Uptdate Pediatrics

UP TO DATE
IN
PEDIATRICS
1ST EDITION
ZUHAIR M. AL-MUSAWI,CABP,IBCLC
Assistant Professor of Pediatrics
Head of Pediatric Department
College of Medicine , University of Kerbala
Consultant Pediatrician , Kerbala Teaching
Hospital for Children , Kerbala , Iraq
1st edition printed in Kerbala , Iraq 2009
I
The recommendations in Up To Date are of a general nature,
they may not be applicable to a specific patient who has unique
clinical characteristics. The opinions expressed herein are solely
those of the authors and may or may not represent the official
position of the cooperating or endorsing medical societies or
associations.
This book is dedicated to my family, the souls of my uncle Ismail

and my cousin doctor Khalid (victims of violence) and to all Iraqi
doctors who stayed in Iraq in spite of wars, sanction and
violence to draw the smile on the lips of Iraqi children.
Lastly I would like to thank Doctor Waleed Khalid for his help in
preparing this edition.
ZUHAIR AL-MUSAWI
JUNE 2009
II
Contents
Part I Psychological Disorders

NOCTURNAL ENURESIS 1
BREATH HOLDING SPELLS 5
Part II Nutrition
FAILURE TO THRIVE 7
HYPOCALCEMIC RICKETS 20
Part III Neonatology

UNCONJUCATED HYPERBILIRUBINAEMIA 27
NEONATAL ENCEPHALOPATHY 39
RESPIRATORY DISTRESS SYNDROME 44
Part IV Infectious Diseases

IMMUNIZATION 49
FEVER 56
TOXIC SHOCK SYNDROME 70
LISTERIA MONOCYTOGENES 73
PERTUSSIS 76
TYPHOID FEVER 81
BRUCELLOSIS 84
MYCOPLASMA PNEUMONIA INFECTION 87
MEASLES 92
III
LEISHMANIASIS 97
Part V The Digestive System

GASTROESOPHAGEAL REFLUX 101
ACUTE GASTROENTERITIS 106
PERSISTENT DIARRHOEA 117
CELIAC DISEASE 120
NEONATAL CHOLESTASIS 125
FULMINANT HEPATIC FAILURE 129
Part VI Respiratory System

CROUP 134
BRONCHIOLITIS 138
PNEUMONIA 143
ASTHMA 151
HYDROCARBON ASPIRATION 162
SUDDEN INFANT DEATH SYNDROME 165
Part VII The Cardiovascular System

MYOCARDITIS 170
VSD 176
ASD 182
TOF 187
SVT 190
KAWASAKI DISEASE 195
IV
Part VIII Diseases of the Blood
IRON DEFICIENCY ANAEMIA 204
THALASSAEMIA 212
SICKLE CELL DISEASE 227
G6PD DEFICIENCY 235
VON WILLEBRAND DISEASE 240
DIC 255
HEMOPHILIA 266
ITP 275
Part IX Nephrology
NEPHROTIC SYNDROME 279
URINARY TRACT INFECTION 288
HEMOLYTIC UREMIC SYNDROME 297
ACUTE RENAL FAILURE 302
CHRONIC KIDNEY DISEASE 306
Part X The Endocrine System

TYPE 1 DIABETIS MELLITUS 315
DIABETIC KETOACIDOSIS 332
CONGENITAL HYPOTHYROIDISM 345
CONGENITAL ADRENAL HYPERPLASIA 354
Part XI The Nervous System

CEREBRAL PALSY 369
FEBRILE SEIZURE 386
V
ACUTE BACTERIAL MENINGITIS 388
VIRAL MENINGITIS 399
EPILEPTIC SYNDROMES 416
NEONATAL SEIZURES 424
GUILLAIN BARRE SYNDROME 429
Part XII What is new in Pediatrics
VI
Psychologic Disorder
Management of nocturnal enuresis in children

Naiwen D Tu, MD , Augustyn, MD
Urinary incontinence is a common problem in children. At 5 years of age, 15 percent of children

remain incompletely continent of urine. Most of these children have isolated, or
monosymptomatic, nocturnal enuresis.
As a general rule, children younger than 7 years of age may be managed expectantly, including
reassuring parents that monosymptomatic nocturnal enuresis will resolve spontaneously in the
majority of these children.
Treatment may involve one or a combination of the following nonpharmacologic and

pharmacologic modalities:
Motivational therapy.
Bladder training.
Fluid management.
Behavioral alarms.
Pharmacological agents.
Motivational therapy Once the child agrees to accept responsibility, he or she can be
motivated by keeping a record of progress. Successively larger rewards, agreed upon in advance,
are given for longer periods of dryness (e.g., a sticker on a calendar for each dry night, a book for
seven consecutive dry nights).
Motivational therapy leads to significant improvement (decrease in enuretic events by 80

percent) in more than 70 percent of patients. It is estimated to be successful (14 consecutive dry
nights) in 25 percent. The relapse rate (more than two wet nights in two weeks) is
approximately 5 percent.
Bladder training Most children with nocturnal enuresis have a functionally small bladder
capacity. Bladder retention training exercises may be undertaken to increase bladder capacity in
these patients (e.g., those whose usual voided urine volume is less than the bladder capacity
expected for age). Bladder capacity in ounces (one ounce = 30 mL) can be estimated in children
1
by adding 2 to the child's age (in years) until 10 years of age. Bladder training requires a highly
motivated child and is a common component of multimodal therapy programs.
Bladder retention training involves asking the child to hold his or her urine for successively
longer intervals ("as long as possible") after first sensing the urge to void. The volume of voided
urine should be recorded once per week in a follow-up diary to evaluate success. The target
volume is based upon the calculated bladder capacity for age.
Nonetheless, a trial of bladder training exercises is recommended before alarms and

pharmacologic agents are tried, because the latter methods may be more demanding and have
adverse effects
Fluid management Asking the parents to record a fluid intake diary can help to assess the
balance of fluid intake throughout the day. For those patients who are found to consume a
disproportionate amount of fluid in the evening hours, a different schedule can be
recommended. Some authors recommend that their enuretic patients drink 40 percent of their
total daily fluid in the morning (7 AM to 12 PM), 40 percent in the afternoon (12 PM to 5 PM),
and only 20 percent in the evening (after 5 PM); beverages consumed in the evening should be
caffeine-free.
Enuresis alarms Conditioning therapy using an enuresis alarm is the most effective means of
controlling nocturnal enuresis. Enuresis alarms are activated when a sensor, placed in the
undergarments or on a bed pad, detects moisture; the arousal device is usually an auditory
alarm and/or a vibrating belt or pager.
The alarm works through conditioning: the patient learns to wake or inhibit bladder
contraction in response to the neurologic conditions present before wetting. At the initiation of
therapy, the child may occasionally fail to awaken; this can be ameliorated if the parents wake
the child when the alarm sounds.
PHARMACOLOGIC THERAPY Two pharmacological agents have been shown to be effective

in the treatment of nocturnal enuresis: desmopressin acetate (DDAVP) and tricyclic
antidepressants (TCAs). Indomethacin may be beneficial.
Desmopressin The suggestion that many children with nocturnal enuresis have an abnormal
circadian rhythm of vasopressin release led to the introduction of desmopressin acetate
(DDAVP) as a treatment option for nocturnal enuresis. The mechanism of action for DDAVP in
nocturnal enuresis is unclear. Successful DDAVP therapy in a boy with nephrogenic diabetes
insipidus and a mutation in the vasopressin 2 receptor suggests that DDAVP acts on a different
receptor, possibly the vasopressin 1b receptor in the brain.
Desmopressin is administered in the late evening to reduce urine production during sleep. The
drug is given orally (the intranasal formulation is associated with increased risk hyponatremic
seizures and is no longer indicated for the treatment of enuresis). Compared to other modes of
2
therapy, desmopressin is relatively expensive. A normal functional bladder capacity is necessary
for response to desmopressin. Desmopressin should not be used in children with hyponatremia
or a history of hyponatremia.
The dose of oral desmopressin is usually titrated to best effect, increasing the dose every 10
days to the maximum recommended dose; the process usually takes a total of 30 days. The oral
formulation is administered at 0.2 mg initially (one tablet) and may be increased to 0.6 mg
(three tablets) as needed over a two-week trial period.
Adverse effects of desmopressin therapy are uncommon. The most serious adverse effect is
dilutional hyponatremia, which occurs when excess fluids are taken in the evening hours.
In December, 2007, the U.S. Food and Drug Administration (U.S. FDA) issued an alert that the
intranasal formulation of desmopressin is no longer indicated for the treatment of enuresis.
The alert was prompted by review of 61 cases of hyponatremic seizures associated with
desmopressin; two cases resulted in death. Thirty-six of the cases occurred with intranasal
formulations; 25 of these occurred in children with enuresis being the most common indication.
To prevent dilutional hyponatremia with oral desmopressin, it is recommended that fluid

intake be limited to eight ounces (240 mL) on any evening that desmopressin is to be
administered. Fluid intake should be limited from one hour before to eight hours after
administration of desmopressin. Treatment with desmopressin should be interrupted during
episodes of fluid and/or electrolyte imbalance (e.g., fever, recurrent vomiting or diarrhea,
vigorous exercise, or other conditions associated with increased water consumption).
Tricyclic antidepressants The tricyclic antidepressants (e.g., imipramine, amitriptyline, and

desipramine) have been recognized as a useful adjunct in the treatment of enuresis since 1960.
Although imipramine is the drug most often used, other TCAs are also effective. TCAs decrease
the amount of time spent in REM sleep, stimulate vasopressin secretion, and relax the
detrusor muscle.
The dose of imipramine is 0.9 to 1.5 mg/kg per day, administered at bedtime. On average, the
bedtime dose is 25 mg for children 5 to 8 years of age and 50 mg for older children. The dose
should not exceed 50 mg in children between 6 and 12 years of age and 75 mg in children 12
years of age. The therapeutic effect of imipramine is quick if the dose is adequate. Imipramine
should be discontinued if there is no improvement after a three-week trial (at an adequate
dose); it may be discontinued abruptly.
Adverse effects of TCA therapy are relatively uncommon. Approximately 5 percent of children
treated with TCAs develop neurologic symptoms including nervousness, personality change, and
disordered sleep. Imipramine, amitriptyline, and other TCAs are required by the United States
Food and Drug Administration to carry a black box warning regarding the possibility of increased
suicidality, particularly in individuals with preexisting depressive symptoms. The most serious
3
adverse effects of TCAs, however, involve the cardiovascular system, including the risk of cardiac
conduction disturbances and myocardial depression, particularly in cases of overdose
Indomethacin Although rarely used, one small randomized controlled trial found that
indomethacin suppository versus placebo significantly increased the number of dry nights in
children older than six years with primary nocturnal enuresis who were treated for three weeks
(9 versus 4 dry nights). No adverse effects were reported. Possible mechanisms of action
include removal of the normal inhibitory effect of prostaglandins on the response to
vasopressin and improvement in bladder function.
Other drugs Anticholinergic drugs, such as oxybutynin, are not effective in treating
monosymptomatic nocturnal enuresis. However, these agents may be useful in children who
also present with significant daytime urgency. The combination of anticholinergic therapy and
desmopressin may be used in these children in an attempt to increase bladder capacity during
sleep.
Other drugs, including phenmetrazine, amphetamine sulfate, ephedrine, atropine,

furosemide, diclofenac, and chlorprotixine have been tried. A systematic review of randomized
trials of drugs other than TCA and desmopressin in the treatment of nocturnal enuresis found
that although indomethacin and diclofenac were better than placebo, none of the drugs was
better than desmopressin.
4
Breath-holding spells
Thien T Nguyen, MD, PhD- Peter W Kaplan, MB, FRCP- Angus Wilfong, MD
Breath-holding spells are common events in infants and young children from six months to six
years of age. Most children (80 to 90 percent) with these spells have their first episode before
18 months of age. Rarely, cases first present as neonates.
The pathogenesis of these syncopal events is not clear. Some studies support a primary role for
dysfunction of the autonomic nervous system. Iron deficiency is more prevalent in children with
breath-holding spells compared with controls and appears to contribute to the occurrence of
breath-holding spells and the underlying dysautonomia. A family history of breath-holding spells
is present in 20 to 35 percent of patients and an autosomal dominant trait has been reported in
some families.
The two clinical types of breath-holding spells are cyanotic and pallid. Both family members
and individual children can demonstrate both types, but usually one predominates.
Cyanotic breath-holding spells In the cyanotic variety, the child becomes angry or upset in
response to a reprimand or a mild injury. The precipitant is often minimal, even trivial. There is a
brief period of crying, typically followed quickly by breath-holding in forced expiration with
apnea and cyanosis, which is then often followed by limpness and loss of consciousness.
Cyanosis can appear faster than anticipated with simple breath-holding; and the loss of tone
often is striking. The sequence is quite reproducible.
If the apnea is prolonged, there may be other clinical manifestations, including decorticate or
decerebrate posturing. A few children have generalized motor seizures characterized by
increased tone followed by loss of tone or clonic activity and prolonged postictal
unconsciousness. Status epilepticus has been reported.
A significant minority of children (15 to 25 percent) have multiple episodes daily. Most children
have one to six spells per week.
Pallid breath-holding spells Pallid infantile syncope is less common than the cyanotic variety
and is more likely to be mistaken for a seizure. The child typically loses consciousness after a
minor fall or blow to the head or upper body. Often, this history is not volunteered by the
patient or family and must be elicited by direct questioning. The loss of consciousness may be
delayed up to 30 seconds after the minor trauma, obscuring the connection between the two
events. The child then stops breathing and becomes pale, diaphoretic, and limp. If the episode
lasts more than a few seconds, this is followed by generalized increased tone of the trunk and
extremities, often with incontinence and occasionally, low amplitude clonus. The entire episode
5
lasts less than one minute, but the child is confused and/or sleepy for several minutes
afterward.
The event is caused by cardiac bradycardia. Events may be reproduced with 10 seconds of
ocular pressure during electrocardiogram (ECG) monitoring, which produces a typical attack
with a profound bradycardia, even asystole, usually lasting 5 to 10 seconds. Cases have been
described in which the heart beat did not return for 30 seconds. If simultaneous
electroencephalography (EEG) monitoring is performed, hypersynchronous, high amplitude
slowing may be observed, followed by flattening if the episode is prolonged.
Diagnosis There is no diagnostic test that confirms the diagnosis of breath-holding spells.
These may be difficult to distinguish from epileptic seizures. A history of any provocation (e.g.,
head injury, crying) should be elicited, as this is typical for breath-holding spells, but not
epileptic seizure. Prominent color change, pallor or cyanosis, also suggests breath-holding spells
rather than seizures. As with other nonepileptic events, video-EEG monitoring can be helpful in
difficult cases.
Other causes of syncope also should be considered. If the episodes are prolonged or frequent,
precipitated by startle or other nontraumatic stimuli, or if a family history of syncope or sudden
death exists, a more in-depth cardiac evaluation, particularly for prolonged QT syndrome, is
indicated.
Because iron deficiency anemia is highly associated with breath-holding spells, evaluation with
complete blood count and serum ferritin is warranted in these children.
Prognosis and treatment The prognosis for children with breath-holding spells is excellent .
The median age of remission is four years; virtually all children stop having episodes by eight
years. Neurologic development is normal.
Iron supplementation in anemic or iron-deficient patients appears to reduce the frequency of

breath-holding attacks, according to observational studies and one clinical trial. Complete
remission of spells reportedly occurs in 32 to 52 percent. A typical dose is 5 to 6 mg/kg per day
of ferrous sulphate. The duration of treatment should be individualized according to the
improvement of clinical episodes and the anemia.
Antiepileptic drugs are not helpful in reducing the breath-holding spells, but may or may not
prevent secondary anoxic seizures if these are frequent.
Piracetam, a GABA-derivative, was shown in one unblinded, randomized trial to reduce the
frequency of breath-holding spells. This finding has not been confirmed, and this drug is not
available in the United States.
In rare patients with severe attacks of pallid infantile syncope associated with prolonged,
severe bradycardia or asystole, atropine and cardiac pacing have been employed to reduce the
frequency of spells.
6
Nutrition
Etiology and evaluation of failure to thrive (undernutrition) in

children younger than two years
Rebecca T Kirkland, MD, MPH
Failure to thrive (FTT) is a sign that describes a particular problem rather than a diagnosis.
The term FTT is used to describe instances of growth failure or, more specifically, failure to gain
weight appropriately. In more severe cases, linear growth and head circumference also may be
affected. Severe malnutrition can cause persistent short stature, secondary immune
deficiency, and permanent damage to various parts of the brain and central nervous system.
Early identification and expeditious treatment of FTT may help to prevent long-term
developmental deficits
MEASUREMENT OF GROWTH Accurate assessment of the child's weight, length, and head
circumference is essential. In the child younger than 2 years, the recumbent length rather than
the standing height should be obtained. This figure, along with weight and head circumference,
should be plotted on the National Center for Health Statistics (NCHS) growth charts and related
to previous measurements. Corrections for gestational age should be made for weight through
24 months of age, for stature through 40 months of age, and for head circumference through 18
months of age. The NCHS growth charts are sex specific and appropriate for all races and
nationalities. Special growth charts exist for some genetic disorders such as Down syndrome.
PATTERNS OF GROWTH The trajectory of growth in weight, length, and head

circumference and the degree to which individual parameters are affected may provide valuable
clues to the etiology of diminished weight.
Growth trajectory The growth trajectory is assessed by plotting the child's growth
parameters at various ages (with correction for gestational age in infants and children who were
born prematurely) on a growth curve standardized for sex, age, and medical condition (e.g.,
Down syndrome). If possible, the growth trajectory should be plotted from birth. Special
attention should be paid to the timing of changes in the slopes of the weight, length, or head
circumference trajectories.
Normal growth parameters at birth with subsequent deceleration in weight, followed (weeks
to months later) by deceleration in stature (referred to as "stunting"), and finally deceleration in
head circumference is characteristic of inadequate nutritional intake. As stunting develops, the
weight for length may return toward normal.
7
Normal growth parameters at birth with simultaneous deceleration in length and weight
before 2 years of age and normal growth velocity after 2 years of age is suggestive of genetic
short stature or constitutional growth delay. These normal growth patterns are often confused
with FTT.
Deceleration of head circumference before deceleration in weight or length is suggestive of a

neurologic disorder (e.g., neonatal encephalopathy).
Premature and SGA infants have increased risk for subsequent undernutrition, but many
infants with these conditions have catch-up growth and subsequent normal growth velocity.
Proportionality, the degree to which individual growth parameters are affected, is assessed by
determining the median age for the child's weight (weight age), length (length age), and head
circumference (head circumference age).
Evaluation of proportionality can be helpful in determining contributing factors to diminished

weight:
Decreased weight in proportion to length ("wasting") reflects inadequate nutritional intake.
Decreased length in proportion to weight is suggestive of an endocrinologic abnormality.
Decreased length with a proportionate weight may be nutritional (if long-standing), genetic, or
endocrine in origin.
When head circumference is impaired as much as, or more than, weight or length, intrauterine
infection, teratogenic exposures, congenital syndromes, and other causes of microcephaly
should be considered.
Failure to thrive In the broadest terms, FTT refers to infants whose weight is less than the
norms for their gestation corrected age, sex, genetic potential, and medical condition. Thus, it
does not include infants and young children with genetic short stature, constitutional growth
delay, prematurity, or intrauterine growth restriction who have appropriate weight for length
and normal growth velocity
There is no consensus regarding the definition of FTT, nor how long a growth concern should
exist before a child meets criteria for FTT. However, the term may be attributed to a child who,
with observation of growth over time, has any of the following:
Weight below the 3rd or 5th percentile for gestation corrected age and sex on more than one
occasion.
Weight less than 80 percent of ideal weight for age, using the standard growth charts of the
NCHS.
Depressed weight for length (i.e., weight age < length age, weight for length <10th percentile.
8
A rate of weight gain that causes a decrease in two or more major percentile lines (90th, 75th,
50th, 25th, 10th, and 5th) from over time (e.g., from 75th to 25th).
Severity assessment There are several methods to categorize the severity of malnutrition in
children who are underweight.
The Gomez method is based upon the ratio of the child's weight to the median weight for age
and sex (e.g., percentage of the median weight for age).
The Waterlow method is based on the ratio of the child's weight to the median weight for
height (e.g., percentage of the median weight for height) for children with acute undernutrition
and the ratio of the child's height to the median height for age (e.g., percentage of the median
height for age) for children with chronic undernutrition.
The McLaren-Read method is based on the ratio of the child's weight/height-for-age to the
median weight/height-for-age (egg, percentage of the median weight/height-for-age)
Risk factors
Medical risk factors for FTT include prematurity, (particularly when associated with
intrauterine growth restriction), developmental delay, congenital anomalies (e.g., cleft lip
and/or palate), intrauterine exposures (e.g., alcohol, anticonvulsants, infection), lead poisoning,
anemia, and any medical condition that results in inadequate intake, increased metabolic rate,
maldigestion or malabsorption.
Psychosocial risk factors for FTT include poverty, certain health and nutrition beliefs (e.g., fear
of obesity or cardiovascular disease, prolonged exclusive breastfeeding), social isolation, life
9
stresses, poor parenting skills, disordered feeding techniques, substance abuse or other
psychopathology, violence, and abuse.
The most useful classification for causes of FTT is based upon pathophysiology: inadequate
intake or absorption, excess metabolic demand, or defective utilization. Within this framework,
each child can be assessed diagnostically and therapeutically along four parameters: medical,
nutritional, developmental/behavioral, and social.
Causes of FTT also can be loosely grouped according to the age of onset as follows:
Prenatal Intrauterine growth restriction; prematurity; prenatal infection, congenital

syndromes; and teratogenic exposures (eg, anticonvulsants, alcohol). FTT with prenatal onset
may be difficult to overcome, even when adequate nutrition is provided for catch-up growth
postnatally.
Neonatal (<1 month) Poor quality of suck (whether breast- or bottle-fed), incorrect formula
preparation; breastfeeding problems; inadequate number of feedings; poor feeding interactions
(e.g., infant gags or vomits during feedings, mother misreads signals of hunger or satiety);
neglect; metabolic, chromosomal, or anatomic abnormalities.
3 to 6 months Underfeeding (possibly associated with poverty); improper formula

preparation; milk protein intolerance; oral motor dysfunction; celiac disease; cystic fibrosis;
congenital heart disease, gastroesophageal reflux.
7 to 12 months Feeding problems (e.g., autonomy struggles, particularly if the parent is a

stickler for cleanliness or unduly anxious about the infant's intake; oral motor dysfunction that
interferes with adaptation to more textured foods, delayed introduction of solids; intolerance of
new foods); intestinal parasites.
10
>12 months Coercive feeding; highly distractible child; distracting environment; acquired
illness; new psychosocial stressor (divorce, job loss, new sibling, death in the family, etc.).
The evaluation involves a careful, thorough history and physical examination, and the judicious
use of laboratory tests and other investigations. Laboratory investigation is unlikely to reveal
an organic cause in the absence of suggestive evidence from the initial history or physical
examination.
Medical history Important aspects of the history include:
Pre- and perinatal history Low birth weight, intrauterine growth restriction, perinatal stress
and prematurity are important predisposing factors to FTT. Prenatal exposures (e.g.,
anticonvulsants, alcohol) may compromise growth and/or affect parent-child interactions.
Past medical history Chronic diseases of any type (e.g., celiac disease, cystic fibrosis,
giardiasis), may affect nutritional intake, absorption, or energy needs; frequent recurrent
illnesses may indicate immunodeficiency; frequent injuries may indicate inadequate supervision.
Family history should include the height and weight of family members (parents and siblings)
and the history of developmental delay or any illnesses that may contribute to slow growth or
constitutional short stature. Shorter parental height and higher parity have been shown to be
related to slow infant weight gain.
Diet and feeding Detailed information regarding nutritional intake and feeding should be
obtained, including information related to the duration of meal times, the type of food, and the
quantity of food consumed. The dietary history should be interpreted with caution, particularly
if psychosocial problems are suspected, because parental guilt may result in inaccuracies in
reporting.
Specific areas of inquiry include:
Vomiting, diarrhea, and rumination, which may result in deficient energy intake related to
increased losses of nutrient.
Food preferences Avoidance of foods with certain textures suggests an underlying oral
motor dysfunction; otherwise unexplained avoidance of specific foods may indicate food
intolerance or allergy for which the young child cannot verbalize symptoms (e.g., nausea,
abdominal discomfort).
Excessive low-calorie liquid or fruit juice ingestion, which may indicate inappropriate nutrient
intake with losses caused by fructose and sorbitol malabsorption.
Deficient protein or vitamin intake in some vegetarian diets.
Dietary restrictions, related to perceived food allergies or dietary beliefs and practices (e.g.,
fear of cardiovascular disease, vegetarianism).
11
The psychosocial history is critical in the evaluation of children with FTT; FTT can be an
indicator for serious social or psychological problems in the family. Psychosocial stressors are
the predominant cause of insufficient nutritional intake in children of all ages. The material
and emotional resources of the caretaker(s) may not be available for the care of the child for a
variety of reasons (e.g., poverty, parental depression, substance abuse, family discord,
maladaptive parenting style, etc.). In addition to identifying psychosocial stressors, it is
important to identify the family's strengths and access to resources that can be used in
formulating a management plan.
Examination The goals of the physical examination of a child with FTT include identification
of signs of genetic disorders or medical diseases contributing to undernutrition, malnutrition
(e.g., vitamin deficiencies), and child abuse or neglect.
Simple observation During the examination, the clinician can observe the warmth, caring,
and responsiveness of the parent to the child's cues as well as the extent to which the child
looks to the parent for comfort and support.Observation of the child being fed when he or she is
hungry may disclose a variety of factors contributing to insufficient intake. Such observation
may occur in the office, hospital, or by an experienced visiting nurse in the child's home
environment. Another method is to ask the child's primary caretaker to videotape the child
eating a meal; the tape can then be reviewed with the family, with specific advice offered based
upon the behaviors noted on the tape.
Important aspects of the feeding observation include:
Is the child adaptively positioned to eat (e.g., in a high-chair)?
For bottle-fed infants, does the caretaker cuddle the infant or merely "prop" the bottle?
Are the child's cues of hunger and satiety clear?
Does the caretaker respond appropriately?
Is there sufficient time for feeding?
Are there oral motor or swallowing difficulties? (e.g., Does the child have an intolerance for
foods of certain textures? Is feeding prolonged?)
Does the caretaker permit age-appropriate autonomy and messiness?
What is the tone of the feeding interaction for the child? For the caregiver (e.g., pleasant?
relaxed? stressful? hurried?)?
Is the child easily distracted during feeding?
Is the child fed in front of the television?
Is the caretaker irritable, punitive, depressed, disengaged, or intrusive?
12
Is the child apathetic, irritable, noncompliant, or provocative?
Laboratory evaluation for organic disease should be guided by the signs and symptoms found
in the initial evaluation. A careful history and physical examination in the child with FTT may
suggest clues to an organic disease.
Laboratory studies that are not suggested on the basis of the initial history and examination
rarely are helpful. One study revealed that only 1.4 percent of the laboratory studies
performed in evaluating children with FTT were useful diagnostically. Simple routine testing,
including complete blood count, urinalysis, blood urea nitrogen, electrolyte levels, and lead
testing, is appropriate.
In children with severe malnutrition (, additional laboratory evaluation may include albumin,
alkaline phosphatase, calcium, and phosphorous to assess protein status and the presence of
biochemical rickets.
Diagnostic imaging studies should be guided by the signs and symptoms found in the initial
evaluation. Studies that may be helpful in identifying organic problems contributing to FTT
include upper gastrointestinal series with small bowel follow-through, studies of swallowing
function, and radionuclide gastric emptying scans.
Management of failure to thrive (undernutrition) in children

younger than two years
The primary goal of management of FTT is improved nutritional status through provision of
adequate nutritional intake for catch-up growth. Provision of adequate nutritional intake may
require changes to the diet, feeding schedule, or feeding environment; psychosocial stressors
contributing to undernutrition also must be addressed. Another goal is to enhance the nurturing
ability of the caretakers by educating them about appropriate diet and feeding styles. The
caretakers should be involved as much as possible in the formulation of the treatment plan.
The initial management depends upon the severity and chronicity of undernutrition and the
presence of underlying medical disorders
Mild FTT Children with mild FTT without an underlying medical disorder can generally be
managed by the primary care clinician in the outpatient setting, although some of these patients
also benefit from multidisciplinary management. Children with underlying medical conditions
(e.g., small for gestational age infants, prematurity, fetal alcohol syndrome, etc.) are best served
by multidisciplinary management.
Simple interventions may include:
13
The provision of dietary advice by the primary care clinician or a pediatric dietitian, focusing on
ways to increase oral intake (e.g., concentration of infant formula, limit the intake of fruit juice,
etc.).
Suggestions for changes to the feeding environment (eg, minimize distractions and battles over
feeding).
Home-based support (e.g., visiting nurse or other appropriately trained home visitor).
Referral to community, state, or federal assistance programs (e.g., food pantries, food stamps,
Supplemental Nutrition for Women Infants and Children [WIC] in the United States).
Moderate FTT Children with moderate FTT may benefit from the involvement of an
interdisciplinary team. The team may include dietitians, occupational or speech therapists, social
workers, nurses, developmental specialists, child-life workers, psychiatrists, and/or workers
from social and educational services in the community. Social and psychosocial factors (e.g.,
poverty, maternal depression) contributing to undernutrition must be addressed.
Severe FTT Children with severe FTT should be hospitalized for initial management by an
interdisciplinary team. Hospitalization may help to prevent sequelae of further malnutrition and
permits controlled refeeding.
Indications for hospitalization include:
1. Severe malnutrition.
2. Significant dehydration.
3. Serious intercurrent illness or significant medical problems.
4. Psychosocial circumstances that put the child at risk for harm.
5. Failure to respond to several months of outpatient management.
6. Precise documentation of energy intake.
7. Extreme parental impairment or anxiety.
8. Extremely problematic parent-child interaction.
9. Practicality of distance, transportation, or family psychosocial problems preclude
outpatient management.
During hospitalization, daily food consumption should be recorded, energy intake should be
estimated, and weights should be plotted. The approach to feeding should be the same as the
anticipated treatment at home after discharge. The caretakers should be involved as much as
possible in the formulation of the treatment plan. Caretakers of children with growth failure
often feel a sense of failure that may be exacerbated by the success of the hospital staff in
feeding the child and achieving weight gain.
Nutritional therapy is the mainstay of management. The goal of nutritional therapy is to

enable "catch-up" weight gain (i.e., weight gain at a rate that is two to three times greater than
14
average for age) so that the weight deficit is repaired or overcome. The pace and aggressiveness
of nutritional repletion is determined by the degree of malnutrition.
Requirements
Energy and protein All children with FTT require a high-calorie diet for catch-up growth. A
child with FTT will not experience "catch-up" growth unless energy intake is higher than the
Dietary Reference Intake (DRI) for age, which accounts for the basal energy requirement for age
and the energy required for physical activity:
0 to 6 months 108 kcal/kg per day
6 to 12 months 98 kcal/kg per day
1 to 3 years 102 kcal/kg per day
A common regimen for catch-up growth is energy intake that is 50 percent greater than the
DRI (e.g., 150 kcal/kg per day in a 1-year-old child)
Another method to estimate the energy intake for catch-up growth is to multiply the average
DRI for energy for age by the median weight for the child's current length and divide by the
child's actual weight. As an example, in a 15-month-old boy whose weight is 9 kg and length is
78 cm, the median weight for length is 10.4 kg and estimated energy intake for catch-up growth
is 118 kcal/kg per day ((102 kcal/kg per day x 10.2 kg) 9 kg).
A similar method can be used to estimate the protein requirement for catch-up growth, using
2.2 g/kg per day as the basal requirement for protein. Using the same child as in the previous
example, the estimated daily protein intake for catch-up growth is 2.5 g/kg per day ((2.2 g/kg
per day x 10.4 kg) 9 kg).
The target energy intake should be achieved over five to seven days. Malnutrition is often
accompanied by some degree of anorexia. In addition, feedings with increased caloric density
are usually hyperosmolar and may lead to diarrhea and/or malabsorption if advanced too
quickly. More importantly, rapid refeeding may lead to hypokalemia and hypophosphatemia
(i.e., refeeding syndrome or nutritional recovery syndrome).
Vitamins and minerals During the catch-up growth phase, existing stores of vitamins and
minerals may not be sufficient. We recommend a multivitamin preparation that includes iron
and zinc for children who are being treated for FTT.
Increasing intake Strategies to achieve adequate intake of energy and protein vary
depending upon the age and dietary preferences of the child.
The child whose primary reason for undernutrition is nutritional deprivation and who can take
food by mouth should be the guide as to when to increase the intake (i.e., feeding should be
allowed to proceed ad libitum). Food should be offered frequently, but the child should not be
15
forced to eat it; starting with small amounts of food and offering more is preferable to offering
large quantities. The caretaker may need help in recognizing and responding to the child's cues
for hunger and satiety.
For infants
Human milk The caloric density of human milk for term infants can be increased by adding
term formula powder or concentrate. The caloric density of human milk should not be increased
by the addition of carbohydrate (eg, polycose) or fat (eg, medium chain triglyceride) since the
protein concentrate of such a mixture is inadequate for optimum growth.
Infant formula The caloric density of infant formula can be increased by adding less water to
powder or concentrated formula or by adding modular supplements such as glucose polymers
(e.g., polycose) or fat (e.g., medium chain triglycerides, corn oil). Increasing the caloric density of
commercial infant formula through concentration or the addition of glucose polymers and
medium chain triglycerides increases the osmolality of the formula, which can cause diarrhea or
malabsorption. For this reason, formulas usually are not concentrated beyond 24 kcal/oz unless
fluid restriction is a consideration. In this setting, a dietitian should be certain that individual
nutrients are not provided in excessive amounts. Additional increases in the caloric density of
formulas should be made gradually.
For older children For older infants and children, energy intake can be increased by
increasing the caloric density of foods that the child likes to eat (e.g., by adding rice cereal or
formula powder to pureed foods; using high-calorie milk drinks instead of milk; adding cheese,
butter, or sour cream to vegetables). The caretaker may need help in recognizing the child's
food preferences and understanding that during catch-up growth, intake of total energy and
protein is more important than variety.
Feeding schedule The feeding schedule for infants varies depending upon the infant's
nutritional needs and hunger cues; infants are typically fed "on demand". Infants between 0 and
4 months require frequent feedings, typically 8 to 12 per day; older infants typically require four
to six feedings per day.
The older child should eat often (every two to three hours, but not constantly). He or she
should have three meals and three snacks on a consistent schedule; "grazing" on low-nutrient
snack foods throughout the day and constant sipping on low-calorie liquid, fruit juice, or
carbonated drinks should be avoided. Snacks should be timed so that the child's appetite for
meals will not be spoiled (e.g., snack time should not occur within one hour of meal time; snacks
should be avoided immediately after an unfinished meal). At meal and snack time, solid foods
should be offered before liquids.
Feeding environment Changes to the feeding environment may help to ensure adequate
energy intake for catch-up growth. It is helpful to meet with all caretakers to ensure that the
feeding program is consistent.
16
Some general guidelines to optimize the feeding environment include:
The child should be positioned so that the head is up and the child is comfortable.
Children should be allowed to feed themselves.
Meal time distractions should be minimized.
Meal time should be relaxed and social; eating with other family members and pleasant
conversation not related to food should be encouraged.
Meal time should be free of battles over eating; caretakers should encourage, but not force,
the child to eat; food should not be withheld as punishment.
The child should be praised when he or she eats well, but not punished when he or she does
not.
Additional tips for caretakers are provided in the table.
Appetite stimulants, such as cyproheptadine, may be helpful in selected circumstances, but

have no proven long-term benefit.
OTHER INTERVENTIONS
Medical Medical management of children with FTT entails intervention as indicated for
pathologic conditions contributing to undernutrition (eg, referral to allergist for management of
food allergies, to a gastroenterologist for management of gastroesophageal reflux).
In addition, medical consequences of undernutrition should be anticipated and prevented as

much as possible. As an example, children with undernutrition are at increased risk for recurrent
infections; such infections should be treated promptly to prevent prolonged periods of
decreased intake or increased losses associated with intercurrent illness. Immunizations should
be administered according to the standard schedule and updated in children who have fallen
behind.
Psychosocial The primary goal for improved nutrition must be accompanied by addressing
the psychosocial difficulties. Effective treatment, whether inpatient or outpatient, requires
involvement and support of the caretakers.
Psychosocial interventions should be provided to enhance the quality of caretaking and to

address environmental effects on the caretaker's ability to provide adequate nutrition to the
child. Potential psychosocial interventions include:
Home visitation by professional or appropriately trained lay personnel, which may be helpful in
providing guidance, support, and monitoring.
17
Facilitation of access to WIC, food stamps, and Temporary Assistance for Needy Families
(formerly Aid to Families with Dependent Children) in the United States, and similar programs in
other countries.
Provision of additional guidance and support to caretakers (e.g., housing advocacy, job
training, substance abuse treatment, respite care).
RESPONSE TO THERAPY
Adequate response Response to therapy is defined by achievement of catch-up growth (i.e.,

a rate of weight gain that is two to three times the normal rate for age). With adequate
nutritional intake, catch-up growth is generally initiated within two days to two weeks,
depending upon the severity of the initial deficit. Four to nine months of accelerated growth
rates must be maintained to restore a child's weight for height. As the deficits are repleted,
intake and rates of growth spontaneously decelerate toward normal levels. Catch-up growth in
height lags behind that in weight by several months, but will occur if dietary treatment is
continued appropriately.
Nutritional recovery syndrome During refeeding, some children experience the

symptoms of a nutritional recovery syndrome, including sweatiness, increased body
temperature, hepatomegaly (caused by increased glycogen deposition in the liver), widening of
the sutures (the brain growth is greater than the growth of the skull in infants with open
sutures), increased periods of sleep, and fidgetiness or mild hyperactivity. They also may
develop hypophosphatemia and hypokalemia during the first week of refeeding because of
rapid changes in tissue mineral content. Children with severe undernutrition should be
monitored carefully for these complications during the first week of refeeding.
Nasogastric feedings Supplementation of oral feedings with day-time or night-time

nasogastric feedings may be necessary in children with severe malnutrition who fail to achieve
adequate catch-up growth despite four to six weeks of adequate oral intake .
For mild or moderate malnutrition, nasogastric tube feedings may be initiated in the outpatient
setting if adequate parental instructions for refeeding and periodic monitoring can be provided
by home care personnel. For severe, malnutrition, nasogastric tube feedings should be
instituted in the hospital setting where monitoring for the refeeding syndrome can be
performed.
Nasogastric feedings can be discontinued after consistent weight gain has been demonstrated
for four to six months. If weight gain remains inadequate after three to four months of
nasogastric tube feeding, gastrostomy tube placement may be appropriate.
PROGNOSIS The ultimate growth potential of a child with FTT is determined by a number of
factors. These include genetic potential, the timing of malnutrition (e.g., intrauterine versus
18
neonatal versus later infancy), the severity of malnutrition, the presence of underlying medical
problems and whether these problems can be successfully managed.
Although the prognosis with respect to weight gain and growth is good, between 25 and 60
percent of infants with FTT remain small for age (weight or height <20th percentile for age and
sex)
Children with FTT are at risk for cognitive deficits. Cognitive function is below normal in one-
half of children with FTT, and a high frequency of behavior problems and learning difficulties is
found at follow-up. Whether these findings are a direct result of FTT or are the result of
continued adverse social circumstances is not known. However, support that cognitive deficits
are related to adverse social circumstances is provided by two follow-up studies of school-age
children with a history of FTT in infancy. These studies demonstrated that maternal IQ was the
strongest predictor of reading scores and other cognitive abilities.
19
Etiology and treatment of hypocalcemic rickets in children
Frank Rauch, MD
Calcipenic rickets comprises a group of disorders in which intestinal absorption of calcium is

too low to match the calcium demands imposed by bone growth. The primary abnormality may
be dietary deficiency or insufficient intestinal absorption of calcium caused by vitamin D
deficiency or decreased vitamin D activity (e.g., lack of conversion to the active metabolite or
resistance to the active metabolite). Patients with calcipenic rickets have secondary
hyperparathyroidism and characteristic changes of the growth plates and metaphyseal bone.
Calcipenic rickets has several causes, including:
Vitamin D deficiency (the "classical" form of rickets).
Defect of 1-alpha hydroxylase, the enzyme that activates vitamin D.
Dysfunction of the vitamin D receptor .
Dietary calcium deficiency.
Chronic renal failure (the kidney is the main site of 1-alpha hydroxylase activity).
VITAMIN D DEFICIENCY
Etiology The vitamin D status of an infant depends upon the amount of vitamin D
transferred from the mother prenatally and upon the amount of vitamin D ingested or produced
by the skin during exposure to ultraviolet light postnatally. Materno-fetal transfer of vitamin D is
mostly in the form of calcidiol (25-OH vitamin D), which readily crosses the placenta. The half-
life of calcidiol is approximately three to four weeks. Thus, the serum concentration of vitamin D
falls rapidly after birth unless additional sources are available.
The traditional view holds that vitamin D is not essential for normal intrauterine bone
development. However, this view is contradicted by reports of newborns that were born to
vitamin D-deficient mothers and had signs of rickets at birth. Vitamin D-deficiency rickets more
commonly presents between three months and three years of age, when growth rates (and
calcium needs) are high, and exposure to sunlight may be limited.
20
Breast-feeding The main reasons for inadequate vitamin D supply in infants from Western
countries are prolonged breast-feeding without vitamin D supplementation and concomitant
avoidance of sun exposure. The recommended adequate intake of vitamin D to prevent
deficiency in normal infants and young children is 400 IU/day. Human milk typically contains less
than 25 IU of vitamin D per liter unless the mother receives vitamin D supplementation in high
doses (e.g., 2000 IU per day). Dark skin is an additional risk factor for developing rickets in
breast-fed infants because dark-skinned individuals produce less vitamin D in response to
sunlight. The vitamin D concentration of the breastmilk of dark-skinned mothers is less than that
of lighter-skinned individuals. In high-risk populations, most mothers of breast-fed infants with
rickets also are deficient in vitamin D. Thus, all at-risk mothers should be evaluated for vitamin D
deficiency. Although siblings were not evaluated in either study, they should also be considered
at high risk for vitamin D deficiency and be appropriately evaluated.
Other causes of vitamin D deficiency caused by diminished absorption are gastrectomy, celiac
disease, malabsorption, extensive bowel surgery, inflammatory bowel disease, and advanced
cystic fibrosis.
Vitamin D supplementation (400 IU/day) is recommended for each of the following groups:
1. All breast-fed infants; supplementation should start in the first week of life.
2. All nonbreast-fed infants who are ingesting less than 1000 mL of vitamin D fortified
formula or milk per day.
3. Children and adolescents who do not ingest at least 400 IU of vitamin D daily (eg, 1000
mL of vitamin D fortified milk per day), do not get regular sunlight exposure, and do not
take a multivitamin supplement that contains at least 400 IU of vitamin D.
21
Most dietary rickets is prevented by adherence to these guidelines. Infants born to mothers
with severe vitamin D deficiency also may develop rickets even if they are fed adequate
amounts of vitamin D fortified formula and are growing normally. Larger doses (up to 800 IU)
may be necessary for premature infants, dark-skinned infants, and those who live at latitudes
above 40.
Clinical course Vitamin D-deficiency rickets has three stages with increasing severity.
Stage one arises from impaired intestinal calcium absorption, resulting in hypocalcemia.
Hyperaminoaciduria and hyperphosphaturia are absent, and serum inorganic phosphorus is
normal. Hypophosphatemia develops in stages two and three. Serum calcium is normal in stage
two, but low in stage three, when the clinical and radiological findings of rickets are severe. The
hyperaminoaciduria and hyperphosphaturia (due to renal phosphate wasting) that occur in the
later stages provide indirect evidence of severe secondary hyperparathyroidism. Serum
parathyroid hormone concentrations are elevated in all three stages.
Treatment The most widely used treatment for vitamin D deficiency consists of vitamin D2
(ergocalciferol). The following dosing scheme is commonly recommended for treatment of
vitamin D deficient rickets.
1000 IU daily for infants <1 month old.
1000 to 5000 IU daily for infants 1 to 12 months old.
5000 IU daily for children one year and older.
Treatment is continued at the above doses until radiographic evidence of healing is seen; then
the dose of vitamin D is reduced to 400 IU daily thereafter. In our practice, we check
radiographs for evidence of healing after three months of treatment. Other providers repeat the
radiograph earlier.
Calcium intake should be maintained at approximately 1000 mg per day to avoid the so-called
"hungry bone" syndrome (worsening hypocalcemia after the start of vitamin D therapy).
This is usually accomplished by administering supplements of 30 to 75 mg/kg of elemental
calcium per day in three divided doses. This regimen should lead to the resolution of
biochemical and radiological abnormalities within three months. Reappearance of urinary
calcium excretion shows that the body's vitamin D and calcium stores have been refilled. If the
patient has no detectable calciuria after three months of treatment, continuation of the same
treatment regimen for another three months is advisable.
Orthopedic consultation usually is not indicated because skeletal deformities regress

completely after successful medical therapy. However, orthopedic intervention may be
necessary if deformities do not improve once the radiologic appearance of the growth plates
has normalized.
22
An alternative treatment protocol is the so-called "stosstherapy," which consists of a high dose
of oral vitamin D (600,000 IU) given on a single day. This amount of vitamin D approximately
corresponds to a three-month course of 5000 IU per day and should be sufficient to induce
healing within three months. Stosstherapy may be advantageous when compliance with therapy
and/or follow-up is a problem. However, such high doses of vitamin D can lead to
hypercalcemia. Doses of 150,000 or 300,000 IU appear to be equally effective, but with less
risk of hypercalcemia.
Monitoring Serum calcium, phosphorus, alkaline phosphatase, and urinary

calcium/creatinine ratio should be measured four weeks after the start of therapy in children
who are being treated for vitamin D deficiency. These tests should be repeated after three
months of therapy, at which point radiographs should be obtained to document the healing of
rachitic lesions.
If the radiographs do not show evidence of healing, the possibility of poor adherence to
treatment, malabsorption, or of other forms of rickets should be considered.
PSEUDOVITAMIN D DEFICIENCY Pseudovitamin D-deficient rickets (PDDR) also is called 1-

alpha hydroxylase deficiency and vitamin D-dependent rickets type I (because the clinical and
biochemical evidence of rickets can be corrected with high daily doses of vitamin D). It was
identified first as a unique form of "vitamin D resistant rickets" in 1961.
Compared to X-linked vitamin D-resistant rickets, the skeletal manifestations of pseudovitamin

D deficiency occur earlier (within the first year of life), the hypocalcemia often is severe (with
tetany), hypophosphatemia is moderate, and enamel hypoplasia occurs.
Etiology PDDR, an autosomal recessive disorder, is caused by defective conversion of

calcidiol to calcitriol (1,25-OH2 vitamin D). The characteristic biochemical findings of PDDR are
normal serum levels of calcidiol and low values of calcitriol.
The gene encoding the enzyme that is responsible for the conversion of calcidiol to calcitriol
(25-hydroxyvitamin D 1-alpha-hydroxylase or simply 1-alpha hydroxylase) has been mapped to
chromosome 12q14.
Treatment The treatment of choice for PDDR is replacement therapy with calcitriol. The
dose depends upon the severity of disease and the child's body weight. The initial dose for the
treatment of florid rickets is 1 mcg/day if the child's weight is less than 10 kg and 2 mcg/day in
heavier children. Treatment is continued at this dose until the bone is healed. Thereafter, the
maintenance dose varies between 0.25 and 1 mcg/day.
23
The aim of therapy is to maintain serum levels of calcium, phosphorus, and alkaline
phosphatase within normal limits.
Monitoring Close supervision is needed during the initial phase of treatment and includes a
physical examination and biochemical evaluation every two to three weeks. The biochemical
evaluation should include measurement of serum calcium, phosphorus, alkaline phosphatase,
and parathyroid hormone. Radiographs should show clear improvement after four weeks of
therapy and should be repeated after three months, when the growth plates should have
regained a normal appearance. During administration of maintenance therapy, patients may be
evaluated at three-month intervals. Hand radiographs are performed once per year to check for
the reappearance of rachitic changes.
Possible side effects of calcitriol therapy include hypercalciuria, hypercalcemia,

nephrocalcinosis, and intraocular calcifications. Therefore, checking the urinary
calcium/creatinine ratio and kidney function (e.g., serum creatinine) at each visit is important.
Renal ultrasound and ophthalmologic consultation (slit lamp examination) should be
performed once per year.
VITAMIN D RESISTANCE What had been called type 2 vitamin D-dependent rickets actually
is a form of vitamin D resistance and is known now as hereditary vitamin D-resistant rickets
(HVDRR). It is a very rare form of rickets, with fewer than 50 known affected kindreds. The
clinical spectrum varies widely, probably reflecting the type of mutation within the vitamin D
receptor and the amount of residual vitamin D receptor activity. Affected children usually
appear normal at birth but develop rickets within the first two years of life. A peculiar feature of
the syndrome is alopecia, which appears in approximately two-thirds of cases and is a marker of
disease severity. Alopecia results from the lack of vitamin D receptor action within
keratinocytes.
24
Etiology Hereditary resistance to vitamin D is an autosomal recessive disorder. It is
associated with end organ resistance to calcitriol usually caused by mutations in the gene
encoding the vitamin D receptor; the defect in the receptor interferes with binding of the
hormone-receptor complex to DNA, thereby preventing calcitriol action. In one case, however,
vitamin D-receptor binding was normal, but nuclear localization of the receptor was defective.
Treatment The treatment of hereditary resistance to vitamin D involves a therapeutic trial

of calcitriol and calcium supplementation. The individual response is difficult to predict because
the severity of the receptor defect varies among patients. Therapy may start at daily doses of 2
mcg of calcitriol and 1000 mg of calcium. However, administration of extremely high doses of
calcitriol (up to 30 to 60 mcg/day) and calcium (up to 3 g per day) may be necessary to restore
normocalcemia and to mineralize depleted bones.
Long-term infusion of calcium into a central vein is a possible alternative for severely resistant
patients. This infusion usually must be maintained for many months. Oral calcium therapy may
be sufficient once radiographic healing has been observed.
Monitoring Patients undergoing therapy should be evaluated initially at least once per
week. Serum calcium, phosphorus, alkaline phosphatase, creatinine, 1,25-OH2 vitamin D,
parathyroid hormone, and the urinary calcium/creatinine ratio should be measured.
25
If the biochemical parameters do not respond, the dose of calcitriol should be increased
gradually to reach serum concentrations of up to 100 times the normal mean. Failure of therapy
should be considered if no biochemical response occurs after three to five months of treatment.
CALCIUM DEFICIENCY
Etiology Nutritional rickets remains prevalent in many parts of the world and often is
associated with other conditions. In Ethiopia, for example, rickets affects a large proportion of
children who present with severe infectious diseases.
Because ample sunlight exists in most of the countries where the incidence of rickets is high,
researchers have suggested that insufficient calcium intake rather than primary vitamin D
deficiency is the main causative factor. In fact, studies in South Africa and Nigeria suggest that a
dietary deficiency of calcium may cause rickets and osteomalacia. Most of the children in these
studies had normal serum 25-OH vitamin D concentrations and high serum 1,25-OH2 vitamin D
concentrations, indicating adequate intake of vitamin D. Subsequent studies suggest that many
of these children have increased demand for vitamin D when measured by their response to
vitamin D replacement. Thus, vitamin D requirements may be higher than expected in children
who are calcium deficient.
A randomized, double-blind, controlled trial of 123 Nigerian children with rickets showed that
baseline intake of calcium was very low (about 200 mg per day). These children responded
better to treatment with calcium alone or in combination with vitamin D than to treatment with
vitamin D alone. These children responded better to treatment with calcium (in relatively small
doses) than to treatment with vitamin D, correcting the elevated levels of 1,25(OH)2D and
healing the rickets. However, other factors in addition to calcium intake must play a role
because control children without rickets had similarly low calcium intake. Although most of the
studies on calcium deficiency rickets were performed in Africa, similar dietary deficiencies occur
in North America.
Treatment As shown by the study of Nigerian children described above, a daily intake of
1000 mg of calcium and maintenance of vitamin D at recommended daily value (400 IU/day)
should be sufficient to treat calcium-deficiency rickets.
26
Neonatology
Clinical manifestations of unconjugated hyperbilirubinemia in

term and late preterm infants
Ronald J Wong, BA - Vinod K Bhutani, MD, FAAP
Hyperbilirubinemia in infants 35 weeks gestation is defined as a TSB >95th percentile for

hours-of-age on the Bhutani nomogram. Severe hyperbilirubinemia with a TSB >25 to 30 mg/dL
(428 to 513 micromol/L) is associated with an increased risk for bilirubin-induced neurologic
dysfunction (BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to
brain tissue. The term "acute bilirubin encephalopathy" (ABE) is used to describe the acute
manifestations of BIND. The term "kernicterus" is used to describe the chronic and permanent
sequelae of BIND.
RISK FACTORS
Major risk factors for severe hyperbilirubinemia
1. Pre-discharge TSB or transcutaneous bilirubin (TcB) in a high-risk zone defined as >95th

percentile for age .
2. Jaundice within the first 24 hours of life.
3. Hemolytic disease due to isoimmune-mediated hemolysis from blood group
incompatibility or inherited red cell enzymatic deficiencies or membrane defects (eg,
glucose-6-phosphate dehydrogenase [G6PD] deficiency). Gestational age 35 to 36
weeks.
4. Previous sibling who received phototherapy.
5. Cephalohematoma or significant bruising from birth trauma.
6. Exclusive breastfeeding, particularly if nursing is not going well and weight loss is
excessive (>12 percent of birth weight) .
7. East Asian race.
Minor risk factors included:
1. TSB in a high intermediate range (>75th and 95th percentile for age-in-hours).
2. Jaundice observed before discharge.
3. Macrosomic infant of a diabetic mother.
4. Polycythemia.
5. Male gender.
6. Maternal age 25 years.
27
Factors associated with decreased risk of severe hyperbilirubinemia include:
1. Gestational age 41 weeks.
2. Exclusive bottle-feeding.
3. Neonatal discharge from the hospital after 72 hours.
4. African-American ethnicity, although there appears to be a sub-group of African-American

males with G6PD deficiency who remain at risk.
CLINICAL MANIFESTATIONS The clinical manifestations of hyperbilirubinemia are due to

bilirubin deposition in the skin (jaundice) and/or the brain (bilirubin-induced neurologic
dysfunction [BIND].
28
Jaundice Jaundice is the yellow color produced by the deposition of bilirubin in the skin and
subcutaneous tissues. The examination for jaundice should be performed with adequate
ambient light or under daylight fluorescent light. Pressing on the skin with a finger reduces local
skin perfusion and facilitates detection of jaundice.
Jaundice usually progresses in a cephalocaudal direction, appearing first in the face and sclerae
at bilirubin levels of 4 to 8 mg/dL (68 to 137 micromol/L). The entire body, including palms and
soles, can appear jaundiced at TSB >15 mg/dL (257 micromol/L).
Neurologic manifestations Bilirubin is a potential neurotoxin. Term and late preterm infants
are at risk for bilirubin neurotoxicity when TSB concentrations exceed 25 mg/dL (513
micromol/L). In general, at this threshold, unconjugated bilirubin, which is not bound to albumin
(also referred to as "free" or unbound bilirubin), can enter the brain and cause cell death by
apoptosis (programmed cell death) and/or necrosis.
Acute bilirubin encephopathy may be reversible or result in permanent irreversible

neurologic dysfunction (kernicterus). The brain regions most often affected include the basal
ganglia and the brain stem nuclei for oculomotor and auditory function, accounting for the
clinical features seen in infants with BIND.
Acute bilirubin encephalopathy Acute bilirubin encephalopathy or ABE typically progresses

through three phases:
In the early phase, the clinical signs may be subtle. The infant is sleepy but arousable, and when
aroused has mild to moderate hypotonia and a high-pitched cry.
If there is no intervention, the intermediate phase evolves with progression and persistence of
hyperbilirubinemia. The infant can be febrile, lethargic with a poor suck, or irritable and jittery
with a strong suck. The cry can be shrill and the infant is difficult to console. Mild to moderate
hypertonia develops, beginning with backward arching of the neck (retrocollis) and trunk
(opisthotonos) with stimulation. An emergent exchange transfusion at this stage might
prevent permanent BIND.
The advanced phase is characterized by apnea, inability to feed, fever, seizures, and a
semicomatose state that progresses to coma. Hypertonicity presents as persistent retrocollis
and opisthotonos with bicycling or twitching of the hands and feet. The cry is inconsolable, or
may be weak or absent. Death is due to respiratory failure or intractable seizures.
Infants who are at increased risk for ABE include those who were born <37 weeks gestation,
breastfed, have hemolytic disease, and are discharged home before 48 hours.
29
Kernicterus Kernicterus (the chronic and permanent sequelae of BIND) develops during the
first year after birth. Cognitive function usually is relatively spared. The major features of
kernicterus include:
Choreoathetoid cerebral palsy (chorea, ballismus, tremor and dystonia).
Sensorineural hearing loss commonly manifesting as auditory neuropathy .
Gaze abnormalities, especially limitation of upward gaze.
Dental enamel dysplasia.
Most infants who develop kernicterus have manifested some or all of the findings associated
with ABE. However, there are reported cases of infants who developed kernicterus with high
TSB, but without or with only few signs of ABE.
Therapeutic interventions for infants with hyperbilirubinemia include:
Phototherapy.
Exchange transfusion.
Improving the frequency and efficacy of breastfeeding or supplementing inadequate

breastfeeding with formula.
PHOTOTHERAPY Phototherapy is the most commonly used intervention to treat and

prevent severe hyperbilirubinemia.
Phototherapy reduces the risk that total serum bilirubin (TSB) concentration will reach the level
at which exchange transfusion is recommended. It decreases or blunts the rise of TSB in almost
all cases of hyperbilirubinemia regardless of the patient's ethnicity or the etiology of
hyperbilirubinemia.
Mechanisms Phototherapy exposes the infant's skin to light of a specific wavelength, which
reduces TSB by the following three mechanisms:
Structural isomerization to lumirubin Phototherapy converts bilirubin into lumirubin via

structural isomerization that is not reversible. Lumirubin, a more soluble substance than
bilirubin, is excreted without conjugation into bile and urine. This is the principal mechanism by
which phototherapy reduces TSB concentration.
Photo-isomerization to a less toxic bilirubin isomer Phototherapy converts the stable

4Z,15Z bilirubin isomer to the 4Z,15E isomer, which is more polar and less toxic than the 4Z,15Z
form. Like lumirubin, 4Z,15E isomer is excreted into bile without conjugation.
30
Photo-oxidation to polar molecules Photo-oxidation reactions convert bilirubin to colorless,
polar compounds that are excreted primarily in the urine. This is a slow process and accounts for
a small proportion of bilirubin elimination.
In conventional phototherapy, the irradiance dosing is typically 6 to 12 microW/cm(2) of body

surface area exposed per nm of wavelength (425 to 475 nm) and with intensive phototherapy it
is 30 microW/cm(2)/nm.
For TSB levels 20 mg/dL (342 micromol/L), phototherapy should be administered

continuously, until the TSB falls below 20 mg/dL (342 micromol/L). Once this occurs,
phototherapy can be interrupted for feeding and parental visits.
During phototherapy, the area covered by the diaper should be minimized. The eyes should be
shielded with an opaque blindfold and care should be taken to prevent the blindfold from
covering the nose. With fluorescent lights, the infant should be placed in an open crib, bassinet,
or on a warmer, rather than in an incubator (the top of the incubator prevents the light from
being brought sufficiently close to the infant). Lining the sides of the bassinet or warmer with
aluminum foil or white material increases the exposed surface area of the infant and the
efficiency of phototherapy. The use of reflective white curtains around the phototherapy light
source has also been shown to increase phototherapy efficiency.
Bilirubin absorbs light most strongly in the blue region of the spectrum near 460 nm. Several
light sources, utilizing different wavelengths of light and varying degrees of irradiance, and
devices are available for phototherapy.
Fluorescent blue light Fluorescent special blue light, F20 T12/BB and TL52 tubes, Philips,
should be used. They are the most effective light source in lowering TSB because they deliver
light in the blue-green spectrum, which penetrates the skin well and is absorbed maximally.
Fluorescent special blue light should not be confused with regular blue light or light emitting
diode (LED).
Halogen white light Halogen white lamps are hot and can cause thermal injury. They should
be placed at the distance from the patient recommended by the manufacturer.
Fiberoptic blankets or pads Fiberoptic blankets or pads generate little heat and can be
placed close to the infant, providing higher irradiance than do fluorescent lights. However,
blankets are small and rarely cover sufficient surface area to be effective when used alone in
term infants. They can be used as an adjunct to overhead fluorescent or halogen lights.
Fiberoptic blankets also can be used during feedings when overhead fluorescent or halogen
lights are discontinued. This is particularly helpful for infants with severe hyperbilirubinemia.
Light emitting diode device Light emitting diode (LED) device uses high-intensity blue
gallium nitride and is commercially available as both overhead and underneath devices. These
devices, which deliver high intensity narrow band light in the absorption spectrum of bilirubin,
31
are as effective as conventional fluorescent blue light. The mattress LED device is preferable to
the fiberoptic pad because it is large enough to cover the entire surface (in contact with the
mattress) of a term infant.
Intensive phototherapy For intensive (aggressive) phototherapy, high levels of irradiance

