inhibitor deficiency and can be important in
distinguishing the types of hereditary angioedema and acquired forms.
➢ Properdin deficiency is inherited in a X-linked pattern so often there is a
family history of an uncle or other relative who died from Neisserial
infection at an early age.
27
Hereditary Angioedema (HAE)
Definition:
Is a rare autosomal dominant disease that commonly manifests with episodes
of cutaneous or submucosal angioedema and intense abdominal pain.
Symptoms of angioedema may be confused initially with mast cell-mediated
angioedema, such as allergic reactions.
HAE can be categorized into 3 different Types of HAE:

➢ Type 1: deficit C1-inhibitor levels (HAE-1),
➢ Type 2: HAE with dysfunctional C1-inhibitor (HAE-2)
➢ Type 3: HAE with normal C1-inhibitor function (HAE nC1-INH)
Clinical Picture:
• In about one-third of HAE-1/2 patients, clinical symptoms first present by age
5, and these patients tend to have more severe outcomes than patients whose
symptoms begin later in life.
• Local trauma, infections, and emotional stress may trigger episodes of
angioedema in patients with HAE; however, most attacks are not preceded by
an identified trigger. Menstruation and initiation of oral contraceptives may be
the main trigger in HAE patients with normal C1-INH. Some common causes
of laryngeal or buccal angioedema include oropharyngeal procedures and
dental surgeries.
• Prodromal symptoms prior to angioedema flares include fatigue, rashes such as
erythema marginatum, joint or muscle pain, upset stomach/nausea, and
numbness/tingling in the area of the attack.
28
When to Suspect?
1. Recurrent angioedema, most frequently on the extremities and face, affects

nearly all individuals with HAE and may associate with abdominal pain. The
abdominal pain maybe intense causing unnecessary exploratory surgeries. The
skin is described as nonpitting, not erythematous, nonpruritic, and with ill-
defined margins. HAE patients do not present with urticaria. Episodes of
laryngeal angioedema, maybe a cause of death.
2. Besides pain, gastrointestinal symptoms of HAE may include nausea,
vomiting, and diarrhea. In at least some cases, these symptoms can lead to
hypovolemic shock, ascites, and, in rare cases, circulatory collapse, tetany,
hemorrhagic stools, dysuria, and intussusception of the colon
3. Approximately 75% of patients have a positive family history of similar
symptoms, although the remaining cases result from a de novo mutation
Investigation:
1- C4 level
2- C1-INH (Quantitative)
3- C1-INH ( functional assay)
Treatment:
• Acute treatment during the attacks (by specialist, ER residents and
Immunologists): bradykinin receptor antagonists (icatibant), antifibrinolytic
drugs (tranexamic acid), solvent/detergent-treated plasma (SDP), fresh frozen
plasma (FFP)
• Long-term prophylaxis: C1-INH (IV or subcutaneous), attenuated androgens
(danazol), antifibrinolytics (tranexamic acid), e-aminocaproic acid (EACA),
oral kallikrein inhibitors (BCX7353, avoralstat
• Short-term prophylaxis: C1-INH (IV or subcutaneous), attenuated androgens
(danazol), antifibrinolytics (tranexamic acid), anabolic steroids, fresh frozen
plasma (FFP)
29
Administration of C1-INH (cinryze):
• Pediatric patients (6 to 11 years old) Routine prophylaxis against HAE attacks

500 U, IV every 3 or 4 days. The dose may be adjusted according to individual
response, up to 1,000 U every 3 to 4 days. 1 mL/min (5 min)
• Adults and adolescents (12 years old and above) Routine prophylaxis against
HAE attacks 1,000 Units (U) Intravenous (IV) every 3 or 4 days. For patients
who have not responded adequately to 1,000 U of every 3 or 4 days, doses up
to 2,500 U (not to exceed 100 U/kg) every 3 or 4days may be considered based
on individual patient response. 1 mL/min (10 min)
30
Immunodeficiency with Syndromic Features
This is a heterogeneous group of inborn errors of immunity and is

characterized by defects in both humoral and cellular immunity, with specific
features that accompany these defects in specific syndromes.
Common examples for this category include:
➢ CID with thrombocytopenia: Wiskott Aldrich syndrome

➢ DNA repair syndrome: Ataxia telangiectasia syndrome
➢ Immunosseous dysplasia: cartilage hair hypoplasia
➢ Thymic defects and other congenital anomalies: DiGeorge syndrome
➢ Hyper IgE syndrome
➢ Anhidrotic ectodermal dysplasia: nuclear factor-kappa B essential modulator
deficiency (NEMO) defects
➢ Others
Clinical presentation and when to suspect:

This group of disorders although rare but can be easily identified by recognizing
the specific features of each syndrome.
➢ Failure to thrive
➢ Recurrent diarrhea
➢ Live Vaccine adverse reaction
➢ Skin affection: Eczema (WAS, HIES), Recurrent abscesses
Hyperimmunoglobulin E syndrome (HIES), Anhidrotic ectodermal dysplasia
(NEMO defects), ichthyosis (Netherton syndrome)
➢ Hypocalcemia (DiGeorge syndrome)
➢ Recurrent viral, bacterial infection
➢ Special facies: Bloom syndrome, Ataxia Telangiectasia, kabuki syndrome,
Nijmegen breakage syndrome
➢ Abnormal pigmentation: VICI syndrome, MCM4 deficiency
➢ Neurological disorders: Ataxia telangiectasia, VICI syndrome
➢ Autoimmunity early in infancy
➢ Congenital Thrombocytopenia: Wiskott Aldrich syndrome
31
Investigations:
First-Line Investigation:

CBC with differential WBCs counts and film: To confirm presence or
absence of lymphopenia and to check the platelets count and the mean platelet
volume (MPV) (Values of Lymphocytes should be corrected for age).
Second-Line Investigations:
To be requested and interpreted by Pediatric Immunology specialist and /or
consultant in a qualified immunology lab:
1. Flow cytometry of lymphocyte subsets (CD3, CD4, Cd8, CD19, CD16/56)

2. Serum immunoglobulin assay by nephelometry (IgG, IgM, IgA, IgE)
3. Molecular diagnosis as a final confirmatory step and for genetic counselling.
4. Ophthalmological, neurological, dermatological and clinical genetics

evaluation according to each syndrome.
Vaccinations:
➢ BCG and Live attenuated vaccines including oral polio vaccines should not be
administered to children with combined immune deficiency
➢ Patients on regular immunoglobulin therapy receive passive vaccination with
the immunoglobulins
➢ Household contact should not receive oral polio vaccine.
32
Management:
First-Line Treatment:
Prophylactic antibiotics: trimethoprim-sulfamethoxazole against pneumocystis

jiroveci
1. Treatment of acute infection by antibiotic and antifungal agents according to

culture and sensitivity results.
2. If the child is in need for blood transfusion, irradiated PRBCs should be given
Second-line treatment:
To be decided by Pediatric Immunology specialist and /or consultant in a qualified

Immunology Unit:
1. Intravenous immunoglobulin replacement therapy according to the level of

Immunoglobulins and the specific indications in each syndrome.
2. HSCT from a matched related donor.
33
References:
1- Henao MP, Kraschnewski JL, Kelbel T, Craig TJ. Diagnosis and screening of
patients with hereditary angioedema in primary care. Ther Clin Risk Manag.
2016;12:701-711. Published 2016 May 2. doi:10.2147/TCRM.S86293.
2- Betschel, S., Badiou, J., Binkley, K. et al. The International/Canadian

Hereditary Angioedema Guideline. Allergy Asthma Clin Immunol 15, 72
(2019).
3- Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human

Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical
Classification. J Clin Immunol. 2020 Jan;40(1):66-81. doi: 10.1007/s10875-
020-00758
4- IDF Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency

Diseases, 3rd Edition. Immunodeficiency Foundation.
5- Bousfiha A, Jeddane L, Picard C, Al-Herz W, Ailal F, Chatila T, et al. Human

Inborn Errors of Immunity: 2019 Update of the IUIS Phenotypical
Classification. J Clin Immunol. 2020 Jan;40(1):66-81. doi: 10.1007/s10875-
020-00758
6- IDF Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency

Diseases, 3rd Edition. Immunodeficiency Foundation.
34
35
Neonatology Protocol of EHA

in
Neonatology
for
First Edition
2024
Prepared By
Members of Neonatology Committee
Of
Medical Advisory Council
Of
1
Executive Committee
1. Prof. Lamiaa Mohsen: (Head of the Committee) Professor of pediatrics and

Neonatology Cairo university and Dean of School of Medicine, New Giza university
2. Prof. Iman Fathy Iskander: Professor of pediatrics and Neonatology Cairo
university
3. Prof. Azza Zohdy: MD, FRCPCH, MSc. Head of neonatology Department (GOTHI)
and Professor of pediatrics and Neonatology New Giza University.
4. Prof. Safaa Shafik Imam: Professor of pediatrics and neonatology Faculty of
Medicine Ain Shams University.
5. Prof. Tarek Soubhi: Consultant of neonatology and Head of NICU tamia central
hospital -Fayoum Governorate.
6. Prof. M Osama Hussein: MD, Pediatric & neonatology consultant.
7. Dr. Marwa Helmy Abd Elgayed: (Moderator) Consultant of Pediatric and
neonatology, IBCLC
2

Authority (EHA).
Reviewed By



3
PREFACE

aim of developing these Egyptian Clinical Practice Protocols in Neonatology is to unify
and standardize the delivery of healthcare to all newborns at all health facilities.
The current state of healthcare in which avoidable failures are abound. “We train
longer, specialize more, use ever-advancing technologies, and still we fail.” Part of the
problem, is that the ever-increasing complexity of medicine makes uniform care
excellent repositories of detailed information about the etiology, pathogenesis, clinical
picture, diagnosis, and treatment of a condition. However, for a busy clinician looking
for the best way to manage a sick patient, a standardized path for effective management
of the patient may be impossible to discern. So, it would be a lot easier if we all
managed simple things in a uniform way using the best available evidence and
resources.
In neonatology, busy clinicians have all felt the need for a concise, easy-to-use
resource at the bedside for evidence-based protocols, or consensus-driven care paths
where high-grade evidence is not available.
highest level of evidence available in each case. Our goal is to provide an authoritative
practical medical resource for neonatologists, pediatricians, and other healthcare
providers dealing with newborns after birth. This protocol is the product of

that practicing neonatologists, fellows, nurse practitioners, and other NICU personnel
will find this protocol useful in delivering high-quality clinical care to their patients.
We remain open to feedback and suggestions about how to improve this resource and
how to make it maximally useful to those delivering care at the bedside in the NICU.

In Neonatology
4
Table of Contents
Page
Title
Number
Preface 4
Criteria of Admission & Discharge in NICU 6
Neonatal jaundice 12
Meconium Aspiration Syndrome 21
Hypoxic Ischaemic Encephalopathy (HIE) 24
Total Body Cooling Protocol for Infants with Hypoxic 27
Ischemic Encephalopathy
Seizures 38
Hypocalcemia 44
Intravenous fluid therapy 48
Neonatal sepsis 53
Nutrition & Enteral feeding 61
Neonatal Parenteral Nutrition for Preterm Babies, 71
up to 28 Days after Their Due Birth Date
Neonatal Parenteral Nutrition for Term Babies, 76
up to 28 Days After Their Birth
Transfusion of RBC in the NICU 80
Neonatal hypotension 83
Mechanical support of respiration of the newborn 88
Care for the ELBW infant 96
TRANSPORT AND RETRIEVAL 98
ANNEX 103
5
Criteria of Admission & Discharge in NICU
There should be good clinical reasons for admission to NICU

Avoid unnecessary separation of mother and baby as it affects maternal bonding.
Ensure that all babies born have newborn infant physical examination and check
the saturation between 6-72 hour of birth.
Criteria for Admission from Labour Ward or Postnatal Ward:

• Clinical condition requiring constant monitoring, <34 week’s gestation or birth
weight <1700 grams.
• Unwell baby:
➢ Poor condition at birth requiring prolonged resuscitation for >10 min and/or
cord pH <7.0 (a low cord pH may not in itself necessitate admission to NICU).
➢ Respiratory distress or cyanosis.
➢ Apnoeic or cyanotic attacks.
➢ Signs of encephalopathy.
➢ Jaundice needing intensive phototherapy or exchange transfusion.
➢ Major congenital abnormality likely to threaten immediate survival.
➢ Seizures.
➢ Inability to tolerate enteral feeds with vomiting and/or abdominal distension
and/or hypoglycaemia (blood glucose <36 mg/L for 37 weeks/< 46.8 mg/L for
<37 weeks gestation).
➢ Symptomatic hypoglycaemia or hypoglycaemia not responding to treatment.
➢ Neonatal abstinence syndrome requiring treatment.
➢ Short-term care while mother admitted to ITU.
➢ Pre-& post-operative care of major surgical procedures case.
6
Procedure:
• Manage immediate life-threatening clinical problems (e.g. airway, breathing,
circulation and seizures).
• Show baby to parents and explain reason for admission to NICU.
• Inform NICU nursing staff that you wish to admit a baby, reason for admission and
clinical condition of baby.
• Ensure baby name labels present.
• Document relevant history and examination.
• Complete any local problem sheets and investigation charts.
• Measure and plot birth weight and head circumference on growth chart.
• Measure admission temperature.
• Measure blood pressure using non-invasive cuff.
• Institute appropriate monitoring and treatment in conjunction with nursing and
senior medical colleagues.
Investigations:
For babies admitted to the NICU, Obtain 1 bloodspot on:
• Newborn bloodspot screening (Guthrie) card (TSH&PKU) on (Saturday and
Tuesday).
• Babies <32 weeks/1500 grams weight/unwell/ventilated:
➢ Full Blood Count.
➢ Blood glucose.
➢ Blood gases.
➢ Clotting screen if clinically indicated.
➢ Routine clotting screen in all babies <30 weeks’ gestation is
not recommended.
➢ If respiratory symptoms or support given, chest X-ray.
➢ If umbilical lines in place, abdominal X-ray.
➢ If suspicion of sepsis, blood culture and CRP before starting
antibiotics and consider lumbar puncture.
➢ Additional investigations depend on initial assessment and
suspected clinical problem (e.g. infection, jaundice, etc.).
7
Immediate Management:
• Evaluation of baby, including full clinical examination.
• Define appropriate management plan and procedures with Consultant and perform
as efficiently as possible to ensure baby is not disturbed unnecessarily.
• Aim for examination and procedures to be completed ≤1hr of admission.
• If no contraindications, give vitamin K IM.
• If antibiotics indicated, give within an hour.
• Senior clinician to update parents as soon as possible (certainly within 24hr) and
document discussion in notes.
Respiratory Support:
• If required, this takes priority over other procedures.
• Including; incubator oxygen, nasal oxygen, continuous positive airway pressure

(CPAP) or mechanical ventilation.
Intravenous Access:
• If required, IV cannulation and/or umbilical venous catheterization (UVC).
Monitoring:
• Use minimal handling
• Cardiorespiratory monitoring through skin electrodes.
• Pulse oximetry. Maintain SpO2 not less than 95%.
• Temperature.
• Blood glucose.
• If ventilated, monitoring blood pressure and blood gases.
8
Criteria for Admission to Transitional Care:

The following are common indications for admitting babies to transitional care:
• Preterm 34–36 weeks’ gestation and no other clinical concerns.
• Minor congenital abnormalities likely to affect feeding, e.g. cleft lip and palate.
• Requiring support with feeding.
• Babies of substance abusing mothers.
• Receiving IV antibiotics.
• Unknown babies.
Neonatal Levels of Care
9
Discharge from Neonatal Unit:
Decision to Discharge:
• Only consultant or specialist may discharge.
• Medical and nursing staff to agree discharge date with parents or persons with
parental responsibility.
• Nursing team perform majority of discharge requirements.
Discharge Checklist:
Where appropriate, the following must be achieved before discharge:
Parental Competencies:
• Administration of medications when required.
• Baby cares (e.g. nappy changes, bathing etc.)
• Feeding.
• Nasogastric tube feeding where necessary.
• Stoma care (surgical babies).
Parent education:
In addition to above, it is best practice to offer parents education on:
• Basic neonatal resuscitation.
• Common infectious illnesses.
• Immunizations, if not already received (give national leaflet).
Parent communication:
• Instructions about immunizations given and dates and care of other immunizations.
• Give parents copy of discharge summary and time to ask questions after they have
read it. (Clarify red flags for seeking medical advice).
• Ensure parents have information regarding breastfeeding.
• Ensure parents have up-to-date safety information.
• If transporting in a car, use suitable car seat.
• If transferring to another unit, ensure parents understand reason for transfer. Provide
information about receiving unit.
10
Procedures/investigations:
• Complete audiology screening and hearing test.
• All babies receiving CPAP or M.V or treated with O2 should have a fundus
examination by an ophthalmologist to screen for retinopathy of prematurity (ROP).
Medical team:
• Complete discharge summary by date of discharge
• Complete neonatal dataset by date of discharge follow-up
Appointments:
• Ensure these are written on discharge summary Likely appointments could include
any of the following depending on the clinical condition:
➢ Neonatal/ Paediatric consultant outpatient clinic.
➢ Ophthalmology screening.
➢ Audiology referral.
➢ Cranial ultrasound.
➢ Brain US/MRI scan.
➢ Physiotherapy.
➢ Hip or renal ultrasound.
➢ Dietitian.
➢ Community paediatrician.
➢ Child development center.
➢ BCG immunization.
SOURCES:
1. National institute for health and care excellence (NICE)
2. Bedside clinical guidelines partnership in association with Partners in pediatrics
11
Neonatal Jaundice
Recognition and Assessment:
Risk Factors for Hyperbilirubinaemia:

• <38 weeks’ gestation
• Previous sibling required treatment for jaundice
• Mother intends to exclusively breastfeed
• Visible jaundice in baby aged <24 hour
Risk Factors for Kernicterus:
• High bilirubin level (>20 mg/dl in term baby)
• Rapidly rising bilirubin level (>0.5 mg/dl /hour)
• Clinical features of bilirubin encephalopathy
Symptoms and Signs:
• When looking for jaundice (visual inspection):
• Check naked baby in bright and preferably natural light
• Examine the sclerae and gums, and press lightly on skin to check for signs of
jaundice in 'blanched' skin
Assess:
• Pallor (haemolysis)
• Poor feeding, drowsiness (neurotoxicity)
• Hepatosplenomegaly (blood group incompatibility or cytomegalovirus)
• Splenomegaly (spherocytosis)
Causes:
• Physiological
• Prematurity
• Increased bilirubin load:
• Blood group incompatibility (rhesus or abo)
• G6pd deficiency and other red cell enzyme deficiencies
• Congenital spherocytosis
• Cephalhaematoma, bruising
• Rarely infection (e.g. UTI, congenital infection)
• Metabolic disorder
12
Persistent Jaundice After 14 Days of Age (see Liver dysfunction guideline):

• Breast milk jaundice
• Hypothyroidism
• Liver disease (e.g. extra hepatic biliary atresia and neonatal hepatitis)
• Alpha-1-antitrypsin deficiency
• Galactosaemia
• TPN-induced cholestasis
Investigations:
Assessment of Jaundice:
• Babies aged <72 hour, at every opportunity (risk factors and visual inspection)
• Babies with suspected or obvious jaundice, measure and record bilirubin level
urgently
• <24 hour: within 2 hour
• ≥24 hour: within 6 hour
• If serum bilirubin >5.8 mg/dl in first 24 hour
• Repeat measurement in 6–12 hour
• Urgent medical review as soon as possible (and within 6 hour)
• Interpret bilirubin results in accordance with baby’s gestational and postnatal age
according to Table
Jaundice Approaching Treatment Level:

• If baby well, ≥38 weeks, aged >24 hour and
• Serum bilirubin ≤3 mg/dl below treatment threshold, repeat measurement in 18 hour
if risk factors and 24 hour if no risk factors
• Serum bilirubin >3 mg/dl below treatment threshold, no further routine
measurements required
13
Jaundice Requiring Treatment:

• Total bilirubin
• Baby’s blood group and direct Coombs test (interpret result taking into account
strength of reaction and whether mother received prophylactic anti-D
immunoglobulin during pregnancy)
• Mother’s blood group and antibody status (should be available from maternal
healthcare record)
• PCV
Plus (if clinically indicated):

• Full infection screen (in an ill baby)
• G6PD level and activity (if indicated by ethnic origin: Mediterranean, Middle
Eastern, South East Asian)
• Full blood count and film
Persistent Jaundice >14 days in term baby; OR >21 days in preterm baby (see
Liver dysfunction guideline), Check:
• Total and conjugated bilirubin
• Examine stool colour
• Full blood count
• Baby’s blood group and direct Coombs test (interpret result taking into account
strength of reaction and whether mother received prophylactic anti-D
immunoglobulin during pregnancy)
• Ensure routine metabolic screening performed (including screening for
hypothyroidism)
• Urine culture
Baby with Conjugated Bilirubin >25 mg/dl,

Refer Urgently to A Specialized Center.
14
Second Line Investigations (not in NICE guideline):

• Liver function tests (ALT, AST, albumin, GGT)
• Coagulation profile
• G6PD screen in African, Asian or Mediterranean babies
• Thyroid function tests: ask for free T4 priority and then TSH’
• Congenital infection screen
• Urine for CMV PCR, toxoplasma ISAGA-IgM and throat swab for HSV
culture/PCR
• Metabolic investigations e.g:
➢ Blood galactose-1-phosphate
➢ Urine for reducing substances
➢ Alpha-1-antitrypsin
Treatment of hyperbilirubinemia with duration <7 days:
Do Not Start Treatment if Serum Bilirubin is Below Treatment Threshold
Babies ≥38 weeks’ gestation:

• Use conventional blue light phototherapy (not fibre optic) as treatment of choice
• Use continuous multiple phototherapy for babies who:
➢ Fail to respond to conventional phototherapy (bilirubin does not fall within 6
hour of starting treatment)
➢ Have a rapid rise in bilirubin (>0.5 mg/dl /hour)
➢ Have a bilirubin level within 3 mg/dl of exchange transfusion threshold
• When level falls to >3 mg/dl below threshold reduce intensity of phototherapy
Babies <38 weeks’ gestation:

• Use fibre optic or conventional blue light as first line treatment
• based on gestational age and postnatal age, use Threshold graphs
(http://www.nice.org.uk/guidance/CG98 under ‘Tools and resources’ then ‛CG98
Neonatal Jaundice: treatment threshold graphs’) to determine threshold for
phototherapy
• Indications for multiple phototherapy as term babies
15
Management During Phototherapy:

• Offer parents information on procedure
(www.nice.org.uk/guidance/cg98/resources/jaundice-in-newborn- babies-318006690757)
• Unless other clinical conditions prevent, place baby in supine position turn
frequently
• Ensure treatment applied to maximum area of skin
• Monitor baby’s temperature
• Monitor hydration by weighing baby daily and assessing wet nappies
• Use eye protection and give routine eye care
• Provided bilirubin not significantly elevated, encourage breaks of up to 30 min for
breastfeeding, nappy change and cuddles
• Do not give additional fluids routinely
• During multiple phototherapy:
➢ Do not interrupt for feeds
➢ Continue lactation/feeding support so that breastfeeding can recommence when
treatment stops
Monitoring During Phototherapy:
• Repeat serum bilirubin 4–6 hour after starting treatment
• Repeat serum bilirubin 6–12 hourly when bilirubin stable or falling
• Stop phototherapy once serum bilirubin has fallen to at least 3 mg/dl below threshold
• Check for rebound jaundice with repeat serum bilirubin 12–18 hour after stopping
phototherapy. Babies do not necessarily need to remain in hospital for this to be done
Discharge and Follow-Up:
• GP follow-up with routine examination at 6–8 weeks
• If exchange transfusion necessary or considered, request developmental follow-up
and hearing test
• In babies with positive Coombs test who require phototherapy:
➢ Check haemoglobin at aged 2 and 4 weeks due to risk of continuing haemolysis
➢ Give folic acid 1 mg daily
16
Table: Limits for Phototherapy and Exchange Transfusion For

Babies ≥38 Weeks’ Gestation
Serum Bilirubin Serum Bilirubin Serum Bilirubin Serum Bilirubin

Age (hours)
(micromol/L) (micromol/L) (micromol/L) (micromol/L)
0 – – >100 >100
6 >100 >112 >125 >150
12 >100 >125 >150 >200
18 >100 >137 >175 >250
24 >100 >150 >200 >300
30 >112 >162 >212 >350
36 >125 >175 >225 >400
42 >137 >187 >237 >450
48 >150 >200 >250 >450
54 >162 >212 >262 >450
60 >175 >225 >275 >450
66 >187 >237 >287 >450
72 >200 >250 >300 >450
78 – >262 >312 >450
84 – >275 >325 >450
90 – >287 >337 >450
96+ – >300 >350 >450
Consider
Repeat phototherapy
transcutaneous (repeat
Perform exchange
Action bilirubin/serum transcutaneous Start phototherapy
transfusion
bilirubin bilirubin/serum
(6–12 hour) bilirubin in 6
hour)
NB: To Convert from (Mmol/L) to (mg / dl) divided by 17
SOURCE:
▪ http://www.nice.org.uk/guidance/CG98
▪ Treatment graphs giving the phototherapy and exchange transfusion limits for each
gestational age can be printed from http://www.nice.org.uk/guidance/CG98 under ‘Tools
and resources’ then ‛CG98 Neonatal Jaundice: treatment threshold graphs’
17
Bind Score
18
Exchange Transfusion:
• Exchange transfusion replaces withdrawn baby blood with an equal volume of donor
blood
NB: Discuss all cases with “Neonatal consultant”
Indications:
Haemolyticanaemia:
• A newborn who has not had an in-utero transfusion (IUT) with a cord Hb <120 g/L
and is haemolysing. May require urgent exchange transfusion to remove antibodies &
correct anemia, if Hb < 100g/L: discuss urgently with consultant &proceed to exchange
transfusion level, use intravenous immunoglobulin (IVIG).
• A newborn who has had IUTs & whose Kleihauer test (this test may not be available
in your hospital) demonstrates a predominance of adult Hb, anemia can be managed
using a top-up transfusion of irradiated, CMV-negative blood.
Hyperbilirubinaemia:
• Discuss promptly with consultant. If bilirubin values approaching guidance below;
senior decision required: guidance as determined by exchange transfusion line on
gestation-specific NICE jaundice chart.
• If bilirubin rises faster than 0.5mg/dl/hr. despite phototherapy, anticipate need for
exchange transfusion.
Other Indications:
• Chronic feto-maternal transfusion.
• Disseminated intravenous coagulation (DIC).
Complications:
• Cardiac arrhythmia.
• Air embolism.
• Necrotizing enterocolitis.
• Coagulopathy.
• Apneas & bradycardia.
• Sepsis.
• Electrolyte disturbances.
• Acidosis owing to non-fresh blood.
• Thrombocytopenia.
• Late hyporegenerative anemia.
19
Procedure:
Prepare:
• Ensure full intensive care space & equipment available &ready.
• Allocate 1 doctor/practitioner & 1 other member of nursing staff, both experienced
in exchange transfusion, to care for each baby during procedure; document their names
in baby’s notes.
• Obtain written consent & document in babies notes.
• Phototherapy to be continued during exchange.
• Calculate volume of blood to be exchanged: double volume exchange removes 90%
of baby’s red cells & 50% of available intravascular bilirubin.
Use:
➢ Term babies: 160ml/kg.
➢ Preterm babies: 200ml/kg.
• Order appropriate volume (usually 2 units) of blood from blood bank, stipulating
that it must be:
➢ Crossmatched against mother’s blood group & antibody status, & (if
requested by your blood bank) baby’s blood group.
➢ CMV negative,
➢ Irradiated (shelf-life 24 hr.) for any baby who has had an in-utero blood
transfusion.
➢ As fresh as possible, & certainly <4 days old.
➢ Plasma reduced red cells for exchange transfusion (haematocrit 0.5-0.6),
not SAG-M blood & not packed cells.
20
Meconium Aspiration Syndrome
Most infants born to mothers with meconium-stained amniotic fluid are

asymptomatic.
MAS occurs in term or post-term infants born through meconium-

stained amniotic fluid.
Diagnosis:
• Meconium passage
• Respiratory distress
• Characteristic x-ray findings
Investigations:
CXR:
• May demonstrate a spectrum of disease from widespread patchy infiltration, +/-
small pleural effusions, to diffuse homogenous opacification with severe disease a
picture similar to CLD can be seen as the disease progresses.
Blood Tests:
• Full Blood Count.
• ABG.
• Blood cultures.
• CRP
Echocardiography:
• Where there is suspicion of PPHN, it is advisable to obtain an echocardiogram as
early as possible to help guide further therapy.
21
Management:
General Measures:
• Nurse in a thermo-neutral environment.
• Minimal handling.
• Consider need for CFM +/- therapeutic hypothermia.
• Establish appropriate vascular access.
• Avoid/manage systemic hypotension.
• Antibiotics.
• Nutrition: consider early Parenteral Nutrition
Respiratory Care:
• Assess degree of respiratory compromise:
➢ Infants should be managed with adequate respiratory support dependent
upon their clinical condition as indicated by:
➢ Effort of breathing.
➢ Oxygen requirement: aim to keep pre-ductal oxygen saturations 95-98%.
➢ Blood gas indices.
Mild Respiratory Distress:
• Humidified oxygen.
• Consider High Flow Nasal Cannula oxygen.
• Pneumothorax
➢ Non-tension may not need treatment.
➢ Transilluminate +/- chest x-ray
Moderate-Severe Respiratory Distress:

• CXR
• Hyperexpanded
• Patchy infiltrations
• Small pleural effusions
22
Ventilation:
• Critical to maintain PaO2 >10kPa
• Aim for normal PaCO2 and pH
• Use conventional ventilation initially
• Avoid high PEEP where possible
• Sedation may be required
• Surfactant 200mg/kg
• Aim for early echocardiogram if PPHN is suspected
• Aim to maintain systemic BP ≥ normal values
• Consider inhaled Nitric Oxide [iNO]
• Consider ECMO
REFERENCES:
1. National Institute for Health and Clinical Excellence. Intrapartum care for healthy
women and babies [CG190] 2014 (last updated Feb 2017)
2. Resuscitation and support of transition at birth Resuscitation Council (UK) 2015
3. Management of meconium aspiration: North Trent Neonatal Network Clinical
Guideline July 2012
4. Respiratory Support in Meconium Aspiration Syndrome: a Practical Guide. Dargaville
PA. Int J Ped 2012 (2012) ID 965
23
Hypoxic Ischaemic Encephalopathy (HIE)
Immediate Treatment:
• Prompt and effective resuscitation
• Maintain body temperature, avoid hyperthermia
• IV access
• Isotonic glucose-containing IV fluids at 40 mL/kg/day (see Intravenous fluid therapy
guideline)
Subsequent Management:
Continue with management below if baby not transferred to cooling center, or
in cooling center without local guideline for active cooling. NOTE that some of the
target values are different to those recommended if a baby is being actively cooled.
1. Oxygen:
• Avoid hypoxaemia. Maintain PaO2 10–12 kPa and SpO2 >94%
• Episodes of hypoxaemia (possibly associated with convulsions) are an indication for
IPPV
2. Carbon Dioxide:
• Maintain PaCO2 5.0–7.0 kPa
• Hypoventilation leading to hypercapnia (>7.0 kPa) is an indication for IPPV
• Hyperventilation is contraindicated but, if baby spontaneously hyperventilating,
mechanical ventilation, may be necessary to control PaCO2
3. Circulatory Support:
• Maintain mean arterial blood pressure at ≥40 mmHg for term babies
• If cardiac output poor (e.g. poor perfusion: blood pressure is a poor predictor of
cardiac output) use inotropes
• Avoid volume replacement unless evidence of hypovolaemia، maintain fluid balance
and monitor renal function
• Start fluids at 40 mL/kg/day (see Intravenous fluid therapy guideline)
• Some babies develop inappropriate ADH secretion at 3–4 days (suggested by hypo-
osmolar serum with low serum sodium, associated with an inappropriately high
urine sodium and osmolality)
• Further fluid restriction if serum sodium falls and weight gain/failure to lose weight
• If in renal failure, follow Renal failure guideline
24
4. Acidosis
• Will normally correct itself once adequate respiratory and circulatory support
provided (correction occasionally required during initial resuscitation)
• Sodium bicarbonate correction is rarely required post resuscitation and it is better
to allow spontaneous correction
5. Glucose
• Regular blood glucose monitoring
• Target >2.6 mmol/L (> 45 mg/dl)
• Fluid restriction may require use of higher concentrations of glucose to maintain
satisfactory blood glucose
• Avoid hyperglycaemia (>8 mmol/L) (>140 mg/dL)
6. Calcium
• Asphyxiated babies are at increased risk of hypocalcaemia
• Treat with calcium gluconate when serum corrected calcium <1.7 mmol/L
(7mg/dL) or if ionized calcium <0.8 (<3 mg/dL)
7. Seizures
• Prophylactic anticonvulsants not indicated
• In muscle-relaxed baby, abrupt changes in blood pressure, SpO2 and heart rate can
indicate seizures
• Treat persistent (>3/hour) or prolonged seizures (>3 min, recur >3 times/hour) (see
Seizures guideline)
• Give phenobarbital − if ineffective or contraindicated, give phenytoin. If no
response, give clonazepam or midazolam (see Seizures guideline)
• Seizures associated with HIE can be notoriously difficult to control (preventing
every twitch is unrealistic)
• Regular seizures causing respiratory insufficiency are an indication for IPPV
• Once baby stable for 2–3 days, anticonvulsants can usually be withdrawn, although
phenobarbital can be continued for a little longer (duration can vary depending on
individual practice and clinical severity of seizures)
• Avoid corticosteroids and mannitol
25
8. Thermal Control
• Maintain normal body temperature (36.5–37.2°C).
• Avoid hyperthermia
9. Gastrointestinal System
• Term babies who suffer a severe asphyxial insult are at risk of developing NEC [see
Necrotising enterocolitis (NEC) guideline]
• In other babies, gastric motility can be reduced: introduce enteral feeds slowly
10. Cranial Ultrasound
• Generalised increase in echogenicity, indistinct sulci and narrow ventricles
• After aged 2–3 days, increased echogenicity of thalami and parenchymal
echodensities
• After 1 week, parenchymal cysts, ventriculomegaly and cortical atrophy may
develop
• Cerebral Doppler used early, but does not affect management
• Relative increase of end-diastolic blood flow velocity compared to peak systolic
blood flow velocity (Resistive Index <0.55) in anterior cerebral artery predicts poor
outcome (repeat after 24 hour)
• MRI scan of brain between days 5–14 of life for baby with moderate and severe
encephalopathy and in baby with seizures due to encephalopathy
• Areas of altered signal in thalamus, basal ganglia and posterior limb of the internal
capsule indicate poor outcome
SOURCES:
1. Bedside clinical guidelines partnership in association with Partners in pediatrics
2. National Institute for Health and Care Excellence (NICE)
26
Total Body Cooling Protocol for Infants with

Hypoxic Ischemic Encephalopathy
Practice Statement:
Upon the order of the attending Senior Resident or Neonatal Consultant the
nurse shall initiate, monitor and discontinue total body cooling therapy on infants with
moderate to severe Hypoxic Ischemic Encephalopathy (HIE).
Purpose:
Total body cooling has been proven to decrease moderate and severe disability
or death in infants born with moderate to severe asphyxia.
Current evidence indicates that moderate induced hypothermia (cooling) to a
rectal temperature of 34C improves survival and neurological outcomes to 18 months
of age in infants with moderate or severe perinatal asphyxial encephalopathy (BMJ.
2010 Feb 9;340:c363).
Equipment:
• Blanketrol II Model 222R
• Distilled Water
• Rectal/Esophageal Sterile Temperature Probe
Eligibility Criteria:
• 36 weeks or more gestation
• 1800 grams weight or more
• Within 1st 6 hrs. of life
• Diagnosis of neonatal depression, acute perinatal asphyxia or encephalopathy
Cooling is not appropriate if:

• The infant is likely to require surgery during the first 3 days after birth
• There are other abnormalities indicative of poor long-term outcome
Cooling may not be appropriate if the infant appears moriband or has persisting
extremely severe encephalopathy such that further treatment is likely to be futile, for
example if the AEEG/EEG is isoelectric beyond 12-24 hours of age.
27
Consider treatment with cooling in infants that meet the following criteria:
A. Infants ≥36 completed weeks gestation admitted to the neonatal unit with at
least one of the following:
• Apgar score of ≤5 at 10 minutes after birth
• Continued need for resuscitation, including endotracheal or mask ventilation, at 10
minutes after birth
• Acidosis within 60 minutes of birth (defined as any occurrence of umbilical cord,
arterial or capillary pH <7.00)
• Base Deficit ≥ 16 mmol/L in umbilical cord or any blood sample (arterial, venous
or capillary) within 60 minutes of birth
Infants that meet criteria A should be assessed for whether they meet
the neurological abnormality entry criteria (B):
B. Seizures or moderate to severe encephalopathy, consisting of:

• Altered state of consciousness (reduced response to stimulation or absent response
to stimulation) and
• Abnormal tone (focal or general hypotonia, or flaccid) and
• Abnormal primitive reflexes (weak or absent suck or Moro response)
Infants who meet criteria A and B may be considered for treatment

with cooling.
If an infant meets these criteria, but cooling is Not offered, the reasons for this
should be clearly documented in the medical notes. It is possible that this decision
may need to be justified in the future.
28
The Criteria for Defining Moderate and Severe Encephalopathy are Listed in
this Table “At Least 3 of the Following Should Be Present”
Parameter Moderate Encephalopathy Severe Encephalopathy
Level of Reduced response to Absent response to

Consciousness stimulation stimulation
Spontaneous Activity Decreased Activity No activity
Posture Distal flexion, complete

Decerebrate
extension
Tone Reflexes Hypotonia (focal or general) Flaccid
Suck Weak Absent
Moro Incomplete Absent

Full neurological assessment should be done especially for signs of lateralization:
pupils, tone, reflexes and cooling team should be notified.
AEEG assessment:
• The amplitude integrated EEG (AEEG) must be recorded in all infants treated with
cooling but cooling need not be delayed until the AEEG is initiated.
• A normal AEEG record (confirmed by assessing the underlying EEG and excluding
artefact distortion of AEEG indicates a high probability of normal outcome, and
clinicians may consider that treatment with cooling is not required.
EEG/AEEG recording for at least 30 min within 5.5 hrs after birth, no
anticonvulsants within 30 min before recording; recording may be performed
from 1 hour of age:
1. Standard EEG:
• Burst suppression
• Continuous low voltage < 25 μV
• Seizures
2. AEEG:
• Burst suppression
• Lower amplitude < 5 μV
• Upper amplitude < 10 μV
• Seizures
29
Starting cooling and consent:

• Clinicians should discuss the option of treatment with the parents and seek parental
consent for the baby to be transferred for treatment with cooling.
• Following parental consent, cooling should be initiated prior to and during the
transfer to the cooling center.
• Cooling outside the treatment center is started by turning off heating equipment, and
removing coverings from the baby. If necessary a fan can help induce cooling (see
passive cooling protocol).
• The baby’s age at the time heating equipment is turned off should be entered as the
time cooling started on the data collection form.
• The baby should be monitored and observation data collected during this period.
This includes continuous monitoring of rectal temperature, blood pressure and heart
rate.
• If immediate transfer to a cooling treatment center is not possible, for example
because of a lack of intensive care costs, passive cooling should be continued with
guidance from the cooling center.
Seizures:
• The management of seizures will be guided by local protocols.
• In general, symptomatic seizures or frequent (>3/hour) subclinical (EEG) seizures
will be treated with anticonvulsants.
• Cooling may affect the metabolism of several drugs, including anticonvulsants and
sedatives, and toxic drug levels may occur even with normal doses.
• 1st line anticonvulsants may be phenobarbital or phenytoin. Phenytoin should be
administered at a rate no faster than 1mg/minute.
• Benzodiazapines such as midazolam, or clonazapam are commonly used if seizures
persist. The dose should be adjusted according to response
Ventilation:
• Almost all infants treated with cooling will initially require mechanical ventilation.
• Blood gases will guide ventilatory requirements; as a guide PaO2 should be
maintained between 6-10 KPa and the PaCO2 between 5-7 KPa.
• Ventilator gases should be warmed and humidified in the normal way, according to
local policy.
30
Cardiovascular Support:
• Alterations in heart rate and blood pressure are common during cooling. In general,
the heart rate is reduced and blood pressure increases with a reduction in body
temperature.
• Most infants with a rectal temperature of 33-34°C (the target rectal temperature for
whole body cooling) will have a heart rate around 100 bpm and a mean blood
pressure greater than 40 mmHg.
• A rapid rise in body temperature may cause hypotension by inducing peripheral
vasodilatation.
• Treatment with volume replacement and/or inotropes should be considered if the
mean arterial blood pressure is less than 40 mmHg.
• Infants being treated with cooling should not be treated with steroids (other than for
treatment of hypotension), or mannitol as brain dehydrating measures.
Fluid Management:
• Renal function is commonly impaired following severe perinatal asphyxia. The
infant’s weight, blood creatinine and electrolytes and urine output will guide fluid
management.
• As a guide infant will require about 40-60 ml/kg/day. Infants in renal failure should
receive a total of 30 ml/kg/24 hours plus any measured losses. Boluses of 0.9% saline
may be required to avoid hypovolaemia if diuresis occurs in the infant or if
vasodilatation occurs during rewarming.
• Enteral feeding can be cautiously introduced once the initial biochemical and
metabolic disturbance are corrected, usually after about 24 hours.
31
Cooling Procedures:
Peripheral and Central Vascular access (umbilical venous catheter)

should be secured before initiation.
1. Pre-cool the blanket:

A. Attach the hypothermia blankets to the hypothermia machine.
B. Fill the cooling unit reservoir with Distilled Water till the water is touching the
strainer and visible from the water fill opening.
C. Plug in the system.
D. POWER ON - status light will come on which says "Check Set Point". Make sure
the temperatures are reading in the Celsius mode. The switch is on the front of the
unit beside the "On/Off Switch".
E. Push "TEMP SET" switch to pre-cool and lower temperature to 5°C by pushing the
down arrow▼. (Do not go <5° or the blanket will alarm).
F. Press MANUAL CONTROL to start cooling blanket (the blanket's motor should
come on).
2. Place the temperature rectal probe 5 cm into rectum.

3. Place the infant on the pre-cooled blanket. The blanket should be kept dry.
The infant may be placed directly on the blanket or one thin sheet may be
placed over the blanket, under the infant.
4. Make sure none of the hoses are kinked.
5. Turn the infant’s incubator to manual mode and decrease heat output to 0.
There should be no external heat source. Maintain temperature probe so the
skin temperature reading is on.
6. Press “TEMP SET” on the blanket and adjust the temperature to 33.5oC with
the ▲ arrow.
7. Goal temperature 33.5 degrees C with an acceptable temperature range of

32.5 – 34.5 º C.
32
8. Achieve target temperature by 60 minutes of commencing cooling If using

manual mode, on reaching 34.5 degree increase temp by 5 degree for each
0.5-degree rectal temp to avoid further decrease in temp < 32.5c.
9. Record rectal and skin temperature continuously for 72 hours.
10. Record heart rate and blood pressure at baseline, hourly for 12 hours, then
every 2 hours. If infant requires inotropic support record blood pressure at
baseline, then hourly while on inotropic support. Anticipate bradycardia and
hypotension (≥ 2SD below normal for age and sex).
11. Thompson score should be done daily and recorded

Score Sign 0 1 2 3
Tone Normal Hyper Hypo Flaccid
LOC
(level of Normal Hyperalert, stare Lethargic Comatose
consciousness)
Fits
None < 3/day >2/day
(seizures)
Strong distal
Posture Normal Fisting, cycling Decerebrate
flexion
Moro response Normal Partial Absent
Grasp reflex Normal Poor Absent
Suckling reflex Normal Poor Absent ± bites
Respiration Normal Hyperventilation Brief apnea IPPV (apnea)
Fontanelles Normal Full, not tense Tense
Total Score = sum of all 9 parameters interpretation:

• Minimum total score=0
• Maximum total score=22
• Total score =15 or more correlated with poor neurodevelopmental outcome at 1 year
REFERENCE:
▪ Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et
al. The value of a scoring system for hypoxic ischaemic encephalopathy in predict ing
neurodevelopmental outcome. Acta Paediatr. 1997;86:757–61
33
12. obtain venous blood gases at baseline, 4, 8, 12, 24, 48 and 72 hrs of age.
Record infant temperature on blood gas slip
13. Obtain serum electrolytes, BUN, and creatinine at baseline, 24, 48, and at 72
hours.
14. Follow up blood glucose and coagulation profile.
15. Check skin condition every 4 hours for areas of skin breakdown. Notify the
consultant of areas of redness.
16. Use pulse oximetry cautiously, if at all Obtain Consultant orders to

discontinue pulse oximetry during hypothermia if not functioning properly.
17. Notify attending if temperature drops below 32ºC.
18. A cranial US shall be performed within 24 hours as clinically indicated. Soon

after decision of cooling especially if signs of lateralization
19. Echocardiography should be done before starting (as possible) and during
cooling then during rewarming.
20. EEG should be done before rewarming (better AEEG).
21. Pain management should be considered.
22. The infant is to remain on the hypothermia blanket continuously for 72 hours.
23. After 72 hours rewarming orders will be initiated.
34
Stop Cooling If:

• Persistent hypoxemia in 100% oxygen
• Life threatening coagulopathy despite treatment
• Arrhythmia requiring medical treatment (not sinus bradycardia)
Re-warming procedures (at the end of 72 hours from commencement,

should be done in Shift A with continuous EEG monitoring, unless cooling is
mandatory to be stopped earlier)
Electrical / clinical seizures during re-warming is an indication for continuation of
cooling until cessation of seizures (re-cooling policy to be revised):
1. Avoid rapid re-warming of the infant.
2. Increase the temperature on the cooling unit by 0.5ºC every hour until the set point
temperature on the cooling unit is on 36.5 º C. Record rectal and skin temperature,
heart rate, blood pressure and blanketrol readings continuously on the rewarming
worksheet.
3. Once the set point on the cooling unit has been on 36.5 for one-hour switch the
cooling unit to monitor only.
4. Switch the radiant warmer temperature mode from manual to servo and set the servo
control temperature to 0.5ºC above infant’s skin temperature.
5. Increase the servo control temperature by 0.5ºC each hour until the servo control
reading is set 36.5ºC. Record rectal and skin temperature, heart rate and blood
pressure readings continuously on the rewarming worksheet.
6. Once the infant’s skin temperature reaches 36.5ºC remove cooling blanket and rectal
probe.
The infant’s temperature must be carefully monitored for 24 hours after
normothermia has been achieved to prevent rebound hyperthermia, as this might
be detrimental.
7. Obtain further vital sign per level of care and document on the NNICU flowsheet.
8. An MRI should be performed at discharged or at 44 weeks post conceptual age per
standard of care.
35
Systemic Complications of Therapeutic Hypothermia in the NICU:
Cardiovascular and Pulmonary Complications of Hypothermia
1. Sinus bradycardia
2. Hypotension
3. Lower cardiac output and stroke volume (without hypotension)
4. Cardiac arrhythmia
5. Hyperviscosity
6. Pulmonary vasoconstriction with development of pulmonary hypertension
Hematological Adverse Effects
1. Coagulation abnormalities include platelet dysfunction, increased fibrinolytic

activity, and inhibition of enzymatic reactions of the coagulation cascade with
substantial prolongation of PT and PTT
2. Thrombocytopenia
Renal Impairment with Cooling
1. Antidiuretic hormone suppression

2. Decrease in renal perfusion and glomerular filtration rate.
Immunologic Adverse Effects of Cooling
1. Immunosuppressive and anti-inflammatory effects
36
Effects of Cooling on Laboratory Values During Hypothermia:
Ventilation, Blood Gases and Cooling
• With each degree Celsius decrease in core temperature, pH increases by 0.015,

PCO2 and PO2 decrease by 4% and 7% respectively.
Serum Electrolytes and Cooling
• Hypothermia causes an intracellular shift of potassium. Aggressive correction of

hypokalemia during hypothermia may result in hyperkalemia on rewarming.
• Hypocalcemia
• Hypomagnesemia
• Hypoglycemia
Serum Lactate
• Hypothermia reduces tissue perfusion and shifts the hemoglobin oxygen dissociation
curve to the left reducing oxygen availability to tissues; both lead to metabolic
acidosis. However, if perfusion is reduced proportionately with reduced demand,
then there would be no increase in anerobic metabolism.
37
SEIZURES
Neonatal seizures are a manifestation of neurological dysfunction. Seizures
occur in 1–3% of term newborn babies and in a greater proportion of preterm babies.
They can be subtle, clonic, myoclonic or tonic.

Physical Signs
In addition to obvious convulsive movements, look for:
• Eyes: staring, blinking, horizontal deviation
• Oral: mouthing, chewing, sucking, tongue thrusting, lip smacking
• Limbs: boxing, cycling, pedaling
• Autonomic: apnoea, tachycardia, unstable blood pressure
• Focal (1 extremity) or multifocal (several body parts)
• Perform a detailed physical examination and neurological assessment
• Jitteriness: tremulous, jerky, stimulus-provoked and ceasing with passive flexion
• Benign sleep myoclonus: focal or generalized, myoclonic limb jerks that do not
involve face, occurring when baby is going to or waking up from sleep; EEG normal;
resolves by aged 4–6 months
• Differentiation between jitteriness and seizures
38
Investigations:
First Line:
• Blood glucose
• Serum electrolytes including calcium, magnesium
• Full blood count coagulation (if stroke suspected, thrombophilia screen)
• Blood gas
• Blood culture
• CRP
• Liver Function Tests
• Serum ammonia, amino acids
• Urine toxicology, amino acids, organic acids
• Lumbar puncture – CSF microscopy and culture (bacterial and viral PCR for herpes
simplex including enterovirus)
• Discuss CSF sample for further metabolic testing [e.g. glycine, lactate etc. (as guided
by metabolic testing)] with consultant
• Cranial ultrasound scan (to exclude intracranial haemorrhage)
• EEG (to identify electrographic seizures and to monitor response to therapy).
Consider cerebral function monitor (CFM–aEEG)
Second Line:
• Congenital infection screen (TORCH screen)

• MRI scan
• Screen for maternal substance abuse
• Serum acylcarnitine, biotinidase, VLCFA, uric acid, sulphocysteine, total and free
homocysteine
• Trial of pyridoxine treatment, preferably during EEG monitoring, may be diagnostic
as well as therapeutic
• If further advice required, contact metabolic team
39
Treatment:
• Ensure ABC
• Treat underlying cause (hypoglycaemia, electrolyte abnormalities, infection)
• Hypoglycaemia: give glucose 10% 2.5–5 mL/kg IV bolus, followed by maintenance
infusion. Wherever possible, obtain ‘hypoglycaemia screen’ (see Hypoglycaemia
guideline) before administration of glucose bolus
• Hypocalcaemia (total Ca <1.7 mmol/L (7 mg/dL) or ionized Ca <0.64 mmol/L
(3mg/dL)): give calcium gluconate 10% 0.5 mL/kg IV over 5–10 min with ECG
monitoring (risk of tissue damage if extravasation) (see Hypocalcaemia guideline)
• Hypomagnesaemia (<0.68 mmol/L): give magnesium sulphate 100 mg/kg IV or
deep IM (also use for refractory hypocalcaemic seizure)
• Pyridoxine (50−100 mg IV) can be given to babies unresponsive to conventional
anticonvulsants or seek neurologist opinion Initiation of anticonvulsants (for
immediate management follow flowchart)
• Start anticonvulsant drugs when:
➢ Prolonged: >2–3 min frequent: >2–3/hour
➢ Associated with cardiorespiratory compromise (frequent apnoeas and
bradycardia requiring intervention)
Administration:
• Slowly IV to achieve rapid onset of action and predictable blood levels
• To maximum dosage before introducing a second drug
• If no IV access and glucose and electrolyte abnormalities excluded, consideration
can be given to buccal/intranasal midazolam
Maintenance and Duration of Treatment:

• Keep duration of treatment as short as possible. This will depend on diagnosis and
likelihood of recurrence
• May not require maintenance therapy after loading dose
• If maintenance therapy is required: monitor serum levels develop emergency seizure
management plan, including, if required, a plan for buccal/intranasal midazolam
40
Stopping Treatment:
• Consider seizures have ceased and neurological examination is normal or abnormal
neurological examination with normal EEG
Anticonvulsant Drug Therapy Schedule
41
Discharge and Follow-Up:
Discharge:
• Ensure parents are provided with appropriate discharge documentation
• Seizure emergency management plan
• Copy of discharge summary, including: types of seizures,
medications/anticonvulsants administered
Follow-Up:
• Follow-up will depend on cause of seizures and response to treatment
• Consider: specialist follow-up for babies discharged on anticonvulsant drugs
Further Information for Parents:
▪ www.bcmj.org/sites/default/files/HN_Seizures-newborns.pdf
42
Flowchart: Immediate Management
43
HYPOCALCAEMIA
• Term or preterm infants birth weight ≥1500 g, total serum calcium <2 mmol/L (8
mg/dL) or ionized fraction <1.1 mmo/L (4.4 mg/dL)
• Preterm infant, birth weight <1500 g, total serum calcium <1.75 mmol/L (7 mg/dL)
or ionized fraction <1 mmol/L (4 mg/dL)
Symptoms and Signs:
• Early onset occurs in first 2−3 days of life and is usually asymptomatic
• Late onset develops after first 2−3 days of life and typically occurs at the end of the
first week
• Most infants are asymptomatic and identified on screening
• Characteristic sign is increased neuromuscular irritability including:
• Jitteriness and irritability
• Generalized/focal seizures
• Non-Specific symptoms e.g.:
➢ Poor feeding
➢ Lethargy
➢ Apnoea
• Prolonged QTc on ECG
• Rare presentations:
➢ Stridor
➢ Bronchospasm
➢ Pylorospasm
44
Causes:
Early Onset Late Onset
• Prematurity • High Phosphate Load – Cow’s Milk,

Renal Failure
• Intrauterine Growth Restriction
• Hypomagnesaemia
• Infants of Diabetic Mother
• Parenteral Nutrition
• Hypoxic Ischaemic Encephalopathy
• Exchange Transfusion
• Hypomagnesaemia
• Alkalosis
• Hypoparathyroidism
• Maternal Hypercalcemia
• Syndromes e.g. Digeorge Syndrome
• Maternal Vitamin D Deficiency
• Maternal Hyperparathyroidism
• Transient Hypoparathyroidism
• Syndromes and Genetic Mutations e.g.

Digeorge and Kenny-Caffey Syndromes
Investigations:
• Serum calcium
• Only monitor if risk factors, most infants with hypocalcaemia are asymptomatic
• Well preterm infant with birth weight >1500 g and well term infants of diabetic
mothers receiving milk feedings on day 1 of life do not need testing routinely
• Ionized calcium preferred
• If using total calcium, measure albumin and correct for hypoalbuminemia
• Phosphate
• Magnesium
45
• Persistent hypocalcaemia or severe hypocalcaemia despite adequate calcium therapy

➢ 25-hydroxyvitamin D level
➢ Renal function tests
➢ Liver function test
➢ Alkaline phosphatase
➢ Parathyroid hormone level
➢ Urinary calcium:creatinine ratio
➢ ECG for prolonged QTc interval
➢ If pseudohyperparathyroidism suspected, X-ray hand
➢ Chest X-ray for thymic shadow
➢ If hypoparathyroidism suspected, renal ultrasound
➢ If DiGeorge syndrome suspected, echocardiography
➢ Genetic test for gene mutations or suspected syndrome e.g. DiGeorge syndrome
Management:
Asymptomatic Infants Symptomatic Hypocalcaemia
• Most infants with early onset • If seizures, prolonged QT interval,

hypocalcaemia recover with nutritional apnoea, unstable or poor feeding give IV
support; so early feeding provides calcium gluconate 10% 0.11 mmol/kg (=
adequate calcium 0.5 mL/kg) over 5−10 min followed by
maintenance
• Infants requiring IV fluid: add calcium
gluconate 10% 0.46 mmol/kg/day (= 2 • Dilute with sodium chloride 0.9% or
mL/kg/day) to IV fluid and give as glucose 5% 4 mL to each 1 mL calcium
continuous infusion gluconate 10% to give a concentration of
45 micromol/mL. Can be given undiluted
• Infant tolerating oral feeds: give 0.25 via central line in an emergency
mmol/kg oral 6-hourly
• Doses up to 0.46 mmol/kg (= 2 mL/kg
calcium gluconate 10%) have been used
• Maximum rate of administration 22

micromol/kg/hour
46
• Stable baby or following acute treatment:

➢ Oral calcium dose 0.25 mmol/kg 6-hourly
➢ If enteral feeds not tolerated add calcium gluconate 10% 0.46 mmol/kg/day to
IV fluid as above
➢ If symptomatic hypocalcaemia: hypomagnesaemia − magnesium sulphate 100
mg/kg IV/IM 12-hourly for 2−3 doses
• Vitamin D deficiency give 1000 units daily and adjust dose according to response
• Hyperphosphataemia
• High calcium, low phosphate diet
• Human milk is preferable, if not available, use formula with low phosphate 60/40
and oral calcium IV calcium precautions and considerations
• Extravasation can cause skin and subcutaneous tissue necrosis (see Extravasation
guideline). Monitor IV site closely
• Continuous infusion preferred to bolus, but use bolus for initial management in
symptomatic hypocalcaemia
• Bolus IV calcium can cause dysrhythmias − administer slowly over 5−10 min with
cardiac monitoring
• Calcium can be given via UVC provided catheter tip is in vena cava
• Inadvertent administration into portal vein can cause hepatic necrosis
• Do not mix calcium solutions with those containing phosphorus or bicarbonate as
this can cause precipitation
• Monitor bone profile and phosphate levels according to clinical need

• If calcium normal after 48 hour treatment, halve maintenance dose
• If calcium fails to normalize investigate for underlying cause
• Hyperphosphataemia – calcium and phosphate normalize in 3−5 days. Stop calcium
after 1 week and switch to normal formula in 2−4 weeks
47
INTRAVENOUS FLUID THERAPY
Hyponatraemia (<130 mmol/L):

Response to treatment should be proportionate to degree of hyponatraemia.
Causes:
Excessive Free Water:
• Reflection of maternal electrolyte status in first 24 hour
• Failure to excrete fetal extracellular fluid will lead to oedema without weight gain
• Water overload: diagnose clinically by oedema and weight gain
• Excessive IV fluids
• Inappropriate secretion of ADH in babies following major cerebral insults, or with
severe lung disease
• Treatment with indometacin or ibuprofen
Excessive Losses:
• Prematurity (most common cause after aged 48 hour)
• Adrenal insufficiency
• GI losses
• Diuretic therapy (older babies)
• Inherited renal tubular disorders
Inadequate Intake:
• Preterm breastfed babies aged >7 days
“Management Depends on Cause”

Excessive IV fluids and failure to excrete fetal ECF:
Management:
• Reduce fluid intake to 75% of expected
48
Inappropriate ADH:
Clinical Features:
• Weight gain, oedema, poor urine output
• Serum osmolality low (<275 mOsm/kg) with urine not maximally dilute (osmolality
>100 mOsm/kg)
Management:
• Reduce fluid intake to 75% of expected
• Consider sodium infusion only if serum sodium <120 mmol/L
“Risk of Accidental Hypernatraemia When Using Sodium Chloride 30%.

Use with Caution and Always Dilute Before Use”
Acute Renal Failure:
Management:
• Reduce intake to match insensible losses + urine output
• Seek advice from middle grade doctor/consultant
Excessive renal sodium losses

Management:
“If Possible, Stop Medication (Diuretics, Caffeine) That Causes Excess

Losses”
• Check urinary electrolytes
• Calculate fractional excretion of sodium (FE Na+ %):
• FE Na+ = [(urine Na ´ plasma creatinine)/(urine creatinine ´ plasma Na)] ´ 100
• Normally <1% but in sick preterm babies can be up to 10%
• Affected by sodium intake: increased intake leads to increased fractional clearance
• if >1%, give sodium supplements
• Calculate sodium deficit
• = (135 − plasma sodium) ´ 0.6 ´ weight in kg
• Replace over 24 hour unless sodium <120 mmol/L or symptomatic (apnoea, fits,
irritability)
• Initial treatment should bring serum sodium up to approximately 125 mmol/L
• Use sodium chloride 30% (5 mmol/mL) diluted in maintenance fluids. Ensure bag
is mixed well before administration
49
Adrenal Insufficiency:
Clinical Features:
• Hyperkalaemia
• Excessive weight loss
• Virilization of females
• Increased pigmentation of both sexes
• Ambiguous genitalia
Management:
• Seek consultant advice
Inadequate Intake:
Clinical features:
• Poor weight gain and decreased urinary sodium
Management:
• Give increased sodium supplementation
• If taking diuretics, stop or reduce dose
Excessive Sodium Intake Leading To Water Retention:

Clinical features:
• Inappropriate weight gain
Management:
• Reduce sodium intake
Treatment of Acute Symptomatic Hyponatraemia with Seizures:

• Do not manage hyponatraemic encephalopathy using fluid restriction alone
• Give sodium chloride 2.7% 2 mL/kg IV over 10-15 min
• If symptoms still present, repeat
• Measure serum sodium hourly until symptoms resolve
• When symptoms resolved, ensure serum sodium does not increase by >12
mmol/L/24 hour
50
Causes (common causes in bold)
Fluid Overloaded Euvolemic Dehydrated
• IV fluid • Administration of enteral • GI losses and rehydration

administration in hypotonic fluids (including with free water
excess of the child’s dilute formula, Oral • Gastroenteritis
needs Rehydration Solutions, • Secretory/osmotic
• Nephrotic syndrome excessive water intake) diarrhoeas
• Cirrhosis • Psychogenic Polydipsia • Ostomies
• Heart Failure • Increased ADH secretion • Skin losses (CF / burns)
• Acute/ Chronic Renal • Pulmonary: pneumonia, • Abdominal 3rd spacing
Failure bronchiolitis, mechanical • High rate fluid consumption
• Obstructive uropathy ventilation post exercise
• CNS: infections, injury, • Hyperglycaemia
tumour • Renal Losses
• Post-operative, trauma, • Thiazide Diuretic
pain • Cerebral salt wasting
• Endocrine: Hypothyroid, • Primary renal Tubular
low cortisol Disorders
• Medications • Hypoaldosteronism
• Chemotherapy • Metabolic alkalosis
(cyclophosphamide,
vincristine, platinum based
agents)
• Antiepileptics (valproate,
carbamazepine,
oxcarbazepine)
• Vasopressin
51
The Royal Children's Hospital Melbourne
52
NEONATAL SEPSIS
A. Early Onset Neonatal Sepsis:
Risk factors for infections:

1. Invasive Group B streptococcal infection in a previous baby
2. Maternal Group B streptococcal colonization, bacteriuria or infection in the current
pregnancy
3. Pre‐labour rupture of membranes
4. Preterm birth (<37 weeks) following spontaneous labour
5. Suspected or confirmed rupture of membranes for >18 hour in a preterm birth
6. Intrapartum fever >38°C, or confirmed or suspected chorioamnionitis
7. Mother given parenteral antibiotics for confirmed or suspected invasive bacterial
infection
8. Suspected or confirmed infection in a co‐twin
Red Flag Signs and Clinical Indicators Suggestive of Neonatal Infection:
1. Systemic antibiotics given to mother for suspected bacterial infection during labour
or within 24 hour either side of birth
2. Suspected or confirmed infection in a co‐twin
3. Respiratory distress starting >4 hour after birth
4. Seizures
5. Signs of shock
6. Need for mechanical ventilation in a term baby
REFERENCE:
▪ An online calculator interface which provided clinicians with guidance regarding
the risk ofEOS and clinical action
(https://neonatalsepsiscalculator.kaiserpermanente.org/)
53
ACTIONS:
Any red flags or no red flags but 2 risk factors or clinical indicators perform
investigations, including blood cultures, and start antibiotics.
Investigations before Starting Antibiotics:

1. Blood culture (in all)
2. Measure CRP at presentation and 18‐24 hour after
3. If strong clinical suspicion of infection or signs/symptoms of meningitis, perform
lumbar puncture (LP) and baby does not respond satisfactorily to antibiotics
clinically &/or laboratory (CRP persistent or rising), if safe to do but if performing
LP will delay antibiotics, give antibiotics first
4. Do not carry out routine urine MC&S
5. Take skin swabs only if clinical signs of localised infection
6. If purulent eye discharge: collect eye swabs for urgent MC&S and swabs in viral
transport media for viral PCR, especially if looking for chlamydia or gonococcus
start systemic antibiotics while awaiting results
7. If signs of umbilical infection, including purulent discharge or periumbilical
cellulitis, perform blood culture, take swab for MC&S and start flucloxacillin and
gentamicin IV if microbiology results indicate infection not due to Gram‐ negative
infection stop gentamicin
Early Onset Sepsis Most Common Organisms:

• E. coli, Klebsiella species, and S. aureus
• The combination of IV benzylpenicillin and gentamicin is an appropriate choice for
empirical therapy.
54
Early onset sepsis Meningitis:

CSF Gram Stain:
• Uninformative treat with IV amoxicillin and cefotaxime
• Gram negative infection stop amoxicillin and treat with cefotaxime alone
• Gram‐positive infection continue treatment with IV amoxicillin and
cefotaxime while awaiting the CSF culture result
CSF Culture:
According to C/S after making sure it passes BBB
Usual duration of treatment:

• 5 days if blood culture negative and baby is well with no strong clinical suspicion of
infection nor CRP >6
• 7days if blood culture +ve or strong clinical suspicion of infection or CRP >6
• >7days if baby is not fully recovered or advisable based on blood culture
55
B. Late Onset Neonatal Sepsis:
Definition:
Infection after first 72 hour of life

Presentation:
Can be vague and non‐specific

Symptoms:
1. Respiratory 7. Temperature instability 13. Jaundice

distress (high or low)
14. Seizures
2. Apnoea/bradycardia 8. Glucose instability
15. Vomiting
3. Cyanosis or poor 9. Hypotonia
colour 16. Abdominal distension
10. Irritability
4. Poor perfusion 17. Nursing staff may
(CRT >3 sec; toe‐core 11. Lethargy/inactivity describe babies with a
temperature gap >2°C; mixture of these symptoms
mottling) 12. Poor feeding and poor as not doing well’
suck
5. Hypotension
6. Tachycardia
56
Signs:
1. Systemic signs of 3. Bulging of the 5. Petechiae, bleeding

sepsis such as fontanelle (rare in babies diathesis
tachycardia, poor with neonatal meningitis)
perfusion, reduced 6. Septic spots in eyes,
tone, quiet, lethargy, 4. Abdominal distension umbilicus, nails and skin
unsettled and and tenderness, bowel
crying/moaning sounds, Inspect stool for 7. Decreased movement or
visible blood tenderness in joints and
2. Tachypnoea and limbs
intercostal and/or
subcostal recession
Investigations:
1. Swabs or ETT 4. Clotting profile 7. Lumbar puncture (LP):

secretions for culture (evidence of bleeding IF baby unstable,
+ Swab suspicious diathesis or in severe deranged clotting or
lesion infection thrombocytopenia
(consultant advise) CSF
2. Blood cultures 5. CRP: delay 24 hour for Gram‐stain &
between onset of culture, protein &
3. Full blood count: symptoms & rise in glucose +/‐ PCR for
neutrophil count serum CRP, for bacteria and viruses
<2000 or>15000/mm, support of diagnosis & where indicated
platelet count follow up
of<100.000, toxic 8. Chest X‐ray
granulation in 6. Urine microscopy,
neutrophils [or if culture & sensitivity by 9. If abdominal distension
measured, an clean‐catch or supra‐ noted, abdominal X‐ray
immature:total (I:T) pubic aspiration
neutrophil ratio >0.2]
57
Treatment:
“Every Hospital Must Have Its Own Protocol”

• Do not use vancomycin routinely
• Do not use oral antibiotics to treat infection in babies
• For babies with indwelling catheters and on parenteral nutrition, unless they are very
unwell to treat endotracheal secretion colonisation with CoNS
• When culture results available, always change to narrowest spectrum antibiotic, or
stop antibiotics if negative cultures, inflammatory markers not raised and no clinical
signs of infection
First Line:
• Flucloxacillin + Gentamicin as initial antibiotics for late onset sepsis in a stable
neonate
Second Line:
• Vancomycin + Gentamicin (with caution)
• Vancomicin + Third‐generation cephalosporin (e.g. cefotaxime) (in areas where
MRSA is prevalent)
• Vancomicin + Piperacillin/Tazobactam
Third Line:
• Meropenem, Ciprofloxacin + Vancomycin
For Meningitis:
First Line:
• Cefotaxime + Amoxicillin + Gentamicin
Second Line:
• Meropenem
58
Meningitis:
• For all babies with a positive blood culture, other than Coagulase‐negative
staphylococci (CoNS), discuss the need for an LP.
• Empirical treatment whilst CSF results pending
• CSF visually clear, give first line antibiotics as in late onset sepsis
• CSF cloudy or high clinical suspicion of meningitis, give high dose cefotaxime
• Treat with high dose cefotaxime for 14–21 days, depending on organism
Table of Normal CSF Values
White cell
Protein Glucose
Gestation count
(g/L ) (mg/dl)
(count/mm3)
Preterm < 28 days 9 1 55
Term < 28 days 6 0.6 55
Values are mean (range)
Note:
Protein levels are higher in first week of life and depend on RBC count. WBC of
>21/mm3 with a protein of >1.0 g/L with <1000 RBC is suspicious of meningitis
59
Fungal Infection:
• Risk factors for prophylactic antifungal treatment to be considered according to
consultant opinion
• <1500 g
• Parenteral nutrition
• Indwelling catheter
• No enteral feeds
• Ventilation
• H2 antagonists
• Exposure to broad spectrum antibiotics, especially cephalosporins
• Abdominal surgery
Treatment:
First choice:
• Standard amphotericin starting at 1 mg/kg. Can increase dose as tolerated to 1.5
mg/kg, yet use carefully to avoid its nephrotoxicity & hypokalemia risk
• Liposomal amphotericin 1 mg/kg (if available), increasing to a maximum of 5 mg/kg
have less side effects
• Alternatives fluconazole and vefungin
REFERENCES:
1. The National Institute for Health and Care Excellence (NICE) 2021
2. Neonatal guidelines 2019- 2021 (the Bedside Clinical Guidelines Partnership)
3. Puopolo et al, 2018 (AAP publications)
4. Procianoy & Silveira, 2019
5. Odabasi & Bulbul, 2020
6. Singh et al, 2021 (StatPearls )
60
Nutrition and Enteral Feeding
AIMS:
To Achieve:
Growth and nutrient accretion similar to intrauterine rates
Best possible neurodevelopmental outcome
To Prevent:
Specific nutritional deficiencies
Principles:
• Early enteral feeds promote normal gastrointestinal structure and function, motility
and enzymatic activity
• Delayed nutrition can result in growth restriction with long-term complications of
parenteral nutrition, dysbiosis of the intestine, poor organ growth and poorer
neurological outcomes
• There is robust evidence that feeding maternal colostrum and breast milk is
protective for necrotizing enterocolitis (NEC), sepsis and retinopathy when
compared to formula milk
• Manage feeding on an individual basis dependent upon gastrointestinal tolerance
and availability of breast milk
Nutritional Requirements:
Daily recommended intake of nutrients for stable/growing preterm infants
61
Feeding Guide:
When to Start Feeding?
• Commence enteral feeds in preterm infants as close to birth as possible (unless
clinically contraindicated)
Buccal Colostrum:
Aim:
• To provide the benefits of colostrum to all sick and premature infants who cannot
access oral breast feeds
• Place 0.3 mL (0.15 mL per side) colostrum in buccal cavity by syringe/gloved finger
at 3-hourly intervals for first 48 hour of life)
• Colostrum is absorbed locally by the buccal mucosa
• Can be administered even to critically-ill, ventilated, fragile infant
• Counsel all mothers anticipating delivery of sick/preterm infant about benefits of
colostrum
• Advise mothers to hand express as soon after delivery as possible (ideally within 1
hour)
• Initiate administration of buccal colostrum as soon as colostrum available (ideally
within 2 hour of birth)
Patient Group:
• Preterm infants (born <34 weeks’ gestation) admitted to NNU or
• Any infant ≥34 weeks’ gestation admitted to NNU and not receiving oral feeds
Contraindicated:
• Any contraindication for receiving mother’s own milk e.g. maternal HIV infection
• Oral breastfeeding: will receive colostrum orally as first few feeds after birth
62
Enteral Feeds:
Route of Administration:
• Infants <34 weeks are not mature enough to co-ordinate sucking, swallowing and
breathing to feed effectively and must be tube fed
• Use gastric feeding with either naso- or orogastric tube
Initiating and Advancing Enteral Feeds
• Make every effort to use mother’s fresh expressed colostrum and breast milk
• If mother’s expressed breast milk (MEBM) not available within 48 hour of birth, use
preterm formula
Trophic Feeds:
• Small volumes (10−20 mL/kg/day) of milk given to stimulate the bowel
• Maintain for up to 7 days
• Not intended to contribute to nutrition
• Use in infants where feeds cannot be advanced in order to utilize maternal colostrum
and stimulate gut trophic hormones
63
Which Milk to Use?
MEBM:
• Mother’s own breast milk remains the ideal milk for term and preterm infants and
should be strongly recommended
• If MEBM still insufficient at 48 hour of life, use alternative feeds as tolerated in line
with algorithm above
• Add breast milk fortifier (BMF) when volumes reach ≥150 mL/kg/day and advance
to 180 mL/kg/day as tolerated
• Commence gradual introduction of alternative feeds once full volumes achieved
(minimum150 mL/kg/day) and infant aged ≥14 days (see Slow change to a different
type of milk feed)
BMF:
• All preterm infants born <34 weeks fed exclusively on MEBM require addition of
BMF to meet protein requirements for growth
• Add BMF when MEBM volumes reach 150 mL/kg/day
• Increase volume of MEBM + BMF to full feeds of 180 mL/kg/day
• Use full strength
• Prepare as per manufacturer’s instructions
• Continue BMF until 37 weeks’ CGA
• At 37 weeks’ CGA
• If growth velocity adequate stop BMF
• If growth insufficient or catch up required continue BMF as fortified breast milk
supplements
• If more than half of feed requirement provided by preterm formula, BMF not
required unless there is poor growth and intolerance of volume
64
Preterm Milk Formula:
• Indicated for infants born <34 weeks’ gestation and <2 kg

• Preterm milk formula formulated to meet the nutrient needs of preterm infants <2
kg where insufficient MEBM to meet requirements
• Nutrient enriched post-discharge formula (NEPDF) formulated to meet the ongoing
enhanced nutrient needs of infants born <34 weeks, once they reach 37 weeks
CGA/≥2 kg/at discharge from NNU
• Not all preterm infants require post-discharge formula for extended periods. Infants
with normal growth velocity and no requirement for catch-up growth can be
discharged on term formula with appropriate vitamin and mineral supplementation
• NEPDF especially useful for infants who have higher nutritional requirements (e.g.
CLD on oxygen) or infants who have ongoing poor growth (e.g. have crossed down
>2 centiles on growth chart during neonatal stay)
• Volumes >180 mL/kg are not usually necessary and other reasons for poor growth
should be sought before further volume increases introduced (see Inadequate
growth)
Specialized Preterm Formulas:
• These formulas may be suitable for infants who fail to tolerate/progress on standard
preterm formula or have a family history of CMPI or require MCT for proven fat
malabsorption
• These formulas do not provide adequate nutrition for preterm infants at standard
dilution and will require modification to ensure individual requirements met. Use
only where absolutely necessary and always under direction of paediatric/neonatal
dietitian
65
Appropriate Maintenance Feeds for Neonates Based on

Gestational Age and/or Weigh
Gestational Age and/or Weight Maintenance Feed
• D/MEBM + BMF: aim 180 mL/kg/day

<30 weeks and/or <1 kg
• Preterm milk formula: aim 165−180 mL/kg/day
Born between or on reaching 30+1–33+6 weeks • MEBM + BMF: aim 180 mL/kg/day
• MEBM + BMF: aim 180 mL/kg/day

• Introduce oral feeds (see Progression to oral
At 34 weeks and <2 kg
feeding guideline)
• consider fortified breast milk supplements as
breastfeeding increases
• MEBM + BMF: aim 180 mL/kg/day

• Post-discharge formula: aim 165−180 mL/kg/day
• Introduce oral feeds (see Progression to oral
At 34 weeks and ≥ 2 kg
feeding)
• Allow natural reduction in BMF as breastfeeding
increases
• MEBM: aim 160−180 mL/kg/day or modified

responsive breastfeeding + half strength BMF
Born 34 - 37 weeks and <2 kg • Post-discharge formula modified responsive bottle
feeding
• Discharge on breast milk or term formula
• MEBM 180 mL/kg/day via naso-/orogastric tube or

modified responsive breastfeeding
Born ≥37weeks • Term formula 165−180 mL/kg/day via naso-
/orogastric tube or modified responsive bottle
feeding
• Infants >37 weeks with normal growth velocity

and no requirement for catch-up growth
• Allow natural reduction in BMF as breastfeeding
increases
• if insufficient MEBM and growth velocity
Preterm infants (born<34 weeks) at discharge satisfactory use term formula at discharge
• Infants <36+6 weeks CGA and/or poor growth
velocity or requiring catch-up growth:
• Use fortified breast milk supplements as oral
breastfeeding increases
• If insufficient MEBM to meet requirements use
NEPDF on discharge
66
Iron and Vitamin Supplementation
▪ Preterm infants fed exclusively on breast milk should receive supplementary phosphorus
titrated against normal serum phosphate and ALT levels.
▪ If ≤33+6 weeks’ gestation at birth with PO4 <1.8 mmol or >34 weeks’ gestation with PO4
<1.4 mmol, send paired urine and blood phosphate to measure tubular reabsorption of
phosphate (TRP)
TRP Calculated As:
▪ 1 – (urine phosphate - plasma creatinine/plasma phosphate - urine creatinine) 100%

with all units in mmol/L. If >95% start PO4 supplementation - Alkaline phosphate not
sensitive or specific to osteopaenia of prematurity
67
Evaluation:
Monitoring of feed tolerance, growth and biochemical balance is critical in
nutritional management of preterm infants to ensure optimal outcomes
Assessment Feed Tolerance:

• Poor gut motility is common among VLBW/ELBW infants and some will have
episodes requiring temporary discontinuation of feeding or delay in advancing feeds
• If failure to progress feeds continues over several days, seek advice early from
neonatal/paediatric dietitian assessment of gastric residuals (GR)
• Routine aspiration of GR not recommended in preterm infants
• Advance feeds as tolerated after feed tolerance evaluation 4-hourly (see below)
• Do not use GR volumes in isolation when deciding to limit advancement of feeds
68
Nutritional Assessment of Enterally-fed Preterm Infants:
Biochemical Monitoring:
• Measure plasma urea, electrolytes, calcium, phosphate and albumin weekly in stable
preterm infants to monitor nutritional status
• Monitor glucose closely in initial few days
69
Inadequate Growth:
• Preterm infants with weight gain <16 g/kg/day require further assessment
• Review proportional growth (weight, head, length) on age and gender appropriate
growth chart
• Ensure infant prescribed recommended nutritional intake
• Ensure infant receiving prescribed nutritional intake
• Ensure on maximum advised volume of age/weight appropriate feed – see
maintenance feed volume/type charts
• Calculate energy and protein intake per kg/day and compare with ESPGHAN
recommended requirements for weight/gestational age
• Check adequate total body sodium by ensuring sodium excretion in urine ≥20
mmol/L (only useful in infants not receiving diuretics)
• Add extra supplements as necessary
• In infants receiving MEBM use hind milk (see Breast milk expression guideline)
• If tolerated, increase feed volumes beyond that recommended
• If receiving MEBM + BMF: ≤220 mL/kg/day
• If receiving preterm formula: ≤200 mL/kg/day
• If infant receiving MEBM + BMF does not tolerate increased volumes, or if
insufficient MEBM to increase
• Volumes, replace 25−50% MEBM + BMF with gestational age/weight appropriate
formula
• <2 kg preterm formula
• ≥2 kg high energy term formula
• Breastfeeding/MEBM: use BMF as a concentrated solution (known as fortified
breast milk supplement, give 1 sachet dissolved in 3 mL MEBM via syringe/teat
before 4 breastfeeds, equally spread throughout 24 hour period. Reduce BMF by 1
sachet/day every 2 weeks until 6 weeks post-term or 3.5 kg, whichever soonest, then
stop fortified breast milk supplements
• Refer to neonatal/paediatric dietitian for assessment and advice
70
Neonatal Parenteral Nutrition for Preterm Babies,

up to 28 Days after Their Due Birth Date
Indications for Starting NPN:

For newborn preterm babies start NPN in:
• Babies born before 31+0 weeks
• Babies born at or after 31+0 weeks if sufficient progress is not made with enteral
feeding in the first 72 hours after birth
• Babies who are unlikely to establish sufficient enteral feeding, for example, babies
with a congenital gut disorder or critical illness such as sepsis.
For preterm babies who have previously established some enteral feeds start
NPN in:
• Babies whose enteral feeds have to be stopped and it is unlikely they will be restarted
within 48 hours
• Babies whose enteral feeds have been stopped for >24 hours and there is unlikely to
be sufficient progress with enteral feeding within a further 48 hours.
When a preterm baby meets the indications for parenteral nutrition, start it as soon as
possible, and within 8 hours at the latest.
Administration of NPN:
Venous Access:
• Use a central venous catheter to give neonatal parenteral nutrition. Only consider
using peripheral venous access to give neonatal parenteral nutrition if:
➢ It would avoid a delay in starting parenteral nutrition
➢ Short-term use of peripheral venous access is anticipated, for example,
less than 5 days
➢ It would avoid interruptions in giving parenteral nutrition
➢ Central venous access is impractical.
• Only consider surgical insertion of a central venous catheter if:
➢ Non-surgical insertion is not possible
➢ Long-term parenteral nutrition is anticipated, for example, in short bowel
syndrome.
71
Protection from Light:

• Protect the bags, syringes and infusion sets of both aqueous and lipid parenteral
nutrition solutions from light
Standardized Bags:
• When starting neonatal parenteral nutrition for preterm babies, use a standardized
parenteral nutrition formulation (‘standardized bag’).
• Continue with a standardized bag unless an individualized parenteral nutrition
formulation is indicated, for example, if the baby has:
➢ Complex disorders associated with a fluid and electrolyte imbalance
➢ Renal failure.
• Standardized neonatal parenteral nutrition (‘standardized bags’) should be
formulated in concentrated solutions to help ensure that the nutritive element of
intravenous fluids is included within the total fluid allowance.
72
Amounts for Constituents of Neonatal Parenteral Nutrition

If starting NPN
If starting NPN in the first 4 days after birth more than 4 days
after birth
Increasing From
Starting Range on Give
Starting To Maintenance Range
First Day
Maintenance
40-60
Energy 75-120 kcal/kg/day 75-120 kcal/kg/day
kcal/kg/day
Gradually, for
Glucose 6-9 g/kg/day 9-16 g/kg/day 9-16 g/kg/day
example over
Amin 4days
o 1.5-2 g/kg/day 3-4 g/kg/day 3-4 g/kg/day
acids
Gradually, for
example in
Lipids 1-2 g/kg/day 3 - 4 g/kg/day 3-4 g/kg/day
increments of 0.5-1
g/kg/day
If starting NPN
If starting NPN in the first 48 hours after birth more than 48 hours
after birth
Increasing from
Starting Range Maintenance
Starting to Give
on First Day Range
Maintenance
Calcium 0.8-1 mmol/kg/day After 48 hours 1.5-2 mmol/kg/day 1.5-2 mmol/kg/day
Phosphate 1 mmol/kg/day After 48 hours 2 mmol/kg/day 2 mmol/kg/day
Ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids
• Use a non-nitrogen energy to nitrogen ratio range of 20 to 30 kcal of non-nitrogen

energy per gram of amino acids (this equates to 23 to 34 kcal of total energy per gram
of amino acid)
• Provide non-nitrogen energy as 60% to 75% carbohydrates and 25% to 40% lipid.
73
Monitoring NPN:
Other Constituents of Neonatal Parenteral Nutrition – General Principles

• Do not give intravenous parenteral iron supplements to preterm babies <28 days old.
Iron • For preterm babies 28 days or older, monitor for iron deficiency and treat if
necessary.
• Give daily fat-soluble and water-soluble vitamins (in the intravenous lipid
Vitamins emulsion) fromthe outset or as soon as possible after starting parenteral
nutrition.
• Give sodium and potassium in parenteral nutrition to maintain
Electrolytes standard dailyrequirements.
• Give magnesium in parenteral nutrition from the outset or as soon as

Magnesium possible afterstarting parenteral nutrition.
Trace • Give daily trace elements from the outset or as soon as possible after starting
Elements parenteralnutrition.
Lipid • For preterm babies with parenteral nutrition-associated liver disease, consider
Emulsions giving acomposite lipid emulsion rather than a pure soy lipid emulsion.
Phosphate • Giver higher dosage if indicated by serum phosphate monitoring.
General Principles for Monitoring NPN:
When taking blood samples to monitor neonatal parenteral nutrition:

• Collect the minimum blood volume needed for the tests, and liaise with the local
clinical laboratory to retrieve as much information as possible from the sample
• Coordinate the timing of blood tests to minimize the number of blood samples
needed.
74
Minimum Blood Monitoring Requirements
Test Starting Maintenance Increased frequency

1-2 hours after • Previous hypoglycaemia or
1-2 hours after each change of hyperglycaemia
Glucose first starting NPN bag • Dosage has been changed
NPN (usually24-48 • Clinical reasons for concern, for
hours) example,sepsis or seizures
• If levels have been outside normal range
Daily when Twice weekly
Blood pH, potassium, • Dosages have been changed
starting and afterreaching a
chloride, and calcium • Clinical reasons for concern, for
increasing NPN maintenance NPN
example,critically ill babies
• If level is elevated
Weekly after
Daily while • Clinical reasons for concern, for
reaching
Serum Triglycerides increasing
maintenance
example, critically ill babies or
lipids babies with a lipaemic blood
lipid dosage
sample
Weekly after • If level has been outside normal range
Daily
reaching • Clinical reasons for concern, for
Serum or Plasma while
maintenance example,metabolic bone
Phosphate increasing
phosphate disease
phosphate
dosage • Born <32 weeks
Measure ferritin, iron and transferrin saturation if a preterm baby is on parenteral
Iron Status nutritionfor >28 days
• If levels have been outside the normal
Liver Function Weekly range
• Clinical concerns
Stopping NPN:
Factors to take into account when deciding when to stop parenteral nutrition:
• Tolerance of enteral feeds
• Nutrition being delivered by enteral feeds (volume and composition)
• Relative contribution of parenteral nutrition and enteral nutrition to baby’s total
nutritional requirement
• Likely benefit of nutritional intake compared with risk of venous catheter sepsis
• Individual baby’s circumstances, for example, a baby with complex needs such as
short bowel syndrome, increased stoma losses or slow growth, may need long-term
parenteral nutrition.
Depending on the above factors, consider stopping parenteral nutrition within 24

hours once the following enteral feed volumes are tolerated
• For preterm babies born before 28 weeks: 140 to 150 ml/kg/day

• For preterm babies born at or after 28 weeks: 120 to 140 ml/kg/day
• SOURCE:
▪ National institute for health and care excellence (NICE)
75
Neonatal Parenteral Nutrition for Term Babies,

up to 28 Days After Their Birth
Indications for Starting NPN:

For newborn term babies start NPN in:
• Babies who are unlikely to establish sufficient enteral feeding, for example, babies
with a congenital gut disorder or critical illness such as sepsis
For term babies who have previously established some enteral feeds start NPN
in:
• Babies whose enteral feeds have to be stopped and it is unlikely they will be restarted
within 72 hours
• Babies whose enteral feeds have been stopped for >48 hours and there is unlikely to
be sufficient progress with enteral feeding within a further 48 hours.
When a term baby meets the indications for parenteral nutrition, start it as soon as
possible, and within 8 hours at the latest.
Administration of NPN:
Venous Access:
• Use a central venous catheter to give neonatal parenteral nutrition. Only consider
using peripheral venous access to give neonatal parenteral nutrition if:
➢ It would avoid a delay in starting parenteral nutrition
➢ short-term use of peripheral venous access is anticipated, for example,
less than 5 days
➢ It would avoid interruptions in giving parenteral nutrition
➢ Central venous access is impractical.
• Only consider surgical insertion of a central venous catheter if:
➢ Non-surgical insertion is not possible
➢ Long-term parenteral nutrition is anticipated, for example, in short bowel
syndrome.
76
Protection from Light:
• Protect the bags, syringes and infusion sets of both aqueous and lipid parenteral
nutrition solutions from light.
Standardized Bags:
• When starting neonatal parenteral nutrition for term babies, use a standardized
parenteral nutrition formulation (‘standardized bag’).
• Continue with a standardized bag unless an individualized parenteral nutrition

formulation is indicated, for example, if the baby has:
➢ Complex disorders associated with a fluid and electrolyte imbalance
➢ Renal failure.
• Standardized neonatal parenteral nutrition (‘standardized bags’) should be

formulated in concentrated solutions to help ensure that the nutritive element of
intravenous fluids is included within the total fluid allowance.
77
Starting, Increasing and Maintaining NPN

Amounts for Constituents of Neonatal Parenteral Nutrition
If starting NPN
If starting NPN in the first 4 days after birth more than 4 days
after birth
Increasing From
Starting Range on Give
Starting To Maintenance Range
First Day
Maintenance
40-60
Energy 75-120 kcal/kg/day 75-120 kcal/kg/day
kcal/kg/day
Gradually, for
Glucose 6-9 g/kg/day example over 9-16 g/kg/day 9-16 g/kg/day
4days
Amino
1-2 g/kg/day 2.5 - 3 g/kg/day 2.5 - 3 g/kg/day
acids
Gradually, for
example in
Lipids 1-2 g/kg/day 3 - 4 g/kg/day 3 - 4 g/kg/day
increments of 0.5 -1
g/kg/day
If starting NPN
If starting NPN in the first 48 hours after birth more than 48 hours
after birth
Increasing
Starting Range from Starting Maintenance
Give
on First Day to Range
Maintenance
Calcium 0.8-1 mmol/kg/day After 48 hours 1.5-2 mmol/kg/day 1.5-2 mmol/kg/day
Phosphate 1 mmol/kg/day After 48 hours 2 mmol/kg/day 2 mmol/kg/day
Other constituents of neonatal parenteral nutrition – general principles

Iron • Do not give intravenous parenteral iron supplements to term babies <28 days old.
• Give daily fat-soluble and water-soluble vitamins (in the intravenous lipid emulsion)
Vitamins
from the outset or as soon as possible after starting parenteral nutrition.
Electrolytes • Give sodium and potassium in parenteral nutrition to maintain standard daily
requirements.
Magnesium • Give magnesium in parenteral nutrition from the outset or as soon as possible after
starting parenteral nutrition.
• Give daily trace elements from the outset or as soon as possible after starting
Trace elements
Lipid Emulsions • For term babies with parenteral nutrition-associated liver disease, consider giving a
composite lipid emulsion rather than a pure soy lipid emulsion.
Phosphate • Giver higher dosage if indicated by serum phosphate monitoring.
• For term babies who are critically ill or have just had surgery, consider giving
Energy
parenteral energy at the lower end of the starting range.
Ratios of non-nitrogen energy to nitrogen, and carbohydrates to lipids
• Use a non-nitrogen energy to nitrogen ratio range of 20 to 30 kcal of non-nitrogen energy per gram of
amino acids (this equates to 23 to 34 kcal of total energy per gram of amino acid)
• Provide non-nitrogen energy as 60% to 75% carbohydrates and 25% to 40% lipid.
78
Test Starting Maintenance Increased frequency

1-2 hours after • Previous hypoglycaemia or
1-2 hours after each change of hyperglycaemia
Glucose first starting NPN bag • Dosage has been changed
NPN (usually24-48 • Clinical reasons for concern, for
hours) example,sepsis or seizures
• If levels have been outside normal range
Daily when Twice weekly
Blood pH, potassium, • Dosages have been changed
starting and after reaching a
chloride, and calcium • Clinical reasons for concern, for
increasing NPN maintenance NPN
example,critically ill babies
• If level is elevated
Weekly after
Daily while • Clinical reasons for concern, for
reaching
Serum Triglycerides increasing
maintenance
example, critically ill babies or
lipids babies with a lipaemic blood
lipid dosage
sample
Weekly after • If level has been outside normal range
Daily
reaching • Clinical reasons for concern, for
Serum or Plasma while
maintenance example,metabolic bone
Phosphate increasing
phosphate disease
phosphate
dosage • Born <32 weeks
• If levels have been outside the normal
Liver Function Weekly range
• Clinical concerns
Monitoring NPN:
Stopping NPN:
Factors to take into account when deciding when to stop parenteral nutrition:
• Tolerance of enteral feeds
• Nutrition being delivered by enteral feeds (volume and composition)
• Relative contribution of parenteral nutrition and enteral nutrition to baby’s total
nutritional requirement
• Likely benefit of nutritional intake compared with risk of venous catheter sepsis
• Individual baby’s circumstances, for example, a baby with complex needs such as
short bowel syndrome, increased stoma losses or slow growth, may need long-term
Depending on the above factors, consider stopping parenteral nutrition within 24

hours once the enteral feed volume tolerated is 120 to 140 ml/kg/day
79
Transfusion of RBC in the NICU
Indications:
• Acute blood loss with haemodynamic compromise or 10% blood volume loss.In
emergency, use Group O RhD negative blood & transfuse 10 mL/kg over 30 min.
Further transfusion based on haemoglobin (Hb)
• Top-up blood transfusion, if Hb below threshold levels quoted in the following
situations
Baby Hb (g/L)
Post Natal
Suggested transfusion threshold Hb (g/L)
age
Other non-invasiverespiratory support

Ventilated No Respiratory Support
(CPAP/BiPAPHFNC/O2)
First 24
< 120 < 120 < 100
hour
Week 1 (day
< 120 < 100
1-7)
< 95
< 85 if symptoms of anaemia (e.g.
poorweight gain or significant
Week 2 (day apnoeas) or poor reticulocyte of
8-14) anaemia (e.g. poorweight gain or
significant apnoeas) or poor
reticulocyte response (<4% or count
< 100
<100 X 109/L)
<75 if asymptomatic
andgood
≥Week 3
reticulocyte response
(Fday 15 < 85
(4% or
onwards)
reticulocyte count
≥100 X109/L)
NB: To convert from (g /L) to (mg / dl) divide the number by 100
80
Pre-Transfusion:
Communication:
• If possible, inform parents that baby will receive blood transfusion.
Cross Match:
• For top-up transfusions in well baby, arrange with blood bank.
• Crossmatch against maternal serum (or neonatal serum if maternal serum not
available) for first 4months
• For first transfusion, send samples of baby's and mother's blood
Direct Coombs Testing:

• Laboratory will perform direct Coombs test (DCT) on maternal serum for any
atypical antibodies
• If maternal DCT negative, blood issued will be crossmatched once against maternal
serum.
• If maternal DCT positive, crossmatching of donor red blood cells against maternal
serum is required every time
Premature babies receiving breast milk or with Hb<10 g/dl should receive oral
iron supplementation at age 4 weeks
Transfusion:
Volume of Transfusion:
• Give 15 mL/kg of red cell transfusion for non-bleeding neonates irrespective of pre-
transfusion Hb
• Give 20 mL/kg of red cell transfusion in case of massive haemorrhage
Rate of Administration:
• Administer blood at 15 mL/kg over 3-4 hour
• Increase rate in presence of active haemorrhage with shock via peripheral venous or
umbilical venous line
• Routine use of furosemide is not recommended except with chronic lung disease,
with haemodynamically significant PDA, in heart failure with edema or fluid
overload
81
Hazards of Transfusion:
• Infections bacterial/viral
• Hypocalcaemia
• Volume overload
• Citrate toxicity
• Rebound hypoglycaemia (following high glucose levels in additive solutions)
thrombocytopenia after exchange transfusion
Use of Furosemide:
• Routine use not recommended

• Consider soon after blood transfusion for babies:
➢ With chronic lung disease
➢ With haemodynamically significant PDA
➢ In heart failure
➢ With oedema or fluid overload
Documentation and Good Practice:
• Clearly document indication for transfusion and consent in the note

• Ensure blood transfusion volume and rate is prescribed in appropriate infusion chart
• Observations, including:
➢ SpO2
➢ Hourly temperature and BP (recorded before, during and after transfusion)
➢ Document pre- and post-transfusion Hb levels
SOURCE:
1. The National Institute for Health and Care Excellence (NICE)

3. British Committee for Standards in Haematology recommendations
82
NEONATAL HYPOTENSION
Hypovolaemia is an uncommon cause of hypotension in the preterm newborn.
Excessive volume expansion can increase mortality.
Definition:
Thresholds for intervention:
Aim to maintain mean arterial BP (MABP) gestational age in weeks
Aim for even higher MABP in case of persistent pulmonary hypertension of the
newborn
Assessment of BP:
• Measure MABP: by direct intra-arterial BP if possible since Dinamap has limited
accuracy in hypotensive preterm babies; usually overreads BP in the lower ranges
• Identification of hypotension should not be based solely upon BP thresholds, but
must assess other indices of tissue perfusion (e.g. capillary refill time (>3 sec), toe-
core temperature difference (>2°C), urine output (<1 mL/kg/hour), rising lactate
Causes of Hypotension:
• Sepsis
• Extreme prematurity
• Tension pneumothorax
• Blood loss
• Large patent ductus arteriosus (PDA)
• Poor myocardial contractility (e.g. VLBW, hypoxia, cardiomyopathy)
• Polyuria secondary to glucosuria
• Third spacing (NEC/perforation/malrotation/obstruction)
• High positive intrathoracic pressure (high MAP on conventional/HFOV)
• Severe acidosis (pH <7)
• Drugs (morphine, muscle relaxants and anti-hypertensives)
83
Immediate Treatment:
“Aim is to treat cause and improve organ perfusion, not to correct a ‘BP reading”
Transilluminate chest to exclude pneumothorax:
Fluid:
➢ Give if hypovolaemic (not >10 mL/kg) unless there is evidence of fluid/blood
loss/sepsis, Otherwise, start inotropes first
➢ If clinical condition poor, BP very low, or mother has been treated with IV anti-
hypertensive agent, give inotrope after fluid bolus
➢ Use sodium chloride 0.9% 10 mL/kg over 10-15 min except when there is
coagulopathy with bruising: give fresh frozen plasma 10 mL/kg over 30 min or
acute blood loss: give packed cells 10 mL/kg over 30 min
“Reassess clinically within 10 min of bolus”

Inotropes:
• Start dopamine at 5 microgram/kg/min
• Reassess every 15– 20 min
• If still hypotensive, increase dopamine to 10 microgram/kg/min
• If still hypotensive, add dobutamine at 10 microgram/kg/min
• If still hypotensive, increase dobutamine up to 20 microgram/kg/min
• If still hypotensive, increase dopamine up to 20 microgram/kg/min
• Give hydrocortisone 2.5 mg/kg IV (over 3-4 min) followed by 2.5 mg/kg IV 6-8
hourly for 2 3 days as necessary
“Do not use >20 microgram/kg/min of dopamine”

(alpha effect causes vasoconstriction)
• In babies with poor cardiac function, consider starting dobutamine first (also discuss
with cardiologist)
• In term babies requiring inotropes for pulmonary hypertension an infusion of
noradrenaline or adrenaline may be required
• Consider milrinone in PPHN after evaluation of cardiac function
84
Caution:
• Inotropes ideally given via central line
• When peripheral line used during emergency monitor site carefully for extravasation
injury
Continuing Hypotension:
• Echocardiogram where possible to assess myocardial dysfunction/congenital heart
disease
Refractory Hypotension:
• Seek senior advice before starting adrenaline infusion.
• Discuss alternative agents (e.g. noradrenaline, vasopressin)
• If acidotic with severe hypotension, but not hypovolaemic, give adrenaline 100-1000
nanogram/kg/min & if baby requires >1000 nanogram/kg/min, consider other
inotropes but monitor limb perfusion and urine output
Monitoring:
• BP via arterial line

• Check effective delivery of drugs
• Chest X-ray
• Signs of tissue perfusion
• Echocardiogram where possible to assess function and structure
• If already on morphine and muscle relaxant infusion, reduce dosage if possible

• If ventilated, try to reduce mean airway pressure without compromising chest
inflation and oxygenation
• If baby acidotic and not responding to treatment, consider sodium bicarbonate
• Weaning inotropes if hypotension improves
Wean inotropes (dopamine or dobutamine) in 5 microgram/kg/min decrements

and adrenaline in 100 nanogram/kg/min decrements) as tolerated and directed by
senior advice
85
Flowchart: Management of Hypotension
Aim for mean BP gestational age
Fluid bolus (if hypovolaemic) 10 mL/kg

If fluid/blood loss or sepsis consider further bolus
Still hypotensiveafter
10 min
Dopamine 5 microgram/kg/min Increase to 10
microgram/kg/min if stillhypotensive after 15– 20 min Still hypotensive
after 15-20 min
Seek Senior help
Dobutamine 10 microgram/kg/min
Still hypotensive
after 15-20 min
Increase dobutamine by 5 microgram/kg/min every 15-20
minto 20 microgram/kg/min15– 20 min
Still hypotensive
after 15-20 min
Increase dopamine by 5 microgram/kg/minevery 15-20 min
to 20 microgram/kg/min to 20 microgram/kg/min
15– 20 min
Still hypotensive
after 15-20 min
Hydrocortisone 2.5 mg/kg IV followed by
2.5 mg/kg IV 6– 8 hrly
Continuing hypotension
Echocardiogram if possible to assessmyocardial

dysfunction or congenitalheart disease
Refractory
Hypotension
Seek senior advice
Adrenaline 100-1000 nanogram/kg/min
Caution in extremely preterm babies
Consider noradrenaline or vasopressin
86
Neonatal Period by Gestational Age
SOURCE:
1. The National Institute for Health and Care Excellence (NICE)

87
MECHANICAL SUPPORT OF RESPIRATION OF

THE NEWBORN
Standard CPAP:
Equipment:
• Short binasal prongs and/or nasal mask, Circuit, Humidifier (ESSENTIAL: to have
heated humidified gas), CPAP generating device with gas mixing and pressure
monitoring
• All require high gas flow (usual starting rate 8 L/min)
Fixing Nasal CPAP Device:

Short binasal prongs (preferred):
A. To avoid loss of pressure, use largest prongs that fit nostrils comfortably
B. Ensure device is straight and not pressed hard against nasal septum or
lateral walls of nostrils. Excessive pressure can cause tissue damage
Nasal mask has to fit securely over nose

Consider alternating mask with prongs, particularly if baby developing
excoriation or erosion of nasal septum.
Procedure:
Position:
• Prone position is preferable. Avoid excessive flexion, extension or rotation of the
head
• After connecting start at 5–6 cm H2O initially and increase by 1 cm H2O increments.
Optimum pressure depends on illness type and severity – watch baby and use lowest
pressure required to improve work of breathing (Do not exceed 8 cms H2O unless
consultant orders)
Reassess frequently:
• If baby not improving CHECK: Air entry, secretions, close mouth, revise flow and
pressure delivery, decompress stomach with orogastric tube.
• If still deteriorating, consider INTUBATION
Wean:
• Reduce CPAP pressure one by one after FiO2 is weaned <40%. Disconnect at PEEP
4-5 and FIO2 30%
88
Conventional Ventilation:
“The aim of MV is to provide “acceptable” blood gases whilst avoiding lung injury”
Ventilator Parameters:
PIP:
• Use lowest possible PIP to achieve visible chest expansion and adequate gas
exchange on blood gas analysis
• To minimize lung injury from barotrauma and inadvertent over-distension, avoid
excessive PIP.
PEEP:
• Start with a PEEP of 5 cms and increase incrementally up to 8 cm (for babies with
RDS) for improving oxygenation (when PEEP >6 cm is necessary consult first)
Inspiratory Time (Ti):

• Usually between 0.3–0.4 sec
• Avoid Ti >0.5 sec except in term babies with parenchymal lung disease (consult
first)
Rate:
• Rapid rates (≥60/min) are associated with fewer air leaks and less asynchrony in
PRETERM babies compared to slow (20–40/min) rates. Use slower rates in
obstructive illness.
Flow:
• 5–8 L/min is generally sufficient.
• Consider higher flows at faster ventilator rates or shorter inspiratory times (some
ventilators auto regulate flow)
Tidal Volume (Vt):

• Target is 4–6 mL/kg
Setting Up Ventilator:
1. Make sure connections are correct, make sure humidifier is set and water is up
to the mark
2. Adjust ventilator settings depending on chest movement (chest movement has to
be observed but not extensive to avoid over inflation), SpO2, (target and
measured Vt).
89
3. Don’t forget to set trigger if synchronization is needed. Trigger is set to almost

highest trigger sensitivity (just above the lowest setting (1: bar is mostly
unshaded on the dragger machine and set to 0.3 in the preterm <28 weeks on
SLE).
4. Sample blood gas within 30 min of commencing ventilator support.
For babies with normal lungs requiring supportive ventilation such as term
babies with respiratory depression (asphyxia or drugs), babies with neuromuscular
disorders or, in the post-operative period, and preterm babies with recurrent
apnoea use low settings with a minimum rate of 40-50/min.
Oxygen is a drug and should be prescribed as with other medications. This
should be done by specifying intended target range: for preterm babies: 91−95%,
for term babies with PPHN: 96–100%, Target pCO2 > 35 cm H20. If low PCO2
wean ventilation without delay and recheck within 1 hour of low measurement
Modes of Ventilation:
AC, SIPPV, PTV:
• Preferred mode for sick babies.
• Patient triggered: patient decides the rate (make sure the trigger is set to being highly
sensitive (very close to the lowest setting), set a backup rate. All other settings are
set by the operator (PIP, PEEP, Ti and FiO2)
SIMV:
• Is operator set in all parameters but Trigger sensitivity should be set in order to
synchronize set rate with the patient rate.
PSV:
• Patient decides Rate (using trigger) and Ti (set using flow termination criteria which
is set to 5-10% of peak flow).
• Operator sets PIP and PEEP. Back up rate is also set.
• Make sure leak is minimal
Targeted Tidal Volume or Volume Guarantee:

• Pre-set the tidal volume required at 5 ml. or use the previous achieved TV noted
while on SIMV, make sure there is minimal leak around the ETT. Set pressure limit
to 30% higher than the PIP Level that allows adequate chest expansion
90
If baby is deteriorating , Always Re-Evaluate the Baby Before Raising the

Settings:
• Is baby’s chest moving adequately? Is there good bilateral equal air entry? If less
on one side: trans illuminate to exclude pneumothorax
• Check Ventilator and tubing, check tidal volume. Are the measured ventilator values
markedly different to the set ones? • is there a large (>40%) endotracheal tube (ETT)
leak?
• Always exclude airway problems (blocked/displaced ETT) and air leaks in case of
deterioration of blood gases.
Babies Fighting Ventilator (Asynchrony):

• Ensure baby is not hypoxic or under-ventilated
• Exclude blocked ETT
• Look for obvious pain e.g. necrotising enterocolitis
• If possible, change to synchronised form of ventilation (SIPPV/PTV/Assist
Control/SIMV)
• Ensure adequate sedation
91
Weaning:
1. Reduce PIP (usually by 1–2 cm) until MAP 7−8 cm reached.
2. Reduce PEEP to 5 cms.
3. Finally reduce rate to 30/min, usually in decrements of 5–10 breaths/min.
4. Extubating to nasal CPAP if baby <31 weeks or to non-invasive PPV (start
caffeine before weaning).
Ventilation: High Frequency Oscillatory Ventilation (HFOV):
• Decision to initiate HFOV must be made by a consultant.

• Do not start HFOV unless you have the experience.
Indications for HFOV:

• Rescue following failure of conventional ventilation (e.g. PPHN, MAS).
• To reduce barotrauma when conventional ventilator settings are high.
• Air leak (pneumothorax, PIE).
• Can be used as an initial therapy in babies with RDS to maintain lung open, in
experienced hands.
Terminology:
Frequency:
• High frequency ventilation rate (Herz, cycles/sec)
Mean Airway Pressure (cm H2O):
• MAP
Amplitude (Delta P):
• Is the variation around the MAP
Mechanism:
• Oxygenation and CO2 elimination are independent.
• Oxygenation is dependent on MAP (provides constant distending pressure
equivalent to CPAP, inflating the lung to constant and optimal lung volume,
maximizing area for gas exchange and preventing alveolar collapse in the expiratory
phase) and FiO2.
• Ventilation (CO2 removal) dependent on amplitude (The wiggle superimposed
around the MAP achieves alveolar ventilation and CO2 removal) and less
importantly the frequency.
92
Management:
Preparation for HFOV:
• If significant leakage around ETT, insert a larger one.
• Optimize blood pressure and perfusion, complete any necessary volume replacement
and start inotropes, if necessary, before starting HFOV.
• Invasive blood pressure monitoring if possible.
• Correct metabolic acidosis.
• Ensure adequate sedation.
Setting the Machine:

MAP:
• High volume strategy preferred but consider low volume strategy when air leaks
present
• Setting high lung volume strategy (aim to maximize recruitment of alveoli):
➢ If changing from conventional ventilation, set MAP 2–4 cm H2O above MAP
on conventional ventilation
➢ If starting immediately on HFOV, start with MAP 8 cm H2O and increase in
1–2 cm H2O increments until optimal SpO2 achieved
• Setting low volume strategy (aim to minimize lung trauma).
• Set MAP equal to MAP on conventional ventilation.
Frequency:
• Set to 10 Hz.
Amplitude (delta P on SLE ventilator):

• Gradually increase amplitude until chest seen to wiggle well. Wiggle should not be
felt below the umbilicus.
• Obtain early blood gas (within 20 min) and adjust settings as appropriate.
• Change frequency only after discussion with consultant.
Adjusting Settings:
Oxygenation:
• Adjusted by changing MAP by 1-2 cms H2O at a time (both over and under-inflation
can result in hypoxia. If in doubt, perform chest X-ray)
93
Ventilation:
• Adjusted by changing amplitude (increase amplitude in high CO2 and vice versa).
If wiggle on chest is imperceptible: amplitude is too low!
Monitoring:
• Oxygen saturations
• Amplitude: With chest wiggle (has to be observed)
• Frequent blood gas monitoring (every 30–60 min) in early stages of treatment as
PaO2 and PaCO2 can change rapidly (transcutaneous Carbon dioxide monitoring is
preferred if available)
• CO2 diffusion coefficient (DCO2): is a reading on the ventilator screen. It is an
indicator of CO2 elimination which correlates well with PaCO2 for an individual
baby (frequency × (tidal volume)2). Observe its trend (Falling DCO2 : Suggests
rising PaCO2)
• Chest X-ray:
➢ Within 1 hour to determine baseline lung volume on HFOV (aim for 8 ribs at
midclavicular line)
➢ If condition changes acutely and/or daily to assess expansion/ETT position,
repeat chest X-ray
Troubleshooting On HFOV:
Chest Wall Movement:
• Suction indicated for diminished chest wall movement indicating airway or ETT
obstruction (use an in-line suction device to maintain PEEP)
• Increase FiO2 following suctioning procedure
• MAP can be temporarily increased by 2–3 cm H2O until oxygenation improves
Low PaO2
• Suboptimal lung recruitment: increase MAP (consider chest X-ray)
• Over-inflated lung: reduce MAP: does oxygenation improve? Check blood pressure
(consider chest X-ray)
94
ETT Patency:
• Check head position and exclude kinks in tube
• Check for chest movement and breath sounds
• Check there is no water in ETT/T-piece
• Air leak/pneumothorax
• Trans illumination or urgent chest X-ray
High PaCO2
• ETT patency and air leaks (as above)
• Increase amplitude, does chest wall movement increase?
• Increased airway resistance (MAS or BPD) or non-homogenous lung disease, is
HFOV appropriate?
Persisting Acidosis/Hypotension
• Over-distension
• Exclude air leaks; consider chest X-ray
• Reduce MAP: does oxygenation improve?
Spontaneous Breathing:
• Usually not a problem but can indicate suboptimal ventilation (e.g. kinking of ETT,
build-up of secretions) or metabolic acidosis
Weaning:
• Reduce FiO2 to <0.4 before reducing MAP (unless there is over-inflation:
diaphragm below 9th rib: reduce MAP)
• In air leak syndromes (using low volume strategy), reducing MAP takes priority over
weaning the FiO2
• Reduce MAP in 1–2 cm decrements to 8–9 cm 1–2 hourly or as tolerated (If
oxygenation lost during weaning, increase MAP by 3–4 cm and begin weaning again
more gradually).
• Wean the amplitude in small increments (5–15%) depending upon PCO2
• Do not wean frequency
• When MAP <8 cms H2O and amplitude between 20-25 with satisfactory blood
gases, switch to CPAP
• In the presence of a lot of chest secretions, switching to low setting conventional
ventilation for a short period can be done before extubation
SOURCE:
1. Neonatal guidelines 2019-2021 (the Bedside Clinical Guidelines Partnership)
95
CARE FOR THE ELBW INFANT

1. In utero transport, prenatal steroids to mother and delivery in level 3-4 NICU
2. Special Precautions during Resuscitation (page …)
3. Bundles:
A. Prevention of Hypothermia
• Start from delivery room, warm transport incubator, warm humidified NICU
incubator, monitoring temp.
B. Respiratory Support:
• Blender and pulse oximeter in delivery room
1. In the spontaneously breathing infant start nasal CPAP at 6-8 cms water with
30% Oxygen. Monitoring pulse oximetry is essential to keep saturation between
90-95%. If oxygen requirement is increasing, give surfactant using the LISA
technique
2. If baby not breathing spontaneously, start PPV using a T piece resuscitator
(provides regulated PIP and PEEP), low tidal volume (4-5 ml/kg) and rapid rate.
This is followed in the NICU by MV with volume guarantee and adequate PEEP.
Surfactant therapy should be initiated following intubation as early as possible
3. Caffeine therapy initiated early
4. Avoid hypoxia and hyperoxia. Maintain oxygen saturations at 90-95%
C. Intravenous Access:
1. Under complete aseptic conditions, insert a peripheral catheter soon after birth
followed by an umbilical venous catheter within 24 hours
2. By day 7-10 shift to PICC line, if baby still needs long term IV access
3. Minimize punctures
D. Intravenous fluids:
1. Use a humidified incubator
2. If baby is 25-26 weeks give 80-100 ml/kg/day
3. Monitor blood pressure, urine output, daily weight and serum electrolytes
(diuresis and natriuresis usually occur by third day, close monitoring for
dehydration)
4. Start with Dextrose solution, monitor blood sugar and regulate intake (maintain
blood glucose at >45-50 mg/dL). No electrolytes for the first 48 hours unless lab
confirmation is available and adequate urine output.
96
E. Nutrition:
1. Start TPN as early as possible. Initiate protein within day 1 day of life
2. Start trophic feeds with mother own milk early (Day 1-2)
3. Advance feeds regularly as tolerated
4. Provide sufficient calories for growth (target 110-120 kcal/kg/day)
F. Cardiovascular Support:
1. Delay cord clamping in the DR when possible. Maintain blood pressure in
normal range (Table)
2. Careful management of fluid boluses for hypotension (limit to 10-20 ml/kg)
3. Dopamine and/or corticosteroids may be used as indicated
4. Avoid fluid overload to promote closure of the ductus (monitor by D2-3)
5. If PDA is hemodynamically significant start medical closure
G. Infection Control:
1. Scrupulous hand washing
2. Minimize punctures and invasive procedures. Close attention to skin care to
maintain integrity (emollients)
3. Care of the lines and minimize dwell time by promotion of entral feeds
4. Minimize unnecessary suctioning and promote early weaning from MV
H. Transfusions:
1. Avoid by: Delayed cord clamping, microsampling techniques, essential labs
only, strict criteria for transfusion
2. Minimize donor exposure by identifying a specific unit to a patient and splitting
it into small aliquots
REFERENCE:
▪ Manual of Neonatal Care (2021) - Chapter 13. p 172-185
97
TRANSPORT AND RETRIEVAL
Introduction:
The aim of a safe transfer policy is to ensure the highest standard, streamlined
care. In the majority of cases transfer will be performed by a dedicated transfer team,
but in certain cases the referring team may perform the transfer. In all cases the accept
model (Table 1) can be used.
Indications for Transfer:
• Uplift for services not provided at referring unit (including diagnostic and drive-
through transfers)
• Repatriation
• Resources/capacity
Table 1: Accept Model

A ASSESSMENT
C CONTROL
C COMMUNICATION
E EVALUATION
P PREPARATION AND PACKAGING
T TRANSPORTATION
Assessment:
• Key questions are:
➢ What is the problem?
➢ What is being done?
➢ What effect is it having?
➢ What is needed now?
Control:
• Following initial assessment control the situation:
➢ Who is the team leader?
➢ What tasks need to be done (clinical care/equipment and resources)?
➢ Who will do them (allocated by team leader)?
➢ Who will transfer baby (if relevant)?
98
Clinical Care:
Preparation for transport begins at the referring health care facility with the
referring team as soon as decision is made to transfer baby, even if being performed by
another team
Airway/Breathing:
• If baby unstable or on CPAP with FiO2 >0.4, intubate and ventilate
• Adjust ETT and lines depending on chest X-ray position; document all positions and
adjustments and consider if repeat X-ray required; secure all lines and tubes
• If indicated, give surfactant [see Surfactant replacement therapy including less
invasive surfactant administration (LISA) technique guideline]
• If pneumothorax is present, connect chest drains to a flutter valve
• Check appropriate type of ventilator support is available for transfer (e.g. high-
flow/BiPAP/SiPAP/volume guarantee/oscillation may not be provided in transport)
-if not, discuss other options
• If ventilated perform blood gas and adjust ventilation settings as necessary
• If non-invasive ventilation support, have recent (<6 hour) blood gas result available
Circulation:
• If baby is dependent on drug infusions (e.g. inotropes, prostaglandin), 2 reliable
points of venous access must be inserted
• Check whether receiving unit will accept central lines
• If baby is receiving bicarbonate, insulin or inotropes insert double lumen UVC
• Ensure catheters secured with suture and tape
• Check all access is patent and visible
• Optimize blood pressure (see Hypotension guideline)
Drugs:
• Antibiotics [see Infection in first 72 hours of life guideline and Infection (late onset)
guideline]
• Decide whether infusions need to be concentrated
• Check vitamin K IM has been given
• Decide whether sedation is needed for transfer
99
Environment:
• Monitor temperature throughout stabilization – in the extreme preterm baby
chemical gel mattress may be required
• Cooling babies [see Cooling in non-cooling centers (referral and preparation of
babies eligible for active cooling) guideline]
Fluids:
• Ensure all fluids and infusions are in 50 mL syringes and are labelled
• If requested, change PN to maintenance fluids
• Volume as per Intravenous fluid therapy guideline
• Monitor intake and output
Infection:
• Check if any evidence of infection and inform receiving unit
Parents:
• Update with plan of care
• Discuss how parents will get to receiving unit
Communication:
Referring Center:
• Locate NICU/paediatric intensive care unit (PICU)/specialty bed
• For specialty or other PICU bed,
• Call receiving clinician
• All transfers, provide:
➢ Clinical details to transfer team
➢ History and clinical details
➢ Urgency of transfer
➢ Interventions, investigations and results
➢ Medications
• Document advice given/received
• Prepare transfer information/discharge summary and arrange for images to be
reviewed at receiving hospital
Receiving Center:
• Ensure consultant and nurse coordinator accept referral and agree with advice given
100
Evaluation:
• Referring clinician, transfer team and receiving team evaluate urgency of transfer
and decide who will do it
• Neonatal transfers are classified as:
➢ Time critical (e.g. gastroschisis, ventilated tracheoesophageal fistula, intestinal
perforation, duct- dependent cardiac lesion not responding to prostaglandin
infusion and other unstable conditions)
➢ To be performed within 1 hour
➢ To be performed within 24 hours
➢ To be performed after 24 hours
• In the event of transfer team being unable to respond within an appropriate time
period, referring unit may decide to perform transfer themselves in the best interests
of the baby
Preparation and Packaging:

• Three components:
1. Clinical care (see above)
2. Location and checking of equipment
3. Allocation of team
• Transport equipment must not be used for any other purpose
• Team undertaking transfer must be trained in use of all equipment and drugs and be
competent to perform any necessary procedures en-route
• Ensure air and oxygen cylinders are full before departure
• ETT and lines must be secured before transferring baby to transport incubator
• Baby must be secured in transport incubator
Transport:
Before Leaving Referring Unit:
• Change to transport incubator gases (check cylinders are full)
• Check blood gas 10 min after changing to transport ventilator. Make any necessary
changes
• Check lines and tubes are not tangled; check infusions are running
• Record vital signs
• Allow parents to see baby
“Only leave referring unit when team leader is confident that baby is stable for
transfer”
• Contact receiving hospital to confirm cot still available.
101
On Arrival at Ambulance:
• Ensure incubator and equipment are securely fastened/stowed
• Plug in gases and electrical connections
• Ensure temperature in ambulance is suitable
• Check all staff are aware of destination
• Discuss mode of progression to hospital (e.g. category of transfer)
• Ensure all staff are wearing seatbelts before vehicle moves
During Road Transit:

• Record vital signs
• If baby requires clinical intervention, stop ambulance in a safe place before staff
leave their seats
• Make receiving team aware of any major changes in clinical condition
On Arrival at Receiving Hospital:

• Follow the ACCEPT structure
• Handover to receiving team then transfer baby to the unit’s equipment
• Transfer and receiving teams to agree order in which transfer happens
• After transfer, dispose of any partially used drugs and infusions before returning to
ambulance.
N.B: There is an On-Going Plan for a New Protocol for “AVIAN-TRANSPORTATION”
102
ANNEX
103
Hyperglycaemia
• Increase the insulin by increments of 0.05–0.1 units/kg/hour. Target blood glucose

while on insulin is 6–8 mmol/L
• Once blood glucose stable, continue to monitor blood glucose 4-hourly
• When a baby is on insulin it is very important to prevent hypoglycaemia – see below
Preventing Hypoglycaemia
• Recheck blood glucose 1 hour after reducing dose, then 1–2 hourly until stable, then
4-hourly when stable
• If unable to wean off insulin after 1-week, transient neonatal diabetes is possible;
consult paediatric endocrinologist
• Early introduction of PN and early trophic enteral feeding will help reduce incidence
of hyperglycaemia requiring insulin
Administration of Actrapid Insulin (Soluble Insulin):

• Follow instructions in Neonatal Formulary for making up insulin infusion
• Administer Actrapid insulin infusion via a central line or dedicated peripheral
cannula
• Before starting infusion, prime all IV connecting and extension sets and T-
connectors with insulin Infusion fluid. Check manufacturer’s guide on lumen
capacity for priming volumes (insulin can adhere to The plastic of the syringe)
104
Summary of Neonatal Hyperglycaemia Management
105
Hyperkalaemia:
Flowchart: Management of Hyperkalaemia in Neonates
106
Hypernatraemic Dehydration:
107
Management
108
Hypoglycaemia:
Flowchart 1: Management of babies ≥37 weeks at risk of hypoglycaemia
109
Flowchart 2: Pre-feed blood glucose 1.0-1.9 mmol/L and

no abnormal
110
Flowchart 3: Blood glucose <1.0 mmol/L and/or clinical signs consistent with
hypoglycaemia
* If glucose infusion rate >8 mg/kg/min, test for hyperinsulinism
111
Flowchart 4: Management of reluctant feeding in healthy breastfed infants ≥37

weeks
112
Patent Ductus Arteriosus:

• Prostaglandin inhibitor not indicated (≥34 weeks with cardiac failure not controlled
by diuretics)
• Prostaglandin inhibitor ineffective (usually after giving second course). Paracetamol
used as third course If not used before, while considering surgical ligation
• Discuss further cardiac assessment and surgical ligation of PDA with cardiologist at
regional cardiac Center and transport team − follow local care pathway (e.g. West
Midlands PDA Ligation Referral Pathway)
• After surgical ligation, keep baby nil-by-mouth for 24 hour before gradually building
up feeds (because of risk of NEC)
Discharge Policy for Persistent PDA:

• If PDA persistent clinically or echocardiographically at discharge or at 6 weeks
follow-up, arrange further follow-ups in cardiac clinic (locally or at cardiac center
depending on local practice)
• If PDA reviewed locally still persistent at aged 1 yr or if clinically significant during
follow-up (cardiac failure or failure to thrive), refer to paediatric cardiologist at
regional cardiac center to consider closure (first option is usually catheter closure)
Medical Treatment of Persistent PDA <34 weeks’ gestation
113
Hypocalcaemia:
Asymptomatic Infants Symptomatic Hypocalcaemia
• Most infants with early onset • If seizures, prolonged QT interval,

hypocalcaemia recover with apnoea, unstable or poor feeding
nutritional support; so early feeding give IV calcium gluconate 10% 0.11
provides adequate calcium mmol/kg (= 0.5 mL/kg) over 5−10
min followed by maintenance
• Infants requiring IV fluid: add
calcium gluconate 10% 0.46 • Dilute with sodium chloride 0.9% or
mmol/kg/day (= 2 mL/kg/day) to IV glucose 5% 4 mL to each 1 mL
fluid and give as continuous infusion calcium gluconate 10% to give a
concentration of 45 micromol/mL.
• Infant tolerating oral feeds: give Can be given undiluted via central
0.25 mmol/kg oral 6-hourly line in an emergency
• Doses up to 0.46 mmol/kg (= 2

mL/kg calcium gluconate 10%) have
been used
• Maximum rate of administration 22

micromol/kg/hour
SOURCE:
▪ 2019–21 Bedside Clinical Guidelines Partnership (University Hospital of
North Midlands NHS Trust) - Page:155
114
Hyponatraemia:
115
Initiation and Advancing Enteral Feeding:
116
Neonatal Resuscitation Program (Quick Equipment Checklist):
117
Phototherapy and Exchange Transfusion Guidelines for Preterm Infants <

35 Weeks Gestational Age:
Use total bilirubin (add conjugated and unconjugated bilirubin). If conjugated

bilirubin is > 50% of total serum bilirubin, consult staff physician to determine levels for
therapy.
NB: To Convert from (Mmol/L) to (mg / dl) divide the number by 17
118
NB: To Convert from (Mmol/L) to (mg / dl) divide the number by 17
119
Providing and Discontinuing Phototherapy:

• The purpose of phototherapy is to prevent the need for exchange transfusion. With
phototherapy, the serum bilirubin should decrease by approximately 20-35
micromol/litre in 4-6 hours.
• Use gestational age for the first 7 days of age and then postmenstrual age for
determining phototherapy initiation levels. For example, if the infant is born with a
gestational age of 29 2/7 weeks, use the 28 0/7 to 29 6/7 weeks category until the
infant is 7 days of age; then after 7 days of age, use the TSB level for 30 0/7 weeks.
• Discontinuing phototherapy: discontinue phototherapy when the TSB is 20-35
micromol/litre below the initiation level. Check TSB 6-12 hours after discontinuing
phototherapy to assess for rebound.
Rationale for Levels (see reverse for references):

• Treatment thresholds are based on published expert opinion that utilized best
available, but limited data.
• Phototherapy levels in the first 24 hours of age were adapted from National Institute
for Health and Clinical Excellence (NICE) United Kingdom (U.K.) guidelines.
• Phototherapy levels between 24 and 72 hours of age were adapted from a
combination of NICE guidelines and Maisels et al (2012) guidelines.
• Exchange levels before 72 hours of age were adapted from Maisels et al (2012)
guidelines.
• Phototherapy and exchange levels beyond 72 hours of age, (EXCEPT for GA 34
weeks): levels were adapted from Maisels et al (2012) guidelines as these treatment
thresholds are lower than NICE guidelines.
• Phototherapy and exchange levels beyond 72 hours, for gestational age (GA) 34
weeks: levels were adapted to align with AAP/CPS levels for GA ≥35 weeks.
120
REFERENCES:
Phototherapy table adapted from:
1. Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. Journal of
Perinatology (2012) 32, 660–664.
2. National Institute for Health and Clinical Excellence. Neonatal Jaundice. National Institute
for Health and Clinical Excellence, 2010, www.nice.org.uk/CG98
3. Morris BH, Oh W, Tyson JE, Stevenson D, Phelps DL, O’Shea TM et al. Aggressive vs
conservative phototherapy for infants with extremely low birth weight. New Engl J Med 2008;
359: 1885–896.
4. Fetus and Newborn Committee, Canadian Pediatric Society. Guidelines for detection,
management and prevention of hyperbilrubinemia in term and late preterm newborn infants
(35 or more weeks’ gestation). Paediatric Child Health 2007;12 (suppl B):401-7.
5. American Academy of Pediatrics. Subcommittee on hyperbilirubinemia. Clinical practice
guideline: management of hyperbilirubinemia in the newborn infant 35 or more weeks of
gestation. Pediatrics 2004; 114: 297–316.
Exchange transfusion table adapted from:
1. Maisels MJ, Watchko JF, Bhutani VK, Stevenson DK. An approach to the management of
hyperbilirubinemia in the preterm infant less than 35 weeks of gestation. Journal of
Perinatology (2012) 32, 660–664.
2. Fetus and Newborn Committee, Canadian Pediatric Society. Guidelines for detection,
management and prevention of hyperbilrubinemia in term and late preterm newborn infants
(35 or more weeks’ gestation). Paediatric Child Health 2007;12 (suppl B):401-7.
3. American Academy of Pediatrics. Subcommittee on hyperbilirubinemia. Clinical practice
guideline: management of hyperbilirubinemia in the newborn infant 35 or more weeks of
gestation. Pediatrics 2004; 114: 297–316.
121
PPHN:
In newborns >34 weeks' gestation, the maximum

recommended dose of nitric oxide is 20 ppm and this
dose should not be exceeded. Starting as soon as
possible, and in the first 4 to 24 hours of therapy, the
dosage must be reduced gradually to 5 ppm or less,
Nitric Oxide (inhaled)
titrating it to the needs of the individual patient.
Treatment can be continued until the oxygen
desaturation is resolved and the patient is ready for
gradual withdrawal. The required duration varies but
should be as brief as possible, and is typically less
than 4 days
Initially 2 nanograms/kg/minute adjusted according to

response; usual maximum dose 20
Epoprostenol (intravenous) nanograms/kg/minute (rarely up to 40
nanograms/kg/minute) by continuous intravenous
infusion.d
Initially 200 mg/kg (0.8 mmol/kg Mg2+) magnesium

sulfate heptahydrate over 20–30 minutes; if response
Magnesium Sulfate (intravenous) occurs, then 20–75 mg/kg/hour (0.08–0.3
mmol/kg/hour Mg2+) by continuous intravenous
infusion for up to 5 days.d
0.25 to 0.75 micrograms/kg/min by continuous

Milrinone (intravenous)
intravenous infusion for up to 35 hours.g
Initially 250–500 micrograms/kg every 4–8 hours,

adjusted according to response; max. 30 mg daily;
Sildenafil (oral)
start with lower dose and frequency especially if used
with other vasodilators.d
A trial (NCT01720524) is ongoing using intravenous

sildenafil at a loading dose of 0.1 mg/kg over 30
Sildenafil (intravenous) minutes followed by a maintenance dose of 0.03
mg/kg/hour for a minimum of 48 hours and maximum
of 14 days
SOURCE:
▪ Pulmonary hypertension in neonates:
• Sildenafil Evidence summary Published: 29 March 2016
• www.nice.org.uk/guidance/esuom51
122
Management of Persistent Pulmonary Hypertension of the Newborn:
SOURCE:
▪ Sheffield Children’s (NHS) Foundation Trust
• Nair J, Lakshminrusimha S. Update on PPHN: Mechanism and Treatment Semin
Perinat. 2014 March; 38 (2) 78-91
• North Trent Neonatal Network Clinical Guideline Persistent Pulmonary Hpyertension
of the Newborn
• Guy’s Paediatric Formulary Monograph Argipressin (8-Arginine vasopressin) July
2015
123
Practical Approach Persistent Pulmonary Hypertension of the Newborn:
Figure Legend:
• Algorithm showing practical approach to persistent pulmonary hypertension of the
newborn (PPHN) based on oxygenation, systemic blood pressure, and cardiac
function. See text for details.
• ECMO=extracorporeal membrane oxygenation; IV=intravenous; LR=lactated
ringers solution; NO=nitric oxide; OI=oxygenation index; Paw=mean airway
pressure; PEEP=positive end-expiratory pressure; PGE1=prostaglandin E1;
PGI2=prostaglandin I2; PO-OG=per oral or orogastric.
SOURCE:
▪ Copyright © 2022 American Academy of Pediatrics - Satyan Lakshminrusimha.
124
Prophylaxis of Respiratory Syncytial Virus

( RSV )
RSV accounts for approximately 50% of all cases of pneumonia and up to 90%
of the reported cases of bronchiolitis in infancy.
RSV infection frequently progresses to the lower respiratory tract, where it can
cause wheezing, cough, and dyspnea in infants, these symptoms usually appear 1 to 3
days after the onset of rhinorrhea.
High Risk population
• Higher-Risk Populations Include Preterm Infants and Children <2 Years Old With
BPD or HSCHD.
• Hospitalization rates are higher in high-risk groups, including premature infants and
those with underlying cardiac or pulmonary diseases.
Prophylaxis: Palivizumab
Passive prophylaxis with palivizumab decreases the frequency of hospitalization

for RSV in high-risk infants. It is cost-effective only for infants at high risk of
hospitalization.
1-Children born at 35 weeks of gestation or less and less than 6 months of age at the
onset of the RSV season.
2- Children less than 2 years of age and requiring treatment for bronchopulmonary
dysplasia within the last 6 months.
3- Children less than 2 years of age and with hemodynamically significant congenital
heart disease.
NB:
• Palivizumab should be administered up to a maximum of 5 monthly doses (15
mg/kg per dose administered intramuscularly once every 30 days) during the
RSV season to infants who qualify for prophylaxis in the first year of life.
• A child with a history of a severe allergic reaction following a dose of
Palivizumab should not receive additional doses.
• Palivizumab is not approved or recommended for the treatment of RSV disease
• Palivizumab does not interfere with routine childhood immunizations.
125
REFERENCES:
1. Piedimonte G, Perez MK. Pediatr Rev. 2014;35(12):519-530.
2. Wat D. Eur J Intern Med. 2004;15(2):79-88.
3. Domachowske JB, Rosenberg HF. Clin Microbiol Rev. 1999;12(2):298-309.
4. Karron R. Plotkin’s Vaccines. 7th ed. Elsevier; 2018:943-949.
5. Erdoğan S, et al. Turk J Anaesthesiol Reanim. 2019;47(4):348-351. . Piedimonte G, Perez
MK. Pediatr Rev. 2014;35(12):519-530.
6. Wat D. Eur J Intern Med. 2004;15(2):79-88. Domachowske JB, Rosenberg HF. Clin
Microbiol Rev. 1999;12(2):298-309.
7. Respiratory syncytial virus infection (RSV): symptoms and care. Centers for Disease
Control and Prevention. Updated June 26, 2018. Accessed December 21, 2021.
(https://www.cdc.gov/rsv/about/symptoms.html).
8. Piedimonte G, et al. Pediatr Rev. 2014;35(12):519-530.
9. Sommer C, et al. Open Microbiol J. 2011;5(Suppl 2-M4):144-154
10. World Health Organization. Preterm birth. Published February 19, 2018.
(https://www.who.int/news-room/fact-sheets/detail/preterm-birth).
11. Jensen EA, et al. Clinical and Molecular Teratology. 2014;100(3):145-157
12. Rezaee F, et al. Curr Opin Virol. 2017;24:70-78.
126
127
Pediatric Nephrology Protocol of EHA

in
Pediatric Nephrology
for
First Edition
2024
Prepared by
in
Pediatric Nephrology
for
1
Executive Committee
1. Prof.DR. Fatina Fadel: (Head of the Committee) Professor of pediatrics Cairo

university
2. Prof. Dr. Hafez Bazaraa: Professor of pediatrics, Head of PICU, Cairo University.
Pediatrics Armed Forces College of Medicine.
3. Prof Dr. Maher Abd El Hafez: Professor of pediatrics, Faculty of Medicine Tanta
University
4. Prof.DR. Samar Sabry: Professor of pediatrics Faculty of Medicine Cairo
University.
5. Prof.DR. Rasha Esam: Professor of pediatrics Faculty of Medicine Cairo
University.
6. Prof.DR. Doaa Yousef: Professor of pediatrics Faculty of Medicine Elzagazig
University, head of pediatric department of Suez university
7. Dr. Ragia Marei: Assistant professor of pediatrics faculty of Medicine Ain Shams
University
8. Dr. Ahmed Hussein.: Assistant professor of pediatrics faculty of Medicine Ain
Shams university
9. Dr. Sara Abu Elenein: Pediatric Nephrology consultant Health Insurance
Organization , moderator of the committee
2
Disclaimer

under their care.
3

Authority (EHA).
Reviewed By



4
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric Nephrology
is to unify and standardize the delivery of healthcare to any child at all health facilities.
Pediatric Nephrology service is usually offered to children below 16 years of

age in Egypt.
Regarding Pediatric Nephrology, busy clinicians have all felt the need for a

to those delivering care at the bedside in for patients in Pediatric Nephrology.
In Pediatric Nephrology
5
Table of Contents
Page
Title
Number
Preface 5
Nephrotic Syndrome 7
Acute Glomerulonephritis 21
Chronic kidney disease 25
Pediatric Acute Kidney Injury 29
Urinary Tract Infection 41
Urinary Incontinence 45
Hemolytic Uremic Syndrome (HUS) 49
6
Nephrotic Syndrome
Treat-To-Target
✓ Achieve freedom from recurrence
✓ Minimize side effects
✓ improve quality of life
 Definitions:
 Nephrotic-Range Proteinuria: Urinary protein creatinine ratio (UPCR)≥2

mg/mg in a spot urine, or proteinuria ≥1000 mg/m2 per day in a 24-h urine
sample corresponding to 3+or 4+by urine dipstick
 Nephrotic Syndrome: Nephrotic-range proteinuria and either
hypoalbuminemia (serum albumin < 3gm/dl) or edema if serum albumin not
available.
 Complete Remission: UPCR (based on first morning void or 24 h urine
sample) ≤0.2 mg/mg or <100mg/m2/day, respectively, or negative or trace
dipstick on three or more consecutive days.
 Partial Remission: UPCR (based on first morning void or 24 h urine sample)
>0.2 mg/mg but <2mg/mg and serum albumin ≥3.0gm/dl.
 Steroid-Sensitive Nephrotic Syndrome (SSNS): Complete remission within
4 weeks of prednisone (PDN) at standard dose (60 mg/m2 /day or 2
mg/kg/day, maximum 60 mg/day).
 Steroid-Resistant Nephrotic Syndrome (SRNS): Lack of complete remission
within 4 weeks of treatment with PDN at standard dose.
 Relapse: Nephrotic range proteinuria with or without reappearance of edema
in a child who had previously achieved complete remission.
 Infrequently Relapsing Nephrotic Syndrome: <2 relapses in the 6 months
following remission of the initial episode or fewer than 3 relapses in any
subsequent 12-month period.
7
 Frequently Relapsing Nephrotic Syndrome (FRNS): ≥2 relapses in the first

6-months following remission of the initial episode or≥3 relapses in any 12
months.
 Steroid-Dependent Nephrotic Syndrome (SDNS): A patient with SSNS who
experiences 2 consecutive relapses during recommended PDN therapy for
first presentation or relapse or within 14 days of its discontinuation
 Steroids Toxicity:
▪ New or worsening obesity/overweight, sustained hypertension,
hyperglycemia
▪ Behavioral/psychiatric disorders, sleep disruption
▪ Impaired statural growth (height velocity <25th percentile and/or height
<3rd percentile in a child with normal growth before start of steroid
treatment
▪ Cushingoid features, striae rubrae/distensae, glaucoma, ocular cataract,
osteopenia, avascular necrosis
 Sustained Remission: No relapses over 12 months with or without therapy
 Clinical Assessment
• Spot urine analysis is indicated in any patient with edema or eye puffiness.
• Using spot urine samples, preferably a first morning void, or alternatively a
24-h urine sample to assess proteinuria.
 Initial Diagnostic Work Up

Clinical Evaluation
 Relevant Patient History:
✓ Presence of gravity-dependent edema
✓ Fever episodes, pain, abdominal discomfort, fatigue
✓ Search for risk factors for secondary causes (e.g., lymphoma, systemic
lupus erythematosus, medications)
8
 Physical Examination
✓ Blood pressure, assess volume status and extent of edema (ascites,
pericardial and pleural effusions), lymphadenopathy.
✓ Signs of infection (respiratory tract, skin, peritonitis, urinary tract).
✓ Extrarenal features, e.g., dysmorphic features or ambiguous genitalia or
eye abnormalities (microcoria, aniridia), rash, arthritis. Further work-up is
recommended.
 Anthropometry:
✓ Growth chart: height/length, weight, and head circumference (<2 years).
 Vaccination Status:
✓ Check/complete according to national standards.
✓ This is recommended before starting immunosuppressant medications
other than steroids.
 Family History:
✓ Kidney disease in family members
✓ Extrarenal manifestations
✓ Consanguinity
 Biochemistry:
✓ Spot Urine:
o Protein/creatinine ratio (in first morning void) Recommended at least once

before starting treatment of the first episode).
o Urine analysis.
✓ Blood:
o Complete blood count, creatinine, eGFR, urea, electrolytes, albumin

o Complement C3, C4, antinuclear and anti-streptococcal antibodies, and ANCA
in cases suspected to have secondary nephrotic syndrome.
9
 Imaging Kidney ultrasound:

✓ Consider a kidney ultrasound in all children with INS to exclude kidney
malformations and venous thrombosis and in patients with reduced eGFR,
hematuria or abdominal pain and always before kidney biopsy .
 Kidney biopsy:
✓ Patients with atypical features including macroscopic hematuria, low C3

levels, AKI not related to hypovolemia, sustained hypertension, arthritis
and/or rash
✓ Patients with infantile onset NS if genetic screening is not available (age
3–12 months)
✓ Patients>12 years of age on a case-by-case basis
✓ Patients diagnosed with SRNS
 Genetic testing:
✓ Congenital NS (nephrotic syndrome in the first 3months of life),
✓ Syndromic features and/ or family history suggesting
syndromic/hereditary SRNS
✓ Infantile onset NS (age 3-12 months)
✓ SRNS specially if non-response to CNI,
✓ Onset of disease during infancy
✓ Before kidney transplant.
 Indications of referral:
✓ Congenital NS (nephrotic syndrome in the first 3months of life),
✓ Syndromic features and/ or family history suggesting
syndromic/hereditary SRNS
✓ Nephrotic syndrome secondary to systemic illness
✓ Steroid dependent NS
✓ Steroid resistant NS
10
❖ CNS: Congenital Nephrotic Syndrome

❖ DMS: Diffuse Mesangial Sclerosis
❖ MCD: Minimal Change Disease
❖ FSGS: Focal Segmental Glomerulosclerosis
❖ PDN: Prednisone
11
 Therapy for the First Episode

Supportive Care and Management of Complications
 General measures:
✓ Evaluating the volume status of a child in the acute nephrotic state.
✓ Routine fluid restriction is not recommended in SSNS patients, it is only
suggested in case of hyponatremia (<130mEq/L) and/or severe edema in a
hospital setting
✓ Low-salt diet (suggested maximum dose of 2–3 mEq/kg/day) during
relapses with moderate or severe edema, and normal salt intake while in
remission.
✓ Monitoring for hypertension in all children with SSNS and following
current hypertension guidelines in children with confirmed, persistent
hypertension.
✓ It is not recommended to use ACEI (angiotensin converting enzyme
inhibitors) or ARBs (angiotensin receptor blockers) in SSNS to control
edema or high blood pressure in relapse.
Prednisone therapy
• Daily prednisone for 4 weeks at 60 mg/m2 or 2 mg/kg (maximum dose 60
mg/day), followed by alternate day at the same dose.
• A tapering schedule during alternate day dosing: in the first attack rapid
tapering over 1 month is suggested, in subsequent relapses slow tapering is
suggested.
• Prednisone dose is calculated by either weight or body surface area based on
the estimated dry weight.
12
Treatment of complications and indications of IV albumin infusion

 In case of hypovolemia or AKI:
✓ In patients with signs of hypovolemia, withholding diuretics is
recommended due to the risk of thrombosis, hypovolemic shock and AKI,
and discontinue ACEI or ARBs.
✓ Use 20% albumin infusions in patients with signs of hypovolemia
(including oliguria, AKI, prolonged capillary refill time, tachycardia, and
abdominal discomfort) and add furosemide (1–2 mg/ kg given IV) in the
middle and/or at the end of the infusion if volume has been restored and
urine output is insufficient.
✓ In cases of AKI without hypovolemia, general management of AKI
including fluid management, avoidance of nephrotoxic agents and
modification of medication dosage when appropriate .
13
Other measures
 Prevention of thrombosis:
✓ Avoiding immobilization and intravascular volume contraction during

acute nephrotic episodes.
✓ Routine prophylactic anticoagulation or antiplatelet treatment for children
and adolescents in the acute nephrotic stage is NOT recommended.
✓ Considering preventive anticoagulation during relapses in case of
identified increased risks for thromboembolic complications.
 Prevention and treatment of viral and bacterial infections

✓ Antibiotics
o Antibiotic prophylaxis should not be given routinely to children with SSNS.

o Prompt antibiotic treatment in the case of a suspected bacterial infection
o Treating peritonitis with IV antibiotics targeting Streptococcus pneumoniae.
✓ Vaccinations
o Reviewing the child’s vaccination status at disease onset and completing all
inactivated vaccinations following the vaccination schedule that is
recommended for healthy children without delay, especially for encapsulated
bacteria (pneumococcus, meningococcus, haemophilus influenzae).
o Administering inactivated influenza vaccine annually.
o Avoid administrating live vaccinations in patients on high-dose
immunosuppression and in the first 6 months after RTX treatment.
o Vaccinating the household against influenza annually, against COVID-19 and
with live vaccines if live vaccines are contraindicated in the child with SSNS.
✓ Varicella
o In case of exposure to chickenpox in children with immunosuppressive
treatment who have not been immunized against VZV, prophylactic treatment
with specific VZV IVIGs or oral acyclovir or valacyclovir for 5–7 days starting
within 7–10 days of the exposure is recommended.
o VZV infection is treated with intravenous high-dose acyclovir for 7–10 days
o Vaccinating non-immunized patients while in remission and not on high-dose
immunosuppressive medications, as well as vaccinating non-immunized
siblings and parents against.
14
 Preservation of bone health:

✓ Avoiding prolonged steroid exposure as a risk factor for osteopenia by
administering the minimum effective dose, by changing to alternate-day
therapy while in remission after relapses, by limiting the duration, and by
considering steroid-sparing agents in case of emerging toxicity.
✓ Ensuring adequate dietary calcium intake in all children with SSNS and
oral calcium supplementation in those with insufficient calcium intake.
✓ Assessing 25-OH-vitamin D levels annually in patients with SDNS or
FRNS during the remission phase (after three months of remission, if
possible) aiming for levels>20 ng/mL (>50 nmol/L).
✓ In case of vitamin D deficiency, we recommend follow national treatment
guidelines.
 Therapy of Relapses
First line therapy of relapsing SSNS
• SSNS relapse is to be treated with single daily dose of prednisone (2 mg/kg
per day or 60 mg/ m2 per day, maximum 60 mg) until complete remission
(UPCr≤20 mg/mmol (0.2 mg/mg) or negative or trace dipstickon 3 or more
consecutive days) and then decreased to alternate day prednisone with slower
tapering than the first episode.
15
Frequent relapses and steroid dependence

 Algorithm for treatment of SSNS:
16
✓ In patients with FRNS, either the introduction of a steroid-sparing agent as

detailed below or low-dose maintenance PDN given as an alternate-day or
a daily dose.
✓ Introduction of a steroid-sparing agent in children: – who are not controlled
on therapy, or – who suffer a complicated relapse, or – with SDNS
✓ The introduction of one of the following steroid-sparing agents:
levamisole, cyclophosphamide , calcineurin inhibitors (CNIs) and
mycophenolate mofetil (MMF)/ mycophenolic sodium (MPS).
✓ RTX as a steroid-sparing agent is recommended in children with FRNS or
SDNS who are not controlled on therapy after a course of treatment with
at least one other steroid-sparing agent at adequate dose, especially in case
of non-adherence .
✓ Switching to a different steroid-sparing agent is recommended when a
patient is not controlled on therapy with the initial agent.
✓ Tapering and discontinuation of maintenance treatment with prednisone
and immunosuppressives is recommended in all children in sustained
remission for at least 12 months.
17
 Steroid Resistant Nephrotic Syndrome
Definition
Lack of complete remission despite 4 weeks daily therapy with

prednisone.
The guidelines advise that patients with partial remission at 4 weeks be
followed up for an additional 2 weeks, with intensified or similar therapy.
Patients showing complete remission following additional therapy are
labeled as late steroid responder.
“SRNS is an indication for referral to Pediatric Nephrologist”
18
References
1) Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases

Work Group (2021) KDIGO 2021 clinical practice guideline for the
management of glomerular diseases. Kidney Int 100:S1–S276.
2) Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui

NK, Boyer O, Saleem MA, Feltran L, MüllerDeile J, Becker JU, Cano F, Xu
H, Lim YN, Smoyer W, Anochie I, Nakanishi K, Hodson E, Hafner D;
International Pediatric Nephrology Association (2020) IPNA clinical practice
recommendations for the diagnosis and management of children with steroid
resistant nephrotic syndrome. Pediatr Nephrol 35:1529–1561 6.
3) Trautmann A , Boyer O, Hodson E, Bagga A, Gipson DS, Susan Samuel S,

Wetzels J, Alhasan K, Banerjee S, Bhimma R, Bonilla-Felix M, Cano F,
Christian M, Hahn D, Kang HG, Nakanishi K, Safouh H, Trachtman H, Xu
H, Cook W, Vivarelli M, Haffner D; International Pediatric Nephrology
Association. IPNA clinical practice recommendations for the diagnosis and
management of children with steroid-sensitive nephrotic syndrome. Pediatr
Nephrol, 2023 Mar;38(3):877-919.doi: 10.1007/s00467-022-05739-3. Epub
2022 Oct 21.
4) Vasudevan A, Thergaonkar R, Mantan M, Sharma J, Khandelwal P, Hari P,

Sinha A, Bagga A; Expert group of the Indian Society of Pediatric Nephrology
(2021) Consensus guidelines on management of steroid-resistant nephrotic
syndrome. Indian Pediatr 58:650–666.
19
❖ Hematuria: presence of > 5 RBCs/HPF of 10 ml freshly voided centrifuged

urine sediment (microscopic), if the urine by naked eye is red (usually RBCs
> 100/HPF) its gross or macroscopic hematuria.
❖ Proteinuria: presence of protein in urine > 4 mg/m2/h or 1st sample urinary
protein/creatinine ratio > 0.2 mg/mg (200 mg/g).
20
Acute Glomerulonephritis
 Essentials for Diagnosis

• Hematuria (dark brown urine, tea or Cola colored), proteinuria ( significant= 4
– 40 mg/m2/h), oedema, hypertension and oliguria
 Post Streptococcal GN is diagnosed by

1. Evidence of streptococcal infection in throat (1 – 2 weeks ago) or skin( 2-4
weeks ago) by history or high ASOT or throat culture.
2. Low serum level of C3 and normal C4. Normalization of C3 level after 8
weeks.
 History
1. True bright red blood in the urine is more likely a consequence of non
glomerular cause as urolithiasis.
2. Urine color in AGN is uniform throughout the stream.
3. The gross hematuria of AGN is virtually always painless, dysuria

accompanying gross hematuria points to acute hemorrhagic cystitis.
4. A history of recurrent gross hematuria would point to an exacerbation of a

chronic process such as IgA nephropathy and must be referred.
5. The family history for autoimmune disorders, as SLE is essential.
6. A family history of renal failure (asking about dialysis and kidney

transplantation) may be the first clue to a process such as Alport syndrome,
which may initially present with an AGN picture.
 Systemic Review: To Exclude Other Causes of AGN.
1. Particular attention should be paid to rash, joint discomfort, recent weight

change, fatigue, appetite changes, respiratory complaints, and recent
medication exposure.
2. Complicated cases may present with shortness of breath or exercise intolerance

from fluid overload or headaches, visual disturbances, or alteration in mental
status from hypertension.
21
 Workup at Presentation
1. Blood pressure monitoring Q 6h.