(usually 30 microW/cm(2) per nm) are delivered to as much of the infant's surface area as
possible. The necessary irradiance can be achieved with a bank of special blue fluorescent lights
placed at a distance of 10 to 12 cm from the infant's body and a fiberoptic pad, LED mattress, or
special blue lights below the infant. LED lights at the distance dictated by the device also provide
an irradiance of 30 microW/cm2/nm.
Home phototherapy As an alternative to readmission to the hospital, phototherapy can be

administered to term infants at home. Home phototherapy is less disruptive to the family and
can be considered for otherwise healthy term infants (>38 weeks gestation) without hemolysis
or other risk factors who have TSB levels 2 to 3 mg/dL (35 to 50 micromol/L) below the
recommended threshold level for initiation of hospital phototherapy, are feeding well, and can
be closely followed .
Guidelines for phototherapy are as follows:
For infants at low risk ( 38 weeks gestation and without risk factors), phototherapy is started at
the following TSB values.
24 hours of age: >12 mg/dL (205 micromol/L)
Infants in this category who have TSB levels 2 to 3 mg/dL (35 to 51 micromol/L) below the
recommended levels may be treated with fiberoptic or conventional phototherapy at home.
For infants at medium risk ( 38 weeks gestation with risk factors or 35 to 37 6/7 weeks
gestation without risk factors), phototherapy is started at the following TSB values.
The threshold for intervention may be lowered for infants closer to 35 weeks and raised for
those closer to 37 6/7 weeks.
For infants at high risk (35 to 37 6/7 weeks gestation with risk factors), phototherapy is
initiated at the following TSB values.
32
72 hours of age: >13.5 mg/dL (231 micromol/L)
Efficacy of phototherapy Although there are no data showing that phototherapy improves
neurodevelopmental outcome, phototherapy does reduce the likelihood that TSB reaches a
level associated with an increased risk of kernicterus or at which exchange transfusion is
recommended .
Intensive phototherapy results in a decline of TSB of at least 2 to 3 mg/dL (34 to 51

micromol/L) within four to six hours. A decrease in TSB can be measured as soon as two hours
after initiation of treatment. In infants 35 weeks gestation, 24 hours of intensive phototherapy
can result in a 30 to 40 percent decrease in the initial TSB. With conventional phototherapy, a
decline of 6 to 20 percent can be expected in the first 18 to 24 hours.
The rate of decline of TSB during phototherapy is affected by a number of factors.
1. Increased irradiance increases the rate of TSB decline.
2. Greater surface area exposure to phototherapy increases the rate of TSB reduction.
3. The higher the initial TSB, the more rapid is the rate of decline (as much as 10 mg/dL [171
micromol/L] within a few hours).
4. However, phototherapy is less effective in infants whose hyperbilirubinemia is due to

cholestasis or hemolysis than in infants with other causes.
Monitoring During phototherapy, the dose of phototherapy (irradiance) and the infant's
temperature, hydration status, time of exposure, and TSB are monitored. Phototherapy may
increase both the body and environmental temperature resulting in increased insensible fluid
loss. LED-based devices emit low levels of heat, and thus fluid loss is less of a concern with these
devices.
The TSB measurement should be repeated two to three hours after initiation of phototherapy
to assess the response. When phototherapy is started for a rising TSB, which should be always at
a lower initial TSB values, TSB should be measured after 4 to 6 hours and then within 8 to 12
hours, if TSB continues to fall.
If, despite intensive phototherapy, the TSB is at or approaches the threshold for exchange
transfusion, blood should be sent for immediate type and crossmatch. In addition, if exchange
transfusion is being considered, the serum albumin level should be measured so that the serum
bilirubin/albumin (B/A) ratio can be used in conjunction with the TSB level and other factors to
determine the need for exchange transfusion.
33
Hydration It is important to maintain adequate hydration and urine output during
phototherapy since urinary excretion of lumirubin is the principle mechanism by which
phototherapy reduces TSB. Thus, during phototherapy, infants should continue oral feedings by
breast or bottle. For TSB levels that approach the exchange transfusion level, phototherapy
should be continuous until the TSB has declined to about 20 mg/dL (342 micromol/L). Thereafter
phototherapy can be interrupted for feeding.
Intravenous hydration may be necessary to correct hypovolemia in infants with significant

volume depletion whose oral intake is inadequate; otherwise, intravenous fluid is not
recommended.
Breastfeeding Breastfed infants whose intake is inadequate, with excessive weight loss (>12
percent of birth weight), or who have evidence of hypovolemia, should receive
supplementation with expressed breast milk or formula. The temporary interruption of
breastfeeding with the substitution of cow's milk-based or soy formula may enhance the
efficacy of phototherapy by decreasing the enterohepatic circulation of bilirubin .
Discontinuation For infants who have been readmitted for phototherapy, we discontinue
the phototherapy when the TSB has reached 14 mg/dL (239 micromol/L). For those who
required phototherapy during the birth hospitalization, phototherapy is started at a significantly
lower level and, therefore, is stopped at a lower level. For these infants, we generally
discontinue phototherapy when the TSB has fallen to, or below, the level at which phototherapy
was initiated because, by this time, the infant is significantly older and the level for initiation of
phototherapy has, consequently, increased.
TSB is measured 18 to 24 hours after phototherapy is terminated. This is important in infants

who need phototherapy during their birth hospitalization but might not be necessary in those
who have been readmitted where the risk of rebound is much lower. The readmitted infant
should not be kept in the hospital pending measurement of rebound. If necessary, this can be
done as an outpatient.
Adverse effects Phototherapy is considered safe. Side effects include transient

erythematous rashes, loose stools, and hyperthermia. Increased insensible water loss may lead
to dehydration.
The "bronze baby syndrome" is an uncommon complication of phototherapy that occurs in

some infants with cholestatic jaundice. It is manifested by a dark, grayish-brown discoloration of
the skin, serum, and urine. The bronze color is thought to result from impaired biliary excretion
of bile pigment photoproducts (eg, copper porphyrins) due to cholestasis. The condition
gradually resolves without sequelae within several weeks after discontinuation of phototherapy.
Although the effect of phototherapy on the eyes of infants is not known, animal studies
indicate that retinal degeneration may occur after 24 hours of continuous exposure. As a result,
34
it is essential that the eyes of all neonates treated with phototherapy are sufficiently covered to
eliminate any potential eye exposure.
EXCHANGE TRANSFUSION Exchange transfusion is used to remove bilirubin from the

circulation when intensive phototherapy fails or in infants with signs of bilirubin-induced
neurologic dysfunction (BIND). Exchange transfusion is especially useful for infants with
increased bilirubin production resulting from isoimmune hemolysis because circulating
antibodies and sensitized red blood cells also are removed.
Procedure The infant's circulating blood volume is approximately 80 to 90 mL/kg. A double-

volume exchange transfusion (160 to 180 mL/kg) replaces approximately 85 percent of the
infant's circulating red blood cells with appropriately cross-matched reconstituted (from packed
red blood cells and fresh frozen plasma) blood.
The procedure involves placement of at least a central catheter and removing and replacing
blood in aliquots that are approximately 10 percent or less of the infant's blood volume.
Exchange transfusion usually reduces TSB by approximately 50 percent. Infusion of albumin (1
g/kg) one to two hours before the procedure shifts more extravascular bilirubin into the
circulation, allowing removal of more bilirubin, although this has not been shown to decrease
the need for repeat exchange transfusion.
Exchange transfusions are indicated in the following settings:
1. Jaundiced infants with signs of ABE, such as significant lethargy, hypotonia, poor sucking, or
high-pitched cry, irrespective of the TSB level.
2. Infants with a TSB greater than threshold values established by the AAP.
3. In infants who have not yet been discharged from the birth hospital, exchange transfusion is
recommended if the TSB reaches the threshold level despite intensive phototherapy.
4. Infants who have been discharged from the nursery to home and have TSB concentrations
that are approaching or exceed threshold values for exchange transfusion are initially treated
with intensive phototherapy. If TSB remains above the threshold TSB after about six hours of
intensive phototherapy, then exchange transfusion is indicated. This approach reduces the
number of infants requiring an invasive therapy that has significant morbidity and mortality.
For infants at low risk ( 38 weeks gestation and without risk factors), exchange transfusion is
indicated for the following TSB values.
35
Any age greater than 72 hours: 25 mg/dL (428 micromol/L)
For infants at medium risk ( 38 weeks gestation with risk factors or 35 to 37 6/7 weeks
gestation without risk factors), exchange transfusion is indicated for the following TSB values.
For infants at high risk (35 to 37 6/7 weeks gestation with risk factors), exchange transfusion is
indicated for the following TSB values.
Special circumstances In infants with isoimmune hemolytic disease and rising TSB despite
intensive phototherapy, administration of intravenous immunoglobulin (IVIG) is recommended
since it may avoid the need for exchange transfusion.
Exchange transfusion should be considered in infants receiving phototherapy who develop the
"bronze baby" syndrome, if phototherapy has been ineffective in reducing TSB below the
threshold range for intensive phototherapy.
Bilirubin/albumin ratio The bilirubin/albumin (B/A) ratio can be used as an additional factor
in determining the need for exchange transfusion; it should not be used alone but in conjunction
with TSB values.
For infants 38 weeks gestation, consider exchange transfusion when TSB (mg/dL)/albumin
(g/dL) ratio is >8.0 or TSB (micromol/L)/albumin (micromol/L) is >0.94.
For infants 35 to 37 6/7 weeks and well or 38 weeks with high risk (e.g., isoimmune
hemolytic disease or G6PD deficiency), consider exchange transfusion when TSB
(mg/dL)/albumin (g/dL) ratio is >7.2 or TSB (micromol/L)/albumin (micromol/L) is >0.84.
For infants 35 to 37 6/7 weeks with high risk (eg, isoimmune hemolytic disease or G6PD
deficiency), consider exchange transfusion when TSB (mg/dL)/albumin (g/dL) ratio is >6.8 or TSB
(micromol/L)/albumin (micromol/L) is >0.80.
Efficacy After a successful procedure, TSB typically falls to approximately one-half of the
pre-exchange value, then increases to approximately two-thirds of that of the pre-exchange
concentration because there is re-equilibration between extravascular and vascular bilirubin.
36
Observational studies report that exchange transfusions decreased the risk for prominent
neurologic abnormalities in term infants with TSB >20 mg/dL (342 micromol/L) and improved
abnormal brainstem auditory evoked response (BAERs) in infants with severe
hyperbilirubinemia .
Risks The risks of exchange transfusion result from the use of blood products and from the
procedure itself. Complications include:
1. Blood-borne infection.
2. Thrombocytopenia and coagulopathy.
3. Graft-versus-host disease.
4. Necrotizing enterocolitis.
5. Portal vein thrombosis.
6. Electrolyte abnormalities (eg, hypocalcemia and hyperkalemia) .
7. Cardiac arrhythmias.
PHARMACOLOGIC AGENTS Pharmacologic agents including intravenous immunoglobulin

(IVIG), phenobarbital, ursodeoxycholic acid, and metalloporphyrins can be used to inhibit
hemolysis, increase conjugation and excretion of bilirubin, increase bile flow, or inhibit the
formation of bilirubin, respectively. However, currently only IVIG is used to treat unconjugated
hyperbilirubinemia.
Intravenous immunoglobulin IVIG can reduce the need for exchange transfusion in infants
with hemolytic disease caused by Rh or ABO incompatibility.
IVIG is recommended in infants with isoimmune hemolytic disease if the TSB is rising despite
intensive phototherapy or is within 2 or 3 mg/dL (34 to 51 micromol/L) of the threshold for
exchange transfusion. The dose may be repeated in 12 hours if necessary.
The mechanism is uncertain, but IVIG is thought to inhibit hemolysis by blocking antibody
receptors on red blood cells.
Phenobarbital Phenobarbital increases the conjugation and excretion of bilirubin and

decreases postnatal TSB levels when given to pregnant women or infants. However, prenatal
administration of phenobarbital may adversely affect cognitive development and reproduction.
As a result, phenobarbital is not routinely used to treat indirect neonatal hyperbilirubinemia.
Ursodeoxycholic acid Ursodeoxycholic acid increases bile flow and helps to lower TSB levels.
It is also useful in the treatment of cholestatic jaundice.
37
Metalloporphyrins Synthetic metalloporphyrins, such as tin mesoporphyrin (SnMP), reduce
bilirubin production by competitive inhibition of heme oxygenase. There are limited data upon
the safety of SnMP, and SnMP is not available for general use.
38
Clinical features, diagnosis, and treatment of neonatal
encephalopathy
Yvonne Wu, MD, MPH
INTRODUCTION Neonatal encephalopathy is a heterogeneous syndrome characterized by

symptoms of central nervous system dysfunction in newborns born at or near-term ( 36 weeks
gestation). An infant with neonatal encephalopathy may exhibit abnormal level of
consciousness, seizures, tone and reflex abnormalities, apnea, and feeding difficulties.
Neonatal encephalopathy can result from a wide variety of conditions and often remains
unexplained. Birth asphyxia and hypoxic-ischemic encephalopathy are responsible for some, but
not all cases of neonatal encephalopathy. Given that the underlying nature of brain injury
causing neurologic impairment in a newborn is often poorly understood, "neonatal
encephalopathy" has emerged as the preferred terminology to describe central nervous system
dysfunction in the newborn period, as it does not imply a specific underlying pathophysiology.
CLINICAL MANIFESTATIONS AND NEONATAL ASSESSMENT The neonate who is

encephalopathic may have an abnormal state of consciousness (e.g., hyperalert, irritable,
lethargic, obtunded), respiratory or feeding difficulties, poor tone or seizure activity. In the
delivery room, the infant will often exhibit low Apgar scores and a weak or absent cry.
The diagnosis of neonatal encephalopathy necessitates a search for potential etiologies. A

gross and histologic examination of the placenta and cord may provide evidence of a possible
cause, such as a placental vascular lesion or infection, or a cord thrombosis. A thorough
maternal and family history is recommended, including a history of thromboembolic disorders,
prior pregnancy loss, maternal infection, and maternal drug use. Samples are drawn to
determine arterial cord pH and base deficit. The presence of oliguria, cardiomyopathy, or
abnormal liver function tests may suggest a global hypoxic-ischemic event. Metabolic
derangements, unusual odors, dysmorphic features, and congenital anomalies may suggest the
presence of an inborn error of metabolism or genetic disorder.
Cranial sonography Cranial sonography has the advantage of being noninvasive and
available at the infant's bedside. Cranial sonography has a high sensitivity and specificity (91
and 81 percent, respectively) for locating hemorrhages and defining ventricular size. It may also
detect severe parasagittal white matter damage and obvious cystic lesions, but it does not
adequately image the outer limits of the cerebral cortex, nor is cranial sonography a sensitive
tool for identifying milder white matter abnormalities that can be appreciated on head MRI.
Cranial sonography can be used to detect severe cerebral edema. Findings include increased
echogenicity that causes sulci and fissures to be obscured, blurring of other anatomical
landmarks, decreased arterial pulsations, and compression of the ventricles.
39
Head CT This is the most useful imaging modality for diagnosing intracranial hemorrhage
and brain calcifications. Cerebral edema, denoted by decreased attenuation of white matter
and difficulty distinguishing gray from white matter, may also be appreciated on head CT, along
with cerebral atrophy, ventricular size, and severe white matter lesions. However, the white
matter in a term newborn brain contains high water content, and therefore milder degrees of
edema and white matter injury can be difficult to appreciate on head CT. Abnormalities of the
posterior fossa are also often obscured by bony artifact.
Head MRI A number of studies have described the increasing role that MR imaging plays in
the diagnosis of neonatal encephalopathy. A head MRI is the most sensitive imaging tool for
detecting periventricular white matter injury, deep gray matter lesions, arterial infarction,
hemorrhage, developmental brain malformations, and other underlying causes of neonatal
encephalopathy. Deep gray matter lesions involving the bilateral basal ganglia and thalami are
particularly common findings on brain MRI in encephalopathic term infants with a recognized
preceding sentinel hypoxic-ischemic event such as placental abruption, uterine rupture, and
cord prolapse.
The American Academy of Neurology (AAN) practice parameter suggests that a head CT be
performed in cases of neonatal encephalopathy to rule out hemorrhagic lesions. However, a
head MRI is recommended in order to establish a pattern of injury and to predict neurologic
outcome if the findings on head CT are inconclusive.
In addition to conventional MRI, MR spectroscopy and diffusion-weighted imaging (DWI)

techniques can provide useful information regarding timing and outcome of brain injury
resulting in neonatal encephalopathy.
Electroencephalography An electroencephalogram (EEG) can help to distinguish neonatal

seizures from other phenomena, and can also identify subclinical seizures. Although the EEG is
not helpful for determining the cause of neonatal encephalopathy, it can provide evidence for
the presence and severity of encephalopathy, as well as provide prognostic information.
Amplitude integrated EEG, a continuous single channel recording of background cerebral

electrical activity, is easy to use and interpret at the bedside, and has been used to distinguish
mild from severe neonatal encephalopathy in large clinical trials.
DIAGNOSIS OF NEONATAL ASPHYXIA It is unclear how often birth asphyxia is responsible

for neonatal encephalopathy, as there is no gold standard for determining the presence of
hypoxic-ischemic encephalopathy. It is well known that the various clinical signs of birth
asphyxia including Apgar scores, low cord pH, neonatal seizures and encephalopathy are
nonspecific, and may occur in the absence of global hypoxic-ischemic brain injury or long-term
neurologic sequelae.
ACOG criteria Although its true incidence is unclear, birth asphyxia is a well-known and
important contributor to neonatal encephalopathy. In order to identify cases of perinatal brain
40
injury due to birth asphyxia, the American College of Obstetricians and Gynecologists (ACOG)
developed a consensus statement regarding the criteria needed to define an intrapartum
event that is severe enough to cause cerebral palsy. The following four criteria are required:
1. Profound metabolic acidosis (pH less than 7.00 and base deficit 12 mmol/L) on an umbilical
cord arterial blood sample.
2. Early onset of severe or moderate neonatal encephalopathy in infants born at 34 or more

weeks of gestation .
3. Cerebral palsy of the spastic quadriplegic or dyskinetic type.
4. Exclusion of other identifiable etiologies such as trauma, coagulation disorders, infectious

conditions, or genetic disorders.
Additional criteria suggesting an intrapartum timing, but nonspecific to asphyxia, include a

sentinel hypoxic event during labor, severe electronic fetal monitoring abnormalities, Apgar
score of 0 to 3 beyond five minutes, onset of multisystem involvement within 72 hours of birth,
and early imaging study showing evidence of acute nonfocal cerebral abnormality.
Although definitions vary, the degree of neonatal encephalopathy has been defined by some as
follows:
Mild: hyperalert, hyperexcitable, normal muscle tone, no seizures.
Moderate: hypotonia, decreased movements, and often seizures.
Severe: stuporous, flaccid, and absent primitive reflexes, usually with seizures.
Using these definitions, term infants with mild neonatal encephalopathy in the neonatal period
have a very high probability of being completely normal at follow-up. Infants with moderate
encephalopathy have a 20 to 35 percent risk of later sequelae from the insult, although those
whose neurologic examinations are completely normal within one week have a good likelihood
of normal outcome. Infants with severe encephalopathy have a 75 percent risk of dying in the
neonatal period, and among survivors, an almost universal risk of sequelae exists.
Neuroimaging predictors Neuroimaging findings can be helpful for predicting long-term

outcome following neonatal encephalopathy. Abnormal signal in the posterior limb of the
internal capsule appreciated on a head MRI obtained in the first two weeks of life has been
shown to predict adverse neurologic outcome. In term infants with neonatal encephalopathy,
lesions affecting bilateral basal ganglia and thalami that are detected by MRI in the first weeks
of life have been associated with poor neurologic outcomes and death.
41
EEG predictors Findings on electroencephalogram (EEG) can also be used to help
prognosticate. An EEG that shows severe background abnormalities including burst suppression,
isoelectricity or extremely low voltage portends a high likelihood of death or significant long-
term neurologic sequelae. Since severe MRI abnormalities are usually associated with marked
EEG abnormalities and poor outcome, the EEG may be especially helpful as a prognostic tool in
the setting of moderate MRI abnormalities.
Although severe abnormalities seen on EEG within the first 24 hours of life can be a useful
predictor of outcome, a follow-up EEG showing recovery of normal electrical activity may be
associated with a much improved outcome, indicating the importance of serial EEG
examinations.
TREATMENT The management of moderate and severe encephalopathy should take place in
a neonatal intensive care unit. The main goal in the treatment of an infant with neonatal
encephalopathy is supportive :
1. Maintain adequate ventilation.
2. Maintain sufficient brain and organ perfusion.
3. Maintain normal metabolic status (egg, glucose, fluids, nutritional status, pH).
4. Control seizures.
Other aspects of treatment include general supportive measures to ensure adequate

nutritional and ventilatory support, and maintaining blood pressure and normoglycemia.
Therapeutic hypothermia Available evidence suggests that treatment with hypothermia

improves outcome after neonatal asphyxia and/or neonatal encephalopathy. This conclusion is
supported by a 2007 meta-analysis that evaluated randomized trials of therapeutic hypothermia
to treat neonatal encephalopathy.
Aside from treatment with hypothermia, suggested management of HIE includes the
following recommendations:
Evaluate with an electroencephalogram (EEG) to gather information regarding diagnosis,

treatment and prognosis of neonatal encephalopathy. Serial EEGs may be helpful in further
defining the prognosis. The amplitude integrated EEG may be helpful for predicting outcome
and identifying seizure activity in infants with neonatal encephalopathy.
Obtain a head imaging study, preferably with MRI. Cranial sonography is not as sensitive as
head MRI or CT. Specific findings on head MRI can be useful for establishing the pathogenesis
and prognosis of neonatal encephalopathy.
Treat seizures with phenobarbital, lorazepam or fosphenytoin. The optimal therapeutic agent,
as well as the duration of treatment, has not been adequately evaluated.
42
Perform a lumbar puncture to assess for intracranial bleeding or infection, especially since
meningitis can mimic the signs and symptoms of neonatal encephalopathy. Antibiotics are
started until infection is ruled out, and acyclovir is initiated if herpes simplex virus is suspected.
Use high frequency ventilation, nitric oxide, or extracorporeal membrane oxygenation

therapies, as available, for infants with persistent fetal circulation syndrome to maintain
oxygenation.
Replace volume and use inotropic agents as required to maintain blood pressure and adequate
cerebral perfusion. However, systemic hypertension and volume overload, which can worsen
cerebral edema, should be avoided.
Arterial blood gases and serum calcium, magnesium, glucose, and electrolytes should be
assessed early in the course and as needed. Liver enzymes and serum creatinine are measured
to determine injury to other end organs.
Early treatment may be crucial to outcome if a metabolic disorder is suspected. Feeds should
be stopped, acidosis and hypoglycemia corrected, and specific treatment such as vitamin
supplementation or hemodialysis considered after consultation with a geneticist. Specific testing
for ammonia, lactate and pyruvate, serum amino acids and urine organic acids are also required
to rule out a metabolic cause of neonatal encephalopathy.
43
Treatment and complications of respiratory distress syndrome in
preterm infants
Stephen E Welty, MD
Respiratory distress syndrome (RDS), also known as hyaline membrane disease, is the major
cause of neonatal respiratory distress, especially in preterm infants. The lungs of preterm infants
lack adequate pulmonary surfactant, one of the constituents of the air-liquid interface that lines
the alveolar surfaces and terminal airways. RDS is a result of surfactant deficiency, which
increases the surface tension in the air-liquid interface of the terminal respiratory units.
Surfactant deficiency leads to atelectasis, increases ventilation perfusion mismatch, and leads to
lung injury, which is mediated by a marked pulmonary inflammatory response.
As RDS is due to lung immaturity, the best intervention would be to prevent premature birth.
However, if premature birth cannot be avoided, RDS may be prevented with the use of
antenatal steroid therapy and the prophylactic (early) administration of exogenous surfactant.
Despite the initiation of preventive care, RDS may still develop and is associated with both
acute and chronic complications. Once the diagnosis of RDS has been established, management
is directed toward specific measures to replace surfactant and ensure adequate oxygenation
and ventilation, as well as general supportive measures.
SURFACTANT THERAPY Prior to the introduction of exogenous surfactant, RDS was

associated with significant morbidity and mortality.
Types of surfactant A wide variety of surfactant preparations, which include natural and
synthetic products, have been developed. At the present time, only natural surfactant
preparations are available.
Indications
Rescue therapy As recommended by the American Academy of Pediatrics and European

consensus guidelines, rescue surfactant should be given when the diagnosis of RDS is
established. The diagnosis is based upon the infant's oxygen requirement, clinical examination,
and chest radiograph.
In infants older than 30 weeks, the diagnosis of RDS is established when the arterial to alveolar
oxygen ratio is less than 0.22 to 0.3. This corresponds to an arterial PaO2 value of less than 80
mm Hg with oxygen administration of greater than 40 percent. These older infants typically have
not received prophylactic or early surfactant as they have a lower risk of developing the
disorder. Numerous trials have shown benefits of rescue surfactant therapy in this group of
neonates.
44
Post-prophylactic or early therapy In infants less than 30 weeks gestation, the standard of
therapy is to provide prophylactic or early surfactant. Additional doses of surfactant therapy is
administered if the patient has an oxygen requirement >30 percent.Subsequent surfactant
administration decreases mortality and morbidity in infants less than 30 weeks gestation with
RDS
Continued therapy After the initial dose of surfactant given for treatment of RDS, the
patient's response is assessed based upon their continued oxygen requirements. If there is
clinical evidence of persistent disease, we continue surfactant therapy. Based upon clinical
practice, we define persistent RDS as a continual or recurrent oxygen requirement of greater
than 30 percent, independent of age.
MECHANICAL VENTILATION AND CPAP Surfactant deficiency results in impaired lung

expansion (atelectasis) due to decreased surface tension in the air liquid interface at the
terminal respiratory units that results in RDS. As the disease progresses, it may lead to
respiratory failure secondary to inequalities in ventilation perfusion matching and to increases in
intra- and extra-pulmonary shunting.
In patients with RDS, intubation and mechanical ventilation with positive end-expiratory
pressure (PEEP) has been used to correct atelectasis and facilitate the repeated administration
of exogenous surfactant. In addition, other supportive measures aimed at improving hypoxemia
(i.e., arterial oxygenation) include increasing the concentration of supplemental oxygen and
increasing the mean airway pressure.
Continuous positive airway pressure (CPAP) Among premature infants without respiratory
failure, continuous positive airway pressure (CPAP) is an alternative to mechanical ventilation to
prevent atelectasis because mechanical ventilation is associated with an increased risk of BPD.
Evidence clearly supports the role of CPAP in larger infants (birth weight 1500 g). However,
data are more limited upon the benefit CPAP in very low birth weight infants (birth weight
<1500 g).
Larger preterm infants In larger babies with RDS, CPAP is the preferred modality based upon
a meta-analysis that reported a lower mortality and morbidity rate in infants with birth weights
greater than 1500 g who were placed on CPAP compared to those initially supported with
mechanical ventilation.
Very low birthweight infants The potential benefit of CPAP compared to intubation and
mechanical ventilation is less clear in infants born before 30 weeks gestation or with
birthweights below 1500 g with RDS.
Our approach Based upon the above observations, our current recommendation is that
after intubation and administration of surfactant, preterm infants with RDS, regardless of
birth weight, can be extubated and stabilized on CPAP if the infant is active, exhibits
45
spontaneous respiratory effort, and is not in respiratory failure. In larger preterm infants,
CPAP is the initial therapy for respiratory symptoms.
Nasal intermittent positive pressure ventilation (NIPPV) augments nasal CPAP by delivering
ventilator breaths via the nasal prongs. NIPPV compared to nasal CPAP has been shown to
reduce extubation failure in infants who required intubation and ventilation.
Mechanical ventilation The best mode of ventilation remains unclear in patients in whom
mechanical ventilation is necessary because of respiratory failure. Mechanical ventilation
modalities include pressure control ventilation, patient triggered ventilation, volume control,
and high frequency positive pressure ventilation.
Summary At the present time, there are no studies that suggest that any one mode of
conventional ventilation is better than another regarding long-term outcomes. Different modes
may be beneficial in select clinical settings and is dependent upon the knowledge and
experience of the clinician caring for the patient.
No matter which mode of ventilation is selected, it is crucial to minimize the time on

mechanical ventilation and optimize management to facilitate weaning from ventilator support.
Criteria for mechanical ventilation Assisted ventilation should be initiated when respiratory
failure occurs. Respiratory failure is verified by one of the following:
1. Respiratory acidosis, documented by an arterial pH <7.20 and a PaCO2 >60 mm Hg.

2. Hypoxia, documented by an arterial PaO2 <60 mm Hg despite oxygen supplementation
of 70 percent on nasal CPAP.
3. Severe apnea.
These are general guidelines for respiratory failure and the measurements need to be taken
into the context of other assessments of the patient's cardiopulmonary function. If the patient
meets the general criteria for respiratory failure in neonates, we initiate mechanical ventilation
using these initial settings:
Rate of 60 breaths per minute.
Inspiratory time of 0.2 seconds.
End expiratory pressure of 5.
Peak inspiratory pressure that adequately expands the chest wall that is titrated to the lowest
level that will ensure adequate ventilation.
INHALED NITRIC OXIDE It is well established that inhaled nitric oxide (iNO) provides benefit
in the treatment of term or near-term infants with persistent pulmonary hypertension. In
addition, animal studies demonstrated that iNO reduced lung inflammation, improved
surfactant function, attenuated hyperoxic lung injury, and promoted lung growth.
46
Postnatal corticosteroid therapy, when given to premature infants in the first day of life,
improves pulmonary and circulatory function and decreases the incidence of BPD.
Unfortunately, short-term complications, such as intestinal perforation, and metabolic
instability; and more importantly, long-term abnormal neurodevelopmental outcomes in
treated infants have led to strict restriction in the use of postnatal corticosteroid therapy. The
Committee on the Fetus and Newborn of the American Academy of Pediatrics does not
recommend postnatal steroid administration, unless the infant is doing poorly on maximal
supportive care.
SUPPORTIVE CARE Additional supportive care for the preterm infants is needed to optimize
the previously discussed specific measures for treating RDS.
Thermoregulation Infants should be maintained in a thermal neutral environment to limit

energy expenditure to maintain core body temperature. Proper thermoregulation reduces
oxygen consumption and caloric needs.
Rectal temperatures should not be obtained in infants with RDS because of the greater risk
of trauma or perforation associated with their use. As a result, abdominal temperatures should
be used to set the servo-controlling temperatures in incubators and in radiant warmers. The
ambient temperature should be selected to maintain an anterior abdominal skin temperature of
36.9C in small premature infants (less than 1000 grams) and 36.5C in larger infants, which
correlates to a rectal temperature of 37C.
Fluid status must be carefully monitored as excessive fluid increases the risk of patent ductus
arteriosus, necrotizing enterocolitis (NEC), pulmonary edema, and death. Excessive fluid may
also increase the risk of BPD.
Fluid balance is complex as immature kidneys have limited concentrating abilities and
insensible losses vary with gestational age, use of radiant heaters and phototherapy, and the
water content of inspired air. Fluids should be adjusted to maintain neutral or slightly negative
water balance, and positive water balance should be avoided. In addition, as shown in a
systematic analysis, there is no evidence to support the routine use of diuretics in preterm
infants with RDS.
Cardiovascular management Systemic hypotension and failure of closure of the patent

ductus arteriosus increase the risk of developing NEC and BPD.
Systemic hypotension occurs commonly in the early stages of RDS. In patients with moderate
to severe RDS, continuous arterial pressure is monitored through the umbilical artery catheter.
Hypotension is treated with vasopressor support and cautious use of crystalloid solutions for
intravascular expansion. In patients with persistent hypotension unresponsive to vasopressor
and volume therapy, assessing serum cortisol levels should be considered and treatment with
stress doses of hydrocortisone may be necessary.
47
Patent ductus arteriosus (PDA) is common in preterm infants with RDS. It may contribute to
difficulties in weaning from mechanical ventilation and predispose the patient to BPD.
COMPLICATIONS Therapy with exogenous surfactant and antenatal corticosteroids have
lowered the mortality and morbidity associated with RDS. Nevertheless, complications and
deaths still persist. Complications are most often due to the therapeutic interventions, including
placement of arterial catheters, supplemental oxygen, positive pressure ventilation, and the use
of endotracheal tubes.
Endotracheal tube complications Displacement or misplacement of the endotracheal tubes

occurs commonly. Endotracheal tube placement into a main stem bronchus leads to
hyperinflation of the ventilated lung and atelectasis of the contralateral lung. The hyperinflation
may contribute to air leaks and the air-block syndrome.
Other complications from intubation include subglottic stenosis and atelectasis postextubation.
Esophageal and pharyngeal perforations rarely occur and may be confined to the mediastinum
or extend into the pleural cavity.
Pulmonary air leaks, also known as air block syndrome, is the most common acute
complication of RDS. Air leaks are due to the rupture of an overdistended alveolus usually from
positive pressure due to mechanical ventilation. The air from the ruptured alveoli dissects along
the perivascular connective tissue sheath. This dissection can move toward the hilum, resulting
in a pneumomediastinum, or into the pleural space, producing a pneumothorax. Less
commonly, air may dissect into the pericardial space, subcutaneous tissue, or peritoneal space,
causing pneumopericardium, subcutaneous emphysema, and pneumoperitoneum, respectively.
Bronchopulmonary dysplasia (BPD), also referred to as chronic lung disease of the neonate
(CLD), is the main chronic complication of RDS. Despite improvements in the management of
RDS, the incidence of BPD is still substantial.
The etiology of BPD is multifactorial. Inflammation, caused by volutrauma, barotrauma, oxygen

toxicity, or infection, plays an important role in its development.
The lung appears to be most vulnerable before the alveolar stage of development (which
occurs at approximately 31 to 34 weeks gestation), when alveolar formation is initiated. This is
due to the premature lung's structural and functional immaturity, including poorly developed
airway support structures, surfactant deficiency, decreased compliance, underdeveloped
antioxidant mechanisms, and inadequate fluid clearance.
48
Infectious Diseases
Standard childhood immunizations
Jan E Drutz, MD
Prevention of disease is essential for both patient health and control of medical costs. With
rapid advances in virology, immunology, cell biology, and genetics, newer and more effective
vaccines have been licensed and produced.
STANDARD CHILDHOOD IMMUNIZATIONS Immunization against hepatitis A and B,

diphtheria, tetanus, pertussis, Hib, polio, rotavirus, measles, mumps, rubella, varicella-zoster
virus (VZV), pneumococcus, influenza, meningococcus, and human papillomavirus is considered
the standard for the United States .
The use of combination vaccines (eg, hepatitis B/Hib [Comvax], hepatitis A and B [Twinrix],
diphtheria, tetanus, acellular pertussis (DTaP)/hepatitis B/inactivated poliovirus (IPV)
*Pediarix+, DTaP/Hib/IPV *Pentacel+, and DTaP/IPV *Kinrix +) can help to reduce the number
of inoculations at each visit and improve vaccination coverage.
Administration of injectable vaccines Injectable vaccines should be administered using

aseptic technique. It is not necessary to change needles between drawing a vaccine into a
syringe and injecting it. A different needle and syringe should be used for each injection.The
injection site should be as free as possible from risk of local neural, vascular, or tissue injury. The
anterolateral aspect of the thigh is the preferred site for injection in infants younger than 12
months. Either the anterolateral aspect of the thigh or deltoid area of the upper arm may be
used for children older than 12 months; the anterolateral thigh is preferred for children
younger than two years. The deltoid area of the upper arm is the preferred site for adolescents
and young adults.
When multiple vaccines are required at a single visit, separate sites should be used if possible.
However, if necessary, two or more vaccines can be given in the same limb (usually the
anterolateral thigh). The injections should be separated by at least one inch (if possible) to avoid
overlap of local reactions.
The needles used for intramuscular injections should be long enough to reach the muscle
mass, thereby decreasing the risk of local reaction. However, they should not be so long as to
involve underlying nerves, blood vessels, or bone. Penetration into the bone can cause pain,
damage to the periosteum, and detachment of the needle from the syringe). For subcutaneous
injections a 23- or 25-gauge needle 5/8 to 3/4 inch (16 to 19 mm) long is recommended.
Vaccine specific reportable events include:
49
Tetanus Brachial neuritis within 28 days.
Pertussis Encephalopathy or encephalitis within seven days.
Measles, mumps, and or rubella Encephalopathy or encephalitis within 15 days.
Rubella Chronic arthritis within six weeks.
Measles Thrombocytopenic purpura within 7 to 30 days; vaccine-strain measles infection in

an immunodeficient recipient within six months of measles vaccination.
Oral polio Paralytic polio or vaccine-strain polio within 30 days to six months .
Rotavirus Intussusception within 30 days of rotavirus immunization.
HEPATITIS B VACCINE : Although acute HBV infection can occur at any age, the number of
cases increases during adolescence. Acquisition of HBV at a younger age is associated with an
increased probability of developing chronic HBV infection, cirrhosis, or hepatocellular
carcinoma. HBV is transmitted from exposure to contaminated blood, sexual intercourse, and
vertically from mother to infant at the time of delivery.
Preparations Two recombinant hepatitis B vaccines, Engerix-B and Recombivax HB, are
available for use.
Dosing schedule Routine screening of all pregnant women for hepatitis B surface antigen
(HBsAg) is now mandatory because the timing of HBV vaccine administration and the need for
hepatitis B immune globulin (HBIG) for infants depend upon whether or not the mother is
HBsAg-positive.
HBsAg-negative mother The HBV vaccine should be administered in three doses: ideally, to
infants during the birth hospitalization; at 1 to 2 months of age; and at 6 to 18 months of age.
Only monovalent HBV vaccine can be used for the birth dose. Monovalent or combination
vaccines containing HBV vaccine can be used for subsequent doses if the infant is at least 6
weeks of age. Four doses of vaccine may be administered to infants who receive a dose at birth
(monovalent) and combination vaccines to complete the series. In either case, the minimum age
for the final dose of HBV vaccine is 24 weeks of age.
Vaccine-induced protection should result in antibody levels of 10 mIU/mL or higher. Adults and
immunocompetent children do not need booster doses or routine serologic testing.
HBsAg-positive mother Infants of HBsAg-positive mothers should receive HBIG shortly after
birth and should be immunized with monovalent HBV vaccine, preferably within 12 hours of
age. These infants should be given their second and third doses of HBV vaccine at 1 and 6
months of age, respectively. Testing for HBsAg and anti-HBs antibody should be performed at 9
to 18 months of age. If the HBsAg test is negative and the anti-HBs antibody level <10 mIU/mL,
50
a fourth dose should be administered. If on subsequent testing, the level remains low, up to
two more doses of HBV vaccine may be given.
Mother's HBsAg status unknown An infant born to a mother with unknown HBsAg status
should receive the first dose of monovalent HBV vaccine soon after birth. The schedule for the
remaining doses of HBV vaccine depends upon subsequent HBsAg testing of the mother. If she is
found to be HBsAg-positive, the infant must be given HBIG no later than one week after birth.
Contraindications and precautions HBV vaccination is contraindicated in individuals with a

history of hypersensitivity to yeast or any of the vaccine components. Vaccination is not
contraindicated in persons with a history of multiple sclerosis, Guillain-Barre syndrome,
autoimmune disease, or other chronic disorder; nor is it contraindicated in pregnancy.
DIPHTHERIA, TETANUS, AND/OR PERTUSSIS VACCINES Diphtheria is an acute respiratory or

cutaneous illness caused by Corynebacterium diphtheriae. Tetanus is a nervous system disorder
characterized by muscle spasms that is caused by the toxin-producing anaerobe, Clostridium
tetani. Pertussis, or "whooping cough", is an acute communicable disease resulting from an
infection of the respiratory airways by the small, Gram-negative coccobacillus, Bordetella
pertussis.
Preparations Preparations of diphtheria, tetanus, and pertussis vaccinations include

diphtheria toxoid (at varying doses), tetanus toxoid, and either whole cell or acellular pertussis
vaccine. Whole cell pertussis-containing vaccines are no longer recommended in the United
States. Acellular pertussis vaccines contain only certain antigens of the whole pertussis
bacterium and produce fewer local reactions (erythema and induration at the injection site),
fever, and systemic symptoms (drowsiness, irritability, and anorexia).
Primary series Three federally licensed combined diphtheria-tetanus-acellular pertussis

(DTaP) vaccines (Tripedia, Infanrix, Daptacel) are currently available in the United States for
the primary vaccine series. Tripedia and Infanrix are approved for all five doses. Daptacel is
approved for the first four doses.
DTaP is also available in four combination vaccines: DTaP (Tripedia) and HbCV (ActHIB):
Trihibit, approved for use only as the fourth dose of DTaP in children 15 months or older
Hepatitis B/DTaP/ poliovirus: Pediarix, approved for the first three doses beginning at 2 months
of age DTaP, inactivated poliovirus (IPV), and Hib: Pentacel, approved for use in infants and
children at 2, 4, 6, and 15 through 18 months of age. The fourth dose of DTaP-IPV/Hib may be
administered as early as 12 months of age if at least 6 months have elapsed since the third dose
of DTaP-IPV/Hib and the clinician is concerned about missing an opportunity to vaccinate later.
DTaP and IPV: Kinrix , approved for the fifth dose of DTaP and the fourth dose of IPV at four to
six years in children whose previous DTaP doses were with Infanrix or Pediarix or both.
51
For patients in whom it is desirable to avoid the pertussis component, there are two
preparations that contain only diphtheria and tetanus toxoids: DT and Td (or dT), which contains
a reduced dose of diphtheria toxoid.
Booster vaccines In addition to the tetanus-reduced diphtheria toxoid vaccine (Td), two
booster vaccines containing tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis
(Tdap) have been approved by the FDA: Boostrix is approved for use in children and
adolescents 10 to 18 years of age ADACEL is approved for use in individuals 11 to 64 years of
age.
Dosing schedule
Primary series Combined diphtheria, tetanus, and acellular pertussis (DTaP) immunization is
recommended for all children at 2, 4, and 6 months of age. In areas of endemicity or during
outbreaks of diphtheria or pertussis, DTaP may be given to infants as young as four weeks old.
Normally, the minimum age for administration is 6 weeks. The second and third doses should be
given at minimum intervals of one month and the fourth dose delayed for at least six months
after the third.
Booster doses should be given at 15 to 18 months and four to six years of age. Four years is
the minimum age for the final dose. If the fourth dose of the vaccine is delayed for some reason
until after the patient is four years old, the fifth dose is unnecessary. For children who have
absolute contraindication to pertussis vaccine, diphtheria and tetanus toxoid (DT) is an
acceptable alternative.
Booster doses Children should receive a booster dose of tetanus toxoid and the reduced
diphtheria toxoid, preferably at 11 to 12 years of age, and at 10-year intervals throughout life.
These booster doses may contain acellular pertussis (ie, Tdap).
The ACIP and the AAP recommend a single booster dose of Tdap (0.5 mL IM) for adolescents.
The ACIP and AAP recommendations include:
Tdap, rather than Td, should be administered to adolescents between 11 and 18 years who
require a booster dose (provided they have completed the recommended primary diphtheria-
tetanus-pertussis vaccine series in early childhood and have not received Td). The preferred age
for Tdap immunization is 11 to 12 years. Immunization with Tdap is encouraged for adolescents
11 to 18 years of age who completed the primary series of diphtheria-tetanus-pertussis vaccines
in early childhood and already received a Td booster. This recommendation is made to protect
these adolescents against pertussis, but more importantly, to prevent the spread of pertussis
disease to infants and young children. A five-year interval between Td and Tdap is suggested.
However, in settings of increased risk of pertussis, shorter intervals can be used.
52
Contraindications An anaphylactic reaction to the diphtheria-tetanus-pertussis vaccine or
vaccine constituent and encephalopathy (not caused by another identifiable cause) within seven
days of the administration of a previous diphtheria-tetanus-pertussis vaccine are considered
true contraindications. Moderate or severe illness with or without fever is considered a
temporary contraindication, with immunization given upon recovery. Mild acute illness with or
without fever is not a contraindication to vaccine administration.
Precautions If a child develops one of the following within 48 hours of having received a
previous dose of diphtheria-tetanus-pertussis vaccine, a subsequent dose should be given only
with caution:
1. Temperature 104.8F, not attributable to another identifiable cause.

2. Collapse or shock-like state.
3. Persistent, inconsolable crying lasting three hours or longer.
4. Development of a seizure within three days of having received a prior dose of either
preparation.
One approach is to give acetaminophen to patients before they receive the vaccine and every
four hours for 24 hours thereafter in order to minimize a febrile response. This caution
particularly applies to children with a personal history or family history (siblings or parents) of
febrile convulsions.
Adverse reactions Adverse reactions to the diphtheria-tetanus-acellular pertussis

vaccination include local reactions, anaphylaxis, seizures, fever, prolonged crying, and
hypotonic-hyporesponsive episodes. Each of these events occurs less frequently than after
immunization with whole cell DTP vaccine, which is no longer recommended for use in the
United States, but is available worldwide. Whole cell DTP vaccine should not be administered
to children older than seven years of age because of an increased possibility of adverse
reaction.
MMR VACCINE The measles virus causes an acute infection characterized by fever, cough,
coryza, conjunctivitis, rash, and enanthem that may be followed by severe complications,
including encephalitis. The mumps virus causes an acute self-limited viral syndrome, which
occurred principally in school-children before the widespread use of mumps vaccine. Rubella
virus causes German measles, a generally mild infection with a characteristic rash, that can
affect both children and adults. However, rubella infection can cause significant birth defects if it
occurs early in fetal life. Preparations Measles, mumps, and rubella live-virus vaccines can be
administered as single antigens, but are given preferably as the combination MMR vaccine,
which is administered subcutaneously.
In addition, a combination measles, mumps, rubella, and varicella vaccine (MMRV, Oka/Merck,
ProQuad) was approved by the FDA in September 2005. It is indicated for simultaneous
immunization against measles, mumps, rubella, and varicella among children 12 months to 12
years of age.
53
Dosing schedule The first dose of MMR is administered at 12 to 15 months of age. A
second dose is recommended routinely at school entry (between four and six years of age)
and by 11 to 12 years of age if not previously administered. However, the second dose may be
administered as early as four weeks after the first dose, provided that both doses are
administered after at least 12 months of age. Such a dosing schedule may be considered during
an outbreak or before international travel. At least one month should elapse between
administration of MMRV and a dose of measles containing vaccine.
Immune globulin recipients The receipt of parenterally administered immune globulin or

blood products can blunt or block the host response to certain live-virus vaccines. The suggested
interval between receipt of these products and administration of MMR or monovalent measles
vaccine varies between three and 11 months depending upon the product. In addition, if
immune globulin or blood products must be given within 14 days after administration of MMR
or monovalent measles vaccine, another dose of the vaccine should be administered after the
interval suggested.
HIV infection MMR should be administered to all asymptomatic HIV-infected persons and to
HIV-infected persons who are not severely immunocompromised and who have no evidence of
measles immunity. Routine immunization of the severely immunocompromised HIV-infected
individual remains controversial. Should a person in this latter group be at risk for measles
exposure during an outbreak, the choice between measles vaccination and immune globulin
prophylaxis should be considered.
Other considerations For individuals who are older than 12 years, who were born after
1957, or who do not have adequate history or documentation of having received two doses of
MMR, one or two doses of MMR vaccine should be given. This recommendation is particularly
important for healthcare workers, for people involved in post-high school education, and during
measles epidemics.
Contraindications True contraindications to administration of MMR vaccine include

pregnancy, known altered immunodeficiency states such as congenital immunodeficiencies,
long-term immunosuppressive therapy, and hematologic or solid tumors. Immunization should
be withheld temporarily from patients with moderate or severe febrile illnesses until the acute
phase has subsided. Patients experiencing thrombocytopenia within six weeks of having had
MMR vaccine probably should not receive a subsequent dose.
Precautions Women who are vaccinated with MMR should be advised to avoid pregnancy
for at least 28 days after vaccination. The Advisory Committee on Immunization Practices
(ACIP) shortened the recommended interval from three months to 28 days after review of data
from the United States, United Kingdom, Sweden, and Germany confirmed no cases of
congenital rubella syndrome in infants born to mothers who were vaccinated between two
weeks before and six weeks after conception .
54
Adverse reactions Adverse reactions to the MMR vaccine include fever, rash, joint
complaints, hypersensitivity reactions, the development of idiopathic thrombocytopenic
purpura, and seizures. These reactions occur more frequently with the first than with the
second dose. Fever (>39.4C) develops in 5 to 15 percent of MMR recipients, usually within 6 to
12 days after immunization.
The risk of encephalopathy after MMR vaccine was evaluated in a retrospective case-control
study including 452 children with encephalopathy and related conditions and up to three
controls for each case. Cases were no more likely than controls to have received MMR vaccine
during the 90 days before onset of encephalopathy.
Possible association with autism Concern has been raised periodically about a possible link
between receipt of MMR vaccine and autism and other chronic diseases (e.g., multiple sclerosis
and diabetes mellitus).
NEW TECHNOLOGY Impressive efforts are being made to develop new effective vaccines and
mechanisms for optimal delivery. Biodegradable polymer technology is being considered as a
mechanism for delivering multiple doses of a vaccine after a single injection (eg, a single
injection of DTaP could be given with timed release at 2, 4, and 6 months of age).
In the near future, newer more effective adjuvants for vaccine delivery may be available. Use
of these adjuvants may allow for the needle-free administration of vaccines by direct application
of vaccine antigen(s) to skin surfaces. Using DNA technology, genomic sequencing of particular
organisms may be feasible and would allow for the elimination of virulent segments of a
particular organism while preserving those portions essential for immune protection. The best
vaccines to be produced and presumably the easiest to deliver will be those that can be
administered orally or via the intranasal route. Once vaccine antigen(s) come in contact with
mucosal lymphocytes, they can be transported throughout the body, stimulating appropriate
immune response.
Growing vaccines in certain fruits and/or vegetables (e.g., banana plants, peas, potatoes,
cucumbers) by using genetic engineering techniques may allow children to be immunized by
simply ingesting the particular food. Potential vaccines to be administered in this fashion may
include those used to protect against certain enteric organisms (e.g., Vibrio cholera, Shigella
sp., Escherichia coli). No special refrigeration will be required, and the cost of these vaccines
may be minimal compared to the cost of vaccines produced by more expensive technology.
55
Fever
Keith R. Powell
Fever is a controlled increase in body temperature over the normal values for an individual.
Fever may be caused by infection, vaccines, biologic agents (granulocyte-macrophage colony-

stimulating factor, interferons, interleukins), tissue injury (infarction, pulmonary emboli,
trauma, intramuscular injections, burns), malignancy (leukemia, lymphoma, hepatoma,
metastatic disease), drugs (cocaine, amphotericin B, drug fever), immunologic-rheumatologic
disorders (systemic lupus erythematosus, rheumatoid arthritis), inflammatory diseases (e.g.,
inflammatory bowel disease), granulomatous diseases (sarcoidosis), endocrine disorders (e.g.,
thyrotoxicosis, pheochromocytoma), metabolic disorders (gout, uremia, Fabry disease, type 1
hyperlipidemia), genetic disorders (familial Mediterranean fever), and unknown or poorly
understood entities. Factitious fever, or self-induced fever, may be due to intentional
manipulation of the thermometer or injection of pyrogenic material.
CLINICAL MANIFESTATIONS
Although fever patterns per se are not often helpful in determining a specific diagnosis,
temperatures in excess of 41C are most often associated with a noninfectious cause.
Causes of very high temperatures (>41C) include central fever (resulting from central
nervous system dysfunction involving the hypothalamus), malignant hyperthermia,
malignant neuroleptic syndrome, drug fever, or heatstroke. Temperatures that are lower
than normal (<36C) can be associated with overwhelming sepsis but are more
commonly related to cold exposure, hypothyroidism, or overuse of antipyretics.
The relationship between a patient's pulse rate and temperature can be informative.
Relative tachycardia, when the pulse rate is elevated out of proportion to the
temperature, is usually due to noninfectious diseases or infectious diseases in which a
toxin is responsible for the clinical manifestations. Relative bradycardia (temperature-
pulse dissociation), when the pulse rate remains low in the presence of fever, suggests
typhoid fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of
fever also may be a result of a conduction defect resulting from cardiac involvement with
acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis.
TREATMENT
Fever with temperatures less than 39C in healthy children generally does not
require treatment.
Hyperpyrexia (>41C) indicates greater risk for severe infection, hypothalamic disorders, or
central nervous system hemorrhage, and should always be treated with antipyretics. High fever
during pregnancy may be teratogenic.
56
Acetaminophen, aspirin, and ibuprofen are inhibitors of hypothalamic cyclo-
oxygenase, thus inhibiting PGE2 synthesis. These drugs all are equally effective
antipyretic agents. Because aspirin has been associated with Reye syndrome in children
and adolescents, it is not recommended for the treatment of fever.
Acetaminophen, 1015 mg/kg orally every 4 hr, is not associated with significant
adverse effects; however, prolonged use may produce renal injury, and massive overdose
may produce hepatic failure.
Ibuprofen, 510 mg/kg orally every 68 hr, is also effective and may cause dyspepsia,
gastrointestinal bleeding, reduced renal blood flow, and rarely, aseptic meningitis, hepatic
toxicity, or aplastic anemia. Serious injury from ibuprofen overdose is unusual.
Alternating acetaminophen and ibuprofen Q 46 hr or giving both drugs at the
same time are also effective.
Tepid sponge bathing in warm water (not alcohol) is another recommended method of
reducing hyperpyrexia due to infection or hyperthermia resulting from external causes
(heatstroke). The decline of body temperature after antipyretic therapy does not
distinguish serious bacterial from less serious viral diseases.
Fever Without a Focus

Fever is a common manifestation of infectious diseases but is not predictive of severity. Many
common viral (rhinitis, pharyngitis, pneumonia) and bacterial (otitis media, pharyngitis,
impetigo) infections are usually benign in normal hosts and respond well to appropriate
antimicrobial or supportive therapy. Other infections (sepsis, meningitis, pneumonia,
osteoarticular infections, pyelonephritis), if untreated, may have significant morbidity or
mortality.
INFANTS <3 MO OF AGE.

An infectious agent, usually viral, is identified in 70% of infants <3 mo of age with
fever; the remainder are presumed to have self-limited but undiagnosed viral infections.
However, fever in an infant <3 mo of age should always suggest the possibility of
serious bacterial disease. Serious bacterial infections are present in 1015% of
previously healthy full-term infants presenting with rectal temperatures of 38C. These
infections include sepsis, meningitis, urinary tract infections, enteritis, osteomyelitis, and
suppurative arthritis. Bacteremia is present in 5% of febrile infants <3 mo of age;
organisms responsible for bacteremia include group B streptococcus and Listeria
monocytogenes (late-onset neonatal sepsis and meningitis) and community-acquired
pathogens including Salmonella (enteritis), Escherichia coli (urinary tract infection),
Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type b
(sepsis and meningitis), and Staphylococcus aureus (osteoarticular infection).
Pyelonephritis is more common in uncircumcised infant boys, neonates and infants with
urinary tract anomalies, and young girls. Other potential bacterial diseases in this age
57
group include otitis media, pneumonia, omphalitis, mastitis, and other skin and soft tissue
infections.
The approach to febrile patients <3 mo of age includes a careful history and
physical examination.
Ill-appearing (toxic) febrile infants <3 mo of age require prompt hospitalization and
immediate parenteral antimicrobial therapy after cultures of blood, urine, and
cerebrospinal fluid (CSF) are obtained. Ceftriaxone (50 mg/kg/dose every 24 hr with
normal CSF findings, or 80 mg/kg/dose every 24 hr with CSF pleocytosis) or cefotaxime
(50 mg/kg/dose every 6 hr), plus ampicillin (50 mg/kg/dose every 6 hr) to cover for L.
monocytogenes and enterococcus, is an effective initial antimicrobial regimen for ill-
appearing infants without focal findings. This regimen is effective against the usual
bacterial pathogens causing sepsis, urinary tract infection, and enteritis in young infants.
However, if meningitis is suspected because of CSF abnormalities, vancomycin (15
mg/kg/dose every 6 hr) should be given to cover for possible penicillin-resistant S.
pneumoniae, in addition to the ceftriaxone/cefotaxime and ampicillin, until the results of
culture and susceptibility tests are known.
Infants <3 mo of age with fever who appear generally well; who have been previously
healthy; who have no evidence of skin, soft tissue, bone, joint, or ear infection; and who
have a total white blood cell (WBC) count of 5,00015,000 cells/L, an absolute band
count of <1,500 cells/L, and normal urinalysis and negative culture results are unlikely
to have a serious bacterial infection. The negative predictive value with 95% confidence
of these criteria for any serious bacterial infection is >98%, and >99% for bacteremia. Of
all serious bacterial infections, pyelonephritis is common and may be seen in well-
appearing infants without a focus or in those who appear ill. Bacteremia is present in less
than 30% of infants with pyelonephritis. Urinalysis may be negative in infants 12 mo
of age .
OCCULT BACTEREMIA IN CHILDREN 3 MO TO 3 YR OF AGE.