2. 24h urine collection for volume and protein content
3. Urine analysis
4. Blood urea and creatinine
5. Serum electrolytes, CBC
6. Serum albumin
7. Body weight and edema monitoring daily
8. ASOT or throat culture
9. C3 and C4 serum levels
10. Renal ultrasound
❖ Notes:
1. The presence of red blood cell casts is diagnostic of GN if present.

2. The combined presence of glomerular hematuria and proteinuria is diagnostic of
GN.
3. AGN is an inflammatory process, so it is common to see white blood cells in
nephritic urine (sterile pyuria). Unfortunately, this occasionally leads to an
inappropriate diagnosis of urinary tract infection.
4. The microscopic hematuria in poststreptococcal AGN may persist for a long
time, even a year.
5. The best indicator of resolution of the disease is the return of the C3 level to
normal. This generally occurs within 6 to 8 weeks.
6. Persistent decrease in C3 by this time merits consultation of pediatric
nephrologist, as this could be an indicator of the initial presentation of a more
chronic process such as MPGN.
22
 Treatment
1) Children with AGN will require immediate referral or consultation of a

pediatric nephrologist in the following situation
o Severe hypertension (more than 5mm above the 99th percentile)
o Significant renal insufficiency
o AGN is accompanied by a nephrotic syndrome ( nephrotic range
proteinuria in a child with nephritis)
2) Beyond these situations AGN can be managed in the primary care setting
o The APSGN is self-limited but requires good monitoring
o For hypertension (blood pressure between the 95th and 99th percentiles):
restrict fluid and salt intake, Antihypertensives ; diuretics ( lasix 1-2 mg/kg
Q 12h orally or slowly IV), Ca channel blockers, ACI and others as
indicated
o Hypertensive emergency ( sublingual nifedipine, IV lasix or nitroprusside,
nitroglycerine or labetolol ) then referral.
o Antibiotics : Penicillin or erythromycin to limit spread of streptococci
although it does not change disease course
23
 Other Causes of Acute Glomerulonephritis

Work up
1. Routine as APSGN
2. ANA, anti ds DNA
3. Anti GBM antibodies
4. Serology for HBV, HCV, HIV and EBV
5. Serum C3 and C4 levels
6. Renal biopsy is indicated in
o Persistent low C3 levels > 8 weeks ( MPGN, C3 GN, Lupus, hepatitis B

or C and immune complex mediated as endocarditis or shunt
nephropathy).
o GN with normocomplementemia ( IgA nephropathy , IgA vasculitis or
ANCA associated vasculitis).
o Rapidly declining renal function = rapidly progressive GN( pauci
immune GN or anti GBM disease, Goodpasture disease).
Recommendations
 Refer to pediatric nephrologist
Treatment
 As per diagnosis protocols
Rapidly Progressive GN
 Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the

kidney that is characterized by a rapid loss of kidney function, (usually
a 50% decline in the glomerular filtration rate (GFR) within 3 months)
with glomerular crescent formation seen in at least 25% of glomeruli
seen on kidney biopsies.
❖ Recommendation
1) Refer to or consult pediatric nephrology unit with dialysis facility.

2) Don't wait renal biopsy results, it's medical emergency.
24
Chronic Kidney Disease
• Renal disease in pediatric population may be asymptomatic and detected

accidentally during a routine physical examination.
• Unexplained symptoms like fever, pains, unexplained anemia, gastrointestinal
symptoms, abdominal mass, edema, hypertension, and metabolic acidosis maybe
early signs of renal disease.
• Chronic kidney disease (CKD) may present by anorexia, lassitude, anemia, growth
failure and/or hypertension.
• CKD nomenclature as defined by KDIGO
• CKD is defined as abnormalities of kidney structure or function, present for >
3 months, with implications for health. CKD is classified based on Cause, GFR
category (G1-G5), and Albuminuria category (A1-A3), abbreviated as CGA.
 Green, low risk (if no other marker of kidney disease, no CKD);

 Yellow, moderately increased risk;
 Orange, high risk;
 Red, very high risk.
 GFR; glomerular filtration rate
25
 High risk populations at risk for CKD
i. Prematurity and being small for gestational age.

ii. Congenital abnormalities of the kidney and urinary tract.
iii. H/o poor growth or failure to thrive.
iv. Family history of kidney diseases and relatives on dialysis or transplant.
v. Electrolyte or acid-base abnormalities.
vi. Body mass index (BMI) > 95th percentile.
vii. Blood pressure greater than the 95% recorded on multiple visits.
viii. Polyuria or inappropriately dilute urine.
ix. Gross hematuria.
x. Dysfunctional voiding, urinary incontinence, or prolonged enuresis.
xi. H/o recurrent UTI.
 Work-Up
• Initial testing in a child with suspected chronic kidney disease (CKD) must
include an examination of the urine and estimation of the glomerular filtration
rate (GFR).
• Plasma creatinine, arterial blood gases, complete blood picture.
• Imaging studies such as ultrasonography and radionuclide studies help in
confirming the diagnosis of chronic kidney disease and may also provide clues
to its etiology.
• Bone age can help differentiate AKI from CKD
• Blood pressure measurement
• Echocardiography
 Refer children and adolescents to specialist kidney care services in the

following circumstances
• An ACR of 30 mg/g [3 mg/mmol] OR a PCR of 200 mg/g [20mg/mmol] or

more, confirmed on a repeat first morning void sample, when well and not
during menstruation,
• Persistent hematuria,
• Any sustained decrease in egfr,
• Hypertension,
• Kidney outflow obstruction or anomalies of the kidney and urinary tract,
• Known or suspected CKD,
• Recurrent urinary tract infection.
26
 Precautions when dealing with CKD patients
Vascular access
• Vein preservation is of particular importance for future AVF creation.

• Upon diagnosis of CKD in a child, patients and families should be educated
on the importance of protecting veins, especially in the non-predominant
arm.
• Venipunctures for blood samples and intravenous lines should be performed
at distal sites of the dominant arm whenever possible.
Medication Prescription
• Some medications (eg, nonsteroidal anti-inflammatory drugs [NSAIDs])

and radiocontrast agents are contraindicated in children with chronic kidney
disease (CKD) because of the risk of deterioration of kidney function.
• Dose modification is required for a wide variety of drugs belonging to
different categories.
 Anemia in CKD
Diagnosis and evaluation of anemia in CKD

• Diagnose anemia in children with CKD if Hb concentration is <11.0g/dl in
children 0.5–5years, <11.5 g/dl in children 5–12 years, and <12.0 g/dl in
children 12–15 years.
Investigations of anemia
• In patients with CKD and anemia (regardless of age and CKD stage), include
the following tests in initial evaluation of the anemia:
✓ Complete blood count (CBC), which should include Hb

concentration, red cell indices, white blood cell count and
differential, and platelet count
✓ Absolute reticulocyte count
✓ Serum ferritin level
✓ Serum transferrin saturation (TSAT)
✓ Serum vitamin B12 and folate levels
27
 CKD-Mineral Bone Disorder (CKD-MBD)
Diagnosis of CKD-MBD: biochemical abnormalities
1. We recommend monitoring serum levels of calcium, phosphate, PTH, and

alkaline phosphatase activity in children beginning in CKD G2.
2. In patients with CKD G3a–G5D, it is reasonable to base the frequency of
monitoring serum calcium, phosphate, and PTH on the presence and
magnitude of abnormalities, and the rate of progression of CKD.
Reference
1) Guidelines based on kdigo 2023 clinical practice guideline for the evaluation
and management of chronic kidney disease, public review draft july 2023.
28
Pediatric Acute Kidney Injury
 Scope
• Designed for individuals up to 18 years of age. Many concepts are similar in

adolescents
• Applicable to the broader spectrum of acute kidney injury (AKI). AKI can
occur due to acute renal disorders, in patients with chronic kidney disease
(CKD) as well as in various acute care settings.
• While those with known kidney disease will often have been under the care
of a pediatric nephrologist, many patients with AKI will not. Early
involvement of nephrologists is desirable, and will be essential in some
cases:
✓ When Managing Intrinsic Kidney Disease
✓ In Those with CKD And Transplant Recipients
✓ When Dialysis Is Needed?
• Because AKI is frequent in critically ill patients, management of AKI could

constitute part of the system support integral to critical care. Higher level
intensive care units should generally be capable of providing acute dialysis.
Qualified personnel and equipment are needed and logistic plans should be
present to address cases of AKI.
• The specific treatment of intrinsic renal and urological diseases causing AKI
is not included in this protocol, neither are the details of dialysis modalities.
 Disclaimer
• Protocols and guidelines outline the recommended or suggested clinical

practice; however, they cannot replace sound clinical judgment by
appropriately trained and licensed physicians.
• The physician is ultimately responsible for management of individual
patients under their care.
29
AKI is defined by acute increase in serum creatinine &/or oliguria-anuria

 A recent increase in creatinine of >1.5x or 0.3mg/dL
 From a previous baseline; or
 Above the upper limit of the reference interval for age
 Usually associated with a fall in urine output <0.5ml/kg/hr for at least 8 hours
Oliguria is not essential for diagnosis of AKI

 The cut-off for oliguria may be higher (up to 1mL/Kg/h) in infants.
 Inappropriate polyuria is also an abnormal urine output and may be
associated with tubular injury or tubulointerstitial nephritis.
Acute reduction in GFR is essential to diagnose AKI

 GFR = glomerular filtration rate.
 Despite that creatinine rise could take some time after GFR loss, diagnosis and
staging of AKI based on GFR or estimated GFR is NOT recommended.
 This is due to difficulties in measurement and inaccuracy of formula-based
estimates with acute changes in creatinine
 Stages of AKI (KDIGO)
Stage Serum Creatinine Urine Output

SCr ≥ 26.5µmol/l
1 ( ≥ o.3 mg/dl ) <0.5ml/kg/h (>6h)
Or SCr ≥ 1.5-2x
2 SCr >2-3x <0.5ml/kg/h (>12h)
SCr > 3x
Or SCr to ≥ 353.6 µmol/l
<0.3ml/kg/h (24h)
3 (≥4 mg/dl)
Or anuria (12h)
Or initiation of renal
replacement therapy
30
 Reference values for serum creatinine according to age
Reference Range AKI Cut-Off*

Age Group
μmol/L mg/dL mg/dL
Preterm Neonates 29-87 0.33-0.99 1.50
Full Term Neonates 27-77 0.31-0.87 1.30
Infants 14-34 0.16-0.39 0.60
1- <3 yrs 15-31 0.17-0.35 0.53
3- <5 yrs 23-37 0.26-0.42 0.63
5- <7 yrs 28-52 0.32-0.59 0.90
7- <9 yrs 35-53 0.40-0.60 0.90
9- <11 yrs 34-65 0.39-0.74 1.10
11- <13 yrs 46-70 0.52-0.80 1.20 (1.10)
13- <15 yrs 50-77 0.57-0.87 1.30 (1.17)
15y +; female 44-80 0.50-0.91 1.37 (1.20)
15y +; male 62-106 0.70-1.20 1.80 (1.50)
❖ 1.5x upper limit for age. Values between parentheses are based on 0.3mg/dL rise
❖ Serial Measurements of serum creatinine may be more important than single values,
particularly when these values are close to the upper limit/ cut-off value
❖ Neonatal values refer to those at birth. Normally, a decline occurs over a few days
reaching values similar to those of infants
 High Risk Patients

Vast Venom
 Vasoactive Medications*
 Sepsis
 Thrombocytopenia
 Ventilation/Volume Depletion
 Nephrotoxic Medications
 O2 Low (Hypoxia)
 Multiorgan Failure
➢ Monitor urine output and serum creatinine in these cases, who are at
an increased risk for AKI
“It is the pathological process requiring vasopressors that causes the risk and
withholding necessary vasopressor support could increase the risk further”
31
 Etiology of AKI
❖ Prolonged hypovolemia (pre-renal) may lead to ATN (intrinsic renal)
32
 Initial Assessment
Etiology
 History of renal disease or transplantation
 History or signs of dehydration
 History of polyuria or other losses particularly with limited access to
fluids
 Shock, low cardiac output, sepsis or tissue hypoxia
 Recent viral illness, sore throat or skin infection
 Urinary tract, cardiac, liver or systemic autoimmune disease
 Drug exposure
 Malignancy, chemotherapy
 Trauma, myoglobinuria or hemolysis
 Change in urine amount or color (esp. brown, smoky or tea-colored
urine)
 Dysuria, suprapubic or loin pain
Manifestations
 Fluid assessment: oedema, dehydration, urine output, fluid intake and
recent weight changes (eg since admission)
 BP, pulse, perfusion, pallor, cardiac exam and signs of HF
 RR and chest exam (metabolic acidosis, pulmonary congestion or
oedema, effusion)
 Neurological exam (uremic or hypertensive encephalopathy,
electrolyte disturbances or associated stroke)
Investigations
 All Cases
✓ Urea, creatinine, blood gases, Na, K, Ca, P, ALP/ PTH, albumin in
oedematous patients
✓ CBC
✓ Urinalysis, and culture if pyuria or clinically suspected infection
✓ Abdominal ultrasound : Urgent to rule out obstruction, size, echogenicity
and differentiation
33
 Stage II-III
✓ Chest X-ray/ Echocardiography/ bedside functional US:
o Cardiac size & contractility, effusions, fluid status at IVC and lungs
✓ Other tests for etiology
o Glomerulonephritis: complement C3, C4, ANA, ANCA, AntiGBM,
ASOT
o Hemolysis/ TMA: Reticulocytic count, T & D bilirubin, LDH, Coomb’s
and fragmented RBCs in blood film
o Vascular causes: Renal Duplex
❖ N.B. children with undiagnosed CKD, even ESKD, may present with
apparently AKI due to:
o An acute insult on top (eg infection, drug) ; or
o Neglected ckd presenting with complications
 Differentiation depends on
✓ Past history suggestive of CKD (anorexia, bony pains, growth failure,
anemia, oedema, urinary abnormalities as hematuria, recurrent UTI,
polyuria or secondary enuresis)
✓ Family history of genetic renal disease or renal failure
✓ Clinical signs of growth failure, bone deformities, unexplained pallor or
earthy look
✓ Small echogenic kidneys with impaired/ absent corticomedullary
differentiation by ultrasound
 Indications for referral to/ management by pediatric nephrologist

Immediate consultation/ referral
 K> 6.5 mmol/L
 Na< 125 mmol/L with anuria or oliguria
 Persistent or worsening metabolic acidosis
 Pulmonary oedema or hypertension not responding to diuretics
 Urea >240 mg/dL (40mmol/L) not responsive to fluid challenge
Any AKI
 In patient with CKD or renal transplant
 Suspected intrinsic renal disease (e.g. nephritis / HUS)
AKI stage 2 or 3 or AKD
34
35
 Conservative Management of AKI

1) Establish and maintain appropriate renal perfusion (BP, CO & tissue
perfusion) and oxygenation.
“Do Not Keep Any Patient Hypovolemic and Do Not Withhold Necessary
Vasopressors!! Hypoxia And Anemia Should Be Corrected”
2) Urinary tract obstruction needs to be ruled out quickly

• Patients with suspected retention or UT obstruction and those in whom accurate
monitoring of urine output is not otherwise possible should be catheterized
3) Manage fluid balance
4) Monitor electrolytes and manage disturbances

• Significant metabolic acidosis is corrected with NaHCO3. Maintenance bicarbonate
(starting at 2 mEq/Kg/day divided q6h) may be needed. Concerns: volume, Na content,
will lower Ca & K
• Dilutional hyponatremia is managed by fluid restriction; only severe symptomatic or
resistant cases need hypertonic saline if bicarbonate correction will not be given (contains
more Na than hypertonic saline!)
• Maintenance K is avoided in anuric or oliguric patients but cautious correction of
hypokalemia can and should be done
• Moderate & severe hyperkalemia warrant emergency medical treatment; which should be
initiated even when dialysis is being arranged
• Severe or symptomatic hypocalcemia should be corrected with IV calcium
• Phosphate binders may be necessary
5) Medications
• Control of BP with antihypertensives may be needed. Age-appropriate references should
be used. Excessive (<50th centile) or too rapid reduction of BP should be avoided. The
use of ACE inhibitors may exaggerate renal ischemia and hyperkalemia
• Control of convulsions if present
• Avoid nephrotoxic agents (unless critically needed), use less toxic alternatives (when
possible) and adjust doses of renally-excreted medications
• Others as indicated
6) AKI is not a contraindication for feeding

• Adequate caloric intake, age-appropriate protein intake should be targeted.
• Sodium restriction in hypertensive, oliguric or oedematous patients.
• Potassium and phosphorous restriction unless/ until losses are present.
7) Identify & manage conditions with specific treatment eg aHUS, RPGN, etc
36
 Fluid Management During AKI

Assessment of Fluid Status
 Oedema
 Systemic and pulmonary congestion: jugular venous pressure, new/ tender
hepatomegaly, chest crepitations, bedside U/S (lung, IVC and heart)
 Signs of dehydration
 Weight changes and previous fluid balance if available
 BP: Hypotension (late) and hypoperfusion can denote hypovolemia,
hypertension can be a sign of overload (poor sensitivity and not specific)
Initial volume administration (avoided in presence of intravascular fluid
overload):
 Correct shock if present (refer to shock guideline)
 In euvolemic patients, a 10mL/ Kg challenge with normal saline may be
given over 30-60 min
Furosemide (avoided in dehydration and UT obstruction):
 In case of fluid overload (from the start)
 In case of euvolemia with persistent anuria/ severe oliguria not responsive
to fluid challenge (expect response in 2h)
✓ 3-6 mg/ Kg (max 250 mg)
✓ May be repeated q6-12h or followed by continuous infusion (0.5-1mg/Kg/hr)
to maintain response, but NOT in initial non-responders. Max total dose 1 g in
24h
✓ On-going treatment with furosemide needs to be followed by a senior clinician
“The use of Dopamine or mannitol to induce diuresis is not recommended and
may be harmful”
Subsequent fluid management
 Maintenance requirements should be based on
✓ Insensible loss 400mL/m2/24h; more in fever and spontaneous
hyperventilation, less on MV/ humidified oxygen
✓ Actual urine output (based on last known output; per hr or last 24h, may be zero
in anuric patients, update based on monitored urine output)
✓ Any abnormal losses eg diarrhea, vomiting, drains
“These requirements should be revised frequently based on measured urine output,
other losses and state of hydration. Type of fluids should depend on Na and
glucose required”
Patients with intravascular or extravascular fluid overload ➔ A NEGATIVE balance is necessary
Give 50-70% of required maintenance, restrict further to essential requirements (eg
medications, to avoid hypoglycemia, essential transfusions) during treatment of pulmonary
oedema
Patients with normovolemia ➔ A ZERO balance is necessary. Intake = maintenance
Patients with dehydration ➔ Deficit amount should be ADDED until euvolemia is achieved
Recovery may be associated with diuresis and electrolyte losses
that must be replaced with adequate fluids, Na & K taking in consideration oral/ enteral intake
37
 Ongoing Management “Monitor, Maintain, Minimize”

1) Monitor
 Initial weight and height on a growth chart
 At least daily weight, at the same time of the day
 Strict and accurate input / output and hydration status. At least 4-hourly in
those with dehydration, intravascular overload, critical or rapidly changing
status. At least daily in all others
 Blood pressure, initially at least 4-hourly
❖ Investigations:
o Electrolytes and serum bicarbonate. Initially at least daily, more frequently when
following or correcting abnormalities
o Urea and creatinine. Initially daily
o Others as needed
2) Maintain
 Ensure adequate circulatory volume – address hypoperfusion urgently with
fluid boluses (10 ml/kg) and inotropic support once volume is restored.
3) Minimize
 Further harm should be reduced by stopping nephrotoxic drugs when
possible, dose adjustments and avoiding intravenous contrast.
 Indications of Dialysis
1) AKI
 Fluid overload:
✓ Hypervolemia, pulmonary edema
✓ Refractory extravascular overload >10%
✓ Potential overload: persistent oliguria with +ve balance if not tolerated eg
cardiac condition or obligatory fluid needs such as transfusions, nutritional
support, etc
 Severe/ refractory electrolyte imbalance
✓ (Mainly hyperkalemia, sometimes extreme hyperphosphatemia, rarely others)
 Metabolic acidosis when correction with bicarbonate is ineffective or not
possible
 Clinically significant uremia (eg with bleeding, encephalopathy, etc)
 There is no absolute cut-off value for urea or creatinine. However, high or
rapidly increasing values should be considered in view of the overall
patient’s condition
2) CKD
 Acute indication (as AKI) in a patient with CKD (on conservative treatment
or just diagnosed)
 ESKD
38
 Acute Dialysis Options

Choice is guided by:
 Patient characteristics (disease/symptoms, hemodynamic stability)
 Goals of therapy (fluid removal, electrolyte correction)
 Availability, expertise, and cost
Peritoneal dialysis (PD)

 Fluid removal follows an osmotic gradient, therefore more dependent on concentration
of dialysis solution. A short dwell time increases fluid removal.
 Clearance achieved by PD depends on volume of dialysis fluid, size of molecule, dwell
time and number of exchanges
 Simple, inexpensive, not equipment-dependent, possible in hemodynamically unstable
patients. The easiest to achieve competency
 Contraindications: defect in peritoneal membrane, abdominal problems
 Treatment is slow and moderately predictable
Intermittent hemodialysis
 Extracorporeal exchange of fluid and solute that occurs across an artificial
semipermeable membrane between blood and dialysis fluid moving in opposite directions
 Children have to be hemodynamically stable and be able to tolerate interval between
dialysis runs. Not suitable for small infants (except with special circuits)
 Predictable fluid removal that can be rapid if needed
 Most rapid solute clearance
 Precautions are needed to avoid disequilibrium with rapid urea clearance in severely
uremic patients
 Vascular access & anticoagulation needed (but sessions can be done with high flow,
repeated saline flush & no anticoagulation)
 Moderate needs in terms of equipment, cost & required expertise. But a HD machine &
water treatment unit is needed in the ICU or the patient should be fit for transport to the
hospital HD unit
Continuous Renal Replacement Therapy (CRRT)

 Extracorporeal therapy using a special machine that’s transportable and not dependent
on HD or water treatment unit
 Treatment is well controlled, continuous and slow (most physiological). Rapid fluid
removal is still possible if needed
 Better tolerated than HD and not dependent on abdominal cavity
 Different treatments are possible in various combinations (dialysis, hemofiltration with
replacement or a combination)
 Vascular access & anticoagulation needed
 High cost, human resource intensive and needs expertise
Prolonged intermittent renal replacement therapy (sustained low efficiency

dialysis)- PIRRT or SLED
 Prolonged daily (6-23hrs), but not continuous, extracorporeal therapy using a HD
machine and circuit
 Treatment is applied slowly to approximate CRRT at a lower cost and using existing HD
machines when there is a HD unit and trained HD staff
39
References
Primarily Adapted From:
1) Brighton and Sussex University Hospitals Paediatric Clinical Practice

Guideline; AKI. Lazner M. (ed). Revised 2023.
2) Cairo University pediatric PreICU guide version 5, 2021.
3) Egyptian Healthcare Authority PICU protocols. Ibrahim H. (ed) 2022.
4) ESPNT protocols and Guidelines in Pediatric Nephrology. Sawires H. (ed)
2019.
Other Sources:
1) Andreoli SP. Acute kidney injury in children. Pediatr Nephrol.

2009;24(2):253-63.
2) Ciccia E, Devarajan P. Pediatric acute kidney injury: prevalence, impact and
management challenges. Int J Nephrol Renovasc Dis. 2017;10:77-84.
3) Doi K, Nishida O, Shigematsu T, Sadahiro T, Itami N, Iseki K, et al. The
Japanese Clinical Practice Guideline for acute kidney injury 2016. J Intensive
Care. 2018;6:48.
4) James M, Bouchard J, Ho J, Klarenbach S, LaFrance JP, Rigatto C, et al.
Canadian Society of Nephrology commentary on the 2012 KDIGO clinical
practice guideline for acute kidney injury. Am J Kidney Dis. 2013;61(5):673-
85.
5) McCaffrey J, Dhakal AK, Milford DV, Webb NJ, Lennon R. Recent
developments in the detection and management of acute kidney injury. Arch
Dis Child. 2017;102(1):91-6.
6) Palevsky PM, Liu KD, Brophy PD, Chawla LS, Parikh CR, Thakar CV, et al.
KDOQI US commentary on the 2012 KDIGO clinical practice guideline for
acute kidney injury. Am J Kidney Dis. 2013;61(5):649-72.
7) Sutherland SM, Kwiatkowski DM. Acute Kidney Injury in Children. Adv
Chronic Kidney Dis. 2017;24(6):380-7.
8) https://www.grepmed.com/images/3937/differential-nephrology-postrenal-
diagnosis-prerenal-failure-kidney
9) https://www.thinkkidneys.nhs.uk/aki/wp-
content/uploads/sites/2/2016/05/Guidance_for_paediatric_patients_Final.pdf
10) https://www.nuh.nhs.uk/download.cfm?doc=docm93jijm4n840
40
Urinary Tract Infection in Pediatrics

for Pediatricians
• Urinary tract infection is a common health problem in children and presentation can
vary in different age groups within Pediatric and Adolescent cohort.
• Identifying this type of infection (not confusing UTI with other infections) can
prevent faulty treatment and point out at risk group.
 Definition of UTI: Prescence of symptoms* +

 Urine CFU >50.000/ml if catheterized or mid-stream clean-void in circumcised boy
 Urine CFU >100.000/ml if uncircumcised boy or mid-stream clean-void in girls.
 Supra-pubic sample with growth of any organism except 2000-3000 CFU/ml
Symptoms
Age Groups Most Common Least Common
Fever Abdominal pain

Poor feeding
Vomiting Jaundice
Infants< 3 mo Failure to thrive
Lethargy Offensive urine
(FTT)
irritability Hematuria
Abdominal pain Lethargy

Pre-Verbal Fever Vomiting Irritability
Poor feeding FTT
Infants and
Children >3 mo Fever
Voiding
Frequency vomiting
Verbal dysfunction
Dysuria Malaise
Abdominal pain
Cloudy urine
41
 How to approach a case of UTI
42
 Reliable methods of Urinary collection

 Clean-catch sample is an easy and quick method of urinary collection (quick wee
in infants)
 Catheterization is a more accurate but invasive method
 Sonar guided supra-pubic aspirate is the method of choice (most accurate but also
most invasive).
 Urine bag collection is only good for screening but not for urine culture and
sensitivity (can’t document a UTI).
❖ N.B.
o Whatever the accepted method for urinary collection, stick to the
colony count accepted for each method.
 Important Notes
I. Differences between Upper and lower UTI
Upper UTI (Pyelonephritis) Lower UTI

(Cystitis)
Fever, rigors, vomiting and loin Dysuria, urgency, frequency,
Symptoms
pain. incontinence and enuresis
 WBCs elevated  Normal WBCs

 CRP positive  CRP negative
Investigations
 Poor urine concentrating ability  Good urine concentrating ability
 DMSA study confirms upper UTI  DMSA study is non revealing
II. Empiric management of UTI (prior to culture)

 Early initiation of antimicrobial therapy is particularly important if:
✓ Fever (especially >39°C or >48 hours)
✓ Ill appearance
✓ Costovertebral angle tenderness
✓ Known immune deficiency
✓ Known urologic abnormality
43
Antibiotic Dose Frequency Route

Cefpodoxime 5 mg/kg/dose Q12h Oral
Cefixime 8 mg/kg/d§ Q12h (or single) Oral
Cefdinir 14 mg/kg/d Q12h Oral
TMP-SMX 8mg (TMP)/kg/d Q12h Oral
Nitrofurantoin 5-7 mg/kg/d Q 6-8h Oral
Amoxicillin 25-50 mg/kg/d Q8h Oral
Amox. + clav. 25-50 mg/kg/d Q8-12h Oral
III. When to refer to a pediatric Nephrologist
A. High Risk Group
1. Known Patient With:

o Structural abnormalities
o Stones
2. VUR
3. Abnormal Voiding pattern.
4. Abdominal mass.
5. Previous UTI.
B. Recurrent UTI
➢ Two or more episodes of UTI documented on proper urine culture.
C. Atypical UTI
➢ Seriously ill child or infant / septicemia.

➢ Abnormal voiding pattern.
➢ Impaired kidney function tests.
➢ Mechanical/ functional obstruction of urinary tract.
➢ Failure to respond to treatment with suitable antibiotics within 48
hours.
➢ Infection with non E-coli organisms.
44
Urinary Incontinence
 Monosymptomatic nocturnal enuresis (NE): is also known as bedwetting.

There is a gender difference in the incidence: two boys to one girl at any
age.
Enuresis: Intermittent incontinence while asleep in a child >5 years of age
Monosymptomatic enuresis: Enuresis with no other lower urinary tract
symptoms
Non-monosymptomatic enuresis: Enuresis with other, mainly daytime, lower
urinary tract symptoms or bowel dysfunction.
• Nocturnal enuresis is considered primary when a child has not yet had a prolonged
period of being dry (six months).
• The term “secondary NE” is used when a child or adult begins wetting again after
having stayed dry.
❖ The Pathophysiology of enuresis is complex, involving the central nervous system

(several neurotransmitters and receptors), circadian rhythm (sleep and diuresis), and
bladder function derangements.
 Causes:
 Congenital anatomical abnormalities such as ectopic ureter, or
bladder exstrophy.
 Neurologic abnormalities as myelomeningocele (MMC).
 Functional bladder problems.
 Deep poor sleepers due to high arousal thresholds and frequently
disturbed sleep: the child does not wake up when the bladder is full.
 Management
Diagnostic evaluation
The diagnosis is mainly obtained by:
 History-taking.
✓ Focused questions to differentiate; monosymptomatic vs. non-
monosymptomatic.
✓ Primary Vs. Secondary.
✓ Comorbid Factors Such as Behavioral Or Psychological Problems and Sleep
Disorder Breathing.
45
❖ In addition, a two-day complete micturition and drinking diary, this records day-
time bladder function and drinking habits.
 Physical examination should be performed with special attention to:

✓ The Back Of The Child (To Exclude Any Neurological Problem)
✓ The external genitalia and surrounding skin, as well as to the condition of the
clothes (wet underwear or encopresis).
✓ Urine analysis is indicated if there is a sudden onset of bedwetting, a suspicion
or history of UTIs, or inexplicable polydipsia.
 The Treatment
 A multimodal approach, involving strategies such as
✓ Management of underlying and potentially complicating conditions such
as constipation and UTIs.
✓ Supportive treatment measures Initially:
➢ Normal and regular eating and drinking habits should be reviewed.
➢ Stressing normal fluid intake during the day and reducing fluid intake in
the hours before sleep.
✓ Medical management
➢ Desmopressin either as tablets (200-400 μg), or as sublingual
Desmopressin oral lyophilisate (120-240 μg).
➢ A nasal spray is no longer recommended due to the increased risk of
overdose.
➢ Medication should be taken 1 h before the last void before bedtime to
allow timely enhanced concentration of urine to occur.
➢ Fluid intake should be reduced from 1 h before desmopressin
administration.
➢ Desmopressin is only effective on the night of administration; therefore, it
must be taken on a daily basis.
➢ If patients are dry on treatment after this initial period, breaks are
recommended to ascertain whether the problem has resolved and therapy
is no longer necessary.
➢ If the child does not achieve complete dryness, or if wetting resumes once
treatment is withdrawn, it should be resumed.
➢ If a second voiding diary indicates nocturnal urinary production is not
reduced, consider a dose increase (if maximum recommended dose has not
been reached); otherwise, refer the child to a specialist.
46
✓ Behavioral modification, is a term which covers all non-pharmacological

and non-surgical treatment modalities.
➢ Standardization of fluid intake
➢ Bowel management; timed voiding and basic relaxed voiding education.
➢ Referral for psychological support should be advised and followed-up for
patients with NE and their families, especially if the NE comorbid factor
is developmental, attention or learning difficulties, family problems,
parental distress and possible punishment of the child are observed.
✓ Wetting alarm treatment; the nocturnal alarm treatment relies on the use
of a device that is activated by getting wet.
➢ The goal of this therapeutic approach is that the child wakes up by the
alarm, which can be acoustic or tactile, either by itself or with the help of
a caregiver.
➢ Their method of action is to repeat the awakening and therefore change
the high arousal to a low arousal threshold, specifically when a status of
full bladder is reached.
➢ The recommended length of therapy with the alarm treatment continues to
be uncertain, varying from 8-12 weeks to 16-20 weeks.
47
48
Hemolytic Uremic Syndrome

(HUS)
49
50
First Line
Anti C5
Anti C5 or plasma exchange + Anti C5 (Eculizumab &

Steroid ± Immunosuppressant Ravulizumab)
CFH, CFI, CFB and C3

mutations: plan for liver
transplantation
51
 Transplantations in atypical HUS patients with end stage renal disease

 There are three main strategies of transplantations for patients with
atypical HUS:
✓ Combined liver kidney transplantation
✓ Isolated liver transplantation
✓ Isolated kidney transplantation
 The majority of complement regulatory proteins, including CFH, CFI,
CFB, and C3, are synthesized in the liver; therefore, liver transplantation
is a rational therapeutic option for patients with aHUS caused by defects
in these genes.
 Renal transplantation offers a functional graft kidney and prevents the
morbidity and mortality of patients with aHUS with ESKD on chronic
dialysis.
 However, transplantation and chronic immunosuppressant use carry the
risks of infection, complement overactivation, and aHUS relapse.
Therefore, the advantages and risks of transplantation should be weighted
in patients with aHUS.
Anti C5 prophylaxis
Source:
▪ Min-Hua Tseng a, Shih-Hua Lin b, Jeng-Daw Tsai c, Mai-Szu Wu d,e, I-Jung Tsai f,
Yeu-Chin Chen g, MinChih Chang h, Wen-Chien Chou i, Yee-Hsuan Chiou j,**,
Chiu-Ching Huang k . Atypical hemolytic uremic syndrome: Consensus of diagnosis
and treatment in Taiwan. Clinical Practice
52
 Anti-C5 therapy (Ravulizumab/Eculizumab) should be started as rapidly

as possible in all children with aHUS at a standard dose.
 Vaccination status should be evaluated for all meningococcal strains and
for Streptococcus pneumoniae and Hemophilus influenzae; these
vaccinations are completed as soon as possible, and subsequently kept up
to date during prolonged complement blockade.
 If vaccination is not possible or until 15 days after it is completed,
antibiotic prophylaxis against meningococcal infection must be
administered.
 In children < 5 years of age, in immunosuppressed individuals, and in
those who live in communities, low- dose prophylactic antibiotics may be
advisable even with a complete vaccination schedule.
 Patients receiving anti-C5 treatment should be advised of the risk of
meningococcal infection, albeit low, instructed on early identification of
warning signs and symptoms, and provided with an information card to
carry at all times allowing for prompt recognition of their disease and
treatment upon hospital admittance.
 For patients with aHUS triggered by autoantibodies, in addition to anti-
complement therapy at disease presentation, an antibody reduction
strategy is done.
 This entails either use of plasma exchange or therapy with
immunosuppressive medications (cyclophosphamide, rituximab.
53
 Transplantation:
 aHUS patients may require some combination of plasma therapy and/or
anti-C5 therapy prior to and post-transplant; prophylactic treatment
should be based on the risk of recurrence.
 Prophylactic PE/PI (started just before transplantation) has been
recommended and should be used when anti complement therapy is not
available.
 Whenever possible, anti-complement therapy should be used to prevent
recurrence starting just prior to renal transplantation in all forms of
aHUS based on quantification of the risk of recurrence.
 High-risk patients are defined as those with a previous recurrence of
aHUS on a renal allograft, or harboring pathogenic variants of FH, C3, or
FB genes;
 Moderate risk are patients with a negative complement screening or with
a pathogenic variant in FI gene or with detectable circulating anti-FH
antibodies;
 Low-risk patients are those with undetectable circulating anti-FH anti
bodies who previously were positive and patients harboring MCP or
DGKE isolated mutation.
 The use of prophylactic anti-C5 therapy should be done starting
immediately prior to transplant in patients with a moderate and high risk
of recurrence.
 Liver transplantation corrects the complement abnormality and prevents
disease recurrence in patients with defects in genes encoding circulating
complement proteins that are synthesized in the liver.
 IT is an attractive option for treatment of atypical HUS in patients who
cannot afford long-term treatment with complement factor 5 inhibitors,
and also in resource-limited conditions.
54
Eligibility for combined liver and kidney transplant or liver transplant alone
 CH or CFI mutation
 Less than 10% normal CFH levels in plasma Patients who have identified
mutations of genes encoding and have aHU recurrence after isolated
kidney transplantation or have a family member who had the same
mutation and had aHUS recurrence after isolated kidney transplantation
 HUS recurrence after isolated kidney transplantation in patients with
identified mutations of genes that may have both hepatic and nonhepatic
sites of expression and protein synthesis.
Eligibility for isolated kidney transplantation

 No evidence of CPH, CF, CFB, or C3 gene mutations
 MCP mutation
 Mutations associated with successful isolated kidney transplantation in
affected family members
 Anti-factor H autoantibodies
“Split or whole liver transplantation is indicated adequate liver mass must be

provided. Auxiliary liver transplantation is not recommended. Living related
donation is not recommended.”
References:
▪ Saland, Jeffrey M.; Ruggenenti, Piero; Remuzzi, Giuseppe and the Consensus Study
Group. Liver-Kidney Transplantation to Cure Atypical Hemolytic Uremic Syndrome.
Journal of the American Society of Nephrology 20(5):p 940-949, May 2009. | DOI:
10.1681/ASN.2008080906
55
Anti C5 prophylaxis
56
Pediatric Nutrition Protocol of EHA

in
Pediatric Nutrition
for
First Edition
2024
Prepared by
in
Pediatric Nutrition
for
1
Executive Committee
1. Prof. Dr. Sanaa Yousef Shabaan: (Head of the Committee) Professor of

Pediatrics and Consultant of Pediatric Clinical Nutrition, Ain Shams University,
Board member of Egyptian National Guideline Committee (Egyptian Clinical
Practice Guidelines).
2. Prof. Dr. Tarik Elsayed Barakat: Professor of pediatrics/Gastroenterology,
Hepatology and Nutrition, Mansoura University.
3. Prof. Dr. Osama Mahmoud Elasheer: Professor of pediatrics, Assiut
University, Head of Clinical Nutrition Unit, Assiut University Children
Hospital.
4. Dr. Khalil AbdelKhalek Mohamed Ahmed: Assist Professor of Pediatrics,
Cairo University.
5. Dr. Yasmine Gamal El-Gendy: Associate professor of pediatrics, Ain Shams
University. Member of the Scientific Council of Clinical Nutrition, Ain Shams
University, Member of the Higher Committee for Clinical Nutrition in
University Hospitals.
6. Dr. Mariane Abd El Masseh Fahem: (Moderator of the Committee) Pediatric
Specialist

written permission from EHA and authors.
2

• Consultant Pediatrician of Egyptian Military Medical Services.
• Professors of Pediatrics Military Medical Academy
• Head of Training Committee of Pediatrics of Egyptian Military Medical Board
• Consultant Pediatrician of the Medical Advisory Council of Egypt Healthcare
Authority (EHA).
Reviewed By



3
PREFACE

competency-based assessments to ensure the delivery of high-quality healthcare
services. The aim of developing these Egyptian Clinical Practice Protocols in
nutritional Disorders is to unify and standardize the delivery of healthcare to any
child at all healthcare facilities.
The main objective of the guidelines is to assist clinicians in recognizing when

to suspect nutritional disorders or identifying children at risk and to provide guidance
on care steps till referral to a specialized center is feasible.
Despite longer training, increasing specialization, and the use of advanced

technologies, avoidable failures still occur frequently in the current healthcare
system.
The growing complexity of medicine makes it difficult to provide consistent

care unless healthcare providers have access to protocols, checklists, or care paths to
follow.
Busy clinicians have all felt the need for a concise, easy-to-use resource at the
bedside for evidence-based protocols, or consensus-driven care paths.
In this protocol, we offer thorough reviews of selected topics and evidence-
based recommendations on management approaches.
Our goal is to provide an authoritative practical medical resource for
pediatricians.
Our aim is that this approach will motivate clinicians to incorporate available
evidence into their practice and monitor adherence to recommended practices. We
anticipate that practicing pediatricians, fellows, and practitioners will find these
protocols beneficial in providing high-quality clinical care to their patients. We
welcome feedback and suggestions on how to enhance this resource and maximize its
usefulness for healthcare professionals treating patients with nutritional disorders.
In Pediatric Nutrition
4
Table of Contents
Title Page Number

Preface 4
Childhood Obesity 6
Faltering Growth 11
South East London Guideline for the Management of 16
cows’ milk protein allergy in Primary Care
ANNEX 26
5
Childhood Obesity
Algorithm for the Assessment and Management of Childhood Obesity in

Patients 2 Years and Older:
❖ This algorithm is based on the 2007 Expert Committee Recommendations,1 new evidence
and promising practices
❖ This algorithm was developed by the American Academy of Pediatrics Institute for
Healthy Childhood Weight (Institute).
❖ The Institute serves as a translational engine, moving policy and research from theory into
practice in healthcare, communities, and homes.
❖ The Institute gratefully acknowledges the shared commitment and support of its Founding
Sponsor, Nestlé.
6
Management and Treatment Stages for Patients with Overweight or Obesity:

• Patients should start at the least intensive stage and advance through the stages
based upon the response to treatment, age, BMI, health risks and motivation.
• An empathetic and empowering counseling style, such as motivational
interviewing, should be employed to support patient and family behavior
change.8,9
• Children age 2 – 5 who have obesity should not lose more than 1 pound/month;
older children and adolescents with obesity should not lose more than an average
of 2 pounds/week.
7
References:
1. Barlow S, Expert Committee. Expert committee recommendations regarding prevention,
assessment, and treatment of child and adolescent overweight and obesity: Summary
report. Pediatrics. 2007;120(4):S164-S192.
2. US Department of Health and Human Services. Expert panel on integrated guidelines for
cardiovascular health and risk reduction in children and adolescents: Full report. 2012.
3.American Diabetes Association. Classification and diagnosis of diabetes. Sec.2. In Standards

of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl.1):S8-S16.
4. Taveras EM, Rifas-Shiman SL, Sherry B, et al. Crossing growth percentiles in infancy and
risk of obesity in childhood. Arch Pediatr Adolesc Med. 2011;165(11):993-998.
5. Copeland K, Silverstein J, Moore K, et al. Management of newly diagnosed type 2 Diabetes

Mellitus (T2DM) in children and adolescents. Pediatrics. 2013;131(2):364-382.
6. Estrada E, Eneli I, Hampl S, et al. Children's Hospital Association consensus statements for
comorbidities of childhood obesity. Child Obes. 2014;10(4):304-317.
7. Haemer MA, Grow HM, Fernandez C, et al. Addressing prediabetes in childhood obesity
treatment programs: Support from research and current practice. Child Obes.
2014;10(4):292-303.
8. Preventing weight bias: Helping without harming in clinical practice. Rudd Center for
Food Policy and Obesity website. http://biastoolkit.uconnruddcenter.org/.
9. Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling

for obesity in primary care: An RCT. Pediatrics. 2015;134(4): 649-657.
8
Endocrine Society Guidelines

Diagnosis and Management:
❖ BMI, body mass index; CNS, central nervous system
Genetic Obesity Evaluation:
❖ Measure insulin and proinsulin in patients with clinical features of PCSK1 deficiency.
BDNF, brain-derived neurotropic factor; KSR2, kinase suppressor of Ras 2; MC4R,
melanocortin 4 receptor; PCSK1, prohormone convertase 1; POMC,
proopiomelanocortin; SH2B1, Src-homology 2B adaptor protein 1; SIM1, single-
minded homolog 1; TrkB, tyrosine receptor kinase B; Tub, tubby gene
Source:
❖ Styne et al. Clin Endocrinol Metab 2017;102:709–757
9
Source:
❖ Pediatr Gastroenterol Hepatol Nutr 2019 January 22(1):1-27
10
Faltering Growth
Flow Chart for Managing Faltering Growth:
11
Faltering Growth Additional Notes:

Symptoms and Diagnosis:
• It is not a condition in itself – there are lots of different possible explanations,

with feeding problems being the most common.
• UK WHO growth charts should be used to plot weight, length and head
circumference.
• The weight / length of an infant need to be measured properly to interpret changes
in pattern:
✓ Use only appropriate scales/equipment that are regularly serviced and/or
calibrated
✓ Remove clothing and nappies before weighing
✓ Ensure staff is skilled and well-trained
• Pre-term birth, neurodevelopmental concerns and maternal postnatal
depression/anxiety are factors associated with faltering growth.
• When a child's growth deviates from the expected rate, it is crucial to identify this
deviation early and promptly investigate the underlying causes. e.g. dehydration,
acute illness, iron deficiency anaemia, CMPA, Coeliac disease, GORD or a child
safeguarding issue (abuse / neglect).
• In the majority of cases, there isn’t an underlying medical problem and a baby
can be successfully treated at home. However, recognize that a range of factors
may contribute to the problem and it may not be possible to identify a clear cause.
• There may be difficulties in the interaction between an infant and the parents or
careers that may contribute to the problem.
Treatment:
• Early days: provide feeding support as per NICE guideline CG37 “postnatal care
up to 8w after birth”.
• Under 6 months: Check frequency and timing/volume of feeds, as well as
breastfeeding and/or bottle preparation technique. An infant’s requirements are
around 150mls/kg/day and most will need one or more feeds during the night.
• 6 months and over: Ensure appropriate solids are offered at regular intervals; ask
about volume and frequency of milk and solids food. Once a food routine is
established, milk intake should be around 500-600mls a day. More than that may
compromise appetite for solids.
12
Review and Discontinuation of Treatment:
• All infants on high energy formula will need growth (weight and length)
monitored to ensure catch up growth occurs but also prevent excessive weight
gain.
• Pediatric Dietitians or Pediatricians should advise if/when the formula should be
stopped.
“We don’t have SMA available in our market, resource junior (Nestle) is
available in our market.”
Useful resources for parents and health professionals:
❖ NHS choice website: www.nhs.uk/Conditions/pregnancy-and-baby/Pages/help-baby-

enjoyfoods. aspx
❖ Royal college of Pediatric and Child health website for WHO growth charts and
tutorial: www.rcpch.ac.uk/growthcharts
13
SYMPTOMS BASED:
14
15
South East London Guideline for the Management of cows’

milk protein allergy in Primary Care
Cows’ Milk Protein Allergy Algorithm:
16
Introduction:
• The management of infants and children with suspected cows’ milk protein
allergy (CMPA) is complex. This guideline aims at supporting doctors and health
visitors in primary care, for the management of children with cows’ milk protein
allergy, at the point at which they present. Cows’ milk protein allergy is an
immune-mediated allergic response to proteins in milk. It includes referral
guidance for children with cows’ milk protein allergy to pediatric dietetic and
allergy clinics.
• This guideline is consistent with the international Milk Allergy in Primary Care
iMAP guidelines2 and provides recommendation on the presentation, diagnosis
and management of cows’ milk protein allergy in primary care.
Background:
• Cows’ milk protein allergy typically presents in the first year of life and affects
approximately 2-3% of infants.
• Most children outgrow immunoglobulin E (IgE) mediated allergy by 5-6 years,
non-IgE mediated CMPA is usually outgrown sooner.
• Children can continue to achieve tolerance well into adolescence.
• Milk allergy is more likely to persist in individuals with multiple food allergies
(e.g. egg /peanut/fish/wheat…. allergy) and/or concomitant asthma and allergic
rhinitis.
IgE and non IgE mediated cows’ milk protein allergy:
• The immune response to cows’ milk protein can be subdivided into IgE-mediated
allergy and non-IgE-mediated allergy (previously cows’ milk intolerance) see
NICE CG1164.
17
Table 1: Signs and Symptoms of Cows’ Milk Protein Allergy
Non-IgE-
IgE-
mediated4 (previously
Presentation mediated
cows’ milk intolerance)
Acute allergic reaction usually occurring minutes

Delayed reaction presenting several hours after milk ingestion, with the majority within 1
and up to 72 hours after milk ingestion. hour (can
occur up to 2 hours).
• Pruritus
• Pruritus • Erythema
Skin • Erythema • Acute urticaria
• Significant atopic eczema • Acute angioedema
• Acute flare of atopic eczema
• Infantile colic
• Vomiting • Loose/frequent
• Gastro- stools
oesophageal • Perianal redness
Gastrointestinal
reflux disease • Constipation
• Angioedema of the lips, tongue and palate
(GORD) with • Faltering growth
• Extreme colic
poor response • Abdominal
• Vomiting
to anti-reflux discomfort
• Diarrhoea
medication • Blood and/or
(see appendix mucus in stools
3) • Pallor and
• Food tiredness
refusal/aversion
Respiratory • Rhinorrhoea
(usually in • Sneezing • Cough
• Rhinorrhoea
combination • Nasal congestion • Wheezing
with other • Nasal congestion
• Anaphylactic • Shortness of breath
symptoms) reaction
18
STEP 1 – Assess likelihood of IgE or non-IgE-mediated allergy:
• Feeding history – check the source of cows’ milk e.g. is the infant milk fed
(breast fed/formula fed) or weaned onto solids.
• Ask about age of first onset, speed of onset / severity and reproducibility
following milk ingestion. Also ask about previous management including
medication use and response.
• An allergy-focused clinical history is the cornerstone of the diagnosis. A history
of eczema, asthma, allergic rhinitis or food allergy is more likely in IgE-mediated
food allergy.
• A family history of atopic disease in parents or siblings makes IgE-mediated
allergy more likely.
• Anthropometric measurements to assess growth.
• Examine the child to check for signs of allergy related comorbidities e.g. atopic
eczema.
• Discourage parents / careers from seeking advice from unregulated alternative
allergy practitioners.
STEP 2a – Confirming diagnosis and manage Non-IgE-mediated cows’ milk

protein allergy:
1.Advise a trial elimination of cows’ milk for a period of 4-6 weeks:
• Verbal and written advice should be provided on the avoidance of food

containing cows’ milk protein. Patient information sheets are available from
Allergy UK, British Dietetic Association BDA and NHS.
• If symptoms do not improve (and exclusion has been adhered to) then it is not
CMPA, consider alternative diagnosis.
• If symptoms improve on exclusion, then CMPA is likely but a re-challenge is
essential to confirm diagnosis (especially if other treatment options have been
started concurrently).
• See step 3 for exclusion and replacement advice; consider both maternal & infant
diet (milks and solids) as appropriate.
• Consider additional soya exclusion if remains symptomatic, seek advice from
pediatric dietician.
19
2.Re-challenge to confirm the diagnosis of Non-IgE-mediated cows’ milk protein

allergy (after 4-6-week exclusion):
• Explain to parents why the reintroduction phase is essential.

• If the infant is exclusively breastfed introduce cows’ milk back into the diet of the
mother.
• If the child is formula or mixed-fed reintroduce cows’ milk formula. The iMAP
guide on re-challenging with CMPA gives parents a structured approach to
formula reintroduction.
• If the child has been weaned onto solid foods, then reintroduce cows’ milk into
the diet and / or cows’ milk-based formula.
• If symptoms do not return then the diagnosis is not CMPA, or the CMPA has
been outgrown.
• If symptoms return with the challenge, then return the child to a strict CMPA free
diet and see next step.
3.Ongoing management of non IgE-mediated cows’ milk protein allergy:
• Strict avoidance of cows’ milk protein for at least 6 months or until the child is 9-
12 months old.
• Evaluate the child every 6 months. Monitor the child’s weight to assess growth,
nutrition and assess whether they have developed any tolerance to cows’ milk
protein with a challenge of cows’ milk protein. If symptoms recur, continue
cows’ milk avoidance management.
• Seek advice from a pediatric dietitian for guidance on nutritional adequacy and
re-introduction of milk protein.
20
STEP 2b – Manage IgE-mediated cows’ milk protein allergy:
• Consider a cows’ milk specific IgE antibody test, only after taking an allergy
focused clinical history.
• If negative, consider management in line with non-IgE-mediated symptoms or an
alternative diagnosis, (see step 2a).
• A positive result is ≥0.35kuA/L and along with a positive clinical history would
support the diagnosis of IgE-mediated cows’ milk protein allergy. Also check
specific IgE to egg and peanut in children with resistant eczema.
• Advise total exclusion of cows’ milk from diet.
• Recommend cows’ milk replacement. Extensively Hydrolysed Formula (eHF)
as first-line for mild to moderate IgE-mediated CMPA. See step 3.
• Consider Amino Acid Formula (AAF) if severe CMPA, (see step 3).
• Provide the parents/carers with appropriate information on what cows’ milk
protein allergy is, and the potential risks of a severe allergic reaction.
• Information sheets from Allergy UK12 and BDA13 websites.
• Discuss the diagnostic process and direct the parents/carers to relevant support
groups (Allergy UK, Anaphylaxis Campaign14).
• Provide a management plan to parent/carers. Templates for management plans are
available on the British Society for Allergy and Clinical Immunology website.
• Infants with IgE mediated cows’ milk protein allergy should be referred to
the pediatric allergy clinic following recommendation of an appropriate milk
substitute.
21
STEP 3 – Advise about cows’ milk free diet:

Table 2: General recommendations for milk free feeds
Exclusively breastfed Formula (+/- Breastmilk) Taking solids
• Recommend exclusive • Advise on the replacement of cows’ • Advise parents/carers to

breastfeeding for 26 weeks (6 milk-based formulas with an exclude cows’ milk protein
months) extensively hydrolysed formulas from the child’s diet.
(eHF) as first line. • Advise on a suitable milk
• If an exclusively breastfed child • For mixed fed infants, if symptoms alternative.
is symptomatic, advise mother to occur only with the introduction of • OTC soya formula can be
exclude cows’ milk protein from top-up formula feeds, replace these recommended for infants > 6
her diet. A maternal milk with eHF top-ups. The mother can months, but if this is not
substitute should be advised e.g. continue to consume foods tolerated (suggesting a soya
soya milk. Refer to a dietitian if containing cows’ milk protein allergy/a soya intolerance) a
appropriate. (CMPA). milk-free formula should be
• For mixed feeding refer mother to prescribed. Infants who have
• Women on a milk free diet local specialist/additional been prescribed formula < 6
should take a daily supplement breastfeeding support for support months can continue this after
of 1000mg calcium and 10mcg with return to exclusive 6 months of age.
Vitamin D. breastfeeding or increased • Introduce milk free solids no
breastmilk if this is mother’s choice. earlier than 17 weeks.
❖ Prescribing Advice of formula milk:
➢ Prescribe only 2-3 tins initially until compliance/tolerance is established to

avoid waste. Review at 1-2 weeks or issue a second prescription with enough
to last 1 month if the baby tolerates this milk formula, review at 3-4 weeks.
Table 3: Suggested monthly amounts (vary with large size and stage of weaning)
Age General advice Formula quantity
<6 months Infants under 6 months being exclusively formula fed and drinking 13 x 400g
150ml/kg/day of a normal concentration formula.
6-12 months Infants 6-12 months requiring less formula as solid food intake increases. 7-13 x 400g
12 months plus Children over 12 months requiring less formula as solids are the primary 7 x 400g
source of nutrition.
• Some children may require larger quantities e.g. faltering growing. Review recent
correspondence from the pediatrician or pediatric dietitian.
• Please refer to pediatric dietetic service if there are problems with introduction of
solids at this stage.
• Prescribing of hypoallergenic milks is governed by the Advisory Committee on
Borderline Substances (ACBS). ACBS advice takes the form of its
‘recommended list’ which is published as Part XV of the Drug Tariff. Endorse
prescription for formula feed with ‘ACBS’.
22
❖ Please note some key points:
• Extensively Hydrolysed Formula (eHF) should be used first-line. Patients

unresponsive or partially responsive to a trial of two different eHFs can be
progressed to Amino Acid Formula (AAF). At least 90% of children with proven
CMPA should tolerate these feeds.(e.g, Althera)
• AAF should only be prescribed for severe IgE-mediated allergy, enterocolitis,
faltering growth, multiple food allergies, GORD, severe early onset eczema when
breastfed, breastfeeding infants still symptomatic on maternal elimination diet or
if no improvement after 4 weeks on eHF. Only 10% of infants with CMPA
should require management with AAF.
• Soya based formula can be used first line from 6-12 months, (not to be
prescribed). Soya should not be used at all for those under 6 months due to high
phyto-oestrogen content.
• Full fat soya milk is suitable for children from 1 year of age after the child’s diet
is assessed as adequate, (not to be prescribed).
• Although significant advancements have been made in recent years in our
understanding of soy properties, substantial gaps in our knowledge still exist; for
many reasons, it is still difficult to establish whether soy-based food consumption
early in life is safe and beneficial; thus, we recommend that soy drinks should not
be used as a substitute for infant formulas or cow's milk in children younger than
24 months. Further additional studies will be needed to clarify the effects of soy
on the reproductive system, long-term effects on neurodevelopment, the effects of
glyphosate, effects on the microbiome, and, generally, all the long-term
consequences of soy. (Verduci, et al., 2020)
• Using soy-based formula in the treatment of CMA in infants has long been an
area of controversy. Soy formulas have been shown to promote appropriate infant
growth patterns, but some studies suggest lower weight gain in infants fed soy
formula compared to cow’s milk formula. A randomized controlled trial of 170
infants with confirmed CMA reported allergic responses in 10% of infants fed
soy formula. Adverse reactions to soy were similar in IgE-mediated and non-IgE–
mediated CMA, and reactions were more common in infants younger than 6
months of age.7,12,17 A randomized-order, double-blind test of 50 adult
participants (mean age of 34.4 years) comparing 12 different milk alternatives for
infants with CMA based on taste, texture, and smell found soy formula to have
the highest overall scores, followed by soy and rice hydrolysates. Soy-based
formulas are also more affordable than extensively hydrolyzed formulas. Soy-
based formula limitations are the unknown effects of phytate and phytoestrogens
found in soy and cross-reactivity with CMA, especially in younger infants.
(Kipfer et al., 2021)
23
• If child is allergic to soya and cows’ milk then refer to a dietitian.

• Alternative plant milk drinks are suitable for children from 2 years of age or from
6 months if used for food preparation (unless advised by a dietician). They must
be non-organic in-order to contain sufficient calcium. Some alternative calcium
fortified, plant-based milk drinks are suitable as a drink from 1 year of age if
advised by a dietitian once the child’s diet has been assessed.
• Children under 5 years of age should not be fed rice milk as it contains arsenic.
• Other mammalian milk proteins (including unmodified cow, sheep, buffalo,
donkey, camel, horse, or goats' milk/formula) are not recommended for infants
with cows' milk protein allergy. Most are not adequately nutritious to provide the
sole food source for infants and there is a risk of allergenic cross-reactivity with
cows’ milk.
• All children under 5 years of age require vitamin D supplements unless they are
taking > 500mls infant formula per day. See BDA Food Fact Sheet - vitamin
D13 and NHS vitamin D.
• Infants on a milk free diet should be weighed 6 weeks after initiation of new
feed and then regularly thereafter by the health visitor and their weights
plotted in the Growth curves.
• Information about achieving adequate calcium requirements can be provided
from the BDA and NHS. See BDA food fact Sheet - calcium13 and NHS
calcium.
• If symptoms do not improve on an elimination diet, re-introduce cows’ milk
protein and refer to a pediatrician.
• Do not routinely prescribe formula for children over 2 years of age unless
recommended by dietitian or pediatrician.
24
STEP 4 – When to refer:

Note: Seek advice and guidance via electronic Referral System (eRS) if any
uncertainty
Refer to pediatric dietetic service:
• Every child with CMPA should have a dietary/nutritional assessment with a suitably
qualified healthcare professional e.g. dietitian, GP or healthcare visitor.
• If there is concern about the nutritional adequacy of the child’s diet and faltering growth
across 2 centiles on a milk free diet, refer to pediatric dietitian.
• If the mother is having difficulty getting the baby to take a milk free formula.
• If the parents would like support around reintroduction of cows’ milk protein.
• Refer breastfeeding mothers for dietetic support (adult) if they wish to remove milk
from their own diets and there are additional risk factors or concerns about their
nutritional status.
• Referral criteria and access to community/specialist support vary across South East
London. Please follow local pathway.
Refer to pediatric allergy service (which includes pediatric allergy dietetic

assessment and advice):
❖ Patients who present with, or develop any of the following symptoms/situations

during primary care management:
• A clinical history strongly suggestive of IgE-mediated cows’ milk allergy (with positive
or negative allergy tests)
• An acute systemic reaction involving wheezing, difficulty breathing, drowsiness, loss of
consciousness
• A severe delayed reaction
• A history of reacting to other foods (multiple food allergies)
• Has or develops asthma (which puts him/her into a higher risk group for having a more
severe allergic response to milk following accidental ingestion).
• Faltering growth, especially in combination with any gastro-intestinal symptoms
• If symptoms do not respond to exclusion of cows’ milk
• Persisting parental/carer suspicion of food allergy or concern once primary care
measures have been tried.
Risk of developing Other Allergies:

• Children with cows’ milk protein allergy are more likely to develop other allergies. If an
infant is reacting to other food proteins in addition to cows’ milk (for example egg) it is
vital that this food protein and its derivatives are removed from the diet as well.
Children with multiple food allergies should be referred to a pediatric allergy service.
• The risk of nutritional deficiencies is increased when multiple food groups are excluded
from the diet. Unnecessary food exclusion should be avoided, and multiple food
avoidance should be supervised in a pediatric allergy clinic.
25
Annex
Appendix 1: Allergy Testing Advice for Children from General Practice
Introduction:
• Allergic diseases are common, affecting up to 40% of British children. Although
specialist advice within hospitals is available for difficult cases, many children with
straight forward allergies can be managed in general practice.
Taking a History:
• Diagnosis of allergic diseases is primarily made by taking a detailed history of exposure
and reactions, and by physical examination. Children from families where other family
members also have allergic disease are particularly at risk. On the basis of the history,
clues should emerge which can then be confirmed by performing allergy tests.
Allergy Tests:
• The most appropriate tests for diagnosing allergy in general practice are specific IgE
tests (RAST tests). These should only be performed to confirm a suspected diagnosis.
Allergy tests may not be needed in children presenting with non-IgE-mediated cows’
milk protein allergy and it does not influence management. Screening, using large
panels of tests is inappropriate. Testing should be considered in children aged 2 months
and above presenting with allergic conditions.
Allergic Conditions:
• The immunology laboratory can measure specific IgE to an enormous variety of
allergens. If the patient presents with a specific allergy, then request IgE to the
particular allergen. The following is a list of allergic conditions with their commonly
associated allergens. Specific IgE blood tests are available to all these allergens (this is
not an exhaustive list):
Allergens
Food Allergy Cows’ milk, egg white, wheat, soya, peanuts, tree nuts, fish, shellfish, sesame
Atopic eczema Cows’ milk, egg, soya, wheat, house dust mite, cat, dog, tree pollen, grass
Asthma House dust mite, cat, dog, tree pollen, grass pollen, mould
Seasonal rhinitis/conjunctivitis Grass pollen, tree pollen, mould
Perennial rhinitis/conjunctivitis House dust mite, cat, dog
Bee and wasp stings Bee and wasp venom
Latex allergy Natural rubber latex
Requesting an allergy test:

• Selection of allergens to be tested should be based on the history of exposure and
reactions.
• It will be necessary to limit the number of tests in very small children. to those thought
to be the most important. Please specify which individual allergens you would like the
child tested for.
26
Interpreting the test:

• Specific IgE results (see table 4) should be read in conjunction with the clinical history.
A test result of >0.35 kuA/L indicates sensitisation.
• Higher values are more likely to indicate clinical allergy. A low level of specific IgE
(grade 1 or 2) may be more significant in younger children (less than 2 years of age),
and an intermediate level of specific IgE (grade 2 or 3) may be less significant in a
child with severe atopic dermatitis or a child who is outgrowing a more severe allergy.
Some patients have a positive specific IgE but do not react on exposure to the allergen,
whilst others may have a negative specific IgE yet still react to allergen. Where there is
a discrepancy between the clinical history and the specific IgE result, patients
should be referred to a pediatric allergy clinic for further evaluation.
Table 4: Interpreting Test Results
Level of allergen
*ImmunoCAP specific
IgE antibody Comment
Grade
(kuA/L)
6 – Strong positive 100+ Very high. Refer to patient history.
5 – Strong positive 50-100 Very high. Refer to patient history.
4 – Strong positive 17.5-50 Very high. Refer to patient history.
High. Grades 1-3 vary in significance dependent on allergen.

3 – Positive 3.5-17.5 Consider patient history and risk of severe
reaction/anaphylaxis.
2 – Positive 0.7-3.5 Moderate
1 – Low, weak Low. Grade 1 to inhaled allergens is of doubtful significance.