Approximately 30% of febrile children 3 mos to 3 yr of age have no localizing signs of
infection.
Risk factors indicating increased probability of occult bacteremia include temperature

39C, WBC count 15,000/L, or an elevated absolute neutrophil count, band count,
erythrocyte sedimentation rate, or C-reactive protein. The incidence of bacteremia among
infants 336 mo of age increases as the temperature and WBC count increase. However,
no combination of laboratory tests or clinical assessment is completely accurate in
predicting the presence of occult bacteremia.
Without therapy, occult bacteremia may resolve spontaneously without sequelae, may
persist, or may lead to localized infections, such as meningitis, pneumonia, cellulitis,
pericarditis, osteomyelitis, or suppurative arthritis.
58
Treatment of toxic-appearing febrile children 336 mo of age that do not have focal
signs of infection includes hospitalization and prompt institution of antimicrobial therapy
after specimens of blood, urine, and CSF are obtained for culture.
Consensus practice guidelines published in 1993 recommended that infants 336 mo of

age that have a temperature of <39C and who do not appear toxic can be observed as
outpatients without performing diagnostic tests or administering antimicrobial agents. For
nontoxic-appearing infants with a rectal temperature of 39C, 2 options were suggested:
(1) obtain a blood culture and give empirical antimicrobial therapy (ceftriaxone, a single
dose of 50 mg/kg, not to exceed 1 g) or (2) if the WBC count is 15,000/L, obtain a
blood culture and begin empirical antimicrobial therapy.
FEVER WITH PETECHIAE

Independent of age, fever with petechiae in an ill-appearing patient with or without
localizing signs indicates high risk for life-threatening bacterial infections such as
bacteremia, sepsis, and meningitis. From 8 to 20% of patients with fever and petechiae
have a serious bacterial infection, and 710% have meningococcal sepsis or meningitis
Management includes prompt hospitalization, culture of blood and CSF, and
administration of appropriate parenteral antimicrobial agents.
Well-appearing patients with fever and petechiae can be evaluated with a complete
blood count and platelet count as well as a blood culture with observation in the office or
emergency room. If no further petechiae develop or if they are secondary to emesis or
coughing and the patient remains well, the patient can be managed as an outpatient with
or without antibiotics depending on the most likely cause of the petechiae.
FEVER IN PATIENTS WITH SICKLE CELL DISEASE

Infection is the most common cause of death among children with sickle cell disease.
The incidence of infection is greatest among children <5 yr of age. The increased risk for
infection in these children is due in part to functional asplenia and a defect in the
properdin (alternate complement) pathway. Fever without localizing signs in patients
with sickle cell disease is a common presentation of infection caused by S. pneumoniae
(sepsis, pneumonia, meningitis), H. influenzae type b (meningitis), S. aureus
(osteomyelitis), Salmonella (osteomyelitis), and E. coli (pyelonephritis).
The management of patients with sickle cell hemoglobinopathies requires culture of

blood and, if indicated, CSF, stool, and bone, and administration of antimicrobial agents.
Children who appear seriously ill, have temperatures of 40C, have a WBC count of
<5,000/L or >30,000/L, or who have pulmonary infiltrates or complications of sickle
cell disease or severe pain should be hospitalized. Other febrile infants with sickle cell
disease can be given intramuscular ceftriaxone and cared for as outpatients after
appropriate specimens have been obtained for culture. These children should be re-
evaluated within 24 hr, or earlier if their condition deteriorates or new symptoms
develop.
59
Prevention of pneumococcal sepsis is possible by instituting long-term penicillin
therapy continued until adolescence (oral penicillin V, 125 mg twice daily for children <5
yr of age and 250 mg orally twice daily for children 5 yr of age). Pneumococcal and H.
influenzae vaccines provide some protection but do not supplant long-term antimicrobial
therapy.
FEVER OF UNKNOWN ORIGIN

The term fever of unknown origin (FUO) is best reserved for children with a fever
documented by a health care provider and for which the cause could not be identified
after 3 wk of evaluation as an outpatient or after 1 wk of evaluation in hospital.
ETIOLOGY.
The principal causes of FUO in children, using these rigorous criteria, are infections and
rheumatologic (connective tissue or autoimmune) diseases. Neoplastic disorders should
also be seriously considered, although most children with malignancies do not have fever
alone. The possibility of drug fever should be considered if the patient is receiving any
drug. Drug fever is usually sustained and not associated with other symptoms.
Discontinuation of the drug is associated with resolution of the fever, generally within 72
hr, although certain drugs, such as iodides, are excreted for a prolonged period with fever
that may persist for as long as 1 mo after drug withdrawal.
Diagnostic Considerations of Fever of Unknown Origin in Children

Abscesses: abdominal, brain, dental, hepatic, pelvic, perinephric, rectal,
subphrenic, psoas
Infections
Bacteria
Caused by specific organism
Actinomycosis
Bartonella henselae (cat-scratch disease)
Brucellosis
Campylobacter
Francisella tularensis (Tularemia)
Listeria monocytogenes (Listeriosis)
Meningococcemia (chronic)
60
Mycoplasma pneumoniae
Rat-bite fever (Streptobacillus moniliformis; streptobacillary form of rat-bite
fever)
Salmonella
Tuberculosis
Yersiniosis
Localized infections
Cholangitis
Infective endocarditis
Mastoiditis
Osteomyelitis
Pneumonia
Pyelonephritis
Sinusitis
Spirochetes
Borrelia burgdorferi (Lyme disease)
Relapsing fever (Borrelia recurrentis)
Leptospirosis
Rat-bite fever (Spirillum minus; spirillary form of rat-bite fever)
Syphilis
Fungal diseases
Blastomycosis (extrapulmonary)
Coccidiodomycosis (disseminated)
Histoplasmosis (disseminated)
Chlamydia
Lymphogranuloma venereum
Psittacosis
Rickettsia
Ehrlichia canis
Q fever
Rocky Mountain spotted fever
Tick-borne typhus
61
Viruses
Cytomegalovirus
Hepatitis viruses
HIV
Infectious mononucleosis (Epstein-Barr virus)
Parasitic diseases
Amebiasis
Babesiosis
Giardiasis
Malaria
Toxoplasmosis
Trichinosis
Trypanosomiasis
Visceral larva migrans (Toxocara)
Rheumatologic diseases
Behet disease
Juvenile dermatomyositis
Juvenile rheumatoid arthritis
Rheumatic fever
Systemic lupus erythematosus
Hypersensitivity diseases
Drug fever
Hypersensitivity pneumonitis
Pancreatitis
Serum sickness
Weber-Christian disease
Neoplasms
Atrial myxoma
Cholesterol granuloma
Hodgkin disease
Inflammatory pseudotumor
62
Leukemia
Lymphoma
Neuroblastoma
Wilms tumor
Granulomatous diseases
Crohn disease
Granulomatous hepatitis
Sarcoidosis
Familial-hereditary diseases
Anhidrotic ectodermal dysplasia
Fabry disease
Familial dysautonomia
Familial Mediterranean fever
Hypertriglyceridemia
Ichthyosis
Sickle cell crisis
Miscellaneous
Chronic active hepatitis
Diabetes insipidus (non-nephrogenic and nephrogenic)
Factitious fever
Hemophagocytic syndromes
Hypothalamic-central fever
Infantile cortical hyperostosis
Inflammatory bowel disease
Kawasaki disease
Kikuchi-Fujimoto disease
Pancreatitis
Periodic fevers
Poisoning
Pulmonary embolism
Thrombophlebitis
63
Thyrotoxicosis
Recurrent or relapsing fever
Undiagnosed fever
Persistent
Recurrent
Resolved
Most fevers of unknown or unrecognized origin result from atypical presentations of

common diseases. In some cases, the presentation as an FUO is characteristic of the
disease, such as juvenile rheumatoid arthritis (JRA), but the definitive diagnosis can be
established only after prolonged observation because initially there are no associated or
specific findings on physical examination and all laboratory results are negative or
normal.
JRA and systemic lupus erythematosus are the connective tissue diseases associated
most frequently with FUO. Inflammatory bowel disease, rheumatic fever, and Kawasaki
disease are also commonly reported as causes of FUO. If factitious fever (inoculation of
pyogenic material or manipulation of the thermometer by the patient or parent) is
suspected, the presence and pattern of fever should be documented in the hospital.
Prolonged and continuous observation, which may include electronic surveillance, of
patients is imperative.
FUO lasting more than 6 mo is uncommon in children and suggests granulomatosis or

autoimmune disease. Repeat interval evaluation, including history, physical examination,
and roentgenographic studies, is required.
DIAGNOSIS.
The evaluation of FUO requires a thorough history and physical examination
supplemented by a few screening laboratory tests, and additional laboratory and
radiographic tests as indicated by the history or abnormalities found on examination or
initial screening
64
65
History.
The age of the patient is helpful in evaluating FUO. Children <6 yr of age often have a
respiratory or genitourinary tract infection, localized infection (abscess, osteomyelitis),
JRA, or, rarely, leukemia. Adolescent patients are more likely to have tuberculosis,
inflammatory bowel disease, autoimmune processes, or lymphoma, in addition to the
causes of FUO found in younger children.
Any history of pica should be elicited. Ingestion of dirt is a particularly important clue
to infection with Toxocara (visceral larva migrans) or Toxoplasma gondii
(toxoplasmosis).
A medication history should be pursued rigorously. This should include over-the-

counter preparations and topical agents, including eye drops, which may be associated
with atropine-induced fever.
Physical Examination.
Sweating in a febrile child should be noted. The continuing absence of sweat in the
presence of an elevated or changing body temperature suggests dehydration due to
vomiting, diarrhea, or central or nephrogenic diabetes insipidus. It also should suggest
anhidrotic ectodermal dysplasia, familial dysautonomia, or exposure to atropine.
A careful ophthalmic examination is important. Red, weeping eyes may be a sign of

connective tissue disease, particularly polyarteritis nodosa. Palpebral conjunctivitis in a
febrile patient may be a clue to measles, coxsackievirus infection, tuberculosis, infectious
mononucleosis, lymphogranuloma venereum, and cat-scratch disease. In contrast, bulbar
conjunctivitis in a child with FUO suggests Kawasaki disease or leptospirosis. Petechial
conjunctival hemorrhages suggest infective endocarditis. Uveitis suggests sarcoidosis,
JRA, systemic lupus erythematosus, Kawasaki disease, Behet disease, and vasculitis.
Chorioretinitis suggests CMV, toxoplasmosis, and syphilis. Proptosis suggests orbital
tumor, thyrotoxicosis, metastasis (neuroblastoma), orbital infection, Wegener
granulomatosis, or pseudotumor.
The ophthalmoscope should also be used to examine nailfold capillary abnormalities

that are associated with connective tissue diseases such as juvenile dermatomyositis and
systemic scleroderma. FUO is sometimes due to hypothalamic dysfunction. A clue to this
disorder is failure of pupillary constriction due to absence of the sphincter constrictor
muscle of the eye. Tenderness to tapping over the sinuses or the upper teeth suggests
sinusitis. Recurrent oral candidiasis may be a clue to various disorders of the immune
system.
Fever blisters are common findings in patients with pneumococcal, streptococcal,

malarial, and rickettsial infection. They also are common in children with meningococcal
meningitis (which usually does not present as FUO) but rarely are seen in children with
66
meningococcemia. Fever blisters also are rarely seen with Salmonella or staphylococcal
infections.
Hyperemia of the pharynx, with or without exudate, suggests infectious mononucleosis,

CMV infection, toxoplasmosis, salmonellosis, tularemia, Kawasaki disease, or
leptospirosis.
The muscles and bones should be palpated carefully. Point tenderness over a bone may
suggest occult osteomyelitis or bone marrow invasion from neoplastic disease.
Tenderness over the trapezius muscle may be a clue to subdiaphragmatic abscess.
Generalized muscle tenderness suggests dermatomyositis, trichinosis, polyarteritis,
Kawasaki disease, or mycoplasmal or arboviral infection.
Rectal examination may reveal perirectal lymphadenopathy or tenderness, which

suggests a deep pelvic abscess, iliac adenitis, or pelvic osteomyelitis. A guaiac test should
be obtained; occult blood loss may suggest granulomatous colitis or ulcerative colitis as
the cause of FUO.
Repetitive chills and temperature spikes are common in children with septicemia
(regardless of cause), particularly when associated with renal disease, liver or biliary
disease, infective endocarditis, malaria, brucellosis, rat-bite fever, or a loculated
collection of pus. The general activity of the patient and the presence or absence of rashes
should be noted. Hyperactive deep tendon reflexes may suggest thyrotoxicosis as the
cause of FUO.
Laboratory Findings.
Ordering a large number of diagnostic tests in every child with FUO according to a
predetermined list may waste time and money. Alternatively, prolonged hospitalization
for sequential tests may be more costly. The tempo of diagnostic evaluation should be
adjusted to the tempo of the illness; haste may be imperative in a critically ill patient, but
if the illness is more chronic, the evaluation can proceed more slowly and deliberately
and, usually, in an outpatient setting. If there are no clues in the patient's history or on
physical examination that suggest a specific infection or area of suspicion, it is unlikely
that diagnostic studies will be helpful.
A complete blood cell count with a differential WBC count and a urinalysis should be
part of the initial laboratory evaluation. An absolute neutrophil count of <5,000/L is
evidence against indolent bacterial infection other than typhoid fever. Conversely,
patients with a polymorphonuclear leukocyte count of >10,000/L or a nonsegmented
polymorphonuclear leukocyte count of >500/L have a high likelihood of having a severe
bacterial infection. Direct examination of the blood smear with Giemsa or Wright stain
may reveal organisms of malaria, trypanosomiasis, babesiosis, or relapsing fever.
An erythrocyte sedimentation rate (ESR) of >30 mm/hr indicates inflammation and the
need for further evaluation for infectious, autoimmune, or malignant diseases. An ESR of
67
>100 mm/hr suggests tuberculosis, Kawasaki disease, malignancy, or autoimmune
disease. A low ESR does not eliminate the possibility of infection or JRA. C-reactive
protein is another acute-phase reactant that becomes elevated and returns to normal more
rapidly than the ESR. Although experts may prefer use of one over the other, there is no
evidence that there is value in measuring both the ESR and C-reactive protein in the same
patient.
Blood cultures should be obtained aerobically. Anaerobic blood cultures have an

extremely low yield and should be obtained only if there are specific reasons to suspect
anaerobic infection. Multiple or repeated blood cultures may be required to detect
bacteremia associated with infective endocarditis, osteomyelitis, or deep-seated
abscesses. Polymicrobial bacteremia suggests factitious self-induced infection or
gastrointestinal pathology. The isolation of leptospires, Francisella, or Yersinia may
require selective media or specific conditions not routinely used. Urine culture should be
obtained routinely.
Tuberculin skin testing (TST) should be performed with intradermal placement of 5

units of purified protein derivative (PPD) that has been kept appropriately refrigerated.
Radiographic examination of the chest, sinuses, mastoids, or gastrointestinal tract may

be indicated by specific historical or physical findings. Radiographic evaluation of the
gastrointestinal tract for inflammatory bowel disease may be helpful in evaluating
selected children with FUO and no other localizing signs or symptoms.
Examination of the bone marrow may reveal leukemia; metastatic neoplasm;

mycobacterial, fungal, or parasitic diseases; and histiocytosis, hemophagocytosis, or
storage diseases. If a bone marrow aspirate is performed, cultures for bacteria,
mycobacteria, and fungi should be obtained.
Serologic tests may aid in the diagnosis of infectious mononucleosis, CMV infection,
toxoplasmosis, salmonellosis, tularemia, brucellosis, leptospirosis, cat-scratch disease,
Lyme disease, rickettsial disease, and, on some occasions, JRA.
Radionuclide scans may be helpful in detecting abdominal abscesses as well as

osteomyelitis, especially if the focus cannot be localized to a specific limb or multifocal
disease is suspected. Gallium citrate (67Ga) localizes in inflammatory tissues (leukocytes)
associated with tumors or abscesses. 99mTc phosphate is useful for detecting osteomyelitis
before plain roentgenograms demonstrate bone lesions. Granulocytes tagged with indium
(111In) or iodinated IgG may be useful in detecting localized pyogenic processes.
Echocardiograms may demonstrate the presence of vegetation on the leaflets of heart
valves, suggesting infective endocarditis. Ultrasonography may identify intra-abdominal
abscesses of the liver, subphrenic space, pelvis, or spleen.
Total body CT or MRI permits detection of neoplasms and collections of purulent

material without the use of surgical exploration or radioisotopes. CT and MRI are helpful
in identifying lesions of the head, neck, chest, retroperitoneal spaces, liver, spleen, intra-
68
abdominal and intrathoracic lymph nodes, kidneys, pelvis, and mediastinum. CT or
ultrasound-guided aspiration or biopsy of suspicious lesions has reduced the need for
exploratory laparotomy or thoracotomy. MRI is particularly useful for detecting
osteomyelitis if there is concern about a specific limb. Diagnostic imaging can be very
helpful in confirming or evaluating a suspected diagnosis but rarely leads to an
unsuspected cause.
Biopsy is occasionally helpful in establishing a diagnosis of FUO. Bronchoscopy,

laparoscopy, mediastinoscopy, and gastrointestinal endoscopy may provide direct
visualization and biopsy material when organ-specific manifestations are present.
TREATMENT
Fever and infection in children are not synonymous; antimicrobial agents should not
be used as antipyretics, and empirical trials of medication should generally be avoided.
An exception may be the use of antituberculous treatment in critically ill children with
suspected disseminated tuberculosis. Empirical trials of other antimicrobial agents may
be dangerous and can obscure the diagnosis of infective endocarditis, meningitis,
parameningeal infection, or osteomyelitis. Hospitalization may be required for laboratory
or radiographic studies that are unavailable or impractical in an ambulatory setting, for
more careful observation, or for temporary relief of parental anxiety. After a complete
evaluation, antipyretics may be indicated to control fever and for symptomatic relief
PROGNOSIS.
Children with FUO have a better prognosis than do adults. The outcome in a child is
dependent on the primary disease process, which is usually an atypical presentation of a
common childhood illness. In many cases, no diagnosis can be established and fever
abates spontaneously. In as many as 25% of cases in which fever persists, the cause of the
fever remains unclear, even after thorough evaluation.
69
Treatment of streptococcal toxic shock syndrome
Dennis L Stevens, MD, PhD
Group A streptococcus (GAS, e.g., Streptococcus pyogenes) is an aerobic gram-positive coccus

that causes pharyngitis and a spectrum of skin and soft tissue infections such as impetigo,
erysipelas, and localized cellulitis. Less commonly, GAS causes invasive disease such as
bacteremia, necrotizing fasciitis, pneumonia and post-partum sepsis, and the infection may be
complicated by toxic shock syndrome in approximately one-third of these patients.
DIAGNOSIS GAS TSS must be considered in any patient presenting from the community in
shock. A history of recent trauma and severe pain and fever favor a diagnosis of GAS TSS.
The Working Group on Severe Streptococcal Infections established the following clinical
guideline for diagnosis of GAS TSS:
Isolation of GAS from a normally sterile site (e.g., blood cerebrospinal, pleural, or peritoneal
fluid, tissue biopsy, or surgical wound) plus
Hypotension (systolic blood pressure 90 mm Hg in adults or <5th percentile for age in

children)
plus two or more of the following:
Renal impairment (creatinine in adults, 2 mg/dL; in children, two-times upper limit of normal
for age; in patients with pre-existing renal disease twofold elevation over baseline).
Coagulopathy (e.g., thrombocytopenia, disseminated intravascular coagulation).
Liver involvement (e.g., two-times upper limit of normal for age of transaminases or bilirubin;
in patients with pre-existing liver disease twofold elevation over baseline).
Adult respiratory distress syndrome.
Erythematous macular rash, may desquamate.
Soft tissue necrosis (eg, necrotizing fasciitis, myositis, or gangrene).
If GAS is isolated from a nonsterile site (e.g., throat, vagina, skin lesion) but the patient
fulfills the other criteria noted above, a diagnosis of probable GAS TSS can be made if no other
etiology for the illness is identified.
Recovery of the organism from blood cultures usually takes from 8 to 24 hours. When surgery
is performed for debridement of infected fascia or muscle, Gram's stain of involved tissue
showing gram-positive cocci in pairs and chains provides an early and definitive diagnosis in the
vast majority of cases.
70
Laboratory findings Although initial laboratory studies may reveal only mild leukocytosis,
the mean percentage of immature neutrophils (including band forms, metamyelocytes, and
myelocytes) may reach 40 to 50 percent.
The serum creatinine concentration is frequently elevated, and precedes the development of
hypotension in 40 to 50 percent of cases. Hypotension, myoglobinuria and hemoglobinuria (due
to toxin induced hemolysis) can contribute to the development of acute renal failure.
Other common findings include hypoalbuminemia, hypocalcemia, positive blood cultures (in
approximately 60 percent of cases), and an increase in the serum creatinine kinase
concentration, which suggests the presence of necrotizing fasciitis or myositis.
MANAGEMENT Treatment includes management of the complications of sepsis, aggressive

surgical debridement if a site of infection is identified, and antibiotics for the underlying
infection
Hemodynamic support Massive amounts of intravenous fluids (10 to 20 L/day) are often
necessary to maintain perfusion because of intractable hypotension and diffuse capillary leak,
even though anasarca is a predictable complication. Although the blood pressure may improve
with fluids alone, vasopressors (e.g., dopamine and/or norepinephrine) may also be required.
Surgical therapy Prompt and aggressive exploration and debridement of suspected deep-
seated S. pyogenes infection is mandatory. Surgical intervention should be considered in
patients who initially have fever and excruciating pain followed by progression to soft tissue
swelling and the formation of violaceous or bluish vesicles and bullae.
Antibiotic therapy Presumptive therapy should be initiated pending culture results because
of the severity of the illness. S. pyogenes remains exquisitely susceptible to beta-lactam
antibiotics. Numerous studies have demonstrated the efficacy of penicillin preparations in
treating erysipelas, impetigo, and cellulitis.
However, aggressive GAS infections such as necrotizing fasciitis, empyema, burn wound sepsis,
subcutaneous gangrene, and myositis are associated with a high mortality and extensive
morbidity despite penicillin therapy.
Clindamycin The shortcomings of penicillin in treating GAS infections has prompted a search
for alternative antibiotic therapies. Clindamycin has several potential advantages in treating GAS
infections.
The efficacy of clindamycin is not affected by inoculum size or stage of growth.
Clindamycin suppresses the synthesis of bacterial toxins .
71
Clindamycin facilitates phagocytosis of S. pyogenes by inhibiting synthesis of the antiphagocytic
M-protein.
Clindamycin suppresses synthesis of penicillin-binding proteins, which, in addition to being

targets for penicillin, are involved in cell wall synthesis and degradation.
Clindamycin has a longer postantibiotic effect than beta-lactams such as penicillin.
Clindamycin causes suppression of tumor necrosis factor.
A retrospective analysis demonstrated that clindamycin use was associated with better
outcomes than beta-lactam antibiotics in patients with GAS TSS.
We recommend empiric therapy, for an adult who presents with the clinical manifestations of
GAS TSS prior to the identification of GAS by culture, with broad-spectrum antibiotics such as:
Clindamycin (900 mg IV every eight hours)
plus one of the following:
A carbapenem (e.g., imipenem 500 mg every six hours or meropenem 1 g every eight hours)
A combination drug containing a penicillin plus beta-lactamase inhibitor (eg, ticarcillin-

clavulanate 3.1 g every four hours or piperacillin-tazobactam 4.5 g every six hours)
Once the diagnosis of GAS TSS is established, we recommend therapy with clindamycin (900
mg IV every eight hours) in addition to penicillin G (4 million units IV every four hours in patients
with normal renal function). In vitro there is no additive, synergistic or antagonistic effects of
penicillin when added to clindamycin. Penicillin is added to clindamycin primarily to cover the
patient in the rare event that the organism is resistant to clindamycin; this occurs in less than
one percent of isolates in the United States.
Duration of therapy There are no clinical studies addressing the optimal duration of
antibiotic therapy in GAS TSS. We recommend that the duration of antibiotic therapy be
individualized. Patients who are bacteremic are treated for a minimum of 14 days. In patients
with complicating deep-seated infections, such as necrotizing fasciitis, length of therapy
depends on the clinical course and the adequacy of surgical debridement; therapy is usually
continued for 14 days from the last positive culture obtained during surgical debridement.
Adjunctive therapy Several other modalities have been used in patients with GAS TSS:
intravenous immune globulin (IVIG), hyperbaric oxygen, and anti-TNF antibody.
PROGNOSIS The overall mortality rate in GAS TSS varies in different series from 30 to 70
percent. Mortality rates are lower in children than adults, with a mortality rate of 18 percent
reported in one series.
72
Clinical manifestations and diagnosis of Listeria monocytogenes
infection
Michael S Gelfand, MD
Listeria monocytogenes is an important bacterial pathogen in neonates, immunosuppressed

patients, elderly adults, pregnant women, and occasionally, previously healthy individuals.
CLINICAL SYNDROMES Listeria monocytogenes is thought of as a pathogen that causes

invasive disease including meningitis, meningoencephalitis, or bacteremia in immunosuppressed
patients, individuals at the extremes of age including neonates and elderly adults, and pregnant
women. However, Listeria is also a cause of self-limited febrile gastroenteritis in normal hosts
who ingest high numbers of organisms.
Listeria infection is more common in the summer. The incubation period ranges from 6 hours
to 90 days, but occurs at a mean of about 24 hours (range 6 to 240 hours) during outbreaks of
febrile gastroenteritis
Febrile gastroenteritis secondary to listerial infection typically occurs after ingestion of a large
inoculum of bacteria from contaminated food. The attack rate in various outbreaks of
gastroenteritis varied from 50 to 100 percent and the mean incubation period was about 24
hours (range 6 to 240 hours). Common symptoms include fever, watery diarrhea, nausea,
vomiting, headache, and pains in joints and muscles.
Sepsis of unknown origin Listerial sepsis occurs in patients of all ages. Neonates probably
acquire infection during or after birth. Infection in the first week of life is usually manifested by
sepsis, while disease manifestations after the first week are more variable and often include
meningitis. Early onset sepsis is characterized by high neonatal mortality in association with
maternal illness and premature delivery. With late-onset disease, babies generally are full-term
and have no history of perinatal complications. Listeria meningoencephalitis most often occurs
in neonates after three days of age and in immunocompromised and elderly adults. Although
Listeria may cause sepsis in immunocompromised children, it is relatively infrequent.
CNS infection The most common central nervous system manifestation of listerial infection
is meningoencephalitis. Cerebritis, which infrequently progresses to brain abscess, and
rhombencephalitis (brain stem encephalitis) are less common.
Meningoencephalitis Listeria meningoencephalitis most often occurs in neonates after

three days of age and in immunocompromised and elderly adults.
DIAGNOSIS The diagnosis of Listeria infection may be suspected from the clinical findings.
However, there is no clinical way to separate Listeria infection from many other infectious
diseases that can lead to fever and constitutional symptoms. As a result, the diagnosis can only
be established by culture of the organism from CSF or blood.
73
Listeria is the one cause of bacterial (nontuberculous) meningitis in which a substantial number
of lymphocytes (>25 percent) can be seen in the CSF differential count in the absence of
antibiotic therapy. In the review of 820 patients, the CSF protein concentration was moderately
elevated in almost all patients (mean 168 mg/dL), and the CSF glucose concentration was
reduced in 39 percent. Gram's stain of the CSF in Listeria meningitis has a low sensitivity, being
positive in only about one-third of patients. Furthermore, when organisms are seen, Listeria may
resemble pneumococci (diplococci) or diphtheroids (Corynebacteria) or be gram-variable and be
confused with Haemophilus species. Thus, Listeria should always be considered when
"diphtheroids" are reported to be growing from blood or cerebrospinal fluid (CSF) cultures and
one should be cautious or suspicious of a presumptive diagnosis of viral (aseptic) meningitis in
an immunocompromised, chronically ill or elderly patient with a negative Gram's stain and acute
meningitis.
We recommend MRI with contrast in all patients with listerial meningitis, patients with listerial
bacteremia and central nervous system signs or symptoms, and patients suspected of having
intracranial listeriosis. MRI evidence of isolated brain-stem involvement in the appropriate
clinical setting strongly suggests listerial infection.
TREATMENT
Ampicillin or penicillin G are the drugs of choice.
The dose of ampicillin or penicillin G varies according to age.
Infants 7 days Ampicillin (100 mg/kg per day divided in two doses for infants with weight
<2000 g; 150 mg/kg per day divided in three doses for infants with body weight >2000 g).
Infants 8 days to one month Ampicillin (150 mg/kg per day divided in four doses for infants
with weight <2000 g; 200 mg/kg per day divided in four doses for infants with weight >2000 g).
Children Ampicillin (300 mg/kg per day IV in four to six divided doses; maximum dose 10 to
12 g/day); penicillin G (250,000 to 400,000 units/kg per day in four to six divided doses;
maximum dose: 24 million units/day)
Ampicillin and penicillin G demonstrate delayed in vitro bactericidal activity at concentrations

attainable in the CSF. As a result, we usually treat listerial CNS infections, endocarditis, and
infections in neonates and immunocompromised patients with combination therapy, with the
bactericidal agent gentamicin being added to achieve synergy.
Penicillin-allergic patients can be skin tested and desensitized if necessary or treated with
trimethoprim-sulfamethoxazole (20 mg/kg per day of the trimethoprim component IV in four
divided doses).
Trimethoprim-sulfamethoxazole is bactericidal against Listeria, achieves adequate levels in

serum and CSF, and has documented clinical efficacy. A retrospective study in 22 patients with
74
meningoencephalitis suggested that the combination of ampicillin and trimethoprim-
sulfamethoxazole may be more effective than the combination of ampicillin and gentamicin.
Alternative drugs Imipenem and meropenem (2 g IV every eight hours in adults; 120 mg/kg
per day in three divided doses in children, maximum dose 6 g/day) have excellent in vitro
activity against Listeria. These drugs may prove to be useful for listerial infections. Although they
have not yet been approved for this indication, meropenem has been approved for bacterial
meningitis and has been used successfully to treat listeriosis.
In high risk patients For patients with listerial CNS infection, bacteremia, endocarditis, or
infection in an immunocompromised host, we treat with ampicillin plus gentamicin at the doses
recommended above. Among patients who are allergic to penicillin, we treat with trimethoprim-
sulfamethoxazole (5 mg/kg of the trimethoprim component IV every six hours) or meropenem
(2 g IV every eight hours in adults; 120 mg/kg per day in three divided doses in children,
maximum dose 6 g/day). There is some possibility of cross-allergenicity between meropenem
and penicillins.
Duration of therapy The optimal duration of ampicillin therapy is unknown, and varies with
the patient and the type of infection. Among patients with CNS infection, treatment is continued
until the CSF culture is negative and brain MRI is significantly improved, but for at least as long
as the following recommendations:
In immunocompetent patients, two weeks is sufficient for bacteremia and two to four weeks
for CNS infection.
Relapses have occurred in immunocompromised patients after two weeks of treatment. As a

result, three to six weeks is preferable in such patients who have bacteremia and four to eight
weeks in those with CNS infection. The longer duration particularly applies to patients with
cerebritis or brain abscess.
When given, gentamicin is continued until the patient improves (usually 10 to 14 days) or, in
poor responders, for up to three weeks if there are no signs of nephrotoxicity or ototoxicity.
75
Treatment and prevention of Bordetella pertussis infection in
infants and children
Sylvia Yeh, MD
Pertussis infection often results in a protracted illness. Frequent coughing paroxysms interfere
with daily function. Young infants can develop serious complications, including failure to thrive,
apnea, pneumonia, respiratory failure, seizures, and death. Throughout much of the protracted
illness, the child is contagious.
SUPPORTIVE CARE Supportive care is the mainstay of management for B. pertussis

infection. Supportive care may include hospitalization for close monitoring of respiratory status
and fluid or nutritional support. In addition, known triggers (e.g., exercise, cold temperatures)
for coughing paroxysms should be avoided.
Indications for hospitalization in infants and children with pertussis infection or suspected
pertussis infection include:
1. Respiratory distress including tachypnea, retractions, nasal flaring, grunting, and the
use of accessory muscles.
2. Evidence of pneumonia.
3. Inability to feed.
4. Cyanosis or apnea, with or without coughing.
5. Seizures.
Minimum criteria for discharge include the following:
1. The infant can tolerate coughing episodes without becoming hypoxic and/or
bradycardic .
2. The infant can feed enough to gain weight.
3. Caretakers are reliable and comfortable with the child's condition.
4. Close outpatient follow-up can be assured.
Fluids and nutrition Infants and children with frequent paroxysms of cough may have
increased fluid and energy needs, which can be difficult to meet if the infant is coughing or
vomiting. Thus, close attention should be paid to the child's fluid and nutritional status, whether
the child is admitted to the hospital or cared for at home. Intravenous hydration and nasogastric
feeding may be required for some patients. The nasogastric tube may stimulate the cough reflex
in some infants; however, nasogastric feedings should be attempted before parenteral nutrition
for infants who are unable to gain weight because of severe coughing paroxysms.
76
Adjunctive treatments Adjunctive treatments including bronchodilators, corticosteroids,
and antitussive agents have not been proven to be beneficial in patients with pertussis.
B. pertussis immunoglobulin In a multicenter, prospective, blinded trial, children who were

treated with immunoglobulin (Ig) enriched for B. pertussis toxin antibodies (BPIG) showed an
improvement in frequency of whoops compared to controls. However, further development of
BPIG has not been pursued, and it is not currently available for routine patient care.
Commercially available IVIG preparations have not been evaluated, nor are they routinely
screened for pertussis antibodies, and thus are not likely to offer significant benefit to pertussis
patients.
ANTIMICROBIAL THERAPY Antimicrobial therapy for pertussis, when administered early in

the course, may shorten the duration of symptoms and decrease transmission to susceptible
contacts. We recommend treatment for all children with clinical pertussis (with or without
laboratory confirmation). We also recommend treatment for children with culture or
polymerase chain reaction (PCR) confirmed pertussis even if they are asymptomatic at the time
of confirmation.
Treatment of B. pertussis infection has two goals: decreased severity of symptoms in the
index case and decreased spread of infection to close contacts.
Treatment indications
We recommend antimicrobial treatment for all individuals who have B. pertussis isolated from
pertussis cultures or positive polymerase chain reaction (PCR), regardless of their age or
whether they continue to have symptoms.
We also recommend treatment for patients with a clinical diagnosis of pertussis who have had
symptoms for less than 21 days.
Antimicrobial therapy also may be indicated for patients who have had more than 21 days of
symptoms, particularly those who are likely to be in contact with high-risk individuals, although
the utility of therapy in such patients is less clear.
Choice of agent
Children 6 months The antimicrobials of choice are macrolide antibiotics, including

erythromycin and new-generation preparations such as clarithromycin and azithromycin.
Erythromycin-resistant B. pertussis rarely has been reported; however, macrolide sensitivity
testing using standard methods should be performed.
Clarithromycin and azithromycin may be better tolerated than erythromycin. These drugs have
excellent in vitro activity, and have been evaluated in several clinical trials. In the largest of
these, 477 children with confirmed or suspected pertussis were randomly assigned to treatment
with erythromycin or azithromycin. Pertussis was eradicated from the nasopharynx of children
77
who had positive cultures (24 percent of the total), regardless of which antibiotic they received.
However, 90 percent of children who took azithromycin completed therapy, compared to 55
percent who took erythromycin.
Trimethoprim-sulfamethoxazole (TMP-SMX) may be an alternative for patients who have a

contraindication to or cannot tolerate macrolide agents. TMP-SMX should not be used in
pregnant or nursing women because of the potential risk of kernicterus related to bilirubin
displacement in the fetus or infant, respectively.
Infants <6 months Treatment is particularly important for infants younger than 6 months
because they are at increased risk for complications. In addition, if not treated, they remain
culture positive for longer periods than do older children and adults.
Infants <1 month of age The 2006 Report of the AAP Committee on Infectious Diseases and
CDC prefer the use of azithromycin for infants younger than 1 month of age. Erythromycin is an
alternative; clarithromycin is not recommended. TMP-SMX should not be used in infants
younger than 2 months of age because of the potential risk of kernicterus related to bilirubin
displacement. For the same reason, it should not be used in pregnant or nursing women.
Dose and duration
Erythromycin should be administered for 14 days Clarithromycin should be administered for

seven days Azithromycin should be administered for five days Trimethoprim-
sulfamethoxazole should be administered for 14 days.
Adverse effects The administration of oral erythromycin and azithromycin to young infants
for postexposure prophylaxis or treatment of pertussis has been associated with [infantile
hypertrophic pyloric stenosis (IHPS). The greatest risk appears to occur in infants given the
medication within the first two weeks of life. It is not known if clarithromycin poses the same
risks for IHPS.
ANTIMICROBIAL PROPHYLAXIS Initiation of postexposure prophylaxis in asymptomatic

contacts within 21 days of the onset of cough in the index case can prevent the development of
symptoms. The utility of postexposure prophylaxis after 21 days of onset of cough in the index
case is unclear. We suggest antimicrobial prophylaxis for close contacts of the index case and for
exposed individuals at high risk for severe or complicated pertussis, as discussed below.
Prophylaxis indications Factors that must be considered in the decision include the
contagiousness of the patient, the intensity of the exposure, the potential for consequences of
severe pertussis in the contact, and the possibility for secondary exposure of persons at high risk
of severe infection from the contact. The benefits of prophylaxis must be weighed against the
potential adverse effects of therapy.
The AAP recommends antimicrobial prophylaxis for all close contacts, such as child care
workers or household members, regardless of their immunization status. The AAP generally
78
does not recommend extensive prophylaxis for entire classrooms or schools; local public health
officials should be consulted for recommendations regarding control of pertussis in schools.
Antimicrobial prophylaxis in conjunction with therapy of infected patients has been shown to
be effective for the termination of nosocomial outbreaks of pertussis. Thus, prophylaxis should
be given to exposed healthcare workers and patients.
Close contacts are defined by:
Face-to-face exposure within three feet of a symptomatic patient.
Direct contact with respiratory, oral, or nasal secretions from a symptomatic patient.
Sharing the same confined space in close proximity with a symptomatic patient for 1 hour.
Risk factors Persons at high risk for severe or complicated pertussis include:
1. Infants younger than 1 year, particularly those younger than 4 months.

2. Persons with immunodeficiency.
3. Persons with underlying medical conditions (chronic lung disease, respiratory
insufficiency, cystic fibrosis).
Because of the risk of severe disease in infants younger than 1 year of age, especially those
younger than 4 months of age, women in the third trimester of pregnancy should be given
postexposure prophylaxis.
Isolation Standard precautions, as well as droplet precautions (mask within three feet), are
recommended for children with pertussis who are admitted to the hospital. These precautions
should be in effect until five days of effective therapy have been administered or three weeks
after the onset of symptoms in untreated patients.
Vaccination Routine vaccination of children and adolescents is the most important

preventive strategy. The CDC's Advisory Committee on Immunization Practices recommends five
doses of diphtheria and tetanus toxoid and acellular pertussis (DTaP) vaccine at ages 2, 4, 6, 15-
18 months, and 4-6 years of age.
Immunization of contacts Close contacts of the index case who are younger than 7 years of
age who are unimmunized or underimmunized should have pertussis immunization initiated or
continued according to the recommended schedule. A booster dose of Tdap should be
administered to persons 11 years of age or older if they have not received Tdap and if it has
been more than 2 to 5 years since they last received diphtheria-tetanus toxoid (Td) vaccination.
Immunization after pertussis infection Well-documented pertussis infection (e.g., a

positive culture for B. pertussis or an epidemiologic link to a culture-positive case) is likely to
confer immunity against pertussis. However the duration of immunity is unknown. The AAP
recommends that children who have had well documented pertussis disease complete the
79
primary diphtheria-tetanus-pertussis vaccine series with at least the diphtheria and tetanus
components of the vaccine. We suggest that such patients also receive the acellular component
(i.e., that they receive a full series of diphtheria-tetanus-acellular pertussis vaccine [DTaP]),
provided there are no contraindications and the DTaP vaccine is available.
Neonatal immunization Early neonatal immunization is a strategy that is being studied, but
is not yet recommended.
School or day care Because of the high risk of transmission, infected children should be
excluded from school or day care until they have completed five days of effective antimicrobial
therapy, or if they are not treated, 21 days after the onset of symptoms. Contacts of an infected
child should be closely observed for development of respiratory symptoms for at least 21 days
after the last contact with the infected individual.
80
Treatment and prevention of typhoid fever
Elizabeth L Hohmann, MD
Typhoid fever and paratyphoid fever (also known as enteric fever, but collectively referred to
here as typhoid fever) are severe systemic illnesses characterized by sustained fever and
abdominal symptoms.
PREVENTION Typhoid fever results from the ingestion of contaminated food or water. For
travelers, ingestion of the local cuisine is the main mechanism of acquiring infection, and the
inoculum in food is likely higher than that in contaminated water. A simple rule of thumb is "boil
it, cook it, peel it, or forget it."
TREATMENT Treatment of typhoid fever has been complicated by the development and
rapid dissemination of typhoidal organisms resistant to ampicillin, trimethoprim-
sulfamethoxazole, and chloramphenicol, which were previously considered the drugs of choice.
Antimicrobial regimens Typhoid fever is usually treated with a single antibacterial drug. The
choice of drug and duration of therapy for both children and adults is still an area of active
investigation. Choice will depend upon local resistance patterns, patient age, whether oral
medications are feasible, the clinical setting, and available resources. There may be locations
where older agents such as chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole are
appropriate, but these drugs are generally not used widely because of high levels of resistance.
Oral chloramphenicol is no longer available in the United States but can be obtained elsewhere
and is still used in other parts of the world. Successful treatment usually results in clinical
improvement within three to five days in uncomplicated cases. It is reasonable to begin with a
parenteral agent and then complete therapy with an oral drug once symptoms improve.
The practice preferences for children treated outside the United States, particularly in endemic
countries in Southeast Asia, more closely mirror treatment regimens used for adults including
one of the following:
ciprofloxacin 15 mg/kg daily, maximum 1000 mg and 800 mg per day either orally or
parenterally for 10 to 14 days.
ofloxacin 15 mg/kg daily, maximum 800 mg per day either orally or parenterally for 10 to 14
days
In children with infection due to a fully susceptible S. typhi strains one of the following
alternative regimens may be used:
chloramphenicol 100 mg/kg per day divided every six hours, maximum 3 g per day for 14 to 21
days.
ampicillin 100 mg/kg per day divided every eight hours, maximum 4 g per day for 10 to 14 days.
81
trimethoprim-sulfamethoxazole 8 mg/kg trimethoprim/40 mg/kg sulfamethoxazole per day
divided every six hours, maximum 320 mg trimethoprim/1600 mg sulfamethoxazole per day for
10 to 14 days.
Alternative agents in children with infection due to multiple resistant isolates, including
nalidixic acid-resistant S. typhi, include:
ceftriaxone 60 mg/kg per day intravenously once daily, maximum 2 g per day.
cefotaxime 80 mg/kg per day intravenously in three to four equally divided doses, maximum
12 g per day for 10 to 14 days.
ciprofloxacin or ofloxacin (20 mg/kg daily, maximum 1000 mg and 800 mg per day,
respectively), either orally or parenterally for 10 to 14 days.
Differences in practice preferences in children are in part due to concern in the United States
about the use of fluoroquinolones because of the well-known cartilage toxicity of these drugs in
immature animals. Fortunately, large series have found no evidence of acute adverse bone or
joint events or of adverse effects on growth in humans. These findings are reassuring and
suggest that, for a serious illness such as infection with MDR S. typhi, a fluoroquinolone may be
reasonably used in children when other less toxic agents are not available or appropriate.
The optimal duration of third generation cephalosporin therapy in children has not been firmly
established, but the following observations have been made:
A seven day course does not appear to be sufficient. In two randomized trials, seven days of
ceftriaxone (50 to 75 mg/kg per day) resulted in relapse within four weeks in 14 percent of
children. In one of these studies, children ages 4 to 17 were assigned to seven days of therapy
with either azithromycin (10 mg/kg per day; maximum 500 mg) or ceftriaxone (75 mg/kg per
day, maximum 2.5 g per day). There were four relapses with ceftriaxone compared to none with
azithromycin (14 versus 0 percent). Among the third generation cephalosporins, ceftriaxone
may be superior to cefotaxime. Oral cefixime is probably comparable to ceftriaxone for
uncomplicated typhoid although the two drugs have not been extensively studied head-to-head.
Based upon these observations, ceftriaxone or cefixime is probably best given for 10 to 14 days
to minimize risk of relapse.
Corticosteroids Early studies with chloramphenicol suggested that concomitant

corticosteroid therapy might be beneficial in patients with typhoid fever. In a randomized,
prospective, double blind study performed in Indonesia in the early 1980s, the administration of
3 mg/kg of dexamethasone as an initial dose with chloramphenicol was associated with a
substantially lower mortality in critically ill patients (shock, obtundation) with typhoid fever
compared with those who received chloramphenicol alone (10 versus 55 percent). Whether
these findings would be confirmed in the "post-chloramphenicol era" and in different clinical
settings is a question for debate, but severe typhoid fever remains one of the few indications for
82
corticosteroid therapy among acute bacterial infections. The recommended dose in adults and
children with severe disease (delirium, obtundation, stupor, coma or shock) is an initial dose of 3
mg/kg followed by 1 mg/kg every 6 hours for a total of 48 hours.
83
Clinical manifestations; diagnosis; and treatment of brucellosis
in children
E Dale Everett, MD
Brucellosis (also called undulant, Mediterranean, or Malta fever) is a zoonotic infection with
protean manifestations. Four species, Brucella melitensis, B. abortus, B. suis and B. canis, are
known to cause disease in humans. Brucella sp. are Gram negative, facultative intracellular
coccobacilli.
CLINICAL MANIFESTATIONS Brucellosis is a well-documented cause of fever of unknown

origin, with varied and nonspecific symptoms. In addition to fever, other prominent symptoms
include sweats, malaise, anorexia, fatigue, weight loss, and depression. The onset of symptoms
of brucellosis may be abrupt or insidious, developing over several days to weeks.
Virtually any organ system can be involved with brucellosis, and localization of the process may
cause focal symptoms or findings. In one report of 530 cases studied prospectively, 32 percent
developed a focal complication. Duration of symptoms for more than 30 days before diagnosis
was the major risk factor for developing focal disease.
The most common sites for localization are:
Osteoarticular, especially sacroiliitis 20 to 30 percent.
Genitourinary, especially epididymoorchitis 2 to 40 percent of males.
Neurobrucellosis, usually presenting as meningitis 1 to 2 percent; less common neurologic

complications include papilledema, optic neuropathy, radiculopathy, stroke, and intracerebral
hemorrhage.
Endocarditis 1 percent. ; most cases of endocarditis are left-sided, and about two-thirds
occur on previously damaged valves .
Hepatic abscess 1 percent.
In one large series of childhood brucellosis, the most common clinical manifestations among
102 patients were fever (91 percent), arthralgia (73 percent), malaise (60 percent), and weight
loss (48 percent). The most frequent abnormalities on physical examination were arthritis (37
percent), splenomegaly (35 percent), and hepatomegaly (28 percent). Large joints are affected
most commonly in children with osteoarticular manifestations of brucellosis. Hepatic or splenic
abscesses are extremely rare in children.
84
A syndrome termed chronic brucellosis manifested by malaise, asthenia, and depression, was a
relatively common diagnosis in the 1950s. However, most patients who had that diagnosis likely
represent the current population receiving a diagnosis of chronic fatigue syndrome.
DIAGNOSIS The diagnosis of brucellosis should be considered in an adult with otherwise

unexplained chronic fever and nonspecific complaints. Such patients should be questioned for
possible sources of exposure to Brucella, including contact with animal tissues or ingestion of
unpasteurized milk or cheese. The same sources should be sought for children with suspected
brucellosis. However, in the neonate, transplacental transmission or breast-milk-borne infection
may occur; these modes of transmission are especially important to consider in highly endemic
areas. The differential diagnosis varies, depending upon the presence or absence of focal
features.
Routine laboratory studies are nonspecific. White blood cell counts usually are normal to low
(pancytopenia can occur), and minor disturbances in hepatic enzymes are relatively common.
Although studies such as radiographs, bone scans, ultrasound scans, computerized tomography,
magnetic resonance imaging, and echocardiography may be helpful in isolating or delineating
focal disease, they do not provide a definitive diagnosis. In neurobrucellosis, abnormalities of
the cerebrospinal fluid (CSF) typically include a pleocytosis of 10 to 200 white blood cells that
are predominantly mononuclear, elevated levels of protein and hypoglycorrhachia.
Cultures Both cultures and serologic tests can be used to establish the diagnosis of
brucellosis. Ideally, the diagnosis is made by isolation of the organism from cultures of blood or
other sites, especially bone marrow or liver biopsy specimens. However, cultures are not always
positive; in one large series, for example, blood cultures were positive in only 80 percent of
initial infections.
An important problem is that Brucella sp. tend to be slow growing, which can lead to erroneous
results. Classically, the performance of cultures on biphasic media (Ruiz-Castaneda) or some
modification thereof has been recommended. Using these techniques, cultures generally
become positive between 7 and 21 days but may take up to 35 days. However, the use of
biphasic media is not routine in clinical laboratories, many of which use automated blood
culture systems such as BACTEC, routinely hold bottles for 5 to 7 days, and do not perform blind
subcultures of "negative" bottles. Although some isolates may grow and be detected in the
BACTEC system, cultures are unlikely to be positive in the 5- to 7-day period. Therefore, febrile
patients with unsuspected brucellosis likely will have negative cultures with standard blood
culture techniques.
Serologic tests Numerous diagnostic serologic tests have been developed for the diagnosis
of brucellosis:
Serum agglutination (standard tube agglutination).
Complement fixation.
85
Rose Bengal agglutination.
Antibrucella Coombs.
ELISA (enzyme-linked immunosorbent assay).
Most published results are derived from tube agglutination testing. The general consensus is
that a single titer of >1:160 in the presence of a compatible illness supports the diagnosis.
Demonstration of a fourfold or greater increase or decrease in agglutinating antibodies over 4 to
12 weeks provides even stronger evidence for the diagnosis.
TREATMENT
Children Avoiding the use of tetracyclines in children younger than 8 years is desirable. One
regimen that has been effective in children is oral trimethoprim-sulfamethoxazole (10 to 12
mg/kg per day of the trimethoprim component, 50 to 60 mg/kg per day of the sulfa component
in two divided doses) plus rifampin (15 to 20 mg/kg per day of rifampin up to a maximum of 600
mg PO daily in two divided doses) for six weeks; the relapse rate with this regimen is
approximately 3.5 percent.
Others have recommended trimethoprim-sulfamethoxazole plus rifampin with a short course

(14 days) of gentamicin for more serious infection or complications of brucellosis such as
endocarditis or meningitis.
Neurobrucellosis Neurobrucellosis requires special attention. Most authorities recommend

two or three drugs that cross the blood-brain-CSF barrier (such as doxycycline, rifampin, and
trimethoprim-sulfamethoxazole). The duration of therapy generally is prolonged, varying from 1
to 19 months. Therapy needs to be individualized according to signs and symptoms but
generally should be continued until analysis of the CSF has returned to normal.
The prognosis is variable in neurobrucellosis. In one report of 18 patients, only 11 showed

complete recovery of neurologic function. Corticosteroids have been used, but their role is not
clearly delineated.
Endocarditis Brucella endocarditis rarely is cured by medical therapy alone, despite therapy
with three or four drugs. Thus, most patients need valve replacement followed by several weeks
to months of antimicrobial therapy.
PREVENTION Prevention of brucellosis is largely through vaccination of domesticated herds

and flocks and serologic testing and slaughter of infected animals. Vaccinating cattle with live
attenuated vaccines, B. abortus strain 19, and sheep and goats with B. melitensis Rev-1, are
effective measures, but a sustained vaccination program over several years is required. No
vaccine is available for swine. Other measures include the quarantine of herds and the slaughter
of infected animals. Pasteurization of milk is very important for the prevention of transmission
to humans.
86
Mycoplasma pneumoniae infection in children
Dori F Zaleznik, MD - Jesus G Vallejo, MD
Mycoplasma pneumoniae is one of three species of Mycoplasma that frequently produce

infection in humans. Mycoplasmas are ubiquitous and are the smallest bacteria that can survive
alone in nature. M. pneumoniae causes a wide variety of clinical manifestations in children and
adults, principally pneumonia.
MICROBIOLOGY The term "mycoplasma" is widely used to refer to any organism within the
class Mollicutes, which is composed of five genera (Mycoplasma, Ureaplasma, Acholeplasma,
Anaeroplasma, and Asteroloplasma). More than 120 named Mycoplasma species exist, and 13
Mycoplasma species, two Acholeplasma species, and one Ureaplasma species have been
isolated from humans. However, only three species are well-established human pathogens:
Mycoplasma pneumonia.
Mycoplasma hominis.
Ureaplasma urealyticum.
M. pneumoniae grows under both aerobic and anaerobic conditions and can be isolated on
media supplemented with serum. The organism is fastidious, and isolation is not commonly
performed in clinical laboratories.
EPIDEMIOLOGY M. pneumoniae is transmitted from person to person by infected

respiratory droplets during close contact. The incubation period after exposure averages three
weeks. Infection occurs most frequently during the fall and winter but may develop year-round.
Although the frequency of pneumonia caused by all respiratory pathogens decreases in

children older than the age of five years, the relative importance of M. pneumoniae rises during
the school years. M. pneumoniae accounts for approximately 20 percent of acute pneumonias
in middle and high school students and up to 50 percent of cases in college students and military
recruits. The cumulative attack rate in families approaches 90 percent, and immunity is not long-
lasting.
CLINICAL FEATURES Many infections caused by M. pneumoniae are asymptomatic. When

present, the signs and symptoms vary according to the stage of illness. The onset of the illness is
gradual and usually is heralded by headache, malaise, and low grade fever. Chills are frequent,
but rigors are rare. Patient complaints usually exceed objective findings because abnormalities
on physical examination often are minimal.
Symptoms and signs caused by M. pneumoniae infection can be divided into those caused by
respiratory tract or extrapulmonary disease. None of these manifestations are unique to M.
pneumonia.
87
Respiratory tract disease Many more patients with respiratory infection caused by M.
pneumoniae have a respiratory tract illness without pneumonia than have pneumonia. In one
review, for example, 75 to 100 percent of infected patients had an intractable, nonproductive
cough, while only 3 to 10 percent developed pneumonia. The cough caused by M. pneumoniae
infection ranges from nonproductive to mildly productive. Wheezing and dyspnea also may
occur, although dyspnea is not a common complaint. Chills are common, but rigors are very
rare.
There may be no findings on chest auscultation even if pneumonia is present early in the course
of disease. However, scattered rales, wheezes, or both may develop later.
Extrapulmonary disease Extrapulmonary abnormalities are an important part of

mycoplasma disease and may suggest the diagnosis. These manifestations include hemolysis,
skin rash, joint involvement, and symptoms and signs indicative of gastrointestinal tract, central
nervous system (CNS), and heart disease. Whether the pathogenesis of some or all of these
entities is caused by immune mechanisms or to the direct action of the organisms is not clear.
Hemolysis Antibodies (IgM) to the I antigen on erythrocyte membranes appear during the
course of infection and produce a cold agglutinin response in approximately 60 percent of
patients. Why mycoplasma infections promote the production of such antibodies and their
significance in pathogenesis is not known. Although hemolysis may be severe, usually it is not
clinically significant
88
Skin disease Dermatologic manifestations may range from a mild erythematous
maculopapular or vesicular rash (which is most commonly seen accompanying respiratory tract
infections) to the Stevens-Johnson syndrome. In one report, for example, 16 percent of patients
with Stevens-Johnson syndrome have evidence of mycoplasma infection, which may be the
most common infectious agent associated with this syndrome. Antibiotics may intensify the
dermatosensitive potential of M. pneumoniae.
CNS involvement CNS manifestations occur in approximately 0.1 percent of all patients with
M. pneumoniae infections and in as many as 7 percent of patients requiring hospitalization. CNS
involvement occurs most frequently in children and includes aseptic meningitis,
meningoencephalitis, peripheral neuropathy, transverse myelitis, cranial nerve palsies, and
cerebellar ataxia. The pathogenesis of the CNS disease is uncertain. Possibilities include direct
infection and an immune-mediated reaction.
In cases of CNS involvement caused by M. pneumoniae, a history of an antecedent respiratory

illness usually, but not always, is found. In one retrospective review of cases at the Mayo Clinic,
for example, 7 percent of patients with M. pneumoniae pneumonia had CNS involvement.
Although uncommon, CNS involvement is associated with significant morbidity and mortality.
One study evaluated 61 individuals with neurologic disease attributed to M. pneumoniae and
found that five (8 percent) patients died and 14 (23 percent) had severe sequelae.
Gastrointestinal symptoms range from nonspecific (common) to those of pancreatitis (rare);

the latter disorder may be due in part to antibodies to M. pneumoniae.
Rheumatologic symptoms, including tender joints and muscles and a polyarthritis, can occur.
Although arthralgias are common, actual arthritis is rare. Arthritis is believed to result from
immune-mediated mechanisms; however, M. pneumoniae has been isolated from synovial fluid
in some patients with polyarthritis, suggesting a possible role for direct infection.
Cardiac and renal involvement is unusual. Cardiac manifestations include rhythm disturbances,
congestive heart failure, chest pain, and conduction abnormalities on the electrocardiogram.
Myocarditis rarely has been described in autopsy reports because the disease usually is not
fatal. Clinically significant glomerulonephritis is a rare complication that is presumed to be
secondary to immune complex deposition. In one case report, the glomerular disease correlated
with high titer cold agglutinins and the patient developed chronic renal failure. However, a
cause-and-effect relationship was not proven.
M. pneumoniae involving the lung results in four frequently described chest radiograph
patterns:
Bronchopneumonia.
Plate-like atelectasis.
89
Nodular infiltration.
Hilar adenopath.
The most common radiographic finding is the peribronchial pneumonia pattern, which consists
of a thickened bronchial shadow, streaks of interstitial infiltration, and areas of atelectasis;
these changes have a predilection for the lower lobes. Hilar adenopathy was noted in 34 percent
of children in one study. The finding of hilar adenopathy in children with suspected M.
pneumoniae infection should broaden the differential diagnosis to including tuberculosis.
Pleural effusions can be seen in as many as 20 percent of patients when lateral decubitus films
are performed. Empyema is a rare complication of M. pneumoniae pneumonia.
High-resolution CT (HRCT) scan is more sensitive for demonstrating abnormalities than is chest
radiography in cases of M. pneumoniae pneumonia.
Laboratory features Subclinical evidence of hemolytic anemia is present in most patients

with pneumonia, as suggested by a positive Coombs test and an elevated reticulocyte count.
Cold agglutinin titers are elevated in 50 percent of adult patients with mycoplasma disease, and
the titer usually exceeds 1:128 in patients with pneumonia. Less well studied in children, the
accuracy of the cold agglutinin test in detecting upper respiratory infection caused by M.
pneumoniae is not known, and specificity is low if the titer is less than 1:64 because a variety of
other respiratory pathogens may induce an increase in cold agglutinins. The peripheral white
blood cell count (WBC) is normal or slightly elevated with neutrophilia. Thrombocytosis can
occur and probably represents an acute phase response. Reported erythrocyte sedimentation
rates range from 20 to more than 100 mm/hr, with higher rates suggestive of more severe
pulmonary disease.
In patients with neurologic involvement, the cerebrospinal fluid (CSF) typically reveals a
lymphocytic pleocytosis, elevated protein, and normal glucose. Isolation of M. pneumoniae in
the CSF is possible but rare.
DIAGNOSIS There are no distinguishing clinical or radiologic manifestations that allow a

secure diagnosis of mycoplasma pneumonia versus chlamydial or viral pneumonia. Compared to
those with pyogenic pneumonia, however, patients with mycoplasma pneumonia tend to have a
more gradual onset of symptoms, less respiratory distress, and usually a normal white blood cell
count. However, these findings are neither sufficiently sensitive nor specific to exclude other
etiologies. A positive Gram stain and sputum culture can establish the diagnosis of bacterial
pneumonia, but young children cannot produce sputum and those that can may have a false
negative result because they have already been treated with antibiotics.
Cold agglutinins This test is probably the most commonly sent study for the diagnosis of
mycoplasma pneumonia. It is not a cost-effective approach because the study is neither
sensitive nor specific, and we do not recommend ordering it routinely.
90
Serology The most widely used approach for serodiagnosis is the complement fixation (CF)
test, which measures "early" IgM (predominantly) and IgG antibody (to a lesser extent) to M.
pneumoniae. A positive result is defined as:
A fourfold or greater increase in titer in paired sera OR
A single titer of greater than or equal to 1:32.
New diagnostic techniques Newer technology has been evaluated in an attempt to establish
the diagnosis when patients first present to medical attention. These tests include antigen
detection and polymerase chain reaction (PCR).
Thus, although not yet readily available clinically, PCR shows considerable promise in the
diagnosis of pathogens causing atypical pneumonia. The availability of a rapid diagnostic
technique would have enormous utility in distinguishing between pyogenic causes of
community-acquired pneumonia and the major pathogens causing atypical pneumonia.
TREATMENT The benefits of antimicrobial therapy for the treatment of upper respiratory
tract symptoms caused by M. pneumoniae have not been adequately studied in adults or
children. However, limited data in children suggest that a macrolide antibiotic or a tetracycline
should be prescribed when a lower respiratory tract infection is likely to be caused by M.
pneumoniae. One study from France, for example, measured pulmonary function six months
and one year after a documented mycoplasma infection; children who received macrolide
antibiotics started more than 10 days after symptom onset were more likely to have abnormal
lung diffusion capacity than those treated earlier (73 versus 30 percent).
Recommended regimens include erythromycin (30 to 40 mg/kg per day in four divided doses
for 10 days), clarithromycin (15 mg/kg per day in two divided doses for 10 days) or azithromycin
(10 mg/kg in one dose on the first day and 5 mg/kg in one dose for four days). Azithromycin and
clarithromycin have the advantages of less frequent dosing and fewer gastrointestinal
disturbances.
Tetracycline (20 to 50 mg/kg per day in four divided doses, maximum daily dose 1 to 2 g) and
doxycycline (2 to 4 mg/kg per day in one or two divided doses, maximum daily dose 100 to 200
mg) for ten days are equally effective and may be used in children eight years of age or older.
For hemolytic anemia, case reports indicate some patients respond to warming, steroid
therapy, and possibly plasmapheresis.
For CNS disease, therapy with steroids, antiinflammatory drugs, diuretics, and plasma exchange
have been used in addition to antibiotics without clear indication of benefit from any of these
modalities.
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Prevention and treatment of measles
David Bekhor, MD - Jorge L Barinaga, MD, MS - Paul R Skolnik, MD
Measles is one of the most contagious infectious diseases. Mathematical models have
estimated that the average number of secondary infections that follow a single introduction of
measles into a susceptible population ranges from 12 to 18. Despite the availability of safe and
effective vaccines since 1963, the World Health Organization (WHO) estimates that 530,000
children aged <15 years died of measles and its complications in 2003.
Of paramount importance in the prevention of measles is control of outbreaks. The Centers for
Disease Control and Prevention (CDC) defines a measles outbreak as a single confirmed case.
Case definitions Several case definitions have been established to standardize the approach
to measles outbreaks.
Suspected case A suspected case is defined as a febrile illness accompanied by rash.
Clinical case A clinical case is defined as an illness characterized by cough, coryza, or

conjunctivitis, a generalized rash lasting for more than three days, and a temperature >38.3C
(>101F).
Probable case A probable case meets the clinical case definition but is not linked
epidemiologically to a confirmed case and lacks serologic or virologic proof of disease.
Confirmed case A confirmed case meets the laboratory criteria for measles (independent of
clinical features) or meets the clinical case definition and is epidemiologically linked to a
confirmed case.
Outbreaks among infants In the case of infants exposed to measles, those aged 6 to 11
months can receive live measles vaccine, although they must be reimmunized at age 12 to 15
months and again before school entry. However, for infants exposed to measles within the
household, immunoglobulin administration may be preferable since they are at higher risk for
acquiring the infection.
Immune globulin Intramuscular immune serum globulin, if given to a susceptible person

within six days of exposure to measles, can prevent or modify disease. The CDC recommends a
dose of 0.25 mL/kg of body weight to a maximum dose of 15 mL. In the immunocompromised
host, the recommended dose is 0.5 mL/kg body weight to a maximum dose of 15 mL.
The administration of immune serum globulin may be especially indicated in exposed

individuals for whom the risk of complications of measles is increased such as pregnant women,
92
contacts less than one year of age, and immunocompromised hosts. Individuals previously
vaccinated, but now immunocompromised, should also receive IG for an exposure.
Live vaccine should be administered three months later to anyone receiving immune serum
globulin as long as they are at least 15 months of age at that time and there is no
contraindication to vaccination. The passively-acquired measles antibodies from the immune
serum globulin should have dissipated by three months. For contacts not belonging to these
high-risk groups, the administration of live measles vaccine within 72 hours of the exposure is
preferable to immune serum globulin administration.
MEASLES VACCINATION Measles vaccination has markedly reduced the incidence of

measles throughout the developed world. However, measles cases still occur in low-incidence
countries through importation by travelers. The maintenance of immunity in the population,
even in countries with a low incidence of measles, is important since waning immunity can
result in large measles outbreaks after a single imported case. The importance of maintenance
of immunity is underscored by a CDC analysis of United States measles cases reported from
2001 to 2004, which found that the majority of cases could have been prevented by vaccination.
Immunization is also important in preventing severe sequelae of measles infection, including
subacute sclerosing panencephalitis.
Vaccine effectiveness Ninety-five percent of children vaccinated with the current measles
vaccine develop anti-measles antibody if vaccinated at age 12 months and 98 percent if
vaccinated at age 15 months. If the first dose of the two-dose measles vaccination series is given
no sooner than 12 months of age, greater than 99 percent of recipients develop anti-measles
antibody. Measles vaccination usually leads to long-term immunity. Loss of immunity after
vaccination, termed secondary vaccine failure, has been reported but is considered rare.
Vaccination at age nine months is not normally done in the United States, but this approach is
used in many other countries. Estimates vary for the effectiveness of vaccination at this age, but
it may be approximately 85 percent.
Unless any of its components are contraindicated, MMR is the vaccine of choice for protection
against measles, mumps, and rubella rather than the monovalent and bivalent vaccines. Doses
of MMR and other measles-containing vaccines administered before the first birthday should
not be counted when determining the adequacy of measles vaccination. In September 2005, the
FDA approved the quadrivalent MMRV vaccine (measles, mumps, rubella, and varicella) for
persons aged 12 months to 12 years.
In developing countries with high measles incidence, maternal antibody levels against measles
may be low, and severe outbreaks can occur among infants before the recommended age of
vaccination at 9 months. In such circumstances, early vaccination (as early as 4.5 months of
age) may improve measles control but should not replace the doses given at 9 to 15 months
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Possible association with autism Concern has been raised periodically about a possible link
between receipt of MMR and autism. A number of studies have now been performed which fail
to demonstrate any such association.
CONTRAINDICATIONS TO MEASLES VACCINATION A number of patients are considered to

have absolute or relative contraindications to measles vaccination
Pregnancy Although no increase in risk of birth defects has been observed in mothers who
were given live measles or MMR vaccine during pregnancy, there is a theoretical risk of such
events. Thus, the vaccine is considered contraindicated in pregnant women. Women of
childbearing age should be counseled to avoid pregnancy for 30 days after vaccination.
Concurrent illness Vaccination should be delayed in persons with moderate to severe febrile
illnesses until resolution of the acute phase of the illness as long as the vaccine is not being
administered for an exposure. However, mild febrile or non-febrile illnesses do not mandate
delay of vaccination.
Allergies A history of anaphylaxis after ingestion of gelatin is associated with an increased