0.36-0.7
positive Grade 1 to foods or moulds of greater significance.
0 – Undetectable,
negative 0.35 Absent or undetectable.
❖ A sensitive blood test that measures the concentration of immunoglobulin E (IgE),

which is an indicator of allergic sensitisation.
27
Appendix 2: Other Milk Related Conditions
1. Cows’ Milk Protein Proctocolitis:
• Presents with blood or mucus in the stool of happy, thriving breast fed babies, following
ingestion of, or maternal ingestion of milk protein. It improves when cows’ milk protein
is eliminated from the maternal diet. If mother wishes to introduce formula offer a
suitable milk free formula. This usually resolves by a year of age, when normal cows’
milk can be re-introduced. This is a non-IgE-mediated cows’ milk protein allergy.
2. Lactose Intolerance:
• This is a condition which occurs as a result of a deficiency of the lactase enzyme in the
intestine, it is not the same as cows’ milk protein allergy. It usually occurs in children
who were previously able to tolerate cows’ milk. Symptoms occur as a result of lactose
malabsorption; abdominal distension, abdominal pain and diarrhoea.
➢ Primary lactose deficiency occurs in up to 70% of the world population, although it

is uncommon in Western Europe. It is due to a decline in activity of the lactase
enzyme, which can occur at varying rates, from a few months of age.
➢ Secondary lactose intolerance is a temporary phenomenon, which results from

injury to the gut wall following acute gastroenteritis. This usually resolves within a
2-4 weeks. Treat with a lactose free diet including lactose free milk. For infants
under 1-year lactose free milk formula is available OTC. If exclusively breastfed,
breastfeeding should continue. If not breastfed soya formula can be used in children
from 6 months onwards. For infants over 1-year lactose free milk can be
purchased over the counter by the parents/carers.
3. FPIES (Food Protein-Induced Enterocolitis Syndrome):
• FPIES is a rare condition which presents in infants with profuse vomiting, diarrhoea,
acidosis and shock, 1-3 hours after ingestion of milk or other food proteins.
➢ The child may be assessed for sepsis.
➢ It may be associated with a raised white cell count but the child is afebrile and stool
samples are clear.
➢ FPIES requires hospital referral.
➢ This is a non-IgE-mediated food allergy.
28
Appendix 3: Gastro-Oesophageal Reflux
GASTRO-OESOPHAGEAL REFLUX
Gastro- oesophageal reflux (GOR) is the passage of gastric contents into the oesophagus. It is a normal physiological
process that usually happens after eating in healthy infants, children, young people and adults. Gastro-
oesophageal reflux disease
(GORD) occurs when the effects of GOR leads to symptoms severe enough to require medical treatment.
Symptoms of GORD
Unexplained feeding difficulties (refusing to feed, gagging or choking), vomiting, regurgitation, distressed behaviour,
faltering growth, chronic cough, hoarseness and a single episode of pneumonia.
Treatment of GOR and GORD
• In well infants with/without effortless regurgitation of feeds, provide reassurance and monitor. Symptoms resolve
in 90% of infants by aged 1 year of age. Do not routinely investigate if presenting with only one of above symptoms.
Seek advice from a health visitor on responsive, paced bottle feeding and/or breastfeeding specialist.
• In breastfed or formula fed infants with frequent regurgitation and marked distress take a stepped care approach
(as per NICE guidelines NG1: Gastro-oesophageal reflux disease in children and young people: diagnosis and
management.
Breastfeeding Formula feeding
1. Complete feeding assessment 1. Review feeding history including overfeeding, positioning and
advise patient to see health activity.
visitor/infant feeding advisor. 2. Trial smaller, more frequent feeds 6-
2. Alginate therapy for a trial period of 7 x day (aim to meet requirements of
1–2 weeks. If successful continue 150ml/kg)
but try stopping at intervals to see 3. 1-2 week trial of OTC thickened formula (see below).
whether it is still required. DO NOT PRESCRIBE.
3. Consider cows’ milk exclusion. 4. Stop thickened formula and offer alginate therapy for a trial period
of 1–2 weeks.
5. Consider cows’ milk protein allergy.
Review
• If symptoms persist despite stepped care approach, consider pharmacological treatment (e.g. H2 antagonists),
sharing risks and benefits of medication with parents (refer to NG1), or a trial of cows’ milk protein exclusion (see Red
Flags for CMPA).
• There is little evidence for the efficacy of PPI’s in infants <1 year, in this group use H2 antagonists. In older children
PPI can be trialled. Use a 4 – 8 weeks trial of acid suppression then wean if symptoms improved.
Red Flags
Red Flags for possible CMPA – if present, consider 2- 4 weeks of cows’ milk protein exclusion (maternal if
breastfed, eHF if formula fed) under dietetic guidance, before a trial of H1 antagonist16:
• Existing atopic disease, in particular eczema in infants
• First degree relative with food allergy or atopic disease
• More than one of the following are present: GOR/GORD, chronic loose stools, blood or mucus in stools,
abdominal pain, food refusal or aversion, constipation, peri-anal redness, pallor and tiredness, faltering
growth in conjunction with one or more gastrointestinal symptoms (with or without atopic eczema).
Referral onwards
Urgent (same day) referral is required if a child presents with:

• Bile, blood stained vomit, projectile vomiting, melaena and/or dysphagia.
Referral to secondary care is required in infants presents with:
• Persistent pain (requiring on-going medical therapy), faltering growth, iron deficiency anaemia, regurgitation
persisting beyond 12 months old, suspected Sandifer's syndrome and persistent feeding aversion.
Referral to gastroenterology services is also required after failed trial of milk exclusion / H1 antagonist in infants with
red flags for CMPA or after a failed trial of H1 antagonists only, in infants with no red flags for CMPA.
29
Table 5: Thickened Formula
Thickened Formula - Available OTC

DO NOT Prescribe
Aptamil® Anti-Reflux (900g) (Milupa) Contains carob bean gum
Cow and Gate® Anti-Reflux (900g) Contains carob bean gum

From birth until 12 months
SMA® Anti-Reflux (800g) Contains corn starch
NOTES
• Alternatively, prescribe Carobel to add to regular milk formula and titrate as

needed
• Do not use thickened formula alongside alginate therapy e.g. Gaviscon.
• Parents should refer to manufacturers’ guidance on how to prepare
thickened formula.
Note: This is currently not in line with DOH guidance on safe preparation of
infant formula and parents should be made aware of the risk of infection.
• If symptoms resolve continue but review and trial infant first milk at
intervals.
30
References:
1. Milk Free Diet Information For Babies and Children Advice provided. Available at:
https://www.allergyuk.org/assets/000/001/207/Cow's_Milk_Free_Diet_Information_for_Babie
s_and_Children_original.pdf?1501228993.
2. International Milk Allergy in Primary Care (iMAP) cow's milk allergy guideline. Published 15
November 2017, available at: https://www.guidelines.co.uk/pediatrics/imap-cows-milk-allergy
guideline/453783.article#iMAP_guidelinepresentation_of_suspected_cows_milk_allergy_in_the
_first_year_of_a_childs_life.
3. Luyt D., Ball Hy., Makwana N., Green MR Bravin K., Nasser SM Clark AT. BSACI guidelines for
the diagnosis and management of cows’ milk allergy. Clinical & Experimental Allergy 2014;
44:642-672.
4. National Institute for Health and Care Excellence, Food allergy in under 19s: assessment and
diagnosis, Clinical guidance [CG116]. Published February 2011, available at:
https://www.nice.org.uk/guidance/CG116.
5. National Institute for Health and Care Excellence Clinical Knowledge Summaries – Cows’ milk
protein allergy in children. Available at: https://cks.nice.org.uk/cows-milk-protein-allergy-in-
children .
6. Venter C, Brown T, Shah N, Walsh J, Fox AT. Diagnosis and management of non-IgE-mediated
cows’ milk allergy in infancy – a UK primary care practical guide. Clin Transl Allergy 2013;3(1):23.
Available at: http://www.ctajournal.com/content/3/1/23.
7. British Society for Allergy and Clinical Immunology (BSACI) website. Available at
http://www.bsaci.org/index.htm
8. Allergy UK factsheets. Available at: https://www.allergyuk.org/information-and
advice/conditions-and-symptoms.
9. British Dietetics Association, Milk allergy. Available at:
https://www.bda.uk.com/foodfacts/milk_allergy.
10. National Health Service: What should I do if I think my baby is allergic or intolerant to cows'
milk? Available at: https://www.nhs.uk/common-health-questions/childrens-health/what-
should-i-do-if-i-think-my-baby-is-allergic-or-intolerant-to-cows-milk/.
11. iMAP Milk Ladder. Published Oct 2013, available at: http://ifan.ie/wp-
content/uploads/2014/02/Milk-Ladder-2013-MAP.pdf.
12. Allergy UK, Types of food allergy. Available at: https://www.allergyuk.org/information-and-
advice/conditions-and-symptoms/36-types-of-food-allergy.
13. British Dietetics Association, Food factsheets. Available at
https://www.bda.uk.com/foodfacts/home.
14. Anaphylaxis Campaign, available at: https://www.anaphylaxis.org.uk/.
15. Rosen R. et al., Pediatric gastrooesphageal reflux clinical practice guidelines: Joint
recommendations of the north American Society for Pediatric Gastroenterology, Hepatology and
Nutrition and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition. J
Paediatr Gastroenterol Nutr 2018; 66(3) 516-554.
16. National Institute for Health and Care Excellence Guidance on Gastro-oesophageal reflux
disease in children and young people: diagnosis and management (NG1). Published January
2015. Available at: http://www.nice.org.uk/guidance/ng1.
31
32
Pediatric Cardiology Protocol of EHA
0

in
Pediatric Cardiology
for
First Edition
2024
Prepared By
Members of The Pediatric Cardiology Committee,
Medical Advisory Council,
1
Executive Committee

1. Prof. Alyaa Kotby: Professor of Pediatrics and Pediatric Cardiology, Former
Head of the Pediatric Department and Pediatric Cardiology Unit, Children’s
Hospital, Ain Shams University.
2. Prof. Hala Agha: Professor of Pediatrics and Pediatric Cardiology, Head of

Pediatric Cardiology Division, Cairo University.
3. Prof. Mona El Ganzory: Former Head of Pediatric Department, Head of
Pediatric Cardiology Department, Ain Shams University.
4. Dr. Antoine Fakhry AbdelMassih: Lecturer of Pediatrics and Consultant of
Pediatric Cardiology, Cairo University.
5. Prof. Nevin Mohamed Mamdouh Habeeb: MD, FSCAI, FPICS, Professor of
Pediatrics, Ain Shams University.
6. Prof. Mohamed Magdy Abou-Elkheir: MD Former Head of Pediatric
Department, Faculty of Medicine, Mansoura University, Professor of Pediatrics &
Pediatric Cardiology, Former Head of Pediatric Cardiology Unit Mansoura
University Children's Hospital, Member of The Pediatric Cardiology Working
Group of the Egyptian Society of Cardiology.
7. Dr. Baher Mata Nashed: Associate Professor of Pediatrics and Pediatric
Cardiology, Cairo University, AFCM.
8. Prof. Sonia Ali El-Saiedi: Prof of Pediatric Cardiology, Cairo University, Head of
Cardiomyopathy clinic, Head of Pediatric Cardiac ICU, Previously Head of Cath
Lab, Founder of The Egyptian Society of Pediatric Cardiology, Fellow of SCAI and
AEPC.
9. Prof. Wael Lotfy: Professor of Pediatrics and Pediatric Cardiology, Cairo
University, MRCP, FRCPCH (UK), DU, AFSA Pediatric Cardiology, Vice
President of the Egyptian Lactation Consultants' Association, Director of the
Arrhythmia Service at CUPH.
10.Prof. Hany Adel: Prof Pediatric Cardiology, University of Alexandria.
2
Disclaimer

under their care.
3

Authority (EHA).
Reviewed By


4
PREFACE

aim of developing these Egyptian Clinical Practice Protocols in Pediatric Cardiology
is to unify and standardize the delivery of healthcare to all pediatric patients at all health
facilities.
We train longer, specialize more, use ever-advancing technologies, and still we
fail. Part of the problem, is that the ever-increasing complexity of medicine makes
uniform care delivery impractical or impossible. That is, unless there are protocols,
checklists, or care paths that are readily available to providers.
excellent repositories of detailed information about the etiology, pathogenesis, clinical
picture, diagnosis, and treatment of a condition. However, for a busy clinician looking
for the best way to manage a sick patient, a standardized path for effective management
of the patient may be impossible to discern. So, it would be a lot easier if we all
managed simple things in a uniform way using the best available evidence and
resources.
For the management of pediatric cardiology patients, busy clinicians have all felt
the need for a concise, easy-to-use resource at the bedside for evidence-based
protocols, or consensus-driven care paths where high-grade evidence is not available.
comprehensive advice about management approaches based,
Our goal is to provide an authoritative practical medical resource for
pediatricians.

that practicing pediatricians, fellows, nurse practitioners, will find this protocol useful
in delivering high-quality clinical care to their patients. We remain open to feedback
and suggestions about how to improve this resource and how to make it maximally
useful.
In Pediatric Cardiology
5
Table of Contents
Page
Title
Number
Preface 5
Approach to a Child with Suspected Arrhythmia 8
Pediatric Advanced Life Support 10
Syncope 15
An Approach to A Cyanotic Neonate 21
Pediatric Heart Failure 28
Guidelines of Hypertension (HTN) 31
Pediatric Chest Pain 36
Guidelines on Fever with Rash/Kawasaki Recognition 42
Recurrent Chest Infections 51
Failure to Thrive (Slow Weight Gain) 52
Diagnostic Utility of Anti-Streptolysin O Titer in Pediatric 55
Cardiology Practice
Cardiac Murmurs 62
6
ECG Electro Cardio Gram
VF Ventricular fibrillation
TGA Transportation of the great vessels
TOF Tetralogy of Fallot

Total anomalous pulmonary venous
TAPVC
connection
COA Coarctation of aorta
PDA Patent ductus arteriosus
AR Aortic regurge
AV Arterio-venous fistulas
KD Kawasaki disease
FBC full blood count
UEC Urea ,electrolytes, creatinine
LFT Liver function test
7
Approach to a Child with Suspected Arrhythmia
Symptoms:
• Any suspected cardiac symptom particularly palpitations and chest pain are an
indication for rhythm evaluation.
Signs:
• A regular pulse with a rate normal for age is essential in any clinical exam,
cardiac or otherwise.
• In the presence of any rhythm disturbance a reference of pediatric heart rate
and normal of ECG is essential in evaluation, a 12-lead is the standard. (Vitals
are shown in table p.6)
N.B:
1. A monitor rhythm strip is not a replacement for an ECG.

2. During the evaluation of any cardiac disease, a 12 leads ECG is essential. If
the cardiac disease is chronic, a Holter is needed as well.
3. While asystole represents 80% of pediatric arrests, an ECG monitor is
needed in every resuscitation to detect the common asystole, less common
ventricular fibrillation (19%) or the uncommon electro-mechanical
dissociation (1%).
4. Whenever in doubt, consult a specialist or a senior person.
5. Children have been known to fully recover after prolonged CPR if
effectively done, do not lose hope early.
8
9
Pediatric Advanced Life Support
10
11
12
13
14
Syncope in Pediatrics
Causes:
✓ Neutrally mediated: most common, benign (70%)
✓ Cardiac: arrhythmia or structural heart disease
✓ Neurological: seizures, head injury
✓ Orthostatic hypotension
✓ Metabolic: dehydration, hypoglycemia
Red Flags for Cardiac Syncope:
✓ Lack of a prodrome
✓ Palpitation or chest pain
✓ Exercise induced syncope
✓ Past cardiac history
✓ Family history of early cardiac death, arrhythmia or sudden death
15
Work Out:
1. History and Physical Examination:
2. Blood Glucose
3. CBC
16
4. ECG
5. Echocardiography
6. If arrhythmia is suspected 24-hour Holter
7. If history is not conclusive and neurocardiogenic syncope is suspected, do tilt
table testing
“Data collected from history, examination and investigations will be

interpreted through the following chart”
17
Chart for interpretation of data of patient with syncope
“Neurocardiogenic syncope is the most common form, and it is benign”
18
Treatment:
• The patient is advised to avoid dehydration, long periods of standing and

irregular mealtimes. Other simple measures include water and table salt intake
to increase plasma volume.
• Some people have been able to abort an episode of vasovagal syncope by
immediately engaging in muscle-tensing exercises. These exercises apparently
reduce blood vessel dilation and increase the amount of blood being returned to
the heart. Examples include:
➢ Crossing your leg while tensing the legs, abdomen, and buttocks
➢ Tensing the arms with clenched fists
➢ Tensing your leg muscles
➢ Squeezing a rubber ball
• When syncope persists despite behavioral changes, medical therapy can be used
and usually includes:
➢ Beta-blocker or
➢ Fludrocortisone
➢ Serotonin re uptake inhibitor (paroxetine)
“Patients with cardiac or neurological syncope should be referred to a

specialist”
19
References:
1. 2018 ESC Guidelines for the diagnosis and management of syncope.

2. Michele Brignole, Angel Moya, Frederik J de Lange, Jean-Claude Deharo, Perry
M Elliott, Alessandra Fanciulli, Artur Fedorowski, Raffaello Furlan, Rose Anne
Kenny, Alfonso Martín ... Show moreAuthor Notes.
3. European Heart Journal, Volume 39, Issue 21, 01 June 2018, Pages 1883–1948,
https://doi.org/10.1093/eurheartj/ehy037- Published: 19 March 2018.
20
An Approach to A Cyanotic Neonate
Cyanosis Definition:
Blue coloration of the skin and mucous membranes due to the presence of
deoxygenated hemoglobin occurs when the oxygen saturation of arterial blood falls
below 85-90% (5g/dl deoxyhemoglobin).
➢ Central Cyanosis: Affects “central” parts of the body (mouth, tongue, head
and torso).
➢ Peripheral Cyanosis: Appears at the hands, fingertips, toes +/- circumoral
and periorbital areas, it is rarely life-threatening.
➢ Differential Cyanosis: It is cyanosis at both lower extremities with a pink
right upper extremity.( Lundsgaard and Van Slyk - 1928)
➢ Causes:
Respiratory Causes:
✓ Aspiration
✓ Pierre robin syndrome
✓ Choanal atresia
✓ Hyaline membrane disease
✓ Pulmonary edema, pneumonia, pneumothorax, pleural effusion,
✓ Congenital Diaphragmatic Hernia
Cardiac Causes:
✓ Congenital heart disease presenting since birth e.g. (TGA)+ others
Lundsgaard and Van Slyk
CNS:
✓ Central nervous system dysfunction
✓ Asphyxia
Miscellaneous:
✓ Sepsis
✓ Hypocalcemia, hypoglycemia, Hypomagnesemia, Hypothermia
Cyanosis with Normal Po2:

✓ Methemoglobinemia
21
Cardiac Causes of Cyanosis in the Neonatal Period:
Source:
▪ Diagnostic Approach, Dr. D. Muthukumar MD, Medical College,
Webpage: https://slideplayer.com/slide/10500980/
Cardiac Evaluation:
Work Up
✓ Full history
✓ CLINICAL EXAMINATION (blood pressures measurement in all four limbs)
✓ PULSE OXIMETER
✓ Blood gases analysis & Hyperoxia test
✓ Full laboratory tests
✓ EEG & X-RAY CHEST.
✓ Echocardiography
✓ Cardiac catheterization in selected cases
✓ Ct angiography in selected cases(Expert Opinion).
22
Important Points During Examination:
✓ Inspection; Features denoting certain Syndrome: i.e., Di George Syndrome.

✓ Cyanosis & differential cyanosis, pallor, tachypnea, dyspnea, other congenital
malformations
✓ Palpation: hyperactive precordium is characteristic of high-volume overload as
large Lt to Rt shunts or severe valve regurgitation.
✓ Thrill is often of real diagnostic value.
✓ Peripheral pulses; Strong arm pulses and week leg pulses suggest COA.
✓ Bounding pulses are found in aortic run-off lesions eg: PDA, AR, AV fistulas.
✓ Weak, thread pulses indicate circulatory shock.
✓ Blood pressure: Upper & lower limbs.
✓ Auscultation: For heart sounds, audible murmurs
✓ Cover the genitalia with a sheet and slightly abduct the thigh. Press deeply,
below the inguinal ligament and about midway between symphysis pubis and
anterior superior iliac spine. Use two hands one on top of the other to feel
the femoral pulse. Note the adequacy of the pulse volume.
✓ Pulse Oximetry Screening to Detect Critical Congenital Heart Disease
(CHD)&hyperoxia test(Expert Opinion).
Hyperoxia Test:
✓ It differentiates between cardiac cyanosis and other causes of cyanosis as

pulmonary or CNS causes
✓ Method: breathing 100% oxygen to the neonate increases arterial blood PO2
above 100mmhg if cyanosis is due to non-cardiac cause
✓ If there is RT to LT shunt arterial PO2 does not exceed 10 to 30mmhg.
23
CCHD Protocol:
CCHD Screening Protocol
➢ Screening Recommendations:
• Right hand and one foot (parallel or in sequence)
➢ Positive Screening:
• <90%
• <95% in both extremities on 3 measurements, separated by 1 hour
• >3% difference in SpO2 between right hand and foot on 3 measurements,
separated by 1 hour
Source:
▪ Dr. KEMPER’S PROTOCOL USED IN THE US WHERE THE SCREENING HAS
BEEN MADE MANDATORY IN SEPT.2011
24
Approach to A Cyanotic Neonate
Low PaO2, SaO2
Symptoms & Pulmonary or

Cardiac
Signs Other
decreased
increased cyanosis CRYING
cyanosis
retractions,
RESPIRATOR
tachypnea, slow, deep grunting,
Y DISTRESS
tachypnea, apnea
normal or decreased PaCO2 increased
responsive
minimal response FIO2
(usually)
CARDIAC
murmur, week zpulses normal
EXAM
can be abnormal ECG normal
normal,
Abnormal ECHO pulmonary
hypertension
heart abnormal or normal size situs

inversus (complex) CHEST X-RAY lung disease
reduced pulmonary blood flow
Source:
▪ Lundsgaard C, Van Slyke DD. Cyanosis. Medicine. 1923;2:1–76.
25
Algorithm for Management of Neonatal Cyanosis:
Source:
▪ Dasgupta, S., Bhargava, V., Huff, M., Jiwani, A. K., & Aly, A. M. (2016).
▪ Evaluation of The Cyanotic Newborn: Part I—A Neonatologist's
Perspective. NeoReviews, 17(10), e598-e604
26
References:
1. Dasgupta, S., Bhargava, V., Huff, M., Jiwani, A. K., & Aly, A. M. (2016).
2. Evaluation of The Cyanotic Newborn: Part I—A Neonatologist's Perspective.
NeoReviews, 17(10), e598-e604
3. Diagnostic Approach, Dr. D. Muthukumar MD, Medical College,
4. Webpage: https://slideplayer.com/slide/10500980/
5. Dr. KEMPER’S PROTOCOL USED IN THE US WHERE THE SCREENING
HAS BEEN MADE MANDATORY IN SEPT.2011
6. Lundsgaard C, Van Slyke DD. Cyanosis. Medicine. 1923;2:1–76.
27
Pediatric Heart Failure
Definition:
• Heart failure is a clinical syndrome based on the presence of clinical

manifestations suggestive of inability of the heart to meet the metabolic needs
of the body
Causes, when to suspect and severity classification:
Heart
Failure
Preserved ventricular functions Impaired ventricular functions
Left to right shunt such as VSD Primary cardiomyopathies such as DCM
Secondary cardiomyopathies such as

Valvular regurge: Aortic, Mitral
anthracycline induced
Chronic Anemia: Sickle, Inflammatory: early Kawasaki, or
Thalassemia myocarditis
Endocrinal: hypothyroidism
Prolonged pressure load such as aortic

stenosis, coarctation
Neglected Tachyarrhythmia
Symptoms:
✓ Dyspnoea on exertion (poor feeding in infants)

✓ Sweating
✓ Failure to thrive
✓ Recurrent chest infections
28
Signs:
✓ Tachypnoea
✓ Tachycardia
✓ Weak and thready pulses
✓ Gallop rhythm
✓ Murmur
✓ Edema
✓ Cardiomegaly – very useful sign
✓ Tender hepatomegaly
✓ Basal crackles
✓ Cold and wet skin
✓ Some children present in extremis (cardiogenic shock)
Clinical Pearl:
▪ New-onset heart failure may be less overtly symptomatic in older children.

Symptoms of abdominal pain and nausea and anorexia can be present,
sometimes diverting attention from the real cause.
Classifications: Modified Ross Classification
Infant Child
Stage I Asymptomatic with underlying lesion
Mild tachypnoea and

Stage II diaphoresis on feeding Mild Dyspnea on exertion
No growth failure
Marked tachypnoea and

Stage III diaphoresis on feeding Marked dyspnea on exertion
Growth failure
Stage IV Diaphoresis at rest Dyspnea at rest
29
Management:
• Once suspected refer to tertiary care for X ray, Echocardiography

• Management according to previously mentioned staging:
Stage I ACE I
Stage II Add loop diuretics and aldosterone antagonist
Refer to Pediatric Cardiology tertiary center of

care:
Stage III
The cardiologist might recommend use of
advanced treatments such as Ivabradine/Entresto
or Carvedilol
ICU admission in tertiary care center with

Stage IV Pediatric Cardiology supervision to start IV
inotropes+/- mechanical support
References:
▪ Masarone, Daniele et al. 2017. “Pediatric Heart Failure: A Practical Guide
to Diagnosis and Management.” Pediatrics & Neonatology 58(4): 303–12.
https://linkinghub.elsevier.com/retrieve/pii/S1875957217300505.
30
Guidelines of Hypertension (HTN)
1) General Considerations:
History:
✓ Headache/vomiting
✓ Blurred vision
✓ Change in mental state
✓ Seizures
✓ Chest pain/palpitations
✓ Shortness of breath
✓ Cardiac failure
✓ Past history of Acute Kidney Injury (AKI)
Examination:
• Confirm hypertension (See measuring blood pressure section below)
• Vitals: tachycardia, four limb BP for upper and lower limb discrepency
• Height and weight: obesity, growth retardation
• Signs of end organ damage

➢ Fundoscopy: hypertensive retinopathy
➢ Cardiovascular: apical heave, hepatomegaly, oedema
➢ Chronic renal failure: palpable kidneys
➢ Focal neurology (eg facial nerve palsies)
• Signs of underlying cause

➢ General appearance: Cushingoid, proptosis, goiter, webbed neck (Turner
syndrome), elfin facies (William's syndrome)
➢ Skin: Cafe-au-lait spots, neurofibromas, acanthosis nigricans, hirsutism, striae,
acne, rash (vasculitis)
➢ Cardiovascular: murmurs +/- radiation, apical heave, reduced femoral pulses,
oedema, hepatomegaly (CCF)
➢ Abdomen: masses, palpable kidneys, flank bruits
➢ Genitourinary: ambiguous/virilized genitalia (eg CAH)
31
2) Ranges of BP to suspect HTN and determination of severity:
• Ensure the correct cuff size is selected for each patient, favoring a larger rather
than smaller cuff (smaller cuff creates artificial hypertension)
✓ BP cuff width should be 40% of the length of the arm measure from the shoulder
tip to the elbow
✓ Abnormal oscillatory BP measurement needs checking with a manual BP from the

child's arm
• The table below identifies BP levels requiring further evaluation, starting with
repeating the BP manually ensuring accurate measurement
*Screening BP Values Requiring Further Evaluation
Age (years) Blood pressure (mmHg)
Boys Girls
Systolic Diastolic Systolic Diastolic
1 98 52 98 54
2 100 55 101 58
3 101 58 102 60
4 102 60 103 62
5 103 63 104 64
6 105 66 105 67
7 106 68 106 68
8 107 69 107 69
9 107 70 108 71
10 108 72 109 72
11 110 74 111 74
12 113 75 114 75
≥13 120 80 120 80

* 90th centile for a child at average height
32
Blood Pressure Classification in Children and Adolescents

For children aged 13-17
For children aged 1 to 13 years
years
Normal Blood
<90th centile <120/<80 mmHg
Pressure
≥90th centile to <95th centile or 120/80
Elevated Blood
mmHg to <95th centile (whichever is 120/<80 to 129/<80 mmHg
Pressure
lower)
≥95th centile to <95th centile + 12 mmHg or
Stage 1
130/80 to 139/89 mmHg (whichever is 130/80 to 139/89 mmHg
Hypertension
lower)
Stage 2 ≥95th centile + 12 mmHg, or ≥140/90
≥140/90 mmHg
Hypertension mmHg (whichever is lower)
Severe Hypertension
>180/120
>95th centile + 30 mmHg without
Hypertensive without symptoms/signs of
symptoms/signs of target end organ
Urgency target end organ damage (See
damage (See Examination)
Examination)
>180/120
>95th centile + 30 mmHg associated with associated with
encephalopathy, encephalopathy,
Hypertensive eg headache vomiting, vision changes and eg headache vomiting, vision
Emergency neurological symptoms (facial nerve palsy, changes and neurological
lethargy, seizures, coma) +/- target-end symptoms (facial nerve palsy,
organ damage lethargy, seizures, coma) +/-
target-end organ damage
* Use this AAP Pediatric Hypertension Guidelines - MDCalc for plotting the exact centile
33
3) Management
34
Medical Management:
• Should be commenced if:
✓ Conservative measures have failed

✓ Symptomatic hypertension develops
✓ Stage 2 hypertension with no modifiable risk factors
✓ Hypertension in setting of chronic kidney disease/diabetes
• Medical management should only be commenced in consultation with a general

or renal pediatrician
✓ Long-acting calcium channel blockers such as amlodipine or captopril +/

frusemide are recommended as first line therapy.
Consider consultation with local pediatric team when:
• Red flags (see history section above) or ongoing concerns are present
• Hypertensive urgency or hypertensive emergency
References:
1. Dionne, J. Updated guideline may improve the recognition and diagnosis of

hypertension in children and adolescents; review of the 2017 AAP blood
pressure clinical practice guideline. Current Hypertension Reports. 2017. vol 19
(10), p84.
2. Flynn, J.T et al. Clinical practice guideline for screening and management of
high blood pressure in children and adolescents. Pediatrics. 2017 vol 140 (3)
35
Pediatric Chest Pain
• The majority of children presenting with chest pain as a primary complaint do not
have a cardiac or other serious underlying disorder.
Major features of the principal causes of chest pain in children and

relevant investigation/treatment:
Signs and Symptoms Diagnosis Prognosis/Management
1-Musculoskeletal: 25-55% a-Costochondritis Pain resolves with NSAIDs and rest.

May last many months, very rarely
Sharp, anterior chest wall pain
needs intra-articular steroids
over multiple costochondral
junctions
• Usually first to fifth ribs
• Pain on palpation. No
swelling
Sharp localised pain at one

Pain resolves with NSAIDs and rest.
costochondral junction
Lasts up to 2 months 7
• Tender, swollen (1–4 cm
mass), not hot b-Tietze’s syndrome
• Most frequently 2nd or 3rd

costochondral junction
Sudden short sharp pains often Reasurrance

on left side of chest, usually
in healthy teenagers and young c- Precordial
adults. The origin of this pain "catch"
is unknown
36
2-Respiratory: 7-20%
Wheeze ± dyspnea a-Asthma/wheeze Trial of bronchodilator2
Exercise-induced asthma can
often cause chest pain with
exercise even in the absence of
wheeze
Sharp, sudden onset chest pain CXR

with significant dyspnoea
b.Pneumothorax Conservative/interventional
• Pain diffuse on the affected management
side with radiation to
ipsilateral shoulder
3-GIT: 3-6%
Retrosternal burning Gastro-oesophageal Trial of reflux treatment
reflux,oesophagitis,
• Pain associated with posture,
gastritis
eating
• Epigastric tenderness
• Associated dysphagia
suggests oesophageal origin
4-Non –organic 1-9% Psychogenic Reassurance ± psychological support

Pain often fleeting or vague or
localised over precordium +/or
left arm
• History of stressful events
• Other recurrent somatic
complaints, including
headache or abdominal or
extremity pain
37
5- Idiopathic: 12-52% Reassurance
6- Miscellaneous: 4-11%
Acutely painful vesicular rash Herpes Zoster Analgesic
Pain may precede rash
7-Cardiac 0.6-1% a-Pericarditis ECG to assess for widespread ST

elevation
• Sharp (anterior/precordial)
Inflammatory markers/ Cardiology
• Exacerbated by leaning
referral
forward
• ± systemic upset
ECG (± prolonged ECG monitoring

Palpitations
b-Arrhythmia such as Holter Monitor) ± cardiology
• Dyspnoea referral
Syncopal episodes (especially ECG reviewing QTc and PR intervals,

on exercise) delta waves, T wave changes
c-HOCM/aortic
• ± abnormal cardiac Cardiology referral
stenosis/long QT,
examination findings
• ± family history of hereditary
heart disease
Central crushing chest pain ±

radiating to jaw and arm ECG for signs of ischaemia
d-Myocardial
• Associated sweating, nausea ischaemia Cardiology referral
and pallor
38
Cardiac Red flag:
1. Personal past or current history of acquired or congenital cardiac disease

2. Exertional syncope
3. Exertional cardiac-type chest pain
4. Hypercoagulable or hypercholesterolaemic state
5. Family history of sudden death under 35 years of age young onset ischaemic
heart disease, inherited arrhythmias such as long QT syndrome or Brugada
6. Implantable cardioverter defibrillators in situ
7. Connective tissue disorders
8. History of cocaine/amphetamine use
The most important step in initial assessment is identifying signs of

cardiorespiratory distress:
✓ Dyspnoea, tachypnoea, increased work of breathing

✓ Hypoxia
✓ Abnormal pulse or blood pressure
✓ Poor perfusion
✓ Distended neck veins, muffled heart sounds
✓ Depressed mental state
39
Pediatric Chest Pain Flowchart
40
References:
1. Collins SA, et al. Arch Dis Child Educ Pract Ed 2014;99:122–126.

doi:10.1136/archdischild-2013-303919
2. Gal Garbut et al. Paediatric Chest Pain. Paediatrics in Review AAP. 2020
https://publications.aap.org/pediatricsinreview/articleabstract/41/9/469/958/Ped
iatric-Chest-Pain
3. Anne M. Proulx. Paediatric Chest Pain. Am Fam Physician. 2009. 80(6):617-
620. https://www.aafp.org/afp/2009/0915/p617.html
4. Turner, A et al. Boerhaave Syndrome Stat Pearls. 2021/
https://www.ncbi.nlm.nih.gov/books/NBK430808
5. Royal Children’s Hopsital COVID-19 Clinical Practice Guideline
https://www.rch.org.au/clinicalguide/guideline_index/COVID-19
41
Guidelines on Fever with Rash/Kawasaki Recognition
Background:
• Kawasaki Disease (KD) is the second most common vasculitis in childhood after
Henoch Schönlein purpura, and is the most common cause of acquired heart
disease in children in high-income countries. Lack of appropriate treatment leads
to coronary artery aneurysms (CAA) in approximately 25% of cases.
• Worldwide distribution, although more common in Asian children.
• Approximately 75% of cases occur under 5 years of age.
• Less common in children <6 months and >5 years; however, these children are
more likely to develop CAA.
• Can present without all diagnostic criteria (see flowchart below) which can
present a significant diagnostic challenge.
Assessment:
History:
• Physical findings can present sequentially over a number of days; thus, history
should include asking about diagnostic features that may have resolved by the
time of presentation.
42
Examination:
Kawasaki disease: Diagnostic Criteria
Fever persisting for 5 days, PLUS 4 of the 5 following criteria:

• A diagnosis earlier than 5 days can be made with a typical presentation in consultation with an
experienced clinician
• KD can be diagnosed with less than four of the following features if coronary artery abnormalities are
present
Criterion Features
Conjunctival Injection
Bilateral, non-exudative, painless. Often with limbic sparing (zone
around the iris is clear)
Rash
Erythematous polymorphous rash occurs in the first few days,
involving trunk and extremities Variable presentations, most commonly
maculopapular, erythema multiforme-like or scarlatiniform Bullous,
vesicular, or petechial rashes are not typical in KD
Oral Changes
Strawberry Tongue
Erythema, dryness, cracking and bleeding of the lips DiPuse
oropharyngeal erythema
Exudates are not typical of KD
Extremity Changes
Hyperaemia and painful oedema of hands and feet that progresses to
desquamation from the second week of illness
Lymphadenopathy
Cervical, most commonly unilateral, tender. At least one node >1.5cm.
Less common feature and seen in older children
43
Common findings in addition to the diagnostic criteria include:

✓ Neurological: irritability, aseptic meningitis
✓ GIT symptoms: abdominal pain, vomiting, diarrhea, gallbladder hydrops
✓ Arthralgia / arthritis
✓ Dysuria
✓ Inflammation at recent (within 6 months) BCG vaccination site
"KD is a medium vessel vasculopathy; any organ system can be affected"
Incomplete Kawasaki Disease:
Consider in a child with a clinical presentation suggestive of KD but not meeting

the full diagnostic criteria:
• Requires abnormal investigation results to support the diagnosis (see flowchart)

• Infants and adolescents often present with an incomplete picture and are at a
higher risk for cardiac complications
Consider incomplete KD in:
• A child with fever for at least 5 days combined with 2 or 3 of the principal
clinical features OR
• An infant with one/more of the following features:
✓ Fever *7 days +/- irritability without other explanation
✓ Prolonged fever and unexplained aseptic meningitis
• A child or infant with prolonged fever and:

✓ Shock
✓ Cervical adenitis not responsive to oral antibiotics
• Incomplete KD can present a significant diagnostic dilemma, however once the

diagnosis is made, the treatment for KD and incomplete KD is identical
44
Incomplete Kawasaki
Source:
▪ Adapted from the American Heart Association (2017).
Differential Diagnosis:
✓ Group A streptococcal infections: tonsillitis, scarlet fever, acute rheumatic
fever
✓ Viral infections including EBV, CMV, Adenovirus, HHV-6, SARS-CoV-2
✓ Systemic juvenile idiopathic arthritis (JIA)
✓ Sepsis
✓ Toxic shock syndrome (staphylococcal or streptococcal)
✓ Stevens-Johnson syndrome
✓ Drug reaction
✓ Malignancy
45
Management:
Investigations:
• There is no diagnostic test for KD. Laboratory tests provide support for
diagnosis, assessment of severity, and monitoring of disease and treatment.
• Echocardiogram: discuss with cardiology specific timing of initial and follow-
up studies, Suggested schedule:
✓ At presentation (this should not delay initiation of treatment)
✓ 2 weeks
✓ 6 weeks
“Coronary artery lesions should be managed in consultation with pediatric

cardiology and haematology services”
• In all patients consider:

✓ FBC, CRP, ESR, UEC, LFT (note ESR result unreliable after IVIg
administration)
✓ Blood culture
✓ ASOT
✓ Serum to store (prior to IVIg administration)
✓ Urinalysis and culture (sterile pyuria)
✓ COVID-19 swab
✓ ECG
“Common abnormalities include elevation of ESR, CRP and neutrophils

Thrombocytosis is common in the second week of illness”
46
Treatment:
1. Intravenous Immunoglobulin (IVIg): 2 g/kg as a single IV infusion on diagnosis
• IVIg should be given within the first 10 days of illness but should also be given to
children diagnosed after 10 days if there is evidence of ongoing fever and/or
inflammation
• A second dose of 2 g/kg IVIg should be given to children who do not respond to the
first dose, as demonstrated by persistent or recurrent fevers 36 hours after the end of
the first IVIg infusion. Seek specialist advice
• The National Blood Authority and BloodSTAR coordinate and authorise the use of
blood products. IVIg is a product that must be ordered via their website
(https://www.blood.gov.au/bloodstar)
• Haemolytic anaemia is an uncommon but recognised adverse effect of IVIg infusion,

particularly for children receiving multiple doses. It typically occurs up to a week after
IVIg administration
• Post IVIg vaccination: live vaccines (eg measles and varicella) should be deferred after
IVIg administration, see the National Immunisation Handbook
(https://immunisationhandbook.health.gov.au/resources/handbook-tables/table-
recommended-intervals-between-immunoglobulins-or-blood-products-and). If the
child is at high risk of measles, vaccinate and re-vaccinate after the appropriate period
2. Aspirin:
• Acute phase 50 mg/kg/day taken with IVIg
• Then continue with 3-5 mg/kg orally as a daily dose until normal echo on follow up
(minimum 6 weeks)
• There is minimal risk of Reye syndrome with low-dose aspirin
• Avoid non-steroid anti-inflammatory medications whilst on aspirin
47
3. Corticosteroids:
• Evidence for indication and optimal dose/duration of adjunctive steroids in the primary
treatment of KD is limited
• Corticosteroid use in KD should be considered in consultation with specialist advice
• Consider use in high-risk groups and in recurrent KD

4. Additional Treatments:
• A number of therapies are available for consideration in patients who are not
responsive to initial IVIg. These options should only be used in consultation with KD
specialists and include biological medicines such as infliximab
Consider Discharge When:
• Afebrile and well at least 36 hours after treatment
• Children are on a daily dose of aspirin (see treatment point 2 above)
• A follow-up plan is in place including general pediatric review and repeat

echocardiograms planned with pediatric cardiology
48
References:
1. American Heart Association. (2017). Diagnosis, treatment, and long-term
management of Kawasaki Disease. Circulation, 135.
2. DOI: 10.1161/CIR.0000000000000484
3. Bernard, R., Whittemore, B., & Scuccimarri, R. (2012). Hemolytic anemia
following intravenous immunoglobulin therapy in patients treated for Kawasaki
disease: a report of 4 cases. Pediatric Rheumatology Online Journal. 10. doi:
10.1186/1546-0096-10-10 (https://dx.doi.org/10.1186%2F1546-0096-10-10)
4. Butters, C., Curtis, N., Burgner, D. P. (2020). Kawasaki disease fact check:
Myths, misconceptions and mysteries. J Paediatr Child Health, 56(9), 1343-
1345.
5. Cohen, E. & Sundel, R. (2016). Kawasaki Disease at 50 years. JAMA
Paediatrics, 170(11). Pp. 1093 — 1099.
6. Dallaire, F. et al. (2017). Aspirin dose and prevention of coronary abnormalities
in Kawasaki Disease. Paediatrics, 139(6). DOI: e20170098
7. Dhanrajani, A., Chan, M., Pau, S., Ellsworth, J., Petty, R., & Guzman, J. (2017).
Aspirin dose in Kawasaki Disease: the ongoing battle. Adhritis Care & Research,
70(10), pp. 1536-1540. DOI: 10.1002/acr.23504
8. Guo Yang Ho, L. Curtis, N. (2017). What dose of aspirin should be used in the
initial treatment of Kawasaki Disease? Archives of Disease in Childhood, 0, pp
1 — 3. Doi: 10.1136/archdischiId-2017-313538
9. Hedrich, C. M., Schnabel, A., & Hospach, T. (2018). Kawasaki Disease.
Frontiers in Pediatrics, 6(198). doi: 10.3389/fped.2018.00198
10.Ho, L. G. Y., Curtis, N. (2017). What dose of aspirin should be used in the initial
treatment of Kawasaki disease? Arch Dis Child,
11.102(12), 1180-1182
12.Huuang, X., Huuang, P., Zhang, L., Xie, X., Gong, F., Yuuan, J., & Jin, L.
(2018). Is aspirin necessary in the acute phase of Kawasaki disease? Journal of
Paediatrics and Child Health, 54, pp. 661-664. doi:10.1111/jpc.13816
13.Jiang, L., Tang, K., Levin, M., Irfan, O., Morris, S. K. et al. (2020). COVID-19
and multisystem inflammatory syndrome in children and adolescents. Lancet
Infectious Diseases. DOI:https://doi.org/10.1016/S1473-3099(20)30651-4
(https://doi.org/10.1016/S1473- 3099(20)30651-4)
49
14.Marchesi, A. et al. (2018). Kawasaki disease: guidelines of the Italian Society of

Pediatrics, part I — definition, epidemiology, etiopathogeneis, clinical
expression and management of the acute phase. Italian Journal of Pediatrics
44(102). doi.org/10.1186/s13052-018-0536-3
15.Perth Children’s Hospital clinical practice guidelines. (2018). Kawasaki
Disease. https://pch.health.wa.gov.au/For-health- professionals/Emergency-
Department-Guidelines/Kawasaki-disease (https://pch.health.wa.gov.au/For-
health- professionals/Emergency-Department-Guidelines/Kawasaki-disease)
16.Phuong, L., K., Chen, K. Y., Burgner, D. P., & Curtis, N. (2020). What
paediatricians need to know about the updated 2017 American Heart Association
Kawasaki disease guideline. Arch Dis Child 105(1), 10-12
17.Phuong, L. K., Curtis, N. Gowdie, P., Akikusa, J., & Burgner, D. (2018).
Treatment options for resistant Kawasaki Disease.
18.Paediatric Drugs, 20(1), 59-80.
19.Rigante, D., Andreozzi, L., Fastiggi, M., Bracci, B., Natale, M. F., & Esposito
S. (2016). Critical overview of the risk scoring systems to predict non-
responsiveness to intravenous immunoglobulin in Kawasaki Syndrome.
International Journal of Molecular Sciences, 17 (278).
doi:10.3390/ijms17030278
20.Sevenoaks, L., & Tulloh, R. (2020). Should we use steroids as primary therapy
for Kawasaki disease† Archives of Disease in Childhood Published Online First:
03 August 2020. doi: 10.1136/archdischiId-2020-319231
21.Singh, S., Jindal, A. K., & Pilania, R. K. (2018). Diagnosis of Kawasaki disease.
International Journal of Rheumatic Diseases, 2f, pp. 36-44.
22.Starship Clinical Guidelines. (2015). Kawasaki Disease.
https://www.starship.org.nz/guidelines/kawasaki-disease/
(https://www.starship.org.nz/guidelines/kawasaki-disease/)
23.Wardle, A. J., Connolly, G. M., Seager, M. J., & Tulloh, R. M. R. (2017).
Corticosteroids for the treatment of Kawasaki disease in children (Review).
Cochrane Database of Systematic Reviews. DOI:
10.1002/14651858.CD011188.pub2.
24.Younger, D. (2019). Epidemiology of the Vasculitides. Neurologic Clinics, 37
(2), pp. 201
50
Recurrent Chest Infections
• Recurrent lower respiratory tract infection can be regarded as ≥3 annual episodes

of documented bronchitis, bronchiolitis, or pneumonia and may merit further
investigation for an underlying cause
2) Red flags suggesting an underlying cardiac disease and prompting
Echocardiography:
• Family history or features suggestive of a genetic disorder
• Signs of chronic illness, such as lethargy and recent weight loss
• Abnormal physical signs when the child is well, including digital clubbing and
abnormal auscultatory signs
• Wet cough for >8 weeks continuously, no matter how well the child seems
• Failure to thrive
3) Common confounding differential diagnosis:
✓ Persistent bacterial bronchitis
✓ Tuberculosis
✓ Pertussis
✓ Asthma
✓ Foreign body
4) Algorithm for management:
Red flags present
Yes:
No: Refer for

Echocardiography
Proceed with adequate
caloric intake
Source:
▪ Couriel J. Assessment of the child with recurrent chest infections. Br Med Bull.
2002;61:115-32. doi: 10.1093/bmb/61.1.115. PMID: 11997302.
51
Failure to Thrive (Slow Weight Gain)
Background:
Slow weight gain describes a child or infant whose current weight, or rate of
weight gain is significantly below that expected for age and sex, or if weight has
dropped ≥2 major percentile lines.
Growth Charts:
• <2 years of age: WHO growth standards. Correct for prematurity (<37 weeks)
until 2 years old
• ≥2 years of age: CDC growth reference charts
• Use specific growth charts (eg Down, Turner syndrome) where appropriate
Source:
▪ Growth charts for Down syndrome and Turner syndrome are available at:
✓ http://www.rch.org.au/genmed/clinical_resources/Growth_Resources/
✓ https://www.magicfoundation.org/Growth-Charts/
✓ https://www.cdc.gov/ncbddd/birthdefects/downsyndrome/growth-charts.html
Average Growth:
• Although the use of a growth chart is the most accurate indication of overall
growth the use of average weekly weight gain for children who are followed
up at frequent intervals may be required the rate of weight gain per week is
variable.
• The table below is a guide to the expected average weight gain per week (it is
not the minimally acceptable weight gain)
0 to 3 months 150–200 g/week
52
2) Red Flag Signs and Symptoms Suggesting cardiac Causes of Failure to

Thrive:
✓ Murmur
✓ Edema
✓ Jugular venous distention
✓ Dysmorphic features
✓ Failure to gain weight despite reinstitution of adequate caloric intake
✓ Recurrent or severe respiratory infection
✓ Dysphagia (vascular ring)
✓ Cyanosis
3) Algorithm of Management:
Consider consultation with local pediatric team and transfer when:

✓ Significant malnutrition, illness or dehydration
✓ Failed outpatient management
✓ Concern about potential child abuse or neglect
✓ Significant mental health concern in parent
✓ For further assessment of feeding technique, parent–child interaction and
involvement of a multidisciplinary team
✓ Severe malnutrition, underlying cause or contributing factors requiring specialist
input
✓ Child requiring care beyond comfort level of local services
53
References:
1. Homan, G 2016, Failure to thrive: A practical guide, Am Fam Physician, vol.
94, no. 4, pp. 295-299
2. Jaffe, C 2011, Failure to thrive: Current clinical concepts, Pediatrics in
Review March, vol. 32, no. 3, pp. 100-108
3. Nice guideline 2017, Faltering growth: Recognition and management of
faltering growth in children. Nice guideline [NG75} Nice guideline, Viewed
May 2020 https://www.nice.org.uk/guidance/NG75
4. Marchand, V 2012, The toddler who is falling off the growth chart, Paediatr
Child health, vol. 17, no. 8, pp 447-450
5. McAlpine, J 2019, Growth Faltering: The New and the Old, Clin Pediatri, vol.
2, article 1012
6. Motil KJ 2020, Poor weight gain in children younger than two years in
resource-rich countries: Etiology and evaluation up to date, Up to date, Viewed
May 2020 https://www.uptodate.com/
7. Queensland Government 2015, Chronic Conditions Manual: Prevention and
management of chronic conditions in Australia, Queensland Government
Publications, Viewed May
2020 https://www.publications.qld.gov.au/dataset/chronic-conditions-manual
8. Starship clinical guidelines 2016, Faltering growth -failure to thrive, Starship,
Viewed May 2020 https://www.starship.org.nz/guidelines/faltering-growth-
failure-to-thrive/
9. Standish, J 2020, Slow Growth, Paediatric Handbook 10th Ed, WILEY
Blackwell, The Royal Children’s Hospital, Melbourne
10.The Sydney children’s hospitals network, Common newborn concerns, The
Sydney Children’s hospitals network, Viewed May
2020 https://www.schn.health.nsw.gov.au/fact-sheets/common-newborn-
concerns
11.Women’s and Children’s Hospital 2017, Tips for gaining weight for infants and
toddlers factsheet, Women’s and Children’s Health network , Viewed May
2020 http://www.wch.sa.gov.au/services/az/other/nutrition/underweight.html
54
Diagnostic Utility of Anti-Streptolysin O Titer

in Pediatric Cardiology Practice
I.Pattern of rise of Antistreptolysin O (ASO) antibodies following pharyngeal

infection:
• Antistreptolysin O (ASO) antibodies are produced about a week to a month after an

initial clinical or subclinical streptococcal pharyngeal, but not, skin infection. The
amount of ASO antibody titer peaks at about 4 to 6 weeks after the illness and then
tapers off but may remain detectable for several months after the streptococcal
infection has resolved.
II.Indications of ASO Titer testing:
1. Children seen with symptoms or signs suggestive of either of rheumatic fever

(RF), acute glomerulonephritis or poststreptococcal reactive arthritis (PSRA) in
order to document a recent streptococcal infection with group A beta hemolytic
streptococci had occurred to establish a causal relationship.
2. Children with recurrent sore throat to document that the recurrence is primarily
related to repeated streptococcal infection with group A (GAS) rather recurrent
viral pharyngitis, particularly if throat culture is positive that may represent a
carrier state rather a concurrent GAS infection
3. Children with past the history of rheumatic fever or rheumatic heart disease
(RHD) and under prophylactic therapy with benzathine penicillin G (BPG) for
secondary prevention. An elevated or rising titer is a proof of recent or recurrent
subclinical streptococcal pharyngitis and subsequently failed secondary
prevention and liability for future rheumatic fever recurrence
55
III.ASO level in Egyptian children:
1. In healthy adults a titer more than 200 IU /mL is considered an elevated titer
2. The ULN (80th percentile) of ASO titer in asymptomatic healthy Egyptian
children is 400 IU/mL owing to repeated subclinical streptococcal infection in
our community, a level more than this 400 IU/mL is considered elevated titer.
3. The ULN (80th percentile) of ASO titer in children with history of recurrent
streptococcal pharyngitis may reach up to 1600 IU/mL and is related to repeated
infections that results in sustained or continuously rising titer.
IV.Clinical scenarios, interpretation and action plan in children seen with

elevated ASO titer more than 400 IU/ Ml:
• The management of children presenting with elevated ASO titer is related to the
clinical scenarios and the indications for ASO titer testing as requested by the
pediatrician.
Clinical scenario Interpretation Action Plan
Children presenting without

clinical symptoms or signs A higher titer is not related
suggestive of major to the current minor illness Parents has to be assured
manifestation of rheumatic and simply reflect, a recent for this benign phenomenon
fever eg: vague extremity or recurrent uncomplicated and BPG should not be
pain, growing pain, chest streptococcal pharyngitis prescribed or given in a
pain of musculoskeletal that is totally unrelated to clear-cut message
cause or innocent murmur the current minor problems.
that is made louder by fever
Note:
▪ The pediatrician should NOT order for ASO titer in these previous
scenarios
56
Clinical Scenario Interpretation Action Plan
A higher titer supports the Patients should be treated

Children presenting with diagnosis of RF by strict as the initial attack of
migratory polyarthritis or application of updated rheumatic fever and
carditis criteria for diagnosis of RF,
managed accordingly
2015
Note:
▪ Evidence of a preceding streptococcal infection will reduce, but not
eliminate, the possibility of other diseases presenting with polyarthritis
as JIA, SLE, serum sickness or leukemia. Such diseases need to be in
mind before a definitive diagnosis of RF is made. Also, revision of the
initial diagnosis as RF is justified if the therapeutic response to acetyl
salicylic acid is absent or delayed
Children presenting with

arthritis of acute onset,
symmetric or asymmetric, A high ASO titer support Patient should be treated as
non-migratory affecting any the diagnosis of Post- PSRA with anti-
joint, persistent or recurrent streptococcal reactive inflammatory therapy and
with poor response to arthritis (PSRA) secondary prevention is
salicylate or NSAIDs justified for 2 years
together with lack of other
major manifestations of RF.
57
Tonsillectomy is
recommended (by applying
Children presenting with the current indications for
history of recurrent sore tonsillectomy in children
throat that might reflect A high ASO titer confirm with recurrent tonsillitis)
either recurrent the diagnosis of recurrent oral penicillin short term 3-6
streptococcal pharyngitis or streptococcal pharyngitis months of BPG every two
recurrent viral pharyngitis weeks if the frequency of
recurrence is less than
required for tonsillectomy.
Every effort must be done

Children with history of RF
to ensure good compliance
(arthritis or chorea) or A rising titer confirms the with BPG by revision of the
established RHD and diagnosis of recurrent dose and the frequency of
assumed to be under subclinical streptococcal injections or encouraging
secondary prevention pharyngitis and possible more compliance eg by
program with BPG prophylaxis failure. adding lidocaine to BPG
prophylaxis.
prior to IM injection.
58
V.Clinical scenarios in which the diagnosis of the initial attack of rheumatic

fever is definite
• Definite initial episode of ARF is established by: 2 major manifestations +

evidence of preceding group A Streptococcal infection, or 1 major + 2 minor
manifestations + evidence of preceding group A Streptococcal infection
Major Manifestations:
✓ Carditis (including subclinical evidence of rheumatic valvulitis on echocardiogram):
new murmur suggestive of mitral and /or aortic regurgitation with or without cardiac
enlargement, heart failure or pericarditis
✓ Polyarthritis: always migratory affecting large joints
✓ Sydenham chorea
✓ Erythema marginatum
✓ Subcutaneous nodules
Minor Manifestations:
✓ Fever ≥38.5 °C
✓ Polyarthralgia
✓ ESR ≥60mm/h or CRP ≥6mg/dL
✓ Prolonged P-R interval on ECG
59
VI.Clinical scenarios in which the diagnosis of the initial attack of rheumatic

fever is probable:
• Children with age between 5:15 years presenting with clinical presentation in
which ARF is considered a likely diagnosis but it falls short in meeting the
criteria as:
A. Recent history (maximum 4 weeks) with overt joint pain in large joints of migratory
nature without objective findings (migratory polyarthralgia) or
B. Recent history of clinical evidence of mono-arthritis in a large joint after exclusion
of trauma or septic arthritis. These patients have to be managed as follows:
I.Action Plan(A-G):
✓ Avoid premature administration of anti-inflammatory therapy and even withhold
it if prescribed in sub therapeutic dose. paracetamol is a good choice to control
pain
✓ Begin antibiotic therapy for possible previous GAS infection for 10 days to abate
the immune response to possible streptococcal antigen.
✓ Close bed side clinical assessment for evolution of typical migratory joint
involvement or clinical carditis (major criteria)
✓ Exclude subclinical carditis by color Doppler echocardiography initially and
within the ongoing two weeks (major criteria).
✓ Establish a recent evidence of GAS infection by rising titer of ASO so that such
rise is causally related rather a mere coincidence
✓ Fulfill the requirement of strong positive acute phase reactants by elevated ESR
=>60mm/h or CRP=> 6mg/dl
✓ Gather all physical and laboratory findings to rule out other possible causes of
joint diseases as juvenile idiopathic arthritis (JIA), reactive arthritis secondary
to recent viral infection, SLE, serum sickness or possible malignancy
II.Establishment of the diagnosis of probable rheumatic fever:
• Mono-arthritis or migratory polyarthralgia may occur with increasing

frequency in rheumatic fever, so a probable rheumatic etiology of such pure
joint involvement is established and managed accordingly if associated with the
combination of the following three requirements:
1. A significant acute phase response (ESR:60mm /H, or CRP =>6mg/dl),
2. Recent evidence of GAS infection by rising titer of ASO (two samples at least
one week apart), so that such rise is causally related,
3. Other possible or overt causes of joint involvement as JIA, viral, autoimmune
septic arthritis are ruled out.
60
VII.Major differentiating points between growing pains and subacute

rheumatic arthralgia:
Joint Pains of Subacute Rheumatic Fever Growing Pains
During entire day, disappears on getting At end of day or soon after

Timing warm in bed, worse on first getting out of falling asleep, free of pain in
bed in the morning morning
In muscles of thigh or legs. No

In joints. Pain on motion. Child points out
pain on motion. Child vague in
Location pain in joints. Involves joints in upper
pointing out site of pain. Pain in
extremities. May cause limping.
upper extremities unusual
References:
1. Ayoub EM, Ahmed S: Update on complications of group A streptococcal

infections. Curr Probl Pediatr. 1997, 27 (3): 90-101.
2. Gewitz MH, Baltimore RS, Tani LY, et al. Revision of the Jones Criteria for the
diagnosis of acute rheumatic fever in the era of doppler echocardiography: a
scientific statement from the american heart association. Circulation 2015;
131:1806–18.
3. Kotby AA, Habeeb NM, El Elarab SE. Antistreptolysin O titer in health and
disease: levels and significance. Pediatr Rep 2012; 4:68–70.
4. Riise OR, Lee A, Cvancarova M, Handeland KS, Wathne KO, Nakstad B:
Recent-onset childhood arthritis--association with Streptococcus pyogenes in a
population-based study. Rheumatology. 2008, Oxford, 47 (7): 1006-11.
10.1093/rheumatology/ken122.
5. Shet A, Kaplan EL. Clinical use and interpretation of group A streptococcal
antibody tests: a practical approach for the pediatrician or primary care physician.
Pediatr Infect Dis J 2002; 21:420–426.
61
Cardiac Murmurs
Red Flags of Cardiac Illness:
• Symptoms of age-related exertional dyspnea / exercise intolerance; recurrent

chest infections; chronic cough; syncope; cyanosis; palpitations; chest pains;
developmental delay
• Signs of abnormal growth; dysmorphism; delayed capillary refill; weak femoral
pulse; displaced apical impulse; parasternal heave/ thrill; abnormal S2;
hepatomegaly; edema
• History of antenatal maternal illness or drug exposure; familial sudden
unexplained death, congenital heart disease or rheumatic heart disease
Reference:
▪ Frank JE & Jacobe JM. Evaluation and Management of Heart Murmurs
in Children. Am Fam Physician. 2011 Oct 1;84(7):793-800.
62
63
64
Pediatric Neurology Emergencies Protocol of EHA
Protocol of EHA
0
Protocol of EHA

in
Pediatric Neurology Emergencies
for
First Edition
2024
Prepared by
of
in
Pediatric Neurology Emergencies
for
1
Protocol of EHA
Executive Committee
1. Prof..Omnea Elrashidy: Professor of Pediatric Neurology, Ain Shams University.
2. Prof. Marian Yousry: Professor of Pediatric Neurology, Cairo University.

3. Prof. Hoda Tamoum: Professor of Pediatric Neurology, Ain Shams University.
4. Prof. Abdelrahim Abdrabou Sadek: Professor of Pediatric Neurology, Sohag
University.
5. Prof. Hanan Azouz: Professor of Pediatric Neurology, Alexandria University.
6. Dr.Walaa Elnaggar: Assistant Professor of Neurology, Cairo University.
7. Dr. Sherry Kodsy Abdel-Massih: Pediatric Neurology Consultant, AFCM
(Moderator)
2
Protocol of EHA
Disclaimer

under their care.
3
Protocol of EHA

Authority (EHA).
Reviewed By



4
Protocol of EHA
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric Neurology
Emergencies is to unify and standardize the delivery of healthcare to any child at all
health facilities.
Pediatric Neurology Emergencies service is usually offered to children below 16

years of age in Egypt.
Regarding Pediatric Neurology Emergencies, busy clinicians have all felt the
need for a concise, easy-to-use resource at the bedside for evidence-based protocols,
or consensus-driven care paths.

to those delivering care at the bedside in for patients in Pediatric Neurology
Emergencies.
In Pediatric Neurology Emergencies
5
Protocol of EHA
Table of Contents
Page
Title
Number
Preface 5
Altered Mental Status 9
CNS Infection 14
Acute Disseminated Encephalomyelitis 22
Stroke 31
Status Epilepticus 41
Acute Flaccid Paralysis 47
Appendix 52
Investigations And Drugs 54
6
Protocol of EHA
AChR Acetylcholine Receptor Antibodies
ABG Arterial Blood Gases
ADEM Acute Disseminated Encephalomyelitis
AIS Arterial Ischemic Strokes
ALT Alanine Transaminase
AMS Altered Mental Status
ANA Antinuclear Antibodies
ANCA Antineutrophilic Cytoplasmic Antibody
Anti DNA Anti Deoxyribonucleic Acid
APTT Activated Partial Thromboplastin Time
AST Aspartate Transaminase
BP Blood Pressure
BUN Blood Urea Nitrogen
CA Catheter Angiography
CBC Complete Blood Count
CPK Creatinine Phosphor-Kinase Enzyme Assay
CPR C-Reactive Protein
CSF Cerebro-Spinal Fluid
CSVT Cerebral Sinovenous Thrombosis
CT Computerized Tomography
ECG Electrocardiogram
ED Emergency Department
EEG Electroencephalogram
EGRIS Erasmus Gbs Respiratory Insufficiency Score
ESR Erythrocyte Sedimentation Rate
GBS Guillain Barre Syndrome
GCS Galasgow Coma Score
GGT Gamma Glutamyl Transferase
HIV Human Immunodeficiency Virus
HR Heart Rate
HSV Herpes Simplex Virus
ICHs Intracranial Hemorrhages
ICP Intracranial Pressure
IM Intramuscular Injection
IPMSSG International Pediatric Multiple Sclerosis Society Group
IV Intravenous
IVIG Intravenous Immunoglobulins
K Potassium
7
Protocol of EHA
LDH Lactate Dehydrogenase

LMWH Low Molecular Weight Heparin
LP Lumbar Puncture
MCA Middle Cerebral Artery
MELAS Mitochondrial encephalomyopathy, lactic
acidosis, and stroke-like episodes
Mg Magnesium
MMR Measles, mumps, and rubella
MRA Magnetic resonance angiography
MRI Magnetic resonance imaging
MRI Magnetic resonance imaging of the brain
MTHFR Methylene Tetrahydrofolate Reductase
Deficiency
Na Sodium
NCV/EMG Nerve conduction velocity/ Electromyogram
NMO Neuromyelitis optica
PCR polymerase chain reaction
PICU Pediatric Intensive Care Unit
PRES Posterior reversible encephalopathy syndrome
PT Prothrombin time
RCTs Randomized controlled trials
RDS Respiratory Distress Syndrome
RR Respiratory rate
SCD sickle cell disease
SCIG subcutaneous immunoglobulin
SpO2 Oxygen saturation
TIA Transient Ischemic Attack
tPA tissue plasminogen activator
TPE Total Plasma Exchange
TRALI transfusion-related acute lung injury
TRFs Treatment related fluctuations
TSH thyroid stimulating hormone
UTI Urinary tract infection
VZV Varicella zoster virus
8
Protocol of EHA
Altered Mental Status
➢ How to approach the child presenting to the emergency department (ED)

with altered mental status (AMS)?
History taking: To search for the possible Etiology
a) History of consanguinity, developmental history and history of seizures: for

possible underlying inborn error of metabolism.
b) Infection: intracerebral (meningitis, encephalitis), extracerebral (pneumonia, UTI),
and
c) Para-infectious: ADEM/ Autoimmune encephalitis: history of preceding infection/
vaccination.
d) Metabolic: hypoxia, electrolyte derangement, hypoglycemia, and
renal/pulmonary/hepatic insufficiency, hypothyroidism/ thyrotoxicosis.
e) Trauma (accidental/ non-accidental injury).
f) Toxins or drugs: steroids, anticonvulsants, narcotics, and recreational drugs, heavy
metals.
g) Vascular: TIA, stroke, intracranial hemorrhage, and hypertensive encephalopathy.
h) Endocrine: thyroid, adrenal, and parathyroid dysfunction.
i) CNS pathology: mass lesion, epilepsy (post-ictal, status epilepticus, nonconvulsive
status epilepticus), and paraneoplastic (autoimmune) encephalopathies.
j) Hydrocephalus: 1st episode (post intraventricular hemorrhage, CNS infection,
tumor), or due to shunt failure.
k) Psychiatric (diagnosis of exclusion).
l) History of chronic illness/ drug history: e.g. in PRES
9
Protocol of EHA
Examination findings
a) Vital signs (heart rate, respiratory rate, temperature, blood pressure, capillary refill
time).
b) Pallor, bulging Fontanelles.
c) Signs of mastoiditis, otitis media.
d) Evidence of drug use (e.g. skin marks).
e) Evidence of non-accidental injury: bruises – burns- fractures.
f) New heart murmur (cardioembolic events).
g) Organomegaly: e.g. hepatomegaly in Wilson disease, Reye and Reye like
syndromes, sepsis...etc.
h) Evidence of underlying systemic vasculitis/ collagen disease: rash– alopecia-
arthralgia.
i) Full neurologic exam (attention to: level of alertness, pupillary responses, CNS
deficits, withdrawal to pain, and nystagmus/ finger-nose- finger exam).
j) Bedside fundus exam: retinal hemorrhage, papilledema.
Glasgow Coma Score: (See appendix)
• Consider assessing and recording conscious level at presentation using the Glasgow
Coma Score/modified Glasgow Coma Score (GCS) in a child who presents with a
decreased conscious level.
• Consider assessing and recording the Glasgow Coma Score/modified Glasgow
Coma Score (GCS)every 15 minutes in a child with a decreased conscious level if
GCS is equal to or less than 12.
10
Protocol of EHA
ABC Airway, Breathing and Circulation++
 CBC w/ diff, CRP, ESR  Blood culture

Labs: Before  Chemistry*  Full toxicology screen.
 Finger stick glucose  TSH, free T4
Treatment
 PT/PTT, INR,  ABG
 Urine analysis, urine culture  Ammonia, Lactate
ECG  For associated arrhythmia/ ischemia
 If GCS less than 8

Intubate  If evidence of herniation (see)
 If unable to protect the airway
Evidence of  Give mannitol bolus 1 g/kg

 PICU request
Herniation
 Neurosurgery consultation.
 If evidence of motor status/subtle status (eg: tonic eye deviation or

TTT of status nystagmus) see epilepsy protocol
 Non contrast Brain CT (if MRI unavailable in ED)

Neuroimaging  MRI brain +C/ DWI/ACD when stable; consider MRA/MRV stroke protocol
according to the presentation (e.g., signs of lateralization). Add sagittal T2
in cases of query ADEM/other demyelinating syndromes.
11
Protocol of EHA
In cases of potential CNS  Start empirical antibiotics + Antiviral (Acyclovir) + IV

infection: dexamethasone (0.15 mg/kg/dose qds). (See in meningitis plan)
(if any of the following): Consider antifungal therapy$
-Any child < 12 months  DO NOT POSTPONE ANTIMICROBIAL THERAPY for lumbar
-Fever puncture or NEUROIMAGING.
-Seizures  Neuroimaging (at least CT brain) should be obtained before LP.
-Signs of meningeal  Lumbar puncture (LP) See later
irritation  CSF should be observed for tension/ turbidity and sent for cytology,
-History of otitis media/ chemistry (glucose, proteins, lactate**, glycine**), culture and
mastoiditis.etc sensitivity, Gram stain, bacterial and viral panel PCR, may add
-History of antibiotics Fungal culture$ and ZNS/ PCR for M-TB^
(partially treated meningitis)
 Labs (in addition to above): urine organic acids, extended metabolic

screening
 Nutrition:
o Stop feeds
o Start IV fluids in the form of NS in D10 ratio 1:1, with potassium
according to urine output and serum potassium level
In Query IEM  Acid/base & electrolytes: follow up samples every 6 hours
 Bicarbonate: Up to 20–40 mmol/kg to correct metabolic acidosis
 Na benzoate: 250 mg/kg load, then 250 mg/kg/d infusion or NG: 250-
500 mg/kg/day in divided doses.
 Supplements:
o Vit. B12 1 mg IM
o Biotin 10 mg once a day
o Thiamine 50 mg once a day
o L-carnitine 25 mg/kg/dose /6h (total dose 100 mg/kg/day)
PICU request:
 Head position: Head midline and elevated 30°C
 Hypertonic saline: Goal serum Na+ 145–155. For 23% NS, give 15–30 cc via
central line and then q6h. For 3% NS, up to 50 cc/h per peripheral line up to
Management 12 h, a central line required.
 Mannitol: Bolus 1 mg/kg bolus over 10–20 min and then Q6h.
of increased
Contraindicated with low BP, anuria. Hold further doses if serum osmolarity
ICP >320, serum Na+>160
(irrespective  Hyperventilate: pCO2 goal of ~30 mm Hg
of cause)  Labs: serum osmolarity, fluid balance q6h
 Neurosurgery consult: Hydrocephalus, persistent increased ICP, mass effect,
large stroke, and posterior fossa mass/hemorrhage
 Treat seizures: Seizures will further increase ICP
 Temp: maintain normothermia
 Blood sugar: maintain euglycemia
 Collagen markers (ANA, Anti DNA, C3, C4, ANCA) in cases with query vasculitis.
Additional tests  Serum ceruloplasmin & Slit lamp exam in cases of query Wilson disease
(Non-exhaustive List)  Consider pelvi-abdominal sonography/ CT for patients with autoimmune CNS disease
(paraneoplastic phenomena)
 Consider Urine catheter insertion by pediatric surgery team. Consider assessing and recording
the Glasgow Coma Score/modified Glasgow Coma
 Chemistry: Na, K, BUN, Creatinie, Albumin, Total protein, Calcium, Phosphorus, ALT, AST,
ABG with AG, Alkaline phosphatase, GGT, Mg, total and direct billirbin, LDH, uric acid.
12
Protocol of EHA
How to suspect brain herniation:

 Impaired mental status,
 Fixed mid-position of the pupils, impaired upward gaze
 Central neurogenic hyperventilation
 Decorticate followed by decerebrate posturing
 Pupils constricted and breathing irregular.
 Unilateral CN III palsy, with contralateral hemiparesis
 Neck stiffness, lower cranial nerve neuropathy.
“THIS can be verified by neuroimaging.”
Idiopathic increased intracranial hypertension (IIH/ pseudotumor cerebri)
•
 Typically, the headache pain is • Lumbar puncture with CSF manometry) provides
moderate and chronic and may be critical diagnostic information. For diagnosis, we need to
progressive. establish increased pressure as greater than 250 mm
 Headaches often resemble migraine CSF measured by lumbar puncture performed in the
or a tension-type headache. lateral decubitus position and without sedative
 Physical activity, including the medications. [ May need neurosurgeon for CSF
Valsalva maneuver and postural manometry to verify the diagnosis]
changes, can aggravate the pain.
 Neck stiffness and transient visual
disturbances may be present. • Neuroimaging is needed to exclude other causes. MRI,
MR Venography, and CT studies usually yield normal
results.
The majority of patients with IIH have
papilledema.
• IIH can be caused by multiple disorders, including
endocrinopathies (e.g., hypothyroidism), Addison’s
disease, oral steroid use, pregnancy, medications
(including tetracycline, sulfonamides, lithium,
cyclosporine, and oral contraceptive agents), vitamin A
intoxication, anemia, systemic lupus erythematosus,
chronic sinopulmonary infection, and obesity, or may be
idiopathic.
Acetazolamide can be used to lower CSF pressures, most likely as a result of a diuretic mechanism.
The dose is typically 250 mg twice a day up to 1000 mg per day. Recovery is slow, over weeks or
months. If obesity is a contributing factor, a weight-loss program is strongly recommended. If the
visual symptoms are severe or progressive, or if there is visual compromise, surgical intervention
may be necessary, with performance of an optic nerve sheath fenestration.
13
Protocol of EHA
CNS Infection
Algorithm for management of encephalitis

Clinical Features Suspicious of Encephalitis *
Clinical Contraindication to Immediate LP? (See appendix)
NO YES
If delay (>6 hours)

If delay (>6 hours)
expected: Start IV
Urgent CT expected: Start IV
Aciclovir whilst
Aciclovir whilst results pending
results pending
Radiological contraindication
NO to Immediate LP (see appendix)
YES
Lumbar Puncture Opening pressure: CSF Review every

and serum glucose: CSF Protein, Microscopy, 24 hours:? LP
Culture and sensitivity, Virology PCR: lactate.
NO YES IV Aciclovir
Repeat LP after CSF findings
24-48 hours suggest (adjust for renal failure) Given
Encephalitis? 8 hourly: Neonate-3 months:
20mg/kg 3 months-12 years:
500mg/m >12 years: 10mg/kg
Neuro-imagining if not yet performed (Ideally MRI <24-48 hours)
HSV/VZV Encephalitis confirmed

HSV PCR in the CSF is
negative on two
Immunosuppressed? Or age 3 months-12 years? occasions 24-48 hours
apart, and MRI Alternate
imaging is not Diagnosis
NO YES characteristic for HSV
Encephalitis ****
14 days IV Aciclovir 21 days IV Aciclovir
Aciclovir can be
Repeat LP stopped in an
PCR positive? immunocompetent Treatment as
child appropriate
NO YES
Stop Aciclovir 7 days IV Aciclovir

14
Protocol of EHA
*Clinical features suspicious of Encephalitis
 The constellation of a current or recent febrile illness with altered

behavior, cognition or consciousness or new onset seizures or new
focal neurological signs should raise the possibility of Encephalitis.
 Encephalopathy is suspected if a past history of similar episodes,
symmetrical neurological findings, myoclonus, clinical signs of liver
failure, a lack of fever, acidosis or alkalosis.
****The differential diagnosis of viral encephalitis:
 Metabolic, toxic, autoimmune causes or sepsis outside the cns)

should be considered early, especially if there are a past history of
similar episodes, symmetrical neurological findings, myoclonus,
clinical signs of liver failure, a lack of fever, acidosis or alkalosis
 Adem and acute necrotizing encephalitis (refer to management of
adem)
 Many patients will need a CT before a LP, because of their clinical

contraindications to an immediate LP; such patients should have a
CT, and then ideally a LP should be considered on a case by case basis
(if still indicated and no radiological contraindications are identified)
within 6 hours.
15
Protocol of EHA
Acute necrotizing encephalitis caused by Covid 19
Child presented with respiratory symptoms (fever, cough, RDS) associated

with
Neurological Symptoms: irritability, altered mental status , apnea up to
convulsions and coma
Lumbar Puncture (if no contraindication): CSF monocytosis, high protein,

normal glucose
CT /MRI BRAIN: bilateral symmetrical swollen thalamic nuclei ad bilateral
temporal lobe affection
 C.B.C.: Lymphopenia
 CRP: Positive
 Rapid test or Nasopharyngeal swab PCR: Positive
YES NO
Other differential diagnosis:

Acute necrotizing encephalitis VIROLOGY PCR PANEL
due to Covid 19 e.g. Influenza encephalitis or other
viral encephalitis
Start treatment ASAP

1. PICU admission
2. IVIG 2gm/KG over 5 days
3. I.V. Solumedrol 30mg/kg for 5 days
16
Protocol of EHA
Diagnosis and treatment of acute bacterial meningitis

Clinical characteristics in children with bacterial meningitis
• Neonates with bacterial meningitis: often present with nonspecific symptoms
such as irritability, poor feeding, respiratory distress, pale or marble skin and
hyper- or hypotonia. Fever is present in a minority (6–39%) of cases. Seizures
are present in less than 30%. Respiratory distress or failure is frequently reported
as one of the initial symptoms of neonatal meningitis. The diagnosis of neonatal
meningitis cannot be ruled out by clinical examination alone, and therefore a low
threshold should be kept in neonates with suspected bacterial meningitis to
perform a lumbar puncture
• In children beyond the neonatal age: the most common clinical characteristics
of bacterial meningitis are fever, headache, neck stiffness and vomiting. There
is no clinical sign of bacterial meningitis that is present in all patients. Bacterial
meningitis in children can present solely with nonspecific symptoms
• In all children with suspected bacterial meningitis: It is strongly recommends
cerebrospinal fluid examination, unless contraindications for lumbar puncture
are present (see in Fig.1 causes of Imaging before lumbar puncture).
• In neonatal meningitis, CSF leukocyte count, glucose and total protein levels
are frequently within normal range or only slightly elevated.
• In children, classic characteristics (elevated protein levels, lowered glucose
levels, CSF pleocytosis) of bacterial meningitis are present in _90% of patients .
Normal Bacterial Viral Tuberculous Fungal

Opening
Normal /
Pressure 12–20 Raised Raised Raised
mildly raised
(Cm CSF)
Purulent,
Clear or
Appearance Clear turbid, Clear Clear or cloudy
cloudy
cloudy
<5 mainly
CSF WBC Raised Raised (5– Raised (5–
mononuclear Raised (5–100)
(cells/μL) (>100) 1000) 100)
cells
Predominant
n/a Neutrophils Lymphocytes Lymphocytes Lymphocytes
Cell
CSF Protein Markedly
20-40mg/dl Raised Mildly raised Raised
(mg/dl) raised
CSF/ Plasma Normal /
>0.66 Very low Very low Low
Glucose Ratio slightly low
CSF Glucose Normal /
45–65 Very low Very low Low
(mg/dl) slightly low
Lactic Acid
<3.5 raised Not raised Mildly raised Mildly raised
(mmol/l)
17
Protocol of EHA
Neonates with bacterial meningitis

often present with nonspecific
symptoms. Patient with suspected meningitis
In children, the most common

clinical features are fever,
headache, neck No contraindications: Do lumbar Contraindication for
stiffness and vomiting. Puncture (CSF glucose, protein, LB: - Do blood
cytology, culture and sensitivity, Gram culture - brain
stain, bacterial and viral panel PCR imaging (4-8)
Delay lumbar puncture if:1- signs of
sepsis or shock,2-anticoagulant
therapy or thrombocytopenia,3- Start Start
local infection at site of L.B.,4- dexamethazone dexamethazone
respiratory or cardiac compromise,5- and impric and impric
focal neuralgic signs, 6-papilledema, antibiotic antibiotic
7-continuous uncontrolled treatment treatment
seizures,8- GCS≤ 10-12 according to
expert opinion
CSF findings are consistent If

with meningitis with If negative contraindicatio
- Start antibiotic therapy as soon as If no more ns are still
positive culture or Gram CSF findings,
possible s. The time period until stain, treat according to it.
causes to present,
consider delay Lumbar continue
antibiotics are administered should not
exceed 1 hr. Whenever lumbar puncture - If not, continue impric alternative Puncture, do dexamethason
is delayed, empiric Treatment must be treatment for a minimum diagnosis it and mange e with impric
started immediately on clinical suspicion, of 2 weeks or consider PCR treatment for a
accordingly
even if the diagnosis has not been minimum of 2
established. weeks
- Dexamethasone should be started
either shortly before or simultaneously
with antibiotics (iv) 6-hourly. Up until 12
hours after Antibiotic initiation,
dexamethasone can still be started.
The advised dexamethasone

regimen in children is 0.15 mg/kg
every 6 hours , for a duration of 4
days. Corticosteroids significantly
reduced hearing loss and neurologic
sequelae
Figure (1): Algorithm for diagnosis and treatment of acute bacterial

meningitis
18
Protocol of EHA
Table (1): Empiric antibiotic in-hospital treatment for community-acquired

bacterial meningitis
Reduced Streptococcus S.
Patient pneumoniae pneumoniae
Intravenous doses
Group antimicrobial sensitivity to susceptible
penicillin to penicillin
Age <1 week: cefotaxime
50 mg/kg q8h;
ampicillin/amoxicillin
50 mg/kg q8h; gentamicin
Amoxicillin/ampicillin/penicillin
2.5 mg/kg q12h
plus
Neonates <1 Age 1–4 weeks: ampicillin
cefotaxime, or
month old 50 mg/kg q6h; cefotaxime
amoxicillin/ampicillin
50mg/kg q6–8h;
plus an aminoglycoside
gentamicin 2.5 mg/kg q8h;
tobramycin
2.5 mg/kg q8h; amikacin
10 mg/kg q8h
Vancomycin 10–15 mg/kg

q6h to achieve serum trough
concentrations of 15–20
μg/mL; rifampicin 10 mg/kg
Cefotaxime or ceftriaxone plus Cefotaxime or
Age 1 month q12h
to 18 years vancomycin or rifampicin ceftriaxone
up to 600 mg/day; cefotaxime
75 mg/kg q6–8h; ceftriaxone
50 mg/kg q12h (maximum 2 g
q12h)
Other adjunctive treatments:

• Osmotic agents such as mannitol or hypertonic saline have not been studied in RCTs or
comparative studies of bacterial meningitis patients. Therefore, there is insufficient
evidence to guide advice on this treatment.
• Routine adjuvant therapy with acetaminophen, antiepileptic drugs is not recommended.
They must be used only when are indicated. Hypothermia are contraindicated in bacterial
meningitis
• Use of intracranial pressure/cerebral perfusion pressure monitoring and treatment can be
life-saving in selected patients but cannot be recommended as routine management.
19
Protocol of EHA
Specific antibiotic in-hospital treatment for community-acquired bacterial meningitis
Microorganism Standard treatment Alternatives Duration

Streptococcus pneumoniae
Penicillin susceptible (MIC <0.1 μg/mL), Penicillin or Ceftriaxone, cefotaxime 10–14 days
amoxicillin/ampicillin
Penicillin resistant (MIC >0.1 μg/mL),

third-generation cephalosporin Ceftriaxone, cefotaxime Cefepime, meropenem, 10–14 days
susceptible (MIC <2 μg/mL) moxifloxacin
Cephalosporin resistant (MIC ≥ 2 Vancomycin plus

μg/mL) Vancomycin plus 10–14 days
aminoglycosides (neonate),
moxifloxacin, linezolid
or
vancomycin plus
ceftriaxone or
cefotaxime, or rifampicin
plus ceftriaxone or
cefotaximec
Neisseria meningitidis
Penicillin or
Penicillin susceptible (MIC <0.1 μg/mL) amoxicillin/ampicillin
Ceftriaxone, cefotaxime, 7 days
Ceftriaxone or cefotaxime
Penicillin resistant (MIC _0.1 μg/mL) Cefipime, meropenem, 7 days
ciprofloxacin or
chloramphenicol
Listeria monocytogenes Amoxicillin or ampicillin, meropenem, linezolid At least 21 days

penicillin G, aminoglycoside
Haemophilus influenzae
β-Lactamase negative Amoxicillin or ampicillin Ceftriaxone, cefotaxime 7–10 days
Cefepime, ciprofloxacin
Ciprofloxacin
β-Lactamase positive Ceftriaxone or cefotaxim 7–10 days
β-Lactamase negative ampicillin Ceftriaxone or cefotaxime 7–10 days

resistant plus meropenem
Staphylococcus aureus
Methicillin sensitive Flucloxacillin, oxacillin Vancomycin, linezolid, At least 14 days
Methicillin resistant Vancomycinf linezolid, At least 14 days
Vancomycin resistant (MIC >2.0 μg/mL) Targocid linezolid, At least 14 days

The specific antibiotic treatment in bacterial meningitis patients is based on antimicrobial susceptibility testing.
20
Protocol of EHA
Acute Disseminated Encephalomyelitis
 Definition
Acute disseminated encephalomyelitis (ADEM) is an immune-mediated,
inflammatory demyelinating disease of the central nervous system (CNS).
 Diagnosis
➢ The diagnosis of ADEM is clinical and confirmed by neuroimaging.
➢ International Pediatric Multiple Sclerosis Society Group (IPMSSG)

diagnostic criteria For ADEM
(All Are Required)
✓ A first polyfocal, clinical central nervous system event with presumed
inflammatory demyelinating cause*.
✓ Encephalopathy that cannot be explained by fever.
✓ No new clinical and MRI findings emerging three months or more after the onset;
✓ Brain MRI is abnormal during the acute (three months) phase.
✓ Typically, on brain MRI:
• Diffuse, poorly demarcated, large (>1–2 cm) lesions involving predominantly
the cerebral white matter.
• T1 hypointense lesions in the white matter are rare;
• Deep grey matter lesion (e.g., thalamus or basal ganglia) can be present.
•
❖ Detailed Information:
❑ Clinical Presentations
✓ It is thought to be the result of an autoimmune and inflammatory process of
the CNS triggered by an environmental event, such as infection or
vaccination occurring in genetically susceptible individuals.
✓ Typically, patients show prodromal symptoms; fever, headache, malaise,
nausea, and vomiting.
✓ Encephalopathy; altered behavior (e.g., irritability, confusion) and
consciousness (lethargy, stupor, coma)
✓ Multifocal or focal neurological deficits depending on the area involved in
the demyelinating process (blindness, aphasia, pyramidal affection, sensory
deficits and parathesia of limbs, cranial nerves affection, spinal cord lesions
leads to flaccid paralysis and sphincteric disturbances)
✓ Seizures
21
Protocol of EHA
 Approach to cases of possible ADEM
Acute Encephalopathy, Neurologic and Systemic

Manifestations
Detailed History and Examiantion

Consider CBC*, CSF analysis**, culture, viral PCR if
available and blood culture, ESR***, CRP****
If positive for CNS infection,

If negative for CNS infection#
treat accordingly
do MRI Brain
Suspect Consider
demyelinating Differential
disease diagnoses*#
- If fulfil ADEM criteria, treat as ADEM

and
- Assess for myelitis
- Assess for optic neuritis
Do antibodies if available:
- Aquaporin 4IgG
- MOG antibodies
-Zoligoclonal bands and Igg index
 *Leukocytosis is common (predominantly due to lymphocytosis)
 **Refer to guidelines of Lumbar Puncture in Meninigitis
 ***The erythrocyte sedimentation rate
 **** C-reactive protein concentration may be increased
 #CSF: Evidence of inflammation is common in cerebrospinal fluid (CSF), with
pleocytosis(lymphocytic and monocytic predominance) and/or increased protein concentration in the
majority of patients. However, the CSF can also be normal.
 *#Differential Diagnosis
• If polysymptomatic encephalopathy occurs (movement disorder, seizures, psychosis);
autoimmune encephalitis should be considered such as anti-NMDA receptor encephalitis,
limbic encephalitis, Hashimoto encephalitis and Rasmussen encephalitis
• Metabolic conditions should be considered in very young age and family history
• CNS malignancies,
• Nutritional,
• Toxic
• Neurometabolic disorders (especially Mitochondriopathies)
22
Protocol of EHA
“ADEM must be distinguished from other central inflammatory demyelinating conditions of
childhood, including multiple sclerosis and clinically isolated syndromes that include optic neuritis,
transverse myelitis, and neuromyelitis optica spectrum disorders”
 Approach to treatment of cases of ADEM
Hospital admission,
supportive care and
Rehabilitative services
IV methyl prednisolone at 10-

30mg/kg/day or Dexamethasone at
1mg/kg/d
for 3-5 days the followed by oral
steroids tapered over 4-6 weeks
NO response or NO reposonse or
contraindication to contraindications to
steroids steroids or
fulminant ADEM
IV IG 2gm/kg
given over 2-5 days Plassma Pharesis
+/- second steroids for 4-6 cycles
pulse therapy
23
Protocol of EHA
 Treatment of ADEM
The mainstay of treatment for ADEM is high-dose

intravenous Corticosteroids. Corticosteroids may be
started at the time of the patient's presentation and can
be used concurrently with antibiotics and acyclovir.
Bacterial and viral meningitis or encephalitis must be
considered and ruled out. Empiric treatment with
broad-spectrum antibiotics and acyclovir should be
considered until an infectious etiology is excluded.
First Tire Management Intravenous methyl prednisolone (10 to 30 mg/kg per
day, maximum 1000 mg daily) or
Intravenous Corticosteroids
Dexamethasone (1 mg/kg per day) for three to five
days, followed by oral corticosteroids taper over four
to six weeks.
(taper with oral prednisone 1-2 mg/kg per day up to a

maximum of 60 mg per day and then reduce the dose
by 10 mg every five days to allow for a total tapering
duration of four to six weeks)
• (IVIG) is beneficial as rescue therapy in patients with
Second Tire ADEM who fail to respond or have an insufficient
response to methylprednisolone or as initial therapy
• Considered first line in patients have contraindications
Intravenous Immune Globulin to steroid therapy or recurrent episodes.
(IVIG): • Regimen: IVIG for a total dose of 2 g/kg given over
2–5 days
• It is used in steroid-resistant ADEM
• In patients with contraindications to steroids, as an
alternative to IVIG
• A rescue therapy when response to IVIG is not
Third Tire satisfactory
• For patients with ADEM who have longitudinally
extensive transverse myelitis
Plasma Exchange • In early stages if patients have fulminant course
• Regimen: a total of six exchanges, one every other

day, with each exchange consisting of 1 to 1.5 plasma
volumes.
It is important to start a program of early rehabilitation

to ensure mobilization and the improvement of gait,
Rehabilitation Therapy muscle strength, coordination skills, and cognitive
skills
24
Protocol of EHA
 Follow up and prognosis and specific entities
➢ Follow-up MRI shows complete or partial resolution of abnormalities in the

majority of ADEM cases. However, residual gliosis and demyelination persist
in some.
➢ It is suggested that reassessing patients is advisable with at least 2 additional
MRIs (e.g., 3 months and 9-12 months after clinical onset) to rule out ongoing
disease activity indicating a diagnosis other than ADEM.
➢ However, frequency and timing of reimaging will have to consider age and
clinical characteristic.
➢ Long-term follow-up should be performed to document recovery and to
confirm the diagnosis of ADEM.
➢ The occurrence of relapses suggests alternative diagnoses, such as multiphasic
ADEM or multiple sclerosis.
➢ Most children with ADEM make a full recovery, usually slowly over four to
six weeks.
➢ At follow-up, approximately 60 to 90 percent have minimal or no neurologic
deficits.
25
Protocol of EHA
The clinical features of ADEM typically follow a monophasic disease course, although
they can fluctuate in severity and evolve in the first three months following disease onset.
Monophasic ADEM Any new and fluctuating symptoms occurring within three months of the initial event are
considered to be part of the same inciting event.
Is defined as two episodes consistent with ADEM separated by three months, irrespective
of glucocorticoid use, but not followed by any further events. The second ADEM event
Multiphasic ADEM can involve either new or a re-emergence of prior neurologic symptoms, signs and MRI
findings. By definition, both the first and second event must include a clinical presentation
with encephalopathy
Relapses beyond a second event are no longer consistent with ADEM, and indicate a
chronic disorder such as multiple sclerosis or neuromyelitis optica. The initial ADEM
event is considered the first attack of the chronic disease in this regard
Relapses beyond a
A second or additional attack that does not include encephalopathy and occurs three or
second event more months after the first episode can be considered to either represent multiple sclerosis
if the MRI findings meet the radiologic criteria for dissemination in space, or to represent
neuromyelitis optica if associated criteria are met
 Severe involvement may progress to an acute hemorrhagic
Acute Hemorrhagic leukoencephalopathy (Hurst disease)
Leukoencephalopathy  With large lesions, edema, mass affect,
(Hurst disease)  A polymorphonucleated cell pleocytosis (in contrast to lymphocytic
pleocytosis in the CSF noted in typical ADEM)
 It is a rare, severe encephalopathy seen more commonly in Asian countries.
 It is thought to be triggered by a viral infection (influenza, HHV-6) in a
genetically susceptible host.
Diagnostic Criteria
1. Acute encephalopathy following (1-3 days) a febrile disease. Rapid
deterioration in the level of consciousness. Seizures.
2. No cerebrospinal fluid pleocytosis. Increase in cerebrospinal fluid protein.
3. CT or MRI evidence of symmetric, multifocal brain lesions. Involvement of
the bilateral thalami. Lesions also common in the cerebral periventricular white
matter, internal capsule, putamen, upper brainstem tegmentum and cerebellar
medulla. No involvement of other central nervous system regions.
4. Elevation of serum aminotransferases of variable degrees. No increase in
blood ammonia.
5. Exclusion of resembling diseases.
A. Differential diagnosis from clinical viewpoints.
Acute Necrotizing Overwhelming bacterial and viral infections, and fulminant hepatitis; toxic shock,
Encephalopathy hemolytic uremic syndrome, and other toxin-induced diseases; Reye syndrome,
hemorrhagic shockand encephalopathy syndrome, and heat stroke.
B. Differential diagnosis from radiologic viewpoints.
Leigh encephalopathy and related mitochondrial cytopathies;glutaric acidemia,
methylmalonic acidemia, and infantilebilateral striatal necrosis; Wernicke
encephalopathy andcarbon monoxide poisoning; acute disseminated
encephalomyelitis, acute hemorrhagic leukoencephalitis,other types of
encephalitis, and vasculitis; arterial or venousinfection, and the effects of severe
hypoxia or head trauma
The elevation of hepatic enzymes without hyperammonemia is a unique feature.
A familial or recurrent form is associated with mutations in the RANBP2 gene and
is designated ANE1.
MRI finding are characterized by symmetric lesions that must be present in the
thalami.
The prognosis is usually poor.
26
Protocol of EHA
 Pharmacopeia
Intravenous Immunoglobulin (IVIG)
❑ Pretreatment is given for IVIG:
✓ Acetaminophen (15 mg/kg),

✓ Diphenhydramine (1.5 Mg/Kg, Maximum Dose 25 Mg), And
✓ Dexamethasone (1 Mg).
❑ Infusion rate
• Infusions are started at a rate of 0.5 to 1 mL/kg/hour for the first 15 to 30 minutes,
and if no adverse reaction occurs, then the rate can be increased subsequently
every 15 to 30 minutes to a maximum of 3 to 6 mL/kg/hour.
• Dose fractionation should also be considered to decrease the possibility of any
adverse reaction.
❑ Adverse Effects
• Adverse reactions can be either immediate or delayed and can be of different

severity.
• Immediate reactions can be mild, moderate, and serious.
• These occur within 30 to 60 minutes of the start of IVIG infusion and are reported
in 5% of patients.
• The most common generalized side effects are mild in severity and include
headache, fever, chills, and fatigue. These effects are attributable to the excipients
and stabilizers contained in the preparation.
• Sugar-depleted preparations are now available with only amino acids as a
stabilizing agent.
• Most of these reactions are mild and transient and attributed to a particular IVIG
product and its infusion rate.
• Vomiting, chest pain, and headache classify as moderate reactions.
• Mild-to-moderate reactions can be mitigated with symptomatic treatment,
premedication, slowing the transfusion rate, lowering the dose or withdrawing,
and replacing with a different IVIG preparation.
27
Protocol of EHA
❑ Serious Adverse Reactions
• The most common of these include headache, myalgia, back pain, nausea, vomiting,
rash, fatigue, malaise, tachycardia, erythema, flushing, fever, hypotension or
hypertension, and fluid overload.
• Severe uncommon side effects include urticaria, severe headaches, dyspnea, pruritus,
thromboembolic events, and hemolytic reactions. Serious rare effects are transfusion-
related acute lung injury (TRALI), acute renal failure, anaphylaxis to IgE or IgG
antibodies to IgA (in IgA deficiency), arrhythmias, aseptic meningitis, arthritis,
hepatitis, pleural effusion, or other dermatological manifestations.
❑ Delayed reaction
• Less than 1% of patients may have a delayed reaction, including renal impairment,
transfusion-related infection, and hematological and neurological disorders.
• Solvent-related adverse effects such as the high volume of infusions as needed in some
liquid formulations can lead to volume overload in patients with cardiac or renal
conditions and require appropriate attention using concentrated IVIG preparations or
subcutaneous immunoglobulin (SCIG) therapy.
• Adverse effects are preventable with certain premedication, including non-steroidal anti-
inflammatory drugs, antihistamines, corticosteroids, or saline for pre-hydration.
❑ Contraindications
 Thus the contraindications are related to the particular component of the

IVIG product.
1. Sugar-stabilized IVIG products should be avoided in patients with renal failure or
diabetes.
2. Hyperosmolar IVIG products are not for post-transplantation patients due to the risk
of renal failure and osmotic nephropathy.
3. High sodium-containing products should be used cautiously for individuals with
cardiac conditions and hypertension.
4. Severe anaphylactic reactions are rare and have been reported when using IVIG
products due to the presence of IgG or IgE anti-IgA antibodies in patients with IgA
deficiency. Paradoxical use of IgA-depleted IVIG or a SCIG preparation is suggested
in the treatment of patients with IgA deficiency.[81]
5. Measles, mumps, and rubella (MMR) vaccine should not be administered in children
receiving IVIG therapy, as the IgG could counter the attenuated virus in the vaccine
preparation and render them inactive. Thus vaccines should be delayed for at least
nine months after the IVIG therapy or vice versa.
28
Protocol of EHA
❑ Toxicity
 There are reports of renal toxicity with sucrose-containing products, in patients

greater than or equal to 65 years, patients receiving concomitant nephrotoxic
agents, patients with diabetes mellitus, those with pre-existing renal disease,
hypovolemia, and sepsis. These patients are all at increased risk for acute renal
failure and renal insufficiency.
 Urine output, blood urea nitrogen, and creatinine require assessment in patients
with an increased risk of developing acute renal failure. There is also a report of
cardiac toxicity after IVIG therapy in a patient with scleromyxedema, where it
resulted in myocardial infarction.
 Hematological toxicities, including various cytopenias and thrombotic
complications, have also been reported and should be considered in patients with
an increased risk of thrombosis.
Intravenous Methylprednisolone (Available in Egypt as Solumedrol)
• For intravenous infusion the initially prepared solution may be diluted with 5%
dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline
solution.
• To avoid compatibility problems with other drugs Methylprednisolone powder for
injection/infusion should be administered separately, only in the solutions
mentioned.
❑ Contraindications
 Methylprednisolone powder for injection/infusion is contraindicated:

• In patients who have systemic fungal infections unless specific anti-infective
therapy is employed and in cerebral oedema in malaria.
• In patients with known hypersensitivity to methylprednisolone or any
component of the formulation.
• For use by the intrathecal route of administration.
➢ Administration of live or live, attenuated vaccines is contraindicated in patients
receiving immunosuppressive doses of corticosteroids.
29
Protocol of EHA
❖ Side Effects
 Methylprednisolone can cause short-term and long-term side effects.
A. Side effects that can occur during or shortly after an infusion include:
✓ Blood-pressure changes,
✓ Heart rate changes,
✓ Irregular heart rate,
✓ Electrolyte imbalances,
✓ Elevated blood sugar,
✓ Flushing of the skin,
✓ Sweating,
✓ Metallic taste,
✓ Difficulty sleeping,
✓ Mood or behavior changes,
✓ Psychosis,
✓ Seizures,
✓ Increased susceptibility to infection,
✓ And anaphylaxis (serious allergic reaction).
B. Long-term side effects of corticosteroids include (but are not limited to):
✓ weight gain,
✓ acne,
✓ thinning of skin,
✓ stretch marks,
✓ elevated blood sugar,
✓ elevated cholesterol,
✓ peptic ulcers,
✓ cataracts,
✓ glaucoma,
✓ weight gain,
✓ decreased bone density,
✓ increased risk of osteonecrosis of the bone,
✓ growth suppression,
✓ muscle wasting,
✓ increased susceptibility to infection.
30
Protocol of EHA
Stroke
Approach to a Child presenting with possible Stroke

(Focal neurological deficit or hemiplegia)
Consider stroke if any of

the following are
Suspect Stroke: Do not exclude
present:
- Acute focal stroke based on
neurological deficit • New onset focal seizures the presence of:
- Speech • New onset severe • Fever
disturbance headache
•Nausea/vomiting
- Unexplained, • Ataxia
persistent change • Change in
• Dizziness behaviour
in conscious level
• Resolved acute focal
neurological deficit
Obtain urgent brain imaging (within one hour of arrival at hospital)

Transfer images immediately to regional centre for review
Medical Management:
Consider intubation - Protect airway Use high flow O2 (target SpO2 >92%)
and ventilation if:
- Establish IV access and take blood samples
• GCS < 8
- Give fluid bolus 10ml/kg 0.9% NaCl
• Loss of airway
reflexes -Treat hypoglycaemia/seizures
• Signs of raised ICP - Send blood for: Venous or capillary blood
- Monitor: BP, temperature, SpO2, HR, RR, GCS
31
Protocol of EHA
 The most common underlying conditions of arterial ischemic strokes (AIS)

are:
➢ Sickle Cell Disease (SCD) And Congenital Or Acquired Heart Disease. (For
Both AIS And CSVT)
➢ Head trauma appears to be a trigger for arterial stroke.
➢ Vasculopathy (see)
➢ Anemia, leukocytosis, and prothrombotic disorders are risk factors. (for both
AIS and CSVT)
➢ Emboli: Cardiac (arrythmia, infective), fat (long bone fracture), air (surgery)
 The most common risk factors for Cerebral sinovenous thrombosis (CSV)
are:
➢ Dehydration
➢ Prothrombotic disorders
➢ Infections, including varicella, meningitis, tonsillitis, and otitis media, and
➢ Heart disease and chronic anemia (including SCD and _-thalassemia) also are
risk factors for CVST
➢ Others including trauma, cancer/ chemotherapy, and systemic disease.
➢ An estimated 10% of intracranial hemorrhages (ICHs) in the young result
from CVST.
32
Protocol of EHA
 Investigations required for ischemic stroke:
First Line Tests Second Line Tests Third Line Tests

(Within 24 hours) (Within first week if indicated) (Electively)
• MRI brain and neck • ECG, ECHO, Carotid Doppler, • HIV, mycoplasma,
• MRA Holter • Lyme disease, Cat scratch
• CTangiography • Hypercoagulable state: Serology
• Conventional Protein C and S (activity, antigen) • Cardiac MRI
angiography** Antithrombin III. -Anticardiolipin • Transesophageal ECHO
• CBC, ESR antibodies Antiphospholipid • Cerebral angiogram
• PT/APTT antibodies Factor V (Leiden) • Muscle biopsy
• Blood sugar mutation Lupus anticoagulant • Leptomeningeal biopsy
• Liver and kidney Rheumatoid factor • DNA study for MELAS
function tests • Serum amino acids • Serum homocysteine
• Serum electrolytes • Complement profile
• Chest X-ray • Hemoglobin electrophoresis
• ANA • Urine for organic acids
• Urinalysis • Serum lactate, pyruvate, ammonia
• Urine drug screen • CSF analysis
• Lipid profile
 ** Not in all cases
33
Protocol of EHA
Reported Causes of Hypercoagulable States

o Primary (hereditary) hypercoagulable states
✓ Antithrombin deficiency
✓ Protein C deficiency
✓ Protein S deficiency
✓ Activated protein C resistance with or without
factor V Leiden mutation Cerebral
✓ Prothrombin gene mutation G20210A Vasculopathies in
✓ Thermolabile variant of MTHFR children
✓ Disorders of fibrinogen
✓ Disorders of plasminogen activator inhibitor o Focal cerebral
✓ Anticardiolipin antibodies and lupus arteriopathy of
anticoagulant childhood
✓ Factor VII elevation o Cervicocephalic arterial
✓ Factor VIII elevation dissections
✓ Factor XII deficiency o Moyamoya disease and
✓ Protein C deficiency moyamoya syndrome
✓ Antithrombin deficiency o Vasculitis
✓ Protein S deficiency o Transient cerebral
o Selected secondary (acquired) hypercoagulable arteriopathy
states: Malignancy- Pregnancy (especially o Postvaricella angiopathy
postpartum period) -Oral contraceptives -Ovarian o Ergotism
hyperstimulation syndrome- Other hormonal o Traumatic
treatments (eg, anabolic steroids, erythropoietin) - cerebrovascular disease
Nephrotic syndrome -Polycythemia vera. o Radiation-induced
o Essential thrombocythemia arteriopathy
o Paroxysmal nocturnal hemoglobinuria o Tumoral encasement of
o Diabetes mellitus cervicocephalic vessels
o Hyperlipidemia o Hypoplasia and agenesis
o Elevated lipoprotein(a) of cervicocephalic vessels
o Heparin-induced thrombocytopenia o Congenital arterial
o Homocystinuria fenestration
o Hyperviscosity
o Congestive heart failure
o Sickle cell disease
o Thrombotic thrombocytopenic purpura
o Chemotherapeutic agents (ie, L-asparaginase,
mitomycin, adjuvant breast cancer therapy)
34
Protocol of EHA
 Treatment:
First week till you establish an etiology
• Low molecular weight heparin(LMWH)

0-7 days Or
• Aspirin (1 To 5 Mg/Kg/D) (Until Dissection And Embolic
Causes Have Been Excluded)
❑ According to etiology is the choice of intervention:

 A disturbance of the coagulation system is more likely in:
✓ CSVT and
✓ AIS secondary to arterial dissection,
✓ Cardiogenic thromboembolism,
✓ Prothrombotic states.
➢ Therefore, LMWH is suggested in these conditions
 Most other vasculopathies and many idiopathic strokes more likely involve
platelet-mediated mechanisms.
➢ Therefore, aspirin is suggested in those conditions
Chest Guidelines: 2008 Recommendation
Cardiac
Anticoagulation should be discussed
Or (Possibly LMWH for >6 weeks)
Dissection of neck vessels
Initial LMWH,
Cerebral sinovenous thrombosis then LMWH or Warfarin for 3months, and possibly
further 3months if not fully canalized.
35
Protocol of EHA
Protocol for Using LMWH in Children

Enoxaparin,
age-dependent dose, Initial treatment dose Initial prophylactic dose
mg/kg per 12 h
< 2 mo 1.5 0.75
>2 mo 1.0 0.5
Warfarin Anticoagulation Protocol for Children
❑ Contraindications to anticoagulation include:

 Significant Haemorrhagic Transformation
 Uncontrolled Hypertension, Or
 Known Bleeding Disorder.
36
Protocol of EHA
❑ Aspirin
• Is a reasonable option for the secondary prevention of AIS in children whose

infarction is not due to SCD and in children who are not known to have a high risk
of recurrent embolism or a severe hypercoagulable disorder.
• A dose of 3 to 5 mg/kg per day is a reasonable initial aspirin dose for stroke
prevention in children. If dose-related side effects occur with this aspirin dose, a
dose reduction to 1 to 3 mg/kg may be considered.
• In children taking aspirin for stroke prevention, it is reasonable to vaccinate for
varicella and to administer an annual influenza vaccine in an effort to reduce the
risk of Reye’s syndrome. It is reasonable to withhold aspirin during influenza and
varicella infections.
❑ Consider suitability for other emergency treatments:

 Surgical and endovascular intervention
• Selected paediatric patients benefit from decompressive craniectomy and

that recovery with good quality of life is possible even with extensive
infarction of the dominant MCA territory. Decompressive craniectomy may
also be beneficial following posterior fossa infarction in children and young
people
• Refer children and young people with moyamoya to a paediatric
neurosurgical centre with expertise in surgical revascularisation.
 Referral to interventional neuroradiology and the use of tissue

plasminogen activator (tPA) could be considered in children presenting with
AIS on a case-by-case basis.
37
Protocol of EHA
 Be aware of the following possible complications
Swallow safety for eating, drinking

Swallow and saliva control should be assessed.
Dysfunction Monitor for aspiration
If aspiration is considered likely Consider the placement of a

undertake clinical assessment, nasogastric tube
monitor oxygen saturations, blood • facilitate regular position changes in
Aspiration gases and obtain chest X ray bed and early mobilization
• ongoing management of eating,
drinking and swallow
Provide regular clinical assessment Dexamethasone may be used to reduce
sensitive to the detection of raised the severe intracranial pressure, unless
intracranial pressure (ICP); there is a definite contraindication for
this should include using it.
• Monitoring of conscious level, Mannitol can be used along with
pupil size and response, dexamethasone to reduce intracranial
• Blood pressure and heart rate tension rapidly. The combination of
Raised
• Hypertension and bradycardia acutely increased intracranial pressure
Intracranial • Reduction in conscious level is and large venous infarcts is dangerous,
Pressure ominous. (even if transient and patients can die within hours from
consider ICP monitoring) cerebral herniation.
Head should be kept elevated to 30–40
degrees and supplemental oxygen may
be given if level of consciousness is
decreased. Seizures should be treated
with appropriate anticonvulsants.
Assess clinically rather than routinely • Seizures should be managed
with electroencephalogram (EEG) according to protocol.
except when clinical assessment is not • New onset seizures may signal
possible in paralyzed and sedated further stroke or haemorrhagic
Seizures patients or when distinction between conversion and repeat brain imaging
seizure and movement disorder is not should be considered
possible on clinical grounds. • There is no evidence to support the
use of prophylactic anticonvulsant
medication
Serum electrolytes (sodium and • Maintain sodium and glucose levels
glucose) should be measured at within normal range.
Endocrine
presentation with the frequency of • Administer 3mls/kg 3% NaCl if the
Derangement repeat measurements determined sodium is less than 125mmol/L
individually
38
Protocol of EHA
Nontraumatic Hemorrhagic Stroke
Brain hemorrhage in older children presents much like in adults, with acute
headache, vomiting, and rapid deterioration of neurological function. However,
the presentation may be subtler in younger children unless the hemorrhage
involves the motor pathways or brainstem. The signs and symptoms of an ICH
can be more subtle and less specific in infants and neonates than in older children,
especially with smaller hemorrhages.
 Causes of nontraumatic intraparenchymal brain hemorrhage
39
Protocol of EHA
 Recommendations:
• Children with nontraumatic brain hemorrhage should undergo a thorough risk factor
evaluation, including standard cerebral angiography when noninvasive tests have
failed to establish an origin, in an effort to identify treatable risk factors before
another hemorrhage occurs.
• Children with a severe coagulation factor deficiency should receive appropriate
factor replacement therapy, and children with less severe factor deficiency should
receive factor replacement after trauma.
• Given the risk of repeat hemorrhage from congenital vascular anomalies, these
lesions should be identified and corrected whenever it is clinically feasible.
Similarly, other treatable hemorrhage risk factors should be corrected.
• Stabilizing measures in patients with brain hemorrhage should include optimizing
the respiratory effort, controlling systemic hypertension, controlling epileptic
seizures, and managing increased intracranial pressure.
 Follow up
• Stroke management requires multidisciplinary approach including neurologist,
hematologist and neurosurgeon and experienced radiologist in the least in addition
to the rehabilitative service.
• Be aware that MRI is the modality of choice for follow-up imaging of children and
young people with AIS as it provides the best assessment of the extent of any
permanent structural damage and of the cerebral circulation without using ionising
radiation.
• Consider the clinical circumstances and the presence of conditions predisposing to
recurrence (e.g. moyamoya or other arteriopathy) when considering the frequency
and duration of follow-up imaging in childhood AIS.
• Catheter angiography (CA) should be undertaken in children and young people with
occlusive arteriopathy, who are being considered for revascularisation; if surgery is
undertaken CA should be repeated a year after surgery.
40
Protocol of EHA
Status Epilepticus
Convulsive Status Epilepticus

In established epilepsy, status may be precipitated by:
Drug Withdrawal, Missed Doses, Intercurrent Illness, Metabolic Disturbances, Or the Progression
of The Underlying Disease, And Is Commoner in Symptomatic Epilepsy.
Most Episodes of Status, However, Develop De Novo Due to Acute Cerebral Disturbances; E.G.
Cerebral Infection, Trauma, Tumor, Acute Toxic or Metabolic Disturbances and Febrile Illness.
 Definition:
5 min or more of (i) continuous clinical and/or electrographic seizure activity
or (ii) recurrent seizure activity without recovery (returning to baseline) between
seizures.
1. Stabilize patient (airway, breathing, circulation, disability)
2. Time seizure from its onset, monitor vital signs
3. Assess oxygenation, give oxygen via nasal cannula/mask, consider intubation if needed
4. Initiate ECG monitoring
0-5 Minutes
5. Collect finger stick blood glucose. If glucose < 60 mg/dl then administer 2 mL/kg of 25% dextrose
water (D25W) via central line, or 5 mL/kg of 10% dextrose water (D10W) by peripheral IV. When the
Stabilization
patient is hypoglycemic, glucose level should be rechecked 3 to 5 minutes post-bolus, and a repeat
bolus administered if necessary.
6. Attempt IV access and collect electrolytes (Na, Ca & Mg), hematology, toxicology screen, (if
appropriate, do anticonvulsant drug levels).
At 5 Minutes Choose ONE of

Initiate
therapy • Intravenous diazepam (0.15-0.2 mg/kg/dose, max: 10 mg/dose, may repeat dose once)
Repeat at 10 • Intramuscular midazolam 0.3mg/kg OR 5mg (if the child weighs 13-40Kg), 10mg (>40Kg), single dose.
minutes if If none of the above available/ no IV access/ prehospital setting:
seizures • Rectal diazepam (0.2-0.5 mg/kg/dose, max: 20 mg/dose, single dose)
persisted • Intranasal or buccal midazolam 0.3 mg/kg per dose via the buccal route, max single dose 10mg
Choose ONE of the following second line options and give as a single dose
At 15 • Intravenous levetiracetam (60 mg/kg, max: 4500 mg/dose, single dose)
Minutes • Intravenous phenytoin (20 mg/kg, max: 1500 mg/dose, single dose)
Secondary If none of the above available, give
• Intravenous phenobarbital (15 mg/kg, max: 1000mg, single dose)
There is no clear evidence to guide therapy in this phase:

30-40 Transfer to PICU
Minutes Options include the use of another (different) second-line medication, or proceeding to the use of
Third anesthetic doses of either thiopental, midazolam, pentobarbital, or propofol (all with continuous EEG
monitoring)
41
Protocol of EHA
Pyridoxine
• For children younger than 18 months of age, seizures may be caused by an undiagnosed
metabolic disorder, especially Pyridoxine-Dependent Epilepsy (PDE).
• A trial of pyridoxine (vitamin B6) is worthwhile.
• Traditionally, a trial of 100 mg pyridoxine intravenously while monitoring the EEG,
oxygen saturation and vital signs should be considered if there is a failure to respond to
the medications described above.
• In most patients with PDE, clinical seizures will cease and a corresponding change in the
EEG will be noted. If a response is not demonstrated, the dose should be repeated up to a
maximum of 500 mg. In some patients with PDE, significant neurologic and
cardiorespiratory adverse effects followed this trial; therefore, close systemic monitoring
is essential.
• For patients who are experiencing shorter seizures which occur at least daily, the diagnosis
can be made by administering 30 mg/kg/day of pyridoxine orally/IM. Patients with PDE
who are treated in this fashion should stop having clinical seizures within a week.
 Expert Opinion
• Since there is no available B6 IV in Egypt we can use the IM form instead
❑ Seizure First Aid:
 Ease the person to the floor.
 Turn the person gently onto one side. This will help the person breathe.
 Clear the area around the person of anything hard or sharp. This can prevent injury.
 Put something soft and flat, like a folded jacket, under his or her head.
 Remove eyeglasses.
 Loosen ties or anything around the neck that may make it hard to breathe.
 Time the seizure.
 Never do any of the following:

 Do not hold the person down or try to stop his or her movements.
 Do not put anything in the person’s mouth. This can injure teeth or the jaw.
 Do not try to give mouth-to-mouth breaths (like CPR). People usually start
breathing again on their own after a seizure.
 Do not offer the person water or food until he or she is fully alert.
 When to do EEG
✓ After clinical control of convulsion to diagnose subclinical status epilepticus .
✓ After midazolam or thiopental or propofol infusion to document burst
suppression.
❑ For Second Line Drugs:
 (IV or IO access must be obtained and the on-call anaesthetist alerted)
42
Protocol of EHA
Phenytoin
❑ Route and method of administration
 Only IV:
• Give slowly, no greater than 1 mg/kg/minute. Flush with sodium chloride 0.9% before
administration.
 Loading dose:
• Should be given over approximately 1 hour via syringe pump with minimum volume
line.
• Administer as 5 mg/mL or more dilute to produce a 5 mg/mL solution. (Withdraw 1
mL of 50 mg/mL solution (50 mg) and add to 9 mL of sodium chloride 0.9% in a 10
mL syringe = 5 mg/mL)
• Once prepared, use within 1 hour.
• Following administration of exact dose of Phenytoin, infuse 2 mLs of Sodium Chloride
0.9% via the syringe pump.
• Following completion of the infusion and flush, disconnect and discard syringe and
line used for the infusion.
❑ Side Effects
 Rapid IV infusion may cause hypotension, arrythmias, bradycardia, cardiovascular
collapse and/or respiratory distress.
 Vomiting, gastric irritation.
 Thrombocytopenia, leukopenia, agranulocytosis.
 Macrocytosis and megaloblastic anaemia which respond to folic acid therapy.
 Toxicity will cause cardiovascular collapse and/or CNS depression.
 Tissue necrosis and inflammation at injection site from extravasation.
 Skin rash drug should be discontinued.
 Hypoinsulinaemia, hyperglycaemia, glycosuria.
❑ Precautions
 Observe IV site for phlebitis or tissue inflammation.
 Phenytoin is highly unstable in dextrose 5%. Therefore, dilute in sodium chloride 0.9%.
 Avoid using in central lines because of the risk of precipitation.
 If needed Maintenance dose to start 8- 12 hours after loading dose.
❑ Maintenance doses
• Given over at least 15 minutes via syringe pump.

• Or can be given orally.
• Ensure that phenytoin serum levels are monitored.
• Sample should be taken immediately before the next dose.
43
Protocol of EHA
Phenobarbitone
 Dilute to 20mg/mL in 0.9% sodium chloride.
 Administer by slow intravenous injection. Each dose must be administered over at least
20 minutes. Do not exceed 1 mg/kg/minute.
❑ Side effects
 Dose dependent respiratory depression (enhanced by diazepam), drowsiness; cutaneous
and allergic reactions, sometimes severe;
 Hypotension, apnoea, laryngospasm, shock, especially if administered too rapidly by iv
route.
 Monitor closely respiration and blood pressure during and after administration.
❑ Precautions
 Do not administer in patients with severe respiratory depression.
 Do not administer by SC route (risk of necrosis).
 Administer with caution in children, the elderly and patients with respiratory
insufficiency.
 Ensure that respiratory support (Ambu bag via face mask or intubation) and IV solutions
for fluid replacement are ready at hand.
❑ Maintenance dose
• Maintenance dose: 2.5mg - 5mg/kg (max. 300mg) once or twice daily.

• Start maintenance dose 12 hours after loading dose.
• It is given over 10minutes (no faster than 1mg/kg/minute).
44
Protocol of EHA
Levetiracetam
 It should be diluted in 100ml of sodium chloride 0.9% and administered over 10-15
minutes.
❑ Maintenance dose
• 10 – 30 mg/kg/dose q12 hours.

❑ Ongoing AED treatment
 If a patient requires 2nd line treatment, antiepileptics that have been loaded should be
continued at maintenance doses and discussed with neurology.
 The first maintenance dose of levetiracetam is close to 12 hours (10-14 hours is
acceptable) after the loading dose in order to allow regular maintenance dose
administration.
 The first maintenance intravenous dose of phenytoin should be prescribed after 6-8
hours after the loading dose.
 The first maintenance intravenous dose of phenobarbiton should be prescribed 12 hours
after the loading dose
❑ Rapid Action
 If at any point more than 30 minutes have elapsed since seizure onset, general anesthesia
should not be delayed and third line drug treatments commenced.
45
Protocol of EHA
Intervention
Rapid sequence intubation
Midazolam Continuous Infusion
• IV 0.15 mg/kg bolus then 2 g/kg/min

• Increase as needed by 2 g/kg/min q5 minutes if still convulsing
• Bolus 0.15 mg/kg with each increase in infusion rate
• Maximum infusion rate 2 mg/kg/hr ( 34 g/kg/min)
• Establish goals with guidance from specialist in neurology/critical care
• Maintain phenobarbital and phenytoin at therapeutic serum level (phenytoin
goal level, 20-30 mg/mL; phenobarbital goal level, 40-50 mg/mL).
Yes
Consider thiopental/
Do seizures pentobarbital/ propofol bolus and
persist? continuous infusion
No
No
Do seizures Taper drug if using
If no seizures for 24-48 hours: continuous infusion
persist?
Taper midazolam decreases by 1
g/kg/min every 3 hours Yes
*Individualized therapy in consultation with

neurology, critical care
*Consider add-on medications including

Levetiracetam (if not already used), Topiramate,
Ketamine, Valproic Acid, and ACTH or surgical, VNS,
Ketogenic diet options
Yes
Do seizures recur? Reinstate midazolam for another 48 hours
No
• Continue tapering midazolam

• Maintain phenobarbital and phenytoin
within therapeutic serum level
46
Protocol of EHA
Acute Flaccid Paralysis
Diagnostic Approach to Acute Flaccid Paralysis
Acute Flaccid
b Paralysis
Symptoms of Encephalopathy
No Ye
s
Distribution (Refer to Altered

mental status
chapter)
Lower Limbs Upper and Lower

Limbs
Symmetric
Unilateral Bilateral Sensory al
level
IM
No Yes
Nerve
Conduction MRI Spine + Contrast Ass deep tendon reflexes
Study
Abnormal:
✓ Tumor
Sciatic Nerve
Injury
✓ Myelitis Lost Presen
✓ Hematoma Normal
✓ Tuberculosis t
osteomylitis CPK
NCV/EM
G
Normal: Abnormal: Normal Elevated

Conversion ✓ GBS
Reaction ✓ Vit.B1 polyneuropathy
✓ Polio
✓ Botulism Myositis
✓ Spinal muscle atrophy
✓ Tick paralysis
47
Protocol of EHA
 Investigations needed to reach diagnosis:

1- Serum potassium to exclude periodic paralysis within hours
2- NCV/EMG is mandatory in all cases even if myelopathy is suspected and may
be repeated after 1 week if indicated
 If myelopathy is suspected:
a) Do MRI spine to exclude spinal trauma, transverse myelitis, infarction, or
compression by mass lesion as tumour or granuloma (T.B.).
b) Do lumbar puncture for infections and transverse myelitis
c) Do serum aquaporin-4 IgG and visual acuity to diagnose NMO
d) Serum vitamin B12 assay for subacute combined degeneration of spinal cord
 If axonal degeneration or delayed nerve conduction velocity:

 Suspect GBS and do lumbar puncture after 1st week for assessment of
protein-cell dissociation if diagnosis is still uncertain.
 If neuromuscular junction affection:

a) If acute descending with cranial nerve involvement after food intake suspect
Botulinism
b) If myathenic pattern in EMG with fluctuating diurnal pattern suspect
Myathenia gravis: do A Ch R antibodies
 If myopathic pattern in EMG:

a) Do CPK if ꝉꝉ with muscle pain ; acute myositis
b) If periodic paralysis: do serum potassium and thyroid function
3- Thyroid Function Tests
48
Protocol of EHA
 Clinical practice guidelines for the treatment of Guillain-Barré` Syndrome

among children
Diagnostic Criteria for (GBS)
Features that strongly Features that cast doubt on the

Features required
support diagnosis
Progressive bilateral Progressive phase lasts from days Increased numbers of mononuclear or
weakness of arms and legs to 4 weeks (usually <2 weeks) polymorphonuclear cells in CSF (>50 ×
(initially only legs may be 106/l)
• Relative symmetry of symptoms
involved)
and signs • Marked, persistent asymmetry of
• Absent or decreased weakness
•Relatively mild sensory
tendon reflexes in affected
symptoms and signs (absent in • Bladder or bowel dysfunction at
limbs (at some point in
pure motor variant) onset or persistent during disease
clinical course)
course
•Cranial nerve involvement,
especially bilateral facial palsy • Severe respiratory dysfunction with
limited limb weakness at onset
• Autonomic dysfunction
• Sensory signs with limited weakness
• Muscular or radicular back or
at onset
limb pain
• Fever at onset
•Increased protein level in
cerebrospinal fluid (CSF); normal • Nadir <24 h
protein levels do not rule
• Sharp sensory level indicating spinal
out the diagnosis cord injury
•Electrodiagnostic features of • Hyper- reflexia or clonus

motor or sensorimotor
• Extensor plantar responses
neuropathy (normal
• Abdominal pain
electrophysiology in the early
stages does not rule out the • Slow progression with limited
diagnosis) weakness without respiratory
involvement
• Continued progression for >4 weeks

after start of symptoms
• Alteration of consciousness (except

in Bickerstaff brainstem encephalitis)
49
Protocol of EHA
When to start treatment When to admit to ICU

One or more: One or more:
• Inability to walk >10 m independently • Rapid progression of weakness
• Rapid progression of weakness •Severe autonomic or swallowing dysfunction
• Severe autonomic or swallowing dysfunction • Evolving respiratory distress
• Respiratory insufficiency
Treatment Options Monitoring

• Intravenous immunoglobulin (0.4 g/kg daily for Regularly Assess:**
5 days)
• Muscle strength
• Plasma exchange (200–250 ml/kg for 5 sessions)
• Respiratory function
• Swallowing function
• Autonomic function
• Blood pressure
• Heart rate/rhythm
• Bladder/bowel control
Early Complications Clinical Progression

• Choking Treatment-related fluctuation:
• Cardiac arrhythmias • Repeat same treatment
• Infections
• Deep vein thrombosis No initial response or incomplete recovery:
• Pain • No evidence for repeating treatment
• Delirium
• Depression
• Urinary retention
• Constipation
• Corneal ulceration
• Dietary deficiency
• Hyponatraemia
• Pressure ulcers
• Compression neuropathy
• Limb contractures
**Frequency of monitoring is dependent on the clinical picture and should be assessed in
individual patients. CSF, cerebrospinal fluid; *EGRIS, Erasmus GBS Respiratory
Insufficiency Score; GBS, Guillain- Barré syndrome; ICU, intensive care unit;
50
Protocol of EHA
Specific Treatment Measures

a) Intravenous Immunoglobulins (IVIG)
• Intravenous immunoglobulins 2 g/kg (body weight)) divided over 2 days or 5 days.
b) Total Plasma Exchange (TPE)
• Total plasma exchange (200–250 ml plasma/kg body weight in five sessions) is an
effective treatment for GBS
• TPE can accelerate motor recovery, decrease time on the (IVIG) (ventilator, and
decrease time to attainment of other clinical milestones.
“In clinical settings where resources are limited, small-volume plasma exchange might
be an economical and relatively safe alternative to conventional plasma exchange, but
this approach cannot be recommended for general use until its efficacy has been
established in further trials.”
c) IVIG combined to TPE:
• Both IVIG and TPE are equally effective treatments for GBS.
• IVIG is also easier to administer and generally more widely available than plasma
exchange plasma exchange followed by IVIG is no more effective than either
treatment alone.
• Treatment related fluctuations (TRFs) are observed in 6–10% of patients with GBS
and are defined as disease progression occurring within 2 months following an initial
treatment-induced clinical improvement or stabilization. Those might benefit from
further treatment, and repeating the full course of IVIG or plasma exchange in these
patients is a common practice.
Assessment of Outcome of Treatment

• Ability to walk after 4 weeks.
• GBS Disability Scale: It is a widely accepted scoring system to assess the functional
status of patients with GBS.
Rehabilitation
• Planning rehabilitation before the patient is discharged.
• The long- term effects (incomplete recovery of motor and sensory function, as well as
fatigue, pain and psychological distress) of GBS should be considered and managed.
 GBS Disability Scale
51
Protocol of EHA
Appendix
1. Glasgow Coma Score/Modified Glasgow Coma
52
Protocol of EHA
2. Lumbar puncture
 LP is performed at or below the L4 level.
 The conus medullaris finishes near L3 at birth, but at L1-2 by adulthood.
 It is preferable to obtain a CSF specimen prior to antibiotic administration; however,
antibiotics must not be unduly delayed in a child with signs of meningitis or sepsis.
 In a child with fever and purpura, in whom meningococcal infection is suspected, LP
may not change the management and may cause deterioration.
 In term infants, the seated position has been shown to be the best tolerated and to also
have the best chance of obtaining CSF.
 If a LP is unsuccessful on two occasions, refer to a senior colleague, reassess the need
for LP and consider image guidance to assist.
 CT scans are not helpful in most children with meningitis and a normal CT scan does
not exclude raised intracranial pressure (ICP).
Contraindications
❑ Absolute
 GCS <10 or deteriorating/fluctuating level of consciousness
 Signs of raised intracranial pressure (ICP): diplopia, abnormal pupillary responses, decerebrate
or decorticate posture, low HR + elevated BP + irregular respirations, papilloedema
 A bulging fontanelle in the absence of other signs of raised ICP is not a contraindication
❑ Relative
 Septic shock or haemodynamic compromise
 Significant respiratory compromise (eg apnoe)
 New focal neurological signs or seizures
 Seizure within previous 30 min +/- normal conscious level has not returned following a seizure
 INR >1.5 or platelets <50, 000 or child on anticoagulant medication
** Clinical contraindications to lumbar puncture without neuro-imaging

- Moderate-severe impairment of consciousness
- Reduced of fluctuating GCS<10-12 according to expert openion or fall >2 within 1-2 hours
- Focal neurological signs (e.g. unequal, dilated or poorly responsive pupils)
- Abnormal posture or posturing
- Papilledema
- After seizures until stabilized
- Relative bradycardia with hypertension
- Abnormal ‘doll’s eye’ movements
- Immunocompromized
- Systemic shock
- Coagulation abnormalities: Results (if obtained) outside the normal range
• Platelet count <100x10 /L
• Anticoagulant therapy
- Local infection at lumbar puncture site
- Respiratory insufficiency
- Suspected meningoccal septicaemia
***Radiological Contraindications to LP:

- Significant brain shift/swelling
- Tight basal cisterns
- Alternative diagnosis made
53
Protocol of EHA
Investigations and Drugs
Laboratory:
 Acetyl Choline receptors antibodies

 Anticardiolipin antibodies
 Antiphospholipid antibodies
 Antithrombin III.
 Blood culture
 Blood gases with anion gap ( serum chloride)
 CBC w/ diff, CRP, ESR
 Chemistry: Na, K, BUN, Creatinine , Albumin, Total protein, Calcium, Phosphorus, ALT,
AST, Alkaline phosphatase, GGT, Mg, Billirubin, LDH, uric acid.
 Complement profile
 COVID PCR
 CPK
 CSF and serum Oligoclonal bands and IgG index
 CSF for cytology, chemistry (glucose, proteins, lactate**, glycine**), culture and sensitivity,
Gram stain, bacterial and viral panel PCR, may add Fungal culture and ZNS/ PCR TB
 Factor V (Leiden) mutation
 Finger stick glucose
 Full toxicology screen.
 Hemoglobin electrophoresis
 HIV, mycoplasma,Lyme disease, Cat scratch Serology
 Lipid profile
 Lupus anticoagulant
 Muscle biopsy
 Protein C and S (activity, antigen)
 PT/PTT, INR,
 Rheumatoid factor
 Serum Anti-MOG antibodies
 Serum Aquaporin 4 antibodies
 Serum homocysteine
 Serum vitamin B 12
 TSH, free T4
 Urine analysis, urine culture
 In Certain Cases, may need:
 Collagen markers (ANA, Anti DNA, C3, C4, ANCA) in cases with query vasculitis.
 Serum ceruloplasmin
 Ammonia, Lactate
 Aminoacid/ acyl carnitine and urine organic acid
 Blood and CSF glycine
54
Protocol of EHA
Radiology:
 Cardiac MRI
 Cerebral angiogram
 Chest x ray
 Conventional angiography
 CTangiography
 ECG, ECHO, Carotid Doppler, Holter
 MRI brain +C/ DWI/ACD , MRA/MRV
 MRI spine with contrast
 NCV and EMG
 Non contrast Brain CT (in ED)
 Pelvi-abdominal sonography/ CT
 Transesophageal ECHO
Drugs:
 Acetazolamide tablets 250 mg.

 Acyclovir ampoule 250 mg and 500 mg
 Aspirin tablets (75 mg)
 Bicarbonate 8.4% , 5% ampoules.
 Biotin 5mg ,10 mg tablets
 Dexamethasone ampoule 8mg.
 Diazepam ampoule 10 mg
 Hypertonic saline solution(3% NaCl).
 Intravenous immunoglobulin ampoules 2.5 gm, 5 gm, 10 gm.
 L-carnitine IV ampoules and syrup.
 Levetiracetam ampoule 500 mg
 Low molecular weight heparin(LMWH)- Enoxaparin ampoule , 40mg and 60 mg.
 Mannitol IV solution 5%, 10% ,15%
 Methyl prednisolone ampoule 500mg , 1gm
 Midazolam ampoule 15mg, 5mg
 Na benzoate injectable solution (1gm\5ml) and powder .
 Phenobarbital ampoule 40 mg
 phenytoin ampoule 100 mg ,250 mg
 Plasma exchange .
 Thiamine 50 mg tablets
 Tissue Plasminogen Activator (tPA) ampoules
 Tocilizumab 80mg , 200 mg, 400 mg.
 Vitamin B12 ampoules (1000 microgram)
 Warfarin tablets ( 1mg , 3mg, 5mg)
55
Protocol of EHA
56
PICU Protocol of EHA

in
Pediatric Intensive Care Units
for
First Edition
2024
Prepared by
in
Pediatric Intensive Care Units
for
1
Executive Committee
1. Prof. Dr. Hanan Ibrahim: (Head of the Committee) Professor of pediatrics- ASU,
Head of PICUs-ASU, Head of Egyptian Society of Pediatrics and pediatric Critical
Care (ESPPCC).
2. Prof. Dr. Hafez Bazaraa: Professor of pediatrics, Head of PICU, Cairo University.
Pediatrics Armed Forces College Of Medicine.
3. Prof. Dr. Azza Ahmed El-Tayeb: Professor of pediatrics, Assiut University.
4. Prof. Dr. Khaled Talaat: Professor of pediatrics, Tanta University.
5. Prof. Dr. Soha Adly Hashem: Consultant of Pediatrics, Neonatology, Emergency
Cases and PICU. International Coordinator and Trainer of PALS, American Heart
Association.
6. Dr. Sondos Mohamed Magdy: Lecturer of Pediatrics and PICU, Ain Shams
University.
7. Dr. Huda Karam: (Moderator of the Committee) Pediatric Specialist, Moderator
& coordinator of Medical Advisory Council of Egypt Healthcare Authority (EHA)
Disclaimer
under their care.
2

Authority (EHA).
Reviewed By



3
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric Intensive
Care Units is to unify and standardize the delivery of healthcare to any child at all
health facilities.
Regarding Pediatric Intensive Care Units, busy clinicians have all felt the need
for a concise, easy-to-use resource at the bedside for evidence-based protocols, or

to those delivering care at the bedside in for patients in Pediatric Intensive Care Units.
In Pediatric Intensive Care Units
4
Table of Contents
Page
Title
Number
Preface 4
Standards for PICU Preparation 6
Pediatric Resuscitation 8
Basic Fluid Therapy 16
Shock 26
Acute Severe Asthma 41
Status Epilepticus 52
Diabetic ketoacidosis 61
Hypoglycemia 74
Adrenal Crisis 76
Acute kidney Injury (AKI) 80
Comatose Child 87
Cerebral Oedema 88
Blood Product Prescription 92
Clinical Practice Guidelines on Prevention and 98
Management of Pain
Basic Mechanical Ventilation 106
Poisoning Protocol 116
5
Standards for PICU Preparation
Human resources needed for every five beds:

✓ Doctors; one consultant, one specialist and four residents
✓ Clinical pharmacy; one
✓ Nurses; one head nurse, three nurses and three assistant nurses
✓ Two porters
✓ One infection control specialist
PICU structural composition:

1-Take in consideration the proximity to OR
2-also to be near to ER
3-8 meters are the area needed for each ICU bed
4-PICU should contain: procedure room, operating room and preparatory room
5-AC system with hepa filter
6-Entrance different from exit
7-Central sterilization unit
Laboratory requirements for any PICU

• Emergency lab 24 hours 7days or lab to lab deal
• CBC, blood gases, electrolytes coagulation profile, LFT, KFT
Pharmacy:
• Emergency stock of medication for each unit
• Internal pharmacy 24 hours /7 days
• Each governorate should contain TPN center preferred to be in largest hospital
• Blood bank for each governorate
6
Security cameras for PICU beds

Doctors& nurse rooms with toilet and for each five beds one toilet
Store room
For each five beds one sterilization basin
Equipment:
1-Central station
2- Portable x ray and U/S with duplex probe
3-For each PICU bed;
Monitor +4 syringe +2 infusion pump+ 1 warmer+ 2 oxygen outlets +1 air outlet
+1 suction outlet +12 electric outlets on UPS with stabilizer
4-For every five beds we need 5 MV +2 high frequency MV +2 noninvasive
ventilation +1 crash car with D/C unit +ECG + augmented EEG
5- Air mattress
Transportation:
• Separate portable ventilator or one of the unit ventilators if it also could be
used as portable ventilator
• Four oxygen cylinders
• Two portable monitors
• Two incubators
NB:
▪ Two CRRT machines for each governorate in same place or if there is a
dialysis unit it should be in it
7
Pediatric Resuscitation
Scope:
• Applicable to individuals up to 12 years of age
• Resuscitation of neonates in the delivery room is NOT within the scope of this protocol
• This protocol applies to healthcare settings. Basic life support by lay by-standers is not
the intended scope
Recognition:
• CPR is indicated when there is no reliable central pulse with a rate of at least
60/min. in a patient who is unconscious and unresponsive
• Central pulse may be assessed in the Carotid, Brachial or Femoral arteries
• Duration of assessment may NOT exceed 10 seconds
• Hospitalized critical patients will be already on continuous monitoring. Note that
those with pulseless electrical activity will show cardiac electrical activity (ECG
pattern) on the monitor in absence of a central pulse. CPR is still necessary
• Hemodynamically stable patients with HR less than 60/min may require
alternative approaches
• Rescue breathing is indicated
(a) Together with chest compressions during CPR
(b) In patients with absent or grossly ineffective (eg gasping) breathing even if there is a
reliable pulse Airway opening is necessary for rescue breathing
• Immediate defibrillation is needed for those with recognized pulseless shockable
rhythm (VF, VT) once it is available.
• CPR should be performed until a shockable rhythm is recognized and a
defibrillator is ready
o CPR is not indicated when there are obvious signs of life such as a reliable
central pulse ≥60/min., regular breathing, eye opening, speech, cough, etc.
o However, this does not rule out a critical or unstable condition. System
support may be required. Recognition and management of system failures
before cardiac arrest occurs and after return of spontaneous circulation are
keys to survival
• CPR is a team process; Pre-assignment of teams and appropriate training
improve outcomes. While CPR can and should be initiated by a single
individual, calling for help is then necessary to continue effective management.
Required equipment, medications and supplies must be readily available and
checked regularly and after each use
8
Sequence of Actions:
1. Recognize the case, ensure safety, call for help and position the patient
• It is important to ensure the patient is not in ongoing danger and it is important

that the rescuer approach safely so he would not be endangered. Approach with
care
• Inside the hospital, scene safety should be easy to maintain
• A sole rescuer may initiate a cycle of CPR first if calling for help requires him
to leave the patient
• A defibrillator/ monitor should be available or brought with coming help
• Patient should be positioned supine on a flat hard surface. A bed mattress is too
soft; a board may be used under the patient, but make sure it can take the force
of chest compressions and its edge is away from the patient’s back
• If the patient needs to be moved or turned, do that with care to avoid injury
2. If there is no central pulse ≥60/min., start chest compressions
3. Open airway, check breathing and start rescue breaths
• If there is no pulse, starting chest compressions immediately, followed by

airway-breathing support is recommended (C-AB). If there is a pulse, the usual
ABC approach; starting with airway & breathing, is recommended. Conscious
patients with a FB airway obstruction will require specific management
4. Identify a shockable rhythm (VF/VT) & give DC shock
5. Immediate vascular access for drug ± fluid administration
• Shockable rhythms are not the commonest causes of pediatric cardiac arrest;
however, early recognition & treatment could markedly improve outcome. Do
NOT unnecessarily interrupt CPR but identify rhythm as soon as available.
When cardiac arrest is associated with an attended VF/VT (in a monitored
patient), an immediate DC shock is given if available
6. Check and correct correctable factors
• This should occur throughout resuscitation
9
• EMD (electromechanical dissociation) = pulseless electrical activity

• The first DC shock may be 2-4J/Kg
10
Chest Compressions
Site: midline on the lower sternum
• NOT the xiphisternum, NOT on the left precordium
Rate: 100-120/min
Depth/ force: need to depress 1/3 the AP chest diameter
• Two hands for older children
• One hand for younger children
• Only use the heel of the hand(s), fingers should NOT be applied to the chest
• Two fingers for infants
• Both thumbs with hands encircling the chest
• Index and middle fingers (preferred for single rescuer)
Quality: compression NOT rocking motion, allow FULL RECOIL between

compressions, MINIMAL INTERRUPTION (preplan before you interrupt)
Airway-Breathing Support
Airway
• Head tilt chin lift to open airway. Cannot use this technique if there is a need to
immobilize the cervical spine. Only jaw thrust can be used in this case
• Check for breathing (look, listen and feel). Remove obvious FB. Suction
secretions, blood, etc.
• Maintain airway
• Oropharyngeal, nasopharyngeal or laryngeal mask airways may be helpful
• Endotracheal intubation once possible
• ETT position must be confirmed
• Surgical airway is rarely necessary
Breathing
• With airway open, use bag & mask to ventilate

• Use the highest possible oxygen (100%)
• Check for a visible chest rise during ventilation
• Use bag and ETT once placed
• If you started with breathing & are not doing CPR, give 5 initial breaths then
reassess circulation
• Oxygen recommendations are different in neonatal resuscitation
• Lack of adequate chest rise: verify airway, proper mask seal, absence of a leak
or FB obstruction
11
Synchronizing breaths & chest compressions
• Generally, 15:2 (2 breaths after every 15 chest compressions). Five such

sequences represent one cycle (1-2min)
• 30:2 has been suggested for child CPR with a single rescuer, although 15:2 can
still be used
• With advanced airway (ETT): no need. Provide breaths continuously at 12/min.
Increase to 20/min. if there is (return of) spontaneous circulation
• Hyperventilation during cardiac arrest is not beneficial and may be harmful
In case of choking/ FB obstruction
• An obvious FB can be removed, blind finger sweeps should be avoided

• A conscious patient with effective cough should be allowed to cough &
monitored
• If there is no/ loss of effective cough in a conscious patient, apply alternately 5
back blows, 5 abdominal thrusts (children NOT infants), 5 chest thrusts (can use
in infants)
• If patient unconscious/ lost consciousness start CPR
• Direct laryngoscopy & removal under vision may be possible
VASCULAR ACCESS
• The best time to establish vascular access is before cardiac arrest
• Peripheral lines can be used during resuscitation. A small bolus of normal saline
can be given after each injection to improve drug delivery to the central
circulation
• In absence of an alternative, intraosseous or femoral vein access will not
significantly interfere with resuscitation. All resuscitation medications can be
given intraosseous
• Volume (10-20mL/Kg isotonic crystalloid) is given in hypovolemic patients.
This should not delay CPR, adrenaline administration or defibrillation
• Endotracheal and intracardiac routes for medications are no longer
recommended
12
DRUGS
Adrenaline
• During CPR for cardiac arrest, give 10μg/ Kg adrenaline IV and repeat every 2
cycles (3-5min)
• For pulseless VT/VF, give adrenaline after the third shock (if patient still
pulseless in shockable rhythm) and repeat every 2 cycles
• 10μg/ Kg equals 0.01 mg/Kg or 0.1mL/Kg using diluted solution (1/10,000 or 1
ampoule of 1 mg in 10mL). The max. adult dose is 1 mg
• There is NO evidence to support higher single doses
• Following return of spontaneous circulation, consider starting an adrenaline
infusion and titrate rate to response
Amiodarone
• Used for pulseless VT/VF that has not responded after the third DC shock
• Dose: 5mg/Kg, may be repeated ONCE after the 5th shock
• Lidocaine (1mg/Kg followed by 20-50μg/ Kg/min) may be an alternative
“Glucose, Ca, Mg, bicarbonate and atropine are not routinely recommended
during CPR”
Glucose
• Should be avoided except if there is hypoglycemia
Calcium
• Is indicated for hypocalcemia, massive transfusion, hyperkalemia,
hypermagnesemia and calcium channel blocker toxicity
Magnesium
• Is indicated for hypomagnesemia and torsade de pointes
Sodium bicarbonate
• May be considered after establishment of adequate ventilation, chest
compressions and giving adrenaline if there is severe metabolic acidosis,
hyperkalemia, tricyclic antidepressant toxicity or prolonged CPR
“Naloxone reverses opioid-induced CNS depression but it cannot substitute

breathing support and can precipitate withdrawal in opioid-dependent patients”
13
Shockable Rhythms
• Patients with cardiac arrest and a shockable rhythm (VT or VF) must receive
immediate DC shock
• CPR must start/ continue until the rhythm is identified and defibrillator is ready
• Check rhythm after every CPR cycle if available
• DC may be delivered manually or using AED
Manual: use 2-4J/Kg for the first shock and 4J/Kg for all subsequent shocks.
Make sure the Synchronize button is not accidentally on with VF as it will lead
to failure of giving the shock
AED: when attached, it will analyze rhythm and display if a shock is needed.
You still need to press the shock button to have it delivered. For children 1-
8years of age, use an attenuator. For infants, use a manual defibrillator. If
unavailable, use whatever is available.
Either case, paddles must be properly positioned and must not contact each
other. Smaller sized paddles are needed for those <10Kg. Apply conducting gel/
cream if available
• Confirm all is clear, with no one touching the patient or bed, before delivering
the shock
• Once delivered, immediately remove paddles and resume CPR. do not stop to
check response. Provide 1 cycle of CPR first.
• Make interruptions of CPR for checking rhythm as brief as possible. If another
shock is needed, continue CPR until defibrillator charged and ready.
• If the patient is still in cardiac arrest:
And rhythm still shockable➔ repeat a shock after every CPR cycle, give
adrenaline & amiodarone after the 3rd shock, repeat adrenaline every 2 cycles
and amiodarone only once after the 5th shock
And rhythm changed to non-shockable➔ give adrenaline and continue CPR
• Antiarrhythmic drugs cannot replace a DC shock in the context of cardiac arrest
14
Correctable Factors
✓ Hypoxia
✓ Hypovolemia
✓ Hypothermia
✓ Hypo/hyperkalemia (& other metabolic)
✓ Tension pneumothorax
✓ Tamponade
✓ Thrombosis (PE, coronary)
✓ Toxic
Post-Resuscitation Management
• Assess and support for any system dysfunction, correct any correctable factors,
address the underlying disease. Continue to monitor patient and determine the
appropriate location for care (eg ICU). Key points include:
Respiration: maintain adequate ventilation and oxygenation. Most patients will

require an ETT and positive pressure ventilation. Obtain blood gases and use
pulse oximetry to guide oxygen therapy.
Circulation: assess cardiac rate and rhythm, pulses, BP and perfusion (capillary
refill, peripheral temperature & color, distal pulses, etc). Apply shock protocol
if needed. Patients may have myocardial dysfunction
Neurological: patients may develop convulsions or cerebral oedema
Metabolic: normothermia, glucose, fluid, electrolyte & acid-base status
Surgery or interventions may be needed to manage trauma, achieve hemostasis

or address other life-threatening emergencies. The correct timing and patient
support are necessary to maximize benefit and minimize risk
15
Basic Fluid Therapy

Scope:
• This protocol addresses intravenous fluid therapy in infants and children.
• Neonates are not specifically covered.
• Although the overall principles are similar, some conditions may have different
fluid requirements; such as diabetic ketoacidosis, perioperative fluid
management, burns, etc.
• For details of fluid management in shock, refer to shock protocol.
Disclaimer:
• Protocols and guidelines outline the recommended or suggested clinical practice;
however, they cannot replace sound clinical judgment by appropriately trained
and licensed physicians. The physician is ultimately responsible for management
of individual patients under their care.
Objectives:
✓ Provision of maintenance requirements
✓ Replacement of ongoing (excessive/ abnormal) losses
✓ Correction of deficit/ dehydration
✓ Volume expansion (mainly shock)
Maintenance Requirements:
Normal maintenance per 24hrs
Weight Calculation Max.

-10 Kg (excludes neonates) 100 mL/Kg 1000 mL/ 10Kg
>10- 20 Kg + 50 mL/kg 1500 mL/ 20 Kg
>20 Kg + 20 mL/Kg 2400 mL
All patients 1500 mL/m2
• Insensible losses are 400mL/m2/day
• Normal maintenance replaces normal urine and insensible losses; since sweat,
stool and abnormal losses are normally negligible
• This calculation tends to overestimate requirements of most acutely ill patients
after the resuscitation phase. It is suggested to use 70% of this as a starting point
in these cases.
16
Normal maintenance applies provided that:
• Patient is normally hydrated (not dehydrated or oedematous; in which case a +ve

or –ve ‘respectively’ balance relative to maintenance is required)
• No fluid restriction is necessary eg HF, SIADH, etc
o Generally, 60-70% of normal maintenance is given in such cases
• There are no abnormal losses (radiant warmer, fever, diarrhea, drains, 3rd space,
burns, etc). Measured or estimated non-urinary abnormal losses need to be added
to normal maintenance.
• Urine output is normal
o In anuric, oliguric or polyuric patients; maintenance shall equal insensible
losses + patient’s urine output + abnormal losses if present.
Amount and type of fluids:
Condition Amount Type Example
Normal Normally 1500 mL/m2/day 0.5NS(a), glucose-saline
maintenance hydrated, no Or check table above 5-10% 1:1 with KCl
restrictions, glucose(b), (0.5-
normal urine 10-20mEq/L 1mL/100mL)
&no K
abnormal
losses
Restricted Oedema, HF, Generally 60-70%, 0.5NS-NS(c), Glucose-saline
maintenance SIADH, etc higher restrictions 5-10% 1:1 or NS, with
may apply glucose(b), KCl
10-20mEq/L (0.5-
K 1mL/100mL)
Dehydration Maintenance + 0.5NS-NS, Glucose-saline
deficit 2.5-5%(b) 1:1 or NS, with
glucose, 20- KCl
40mEq/L K (1-2mL/100mL)
Insensible Anuria 400mL/m2, may ≥10% glucose
loss only omit in case of
overload
Insensible Oliguria 400mL/m2/day As normal maintenance,
loss + urine Plus actual patient’s with/without K
output urine output per
1,4,12 or 24h(d)
Polyuria 0.5NS, Glucose-saline
≤5%glucose, 1:1 with KCl
20mEq/L K(e) (1mL/100mL)
Abnormal Other than in Add amount equal to Depends on type of fluid lost(f)
losses urine losses in 1,4,12 or
24hrs(d)
PD/ CRRT Consider patient & therapy balance together
17
NOTES:
• Oral/ enteral fluids, medications, drug infusions, blood products, etc are part of
maintenance/ replacement fluids. Only 85% of milk is fluid.
• Na, K should be monitored and adjusted accordingly. Do Not add maintenance
potassium in anuric patients. All stated Na, K, glucose requirements are starting points.
Modify based on actual level monitoring.
(a) In critically-ill children (not small infants), 0.5NS is be preferable in the first 24hrs,
rather than lower Na (eg Neomaint, 4:1 glucose-saline used in neonates & small
infants). Normal saline may be preferred with hyponatremia or CNS injury. Na content
must be adjusted based on at least daily serum electrolyte checks.
(b) Many acutely ill children (>6Mo) will not require glucose initially. If needed to
maintain blood glucose, prevent catabolism & ketosis, 10% glucose in maintenance
fluids may be necessary if tolerated. Higher concentrations require central access
unless for a very short term. Blood glucose should not consistently exceed 180-200
mg/dL. Higher infusion rates (eg in dehydrated patients) require reducing glucose
concentration. Patients with liver cell failure, adrenal insufficiency or metabolic crisis
should receive at least 10% glucose, even if insulin is required. Very rapid replacement
(eg severly polyuric patients) may not tolerate even 2.5% so use glucose-free fluids (±
low rate glucose 10% as a separate infusion).
(c) Unless sodium restriction is also necessary
(d) Interval depends on patient’s condition and how changing it is. As a start, use 1hr
for immediate postcardiac surgery, posttransplantation and those on CRRT; use 12-
24h for values close to normal maintenance (i.e. slight increase or decrease) and 4h for
most other cases. Increase interval when stable
(e) Extremely polyuric patients are expected to need higher Na and lower K content
(f) For example, upper GI losses by Ringer plus 20 mEq/l potassium, diarrhea by usual
rehydration solutions, drains with Ringer lactate, etc
18
Dehydration & Deficit Therapy
Dehydration Mild Moderate Severe

Description History of ECF Significant Hypovolemic shock,
loss, acute wt loss, dehydration: score 3- lethargy* or severe
just detectable 7, or TWO of metabolic acidosis*
dehydration, score (sunken eyes, poor Score 8+ two of (sunken
1-2 skin turgor, thirst, eyes, very poor skin turgor,
irritability) lethargy* or inability to
drink*)
*of no other cause
Deficit (mL/Kg) 30-50 60-90 100-150
‘higher values for
smaller patients’
• Score allocates 2 points (0=normal, 1=mild, 2=severe) for each of fontanel,

tongue, eyes & skin turgor. Two points are added for each of shock, lethargy and
metabolic acidosis if present.
Deficit Therapy:
• Shock should be treated as needed. Patients with severe dehydration who are not
shocked may still be given a rapid bolus of 10-20mL/Kg isotonic crystalloid
(normal saline) over 30-60 min; which is then subtracted from deficit
There are rapid, slow & very slow methods for correction of dehydration:
Rate Rapid Slow Very slow

Duration ≤ 6hrs 24hrs ≥48 hrs
of
correction
Indications - Rapid fluid losses Most hospitalized Concerns of osmotic
- Acute severe dehydration (eg cases shifts
GE) (eg DKA,
In children with no concerns hypernatremia)
from rapid hydration (eg HF,
electrolyte disturbance, etc)
Technique Give deficit over 6h Give 24h maintenance Give maintenance +
(? 3-4h in children >2yrs) + deficit over 24hrs 30-50 mL/kg/day until
Other approaches: corrected (typically
- Give ½ deficit (+1/3 will take 2-3 days)
daily maint.) in 8h,
then ½ deficit (+2/3
daily maint) in 16h
- Give deficit + (½
daily maint) over 12h
19
• Type of fluid: 0.5NS –NS with glucose 2.5% (rapid)-5% (slow) and 20 mEq/l
potassium (more if needed). Premixed rehydration fluids with 77—142mEq/L
Na may be used (care of K content)
• Potassium should not be added in anuric or hyperkalemic patients although
hypokalemia may still be corrected (by formula, without maintenance K) in
anuric patients if needed.
• Dehydration should be reassessed frequently.
o Severity may be different from initial assessment and patients may have
abnormal losses or have/ develop acute kidney injury.
Hyponatremia
Hyponatremia denotes a free water excess relative to Na content; however, ECF
volume may be increased, normal or decreased
ECF volume Pathophysiology Examples Management strategy
Reduced Na loss > GE, diuretics, Rehydrate with higher Na
(hyponatremic water loss adrenal
dehydration) insufficiency, Crude: use NS or 3/4NS
salt-losing & modify according to
nephropathies, rate of Na rise
etc
Accurate: add 10 ml/kg
hypertonic saline to total
daily fluids
Normal Free water gain SIADH Water restriction (60-
Increased Water> salt Congestive HF, 70%)
retention hepatic failure,
nephrotic Use 0.5NS - NS (unless
syndrome Na restriction is also
needed)
• NS, 3/4NS & ½ NS refer to Na content. Appropriate glucose & K should be
added.
• Correction rate at no more than 0.5 mEq/Kg hourly (12/day), preferably even
slower (8/day). Check & modify rate of rise after 6h.
• Severe symptomatic cases may warrant initial partial correction with 5-10 ml/Kg
hypertonic saline to raise Na 4-8 mEq/L which is adequate to reverse acute
symptoms), followed by more gradual correction. Approaches include 5mL/kg
over 1-2 h (30 min for severe brain oedema) which may be repeated once.
Alternatively, 2mL/Kg over 15-30 min, which may be repeated once if
symptoms persist and for a 3rd time after checking serum Na if symptoms still
persist.
20
Hypernatremia
Hypernatremia denotes a free water deficit relative to Na content; however, ECF
volume may be increased, normal or decreased
ECF volume Pathophysiology Examples Management strategy

Reduced Water loss> GE Give maintenance +
(hypernatremic Na loss 40mL/Kg/day with 1/3NS-
dehydration) ½ NS
Modify according to rate

of Na drop:
- If too slow: ↑rate or ↓Na
content, & vice versa
Normal Free water loss DI Give 40mL/Kg free water
Increased Hypertonic Na Concentrated (eg G5%) per 24h and the
intake formula, sea remaining fluids as usual
water, Na
bicarbonate, etc
• ½ NS & 1/3NS refer to Na content. Appropriate glucose & K should be added.
• Na content can be given as bicarbonate in acidotic patients (eg 30mL bicarbonate

in 500 mL glucose 5% + 5mL KCl will be 60meq/L Na – between 1/3NS & ½
NS)
• Correction rate at no more than 0.5 mEq/Kg hourly (12/day). Check & modify
rate of drop after 6h.
• An accurate calculation is possible, based on urine vol, urine Na, insensible loss
& current ECF volume status to determine 24h maintenance water & Na
requirements separately. Then, allocate 40 mL/kg of the total volume as free
water and give the remainder with the proportional amount of calculated Na.
• PD is needed for refractory hyperNa, intractable acidosis or associated AKI with

need for dialysis
21
Hypokalemia
• Interpret K together with pH (a low pH ➔ extracellular shift of K so level will

increase; correction will lower K correspondingly)
• Mild hypokalemia which is non-progressive may be corrected by increasing K

intake.
• Otherwise, correction can be achieved using the formula:
"Body weight X deficit (target-actual K) X 0.6 mEq (0.3 mL)"
• Amount to be diluted in normal saline & given over few hrs (correct 0.5mEq/l
per hr).
• Never give concentrated KCL.
• Target K is 3.0 for chronic hypokalemia & where complete correction is risky
or not necessary, 4.0 for those with or at risk for arrhythmia or during correction
of acidosis & 3.5 for most cases
• An empiric correction using 0.5mEq/Kg (0.25mL/Kg), DILUTED and given

over 1-2 hr may be used
Hyperkalemia
• Interpret K together with pH (correction of acidosis could correct hyperkalemia)
• Emergency measures for hyperkalemia: (K> 7 mEq/L, rising or with ECG
changes)
(all may be temporary & K can rebound so if hyperkalemia is severe and K
cannot be eliminated from the body, dialysis will be needed)
• Calcium gluconate IV to reverse membrane effects of K
• Intracellular shift with bicarbonate, iv or nebulized salbutamol &/or glucose-
insulin
• Potassium removal can be achieved using loop diuretics, cation exchange resin
(Ca or Na polystyrene sulfonate) or dialysis. The administration of
corticosteroids & fluids in cases of hyperkalemia secondary to adrenal
insufficiency is also effective.
22
Fluids & mixtures by sodium content
Na (mEq/L) Examples Glucose & K content

Isotonic ±150 Normal saline None K (4-5 mEq/L) in
Ringer & lactated Ringer (Na ringer & LR
slightly less)
3/4 NS ±110 Glucose: saline 1:3 1/4th source glucose (2.5%
if using 10%), No K
80-90 IV rehydration premixed Glucose <5%
solutions K varies by brand (8-
30mEq/L)
½ NS 77 Glucose: saline 1:1 ½ source glucose (5% if
Half normal saline using 10%, 2.5% if 5%),
No K
1/3 NS ±50 No K. Using 5%, final
glucose:
Glucose: saline 2:1 3.3% (6.7% with 10%)
Glucose: ½ NS 1:2 1.7%
1:19 bicarb: glucose 5%
(25mL/500) 5% & higher Na(60mEq/L)
1:16 bicarb: glucose
(30mL/500)
0.2NS ±30 Glucose 10%: saline 4:1 8%, No K
Glucose 10%: 25%: saline 11%, No K
3:1:1 12%, K 10mEq/L
Neomaint 10%, K 20mEq/L, higher
Pedimaint Na (37)
0 Glucose (all conc.)
Glucose 25% can be used to increase final mixture glucose concentration. Kadalex is
glucose 5% with 27mEq/L potassium. To increase K by 20 mEq/L add 5mL KCl per
500 mL, or 1 mL/100Ml
Formulae & Calculations
Body surface area (m2) = weight (kg) x 4 + 7

weight (Kg)+90
10 Kg ≈ 0.5m , 20 Kg ≈ 0.8m2, 30 Kg ≈1m2, adult ≈1.7m2
2
mL/day to drops/ min: divide by 100
eg 10 Kg with maintenance 100 mL/Kg/d = 1000 mL/day

Rate (drops per min. by ordinary IV set) = 1000 (mL/day)/ 100 = 10 (drops/ min.)
23
Limit of oliguria:
-400 mL/m2/day
-25% normal maintenance
-1mL/Kg/hr up to 10 Kg, 0.5mL/Kg/hr >10Kg, 20mL/hr in those >40kg
eg 10 Kg: 1 mL/kg/h = 10 mL/h = 240 mL/day

30 Kg= 1 m2 body surface area = 400 mL/day
Limit of polyuria:
-2000 mL/1.7m2/d
- 0.8-1.0 x normal maintenance
- 3mL/kg/hr up to 10 Kg
eg 10 Kg: 30 mL/hr= 720 mL/day

30 Kg= 1m2 body surface area = 1200 mL/day (2000mL/1.7m2)
Universal fluid balance formula:
Obligatory intake (medications, infusions, transfusions) + enteral*&parenteral

nutrition + IV fluids= Insensible loss + Urine output + Abnormal losses +
Ultrafiltration
*only calculate oral/enteral fluids and water content of foods (eg 85% of milk formula)
Metabolic acidosis:
Weight x deficit x 0.33 = mEq NaHCO3 (or mL 8.4% solution)
Deficit= base deficit -5, also ½ base deficit or 15- patient bicarbonate
eg 10 Kg, base excess -20 mEq/L
Deficit (base deficit - 5) = 20 - 5 = 15
Amount of 8.4% bicarbonate: 10 (weight) X 15 (deficit) X 0.33 = 50 mL
Hypokalemia:
Weight x deficit x 0.6 = mEq KCl (or 0.3 = mL KCl)
KCl MUST BE DILUTED in normal saline

Deficit= target K – patient K , Target K can be 3-4 meq/L depending on the condition
Correct a deficit of 0.5/hr
Hyponatremia:
Rapid correction 5-10 mL/ Kg hypertonic saline in 2hrs
24
Glucose: insulin for hyperkalemia:

MIX 0.5g/kg glucose (eg 5ml/kg glucose 10%, 2mL/Kg 25%) with 0.1 u/kg soluble
insulin & give over ½ hr. May double both, i.e. 1g/kg glucose & 0.2 u/Kg insulin
eg 20 Kg
GLUCOSE: 40 mL of 25% or 100 mL of 10%
INSULIN: 2 u soluble insulin
24-hr infusion calculation:

Basic formula 1.44 mg/Kg/day (or 1.5 mg/25hrs) = 1 mcg/Kg/min
Body weight (Kg) x target dose (mcg/Kg/min.) x 1.44 mg ➔ dilute to 24mL & give
at 1 mL/hr
eg 20 Kg, Noradrenaline 0.1 μg/Kg/min

20 (body weight) X 0.1 (target dose) X 1.44 ≈ 3 mg
3 mg diluted to 24 mL and give at 1 mL/hr
1 mL/hr = 0.1 μg/Kg/min. Adjust rate according (eg 1.5mL/hr= 0.15 μg/Kg/min.)
25
Shock
Definition:
Shock is an acute process characterized by the body’s inability to deliver

adequate oxygen to meet the metabolic demands of vital organs and tissues.
Table (1): Types of Shock (Nelson 20th edition)

Hypovolemic Cardiogenic Distributive Septic Obstructive
Decreased Cardiac pump Abnormalitie Encompasses Decreased
preload failure secondary s of multiple forms of cardiac output
secondary to to poor vasomotor shock secondary to
internal or myocardial tone from Hypovolemic; direct
external losses function loss of third spacing of impediment
venous and fluids into the to right- or
arterial extracellular, left- heart
capacitance interstitial space outflow or
Distributive: early restriction of
shock with all cardiac
decreased afterload chambers
Cardiogenic;
depression of
myocardial function
by endotoxins
Potential Congenital heart Anaphylaxis Bacterial Viral Fungal Tension
etiologies disease Neurologic: (Immunocompromise pneumothora
Blood loss: Cardiomyopathies loss d patients are at x Pericardial
hemorrhage; : infectious or of increased risk) tamponade
Plasma loss: acquired, dilated sympathetic Pulmonary
burns, nephrotic or restrictive vascular tone embolism
syndrome; Ischemia secondary to Anterior
Water/electrolyt Arrhythmias spinal cord or mediastinal
e loss: vomiting brainstem masses
diarrhea injury Critical
Drugs coarctation of
the aorta
26
Table (2): Hemodynamic variables in different shock states

(nelson 20th edition)
Type of Cardiac Systemic Mean Capillary Central

shock output vascular arterial wedge venous
resistance pressure pressure pressure
Hypovolemic ↓ ↑ ↔ or ↓ ↓↓↓ ↓↓↓
Cardiogenic*
Systolic ↓↓ ↑↑↑ ↔ or ↓ ↑↑ ↑↑
Diastolic ↔ ↑↑ ↔ ↑↑ ↑
♦ ♦
Obstructive ↓ ↑ ↔ or ↓ ↑↑ ↑↑
Distributive ↑↑ ↓↓↓ ↔ or ↓ ↔ or ↓ ↔ or ↓
Septic
Early ↑↑↑ ↓↓↓ ↔ or ↓□ ↓ ↓
Late ↓↓ ↓↓ ↓↓ ↑ ↑ or ↔
Systolic or diastolic dysfunction
Wedge pressure, central venous pressure, and pulmonary artery diastolic
pressures are equal
Wide pulse pressure
Sepsis:
• Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host
response to infection (new definition JAMA 2016).
• Organ dysfunction can be identified as an acute change in total SOFA score 2 points
consequent to the infection.
• The baseline SOFA score can be assumed to be zero in patients not known to have
preexisting organ dysfunction.
27
SOFA Score:
Table (3): Sequential [Sepsis-related] organ failure assessment score
(JAMA 2017)
qSOFA Score:
• Patients with suspected infection who are likely to have a prolonged ICU stay or to
die in the hospital can be promptly identified at the bedside with qSOFA, ie, alteration
in mental status, systolic blood pressure 100 mm Hg, or respiratory rate 22/min.
Box 4. qSOFA (Quick SOFA) Criteria (JAMA 2016)

- Respiratory rate ≥ 22/min.
- Altered mentation
- Systolic blood pressure ≤ 100 mmHg
28
Septic shock
• Septic shock is a subset of sepsis in which underlying circulatory and cellular/
metabolic abnormalities are profound enough to substantially increase mortality.
Patients with septic shock can be identified

• With a clinical construct of sepsis with persisting hypotension requiring
vasopressors to maintain MAP 65 mm Hg and having a serum lactate level >2 mmol/L
(18 mg/dL) despite adequate volume resuscitation. With these criteria, hospital
mortality is in excess of 40%.
How to differentiate between cold and warm shock?
Cold shock Warm shock

Capillary refill > 2 seconds Flash capillary refill
Peripheral pulses Diminished Bounding
Mottling of skin Present Absent
Pulse pressure Narrow Wide
How to proceed? (JAMA 2016)
29
Management of Septic Shock (nelson 21th edition)
30
Early Goal Directed Therapy: (The 2012 Surviving Sepsis Campaign

Guidelines)
During the first 6 hours of resuscitation, the goals of initial resuscitation of
sepsis-induced hypoperfusion should include all of the following as one part of a
treatment protocol:
● Central venous pressure (CVP) 8-12 mm Hg
● Mean arterial pressure (MAP) ≥65 mm Hg
● Urine output ≥0.5 mL/kg/hr
● Cardiac index > 3.3 < 6.0L/min/m2 in PICU
● Central venous (superior vena cava) or mixed venous oxygen saturation
● ≥70 percent or ≥65 percent, respectively
Therapeutic Endpoints
Clinical
● Heart Rate normalized for age
● Capillary refill < 2sec
● Normal pulse quality
● Warm extremities
● Blood pressure normal for age
● Urine output >1 mL/kg/h
● Normal mental status
● CVP >8 mmHg
● No difference in central and peripheral pulses
Threshold rates Heart rate (bpm) Mean arterial pressure

Term newborn 120-180 55
Up to 1 yr 120-180 60
Up to 2 yrs 120-160 65
Up to 7 yrs 100-140 65
Up to 15 yrs 90-140 65
Laboratory:
● Decreasing lactate
● SvO2 >70%
31
Table (4): Vasodilators/Afterload Reducers (nelson 20th edition)

Drug Effect(s) Dosing range Comment(s)
Nitroprusside Vasodilator (mainly 0.5-4.0 µg/kg/min Rapid effect
arterial) Risk of cyanide
toxicity with
prolonged use (>
96 hr)
Nitroglycerin Vasodilator (mainly 1-20 µg /kg/min Rapid effect Risk of
venous) increased
intracranial pressure
Prostaglandin E1 Vasodilator 0.01-0.2 µg /kg/min Can lead to
Maintains an open hypotension Risk of
ductus arteriosus in the apnea
newborn with ductal-
dependent congenital
heart disease
Milrinone Increased cardiac Load 50 µg /kg over Phosphoodiesterase
contractility Improves 15 min inhibitor
cardiac diastolic function 0.5-1.0 µg/kg/min – slows cyclic
Peripheral vasodilation adenosine
monophosphate
breakdown
32
Table (5): Cardiovascular Drug Treatment of Shock (nelson 20th edition)

Drug Effect(s) Dosing range Comment(s)
Dopamine ↑ Cardiac contractility 3-20 µg/kg/min ↑ Risk of
arrhythmias at high
doses
Significant peripheral
vasoconstriction at > 10
g/kg/min
Epinephrine ↑ Heart rate and ↑ cardiac 0.05-3.0 µg/kg/min May ↓ renal
contractility perfusion at high
Potent vasoconstrictor doses
↑ Myocardial O2
consumption
Risk of arrhythmia at
high doses
Dobutamine ↑ Cardiac contractility
Peripheral vasodilator
Norepinephrine Potent vasoconstriction 0.05-1.5 µg/kg/min ↑ Blood pressure
secondary to ↑
No significant effect on systemic vascular
cardiac contractility resistance
↑ Left ventricular
afterload
Phenylephrine Potent vasoconstriction 0.05-2.0 µg/kg/min Can cause sudden
hypertension
↑ O2 consumption
Terlipressin dose in septic shock:

● Loading dose 20 mic/kg/ dose followed by continuous infusion 4- 20 mic/ kg/ hour
33
REFERENCES:
▪ David A. Turner and Ira M. Cheifetz, shock Chapter 70 Part IX

516:528 nelson textbook of pediatrics 20th edition 2015
▪ Mervyn Singer, Clifford S. Deutschman, Christopher Warren
Seymour, Manu Shankar-Hari, Djillali Annane, Michael Bauer et
al., The Third International Consensus Definitions for Sepsis and
Septic Shock(Sepsis-3) JAMA.2016; 315(8):801-810.
▪ Rodriguez-Nunez A, Lopez-Herce J, GilAntonJ, et al: Rescue
treatment with terlipressin in children with refractory septic shock:
A clinical study. Crit Care 2006; 10: R20 (doi:10.1186/cc3984)
34
Anaphylactic Shock:
Emergency Treatment:
• Patients with anaphylaxis should be placed on their back with lower extremities
elevated. If short-of-breath and/or vomiting, patient should be placed semi-upright in
a position of comfort with the lower extremities elevated.
➢ Intramuscular epinephrine 1: 1000 (1 mg/ml) at a dose of 0.01 mg/kg body

weight up to a maximum dose of 0.3 mg injected into the lateral thigh (vastus
lateralis).
➢ The dose can be repeated at 5-15 min intervals.
➢ The intramuscular route is preferred because epinephrine has a vasodilator
effect in skeletal muscle. After IM injection into the vastus lateralis, absorption
is rapid, and epinephrine reaches the central circulation rapidly.
➢ The maximum dose of epinephrine in anaphylaxis is lower than the dose used
in cardiopulmonary resuscitation.
➢ Failure to inject it promptly before the patient gets acute cardio-respiratory
failure and shock potentially increases the risk of death and the risk of biphasic
anaphylaxis (late phase reaction).
• Support the airway and ventilation
• Give supplementary oxygen 6-8 L/min
• Resuscitate with intravenous saline 0.9% (20 ml/kg body weight, repeated up to a
total of 50 ml/kg over the first half an hour.
• Other lines of treatment:
➢ Nebulized beta-2 stimulants: Decrease wheeze but are not life-saving H1-
antihistamines: Decrease itch and hives but not life saving
➢ Dose of diphenhydramine (Pirafene 50 mg/ml):
✓ 2-6 years: 6.25 mg 6-12 years: 12.2-25 mg > 12 years: 25-50 mg
➢ Corticosteroids: effects take several hours: not lifesaving. Used to prevent
biphasic; however, there is no evidence that this occurs.
➢ Dose of Hydrocortisone : 2.5- 5mg / kg
35
Refractory Cases:
• IV epinephrine: central line – 1:10,000 solution – infusion pump ⁻ Intubation
• Cricothyrotomy
• Vasopressors
• Glucagon: exerts positive inotropic and chronotropic effects on the heart,

independent of catecholamines. Therefore, glucagon, 1 mg intravenous bolus, followed
by an infusion of 1 to 5 mg per hour, may improve hypotension in one to five minutes,
with a maximal benefit at five to 15 minutes. (The U.S. Food and Drug Administration
have not approved glucagon for this use.) Nausea and vomiting may limit therapy with
glucagon.
Duration of Monitoring:
• Protracted or biphasic anaphylaxis (up to 72 hours; usually within 10 hours) occurs

in up to 20% of adults and 6% of children. ⁻ Patients should ideally be monitored for
at least 4, and preferably 8-10 hr.
• Some cases require monitoring for ≥ 24 hours.
36
• IV epinephrine: central line – 1:10,000 solution – infusion pump

• Intubation
• Cricothyrotomy
• Vasopressors: noradrenaline or dopamine
• Glucagon
Acknowledgment:
▪ Thanks to Prof. Dr. Elham Hosni, for participating in this chapter.
37
REFERENCE:
▪ Simons FER et al., for the WAO. J Allergy Clin Immunol 2011; 127: 587-
93-e22 and WAO Journal 2011; 4: 13-36. Illustrator: J Schaffer
38
39
40
Acute Severe Asthma
41
Managing exacerbations in acute care settings
42
Primary care management of acute asthma or wheezing in pre-schoolers
43
Treatment of Acute Severe Asthma in PICU:

1. Monitoring:
• Noninvasive blood pressure and oxygen saturations (SpO2). Those with respiratory
failure requiring mechanical ventilation should undergo the placement of central
venous, arterial, and urinary bladder catheters.
2. Oxygen:
• Oxygen should be used as carrier gas for intermittent or continuous nebulization and
to keep oxygen saturation above 92%.
3. Steroids:
• Methylprednisolone loading dose of 2 mg/kg followed by 0.5 to 1 mg/kg every 6
hours.
4. Bronchodilator:
• The usual dose for continuous albuterol nebulization ranges from 0.15 to 0.5
mg/kg/h.
• Nebulized ipratropium, in 0.25 to 0.50 mg doses, can be used every 20 minutes
during the first hour, followed by the same dose range every 6 hours.
5. Magnesium Sulfate:
• The dose of magnesium sulfate is 25 to 50 mg/ kg/dose (maximum 2 g), infused for
20 to 30 minutes, and followed by continuous infusion dependent on the patient’s
weight.
• Children weighing < 30 kg: of 25 mg/kg/h
• Children weighing > 30 kg may receive 20 mg/kg/h,
• Infusion rates must not exceed 2 g/h in any patient. Titration to the desired clinical
effect should be based on serum magnesium concentrations and tolerability.
Keep serum magnesium level below 6 mg /dl
• Observation of magnesium sulphate side effects:
Serum magnesium concentrations above 9 mg/dL causes:

Nausea, flushing, somnolence, vision changes, muscle weakness and hypotension
Serum magnesium concentrations above 12 mg/dL causes:

Respiratory depression and arrhythmias
44
6. Methylxanthines:
• The theophylline dose is 80% of the aminophylline dose.

• A loading intravenous dose, 5mg/kg of theophylline or 6 mg/kg of aminophylline,
given during 20 minutes is needed to achieve a therapeutic concentration.
• After the loading dose, a continuous infusion should be started. Infants younger than
6 months are 0.5 mg/kg/h
• Infants 6 months to 1 year 0.85 to 1 mg/kg/h
• Children 1 to 9 years, 1 mg/ kg/h
• Children older than 9 years, 0.75 mg/kg/h.
Serum drug concentrations should be obtained:
• 30 to 60 minutes after the loading dose is finished

• At 12 hours after the beginning of the continuous infusion
• Every 12 to 24 hours or when toxicity is suspected.
7. Mechanical ventilation of asthmatic patients:
Bilevel Positive Airway Pressure
• Noninvasive positive pressure ventilation (NPPV) in addition to conventional

therapy showed clinical improvement and correction of gas exchange abnormalities in
children and adults with asthma. NPPV was well tolerated in children, including
patients as young as 1 year
• Typically, recommended settings include an inspiratory positive airway pressure of
10 cm H2O, an expiratory positive airway pressure of 5 cm H2O, with or without a
low back-up ventilation rate.
Criteria for selecting severe asthmatic patients for NPPV trial

✓ Tachypnea above normal limit of age
✓ Tachycardia above normal limit of age
✓ Use of accessory muscles of respiration
✓ Hypoxia with a Pa,O2/FI,O2 ratio >200 mmHg
✓ Hypercapnia with Pa, CO2, 60 mmHg FEV1< 50% pred"
45
Absolute and relative contraindication for noninvasive positive pressure

ventilation (NPPV) trial
Absolute contraindications:
✓ Need for immediate endotracheal intubation
✓ Decreased level of consciousness
✓ Excess respiratory secretions and risk of aspiration
✓ Past facial surgery precluding mask fitting
Relative contraindication:
✓ Hemodynamic instability
✓ Severe hypoxia and/or hypercapnia, Po2/Fio2 ratio of [ 200 mmHg,
Pco2 ] 60 mmHg
✓ Poor patient cooperation
✓ Severe agitation
✓ Lack of trained or experienced staff
Invasive Mechanical Ventilation:
1. Criteria for intubation

2. Recommendations for intubation technique
3. Recommendations for appropriate ventilator settings
4. Management in the immediate postintubation period
5. Medical management of asthma in the ventilated patient 6- Prevention
and treatment of complications.
6. Prevention and treatment of complications.
46
47
Criteria for Intubation:

Clinical:
• Cardiac arrest
• Respiratory arrest
• Progressive exhaustion
• Altered sensorium such as lethargy or agitation, interfering with oxygen delivery or
anti-asthma therapy.
Laboratory:
• pH less than 7.2, carbon dioxide pressure increasing by more than 5 mm Hg/h or
greater than 55 to 70 mm Hg, or oxygen pressure less than 60 mm Hg on 100% oxygen
delivered through a mask.
• Failure to reverse severe respiratory acidosis despite intensive therap.
1. Recommendation for intubation:
✓ Orotracheal intubation with sedation and neuromuscular

blockade are preferred for asthmatic patients in critical respiratory
distress.
✓ Intubation medication
• Atropine at a dose of 0.02 mg/kg IV (minimum 0.1 mg, maximum 0.5 mg child, 1
mg adolescent) used to attenuate the vagal reflexes that lead to laryngospasm and
worsen bronchospasm
• Ketamine: 1.0 to 1.5 mg/kg I.V and 1.0 to 1.5 mg/kg succinylcholine I.V
o It stimulates the release of catecholamines leading to bronchodilation; Side
effects include hypersecretion, hypotension and hypertension, arrhythmias,
and hallucinations
• Or propofol 2 mg/kg administered I.V over 2 minutes with succinylcholine,

preferred in patients with hypertension, and succinylcholine should be avoided in
patients with hyperkalemia.
48
2. Mechanical ventilation recommendations:
➢ Low rate
➢ Low PEEP
➢ Prolonged expiratory time
➢ Allow hypercapnia: till pH as low as 7.15 and a Pa CO2 of up to 80 mmHg
All these settings to avoid hyperinflation and auto-PEEP
1. Deal with expected complications:
❖ Hypotension:
Look for:
✓ Pneumothorax
✓ Hypovolemia
✓ High auto PEEP
❖ Cardiac arrest:
Look for:
✓ Hypoxia
✓ Exclude right mainstem intubation (21 cm at incisors)
✓ Exclude pneumothorax and place pleural drain
✓ Exclude pneumonia and other lung disease
✓ Pneumothorax
49
Mechanical ventilation algorithm
50
References:
▪ Nievas IF, Anand KJ, Severe acute asthma exacerbation in children: a
stepwise approach for escalating therapy in a pediatric intensive care unit.
J Pediatr Pharmacol Ther. 2013 Apr;18(2):88-104. doi: 10.5863/1551-6776-
18.2.88.
▪ Barry Brenner, Thomas Corbridge, and Antoine Kazzi Intubation and

Mechanical Ventilation of the Asthmatic Patient in Respiratory Failure
Proc Am Thorac Soc Vol 6. pp 371–379, 2009
▪ A. Soroksky, E. Klinowski, E. Ilgyev, A. Mizrachi, A. Miller, T. M. Ben

Yehuda, I. Shpirer, Y. Leonov Noninvasive positive pressure ventilation in
acute asthmatic attack Eur Respir Rev 2010; 19: 115, 39–45.
▪ Asthma clinical care guidelines, Children’s Hospital Colorado
▪ Soroksky, E. Klinowski, E. Ilgyev, A. Mizrachi, A. Miller, T. M. Ben

Yehuda, I. Shpirer, Y. Leonov 2010 Noninvasive positive pressure
ventilation in acute asthmatic attack, Eur Respir Rev 2010; 19: 115, 39–45
51
Status Epilepticus
Definition:
5 min or more of (i) continuous clinical and/or electrographic seizure activity or (ii)
recurrent seizure activity without recovery (returning to baseline) between seizures.
52
53
Table (6): Intermittent drug dosing in SE (Brophy et al., 2012)
54
Table (7): Pharmacological and non-pharmacological therapies

for the treatment of RSE/SRSE (A. Vasquez, et al., 2018)
Mechanism of Adverse Clinical Level of
dose
action events considerations evidence
Pharmacological therapies
Benzodiazepines
Midazolam Positive Loading Hypotensi Prolonged use Class
allosteric dose: 0.2 on, may cause IIA,
modulation of mg/kg; respiratory tachyphylaxis Level B
administer at depressio and drug Class IV
GABA-A
an infusion n accumulation
receptors, rate of 2
Increases mg/min
frequency of CI Infusion rate:
channel 0.05– 2
opening mg/kg/h
Breakthrough
SE: 0.1–0.2
mg/kg bolus,
increase
rate by 0.05–
0.1
mg/kg/h.
every 3–4 h
IV anesthetic Activation of Long half-life
Loading Hypotension, Class
GABA (15–
agents Barbiturates Receptors
dose: 5– 15 cardiac and 50 h) Requires IIB,
increase
Pentobarbital mean CI
mg/kg; respiratory mechanical Level B
channel
opening
infusion rate depression, ventilation. Can Class IV
duration,
inhibition of paralytic
≤ 50 mg/min exacerbate
NMDA ileus,
receptors, porphyria
Infusion rate: infection
alteration in Hepatic
conductance of
0.5– 5 enzyme inducer
Cl, K+
, Ca2+ ion Drug
mg/kg/h
channels. accumulation
Same as with prolonged
Breakthrough
Pentobarbital use
SE: 5 mg/kg
bolus,
increase rate
by 0.5– 1
mg/kg/h.
every 12 h
55
Mechanism of Adverse Clinical Level of

dose
action events considerations evidence
Pharmacological therapies
Thiopental Same as the 2–7 mg/kg, Hypotension, Requires Class IV

mechanism
infusion rate cardiac and mechanical
described
ventilation,
Above ≤ 50 mg/min respiratory
titrate
Infusion/ depression infusion rates to
EEG burst-
maintenance
rate: 0.5–5 suppression

mg/kg/h
Breakthrough
SE:1– 2
mg/kg bolus,
titrate by 0.5–
1 mg/ kg/h.
every 12 h
Propofol Chloride channel Initial loading PRIS, Requires Class
mechanical
conductance, dose: 1–2 hypotension, ventilation IIB,
enhances
GABA-A receptor mg/kg Initial cardiac and Prolonged Level B
infusion
infusion rate respiratory of propofol is a Class IV
20 depression relative
mcg/kg/min contraindication
in
titrated by 5– children (due to
risk
10 of PRIS) and in
mcg/kg/min patients with
Use with metabolic
acidosis,
caution with mitochondrial
doses > 65 disorders or
mcg/kg/min hypertriglyceride
mia
Breakthrough Reduces ICP
SE: Increase Caution with
infusion rate concomitant use
of
by 5–10 mcg/ steroid or
kg/min every catecholamine
5 min therapy
56
Mechanism of Clinical Level of

Dose Adverse effects
action considerations evidence
Ketamine Noncompetitive 0.5–3 mg/kg Tachycardia, Relative Class IV
NMDA glutamate Infusion rate: hypertension, contraindication in
receptor antagonist 1–10 mg/kg/h ICP elevation patients with ICP.
reduces neuronal Ketamine is an
excitability enzyme inducer and
inhibitor (CYP2C9)
Inhalational Enhancement of Concentration Hypotension High seizure Class IV
Anesthesia GABA-A receptors, 1–5% Titrate requiring use recurrence rate
of
Isoflurane noncompetitive to achieve vasopressors,
antagonist of NMDA burst- atelectasis,
receptor suppression paralytic ileus,
on
EEG infection, deep
vein
thrombosis
Immunomodulatory Alteration of IgG- 1–2 g/kg Hypersensitivit Immunomodulatory Class IV
y
therapy IVIG specific receptors divided over reactions, therapies may be
(FcgR) expression 3–5 days transfusion considered in
and
function (decreases related acute patients with
cytokine lung injury, cryptogenic,
production),
attenuation of thromboemboli autoimmune
c
complement events, renal etiologies of
mediated
cell damage dysfunction RSE/SRSE.
with
concentrated
solutions,
aseptic
meningitis
Corticosteroids: Inhibition of Glucose Class IV
Methyl inflammation 1 g/day for 3– intolerance,
Prednisolone associated proteins 5 days psychiatric
(e.g.
cytokines, disturbances,
chemokines)
and altered
immune
immunosuppressive function,
adrenal
action suppression
57
Mechanism of Clinical Level of

Dose Adverse effects
action considerations evidence
Non-pharmacological alternatives
Ketogenic diet Ketosis 4:1 (ratio fat Hypoglycemia, Contraindicated Class
mediated to hyperlipidemia, inpyruvate IV
decreased carbohydrates weight loss, carboxylase
glycolysis, and proteins) acute deficiency,
increase in free
pancreatitis, disorders of
and
polyunsaturated metabolic fatty acid
fattyacids, anti- acidosis oxidation and
inflammatory metabolism,
action, orporphyria
stabilization of
neuronal
membrane
Hypothermia Reduction of Na+ 32–35C x Deep venous Requires EEG Class
IV
exchange, 24h thrombosis, monitoring
decreased
K+ conductance, Rewarming ≤ infections,
regulation of 0.5 C/ h cardiac
glutamatergic arrhythmias,
synaptic
transmission, electrolyte
disruption of disturbances,
synchronized acute intestinal
discharges ischemia,
coagulation
disorders
Electroconvulsive Enhancement of Variable May induce Relative Class
IV
Therapy GABA protocols seizures and contraindication in
neurotransmission, non-convulsive patients with
increase of seizure SE after cardiovascular
threshold and treatment, conditions
Requires
reduction of neural amnesia, EEG monitoring
metabolic activity headache,
cognitive
impairment
Vagus nerve Modulation of the Surgical Hoarseness, Class
IV
Stimulation locus coeruleus, implantation surgical
thalamus and infection, rarely
limbic
circuit through asystole or
noradrenergic and bradycardia
serotoninergic
projections,
elevation
of GABA levels in
brainstem
58
N.B:
• If patient is less than 18 months give pyridoxine 100 mg i.v
• As regards thiopental infusion:
➢ If thiopental infusion is started stop midazolam infusion
➢ Increase thiopental infusion by 1mg/kg/hour every 30 min and give 2mg/kg

bolus as needed if seizures is occurred on infusion
➢ If convulsion is controlled Taper thiopental infusion after 24- 48hours by 25%

decrease every 12 hours
• As regard propofol infusion:
➢ When seizures have been controlled for 12 hours, the drug dosage should be
slowly reduced over a further 12 hours. If seizures recur, the drug infusion should
be given again for another 12 hours, and then withdrawal attempted again. This
cycle may need to be repeated every 24 hours until seizure control is achieved.
• When to do EEG:
➢ After clinical control of convulsion to diagnose subclinical status epilepticus
➢ After midazolam or thiopental or propofol infusion to document burst

suppression
Acknowledgment:
▪ Thanks to Prof. Dr. Hoda Tomom, and Pediatric Neurology Team for
their help and participation in this chapter.
59
References:
▪ Proposed Algorithm for Convulsive Status Epilepticus From “Treatment
of Convulsive Status Epilepticus in Children and Adults,” Epilepsy
Currents 16.1 - Jan/Feb 2016
▪ Nicholas S. Abend, MD and Dennis J. Dlugos, MD, MSCE, Treatment of

Refractory Status Epilepticus: Literature Review and a Proposed Protocol
PEDIATRIC NEUROLOGY Vol. 38 No. 6 june 2008
▪ Alejandra Vasqueza, Raquel Farias-Moellerb, William Tatumc, Pediatric

refractory and super-refractory status epilepticus, Eur J Epilepsy (2018)
60
Diabetic ketoacidosis
Definition:
Diabetic Ketoacidosis is one of two serious, acute life-threatening complications
of Type I diabetes mellitus (IDDM), or Type II, insulin insufficient diabetes mellitus,
the other being severe hypoglycemia.
The biochemical criteria:
Blood glucose > 200 mg/dL

Venous pH < 7.3
bicarbonate < 15 mmol/L
Ketonemia or Ketonuria
The severity of DKA is categorized by the degree of acidosis

Degree pH HCO3
Mild < 7.3 <15 mmol/L
Moderate < 7.2 <10 mmol/L
Severe < 7.1 <5 mmol/L
Clinical Signs:
1. Dehydration (which may be difficult to detect)
2. Tachycardia
3. Tachypnea (which may be mistaken for pneumonia or asthma)
4. Deep, sighing (Kussmaul) respiration; breath has the smell of acetone
5. Nausea, vomiting (which may be mistaken for gastroenteritis)
6. Abdominal pain that may mimic an acute abdominal condition
7. Confusion, drowsiness, progressive reduction in level of consciousness

and, eventually, loss of consciousness.
61
Management:
Acute management should follow the general guidelines for PALS with
particular attention to the following aspects for the child who presents in DKA.
1. Immediately measure BG and urine ketone concentrations with bedside

meters.
2. Perform a clinical evaluation to identify a possible infection
3. Weigh the patient
4. Assess severity of dehydration:
5% dehydration Prolonged capillary refill time (normal

capillary refill is ≤1.5–2 s)
Abnormal skin turgor (‘tenting’ or inelastic skin)
Abnormal respiratory pattern (hyperpnea).
Dry mucus membranes, sunken eyes, absent tears,
weak pulses, and cool extremities.
≥10% dehydration weak or impalpable peripheral pulses

hypotension
oliguria
5. Assess level of consciousness using Glasgow coma scale (GCS).

6. Additional measures is done of unconscious patient Secure the airway and
empty the stomach by continuous nasogastric suction to prevent pulmonary
aspiration
7. Give oxygen to patients with severe circulatory impairment or shock.
8. A cardiac monitor should be used for continuous electrocardiographic
monitoring to assess T waves for evidence of hyper- or hypokalemia
9. Obtain a blood sample for laboratory measurement of:
✓ Serum or plasma glucose

✓ Electrolytes (including Na, K)
✓ Blood urea nitrogen, creatinine
✓ Serum osmolality
✓ Venous pH, pCO2
62
✓ Complete blood count. Note that an increased white blood cell count
in response to stress is characteristic of DKA and is not indicative of
infection.
✓ Albumin, calcium, phosphorus, magnesium concentrations.
✓ Urine analysis
✓ Cultures (blood, urinary, sputum) only if evidence of infection
✓ HbA1c to assess duration of hyperglycemia
✓ ECG is done if serum measurement of K is delayed
10. Give antibiotics to febrile patients after obtaining appropriate cultures of

body fluids
11. Catheterization of the bladder usually is not necessary, but if the child is
unconscious or unable to void on demand (e.g., infants and very ill young
children) the bladder should be catheterized
Goals of therapy:
a. Correct dehydration
b. Correct acidosis and reverse ketosis
c. Restore BG to near normal
d. Monitor for complications of DKA and its treatment
e. Identify and treat any precipitating event
Calculations:
Anion gap = Na − (Cl + HCO3): normal is 12 ± 2 mmol/L.
o In DKA, the anion gap is typically 20–30 mmol/L; an anion gap >35 mmol/L
suggests concomitant lactic acidosis.
Corrected sodium = measured Na + 2 [(plasma glucose − 100)/100] mg/dL. Patients
with DKA are liable for hyponatremia due to:
Glucose largely restricted to the extracellular space, causes osmotic movement of water
into the extracellular space thereby causing dilutional hyponatremia
the low sodium content of the elevated lipid fraction of the serum in DKA
63
1-Fluid therapy:
Fluid replacement should begin before starting insulin therapy.
I. Antishock therapy:
It is given as required, to restore peripheral circulation.

o Patients not in shock but with volume depletion 0: 20 ml /kg over 1: 2
hours may need to be repeated until tissue perfusion is adequate.
o Patient with DKA in shock: rapidly restore circulatory volume with isotonic
saline in 20 mL/kg boluses infused as quickly as possible through a large
bore cannula with reassessment after each bolus.
II. Deficit therapy:
✓ In moderate DKA 5- 7% (50:70 ml/ kg)

✓ In severe DKA 7-10% (70:100 ml/kg)
o Calculate the subsequent rate of fluid administration, including the provision of

maintenance fluid requirements, aiming to replace the estimated fluid deficit
evenly over 48 h.
o Maintenance fluid: to be calculated based on body weight.

o 100cc/kg for the first 10kg, 50cc/kg for the next 10kg, and 20 cc/kg thereafter
“The rate of fluid administration should seldom exceed 1.5–2 times the usual
daily maintenance requirement.”
64
Table 1: showing maintenance volumes, also after subtraction of initial boluses

given for the patient assuming it was 10-20 ml/
65
Duration of IV fluid therapy:
Divide fluids over remainder of time for replacement: This is calculated based
on serum osmolality (mosmol/kg H2O):
o If s-osmolality 300 - < 320 correct over 24 hours

o If s-osmolality > 320 - < 340 correct over 36 hours.
o If s-osmolality > 340 or initial sNa+>150 meq/L correct over 48hours.
2-Insulin therapy:
Insulin therapy: begin with 0.1 U/kg/h in patients above five years
0.05 U/Kg/h in patients below five years
Insulin drip start 1–2 h AFTER starting fluid replacement therapy.

Dilute 50 units regular human insulin in 500 mL normal saline, (0.1 unit insulin =1 mL).
3-Potassium replacement:
If immediate serum potassium measurements are unavailable, an ECG may
help to determine whether the child has hyper- or hypokalemia.
Signs of hypokalemia in ECG: Prolongation of the PR interval
T-wave flattening and inversion ST
depression, prominent U waves
apparent long QT interval (due to fusion
of the T and U waves)
Signs of hyperkalemia in Tall, peaked, and symmetrical T waves

ECG: shortening of the QT interval
66
4. Bicarbonate Administration:
Bicarbonate administration is not recommended except for treatment of life
threatening hyperkalemia.
Bicarbonate is NOT recommended and has potential hazards in patients with DKA:
1. HCO3 diffuses slowly through BBB
(HCO3 + H+ CO2 + H2O)

CO2 diffuses rapidly paradoxical CNS acidosis * ↑ risk of cerebral edema.
2. Alkalosis is associated with hypokalemia.

3. May ↑ s-Na+ in a patient with hyperosmolar dehydration.
4. HCO3ˉ therapy shifts the OxyHb dissociation curve to the left (decreases O2
release to the tissues) ↑ tissue hypoxia.
67
Indication for bicarbonate therapy in patients with DKA:
(1) A patient with pH < 6.9 who is in shock with decreased cardiac contractility and
peripheral vasodilatation with poor tissue perfusion.
(2) Patients with LIFE THREATENING Hyperkalemia.
In these cases only Give NaHCO3 1-2 meq/kg or 80 meq/m2 body surface area added
to 0.45% saline over 1 hour (never by bolus).
Be careful about s-K+ and DO NOT stop K+ infusion while bicarbonate is being given.
Reassess after 1 hour of finishing bicarbonate infusion.
Rate of I.V fluid administration:
Rate of I.V fluid and insulin drips depend on RBS and rate of decent of RBS/
Hour which should not exceed 90 mg/dL.
RBS level Type of I.V fluid Rate of insulin drip

> 300 mg/dL Saline 0.9 % > 5 years 0.1 IU/kg/h
< 5 years 0.05 IU/kg/h
140 :300 mg/dL Saline 0.9%: glu 5% Same rate
Or rate of decrease
> 90 mg/dL
80: 140 mg/dL Saline 0.9%: glu 10% Same rate
Or rate of decrease
> 90 mg/dL
> 80 mg/dL Saline 0.9%: glu Same rate
Or rate of decrease 12.5%
> 90 mg/dL
> 80 mg/dL Saline 0.9%: glu Decrease to half rate

Or rate of decrease 12.5%
> 90 mg/dL
If rate of blood sugar decrease less than 30 mg/dL or acidosis is not corrected so you
should revaluate:
1. IV fluid calculations
2. Insulin delivery system & dose
3. Need for additional resuscitation
4. Consider sepsis
68
Clinical and biochemical monitoring
There should be documentation on a flow chart of hour-by-hour clinical

observations, IV and oral medications, fluids, and laboratory results. Monitoring
should include the
Following:
• Hourly (or more frequently as indicated) vital signs (heart rate, respiratory rate,
blood pressure).
• Hourly (or more frequently as indicated) neurological observations (GCS) for

warning signs and symptoms of cerebral edema that include:
1) Headache
2) Inappropriate slowing of heart rate
3) Recurrence of vomiting
4) Change in neurological status (restlessness, irritability, increased drowsiness,
incontinence)
5) Specific neurologic signs (e.g., cranial nerve palsies, abnormal pupillary
responses)
6) Rising blood pressure
7) Decreased oxygen saturation
8) Rapidly increasing serum sodium concentration suggesting loss of urinary free
water as a manifestation of diabetes insipidus (from interruption of blood flow to the
pituitary gland due to cerebral herniation)
9) Failure of measured serum sodium levels to rise or a further decline in serum
sodium levels with therapy is thought to be a potentially ominous sign of impending
cerebral edema. Too rapid and ongoing rise in serum sodium concentration may also
indicate possible cerebral edema as a result of loss of free water in the urine from
diabetes insipidus.
• Amount of administered insulin.

• Hourly (or more frequently as indicated) accurate fluid input (including all oral
• fluid) and output.
• Capillary blood glucose concentration should be measured hourly (but must be
cross-checked against laboratory venous glucose, as capillary methods may be
inaccurate in the presence of poor peripheral circulation and acidosis).
• Laboratory tests: serum electrolytes, glucose, blood urea nitrogen, calcium,
magnesium, phosphorus, hematocrit, and blood gases should be repeated 2–4
h, or more frequently, as clinically indicated, in more severe cases.
69
Where Should the Patient be treated? Indications for ICU admission:
1. Patients with severe DKA: (pH < 7.1, shock, or with long duration of symptoms).
2. Patients with altered level of consciousness.
3. DKA in children below 5 years (are at increased risk of cerebral edema).
4. Patients with high BUN, possible oliguria & acute tubular necrosis (for need of a
central venous catheter & dialysis).
5.If cerebral edema develops as a complication of treatment.
Introduction of oral fluids and shift to S.C. insulin
• Can introduce oral fluids after substantial clinical improvement (mild

acidosis/ketosis may still be present).
• Plan to change to SC insulin when ketoacidosis has resolved (pH > 7.3, HCO3>
15, anion gap is normal) + oral fluids are tolerated.
• Best is to shift before a meal time.
• Start S.C. intermediate acting + short acting insulin.
To prevent rebound hyperglycemia, the first SC injection should be given 15–30

min (with rapid acting insulin) or 1–2 h (with regular insulin) before stopping the
insulin infusion to allow sufficient time for the insulin to be absorbed. With
intermediate or long-acting insulin, the overlap should be longer and the rate of IV
insulin infusion gradually lowered.
Calculate insulin dose as:
0.7 U/kg/d in prepubertal children with long standing DM (may need IU/kg/d in
new cases).
1.0 U/kg/d at mid puberty.
1.2 U/kg/d by the end of puberty.
Give the first dose of rapid-acting insulin analogue 15 minutes before stopping
insulin infusion and of regular insulin 1 hour before stopping it.
70
Cerebral edema:
The incidence of clinically overt cerebral edema in national population studies

is 0.5–0.9% and the mortality rate is 21–24%
Diagnosis is established by:
1. One diagnostic criterion or

2. two major criteria or
3. one major and two minor criteria
These have a sensitivity of 92% and a false positive rate of only 4%. Signs that
occur before treatment should not be considered in the diagnosis of cerebral edema.
71
Treatment of cerebral edema:
Initiate treatment as soon as the condition is suspected.
I.Reduce the rate of fluid administration by one-third.
II.Give mannitol, 0.5–1 g/kg IV over 10–15 min, and repeat if there is no
initial response in 30 min to 2 h.
III.Hypertonic saline (3%), suggested dose 2.5–5 mL/kg over 10–15 min, may be
used as an alternative to mannitol, especially if there is no initial response to
mannitol
IV.Hyperosmolar agents should be readily available at the bedside.
V.Elevate the head of the bed to 30.◦
VI.Intubation may be necessary for the patient with impending respiratory

failure.
VII.After treatment for cerebral edema has been started cranial imaging may be
considered as with any critically ill patient with encephalopathy or acute focal
neurologic deficit. The primary concern is whether the patient has a lesion
requiring emergency neurosurgery (e.g., intracranial hemorrhage) or a lesion
that may necessitate anticoagulation (e.g cerebrovascular thrombosis)
References:
▪ ISPAD Clinical Practice Consensus Guidelines 2018 Compendium

▪ Protocol of Management of Type 1 Diabetes Mellitus, the Diabetes Clinic
Children's Hospital - Ain Shams Universit
72
73
Hypoglycemia
Diagnosis:
In addition to the measured glucose concentration thresholds listed below,
symptomatic hypoglycemia is defined by the presence of clinical signs such as:
➢ Tachycardia
➢ Sweating
➢ Altered level of consciousness (agitation, lethargy, or seizures)
Approach for Diagnosis
74
Management of Hypoglycemia:
A. Emergency Treatment:
If hypoglycemia is treated with IV dextrose (0.5 to 1 g/kg), administer one of the

following:
✓ D25W (25% dextrose in water): 2 to 4 mL/kg
✓ D10W (10% dextrose in water): 5 to 10 mL/kg
B. Continuous Treatment for persistent Hypoglycemia:
75
Adrenal Crisis
Definition
it is a physiological event caused by an acute relative insufficiency of adrenal
hormones.
Etiology
• May be precipitated by physiological stress in a susceptible patient.
• Should be considered in patients with congenital adrenal hyperplasia.
• Hypopituitarism on replacement therapy.
• Those previously or currently on prolonged steroid therapy.
Assessment:
A) History and physical examination – look for:
• Glucocorticoid deficiency:
➢ Weakness, anorexia, nausea and/or vomiting, hypoglycemia, hypotension

(particularly postural) and shock.
• Mineralocorticoid deficiency:
➢ Dehydration, hyperkaliemia, hyponatremia, acidosis and prerenal renal failure.
B) Investigations
• Immediate blood glucose.

• Serum glucose, urea, sodium and potassium.
• Arterial or capillary acid base.
“Where the underlying diagnosis not known, collect at least 2 ml of

clotted blood for later analysis (cortisol and 17 hydroxyprogesterone).”
76
Management:
Susceptible patients who present with vomiting but who are not otherwise
unwell should be considered to have incipient adrenal crisis. To attempt to
prevent this from developing further:
• Administer I.M hydrocortisone 2 mg/kg.
• Give oral fluids and observe for 4–6 hours before considering discharge.
• Discuss with appropriate consultant.
For all other children:
1. Give intravenous fluids.
Shock or severe dehydration:

• Normal saline 20 ml/kg I.V. bolus. Repeat until circulation is restored.
• Administer remaining deficit plus maintenance fluid volume as normal saline in
• 5% dextrose evenly over 24 hours.
• Check electrolytes and glucose frequently.
• After the first few hours, if serum sodium is greater than 130 mmol/L, change
to half normal saline.
• 10% dextrose may be needed to maintain normoglycaemia.
Moderate dehydration:
• Normal saline 10 ml/kg i.v. bolus. Repeat until circulation is restored.
• Administer remaining deficit plus maintenance fluid volume as normal saline in
• 5% dextrose evenly over 24 hours.
Mild or no dehydration:
• No bolus.
• 1.5 times maintenance fluid volume administered evenly over 24 hours.
77
2. Give hydrocortisone
Administer hydrocortisone intravenously. If I.V access is difficult, give I.M
while establishing intravenous line.
• 10 mg for infants
• 25 mg for toddlers
• 50 mg for older children
• 100 mg for adolescents
Should be administered as a bolus and a similar total amount given in divided
doses at 6 hr intervals for the 1st 24 hr. These doses may be reduced during the next
24 hr if progress is satisfactory
When stable reduce I.V. hydrocortisone dose, then switch to triple dose oral
hydrocortisone therapy, gradually reducing to maintenance levels (10–15 mg/m2/day).
Equivalent doses (20-25% of the hydrocortisone dose) of prednisone or

prednisolone may be divided and given twice daily.
In patients with mineralocorticoid deficiency, start fludrocortisone at

maintenance doses (0.05-0.2 mg daily) as soon as the patient is able to tolerate oral
fluids.
3. Treat hypoglycemia
• Hypoglycemia is common in infants and small children.
• Treat with I.V. bolus of 5 ml/kg 10% dextrose in a neonate or infant and 2
ml/kg of 25% dextrose in an older child or adolescent.
• Maintenance fluids should contain 5–10% dextrose.
78
4. Treat hyperkalemia
• Hyperkalemia usually normalizes with fluid and electrolyte replacement.
• If potassium is above 6 mmol/L perform an ECG and apply cardiac monitor as
arrhythmias and cardiac arrest may occur.
• If potassium is above 7 mmol/L and hyperkalemic ECG changes are present:
(eg. peaked T waves, wide QRS complex)
Give:
➢ 10 % calcium gluconate 0.5 ml/kg I.V over 3–5 mins.

➢ Commence infusion of insulin 0.1 units/kg/hr I.V together with an infusion of 50%
dextrose 2 ml/kg/hr.
• If the potassium is above 7 mmol/L with a normal ECG :
Give sodium bicarbonate 1–2 mmol/kg I.V over 20 mins, with an infusion of 10%
dextrose at 5 ml/kg/hr.
5. Identify and treat potential precipitating causes such as sepsis.
6. Admit to appropriate inpatient facility.
Prevention
Prevention of a crisis if possible, is essential and may involve:
• Anticipating problems in susceptible patients.
• Giving triple normal oral maintenance steroid dose for 2–3 days during stress (eg.
fever, fracture, laceration requiring suture).
• Giving intramuscular hydrocortisone when absorption of oral medication is
doubtful eg. In vomiting or severe diarrhea.
• Increasing parenteral hydrocortisone (1–2 mg/kg) before anesthesia, with or
without an increased dose postoperatively.
79
Acute kidney Injury (AKI)

Background
AKI =
• A recent increase of >1.5x in creatinine from a previous baseline or a value of >
1.5 x upper limit of the reference interval for age.
• Usually associated with a fall in urine output <0.5ml/kg/hour for 8 hours.
• Creatinine results should be interpreted in the context of age, body and muscle mass,
and ethnicity.
Creatinine Reference Ranges
• Neonates (premature) 0.33-0.98 mg/L 29 - 87 µmol/L

• Neonates (full-term) 0.31-0.87 mg/L 27 - 77 µmol/L
• to 12 months 0.16-0.38 mg/L 14 - 34 µmol/L
• 1to <3 years 0.17-0.35 mg/L 15 - 31 µmol/L
• to <5 years 0.26-0.42 mg/L 23 - 37 µmol/L
• 5 to <7 years 0.32-0.59 mg/L 28 - 52 µmol/L
• 15 years and over
• Male: 0.7 – 1.2 mg/L 62 - 106 µmol/L
Female: 0.5 – 0.9 mg/L 44 - 80 µmol/L
AKI Warning Score
AKI stage Creatinine change from baseline/ upper limit Urine

or eGFR (mL/min/1.73m2) output
1 >1.5-2x or
eGFR < 75
<0.5mL/kg for
2 2-3x or
8 hours
eGFR < 50
3 >3x or
eGFR < 35
80
Assessment
Causes Considerations in the history
Pre-renal
• Hypovolemia • Signs and symptoms of
• Impaired Cardiac output hypovolemia e.g. vomiting or
• Renal vessel occlusion diarrhea, decreased UO,
dizziness, lethargy
• Hepatorenal syndrome
• renal artery stenosis
• Past history: biliary atresia,
cardiac disease
Intrinsic renal disease

• Glomerulonephritis • Recent viral illness
• Involvement of renal • Change in urine color e.g.
microvasculature- HUS, HSP red or “coca cola” colored
• Interstitial nephritis • History of transplant or
• Drugs nephrotoxic drugs
• Acute Tubular necrosis
• Tumour lysis syndrome
Post-renal or obstructive
• Posterior urethral valves

• Abdominal pain Reduced UO
• Bilateral ureteric obstruction
• History of trauma
(trauma, calculi)
• History of kidney stones
• Urethral obstruction (trauma,
• Frequent UTI’s
calculus)
GFR Calculation
In children, eGFR is calculated using the following formula, in which:

k = 30 µmol/L for children <1 year
k = 40 µmol/L for children >1 year
eGFR (mL/min/1.73m2) = k x height(cm)

Serum creatinine (µmol/L)
N.B
(1mg/dl = 88 µmol/L)
81
Management
82
Pediatric nephrology referral to the Renal Team

o Immediate referral for any stage AKI where
▪ K+ >6.5mmol/L
▪ Oligo/anuria and plasma Na+ <125 mmol/L
▪ Pulmonary edema of hypertension unresponsive to diuretics
▪ Plasma urea >40mmol/L unresponsive to fluid challenge
▪ Persistent or worsening metabolic acidosis
o AKI stage 2 or 3 and consider for stage 1
o Any AKI
▪ in CKD patient or patient with a renal transplant
▪ Suspected intrinsic renal disease (e.g. nephritis / HUS)
If any concerns outside of this list, please discuss with ECHL
83
Fluid management in AKI

Clinical Assessment of Fluid Status
• Fluid assessment- peripheral circulation, edema, urine output
• Signs of cardiac failure- raised JVP, hepatomegaly, peripheral pitting edema,
bilateral lung crepitations.
• Blood pressure (changes are late and measurements in isolation not usually helpful)
• Low BP with cool peripheries -> intravascular depletion and shock
• High BP with warm peripheries -> fluid overload
Hypovolemia Overloaded
• Furosemide IV
Initial management
1. Fluid challenge 10
Euvolemia
mL/kg0.9% infusion 3-5
sodium chloride • Fluid challenge 10 mg/kg up to 4
STAT mL/kg 0.9% sodium times
2. Initial fluid chloride over 1 hour a day (max dose
replacement = 250mg;max
insensible losses 1g/day) may be
(400ml/m2/day) + considered but
UO (last24h) this should be a
decision by a
senior clinician
• Replace UO and
Ongoing management
insensiblelosses for
at least 24-48h
Replace ongoing fluid losses
▪ Beware of (insensible at 400ml/m2/d,
increased
urine, GI losses)
losses in fever,
Insensible losses are higher
profuseD&V,
in febrile children and lower in Fluid restrict to
hyperventilating
ventilated children 50-75%of UO
• Beware of polyuric
recoveryphase
“If renal function continues to improve, set a fluid target.

Ongoing management “Monitor, Maintain, Minimize”
84
Monitor
Strict and Accurate Input / Output
✓ At least daily weights

✓ Always plot height and weight on a growth chart
✓ Ideally at the same time each day, especially for small children
✓ Blood pressure at least four hourly
Nutrition
✓ Children with AKI are in a catabolic state and therefore need monitoring to
ensure meeting adequate calorie requirement
Investigations
✓ Bloods: daily U&E. Management of electrolyte abnormalities especially
Hyperkalemia
✓ Urinalysis at least daily
Maintain
✓ Ensure adequate circulatory volume – address hypoperfusion urgently with fluid

boluses (10 mL/kg) and inotropic support once the volume is restored.
Minimize
✓ Further harm should be reduced by stopping nephrotoxic drugs and restarting

when appropriate with dose adjustments
✓ Intravenous contrast should also be avoided
85
ABBREVIATIONS
ACE-I Angiotensin-Converting Enzyme Inhibitor
AKI Acute Kidney Injury
ANA Antinuclear Antibody
ANCA Antineutrophil Cytoplasmic Antibodies
anti-GBM Anti–Glomerular Basement Membrane
ARB Angiotensin II Receptor Blocker
ASOT Antistreptolysin O Titer
C3/4 Complement 3/4
CK Creatine Kinase
CKD Chronic Kidney Disease
D&V Diarrhea and Vomiting
GI Gastrointestinal
HSP Henoch-Schönlein Purpura
HUS Hemolytic Uremic Syndrome
Hx History
JVP Jugular Venous Pulse
LDH Lactate Dehydrogenase
NSAID Non-Steroidal Anti-Inflammatory Drugs
PEWS Pediatric Early Warning Signs
sCr Serum Creatinine
STAT To Be Performed Immediately
U&E Urea and Electrolytes (Sodium “Salt”, Potassium, And
Magnesium)
ULRI Upper Limit Of The Reference Interval
UO Urine Output
USS Ultrasound Scan
References
▪ https://www.grepmed.com/images/3937/differential-nephrology-postrenal-
diagnosis-prerenal-failure- kidney
▪ https://www.thinkkidneys.nhs.uk/aki/wp-
content/uploads/sites/2/2016/05/Guidance_for_paediatric_patients_final.pdf
▪ https://www.nuh.nhs.uk/download.cfm?doc=docm93jijm4n840 Source
▪ O - 5 yeam Roche Cobas® Enzymatic Creatmme lat insen 09-2014 V7 O
▪ 5yeam and over Roche Cobas® Jaffe Creatmme kit insen 10-2015 V11.0
▪ https://bihsoc.org/wp-content/uploads/2017/11/GOSH-BP-flowsheet-
Children-E-Brennan-May-2017-1.pdf
86
Comatose Child
87
Cerebral Oedema
Scope
Applicable to cerebral oedema in infants, children and adolescents
This protocol is NOT intended to address the management of specific etiologies
of cerebral oedema/ increased intracranial pressure
Disclaimer
licensed physicians. The physician is ultimately responsible for management of
individual patients under their care.
Recognition
Cerebral oedema needs a high index of suspicion and must be actively checked
for in any acute neurological condition and in case of neurological deterioration in any
patient.
The most common underlying conditions are:

✓ Traumatic brain injury
✓ Hypoxic/ ischemic brain injury
✓ Intracerebral & subarachnoid hemorrhage
✓ Cerebrovascular stroke
✓ Hypertensive encephalopathy
✓ CNS infectious and inflammatory conditions
✓ Intracranial space-occupying lesions
✓ Hyponatremic encephalopathy
✓ Hepatic encephalopathy
✓ In-born errors of metabolism during acute crisis
✓ During treatment of DKA and severe hypernatremia
✓ Dialysis disequilibrium syndrome
The most important clinical manifestations include:
✓ Altered consciousness; irritability or deteriorating consciousness
✓ Sluggish pupillary reaction and hyperreflexia
✓ Focal neurological abnormalities
✓ Bradycardia and hypertension
✓ Abnormal respiration
88
NB. CT findings are NOT essential before starting therapy. CT may be needed to
evaluate etiology. Assess patient stability and initiate indicated emergency
measures before transfer for imaging.
NB. Increased ICP may also be evaluated through the presence of papilloedema and
CSF pressure measurement.
Treatment of Cerebral Oedema
➢ Ventilation, Oxygenation and Circulation

➢ Control of cerebral metabolism
➢ Fluid and hyperosmolar therapy
➢ Dexamethasone
➢ Specific treatment of the underlying cause
➢ CSF diversion procedures and decompressive craniotomy
Ventilation, Oxygenation and Circulation

Ensure/ secure adequate airway and breathing
• Intubation may be necessary for GCS<8, inability to maintain airway or
hypoventilation
• Consider cervical spine immobilization in trauma victims
Maintain normal ventilation and oxygenation

• Oxygen, keeping patients with borderline oxygen or CO2 is NOT sufficient
• In patients with acute severe increase in ICP, a BRIEF period of MILD
hyperventilation (PaCO2 30mmHg) can be implemented.
“Avoid prolonged or excessive hyperventilation as it can

exaggerate cerebral ischemia”
Maintain adequate B.P. for cerebral perfusion

• Use volume and vasoactive drugs as necessary
• Hypotension can exacerbate cerebral ischemia
Ensure adequate cerebral venous drainage:
• Elevate the head of the bed 30 degrees in neutral position if not contraindicated
• Avoid neck compression
• Wide, bilateral and unnecessary jugular venous lines are not recommended
89
Control of Cerebral Metabolism
Increased cerebral energy requirement in the context of compromised perfusion

can increase cerebral damage:
• Control of any clinical or subclinical (bedside EEG) seizure activity

• Even if this would mean the need for intubation and MV in an ICU setting
• Active normothermia : aggressive management of fever or hyperthermia
• Monitor and correct hypoglycemia
Fluid and Hyperosmolar Therapy
In absence of (or after correcting) hypovolemia or hypotension, a restricted fluid

management is necessary:
• Provide 50-70% of normal maintenance requirements
• If correcting dehydration as in hypernatremia or DKA, reduce the fluid rate by
1/3 provided there is no hypovolemia or hypotension
Avoid rapid reduction or subnormal serum sodium levels, modify sodium content
of fluids
Avoid rapid reduction of blood glucose or urea levels
Hyperosmolar Therapy
IV hypertonic saline (5 mL/Kg of 2.7% NaCl over 30 min & may be repeated
once)
• Treatment may be repeated after several hours as clinically indicated
• Increasing serum Na beyond 155-160mmol/L is not recommended
• Continuous hypertonic saline at a low rate may be used to maintain serum Na
>145mmol/L but is not routine
IV mannitol (0.5-1g/Kg, 20% better than 10%, over 20min)
• Mannitol is effective even in those who cannot receive hypertonic saline
• Mannitol has a higher nephrotoxic potential than hypertonic saline
• Hypertonic saline improves systemic and cerebral perfusion compared to
mannitol
• Both may be given in the same patient
• Repeated regular (eg q6h) doses of mannitol are not recommended
90
Dexamethasone:
• The main value is in cases of inflammatory vasogenic cerebral oedema; as in

cases with vasculitis, cerebral infarctions, infectious, inflammatory and
neoplastic lesions
• In bacterial meningitis, it is initiated with the first dose of antibiotics
• It is not recommended in cases of intracerebral hemorrhage
• Dose: 0.15 mg/kg/6h; a higher initial dose (0.5 mg/Kg) may be used
Specific Treatment of The Underlying Cause
CSF Diversion Procedures and Decompressive Craniotomy
• These should be considered case by case; weighing risks and benefits
• They non-specifically reduce ICP but do not address cerebral oedema itself
• CSF diversion is the specific treatment of acute hydrocephalus
91
Blood Product Prescription
Key Points
• All blood transfusion activity must occur in compliance with the relevant
hospital procedures and guidelines.
• All patients should have consent for blood product administration recorded in
the medical record prior to transfusion.
• A blood transfusion should only be given when the expected benefits to the
patient are likely to outweigh the potential hazards.
• A blood product transfusion may be required to treat acute blood loss associated
with surgery or trauma, or when the body cannot make enough blood cells in the
case of bone marrow failure, cancer or bone marrow suppression.
Background
This guideline is adapted from the National Blood Authority (NBA) Patient
Blood Management Guidelines: Module 6 Neonatal and Pediatrics (2016) as well as
the British Society for Hematology Guidelines on transfusion for fetuses, neonates and
older children (2016). Local procedures or guidelines may vary.
Indications for Red Blood Cell (RBC) transfusion
Table 1: Indications for red blood cell transfusion
Hb Indication
Red Blood Cell (RBC) transfusion is often indicated, however lower
Hb <7 g/dL
thresholds may be acceptable in patients without symptoms (symptoms
may include – tachycardia, flow murmur, lethargy, dizziness, shortness
of breath, and cardiac failure) and where specific therapy (e.g. iron) is
available.
Hb 7-9 g/dL RBC transfusion may be indicated, depending on the clinical setting e.g.
presence of bleeding or hemolysis and clinical signs and symptoms of
anemia.
Hb >9 g/dL RBC transfusion is often unnecessary and may be inappropriate
Transfusion may be indicated at higher thresholds for specific situations:
Children with cyanotic congenital heart disease or on Extra Corporeal Life Support
(ECLS)
Children with Hemoglobinopathies (thalassemia or sickle cell disease) or congenital
anemia on a chronic transfusion program
92
Indications for Platelet Transfusion
Table 2: Indications for platelet transfusion in infants and children
Platelet Indication to trigger platelet transfusions in infants and children

count
(x10^9/L)
<10 ✓ Clinically stable pediatric patients receiving chemotherapy for
leukemia or post hematopoietic stem cell transplantation (HSCT)
(prophylactic).*
✓ Clinically stable patients with solid tumors (prophylactic).*
✓ Critically ill patients with no bleeding.
* Transfusions at higher levels may be required for bladder, brain or
necrotic tumors.
<20 Chemotherapy, HSCT & risk factors (e.g. fever, sepsis, minor
bleeding, mucositis, disseminated intravascular coagulopathy
(DIC) without bleeding)
Critically ill patients with risk factors for bleeding (e.g. sepsis, renal
failure, medications) Nasogastric tube insertion
Intramuscular injections e.g. Erwinia asparaginase
Insertion of a non-tunneled central venous line
<30 ✓ Lumbar puncture (LP) and ongoing chemotherapy-induced
thrombocytopenia
✓ Central nervous system (CNS) tumor and:
• A VP shunt or Ommaya reservoir
• Has a gross total resection and is receiving chemotherapy and/or
radiation
• Has residual tumor and is receiving chemotherapy and/or radiation
<50 LP and new disease induced thrombocytopenia
Patient undergoing invasive procedure (including tunneled central
venous line insertion) Moderate active bleeding (including bleeding
associated with DIC)
CNS tumour and:
A past history of intracranial hemorrhage
Is receiving an anti- angiogenesis agent such as bevacizumab
<75 Major hemorrhage due to trauma or significant post-operative bleeding
<100 Patient undergoing high risk invasive procedure (e.g.

neurosurgery/ophthalmology) ECLS (lower platelets may be
acceptable in stable patients)
93
Platelet transfusion is NOT indicated for the following
• Stable patients with chronic, stable, severe thrombocytopenia due to:

Alloimmunization
• Immune thrombocytopenia (ITP)
• Thrombotic thrombocytopenic purpura (TTP) Aplastic anemia or
myelodysplastic syndrome (MDS)
• These patients should be observed without prophylactic platelet transfusions and
should receive platelet transfusions only with clinically significant bleeding
• Bone marrow aspirate and trephine biopsy Intravenous cannula insertion
Indications for Fresh Frozen Plasma (FFP)

FFP is appropriate for the following
• Acute bleeding in the setting of significant coagulopathy.