risk of anaphylaxis from the MMR or measles vaccine. This history should warrant a skin test for
gelatin allergy. Individuals with anaphylaxis (not contact dermatitis) from neomycin also should
not receive these vaccines because they contain a small amount of this antibiotic. By contrast, a
history of anaphylaxis after egg ingestion is not a contraindication to measles immunization.
Thrombocytopenia Persons with a history of thrombocytopenia are at increased risk of

developing significant thrombocytopenia after MMR vaccination. However, the benefits of
primary vaccination usually outweigh the risks. It may be prudent to avoid a second dose of
MMR in a person who has a history of thrombocytopenia occurring within six weeks of initial
vaccination.
Recent administration of immunoglobulins or blood products Vaccine efficacy is diminished

significantly by prior passive administration of antibody. Vaccination should be delayed for a
period of time after antibody administration. The length of time varies from 3 months to 11
months depending upon the amount of antibody in the preparation. The interval is six month
for those who have received packed red blood cells (unwashed) or whole blood, and seven
months for plasma/platelet preparations.
Immunocompromised patients Whether or not an immunocompromised host should

receive measles vaccination depends upon the degree of immunosuppression and the risk of
natural measles infection. Specific recommendations from the ACIP for measles vaccination in
patients with HIV/AIDS have been published. Live measles vaccine or MMR should be used with
caution in other severely immunocompromised persons.
Close contacts of these persons should be vaccinated appropriately since secondary

transmission has not been reported.
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Corticosteroid therapy It is recommended to delay MMR or live measles vaccination in
patients receiving prednisone (>2 mg/kg or 20 mg daily or every other day for more than 14
days). Vaccine should not be administered until at least one month after the cessation of
treatment.
Leukemia in remission Similar to patients receiving corticosteroids, a delay in vaccination is

advised for patients with leukemia in remission. These patients should be vaccinated no earlier
than three months after the termination of systemic chemotherapy.
ADVERSE EVENTS FOLLOWING VACCINATION A variety of adverse reactions have been

reported following measles and MMR administration.
Minor reactions Transient fever (39.4C or higher occurring one to two weeks after
vaccination) develops in 5 to 15 percent of vaccinees. Transient rash occurs in approximately 5
percent.
Allergic reactions Most hypersensitivity reactions to the vaccine are minor. Anaphylaxis can
occur but is extremely rare. Epinephrine should be available for use at any site that administers
this vaccine.
Thrombocytopenia In prospective studies, thrombocytopenia occurred in one case in 25,000

to 40,000 vaccine doses. This reaction is generally transient and occurs within two months of the
receipt of vaccine, most commonly at two to three weeks. As noted above, the risk may be
higher in those who experienced thrombocytopenia following previous vaccination with MMR.
Neurologic events The incidence of seizures after measles vaccination is low. It is higher in
vaccinees with a history of seizures or with a family history in first degree relatives. Most are
simple febrile seizures. The risk in most cases is outweighed by the benefits of vaccination.
Encephalitis occurs in approximately one of two million persons vaccinated. Guillain-Barr

syndrome is reported to occur following administration of vaccine, but evidence is insufficient to
support a causal link.
TREATMENT OF MEASLES INFECTION The treatment of measles is mostly supportive

because no specific therapy is of proven benefit. Supportive therapy includes antipyretics, fluids,
and treatment of bacterial superinfections such as bacterial pneumonia and otitis.
Vitamin A The first suggestion that vitamin A might be of benefit in the treatment of measles
was made in 1932.
The mechanism of action of vitamin A in measles is not known. It is possible that supplemental
vitamin A corrects a virally-induced state of hyporetinemia.
Guidelines The World Health Organization and UNICEF recommend that vitamin A (100,000
to 200,000 IU PO) be given to all children with measles in areas where vitamin A deficiency is
95
prevalent or where the mortality from measles exceeds one percent. This dose recommendation
is lower than the 400,000 IU dose (200,000 IU given on successive days) used in the referenced
trials.
The recommended regimens for vitamin A supplementation are:
Children 6 to 12 months 100,000 IU (50,000 IU/mL) as a single dose.
Children older than 12 months 200,000 IU (50,000 IU/mL) as a single dose.
For children with ophthalmologic evidence of vitamin A deficiency, repeat doses should be
administered on day 2 and day 28.
Ribavirin Measles virus is susceptible to ribavirin in vitro. While ribavirin in both the
systemic and aerosolized forms has been used to treat severe measles infection, there have
been no randomized controlled trials to assess its benefit. In one case report of three HIV-
infected children with measles who received aerosolized ribavirin, two of the three survived
initially but died within the subsequent three months. Another case series reported a favorable
outcome in five of six adults with severe measles pneumonitis who received intravenous
ribavirin; the patient who died of progressive respiratory failure received the drug on day 22 of
infection, compared to days two to five for the other patients.
96
Diagnosis of leishmaniasis
Karin Leder, MBBS, FRACP, PhD, MPH, DTMH-Peter F Weller, MD, FACP
Leishmaniasis, caused by a heterogeneous group of protozoan parasites belonging to the

genus Leishmania, results in a variety of different clinical syndromes. Since the areas in which
this infection is endemic are predominantly developing countries, diagnosis and therapy are
frequently hampered by suboptimal medical resources.
Laboratory findings in visceral leishmaniasis (VL) include pancytopenia and

hypergammaglobulinemia. Anemia, neutropenia, and thrombocytopenia are associated with
massive splenomegaly , anemia seems to develop from a combination of factors including
hemolysis, hypersplenism, blood loss, and bone marrow suppression. Neutropenia can be
profound, and eosinopenia is usually present. Eosinopenia is defined as a consistently low
percentage or absence of eosinophils in the differential white blood cell count. Abnormal liver
function tests, hypoalbuminemia and hyperbilirubinemia may also be detected.
Hypergammaglobulinemia results from polyclonal B cell activation. In addition to nonspecific

antibodies, increased specific antibodies to Leishmania are common. Circulating rheumatoid
factor and immune complexes are frequently present; the latter may lead to renal involvement
with glomerulonephritis.
Visceral syndromes VL can be diagnosed by aspirate or biopsy of any involved organ. Many
studies have shown splenic aspirates to be the most sensitive for histologic and culture
diagnosis, with one report suggesting a 96 to 98 percent sensitivity. However, some clinicians
prefer not to perform this procedure because of the risk of splenic rupture. Instead, bone
marrow biopsies can be done and are reported to have approximately 60 to 80 percent
sensitivity. Lymph node aspirations may also be positive but are less sensitive than bone
marrow specimens. In India, cultures of peripheral blood buffy coat may be positive for L.
donovani. Immunosuppressed patients with disseminated infections may also have such a high
burden of infection that parasite-containing monocytes may be visible in peripheral blood
smears.
Leishmania in histologic sections of tissue biopsies appear as round or oval intracellular

parasites that are 2 to 3 m in diameter. They can be stained with Giemsa, Wright's or
hematoxylin and eosin stain. The parasites characteristically have a large, dark-purple, eccentric
nucleus, blue-staining cytoplasm, and a characteristic, small, red-staining, rod-shaped
mitochondrial structure known as the kinetoplast. This structure helps to distinguish Leishmania
from Histoplasma species.
SEROLOGY: High parasite-specific antibody titers are frequently observed in patients with
active VL, which can be used as supportive data in the diagnosis.
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Specific tests Serologic tests using enzyme linked immunosorbent assay (ELISA), indirect
immunofluorescence (IFA) and direct agglutination tests (DAT) are available.
Enzyme linked immunosorbent assay The ELISA is the most sensitive and specific of these
methods, but it is also the most expensive and may not be available in developing countries.
Most studies suggest its sensitivity is >90 percent in VL. An ELISA test that can be used to
diagnose VL from urine has also recently been developed. The DAT uses fixed promastigotes and
is not as specific as ELISA. The IFA is approximately as sensitive as ELISA but is less specific.
Serology remains positive for months after cure and thus cannot be used to follow patients after
treatment.
K39 ELISA This assay uses the recombinant K39 protein as the antigen in ELISA assays to
detect antibodies in the serum of patients with VL and has been shown to be more specific in
active visceral disease. It has sensitivity of >95 percent in immunocompetent patients and
approximately 98 percent specificity. It can also be used in following patients after therapy. One
meta-analysis suggested that the K39 assay and the direct agglutination test were comparable in
diagnostic performance. However, this test is still not widely available for commercial use.
Strip tests Other recent advances include strip tests that are designed for easy use in the
field. One study compared a strip test using the rK39 antigen to rK39 ELISA for IgM and IgG
antibodies and the DAT in patients with parasitologically confirmed VL. The rK39 strip test was
positive least often of the three tests (67 versus 91 and 100 percent for the DAT and the rK39
IgG ELISA, respectively); rK39 IgM ELISA was only positive in 56 percent.
Polymerase chain reaction PCR is a sensitive diagnostic tool that also enables species
identification. It can be performed on almost any tissue and has been used in both cutaneous
leishmaniasis and VL. It is also useful for monitoring patients after treatment. Unfortunately, it is
not widely available in many endemic areas. Studies of PCR in VL have generally shown good
sensitivity and specificity. Several authors have reported consistent 100 percent specificity with
increasing sensitivity that overall is between 92 and 99 percent.
Treatment and prevention of leishmaniasis

GENERAL PRINCIPLES The treatment of leishmaniasis depends upon the form in which it
presents. Treatment usually involves a pentavalent antimonial compound, pentamidine, or
amphotericin B; however, many different therapies and combinations have been tried.
PENTAVALENT ANTIMONIAL COMPOUNDS The pentavalent antimony derivatives are the

standard recommended therapy for cutaneous, mucocutaneous, and visceral leishmaniasis in
most situations. There are two agents: sodium antimonylgluconate (or stibogluconate, also
known as Pentostam) and N-methylglucamine antimoniate (or meglumine antimoniate, also
known as Glucantime).
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AMPHOTERICIN B AND LIPID FORMULATIONS Amphotericin B is being increasingly used in
the treatment of visceral leishmaniasis, because of the development of newer, less toxic
formulations of this drug and increasing resistance to other agents. Liposomal preparations of
amphotericin are now considered by many to be the treatment of choice for Indian and
Mediterranean VL.
Liposomal amphotericin B (Ambisome) Liposomal amphotericin (AmBisome) is

recommended at a dose of 3 mg/kg per day on days 1 to 5 and on days 14 and 21, except in
immunocompromised patients who should instead receive 4 mg/kg per day on days 1 to 5, and
days 10, 17, 24, 31, and 38 [31] . Various studies conducted at the same center in India have
demonstrated that low dose and single dose AmBisome are effective in the treatment of VL. An
open label trial of low dose AmBisome (5 mg/kg as a single dose or 1 mg/kg per day for five
days) in 91 patients with positive splenic aspirates for L. donovani showed a complete response
in 92 percent of patients without significant differences between the two regimens.
Amphotericin B lipid complex (Abelcet) An open-label, randomized dose-finding trial in 405

Indian patients assessed the efficacy and safety of a six-day course of amphotericin B lipid
complex (ABLC) for visceral leishmaniasis. Definitive cure at six months after treatment was
approximately 97 percent in all dosing groups and treatment completion rates were excellent.
Miltefosine is a phosphocholine analogue that can be given orally. It has antileishmanial

activity in vitro and in vivo, probably via effects on cell-signaling pathways and membrane
synthesis.
Pentamidine isethionate is an aromatic diamidine compound.
Mechanism of action The exact mechanism of action of this drug in leishmaniasis has not
been clearly defined, but it inhibits dihydrofolate reductase and interferes with aerobic
glycolysis in protozoa. Pentamidine may also inhibit DNA, RNA, and protein synthesis.
Parenteral paromomycin (aminosidine) acts synergistically with antimonials in the treatment

of VL and has shown variable cure rates when used alone. In a randomized, controlled, open-
label study in India comparing paromomycin with amphotericin B in 667 patients with visceral
leishmaniasis, paromomycin was demonstrated to be noninferior to amphotericin B (cure rate
95 versus 99 percent) although adverse events were common in the paromomycin-treated
group (six versus two percent) .
Allopurinol, at best, may have a role as an adjunctive agent with antimonials for VL. However,
most studies do not support significant efficacy.
Immunotherapy with IFN-gamma or with a combination of leishmania promastigote antigens

and live Bacillus Calmette-Gurin (BCG) has also been used with some success. However, most
reports involve uncontrolled studies that are difficult to interpret.
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FOLLOW-UP TO THERAPY Follow-up parasitologic testing is only recommended if patients
have a clinical relapse. Relapse of VL following therapy is suggested by an increase in spleen size,
a fall in hemoglobin, or a fall in white blood cells (especially eosinophils). Relapses usually occur
within two to six months after completing therapy but can be delayed by years, particularly in
individuals who become immunocompromised in the interim. If a patient relapses following
therapy, a higher dose, longer course, or alternative treatment regimen should be considered.
PREVENTION There is no vaccine to prevent the acquisition of infection, although attempts

are in progress. Since protective immunity may not be universal, even after clinical disease, it is
likely that antileishmanial antibodies are not protective against reinfection.
A number of other approaches have been tried to control of leishmaniasis. These include
vector control with insecticides or by reducing breeding sites; control of animal reservoirs;
personal protective measures against sandfly bites; and early diagnosis and treatment of cases.
100
THE DIGESTIVE SYSTEM
Gastroesophageal reflux in infants

Harland S Winter, MD
DEFINITIONS In the following discussion, the term "uncomplicated gastroesophageal

reflux" is used to describe the finding of frequent regurgitation in the absence of pathological
consequences. "Gastroeophageal reflux disease" or GERD, is used when the reflux has
pathological consequences, including esophagitis, nutritional compromise, or respiratory
complications. The term "regurgitate" describes reflux to the oropharynx, and "vomit"
describes expulsion of the refluxate out of the mouth, but not necessarily repetitively or with
force. The terms are not clearly distinguished in clinical practice. In this review, we will use the
term "regurgitate" to describe obvious gastroesophageal reflux, whether or not the refluxate
comes outside of the mouth.
Natural history Gastroesophageal reflux is extremely common in healthy infants, in whom

gastric fluids reflux into the esophagus 30 or more times daily. Many, but not all of these reflux
episodes result in regurgitation into the oral cavity. The frequency of reflux, as well as the
proportion of reflux episodes that result in regurgitation, decreases with increasing age, such
that regurgitation or vomiting decreases toward the end of the first year of life, and is unusual in
children older than 18 months old.
Association with GERD Although the relationship between regurgitation during childhood
and the subsequent development of GERD has not been well studied, one report suggested that
frequent episodes of regurgitation during infancy may be associated with an increased
likelihood of having GERD symptoms in later childhood.
DIAGNOSTIC TESTS
Esophageal pH and impedance monitoring Esophageal pH monitoring (pH probe) is rarely

useful in establishing the diagnosis of gastroesophageal reflux (GER) in infants.
Radiographic studies An upper gastrointestinal series may be helpful to exclude anatomic

abnormalities, but does not contribute to the diagnosis of GERD because infants with and
without GERD may have reflux episodes observed during the study.
Endoscopic studies Upper endoscopy is of diagnostic benefit in patients who have not
responded to dietary or empiric clinical trials and/or are suspected of having dietary protein
101
intolerance. Biopsies of the esophagus, stomach or duodenum may reveal inflammation
characteristic of dietary protein intolerance (often termed "allergy") or other systemic disorders.
CLINICAL APPROACH When evaluating an infant with frequent regurgitation, the clinician
should determine if the symptom is caused by underlying pathological disease, or if there is
evidence that the reflux is causing secondary complications such as esophagitis or failure to
thrive. In most children younger than one year of age who are thriving and who do not have
evidence of gastrointestinal blood loss or recurrent pneumonia, the reflux is uncomplicated, and
little intervention is required.
A small minority of infants develop other symptoms, including failure to thrive, hematemesis,
and anemia, suggesting the possibility of gastroesophageal reflux disease (GERD). A
manifestation consisting of arching of the back, torsion of the neck, and lifting up of the chin
(Sandifer syndrome) can be confused with torticollis. Although irritability and feeding refusal
sometimes are attributed to GERD, the relationship is less clear.
Warning signals of underlying pathology The presence of warning signals suggests that an
infant's reflux may be related to an underlying disease. These findings should prompt further
evaluation for gastrointestinal or systemic disease. Warning signals include:
Symptoms of gastrointestinal obstruction or disease
Bilious vomiting.
GI bleeding: hematemesis, hematochezia.
Forceful vomiting.
Onset of vomiting after six months of life.
Constipation.
Diarrhea.
Abdominal tenderness, distension.
Symptoms suggesting systemic or neurologic disease
Hepatosplenomegaly .
Bulging fontanelle.
Macro/microcephaly.
Seizures.
Genetic disorders (eg, Trisomy 21).
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Other chronic disorders (eg, HIV).
Nonspecific symptoms
Fever.
Lethargy.
Failure to thrive.
Uncomplicated gastroesophageal reflux In most infants presenting with gastroesophageal

reflux in the form of frequent regurgitation, warning signals will be absent. If the infant also has
good weight gain, feeds well, and is not unusually irritable, he or she can be considered to have
"uncomplicated" gastroesophageal reflux. Such children (sometimes referred to as "happy
spitters") usually do not require specific testing. The history and physical examination usually
are sufficient for establishing the diagnosis.
Reflux and poor weight gain Infants with recurrent regurgitation and poor weight gain
should undergo evaluation for the adequacy of caloric intake and the effectiveness of
swallowing. Poor weight gain despite an adequate intake of calories should prompt evaluation
for causes of regurgitation and weight loss other than GERD. This evaluation may include
laboratory testing (stool testing for occult blood, complete blood count, electrolytes, liver
function tests, serum ammonia, glucose, urinalysis, urine ketones and reducing substances, and
a review of newborn screening tests). In older infants who have been exposed to wheat, rye or
barley, serologic screening for celiac disease should be performed (preferably tissue
transglutaminase, tTG, as well as a total IgA to rule out false-negative testing due to IgA
deficiency).
Infants with dietary protein gastroenteropathy may or may not have evidence of colitis as
revealed by gross or occult rectal bleeding. To investigate this diagnosis in formula-fed infants,
an empiric trial of a hypoallergenic formula can be performed. In breast-fed infants cow's milk,
foods containing dairy and beef should be completely eliminated from the mother's diet. A
change in the infant's symptoms may not be seen for a few days, until the offending antigens
clear the breast milk. If there is not a clear response to the diet change within a few weeks,
other diagnoses and treatments should be explored.
If GERD is established or continues to be suspected after the above evaluation, treatment

options include thickening the formula or of expressed breast milk, an increase in the caloric
density of the formula, or suppression of gastric acidity.
If an infant fails to respond to these treatment trials or is ill-appearing, evaluation with upper
endoscopy may be appropriate. Treatment depends on the gross and histological findings.
Apnea or apparent life-threatening events An association between GERD and apparent life-
threatening events (ALTE) is frequently considered, but rarely established with certainty.
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Persistent wheezing Although reflux may be associated with respiratory disorders in infants,
including recurrent stridor, chronic cough, recurrent pneumonia, and reactive airway disease.
The presence of such symptoms should prompt an evaluation for causes other than GERD.
Although associations between wheezing and GERD have been demonstrated in adults and in
some groups of children, there is less evidence for this association in infants.
TREATMENT OPTIONS
Lifestyle changes A number of lifestyle changes have been investigated for infants with
either uncomplicated reflux or GERD.
For uncomplicated reflux no intervention is required, although a trial of a milk-free diet and
thickening of feeds may be considered if the reflux is causing significant adverse effects on
quality of life. Prone positioning is not recommended for these infants. Avoidance of over-
feeding and of tobacco smoke may improve the symptoms.
Milk-free diet Some studies report that up to 40 percent of infants with gastroesophageal
reflux have a cow's milk protein intolerance, or "dietary protein-induced gastroenteropathy".
The majority of these infants will be sensitive to cow's milk protein along, but a substantial
number are also sensitive to soy proteins. thus, in formula-fed infants, substitution of soy-based
formulas is not recommended. Because this is generally a clinical diagnosis, initiating a one- to
two-week trial of a hypoallergenic diet is appropriate, particularly if the condition is complicated
by poor weight gain, irritability, or feeding refusal. If the infant has a history of atopic symptoms,
elimination of additional dietary proteins or use of an amino acid based formula may be
necessary.
Breast-fed infants can be treated with careful elimination of all cow's milk proteins and beef
from the mother's diet. Major sources of soy protein may need to be eliminated as well. The
response to this change is often more delayed than in formula-fed infants because it takes
longer to eliminate the offending protein from breast milk and small amounts of milk or beef
protein may found in foods.
Thickening feeds Milk-thickening agents appear to improve symptoms and some objective
measures of reflux frequency.
In addition, thickening can increase the caloric density of the formula, which may be helpful in
children who are underweight as a result of having GERD. The caloric density of 1 ounce of
formula thickened with 1 tablespoonful of rice cereal is approximately 34 Kcal per ounce (1
tablespoon per 2 ounce formula provides a caloric density of 27 Kcal per ounce).
Positioning therapy Infants younger than 12 months of age should generally be placed in
the supine position for sleep, even if they have reflux. Although the prone position tends to
reduce measures of reflux, it is also associated with a higher risk for sudden infant death
104
syndrome (SIDS), and this risk generally outweighs the potential beneficial effect of prone
sleeping on reflux.
Semi-supine positioning (in an infant seat) is not helpful, as it increases reflux. Similarly,
elevation of the head of the crib has no effect on reflux for infants placed in the supine position,
although the intervention is frequently recommended.
Pharmacotherapy Acid suppression and prokinetic medications have a limited role in the
treatment of infants with regurgitation, and in most patients. They are not valuable in the
treating children less than one year of age with uncomplicated gastroesophageal reflux ("happy
spitters").
A limited trial of acid suppression may be appropriate for infants with suspected
gastroesophageal reflux disease, in whom conservative measures including milk-free diet have
failed. Effective acid suppression is indicated for infants with esophagitis documented by
endoscopy with biopsies, although minor histologic changes may not be clinically significant.
When acid suppression treatment is chosen, a proton pump inhibitor (PPI) is generally
preferred. These agents have been moderately well studied for the short-term treatment of
infants, and are both safe and effective. Infants and younger children metabolize PPIs more
rapidly than older children and require higher per-kilogram dosing than older individuals. To be
most effective, they should be taken 30 minutes prior to the first meal/feeding of the day.
Unlike histamine type 2 receptor antagonists, PPIs do not lose efficacy with prolonged use.
Omeprazole, lansoprazole, esomeprazole, and pantoprazole have all been studied in young
children and some have formulations that facilitate administration to infants and young
children.
Prokinetic agents currently have a minimal role in the treatment of gastroesophageal reflux in
this age group.
For initial treatment of esophagitis in infants, a proton-pump inhibitor (PPI) is most effective
105
Acute Gastroenteritis in Children
Zulfiqar Ahmed Bhutta
The World Health Organization (WHO) suspects that there are >700 million episodes of
diarrhea annually in children <5 yr of age in developing countries. While global mortality may be
declining, the overall incidence of diarrhea remains unchanged at about 3.2 episodes per child
year.
Gastroenteritis is due to infection acquired through the feco-oral route or by ingestion of

contaminated food or water. Gastroenteritis is associated with poverty, poor environmental
hygiene, and development indices. Enteropathogens that are infectious in a small inoculum
(Shigella, Escherichia coli, noroviruses, rotavirus, Giardia lamblia, Cryptosporidium parvum,
Entamoeba histolytica) can be transmitted by person-to-person contact, whereas others such as
cholera are generally a consequence of contamination of food or water supply.
RISK FACTORS FOR GASTROENTERITIS
Major risks include environmental contamination and increased exposure to

enteropathogens. Additional risks include young age, immune deficiency, measles,
malnutrition, and lack of exclusive or predominant breast-feeding. Malnutrition
increases severalfold the risk of diarrhea and associated mortality.
CLINICAL EVALUATION OF DIARRHEA.
The most common manifestation of gastrointestinal tract infection in children is

diarrhea, abdominal cramps, and vomiting. Systemic manifestations are varied and
associated with a variety of causes. The evaluation of a child with acute diarrhea
includes:
Assess the degree of dehydration and acidosis and provide rapid resuscitation and
rehydration with oral or intravenous fluids as required.
Obtain appropriate contact or exposure history. This includes information on

exposure to contacts with similar symptoms, intake of contaminated foods or
water, child-care center attendance, recent travel to a diarrhea-endemic area, and
use of antimicrobial agents.
Clinically determine the etiology of diarrhea for institution of prompt antibiotic

therapy, if indicated. Although nausea and vomiting are nonspecific symptoms,
they are indicative of infection in the upper intestine. Fever is suggestive of an
inflammatory process but also occurs as a result of dehydration or co-infection
(e.g., urinary tract infection, otitis media). Fever is common in patients with
inflammatory diarrhea. Severe abdominal pain and tenesmus are indicative of
106
involvement of the large intestine and rectum. Features such as nausea and
vomiting and absent or low-grade fever with mild to moderate periumbilical pain
and watery diarrhea are indicative of small intestine involvement and also reduce
the likelihood of a serious bacterial infection.
Symptoms Associated with Dehydration
MILD TO
MINIMAL OR NO MODERATE SEVERE
DEHYDRATION DEHYDRATION (3 DEHYDRATION (>9%
(<3% LOSS OF 9% LOSS OF BODY LOSS OF BODY
SYMPTOM BODY WEIGHT) WEIGHT) WEIGHT)
Mental Well;alert Normal, fatigued or Apathetic, lethargic,
status restless, irritable unconscious
Thirst Drinks normally; Thirsty;eager to drink Drinks poorly; unable to
might refuse liquids drink
Heart rate Normal Normal to increased Tachycardia, with
bradycardia in most
severe cases
Quality of Normal Normal to decreased Weak, thready, or
pulses impalpable
Breathing Normal Normal;fast Deep
Eyes Normal Slightly sunken Deeply sunken
Tears Present Decreased Absent
Mouth and Moist Dry Parched
tongue
Skinfold Instant recoil Recoil in <2 sec Recoil in >2 sec
Capillary Normal Prolonged Prolonged;minimal
refill
Extremities Warm Cool Cold;mottled;cyanotic
Urine output Normal to decreased Decreased Minimal
107
Summary of Treatment Based on Degree of Dehydration
DEGREE OF REHYDRATION REPLACEMENT OF
DEHYDRATION THERAPY LOSSES NUTRITION
Minimal or no Not applicable <10 kg body weight: Continue breast-
dehydration 60120 mL oral feeding, or
rehydration solution resume age-
(ORS) for each appropriate
diarrheal stool or normal diet after
vomiting episode; >10 initial hydration,
kg body weight: 120 including
240 mL ORS for each adequate caloric
diarrheal stool or intake for
vomiting episode maintenance[*]
Mild to moderate ORS, 50100 mL/kg Same Same
dehydration body weight over 34 hr
Severe Lactated Ringer solution Same;if unable to Same
dehydration or normal saline in 20 drink, administer
mL/kg body weight through nasogastric
intravenous amounts tube or administer 5%
until perfusion and dextrose normal
mental status improve; saline with 20 mEq/L
then administer 100 potassium chloride
mL/kg body weight intravenously
ORS over 4 hr or 5%
dextrose normal saline
intravenously at twice
maintenance fluid rates
STOOL EXAMINATION.
Stool specimens should be examined for mucus, blood, and leukocytes. Fecal
leukocytes are indicative of bacterial invasion of colonic mucosa, although some patients
with shigellosis have minimal leukocytes at an early stage of infection, as do patients
infected with Shiga toxinproducing E. coli and E. histolytica. In endemic areas, stool
microscopy must include examination for parasites causing diarrhea, such as G. lamblia
and E. histolytica.
Stool cultures should be obtained as early in the course of disease as possible from
children with:
108
Bloody diarrhea in whom stool microscopy indicates fecal leukocytes;
In outbreaks with suspected hemolytic-uremic syndrome (HUS); and
In immunosuppressed children with diarrhea.
In most previously healthy children with uncomplicated watery diarrhea, no

laboratory evaluation is needed except for epidemiologic purposes.
TREATMENT
The broad principles of management of acute gastroenteritis in children include oral rehydration
therapy, enteral feeding and diet selection, zinc supplementation, and additional therapies such
as probiotics
ORAL REHYDRATION THERAPY.
Dehydration must be evaluated rapidly and corrected in 46 hr according to the degree

of dehydration and estimated daily requirements. A small minority of children, especially
those in shock or unable to tolerate oral fluids, require initial intravenous rehydration, but
oral rehydration is the preferred mode of rehydration and replacement of ongoing losses.
Risks associated with severe dehydration that may necessitate intravenous resuscitation
include: age <6 mo, prematurity, chronic illness, fever >38C if < 3 mo or >39C if 3
36 mo, bloody diarrhea, persistent emesis, poor urine output, sunken eyes, and a
depressed level of consciousness. Although, in general, the standard WHO oral
rehydration solution (ORS) is adequate, lower osmolality oral rehydration fluids can be
more effective in reducing stool output. Compared with standard ORS, lower sodium and
glucose ORS (containing 75 mEq of sodium and 75 mmol of glucose per liter, with total
osmolarity of 245 mOsm per liter) reduces stool output, vomiting, and the need for
intravenous fluids without substantially increasing the risk of hyponatremia.
Composition of Commercial Oral Rehydration Solutions (ORS) and Commonly

Consumed Beverages
SODIU POTASSI CHLORI
M UM DE BASE[*] OSMOLAR
CARBOHYDR (MMOL (MMOL/ (MMOL/ (MMOL ITY
SOLUTION ATE (G/L) /L) L) L) /L) (MOSM/L)
ORS
World 13.5 75 20 65 10 245
Health
Organization
(WHO)
[2005]
WHO [2002] 13.5 75 20 65 30 245
109
SODIU POTASSI CHLORI
M UM DE BASE[*] OSMOLAR
CARBOHYDR (MMOL (MMOL/ (MMOL/ (MMOL ITY
SOLUTION ATE (G/L) /L) L) L) /L) (MOSM/L)
WHO (1975) 20 90 20 80 30 311
European
Society of
Paediatric
Gastroenterol 16 60 20 60 30 240
ogy,
Hepatology
and Nutrition
Enfalyte[] 30 50 25 45 34 200
Pedialyte[] 25 45 20 35 30 250
Rehydralyte[ 25 75 20 65 30 305
]
CeraLyte[**] 40 5090 20 NA[] 30 220

COMMONLY USED BEVERAGES (NOT APPROPRIATE FOR DIARRHEA
TREATMENT)
Apple 120 0.4 44 45 N/A 730
juice[]
Coca-Cola[] 112 1.6 N/A N/A 13.4 650
Classic
Cereal-based oral rehydration fluids can also be advantageous in malnourished children

and can be prepared at home. Home remedies including decarbonated soda beverages,
fruit juices, and tea are not suitable for rehydration or maintenance therapy as they have
inappropriately high osmolalities and low sodium concentrations.
Oral rehydration should be given to infants and children slowly, especially if they have
emesis. It can be given initially by a dropper, teaspoon, or syringe, beginning with as
little as 5 mL at a time. The volume is increased as tolerated. Oral rehydration can also be
given by a nasogastric tube if needed.
Limitations to oral rehydration therapy include shock, an ileus, intussusception,

carbohydrate intolerance (rare), severe emesis, and high stool output (>10 mL/kg/hr).
110
ENTERAL FEEDING AND DIET SELECTION.
Continued enteral feeding in diarrhea aids in recovery from the episode and a continued
age-appropriate diet after rehydration is the norm.
Breast-feeding or nondiluted regular formula should be resumed as soon as possible. Foods with
complex carbohydrates (rice, wheat, potatoes, bread, and cereals), lean meats, yogurt, fruits,
and vegetables are also tolerated. Fatty foods or foods high in simple sugars (juices, carbonated
sodas) should be avoided.
In selected circumstances when adequate intake of energy-dense food is problematic, the

addition of amylase to the diet through germination techniques can also be helpful.
With the exception of acute lactose intolerance in a small subgroup, most children with
diarrhea are able to tolerate milk and lactose-containing diets. Withdrawal of milk and
replacement with specialized (and expensive) lactose-free formulations are unnecessary.
Although children with persistent diarrhea are not lactose intolerant, administration of a
lactose load exceeding 5 g/kg/day may be associated with higher purging rates and
treatment failure. Alternative strategies for reducing the lactose load while feeding
malnourished children with prolonged diarrhea include addition of milk to cereals as
well as replacement of milk with fermented milk products such as yogurt.
Rarely, when dietary intolerance precludes the administration of cow's milkbased

formulations or milk it may be necessary to administer specialized milk-free diets such as
a comminuted or blenderized chicken-based diet or an elemental formulation.
Although effective in some settings, the latter are unaffordable in most developing
countries. In addition to rice-lentil formulations, the addition of green banana or
pectin to the diet has also been shown to be effective in the treatment of persistent
diarrhea.
ZINC SUPPLEMENTATION.
There is strong evidence that zinc supplementation in children with diarrhea in

developing countries leads to reduced duration and severity of diarrhea and could
potentially prevent 300,000 deaths. WHO and UNICEF recommend that all children with
acute diarrhea in at-risk areas should receive oral zinc in some form for 1014 days
during and after diarrhea (10 mg/day for infants <6 mo of age and 20 mg/day for those >6
mo). In addition to improving diarrhea, administration of zinc in community settings
leads to increased use of ORS and reduction in the use of antimicrobials.
ADDITIONAL THERAPIES.
The use of probiotic nonpathogenic bacteria for prevention and therapy of diarrhea has
been successful in developing countries. There are a variety of organisms (Lactobacillus,
Bifidobacterium) that have a good safety record; therapy has not been standardized and
the most effective (and safe) organism has not been identified.
111
Antimotility agents (loperamide) are contraindicated in children with dysentery and
probably have no role in the management of acute watery diarrhea in otherwise healthy
children. Similarly, antiemetic agents such as the phenothiazines are of little value and
are associated with potentially serious side effects (lethargy, dystonia, malignant
hyperpyrexia). Nonetheless, ondansetron is an effective and less toxic antiemetic agent.
Because persistent vomiting may limit oral rehydration therapy, a single sublingual dose
of an oral dissolvable tablet of ondansetron (2 mg children 815 kg; 4 mg children <15
30 kg; 8 mg children >30 kg) may be given. However, most children do not require
specific antiemetic therapy; careful oral rehydration therapy is usually sufficient
ANTIBIOTIC THERAPY
Timely antibiotic therapy in select cases of diarrhea may reduce the duration and severity
of diarrhea and prevent complications .While these agents are important to use in specific
cases, their widespread and indiscriminate use leads to the development of antimicrobial
resistance. Nitazoxanide, an anti-infective agent, has been effective in the treatment of a
wide variety of pathogens including Cryptosporidum parvum, Giardia lamblia,
Entamoeba histolytica, Blastocystis hominis, C. difficile, and rotavirus.
Antibiotic Therapy for Infectious Diarrhea

DOSE AND
DURATION OF
ORGANISM DRUG OF CHOICE TREATMENT
Shigella (severe dysentery Ciprofloxacin, ampicillin, ceftriaxone, Ceftriaxone IV,
and EIEC dysentery) or trimethoprim-sulfamethoxazole IM 50100
(TMP-SMX). mg/kg/d qd, bid
7d
Most strains are resistant to many Ciprofloxacin PO
antibiotics. 2030 mg/kg/d bid
710 d
10 mg/kg/d of
TMP and 50
mg/kg/d of SMX
bid 5 d
Ampicillin PO, IV
50100 mg/kg/d
qid 7 d
EPEC, ETEC, EIEC TMP-SMX or ciprofloxacin 10 mg/kg/d of
TMP and 50
mg/kg/d of SMX
bid 5 d
Ciprofloxacin PO
112
DOSE AND
DURATION OF
2030 mg/kg/d qid
for 510 d
Salmonella No antibiotics for uncomplicated See treatment of
gastroenteritis in normal hosts caused by Shigella
non-typhoidal species.
Treatment indicated in infants <3 mo,
and patients with malignancy, chronic
GI disease, severe colitis
hemoglobinopathies, or HIV infection,
and other immunoincompetent patients.
Most strains have become resistant to
multiple antibiotics.
Aeromonas/Plesiomonas TMP-SMX 10 mg/kg/d of
TMP and 50
mg/kg/d of SMX
bid for 5 d
Ciprofloxacin Ciprofloxacin PO
2030 mg/kg/d
divided bid 710
d
Yersinia spp. Antibiotics are not usually required for
diarrhea.
Deferoxamine therapy should be
withheld for severe infections or
associated bacteremia. Treat sepsis as
for immunocompromised hosts, using
combination therapy with parenteral
doxycycline, aminoglycoside, TMP-
SMX, or fluoroquinolone.
Campylobacter jejuni Erythromycin or azithromycin Erythromycin PO,
50 mg/kg/d
divided tid 5 d
Azithromycin PO,
510 mg/kg/d qid
5d
Clostridium difficile Metronidazole (first line) PO 30 mg/kg/d
divided tid 5 d
Discontinue initiating antibiotic
113
DOSE AND
DURATION OF
Vancomycin (2nd line) PO 40 mg/kg/d qid
7d
Entamoeba histolytica Metronidazole followed by iodoquinol PO 3040 mg/kg/d
or paromomycin tid 710 d
PO 3040 mg/kg/d
tid 20 d
PO 2535 mg/kg/d
tid 7 d
Giardia lamblia Furazolidone or metronidazole or Furazolidone PO
albendazole or quinacrine 25 mg/kg/d qid for
57 d
Metronidazole PO
3040 mg/kg/d tid
7d
Albendazole PO
200 mg bid 10 d
Cryptosporidium spp. Nitazoxanide PO treatment may not be Children 13 yr:
needed in normal hosts. In 100 mg bid 3 d
immunocompromised, PO
Children 411 yr:
immunoglobulin + aggressively treat
200 mg bid
HIV, etc.
Adults: 500 mg
bid
Isospora spp. TMP-SMX PO 5 mg/kg/d and
25 mg/kg/d,
respectively, bid
710 d
Cyclospora spp. TMP/SMX PO 5 mg/kg/d and
25 mg/kg/d
respectively, bid
7d
Blastocystis hominis Metronidazole or iodoquinol Metronidazole PO
3040 mg/kg/d tid
710 d
Iodoquinol PO 40
mg/kg/d tid 20 d
bid, 2 times a day; EIEC, Enteroinvasive Escherichia coli;EPEC, Enteropathogenic E.
114
coli; ETEC, Enterotoxigenic E. coli; IM, intramuscular; IV, intravenous; PO, oral; qd,
daily; qid, 4 times a day, SMX, sulfamethoxazole; tid, 3 times a day; TMP, trimethoprim.
PREVENTION
In many developed countries, diarrhea due to pathogens such as Clostridum botulinum, E.

coli 0157 : H7, Salmonella, Shigella, V. cholerae, Cryptosporidium, and Cyclospora is a
notifiable disease and, thus, contact tracing and source identification is important in
preventing outbreaks.
Many developing countries struggle with huge disease burdens of diarrhea where a wider
approach to diarrhea prevention may be required. Preventive strategies may be of
relevance to both developed and developing countries.
PROMOTION OF EXCLUSIVE BREAST-FEEDING
Exclusive breast-feeding (administration of no other fluids or foods for the 1st 6 mo of

life) is not common. Exclusive breast-feeding protects very young infants from diarrheal
disease through the promotion of passive immunity and through reduction in the intake of
potentially contaminated food and water. Breast milk contains all the nutrients needed in
early infancy, and when continued during diarrhea, also diminishes the adverse impact on
nutritional status.
IMPROVED COMPLEMENTARY FEEDING PRACTICES
There is a strong inverse association between appropriate, safe complementary feeding

and mortality in children age 611 mo; malnutrition is an independent risk for the
frequency and severity of diarrheal illness. Complementary foods should be introduced at
6 mo of age while breast-feeding should continue for up to 1 yr (longer period for
developing countries). Complementary foods in developing countries are generally poor
in quality and frequently heavily contaminated, thus predisposing to diarrhea.
Contamination of complementary foods can be potentially reduced through caregivers'
education and improving home food storage. Vitamin A supplementation reduces
childhood mortality by 34%; improved vitamin A status reduces the frequency of
severe diarrhea.
IMPROVED WATER AND SANITARY FACILITIES AND PROMOTION OF PERSONAL AND

DOMESTIC HYGIENE
Much of the reduction in diarrhea prevalence in the developed world is the result of
improvement in standards of hygiene, sanitation, and water supply. In addition, routine
handwashing with plain soap in the home can reduce the incidence of diarrhea in all
environments. Behavioral change strategies through promotion of handwashing indicate
that handwashing promotion and access to soap reduces the burden of diarrhea in
developing countries.
115
IMPROVED CASE MANAGEMENT OF DIARRHEA
Improved management of diarrhea through prompt identification and appropriate

therapy significantly reduces diarrhea duration, its nutritional penalty, and risk of death in
childhood. Improved management of acute diarrhea is a key factor in reducing the burden
of prolonged episodes and persistent diarrhea.
The WHO/UNICEF recommendations to use low osmolality ORS and zinc

supplementation for the management of diarrhea, coupled with selective and
appropriate use of antibiotics, have the potential to reduce the number of diarrheal
deaths among children.
116
Persistent diarrhea in children in developing countries
Mary E Penny, MB, ChB, MRCP
When diarrhea persists for more than 14 days, it is called persistent, intractable, or chronic
diarrhea. Persistent diarrhea is often manifested by a chronic enteropathy, with impaired
mucosal healing and diminished digestive and absorptive capacity.In the developing world,
persistent diarrhea usually follows an acute episode and typically is associated with serial
enteric infections without time to recover between episodes. Children are at risk of
malnutrition and often have other intercurrent illnesses, such as respiratory infections.
PREVALANCE AND MORBIDITY Persistent diarrhea is a common condition. Diarrhea

lasting more than two weeks occurs in up to 3 to 5 percent of the infant population
worldwide.Although fewer than 10 percent of diarrheal episodes become persistent, persistent
diarrhea accounts for more than half of diarrheal deaths, and 30 to 50 percent of deaths overall
among children younger than 5 years of age in the developing world.
Diarrhea may have secretory and/or osmotic components. Secretory diarrhea occurs when
pathogens produce toxins that inhibit absorption and result in unopposed large fluxes of fluid
and electrolytes into the small intestine that overwhelm the absorptive capacity of the more
distal gut. The classic example is cholera and enterotoxigenic E. coli (ETEC) infections.
Osmotic diarrhea occurs when unabsorbed nutrients, especially carbohydrates and sugars,
cause an osmotic gradient, drawing water into the intestine. This may occur in the small or large
intestine. Diarrhea typically is exacerbated by eating, and stools may be acidic and contain
reducing substances.
TREATMENT Treatment of chronic diarrhea includes supportive measures, nutritional

rehabilitation, and drug therapy.
Rehydration Death in most instances of persistent diarrhea is caused either by hypovolemia

(dehydration) or severe malnutrition. Consequently, replacement of fluid and electrolyte losses
is the major early intervention. The ideal form of rehydration is through the oral or nasogastric
route with low osmolarity oral rehydration solution (ORS). The WHO now recommends the use
of low osmolarity ORS in all diarrheal episodes except cholera (the WHO solution contains 75
mMol/L of glucose, 75 mEq/L sodium, and osmolarity 245 mOsm/L). In most cases, breast
feeding should be continued.
Dietary management Nutritional compromise plays a role in most cases of persistent

diarrhea in developing countries, and is the primary target for treatment. Most children will
respond to dietary management using locally available foods designed to provide approximately
150 kcals/kg/day and 10 percent of calories from protein. If possible, at least half the protein
should come from an animal source such as milk, egg, or chicken. Breastfeeding may provide
some of these nutrients, and is continued when possible. This approach is similar to that used
117
for nutritional rehabilitation in other children with malnutrition. However, many infants and
children with chronic diarrhea have secondary disaccharidase deficiencies, caused by damage to
the intestinal epithelium. Consequently, a low-lactose diet and sometimes a diet also low in
sucrose or total carbohydrates may be necessary. It is usually sufficient to reduce lactose by
mixing milk with cereals such as rice or noodles and giving small frequent feedings. However, a
minority of children benefit from a lactose-free diet. Egg or pureed chicken have been
successfully used and are palatable. Lactose-free formulas are an alternative if available. There
is no need to limit fat intake; indeed fat can be beneficial because it provides useful calories.
Micronutrients and vitamins Micronutrient and vitamin supplementation are part of

nutritional rehabilitation, especially in malnourished children from developing countries.
Children with chronic diarrhea and malnutrition are often deficient in vitamin A, zinc, folic acid,
copper, and selenium. Deficiencies in these micronutrients can impair the function of the
immune system and have a direct effect on the structure and function of mucosa.
The WHO recommends zinc supplementation for children with diarrhea in developing
countries, at a dose of 10 mg daily for infants up to 6 months of age, and 20 mg daily for older
infants and children, for 14 days.
The WHO also recommends providing at least two times the recommended daily allowance
(RDA) for folate, vitamin A, iron, copper, and magnesium for two weeks. Vitamin A and zinc
supplementation may have synergistic effects.
Antimicrobials Although nutritional rehabilitation is effective alone for most children with
chronic diarrhea, specific treatment for enteric pathogens is indicated in some cases,
particularly children with bloody diarrhea (usually caused by Shigella or Campylobacter, or
parasites).
Extraintestinal infections (acute lower respiratory infections, urinary tract infections, sepsis,
etc) commonly associated with chronic diarrhea, should be evaluated carefully and treated
promptly.
Children with bloody diarrhea are likely to have Shigella or Campylobacter infection, and can be
treated empirically.
Most authorities suggest that antibiotics be started when shigellosis is suspected clinically,
before culture confirmation. However, because of changing patterns of antibiotic resistance,
susceptibility testing should be performed on all isolates, and empiric therapy changed as
necessary based upon the results.
The recommended first-line parenteral therapy for children with suspected shigellosis when
the antibiotic susceptibility of the organism is unknown is ceftriaxone (50 mg/kg per day
[maximum 1.5 g] in a single daily dose, for five days). Patients with no underlying immune
deficiency or bacteremia who are afebrile after two days may be treated with two doses only
118
Azithromycin In areas with high resistance to TMP-SMX and ampicillin, azithromycin is the
suggested first-line oral treatment for shigellosis in children younger than 18 years of age when
the antibiotic susceptibility of the organism is unknown.
Azithromycin: 12 mg/kg for the first day (maximum 500 mg) and then 6 mg/kg/dose (maximum
250 mg) for an additional four days.
Nalidixic acid (55 mg/kg per day in four divided doses) for five days is an alternative to
azithromycin therapy for children younger than 18 years of age when the antibiotic
susceptibility of the organism is unknown.
Cefixime (8 mg/kg/day in a single dose, maximum 400 mg/day) for five days may be used as an
alternative to azithromycin therapy for children younger than 18 years of age.
Antimicrobial therapy for Campylobacter is only indicated in patients who are at increased risk
or have severe disease, including patients with bloody stools, high fever, or symptoms lasting
longer than one week.
Erythromycin is the "drug of choice" for treatment of Campylobacter gastroenteritis.

Erythromycin stearate is acid resistant, stable, and incompletely absorbed. Thus, in addition to
its systemic effects, it may exert a contact effect throughout the bowel.
For children, a five day course of erythromycin ethyl succinate 40 mg/kg per day is more
suitable.
Recent trends favor shorter courses; results at least as good as a conventional five-day course of
erythromycin have been claimed for a single dose of azithromycin (30 mg/kg).
Serious systemic Campylobacter infections should be treated with an aminoglycoside or a

carbapenem. Resistance to these antimicrobials has remained under 1 percent. Persistent
infection in patients with hypogammaglobulinemia has been cleared by giving a commercial
IgM-containing preparation (Pentaglobin) in conjunction with antimicrobial therapy.
If enteric parasites are identified by laboratory testing, these should be treated according to
standard guidelines. Empiric therapy for intestinal parasites is not recommended, except that
empiric treatment for amebiasis may be considered in a child with persistent bloody diarrhea,
who has failed trials of two different antimicrobials known to be effective against local strains of
Shigella.
Antidiarrheal drugs Drugs that alter intestinal motility, including loperamide, codeine, and
paregoric, are not recommended because they lack efficacy, are associated with potentially
serious side effects, and possibly prolong the excretion of enteric pathogens. Similarly,
antiemetics cause sedation that interferes with oral rehydration therapy, and should not be
given to children with diarrhea .
119
Management of celiac disease in children
Ivor D Hill, MD
Celiac disease is a condition in which there is abnormal small intestinal mucosa that improves
morphologically when treated with a gluten-free diet and relapses when gluten is reintroduced.
WHO TO TREAT
Presumptive celiac disease Treatment with a gluten-free diet is recommended for both
diagnostic and therapeutic purposes for all children in one of the following groups:
1. Children with characteristic findings on intestinal biopsy and symptoms consistent with celiac
disease (including nonspecific symptoms such as constipation or abdominal pain).
2. Children with characteristic findings on intestinal biopsy and belonging to a high-risk group
(eg, relatives of patients with established celiac disease, or patients with type 1 diabetes),
whether or not there are associated symptoms.
3. Patients with dermatitis herpetiformis confirmed by skin biopsy, with or without associated
pathology of the small intestinal mucosa.
Latent/potential celiac disease Patients who are diagnosed with gluten sensitivity by a
positive tissue transglutaminase or IgA endomysial antibody, but who have a normal small
bowel biopsy, are considered to have latent or potential celiac disease. Such patients are
currently not advised to be on a gluten-free diet but should continue to be monitored and
rebiopsied if symptoms develop.
Before considering a patient to have latent celiac disease, it is important to make sure that the
intestinal biopsies were adequate. The histologic abnormalities of celiac disease can be patchy,
so multiple biopsies must be taken from the distal duodenum, and these should be evaluated by
an expert pathologist.
PRINCIPLES OF A GLUTEN-FREE DIET The cornerstone of treatment of celiac disease is the

elimination of gluten in the diet. The principle sources of dietary gluten are wheat, rye, and
barley. The toxicity of oats in celiac disease is now in doubt.
NUTRITIONAL CONSIDERATIONS
Dietary counseling Consumption of a gluten-free diet requires a major lifestyle change since
gluten is contained in a variety of foods that are commonly consumed in a Western diet. Thus, it
is helpful to provide written information and dietary counseling to improve compliance. A
number of resources are available for patients with celiac disease including a variety of
cookbooks, gluten-free prepared foods, and Internet sites (www.csaceliacs.org and
www.celiac.com).
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As general rules, the following advice can be given to all patients:
1. Foods containing wheat, rye, and barley should be avoided.
2. Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are safe.
3. Read labels on prepared foods and condiments carefully, paying particular attention to
additives such as stabilizers or emulsifiers that may contain gluten.
4. Dairy products should be avoided initially since many patients with celiac disease have
secondary lactose intolerance.
5. Most children will tolerate lactose after mucosal healing.
Micronutrient deficiencies An individual patient's overall nutritional status should be

considered so that nutritional and caloric deficiencies can be adequately supplemented. Specific
dietary deficiency such as iron, folic acid, calcium, vitamin D, and, rarely, vitamin B12 deficiency
should be corrected. A gluten-free diet may induce troublesome constipation since it is low in
roughage. This usually responds to the addition of dietary rice bran and ispaghula husks;
psyllium fiber or methylcellulose supplements are also generally gluten-free.
Prevention of bone loss Bone loss (principally osteopenia and less often osteoporosis) is
common in celiac disease, and can occur in patients without gastrointestinal symptoms . Much
of the bone loss is related to secondary hyperparathyroidism, which is probably due to vitamin
D deficiency.
MONITORING THE RESPONSE TO A GLUTEN-FREE DIET The rapidity of the response to a

gluten-free diet is variable. Approximately 70 percent of patients have noticeable clinical
improvement within two weeks. As a general rule, symptoms improve faster than histology,
especially when biopsies are obtained in the proximal intestine. The reason is incompletely
understood; however, a likely explanation is that the less severely damaged distal small
intestine recovers faster than the proximal intestine, which typically is affected more severely
because of relatively increased exposure to gluten.
Antibody testing We suggest measurement of celiac-specific antibodies (tissue

transglutaminase or antiendomysial antibodies) about six months after beginning a gluten-free
diet. A decrease in the antibody titer, with eventual disappearance in most individuals, is an
indirect indicator of dietary adherence and recovery.
We also measure antibodies in children with persistent or recurrent symptoms at any time after
starting a gluten-free diet. A rise in antibody levels may indicate that the individual is knowingly
or inadvertently ingesting gluten again, and should prompt careful review of the diet. If patients
remain asymptomatic, we measure antibodies annually to monitor adherence to the gluten-free
diet.
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Biopsy The need for a follow-up biopsy in patients with clinical improvement has been
debated, especially since serologic testing can be used to monitor recovery and compliance with
the diet. We suggest NOT repeating a biopsy in patients with a definite diagnosis of celiac
disease who have all of the following characteristics:
Symptoms suggestive of celiac disease and elevated tissue transglutaminase, or anti-

endomysial antibodies at presentation.
Initial intestinal biopsy with histologic changes characteristic of celiac disease (Marsh type 3
villous atrophy).
Resolution of symptoms and marked decrease in tissue transglutaminase antibodies on a

gluten-free diet.
For children in whom the diagnosis is less certain because they do not meet one or more of the
above characteristics, we suggest a second small intestinal biopsy 9 to 12 months after
beginning a gluten-free diet to demonstrate histologic improvement. Although histologic
improvement is usually seen by this time, persistent abnormalities have been described, even in
patients with symptomatic improvement. The significance is at the moment unclear, but in
many cases the abnormalities do not appear to be linked with dietary problems. After checking
for dietary non-compliance or inadvertent ingestion of gluten, other causes of villous atrophy
should be considered in these patients.
Gluten rechallenge Gluten rechallenge (a traditional approach to diagnosis of celiac disease)

is generally not required unless the diagnosis remains uncertain.
Furthermore, a rare hazard in giving a gluten rechallenge is the development of fulminant

diarrhea, with resulting dehydration, acidosis, and other metabolic disturbances (a condition
known as "gliadin shock"). Such patients should be treated with corticosteroids.
When gluten rechallenge is chosen for patients in whom the diagnosis remains uncertain, the
patient is asked to ingest at least 10 g of gluten per day (an amount contained in four slices of
regular bread) for four to six weeks, followed by endoscopic biopsies. The biopsy date should be
advanced in patients who develop severe symptoms.
PNEUMOCOCCAL VACCINATION Celiac disease is associated with hyposplenism. As a result,

children with celiac disease should be immunized with a pneumococcal vaccine.
NONRESPONDERS The majority of patients with celiac disease respond to a gluten-free diet.
The most common reasons for a lack of response are poor compliance or inadvertent gluten
ingestion.
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Patients who do not respond despite adherence to a gluten-free diet fall into three main
categories:
1. Patients with clinical or histologic features that are caused by other disorders.
2. Patients with refractory sprue.
3. Patients with ulcerative jejunitis or intestinal lymphoma.
Patients with other disorders Other diagnoses should be considered in patients who,
despite apparent compliance, continue to have symptoms or do not have histologic
improvement.
Concomitant or secondary lactose intolerance is a possible cause of continued diarrhea and

flatulence.
Patients with celiac disease are susceptible to common bowel disturbances such as irritable
bowel syndrome, which affects a large proportion of the general population and may present
with features suggestive of malabsorption.
A small percentage of patients develop small bowel bacterial overgrowth, which may respond to
antibiotics.
A number of diseases associated with small bowel villous atrophy also should be excluded in
patients with persistent symptoms who do not show histologic improvement.
Causes of small intestinal villous atrophy other than celiac disease
1. Bacterial overgrowth.
2. Crohn's disease.
3. Cow's milk protein intolerance (children).
4. Eosinophilic gastroenteritis.
5. Giardiasis.
6. Lymphoma.
7. Peptic duodenitis.
8. Post gastroenteritis.
9. Tropical sprue.
10. Zollinger-Ellison syndrome.
11. Common variable immunodeficiency.
12. Autoimmune enteropathy.
13. Other immunodeficiency states (usually apparent clinically).
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Refractory sprue Refractory sprue (also referred to as "unclassified sprue") occurs almost
exclusively in adults. These patients fall into two clinical categories:
Patients who have no initial response to a gluten-free diet.
Patients who experience initial clinical improvement on a gluten-free diet, but, after a period of
remission, develop disease refractory to gluten abstinence.
DERMATITIS HERPETIFORMIS Celiac disease is associated with a number of skin disorders of

which dermatitis herpetiformis is the most common. Dermatitis herpetiformis is characterized
by an itchy papular vesicular eruption usually located symmetrically on the elbows, knees,
buttocks, sacrum, face, neck, trunk and occasionally within the mouth. The predominant
symptoms are itching and burning that are rapidly relieved with rupture of the blisters.
Improvement in dermatitis herpetiformis following withdrawal of gluten may be considerably

delayed (6 to 12 months) compared to the response of the intestinal manifestations of the
disease. As a result, treatment usually includes medical therapy (such as dapsone) in addition to
gluten avoidance.
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Causes of neonatal cholestasis
Stephanie H Abrams, MD - Robert J Shulman, MD
Neonatal cholestasis is defined serologically as the accumulation of components of bile in the

bloodstream, most frequently manifested as conjugated hyperbilirubinemia in the newborn
period. Cholestasis results from diminished bile flow and/or excretion, which can be the result
of a number of different causes.
Causes of neonatal cholestasis can be divided into the following categories:
Obstruction.
Infection.
Metabolic/genetic diseases.
OBSTRUCTION Cholestasis is a common presentation of extrahepatic biliary obstruction.