• Warfarin reversal, in the presence of significant or life-threatening bleeding or
prior to emergency surgical procedures
• Given in addition to vitamin K
Note:
✓ Vitamin-K dependent clotting factor concentrates (e.g. prothrombinex) may be
given instead of FFP for bleeding secondary to warfarin or emergency warfarin
reversal.
✓ Liver disease, with clinically significant bleeding in the context of coagulopathy
post liver transplantation. Acute disseminated intravascular coagulopathy (DIC)
with bleeding and significant coagulopathy
✓ During massive transfusion or cardiac bypass for the treatment of bleeding
Plasma exchange for the treatment of TTP
✓ Specific factor deficiencies where a factor concentrate is not available
FFP is NOT indicated for the following
✓ The correction of minor coagulation abnormalities (minor prolongation of the

INR/APTT) in the non- bleeding child
✓ Liver disease when there are minor coagulation abnormalities and no-bleeding
✓ For reversal of a INR <2.0 in patients undergoing minor procedures
94
Indications for Cryoprecipitate
✓ Active bleeding and fibrinogen level <1.5 g/L

✓ During massive transfusion or cardiac bypass, for the treatment bleeding when
the fibrinogen level <1.5 g/L or there is hyperfibrinolysis
✓ Acquired fibrinogen deficiency or acute DIC when there is significant bleeding
and the fibrinogen <1.0 g/L
✓ Prior to an invasive procedure when the fibrinogen <1.0 g/L and there is a risk
of significant bleeding associated with the surgery or it is at a critical site (e.g.
neurosurgery or eye surgery)
Cryoprecipitate is NOT indicated for the following
✓ Non-bleeding children with mildly reduced fibrinogen levels

✓ Liver disease when there are minor coagulation abnormalities and no active
bleeding
Management - Transfusion volumes and rates
In children less than 20 kg, transfusion volumes should be calculated based on

weight and prescribed in mLs In children greater than 20 kg, calculate and prescribe
the transfusion volume with consideration to pack sizes for RBC transfusion, prescribe
a single unit followed by clinical reassessment to determine additional transfusion
requirements for platelet transfusions, the usual platelet dose in an adult is one adult
unit All transfusions must be completed within 4 hours of spiking a pack
95
Table 3: Transfusion Volumes and Rates

Blood product RBC Platelets FFP Cryoprecipitate
The formula for Children <20 Children <20 kg: 10 – 20 5 – 10 mL/kg

kg: mL/kg
Calculating Pooled platelets 10
Transfusion mL = wt (kg) x
Hb (g/L) rise mL/kg Apheresis
Volume
(desired Hb – platelets
(mL) 5 – 10 mL/kg
actual Hb) x 0.5
e.g.10 kg child Children >20 kg:
requiring Hb to 1 unit for >20 kg
child
rise from 60 to
80g/L:
10 x 20 x 0.5 =
100mL
Children >20
kg:
1 unit for >20 kg
child
Typical unit Red cell unit ~ Pooled platelet ~ FFP ~284 Cryoprecipitate
Volume 258 ml 334 mL mL
~ 36 mL
Pediatric red Apheresis platelet Pediatric
cells (pedipak) ~181 mL FFP
~ 61 mL (pedipak)
~69 mL
Transfusion Rate 5 mL/kg/hr. 10 – 20 mL/kg/hr. 10 – 20 10 – 20

mL/kg/hr. mL/kg/hr.
Commence at a Faster infusion
slower rate (e.g. rates (e.g. given
half the over
prescribed rate) 30 minutes) may
for the first 15 result in a
minutes (Usual transfusion
maximum rate reaction
150
ml/hr.)
96
Blood product modifications

• Request the appropriate blood component and special requirements:
• Irradiated blood products should be given to:
✓ All immunocompromised patients, including all immunology patients,
oncology patients, children with cardiac disease, and directed blood
donations to prevent graft-versus-host disease.
CMV negative products:
• Leucocyte-depleted blood products are considered an acceptable alternative to

CMV seronegative products.
• CMV-negative products are only indicated for exchange transfusion, pregnant
adolescents and patients with Severe Combined Immunodeficiency Disease
(SCID) who are CMV negative.
Phenotype matched red blood cells:
• Indicated for chronically transfused patients or patients with red cell

alloantibodies
Cryodepleted FFP
• May be requested for patients with Thrombotic Thrombocytopenic Purpura

(TTP), although FFP may be as effective.
IgA deficient products
• Patients with IgA deficiency who have developed an anti-IgA antibody
HLA matched
• For children with immunological refractory thrombocytopenia
97
Clinical Practice Guidelines on Prevention and Management of Pain

Recommendations Strength of Quality of
Recommendation Evidence
Analgesia
1) We suggest that, in critically ill pediatric patients 6 yr. old
and older who are capable of communicating, pain
assessment via self-report be routinely performed using Conditional Low
the Visual Analog Scale, Numeric Rating Scale, Oucher
Scale, or Wong-Baker Faces pain scale.
2) We recommend the use of either the Faces, Legs,
Activity, Cry, and Consolability or COMFORT-B Strong Moderate
scales for assessing pain in non-communicative
critically ill pediatric patients.
3) We recommend the use of observational pain assessment Strong Moderate
tools rather than vital signs alone for assessment of
postoperative pain in critically ill pediatric patients.
4) We suggest the use of observational pain assessment
Conditional Low
tools rather than vital signs alone for assessment of
procedure-related pain in critically ill pediatric patients.
5) We recommend that IV opioids be used as the primary
Strong Moderate
analgesic for treating moderate to severe pain in critically
ill pediatric patients.
6) We recommend the addition of an adjunct NSAID (IV or
oral) to improve early postoperative analgesia in
Strong Moderate
7) We suggest the addition of an adjunct NSAID agent (IV
Conditional Low
or oral) to decrease opioid requirements in the immediate
postoperative period in critically ill pediatric patients.
8) We suggest the addition of adjunct acetaminophen (IV or
oral) to improve early post-operative analgesia in
Conditional Low
9) We suggest the addition of adjunct acetaminophen (IV
Conditional Low
or oral) to decrease opioid requirements intermediate
postoperative period in critically ill pediatric patients.
10) We recommend that music therapy be offered to Strong Moderate
augment analgesia in critically ill postoperative
pediatric patients.
11) We recommend that nonnutritive sucking with oral Strong High
sucrose be offered to neonates and young infants prior to
performing invasive procedures.
98
Quality
Recommendations Strength of
of
Recommendation
Evidence
Sedation
1) We recommend the use of the COMFORT-B Scale or Strong Moderate
the State Behavioral Scale, to assess level of sedation Conditional Low
in mechanically ventilated pediatric patients.
2) We suggest the use of the Richmond Agitation- Conditional Low
Sedation Scale to assess the level of sedation in Conditional Low
mechanically ventilated pediatric patients.
3) We suggest that all pediatric patients requiring MV Conditional Low
are assigned a target depth of sedation using a Conditional Low
validated sedation assessment tool at least once daily.
4) We suggest the use of protocolized sedation in all
critically ill pediatric patients requiring sedation
and/or analgesia during MV.
5) The addition of daily sedation interruption to sedation
protocolization is not suggested due to lack of Conditional Low
improvement in outcomes.
6) During the periextubation period when sedation is
typically lightened, we suggest the following bundle
strategies to decrease the risk of inadvertent device
removal:
a) Assign a target depth of sedation at an increasing
frequency to adapt to changes in patient clinical status
and communication strategies to reach the titration
goal.
b) Consider a sedation weaning protocol.
c) Consider unit standards for securement of
endotracheal tubes and safety plan.
d) Restrict nursing workload to facilitate frequent
patient monitoring, and decrease sedation
requirements, and risk of self-harm.
7) We suggest the use of alpha2-agonists as the primary
sedative class in critically ill pediatric patients
requiring MV.
99
Quality
Strength of
Recommendations of
Recommendation
Evidence
8) We recommend that dexmedetomidine be considered Strong Moderate
as a primary agent for sedation in critically ill
pediatric postoperative cardiac surgical patients
with expected early extubation.
9) We suggest the use of dexmedetomidine for
Conditional Low
sedation in critically ill pediatric postoperative
cardiac surgical patients to decrease the risk of
tachyarrhythmias.
10) We suggest that continuous protocol sedation at
doses less than 4 mg/kg/hr. (67 µg/ kg/min) and Conditional Low
administered for less than 48hr may be a safe
sedation alternative to minimize the risk of
protocol-related infusion syndrome development.
11) Short-term (< 48 hr.) continuous protocol
sedation may be a useful adjunct during the Good practice
periextubation period to facilitate the weaning of
other analog-sedative agents prior to extubation.
12) We suggest consideration of adjunct sedation
with ketamine in patients who are not otherwise at an Conditional Low
optimal sedation depth.
13) During the periextubation period when sedation
Conditional Low
is typically lightened, we suggest the following
bundle strategies to decrease risk of inadvertent
device removal:
a) Assign a target depth of sedation at increasing
frequency to adapt to changes inpatient
clinical status and communicate strategies to
reach titration goal.
b) Consider a sedation weaning protocol.
c) Consider unit standards for securement of
endotracheal tubes and safety plan.
d) Restrict nursing workload to facilitate frequent
patient monitoring, decrease sedation
requirements, and risk of self-harm.
100
Quality
Strength of
Recommendations of
Recommendation
Evidence
Neuromuscular blockade
1) We suggest that train-of-four monitoring be used in Conditional Low
concert with clinical assessment to determine the depth
of neuromuscular blockade.
2) We suggest using the lowest dose of NMBAs required to
achieve desired clinical effects and manage undesired Conditional Low
breakthrough movement.
3) Electroencephalogram-based monitoring maybea useful
adjunct forthe assessment of sedation depth in critically Good practice
ill pediatric patients receiving NMBAs.
4) We suggest that sedation and analgesia should be adequate
Conditional Low
to prevent awareness prior to and throughout NMBA use.
5) We recommend routine use of passive eyelid closure and
eye lubrication for the prevention of corneal abrasions in Strong Moderate
critically ill pediatric patients receiving NMBAs.
ICU delirium
1) We recommend the use of the preschool and pediatric Strong High
Confusion Assessment Methods for the ICU or the
Cornell Assessment for Pediatric Delirium as the most
valid and reliable delirium monitoring tools in critically
ill pediatric patients.
2) We recommend routine screening for ICU delirium using
a validated tool in critically ill pediatric patients upon Strong High
admission through ICU discharge or transfer.
3) Given low patient risk, and possible patient benefit to
reduce the incidence and/or decrease duration or severity
Conditional Low
of delirium we suggest the following non-pharmacologic
strategies: optimization of sleep hygiene, use of
interdisciplinary rounds, family engagement on rounds,
and family involvement with direct-patient care.
4) We suggest performing EM, when feasible, to reduce the
development of delirium . Conditional Low
5) We recommend minimizing benzodiazepine-based Strong Moderate
sedation when feasible in critically ill pediatric
patients to decrease incidence and/or duration or
severity of delirium.
101
Strength of Quality of
Recommendations
6) We suggest strategies to minimize overall sedation exposure
whenever feasible to reduce coma and the incidence and/or Conditional Low
severity of delirium in critically ill children.
7) We do not suggest routine use of haloperidol or atypical
antipsychotics for the prevention of or decrease in Conditional Low
duration of delirium in critically ill pediatric patients.
8) We suggest that in critically ill pediatric patients with
refractory delirium, haloperidol or atypical antipsychotics be Conditional Moderate
considered for management of severe delirium manifestations,
with consideration of possible adverse drug effects.
9) We recommend a baseline electrocardiogram followed by
routine electrolyte and QTc interval monitoring for Strong Moderate
patients receiving haloperidol or atypical antipsychotics
iatrogenic withdrawal syndrome (iws)
1) We recommend use of either the Withdrawal Assessment Strong Moderate
Tool-1or Sophia Observation Scale for the assessment of
IWS due to opioid or benzodiazepine withdrawal in
2) We suggest routine IWS screening after a shorter duration
(3–5 d) when higher opioid or benzodiazepine doses are Conditional Moderate
used.
Good practice
3) Until a validated screening tool is developed, monitoring
for IWS from alpha2-agonists should be performed using
a combination of associated symptoms (unexplained
hypertension or tachycardia) with adjunct use of a
validated benzodiazepine or opioid screening tool.
4) We suggest that opioid-related IWS be treated with opioid Conditional Low
replacement therapy to attenuate symptoms, irrespective
of preceding dose and /or duration or opioid exposure.
5) Benzodiazepine-related IWS should be treated with
Good practice
benzodiazepine replacement therapy to attenuate
symptoms, irrespective of preceding dose and/or duration
of benzodiazepine exposure.
6) Alpha2-agonist–related IWS should be treated with IV
Good practice
and/or or enteral alpha2-agonist replacement therapy to
attenuate symptoms, irrespective of preceding dose and/or
duration of alpha2-agonist exposure.
7) We suggest use of a standardized protocol for
sedation/analgesia weaning to decrease duration of Conditional Low
sedation taper and attenuate emergence of IWS.
102
Strength Quality
Recommendations of of
Optimizing Environment
1) We suggest facilitation of parental or caregiver Conditional Low
presence in the PICU during routine care and
interventional procedures to a) provide comfort to
the child, b) decrease parental levels of stress and
anxiety and c) increase level of satisfaction of
care.
2) We suggest offering patients the use of noise Conditional Low
reducing devices such as ear plugs or headphones
to reduce the impact of non-modifiable ambient
noise (conditional, low-level evidence).
3) We suggest that PICU teams make environmental Conditional Low
and/orbehavioral changes to reduce excessive
noise and therefore improve sleep hygiene and
comfort, in critically ill pediatric patients.
4) We suggest performing EM to minimize the Conditional Low
effects of immobility in critically ill pediatric
Conditional Low
patients.
5) We suggest the use of a standardized EM
protocol that outlines readiness criteria,
contraindications, developmentally appropriate
mobility activities and goals, and safety thresholds
guided by the multidisciplinary team and family
decision-making.
103
104
Schematic summary of the key Pain, Agitation, Neuromuscular Blockade, and

Delirium in critically ill pediatric patients with consideration of the PICU Environment
and Early Mobility (PANDEM) recommendations and representation of the interplay
between sedative and analgesic choice on unintended but related outcomes.
BRAIN MAPS = Bring oxygen, Remove/Reduce deliriogenic drugs, patient Atmosphere,

Immobilization, New organ dysfunction, Metabolic disturbances, Awake, Pain, Sedation
CAPD = Cornell Assessment of Pediatric Delirium
COMFORT-B = COMFORT-Behavior
EEG = electroencephalogram
ETT = endotracheal tube
FLACC = Faces, Legs, Activity, Cry, and Consolability
IWS = iatrogenic withdrawal syndrome
MV = mechanical ventilation
NMBA = neuromuscular blocking agent
NSAID = nonsteroidal anti-inflammatory drug
pCAM- ICU = pediatric Confusion Assessment Method for the ICU
PRIS = propofol-related infusion syndrome
psCAM-ICU = preschool Confusion Assessment Method for the ICU
RASS = Richmond Agitation-Sedation Scale
SBS = State Behavioral Scale
SOS= Sophia Observation Scale
TOF=train-of-four
WAT-I=WithdrawalAssessmentTool-1
105
Basic Mechanical Ventilation

Scope:
MV is a respiratory support modality. Patients requiring MV are likely to require

other therapies; for the underlying disease, for respiratory care (eg physiotherapy,
suction, nebulized medications) and possibly for other system support. This protocol
addresses the MV part; however all aspects of patient care are equally important. MV
is not a contraindication for enteral feeding.
This protocol addresses mechanical ventilation of pediatric patients; beyond the

neonatal period, in the pediatric critical care setting.
Disclaimer:
licensed physicians. The physician is ultimately responsible for management of
individual patients under their care.
Concept Definitions
Ventilation: gas exchange between alveolar and surrounding gas. The volume inspired
(normally = expired) each breath is the tidal volume (Vt). Minute volume is the amount
of ventilation per minute and equals tidal volume x respiratory rate.
RR: respiratory rate is the number of breaths per minute
Cycle: in the context of MV, a respiratory cycle is a breath (inspiration & expiration)
Cycling: in the context of MV, cycling is the end of inspiration. Cycling occurs when
the ventilator ends inspiration allowing passive expiration by the patient
Ti: inspiratory time is the time interval from the beginning of inspiration till the
beginning of expiration
Rise time: the time interval between the beginning of inspiration and reaching the
plateau; during which pressure is rising. It can be expressed in seconds or a percentage
of inspiratory time
106
Oxygenation: (arterial oxygenation) the amount of oxygen reaching arterial blood,

measured as partial pressure (PaO2; normally 80-100mmHg) or as oxygen saturation
(SaO2 or SpO2; normally 95-97%); which is the percentage of oxyhemoglobin.
Arterial oxygenation depends on ventilation, FiO2 and pulmonary gas exchange.
FiO2: The percentage of oxygen in inspired gas. Room air has 21% oxygen.
Compliance: change in volume for change in pressure (∆V/∆P). Low compliance

means more change in pressure is required to achieve a volume change (stiff lungs; as
in pneumonia, collapse, ARDS)
Resistance: airway resistance is the force opposing air flow into or outside the lungs.
Bronchospasm increases airway resistance and this increases the effort necessary to
move air into/ outside the alveoli
Work of Breathing: the energy used (essentially the amount of effort used) in
breathing; aiming to achieve normal ventilation.
PIP: the peak inspiratory pressure; the highest pressure reached during inspiration
PEEP: the positive end-expiratory pressure; during expiration, an amount of +ve

pressure is maintained and it does not drop to zero. The main purpose is to prevent
alveolar collapse during expiration.
MAP: mean airway pressure. The average pressure throughout the respiratory cycle
(inspiration & expiration)
P plateau: the plateau pressure is the pressure at the plateau phase towards the end of
inspiration, measured in an inspiratory pause when there is no air flow. It is correlated
to the alveolar peak pressure; by excluding the pressure gradient needed to overcome
airway resistance.
AP: the pressure difference between plateau pressure and PEEP
107
Indications
• Post CPR management
• Severe hypoxemia (PaO2< 50-55mmHg) despite oxygen therapy. An
SpO2<85% by pulse oximeter is highly suggestive of PaO2<50-55mmHg
• Severe hypoventilation (PaCO2 >60mmHg with respiratory acidosis)
• Sustained or frequent apnea with desaturation
• Unacceptable work of breathing (most common indication in PICU)
• Excessively slow, shallow or irregular breathing
• Severe or increasing respiratory distress (impending exhaustion)
• Airway compromise requiring intubation
• Severe refractory shock
• CNS: deep coma with respiratory weakness or airway compromise, severe
cerebral oedema especially with (even mild) hypoventilation, refractory
status epilepticus needing anesthetic drugs
• Surgery under general anesthesia with neuromuscular blockade (most
common indication)
Objectives of MV
• Normal/ acceptable ventilation
• Normal/ acceptable oxygenation
• Acceptable work of breathing. Eliminating patient effort is not the objective,
but increased WOB on MV is not acceptable either.
• Lung protection. Avoidance of ventilator-induced lung injury
Initiation
Airway Establishment
• Non-invasive ventilation through a face mask may be used for those with
adequate airway and adequate circulation. Response should be assessed after
1hr and invasive MV initiated if response is inadequate.
• ET intubation is the most common approach. Bag-mask ventilation is
effective until preparations are made for intubation and ventilation.
• Tracheostomy should be considered when anticipated duration of MV exceeds
2-4weeks
108
Primary settings
1. Mode:
There are different modes of MV and they are all acceptable provided they are
appropriate to the ventilator specs, user experience and patient’s condition
CMV: Only acceptable when the patient either
(a) Can provide no significant work of breathing due to disease condition or necessary
sedation/ neuromuscular blockade; or
(b) Has severe ARDS or very severe bronchial obstruction and cannot be adequately
ventilated except after eliminating patient efforts by neuromuscular blockade. This
should be employed for the shortest time necessary
SIMV: The strategy is to share the effort between the ventilator and the patient based
on rate. Reducing set ventilator rate can increase patient’s spontaneous rate and vice
versa. The total rate (ventilator + patient) should be appropriate for age and condition.
Weaning depends on reducing set rate.
Assist-Control: The strategy is to assist every breath initiated by the patient.

Ventilatory support is based on patient’s rate, the set rate should be below the patient’s
respiratory rate and acts as a backup. It is important that the given pressure/volume per
breath is sufficient to achieve an acceptable minute volume; without discrepancy
between set Ti and patient Ti and without excessively high respiratory rate. Improved
lung condition is associated with lower PIP achieving normal Vt. Further weaning
requires shift to PSV or SIMV.
Pressure Support: The strategy is also to assist every breath initiated by the patient,
who also determines the inspiratory time. This is pressure controlled. Reducing
pressure support (∆P above PEEP) increases patient work and vice versa. PS can be
applied alone for patients who have a good respiratory drive, or combined with SIMV
to assist breaths above the set rate.
109
2. Primary Control Variable:
• Ventilators give a breath based on delivering a certain tidal volume (volume

controlled) or on increasing pressure to a certain value (pressure controlled) for
the duration of inspiration, followed by a passive expiration.
• Normal Vt is 6 -8mL/Kg. VC may use constant or decelerating (recommended)
flow. The resulting PIP will depend on lung mechanics and is measured
• PC depends on raising pressure to a certain PIP (in some ventilators ∆P above
PEEP). The Vt delivered depends on lung mechanics and is measured
• Both VC and PC aim to provide an appropriate Vt
• There are modes that attempt to combine both methods (Dual modes eg PRVC,
VG, VC+, etc). The principle is setting a target Vt and adjusting pressure based
on actual measured Vt; with many variations. Proportional assist ventilation
depends on giving a variable support depending on patient’s effort aiming to
achieve normal ventilation without increasing patient WOB. These modes can
be helpful and improve patient synchronization when used appropriately. Each
device has its own principles and users should be aware of these before using
such modes.
3. PIP or Vt:
• Other than dual modes, you will set one and monitor the other
• The plateau pressure (pressure at the end of inspiration) should not exceed 28-
30cmH2O to avoid lung injury. Patients with near normal compliance can
achieve normal Vt with MUCH lower pressures; while those with severe ARDS
may not be able to achieve normal Vt at this pressure and a lower Vt (4-5mL/kg)
may be accepted. Both high volume and high pressure should be avoided.
• Note: Plateau pressure is normally close to PIP but can be considerably less in
presence of airway obstruction. Some ventilators set ∆P not PIP (so you need to
add PEEP to get PIP)
• All modern ventilators can measure both delivered Vt and peak/plateau P.
4. Inspiratory Time Ti:
Other than PS and similar modes, you set the Ti after which the ventilator allows
the patient to expire. Setting must consider:
(a) For an I/E ratio near 2 (initially used), the Ti should be 20/ total (patient +
ventilator) rate
(b) Without changing rate, a longer Ti leads to a higher MAP in PC (& you can then
lower PIP if tolerated) and a lower PIP for a given Vt in volume control (both
are favorable). A too short Ti can lead to inadequate Vt or excessive PIP.
(c) Increasing Ti is limited by the need for adequate time for expiration to avoid air
trapping. While stiff lungs can usually tolerate I/E ratio 1:1, those with
obstructive pathology need great caution
(d) A set Ti greatly different from the patient’s own Ti can lead to asynchrony
110
5. Ventilator Rate:
In CMV and SIMV, this is the rate per min. the ventilator should provide.
Initially, a normal rate for age should be set.
6. PEEP:
This prevents end-expiratory collapse and optimizes tidal breaths to a favorable
segment of lung compliance. A starting PEEP can be 5cmH2O and note:
• Those with stiff lungs may need considerably higher PEEP to maintain lung
recruitment
• The best PEEP is that which improves oxygenation and Vt at a relatively low ∆P
• Excessive PEEP can lead to alveolar overstretch, increasing an air leak, reduced
venous return and increased intracranial pressure
7. FiO2 :
• Initially set 100% if the patient is unstable, cyanosed or severely hypoxic with
lung pathology; otherwise set 40-50%. Adjust based on pulse-oximetry to the
FiO2 achieving acceptable oxygenation (saturation around 94%).
• Neonates and especially preterms are more susceptible to the adverse effects of
excessive oxygen
• Those with brain injury, refractory shock, pulmonary hypertensive crisis & CO
poisoning require high FiO2 and maintaining a higher degree of arterial
oxygenation
• The maximum safe duration by FiO2 is as follows:
✓ 100% 3-4h
✓ 80% 24h
✓ 60% 3-4days
✓ 40% 3-4 weeks
8.Flow or Rise Time:

Changing these settings alter how rapidly the peak pressure is attained during
inspiration.
9.Trigger Sensitivity:
Correct setting is associated with:
(a) The ventilator recognizing most patient efforts (no missed triggers); and
(b) There are no false triggers
NB:
▪ Humidifier must be used with appropriate temperature, necessary bacterial
filters must be installed, flow sensor must be installed and calibrated for any
mode other than CMV/IMV, alarm limits must be checked and backup power
must be operational (ventilator battery or UPS).
▪ Interrupting the ventilator circuit should be minimized. ET suction is a sterile
procedure and should be done when necessary. Unnecessary injections of saline
into the ETT should be avoided.
111
Initial Settings Summary

Mode & control CMV only when patient not breathing or with
variable neuromuscular blockade
SIMV, with or without PS, or AC
PC and VC (with decelerating flow) both acceptable
Dual modes when applicable & user experienced in them
PIP or Vt Initial PIP: 15 for normal lungs, 20 for pathological lungs
Check chest expansion/air entry/ expired Vt and adjust PIP
up or down targeting a normal Vt (while beside patient)
Neonates & preterms need lower pressures
Generally will not exceed 30. In severe obstruction Pplateau
should not exceed 30 (PIP might be higher)
VC: set a normal Vt 6-8mL/min. Check resulting airway
pressure and if it exceeds above limits, reduce Vt to 4-
6mL/min. to achieve safe pressure.
Ti Rate Start at an I/E of 1:2 (Ti= 20/ total rate). At age-appropriate
rates:
Infants: Ti 0.5 at a rate of 40
Small children: Ti 0.6-0.7 at a rate of 30
Older children: Ti 1.0 at a rate of 20
Longer Ti may be helpful with stiff lungs

I/E may reach 1:1 with a longer Ti or high RR but ensure
complete expiration before next cycle (auscultation, vent.
Curves). Not recommended with bronchial obstruction.
PEEP Generally 5. Those with stiff lungs may need considerably
higher
FiO2 Start 100% if cyanosed, severely hypoxic or otherwise
unstable
Else, start around 50%
Adjust targeting SpO2 ≥92%; not necessarily close to 100%
(there are some exceptions needing higher SpO2)
Flow or rise time Mostly don’t change ventilator preset
Trigger sensitivity If patient initiating breaths, adjust to avoid missed efforts

and false triggers
112
Monitoring and Adjustment

Monitoring of MV
• Patient monitoring is essential; including continuous ECG, pulse oximetry and

non-invasive blood pressure. Useful data can be obtained by clinical
examination, from ventilator measurements and graphics, blood gases and
imaging studies.
• The patient should be monitored for the objectives of MV.
Note:
▪ Ventilation and oxygenation can be assessed from blood gases; however,

pulse oximetry can be used to assess oxygenation, the ventilator can usually
measure minute volume and capnography may be used for end-tidal CO2.
▪ Pulmonary gas exchange is assessed using oxygen-derived pulmonary
indices:
(1) Oxygenation index (OI) = FiO2 (%) x MAP / PaO2
Higher value ➔ more severe pathology
Above 20 ➔ severe lung pathology
Below 5 ➔ necessary to consider extubation
Cannot apply in patients without positive pressure support (MV or CPAP)
(2) Oxygen saturation index. Uses SpO2 instead of PaO2. Values are
somewhat lower than OI
(3) Arterial/ inspired oxygen ratio= PaO2/ FiO2(fraction 0.21-1.00)
Can be applied with or without positive pressure support
Normally >300. Lower values ➔ more severe pathology
<100 ➔ severe ARDS
▪ The ventilator can usually measure compliance and resistance

▪ Work of breathing is generally assessed clinically. It is also important to
identify patient-ventilator asynchrony (ventilator graphics can help) and
determine the appropriate level of sedation (patient calm and synchronized
but not oversedated)
▪ NB Proper settings and synchronization can be associated with less need
for sedation in many patients. No patient may receive neuromuscular
blockade without deep sedation.
▪ Patients should be monitored for ventilator induced lung injury, including
ventilator parameters that denote overdistension, barotrauma or
atelectrauma, as well as the development of VAP.
113
Adjustment of Settings
Ventilation:
• Increasing tidal volume increases ventilation, but avoid overdistension &
observe ∆P limits
• Increasing rate increases ventilation, but observe for Te adequacy
Oxygenation:
• Ventilation affects oxygenation
• Increasing FiO2 increases oxygenation
• Increasing MAP (PEEP, I/E ratio, lastly PIP) increases oxygenation
• A successful lung recruitment improves oxygenation
WOB:
• Patient work of breathing can be decreased by increasing ventilation provided
by the ventilator, as well as by improving patient-ventilator synchronization
• Where possible and tolerated, reducing ventilation provided by the ventilator,
with equivalent increase in patient contribution, corresponds to lowering the
level of support
NB:
▪ It is acceptable to increase settings during a procedure or in response to
deterioration (particularly FiO2 and ventilator rate). However, it is
mandatory to identify & correct the cause of deterioration. After the reason
is over, aim to return to the preceding settings relatively rapidly.
Acute deterioration on MV:
• The most common causes
✓ Equipment failure: inlet gases, ventilator, circuit leak or obstruction, etc
✓ ETT blockage (secretions, blood) or displacement
✓ Patient (most notably pneumothorax; also bronchospasm, asynchrony,
pulmonary hemorrhage, pulmonary oedema, pulmonary embolism and
collapse. Some of these may cause less sudden deterioration
• If the cause is not immediately obvious, a trial of bag & tube ventilation will
immediately by-pass ventilator, circuit or source gas failure. Further, it will
enable assessment of resistance, chest rise and auscultation.
• A blocked tube should be removed and patient ventilated by bag and mask
until reintubation is done.
• An obvious tension pneumothorax with failure of ventilation should be
immediately drained (using needle thoracentesis if appropriate) without
unnecessary delays. A chest tube will then be required (needle will not be
enough during on-going MV)
114
Beyond adjustment of settings:
• If the patient’s condition is deteriorating/ not responsive despite

increasing/high settings in absence of a rapidly correctable factor, also
consider
Lung Recruitment Maneuver
More conservative goals:
• Permissive hypercapnia or hypoxemia. Accepting lower than usual goals of
ventilation & oxygenation (eg PaCO2 60-65 provided pH>7.15, SpO2 86-
88%) may be appropriate in those with severe lung pathology so long they do
not lead to a decompensation.
Note:
▪ Permissive hypercapnia requires heavy sedation & frequently paralysis.
These goals are NOT TO BE USED in those with CNS injury
Using a different mode:

• As CMV, HFV, ECMO
WEANING
The following general principles apply:
• Once the patient is ventilated and stable, assess readiness for weaning
(decreasing support) at least daily. Based on
(a) Improvement of the underlying cause
(b) Condition of other systems eg hemodynamics, metabolic, neurological
(c) Absence of neuromuscular blockade and absence of heavy sedation. It is
helpful to interrupt sedation for 1-3hrs daily to judge consciousness and
respiratory drive
(d) Patient’s ability to tolerate a reduction in support (eg rate in SIMV, ∆P in
PS) without excessive RR or effort
• When settings are low enough, a spontaneous breathing trial (without
ventilator support) can be used to judge the patient’s ability to breathe
spontaneously. Judge based on ventilation, oxygenation and WOB. Trials
should not be prolonged (1-2h are usually enough)
• FiO2 <40%, PEEP ≤5, PS ≤10, OI<5
• Patients on long-term MV are more difficult to wean so a more gradual
process is needed
• Any correctable factors should be addressed before extubation (volume, BP,
temp, electrolytes, P, Mg, hemoglobin, etc)
• Be prepared to manage laryngeal oedema and to reintubate if necessary. Those
on MV for significant periods may be weaned to mask CPAP
115
Poisoning Protocol
116
117
118
119
120
Pediatric Pulmonology Protocol of EHA
Protocols of EHA

in
Pediatric Pulmonology
for
First Edition
2024
Prepared By
in
Pediatric Pulmonology
for
1
Executive Committee
1. Prof. Eman Mahmoud Fouda:(Head of the Committee) Professor of Pediatrics,

Ain Shams University
2. Prof. Hala Hamdi: Professor of Pediatrics, Cairo University
3. Prof. Mona Mohsen Elattar: Professor of Pediatrics, Cairo University
4. Prof. Tarek Hamed: Professor of Pediatrics, Zagazig University

All Intellectual Property Rights are reserved to EPG. No part of this publication can be
reproduced or transmitted in any form or by any means without written permission
from the EPG and authors.
2
Protocols of EHA

• Consultant Pediatrician of Egyptian Military Medical Services.
• Professors of Pediatrics Military Medical Academy
• Head of Training Committee of Pediatrics of Egyptian Military Medical Board
• Consultant Pediatrician of the Medical Advisory Council of Egypt Healthcare
Authority (EHA).
Reviewed By



3
PREFACE
The Egyptian Clinical Practice Guideline in pediatric pulmonology represent an
evidence-based national perspective for the management of most common respiratory
presentations in children that would be both clinically relevant and practically feasible
for implementation. These guidelines present recommendations for clinical practice as
adapted from ACCP 2006-2020, ERS 2019 & KAAACI 2018. We hope this report to
be a useful resource in the management of chronic cough in children.
This guideline intends to assist the practitioners, namely; pediatricians, primary
health care (PHC) physicians, family practitioners, nurses and clinical pharmacists to
apply the best available evidence-based researches to clinical decisions about the
management of in children below 14 years
This ECPG does not intend to serve as a standard of medical care. Standards of
care should be based on all the clinical data available for an individual case and are
subjected to changes as scientific knowledge and technology advance in patterns of
care evolve .
The ECPG recommendations will neither ensure a successful outcome in every
case nor include all the proper methods of care. Also, they do not exclude other
acceptable methods of care aimed at the same results .
The ultimate judgment must be made by the appropriate physician who is
responsible for clinical decisions regarding a particular clinical procedure or treatment
plan. This judgment should only be made following discussion of the options with the
patient, in light of the diagnostic and treatment choices available. However, it is
advised that significant departures from the ECPGs or any local CPGs derived from it
should be fully documented in the patient’s case notes at the time the relevant decision
is taken.
Finally, we wish the best for all our patients and their families who inspired us.
It is for them this work is being finalized
In Pediatric Pulmonology
4
Protocols of EHA
Table of Contents
Page
Title
Number
Preface 4
Scope and Purpose 6
Chronic Cough 9
Croup 15
Bronchiolitis 18
Asthma Exacerbation 23
Community Acquired Pneumonia in immunocompetent 26
Patient
Prophylaxis of Respiratory Syncytial Virus( RSV ) 33
Appendix 35
5
Scope and Purpose
Disease/Condition:
Management of common respiratory illness in children < 14 years.
Guideline Category:
Management (Diagnosis and Treatment)
Clinical Specialties:
➢ Pediatrics.
➢ Pediatric pulmonology.
➢ Infectious diseases.
➢ Primary health care.
➢ Family practitioners.
Intended User (target users):
➢ Physicians.
➢ Pediatricians.
➢ Primary Health Care (PHC) Physicians.
➢ Family Practitioners.
➢ Nurses .
➢ Clinical Pharmacist.
Guidelines Objectives:
➢ Optimizing the medical management of children with common respiratory

illness.
➢ Providing optimal pharmacotherapy to prevent or minimize adverse effects of
therapy.
6
Protocols of EHA
ACCP American collage of chest physicians
ACEI Angiotensin-converting enzyme inhibitors
AFCM Armed Forces College of Medicine
CCGAG Chronic Cough Guideline Adaptation

Group
CPGs Clinical Practice Guidelines
CT Computed tomography
CVA Cough variant asthma
EBCPG Evidence Based Clinical Practice

Guideline
EBM Evidence-based medicine
EPCG Egyptian Pediatric Clinical Guidelines
EPG Egyptian Pediatric Guidelines
ERS European Respiratory Society
FeNO Fractional exhaled nitric oxide
GER Gastro-esophageal reflux
GERD Gastro-esophageal reflux disease
GOR Grade of Recommendation
H1RAs Histamine 1-receptor antagonists
7
HRCT High resolution computed tomography
Korean Academy of Asthma, Allergy and

KAAACI
Clinical Immunology
LOE Level of Evidence
LTRAs Leukotriene receptor antagonists
Mycobacterium tuberculosis complex

MTB/ RIF
resistance to rifampicn
OSA Obstructive sleep apnea
PHC Primary Health Care
PBB Protracted bacterial bronchitis
pH Potential of hydrogen
Patients, Interventions, Professionals,

PIPOH
Outcomes, Healthcare settings
RCT Randomized controlled trial
TB Tuberculosis
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Protocols of EHA
Chronic Cough
Introduction and Background:
• Chronic cough is defined as the presence of daily cough of more than 4 weeks
duration in children aged <14 years old. It has been divided into specific and
nonspecific cough. Specific cough is usually associated with an underlying
disease and non-specific cough indicates prolonged cough in the absence of any
symptoms, signs, history, or laboratory findings indicating a specific diagnosis
(specific cough pointers).
• Chronic cough is common in the community and causes significant morbidity.

It is a prevalent problem in about 10% of the general populations worldwide and
poses a considerable socioeconomic burden and serious impairment to quality
of life (QOL) of children and their parents.
• Children with chronic cough may experience physical pain, sleep disturbance,
loss of school productivity, and social isolation for several months to years and
successful management requires a treatment program based on accurate
diagnosis and understanding of the cough etiology.
Table (1): Specific Cough Pointers

Abnormality Examples of Etiology
Symptoms or Signs
Auscultatory finding Wheeze
Crepitations-any airway lesions (from secretions) or
parenchymal disease such as interstitial disease
Cardiac abnormalities Associated airway abnormalities, cardiac failure,
arrhythmia
Chest pain Arrythmia, pleural disease, asthma
Chocked Foreign body inhalation
Dyspnea or tachypnea Any pulmonary airway or parenchymal disease
Chest wall deformity Any pulmonary airway or parenchymal disease
Digital clubbing Suppurative lung disease
Daily wet/ productive cough Protracted bacterial bronchitis, suppurative lung
disease, recurrent aspiration, atypical infections, TB,
diffuse panbronchiolitis
Exertional dyspnea Any airway or parenchymal disease
9
Abnormality Examples of Etiology

Facial pain/purulent nasal discharge Chronic sinusitis,(protracted bacterial bronchitis),
primary ciliary dyskinesia
Feeding difficulties Neurological diseases including palatopharyngeal
incoordination
Growth failure Such as Cystic fibrosis
Hoarse voice/stridor Laryngeal cleft/problems, airway abnormalities
Hemoptysis Suppurative lung disease, vascular abnormalities
Hypoxia/cyanosis Any airway or parenchymal disease, cardiac disease
Neurodevelopmental abnormalities Aspiration lung disease
Recurrent pneumonia Immunodeficiency, atypical infections, suppurative
lung disease, congenital lung abnormalities, trachea-
esophageal H-type fistula
Recurrent infections Immunodeficiency
Previous history of chronic lung Multiple causes (eg, second H-type fistula,
disease, esophageal disease (neonatal bronchiectasis, aspiration, asthma)
lung disease, esophageal atresia
Wheeze-monophonic Large airway obstruction (eg, from froing body
aspiration, malacia, and/or stenosis, vascular ring,
lymphadenopathy, and mediastinal tumors)
Wheeze-polyphonic Asthma, bronchiolitis obliterans, bronchiolitis
Tests
• Chest radiograph (other than Any cardiopulmonary disease
peribronchial changes )
• Spirometry abnormalities
Clinical History and Examination:

• The etiology of chronic cough in children can accurately be identified by
observation, a careful history, and progressing to appropriate tests and
therapeutic trials based on pointers obtained in the history. The impact of cough
should be assessed either by recording simple measures such a cough scores out
of 10 (Appendix) or by more detailed, validated measures of cough quality of
life (LCQ or CQLQ).
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Protocols of EHA
Etiology and Differential Diagnosis:

Cause Remarks
• Cough is commonly associated with recurrent wheezing
• Asthma can be manifested only with cough and is then called
Asthma cough-variant asthma or cough-dominant asthma.
• A therapeutic trial of SABA and ICS should be offered if
diagnoses of asthma is being considered
• Clubbing and failure to thrive

• Universal newborn screening
Cyctic fibrosis
• Diagnosis is by measurement of sweat chloride concentration
and genetic identification
• Chronic wet cough
• History of transient neonatal distress is common
• Begins in infancy and persists
Primary ciliary dyskinesia • History of recurrent attacks of otitis media & hearing
impairment
• Diagnosis by electron microscopy and high-speed video-
microscopy analysis
• Bronchiectasis can occur with cystic fibrosis, primary ciliary
dyskinesia, and in some patients with protracted bacterial
Bronchiectasis bronchitis Bronchiectasis unrelated to chronic lung disease is also
seen
• Diagnosis by radiology confirmed by computed tomography
Pertussis (whooping
cough)( pertussis like • Frequent spasms of coughing followed by nausea or vomiting,
cyanosis or apnea . like the barking cough
illness)
• Occasionally cause chronic cough
Tracheomalacia or • Barking quality
• But persists during sleep, unlike habit cough.
trachea-broncho-malacia
• Diagnosed only by bronchoscopy performed with light sedation
so that dynamic movements can be visualized
Diagnosed clinically by:
1) Presence of continuous chronic (>4 weeks’ duration) wet or
productive cough;
Protracted bacterial 2) Absence of symptoms or signs (i.e. specific cough pointers)
bronchitis (PBB) suggestive of other causes of wet or productive cough; and
3) Cough resolved following a 2–4-week course of an appropriate oral
antibiotic.
Diagnosed as PBB-micro by the contents of a broncho-alveolar lavage
Habit cough (tic cough) • Now labled as somatic cough disorder

• Dagnosis should only be made after an extensive evaluation
11
Cause Remarks
Postnasal drip
syndrome/Upper airways • UACS acting as a trigger for cough hypersensitivity although the
mechanism remains obscure
cough syndrome (UACS)
• Causes localizing auscultatory findings.
Foreign body aspiration
• History of sudden shocking
Medications and Adverse
As a side effect of angiotensin converting inhibitors (ACEI), asthma
Events
medications, immediately after inhalation psychostimulant medications
(e.g. dextro-amphetamine resulting in new onset tics)
Cardiac causes
Associated with specific manifestations (cough pointers)
Two or more of these warning signs should alert clinician to the

Immunodeficiency possibility of primary immunodeficiency and merit further assessment
(Appendix)
Gastro-esophageal reflux • GIT manifestations must be present

• (GERD is not commonly identified as the cause of pediatric
disease (GERD)
chronic cough
Uncommon cause of chronic cough
Otogenic etiology
• The ears should always be examined for the presence of any
Arnold's nerve reflex
foreign material
Investigations:
• The investigation and therapeutic trials should include those for common cough-
triggering conditions (rhinitis, rhinosinusitis, asthma, eosinophilic bronchitis,
and GERD) as chest X-rays, spirometry, computed tomography, flexible
bronchoscopy and bronchoalveolar lavage, Other investigations include barium
swallow, video fluoroscopic evaluation of swallowing, echocardiography,
complex sleep polysomnography and immunological studies.
Treatment of Chronic Cough in Children:

• All children with chronic cough should be carefully assessed, as chronic cough
may be due to a serious underlying condition (e.g. inhaled foreign body). In
addition to etiology-based management, it is prudent that children with chronic
cough receive common management interventions as cessation of exposure to
environmental tobacco smoke and other environmental pollutants.
• The present clinical practice guideline aims to address major clinical questions
regarding, practical diagnostic tools for specific and nonspecific chronic cough.
Also, available therapeutic options for chronic cough in children are present.
12
Protocols of EHA
Notes:
➢ For patients seeking medical care complaining of cough, estimating the duration of
cough is the first step in narrowing the list of potential diagnoses.
➢ History should include cough characteristics and the associated clinical history such
as using specific cough pointers as well as symptoms of red flags or other potential
life-threatening symptoms and if present.
➢ Exposure to airborne irritants (e.g. tobacco exposure, combustions, traffic related

exposure etc.), allergens or infection may be a reason for dry chronic cough.
➢ In unexplained or unresponsive chronic cough, obstructive sleep apnea should be

included in the differential diagnosis.
➢ Detailed history of drug intake is needed including ACEI and other drugs such as
bisphosphonates or calcium channel antagonists and prostanoid eye drops.
➢ An empirical approach aimed at treating upper airway cough syndrome due to a

rhinosinus condition, gastroesophageal reflux disease and/or asthma should not be
used unless other features consistent with these conditions are present.
➢ Cough variant asthma (CVA) was originally described as asthma with cough as the
sole symptom and where treatment with bronchodilators improved coughing.
➢ Patients with cough with or without fever, night sweats, hemoptysis, weight loss
and/or contact with TB case and who are at risk of pulmonary TB.
➢ The clinician should recommend chest radiography, but not routinely perform a
chest CT in patients who have normal physical examination and chest X-ray.
➢ The clinician should recommend spirometry (pre and post β2 agonist) when age is
appropriate and if diagnosis of asthma is likely.
13
➢ The clinician should suggest undertaking tests for evaluating recent Bordetella
pertussis infection when pertussis is clinically suspected (if there is post- tussive
vomiting, paroxysmal cough or inspiratory whoop).
➢ Additional test should be individualized and undertaken according the child’s

clinical symptoms and signs like Mantoux, bronchoscopy and cultures.
➢ The clinician should recommend evaluation of the immunologic competence in

presence of criteria suspicious of immunodeficiency.
❖ See Page. 38 (Ten Warning Signs of Primary Immunodeficiency- Appendix)
➢ When risk factors for asthma are present, a short (2-4 weeks) trial of 400
microgram/day of beclomethasone equivalent, and re-evaluated.
➢ For PBB two weeks of antibiotics targeting the common respiratory bacteria
(Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis) and
depending on the local antibiotic sensitivities.
✓ When the wet cough persists after2 weeks of appropriate antibiotics, consider
treatment with an additional 2 weeks of the appropriate antibiotic (Amoxicillin
Clavulanic acid).
✓ When the wet cough persists after 4 weeks of appropriate antibiotics, further
investigations as flexible bronchoscopy with quantitative cultures and
sensitivities with or without chest CT) can be undertaken
14
Protocols of EHA
Croup
Definition:
Croup is a common respiratory illness of the larynx, trachea, and bronchi
characterized by barking cough, often accompanied by inspiratory stridor, hoarseness,
and respiratory distress.
Diagnosis:
Croup is primarily a clinical diagnosis, with typical findings of abrupt onset of
a barking cough, inspiratory stridor, and hoarseness. Many patients will also have
dyspnea and fever.
Levels of Severity for Children with Croup:
Mild:
• Occasional barky cough.
• No audible stridor at rest.
• No to mild suprasternal and/or intercostal indrawing.
Moderate:
• Frequent barky cough.
• Easily audible stridor at rest.
• Suprasternal and sternal wall retraction at rest.
• No or little distress or agitation.
Severe:
• Frequent barky cough.
• Prominent inspiratory stridor.
• Marked sternal wall retractions.
• Significant distress and agitation.
Impending respiratory failure:
• Barky cough (often not prominent).
• Audible stridor at rest (occasionally hard to hear).
• Sternal wall retractions (may not be marked as respiratory failure progresses).
• Lethargy or decreased level of consciousness.
• Often dusky appearance without supplemental oxygen.
15
Management:
Emergency Care:
General Measures:
• Provide physical comfort, avoid agitating the child with unnecessary procedures.
• humidified oxygen to children who are in respiratory distress.
• Mist therapy HAS NOT been shown to have any measurable benefit.
• Antibiotics, oral decongestants, and beta-2 agonists ARE NOT indicated.
Mild Croup:
Glucocorticosteroids are recommended for mild croup, Dexamethasone
0.6mg/kg (max dose 12mg) is the first line glucocorticoid therapy for croup. There is
no difference in PO versus IM dexamethasone or Prednisolone 2mg/kg/day for 3 days.
Relative contraindications include the child with a known immune deficiency.
Moderate/Severe Croup:
• All patients should get dexamethasone 0.6mg/kg (max dose 12mg) given once
orally or intramuscularly if not previously given.
• Administer nebulized epinephrine, (L-epinephrine 1:1000 is as effective as racemic
epinephrine) for severe respiratory distress (i.e., marked sternal wall indrawing and
agitation) for the temporary relief of symptoms of airway obstruction, repeat
racemic epinephrine dose if a poor response to the first treatment or respiratory
symptoms recur after an initial good response.
• Nebulized budesonide IS NOT routinely indicated for the treatment of croup.
Exceptions include patients with: Persistent vomiting or severe respiratory distress,
the appropriate dose concentration of budesonide is 2mg Budesonide may be mixed
with epinephrine and administered simultaneously.
Indications for Admission:
Significant respiratory distress persisting four or more hours after treatment with
corticosteroids Consider admission if:
✓ Lack of timely access to care.

✓ Risk of no observation and follow-up.
✓ Significant parental anxiety.
✓ Multiple emergency department (ED) visits within 24 hours.
16
Protocols of EHA
Inpatient management:
1. All patients should get dexamethasone if not previously given. Epinephrine should
be given
2. Oxygen is indicated for cyanosis, hypoxia, or respiratory distress.
3. Observe for Signs of impending respiratory failure: (a) poor respiratory effort, (b)
severe retractions, (c) poor response to epinephrine, (d) decreased level of
consciousness, (e) cyanosis/hypoxemia.
4. Consider bacterial tracheitis, epiglottitis, or retropharyngeal abscess in children who
appear toxic as they may have an alternative diagnosis and need further workup.
Discharge Criteria:
1. 2hours since last epinephrine.

2. No stridor at rest, tachypnea, intercostal retractions, or other signs of increased
work of breathing.
3. Able to talk and feed without difficulty.
4. The patient is able to return to the ED if symptoms return.
Follow-Up:
NOT required for most children with croup.
17
Bronchiolitis
Diagnosis:
1- It occurs in children under 2 years of age and most commonly in the 1- first year
of life, peaking between 3 and 6 months.
2- Its symptoms usually peak between 3 and 5 days, and that cough resolves in 90%
of infants within 3 weeks.
3- The child usually has a coryzal prodrome lasting 1 to 3 days, followed by:
➢ Persistent cough and
➢ Either tachypnoea or chest recession (or both) and
➢ Either wheeze or crackles on chest auscultation (or both).
4- The following symptoms are common in babies and children with this disease:
➢ Fever (in around 30% of cases, usually of less than 39°C)
➢ Poor feeding (typically after 3 to 5 days of illness).
5- In young infants’ apnea may be the sole presentation.
6- Consider a diagnosis of pneumonia if the baby or child has:
➢ high fever (over 39°C) and/or
➢ persistently focal crackles.
Clinical Examination:
• Examination should include clinically assess the hydration status of babies and
children with bronchiolitis.
• Vital signs are critical.
• Clinical severity assessment is important.
Assessment of Clinical Severity:
18
Protocols of EHA
Indications for Referral:

Immediately refer babies and children with bronchiolitis for emergency hospital
care if they have any of the following:
1. Apnoea (observed or reported).
2. Baby or child looks seriously unwell to a healthcare professional.
3. Severe respiratory distress, for example grunting, marked chest recession,
or a respiratory rate of over 70 breaths/minute
4. Central cyanosis.
5. Difficulty with breastfeeding or inadequate oral fluid intake (50% to 75% of
usualvolume)
6. Clinical dehydration
7. Persistent oxygen saturation of less than 92%, when breathing air.
Red flags:
1. Chronic lung disease (including bronchopulmonary dysplasia).
2. Haemodynamically significant congenital heart disease.
3. Age in young infants (under 3 months).
4. Premature birth, particularly under 32 weeks.
5. Neuromuscular disorders.
6. Immunodeficiency.
Management of Bronchiolitis:
Investigations:
In most children with bronchiolitis no investigations are required:
Investigations should only be undertaken when there is deterioration or
diagnostic uncertainty (eg cardiac murmur with signs of congestive cardiac failure):
• Chest X-ray (CXR) is not routinely indicated and may lead to unnecessary
treatment with antibiotics.
• Blood tests (including blood gas, full blood evaluation (FBE), blood
cultures) have no role in management.
• Virological testing (nasopharyngeal swab or aspirate) has no role in
management of individual patients.
Treatment:
• The main treatment of bronchiolitis is supportive.
➢ This involves ensuring appropriate oxygenation and fluid intake, and minimal
handling
19
Management Approach:
It depends on clinical severity:
MILD MODERATE SEVER
Sutabile for
Likely admission, may Requires admission and
discharge
Likelihood be able to be consider need for
Consider admission
of admission discharged after a transfer to appropriate
if risk factors
period of observation children’s facility/PICU
present
Adequate 1-2 hourly (not
Observations vital assessment in ED continuous) Hourly with continuous
signs (respiratory prior to discharge Once improving and cardiorespiratory
rate, heart rate, (minimum of two not requiring oxygen (including oximetry)
oxygen saturation, recorded for two hours monitoring and close
temperature) measurements of discontinue oxygen nursing observation
every four hours) saturation monitoring
If not feeding adequately
If not feeding
(<50%over 12hrs), or
Hydration adequately (<50%over
Small frequent feeds unable to feed
/nutrition 12hrs), administer NG
administer NG
hydration
hydration
If oxygen saturation
falls below 90%,
administer oxygen to
maintain saturation ≥
Oxygen saturation, 90% Administer oxygen to
oxygen Nil requirement maintain saturation ≥
requirements Once improving and 90%
not requiring oxygen
for 2 hours
discontinue oxygen
saturation monitoring
Begin with nasal

prong oxygen
High flow nasal Consider HFNC or
Respiratory
cannula (HFNC) to be continuous positive
support
used only if nasal airway pressure (CPAP)
prong oxygen has
failed
20
Protocols of EHA
PICU admission:
All severe cases if severity does not improve Consider ICU review/ admission or
transfer to local Centre with pediatric ICU capacity if:
• Severity does not improve.
• Persistent Desaturations.
• Significant or recurrent apnoea associated with desaturations.
• Has risk factors
Drugs for management of bronchiolitis:
• Salbutamol inhalation therapy can be used in children with bronchiolitis
• Hypertonic saline in certain situation after consultation of consultant in duty
• Inhaled corticosteroids may be used in recurrent bronchiolitis
Do not use any of the following to treat bronchiolitis in babies or
children:
• Antibiotics.
• Adrenaline (nebulised).
• Montelukast.
• Ipratropium bromide.
• Systemic corticosteroids.
Oxygen Therapy:
1- Give oxygen supplementation to babies and children with bronchiolitis if their
oxygen saturation is:
a. persistently less than 90%, for children aged 6 weeks and over.
b. persistently less than 92%, for babies under 6 weeks or children of any age
withunderlying health conditions.
2- Consider continuous positive airway pressure (CPAP) in babies and children with
bronchiolitis who have impending respiratory failure.
21
Upper Airway Suction:

1- Do not routinely perform upper airway suctioning in babies or children with
bronchiolitis.
2- Consider upper airway suctioning in babies and children who have respiratory
distress or feeding difficulties because of upper airway secretions.
3- Perform upper airway suctioning in babies and children with bronchiolitis presenting
with apnoea even if there are no obvious upper airway secretions.
Blood Gas:
1- Do not routinely carry out blood gas testing in babies or children with bronchiolitis.
2- Consider carrying out capillary blood gas testing in babies and children with severe
worsening respiratory distress (when supplemental oxygen concentration is greater
than 50%) or suspected impending respiratory failure.
Fluid Therapy:
1- Give fluids by nasogastric or orogastric tube in babies and children with bronchiolitis
if they cannot take enough fluid by mouth.
2- Give intravenous isotonic fluids to babies and children who do not tolerate
nasogastric or orogastric fluids or have impending respiratory failure.
Chest Physiotherapy:
Do not perform chest physiotherapy on babies and children with bronchiolitiswho
do not have relevant comorbidities (for example spinal muscular atrophy, severe
tracheomalacia).
Discharge Criteria:
1- When deciding on the timing of discharge for babies and children admitted to
hospital, make sure that they:
• Are clinically stable.
• Are taking adequate oral fluids.
• Have maintained an oxygen saturation in air at the following levels for 4 hours,
including a period of sleep:
➢ Over 90%, for children aged 6 weeks.
➢ Over 92%, for babies under 6 weeks or children of any age with underlying health
conditions.
2- When deciding whether to discharge a baby or child, take into account factors that
might affect a carer's ability to look after a baby or child with bronchiolitis, for
example:
• Social circumstances.
• The skill and confidence of the career in looking after a baby or child with
bronchiolitis at home.
• Confidence in being able to spot red flag symptoms.
• Distance to healthcare in case of deterioration.
22
Protocols of EHA
Asthma Exacerbation
Definition:
A flare-up or exacerbation of asthma in children is defined as:
An acute or sub-acute deterioration in symptom control that is sufficient to cause
distress or risk to health, to the extent that a visit to a health care provider or treatment
with systemic corticosteroids becomes necessary, they are sometimes called ‘episodes’
Assessment:
Early symptoms of an exacerbation may include any of the following:
1. An acute or sub-acute increase in wheeze and shortness of breath.
2. An increase in coughing, especially while the child is asleep.
3. Lethargy or reduced exercise tolerance.
4. Impairment of daily activities, including feeding.
5. A poor response to reliever medication.
The signs that should be assessed are:
1. Respiratory rate.
2. Pulse rate.
3. Amount of breathlessness (ability to talk and feed).
4. Ability to speak in full sentences.
5. Use of accessory muscles of respiration.
6. Extent and loudness of wheezing (which becomes less audible with increasingly
severe airways obstruction).
7. Level of consciousness and presence of agitation (suggesting hypoxaemia).
Initial Assessment of Severity <5y:
Symptoms Mild Severe
Altered consciousness NO Agitated, confused, Drowsy
SPO2 on presentation >95 % <92 %
Speech sentences Words
Pulse rate < 100 /min >200/min (0-3y) >160(4-5y)
Central cyanosis Absent Likely present
Wheeze intensity Variable May be quit chest
23
Initial Assessment of Severity>5y:
Mild/Moderate Severe
Talks in phrases, prefers sitting to lying, Talks in words, sits hunched forward, agitated
not agitated Respiratory rate increased >30 breaths/minute
Respiratory rate increased <30 Accessory muscles in use
breaths/minute
Pulse rate >120 bpm
Accessory muscles not used
O2 saturation (on air) <92%
Pulse rate 100-120 bpm
PEF ≤50% predicted or best
O2 saturation (on air) >92%
PEF >50% predicted or best
Risk factors for Asthma related Death:

• Any history of near-fatal asthma requiring intubation and ventilation.
• Hospitalization or emergency care for asthma in last 12 months.
• Not currently using ICS, or poor adherence with ICS.
• Currently using or recently stopped using OCS =Severe.
• Over-use of SABAs, especially if more than 1 canister/month.
• Lack of a written asthma action plan.
• History of psychiatric disease or psychosocial problems.
• Confirmed food allergy in a patient with asthma.
24
Protocols of EHA
Management:
Oxygen by face mask to achieve and maintain percutaneous oxygen saturation of 94–98%
5 years and younger 6 years and older

• 2-6puffs of salbutamol by spacer, or 2.5 mg of • For mild to moderate exacerbations, repeated
salbutamol by nebulizer, every 20 minutes for the administration of inhaled SABA (up to 4–10 puffs
first hour. every 20 minutes for the first hour)
For severe exacerbations: Used in all but the mildest exacerbations
give oral prednisolone (1–2 mg/kg up to a 1–2 mg/kg/day oral prednisolone for children
maximum 20 mg for children <2 years old; 30 mg 6–11 years up to a maximum of 40mg/day) or
for children 2–5 years) 200 mg hydrocortisone in divided doses (short
OR, intravenous methylprednisolone 1 mg/kg 6- course)
hourly on day one.
In Moderate to Severe Cases

• Ipratropium bromide at a dose of 250ug by nebulization can be mixed with SABA to be repeated
every 20 minutes (for 1 hour only).
• Nebulized isotonic magnesium sulfate 150 mg can be added in children ≥2 years old.
Assess the child as regards Symptoms:

• If symptoms still persistent or worsening
• If symptoms recur within 4 hours after improvement
Admit
5 years and younger 6 years and older
• If symptoms improved at 1st hour but recurred, give • The dose of SABA required varies from
additional 2–3 puffs SABA per hour 4–10 puffs every 3–4 hours up to 6–10
• Admit to hospital if >10 puffs required in 3–4 hours. puffs every 1–2 hours, or more often.
• Failure to respond at 1 hour, or earlier deterioration, • Continue Oxygen by face mask to
should prompt urgent admission to hospital and a short- achieve and maintain percutaneous
course of oral prednisolone OR, intravenous oxygen saturation of 94–98%
methylprednisolone 1 mg/kg 6-hourly on day one • Continue or intiate 1–2 mg/kg/day oral
• Continue Oxygen by face mask to achieve and maintain prednisolone or 200 mg hydrocortisone
percutaneous oxygen saturation of 94–98% (short in divided doses (short course)
course).
For severe asthma exacerbations in children 2years and above who fail to respond to initial treatment:
give slow IV infusion of magnesium sulfate as a single dose of 50 mg/kg/dose (max. 2gm) over 20-60
minutes in the following setting: Emergency department in hospitals and with close monitoring of the
vital data.
If improved If Not Improving or Deteriorating

Discharge home with: home management plan Follow up Consider PICU ADMISSION
plan
Children can be discharged when:

1. Stable on 3-4 hourly inhaled bronchodilators that can be continued at home.
2. PEFor FEV1should be >75% of best or predicted.
3. PO2>94%
Arrange follow up by primary care service within 2 -7 days
25
Community Acquired Pneumonia

in immunocompetent Patient
Definition of Different Types of Pneumonia:
• Community Acquired Pneumonia: Pneumonia that is acquired outside the
hospital ie caused by community acquired infection in a previously healthy child
• Hospital Acquired Pneumonia: Pneumonia that occurs 48 hours or more after
hospital admission and not diagnosed at the admission time
• Health care associated Pneumonia: Health care-associated pneumonia
community-based patients who have had recent contact with the health care
system, such as those who reside in nursing homes or other long-term care
facilities or visit dialysis centers and infusion centers.
Criteria of Respiratory Distress in Children With Pneumonia:
1. Tachypnea, RR, breaths/min:
• Age 0–2 months >60
• Age 2–12 months > 50
• Age 1–5 Years >40
• Age >5 Years >20
• Dyspnea
2. Retractions.
3. Grunting.
4. Nasal flaring.
5. Apnea.
6. Altered mental status.
7. Pulse oximetry <90% on room air.
26
Protocols of EHA
Etiology of Pneumonia in Different Age Group:
27
Clinical Criteria for diagnosis of CAP:

• No single symptom or sign is pathognomonic for pneumonia in children.
• Combination of fever and cough is suggestive of pneumonia
• Other respiratory findings (eg, tachypnea, increased work of breathing) may precede
cough.
• Cough may not be a feature initially since the alveoli have few cough receptors.
CAP in neonates:
➢ Fever and cough may be absent
➢ tachypnea, and signs of respiratory distress such as grunting, flaring and
retractions.
➢ hypothermia and temperature instability may be observed.
➢ Irritability or poor feeding or Cyanosis
CAP in Infant and Children:
➢ Cough is the most common presenting symptom.
➢ Tachypnea, grunting, Vomiting, poor feeding, and irritability are common.
➢ CAP due to Atypical organisms, such as Mycoplasma pneumonia are
characterized by
➢ wheeze and other constitutional symptoms, such as headache, malaise,
pharyngitis, otalgia, myalgia, pleuritic chest pain, and vague abdominal pain
Indications of admission to hospital?

• Moderate to Severe CAP (Respiratory distress, hypoxemia SpO2 <90%.
• <3–6 months of age with suspected bacterial CAP.
• Children and infants for whom there is concern about careful observation at home
or who are unable to comply with therapy or unable to be followed up.
• Not accepting oral feeding or vomiting.
• Children and infants with suspected or documented CAP caused by a pathogen with
increased virulence, such as community-associated methicillin-resistant
Staphylococcus aureus (CA-MRSA).
28
Protocols of EHA
Indications for PICU Admission

1. Impending respiratory failure.
2. If the child has sustained tachycardia, inadequate blood pressure, or need for
pharmacologic support of blood pressure or perfusion.
3. If the child requires invasive ventilation via a nonpermanent artificial airway
4. If the pulse oximetry measurement is <92% on inspired oxygen of ≥0.50
5. If the child has altered mental status, whether due to hypercarbia or hypoxemia as a
result of pneumonia.
6. If the child acutely requires use of noninvasive positive pressure ventilation (eg,
continuous positive airway pressure or bilevel positive airway pressure).
Preliminary Pediatric Pneumonia Workup:
Pulse Oximetry:
A-Lab investigations:
1. CBC (WBC count <15,000/micro L suggests a nonbacterial etiology, except in the
severely ill patient, who also may be neutropenic and have a predominance of immature
cells).
2. CRP serial measurements for follow up.
➢it cannot be used as the sole determinant to distinguish between viral and
bacterial causes of CAP.
➢cannot be used to confirm diagnosis.
➢Decisions about diagnosis should not be based on inflammatory markers alone.
➢May be useful in assessing the resolution of an inflammatory process.
3. Blood Culture:
➢ Blood cultures are positive in less than 5% of patients with pneumococcal
pneumonia and even less with Staphylococcus.
➢ Repeat blood cultures in children with bacteremia caused by S. aureus,
regardless of clinical status.
4. Examination of Sputum should be considered for patients who do not respond to
empirical antibiotic therapy if the child can produce sputum
29
B-Radiological Investigation:
1. Chest X Ray
• Indications for chest x ray:
➢ Hospitalization.
➢ prolonged and unresponsive.
➢ recurrent pneumonia.
➢ Severe disease.
➢ Expected complications.
NB:
➢ Radiographic findings cannot reliably distinguish between bacterial,
atypical bacterial, and viral etiologies of pneumonia
➢ No need to repeat x ray except if no response after 48 h or if sudden
deterioration.
• When to repeat chest x ray after discharge:
Repeated chest radiographs 4–6 weeks after discharge should be obtained in
patients:
➢ Recurrent pneumonia involving the same lobe
➢ patients with lobar collapse on initial chest radiography with suspicion of an
anatomic anomaly, chest mass, or foreign body aspiration.
2. CT Scan
• Indications for CT Chest
Not indicated in any child with CAP except:
➢ Failed Antibiotic treatment.
➢ Complications, such as pleural effusions.
➢ Treatment decisions surgical debridement of organized empyema or loculated
effusions).
30
Protocols of EHA
Antibiotic protocol for hospitalized child with CAP:

1. Ampicillin- Salbactam and Third-generation parenteral cephalosporin’s
2. Add macrolide (oral), for whom M. pneumoniae are significant considerations as
school aged children.
3. Vancomycin or clindamycin should be provided in addition to β-lactam therapy if
clinical, laboratory, or imaging characteristics are consistent with infection caused
by CA-MRSA
Appropriate Duration of Antimicrobial Therapy for CAP:
• Treatment courses of 10 days.
• Infections caused by certain pathogens, notably CA-MRSA, may require longer
treatment.
Parenteral antibiotics can be shifted to oral therapy:
• As early as 2-3 d after the start of parenteral therapy if:
• Clinical Improvement and starting reduction in peripheral leukocyte counts and/or
CRP or other acute phase reactants and absence of bacteremia.
Criteria for discharge a child with CAP:

• Clinical improvement, level of activity, appetite, and decreased fever for at least 12–24 h.
• Pulse oximetry > 90% in room air for at least 12–24 h.
• Stable and/or baseline mental status.
• Tolerate their home anti-infective regimen
How to follow up the child with CAP for the expected response to therapy?
✓ Children on adequate therapy should start demonstrating clinical and laboratory

improvement within 48–72 hrs.
31
Management of non-responding pneumonia in children (EPCP) committee 2020
1-No improvement or deterioration within 48-72 h of admission and appropriate

antibiotic intake
-persistent high fever and or persistent tachypnea or RD
-persistent elevated of CRP or other inflammatory marker
-Radiological deterioration
-systemic or focal symptoms or signs including: 1. clinically defined “toxicity” based
on clinical judgment or change in mental status 2. sever chest pain reducing the
inspiratory effort 3. inability to maintain oral intake and hydration
2- or significant worsening at any time after initiation of therapy
Admit if he was an outpatient – reassess – consult pediatric pulmonologist
Complicated CAP CAP with resistant CAP with underlying

organism comorbid condition
• Necrotizing pneumonia
• Empyema eg: MRSA or Klebsiella • Foreign body
• Pneumothorax • Immunodeficiency
• Bronchiectasis and
• Organ failure as heart
cystic fibrosis
failure
• Underlying cardiac
• sepsis disease
Investigations
• CT chest or chest ultrasound
• Microbiological studies (sputum, blood, nasopharyngeal swab, gastric aspirate)
• Bronchoscopy and BAL
• Immune studies
• Echocardiography
• Sepsis work up (lactate, LDH, ABG, repeat acute phase reactants)
Treatment
• Empyema: intercostal drainage +/-intra-pleural fibrinolytic instillation
• Resistant organism: adjust antibiotics according to culture
• Necrotizing pneumonia: add clindamycin or linezolid
• Immunodeficiency: consult immunologist
• Heart failure: anti-failure medications
• Sepsis: more broad-spectrum antibiotics and possible PICU
32
Protocols of EHA
Prophylaxis of Respiratory Syncytial Virus

( RSV )
RSV accounts for approximately 50% of all cases of pneumonia and up to 90%
of the reported cases of bronchiolitis in infancy.
RSV infection frequently progresses to the lower respiratory tract, where it can
cause wheezing, cough, and dyspnea in infants, these symptoms usually appear 1 to 3
days after the onset of rhinorrhea.
High Risk population
• Higher-Risk Populations Include Preterm Infants and Children <2 Years Old With
BPD or HSCHD.
• Hospitalization rates are higher in high-risk groups, including premature infants and
those with underlying cardiac or pulmonary diseases.
Prophylaxis: Palivizumab
Passive prophylaxis with palivizumab decreases the frequency of hospitalization

for RSV in high-risk infants. It is cost-effective only for infants at high risk of
hospitalization.
1-Children born at 35 weeks of gestation or less and less than 6 months of age at the
onset of the RSV season.
2- Children less than 2 years of age and requiring treatment for bronchopulmonary
dysplasia within the last 6 months.
3- Children less than 2 years of age and with hemodynamically significant congenital
heart disease.
NB:
• Palivizumab should be administered up to a maximum of 5 monthly doses (15
mg/kg per dose administered intramuscularly once every 30 days) during the
RSV season to infants who qualify for prophylaxis in the first year of life.
• A child with a history of a severe allergic reaction following a dose of
Palivizumab should not receive additional doses.
• Palivizumab is not approved or recommended for the treatment of RSV disease
• Palivizumab does not interfere with routine childhood immunizations.
33
REFERENCES:
1. Piedimonte G, Perez MK. Pediatr Rev. 2014;35(12):519-530.
2. Wat D. Eur J Intern Med. 2004;15(2):79-88.
3. Domachowske JB, Rosenberg HF. Clin Microbiol Rev. 1999;12(2):298-309.
4. Karron R. Plotkin’s Vaccines. 7th ed. Elsevier; 2018:943-949.
5. Erdoğan S, et al. Turk J Anaesthesiol Reanim. 2019;47(4):348-351. . Piedimonte G, Perez
MK. Pediatr Rev. 2014;35(12):519-530.
6. Wat D. Eur J Intern Med. 2004;15(2):79-88. Domachowske JB, Rosenberg HF. Clin
Microbiol Rev. 1999;12(2):298-309.
7. Respiratory syncytial virus infection (RSV): symptoms and care. Centers for Disease
Control and Prevention. Updated June 26, 2018. Accessed December 21, 2021.
(https://www.cdc.gov/rsv/about/symptoms.html).
8. Piedimonte G, et al. Pediatr Rev. 2014;35(12):519-530.
9. Sommer C, et al. Open Microbiol J. 2011;5(Suppl 2-M4):144-154
10. World Health Organization. Preterm birth. Published February 19, 2018.
(https://www.who.int/news-room/fact-sheets/detail/preterm-birth).
11. Jensen EA, et al. Clinical and Molecular Teratology. 2014;100(3):145-157
12. Rezaee F, et al. Curr Opin Virol. 2017;24:70-78.
34
Protocols of EHA
Appendix
Coughing Score:
This is a quantitative scoring system of cough used to assess the severity of

cough and efficacy of treatment. Daytime and nighttime scoring is done, however it
may be difficult to discriminate between grades (Table)
Score Daytime Cough Symptom Score Nighttime Cough Symptom Score
0 No cough No cough
Transient cough when falling sleep
1 Occasional, transient cough
or occasional cough during the night
Frequent cough, slightly
2 Cough slightly influencing sleep
influencing daytime activities
Frequent cough, significantly Cough significantly influencing
3
influencing daytime activities sleep
Source: Chung KF (2006), Irwin RS (2006)
35
Cough Red Flags:
That prompt referral includes:

✓ Significant systemic illness
✓ Change in mental status
✓ Dyspnea (breathlessness)
✓ Pleuritic chest pain
✓ Prolonged or high fever
✓ Abnormal respiratory exam (e.g., wheezing, crackles, stridor)
✓ Increased work of breathing (e.g., respiratory rate >20 breaths/minute, using
accessory muscles to breathe, unable to speak normally)
✓ Cyanosis (e.g., bluish or purple discoloration of lips/mouth, or fingers/hands,
which may feel cold to the touch)
✓ Hemoptysis
✓ Suspicion of inhaled foreign body
✓ Dysphagia
Source: Glashan E, Mahmoud SH,(2019)
36
Protocols of EHA
Ten Warning Signs of Primary Immunodeficiency:

Two or more of these warning signs should alert the clinician to the possibility
of primary immunodeficiency and merit further assessment
1- Four or more new ear infections within 1 year

2- Two or more serious sinus infections within 1 year
3- Two or more month on antibiotics with little effect
4- Two or more pneumonia within 1 year
5- Failure of an infant to gain weight or grow normally
6- Recurrent, deep skin or organ abscesses
7- Persistent thrush in mouth or fungal infection on skin
8- Need for intravenous antibiotics to clear infections
9- Two or more deep-seated infections, including septicemia
10- A family history of primary immunodeficiency
Source: Modell v, et al .2 available at: http://downloads .info4pi .org / pdfs /Physician-

Algorithm—2-pdf
37
38
Pediatric Rheumatology Protocol of EHA

in
Pediatric Rheumatology
for
First Edition
2024
Prepared by
in
Pediatric Rheumatology
for
1
Executive Committee
1. Professor Dr. Hala M Lotfy; Head of Rheumatology Committee, Professor of

Paediatrics and Pediatric Rheumatology, Specialized Children's Hospital, Faculty
of Medicine, Cairo University.
2. Professor Dr. Samia Salah; Professor of Paediatrics and Pediatric Rheumatology,
Specialized Children's Hospital, Faculty of Medicine, Cairo University.
3. Professor Dr. Hala Salah; Professor of Paediatrics and Pediatric Rheumatology,
Specialized Children's Hospital, Faculty of Medicine, Cairo University.
4. Prof. Yasser El Miedany; MD FRCP (London) Prof. Canterbury University H.
Senior Clinical Lecturer, King's college, London, Consultant Rheumatologist.
Fellow of the Academy of Medical Educators and President of Printo Egypt.
5. Professor Dr. Sheren Esam Maher; Professor of Paediatrics, Pediatric
Rheumatology, Children's Hospital, Faculty of Medicine, Minia University.
6. Dr Yomna Mohamed Farag; Associate Professor of Paediatrics, Pediatric
Rheumatology Unit, Specialized Children’s Hospital, Faculty of Medicine, Cairo
University.
7. Dr. Hend Abu-shady; lecturer Paediatrics, Pediatric Rheumatology Unit,
Specialized Children’s Hospital, Faculty of Medicine, Cairo University.
8. Dr. Nesrine Radwan ; Lecturer of Paediatrics, Pediatric Allergy, Immunology and
Rheumatology unit, Children's Hospital. Faculty of Medicine, Ain Shams
University.
9. Dr Naglaa Samy Mohamed Osman; Lecturer of Paediatrics, Pediatric Allergy,
Immunology and Rheumatology Unit, Children's Hospital, Faculty of Medicine,
Assiut.
10.Dr. Sahar Hammad; Consultant of Pediatric Rheumatology. Atfal misr insurance
hospital.
11.Dr. Shaimaa Refaat; Pediatric and neonatology specialist, MD researcher in
Pediatric rheumatology; Ministry of health. (Moderator)
2
Disclaimer
Protocols and guidelines outline the recommended or suggested clinical

practice; however, they cannot replace sound clinical judgment by appropriately
trained and licensed physicians.
under their care.

written permission from the EHA and authors.
3

Board
Authority (EHA).
Reviewed By



4
PREFACE
aim of developing these Egyptian Clinical Practice Protocols in Pediatric
Rheumatology is to unify and standardize the delivery of healthcare to any child at all
health facilities.
Pediatric Rheumatology service is usually offered to children below 16 years

of age in Egypt.
Regarding Pediatric Rheumatology, busy clinicians have all felt the need for a

delivering high-quality clinical care to their patients. We remain open to feedback
and suggestions about how to improve this resource and how to make it maximally
useful to those delivering care at the bedside in for patients in Pediatric
Rheumatology.
In Pediatric Rheumatology
5
Table of Contents
Page
Title
Number
Preface 5
General Referral Guidelines 7
Connective Tissue disease
Guidelines for diagnosis and treatment of systemic lupus 8
Erythematosus in children
Guidelines for treatment of Pediatric Lupus Nephritis 13
Guidelines for diagnosis and management of 18
antiphospholipid syndrome
Guidelines for diagnosis and management of Juvenile 22
Dermatomyositis
Vasculitis
Guidelines for the management of Bechet’s Disease in 26
pediatrics
Guidelines for diagnosis and management of Kawasaki 32
disease
Guidelines for diagnosis and management of IgA 38
vasculitis
Guidelines for management of childhood polyarteritis 42
nodosa (C-PAN)
Inflammatory Arthritis
Guideline for management of child with arthritis 46
Guidelines for management of oligoarticular JIA 49
Polyarticular JIA 52
Systemic juvenile idiopathic arthritis 54
Guidelines for management of macrophage activation 57
syndrome (MAS) in pediatrics
Autoinflammatory Disease
Guidelines for management of Familial Mediterranean 62
Fever (FMF) in pediatrics
Guidelines for management of multisystem inflammatory 66
syndrome of children post-COVID (MIS-C)
Guidelines for the management of Sarcoidosis in 72
pediatrics
6
General Referral Guidelines
When to refer to pediatric rheumatology?

Referral to paediatric rheumatology is indicated in the following cases:
1. Suspicion of inflammatory disease (joint or muscle).