Conditions causing extrahepatic biliary obstruction must be recognized promptly because
surgery can be effective.
Biliary atresia Extrahepatic biliary atresia, which occurs in approximately one in 10,000 to
20,000 births, is characterized by inflammation of the bile ducts leading to progressive
obliteration of the extrahepatic biliary tract. The inflammatory changes develop, or at least
progress, after birth in most patients.
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Clinical features Infants with biliary atresia typically present with icteric sclera and/or
jaundice, hepatosplenomegaly and acholic stools. Laboratory studies typically show elevations in
bilirubin, serum aminotransferases and a disproportionately increased GGTP.
Diagnosis Biliary atresia should be considered early in the evaluation of any infant with
cholestasis as it is important that the diagnosis of biliary atresia be made as soon as possible.
Ideally the diagnosis of BA is made by 8 weeks of age, because the success of surgical
intervention (hepatoportoenterostomy, the Kasai procedure) diminishes with time after 2
months of age.
Evaluation of biliary anatomy begins with an ultrasound which, in the case of biliary atresia, will
generally be notable for absence of the gallbladder. Failure to visualize the gallbladder on
ultrasound may be the result of gall bladder collapse (a frequent finding in infants) or an
inexperienced ultrasonographer. The main utility of the ultrasound is to exclude other anatomic
causes of cholestasis (eg, choledochal cyst).
Patency of the extrahepatic biliary tree can be further assessed by hepatobiliary scintigraphy.
If scintigraphy demonstrates movement of the tracer from the liver to the small bowel, patency
is established. However, failure of excretion of tracer lacks specificity for biliary obstruction and
does not exclude other diseases.
The absence of bilirubin or bile acids in aspirated duodenal fluid may be helpful, but like
scintigraphy, this test lacks specificity and is no longer widely used in practice.
Suspicion of extrahepatic biliary tract obstruction can be supported by findings on liver biopsy.
Characteristic histologic features include: expanded portal tracts with bile duct proliferation,
portal tract edema, fibrosis and inflammation, and canalicular and bile duct bile plugs. Liver
biopsy cannot determine obstruction.
Endoscopic retrograde cholangiopancreatography (ERCP) is available at a few select tertiary

care centers and, when liver biopsy results are equivocal, may clarify the etiology of neonatal
cholestasis and obviate the need for laparotomy.
Treatment and prognosis The primary treatment for biliary atresia is surgical. The Kasai
procedure, or portoenterostomy is undertaken in the attempt to restore bile flow from the liver
to the proximal small bowel. For this procedure, a roux-en-Y loop of bowel is created by the
surgeon and is directly anastomosed to the capsule of the liver following excision of the biliary
remnant and portal fibrous plate.
Whether adjuvant treatment with glucocorticoids after the Kasai procedure improves
outcomes has not been established.
Choledochal cysts Choledochal cysts are a rare but treatable cause of conjugated
hyperbilirubinemia.
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Other causes Other extrahepatic causes of biliary obstruction include: Inspissated bile/plug
syndrome (eg, patients with cystic fibrosis) Gallstones or biliary sludge Tumors.
INFECTIONS Bacterial, protozoal, and viral infections can result in cholestasis. Common
congenitally acquired pathogens include toxoplasmosis, rubella, cytomegalovirus, herpes, and
syphilis. Less frequent causes are echovirus, adenovirus, and parvovirus B19.
Bacterial infections with gram-positive and gram-negative organisms also have been associated
with cholestasis. As an example, jaundice may be the only presenting sign in patients with a
urinary tract infection caused by Escherichia coli. Bacterial infection also contributes to
cholestasis in infants who receive parenteral nutrition.
METABOLIC/GENETIC DISEASES
Alagille syndrome
Clinical features Alagille syndrome is characterized by the paucity of interlobular bile ducts
and the following associated features:
Chronic cholestasis (91 percent)
Cardiac anomalies, most commonly peripheral pulmonic stenosis (85 percent)
Butterfly vertebrae (87 percent)
Posterior embryotoxon (prominent Schwalbe line) of the eye (88 percent)
Dysmorphic facies, consisting of broad nasal bridge, triangular facies, and deep set eyes (95
percent)
Diagnosis Diagnosis of Alagille syndrome in the newborn with cholestasis depends upon
detection of the associated features and characteristic liver biopsy. In addition to direct
hyperbilirubinemia, serum aminotransferases are modestly elevated and GGTP is often
disproportionally increased. Liver biopsy demonstrates a reduced number of bile ducts,
although the progressive destruction of bile ducts may not be apparent in newborns.
Galactosemia Galactosemia is the most common disorder of carbohydrate metabolism that

presents with neonatal cholestasis.
In addition to having conjugated hyperbilirubinemia, affected infants develop vomiting,

diarrhea, failure to thrive, renal tubular acidosis, cataracts, and coagulopathy after the onset of
galactose-containing feedings (eg, human or cow's milk). The diagnosis is suggested by the
presence of reducing substances in the urine and is confirmed by an assay of galactose-1-
phosphate uridyl transferase activity in erythrocytes, leukocytes, or liver. Treatment requires
dietary elimination of galactose and milk products, with substitution of soy or protein
hydrolysate formulas.
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Tyrosinemia Tyrosinemia is a disorder of amino acid metabolism that causes progressive
liver disease, renal tubular acidosis, and neurologic impairment.
Disorders of lipid metabolism Disorders of lipid metabolism, including Wolman, Niemann-

Pick, and Gaucher diseases, occasionally can present with cholestasis.
Alpha-1 antitrypsin deficiency The presentation of AAT deficiency can include neonatal
cholestasis.
Gestational therapy For pregnant women with a previous pregnancy that resulted in an
infant with neonatal hemochromatosis, treatment with high dose intravenous immunoglobulin
(IVIG) dramatically reduces the risk for recurrence of disease.
Cystic fibrosis Neonatal cholestasis is an uncommon presentation of cystic fibrosis, occurring

in fewer than 5 percent of patients.
IDIOPATHIC NEONATAL HEPATITIS Idiopathic neonatal hepatitis is defined as prolonged

conjugated hyperbilirubinemia without an obvious etiology after a complete evaluation has
excluded identifiable infectious and metabolic/genetic causes. Characteristic findings on liver
biopsy are multinucleated giant cells; variable inflammation with infiltration of lymphocytes,
neutrophils, and eosinophils; and little or no bile duct proliferation.
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Fulminant hepatic failure
Eric Goldberg, MD - Sanjiv Chopra, MD
INTRODUCTION Fulminant hepatic failure (FHF) refers to the rapid development of severe
acute liver injury with impaired synthetic function and encephalopathy in a person who
previously had a normal liver or had well compensated liver disease.
Managing patients with FHF requires a thorough understanding of the many complications that
can be present, including encephalopathy, cerebral edema, sepsis, renal failure, circulatory
dysfunction, coagulopathy, gastrointestinal bleeding, and metabolic derangements such as
metabolic acidosis, hypoglycemia, and hypophosphatemia. Because of the complexities
involved, patients with FHF should be managed in an intensive care unit in centers with an
active liver transplant program.
HEPATIC ENCEPHALOPATHY Hepatic encephalopathy is a major complication of FHF,

although the precise mechanism remains unclear. The most widely accepted theory is related to
increased production of ammonia from nitrogenous substances within the gut lumen. Thus,
treatment has been directed toward reducing the production and absorption of nitrogenous
products with modalities such as lactulose, although its use in fulminant hepatic failure is
controversial. If lactulose is used, it should not be administered orally or per nasogastric tube to
patients with advanced encephalopathy unless endotracheal intubation is performed. The
administration of nephrotoxic and aminoglycoside antibiotics such as neomycin should be
avoided in patients with FHF because of the risk of nephrotoxicity.
CEREBRAL EDEMA Cerebral edema develops in 75 to 80 percent of patients with grade IV

encephalopathy. The precise mechanism by which it occurs in FHF is incompletely understood.
Possible contributing factors include osmotic derangement in astrocytes, changes in cellular
metabolism and alterations in cerebral blood flow.
Clinical manifestations The consequences of cerebral edema include elevated intracranial

pressure (ICP) and brainstem herniation, which are the most common causes of death in FHF.
Cerebral edema also can lead to ischemic and hypoxic injury to the brain.
The classic signs of elevated ICP include systemic hypertension, bradycardia, and irregular
respirations (referred to as Cushing's triad). Neurologic manifestations may include increased
muscle tone, hyperreflexia, and altered pupillary responses. However, early in the course of FHF,
these signs and symptoms may be absent or difficult to detect.
The goals of therapy are to maintain the ICP below 20 mmHg and the CPP above 50 mmHg.
These goals can be accomplished using a combination of interventions:
Patients should be placed in an environment with minimal sensory stimulation since

stimulation can raise ICP. For the same reasons, attempts should be made to keep the patient
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from becoming agitated. Placement of a nasogastric tube can cause gagging and thus their use
should be minimized. Similarly, endotracheal suction should be minimized.
Overhydration can elevate ICP. Thus, the fluid status of patients with FHF should be closely
monitored, which often requires placement of a pulmonary artery catheter.
The head of the patient's bed should be elevated to 30 degrees. However, bed elevation can
also reduce cerebral perfusion. Thus, patients should remain supine if the CPP falls below 50
mmHg with bed elevation.
A standard approach has been suggested in patients who develop elevated ICP despite the
above modalities.
Patients with ICP above 20 mmHg should be hyperventilated to keep the PCO2 below 25 mmHg.
However, the effects of hyperventilation at best are temporary, and in some reports have
worsened cerebral ischemia.
If no response or relapse is noted, mannitol (0.5 to 1 g/kg) should be administered as an

intravenous bolus and then on an as-needed basis to maintain the plasma osmolality between
310 and 325 mosmol/kg. It is essential to monitor urinary output closely while using mannitol. In
patients with preserved renal function who have suboptimal diuresis, repeat doses of mannitol
can be used to achieve the above plasma osmolality.
If no response or relapse is noted after mannitol administration, pentobarbital coma should be

induced using a bolus of 3 to 5 mg/kg intravenously.
Dexamethasone has not proven to be effective in the treatment of cerebral edema caused by
FHF and should not be administered.
ACUTE RENAL FAILURE Acute renal failure complicates FHF in approximately 30 to 50

percent of patients. The frequency of acute renal failure is higher (up to 75 percent) for
etiologies of FHF that are known to independently damage the kidneys, such as acetaminophen
intoxication.
The blood urea nitrogen (BUN) concentration may not be a sensitive test to follow renal
function in patients with FHF since hepatic production of urea is decreased.
Treatment Treatment of acute renal failure should focus on prevention because, once
established, the renal failure is usually progressive and associated with a grave prognosis
without liver transplantation. Among the preventive measures are ensuring arterial perfusion by
maintaining an adequate systemic blood pressure, identifying and treating infections promptly,
and avoiding the use of nephrotoxic agents.
INFECTION AND SEPSIS Patients with FHF are at increased risk of infection and sepsis from a
wide variety of causes. This enhanced susceptibility is related to a variety of immunologic
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derangements, including complement deficiency, reduced opsonization, increased gut bacterial
translocation, white blood cell dysfunction, altered killer cell function, and the presence of
central lines.
The most common sites of infection are the respiratory and urinary tracts and blood. Localizing
signs of infection, such as fever and sputum production, are frequently absent and the only
clues to an underlying infectious process may be worsening of encephalopathy or renal
function.Thus, an aggressive approach to diagnosing and treating infections is necessary. This
includes a low threshold for obtaining frequent blood, urine, and sputum cultures, and
diagnostic radiographs, or for performing a diagnostic paracentesis.
The role of prophylactic antibiotics is controversial. Empiric broad spectrum antibiotics should
be considered in the following patients:
1. Presence of or the rapid progression to advanced stages of encephalopathy.
2. Refractory hypotension.
3. Presence of systemic inflammatory response syndrome.
4. Selective intestinal decontamination may reduce the risk of infection due to Gram negative
bacilli. However, at present there are insufficient data to routinely recommend this approach.
METABOLIC DISTURBANCES Common metabolic disturbances in FHF include acid-base and

electrolyte disorders, hypophosphatemia, and hypoglycemia.
Among the acid-base disorders, alkalosis is more frequently encountered than acidosis in the
early stages of FHF, and is frequently a mixed respiratory and metabolic abnormality. As FHF
progresses, patients typically develop metabolic acidosis (due to lactic acidosis) with respiratory
alkalosis. These acid-base disturbances are best managed by treating the underlying abnormality
including infection and tissue perfusion hypoperfusion and by administering antidotes for
certain toxins (eg, acetylcysteine for acetaminophen).
The most common electrolyte disturbances are hypokalemia, hyponatremia, and

hypophosphatemia:
Hypokalemia is common in both fulminant and subfulminant hepatic failure. Several factors
may contribute, including diuretic therapy and increased sympathetic tone, since activation of
the beta-2 adrenergic receptors promotes the uptake of potassium by the cells.
Correction of hypokalemia, if present, is an essential component of therapy. Hypokalemia

increases renal ammonia production; in addition, the often concurrent metabolic alkalosis may
contribute by promoting ammonia entry into the brain by promoting the conversion of
ammonium) (NH4+), a charged particle which cannot cross the blood-brain barrier, into
ammonia (NH3) which can.
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Hyponatremia is more frequently seen in patients with subfulminant hepatic failure. Tissue
hypoperfusion, leading to enhanced release of antidiuretic hormone, and impaired renal
function combine to limit free water excretion.
Hypophosphatemia is especially common in patients with acetaminophen-induced FHF and

those with intact renal function. The fall in plasma phosphate is due to movement into the cells.
Hypoglycemia, which occurs in more than 40 percent of the patients with FHF, results from
both depletion of hepatic glycogen stores and impaired gluconeogenesis. The plasma glucose
concentration should be monitored closely and hypertonic glucose solutions should be
administered as needed to keep the values above 65 mg/dL (3.6 mmol/L).
MALNUTRITION Nutrition is a vital component in the treatment of FHF. In patients with

grade I or II encephalopathy, oral or enteral feeding with a low protein diet is usually sufficient
to meet metabolic requirements. Placement of a nasogastric tube can increase intracranial
pressure (because of gagging) and thus should generally be performed only in patients who are
intubated and sedated.In patients with advanced encephalopathy, parenteral nutrition should
be considered early to prevent catabolism of body stores of proteins.
COAGULOPATHY Patients with FHF can develop severe coagulopathy and bleed due to the
diminished capacity of the failing liver to synthesize coagulation factors. The most common site
of bleeding is the gastrointestinal tract. A reasonable approach to stress ulcer prophylaxis is an
intravenous H2 blocker, preferably by bolus infusion, with sucralfate reserved for patients who
are intolerant of H2 blockers. Proton pump inhibitors also may be effective but have been less
well studied.
Prophylactic administration of fresh frozen plasma is usually not recommended since it has not
been proven to influence mortality, it can interfere with assessments of liver function, and it
may worsen cerebral edema. Fresh frozen plasma (FFP) is indicated only in the setting of active
hemorrhage or prior to invasive procedures, such as placement of intracranial pressure
monitors.
In extreme settings, correction of the coagulopathy is necessary but cannot be achieved

adequately with FFP, particularly in patients who are severely volume overloaded. Small pilot
studies have demonstrated that recombinant human factor VIIa (rFVIIa) has been associated
with improvement or normalization of the serum prothrombin time and control of bleeding in
such patients.
PULMONARY COMPLICATIONS Pulmonary edema and pulmonary infections are

encountered in approximately 30 percent of patients with FHF. Mechanical ventilation may be
required to ensure adequate oxygenation. However, extreme caution must be used with
positive end-expiratory pressure in patients with FHF since PEEP can worsen cerebral edema.
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SPECIFIC TREATMENT Liver transplantation remains the backbone of treatment of FHF.
However, depending upon the etiology of FHF, specific therapies may be applicable. As an
example, N-acetylcysteine, especially when administered early, can dramatically improve
prognosis in patients with acetaminophen toxicity. Furthermore, there may not be a good
history of intoxication since doses as low as 4 g/day can cause hepatotoxicity in regular alcohol
users. Thus, in patients with FHF of unknown etiology, it is wise to assume a possible
acetaminophen overdose and begin treatment with N-acetylcysteine.
A number of interventions may be helpful in other specific settings such as:
Forced diuresis and activated charcoal in patients with Amanita phalloides mushroom
poisoning.
Transjugular intrahepatic portosystemic shunt, surgical decompression or thrombolysis in

patients with acute Budd-Chiari syndrome.
Acyclovir in patients with FHF related to herpes virus infection.
Unhelpful treatments A number of specific interventions have been studied but are
unhelpful for FHF.
Corticosteroids, which may also increase the risk of sepsis .
Hepatic regeneration therapy using insulin and glucagon .
Charcoal hemoperfusion .
Prostaglandin E, which appeared to have promise in uncontrolled studies, but was subsequently
shown to be ineffective in controlled studies .
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RESPIRATORY SYSTEM
Approach to the management of croup
Charles R Woods, MD, MS
Croup (laryngotracheitis) is a respiratory illness characterized by inspiratory stridor, barking

cough, and hoarseness. It typically occurs in children 6 months to 3 years of age and is caused by
parainfluenza virus.
Westley croup score The elements of the Westley croup score describe key features of the
physical examination. Each element is assigned a score, as illustrated below:
Level of consciousness: Normal, including sleep = 0; disoriented = 5
Cyanosis: None = 0; with agitation = 4; at rest = 5
Stridor: None = 0; with agitation = 1; at rest = 2
Air entry: Normal = 0; decreased = 1; markedly decreased = 2
Retractions: None = 0; mild = 1; moderate = 2; severe = 3
The total score ranges from 0 to 17.
Mild croup is defined by a Westley croup score of 2. Typically these children have a barking
cough, hoarse cry, but no stridor at rest. Children with mild croup may have stridor when upset
or crying (ie, agitated) and either none, or only mild chest wall/subcostal retractions.
Moderate croup is defined by a Westley croup score of 3 to 7. Children with moderate croup
have stridor at rest, at least mild retractions, and may have other symptoms or signs of
respiratory distress, but little or no agitation.
Severe croup is defined by a Westley croup score of 8. Children with severe croup have
significant stridor at rest, although stridor may decrease with worsening upper airway
obstruction and decreased air entry. Retractions are severe (including indrawing of the sternum)
and the child may appear anxious, agitated, or fatigued. Prompt recognition and treatment of
children with severe croup are paramount.
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MILD CROUP
Outpatient treatment Children who are seen in the office or emergency department with
mild croup may require little or no therapy, or may have improvement with humidified air.
Randomized controlled trials have demonstrated that treatment with a single dose of oral
dexamethasone (0.15 to 0.6 mg/kg, maximum dose 10 mg) may reduce the need for
reevaluation, shorten the course, improve duration of the child's sleep, and reduce parental
stress.
MODERATE TO SEVERE CROUP
Children with moderate croup (Westley croup score 3 to 70, stridor and retractions at rest
without agitation) should be evaluated in the emergency department or office (provided the
office is equipped to handle acute upper airway obstruction).
Children with severe croup (Westley croup score 8, stridor and retractions at rest with
agitation, lethargy, or cyanosis, marked sternal wall indrawing) should be evaluated in the
emergency department. Such children require aggressive therapy, monitoring, and supportive
care.
Supportive care Supportive care for children with moderate/severe croup includes
administration of humidified air or humidified oxygen as indicated for hypoxemia (oxygen
saturation <92 percent in room air) or respiratory distress.
Monitoring Monitoring should include pulse oximetry and close observation of respiratory
status including level of consciousness, stridor, cyanosis, air entry, and retractions.
Fluids Administration of intravenous fluids may be necessary in some children. Fever and
tachypnea may increase fluid requirements and respiratory difficulty may prevent the child from
achieving adequate oral intake.
Intubation Endotracheal intubation is required in less than 1 percent of those who are seen
in the emergency department and 2 to 6 percent of those who are hospitalized. The need for
intubation should be anticipated in children with progressive respiratory failure so that the
procedure can be performed in as controlled a setting as possible.
Pharmacotherapy Specific pharmacologic intervention depends upon the severity of

symptoms:
For children with mild stridor at rest and mild retractions, we recommend administration of
dexamethasone (0.6 mg/kg, maximum of 10 mg), by the least invasive route possible: oral if oral
intake is tolerated, intravenous if IV access has been established, IM if oral intake is not
tolerated and IV access has not been established. The oral preparation of dexamethasone (1 mg
per mL) has a foul taste. The intravenous preparation is more concentrated (4 mg per mL) and
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can be given orally mixed with syrup. Nebulized budesonide (as described below) is another
option, particularly for children who are vomiting.
For children with moderate stridor at rest and moderate retractions, or more severe symptoms,
we recommend nebulized epinephrine in addition to dexamethasone:
- Racemic epinephrine is administered as 0.05 mL/kg per dose (maximum of 0.5 mL) of a 2.25
percent solution diluted to 3 mL total volume with normal saline. It is given via nebulizer over 15
minutes.
- L-epinephrine is administered as 0.5 mL/kg per dose (maximum of 5 mL) of a 1:1000 dilution.
It is given via nebulizer over 15 minutes.
Nebulized epinephrine can be repeated every 15 to 20 minutes. The administration of three

or more doses within a two- to three-hour time period should prompt initiation of close cardiac
monitoring if this is not already underway.
Children who receive nebulized epinephrine should also receive dexamethasone by the least
invasive route that can be accomplished,
Although it is not routinely indicated in the treatment of croup, nebulized budesonide (2 mg [2

mL solution] via nebulizer) may provide an alternative to IM or IV dexamethasone for children
with vomiting or severe respiratory distress. In children with severe respiratory distress,
budesonide may be mixed with epinephrine and administered simultaneously
Discharge to home Many children with moderate/severe croup have symptomatic

improvement after treatment with nebulized epinephrine and/or corticosteroids.
After three to four hours of observation, children who remain comfortable may be discharged
home if they meet the following criteria:
No stridor at rest
Normal pulse oximetry
Good air exchange
Normal color
Normal level of conscious
Demonstrated ability to tolerate fluids by mouth
Caregivers understand the indications for return to care and would be able to return if necessary
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Hospitalization
Indications Children with moderate/severe croup whose condition worsens or fails to

improve as expected after treatment with nebulized epinephrine and corticosteroids should be
admitted to the hospital for repeated doses of nebulized epinephrine, observation, and
supportive care. Poor response to nebulized epinephrine in conjunction with high fever and
toxic appearance should prompt consideration of bacterial tracheitis.
Additional factors that influence the decision regarding admission include:
Need for supplemental oxygen.
Moderate retractions and tachypnea, indicating increased work of breathing, which may lead to
respiratory fatigue and failure.
Degree of response to initial therapies .
"Toxicity" or clinical picture suggesting serious secondary bacterial infection.
Poor oral intake and degree of dehydration.
Young age, particularly younger than 6 months.
Ability of the family to comprehend the instructions regarding recognition of features that
indicate the need to return for care.
Ability of the family to return for care (eg, distance from home to care site, weather/travel
conditions).
Recurrent visits to the ED within 24 hours.
Interventions Children who are admitted to the hospital should continue to be monitored
for heart rate and oxygen saturation and to receive humidified oxygen as necessary.
Capnography, if it is available, is a useful technique for monitoring ventilation if the child will
tolerate nasal prongs. If the child is unable to tolerate oral intake, maintenance intravenous
fluids should be administered.
Pharmacologic interventions for hospitalized patients may include nebulized epinephrine for
persisting severe respiratory distress. Nebulized epinephrine can be repeated every 15 to 20
minutes. However, children who require repeated doses of epinephrine (eg, three or more
doses within two to three hours, or ongoing administration more frequently than every one to
two hours) should be admitted/transferred to an intensive care unit or other setting where
appropriately close monitoring can be accomplished.
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Repeat doses of corticosteroids are not necessary on a routine basis, and may have adverse
effects. Moderate to severe symptoms that persist for more than a few days should prompt
investigation for other causes of airway obstruction.
Follow-up should continue until the child's symptoms have begun to resolve. The child who
does not improve as expected (over the course of approximately seven days) may have an
underlying airway abnormality or may be developing a complication of croup. Further
evaluation, particularly with a radiograph of the soft tissues of the neck, or consultation with
otolaryngology, may be warranted.
PROGNOSIS Symptoms of croup resolve in most children within three days, but may persist
for up to one week. Fewer than 5 percent of children with croup require hospital admission, and
among those, 1 to 6 percent require intubation. Mortality is rare, occurring in <0.5 percent of
intubated children.
Complications Complications of croup are uncommon. Children with moderate to severe

croup are at risk for hypoxemia (oxygen saturation <92 percent in room air) and respiratory
failure. Other complications include pulmonary edema, pneumothorax, and
pneumomediastinum.
Secondary bacterial infections may arise from croup. Bacterial tracheitis, bronchopneumonia,
and pneumonia occur in a small number of patients. In most instances, the child has been
relatively stable or beginning to improve after several days of illness, but then suddenly
worsens, with higher or recurrent fever, increased (and potentially productive) cough, and/or
respiratory distress.
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Treatment; outcome; and prevention of bronchiolitis in infants
and children
Pedro A Piedra, MD - Ann R Stark, MD
Bronchiolitis is broadly defined as an illness characterized by wheezing and airways

obstruction that is caused by infection with a viral or, less commonly, a bacterial pathogen
resulting in inflammation of the small airways/bronchioles. Respiratory syncytial virus is the
most common cause.
Severity assessment The clinical practice guideline of the American Academy of Pediatrics
(AAP) defines severe disease as "signs and symptoms associated with poor feeding and
respiratory distress characterized by tachypnea, nasal flaring, and hypoxemia". Severe disease is
indicated by persistently increased respiratory effort, apnea, or the need for intravenous
hydration, supplemental oxygen, or mechanical ventilation.
Risk factors for severe disease and/or complications of bronchiolitis include: gestational age
<37 weeks, age <12 weeks, chronic pulmonary disease, congenital heart disease,
immunodeficiency, congenital and anatomical defects of the airways, and neurologic disease.
Environmental and other risk factors such as passive smoking, crowded household, daycare
attendance, concurrent birth siblings, older siblings, and high altitude (>2500 m) can also
contribute to more severe disease.
Indications for hospitalization
1. Toxic appearance, poor feeding, lethargy, and dehydration .

2. Moderate to severe respiratory distress, manifested by one or more of the following
signs: nasal flaring, intercostal retraction, respiratory rate >70 breaths per minute
dyspnea, and/or cyanosis.
3. Apnea.
4. Hypoxemia (oxygen saturation <95 percent on room air) with or without hypercapnia
(arterial carbon dioxide tension >45 mmHg). Although the AAP guideline suggests that
supplemental oxygen is indicated if the oxygen saturation is consistently below 90
percent, it does not provide a room air oxygen saturation threshold for hospitalization.
5. The parent is unable to care for the child at home.
SUPPORTIVE CARE Supportive care in both the outpatient and inpatient settings includes
respiratory support and maintenance of adequate fluid intake. Saline nose drops and nasal bulb
suction may help to relieve partial nasal obstruction.
Monitoring Repeated clinical assessment is the most important component of monitoring

for deteriorating respiratory status in both the outpatient and inpatient settings.
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Hospitalized infants should have continuous monitoring of heart rate, respiratory rate, and
oxygen saturation. Infants with severe distress or who have apnea should be monitored in the
intensive care unit (ICU).
Respiratory support Oxygen should be provided by nasal canula, head box, or face mask to
maintain the arterial oxygen saturation above 90 to 92 percent.
Fluid administration Parenteral fluid administration may be necessary to ensure adequate

hydration and avoid the risk of aspiration in infants and children with bronchiolitis. Fluid and
electrolyte status should be carefully monitored. Children with bronchiolitis may have difficulty
maintaining adequate hydration because of increased needs (related to fever and tachypnea)
and decreased intake (related to tachypnea and respiratory distress). However, plasma
antidiuretic hormone levels may be elevated , leading to fluid retention. Fluid overload should
be avoided, since it may lead to pulmonary congestion.
PHARMACOLOGIC THERAPY
Bronchodilators Although bronchodilators have not been shown to be effective in viral

bronchiolitis in published studies where analysis of group outcomes is reported, it is difficult to
sort out individual patients with a predisposition to airway reactivity or asthma from those with
isolated viral bronchiolitis. Thus, we suggest that infants and children with clinically significant
bronchiolitis receive a trial of inhaled bronchodilators. The effects should be monitored by
evaluating the child before and up to one hour after treatment. Inhaled bronchodilators should
be continued if there is a documented clinical response using an objective means of evaluation.
Inhaled bronchodilators Although widely used and studied, the efficacy of inhaled
bronchodilators (albuterol, salbutamol, and epinephrine) in the treatment of bronchiolitis is
uncertain and the published results have been variable.
The clinical practice guideline of the American Academy of Pediatrics (AAP) recommends that
bronchodilators should not be used routinely in the management of bronchiolitis. However, it
does state that a carefully monitored trial of bronchodilator medication is an option, with
continuation only if there is a documented objective clinical response.
We suggest using salbutamol as the bronchodilator of first choice: 0.5 ml salbutamol diluted in
2.5 ml saline and administered over 5 to 15 minutes; or 4 to 6 puffs via a metered dose inhaler
with spacer and facemask. If no benefit is observed in one hour, we administer a single dose of
nebulized epinephrine: L epinephrine (0. 5 ml/kg of 1/1000 dilution maximum 5 ml).
If no clinical response is seen within one hour of epinephrine treatment, we do not continue
the use of these agents.If there is a response to either salbutamol or epinephrine,
bronchodilator therapy can be administered every four to six hours and discontinued when the
signs and symptoms of respiratory distress improve.
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Oral bronchodilators we do not recommend the use of oral bronchodilators in the
management of bronchiolitis.
Glucocorticoids
We recommend that glucocorticoids should not be used routinely in healthy infants and young
children with a first episode of bronchiolitis. However, glucocorticoids may be beneficial for
patients with chronic lung disease (bronchopulmonary dysplasia) and those with previous
episodes of wheezing (i.e., who may be at risk for asthma).
Prednisolone or prednisone (1 to 2 mg/kg per day in one dose or divided into two doses per
day for three to seven days). An alternative is dexamethasone (0.4 mg/kg per day in one dose
for 3 to 5 days).
Inhaled glucocorticoids Inhaled glucocorticoids have not been shown to be beneficial in the
treatment of bronchiolitis.
Ribavirin Ribavirin is not recommended routinely for treatment of infants and children with
bronchiolitis. However, in immunocompromised patients and those with severe bronchiolitis
due to RSV, antiviral therapy may still play a role.
Antibiotics in children with bronchiolitis, antibacterial medications are warranted only when
there is evidence of a coexisting bacterial infection (e.g., positive urine culture, acute otitis
media, consolidation on chest radiograph).
CLINICAL COURSE In previously healthy infants who are older than 6 months and require
hospitalization for management of bronchiolitis, the average length of hospitalization is three
days. The respiratory status typically improves over two to five days. However, wheezing
persists in some infants for a week or longer. The course may be prolonged in younger infants
and those with comorbid conditions (e.g., chronic lung disease).
DISCHARGE CRITERIA as with admission criteria, there are no established criteria for
discharge, whether from the hospital or from an outpatient setting.
One clinical practice guideline suggests the following:
1. Respiratory rate <70 breaths/min.

2. Caretaker can clear the infant's airway using bulb suctioning .
3. Patient is stable without supplemental oxygen.
4. Patient has adequate oral intake to prevent dehydration.
5. The resources at home are adequate to support the use of any necessary home
therapies (eg, inhalation therapy if the trial was successful and this therapy is to be
continued).
6. Caretaker is confident they can provide care at home.
7. Education of the family is complete.
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OUTCOME Bronchiolitis is a self-limited illness and resolves without complications in most
previously healthy infants. However, severely affected infants, especially those born
prematurely and those with underlying cardiopulmonary disease or immunodeficiency, are at
increased risk for complications.
The overall mortality rate in children hospitalized with RSV bronchiolitis is less than 2 percent.
Mortality is increased in, young infants (6 to 12 weeks), those with low birth weight, and those
with underlying medical conditions (e.g., underlying cardiopulmonary disease, immune
deficiency).
Possible association with asthma Infants hospitalized for LRTI, especially RSV, are at
increased risk for recurrent wheezing and reduced pulmonary function particularly during the
first decade of life. In one report, LRTI with RSV increased the risk for subsequent frequent and
infrequent wheezing (odds ratio 4.3 and 3.2, respectively) and was associated with reduced
forced expiratory volume in children up to 11 years of age. However, this association was lost by
age 13 years, perhaps due to inadequate sample size.
PREVENTION Standard strategies to reduce the risk of bronchiolitis and accompanying

morbidity include careful hand washing (with soap or with alcohol-based rubs) to minimize
transmission of infectious agents, minimizing passive exposure to cigarette smoke, and avoiding
contact with individuals with respiratory tract infections.
Immunoprophylaxis with palivizumab, a humanized monoclonal antibody against the RSV F

glycoprotein, decreases the risk of hospitalization due to RSV illness among infants with chronic
lung disease, premature birth, and congenital heart disease.
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Inpatient treatment of pneumonia in children
William J Barson, MD
Community-acquired pneumonia (CAP) is defined as an acute infection of the pulmonary

parenchyma in a patient who has acquired the infection in the community, as distinguished
from hospital-acquired (nosocomial) pneumonia.
INDICATIONS FOR HOSPITALIZATION The decision to hospitalize a child with pneumonia

must be individualized and is based upon age and several clinical factors.
Hospitalization should be considered for:
1. Most infants younger than 4 months of age, unless a viral etiology or Chlamydia
trachomatis is suspected and they are relatively asymptomatic.
2. A child of any age whose family cannot provide appropriate care and assure compliance
with the therapeutic plan needs to be hospitalized.
3. Hypoxemia (oxygen saturation consistently less than 92 percent).
4. Dehydration, or inability to maintain hydration orally; inability to feed in an infant.
5. Moderate to severe respiratory distress: respiratory rate >70 breaths/min in infants <12
months or >50 breaths/min in older children, difficulty breathing, apnea, grunting.
6. Toxic appearance, which is more common in children with bacterial pneumonia, may
suggest a more severe course of pneumonia (e.g., cardiopulmonary compromise).
7. Underlying conditions that may predispose to a more serious course of pneumonia (e.g.,
cardiopulmonary disease), might be worsened by pneumonia (e.g., metabolic disorder),
or that might adversely affect response to treatment (e.g., immunocompromised host) .
8. Presence of complications (e.g., effusion/empyema).
9. Failure of outpatient therapy (worsening or no response in 24 to 72 hours).
Indications for intensive care Treatment in an intensive care setting should be considered for
patients with:
1. Failure to maintain oxygen saturation 92 percent in FiO2 >0.5 to 0.6.

2. Signs of impending respiratory failure (lethargy, increasing work of breathing, and/or
exhaustion with or without hypercarbia).
3. Recurrent apnea or slow irregular respirations.
4. Cardiovascular compromise with progressive tachycardia and/or hypotension.
SUPPORTIVE CARE Assuring adequate hydration, oxygenation, and appropriate antipyresis

and analgesia are imperative. A supported sitting position may help to expand the lungs and
improve respiratory symptoms. Antitussives should be avoided.
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Antipyresis and analgesia Children hospitalized with pneumonia usually have fever and may
have pleuritic chest pain, which can lead to shallow breathing and impaired ability to cough.
Administration of antipyretics and/or analgesics can be used to keep the child comfortable.
Respiratory support Children hospitalized with pneumonia should receive ventilatory

support as indicated by their clinical condition. In children who are severely ill, it may be
necessary to monitor carbon dioxide via blood gas analysis in addition to oxygen saturation by
oximetry. Hypercarbia is an important sign of impending respiratory failure, particularly in the
tiring young infant who may have preserved oxygenation.
Children with oxygen saturation <95 percent in room air should be treated with supplemental
oxygen to maintain oxygen saturation 95 percent. Gentle suction of the nares may be helpful
in infants and children whose nares are blocked with secretions. Minimal handling seems to
reduce oxygen requirements.
Fluid management Children who cannot maintain adequate fluid intake because of
breathlessness, fatigue, or risk of aspiration may require intravenous fluid therapy.
Chest physiotherapy Chest physiotherapy has no role to play in the management of

uncomplicated CAP.
Monitoring The following clinical parameters should be monitored in children admitted to

the hospital for treatment of pneumonia:
1. Temperature.
2. Respiratory rate.
3. Heart rate.
4. Oxygen saturation.
5. Work of breathing (e.g., presence of retractions, nasal flaring, grunting).
6. Auscultatory findings.
EMPIRIC THERAPY
Overview The initial treatment of children who are hospitalized with pneumonia is empiric.
Factors that must be considered include the spectrum of likely pathogens, efficacy against
respiratory pathogens including resistant strains, the simplicity of the regimen, tolerability,
palatability, safety profile, and cost.
The recommendations of most guidelines are based on observations regarding the

susceptibility of the most likely pathogen or pathogens rather than on evidence of the
superiority of one antibiotic over another. Clinical response to empiric therapy and results of
microbiologic studies, when available, help to determine whether additional evaluation or
changes in therapy are necessary.
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Etiologic clues Certain clinical and epidemiologic features can be used to determine the
most likely pathogen(s) to aid in decisions regarding empiric therapy. Because these features
often overlap, they cannot be used with complete confidence, but are helpful in guiding empiric
therapy until results of microbiologic tests are available.
Viruses Most CAP in children younger than 5 years is caused by viruses. The onset of viral
pneumonia is gradual and associated with preceding upper airway symptoms. Auscultatory
findings are usually diffuse and bilateral. Infiltrates are usually interstitial.
Typical bacterial pneumonia Typical bacterial pneumonia may occur in children of all ages.
Clues to bacterial pneumonia include alveolar infiltrate, lobar or segmental consolidation, large
pleural effusion, elevated CRP, leukocytosis, signs of sepsis, and chills. Other complications
(pneumatoceles, cavitations, necrotizing processes) also are suggestive of typical bacterial
etiology.
Atypical bacterial pneumonia Atypical bacterial pneumonia (M. pneumoniae and Chlamydia
pneumoniae) is most common in children older than 5 years. Clues to atypical bacterial
pneumonia include abrupt onset of constitutional findings (malaise and myalgia, headache,
conjunctivitis, photophobia, sore throat), and gradually worsening non-productive cough
despite improvement of other symptoms, wheezing, rash, and interstitial infiltrates.
Other Significant mediastinal/hilar adenopathy suggests a mycobacterial or fungal etiology.
Viral pneumonia Most children younger than 3 to 5 years of age who are admitted to the
hospital with pneumonia have viral pneumonia (e.g., respiratory syncytial virus). This is
particularly true in the absence of lobar (or lobular) infiltrate and pleural effusion. Viral
pneumonia does not require antibiotic therapy, unless a mixed infection or secondary bacterial
infection is suspected.
No effective antivirals are available for most viral pneumonias. Several drugs are marketed for
the treatment of influenza infection in children, but none has been evaluated as a treatment for
influenza pneumonia.
Bacterial pneumonia Streptococcus pneumoniae is the most common type of bacterial

cause of pneumonia in children of all ages. Other potential bacterial pathogens that may need
to be included in empiric therapy for hospitalized children include S. aureus including
methicillin-resistant S. aureus, Streptococcus pyogenes (Group A streptococcus), Haemophilus
influenzae type b (if unimmunized), nontypeable H. influenzae, and Moraxella catarrhalis.
Alternative empiric antibiotic regimens for uncomplicated bacterial pneumonia in hospitalized

children when S. aureus is not a consideration include:
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Ceftriaxone (50 to 75 mg/kg intravenously [IV] once daily up to a maximum dose of 4 g/day), or
Cefotaxime (150 to 200 mg/kg per day IV in three or four divided doses up to a maximum of 8 to
10 g/day), or
Cefuroxime (100 to 150 mg/kg per day IV in three divided doses; maximum 4 to 6 g/day), or
Ampicillin (150 to 200 mg/kg per day IV in four divided doses; maximum 10 to 12 g/day)
Oral amoxicillin may be appropriate for children older than 6 months with uncomplicated
pneumonia.
A macrolide may be added (dosed as suggested below) if M. pneumoniae, C. pneumoniae, or

legionellosis is suspected.
Atypical pneumonia Atypical bacterial pathogens include C. trachomatis in afebrile infants,

and M. pneumoniae and C. pneumoniae in older children and adolescents. Alternative empiric
antibiotic regimens for atypical bacterial pneumonia in hospitalized children include:
Erythromycin 40 mg/kg per day IV in four divided doses, maximum 4 g/day, or
Azithromycin 5 mg/kg once per day IV, maximum 500 mg/day, or
For children older than 8 years: Doxycycline (4 mg/kg per day IV in two divided doses; maximum
200 mg/day).
Macrolide antibiotics have been reported to be associated with pyloric stenosis in young infants.
For children older than 4 months with presumed atypical bacterial pneumonia, one of the beta-
lactam antibiotics may be added if there is strong evidence of a bacterial cause (e.g., white
blood cell count >15,000/microL, CRP >35 to 60 mg/L (3.5 to 6 mg/dL), chills, no response to
outpatient therapy with a macrolide or doxycycline).
Moderately severe CAP Children with moderately severe CAP may benefit from
combination empiric therapy with a macrolide and a beta-lactam antibiotic (e.g., third-
generation cephalosporin).
Complicated CAP The spectrum of empiric coverage should be broadened for children with
CAP who have complications, such as parapneumonic effusion and/or lung abscess. The
expanded spectrum should include coverage for beta-lactam-resistant isolates, and community-
associated methicillin-resistant S. aureus; coverage for anaerobes and gram-negative organisms
also may be necessary for children with lung abscess.
Appropriate regimens include:
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Clindamycin (30 to 40 mg/kg per day intravenously [IV] in three to four divided doses to a
maximum of 1 to 2 g/day), or, if the local S. pneumoniae resistance to clindamycin is high:
- Ceftriaxone (50 to 75 mg/kg intravenously [IV] once daily up to a maximum dose of 4 g/day),
or cefotaxime (150 to 200 mg/kg per day IV in three or four divided doses up to a maximum of 8
to 10 g/day), plus
- Clindamycin (30 to 40 mg/kg per day IV in three to four divided doses to a maximum of 1 to 2
g/day).
Vancomycin is an alternative for patients allergic to clindamycin: Vancomycin (40 mg/kg per day
IV in four divided doses up to a maximum of 2 to 4 g/day).
Severe CAP Children with life-threatening infections who require admission to the intensive
care unit require broad-spectrum empiric coverage that addresses potential beta-lactam
resistance and community-associated methicillin-resistant S. aureus. Such children should be
treated with:
Vancomycin (40 mg/kg per day IV in four divided doses up to a maximum of 2 to 4 g/day), and
A third-generation cephalosporin (cefotaxime [150 to 200 mg/kg per day IV in three or four
divided doses up to a maximum of 8 to 10 g/day] or ceftriaxone [50 to 75 mg/kg IV once daily up
to a maximum dose of 4 g/d]), and
Azithromycin (5 mg/kg once per day IV, maximum 500 mg/day), and possibly,
Nafcillin (150 mg/kg per day IV in four divided doses; maximum 10 to 12 g/day) if S. aureus is
likely (methicillin-susceptible S. aureus is more rapidly killed by nafcillin than by vancomycin)
Nosocomial pneumonia Empiric treatment of nosocomial pneumonia should afford

coverage for the usual nosocomial pathogens: S. aureus, Enterobacteriaceae, Pseudomonas
aeruginosa, and anaerobes.
Acceptable broad-spectrum empiric regimens include an aminoglycoside plus:
Ticarcillin-clavulanate (300 mg/kg per day IV in four divided doses up to a maximum of 18 to 24

g/day), or
Piperacillin-tazobactam (300 mg/kg per day IV in four divided doses up to a maximum of 12

g/day), or
Meropenem (60 mg/kg per day IV in three divided doses, up to a maximum of 6 g/day) if
extended spectrum or Amp C beta-lactamase-producing gram-negative rods are possible
etiologies
Patients with true beta-lactam hypersensitivity (i.e., type 1 hypersensitivity reaction) can be
treated with a combination of clindamycin plus an aminoglycoside.
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Aspiration pneumonia Empiric antibiotic regimens for community-acquired aspiration
pneumonia must cover oral anaerobes. Appropriate antibiotics regimens for hospitalized
children include:
Ampicillin-sulbactam (150 to 200 mg/kg per day of the ampicillin component IV in four divided
doses; maximum 12 g/day), or
Clindamycin (30 to 40 mg/kg per day IV in three to four divided doses to a maximum of 1 to 2
g/day) if MRSA etiology is suspected.
Appropriate antibiotic regimens for children with nosocomial aspiration who are known to be
colonized with unusual gram-negative pathogens include:
Ticarcillin-clavulanate (300 mg/kg per day IV in four divided doses up to a maximum of 18 to 24

g/day), or
Piperacillin-tazobactam (300 mg/kg per day IV in four divided doses up to a maximum of 12

g/day), or
Meropenem (60 mg/kg per day IV in three divided doses, up to a maximum of 6 g/day)
Immunocompromised host Empiric treatment for pneumonia in immunocompromised

hosts also requires broad-spectrum gram-positive and gram-negative coverage similar to that
afforded for nosocomial pneumonia with the addition of vancomycin if methicillin-resistant
staphylococcus is considered, and possibly trimethoprim-sulfamethoxazole for Pneumocystis
jirovecii (formerly carinii).
DURATION OF TREATMENT
Parenteral therapy There are few data to guide decisions regarding the duration of
parenteral therapy for CAP. It is common to switch to oral therapy in patients who have received
parenteral antibiotics when the patient has become afebrile for 24 to 48 hours and is able to
keep down food.
Total duration No randomized controlled trials have been performed to determine the
appropriate duration of antimicrobial therapy for radiographically confirmed childhood
pneumonia. Current practice assigns a duration of therapy depending upon the host, causative
agent, and severity of the disease.
Uncomplicated cases Seven to 10 days of combined parenteral and oral therapy should be
adequate for routine pathogens causing uncomplicated infection. Some authorities suggest
continuing oral therapy at least one week beyond resolution of fever.
Complicated cases Treatment of complications, such as necrotizing pneumonia and lung

abscess, requires a prolonged course of antibiotic therapy, usually initiated parenterally. The
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duration is determined by the clinical response, but is usually a total of four weeks or two weeks
after the patient is afebrile and has improved clinically.
RESPONSE TO THERAPY From a respiratory standpoint, children with CAP who are
appropriately treated should improve clinically within 24 to 48 hours. However, fevers may
persist for several days after initiation of appropriate therapy.
Treatment failure In children who fail to improve as anticipated, the following possibilities
must be considered:
1. Alternative or coincident diagnoses (e.g., foreign body aspiration).

2. Ineffective antibiotic coverage (lack of coverage for the actual etiology or resistant
organism).
3. Development of complications.
DISCHARGE CRITERIA Discharge criteria for children who have been admitted to the
hospital with CAP have not been standardized, but typically include:
1. Improvement of vital signs.

2. Ability to maintain adequate fluid and nutrition orally.
3. Ability to maintain oxygen saturation 90 percent in room air.
4. Improvement in respiratory distress (tachypnea, retractions, nasal flaring, use of
accessory muscles).
FOLLOW-UP
Clinical course Children with CAP should be seen by their primary care provider soon after
discharge to ensure that clinical improvement continues and antibiotic therapy is being taken as
prescribed.
Children who are appropriately treated for CAP should gradually improve with time. Cough
may persist for as long as three to four months after viral pneumonia or pertussis. Children who
are recovering from typical or atypical bacterial pneumonia may continue to cough for several
weeks and have moderate dyspnea on exertion for two to three months.
Radiographs
Follow-up radiographs are not necessary in asymptomatic children with uncomplicated CAP.
However, follow-up radiographs should be obtained to ensure resolution in children with
complicated CAP who have required intervention. Follow-up radiographs also may be helpful in
children with recurrent pneumonia, persistent symptoms, severe atelectasis, or unusually
located infiltrates. When follow-up radiographs are indicated, they should be obtained two to
three weeks after hospital discharge.
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PROGNOSIS Most otherwise healthy children with pneumonia recover without sequelae,
even if the pneumonia is complicated. Although some data suggest that nearly one-half of
children who are hospitalized for viral pneumonia have symptoms of asthma five years after
hospitalization, it is not clear whether this is related to unrecognized asthma at the time of
presentation with pneumonia or a tendency to develop asthma after CAP.
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Outpatient management of acute asthma exacerbations in
children
Richard J Scarfone, MD, FAAP
Clinical decision making in the management of the child with an acute asthma exacerbation
includes the following questions:
How sick is the child?
Which drugs should be used for treatment?
What are the optimal doses and delivery routes?
When is more aggressive management necessary?
A brief focused history and examination should be obtained before therapy is initiated.
The history should include:
The time of onset of exacerbation.
Current medications and allergies.
Recent use of beta 2-agonists.
Risk factors for severe, uncontrolled disease, such as emergency department visits, hospital
and intensive care unit admissions, repeated courses of oral glucocorticoids, and history of
intubation, rapidly progressive episodes, or food allergy.
The focused examination should include:
Vital signs and pulse oximetry.
Assessment of level of consciousness, anxiety, and agitation;
Assessment of breathlessness, wheezing, air entry, accessory muscle use, and retractions.
Pulmonary index The Pulmonary index score (PIS) is an asthma score based on five clinical
variables: respiratory rate, degree of wheezing, inspiratory to expiratory ratio, accessory muscle
use, and oxygen saturation. Each variable is assigned a score from 0 to 3. Total scores range
from 0 to 15.
151
Score Respiratory rate* Wheezing Inspiratory/ Accessory muscle Oxygen saturation
expiratory ratio use
0 30 None 2:1 None 99-100
1 31-45 End expiration 1:1 + 96-98
2 46-60 Entire expiration 1:2 ++ 93-95
3 >60 Inspiration and 1:3 +++ <93
expiration
* For patients age> 6: through 20, score 0; 21-35, score 1; 36-50, score 2; >50, score 3. The total
score ranges from 0 to 15. In general, a score of less than 7 indicates a mild attack, a score of 7
to 11 indicates a moderately severe attack, and a score of 12 or greater indicates a severe
attack. However, the Pulmonary Index Score may underestimate the degree of illness in an older
child.
If no wheezing due to minimal air entry, score 3.
Peak flow rate A peak flow meter may be used to assess airflow obstruction, providing an
objective assessment of disease severity. However, children younger than six years may not be
able to cooperate with peak expiratory flow rate (PEFR) assessments and severely ill children
may not be able to stand and provide three consecutive recordings, as is recommended. In
addition, the reading is most helpful when the child's personal best PEFR measurement is
known.
Chest radiograph Chest radiographs (CXRs) rarely provide information that alters the
management of children with acute asthma exacerbation, except in the presence of focal
examination findings (e.g., rales or decreased breath sounds), fever (>39C), or severe disease.
Arterial blood gas It is rarely necessary to obtain arterial blood gas (ABG) samples in
children with acute asthma. Oxygen saturation can be assessed with pulse oximetry.
OVERVIEW OF TREATMENT
Goals The goals of therapy for acute severe asthma include:
Rapid reversal of airflow obstruction by repeated administration of inhaled bronchodilators and

early institution of systemic glucocorticoids.
Correction of hypoxemia and/or severe hypercapnia; hypoxemia is alleviated by administration

of supplemental oxygen as necessary; hypercapnea usually improves with reversal of airflow
obstruction.
Reduction of likelihood of recurrence by intensifying baseline therapy.
Supportive care Supportive care for children with acute asthma exacerbations includes
administration of supplemental oxygen and fluids as necessary, and frequent monitoring of
response to therapy.
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Oxygen therapy Nearly all patients with acute asthma have hypoxemia as a result of
ventilation-perfusion (V/Q) mismatch. Beta-2 agonists may worsen this mismatch by causing
pulmonary vasodilation in areas of the lung that are poorly ventilated. Humidified oxygen should
be provided as needed to maintain an oxygen saturation of 92 percent. All nebulized
medications should also be delivered with oxygen, generally at a flow rate of 6 to 8 L/min.
Monitoring The clinical status of children who are being treated for acute asthma should be
monitored frequently. The frequency of monitoring varies depending upon the severity of illness
and response to initial therapy, but for most patients is typically every 20 to 30 minutes for the
first hour of therapy.
Ongoing monitoring of respiratory and heart rates, oxygen saturation, degree of alertness,
accessory muscle use, retractions, and PEFR (in children who are able to perform it) is crucial to
decisions regarding disposition.
General approach The approach to the management of acute asthma exacerbations

described below is geared toward management in the emergency department.
Inhaled short-acting beta 2-agonists are the mainstay of emergent treatment of acute asthma
exacerbations. For children with mild exacerbations, systemic glucocorticoids are usually added
if the symptoms and signs of airway obstruction fail to resolve after the first treatment with
inhaled beta 2-agonists. Children with moderate or severe exacerbations should receive
systemic glucocorticoids as soon as possible. Additional pharmacotherapeutic agents that may
be indicated in children with moderate or severe asthma include nebulized ipratropium
bromide, magnesium sulfate, and parenteral beta 2-agonists.
Mild exacerbation For children with mild asthma exacerbation (PIS <7), we suggest the
following:
Albuterol inhalation therapy administered via small volume nebulizer (SVN) at a dose of 0.15
mg/kg (maximum 5 mg) or salbutamol inhalation therapy administered at a dose of 0.5 ml + 2.5
ml normal saline or metered dose inhaler (MDI-S) at a dose of one-quarter to one-third puff/kg
(maximum 10 puffs). If repeated doses are needed, they should be given every 20 to 30 minutes
for three doses.
Administration of systemic glucocorticoids to those who fail to improve after one inhalation
therapy.( Prednisolone 1-2 mg\kg (maximum 60 mg ) by mouth or Dexamethazone 0.6 mg\kg
(maximum 16 mg )by mouth or iv
Moderate exacerbation For children with moderate asthma exacerbation (PIS 7 to 11), we
suggest the following approach:
Administration of supplemental oxygen if oxygen saturation 92 percent in room air.
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Albuterol nebulization (0.15 mg/kg, maximum 5 mg) or salbutamol nebulization (0.5 ml +2.5 ml
normal saline) combined with ipratropium bromide (250 microgram/dose if <20 kg; 500
microgram/dose if >20 kg) every 20 to 30 minutes for three doses or continuously.
Patients who have received three doses of intermittent therapy and require additional
salbutamol therapy may be treated intermittently every 30 to 45 minutes or may be switched to
continuous therapy.
Administration of systemic glucocorticoids after the first inhalation therapy.
Administration of IV magnesium sulfate (75 mg/kg, maximum 2.5 g administered over 20

minutes) if there is clinical deterioration despite treatment with beta 2-agonists, ipratropium
bromide, and systemic glucocorticoids.
Severe exacerbation For children with severe asthma exacerbation (PIS 12), we suggest
the following approach:
Administration of supplemental oxygen if oxygen saturation 92 percent in room air.
Albuterol nebulization (0.15 mg/kg, maximum 5 mg) or salbutamol nebulization (0.5 ml+2.5ml
normal saline) combined with ipratropium bromide (250 microgram/dose if <20 kg; 500
microgram/dose if >20 kg), every 20 to 30 minutes for three doses or continuously.
Alternatively, terbutaline (0.01 mL/kg of a 1 mg/mL solution) with a maximum dose of 0.4 mg
(0.4 mL) or epinephrine (1\1000) 0.01 mL/kg with a maximum dose of 0.4 mL may be
administered subcutaneously for children with poor inspiratory flow or children who cannot
cooperate with nebulized therapy.
Subsequent management depends upon response to initial therapy. For patients who improve
after the initial treatment, the approach is as described above for moderate exacerbations. For
patients with a poor response to initial treatment, we recommend:
- Administration of IV methylprednisolone (1 to 2 mg/kg, maximum 125 mg).
Administration of IV magnesium sulfate (75 mg/kg, maximum 2.5 g administered over 20

minutes).
For patients who do not respond to these interventions, administration of IV terbutaline may
be indicated: bolus with 10 microgram/kg over ten minutes, then 0.3 to 0.5 microgram/kg per
minute; infusion may be increased by 0.5 microgram/kg per minute every 30 minutes to a
maximum of 5 microgram/kg minute.
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PHARMACOTHERAPY
Inhaled beta agonists Inhaled short-acting beta 2-agonists are the mainstay of
emergent treatment of acute asthma exacerbations. Albuterol and salbutamol are the
most widely used short-acting beta 2-agonist in the acute setting.
Inhaled beta 2-agonists can be administered by intermittent nebulization, continuous

nebulization, or metered-dose inhaler with a spacer (MDI-S).
Glucocorticoids The anti-inflammatory action of glucocorticoids effectively reduces

the airway edema and secretions associated with acute asthma exacerbations.
Systemic glucocorticoids Systemic glucocorticoids are indicated for most children

who present to the ED with acute asthma exacerbation. The effects of systemic
glucocorticoids may be noted within two to four hours of administration.
Ipratropium bromide Ipratropium bromide is an anticholinergic agent.

Anticholinergic agents provide bronchodilation through smooth muscle relaxation.
Ipratropium is indicated in the treatment of children with moderate to severe asthma

exacerbations. It is inexpensive and safe.
Ipratropium can be administered via SVN or MDI-S. The MDI formulation should not be
administered to patients with allergy to peanut or soy because it contains soya lecithin,
which may precipitate an allergic reaction.
Magnesium sulfate There is accumulating evidence that intravenous magnesium

sulfate (MgSO4) benefits adults and children with severe asthma. Magnesium is
inexpensive, has minimal adverse effects at the doses indicated, and is widely available.
We suggest that magnesium sulfate be used in children with severe asthma

exacerbation and in children with moderate asthma exacerbations who have clinical
deterioration despite treatment with beta 2-agonists, ipratropium bromide, and
systemic glucocorticoids. We use a dose of 75 mg/kg (maximum 2.5 g) IV administered
over 20 minutes.
Parenteral beta 2-agonists Parenteral beta 2-agonists include epinephrine and

terbutaline; these drugs may be administered subcutaneously or intravenously.
Subcutaneous The rapid subcutaneous administration of beta 2-agonists may be

superior to inhaled beta 2-agonists for children with severe exacerbations and poor
inspiratory flow or anxious young children who are uncooperative with or have
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suboptimal response to initial aerosolized therapy. In this setting, terbutaline may be
expected to produce fewer adverse effects than epinephrine.
The dose of subcutaneous terbutaline for bronchodilation is 0.01 mg/kg per dose (0.01
mL/kg of a 1 mg/mL solution) with a maximum dose of 0.4 mg (0.4 mL); the dose may be
repeated every 20 minutes for three doses. The dosing interval may be decreased for
children who continue with severe respiratory distress.
The dose of subcutaneous epinephrine for bronchodilation is 0.01 mg/kg (0.01 mL/kg
of 1:1000 solution [1 mg/mL]), with a maximum dose of 0.4 mL (0.4 mg); the dose may
be repeated every 20 minutes for three doses, then every 2 to 6 hours as needed. The
dosing interval may be decreased for children who continue with severe respiratory
distress.
Dosing for intravenous terbutaline is as follows: 10 microgram/kg bolus over 10

minutes, followed by 0.3 to 0.5 microgram/kg per minute; every 30 minutes the infusion
may be increased by 0.5 microgram/kg per minute to a maximum of 5 microgram/kg per
minute.
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Inpatient management of acute asthma exacerbations in
children
Criteria for admission Children who require beta 2-agonist therapy more often than every
two to three hours, have not improved after administration of systemic glucocorticoids, or who
require supplemental oxygen need to be admitted to the hospital.
Other factors that may necessitate hospitalization include:
A history of rapid progression of severity in past exacerbations.
Poor adherence with outpatient medication regimen.
Inadequate access to medical care.
Poor social support system at home.
Management approach Inpatient treatment is typically a continuation of therapies and

monitoring that have been started in the ED. Before arrival to the inpatient unit, patients usually
have received several albuterol or salbutmol treatments (with or without ipratropium bromide),
systemic glucocorticoids, and, when necessary, supplemental oxygen.
Communication between the providers in the ED and those caring for the patient in the
hospital is essential to ensure that treatments ordered in the ED are not missed or duplicated
during the transfer of care.
Inpatient therapy consists of:
Inhaled beta 2-agonists, administered continuously or every two to four hours, depending upon
the patient's degree of illness.
Systemic glucocorticoids.
Supplemental oxygen as necessary to maintain oxygen saturation 92 percent.
Asthma education
Initiation or adjustment of controller agents, based upon classification of severity and/or control
STANDARD THERAPIES Expert guidelines state that standard asthma treatment should
include short-acting beta 2-agonists, systemic glucocorticoids, and supplemental oxygen.
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Short-acting beta 2-agonists We recommend that children who are admitted to the hospital
with acute asthma exacerbation receive therapy with inhaled short-acting beta 2-agonists
(SABA, eg albuterol, salbutamol).
All nebulized treatments should be given with oxygen (generally at a flow rate of 6 to 8
L/min) rather than with compressed air.
Continuous therapy We suggest that patients who have poor improvement after several
albuterol or salbutamol treatments or who require treatments more frequently than every three
hours be treated with continuous albuterol or salbutamol nebulization. However, intermittent
treatments every two hours may be better for younger patients who are unable to tolerate
continuous therapy.
Continuous nebulized albuterol is typically given at a dose of 0.5 mg/kg per hour for children
Glucocorticoids
Systemic glucocorticoids are an important component of the management of asthma

exacerbations due to their ability to decrease airway inflammation and secretions. We
recommend systemic glucocorticoids for children with acute asthma exacerbation who require
hospitalization.
In the rare cases in which glucocorticoids are contraindicated (eg, hypersensitivity reaction,
varicella infection, herpes simplex keratitis), the severity of bronchospasm must be weighed
against the reason for contraindication.
Dose and duration Glucocorticoids may be given as prednisone, prednisolone, or

methylprednisolone. Dosing varies from institution to institution but is typically 1 mg/kg every
12 hours for a total of five days (with a maximum dose of 60 mg per day).
A longer course (e.g., 7 to 10 days) may be indicated for patients who have a severe
exacerbation that is slow to respond to treatment or patients who have had more than one
exacerbation requiring oral glucocorticoids in the previous two months. Greater than 10 days
may be necessary for patients whose control regimen includes oral glucocorticoids.
We suggest that systemic glucocorticoid therapy be tapered in patients who require a course
longer than 10 days.
Glucocorticoid therapy may be tapered in a number of ways; we suggest decreasing the dose
by 50 percent every two to three days (i.e., 2 mg/kg/day for days 1 to 10, 1 mg/kg/day for
days 11 to 12, 0.5 mg/kg/day for days 13 to 14, and 0.25 mg/kg/day for days 15 to 16).
Route Oral administration is preferred to intravenous administration since it is less invasive

and equally efficacious. If the patient cannot tolerate oral glucocorticoids (e.g., gastrointestinal
impairment or repeated spitting of doses), glucocorticoids can be given intravenously.
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Inhaled glucocorticoids are not as effective as systemic glucocorticoids for severe asthma
exacerbations and should not be used as a substitute for systemic glucocorticoids.
THERAPIES RESERVED FOR SPECIAL CIRCUMSTANCES
Systemic beta agonists The addition of systemic to inhaled beta 2-agonists has been used
with some success to treat severe asthma exacerbations. However, there is no evidence to
support the isolated use of intravenous beta 2-agonists. Systemic beta 2-agonists typically are
used in the ED or ICU setting since they require a higher level of monitoring than is available on
regular nursing units.
Theophylline When added to standard therapy for acute asthma exacerbation in children,
intravenous theophylline has little effect on clinical scores, spirometry, or length of stay. In
addition, it is associated with a high incidence of side effects. The 2007 NAEPP guidelines do not
recommend methylxanthines during acute asthma exacerbations.
Antibiotics Routine antibiotic administration has no benefit in acute asthma exacerbations.

However, antibiotics may be necessary to treat comorbid infections (e.g., bacterial pneumonia,
bacterial sinusitis).
Clinical assessment Vital signs and pulse oximetry should be assessed immediately upon
arrival to the inpatient unit. These values should be compared with those obtained in the ED to
determine whether the patient is improving or worsening.
Radiography Chest radiographs are not routinely necessary for children who are admitted to
the hospital with acute asthma exacerbations. However, they may be warranted in patients
with:
Acute worsening of clinical status (to look for potential complications of asthma: atelectasis,
pneumothorax, pneumomediastinum, and pneumonia).
Signs of such complications include: fever 38.5C, focal examination findings (e.g., rales or
decreased aeration), and/or extreme tachypnea or tachycardia.
Lack of response to asthma therapy (to look for other processes that can mimic asthma such as
vascular ring, foreign body aspiration
Laboratory Routine laboratories are not necessary for children who are hospitalized for
acute asthma exacerbation and receiving intermittent inhalation therapy. Children receiving
continuous albuterol or salbutamol nebulization are at risk of transient hypokalemia,
hypophosphatemia, and hypomagnesemia. These decreases are rarely of clinical importance in
children. However, we suggest measuring serum electrolytes daily in patients receiving
continuous albuterol or salbutamol who have been taking diuretics regularly, in patients who
have coexistent cardiovascular disease, and in patients with a known predilection to electrolyte
disturbances.
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Capillary or arterial blood gases may be used to aid in decision making for patients with
tenuous respiratory status or acute worsening despite therapy. Patients in respiratory distress
with normal or elevated PCO2 are at risk for imminent respiratory failure.
FAILURE TO RESPOND Some patients fail to improve or worsen despite frequent or

continuous administration of SABA and systemic glucocorticoids. Signs of impending respiratory
failure include:
Poor air movement .
Worsening hypoxemia.
Fatigue.
Change in mental status.
Carbon dioxide retention.
In such patients, capillary or arterial blood gases may be used to aid in decision making.
Patients in respiratory distress with normal or elevated PCO2 are at risk for imminent
respiratory failure and should be transferred to the ICU.
Other possible reasons for worsening or failure to improve include the development of a
complication (e.g., atelectasis, pneumothorax, pneumomediastinum, pneumonia) or that the
diagnosis of asthma is incorrect and the patient's symptoms are caused by another process.
Chest radiographs and/or consultation with a specialist can help to distinguish among theses
possibilities.
CONSULTATION
Asthma specialist Many children with asthma respond quickly to standard care; the
inpatient management of such patients need not involve an asthma specialist (e.g., pediatric
pulmonologist, pediatric allergist). However, consultation with an asthma specialist may be
warranted in the following circumstances:
The diagnosis is in question or the patient fails to improve.
Life-threatening asthma exacerbation.
Repeated hospital admission, history of ICU admission, frequent ED visits, or need for multiple
or frequent drug therapies at home.
Other conditions complicating asthma (e.g., sinusitis, nasal polyps, chronic lung disease of
prematurity, allergic bronchopulmonary aspergillosis, gastroesophageal reflux, obesity, food
allergy, etc).
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Patients with asthma and other chronic disease (eg, cystic fibrosis, restrictive lung disease,
neuromuscular weakness).
Patient requires extensive education about allergen avoidance, problems with adherence to
therapy, or complications of therapy.
Patient is receiving ongoing care by the asthma specialist.
DISCHARGE CRITERIA The criteria for discharge vary from institution to institution. Patients
can be discharged when:
1. Their asthma symptoms and signs (and scores if utilized) are considered mild.
2. They no longer require supplemental oxygen.
3. They are receiving a treatment regimen that can be reasonably duplicated at home (e.g.,
they are tolerating oral medications and the frequency of inhalation treatments can be
managed by the caregiver). If possible, patients should be observed in the hospital for at
least one interval while receiving the treatments that will be prescribed after
discharge.If patients have been receiving nebulized medications they may be changed to
MDI-spacer upon discharge provided they can demonstrate proper technique.
4. If spirometry is readily available and the patient can perform it, FEV1 should be greater
than 70 percent of expected.
5. Access to medications and appropriate follow-up have to be confirmed.
6. Asthma education is complete.
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Hydrocarbon aspiration
Patricia A Primm, MD
Ingestion of large quantities of hydrocarbons by children is unusual because hydrocarbons are

foul-tasting.
The aspiration hazard of hydrocarbons is inversely related to viscosity and surface tension and
directly related to volatility. Thus, hydrocarbons with decreased viscosity, low surface tension,
and high volatility are more likely to be aspirated and cause pulmonary injury. The low viscosity
permits greater penetration into the distal airways while the low surface tension facilitates
spread over a greater area. As an example, simple petroleum distillates (kerosene, gasoline,
liquid furniture polish) are chiefly aspiration hazards. They have high potential to cause
aspiration pneumonitis but rarely cause systemic symptoms.
CLINICAL MANIFESTATIONS
Vital signs Between 30 and 60 percent of patients with hydrocarbon aspiration have fever at
the time of presentation (38 to 40C).
Respiratory Pulmonary manifestations result from any degree of hydrocarbon aspiration,

although their onset may be delayed for 12 to 24 hours. Immediate signs of aspiration include
coughing, choking, gagging, and vomiting. Respiratory examination findings vary with the degree
of pulmonary injury. Physical findings may include tachypnea, dyspnea, cyanosis, diminished
resonance on percussion, suppressed or tubular breath sounds, and crackles. Displacement of
alveolar gas by vaporized hydrocarbon may aggravate hypoxemia caused by inflammation and
edema.
The major pulmonary complications of hydrocarbon aspiration include asphyxia, necrotizing

chemical pneumonitis, lipoid pneumonia, and hemorrhagic pulmonary edema, which quickly
progresses to shock and respiratory arrest. Pneumothorax, subcutaneous emphysema of the
chest wall, and pleural effusion, including empyema, also may occur. Secondary infection with
bacteria or viruses may occur. Pneumatoceles may develop in areas of extensive consolidation
during the recovery period.
Radiographic findings The radiographic findings of hydrocarbon aspiration often occur

before the development of physical findings. They may be seen within 20 minutes or as late as
24 hours after aspiration.
The initial findings are multiple, small, patchy densities with ill-defined margins . The lesions
become larger and coalesce as the injury progresses. In some cases, the radiographic findings
may be minimal at a few hours and then rapidly progress to extensive infiltrates. Emphysema or
pneumothorax may develop. Radiographic abnormalities typically peak between two and eight
hours after aspiration. The resolution of radiographic changes is gradual and lags behind clinical
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improvement, which usually occurs three to five days after aspiration. Pneumatoceles may
develop in this latent period.
Cardiovascular Cardiac arrhythmia may occur after inhalation. Solvent hydrocarbons can
sensitize the myocardium to catecholamines, leading to fatal arrhythmia ("sudden sniffing
death").
Central nervous system Hydrocarbon ingestion or inhalation may have direct CNS effects,
including somnolence, headache, ataxia, dizziness, blurred vision, weakness, fatigue, lethargy,
stupor, seizures, and coma. In addition, hypoxia caused by hydrocarbon aspiration may cause
secondary CNS depression, including drowsiness, tremors, or convulsions.
Hematologic Leukocytosis occurs early in the clinical course of hydrocarbon aspiration

unrelated to pneumonitis and may last as long as one week. Hemolysis, hemoglobinuria, and
consumptive coagulopathy also may occur with significant ingestion.
MANAGEMENT All children with hydrocarbon aspiration should be observed for at least six
to eight hours in an emergency department setting. Chest radiographs should be obtained in all
patients who have cough or any respiratory symptoms at presentation. Patients with normal
initial radiographs should have them repeated four to six hours after ingestion.
Decontamination The child's clothing should be removed to prevent continued inhalation

exposure. All patients should have their skin cleaned. The eyes should be flushed if any evidence
of redness, tearing, or lid swelling is present.
As a general rule, decontamination of the gastrointestinal tract in children with hydrocarbon

ingestion should avoid gastric emptying or lavage and induction of emesis because of the risk for
aspiration during these procedures.
Pulmonary management The treatment of hydrocarbon pneumonitis is supportive.

Endotracheal intubation is indicated in patients with CNS depression or impaired ventilation.
Additional measures include oxygen, physiotherapy, and continuous positive airway pressure.
Children who have hydrocarbon pneumonitis that is refractory to conventional supportive
therapy may be candidates for receiving extracorporeal membrane oxygenation.
Bronchospasm should be treated with selective beta 2 agonists. Epinephrine and isoproterenol
should be avoided because they can cause fatal ventricular dysrhythmia in the hydrocarbon-
sensitized myocardium.
Corticosteroids have no beneficial effect on the course of hydrocarbon aspiration.

Pneumatoceles rarely rupture and do not require treatment . Pneumonitis caused by
hydrocarbon aspiration should not be treated routinely with antibiotics unless signs of
secondary infection, including the following, are present:
Recurrence of fever after the first 48 hours
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Increasing infiltrate in chest radiograph
Leukocytosis
164
Sudden infant death syndrome
Michael J Corwin, MD
Sudden infant death syndrome (SIDS), also called crib or cot death, is the leading cause of
infant mortality between 1 month and 1 year of age in the United States. It is defined as the
sudden death of an infant younger than 1 year of age, which remains unexplained after a
thorough case investigation, including performance of a complete autopsy, examination of the
death scene, and review of the clinical history.
SIDS is the leading cause of infant mortality between 1 month and 1 year of age in the United
States. The risk of SIDS in the United States is <1 per 1000 live births. Higher rates (two to three
times the national average) are found in black and American Indian/Alaskan native children. A
disproportionately high rate (15 to 20 percent) of SIDS cases occurs in child care settings. The
risk of SIDS is slightly increased in boys.
The median age for SIDS deaths was 11 weeks, the peak incidence was between 2 and 4
months, and 90 percent occurred before 6 months of age.
RISK FACTORS Numerous risk factors for SIDS have been identified in observational and case
control studies. Those that are consistently identified as independent risk factors include:
1. Young maternal age.

2. Maternal smoking during pregnancy.
3. Late or no prenatal care.
4. Preterm birth and/or low birth weight.
5. Prone sleeping position.
6. Sleeping on a soft surface.
7. Overheating.
Maternal risk factors There are two major maternal risk factors for SIDS that are
independent of birth weight .
1. Maternal smoking.
2. Age of the mother under 20 years.
Prematurity Preterm infants are at a higher risk for SIDS than term infants. Among low and
very low birth weight infants, the SIDS rate has consistently been three- to fourfold higher than
in term infants.
Apnea Apnea is a marker of prematurity, but is not specifically increased in SIDS victims.
Low birthweight Infants born small for gestational age (SGA) have an increased risk for SIDS.
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Sleep position The prone sleeping position has been found to be associated with an
increased risk of SIDS in a number of observational and case-control studies.
Sleep environment Various aspects of the sleep environment, including the sleep surface,
sleepwear, bedding, room temperature, and whether or not the bed or room are shared with
parents also appear to affect the risk of SIDS.
Pacifier use A meta-analysis of seven studies of the effects of pacifier (dummy, soother) use
on the risk of SIDS found a protective effect (multivariate summary odds ratio 0.71 [95% CI 0.59-
0.85] and 0.39 [95% CI 0.31-0.50] for usual pacifier use and pacifier use during last sleep,
respectively). The mechanism for this association is unclear; it may be related to the lowered
arousal threshold during pacifier use. Because of this apparent reduction in risk, the AAP
suggests offering a pacifier during sleep, provided that it does not interfere with
establishment of breast feeding.
Breastfeeding The association between breastfeeding and risk of SIDS is inconsistent and is
complicated by confounding factors (eg, maternal age, smoking).
Immunizations SIDS is not associated with diphtheria-tetanus-pertussis (DTP) vaccine or

other vaccines. In fact, immunization may lower the risk of SIDS.
Sibling of SIDS victim Siblings of SIDS victims have a five- to six-fold increase in risk for SIDS.
However, assuming a SIDS rate of 0.56 per 1000 live births (0.06 percent), the risk in subsequent
siblings for most families remains less than 1 percent.
Twins In cohort studies, linking data from birth and death records, the crude risk of SIDS
among twins is approximately twice that of singletons.
SIDS is characterized by several gross and microscopic autopsy features, even though none of
these abnormalities is sufficiently grave to explain the infant's death.
A triple-risk model has been proposed, suggesting that SIDS occurs in infants with underlying
vulnerability (eg, genetic pattern, brainstem abnormality) who experience a trigger event (eg,
maternal smoking, infection), at a vulnerable developmental stage of the central nervous or
immune system.
Underlying vulnerability
Brain abnormalities Emerging evidence suggests that underlying abnormalities in serotonin

(5HT) signaling in the brain play a role in the pathogenesis of SIDS. These abnormalities could be
either genetic in origin, or acquired from exposures in utero.
Genetic factors The role that genetic factors play in susceptibility to SIDS is not clear.
166
Cardiac dysfunction Some studies have suggested the control of cardiac function may be
abnormal in infants at risk for SIDS, but results have been inconsistent.
Infection Infection is clearly the cause in a sub-group of explained sudden unexpected

deaths in infancy. There has not been convincing evidence of a role for infection as a cause of
SIDS. However, similarities between the common autopsy findings and those of toxemic shock
have raised the possibility for a role for infectious triggers in cases of SIDS even in the absence of
a recognizable tissue reaction, which may lead to a toxic shock-like event. Implicated organisms
include enteric bacteria (enterotoxigenic S. aureus and E. coli), and mild viral infections.
Variations in the innate immune system, including polymorphisms that result in an exaggerated
pro-inflammatory response, have been found in a higher proportion of SIDS cases than in
controls.
Developmental timing SIDS usually occurs between the second and fourth months of life, a
period of remarkable developmental changes in cardiac, ventilatory, and sleep/wake patterns in
otherwise normal infants. This coincidence of timing suggests that SIDS infants are vulnerable to
sudden death during a critical period of autonomic maturation.
DIFFERENTIAL DIAGNOSIS SIDS is a diagnosis of exclusion; other causes of sudden

unexpected death in infancy must be considered and excluded before a diagnosis of SIDS can be
167
established. Among these, fatal child abuse and metabolic disease are particularly important,
because they have implications for other children in the family.
MANAGEMENT The appropriate professional response to the death of any infant is

compassionate, empathic, supportive, and nonaccusatory. At the same time, it is essential to
discover the cause of death, if possible.
Personnel in first response teams should be trained to make observations at the scene such as
the position of the infant, marks on the body, body temperature and rigor, type of bed or crib
and any defects, amount and position of clothing and bedding, room temperature, type of
ventilation and heating, and reactions of the caretakers.
In the absence of evidence of injury or significant antecedent illness, the parents can be told
that death appears to be due to SIDS. However, other causes can be excluded only after a
thorough death scene investigation, postmortem examination, and review of the clinical history
have been performed. Parents should understand that these procedures will enable them and
their physician to understand why their infant died and how other children in the family,
including subsequent children, might be affected.
168
The following recommendations are made by the American Academy of Pediatrics, the
Canadian Paediatric Society, and/or the United Kingdom Department of Health:
1. All infants, including infants with a history of prematurity, should be placed to sleep on
their backs for every sleep. Even though they may be able to roll from their backs to the
prone position, infants should be placed on their back to sleep. Although earlier AAP
policy statements suggested that side sleeping was an acceptable alternative to supine
sleeping, side sleeping is no longer recommended. Prone positioning is encouraged
when the infant is awake and observed. Prone positioning facilitates the development of
shoulder girdle strength and avoidance of occipital plagiocephaly.
2. Maternal smoking during pregnancy and exposure of infants to tobacco smoke should
be avoided.
3. Infants should be placed to sleep on a firm surface; polystyrene filled cushions and
sheepskin bedding should be avoided.
4. Soft objects (eg, pillows, stuffed animals) and loose blankets should be kept out of the
crib, bassinet, or cradle.
5. The infant's head should remain uncovered. If blankets are used, the infant's feet should
be placed at the bottom of the crib and the blankets tucked around the mattress to
prevent the infant from moving into a position in which the head could be covered by
the blanket.
6. The safest place for an infant to sleep is in a crib (cradle, bassinet) in the parents' room
for the first six months. Infants should not share a bed during sleep; they should not
sleep on or share a sofa, recliner, armchair, or other type of cushioned chair.
7. Overheating should be avoided; the infant should be lightly clothed for sleep; the
bedroom temperature should be comfortable for a lightly clothed adult (approximately
65F [18C]); if the infant is dressed in a sleeper, no more than a thin blanket should be
necessary. Infants should not sleep next to a radiator or heater or in direct sunshine.
8. The use of a pacifier during sleep may reduce the risk of SIDS. The AAP suggests that the
pacifier should be used when placing the infant to sleep, but not reinserted once the
infant is asleep. The AAP suggests delaying the introduction of the pacifier until 1 month
of age for breastfed infants to ensure that breastfeeding is firmly established. There is
some concern that pacifier use may increase the risk of acute otitis media (AOM).
However, the incidence of AOM is relatively low during the first six months of life when
the risk of SIDS is greatest.
9. Commercial devices, marketed to reduce the risk of SIDS, have not been sufficiently
tested for efficacy or safety.
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The Cardiovascular system
Clinical manifestations and diagnosis of myocarditis in children

Catherine K Allan, MD - David R Fulton, MD
Myocarditis is a condition resulting from inflammation of the heart muscle. Myocellular

damage results in myocardial dysfunction leading to heart failure. The clinical presentation can
be acute or chronic. However, in contrast to adults, the majority of children with myocarditis
present with acute or fulminant disease.
The causes of myocarditis are diverse and include infectious, toxic, and autoimmune etiologies.
Infectious etiologies, particularly viral, are most common in children. The most common causes
of viral myocarditis are enterovirus (coxsackie group B) and adenovirus; cases may be sporadic
or epidemic and have seasonal and geographical variation.
Patients with viral myocarditis, the most common etiology in children, frequently have a
prodrome of fever, myalgia, and malaise several days prior to the onset of heart failure. Those
with myocarditis due to autoimmune disorders may have symptoms of systemic disease.
Infants and children with acute myocarditis often present with signs and symptoms of heart
failure including dyspnea at rest, exercise intolerance, syncope, tachypnea, tachycardia, and
hepatomegaly. Respiratory distress may be the most prominent sign, leading to the incorrect
initial diagnosis of lower respiratory tract infection in many children.
Tachycardia and metabolic acidosis may be important indicators of the extent of myocardial
involvement. Supraventricular and ventricular arrhythmias and complete heart block may be
present.
Acute myocarditis is distinguished from fulminant myocarditis, which is associated with an

acute onset and severe hemodynamic compromise. Children with fulminant myocarditis are
critically ill. They present with signs of decreased cardiac output, including hypotension, poor
pulses, and decreased perfusion, which may progress to cardiovascular collapse. Malignant
arrhythmias are common.
PHYSICAL EXAMINATION In symptomatic patients, the physical examination often reveals

direct evidence of cardiac dysfunction.
Signs of respiratory distress resulting from left elevated atrial pressures and pulmonary venous
congestion include tachypnea and retractions.
170
S3 and occasionally S4 gallops may be present and are important signs of impaired ventricular
function, particularly when biventricular acute myocardial involvement results in systemic and
pulmonary congestion.
If the right or left ventricular dilation is severe, auscultation may reveal murmurs of functional
mitral or tricuspid insufficiency.
In acute fulminant myocarditis, signs of low cardiac output may be present, including
hypotension, poor pulses and perfusion, and altered mental status.
A pericardial friction rub and effusion may become evident in some patients with
myopericarditis.
DIAGNOSTIC STUDIES The initial evaluation of the child with suspected myocarditis includes
chest radiograph, electrocardiogram (ECG), and cardiac enzymes. An echocardiogram should be
performed to evaluate ventricular function and the degree of mitral regurgitation.
Chest radiograph Chest radiographic findings typically include cardiomegaly, although heart
size may be normal. Pulmonary vascular congestion is often present.
Electrocardiogram The ECG in myocarditis may be normal or abnormal. The abnormalities

are nonspecific and include low voltages and inverted T waves. The rhythm is most commonly
sinus tachycardia. However, ventricular premature beats, atrial premature beats,
supraventricular tachycardia, and ventricular tachycardia may be seen. Complete heart block
occurs less often.
Cardiac enzymes Cardiac troponin T and CK-MB may be helpful in distinguishing acute
myocarditis from chronic dilated cardiomyopathy. In a study in children with acute heart failure
and myocardial dysfunction, troponin T and CK-MB levels were higher in myocarditis compared
to dilated cardiomyopathy, reflecting ongoing myocellular damage in the former.
Echocardiogram The echocardiogram typically shows left ventricular dysfunction.

Morphologic findings may distinguish acute from fulminant myocarditis. In one study, left
ventricular diastolic dimensions were increased in acute and near normal in fulminant disease,
while septal thickness was normal in acute and increased in fulminant disease . Doppler studies
often show mitral regurgitation. Patients who also have pericarditis typically have a pericardial
effusion.
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172
Magnetic resonance imaging Magnetic resonance imaging with contrast can document the
location and extent of inflammation. In three studies, gadolinium enhancement was greater in
patients with myocarditis than in normal controls. Areas of enhancement were focal in the first
one to two weeks following onset of symptoms and became more generalized later in the
course.
Other studies Additional laboratory testing should be guided by the clinical presentation.
The erythrocyte sedimentation rate is frequently elevated in myocarditis, but is nonspecific and
not useful in establishing a diagnosis. A complete blood count may show evidence of infection.
Children with acute fulminant myocarditis often have a metabolic acidosis. Although
respiratory distress is typically present, these patients usually have a low arterial PCO2,
indicating respiratory compensation.
Viral infection should be suspected in patients with acute onset of symptoms, especially those
with a prodrome of fever, myalgias, and malaise. Swabs from rectal and nasal mucosa should be
cultured for viruses. In the absence of positive viral cultures, acute and convalescent antibody
titers can be helpful in the diagnosis of a specific viral infection. If an endomyocardial biopsy is
performed, samples should be sent for viral and bacterial culture and, if available, PCR analysis.
Cardiac catheterization Cardiac catheterization typically reveals depressed cardiac index,

elevated left ventricular end diastolic pressure, and elevated mean atrial pressure. Angiography
shows decreased left ventricular function with or without mitral regurgitation. The main
purpose of catheterization is to obtain samples by endomyocardial biopsy (EMB) for pathologic
and microbiologic analysis.
Endomyocardial biopsy EMB is considered the gold standard for the diagnosis of
myocarditis.
SUMMARY
1. Myocarditis should be suspected in a child with the acute onset of heart failure and no
structural heart disease, especially after a viral prodrome.
2. The evaluation should include a chest radiograph, ECG, and cardiac enzymes. An
echocardiogram should be performed to exclude structural heart disease and assess
ventricular function.
3. An endomyocardial biopsy should be performed because it may provide important
diagnostic and prognostic information and can usually be performed safely. In addition
to histopathology, viral cultures and molecular techniques should be used to identify an
infectious etiology.
4. Because of the high risk of arrhythmias and hemodynamic compromise, affected
patients should be monitored in a pediatric intensive care unit.
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Treatment and prognosis of myocarditis in children
The mainstays of therapy for acute or fulminant myocarditis are monitoring, supportive care,
and standard regimens for heart failure. Because of the high risk of arrhythmias and
hemodynamic compromise, affected patients should be monitored in a pediatric intensive care
unit.
Heart failure In the acute phase, diuretics, afterload reducing agents, and inotropic drugs
are used to treat heart failure. Intravenous agents such as dopamine, dobutamine, and
milrinone are used to prevent circulatory collapse in the case of acute fulminant myocarditis.
Sedation, intubation, and mechanical ventilation are used to decrease metabolic demand in
patients with cardiogenic shock. Mechanical ventilation also provides left ventricular afterload
reduction.
For patients who progress from acute myocarditis to chronic heart failure, diuretics,
angiotensin inhibitors, digoxin, and aldosterone inhibitors (ie, spironolactone) are well-accepted
therapies, although there are no conclusive studies that prove benefit of these agents in
pediatrics.
Antiarrhythmic drugs Loss of sinus rhythm may lead to acute deterioration or may
exacerbate the symptoms of heart failure. However, most antiarrhythmic drugs have negative
inotropic activity and may therefore worsen cardiac function and lead to acute hemodynamic
instability. Thus, antiarrhythmic drugs should be used only when the expected benefit exceeds
the risk, and only in consultation with a pediatric cardiologist.
Immunosuppressive therapy Myocardial damage in infectious myocarditis is thought to be

due to both direct viral damage and the immune response to infection. This dual mechanism is
the basis for proposing immunosuppressive or immunomodulatory therapies.
Data regarding the efficacy of immunosuppressive therapy for myocarditis in children are
limited.
Corticosteroids Case series and a small trial are inconclusive with respect to the beneficial
effects of prednisone and/or other immunosuppressive agents (azathioprine, cyclosporine) on
left ventricular function and ventricular arrhythmias in children with myocarditis.
IVIG The administration of intravenous gamma globulin (IVIG) to treat myocarditis was
suggested by its efficacy in other immune-mediated diseases. Its use is also supported by
experimental data in which polyclonal immunoglobulin protects against myocardial or arterial
damage in mouse models of viral and autoimmune myocarditis .
Our approach We use high dose IVIG (2 g/kg over 24 hours) for children with acute
myocarditis demonstrated by endomyocardial biopsy. We reserve the use of corticosteroids or
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other immunosuppressive agents for myocarditis associated with systemic autoimmune
diseases.
PROGNOSIS Little information is available on the natural history of myocarditis in children.

Limitations of these reports include the small number of patients, the inclusion of other causes
of myocardial dysfunction, the lack of biopsy confirmation of myocarditis, and the failure to
distinguish between acute and fulminant myocarditis . Although similar data are not available
for children, complete recovery is more likely in adults with fulminant compared to acute
myocarditis.
In a retrospective review, 41 patients with acute myocarditis proven either by endomyocardial

biopsy or by the presence of cardiac dysfunction and coincident proven viral infection were
followed up to five years following diagnosis. Sixty-six percent showed complete recovery, 10
percent partial recovery, and 24 percent died or required transplantation.
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Management of isolated ventricular septal defects in infants and
children
Kirsten Bourke Dummer, MD - Thomas P Graham, Jr, MD
The management of VSDs varies depending upon several factors including:
1. The size of the defect.

2. The likelihood of spontaneous closure or decrease in size over time.
3. The involvement of one or more cardiac valves.
4. The anticipated difficulty and effectiveness of surgical closure.
Small VSD Infants who have small VSDs and remain asymptomatic at the three to four
week visit usually have follow-up with the cardiologist at eight to ten weeks of age. Those who
continue to have a murmur, but are otherwise asymptomatic and growing well should be seen
again by the pediatric cardiologist at approximately 12 months of age.
If at the 12-month visit with the cardiologist, the murmur is gone, repeat echocardiogram is not
necessary, unless clinical concerns arise (ie, endocarditis). However, some physicians opt to
obtain an echocardiogram to verify closure. If there is no evidence of a defect on examination or
echocardiography, no additional follow-up is necessary. Children in whom closure is associated
with aneurysmal tissue should be followed every two to three years to monitor the possible
development of obstruction to right ventricular outflow.
If the murmur persists at the 12-month cardiology visit, an echocardiogram is recommended to

verify the diagnosis and to evaluate the presence of complicating features. These include
development of subaortic stenosis, right ventricular outflow obstruction, or aortic valve
abnormalities.
Moderate to large VSD Infants with moderate to large VSDs usually become symptomatic
within the first months of life as pulmonary vascular resistance (PVR) declines. The frequency of
cardiology follow-up in these infants depends upon the progression of symptoms and the
response to medical therapy.
The primary care provider should monitor the infant for manifestations of heart failure (e.g.,
poor weight gain, tachypnea, and tachycardia) and for changes in physical examination that
should prompt an earlier appointment with the cardiologist. These include a hyperdynamic
precordium, displacement of the cardiac apex outside the midclavicular line, increased intensity
of the second component of the second heart sound, or the onset of a diastolic murmur.
Although unlikely to occur, if upon follow-up of a small to moderate defect, the murmur is
gone but the pulmonic component of S2 is increased in intensity, an echocardiogram must be
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obtained to rule out pulmonary hypertension with systemic RV pressure. In addition, children
older than 2 years whose defects have not closed should undergo echocardiography if outflow
tract obstruction or aortic regurgitation is suspected. Those with residual small defects are
usually followed every two to five years for overall assessment and re-emphasis of the need for
SBE prophylaxis
Medical therapy, discussed below, should be instituted in infants with obvious cardiac failure.
Infants who respond to medical therapy can be followed closely to see whether the defect
diminishes in size during the first year of life or even closes spontaneously, depending upon the
type of defect.
For those patients with VSDs and pulmonary artery pressure less than 50 percent of systemic
arterial pressure, the risk of developing pulmonary vascular disease is low.
Patients with moderate to large VSDs and pulmonary artery pressure greater than 50 percent
of systemic arterial pressure are at risk to develop pulmonary vascular disease. If pulmonary
artery pressure remains elevated, intracardiac repair is undertaken in the first year [3] . Children
with a left-to-right shunt greater than 2:1 should undergo surgical closure in the first year as
well.
MEDICAL MANAGEMENT Medical therapy, indicated for symptomatic infants, is targeted to

the symptoms: heart failure and poor weight gain. The goals of therapy include: relief of
symptoms, normalization of growth, and minimization of frequency and severity of respiratory
infections.
The symptoms of children with heart failure from left-to-right shunts can improve with medical
therapy, postponing and possibly avoiding the need for surgical correction. However, despite
maximum medical management, 50 percent of patients with moderate to large VSDs continue
to have tachypnea and or/failure to thrive. These patients undergo surgical closure in infancy,
preferably before six months of age (three months in children with Trisomy 21), before the
development of irreversible pulmonary hypertension, which may begin as early as six months of
age.
Dietary interventions Dietary interventions may facilitate weight gain in infants with
moderate to large VSDs. These infants have increased caloric needs due to an increased
metabolic demand and may need greater than 150 kcal/kg per day. In addition, infants with
increased pulmonary blood flow may have difficulty ingesting their daily caloric requirement
because they often tire with feeding. The caloric density of feedings may be increased by the
addition of carbohydrate and/or medium chain triglyceride preparations to conventional
formulas in the setting of failure to thrive. Fluid restriction is usually counterproductive since
delivery of adequate calories is made more difficult. Instead, diuretic therapy should be
instituted to reduce volume overload. Infants with iron deficiency anemia should be treated
with supplemental iron to increase the hematocrit and oxygen carrying capacity.
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Pharmacologic therapy
Diuretics Diuretics are the first line of pharmacologic therapy for infants who present with
tachypnea and failure to thrive.
Furosemide is well-tolerated and commonly used in doses of 1 to 2 mg/kg per dose either two
or three times per day, depending upon the clinical response. If furosemide is used three times
per day, electrolytes should be monitored to assess the need for electrolyte replacement.
Usually, if the infants are hospitalized for heart failure, the electrolytes are checked after the
first 24 hours of therapy. As diuretics are adjusted or added, electrolytes are repeated to assess
the need for electrolyte supplementation. Once the infant is discharged home on a stable
diuretic regimen, the electrolytes can be followed on an as-needed basis.
A second diuretic may be added to enhance diuresis, improve the symptoms of heart failure, or
to spare potassium (to avoid the need for oral KCl, which may be poorly tolerated). Alternative
agents include: Chlorothiazide (10 mg/kg per dose once or twice per day); chlorothiazide is not
potassium-sparing. Spironolactone (administered every 6 to 24 hours, with a total daily dose of
3 mg/kg).
ACE inhibitors Systemic vascular resistance may increase in children with VSD for a variety
of reasons. In this setting, antegrade flow through the aortic valve decreases and left-to-right
shunting through the defect increases. Afterload reducing agents, such as the angiotensin
converting enzyme inhibitors captopril or enalapril are used to reduce systemic vascular
resistance, promoting antegrade flow through the aortic valve and decreasing the magnitude of
the shunt
Digoxin Some physicians use digoxin for additional aid with contractility in large shunt
lesions. Its efficacy in ventricular volume overload with normal underlying ventricular function is
debatable. However, it does have a favorable effect on adrenergic neurohormonal modulation,
which may explain clinical improvement in this setting.
Pulmonary hypertension Patients who have echocardiographic evidence of pulmonary

hypertension estimated by the regurgitant tricuspid jet flow, septal position, or right-to-left
shunting require further assessment. Cardiac catheterization may be helpful in evaluating the
hemodynamic status and PVR in infants and children who have large defects but small left-to-
right shunts or in those patients who are referred for initial assessment late in the first year of
life. This would include infants with normal LV size or mild increase in size who have a large
anatomical VSD, that is, 50 percent or greater in diameter than the aortic annulus.
Quantification of PVR and response to oxygen and pulmonary vasodilators may provide
guidance for pharmacologic intervention in the early post-operative period. As a general rule, if
the calculated PVR is <8 mmHg/L/min/m2 (resistance or Wood units), surgical closure is
recommended. If the calculated PVR is >12 mmHg/L/min/m2, the patient is at high risk for
persistent pulmonary hypertension and surgical closure of the defect is usually not
recommended. Closure of defects with such elevated PVR may result in low cardiac output and
178
increased peri-operative mortality. In these circumstances, there may be consideration for
placement of a restrictive VSD patch, but this is a rare circumstance. When the calculated PVR is
8 to 12 mmHg/L/min/m2, additional information, including the response of PVR to 100 percent
oxygen and pulmonary vasodilators, may guide post-operative management.
Hospitalization Infants with severe heart failure at the time of diagnosis, or any time
thereafter, should be hospitalized for initial management. This may include:
Alleviation of temperature stress.
Supplemental oxygen as indicated (oxygen should be used with caution since it is a pulmonary
vasodilator and may decrease PVR, increasing left-to-right shunt, and exacerbating failure)
Antibiotic therapy if bacterial pneumonia is suspected (after obtaining blood and possibly
tracheal cultures).
Institution of diuretic therapy.
Possible administration of digoxin.
Caloric supplementation.
Possible red blood cell transfusion for significant anemia in the setting of heart failure.
The administration of an ACE inhibitor to reduce the afterload resulting in improving congestive
heart failure symptoms.
SURGICAL MANAGEMENT Decisions regarding surgery, and the type of surgical procedure,
must be made on a case by case basis. Factors to consider include the severity of failure,
likelihood of progression of pulmonary vascular disease or other complications, likelihood of
reduction in size or spontaneous closure of the defect, and the morbidity and mortality of the
procedure in young infants in the center where the surgery is to be performed.
Indications for surgical closure of VSD in infants and young children may include:
1. Infants <6 months (<3 months for those with trisomy 21) who have uncontrolled heart failure
despite maximal medical and dietary interventions or who have pulmonary hypertension.
2. Children less than 12 months with Qp:Qs >2:1, without elevated PVR .
3. Subpulmonic and membranous defects, regardless of size, with aortic regurgitation should be
surgically corrected before the aortic valve is permanently damaged.
The decision to close small defects with aortic valve prolapse without aortic regurgitation is
controversial.
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Contraindications Surgical closure of a VSD in infants and young children is generally
contraindicated if PA pressure is suprasystemic or if PVR is greater than >12 mmHg/L/min/m2
(Wood units).
Procedures The surgical approach and technique vary depending upon the individual surgeon
and center.
Intracardiac repair Direct patch closure of the defect under cardiopulmonary bypass and/or
deep hypothermia is the procedure of choice in most children and at most centers. The
approach (eg, transatrial, right ventriculotomy, apical ventriculotomy) depends upon the type
and location of the defect, as well as the preference of the surgeon. Whenever possible,
ventriculotomies should be avoided.
Transcatheter closure Transcatheter closure for muscular defects has been achieved
successfully where surgical closure is difficult or unsuccessful.
In a report describing transcatheter closure of congenital and postoperative VSDs in 168

patients from a single-center between 1989 and 2003, implantation of a STARFlex device was
feasible in almost all cases and late events caused by the device were rare. However,
periprocedural events were frequent. Most of the adverse events were related to hemodynamic
instability associated with device positioning. Eighteen patients (11 percent) ultimately had one
or more devices explanted secondary to malposition, embolization, or ineffective closure.
Fourteen patients (8 percent) died during follow-up and one of these deaths was directly
attributable to the catheterization.
Complications Current operative mortality in most centers is less than 2 percent. Surgical
complications of VSD repair include residual shunts in any lesion, and right bundle branch block
and complete heart block in patients with membranous or inlet defects. In addition, the risks of
surgery are increased in children who have elevated PVR. These children must be monitored
closely in the postoperative period because PA pressure is labile. Hypoxia may result in sudden
and dramatic changes in resistance.
Long-term outcome The long-term outcome for children who undergo surgical closure of
VSD in childhood is generally excellent. Early surgical repair results in near normal long-term
growth in the vast majority of patients. Most survivors are asymptomatic and lead normal lives,
although they may have diminished exercise performance. Small residual defects are not
uncommon, but repeat surgical closure is not necessary. Late deaths are most common in
patients who have residual hemodynamic abnormalities, particularly increased PVR, a
complicating feature that is mitigated by surgical closure in the first year of life.
Schedule of follow-up The schedule of follow-up varies depending upon the size of the
defect and the style of the individual provider. However, as a general rule, once the diagnosis of
VSD is established in the neonate, the next appointment is usually scheduled at three to four
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weeks of life, provided the infant is well. The visit is timed to coincide with the expected onset
of symptoms (i.e., after the decline of PVR).
Following children with small VSDs requires minimal intervention other than endocarditis
prophylaxis. Physical growth and development should be monitored. Any prolonged febrile
illness, particularly with positive blood cultures, requires cardiology assessment for possible
infectious endocarditis. If a new murmur is auscultated (particularly a diastolic murmur), follow-
up with the cardiologist should be arranged.
Endocarditis prophylaxis The 2007 guidelines of the American Heart Association (AHA)
recommend no antibiotic prophylaxis in children with an isolated VSD, except in the following
circumstances:
1. In children with repaired VSD, which required the use of prosthetic material or device,
prophylactic antibiotics are recommended for dental and respiratory tract procedures
during the first six months after the repair.
2. In children with repaired VSD with a residual defect at the site or adjacent to the site of a
prosthetic device, prophylactic antibiotics is recommended for dental and respiratory tract
procedures.
These guidelines no longer recommend antibiotic prophylaxis for gastrointestinal or

genitourinary tract procedures.
Intercurrent infections Intercurrent infections, particularly respiratory infections can incite

or worsen cardiac failure in infants and children with moderate or large VSDs. Administration of
the influenza vaccine is suggested for all such children who are older than six months of age. In
addition, palivizumab should be administered to those younger than 2 years with
hemodynamically significant lesions.
SUMMARY AND RECOMMENDATIONS Infants with VSD should be followed closely for the
first several months of life during which time falling PVR may cause an increase in left-to-right
shunting. They should be monitored for evidence of heart failure, failure to thrive, and
associated complications. Pertinent physical examination changes, in addition to poor growth,
tachypnea, and tachycardia, include a hyperdynamic precordium, displacement of the cardiac
apex outside the midclavicular line, increased intensity of the second component of the second
heart sound, and the onset of a diastolic murmur.
Infants with congestive heart failure should undergo non-invasive anatomic evaluation. If
failure does not respond to medical therapy, complete repair is undertaken. If failure responds
to medical therapy, including a satisfactory rate of growth, the infant is followed closely through
the first year of life; if pulmonary artery resistance is elevated, intracardiac repair is performed
in the first six months of life. Children with normal PVR, but with a significant left-to-right shunt
should have surgery by 1 year of age.
181
Children older than 2 years whose defects have not closed should undergo echocardiography
to exclude LV and RV outflow tract obstruction as well as aortic prolapse and aortic
regurgitation. Those with residual small defects are usually followed periodically (every two to
five years) for overall assessment.
182
Management and outcome of isolated atrial septal defects in
children
G Wesley Vick, III, MD - Louis I Bezold, MD
Congenital defects of the atrial septum are common, accounting for approximately 7 percent of
congenital heart disorders. They can occur in several different anatomic portions of the atrial
septum, and the location of the defect generally reflects the abnormality of embryogenesis that
led to the anomaly . An atrial septal defect (ASD) can be isolated or can be associated with other
congenital cardiac abnormalities. The sizes of ASDs are variable, and their functional
consequences are related to the anatomic location of the defect, its size, and the presence or
absence of other cardiac anomalies
Secundum ASDs can close spontaneously, remain unchanged, or enlarge. Spontaneous closure,
or a decrease in size, is most likely to occur in defects less than 7 to 8 mm in diameter and with
younger age at diagnosis.
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In many patients with uncorrected moderate to large ASDs, left-to-right shunting increases
with age. As a result, the frequency of heart failure accompanied by fluid retention,
hepatomegaly, and elevated jugular venous pressure increases with advancing age. Most such
patients become symptomatic before 40 years of age. Common symptoms are palpitations
reflecting atrial arrhythmias (the most frequent presenting symptom), exercise intolerance,
dyspnea, and fatigue. The arrhythmias are thought to result from stretching of the atria by the
increased shunting. In some patients, exercise intolerance may develop as early as the second
decade of life.
The right-sided volume overload associated with an ASD is usually well tolerated for years.
Pulmonary vascular disease develops in about 10 percent of older patients with isolated ASDs
but this complication is rare in childhood and adolescence. Pulmonary arteriopathy causes the
symptoms and signs of the Eisenmenger syndrome, including cyanosis from right-to-left
shunting, dyspnea with exertion, and clubbing of the fingers and toes. Progressive pulmonary
hypertension can occur after closure of the defect, even in patients with normal pulmonary
hemodynamics at the time of surgery.
TREATMENT The treatment for isolated secundum ASD is closure of the defect, which can
be achieved by a surgical or percutaneous transcatheter approach. The timing of closure
depends upon the presence of associated symptoms and the likelihood of spontaneous closure.
Monitoring Children with a patent foramen ovale (PFO) or a very small ASD do not require
specific pediatric cardiology follow-up. The child in whom a clinically significant ASD is detected
should be followed by a pediatric cardiologist on an annual or biannual basis. The history and
physical examination during follow-up evaluations should be focused on the development of
signs or symptoms of increased shunting. Echocardiography is indicated when there is concern
that the shunt may be increasing, or to confirm spontaneous closure.
Which ASDs should be closed? The majority of isolated secundum ASDs <6 mm diameter in
infants close spontaneously by two years, and some as late as 5 years of age. Thus, in the
absence of associated symptoms, early closure is not indicated for these defects. Defects of
moderate size (at least 6 to 8 mm in diameter) and larger are relatively unlikely to close
spontaneously. However, closure of even moderate and large isolated secundum ASDs is not
recommended in asymptomatic patients before 2 years of age due to the possibility, however
small, of spontaneous closure.
The generally accepted clinical standard is to repair those isolated secundum ASDs with a large
left-to-right shunt resulting in symptoms or significant right heart enlargement, usually
associated with a ratio of pulmonary to systemic flow (Qp/Qs) exceeding 2:1. The American
Heart Association has recommended a threshold Qp/Qs 1.5:1 *9+ , while the Canadian Cardiac
Society recommended a threshold Qp/Qs >2:1, or >1.5:1 in the presence of reversible
pulmonary hypertension.
184
Cardiac catheterization has been considered the gold standard for Qp/Qs measurement for
many years. However, pulsed Doppler echocardiography may be used for Qp/Qs measurement
once the existence of an acceptable correlation between echocardiographic and catheterization
laboratory estimates of shunt flow has been established for an individual laboratory. Because it
is noninvasive, echocardiography more easily permits serial monitoring. Phase contrast
magnetic resonance imaging is an excellent alternative standard for Qp/Qs measurement.
Small ASDs No large randomized trials have demonstrated a benefit of closure of small ASDs
or PFOs in asymptomatic patients. Without the justification of such data, we do not advocate
closure of such defects in the general population in the absence of symptoms.
The risk of paradoxical embolism through a small ASD or valve-competent PFO is uncertain. The
benefit of ASD closure in reducing the risk of embolism must be weighed against the short and
long term risks of the procedure for closure. These procedure risks are changing as closure
techniques continue to evolve. Closure is recommended by many physicians in patients with a
small ASD or PFO who have experienced embolic strokes or transient ischemic attacks.
Pulmonary hypertension Closure is also controversial when pulmonary hypertension is

present. However, pulmonary vascular disease is an uncommon complication of an isolated ASD,
and when it occurs, the diagnosis is usually made in adulthood.
Surgery Prior to surgery, a comprehensive noninvasive evaluation is essential to exclude

pulmonary hypertension and associated anatomic defects such as anomalous pulmonary and
systemic venous connections. In nearly all cases, echocardiography can resolve these questions,
obviating the need for cardiac catheterization.
Surgical closure is usually performed using a patch of pericardium or Dacron. Small defects are
often closed by direct suturing. However, suture closure of large defects can lead to distortion of
the atrium. Cardiopulmonary bypass is required for the procedure. Repair of sinus venosus
defects requires placement of a patch to direct the right pulmonary venous return into the left
atrium and the systemic venous return into the right atrium.
Transcatheter closure In December 2001, the U.S. Food and Drug Administration's Center
for Devices and Radiological Health approved the Amplatzer Septal Occluder and the Cardio-
Seal Septal Occlusion System for percutaneous closure of secundum ASDs. Sinus venosus
defects, coronary sinus defects, primum ASDs, and complex congenital lesions require surgical
correction.
Transcatheter closure avoids cardiopulmonary bypass, thoracotomy, and atriotomy and is

associated with excellent outcomes. As a result, this approach has largely replaced surgery in
some centers for the closure of small to moderate secundum ASDs that have appropriate
anatomic characteristics
185
.
ENDOCARDITIS PROPHYLAXIS The 2007 guidelines of the American Heart Association (AHA)
recommend no antibiotic prophylaxis in children with an isolated ASD, except in the following
circumstances:
1. In children with a repaired ASD, which required the use of prosthetic material or device,
prophylactic antibiotics are recommended for dental and respiratory tract procedures during
the first six months after the repair.
2. In children with repaired ASD with a residual defect at the site or adjacent to the site of a
prosthetic device, antibiotic prophylaxis is recommended for dental and respiratory tract
procedures.
186
Overview of the management of tetralogy of Fallot
Thomas Doyle, MD - Ann Kavanaugh-McHugh, MD - Thomas P Graham, Jr, MD
Tetralogy of Fallot (TOF) includes the following major features:
Right ventricular outflow tract obstruction .
Ventricular septal defect (VSD).
Deviation of the origin of the aorta to the right so that it overrides the VSD.
Concentric right ventricular (RV) hypertrophy.
187
TOF accounts for approximately 10 percent of all cases of congenital heart disease and is one
of the most common cyanotic congenital heart defects. Reparative surgery, which is usually
performed electively in the first year of life, permits over 85 percent of children with TOF to
survive to adulthood. TOF is also the most common cyanotic malformation to reach adulthood
without surgical repair.
The clinical presentation of patients with TOF depends chiefly upon the degree of RV outflow
obstruction:
Children with severe obstruction have inadequate pulmonary flow, and typically present in the
immediate newborn period with profound cyanosis.
Children with moderate obstruction and balanced pulmonary and systemic flow usually come
to clinical attention during elective evaluation for a murmur.
Children with minimal obstruction may present with increased pulmonary blood flow and
heart failure.
Most children with TOF are symptomatic and cyanotic. In general, the earlier the onset of
systemic hypoxemia, the more likely that severe pulmonary stenosis or atresia is present.
Dyspnea on exertion, clubbing, and erythrocytosis are common.
TREATMENT Almost all patients with TOF undergo intracardiac repair. There is also a role
for medical therapy in symptomatic, severely cyanotic newborns, who require intravenous
prostaglandin to maintain ductal patency and pulmonary flow pending more definitive therapy.
An occasional infant with increased pulmonary blood flow requires digoxin and diuretics for
heart failure. These drugs should be discontinued as RV obstruction progresses.
Tet spells Hypercyanotic (or "tet") spells can be associated with almost total occlusion of the
RV outflow tract (RVOT) and profound cyanosis. They typically occur when an infant awakens
crying from a deep sleep.
These spells may require rapid and aggressive treatment, starting with placing the patient in a
knee-chest position to increase systemic vascular resistance, which promotes movement of
blood from the right ventricle into the pulmonary circulation rather than the aorta.
More aggressive therapy consists of intravenous morphine and a fluid bolus. The mechanism of
action of morphine is unclear, while fluids improve RV filling and pulmonary flow. The role of
bicarbonate therapy to treat an associated lactic acidosis is uncertain.
If these measures fail, intravenous beta blockers (eg, propranolol or esmolol) can be
administered. The presumed mechanism of benefit is relaxation of the RVOT with improved
pulmonary blood flow. If this is insufficient, systemic afterload can be increased with
188
intravenous phenylephrine which, as with assumption of the knee-chest position, promotes
right ventricular flow into the pulmonary circulation rather than the aorta.
Although most children with TOF undergo intracardiac repair as their initial intervention, the
principle of the Blalock-Taussig shunt remains an important palliative procedure for infants who
may not be acceptable candidates for intracardiac repair due to prematurity, hypoplastic
pulmonary arteries, or coronary artery anatomy.
Palliative shunts were initially reserved for infants, and intracardiac repair for children, but the
excellent results of intracardiac repair have made it the current treatment of choice in most
centers. Surgery is usually performed electively in the first year of life and can be performed in
the first three months if necessary. Intracardiac repair is also performed in asymptomatic
acyanotic infants (pink variant) with a low morbidity and mortality; this approach may allow
normal growth of the RVOT and pulmonary annulus.
Perioperative mortality after intracardiac repair in neonates or young infants has ranged for 0
to 3 percent.
POSTOPERATIVE COMPLICATIONS Complications of surgical repair of TOF include

pulmonary regurgitation, residual RVOT obstruction, RV wall motion abnormalities, and
arrhythmias including ventricular tachycardia (VT), which is usually monomorphic.
189
Management of supraventricular tachycardia in children
Anne M Dubin, MD
Supraventricular tachycardia (SVT) can be defined as an abnormally rapid heart rhythm

originating above the ventricles, often (but not always) with a narrow QRS complex; it
conventionally excludes atrial flutter and atrial fibrillation.
The two most common forms of SVT in children are atrioventricular reentrant tachycardia
(AVRT), including the Wolff-Parkinson-White (WPW) syndrome, and atrioventricular nodal
reentrant tachycardia (AVNRT). The relative frequency of these arrhythmias was addressed in a
report of 137 infants, children, and adolescents who underwent careful electrophysiologic
testing. AVRT accounted for 73 percent and AVNRT for 13 percent (almost all cases of AVNRT
occurred after two years of age). The remaining 14 percent were due to primary atrial
tachycardias.
ACUTE MANAGEMENT Acute management of the child who presents in SVT can be a
challenge because the exact mechanism of the tachycardia often is unknown. The treatment
strategy depends upon the patient's presentation and clinical status (hemodynamically stable or
unstable). The approach consists of initiating therapy while continuing to assess the patient's
condition.
Hemodynamic assessment The most important initial clinical determination to make in

children presenting with a tachyarrhythmia is whether signs and symptoms related to the rapid
heart rate are present. These include hypotension, heart failure, signs of shock, pallor, or
decreased level of consciousness. Signs in infants may include irritability, tachypnea, and poor
feeding.
Hemodynamically unstable Unstable patients with hemodynamic compromise, such as

unconsciousness or shock with severe heart failure, require immediate termination of the
tachyarrhythmia.
Cardioversion Direct current cardioversion at 0.5 to 2.0 J/kg should be performed.
Cardioversion in children may be performed with pediatric electrode paddles (surface area 21
cm2). However, the use of adult electrode paddles (surface area 83 cm2) results in lower
transthoracic impedance and therefore higher current flow, which may be preferable in children
over 10 kg.
In general, the child should be given adequate sedation or general anesthesia before the
procedure. Rarely, a child is too critically ill to delay the procedure for administration of general
anesthesia.
The following findings support the presence of SVT:
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1. History incompatible with sinus tachycardia.
2. P waves absent or abnormal Heart rate does not vary with activity.
3. The presence of abrupt changes in heart rate.
4. Rate usually >220 beats/min in infants and >180 beats/min in children.
Vagal maneuvers In children who have mild or no symptoms, vagal maneuvers should be
attempted while supplies and personnel are assembled to proceed to medical therapy, if
needed. These maneuvers should be performed while the ECG is continuously monitored. The
electrocardiographic pattern seen during termination of the tachycardia can help determine its
mechanism.
The vagal maneuver usually used in infants or young children is application of a bag filled with
ice and cold water over the face for 15 to 30 seconds. This elicits the diving reflex, frequently
interrupting the arrhythmia. This maneuver is successful in 30 to 60 percent of cases.
Another method that may be successful in infants is rectal stimulation using a thermometer. In
older children, bearing down (Valsalva maneuver) for 15 to 20 seconds provides vagal
stimulation.
Carotid massage and orbital pressure should not be performed in children.
Antiarrhythmic drugs If the vagal maneuver does not convert SVT that is hemodynamically
stable to normal rhythm, an intravenous catheter should be placed for the administration of
antiarrhythmic drugs. The most commonly used pharmacologic agent for acute management of
SVT is adenosine; procainamide and amiodarone are sometimes given for tachycardia that is
refractory to adenosine.
Digoxin is not usually used because of the delay in achieving therapeutic levels and the narrow
therapeutic margin with the risk of serious toxicity [10] . In addition, digoxin should not be given
if WPW is suspected, since it may potentiate accessory pathway conduction.
Adenosine Adenosine is considered the drug of choice for acute medical conversion of SVT.
Adenosine interacts with A1 receptors on the surface of cardiac cells; the resulting effects
include slowing of the sinus rate and an increase in the AV nodal conduction delay. This
interrupts the reentrant circuit of tachycardias that require the AV node for reentry, which
account for the great majority of cases of SVT in children.
For intravenous adenosine administration, the patient should be supine and should have ECG
and blood pressure monitoring. The drug is administered by rapid intravenous injection over
one to two seconds at a site as close to the central circulation as possible. This is followed
immediately by a 5 mL normal saline flush to speed delivery to the heart, which is needed
because the drug is rapidly metabolized to an inactive form.The usual initial dose is 0.1 mg/kg; if
no response is seen within two minutes, the dose is doubled. An alternative regimen consists of
an initial bolus of 0.05 mg/kg; if no response is seen within two minutes, the dose is increased
191
by 0.05 mg/kg increments every two minutes until termination of the arrhythmia or a maximum
dose of 0.25 to 0.35 mg/kg or 12 mg is given.
The average effective dose is approximately 0.13 mg/kg. However, because adenosine is
metabolized by an enzyme on the red cell surface, a higher dose is required when given through
a peripheral compared to a central vein.
Adenosine terminates 80 to 95 percent of episodes of AVRT, which accounts for almost three-
quarters of episodes of SVT, and approximately 75 percent of episodes due to other causes of
SVT. Early recurrence of the SVT after termination occurs in 25 to 30 percent of cases.
Side effects, including flushing, nausea, vomiting, vague feeling of discomfort, chest pain, and
dyspnea are not uncommon with adenosine, but usually resolve rapidly. Serious side effects,
such as arrhythmias, are rare. Adenosine can precipitate atrial fibrillation, although this usually
terminates spontaneously.
Verapamil Verapamil is an effective acute therapy to slow AV nodal conduction and

terminate the arrhythmia in older children with SVT. Verapamil is administered as an
intravenous infusion in a dose of 0.1 to 0.3 mg/kg with a maximum dose of 10 mg.
Procainamide SVT that is refractory to adenosine may respond to procainamide.

Procainamide is a class IA antiarrhythmic drug that acts primarily by inhibiting phase 0 (sodium-
dependent) depolarization and slows atrial conduction. Unlike adenosine and verapamil,
procainamide acts by slowing conduction within the myocardium itself, rather than by blocking
reentry at the AV node. As a result, procainamide may be used safely in patients with WPW
without the risk of provoking accessory pathway conduction.
Procainamide is administered intravenously. In patients under one year of age, a loading dose
of 7 to 10 mg/kg is given over 30 to 45 minutes. In older children, the loading dose is 15 mg/kg.
This is followed by a continuous infusion of procainamide starting at 40 to 50 mcg/kg per
minute. Plasma levels should be measured four hours after completion of the loading dose,
during the maintenance infusion.
Amiodarone Amiodarone is a class III antiarrhythmic agent. The intravenous preparation,

which is used for the acute therapy of SVT, prolongs the refractory period of the AV node and,
to a lesser degree, the duration of the action potential and the refractory period of both atrial
and ventricular myocardium. It is usually used for SVT that is refractory to other agents
(adenosine, procainamide) and, like procainamide, it can be used safely in patients with WPW.
Amiodarone is administered intravenously, and a variety of regimens have been used. We

typically recommend a bolus infusion of 5 mg/kg over 20 to 60 minutes. If there is no response,
the bolus dose is repeated up to a total of 20 mg/kg. If the patient responds, this is followed by a
continuous infusion of 10 to 15 mg/kg per day.
192
Transesophageal pacing Transesophageal pacing may be a useful adjunct to therapy for SVT
in a child who is hemodynamically stable. It can be used to determine the mechanism of and to
terminate the tachycardia. The technique involves electrical cardiac stimulation until the
tachyarrhythmia resolves or until other therapies can be initiated.
There are two major approaches to transesophageal pacing:
Atrial overdrive pacing, in which atrial pacing commences at a rate slower than the
tachyarrhythmia, with gradual acceleration.
Extrastimulation, in which the atrium is paced at a constant rate, with extra stimuli inserted at
progressively shorter intervals.
Digoxin is not usually used because of the delay in achieving therapeutic levels and the narrow
therapeutic margin with the risk of serious toxicity. In addition, digoxin should not be given if
WPW is suspected, since it may potentiate accessory pathway conduction.
CHRONIC THERAPY After the acute episode is terminated, a 12 lead ECG should be
performed to look for evidence of WPW syndrome (the presence of a wide QRS complex with a
"delta wave"). In addition, an echocardiogram should be obtained to assess for structural heart
disease, since SVT can be associated with congenital disorders (21 percent of patients referred
for catheter ablation in one series)
Expectant management One approach to the chronic management of children with

recurrent episodes of SVT is expectant, with no specific treatment. In this approach, the patient
and family are taught to recognize SVT and to terminate episodes using vagal maneuvers. The
rationale for this strategy is that patients who present at less than five years of age have a high
193
likelihood of outgrowing their SVT and may not require chronic therapy that may be associated
with side effects. In addition, digoxin, which is the most commonly used drug, may not be more
effective than expectant management
If this is the first episode of SVT and there is no evidence of ventricular dysfunction and no
hemodynamic instability, we offer the parents the option of expectant management and no
specific treatment. We monitor the child for at least 24 hours and teach the parents how to
check the heart rate. Vagal maneuvers may include using an ice bag applied to the face,
performing the Valsalva maneuver, assuming a head-down position, inducing the gag reflex, and
other techniques.
First-line agents Our first-line agents for SVT are digoxin and a beta blocker, largely because
they avoid the more serious side effects that can be seen with other antiarrhythmic drugs. In
one report of 101 infants (under age 12 months) treated with digoxin, a beta blocker, or both,
70 percent were free of recurrence while on these agents. As noted above, however, digoxin has
not been proven to have greater efficacy than expectant management.
In infants, we give digoxin (10 mcg/kg per day divided into two doses) and propranolol (2 to 4
mg/kg per day divided into four doses). In older children we use a longer acting beta blocker,
atenolol (1 to 2 mg/kg per day).
Digoxin should not be used in patients with WPW since it can accelerate conduction across the
accessory pathway, particularly in patients who develop atrial fibrillation. Side effects of beta
blockers include hypotension, emotional disturbances and nightmares.
As noted above, verapamil is contraindicated in children less than one year of age and can
cause accessory pathway acceleration and is not often used in WPW.
Drugs that may be effective alone or in combination include flecainide, sotalol, and
amiodarone. The efficacy of these agents ranges from 20 to 100 percent. However, the results
are difficult to interpret because of undocumented natural history, variations in practice, and
lack of controlled trials.
Radiofrequency ablation Radiofrequency ablation (RFA), which was first reported as a

successful alternative to drug therapy in children in 1991, is the definitive therapy for SVT. In
contrast, direct current ablation, which was employed prior to the development of RFA, was
associated with a high incidence of complications and is no longer in clinical use.
194
Clinical manifestations and diagnosis of Kawasaki disease
Robert Sundel, MD
Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most
common vasculitides of childhood. It is typically a self-limited condition, with fever and
manifestations of acute inflammation lasting for an average of 12 days without therapy.
However, complications such as coronary artery aneurysms, depressed myocardial contractility
and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may
develop and lead to significant morbidity and mortality.
KD is characterized by systemic inflammation manifested by fever, bilateral nonexudative

conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes and
lymphadenopathy. These findings are often not present at the same time. Thus, repeated
histories and physical examinations are important in making a timely diagnosis of KD.
Fever Fever is the most consistent manifestation of KD. It reflects elevated levels of
proinflammatory cytokines such as tumor necrosis factor and interleukin-1, which are thought
to mediate the underlying vascular inflammation. Fever is minimally responsive to antipyretic
agents, and remains above 38.5C during most of the illness. Patients are often described as
irritable. The diagnosis of KD should be considered in all children with prolonged unexplained
fever 5 days.
Conjunctivitis Bilateral nonexudative conjunctivitis is present in more than 90 percent of

patients. A predominantly bulbar injection typically begins within days of the onset of fever, and
the eyes have a brilliant erythema, which spares the limbus. Children also are frequently
photophobic, and anterior uveitis may develop. Slit-lamp examination may be helpful in
ambiguous cases; the presence of uveitis provides further evidence for the diagnosis of KD, as it
is more commonly seen in KD than in other diseases with similar presentations.
Mucositis As KD progresses, mucositis often becomes evident. Cracked, red lips and a
strawberry tongue are characteristic; the latter is a result of sloughing of filliform papillae and
denuding of the inflamed glossal tissue. Discrete oral lesions, such as vesicles or ulcers, and
tonsillar exudate, are suggestive of a disease process other than KD.
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Rash The cutaneous manifestations of KD are polymorphous. The rash typically begins as
perineal erythema and desquamation, followed by macular, morbilliform, or target lesions of
the trunk and extremities. Vesicular or bullous lesions are rare, but KD may trigger a
psoriasiform eruption in children not previously recognized to have psoriasis
Extremity changes Changes in the extremities are generally the last manifestation to
develop. Children demonstrate an indurated edema of the dorsum of their hands and feet, and
a diffuse erythema of their palms and soles. The convalescent phase of KD may be characterized
by sheet-like desquamation that begins in the periungual region of the hands and feet, and by
linear nail creases (Beau's lines).
In addition, arthritis has been reported in 7.5 to 25 percent of patients
Lymphadenopathy Cervical lymphadenopathy is the least consistent feature of KD, absent in

as many as half to three-quarters of children with the disease. When present, lymphadenopathy
tends to involve primarily the anterior cervical nodes overlying the sternocleidomastoid muscle.
Diffuse lymphadenopathy or other signs of reticuloendothelial involvement (e.g., splenomegaly)
should prompt a search for alternative diagnoses.
196
LABORATORY FINDINGS No laboratory studies are included among the diagnostic criteria
for typical KD; in ambiguous cases, however, certain findings may support the diagnosis of KD.
Systemic inflammation is characteristic of KD. Typical manifestations include elevation of acute

phase reactants (e.g., C-reactive protein [CRP], or erythrocyte sedimentation rate [ESR]),
leukocytosis, and a left-shift in the white blood cell count. By the second week of illness, platelet
counts generally rise and may reach 1,000,000/mm3 (reactive thrombocytosis) in the most
severe cases.
Children with KD often present with a normocytic, normochromic anemia; hemoglobin

concentrations more than two standard deviations below the mean for age are noted in one-
half of patients within the first two weeks of illness.
Urinary microscopy commonly reveals white blood cells. Pyuria is often of urethral origin and
therefore may be missed on urinalyses obtained by bladder tap or catheterization. In addition,
white cells are mononuclear, and are not detected by dipstick tests for leukocyte esterase. Thus,
children with suspected KD should have a clean voided or bagged urine specimen collected for
microscopic examination.
197
Approximately 30 percent of patients have mild to moderate elevation of transaminases (eg,
serum alanine aminotransferase >50 U/L) because of intrahepatic congestion. In addition, a
minority of children develop obstructive jaundice from hydrops of the gallbladder.
Cerebrospinal fluid (CSF) may display a mononuclear pleocytosis without hypoglycorrhachia or

elevation of CSF protein. In a retrospective review, 46 of 520 children with KD underwent
lumbar puncture. In this subset of patients, 39 percent had elevated CSF white cell counts.
Although cell counts as high as 320/mm3 with up to 79 percent neutrophils were reported, the
median count was 22.5 cells with 6 percent neutrophils and 92 percent mononuclear cells.
COMPLICATIONS Although complications primarily reflect cardiac sequelae including

coronary artery aneurysms, other non-cardiac complications also may be seen.
Cardiac complications The major complication of KD is coronary artery aneurysms, however

other cardiac sequelae occur including decreased myocardial contractility, coronary arteritis
without aneurysms, mild valvular regurgitation (primarily mitral valve involvement), and
pericardial effusion.
Coronary artery (CA) aneurysms occur in 20 to 25 percent of untreated children with KD, but
only 4 percent of those who receive adequate therapy .
Several clinical findings at presentation have been associated with an increased risk of
developing CA aneurysms. Although these risk factors have varied somewhat in different series,
they most consistently include the following:
1. Age younger than one year.