2. Suspicion of multisystem disease (e.g., rash suggestive of vasculitis,
Raynaud's, uveitis, fever of no apparent cause).
3. Limp that is not resolving.
4. Swollen joint(s).
5. Clumsiness (especially if changing from the child normal
6. Back pain.
7. Limb pain.
8. Joint pain that is not resolving.
9. Any red flags in each of the previous conditions.
N.B:
“Pediatric rheumatology referral guidelines depending on the complaints and
the suspected rheumatologic disease”
7
Guidelines for diagnosis and treatment of systemic

lupus Erythematosus in children
Introduction
• Juvenile systemic lupus erythematosus (JSLE) is a chronic, systemic autoimmune

disease that has great impact on the child or young person affected. It shares its
pathogenesis with adult-onset SLE, but generally has a more severe clinical
phenotype (1).
• Clinical heterogeneity, unpredictable course and flares are characteristics of this
disease.
• Tissue damage caused by autoantibodies or immune-complex depositions occurs
in kidneys, heart, vessels, central nervous system, skin, lungs, muscles and joints
leading to significant morbidity and increased mortality (2).
• Evidence-based guidelines are often based on clinical expertise. New data have
emerged on treatment strategies and validated goals of treatment, alternative
regimens of glucocorticoids (GC) and the approval of the first biological therapy
for SLE.
• Aim in management of JSLE is to have a high index of suspicion in diagnosis
and give an effective treatment with the least side effects possible (3).
8
When to suspect JSLE?
• A high degree of suspicion is warranted (especially if female above 8 years), and

it should be considered in:
a. Any child with fever of unknown origin.
b. Thrombocytopenia or autoimmune hemolytic anemia.
c. Neuropsychiatric manifestations including delirium, psychosis and
seizures in absence of offending agents or metabolic derangement.
d. Mucocutaneous manifestations as nonscarring alopecia, malar rash or
persistent oral ulcers.
e. Serositis as pleural or pericardial effusion.
f. Arthritis non-deforming in two or more joints.
g. Renal affection in the form of proteinuria more than 0.5 g/24 hrs.
N.B:
“Pediatric rheumatologist should be consulted upon suspicion of a case of
JSLE after exclusion of infection and malignancy”
Before referral to pediatric rheumatologist, request these investigations:
a. CBC with differential, ESR, CRP with titer

b. ANA with titer and pattern
c. Anti-dsDNA, C3, C4
d. BUN, creatinine, urine analysis, microalbumin in urine
e. Liver transaminases
f. Direct Coomb’s
g. Serum ferritin
Positive ANA specially with titer 1/80 or more is an important entry criterion in
diagnosis of JSLE
• ANAs are present in over 99% of children with SLE.

• However, ANAs are also associated with other rheumatic diseases,
infections, malignancies, drug exposure and first-degree relatives of
patients with autoimmune disease. Also, 33% of normal children may
have a positive test for ANA (4).
9
Classification criteria for SLE (EULAR/ACR 2019) (2)
10
Treatment of JSLE
• JSLE care is multidisciplinary, based on a shared patient-physician decision, and

should consider individual, medical and societal costs.
►► Treatment of organ-threatening/life-threatening SLE includes an initial period

of high-intensity immunosuppressive therapy to control disease activity,
followed by a longer period of less intensive therapy to consolidate response
and prevent relapses.
►► Treatment goals include long-term patient survival, prevention of organ damage

and optimization of health-related quality of life.
Medications
1. HCQ is recommended for all patients with JSLE, unless contraindicated, at a

dose not exceeding 5 mg/kg.
2. Pulses of intravenous methylprednisolone (10-30mg/kg/dose, max 1 gram for
1–3 days) provide immediate therapeutic effect and enable the use of lower
starting dose of oral glucocorticoids (GC).
3. For chronic maintenance treatment, GC should be minimized to less than 7.5
mg/day and, when possible, withdrawn.
4. Prompt initiation of immunomodulatory agents can allow the
tapering/discontinuation of GC.
5. Cyclophosphamide can be used for severe organ-threatening or life-
threatening SLE as well as ‘rescue’ therapy in patients not responding to other
immunosuppressive agents.
6. lupus nephritis: refer to specific guidelines.
7. Antiphospholipid syndrome
a. All patients with SLE should be screened at diagnosis for aPL.
b. Patients with SLE with high-risk aPL profile (persistently positive
medium/high titres or multiple positivity) may receive primary
prophylaxis with antiplatelet agents.
c. For secondary prevention (thrombosis, pregnancy complication/loss), the
therapeutic approach should be the same as for primary
antiphospholipid.
11
References:
1. Groot N, de Graeff N, Avcin N, Bader-Meunier B, Brogan P, Dolezalova P, etal.

European evidence-based recommendations for diagnosis and treatment of childhood-
onset systemic lupus erythematosus: the SHARE initiative.2017 Ann Rheum
Dis;76(11):1788-1796.
2. Fanouriakis A, Tziolos N, Bertsias G, Boumpas DT. Update in the diagnosis and
management of systemic lupus erythematosus. Ann Rheum Dis. 2021 ;80(1):14-25.
3. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, Cervera
R, Doria A, Gordon C, Govoni M, Houssiau F, Jayne D, Kouloumas M, Kuhn A,
Larsen JL, Lerstrøm K, Moroni G, Mosca M, Schneider M, Smolen JS, Svenungsson
E, Tesar V, Tincani A, Troldborg A, van Vollenhoven R, Wenzel J, Bertsias G,
Boumpas DT. 2019 update ofthe EULAR recommendations for the management of
systemic lupus erythematosus. Ann Rheum Dis. 2019 Jun;78(6):736-745.
4. Klein-gitelman M, Beresford M. Systemic lupus erythematosus, Mixed connective
tissue disease and undifferentiated connective tissue disease. Petty R, Laxer R,
Lindsley C, etal. Textbook of Pediatric Rheumatology, 8th edition, 2021:295-345.
12
Guidelines for treatment of Pediatric Lupus

Nephritis
Introduction
• Childhood SLE is rare, with a prevalence of 1.9–25.7 per 1 00 000 children and
incidence of 0.3–0.9 per 1 00 000 children-years worldwide.1
• Childhood SLE in general has a more severe phenotype than adult-onset disease.2
• Fifty to sixty per cent of patients with cSLE will develop lupus nephritis
(LN).2,3,4
• Timely and accurate recognition of renal involvement combined with appropriate
treatment choices will optimize clinical outcome and decrease renal-associated
morbidity and mortality.5
• The long-term aim for treatment of LN should be complete renal response, with
early morning urine protein: creatinine ratio of <50 mg/mmol (or urine albumin:
creatinine ratio of <35 mg/mmol) and normal renal function (estimated glomerular
filtration rate >90 mL/min/1.73 m2).6 Within 6–12 months after initiation of
treatment, partial renal response, defined as ≥50% reduction in proteinuria to at
least sub nephrotic levels and normal or near-normal renal function should be
achieved.7.
13
Treatment
ISN/RPS class I and II LN
Class I LN:
Is more common in cSLE compared with adult-onset SLE, and it could be

treated with low-dose oral corticosteroid therapy.
Class II LN:
• Generally, responds well to low-dose oral corticosteroid therapy (starting

dose 0.25–0.5 mg/kg/day, maximum of 30 mg/day; often 0.25 mg/kg/day is
sufficient), tapered over a 3–6 months period.
• If proteinuria is persistent after 3 months or corticosteroid dose cannot be
effectively weaned, renal biopsy should be re-evaluated.
• Adding a DMARD to the treatment or switching to another DMARD
effective for LN (e.g., MTX to AZA) is recommended
ISN/RPS class III and IV LN with or without class V LN
Class III and IV LN (proliferative LN) are the most common and severe forms
of LN in cSLE. Combination of class III or IV LN with class V LN is prevalent.
Induction treatment
• Low-dose intravenous CYC (fixed dose 500 mg/pulse, six pulses given
every 2 weeks)-euro lupus-, and high-dose CYC (500–750 mg/m2/pulse, if
tolerated increase to 750 mg/m2/pulse, maximum dose 1000–
1200 mg/pulse, 6 monthly pulses), adjusted appropriately in cases of renal
dysfunction.
• MMF (standard dose 1200 mg/m²/day, maximum 2000 mg/day; when poor
response option to increase to maximum of 1800 mg/m²/day, maximum
dose 3000 mg/day, but toxicity increases with higher dose) or
intravenous CYC combined with high-dose prednisone (1–2 mg/kg/day,
maximum 60 mg/day) should be considered for induction treatment of
proliferative LN in cSLE.
14
Maintenance treatment
Duration of maintenance treatment in LN in the cSLE from the literature

search was variable (1–5 years).
• MMF and AZA are good options for maintenance treatment although a
higher relapse rate is seen in patients treated with AZA
• Intravenous CYC can be effective as maintenance treatment, but is not
advised due to higher toxicity when compared with MMF or AZA (e.g.,
increased risk of a reduced ovarian reserve/premature ovarian failure,
inhibition of spermatogenesis, increased risk of bladder carcinoma).
Corticosteroid
• Use as oral prednisone 1–2 mg/kg/day (maximum 60 mg/day) as initial

dosing.
• Intravenous methylprednisolone pulse therapy (30 mg/kg/dose intravenous
for three consecutive days, maximum 1000 mg/dose) may be added to
induction treatment before start of oral prednisone, especially in case of
severe disease (e.g., impaired GFR (<80 mL/min/1.73 m2); nephrotic range
proteinuria (>3.5 g/24 hours); biopsy-proven crescentic glomerulonephritis).
• Prednisone-tapering schedule that may be used is tapering by 10%–20% at
1-week or 2-week interval based on clinical improvement.
ISN/RPS class V LN
• MMF in combination with low-dose oral prednisone (0.5 mg/kg/day) as

induction treatment for pure class V LN in cSLE.
• MMF or AZA are recommended as maintenance treatment. CNI
(ciclosporin, tacrolimus), rituximab or intravenous CYC are recommended
as alternative options or for non-responders, with consideration of their
respective toxicity.
15
Renal flares and refractory disease
• Patient not responding to the prescribed treatment as expected or

developing disease flare, medication non-compliance should first be
explored. Lack of adherence to therapy can be as high as 50%, and has been
associated with higher persistent disease activity and poorer renal outcomes.
• Measuring medication (trough) levels to unmask non-compliance is
advisable. If a patient shows hardly any response within 3 months of
induction treatment, it is generally accepted to change the principal
induction agent.
• Renal flares can occur in up to 50% of patients with cSLE during
maintenance treatment. After excluding non-compliance, restarting or
increasing corticosteroid dose (oral prednisone or intravenous
methylprednisolone pulses) and a switch of DMARD should be considered.
• In refractory cases Rituximab should be considered.
• CNI (tacrolimus, ciclosporin) can be considered as a treatment option for
LN in selected cases, although with the consideration of potential
nephrotoxicity especially related to ciclosporin after long-term use.
16
References:
1- Hiraki LT, Feldman CH, Liu J, Alarcón GS, Fischer MA, Winkelmayer WC, et al.
Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus
nephritis from 2000 to 2004 among children in the US Medicaid beneficiary
population. Arthritis Rheum. 2012 Aug;64(8):2669-76. doi: 10.1002/art.34472.
2- Bader-Meunier B, Armengaud JB, Haddad E, Salomon R, Deschênes G, Koné-Paut I,

et al. Initial presentation of childhood-onset systemic lupus erythematosus: a French
multicenter study. J Pediatr 2005;146:648-53. doi:10.1016/j.jpeds.2004.12.045
3- Font J, Cervera R, Espinosa G, Pallarés L, Ramos-Casals M, Jiménez S,et al. Systemic

lupus erythematosus (SLE) in childhood: analysis of clinical and immunological
findings in 34 patients and comparison with SLE characteristics in adults. Ann Rheum
Dis 1998; 57:456-9. doi:10.1136/ard.57.8.456.
4- Ramírez Gómez LA, Uribe Uribe O, Osio Uribe O, Grisales Romero H, Cardiel MH,
Wojdyla D, et al. Childhood systemic lupus erythematosus in Latin America. The
GLADEL experience in 230 children. Lupus. 2008 Jun;17(6):596-604. doi:
10.1177/0961203307088006. PMID: 18539716.
5- Groot N, de Graeff N, Avcin T, Bader-Meunier B, Brogan P, Dolezalova P, et al.

European evidence-based recommendations for diagnosis and treatment of childhood-
onset systemic lupus erythematosus: the SHARE initiative. Ann Rheum Dis. 2017
Nov;76(11):1788-1796. doi: 10.1136/annrheumdis-2016-210960. Epub 2017 Jun 19.
PMID: 28630236.
6- Wulffraat NM, Vastert B. Time to share. Pediatr Rheumatol Online J 2013; 11:5.
doi:10.1186/1546-0096-11-5.
7- Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, et al.

European League Against Rheumatism and European Renal Association-European
Dialysis and Transplant Association. Joint European League Against Rheumatism and
European Renal Association-European Dialysis and Transplant Association
(EULAR/ERA-EDTA) recommendations for the management of adult and paediatric
lupus nephritis. Ann Rheum Dis. 2012 Nov;71(11):1771-82. doi: 10.1136/annrheumdis-
2012-201940. Epub 2012 Jul 31. PMID: 22851469; PMCID: PMC3465859.
17
Guidelines for diagnosis and management of

antiphospholipid syndrome
Introduction
• Antiphospholipid syndrome (APS) is a systemic autoimmune disorder

characterized by an increased risk of thrombotic events and pregnancy morbidity
in the setting of persistently positive antiphospholipid antibodies (aPL) .
• The concept of “pediatric APS” is typically applied when the disorder occurs in
individuals under the age of 18 years.
• APS may affect children from neonates to adolescents, and is likely
underdiagnosed given that widely-used classification criteria were designed for
adults.
• APS either “primary APS” or in conjunction with another autoimmune condition
“secondary APS” which classically associated with lupus.
18
When to suspect APS?

Clinical presentation
1) Vascular thrombosis:
Venous: Lower-limb deep venous thrombosis (DVT), portal vein thrombosis, upper
extremity DVT, and left atrial thrombus formation. There were also but rare jugular
vein, inferior vena cava, renal vein, and retinal vein.
a. Arterial: ischemic stroke the most common, other rare forms of arterial
thrombosis as peripheral artery thrombosis, retinal artery thrombosis,
myocardial infarction, renal artery thrombosis, and splenic infarction.
b. Small-vessel thrombosis: in the form of digital ischemia or renal
thrombotic microangiopathy
2) Nonthrombotic manifestations:
a. Neurologic manifestations including migraine headache, chorea/athetosis,
epilepsy, pseudotumor cerebri, and mood disorder.
b. Hematologic abnormalities including Evans syndrome, thrombocytopenia
and autoimmune hemolytic anemia.
c. skin disorders as livedo reticularis, Raynaud’s phenomenon, skin ulcers,
pseudo-vasculitic lesions, chronic urticaria and purpura fulminans.
d. kidney disease including CKD due to thrombotic microangiopathy.
e. Primary adrenal insufficiency secondary to adrenal infarction.
f. Antiphospholipid antibodies may be transiently positive in children,
especially in the context of infections, and so confirmatory testing should
always be performed.
g. Catastrophic APS (CAPS) is a life-threatening complication of APS
typically characterized by widespread microvascular occlusions placing
organs such as heart, lungs, and kidneys at significant risk.
N.B:
“So, new classification criteria for pediatric APS are needed that would
incorporate non-thrombotic manifestations in children, in addition to
thrombosis”
19
Investigations
a. Lupus anticoagulant (LA)

b. Anticardiolipin IgG and IgM
c. Anti-β2-glycoprotein-I IgG and IgM.
Treatment of APS
1. In patients with cSLE and aPL, antiplatelet agents could be considered for
primary prevention of thrombosis in addition to hydroxychloroquine.
2. When a patient has suffered a venous thrombotic event associated with
persistent aPL positivity, long-term anticoagulation therapy is indicated, low-
molecular- weight heparin yielding a target anti-Xa.
3. In a patient with pediatric CAPS, immediate combination treatment with
anticoagulants, corticosteroids, plasma exchange with or without intravenous
immunoglobulins should be considered. rituximab or other immunosuppressive
therapy may also be considered as a treatment option.
20
References:
1. Lim W. Antiphospholipid syndrome. Hematology Am Soc Hematol Educ Program. 2013;

2013:675–80. doi: 10.1182/asheducation-2013.1.675. [PubMed] [CrossRef] [Google
Scholar]
2. Jacqueline A. Madison, Yu Zuo, and Jason S. Knight. Pediatric antiphospholipid
syndrome Eur J Rheumatol. 2020 Feb; 7(Suppl 1): S3–S12.Published online 2019 Dec 3.
doi: 10.5152/eurjrheum.2019.19160
3. Noortje Groot, Nienke de Graeff, Tadej Avcin, Brigitte Bader-Meunier, Pavla Dolezalova,
Brian Feldman, Gili Kenet, Isabelle Koné-Paut, Pekka Lahdenne, Stephen D. Marks, Liza
McCann, Clarissa A. Pilkington, Angelo Ravelli,13 Annet van Royen-Kerkhof, Yosef
Uziel, Sebastiaan J. Vastert, Nico M. Wulffraat, Seza Ozen, Paul Brogan, Sylvia
Kamphuis, Michael W. Beresford. European evidence-based recommendations for
diagnosis and treatment of pediatric antiphospholipid syndrome: the SHARE initiative.
Groot N, et al. Ann Rheum Dis 2017;0:1–5. doi:10.1136/annrheumdis-2016-211001
21

Juvenile Dermatomyositis
Introduction
• Juvenile dermatomyositis (JDM) is a rare disease with a characteristic rash and

symmetrical proximal muscle weakness.
• It is classified as a vasculopathy1; however, the pharmacokinetic data suggests
that the microvascular damage may not be limited to the skin2 and muscle 3 and
also may include the vasculature of the gastrointestinal tract.4
• The annual incidence of JDM by race in the USA is 3.4/million for white, non-
Hispanic, 3.3/million for African Americans, and 2.7/million for Hispanic
patients, with an overall girl-to-boy ratio of 2.3 girls:1 boy (11).5
When to suspect juvenile dermatomyositis disease?

• The Clinical features includes cutaneous and muscular:
Cutaneous:
1. Gottron’s sign—linear erythema–localized to the areas of the hands where the

skin is stretched, over joints.
2. Gottron’s papules usually occur in areas of injury—fingers, elbows, and knees.
3. Heliotrope rash on the upper eye lids
4. Calcinosis
5. The shawl sign rash on the upper chest
Muscular:
1. Bilateral symmetrical proximal muscle weakness.
22
• Expected Long term complications if undiagnosed and untreated:

1. Interstitial lung disease
2. Edema, either localized or general—secondary to capillary leak
3. Hair loss—secondary to scalp inflammation/edema.
4. Cardiovascular damage includes impaired cardiac conduction and subsequent
cardiac systolic dysfunction.
1. Do investigation to exclude other causes of myopathy as endocrinal disorders,

thyroid dysfunction, electrolyte disturbance, vitamin D deficiency.
2. Muscle enzymes: (LDH, SGPT, CPK +- aldolase)
3. Other “routine initial” testing:
• ANA (usually speckled)

• CBC with differential
• CRP (elevated in overlap syndrome but not usually in JDM)
• ESR (usually normal range)
• U/A, BUN, Creatinine
Investigations that should be requested only by the pediatric rheumatologist
• Yositis-specific antibodies (antibody-TIF1-γ (transcriptional factor-1-γ), anti-

NXP-2, anti-SRP, melanoma differentiation-associated gene 5(MDA-5),)
• Myositis-associated antibodies (anti-U1 RNP, anti -RO, anti-smith)
• Echo, ECG
• CT chest, PFT
• MRI of muscles or quantitative ultrasound
• EMG
• Assessment of muscle strength at diagnosis and follow up using childhood
myositis assessment scale (CMAS) and Manual muscle test (MMT)
• Swallow function test
• Nailfold capillaroscopy for periungual capillary changes (CAT)
23
High risk patients that require urgent consultation of the pediatric

rheumatologist without delay
Patients who have the following manifestations:
• Severe disability
• Presence of aspiration or dysphagia
• GIT vasculitis
• Myocarditis
• Parenchymal lung disease
• CNS affection in form of seizures or LOC
• Skin ulceration
• Age <1 year
Treatment
• Aim of treatment is:

a. To control disease manifestations
b. To prevent and stabilize organ damage and disease complications like
calcinosis. Accordingly, treatment must be early and aggressive.
c. To prevent relapses
• Assessment of the outcome is done with many tools including patient/parent

report outcome measure at diagnosis and follow up.
Treatment includes:(prescribed by pediatric rheumatologist):
• Physiotherapy
• Initially high dose steroids along with DMD as MTX (15mg/m2),
Cyclosporin and others
• Hydroxychloroquine (5mg/kg/day)
• Vitamin D supplements
• Sun blockers
For refractory cases:
• IVIG on 1-2gm/kg/every month
• MMF
• Cyclophosphamide
• Tacrolimus
• Rituximab
• Infliximab
For calcinosis:
• Bisphosphonates, infliximab, abatacept, diltiazem, probenecid,
intralesional steroids or surgical debridement.
24
References:
1. Papadopoulos C, McCann LJ. The vasculopathy of juvenile dermatomyositis. Front

Pediatr. 2018; 6:284
2. Dugan EM, Huber AM, Miller FW, Rider LG. Photo essay of the cutaneous
manifestations of the idiopathic inflammatory myopathies. Dermatol Online J.
2009;15(2):1.
3. Banker BQ, Victor M. Dermatomyositis (systemic angiopathy) of childhood. Medicine.
1966; 45:261–89.
4. Rouster-Stevens KA, Gursahaney A, Ngai KL, Daru JA, Pachman LM.
Pharmacokinetic study of oral prednisolone compared with intravenous
methylprednisolone in patients with juvenile dermatomyositis. Arthritis Rheum.
2008;59(2):222–6.
5. Mendez EP, Lipton RB, Dyer A, Ramsey-Goldman R, Roftcher P, Bowyer S, et al.
Incidence of juvenile dermatomyositis (JDM) 1995-98: results from the NIAMS
Registry. Arthritis Care Res. 2003; 49:300–5.
6. Pachman LM, Nolan BE, DeRanieri D, Khojah AM. Juvenile Dermatomyositis: New
Clues to Diagnosis and Therapy. Curr Treatm Opt Rheumatol. 2021 Mar;7(1): 39-
62.doi: 10.1007/s40674-020-00168-5. Epub 2021 Feb 6. PMID: 34354904; PMCID:
PMC8336914.
7. Bellutti Enders F, Bader-Meunier B, Baildam E, Constantin T, Dolezalova P Feldman
BM, et al. Consensus-based recommendations for the management of juvenile
dermatomyositis. Ann Rheum Dis. 2017 Feb;76(2):329-340. doi: 10.1136/annrheumdis-
2016-209247.
25
Guidelines for the management of Bechet’s

Disease in pediatrics
Introduction
• Behçet's disease (BD) is a multisystem vasculitis, that can involve vessels of all
sizes and types.
• It was defined first as a disease with triad of recurrent oral, genital ulcers and
uveitis, accompanied with other cutaneous, articular, vascular, neurological and
gastrointestinal manifestation.
• Pediatric patients tend to have more gastrointestinal, articular, neurologic
manifestations and more positive family history than the usual triad observed in
the adult BD. However, better disease outcome with lower severity score and
activity index has been reported in paediatrics.
• The diagnosis is based mainly on the clinical manifestation. It can be challenging
to diagnose the disease due to the absence of a diagnostic test, and the long
interval from the first finding of the disease to the full-blown disease phenotype
in pediatric patients.
• It usually causes recurrent, self-limited disease flares.
• Due to the extensive distribution of the disease among various organs, the
management should be made by multidisciplinary approach.
26
When to suspect Bechet’s disease in pediatrics?
Mucocutaneous Lesions:
1. Recurrent painful oral ulcers (circular, non-scarring, with erythematous
borders, on tongue, oropharyngeal and buccal mucosa).
2. Genital ulcers (on scrotum, labia major or minor).
3. Perianal aphthosis is specific feature for pediatrics.
4. Erythema nodosum, papulopustular lesions, and folliculitis.
Musculoskeletal involvement:
1. Oligoarticular or polyarticular pattern of arthritis.
2. Sacroiliac joint involvement and enthesopathy can be seen.
Ocular involvement:
1. It most often appears 2-3 years after oral ulcers.
2. It includes blurred vision, ocular pain, eye redness, bilateral posterior
uveitis (most important), and non-granulomatous panuveitis.
3. Iridocyclitis, keratitis, episcleritis, vitreous hemorrhage, cataract, glaucoma,
and retinal detachment can also be seen.
Neurologic involvement:
1. Central nervous system involvement is more common than peripheral
nervous system, including recurrent aseptic meningitis, ataxia, epilepsy,
meningoencephalitis, acute onset headache, papillary edema, and
hemiparesis. Chronic neuropsychiatric conditions can be seen.
Vascular involvement:
1. Venous involvement is more common than arterial including deep vein
thrombosis and dural venous sinuses thrombosis.
2. Pulmonary artery aneurysm is the most common cause of mortality in BD.
Gastrointestinal involvement:
1. Usually start 4-6 years after oral ulcers and the most common symptoms are
abdominal pain, nausea, vomiting, dyspepsia, diarrhea, and gastrointestinal
bleeding.
27
Pediatric Criteria for classification of Behçet’s Disease
• Recurrent oral aphthosis: At least three attacks/year.

• Genital ulceration or aphthosis: Typically, with scar.
• Skin involvement: Necrotic folliculitis, acneiform lesions, erythema nodosum.
• Ocular involvement: Anterior uveitis, posterior uveitis, retinal vasculitis.
• Neurological signs: With the exception of isolated headaches.
• Vascular signs: Venous thrombosis, arterial thrombosis, arterial aneurysm.
At least 3 criteria are required for the diagnosis.
• The positive pathergy phenomenon (non-specific cutaneous hypersensitivity

reaction to trauma) is not pathognomonic to BD.
• Oral ulceration is not a mandatory finding.
N.B:
“It should be kept in mind that some of children with BD may not meet the
classification criteria in the early stages of the disease and such patients
should be followed-up carefully in a pediatric rheumatology clinic for further
clinical assessment”
Before referral to pediatric rheumatologist, request these investigations
• CBC with differential

• ESR, CRP
• Liver function test
• Urine analysis
• Ophthalmologic consultation
28
Treatment of Bechet disease
The primary goal for the treatment is preventing the organ damages by
suppressing the ongoing inflammation and forestalling the disease flares.
• Corticosteroids (topical, oral and intravenous route), have strong and rapid
anti-inflammatory effects.
a) Topical corticosteroids for ocular manifestation and oral or genital
ulcers.
b) Systemic steroids (in combination with other anti-inflammatory drugs)
for cutaneous lesions unresponsive to topical steroid or colchicine, and
for ocular, vascular, nervous and, gastrointestinal involvement.
N.B:
“Pulse methyl prednisolone is recommended for acute sight threatening

uveitis for 1–3 days”
• Colchicine is used for mucocutaneous lesions (oral ulcers- erythema nodosum)
and for articular manifestations.
• Azathioprine is used in severe mucocutaneous manifestations, persistent
arthritis, deep venous thrombosis, active posterior uveitis, or isolated anterior
uveitis, gastrointestinal and neurologic involvement.
• Methotrexate is used for ocular and mucocutaneous lesions, as well as in
neuro-Behçet's disease.
• Cyclosporine A is recommended for patients with severe ocular involvement
and persistent mucocutaneous lesions.
• Cyclophosphamide is used for severe manifestations of the disease such as
pulmonary artery involvement, Budd-Chiari syndrome, and parenchymal
neurologic involvement.
• Mycophenolate mofetil can be uses in neuro beçhet disease.
29
• Antiaggregant and anticoagulant therapy used in children with vascular

involvement (Aspirin is usually sufficient).
• IFN-alpha has an immunomodulatory property,with the best efficacy in
uveitis.
• Anti-TNF agents (Etanercept, Adalimumab, and Infliximab) are recommended
in patients who cannot be controlled by conventional immunosuppressive
treatments or in cases with intolerance or allergic reactions to conventional
agents. They are highly recommended in severe neuro Behçet disease,
refractory deep venous thrombosis and arterial involvement, severe eye
involvement, moderate and severe GI Behçet's disease.
• Anti-IL-1 agents (Anakinra) can be used in refractory uveitis, retinal vasculitis
and mucocutanous manifestations.
• Anti-IL-6 agents (Tocilizumab) can be used in refractory BD with good results
in uveitis and has promising results on CNS involvement.
N.B:
“The prognosis depends on the site and severity of involvement.

The leading causes of BD-related morbidity and mortality are ocular,
neurologic, and arterial involvements”
30
References:
1-Yildiz, M., Haslak, F., Adrovic, A., Sahin, S., Koker, O., Barut, K., & Kasapcopur,
O. (2021). Pediatric Behçet's disease. Frontiers in Medicine, 8, 627192.
2-Koné-Paut, I., Shahram, F., Darce-Bello, M., Cantarini, L., Cimaz, R., Gattorno, M.,
... & Ozen, S. (2016). Consensus classification criteria for paediatric Behçet's disease
from a prospective observational cohort: PEDBD. Annals of the rheumatic diseases,
75(6), 958-964.
3-Batu, E. D. (2019). Diagnostic/classification criteria in pediatric Behçet’s

disease. Rheumatology International, 39(1), 37-46.
4-Costagliola, G., Cappelli, S., & Consolini, R. (2020). Behçet’s disease in children:
diagnostic and management challenges. Therapeutics and Clinical Risk Management,
16, 495.
31

Kawasaki disease
Introduction
• Kawasaki disease (KD) is a medium vessel vasculitis, with characteristic
seasonality (1).
• It typically presents in children <5 years of age as an acute, self-limited febrile
disease and is characterized by a combination of characteristic clinical signs,
which include:
a. Polymorphic rash
Non-purulent conjunctival injection
Oropharyngeal and lip mucositis, tongue papillitis
Erythema and edema of the hands and feet
Unilateral cervical lymphadenopathy.
• The disease may affect the coronary arteries but can also affect medium-sized
arteries (4).
• In the developed world, it is the most common cause of acquired cardiac disease
in childhood, with 25% of untreated patients and 5% of treated patients
developing coronary artery aneurysms (7).
When to suspect Kawasaki disease?

• Diagnosis of KD is essentially based on a constellation of clinical signs and
symptoms and supported by laboratory investigations.
32
• Disease states:
I. KD: Fever lasting at least 5 days without any other explanation with at least 4
of the 5 following principal clinical findings:
1. Bilateral bulbar conjunctival injection without exudate.
2. Erythema and cracking of lips, strawberry tongue, and/or erythema of

oral and pharyngeal mucosa.
3. Erythema and edema of the hands or feet (acute phase), and/or

periungual desquamation (subacute phase).
4. Maculopapular, diffuse erythroderma, or erythema multiforme–like

rash.
5. Cervical lymphadenopathy (at least 1 lymph node >1.5 cm in

diameter), usually unilaterally.
33
II. Incomplete KD: Prolonged (> 5 days) unexplained fever in an infant or

child with compatible laboratory markers (elevated
ESR/CRP level, elevated transaminase levels, UA
with leukocyte esterase–negative WBCs) or
echocardiographic findings (coronary artery
dilatation)
III. Acute KD: Initial febrile phase of KD
• Children with < 5 days of fever, or those with incomplete Kawasaki disease may
prove to be more of a diagnostic challenge.
• In patients presenting with Fever, consider the following differential diagnoses.
34
Consider Kawasaki disease in the differential diagnosis of any infant or child

with prolonged fever (> 5 days) plus:
➢ Irritability
➢ Unexplained aseptic meningitis
➢ Unexplained or culture-negative shock
➢ Cervical lymphadenitis unresponsive to antibiotic therapy
➢ Retropharyngeal or parapharyngeal inflammation unresponsive to
antibiotic therapy.
➢ Pediatric rheumatologist should be consulted upon suspicion of a case of
Kawasaki disease after exclusion of other causes of the child complaint.
Before referral to pediatric rheumatologist, request these investigations (2)
a. CBC with differential (leukocytosis, thrombocytosis), ESR , CRP

with titer
Serum albumin Na level
BUN, creatinine, urine analysis (for evidence of sterile pyuria),

microalbumin in urine
Liver transaminases
35
Treatment of Kawasaki disease

Under supervision of pediatric rheumatologist, pediatric cardiology
Source:
▪ 2021 American College of Rheumatology/Vasculitis Foundation Guideline for
the Management of Kawasaki Disease (1)
36
References:
1. Mark Gorelik, Sharon A. Chung, Kaveh Ardalan, Bryce A. Binstadt, Kevin

Friedman, Kristen Hayward et al. 2021 American College of
Rheumatology/Vasculitis Foundation Guideline for the Management of Kawasaki
Disease. Arthritis & Rheumatology. 2022; 586–596.DOI 10.1002/art.42041.
2. Y El Miedany, H Lotfy, S Salah, M. H Abu-Zaid, S. S Mohamed, S Esam Maher

et al.Egyptian consensus-based recommendations for the diagnosis and targeted
management of Kawasaki disease. An initiative by the Egyptian College of
Pediatric Rheumatology. Rheumatology 2022, Volume 61, Issue Supplement_2,
https://doi.org/10.1093/rheumatology/keac495.001.
37
Guidelines for diagnosis and management of IgA

vasculitis
Introduction
• IgA vasculitis (IgAV), formerly known as Henoch Schoenlein purpura (HSP), is

the commonest cause of vasculitis in childhood, with a peak incidence in children
between the ages of 4 and 6 years.
• Pathologically, it is an acute immunoglobulin A (IgA) immune-mediated disorder
characterized by small vessel vasculitis of the skin, joints, kidney, gastrointestinal
tract, and, rarely, the lungs and the central nervous system.
• Renal damage is considered the most common cause of morbidity and mortality in
IgAV.
• Given its potential life-threatening systemic complications, early and accurate
diagnosis represents a major challenge for health care professionals.
38
Classification criteria of IgAV according to the EULAR/PRINTO/Pediatric

Rheumatology European Society (PRES) includes:
• Purpura or petechiae (mandatory) with lower limb predominance and at least one
of the four following criteria:
1. Abdominal pain
2. Histopathology (typically leucocytoclastic vasculitis with predominant
IgA deposit or proliferative glomerulonephritis with predominant IgA
deposit)
3. Arthritis or arthralgia
4. Renal involvement
When to suspect IgAV?
• Raised purpura with lower limb predominance.

• if symptoms do not resolve or improve within days to weeks, as would be
expected in a "self-limited" infectious illness.
• Multisystem involvement should raise possibility of vasculitis.
When to refer to pediatric rheumatologist?
• Persistent symptoms, or atypical course

• Evidence of renal affection/ proteinuria
• When the diagnosis is doubtful
• If the rash distribution or characterization is atypical.
Before referral to pediatric rheumatologist, request these investigations

• To exclude other diseases and to investigate any possible complications
requiring immediate communication with a pediatric rheumatologist:
✓ CBC with blood film: to rule out thrombocytopenia/ leukemia.
✓ CBC, CRP, and clotting: if concerned about sepsis.
✓ Kidney function tests, serum electrolytes, albumin, calcium, phosphate, UP/
UC ratio: if urine dipstick has 2 + or more of proteinuria.
✓ CBC and Clotting: if macroscopic hematuria.
✓ Abdominal ultrasonography if there is abdominal pain
✓ Fecal Occult blood if in doubt of bleeding
39
Treatment of IgA vasculitis
40
References:
1. Mohammed Hassan Abu-Zaid, Samia Salah, Hala M. Lotfy, Maha El Gaafary et al.
Consensus evidence-based recommendations for treat-to-target management of
immunoglobulin A vasculitis. Ther Adv Musculoskelet Dis. 2021; 13:
1759720X211059610.
2. Ozen S, Marks SD, Brogan P, et al. European consensus-based recommendations for

diagnosis and treatment of immunoglobulin A vasculitis-the SHARE
initiative. Rheumatology 2019; 58: 1607–1616.
41
Guidelines for management of childhood

polyarteritis nodosa (C-PAN)
Introduction
• PAN is a necrotizing vasculitis that primarily affects small and medium sized
vessels.
• It manifests in a variety of ways from a benign cutaneous to a sever systemic
type.
• The immunopathogenesis in PAN is heterogenous, infectious triggers have been
implicated as hepatitis B virus, cytomegalovirus, parvo B19 virus and
streptococcal infection. (1)
• C-PAN can be associated with severe complications, therefore early diagnosis
and aggressive treatment are important for improving prognosis without a sequel.
When to suspect polyarteritis nodosa (C-PAN)?
Systemic C-PAN is characterized by combination of the following:
• Constitutional manifestations.
• Neurological manifestations.
• Cutaneous manifestations.
• Renal manifestations.
• Gastrointestinal manifestations.
• Diffuse myalgia, arthralgia, occasionally arthritis.
42
EULAR/PRINTO/PRES Classification of C-PAN (2)

Mandatory
• Histopathological criteria: Evidence of necrotizing
vasculitis in medium or small arteries.
OR
• Radiological criteria: Angiographic abnormality of
medium or small sized artery (aneurysm, stenosis,
occlusion), not due to fibromuscular dysplasia or
other non-inflammatory causes.
One out of five
• Skin involvement (livedo reticularis, skin nodules,
superficial or deep skin infarcts).
• Myalgia or muscle tenderness.
• Hypertension.
• Peripheral neuropathy (sensory, motor or
mononeuritis multiplex).
• Renal involvement (proteinuria, hematuria or
impaired renal function).
Before referral to pediatric rheumatologist, order these investigations:
• CBC.
• ESR, CRP.
• Kidney function tests.
• Liver function tests.
• Urine analysis.
• Echocardiogram, ECG.
43
Treatment
Induction therapy:
• Corticosteroids: Methyl prednisolone or prednisolone.
• Cyclophosphamide.
• Plasmaphereses (in life threatening vasculitis).
• IVIG.
• Anti TNF.
• Tocilizumab.
Maintenance therapy:
• Maintenance therapy should be continued for 12-36 months after successful

induction depending on clinical course, some patients may require longer
treatment.
A- Immune modulatory agents:

• Azathioprine.
• Methotrexate.
• Mycophenolate mofetil.
• Rituximab.
• Anti TNF.
• Tocilizumab.
• IVIG.
B- Anti platelets drugs.
C- Osteoporosis prophylaxis.
D- Antibiotics prophylaxis.
NB:
➢ C-PAN secondary to HBV infection is classified as secondary vasculitis and

requires different therapeutic approach as conventional treatment with
corticosteroids and cyclophosphamide, allows the virus to replicate,
facilitating evolution to chronic hepatitis and liver cirrhosis
➢ The recommended approach is combined plasma exchange and antiviral
medications with corticosteroids to control acute manifestation. (3)
44
References:
1. Hernandez-Rodriguez J, Alba MA, Prieto-Gonzalez S, Cid MC. (2014):

Diagnosis and classification of polyarteritis nodosa. J. Autoimmun. 2014;48–
49:84–89.
2. Ruperto N, Ozen S, Pistorio A, Dolezalova P, Brogan P, Cabral DA, Cuttica R,

Khubchandani R, Lovell DJ, O'Neil KM, Quartier P, Ravelli A, Iusan SM,
Filocamo G, Magalhães CS, Unsal E, Oliveira S, Bracaglia C, Bagga A,
Stanevicha V, Manzoni SM, Pratsidou P, Lepore L, Espada G, Kone-Paut I,
Zulian F, Barone P, Bircan Z, Maldonado Mdel R, Russo R, Vilca I, Tullus K,
Cimaz R, Horneff G, Anton J, Garay S, Nielsen S, Barbano G, Martini A
(2010): Pediatric Rheumatology International Trials Organisation (PRINTO).
EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood
polyarteritis nodosa, childhood Wegener granulomatosis and childhood
Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical
characterisation. Ann Rheum Dis. 69(5):790-7.
3. Guillevin, Loïc, Mahr, Alfred, Callard, Patrice, Godmer, Pascal ; Pagnoux,

Christian, Leray, Emmanuelle, Cohen, Pascal, the French Vasculitis Study
Group (2005): Hepatitis B Virus-Associated Polyarteritis Nodosa: Clinical
Characteristics, Outcome, and Impact of Treatment in 115 Patients. Medicine
(Baltim), 84:313-322.
45
Guideline for management of child with arthritis
Introduction
• Joint pain is a common reason for children to present to primary care.

• The differential diagnosis is large including some diseases that do not primarily
affect the musculoskeletal system.
• Arthritis and arthritis like symptoms can be the presentation of serious systemic
diseases like leukemia, T.B.
• Identification of musculoskeletal emergencies (e.g. septic arthritis, systemic onset
JIA) is very important for management purpose.
➢ Arthritis: Joint pain with signs of inflammation (limitation of range of

movement, tenderness or pain on motion).
➢ Arthralgia: Joint pain without any signs of inflammation.
➢ Monoarthritis: only one joint involved.
➢ Oligoarthritis: 1-4 joints during 1st 6 months of disease.
➢ Polyarthritis: >5 joints during 1st 6 months of disease.
46
Approach to diagnosis
Take a good history including:
1. Child ‘well’ or ‘sick’?

2. History of trauma?
3. whether there is involvement of single or multiple joints.
4. Features suggestive of infection, either localized or systemic?
5. Family history of bleeding diathesis?
6. Nature of the onset?
7. Night pains
Examination
1. General Examination:
a. Pallor, rashes, palpable purpura
b. peeling of the skin, thickening of the skin
c. conjunctivitis, icterus
d. Lymphadenopathy
e. nail pitting, pigmentation
f. psoriasis, oral ulcers, nodules
2. systemic examination:
a. Tachycardia / murmurs
b. Presence of chest infection
c. Hepatosplenomegaly
d. Musculoskeletal system swelling, redness and soft tissue involvement
Investigations (guided by the clinical suspicion)
a. CBC, ESR, CRP

b. Urine analysis, Malta, Widal test if suspected reactive arthritis
c. Coagulation studies
d. Blood culture
e. ASO titre and Throat swab
f. Radiological evaluation, Ultrasound (if effusion and for diagnostic
aspiration in septic arthritis)
g. Echo cardiography
47
Red flags, requiring urgent intervention or referral to a specialist

✓ Fever, malaise, systemic upset (reduced appetite, weight loss,
sweating).
✓ Bone or joint pain with fever.
✓ Refractory or unremitting pain, persistent at night and or waking the
patient from sleep.
N.B
“ When to suspect juvenile idiopathic arthritis and refer to pediatric
rheumatology ”
✓ Morning stiffness.
✓ Duration more than 6 weeks.
✓ Restriction of activities.
✓ Red and painful eyes.
✓ Chronic skin disease such as psoriasis.
✓ Exclusion of other causes of arthritis.
48
Guidelines for management of oligoarticular JIA
Introduction
• According to 2019 ACR juvenile idiopathic arthritis JIA is an umbrella term for
arthritis of unknown causes in children under the age of 16 years.
• Juvenile idiopathic arthritis (JIA) is one of the most common chronic conditions
of childhood. JIA causes joint pain, swelling and stiffness in one or more joints,
and decreased health-related quality of life and risk of permanent joint damage.
• Oligoarthritis JIA refers to JIA presenting with involvement equal to or less than 4
joints without systemic manifestations.
• It may include patients with different categories of JIA (10) who share a limited
number of joints involved in guidance for patients with active uveitis, sacroilitis or
enthesitis.
When to suspect?
• Patient presenting with arthritis in one or up to 4 joints with a duration of more

than 6 weeks after exclusion of other causes of Arthritis
a. Joint swelling
Joint stiffens or limitation of movement
Joint pain, hotness without redness
In known cases of uveitis, sacroiliitis, or enthesitis
Before referral to pediatric rheumatologist Order these investigations:

a. CBC with differential, ESR, CRP
b. Liver enzymes
c. Kidney functions
d. Urine analysis
e. ANA
f. Affected joint ultrasound
49
Classification criteria for oligoarticular JIA

Diagnosis of oligoarticular JIA mainly depends on clinical diagnosis:
• Arthritis affecting from one to four joints.

• Affected joints: large, weight bearing joints such as the knees and the ankles are
typically affected.
• Oligoarthritis JIA child appears to be well despite ambulating with a limp.
• In cases of asymmetric arthritis there is a subsequent leg length discrepancy.
• Muscle atrophy may be present above the affected joint :
✓ Presence of a few small joints in the hand is atypical

✓ Presence of redness in the joint is also atypical
✓ Uveitis is present in 20% or less of those screened by slit lamb
examination, especially with positive ANA.
Treatment
50
References:
1. Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML, et al.
2019 American College of Rheumatology/Arthritis Foundation Guideline for the
treatment of juvenile idiopathic arthritis: therapeutic approaches for non-systemic
polyarthritis, sacroiliitis, and enthesitis. Arthritis Rheumatol 2019;71:846–63.
2. Angeles-Han ST, Ringold S, Beukelman T, Lovell D, Cuello CA, Becker ML, et al.
2019 American College of Rheumatology/Arthritis Foundation Guideline for the
screening, monitoring, and treatment of juvenile idiopathic arthritis–associated uveitis.
Arthritis Rheumatol 2019;71: 864 –77.
3. Karen B. Onel, Daniel B. Horton, Daniel J. Lovell, Susan Shenoi, Carlos A. Cuello,
Sheila T. Angeles-Han, et al. 2021 American College of Rheumatology Guideline for
the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for
Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic
Arthritis, Arthritis & Rheumatology Vol. 0, No. 0, Month 2022, pp 1–17
51
Polyarticular JIA
Introduction
• Polyarticular JIA is defined as arthritis affecting 5 or more joints for the last 6
months with or without positive rheumatoid factor.
• Joint Damage is defined as limited mobility, loss of cartilage thickness, erosion,
loss of joint space that may lead to the need of surgical intervention.
Role of general practitioner
• Suspect the case depending on the previous definition

• Exclude other diseases in the DD of this condition (other causes of arthritis)
including:
a. Malignancy
Infections
Other autoimmune diseases as Juvenile SLE, dermatomyositis.
• Start NSAIDs to relieve pain till finalizing your diagnosis. You can add PPI for
the patient.
• If diagnosis of polyarticular JIA is suggestive, refer to pediatric rheumatologist.
a. CBC with diff, ESR, CRP.

ANA, RF.
Lfts, kidney function tests.
Musculoskeletal U/S on the affected joints better done by an
experienced Healthcare Professional.
52
Treatment of polyarticular JIA

Done by an experienced pediatric rheumatologist by:
1. Monitoring of the patient can be done by Patient & Physician global

assessment, JADAS-27 score, ESR &CRP and Functional ability (CHAQ,
PROMIS).
2. Risk factors assessment before planning the treatment ,these include one or
more of the following:
a. Positive rheumatoid factor

Positive anti–cyclic citrullinated peptide antibodies,
Joint damage
3. Moderate/high disease; score based on the cJADAS-10 >2.5. Low disease
activity Clinical JADAS-10 ≤2.5 and ≥1 active joint.
4. Initial treatment includes DMARDS as initial monotherapy (MTX,
Leflunomide) and/or short course of NSAIDS.
5. If there is incomplete response, shift to the other biological (anti-TNF)
6. Immunizations inactivated vaccines can be given unconditionally, live
activated vaccines are given with special conditions.
7. Nonpharmacologic therapies as Physical therapy; dietary changes; herbal
supplements should be advised.
53
Systemic juvenile idiopathic arthritis
Introduction
• Systemic juvenile idiopathic arthritis (SJIA) is distinct from all other categories of
JIA due to fever, rash, and visceral involvement and is considered by some to be
an autoinflammatory disorder.
• Disease pathogenesis and cytokine involvement in sJIA are different than in other
JIA categories.
• SJIA is suspected in child less than 16 years of age if he starts to experience
arthritis in1 or more joints with, or preceded by, fever of at least 2 weeks’
duration.
• Signs or symptoms must have been documented daily for at least 3 days and
accompanied by 1or more of the following:
b. Evanescent rash.
Generalized lymphadenopathy.
Hepato/splenomegaly and serositis.
Role of general practitioner
1. Suspect the case depending on the previous definition

2. Exclude other diseases in the DD of this condition including:
a. Malignancy as leukemia/lymphoma/neuroblastoma
b. Infections
c. other autoimmune diseases as Juvenile SLE
3. The following investigations may be done guided by clinical presentation and
before referral to paediatric rheumatologist.
a. CBC with diff, ESR, CRP
b. Serum Ferritin
c. ANA, RF
d. peripheral smear.
e. Bone marrow aspirate, pet scan and body imaging are highly
considered to exclude malignancy when there is clinical suspicion.
f. Joint US and doppler to the affected joints may be needed
4. A short course of NSAIDs 1-3 mg/kg/day can be started
5. If diagnosis of sJIA is still possible after exclusion of infection and
malignancy, refer to pediatric rheumatologist.
54
Treatment of systemic JIA

Done by an experienced pediatric rheumatologist through:
1. Monitoring of the patient can by Patient & Physician global assessment,

JADAS-27 score, ESR & CRP and Functional ability (CHAQ, PROMIS).
2. Systemic steroids can’t be a single agent in treatment, it can be used any time
during disease activity with the smallest dose and shortest duration possible to
avoid side effect.
3. Start with IL-1 or IL-6 as initial monotherapy (according to availability) and/or

short course of NSAIDS.
4. If there is residual arthritis, start c DMARD.
5. If there is incomplete response, shift to the other biological (IL-1 or IL-6).
6. If inactivity is achieved, withdraw steroids gradually to stop then taper

biological agent gradually.
55
References:
1. Y. El Miedany, S. Salah, H. Lotfy, M. El Gaafary et al. Updated clinical practice treat-

to-target guidelines for JIA management: the Egyptian College of Pediatric
Rheumatology initiative Egyptian Rheumatology and Rehabilitation volume 49, Article
number: 27 (2022).
2. Ravelli A, Consolaro A, Horneff G et al (2018) Treating juvenile idiopathic arthritis to

target: recommendations of an international task force. Ann Rheum Dis 77:819–828.
3. Ringold S, Angeles-Han ST, Beukelman T, Lovell D, Cuello CA, Becker ML et al

(2019) 2019 American College of Rheumatology/Arthritis Foundation Guideline for the
Treatment of Juvenile Idiopathic Arthritis: therapeutic approaches for non-systemic
polyarthritis, sacroiliitis, and enthesitis. Arthritis Care Res (Hoboken) 71(6):717–734.
56
Guidelines for management of

macrophage activation syndrome (MAS)
in pediatrics
Introduction
• Macrophage activation syndrome (MAS) is a serious, potentially life threatening

hyperinflammatory condition, which can complicate several immunologic and
rheumatic disorders (1).
• Among pediatric rheumatic diseases, MAS is observed most commonly in
patients with systemic juvenile idiopathic arthritis (sJIA), MAS can also be
encountered in juvenile systemic lupus erythematosus, Kawasaki disease, juvenile
dermatomyositis (2) and multi system inflammatory syndrome in children (MIS-
C) (3).
• If untreated, MAS may progress to multi-organ failure and have fatal outcome. So,
early diagnosis and treatment of MAS is critical to improve survival.
When to suspect macrophage activation syndrome?
• A high degree of suspicion is warranted, and it should be considered in any febrile

child with underlying rheumatic disease, although fever may be absent in
patients on biological medications (4).
• Clinically, MAS is characterized by:

1. The acute onset of unremitting high fever.
2. Drop in the three blood cell lines.
3. Hyperferritinemia.
4. Hepatosplenomegaly, lymphadenopathy.
5. Liver dysfunction, clotting abnormalities with Hemorrhagic
manifestations.
6. Central neurological affection.
N.B
“ Pediatric rheumatologist should be consulted upon
suspicion of a case of MAS ”
57
1. CBC with differential.

2. ESR.
3. CRP.
4. Serum ferritin.
5. Liver transaminases.
6. Serum albumin.
7. LDH.
8. Fibrinogen.
9. Triglycerides.
Early diagnostic tools with special considerations
1. Progressive increase in serum ferritin.

2. Relative decrease in platelet count followed by decrease in total leukocytic
count.
3. Relative decrease in fibrinogen level.
Classification criteria of MAS in patient with sJIA according to Pediatric

Rheumatology International Trails Organization (PRINTO) (4)
• A febrile child with known or suspected sJIA is classified as having MAS if the
serum ferritin > 684 ng/mL and ≥ 2 of the following:
• Platelets ≤181×109 /L
• Aspartate aminotransferase (AST) >48 U/L
• Triglycerides >156 mg/dL
• Fibrinogen ≤360 mg/dL
• These classification criteria are used also to classify MAS associated with MIS-C
(4).
• MAS may be the first presentation of juvenile SLE
• Bone marrow aspiration is used for evidence of macrophage hemophagocytosis
in doubtful cases only.
58
Diagnostic guidelines for macrophage activation syndrome as acomplication

of juvenile SLE (5)
• Simultaneous presence of at least 1 clinical criterion and at least 2 laboratory

criteria.
Clinical criteria:
a. Fever (>38°C)
b. Hepatomegaly (≥3 cm below the costal arch)
c. Splenomegaly (≥3 cm below the costal arch)
d. Hemorrhagic manifestations (purpura, easy bruising, or mucosal bleeding)
e. Central nervous system dysfunction (irritability, disorientation, lethargy,
headache, seizures, or coma)
Laboratory criteria:
a. Cytopenia affecting 2 or more cell lineages (white blood Cell count ≤4.0 ×
109/liter, hemoglobin ≤90 gm/liter, or platelet count ≤150 × 109/liter) -
Increased aspartate aminotransferase (>40 units/liter)
b. Increased lactate dehydrogenase (>567 units/liter)
c. Hypofibrinogenemia (fibrinogen ≤1.5 gm/liter)
d. Hypertriglyceridemia (triglycerides >178 mg/dl)
e. Hyperferritinemia (ferritin >500 μg/liter)
Histopathologic criterion:
a. Evidence of macrophage hemophagocytosis in the bone marrow aspirate.
59
Treatment
• The aim of treatment is to control the underlying cytokine activation by using

immunosuppression and controlling the triggering factors.
1. Empirical antibiotics and/or antifungals to cover the probable infectious

trigger.
2. Intravenous immunoglobulin (IVIG), especially in the settings where
underlying infection is a possibility (4).
3. Intravenous methylprednisolone pulse therapy for 3 to 5 days, followed by
oral prednisolone until normalization of haematological abnormalities.
4. dexamethasone palmitate in refractory cases or CNS involvement in MAS.
5. Anti-IL-1 (anakinra) in high dose is recommended in early stage if there is
no response to Intravenous methylprednisolone pulse therapy (6).
6. Rituximab, a monoclonal antibody to CD20, may be considered in EBV
triggered MAS (3).
7. Calcineurin inhibitor cyclosporine should be used with caution in the
acute setting of patients with multiorgan dysfunction due to its neurotoxic
and nephrotoxic side effects
8. Etoposides in refractory cases.
60
References:
1. Alongi A, Naddei R, De Miglio L, Natoli V, Ravelli A. Macrophage activation syndrome in

pediatrics. Pediatr Allergy Immunol. 2020 Feb;31 Suppl 24:13-15.
2. Lerkvaleekul B, Vilaiyuk S. Macrophage activation syndrome: early diagnosis is key.

Open Access Rheumatol. 2018 Aug 31; 10:117-128.
3. Agrawal S, Thapa Karki S, Paudel KP, Shrestha AK, Adhikari BN. A Case Report of
Macrophage Activation Syndrome Complicating Multisystem Inflammatory Syndrome in
Children Associated With COVID-19: A Diagnostic Challenge. Clin Pediatr (Phila). 2022
Feb;61(2):104-106.
4. Bagri NK, Gupta L, Sen ES, Ramanan AV. Macrophage Activation Syndrome in
Children: Diagnosis and Management. Indian Pediatr.2021 Dec 15;58(12):1155-1161.
61
Guidelines for management of

Familial Mediterranean Fever (FMF) in pediatrics
Introduction
• Familial Mediterranean fever (FMF) is the most common monogenic

autoinflammatory disease. It is a mainly diagnosed on clinical basis, supported by
Mediterranean Fever (MEFV) gene mutation analysis (1).
• FMF increases the risk of other inflammatory disorders, such as ankylosing
spondylitis, immunoglobulin A–associated (IgA) vasculitis (formerly Henoch-
Schoenlein purpura), juvenile idiopathic arthritis, polyarteritis nodosa, multiple
sclerosis and Bechet disease.
• The most significant long-term complication of FMF is chronic renal failure
caused by deposition of amyloid protein in the kidneys. Amyloid may also be
deposited in the gastrointestinal tract, liver, spleen, heart, testes and thyroid (2).
When to suspect FMF?
• Patient presents with:
1. History of recurrent attacks of Fever as high as 40° C.

2. Abdominal pain, abdominal distention.
3. Chest pain.
4. Arthralgia or arthritis.
5. Myalgia.
6. Erysipelas-like rash of the lower leg.
7. Scrotal swelling and pain.
8. Rarely pericarditis (3).
• FMF has a broad differential diagnosis, so proper history taking,
documentation of symptoms, accurate clinical examination are required to
exclude other causes with similar presentations.
62
1. CBC with differential count, ESR and CRP (During attack and
attack free period).
2. Liver enzymes.
3. Kidney functions.
4. Urine analysis.
5. Stool analysis.
6. Serum amyloid A.
7. Pelviabdominal ultrasound.
Diagnostic criteria for FMF

Eurofever/PRINTO clinical+ genetic criteria (4)
• Presence of confirmatory MEFV genotype and at least ONE among the following:
1. Duration of episodes 1-3 days

2. Arthritis
3. Chest pain
4. Abdominal pain
OR
• Presence of non-confirmatory MEFV genotype and at least TWO among the

following:
1. Duration of episodes 1-3 days

2. Arthritis
3. Chest pain
4. Abdominal pain
• Clinical classification criteria are used as an indication tool for molecular analysis
or as classification criteria in case genetic testing is not available (5).
63
Eurofever/PRINTO clinical only criteria (> 6 criteria) (4)
• Presence of:
1. Eastern Mediterranean ethnicity
2. Duration of episodes 1 - 3 days
3. Arthritis
4. 4- Chest pain
5. Abdominal pain
• Absence of:
1. Aphthous stomatitis
2. Urticarial rash
3. Maculopapular rash
4. Painful lymph node
Treatment
• The aim of treatment is:
1. To prevent the recurrence of attacks.
2. To normalize inflammatory markers.
3. To minimize subclinical inflammation in attacks-free intervals.
4. To prevent the medium and long-term complications (4).
Colchicine:
a. Should be started as soon as a clinical diagnosis is made.
b. Colchicine is a life-long treatment.
c. Symptoms should be evaluated 3-6 months after initiation of
colchicine treatment.
d. Monitoring of colchicine intolerance and colchicine resistance.
NSAID:
In cases of arthritis and myalgia.
Corticosteroids:
In some colchicine resistant patients.
Anti-IL1 (Anakinra):
Indicated in patients who are unresponsive or intolerant of colchicine
(6).
Tumor necrosis factor (TNF)-inhibitors:
Indicated in colchicine resistant patients, especially with articular
involvement (7).
Treatment of any accompanying inflammatory condition as stated by guidelines.
64
References:
1. Öztürk K, Coşkuner T, Baglan E, Sönmez HE, Yener GO, Çakmak F, Demirkan FG,
Tanatar A, Karadag SG, Ozdel S, Demir F, Çakan M, Aktay Ayaz N, Sözeri B. Real-
Life Data from the Largest Pediatric Familial Mediterranean Fever Cohort. Front
Pediatr. 2022 Jan 20; 9:805919.
2. Balcı-Peynircioğlu B, Kaya-Akça Ü, Arıcı ZS, Avcı E, Akkaya-Ulum ZY, Karadağ Ö,

Kalyoncu U, Bilginer Y, Yılmaz E, Özen S. Comorbidities in familial Mediterranean
fever: analysis of 2000 genetically confirmed patients. Rheumatology (Oxford). 2020
Jun 1;59(6):1372-1380.
3. Heydari S, & NAMDAR H, & BEHZADNIA M. Familial Mediterranean Fever

(FMF): Mysterious Presentations and Challenging Points from Diagnosis to
Management in Acute Care Settings; A Literature Review. INTERNATIONAL
JOURNAL OF TRAVEL MEDICINE AND GLOBAL HEALTH, 7(4), 118- 122.
4. Sag E, Demirel D, Demir S, Atalay E, Akca U, Bilginer Y, Ozen S. Performance of the

new 'Eurofever/PRINTO classification criteria' in FMF patients. Semin Arthritis
Rheum. 2020;50(1):172-175.
5. Maggio M.C, Corsello G. FMF is not always “fever”: from clinical presentation to
“treat to target”. 2020, Ital J Pediatr 46, 7.
6. Ozan S, Bilginer Y, Ayaz N.A, Calguneri M. Anti-Interleukin 1 Treatment for Patients

with Familial Mediterranean Fever Resistant to Colchicine: Table 1. J. Rheumatol.
2010, 38, 516–518. 7- Bilgen S.A, Kilic L, Akdogan A, Kiraz S, Kalyoncu U, Karadag
O, Ertenli I, Dogan I, Calguneri M. Effects of Anti-Tumor Necrosis Factor Agents for
Familial Mediterranean Fever Patients With Chronic Arthritis and/or Sacroiliitis Who
Were Resistant to Colchicine Treatment. JCR: J. Clin. Rheumatol. 2011, 17, 358–362.
65
Guidelines for management of multisystem

inflammatory syndrome of children post-COVID
(MIS-C)
Introduction
•
Multisystem inflammatory syndrome in children (MIS-C) is a newly identified
and serious health condition associated with SARS-CoV-2 infection.
•
Also known as pediatric inflammatory multisystem syndrome temporally
associated with SARS-CoV-2 (PIMS-TS)
•
MIS-C was first described in Europe in April, 2020, and can affect multiple organ
systems.1
MIS-C has different clinical presentations which include:
• Kawasaki like features (conjunctivitis, red or swollen hands and feet,

rash; red cracked lips, lymphadenopathy.
• Gastrointestinal symptoms (abdominal pain, diarrhea, nausea, vomiting,

colitis, hepatitis and questionable appendicitis).
• Toxic shock syndrome-like features with hemodynamic instability and
poor heart function.
• Cytokine storm/ macrophage activation or hyperinflammatory features.
• Thrombosis.
• Acute kidney injury
• Congestive heart failure.
• Pulmonary embolism.
66
When to suspect MIS-C?
• MIS-C should be considered as a differential diagnosis in any child with

persistent fever without a clear clinical source.
• Also, any child presents with fever that is accompanied by multi-system
involvement and history of exposure to a person with recent COVID-19 infection.
The CDC case definition for MIS-C 2

• Age <21 years presenting with fever. AND
• Clinically severe illness requiring hospitalization, with multisystem (≥2) organ
involvement (cardiac, renal, respiratory, hematologic, gastrointestinal,
dermatologic, or neurological). AND
• Laboratory evidence of inflammation. AND
• No alternative possible diagnoses. AND
• Positive for current or recent SARS-CoV-2 (COVID-19) infection by RT-PCR,
serology, or antigen test; or COVID-19 exposure within the 4 weeks prior to the
onset of symptoms.
Initial evaluation:
• History, clinical examination.
• Vital signs.
• Assessment of perfusion.
• Oxygen saturation.
67
Important Notes:
➢ Early consultation and coordination with the nearest pediatric infectious

disease and rheumatologist and pediatric referral center for optimal testing and
management is mandatory.
➢ Patients under investigations of MIS-C, should be admitted to the hospital for
further observation while completing the diagnostic evaluation, especially if
they display the following:
• Abnormal vital signs.

• Respiratory distress of any severity.
• Neurologic deficits or altered mental status.
• Evidence of renal or hepatic injury (including mild injury).
• Markedly elevated inflammatory markers.
• Abnormal ECG, Echo, troponin T or B-type natriuretic peptide
(BNP).
➢ A child under investigations for MIS-C should be also evaluated for other
infectious and noninfectious etiologies that may explain the clinical
presentation.
68
Screening Evaluation
• CBC with differential, CRP, ESR

• ALT, AST
• BUN, creatinine
• Glucose, calcium, Na, k
• Albumin, urine analysis.
• SARS-Cov2-PCR or COVID IgG.
Complete Diagnostic Evaluation

If labs showed:
a. CRP>3 mg/dl or ESR> 40 mm/hour.
b. At least 1 suggestive laboratory feature (ALC<1000/ꭎL, platelets count
<15000/ꭎL, Na<135 mmoles/l, neutrophilia, hypoalbunemia).
1) BNP, troponin T
2) Ferritin, LDH, fibrinogen, triglycerides
3) D dimer, PT, PTT
4) Blood culture
5) Cytokine panel
6) SARA-COVID 19 serology.
7) Cardiac assessment by ECG, Echo.
Important Notes:
➢ If the patient is stable and do not meet criteria for diagnosis of MIS-C,
continue close observation and complete diagnostic evaluation as per
standard of care.
➢ Management of MIS-C is a multi-disciplinary approach involving many
pediatric specialties.
➢ Infection control policies should be followed.
69
Treatment
Management of MIS-C includes:3
A. Treatment of correctable conditions: as hypotension or sepsis by intravenous

fluids, antibiotics, inotropes, if necessary, until bacterial infection has been
ruled out (use sepsis guidelines).
B. IVIG: 2 grams /Kg over 24-36 hours with close observation of hemodynamics
and cardiac functions.
C. Corticosteroids therapy: Dose ranging from 2-30 mg/kg/day depending on
severity of illness.
D. Biologics: Indicated for treatment of MIS-C cases that are refractory to IVIG
and corticosteroids.
1) Anakinra: 4-10 mg/Kg/day subcutaneous.

2) Infliximab: 5-10 mg/kg/day intravenous once (should not be used in
treatment of cases of MIS-C with features of macrophage activation
syndrome).
E. Thromboprophylaxis:
1) Aspirin (3-5 mg/kg/day) should be continued until normalization of platelets

count and confirmed normal coronary arteries 4 weeks after diagnosis
(Aspirin is contraindicated if platelets count< 80000/ꭎL).
2) Consult hematologist for LMWH anticoagulation treatment recommendations.
3) Consult cardiologist and hematologist in cases of MIS-C with features of
Kawasaki disease and coronary arteries affection that needs anticoagulation.
70
References:
1- Abrams JY, Oster ME, Godfred-Cato SE, Bryant B, Datta SD, Campbell AP, Leung JW,
Tsang CA, Pierce TJ, Kennedy JL, Hammett TA, Belay ED. (2021): Factors linked to
severe outcomes in multisystem inflammatory syndrome in children (MIS-C) in the USA:
a retrospective surveillance study. Lancet Child Adolesc Health.;5(5):323-331.
2- Centers for Disease Control and Prevention Health Alert Network (HAN). Multisystem
Inflammatory Syndrome in Children (MIS-C) Associated with Coronavirus Disease 2019
(COVID-19). Available at: https://emergency.cdc.gov/han/2020/han00432.
3- Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, Behrens
EM, Kernan KF, Schulert GS, Seo P, Son MBF, Tremoulet AH, VanderPluym C, Yeung
RSM, Mudano AS, Turner AS, Karp DR, Mehta JJ. (2022): American College of
Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children
Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 3.
Arthritis Rheumatol. 74(4):e1-e20.
71
Guidelines for the management of Sarcoidosis in

pediatrics
Introduction
• Pediatric sarcoidosis is a rare non-necrotizing granulomatous inflammatory

syndrome with multisystemic manifestations, affecting preferentially lungs, lymph
nodes and liver.
• Children are less frequently affected when compared to adults, with a phenotypic
spectrum ranging from a sub-clinical form with only two organs involved to a
severe multi-organic disease.
• Pediatric sarcoidosis remains a "diagnosis of exclusion" that is suggested by
clinical manifestations and needs to be confirmed by the observation of a typical
granuloma at the histologic examination of a biopsied tissue
• Comprehensive investigations for excluding alternative causes of granuloma as
infectious granulomatous conditions (e.g., fungal or mycobacterial tuberculosis),
granulomatous inflammatory disorders (e.g., Crohn’s disease, granulomatosis
with polyangiitis, eosinophilic granulomatosis with polyangiitis, and
lymphomatoid granulomatosis), immune deficiency such as combined
immunodeficiency, tumors as lymphoma, and rarely drug induced
granulomatosis.
• The diagnostic considerations of pediatric sarcoidosis need to be supported with a
compatible clinic-radiographic presentation and the pathologic findings of non-
necrotizing granulomas. There is no reliable diagnostic test for sarcoidosis.
72
When to suspect Sarcoidosis in pediatric age group?
• Pediatric sarcoidosis appears to have two distinct clinical courses depending on

the age of onset. Blau Syndrome and early onset sarcoidosis/BS-EOS in children
under 5 years of age is characterized by a triad of rash, uveitis, and arthritis.
• In contrast, sarcoidosis in older children presents with lymphadenopathy (mainly
hilar), pulmonary involvement, and non-specific signs and symptoms (i.e., fever
and malaise), as in adults.
• Hilar lymphadenopathy, pulmonary infiltration, cutaneous and ophthalmic
manifestation are the most common presentation.
• Pulmonary manifestations as dry hacking cough, with or without mild to
moderate dyspnea, and occasionally chest pain. Bilateral symmetrical hilar
lymphadenopathy with or without parenchymal interstitial involvement is the most
common radiographic finding.
• Peripheral lymphadenopathy and hepatosplenomegaly could be seen.
• Ocular manifestations as uveitis, iritis and conjunctival granuloma.
• Cutaneous manifestations as nodules, hyper or hypopigmented lesions, ulcers,
erythema nodosum and subcutaneous tumors.
• Musculosketetal involvement as peripheral arthritis with boggy tenosynovitis
and painless effusion with good range of motion.
• Renal involvement is rare in children as proteinuria, leucocyturia, hematuria,
concentration defect, hypertension, membranous nephropathy, interstitial
nephritis, and renal failure.
• Moreover, it may involve central nervous system, parotid glands, pancreas and
heart.
73
1. CBC with differential, ESR, CRP

2. Liver function test
3. kidney function test
4. Urine analysis
5. Serum calcium
6. Chest X-ray
7. Abdominal Sonar
8. Opthalmologic examination
74
Treatment
The goal of therapy in sarcoidosis is to prevent or minimize inflammation

and granuloma formation (ie, disease activity) leading to organ system
dysfunction, which may ultimately cause end-stage organ destruction.
• Corticosteroids: are usually the first line treatment for sarcoidosis. (Dose and
duration should be individualized).
• In some cases, corticosteroids can be applied directly to an affected area — via a
cream to a skin lesion or eye drops in cases with uveitis.
• Low-dose Methotrexate has been used to treat a subset of patients with persistent
active or progressive disease that is unresponsive to corticosteroids or those with
joint problems.
• Other immunosuppressive medication as azathioprine, mycophenolate mofetil,
cyclosporin A, and cyclophosphamide can be used according to severity of disease
and response to methotrexate.
• Hydroxychloroquine is helpful for skin lesions and elevated blood-calcium
levels.
• Tumor necrosis factor-alpha (TNF-alpha) inhibitors as infliximab and
adalimumab. They can also be helpful in treating sarcoidosis that hasn't responded
to other treatments.
• Other new biological treatments may be used in refractory cases according to
consensus guidelines
Systemic steroids (oral prednisolone) and methotrexate are cornerstone of

the therapy of sarcoidosis
75
References:
1- Nathan, N., Sileo, C., Calender, A., Pacheco, Y., Rosental, P. A., Cavalin, C., ... &
Silicosis Research Group. (2019). Paediatric sarcoidosis. Paediatric Respiratory
Reviews, 29, 53-59.
2- Chiu, B., Chan, J., Das, S., Alshamma, Z., & Sergi, C. (2019). Pediatric sarcoidosis:
a review with emphasis on early onset and high-risk sarcoidosis and diagnostic
challenges. Diagnostics, 9(4), 160.
3- Lee, S. M., Choi, H., Lim, S., Shin, J., Kang, J. M., & Ahn, J. G. (2022). Pediatric
Sarcoidosis Misdiagnosed as Hepatosplenic Abscesses: A Case Report and
Review. Journal of Rheumatic Diseases, 29(3), 181-186.
4-Gunathilaka, P. K. G., Mukherjee, A., Jat, K. R., Lodha, R., & Kabra, S. K. (2019).
Clinical profile and outcome of pediatric sarcoidosis. Indian Pediatrics, 56(1), 37-40.
5-Shetty, A. K., & Gedalia, A. (2008). Childhood sarcoidosis: a rare but fascinating
disorder. Pediatric Rheumatology, 6(1), 1-10.
76
Pediatric Rheumatology Centers in Egypt:
• Cairo university Pediatric Rheumatology Unit, Specialized Children’s Hospital,

Faculty of Medicine, Cairo University (Abu El reesh hospital)
• Allergy, Immunology and Rheumatology unit, Children's Hospital. Faculty of
Medicine, Ain Shams University.
• Alexandria pediatric rheumatology unit, Alexandria university hospital
• Pediatric Allergy, Immunology and Rheumatology Unit, Children's Hospital,
Faculty of Medicine, Assiut
• Pediatric Rheumatology unit, Children's Hospital, Faculty of Medicine, Minia
University
77
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Child Disability Protocol of EHA

Egyptian Clinical Practice Protocol

1. Prof. Ehab Eid: (Head of committee) Professor of Public Health, Behavioral

Intellectual Property Rights

Supervised & Revised By

➢ General Doctor/ Mourad Alfy Ramzy Tadros

1. Dr. Hala Adel: Pediatric Consultant, Moderator & coordinator of Medical

2. Dr. Huda Karam: Pediatric Specialist, Moderator & coordinator of Medical

Cover Designed & Content Edited By

➢ Mr. Bassam Sayed: Technical Officer at Medical Advisory Council of Egypt

Recently, there is an increasing need to provide programs with accurate

Members of the Working Group

Intellectual Developmental Disorder (IDD)

• Disability is extremely diverse. While some health conditions associated with

• Intellectual Disability (ID) (also known as Intellectual Developmental Disorder

• Intellectual disability is a heterogeneous condition with many different etiologies.

• Deficits in adaptive functioning that result in failure to meet developmental and

• Onset of intellectual and adaptive deficits during the developmental period.

Figure 1: Finnish Approach

Diagnosing Intellectual Disability and its Comorbidities:

• The diagnostic process of ID is similar to any other behavioral and mental

1. Noting chief complaints in chronological order with mode of onset,

II. Physical Examination:

• Detailed physical examination helps to identify the etiology in most cases,

• Examination of major organ systems

III. Behavioral Observation:

Diagnosis of Comorbid Psychiatric Disorder:

• Some mental health, neurodevelopmental, medical and physical

• These neurodevelopmental disorders are specific to the communication

• Intellectual disability is common among individuals with autism spectrum

Overview of Assessments and Evaluation:

Table 2: Physical Investigations in Intellectual Disability

• Treatment needs A Multidisciplinary Team I.e. a collection of different

• Case Manager is any team member with:

• Medications, particularly antipsychotics, may be used to manage challenging

• Some of the conditions which present with ID are nearly completely

Table 3: Summary of Medical Interventions

• Genetic counseling not only provides accurate information on the prognosis of

Management of Comorbid Behavioral and Psychiatric Disorders:

• Nearly 20%–80% of the ID population can have problematic behaviors ranging

• There are few studies on medications in comorbid disorders in ID, namely,

Table 4: Summary of Pharmacological Treatment Options

➢ Functional approach: It is preferable that the tasks taught to the individual

In summary: ID is a developmental disorder that affects general intellectual

Working with Children with Neuro-Disability

• Child Development Centres 0-5 years

• Referrals from GP, nursery, educational psychology

Children with Additional Needs:

Child Development Centers

Autism Spectrum Disorder

Early Warning Signs: First Year:

• People with autism sometimes may have physical symptoms, including

• About a third of people with autism also often have seizures.

Diagnosis of Autism (ASD)

• ASD is diagnosed according to DSM 5 or ICD 11 criteria.

Screening and Diagnostic tools for ASD:

Musculoskeletal Disorders & Examination

1. Hyperkinesia or dyskinesia, characterized by excessive movement.

Bradykinesia (slow movement):