2. Male sex.
3. Fever 14 days.
4. Serum sodium concentration <135 mEq/L.
5. Hematocrit <35 percent.
6. White cell count >12,000/mm3.
7. Age older than six years.
Other complications Non-vascular complications include the following:
Urinary abnormalities and renal disease With the exception of sterile pyuria, urinary
abnormalities and renal disease are uncommonly associated with KD. Among the renal
complications that have been noted in selected cases are acute interstitial nephritis, mild
proteinuria, and acute renal failure (ARF).
Gastrointestinal abnormalities Children with KD may present with a wide variety of

gastrointestinal manifestations. A case series from Italy reported 10 children who were treated
for acute abdominal catastrophes, including five patients with gallbladder hydrops with
cholestasis, three patients with paralytic ileus, one patient with appendicular vasculitis, and one
with hemorrhagic duodenitis.
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Behavioral changes A retrospective study of 65 patients reported an increase in long-term
behavioral problems in children following KD when compared with hospital- and sibling-
matched controls.
Macrophage activation syndrome Macrophage activation syndrome (MAS, also called

secondary hemophagocytic lymphohistiocytosis) is characterized by activation and proliferation
of macrophages and T-lymphocytes. It has been described rarely in children with KD and
persistent fever.
DIAGNOSIS Guidelines for the diagnosis of KD were established by Tomisaku Kawasaki in

1967. Diagnosis of KD requires the presence of fever lasting 5 days, combined with at least
four of the five following physical findings, without an alternative explanation:
1. Bilateral bulbar conjunctival injection.

2. Oral mucous membrane changes, including injected or fissured lips, injected pharynx,
or strawberry tongue.
3. Peripheral extremity changes, including erythema of palms or soles, edema of hands or
feet (acute phase), and periungual desquamation (convalescent phase).
4. Polymorphous rash.
5. Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter).
Delayed diagnosis Treatment with IVIG within the first 10 days of the illness reduces the
prevalence of CA aneurysms five-fold compared to later administration. Thus, it is desirable to
diagnose KD as soon as possible after children meet criteria (i.e., not before the fifth day of
illness), in order to initiate treatment and reduce the risk of coronary artery lesions. However,
timely identification is challenging because the diagnosis is based upon nonspecific clinical signs
and there is no definitive diagnostic test.
199
INCOMPLETE (ATYPICAL) KD Children suspected of having KD who do not fulfill diagnostic
criteria (i.e., have less than four signs of mucocutaneous inflammation) may have incomplete or
atypical KD. "Incomplete" KD is the preferred term, as these patients do not appear to differ
from those with classic KD in any way except that they lack a sufficient number of criteria to
fulfill the epidemiologic case definition.
Laboratory tests Laboratory evaluation is recommended for the following patients with
suspected incomplete KD:
Patients less than six months of age with unexplained fever 7 days, even if they have no
clinical findings of KD.
Patients of any age with unexplained fever >5 days and fewer than three clinical criteria.
The AHA/AAP recommended laboratory evaluation includes the following tests:
Acute phase reactants (CRP and ESR).
Complete blood count (CBC).
Urinalysis (U/A), preferably clean catch.
Serum alanine aminotransferase level.
Serum albumin.
Laboratory findings suggestive of KD include the following:
1. Elevated acute phase reactants (CRP 3.0 mg/dL or ESR 40 mm/hr).

2. White cell count 15,000/microL.
3. Normocytic, normochromic anemia for age.
4. Pyuria: 10 white blood cells/high-power field.
5. Serum alanine aminotransferase level >50 U/L.
6. Serum albumin 3.0 g/Dl.
7. After seven days of illness, platelet cell count 450,000/microL
Echocardiography Echocardiography is recommended depending on the clinical course and

initial laboratory findings. Echocardiography is recommended in the following circumstances
when a diagnosis of KD is being considered:
Elevation of CRP and/or ESR and less than three abnormal laboratory findings. If the
echocardiography is normal and the fever abates, KD is unlikely; if fever persists, repeat
echocardiography and consultation with a clinician who has expertise in KD are recommended.
If there are three or more abnormal laboratory findings, treatment should be initiated
regardless of the results of the echocardiographic evaluation.
200
Normal CRP and ESR and periungual desquamation after resolution of the fever; if the
echocardiography is normal, KD is unlikely.
Criteria for treatment The AHA/AAP criteria to diagnosis incomplete KD and initiate
treatment in a child with features compatible with KD include:
Elevated CRP and/or ESR and three or more abnormal laboratory findings, as described above.
OR
Abnormal echocardiography, as described above.
DIFFERENTIAL DIAGNOSIS KD is most commonly confused with infectious exanthems of

childhood.
Infectious diseases as well as other alternative diagnoses may have the following clinical
features not commonly found in KD:
Exudative conjunctivitis
Exudative pharyngitis
Discrete intraoral lesions
Bullous or vesicular rash
Generalized lymphadenopathy
The differential diagnosis includes:
1. Measles, echovirus, adenovirus, and Epstein-Barr virus. These viral illnesses may share
many of the signs of mucocutaneous inflammation, but they typically have less evidence
of systemic inflammation and generally lack the extremity changes seen in KD.
2. Toxin-mediated illnesses, especially group A streptococcal infections (e.g., scarlet fever
and toxic shock syndrome). These usually lack the ocular and articular involvement
typical of KD, though patients with staphylococcal toxic shock syndrome occasionally
may have conjunctival hemorrhage.
3. Rocky mountain spotted fever and leptospirosis. Headache and gastrointestinal
complaints typically are prominent features of these infections.
4. Drug reactions such as Stevens-Johnson syndrome or serum sickness. These may mimic
KD, but with subtle differences in the ocular and mucosal manifestations.
5. Systemic-onset juvenile rheumatoid arthritis. Children with this condition generally lack
the conjunctival and oral findings of KD. Lymphadenopathy also is generalized, unlike in
KD.
6. Mercury hypersensitivity reaction (acrodynia). In particular, this shares certain clinical
features with KD, including fever, rash, swelling of the palms and feet, desquamation,
201
and photophobia. Unless there is a convincing history of exposure to mercury, however,
treatment of a child with possible KD should not be delayed while awaiting mercury
levels because of the rarity of acrodynia in the developed world.
Initial treatment and prognosis of Kawasaki disease

Guidelines by the American Heart Association (AHA) and the American Academy of Pediatrics
(AAP) have been developed for the treatment of patients who fulfill the diagnostic criteria for
KD and for those who do not (so-called incomplete KD) (show algorithm 1). The recommended
initial therapy includes IVIG (2 gm/kg) administered as a single infusion over 8 to 12 hours and
aspirin (initial dose of 80 to 100 mg/kg daily divided into four doses). Additional agents are
used only for children who fail to respond to standard therapy.
INTRAVENOUS IMMUNE GLOBULIN Since the first report of intravenous immune globulin
(IVIG) therapy in patients with KD in 1983, randomized controlled studies and meta-analyses
have confirmed that IVIG plus aspirin compared to aspirin alone reduces the risk of CA
aneurysms. Although aspirin does not appear to affect aneurysm formation, all trials of IVIG
treatment have included aspirin as well.
A randomized controlled study of 549 patients with KD demonstrated that a single dose of IVIG
(2 gm/kg) compared with a four-day treatment regimen (400 mg/kg for four consecutive days)
led to a more rapid resolution of fever, normalization of laboratory evidence of acute
inflammation, and lower risk of CA abnormalities.
Timing of therapy The effectiveness of IVIG therapy is best established for patients treated
within the first 7 to 10 days of illness.
Adverse effects Despite its advantages, IVIG is an expensive and potentially toxic
intervention. The greatest long-term concern is transmission of bloodborne pathogens.
ASPIRIN Aspirin is used for treatment of KD because of its antiinflammatory and antiplatelet
effects. The dose of aspirin used during the acute phase of illness to achieve an
antiinflammatory effect is relatively high with a recommended range of 30 to 100 mg/kg per day
in four divided doses. Subsequently, aspirin is administered in low doses (3 to 5 mg/kg per day)
for its antiplatelet action. Alternative antiinflammatory agents such as ibuprofen may be used
for prolonged episodes of arthritis.
GLUCOCORTICOIDS Although glucocorticoids (also called corticosteroids) have been

reported to be beneficial in patients with KD who fail to respond to IVIG, it remains unknown
whether they have a role in initial therapy.
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REFRACTORY KD Fever persists or returns in 10 to 15 percent of patients with KD who are
initially treated with IVIG and aspirin. Persistent fever of any magnitude usually indicates
ongoing vasculitis, although other causes of fever should be excluded. Barring extenuating
circumstances, children are not usually retreated until at least 36 hours after the completion of
their initial IVIG infusion, as fever before this time may represent a reaction to the medication.
PROGNOSIS Children without cardiovascular abnormalities detected in the acute and

subacute phase (up to eight weeks after onset of disease) appear to be clinically asymptomatic
10 to 21 years later. However, the long-term effect on cardiovascular health is unknown, and it
is unclear whether these patients will be at increased risk for atherosclerotic heart disease as
adults compared to those who never had KD.
FOLLOW-UP An echocardiogram should be obtained early in the acute phase of illness and
six to eight weeks after onset to confirm the efficacy of treatment. Patients also should have
repeated clinical evaluations during the first two months following diagnosis of KD to detect
arrhythmias, heart failure, valvular insufficiency, or myocarditis.
Physical activity Children generally do not feel completely well for several weeks after KD,
and they therefore tend to limit their own activity level. Restrictions are dependent on the risk
of myocardial infarction and should be imposed only in children with increased risk of
thrombosis during the convalescent stage of disease, particularly those with giant coronary
artery (CA) aneurysms.
Vaccinations The administration of live virus vaccines, including measles and varicella,
should be postponed in children who have been treated with IVIG. Passively acquired antibodies
persist for an extended period of time (up to 11 months) following IVIG administration, and may
interfere with vaccine immunogenicity. Patients may be vaccinated during a measles outbreak
as long as the vaccine is repeated at least 11 months after the administration of IVIG (unless
there is serologic evidence of adequate immunity). Schedules for other routine childhood
vaccinations do not need to be altered.
Patients older than 6 months of age who require long-term aspirin therapy should receive
yearly influenza immunization because of the possible increased risk of Reye syndrome. They
should receive the inactivated vaccine. In addition, patients should also receive the varicella
vaccine because varicella infection increases the risk of Reye syndrome.
203
Diseases of the Blood
Iron deficiency in infants and young children

Donald H Mahoney, Jr, MD
Iron deficiency (ID) is the most common nutritional deficiency in children. The World Health
Organization estimates that anemia, largely caused by iron deficiency, affects between 500
million and two billion people worldwide. In some developing countries, up to 50 percent of
preschool children and pregnant mothers have anemia that principally is caused by iron
deficiency.
IRON BALANCE Iron is an essential nutrient in humans. The majority of iron (75 percent) is
bound in heme proteins (hemoglobin and myoglobin). The remainder is bound in the storage
proteins ferritin and hemosiderin, with a small portion (3 percent) bound in critical enzyme
systems, such as catalase and cytochromes. In normal subjects, only a small amount of iron
enters and leaves the body on a daily basis. Most iron is recycled from the breakdown of old red
blood cells by macrophages of the reticuloendothelial system.
Summarized briefly, iron balance is achieved by control of intestinal absorption, via transport
proteins such as HFE (which is mutated in hereditary hemochromatosis) and the duodenal iron
transporter, rather than urinary or fecal excretion. In adults, 5 percent of daily iron needs comes
from dietary sources and equals the iron loss that primarily occurs from the gastrointestinal
tract. However, in infants and children, 30 percent of daily iron needs must come from diet
because of the growth spurt and increase in body (muscle) mass.
Intestinal iron absorption is a function of three principal factors: body iron stores (transferrin
and ferritin), erythropoietic rate, and bioavailability of dietary iron. Low iron stores increase
receptors in the intestinal mucosa to facilitate increased iron uptake. Iron absorption also is
increased when there is increased erythropoiesis and reticulocytosis or ineffective
erythropoiesis, as in beta thalassemia. On the other hand, mobilferrin in the intestinal cells can
hold onto iron in the iron replete state; this iron is lost when the mucosal cells are sloughed.
Heme dietary sources (fish, poultry, and meat) have a higher bioavailability than do non-heme
(vegetable) sources (30 versus 10 percent). In addition, intraluminal factors can affect
absorption. Ascorbic acid enhances the absorption of non-animal sources of iron such as cereal,
breads, fruits, and vegetables, whereas tannates (teas), bran foods rich in phosphates, and
phytates inhibit iron absorption. Thus, iron deficiency may be a particular problem in vegetarian
children.
204
Developmental aspects Neonates of mothers with iron deficiency are at increased risk of
IDA in early infancy. In one study from India of 55 mothers with anemia, the iron content of cord
blood sample correlated with maternal hemoglobin and serum ferritin levels. Breast milk iron
was also significantly reduced in mothers with severe anemia but appeared to be preserved in
mothers with mild-to-moderate anemia.
At birth, term infants have iron stores of approximately 75 mg/kg, two-thirds of which is bound
in hemoglobin. Failure to achieve a normal hemoglobin concentration (mean 15 to 17 g/dL) at
birth directly affects nonstorage iron and increases the risk for IDA in the first three to six
months of life.
During the first five to six months, the normal term infant is iron replete. However, several
conditions in the newborn period can lead to the early development of IDA:
1. Prematurity.
2. The administration of erythropoietin (EPO) for anemia of prematurity.
3. Fetal-maternal hemorrhage (FMH).
4. Twin-twin transfusion syndrome (TTS).
5. Other perinatal hemorrhagic events.
6. Insufficient dietary intake.
Dietary factors Dietary issues contribute significantly to the evolution of IDA in infancy and
early childhood. Common factors leading to an imbalance in iron metabolism include:
1. Insufficient iron intake.

2. Decreased absorption due to poor dietary sources of iron.
3. Early introduction of whole cow's milk.
4. Occult blood loss secondary to cow's milk intolerance.
5. Medications (e.g., aspirin, nonsteroidal antiinflammatory drugs).
6. Malabsorption states.
Whole cow's milk increases intestinal blood loss in infants. In one study of infants 5 to 6
months of age, for example, switching to cow's milk increased the proportion of guaiac-positive
stools (from 3 to 30 percent) during the first 28 days, whereas the proportion of positive stools
remained low (5 percent) with the feeding of formula.
Iron requirements in otherwise uncomplicated states approximate 0.5 to 0.8 mg/day. Breast
milk contains only 0.3 to 1.0 mg/L iron, but has a high bioavailability (50 percent); in
comparison, proprietary, iron-containing formulas with 12 mg/L iron have only 4 to 6 percent
bioavailability.
Based upon these and other observations, the minimum daily requirements for iron are:
Full-term infant 1 mg/kg (maximum 15 mg), start no later than four months in breastfed
infants.
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Premature 2 mg/kg (maximum 15 mg), start no later than two months in breastfed infants.
Very low birth weight infants (birth weight less than 1500 g) 3 to 4 mg/kg (maximum 15 mg),
start no later than two months in breastfed infants.
In infants with a birth weight of less than 1301 g, one clinical trial demonstrated that a dose of
ferrous sulfate 2 mg/kg per day started when enteral feedings reach a minimum of 100 mL/kg
per day was safe and potentially beneficial. Infants who received early administration of ferrous
sulfate had a reduced risk of infection and number of blood transfusions, and appeared to have
a better neurodevelopment outcome at a median corrected age of 5.3 years.
1 to 10 years old 10 mg/day.
11 years old to adult (female) 15 mg/day.
11 years old to adult (male) 12 mg/day.
Prevention of iron deficiency Recommendations for the prevention of iron deficiency in

infants include:
1. Encourage breastfeeding exclusively for first four to six months; after this time, consider
adding iron-fortified cereals. Two or more servings per day meet an infant's
requirement for iron.
2. For breastfed preterm or low-birth-weight infants, begin iron supplementation (1 to 2
mg/kg per day; maximum 15 mg) at one month and continue until 12 months.
3. For infants younger than 12 months of age who are not breastfed or are partially
breastfed, use only iron-fortified formulas (12 mg of iron per liter).
4. At age six months, encourage one feeding per day of foods rich in vitamin C (eg, citrus
fruits and juices, cantaloupe, strawberries, tomatoes, and dark green vegetables).
Caution should be advised with the use of citrus fruits and strawberries in younger
infants because of potential allergy.
5. After age six months, or when developmentally ready, considering introducing pureed
meats, which increase the absorption of nonheme iron.
6. Avoid low iron formulas or cow's milk until age 12 months.
7. Children aged one to five years should consume no more than 600 mL (20 oz) of milk per
day. They should also consume an adequate amount of iron-containing foods to meet
daily requirements.
In less developed countries, the prevalence of iron deficiency during pregnancy is higher than
in developed countries, which increases the risk of iron deficiency in the infant. Iron
supplementation during pregnancy with continued supplementation during infancy is
recommended. Iron fortification of whole maize flour with sodium iron edetic acid (NaFeEDTA)
also improves the iron status of young children in developing countries.
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SCREENING RECOMMENDATIONS Analysis of the NHANES III database demonstrated that
anemia (hemoglobin level <11 g/dL) is neither a sensitive nor a specific screen for iron
deficiency. As mentioned above, two-thirds of iron deficient children are not anemic (9 percent
of children with iron deficiency versus 3 percent with IDA). In addition, two-thirds of anemic
children had a cause other than iron deficiency for their anemia (6 versus 3 percent).
A careful dietary history is currently the most important screening test and is more useful than
hemoglobin levels. This is illustrated in a report of 305 healthy, African-American inner city
children between the ages of one and five years. A brief dietary history identified children at low
risk of microcytic anemia 97 percent of the time. Dietary deficiency was defined as one or more
of the following: less than five servings each of meat, grains, vegetables, and fruit per week;
more than 480 mL (16 oz) of milk per day; or daily intake of fatty snacks, sweets, or more than
480 mL (16 oz) of soft drink.
These data provide a framework for who should be screened for iron deficiency and includes
the following screening recommendations by the American Academy of Pediatrics in infants and
young children:
In normal healthy infants, risk assessment for iron deficiency is recommended at 4, 18, and 24
months of age, and annually thereafter.A hemoglobin or hematocrit is recommended at 12
months of age.
Children with special health needs (chronic infection, inflammatory disorders, chronic
gastrointestinal dysfunction, restricted diets).
Children two to five years with increased (dietary) risk factors for IDA.
CLINICAL MANIFESTATIONS Iron deficiency anemia is a microcytic, hypochromic,

hypoproductive state. With storage iron deficiency, storage sites are depleted but sufficient iron
remains present within the "labile" iron pool from the daily turnover of red cells for normal
hemoglobin synthesis unless further iron losses occur. IDA is the last stage in this evolution and,
therefore, is the first to recover with iron repletion.
Although typically presenting as a nutritional anemia, IDA may present as part of a complex
medical problem that includes gastrointestinal blood loss, malabsorption syndromes, and
chronic inflammatory diseases. Examples include refractory IDA can be the presenting symptom
of celiac disease, IDA may be associated with helicobacter pylori infections, and IDA is a
confounding finding in anemia of chronic disease.
Neurodevelopmental Impaired psychomotor and/or mental development are well

described in iron-deficient infants, and cognitive impairment can occur in adolescents. Iron
deficiency may also negatively impact infant social-emotional behavior and may be a risk factor
for children with attention deficit hyperactivity disorder.
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The most common presentation of IDA is an otherwise asymptomatic, well nourished infant or
child who has a mild to moderate microcytic, hypochromic anemia. Much less frequent are
infants with severe anemia, who present with lethargy, pallor, irritability, cardiomegaly, poor
feeding, and tachypnea.
Immunity Iron deficiency in children has been associated with mild to moderate defects in
leukocyte and lymphocyte function, including defective IL-2 and IL-6 production. On the other
hand, iron is an essential nutrient for bacterial proliferation. Thus, iron-binding proteins in
humans (transferrin and lactoferrin) have bacteriostatic effects in vitro and demonstrate a
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competitive advantage for binding iron over siderophores produced by the organism that
promote iron uptake and organism growth. However, when the iron-binding proteins are
saturated with iron, the bacteriostatic effect may be lost, with an increased risk for progression
of infection.
Infection In several reports from Africa involving patients with IDA and protein malnutrition,
aggressive treatment with iron resulted in rapid saturation of iron-binding proteins and
reactivation or progression of dormant infections, such as malaria or tuberculosis. However,
there is no conclusive evidence that iron supplementation of 1 to 2 mg/day in the
immunocompetent host, even in the face of active infection, is associated with an increased risk
for progression of infection. In a systematic review of randomized controlled trials, iron
supplementation had no apparent harmful effect on the incidence of infectious illnesses in
children. However, iron administration increased the risk of developing diarrhea (IRR 1.11, 95 %
CI 1.01-1.23).
Exercise capacity Moderately severe IDA is associated with decreased work capacity, in part
because iron is an essential cofactor for enzyme-driven aerobic metabolism. Decreased iron, in
the absence of anemia, is associated with decreased exercise performance in laboratory
animals. Similar findings have been noted in children, particularly adolescent athletes.
Pica and pagophagia Pica refers to a perverted appetite for substances not fit as food, such
as clay or paper products. Pagophagia, or pica for ice, is considered quite specific for the iron-
deficiency state. It may be present in children who are not anemic and responds rapidly to
treatment with iron, often before any increase is noted in the hemoglobin concentration.
Thrombosis Iron deficiency anemia has been reported to be associated with cerebral vein
thrombosis. In a large case-control study from a comprehensive Stroke Registry in Canada,
previously healthy children with stroke (arterial or venous) were 10 times more likely to have
IDA than healthy children without stroke. The mechanisms for this unusual complication are not
clear, but may be related to thrombocytosis (platelet counts approaching 1 million/uL) that can
be seen in IDA.
DIAGNOSIS For infants presenting with a mild microcytic anemia and a presumptive
diagnosis of IDA, the most cost effective strategy is a therapeutic trial of iron. Ferrous sulfate (3
mg/kg of elemental iron, once or twice daily between meals for four weeks) should produce a
rise of greater than 1 gm/dL in patients with iron deficiency.
Several laboratory tests, most of which can be affected by factors other than iron status, can
be used to confirm the diagnosis of IDA. Although an elevated red cell distribution width (RDW)
is the earliest hematologic manifestation of iron deficiency, iron deficiency in infants and
young children usually is identified by a serum ferritin concentration of less than 12 ng/mL and
IDA by a hemoglobin concentration below 11.0 g/dL combined with a low serum ferritin.
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In a child thought to be anemic, a complete blood count, with smear and reticulocyte count,
usually is sufficient for screening for the diagnosis of IDA. Children with a hypochromic
microcytic anemia generally are treated with iron, and further evaluation is performed only if
the response is inadequate. A more complete evaluation for IDA is indicated at presentation in
children with complicated medical histories, which would include serum iron, ferritin, total iron-
binding capacity, and transferrin saturation.
Other laboratory tests, such as erythrocyte protoporphyrin, serum transferrin receptor, and
reticulocyte hemoglobin content, may prove to be more reliable measures of iron deficiency,
but they are not routinely used.
With increasing availability of advanced hematology analyzers, the use of reticulocyte

hemoglobin content may provide a reliable measure of early iron deficient erythropoiesis. As
an example, a prospective observational study of 202 infants (9 to 12 months of age)
demonstrated that reticulocyte hemoglobin content (CHr) 27.5 pg was a more accurate screen
for iron deficiency than a hemoglobin (Hgb) level 11 g/dL. There were six patients with iron
deficiency anemia (3 percent) and 23 patients with iron deficiency (11 percent). CHr <27.5 pg
was more sensitive and less specific than Hgb <11 g/dL in detecting iron deficiency (as confirmed
by transferrin level <10 percent). CHr <27.5 pg detected 20 of 23 patients with iron deficiency,
whereas Hgb <11 g/dL detected only six (sensitivity of 83 versus 26 percent, respectively). On
the other hand, CHr <27.5 falsely identified 50 patients without iron deficiency, whereas Hgb
<11 g/dL falsely detected only nine (specificity of 72 versus 95 percent, respectively).
One problem with using serum ferritin is that ferritin is an acute phase reactant, with serum
levels increasing in liver disease, infection, inflammation, and malignancy. As an example, the
synthesis and release of ferritin by hepatic cells is directly enhanced by inflammatory cytokines
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such as interleukin-1 and tumor necrosis factor. Thus, a patient with iron deficiency and a
concomitant inflammatory disease may have a "falsely" normal ferritin concentration.
Other conditions can produce a mild hypochromic, microcytic anemia and be confused with
IDA. They include mild anemia (decline of 0.5 to 2.0 g/dL) following a recent infection or
immunization, mild hereditary anemias (alpha or beta thalassemia traits, hemoglobin E trait),
and anemia of chronic disease. Combined nutritional anemias (B12 or folate deficiency with
malabsorption states) also may lead to confusion.
Evaluation Once the diagnosis of IDA is established, every child should have a careful dietary
history, be screened for lead poisoning, and have stools screened for occult blood three times.
Among older children and adolescents with moderate to severe IDA, more detailed
investigations for gastrointestinal blood loss should be considered unless the menstrual history
in a girl is thought to be sufficient.
TREATMENT
Oral therapy For infants presenting with a mild microcytic anemia and a presumptive
diagnosis of IDA, the most cost effective strategy is a therapeutic trial of iron. Ferrous sulfate (3
mg/kg of elemental iron, once or twice daily between meals for four weeks) should produce a
rise of greater than 1 gm/dL in patients with iron deficiency. Iron absorption is increased if the
ferrous sulfate is given with juice rather than milk (13.7 versus 5.7 percent absorbed in one
report).
The estimated cost for this approach in a 10 kg child is approximately five dollars in the United
States. Iron should be continued in responders for two to three months to replace storage iron
pools. If the patient has failed to respond after four weeks, one should review for medication
dosing and administration errors, appropriate diet modifications, or history of recent illness.
Other laboratory tests, including a serum ferritin, should be obtained to further evaluate the
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anemia and to rule out conditions simulating (e.g., thalassemias and the anemia of chronic
disease) or complicating (e.g., concomitant vitamin B12 or folic acid deficiency) IDA.
For infants with confirmed IDA, ferrous sulfate (3 to 4 mg/kg of elemental iron, in divided
doses, between meals with juice) remains the standard therapy. Iron-fortified formulas and iron
supplementation at these doses are infrequent causes of gastrointestinal symptoms. Larger
doses rarely are necessary and may produce some degree of intolerance. In patients with
severe IDA, a reticulocyte response may be seen in 72 hours.
In less-developed countries, simple measures, such as cooking food in iron pots, may be
effective.
Potential causes for recurrent or refractory IDA include:
1. Compliance failures.
2. Intolerance to medication (fewer than 10 percent as a "true" cause).
3. Ongoing gastrointestinal blood loss (parasitic infection, Meckel diverticulum, ulcers, or
other anatomic maladies).
4. Chronic inflammatory disease.
5. Incorrect diagnosis.
6. Pulmonary hemosiderosis.
Parenteral therapy There are three different preparations available for parenteral iron
therapy: iron dextran, sodium ferric gluconate, and iron sucrose (saccharate). However, only
iron dextran is used for non-dialysis pediatric patients; the other two products have been
developed for use in dialysis patients.
Parenteral iron therapy should be reserved for patients with severe, persistent anemia who
have proven intolerance to oral supplements, malabsorption, or poor compliance to oral
therapy. Parenteral iron should be used with caution because there is a 2 to 3 percent risk for
anaphylaxis, some cases of which result in death.
Blood transfusion Transfusion therapy is rarely necessary for severe IDA, even with
hemoglobin concentrations of 4 to 5 gm/dL. Transfusions should be reserved for patients in
distress (heart rate greater than 160/min, respiratory rate greater than 30/min, lethargy, not
feeding well) and should be used with caution (transfusion volumes of 5 mL/kg over three to
four hours) to avoid inducing heart failure.
Follow-up In cases in which children present with a hemoglobin concentration below 7.5
gm/dL, an important issue that we have observed is a 60 percent failure to follow-up with
appropriate healthcare providers. This experience suggests a need for the physician to exercise
a proactive plan for follow-up.
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Clinical manifestations and diagnosis of the thalassemias
Edward J Benz, Jr, MD
The major hemoglobin in adults is hemoglobin A, a tetramer consisting of one pair of alpha
globin chains and one pair of beta globin chains. In normal subjects, globin chain synthesis is
very tightly controlled, such that the ratio of production of alpha to non-alpha chains is 1.00
0.05. Thalassemia refers to a spectrum of diseases characterized by reduced or absent
production of one or more globin chains, thus disrupting this closely-regulated ratio.
BETA THALASSEMIA MAJOR

Overview Beta thalassemia is due to impaired production of beta globin chains, leading to a
relative excess of alpha globin chains. Excess alpha globin chains are unstable, incapable of
forming soluble tetramers on their own, and precipitate within the cell, leading to a variety of
clinical manifestations. The degree of alpha globin chain excess determines the severity of
subsequent clinical manifestations, which are profound in patients homozygous for impaired
beta globin synthesis (ie, beta thalassemia major) and much less pronounced in heterozygotes,
who generally have minimal or mild anemia and no symptoms.
Symptoms emerge during the second six months of life when gamma globin chain production
decreases and is normally replaced with the production of beta globin to form adult hemoglobin
(Hb A, alpha2/beta2). However, since newborns with BTM are unable to produce beta chains,
they develop chronic anemia, the stigmata of profound hemolysis, and suffer the noxious effects
of massive ineffective erythropoiesis upon the body. The clinical expression of the severe
phenotype is remarkably heterogeneous, depending upon a variety of factors that alter the
burden of alpha-globin inclusions in the individual patient.
The clinical manifestations of BTM are multifactorial. Even though the primary genetic defect
resides in a single gene (ie, beta globin) expressed only during terminal maturation of red cell
progenitors, many organ systems are affected. Understanding of the symptomatology of BTM
requires recognition that patients suffer simultaneously from the following:
1. The effects of severe and chronic anemia.

2. The stigmata of chronic hemolysis.
3. Organ damage from transfusional iron overload.
4. The profound local and systemic effects of a rapidly and relentlessly expanding mass of
erythroid bone marrow progenitors.
Clinical manifestations The direct effects of BTM on other organs and tissues in the body
are due to the deleterious effects of the profound anemia, the byproducts of hemolysis, and the
intramedullary and extramedullary expansion of erythroid marrow progenitors . However, in
actual practice, patients exhibit both direct and indirect abnormalities of a number of organ
systems. Indirect effects include the accumulation of end-organ damage due to iron overload
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either from blood transfusions or accelerated iron turnover, blood-borne infections (e.g., viral
hepatitis from blood transfusions), or progressive diversion of caloric resources to bone marrow
expansion.
Skeletal changes Skeletal abnormalities are dramatic in these patients and frequently lead
to marked changes in the facial structure and body habitus, producing the characteristic
"chipmunk facies" and delayed skeletal maturation. Skeletal changes are due largely to the
expansion and invasion of erythroid bone marrow, which widen the marrow spaces, attenuate
the cortex, and produce osteoporosis.
The skull and facial bones are strikingly abnormal. Marrow expansion causes dramatic widening
of the diploic spaces and produces a characteristic "hair-on-end" radiographic appearance of the
skull. In addition, there is prominent frontal bossing, delayed pneumatization of the sinuses, and
marked overgrowth of the maxillae. As a result, the upper incisors are "jumbled" and the malar
eminences are especially prominent, producing malocclusion and the characteristic facies.
Liver and gallbladder Hepatomegaly is prominent early in the disease, due to increased red
cell destruction as well as extramedullary erythropoiesis in this organ. Liver enlargement tends
to be somewhat more prominent in children with BTM than in others with other causes for
congenital hemolytic anemia. Later in the first decade of life, hepatomegaly becomes fixed and
not reducible by blood transfusion, due to development of cirrhosis secondary to increased iron
deposition.
Splenomegaly Massive splenomegaly develops early in the course of BTM due increased red
cell destruction and the presence of splenic extramedullary hematopoiesis. Splenomegaly is
progressive and can produce characteristic symptoms such as early satiety and hypersplenism.
Shortened survival of transfused red cells or progressive worsening of the anemia or other
cytopenias in non-transfused patients are indications that removal of the spleen may palliate
symptoms by reducing splenic consumption of red cells. However, children often require
splenectomy whether or not they are transfused.
If splenectomy is performed, children with BTM, like all other splenectomized patients, are at
considerable risk for overwhelming sepsis, due to the loss of clearance of bacteria in the early
stages of infection. Vaccination against pneumococcus and prophylactic use of antibiotics are
essential.
Kidneys The kidneys are frequently enlarged in thalassemia, due to the presence of
extramedullary hematopoiesis. Less well understood is the tendency for the renal tubules to be
dilated. The urine is frequently dark, due to increased concentrations of bile pigments; large
amounts of urate, uric acid, and oxalate are also seen.
Endocrine and metabolic abnormalities Endocrine and metabolic abnormalities are quite
common in patients with BTM, attributable, at least in part, to chronic iron overload. In a study
of 142 chronically transfused patients with hemoglobin E-beta thalassemia or BTM 12 years of
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age and an average serum ferritin 2000 microg/L, the following endocrine/metabolic
abnormalities were noted:
Hypogonadism 40 percent
Growth failure 33 percent
Diabetes 13 percent
Hypothyroidism 10 percent
Growth retardation is frequently profound in these children. This reflects, in part, the diversion
of caloric resources for erythropoiesis, along with the effects of anemia, since hypertransfusion
frequently restores growth rates to normal. However, the adolescent growth spurt is often
delayed, even in children who are hypertransfused, unless intensive iron chelation therapy is
instituted early in life. Normal stature is thus rarely attained, even in well-managed patients
with BTM.
Primary and secondary characteristics of sexual development are usually delayed for both
boys and girls. While there is increasing evidence that hypogonadism may be primarily due to
iron overload, zinc deficiency may also play a role.
Cardiopulmonary complications Cardiac abnormalities are a major feature of BTM. Cardiac

malfunction, including heart failure and fatal arrhythmias, are frequent causes of death, and
cardiac dilatation secondary to anemia is nearly universal. Transfusion usually corrects the latter
abnormality, but may lead to long-term cardiac hemosiderosis due to deposition of transfused
red cell iron in the myocardium. Cardiomegaly and left ventricular dysfunction ensue in the
untreated child, leading to end-stage cardiomyopathy.
Aplastic crisis Parvovirus B19, the etiologic agent of "fifth disease" in children, infects
erythroid precursor stem cells. In normal children, this results in a very mild transient
erythrocytopenia because the impairment of marrow function is transitory and the 120 day
survival of normal red blood cells protects them from acute drops in the red cell count.
In patients with extremely shortened red cell survival, as in BTM, the effect is far more
profound. These patients depend on very high rates of red cell production; moreover, the
shortened red cell survival (four to eight days) causes the red cell count to fall rapidly when
production is stopped. Children with BTM who develop B19 infection thus develop dramatic,
often life threatening drops in hematocrit with reticulocyte counts of nearly zero. This "aplastic
crisis" often requires emergent transfusion support.
Laboratory findings
Red blood cells Profound hypochromic, microcytic anemia accompanied by bizarre red cell
morphology is a hallmark of beta thalassemia major (BTM). The hemoglobin level may be as low
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as 3 to 4 g/dL. Red cell morphology is dramatically abnormal in most patients, with extreme
hypochromia and poikilocytosis, a predominance of microcytes, tear drop and target cells, and
the visibility, even in routine stains, of clumped inclusion bodies representing precipitates of
alpha globin within the red cell. These precipitates (Heinz bodies) can be more readily
appreciated by staining with methyl violet or other supravital stains.
The white blood cell (WBC) count is often strikingly high, and the reticulocyte count surprisingly
low. The latter reflects the severe degree of ineffective erythropoiesis underlying the disorder,
resulting in many fewer than the expected number of reticulocytes being released from the
bone marrow. The high white count may be misleading, since these patients release many
nucleated red blood cells (NRBC) into the peripheral blood. Depending on the counting method
used, NRBC can be miscounted as leukocytes. However, even when corrected for this
phenomenon, a true neutrophilia is often encountered.
The platelet count is usually normal. However, hypersplenism can lower both white cell and
platelet counts. Splenectomy usually produces exaggerated rises in circulating NRBC, WBC, and
platelets in the peripheral blood.
Iron studies Because of the high rate of erythroid cell turnover, the serum iron level is
usually elevated; the transferrin saturation, expressed as the ratio of serum iron to total iron
binding capacity (or transferrin), is very high. The serum is often icteric; increased
concentrations of indirect (unconjugated) bilirubin and lactate dehydrogenase, and low levels of
haptoglobin, findings typical of hemolytic disease, are usually present.
Vitamin and mineral levels relevant to bone marrow homeostasis, such as folic acid, vitamin
B12, and pyridoxine, are usually normal. However, folic acid deficiency can develop in these
patients, due the high rate of cellular turnover. For unknown reasons, serum zinc levels tend to
be particularly low in these patients. Serum and leukocyte ascorbic acid levels are reduced,
possibly as a result of accelerated catabolism in the face of iron overload. Serum levels of
Vitamin E are also sometimes low, perhaps for the same reasons.
Bone marrow examination Bone marrow examination reveals profound erythroid

hyperplasia that is unusual for the degree of immaturity and bizarre morphology of the
erythroid progenitors. Early erythroblasts are abundant, and often appear megaloblastic, likely
reflecting limited supplies of folate and other nutrients. Later erythroid progenitors are less
abundant than expected, due to their intramedullary destruction (ie, ineffective erythropoiesis),
producing a marked "left shift" that was erroneously interpreted as leukemic in the late 19th
and early 20th century descriptions of this disease. Alpha globin inclusions are readily apparent,
particularly if supravital dyes are used.
A dramatic abnormality of the bone marrow, rarely seen in other forms of chronic anemia, is
extramedullary erythropoiesis. In the most severely symptomatic children, erythroid bone
marrow may invade the bony cortex and break through bone, setting up masses of ectopic
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erythroid cell colonies in the thoracic or pelvic cavities or sinuses. These expanding masses can
behave clinically like tumors, causing spinal cord compression and other abnormalities.
Hemoglobin electrophoresis patterns Patients with beta thalassemia major are unable to
make Hb A. In untransfused patients only Hb F and Hb A2 are present on hemoglobin
electrophoresis. When transfused they will have variable amounts of Hb A from the transfused
blood, but will still have increased amounts of Hb F and Hb A2.
Diagnosis The diagnosis of beta thalassemia major will have been made in all patients at
around 6 to 12 months of age due to the presence of pallor, irritability, growth retardation,
abdominal swelling due to hepatosplenomegaly, and jaundice. The laboratory examination at
that time will show severe anemia with markedly abnormal hypochromic, microcytic red cells
and with all of the classical findings of severe hemolytic anemia (e.g., increased indirect bilirubin
and lactate dehydrogenase and reduced or absent haptoglobin).
The diagnosis is confirmed on hemoglobin electrophoresis (show table 1). Hemoglobin A is

absent; only hemoglobins F and A2 are present. Variable amounts of hemoglobin A will
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bepresent in those who are subsequently treated with red cell transfusions, but levels of
hemoglobins F and A2 will remain elevated.
CLINICAL HETEROGENEITY OF BETA THALASSEMIA
Overview The beta thalassemia syndromes are remarkable for their heterogeneity,
particularly in terms of clinical severity. Some of the factors contributing to this variability have
been identified on the basis of differences in the mutations producing the beta thalassemic
lesion (e.g., beta(+) or beta (0) mutations which produce some or no beta globin, respectively),
as well as interactions which modify the alpha-globin inclusion burden (e.g., an accompanying
alpha thalassemia). However, additional variability remains unaccounted for and probably
reflects the impact of as yet unidentified modifying genes upon the ultimate clinical phenotype.
The vast majority of heterozygotes for beta thalassemia (e.g., beta thalassemia trait) are
asymptomatic. This is thought to reflect the ability of the erythrocyte to catabolize some of the
excess unpaired alpha-globin chains effectively; the burden is less because the patient is capable
of producing approximately half the normal amount of beta globin.
Patients "homozygous" for beta thalassemia mutations (that is, inheriting a beta thalassemia
mutation on each chromosome, even if they are not identical) usually exhibit some degree of
alpha globin inclusion body formation, with consequent anemia, hemolysis, and varying degrees
of ineffective erythropoiesis. The amount of alpha globin inclusion body formation and the
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degree of ineffective erythropoiesis correlate best with overall severity. The terms "beta
thalassemia minor" and "beta thalassemia intermedia," attempt to reflect the fact that
individuals carrying beta thalassemia mutations exhibit considerable clinical heterogeneity,
requiring differences in approach to management.
Beta thalassemia minor The terms beta thalassemia minor, beta thalassemia trait, and
silent carrier of beta thalassemia are used to describe heterozygotes who carry one normal beta
globin allele and one beta globin thalassemic allele. The vast majority of these patients are
entirely asymptomatic, but do present an abnormal blood picture that is sometimes erroneously
diagnosed as iron deficiency anemia.
Patients with beta thalassemia minor/trait also tend to have total red blood cell counts higher
than normal, often into the "polycythemic" range.
Patients with beta thalassemia trait almost always have a hematocrit >30 percent, and a mean
corpuscular volume of the red cells (MCV) <75 fL. In contrast, patients with iron deficiency rarely
become microcytic (MCV <80 fL) until the hematocrit has dropped below 30.
Another potentially useful indicator is the red cell distribution width (RDW). The RDW in
patients with thalassemia trait tends to be normal, since virtually all cells are hypochromic and
microcytic. In contrast, there is considerable heterogeneity in cell size in the early and
intermediate stages of iron deficiency, producing an increased RDW.
Splenomegaly occurs in about 15 to 20 percent of patients, but is usually asymptomatic. The

peripheral blood smear often reveals a large number of target cells, more dramatic than is seen
in all but the most profound cases of iron deficiency. Red blood cell survival is either normal or
only slightly shortened; reticulocyte counts are normal or only slightly increased, and overt
hemolysis is generally not present.
Hemoglobin electrophoresis On electrophoresis in patients with beta thalassemia minor,

over 90 percent of the hemoglobin will be hemoglobin A along with an elevation in the
hemoglobin A2 value, sometime as high as 7 or 8 percent, and an increase in Hb F in about 50
percent of patients. However, some forms of beta thalassemia are not associated with an
elevated hemoglobin A2. Therefore, a normal concentration of hemoglobin A2 does not rule out
the presence of beta thalassemia trait.
Beta thalassemia intermedia
Overview The term "beta thalassemia intermedia" refers to patients with symptomatic beta
thalassemia who do not require transfusion during at least the first few years of life, and are
able to survive into the second decade of life without chronic hypertransfusion therapy.
This term is losing favor because it fails to address the genetic or clinical mechanisms for the
phenotype of intermediate clinical severity. However, it remains useful to refer to a category of
patients who present special challenges in management.
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Complications Subjects with thalassemia intermedia, while they may not require chronic
transfusion therapy, have increased absorption of dietary iron, and may ultimately develop signs
and symptoms of iron overload. They may also suffer from the complications of chronic hypoxia,
such as high cardiac output, increased pulmonary vascular resistance, pulmonary hypertension,
and heart failure. As a result, such patients should be monitored frequently for these
complications.
While most patients with thalassemia intermedia do not need regular blood transfusions in
order to survive, the stigmata of the disease, including bone marrow expansion,
hepatosplenomegaly, and chronic hemolytic anemia are present, even in milder forms of the
disorder.
Diagnosis The diagnosis of beta thalassemia minor or intermedia should be entertained in

patients of any age with microcytic, hypochromic red cells. As the beta thalassemias show
considerable heterogeneity, patients may or may not have symptoms referable to anemia, may
have variable degrees of splenomegaly and variable degrees of hemolysis. The major differential
diagnosis in such patients includes iron deficiency and the anemia of chronic inflammation, as
follows:
Patients with iron deficiency will have low levels of serum iron and ferritin and increased levels
of transferrin (total iron binding capacity). A cause for blood loss will be obvious in most
patients.
Patients with the anemia of chronic inflammation will have low levels of serum iron and
transferrin. Levels of ferritin will be normal or increased. An inflammatory, infectious, or
malignant disease is usually the underlying cause.
Patients with thalassemia will have normal to increased levels of serum iron and ferritin. Levels
of transferrin will be normal or decreased. At least one of the patient's parents will also be
affected. A family history of "iron deficiency anemia" not responding to treatment with iron is
common.
The diagnosis of a beta thalassemic condition is confirmed on hemoglobin electrophoresis.

Hemoglobin will be the major hemoglobin present. Levels of hemoglobin A2 are increased in
virtually all patients; levels of hemoglobin F are increased in about 50 percent of patients.
If hemoglobin S is present on electrophoresis along with hypochromic, microcytic red cells, and
iron deficiency is absent, one of the sickle cell/thalassemia conditions is present.
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Treatment of beta thalassemia
DEFINITIONS Certain clinical terms are used to describe the phenotypic expression of beta
thalassemia.
Beta (0) thalassemia Beta (0) thalassemia refers to mutations of the beta globin locus that
result in the absence of production of beta globin. Patients homozygous or doubly heterozygous
for beta (0) thalassemic genes cannot make normal beta chains and are therefore unable to
make any hemoglobin A.
Beta (+) thalassemia Beta (+) thalassemia refers to the mutations that result in decreased
production of beta globin. Patients homozygous for beta (+) thalassemic genes are able to make
some hemoglobin A, and are generally less severely affected than those homozygous for beta
(0) genes.
Beta thalassemia major Beta thalassemia major is the term applied to patients who have
either no effective production (as in homozygous beta (0) thalassemia) or severely limited
production of beta globin. These are the patients originally described by Cooley (Cooley's
anemia). Starting during the first year of life, they have profound and life-long transfusion-
dependent anemia.
Beta thalassemia minor Beta thalassemia minor, also called beta thalassemia trait, is the
term applied to heterozygotes who have inherited a single gene leading to reduced beta globin
production. Such patients are asymptomatic, may be only mildly anemic, and are usually
discovered when a blood count has been obtained for other reasons.
Beta thalassemia intermedia Beta thalassemia intermedia is the term applied to patients
with disease of intermediate severity, such as those who are compound heterozygotes of two
thalassemic variants. These patients have a later clinical onset and a milder degree of anemia,
which usually does not require transfusional support.
TREATMENT Treatment of beta thalassemia varies with the type of disease.
Beta thalassemia minor Beta thalassemia minor (beta thalassemia trait) requires no specific
therapy. Transfusions are occasionally required in pregnant women who may develop a more
severe "physiologic" anemia of pregnancy.
It is important that the condition be diagnosed properly, as it is often confused with iron
deficiency anemia and does not respond to treatment with iron supplements. However, patients
with thalassemia minor share the same general risk as normal individuals for development of
iron deficiency anemia from other causes. They should not be denied iron when true iron
deficiency and beta thalassemia trait coexist.
Beta thalassemia intermedia Patients with beta thalassemia intermedia must be monitored
closely for progression of their anemia, and/or the development of worsening evidence of the
221
complications of hemolysis or extramedullary erythropoiesis. In the majority of these patients,
chronic transfusion therapy will initially have to be implemented, occasionally as late as the
third or fourth decade of life. Symptoms usually develop when the hemoglobin level falls below
7 g/dL, and transfusion may be required during periods of rapid growth, infection-associated
aplastic crises, and pregnancy.
Iron overload Patients with beta thalassemia intermedia eventually develop iron overload
even without the use of blood transfusions, because of the increased iron absorption associated
with high rates of erythropoiesis and red cell destruction. Thus, the level of iron stores in these
patients should be monitored carefully by use of the serum ferritin. If available, MRI or "SQUID"
can be employed to quantitate total body iron. Because the tannins in tea chelate iron in the gut
and prevent its absorption, regular consumption of tea is encouraged, although evidence for its
efficacy is incomplete.
Iron chelation therapy may be indicated if serum ferritin concentrations exceed 1000 ng/mL.
Cardiopulmonary complications Patients with thalassemia intermedia may suffer from the
complications of chronic hypoxia, such as high cardiac output, increased pulmonary vascular
resistance, pulmonary hypertension, and heart failure. Although physical examination can be
used to screen for the presence of these right-sided cardiac changes, it has been suggested that
serial screening via Doppler echocardiography (e.g., Doppler tricuspid gradient measurement)
may be the best noninvasive technique for establishing the presence of these complications.
Other complications Patients with thalassemia intermedia are prone to develop

complications such as leg ulcers, gallstones, aplastic crisis, and secondary folic acid deficiencies
during the latter parts of the first or second decade of life.
A high incidence of thromboembolic complications, especially in splenectomized patients, has

been noted in patients with thalassemia intermedia. Although the use of anticoagulants before
surgery and during pregnancy in these patients has been suggested, controlled studies
indicating the safety and utility of this approach are not available.
Beta thalassemia major The mainstays of therapy for beta thalassemia major are chronic
hypertransfusion, splenectomy, iron chelation, and supportive measures directed at the
complications of the expanded erythron and iron overload.
Chronic hypertransfusion therapy The widespread acceptance of chronic hypertransfusion

as the therapy of choice for severe beta thalassemia has greatly altered the typical clinical
course for patients in areas of the world with sufficient resources to support hypertransfusion
programs.
It is now well established that chronic hypertransfusion improves oxygen-carrying capacity,

cardiac status, and systemic parameters of growth, development, and overall well being.
222
Attendance at school is improved, intercurrent infections appear to be reduced, and overall
health appears to be greatly improved during the first 10 to 15 years of therapy.
Transfusion therapy should be started early in those children clearly exhibiting the stigmata of
beta thalassemia major.
Cardiac monitoring Frequent monitoring of cardiac function in transfusion-dependent

patients may indicate those at risk of developing symptomatic cardiac disease, who might then
be candidates for more intensive and sustained iron chelation therapy.
Splenectomy Indications for splenectomy in patients with beta-thalassemia major and

intermedia are an increase of 50 percent or more in the red cell transfusion requirement over
a 1-year period. Splenectomy is usually associated with a reduction in red cell transfusion
requirement, although the benefit is often transient.
Because such spleens may be quite large, the laparascopic technique may not always be
technically possible, and may be associated with a higher incidence of portal vein thrombosis.
Iron chelation therapy Iron overload is inevitable in patients requiring life-long transfusion
support. Each unit of transfused red cells introduces 200 to 250 mg of elemental iron into the
body. Since iron cannot be actively excreted, and is utilized poorly in patients with ineffective
erythropoiesis, the excess iron is deposited in other viscera, usually the liver, heart, and
endocrine organs. When iron stores overwhelm the ability of reticuloendothelial cells to
sequester them, parenchymal iron overload develops, leading to end-organ dysfunction
(especially heart, liver, and endocrine organs) and death.
The typical thalassemic child receiving a hypertransfusion regimen has an intake of 8 to 16

mg of elemental iron per day, in contrast to 1 to 2 mg/day typical of normal subjects. Even
though hematopoiesis is partially suppressed by hypertransfusion, accelerated oral iron
absorption also contributes to the total iron overload. Aggressive attempts to remove iron from
the body pharmacologically are necessary. Clearly, phlebotomy, the most efficacious way to
remove iron in other patient groups (e.g., hereditary hemochromatosis), is not an option in
subjects requiring transfusion. An iron chelating agent is required.
Osteoporosis Prevention and treatment of osteoporosis, an important cause of morbidity in

adult patients with thalassemia major, requires a concerted, multidisciplinary approach, and
includes such components as:
Bone mineral density studies, starting in adolescence.
Encouragement of moderate to high impact physical activity.
Avoidance of smoking.
Adequate calcium, zinc, and vitamin D intake.
223
Early diagnosis and treatment of diabetes mellitus.
Prevention of hypogonadism .
Adequate iron chelation.
Blood transfusions to inhibit excessive bone marrow expansion.
Potential use of agents which inhibit osteoclast activity (eg, calcitonin, bisphosphonates).
Supportive measures Continuity of care is essential for improving the morbidity and
mortality of children with severe thalassemia. In addition to close monitoring of transfusion and
iron chelation therapy, patients need to be under surveillance for a variety of associated
symptoms of anemia and iron overload. These include close monitoring during the ages
surrounding puberty for development of primary and secondary sexual characteristics, with
appropriate endocrine consultation for intervention if growth, development, and puberty are
delayed. In addition, patients with severe thalassemia are at risk for aplastic crisis from infection
with parvovirus B19, during which time transfusion requirements may increase dramatically.
Repletion with folic acid and a cautious use of ascorbic acid and zinc supplementation are
indicated for reasons outlined above. Use of antioxidant compounds, such as vitamin E, remains
controversial. Although a theoretical basis exists for their use, clinical efficacy has not been
proven.
The cardinal manifestations of untreated beta thalassemia major (e.g., bony fractures,
development of masses of extramedullary hematopoiesis, abnormal facies, and dentition) are
minimized when proper transfusion therapy is utilized. Nonetheless, patients should be
monitored for the development of any suspicious signs or symptoms. Splenectomized patients
require pneumococcal and Haemophilus influenzae vaccination, and the use of prophylactic
antibiotics whenever dental procedures, other invasive procedures, or sudden unexplained
fever or systemic symptoms develop.
Hematopoietic cell transplantation Hematopoietic cell transplantation (HCT) has, during the
past two decades, become established as an important modality for patients with severe beta
thalassemia. There is now extensive experience with HCT in these children, with well over 1000
patients having undergone this procedure.
Certain prognostic features and indicators have been shown to correlate with survival and
intercurrent complications of HCT:
Children with minimal or no hepatomegaly, no portal fibrosis, and adequate iron chelation
therapy (class 1) enjoy a 90 percent probability of cure.
Patients with either hepatomegaly or portal fibrosis (class 2) have an 80 percent probability for
cure, while patients with both complications exhibit only a 50 percent long-term survival.
224
For reasons apparent from consideration of the clinical manifestations and complications of
standard therapy for these disorders, patients in class I are most likely to be young, usually less
than five to eight years of age. HCT should therefore be considered for children who fall into
class 1 or class 2 categories as defined above and who have suitable donors.
Patients in class 3 and older children and adults (who tend to be in higher class) appear to fare
less well with HCT. Thus, its use should be reserved only for patients who deteriorate on medical
therapy and have a suitable donor.
MANIPULATION OF FETAL HEMOGLOBIN SWITCHING The development of pharmacologic

agents capable of promoting substantial levels of fetal hemoglobin synthesis during adult life is a
promising approach, even though clinical efficacy has not yet been demonstrated in patients
with severe thalassemia. Continuation of fetal hemoglobin synthesis would reduce clinical
severity by providing additional hemoglobin for oxygen transport and reducing the burden of
free alpha globin chains.
Hydroxyurea Hydroxyurea (HU), a cytotoxic drug commonly used in the treatment of

myeloproliferative disorders, has been shown to increase fetal hemoglobin synthesis in patients
with beta thalassemia, sickle cell disease, and some individuals with no hemoglobinopathy.
The effect of HU appears to be somewhat unpredictable in terms of the maximum Hb F levels

achieved in an individual patient, but the effect is dose related and reversible within individual
patients. Toxicity of HU is largely that of myelosuppression, which, in contrast to many similar
agents, is rapidly reversible upon dose reduction or cessation of the drug treatment.
HU has achieved increasing clinical usage in sickle cell anemia, where it has been shown to
reduce the frequency and severity of acute chest syndrome and painful crises. The use of HU has
225
also been helpful in some patients with beta thalassemia intermedia, although its successful use
in beta thalassemia major has been less frequently noted.
Histone deacetylase inhibitors The disappointing results obtained with hydroxyurea in

thalassemia have led to a search for other agents capable of increasing the production of
hemoglobin F. The histone deacetylase inhibitors butyrate and trichostatin A activate gamma
globin expression via a p38 mitogen-activating protein kinase (MAPK)-dependent mechanism.
Butyric acid analogs The most promising histone deacetylase inhibitors presently under
study are derivatives of butyric acid, including arginine butyrate, sodium phenylbutyrate, and
related substances. Used alone, these agents are inadequately potent in most patients, except
at doses that are potentially toxic or poorly tolerated because of the requirement for prolonged
intravenous infusions.
Promising results have been obtained with the use of combination therapy with hydroxyurea
and intermittent pulses of butyric acid compounds. For poorly understood reasons, intermittent
pulse therapy appears to increase the potency and sustainability of the hemoglobin switching
effect obtained with butyric acid compounds. Whether this or other combination regimens will
eventually prove to be therapeutically efficacious remains to be proven.
Kit ligand In one study, addition of kit ligand, with or without dexamethasone, to cell
cultures from patients with beta thalassemia intermedia or beta thalassemia major increased
cell proliferation, reduced the percent of apoptotic and dyserythropoietic cells, and induced a
marked increase of gamma globin synthesis.
Confirmatory in vivo studies in experimental animal models of thalassemia will be required

before such treatment can be considered in human subjects, especially since infusions of kit
ligand (stem cell factor, Stemgen) have been associated with potentially severe allergic side
effects
226
Overview of the management of sickle cell disease
Elliott P Vichinsky, MD
Vasoocclusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD).
Vasoocclusion results in recurrent painful episodes (previously called sickle cell crisis) and a
variety of serious organ system complications that can lead to life-long disabilities and even
death.
There are two major components to the management of SCD:
Treatment and prevention of the acute manifestations of sickle cell disease (e.g., infection
prevention and control, pain control).
The use of hydroxyurea to interfere with the sickle hemoglobin polymerization process by
increasing the production of fetal hemoglobin, reducing the incidence of subsequent painful
episodes, hospitalization, and death.
Infection control and prophylaxis
Parents of small children should be instructed regarding early recognition of infection and
the palpation of enlarging spleens to permit early detection of potentially fatal splenic
sequestration crisis.
Children with SCD should be immunized against Streptococcus pneumoniae, Haemophilus

influenzae type B, hepatitis B virus, and influenza.
Prophylactic penicillin should be given as 125 mg penicillin V orally twice daily until two to
three years of age and 250 mg twice daily thereafter until the age of five. Pneumococcal sepsis
does occur in children taking penicillin who have received the pneumococcal vaccine; it is
usually associated with suboptimal compliance with penicillin prophylaxis.
Routine treatments and evaluations
1. Folic acid is given orally in a dose of 1 mg/day.

2. Cerebral blood flow should be evaluated by transcranial Doppler (TCD) since children at
risk for cerebrovascular accidents can be identified with this technique and the
incidence of stroke reduced by chronic transfusion therapy.
3. Retinal evaluation is begun at school age and continued routinely to detect early
proliferative sickle retinopathy.
4. Sexually active women should have routine pelvic examinations and birth control. Oral
contraception with low-dose estrogen can be administered safely. Barrier methods and
depo medroxyprogesterone acetate are also effective.
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5. Hydroxyurea The use of hydroxyurea is a mainstay in the overall management of the
patient with sickle cell disease, and has been definitively shown to reduce the incidence
of acute painful episodes, transfusions, and hospitalization rates in adults.
PAIN MANAGEMENT
Overview The acute painful episode is the most frequent cause for patients with sickle cell
disease to seek medical attention. The approach to the patient presenting with pain consists of
exclusion of causes other than vasoocclusion (e.g., infection), optimal hydration by oral or
intravenous fluid resuscitation (particularly in children); and aggressive pain relief using opiates,
other analgesics, or other modalities.
Patients are often undertreated for pain because many clinicians are unfamiliar with the
pharmacology of analgesia and overly concerned with the potential for addiction, patients with
sickle cell disease do not appear to be more likely than others to develop an addiction.
The optimal approach to the treatment of the painful episode is three-fold:
Initiate treatment within 15 to 30 minutes after arrival in the emergency department or

ambulatory day care center.
Administer an effective initial dose of medication, based whenever possible on the individual's
prior experience with analgesics.
Reevaluate the patient's pain status 15 to 30 minutes after the initial dose, with repeated doses
given as often as every 15 to 30 minutes until the patient's pain is significantly improved.
Opiates Hospitalization and intravenous administration of fluid and opiates are often
required for the treatment of severe painful episodes of SCD.
We recommend an aggressive approach using intravenous morphine, followed by varying

combinations of rescue or maintenance analgesia, continuous infusion, and patient-controlled
analgesia. Frequent monitoring of the patient for respiratory depression is an important part of
any of these approaches. Patients with SCD metabolize opiates rapidly, a factor that must be
taken into account when assessing the dose of opiates necessary in the individual patient to
obtain as well as maintain response.
The suggested initial dose of morphine for most opioid-naive adults with a severe painful
episode due to sickle cell disease that is not responding to oral analgesic agents is in the range
of 0.10 to 0.15 mg/kg IV, with monitoring for respiratory depression and reevaluation of pain
status within 15 to 30 minutes after the first morphine injection. Individualization of the dose is
highly recommended, as "real world" safe and effective initial doses have ranged from 0.05 to
>2.0 mg/kg.
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Fentanyl, a synthetic derivative of morphine, is approximately 100 times more potent. It is also
more lipid-soluble than morphine, which results in a more rapid onset of action, due to
improved penetration of the blood-brain barrier, and a shorter half-life of two to three hours.
Fentanyl usually is administered as a continuous intravenous infusion.
Hydromorphone (Dilaudid) is a semisynthetic opiate agonist which, like fentanyl, has a more
rapid onset of analgesia (within 30 minutes) and a shorter half-life (2.4 hours) than morphine.
Because it is available in a highly concentrated preparation (10 mg/mL), it may be beneficial in
fluid-restricted patients who require large doses of opiates.
Meperidine is NOT recommended for the treatment of painful episodes of SCD, since it is less
effective than morphine and has a higher incidence of side effects.
Newer approaches Newer approaches to the management of acute pain include the use of
potent nonsteroidal antiinflammatory drugs, opioid receptor-binding agents, surfactants that
inhibit cell adherence and aggregation, inhaled nitric oxide, anticoagulants, glucocorticoids, and
epidural anesthesia.
Ketorolac Ketorolac (Toradol) is a potent nonsteroidal antiinflammatory drug that can be

given by injection or orally. As a single parenteral agent it provides analgesia superior to
parenteral meperidine, causes no respiratory depression, and is especially effective for relieving
bone pain in patients with SCD. Ketorolac should be limited to a five day course and should be
given with H2 blockers because of severe gastrointestinal side effects.
Tramadol Tramadol is a centrally acting analgesic that is administered orally. It binds to the
mu-opioid receptor, inhibits norepinephrine and serotonin reuptake, and induces minimal
respiratory depression. Tramadol has a low potential for abuse or addiction, relieves
postoperative pain efficaciously, and is useful in the outpatient management of pain crises.
Inhaled nitric oxide Nitric oxide (NO) has a number of effects that may be beneficial in the
management of patients with SCD, particularly acute chest syndrome.
Anticoagulation Increased plasma levels of prothrombin fragment 1+2, thought to reflect

enhanced endogenous thrombin generation, have been found in patients with SCD. This
observation provided part of the rationale for assessing the efficacy of low dose anticoagulation
as prophylaxis for acute pain episodes. In one report, administration of the vitamin K antagonist
acenocoumarol in low doses achieved a mean INR (International normalized ratio) of 1.64 and
elevated levels of prothrombin activation fragment 1+2 were reduced to 50 percent of
pretreatment levels .
Epidural analgesia Epidural analgesia is a useful adjunct for the treatment of severe painful
episodes unresponsive to the usual therapies. In one series of nine such children, eight had
immediate pain relief that was continuously effective in nine of eleven crises.
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Methylprednisolone The efficacy of methylprednisolone, given as an intravenous infusion of
15 mg/kg to a total dose of 1000 mg on admission and again one day later, was evaluated in a
randomized trial of 36 patients. Although pain relief was superior to placebo (mean duration of
analgesia 41 versus 71 hours), there was an unacceptably high rate of rebound pain after
discontinuation of therapy.
Poloxamer 188 Poloxamer 188 (PP188, ReothRx, CytRx), an experimental agent, is an

artificial nonionic surfactant that reduces sickle erythrocyte adherence to the endothelium. In a
randomized trial in 50 patients with acute painful episodes, poloxamer 188 given as a 48 hour
infusion reduced the total opioid requirement, the duration of pain, and the pain intensity.
Chronic pain In rare patients, sickle cell pain is a chronic syndrome. Therapy in this situation
is similar to that used for the management of the pain of terminal cancer, and includes such
agents as long-acting morphine and fentanyl patches .
MANAGEMENT OF INFECTION Infection is a frequent complication of SCD and is particularly

serious when accompanied by bacteremia. Management of the febrile child with SCD begins
with the following evaluation:
Physical examination.
Complete blood count.
Blood and urine cultures.
Lumbar puncture if meningitis is suspected.
Chest x-ray.
Results of the complete blood count are compared to baseline values. A "left shift" (i.e., the
presence of increased band forms and/or metamyelocytes in the white blood cell differential
count) suggests bacterial infection. In the past, due to the high mortality rate of bacteremia,
children with temperatures higher than 38.5C were hospitalized routinely and given parenteral
antibiotics after blood and cerebrospinal fluid cultures were obtained. However, the proven
efficacy of ceftriaxone has allowed outpatient management of patients with a low risk of sepsis.
Febrile episodes Febrile episodes without localized symptoms are treated according to
estimated risk. We recommend use of the following guidelines for the management of the
febrile patient with SCD:
High risk Patients with sickle cell anemia or sickle cell-beta (0) thalassemia who appear
toxic, have temperatures >40C, or are not receiving prophylactic penicillin should be
hospitalized for administration of ceftriaxone (75 mg/kg IV). A rare complication of intravenous
ceftriaxone therapy in patients with SCD is an immune-mediated hemolytic anemia.
230
Low risk Low risk includes patients with sickle cell anemia or sickle cell-beta (0) thalassemia
with temperatures <40C who are compliant with prophylactic penicillin and those with HbSC
disease or sickle cell-beta (+) thalassemia who have temperatures >38.5C. The recommended
approach for these patients is to obtain blood cultures, administer ceftriaxone (50 mg/kg IV or
75 mg/kg IM up to a maximum dose of 2 g), observe for several hours in the emergency
department, with close outpatient follow-up.
Patients with HbSC disease or sickle cell-beta (+) thalassemia with temperatures <38.5C are
treated symptomatically.
Specific infections Therapy of specific infections varies with the clinical setting:
Bacteremia Several days of parenteral penicillin or ceftriaxone therapy followed by oral

antibiotics is appropriate therapy for documented S. pneumoniae bacteremia.
Meningitis Therapy for meningitis should provide coverage for S. pneumoniae and H.
influenzae type b and should be continued for at least two weeks.
Acute chest syndrome Antibiotics should provide coverage for S. pneumoniae, H.

influenzae type b, Mycoplasma pneumoniae, and Chlamydia pneumoniae. We recommend the
combination of cefuroxime and erythromycin, unless there is an appreciable incidence of high-
grade penicillin-resistant pneumococcal infection in the area. These isolates may also be
resistant to cephalosporins.
Osteomyelitis The diagnosis of osteomyelitis should be confirmed by culture of blood or

infected bone. This infection should be treated with parenteral antibiotics that cover Salmonella
and Staphylococcus aureus until culture results are available. Parenteral antibiotics are
continued for two to six weeks. Surgical drainage or sequestrectomy may be required. Most
patients are cured with this approach, but there may be recurrences.
TRANSFUSION THERAPY Chronic red cell transfusion lowers the percent of sickle
hemoglobin (HbS) in subjects with sickle cell disease by three mechanisms: dilution; suppression
of erythropoietin release secondary to the rise in hematocrit, thereby reducing the production
of new sickle erythrocytes; as well as via the longer circulating lifespan of normal compared to
sickle erythrocytes.
Patients with sickle cell disease receive blood transfusions in three situations:
1. To improve oxygen carrying capacity and as blood volume replacement during an aplastic or
splenic sequestration crisis.
2. To provide protection from imminent danger during acute chest syndrome or septicemia.
3. To improve rheologic properties of blood and prevent initial or recurrent cerebral
thrombosis, to prevent recurrent priapism, and to reduce perioperative complications .
231
Of interest, in the Stroke Prevention Trial (STOP), which randomly assigned children with
abnormal transcranial Doppler ultrasonography to receive chronic transfusion or observation,
transfusion not only reduced the risk of stroke, but also significantly reduced rates of
hospitalization for acute chest syndrome and pain episodes. In addition, patients who received
chronic transfusions for two years had improved growth.
Simple transfusion is used for single transfusions to restore oxygen carrying capacity or blood
volume, while partial exchange transfusions are recommended for acute emergencies and for
chronic transfusion because of the improved viscosity effects and reduced iron burden with this
approach. Regardless of the technique, the hemoglobin concentration should not be raised
much above 10 g/dL because of increases in viscosity and the risk of vasoocclusive episodes.
Despite the most conservative use of transfusions, approximately 70 to 80 percent of patients

with SCD receive at least one transfusion by the age of 20 years.
Transfusion volume The volumes required for simple and exchange transfusions can be
estimated and are particularly important for transfusing children. The general rule for normal
size adults is that each unit of red cells infused will increase the hemoglobin concentration by
approximately 1 g/dL or three percentage points in the hematocrit. Partial exchange transfusion
in adults is accomplished by phlebotomizing 500 mL, infusing 300 mL normal saline,
phlebotomizing another 500 mL, and infusing four to five units of packed red cells. In children,
the following formulae are used for estimation of simple transfusion and partial exchange
transfusion volumes:
Packed red cell volume for simple transfusion (mL) = ([dHCT - iHCT] x TBV) rpHCT
Manual partial exchange volume (mL) = ([dHCT - iHCT] x TBV) (rpHCT - [(iHCT + dHCT) 2])
Where dHCT is the desired hematocrit, iHCT is the initial hematocrit (both given as percent, e.g.,
40 percent), TBV is the estimated total blood volume in mL (80 mL/kg in children), and rpHCT is
the hematocrit of the replacement packed red cells (usually 75 percent).
Iron overload Iron overload was not thought to be an important issue in the past because of
the short lifespan of patients with SCD. However, with the subsequent increase in longevity,
there has been increasing concern about the development of iron overload, and its recognition
and treatment, in chronically transfused patients with SCD.
Phlebotomy cannot be used to remove iron in transfusion-dependent subjects except for those
with higher hematocrits. Thus, chelation with deferoxamine is recommended when the total
body iron is elevated. Chelation guidelines for patients with sickle cell disease are similar to
those for other chronically transfused, iron-overloaded patients (e.g., thalassemia major); serum
ferritin concentrations should be measured every three to four months and should not be
allowed to exceed 2000 ng/mL. Such an approach has been effective in patients with
232
homozygous beta thalassemia who are at much greater risk for development of iron overload
and associated endocrinopathy than are patients with SCD.
Even with institution of iron chelation, patients receiving chronic transfusion therapy for SCD
may still develop increased levels of serum ferritin and hepatic iron overload. In one study of 20
patients with SCD, mean ferritin concentrations rose from 420 ng/mL at the initiation of chronic
transfusion therapy (combined with aggressive iron chelation using deferoxamine) to peak levels
of 4614 1989 ng/ml in 42 24 months. There was a strong correlation between months of
transfusion therapy and quantitative hepatic iron concentration, although a poor correlation
existed between average serum ferritin and HI.
The severity of hepatic inflammation and fibrosis, as determined on liver biopsy, was low,
despite the fact that HI concentrations often exceeded 15 mg/g dry weight, levels that are
associated with increased risks of cardiac disease and early death in patients with beta
thalassemia major. Caution should be exercised when contemplating liver biopsy in these
patients, and the procedure may be contraindicated in those with acute liver disease.
Prediction of adverse outcomes Ideally, the risks of more specific therapies, such as the use
of hydroxyurea or hematopoietic cell transplantation (HCT), should be commensurate with the
risks of untreated sickle cell disease. Potentially curative treatments such as HCT should ideally
be initiated before there is irreversible organ damage. Attainment of this goal requires the
ability to distinguish patients at high risk as early as possible.
Three variables appearing in the first two years of life were significantly associated with an
adverse clinical course:
Early dactylitis (i.e., pain and tenderness in the hands or feet occurring before the age of one
year) relative risk (RR) 2.6
Hemoglobin concentration <7 g/dL RR 2.5
Leukocytosis in the absence of infection RR 1.8
An attempt to identify risk factors was also made in a life expectancy study of 3764 patients
(age range 2 to 66 years) [102] . The acute chest syndrome, renal failure, seizures, a baseline
white blood cell count >15,000/microL, and a low level of fetal hemoglobin (HbF) were
associated with an increased risk of early death.
Long-term survival There is little consistent information describing determinants of long-

term survival in SCD. A small study reported on 102 patients with homozygous SCD who survived
beyond their 60th birthday (range: 60 to 85 years, 65 percent women); none had ever received
hydroxyurea. Their HbF levels averaged 4.9 percent higher than values extrapolated from a
Jamaican cohort study, exceeding 10 percent in 24 and 14 percent of the women and men,
respectively. Coexisting alpha thalassemia did not appear to promote survival in this group.
233
Causes of death The Centralized Pathology Unit for Sickle Cell Disease has collected a series
of 306 autopsies of patients with sickle cell disease, accrued between 1929 and 1996. The mode
of dying was sudden and unexpected in 40 percent, within 24 hours after presentation in
another 28 percent, and followed acute events in 63 percent.
Infection was the most common cause of death for all disease variants and all ages. As an
example, infection was directly or indirectly responsible for 85 percent of deaths in children with
homozygous sickle cell anemia less than three years of age. The portal of entry for infection
was predominantly the respiratory tract in children, while the portal appeared to be dictated
by the sites of underlying chronic organ injury in adults.
For the 244 autopsied cases with homozygous sickle cell anemia, the most common sickle cell-
related causes of death were:
Infection 48 percent
Stroke 10 percent
Complications of therapy 7 percent
Splenic sequestration 7 percent
Thromboembolism 5 percent
Renal failure 4 percent
Pulmonary hypertension 3 percent
234
Clinical manifestations of glucose-6-phosphate dehydrogenase
deficiency
Bertil E Glader, MD, PhD
Glucose 6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most

common enzymatic disorder of red blood cells in humans, affecting 200 to 400 million people.
The importance of this enzyme for red cell integrity was first recognized following the
observation that some African-American soldiers taking the antimalarial drug primaquine
developed acute hemolytic anemia with hemoglobinuria. Subsequently, the activity of G6PD,
one of the enzymes needed to maintain adequate reduced glutathione (GSH) levels, was found
to be deficient in affected red cells.
G6PD deficiency is expressed in males carrying a variant gene that produces sufficient enzyme
deficiency to lead to symptoms. The mean red blood cell enzyme activity in heterozygous
females may be normal, moderately reduced, or grossly deficient depending upon the degree of
lyonization and the degree to which the abnormal G6PD variant is expressed. A heterozygous
female with 50 percent normal G6PD activity, due to inactivation of one X chromosome in each
cell via lyonization, has 50 percent normal red cells and 50 percent G6PD-deficient red cells. The
deficient cells are as vulnerable to hemolysis as the enzyme-deficient red blood cells in males.
The World Health Organization has classified the different G6PD variants according to the
magnitude of the enzyme deficiency and the severity of hemolysis. Classes IV and V are of no
clinical significance.
Class I variants have severe enzyme deficiency (less than 10 percent of normal) and have
chronic hemolytic anemia.
Class II variants, such as G6PD Mediterranean, also have severe enzyme deficiency, but there is
usually only intermittent hemolysis.
Class III variants, such as G6PD A-, have moderate enzyme deficiency (10 to 60 percent of
normal) with intermittent hemolysis usually associated with infection or drugs.
Class IV variants have no enzyme deficiency or hemolysis .
Class V variants have increased enzyme activity.
ACUTE HEMOLYTIC ANEMIA Individuals with the most prevalent G6PD variants, G6PD A-
and G6PD Mediterranean are asymptomatic in the steady state; they have neither anemia nor
an alteration in blood morphology, although a modest shortening of red cell survival can be
demonstrated by isotopic techniques. However, sudden destruction of the more deficient
erythrocytes can be triggered by drugs having a high redox potential, and by selected infections
and metabolic abnormalities (eg, diabetic ketoacidosis).
235
The course of an acute hemolytic episode following the administration of primaquine to
subjects with G6PD A- is an example. At two to four days after drug ingestion, there is the
sudden onset of jaundice, pallor, and dark urine, with or without abdominal and back pain. This
is associated with an abrupt fall in the hemoglobin concentration of 3 to 4 g/dL, and the
peripheral blood smear reveals cell fragments, microspherocytes, and eccentrocytes or "bite"
cells. Sequestration of the damaged red cells occurs in both the liver and spleen.
The anemia induces an appropriate stimulation of erythropoiesis, characterized by an increase

in reticulocytes that is apparent within five days and is maximal at seven to ten days after the
onset of hemolysis. Even with continued drug exposure, the acute hemolytic process ends after
about one week with reversal of the anemia. The spontaneous recovery reflects replacement of
the older, enzyme deficient red cells by younger red cells with sufficient G6PD activity to
withstand oxidative injury. The enzymatic activity of G6PD A- is normal in reticulocytes, but
declines rapidly thereafter, with a half-life of 13 days (normal about 62 days). Although there is
continued loss of aging red cells if the drug is continued, it is compensated by the accompanying
erythropoietic marrow response.
G6PD Mediterranean is more unstable, with a half-life measured in hours. As a result, acute
hemolysis is more severe because there is a larger population of circulating erythrocytes
236
vulnerable to injury; furthermore, the hemolysis continues until well after the drug is
discontinued.
Drugs Primaquine and a number of other drugs can precipitate hemolysis in G6PD deficient
subjects. The common denominator of these drugs is their interaction with hemoglobin and
oxygen, leading to the intracellular formation of H2O2 and other oxidizing radicals. As these
oxidants accumulate within enzyme deficient cells with low GSH levels, hemoglobin and other
proteins are oxidized, leading to loss of function and cell death.
Some drugs and chemicals are predictably injurious for all G6PD-deficient subjects. However,
many hemolytic events that were initially ascribed to drugs actually resulted from infections for
which drugs were given. One such drug is aspirin. Other drugs may produce a modest shortening
of survival of G6PD-deficient red cells but can still be given safely in usual therapeutic doses to
individuals with class II and III G6PD variants; one example is sulfamethoxazole, a component of
the commonly used trimethoprim-sulfamethoxazole.
Infections Infection is probably the most common factor inciting hemolysis in G6PD-
deficient subjects. In one study, for example, an abrupt fall in hemoglobin concentration
occurred in approximately 20 percent of G6PD-deficient subjects with pneumonia. The degree
of hemolysis is usually mild. However, massive intravascular hemolysis resulting in
hemoglobinuric acute renal failure has rarely been described.
A variety of infectious agents has been implicated including salmonella, Escherichia coli, beta-
hemolytic streptococci, rickettsiae, and viral hepatitis. In the last setting, the combination of
increased bilirubin load and a damaged liver results in an exaggerated elevation in the serum
bilirubin concentration.
The factors responsible for accelerated destruction of G6PD-deficient red cells during infection
are not known. One possible explanation is that the red cells are damaged by oxidants
generated by phagocytosing macrophages, a mechanism similar to that seen with drug-induced
hemolysis.
Diabetic ketoacidosis Diabetic ketoacidosis appears to be capable of triggering destruction

of G6PD-deficient red cells, although one study found no such relationship in patients with G6PD
Mediterranean. Both acidosis and hyperglycemia are potential precipitating factors, and
correction of the abnormalities is associated with reversal of the hemolytic process. In some
diabetic patients, occult infection may be a common trigger for inducing both acute hemolysis
and ketoacidosis.
CONGENITAL NONSPHEROCYTIC HEMOLYTIC ANEMIA Patients with class I G6PD variants

have such severe G6PD deficiency that lifelong hemolysis occurs in the absence of infection or
drug exposure. These variants have low in vitro activity and/or marked instability, and most
have DNA mutations at the glucose 6-phosphate or NADP binding sites.
237
Anemia and jaundice are often first noted in the newborn period, and the degree of
hyperbilirubinemia is frequently of sufficient severity to require exchange transfusion.
After infancy, the hemolytic manifestations are subtle and inconstant. Most individuals have
mild to moderate anemia (hemoglobin 8 to 10 g/dL) with a reticulocyte count of 10 to 15
percent. Thus, pallor is uncommon, scleral icterus is intermittent, splenomegaly is rare, and
splenectomy generally is of little benefit. The hemolysis can be exaggerated by exposure to
drugs or chemicals with oxidant potential or exposure to fava beans. Some drugs with relatively
mild oxidant potential that are safe in patients with class II or class III G6PD variants may
increase hemolysis in patients with class I variants.
The typically mild anemia reflects the ability of increased erythropoiesis to compensate for the
hemolysis. Thus, as with other chronic hemolytic anemias, the anemia may be worsened by
diminished erythropoietic capacity due to infection or to parvovirus-induced aplastic crises.
A rare associated abnormality in severely deficient patients is neutrophil dysfunction due to

G6PD deficiency. This defect leads to impaired neutrophil bactericidal activity and recurrent
infections with catalase-positive organisms.
NEONATAL HYPERBILIRUBINEMIA Some G6PD variants can cause hyperbilirubinemia in the

newborn period, evident in one study at less than two hours after birth. Although neonates with
the rare class I variants are at greatest risk, most patients have more common variants and
come from the Mediterranean region or Asia. In one series of 43 cases from Italy, for example,
39 had G6PD Mediterranean, one had G6PD A-, and three had other variants. Among affected
Chinese children, most cases are associated with G6PD Canton.
The cause of neonatal hyperbilirubinemia in G6PD-deficient infants is not clear. It has been
presumed that the combination of increased bilirubin production due to accelerated red cell
breakdown and the immature liver is responsible. Although there is often no obvious external
oxidant responsible for red cell injury, indirect evidence supports the importance of local
environmental variables. As examples: G6PD-deficient infants born in Australia to Greek
immigrants have a lower incidence of neonatal hyperbilirubinemia than deficient infants born in
Greece. Herbs used in traditional Chinese medicine and clothing impregnated with naphthalene
may be contributing factors. Exposure of the mother to oxidant drugs or chemicals in late
gestation has been implicated as the inciting stimulus.
However, most cases of neonatal hyperbilirubinemia occur in the absence of obvious exposure
to external oxidants. Furthermore, there is often no evidence of increased red cell breakdown
in neonates who develop hyperbilirubinemia compared to deficient neonates. These
observations suggest an important role for impaired hepatic clearance of bilirubin. In support
of this hypothesis is the observation that neonates with G6PD Mediterranean have a partial
defect in bilirubin glucuronide conjugation similar to that seen in Gilbert's disease.
238
FAVISM Favism usually results from the ingestion of fresh fava beans. As a result, the peak
seasonal incidence (April and May) coincides with harvesting of the bean. It occurs most
commonly in children, primarily males, between the ages of 1 and 5. The clinical
manifestations begin within 5 to 24 hours after fava bean ingestion and are those of acute
intravascular hemolysis. Headache, nausea, back pain, chills, and fever are followed by
hemoglobinuria and jaundice. The fall in hemoglobin concentration is acute, often severe, and,
in the absence of transfusion, can be fatal.
Individuals who develop favism are almost invariably deficient in G6PD. However, unlike other
offending agents capable of inducing hemolysis, only a few G6PD-deficient individuals are
sensitive to the fava bean. In addition, the response to the bean by the same individual at
different times may not be consistent. It is therefore presumed that some other genetic factor
contributes, perhaps related to the hepatic metabolism of fava bean oxidants.
Two pyrimidine aglycones, divicine and isouramil, have been implicated as the toxic
components of fava beans. Both rapidly overwhelm the already diminished GSH-generating
capacity of G6PD-deficient cells and may also have direct effects on red cell function. In vitro
studies have shown that divicine reduces the activity of catalase which, like the glutathione
pathway, contributes to hydrogen peroxide removal, and requires NADPH for maintenance of
normal activity.
The G6PD variant most commonly implicated in favism is G6PD Mediterranean; thus, favism
occurs most often in Italy and Greece. Africans and African-Americans with G6PD deficiency are
much less susceptible, but there are cases of favism associated with the African variant, G6PD A-
.
239
Clinical presentation and diagnosis of von Willebrand disease
Margaret E Rick, MD
Von Willebrand disease (VWD) is the most common inherited bleeding disorder, affecting up
to 1 percent of the population as assessed by random laboratory screening, although less than 5
percent of these individuals are appreciably symptomatic. It is characterized by mutations that
lead to an impairment in the synthesis or action of von Willebrand factor (VWF). Most cases are
transmitted as an autosomal dominant trait that affects males and females equally. There are
also acquired forms of VWD that are caused by several different pathophysiologic mechanisms.
IMPORTANCE OF VON WILLEBRAND FACTOR Von Willebrand factor (VWF) plays an

important role in primary hemostasis by binding to both platelets and endothelial components,
forming an adhesive bridge between platelets and vascular subendothelial structures and
between adjacent platelets at sites of endothelial injury. It also contributes to fibrin clot
formation by acting as a carrier protein for factor VIII, which has a greatly shortened half-life and
abnormally low concentration unless it is bound to VWF.
CLINICAL PRESENTATION Although VWD is relatively common, only a fraction of patients

come to medical attention because of bleeding symptoms and are diagnosed as having VWD.
This low incidence of bleeding is due to the mild nature of the disease in many patients and to
the lack of bleeding challenges and/or lack of recognition of minor excessive bleeding (e.g.,
heavy menstrual bleeding) in others.
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Bleeding symptoms in VWD occur when von Willebrand factor (VWF) is sufficiently decreased
in the plasma or platelets, or when a qualitative defect in VWF impairs one of its functions.
These abnormalities mostly affect platelet plug formation during the primary hemostatic
response. As a result, many of the usual clinical manifestations of VWD are similar to those seen
in platelet disorders.These include:
Easy bruising.
Skin bleeding.
Prolonged bleeding from mucosal surfaces (eg, oropharyngeal, gastrointestinal, uterine).
An exception to this general pattern of bleeding occurs in type 2N VWD in which there is a
qualitative defect in VWF that affects its binding site for factor VIII. In these patients, the
bleeding is due to low factor VIII levels and mimics the findings seen in classical hemophilia,
including soft tissue, joint, and urinary bleeding, and bleeding after invasive procedures. In
patients with type 3 VWD, both types of bleeding may occur.
Patients with VWD can become symptomatic at any age. A typical history in a patient with mild
to moderate disease includes epistaxis in childhood, lifelong easy bruising, and bleeding with
dental extractions or other invasive dental procedures.
Women with VWD usually have a history of heavy menstrual bleeding, and may have bleeding
during the peripartum period, often at or within hours of delivery and at 5 to 10 days after
delivery; the bleeding can persist for weeks.
In patients with mild VWD, the ingestion of aspirin or other antiplatelet medications such as
nonsteroidal antiinflammatory drugs can precipitate bleeding that may not have occurred
otherwise. Some patients remain asymptomatic, with the diagnosis being made during the
course of screening studies because of a family member with newly-diagnosed severe VWD.
Bleeding manifestations are more serious and tend to occur earlier in life in patients who have
a VWD variant (type 2) or who are homozygous or doubly heterozygous for mutations in VWF
(type 3 VWD). Type 3 patients often have symptoms in infancy (e.g., with circumcision) or when
they begin to be mobile, as bleeding occurs after the usual minor traumas associated with
learning to crawl and walk.
As noted above, soft tissue, joint, and urinary bleeding due to factor VIII deficiency can occur
when there is a marked reduction in binding of factor VIII to VWF. This occurs in type 2N VWD
which has a defect in factor VIII binding, or in type 3 in which there is extremely low or absent
plasma VWF. Eruption of deciduous teeth may also cause bleeding, and affected young women
may have life-threatening hemorrhage when they reach menarche. Serious and often recurrent
and intractable gastrointestinal bleeding also can occur, especially when associated with
angiodysplasia.
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DIAGNOSTIC CONSIDERATIONS
Variations in VWF activity in health and disease Because plasma VWF levels can be
increased for physiologic reasons and because of the apparent overlap of VWF levels and
frequent reporting of bleeding symptoms in normal subjects and in patients with VWD, it is
difficult to establish the diagnosis of mild VWD. As has been noted, there is a continuum of VWF
levels between normal subjects and patients with VWD. The difficulty in distinguishing patients
with mild disease from normal subjects is also compounded by the lack of correlation between
bleeding symptoms and a specific level of VWF in an individual.
In patients with borderline results, it is often helpful to repeat the diagnostic testing on two or
three occasions, separated by four to six weeks, and to study available family members. The
patient's blood type should also be determined, since normal individuals with type O blood
have plasma levels of VWF that are 25 to 30 percent lower than those in type A, B, or AB
individuals. Thus, in individuals with type O blood and moderate reductions in plasma VWF, the
presence or absence of a bleeding history and family studies are needed to confirm or exclude a
diagnosis of VWD.
A number of physiologic or disease states can influence plasma VWF and factor VIII levels, and
must be taken into account when trying to establish a diagnosis of inherited VWD. As an
example, thyroid hormone and estrogen promote VWF synthesis. Deficiency of thyroid
hormone reduces plasma VWF in both normal subjects and patients with VWD. Conversely,
patients with mild VWD who take birth control pills or estrogen replacement therapy may
increase their slightly low VWF levels into the normal range.
Low VWF versus type 1 VWD As indicated above, it is likely that diagnostic criteria for VWD
will become more stringent in the future, and that individuals with mild bleeding symptoms and
mildly decreased VWF levels will be referred to as having "low VWF" rather than being labeled
with a diagnosis of type 1 VWD.
LABORATORY TESTING There are five tests commonly used to screen for VWD:
Plasma VWF antigen (VWF:Ag).
Plasma VWF activity (ristocetin cofactor activity, VWF:RCo).
Factor VIII activity (FVIII) and Activated partial thromboplastin time (aPTT).
Platelet function analyzer (PFA) testing or bleeding time (BT).
If one or more of these tests is abnormal, or if there is still a high index of suspicion for VWD in
the face of normal results, further testing is carried out to evaluate the following:
VWF multimer distribution on gel electrophoresis.
Ristocetin-induced platelet aggregation (RIPA).
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These latter two tests are also performed to determine the subtype of VWD when initial tests
are positive, since the subtype of VWD directs the choice of treatment.
Ristocetin cofactor activity and VWF antigen tests can also be performed on platelet VWF, after
VWF has been isolated from circulating platelets. Decreased platelet VWF has been described as
the sole cause of a bleeding diathesis in a few families whose plasma VWF is within the normal
range.
Ratio of VWF activity to VWF antigen Laboratories are making use of this ratio to detect
patients with type 2 VWD. Since the qualitative defects present in type 2A, 2B, and 2M all
decrease the functional activity of VWF more than the antigen concentration, a low ratio may be
used to predict these type 2 patients. Typically, the VWF:RCo to VWF:Ag ratio (or the VWF:CB to
VWF:Ag ratio) is used.
VWF multimers The VWF multimer assay is a qualitative visual assessment of the size
spectrum and the banding pattern of VWF multimers on gel electrophoresis of the patient's
plasma or platelet VWF. This test is used to identify variants of type 2 VWD that have fewer of
the largest multimers, or have unusually large multimers, or other qualitatively abnormal
"bands" that indicate an abnormal VWF structure.
Coagulation tests: Factor VIII activity and aPTT Since normal VWF protects factor VIII from
proteolysis, decreased plasma VWF or a mutation in the factor VIII binding site in type 2N VWD
can lead to decreased plasma factor VIII concentrations, and if sufficiently decreased, to a
prolonged activated partial thromboplastin time (aPTT). Although factor VIII activity is generally
assessed in a functional assay using a fibrin clot as the end-point (modified aPTT assay), it may
also be measured in a chromogenic assay that is not widely used.
Factor VIII activity is usually slightly higher than VWF activity and factor VIII levels are often in
the low normal range in mild cases of VWD. Exceptions are types 2N and 3 VWD, in which very
low levels of factor VIII are found.
Bleeding time The bleeding time (BT) is a measure of the interaction of platelets with the
blood vessel wall. It is prolonged in patients with moderate and severe VWD, but is often
normal in those with mild VWD. Although the BT does not correlate well with any specific
plasma VWF assay, it is helpful diagnostically if it is abnormal. It has been suggested that the
levels of ristocetin cofactor and VWF:Ag in platelets correlate better with the BT than the
plasma values of these tests.
DIAGNOSIS OF VWD SUBTYPES The classification of VWD is based upon both clinical
laboratory tests and genetic information about the mutations responsible for the disease. VWD
is divided into three major types (types 1, 2 [four subtypes], and 3
Type 1 Type 1 VWD, an autosomal dominant disease, is the most common, accounting for
approximately 75 percent of patients. The clinical presentation of type 1 VWD varies from mild
243
to moderately severe as determined by bleeding symptoms, but some patients are
asymptomatic and detected incidentally in studies investigating a relative with type 3 disease.
Laboratory testing usually reveals the following findings:
Concordant reduction in VWF antigen, ristocetin cofactor activity, and factor VIII activity; factor
VIII activity may be slightly higher than VWF levels.
All VWF multimers are present, although in decreased concentration.
RIPA is impaired if VWF levels are sufficiently low.
Platelet VWF activity and antigen are usually within the normal range, but may be reduced.
Type 2 Type 2 VWD contains four subtypes, in which VWF is qualitatively abnormal, as
demonstrated by VWF multimer patterns, RIPA, an abnormal VWF activity to antigen ratio
(except for type 2N), and other special assays such as quantitative binding assays for factor VIII.
Type 2A Type 2A accounts for approximately 10 to 15 percent of cases of VWD, and is usually
transmitted as an autosomal dominant trait. Affected patients typically present with moderate
to moderately severe bleeding.
These patients have a decrease in the hemostatically active high and intermediate molecular
weight multimers of VWF. Some mutations cause a defect in the intracellular assembly and
transport of normal VWF multimers (group 1), while others affect a normal cleavage site in VWF
and cause increased susceptibility to proteolysis by the VWF-cleaving protease (ADAMTS13)
after secretion (group 2)
.Laboratory testing usually reveals the following findings:
Ristocetin cofactor activity and VWF:Ag levels are often discordant, with ristocetin cofactor
activity being lower than the antigen (ratio <0.5 to 0.7); the antigen may remain within the
normal range.
Factor VIII levels may be normal or reduced.
VWF multimer gel patterns show an absence of the high and intermediate molecular weight
multimers .
RIPA is reduced.
Type 2B Type 2B VWD accounts for approximately 5 percent of cases of VWD, and is
transmitted as an autosomal dominant trait. Affected patients generally present with moderate
or moderately severe bleeding. As mentioned above, the abnormal VWF in this disorder has a
"gain of function", binding more readily to the platelet receptor, glycoprotein Ib. The increase in
binding of larger multimers to platelet GP Ib results in their loss from the circulation and, in
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some patients, thrombocytopenia that is apparently due to clearance or sequestration of the
small platelet aggregates that are formed.
Laboratory testing for type 2B VWD, which should always include low-dose ristocetin-induced
platelet aggregation (RIPA), usually reveals the following findings:
VWF:Ag and ristocetin cofactor activity can be discordant, with the ristocetin cofactor activity
being lower than the antigen.
RIPA is "increased" (aggregation is present at low concentrations of ristocetin). The abnormal

VWF binds to platelets at lower concentrations of ristocetin (<0.6 mg/mL) than does normal
VWF, causing the platelets to aggregate at low concentrations of ristocetin.
Factor VIII may be normal or decreased.
The multimer pattern shows a decrease in the high molecular weight multimers, usually less
severe than in type 2A VWD.
Specialized assays for the diagnosis of VWD type 2B measure the direct binding of VWF to
platelet GPIb in the presence of very low concentrations of ristocetin, but they require
recombinant reagents and monoclonal antibodies that are not generally available to most
laboratories.
Platelet-type VWD A phenotype similar to Type 2B can be produced by rare "gain-of-

function" mutations in platelet GP Ib, called platelet-type or pseudo VWD. A distinction between
abnormal VWF and abnormal platelet receptors can usually be made by using patient platelets
and normal plasma VWF, and patient plasma VWF and normal platelets to perform the RIPA .
Another assay that can differentiate between type 2B VWD and platelet-type VWD uses the
addition of normal VWF (in the form of cryoprecipitate or a purified concentrate) to the
patient's platelet rich plasma. An aggregation response occurs if the platelet receptor GPIb is
abnormal and has a high affinity for the added normal VWF. This assay has been utilized to show
that five families that had been previously diagnosed with type 2B VWD actually had platelet-
type VWD.
Type 2M Type 2M VWD is an uncommon, mostly autosomal dominant disorder characterized

by reduced binding of VWF to GP Ib in spite of the presence of large VWF multimers. Affected
patients typically have significant bleeding symptoms and the following pattern on laboratory
testing:
Ristocetin cofactor is reduced more than VWF:Ag (ratio <0.5 to 0.7).
The full spectrum of VWF multimers is present .
The factor VIII level is reduced if the VWF is sufficiently low.
245
Type 2N Type 2N VWD (N is for Normandy where one of the first patients was described) is
an uncommon disorder that is inherited as an autosomal recessive trait. Patients present with
the type of bleeding associated with factor VIII deficiency, such as soft tissue, joint, and urinary
bleeding, and bleeding after invasive procedures.
Ristocetin cofactor activity, VWF antigen, RIPA, and VWF multimer patterns are normal.
Levels of factor VIII are reduced, usually 5 to 15 percent of normal.
A specialized test to assess binding of normal factor VIII to the patient's VWF demonstrates
decreased binding.
Type 3 Type 3 VWD is a rare disease. Affected patients present with severe bleeding involving
both the skin and mucous membrane surfaces (due to decreased VWF) and soft tissues and
joints (due to the low concentration of factor VIII). In one large study from Iran involving 385
patients with type 3 VWD, hemarthrosis, muscle hematoma, oral cavity bleeding, and epistaxis
were present in 37, 52, 70, and 77 percent, respectively.
Type 3 VWD is characterized by a marked decrease or absence of detectable VWF due to

homozygous or compound heterozygous mutations, some of which result in loss of VWF mRNA
expression. Patients may be misdiagnosed initially as having hemophilia A before results of VWF
testing are available.
VWF antigen is unmeasurable or extremely low.
Ristocetin cofactor activity is usually below the limits of detection.
Factor VIII activity is 1 to 10 percent of normal.
RIPA is absent.
VWF multimers are not usually visible on gel electrophoresis.
Treatment of von Willebrand disease

GENERAL CONSIDERATIONS OF THERAPY Decisions about therapy begin with an accurate
and complete diagnosis of VWD. In addition, the patient's past history of bleeding with various
challenges, response to treatment, general medical condition, and current medications need to
be taken into account. The patient should be specifically questioned about use of aspirin-
containing medications or nonsteroidal antiinflammatory drugs that are commonly available
over-the-counter and aggravate bleeding. If the patient is taking an antiplatelet drug and
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bleeding is serious and not controlled by therapy for VWD, consideration must be given to
correction of the platelet defect, usually by platelet transfusion.
There is no laboratory test for VWF that correlates well with bleeding symptoms. As a result,
there are no absolute guidelines about the best parameter(s) to follow when treating the
patient. In addition to clinical monitoring, many experts follow the ristocetin cofactor and factor
VIII levels; the latter is often the only result available in a timely fashion for clinical decision-
making. It is generally felt that it is not necessary to completely normalize the bleeding time in
order to achieve adequate hemostasis in patients with VWD.
INHERITED VWD There are five classes of medications for the treatment of VWD:
desmopressin; replacement therapy with VWF-containing concentrates; antifibrinolytic drugs;
topical therapy with thrombin or fibrin sealant; and estrogen therapy in some settings in
women. Several reports also indicate a role for recombinant human factor VIIa in the treatment
of patients with severe (type 3) VWD who develop inhibitors to replacement VWF.
Desmopressin Desmopressin (dDAVP) is a synthetic analog of antidiuretic hormone which

retains antidiuretic activity but lacks vasopressor activity, that was first shown in 1977 to
increase VWF and factor VIII levels. It promotes the release of VWF from endothelial cell storage
sites; this response is indirect, since it cannot be reproduced by direct exposure of endothelial
cells to dDAVP. Desmopressin may also have other actions, such as enhanced hemostasis in
patients with platelet function defects.
Desmopressin can be administered intravenously, by subcutaneous injection, or by intranasal

spray. When given intravenously for prophylaxis before invasive procedures or for acute
bleeding episodes, a dose of 0.3 micrograms/kg (maximum 20 micrograms) is diluted in 50 mL
of normal saline and infused over 20 to 30 minutes; the same dose is given with subcutaneous
therapy. A three- to five-fold increase in baseline levels of VWF and factor VIII levels is expected
at approximately 30 to 60 minutes after the infusion, with the response persisting for 6 to 12
hours. The half-life of the released VWF will correspond to the particular half-life of the patient's
own VWF. A repeat dose may be given at 8 to 12 hours. Subsequent doses are often switched to
once daily doses for one to three days; tachyphylaxis and hyponatremia can occur with
prolonged dosing.
Intranasal administration has become a favored choice for many patients who have less
serious bleeding not requiring a hospital visit or who need treatment prior to a planned minor
invasive procedure, since therapy can be performed at home in a timely manner. As an example,
intranasal therapy at the onset of menses has been used by women with VWD to control
excessive menstrual bleeding. Benefits also have been noted for epistaxis or bleeding related to
minor surgery or tooth extraction. The usual dose is 150 micrograms for children weighing less
than 50 kg and 300 micrograms for larger children and adults. In adults, the VWF levels
achieved with 300 micrograms of intranasal spray are approximately equivalent to that seen
with an intravenous dose of 0.2 micrograms/kg.
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Side effects of desmopressin include vasodilatation that causes facial flushing, headache
(which can often be controlled by decreasing the rate of infusion), nausea, and occasional
tingling. Both hypotension and hypertension have been reported, but are not common and are
usually mild. Thrombosis has occurred following desmopressin administration, but it is uncertain
whether the medication is causal. Common sense dictates caution with the use of dDAVP in
patients with known coronary or cerebral arterial vascular disease.
Tachyphylaxis occurs after repeated administration and, because of the persistent antidiuretic
activity, water retention leading to serious hyponatremia, seizures, and even death can occur.
While nonsteroidal antiinflammatory agents (NSAIDs) should not generally be used in patients
with VWD or other bleeding disorders, their inadvertent use by patients receiving dDAVP may
aggravate hyponatremia; accordingly, NSAIDs should be used with caution in patients receiving
dDAVP for any indication. Doses of desmopressin are usually limited to once daily after the first
day for a total of 3 days, water intake is restricted, and serum sodium levels are assessed.
Responses according to VWD type As will be discussed below, the utility of desmopressin
varies with the type of VWD. Because of this variability in response, and in the absence of firm
data from clinical trials, a "test" infusion should be given in advance of a planned procedure to
assess both the VWF and factor VIII responses. Once an adequate response is documented,
desmopressin can be used for subsequent bleeding episodes or invasive procedures without
further therapeutic trials.
Type 1 Desmopressin is effective in almost all patients with mild or moderate type 1 disease.
In comparison, a high proportion of those with severe bleeding symptoms and marked
prolongation of the bleeding time do not respond sufficiently to desmopressin. Desmopressin is
also ineffective in the rare patients with type 1 disease who have normal or decreased levels of
plasma VWF accompanied by absent stores of VWF in platelets.
Type 2A The administration of desmopressin to patients with type 2A disease increases factor
VIII levels, but has a variable effect on the VWF level, the reduced hemostatically active high and
intermediate molecular weight multimers, and the prolonged bleeding time. Patients who do
respond with a reduction in the bleeding time may belong to group 2, which is characterized by
normal VWF secretion but increased susceptibility to proteolysis by the VWF cleaving protease
(ADAMTS13). In one study, for example, desmopressin produced an increase in the higher
molecular weight VWF multimers that persisted for at least 4 hours; these were detectable only
when blood was collected in the presence of protease inhibitors, as opposed to citrate alone.
Type 2B Patients with type 2B often have thrombocytopenia due, as mentioned above, to
increased binding of the abnormal VWF to platelet GPIb, a problem that can worsen after
treatment with desmopressin. It is presumed that increasing the level of abnormal 2B VWF
causes more binding to platelets, resulting in microaggregate formation and sequestration or
clearance of platelets. Despite these concerns, some type 2B patients have benefited from
desmopressin without either marked thrombocytopenia or thrombotic complications. The
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reduction in platelet count is transient, usually normalizing within two hours. Desmopressin
should be considered in type 2B disease only if response to this agent has been documented
after a trial infusion has been conducted. Patients who are markedly thrombocytopenic may
also benefit from platelet transfusion in addition to therapeutic measures that increase the level
of normal VWF.
Type 2M Although data are limited, desmopressin may produce a good response in some
patients with type 2M VWD.
Type 2N Patients with type 2N have normal VWF platelet function but impaired binding to
factor VIII, leading to low factor VIII levels. These patients may benefit from desmopressin,
despite the shorter than normal half-life of the released factor VIII. In one study, for example, a
desmopressin infusion resulted in a 2.3-fold increase of VWF and a variable rise (9.5 7.7 -fold)
in factor VIII; the factor VIII response was more transient than the VWF response, with a
disappearance half-time of approximately three hours.
Type 3 Desmopressin does not increase VWF levels in patients with type 3 VWD, probably
due to a lack of VWF in the storage sites. It is therefore not recommended for use in patients
with type 3 VWD.
Replacement therapy with VWF Patients with type 3 VWD and those with more severe type
2A, 2B, and 2M disease often require replacement therapy with VWF. Replacement therapy is
also indicated in some patients with type 1 VWD who have a more severe decrease of VWF,
particularly in more serious bleeding situations when other measures have failed, or in those
who may need prolonged treatment (e.g., post-surgery).
Preparations Several products are available that contain VWF in high concentration,
including "intermediate purity" factor VIII concentrates (which also contain VWF), more highly
purified VWF concentrates, cryoprecipitate, and a recombinant VWF product that is still in
development. Unless there are special considerations, such as a single related donor or no other
recourse, cryoprecipitate is not recommended because of the risk of viral transmission.
The intermediate purity factor VIII concentrates and higher purity VWF concentrates are
pasteurized or treated with solvent detergent methods to reduce the risk of transmission of
viruses, such as hepatitis viruses and HIV. The manufacturing process must allow for
preservation of the larger (as well as the smaller) VWF multimers, since the larger multimers are
the most hemostatically active. One of the intermediate purity factor VIII concentrates, Humate
P, is approved for use in the United States; it is labeled with ristocetin cofactor activity units,
and a retrospective study of its efficacy in patients with VWD has been published.
Summary Recommendations for replacement doses of VWF are empirical, since no

laboratory tests adequately predict the hemostatic effects. The dose given is also dependent
upon the site and the degree of bleeding.
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In general, the goal is to maintain the activity of factor VIII and of VWF (generally measured as
ristocetin cofactor) between 50 to 100 percent for 3 to 10 days for more serious bleeding or
major surgery. The infusion of 20 to 30 IU/kg of ristocetin cofactor activity as labeled on these
concentrates raises the plasma concentration to 50 to 100 percent, or by approximately 0.7
units/mL (70 percent). Patients with severe VWD (usually type 3) who have mucous membrane
bleeding, particularly gastrointestinal bleeding, may require higher replacement doses of VWF
(80 to 100 percent). If bleeding is not controlled by VWF replacement therapy, these patients
may benefit from the addition of platelet transfusions.
There appears to be a small risk of venous thromboembolism when intermediate purity factor
VIII concentrates are used in high doses as replacement therapy during perioperative periods or
for gastrointestinal bleeding. In some of these cases a high factor VIII level (>200 percent) has
been documented, which may have contributed to the thrombosis. Accordingly, it has been
recommended that factor VIII concentrations be followed on a daily basis to avoid levels in
excess of 200 percent.
Replacement VWF is usually infused over less than 20 minutes at 8 to 12 hour intervals, at a
dose of 20-30 IU/kg to keep VWF levels at 50 percent or to control clinical bleeding. However,
other studies indicate that continuous infusion of VWF may reduce the clearance of the infused
product, thereby lowering the total dose that is consumed by 20 to 50 percent.
In addition to measuring ristocetin cofactor activity, physicians may consider utilizing the
platelet function analyzer (PFA-100) to follow VWF activity after replacement therapy. While the
PFA can be used to follow some patients after treatment, it does not appear to be accurate for
monitoring replacement therapy in patients with type 3 VWD. This limitation is thought to
reflect dependence of the instrument's assessment method on platelet VWF; the latter is very
low or absent in patients with type 3 VWD, even after plasma replacement therapy.
Antifibrinolytic therapy Epsilon aminocaproic acid (EACA) and tranexamic acid have been
used to prevent dissolution of the hemostatic plug that is formed, particularly in mucous
membrane areas with naturally high fibrinolytic activity (eg, to decrease bleeding with dental
procedures). These drugs can be used as the sole therapy in cases of mild bleeding or as an
adjunct to other medications.
Both drugs can be given orally or intravenously. When given orally, they must be given three
or four times over a 24-hour period due to their short half-lives, and the dose must be adjusted
in patients with renal insufficiency. EACA is usually given four times daily in a dose of 25 to 50
mg/kg, and tranexamic acid is given three times daily in a dose of 10 mg/kg IV. When
administered for dental procedures, minor epistaxis, or other similar procedures, the agents are
given for periods varying from three to seven days. Prolonged use of either medication carries a
risk of thrombosis in patients who have an underlying hypercoagulable state. These agents are
contraindicated in the presence of gross hematuria, since unlysed clots may lead to ureteral
obstruction.
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Topical agents Topical agents are most often used for nasal or oral bleeding. With this
approach, supports such as Gelfoam or surgicel are soaked in topical thrombin and applied to
local areas of bleeding. It is recommended that human thrombin be used for this purpose. If
human thrombin is not available, bovine thrombin can be used, although large exposures to
topical bovine thrombin carry a risk of antibody formation against the bovine factor V that is
present in some thrombin preparations. This has been associated with bleeding, since these
antibodies can crossreact with human factor V.
Micronized collagen (Avitene), which is available in strips for packing, and fibrin sealant (using
human thrombin) are other topical agents that can be used.
Estrogen The use of estrogen therapy in patients with VWD was suggested by the incidental
observation that three women with type 1 VWD had significantly less bleeding and improved
hemostasis when they took estrogen either for oral contraception or prevention of menopausal
symptoms [65] . Estrogen acts at least in part by increasing the synthesis of VWF.
Recombinant Factor VIIa Several authors have reported on the successful use of recombinant
factor VIIa in the treatment of patients with type 3 VWD who developed alloantibodies to VWF
after receiving replacement therapy with VWF. Factor VIIa bypasses the need for factor VIII in
the intrinsic coagulation pathway, and binds to activated platelets and initiates the extrinsic
clotting cascade with subsequent formation of thrombin and fibrin.
Whether factor VIIa provides a "bypass" for the platelet-related functions of VWF is not clear,
but clinical hemostasis has been achieved in these severe VWD patients who lack plasma and
platelet VWF. Because of the increased risk of thrombosis when using this agent, factor VIIa
should be used with caution in patients with risk factors for coronary artery disease.
TREATMENT OF ACQUIRED VWD Acquired VWD is associated with a number of different

disease states and is caused by several different pathophysiologic mechanisms. These include
antibody formation, proteolysis, binding to tumor cells with increased clearance, and decreased
synthesis, as in hypothyroidism. Acquired VWD is most frequently described in patients with
lymphoproliferative and autoimmune diseases (systemic lupus erythematosus), some of whom
have demonstrable antibodies to VWF.
Treatment of acquired VWD depends in part upon the pathogenetic mechanism. It may involve
empiric trials to select the best treatment regimen (eg, desmopressin, VWF replacement
therapy, or intravenous immune globulin [IGIV, IVIG]) as well as treatment of the underlying
disease, if possible. Other treatments that are much less often used include plasmapheresis,
extracorporeal immunoadsorption, and immunosuppressive medications for the underlying
disease (e.g., corticosteroids or cyclophosphamide for systemic lupus erythematosus).
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RECOMMENDATIONS
General concerns Decisions about therapy begin with an accurate and complete diagnosis of
VWD (i.e., VWD, type 1,2, or 3, with subgrouping as relevant). Ideally, this should be known or
verified before any treatment is given.
The patient's past history of bleeding with various challenges (e.g., menses, surgery,
pregnancy), response to treatment, general medical condition, and current medications need to
be taken into account, especially the use of aspirin, antiplatelet agents, and nonsteroidal
antiinflammatory drugs. Medical illnesses associated with potential alterations in hemostasis or
thrombosis should also be reviewed (eg, uremia, ischemic vascular disease).
Treatment Treatment of bleeding in a specific patient with VWD depends on the following
variables:
Nature and severity of the type of VWD present.
Location and severity of the bleeding episode or challenge.
Response to the treatment of prior bleeding episodes.
Other medications and illnesses impacting hemostasis .
Trial of DDAVP We recommend that a trial of DDAVP be carried out in all type 1 patients,
most type 2 patients, but not in type 3 patients at the time of diagnosis or when the patient is
not bleeding, in order to assess response prior to its actual need (Grade 1C).
An effective response to DDAVP is a VWF activity level of at least 30 IU/dL; levels of at least 50
IU/dL are optimal. Once an adequate response is documented, DDAVP can be used for
subsequent bleeding episodes or invasive procedures without further therapeutic trials.
Minor bleeding and minor surgery
We suggest the use of IV or intranasal DDAVP as initial treatment of minor bleeding or at the
time of minor surgery in patients who have shown a prior response to this agent (Grade 2C).
VWF ristocetin cofactor activity levels should reach at least 30 IU/dL; 50 IU/dL is optimal. DDAVP
may be used at approximately 12 hour intervals for 2 to 4 doses. Water intake should be
decreased to avoid hyponatremia.
Bleeding should be followed clinically, and as needed with laboratory monitoring if the
expected clinical response is not seen. If the patient continues to have bleeding, we suggest the
use of VWF concentrate (Grade 2C).
We suggest the use of antifibrinolytic and/or topical therapies to supplement the treatments
outlined above (Grade 2C).
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Major bleeding and major surgery
For episodes of major bleeding or major surgical procedures, we recommend that patients be
hospitalized at a location where expertise in management of VWD and laboratory monitoring of
VWF levels are available (Grade 1C).
We suggest the use of VWF concentrate over DDAVP in order to reach a target level of
approximately 100 IU/dL of VWF ristocetin cofactor activity (Grade 2C). This usually requires an
initial dose of 40 to 60 IU/kg; repeated doses of 20 to 40 IU/kg should be given approximately
every 12 hours to maintain a level between 50 to 100 IU/dL of VWF ristocetin cofactor activity.
We suggest that the above levels of VWF ristocetin cofactor activity be maintained for 7 to 14
days or more as needed (Grade 2C). When potential sites of bleeding are visible or easily
detected, treatment duration may be reduced if bleeding is controlled.
Acquired VWD
We suggest that patients with acquired VWD who have bleeding or who need surgery receive a
trial of DDAVP; levels of VWF activity should be monitored for possible rapid clearance (Grade
2C).
In patients who do not respond adequately to DDAVP, we suggest the use of VWF concentrates
in patients with active bleeding or prior to surgery (Grade 2C).
If the patient does not respond to DDAVP, and especially in patients who have documented
antibody-mediated acquired VWD, we suggest a trial of high-dose IVIG (Grade 2C). Treatment of
the underlying disease should be undertaken if feasible.
Pregnancy and childbirth
The obstetrician and a hematologist with expertise in the management of VWD should jointly
evaluate the patient before or as early in the pregnancy as possible and monitor her throughout
the pregnancy and delivery. For delivery, the patient should be hospitalized in a center where
VWF and factor VIII levels can be monitored. Caesarean section should be carried out only for
the usual obstetrical reasons. Excessive bleeding may occur up to 21 or more days following
delivery and should be treated with DDAVP or VWF concentrates as appropriate to the bleeding
episode.
We suggest that VWF ristocetin cofactor activity and factor VIII levels of at least 50 IU/dL be
achieved before delivery and maintained for 3 to 5 days afterward (Grade 2C). For patients who
do not have this degree and length of response on their own or following the use of DDAVP, we
suggest the use of VWF concentrates (Grade 2C).
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In patients who are known to adequately respond to DDAVP, we suggest that DDAVP be given
after the beginning of labor and as close to the time of delivery as can be estimated (Grade 2C).
Subsequent doses may be given as suggested above.
We suggest that regional anesthesia can be considered if VWF and factor VIII levels can be
maintained above 50 IU/dL (Grade 2C).
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Disseminated intravascular coagulation in infants and children
Wendy Wong, MD - Bertil E Glader, MD, PhD
INTRODUCTION Disseminated intravascular coagulation (DIC) is an acquired syndrome

characterized by hemorrhage and microvascular thrombosis. Endothelial tissue damage from a
variety of underlying disorders (e.g., sepsis, trauma, and malignancy) activates the coagulation
cascade, which promotes fibrin production and deposition, and consumption of clotting factors.
The subsequent consumption of coagulation factors and platelets, enhanced fibrinolysis, and
fibrin deposition result in the clinical picture of DIC of a bleeding diathesis accompanied by
thrombosis that may lead to end organ damage .
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DIC is a secondary process caused by the systemic activation of the coagulation system by
tissue damage from a variety of underlying diseases (e.g., sepsis, trauma, and malignancies).
Exposure of blood to procoagulants Tissue damage from the initiating primary disease
releases procoagulants into the bloodstream.
Formation of fibrin in the circulation Tissue procoagulants activate hemostasis primarily

through the interaction of tissue factor and Factor VII, which promotes fibrin formation and
deposition within the microcirculation.
Fibrinolysis Fibrin formation activates the fibrinolysis pathway, which produces plasmin that
cleaves fibrinogen and fibrin, thereby generating fibrin degradation products (FDPs). FDPs
interfere with fibrin polymerization and impair platelet aggregation.
Depletion of clotting factors and platelets Ongoing activation of the coagulation system
and fibrin deposition consume clotting factors and platelets.
End-organ damage Deposition of fibrin into the microcirculation of organs results in tissue
ischemia and damage.
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Hemolysis Intravascular fibrin strands cause mechanical shearing of red blood cells resulting
in microangiopathic hemolytic anemia.
ETIOLOGY DIC occurs in a variety of clinical conditions. In older infants and children, the
major causes of DIC include sepsis, trauma, and malignancies. In the neonate, DIC is caused
primarily by sepsis and perinatal complications (eg, birth asphyxia).
Older infants and children The following discussion is a summary of the causes of DIC in
older infants and children, which are similar to those seen in adults.
Sepsis Sepsis is the most common cause of DIC in older infants and children. DIC was
classically recognized as a complication of endothelial damage produced by meningococcemia.
Viral, rickettsial, fungal, parasitic, and other bacterial infections are also associated with DIC
Trauma and tissue injury In children, DIC potentially is a serious complication of any major
trauma or tissue injury. These include crush injury, massive burns, extensive surgery, severe
hypothermia, heat exhaustion, and shock. In all these cases, release of tissue enzymes and
phospholipids from damaged tissue into the systemic circulation triggers activation of the
coagulation system. Brain tissue is a potent thromboplastin and patients who sustain severe
brain injury are especially at risk for DIC.
Malignancy In children with leukemia, laboratory abnormalities in the clotting system are
common. DIC is rare in children with acute lymphocytic leukemia, although it has been reported
in patients with the uncommon translocation. Patients with acute promyelocytic leukemia can
present with acute hemorrhage due to DIC. In these patients, granules within the blast cells
contain procoagulants that directly trigger the coagulation system.
Miscellaneous Other causes of DIC in children include:
Acute hemolytic transfusion reactions Release of adenosine diphosphate and

phospholipids from the hemolyzed red cell activate platelet and the coagulation system
respectively.
Kasabach Merritt (KM) syndrome Patients with kaposiform hemangioendothelioma, an

aggressive form of giant hemangioma, can develop KM syndrome, a localized form of DIC. The
large hemangioma consumes fibrinogen and platelets resulting in thrombocytopenia and
consumptive coagulopathy.
Snake and spider bites The venom of some snakes and spiders (e.g., rattlesnakes and
Russell's viper) can directly activate the coagulation system and lead to DIC.
Liver disease DIC may be seen in patients with acute or chronic hepatocellular disease
including Reye's syndrome.
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Neonates Newborn infants, particularly preterm infants, are vulnerable to DIC because the
anticoagulants, antithrombin, and protein C are normally low at this age. The main causes of DIC
include sepsis, birth asphyxia, respiratory distress syndrome (RDS), and necrotizing enterocolitis
(NEC).
Sepsis Neonatal viral infections (e.g., rubella, herpes, cytomegalovirus, and enterovirus),
systemic candidiasis, and bacterial sepsis (e.g., Group B streptococcus and gram-negative
organisms) are causes of neonatal DIC. Perinatal acquired infections (e.g., TORCH infections) are
also associated with DIC.
Perinatal conditions Perinatal conditions associated with DIC include complications from
pregnancy and delivery that lead to birth asphyxia, and diseases linked to prematurity.
Obstetric complications Obstetric complications resulting in fetal anoxia/birth asphyxia may

cause neonatal DIC. These include abruptio placentae, preeclampsia, eclampsia, and fetal
distress during labor.
Conditions associated with prematurity DIC is associated with necrotizing enterocolitis

(NEC) and respiratory distress syndrome (RDS), both of which are seen more frequently in
premature infants. In patients with NEC, ischemic bowel tissue releases tissue factor, which
activates the coagulation system. Patients with severe RDS are also at risk for DIC presumably
due to tissue damage from hypoxia. Autopsy studies in preterm infants with RDS have
demonstrated fibrin deposition not only in the lungs but also the liver and kidney.
Miscellaneous Rare causes of neonatal DIC include hypothermia and massive hemolysis,
such as seen in Rh incompatibility.
Congenital disorders Congenital homozygous deficiency of protein C and S can present in

the neonatal period with DIC and purpura fulminans, while neonates who have large
hemangiomas can develop Kasabach Merritt syndrome.
CLINICAL MANIFESTATIONS Although the clinical spectrum and causes of DIC are variable in
infants and children, the pathophysiology is the same, with an overwhelmed hemostatic system
that is unable to compensate for the ongoing consumption of clotting factors and platelets. In
these patients, clinical bleeding and microthrombosis occur, and coagulation tests are often
abnormal.
Clinical findings vary depending on the severity of DIC. In mild cases, bleeding may only be
noted at venipuncture sites, but in other cases there may be severe hemorrhage and thrombosis
with end-organ damage to the kidney, liver, lung, central nervous system (CNS), and extremities.
Hemorrhage is the most common presentation followed by skin manifestations of purpura and
acral gangrene (purpura fulminans).
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In neonates, the most common sites of bleeding are the gastrointestinal tract and venipuncture
sites. In severe cases, intrapulmonary and intraventricular hemorrhages occur. Risk factors for
DIC in neonates include prematurity, low birth weight, and low Apgar scores.
LABORATORY FINDINGS Laboratory findings in DIC are classified based upon the pathologic
process:
Consumption of coagulation factors and platelets.
Increased fibrin formation.
Increased fibrinolysis.
Consumption Tests that show consumption of clotting factors and platelets include the
following:
Platelet count Thrombocytopenia (platelet count <100,000 per mm3) usually is present in
patients with DIC. On the peripheral smear, platelets are large, suggesting a destructive process.
Prothrombin time (PT) The PT is prolonged in 50 to 75 percent of cases. A prolonged PT

reflects a reduction in the activity of the extrinsic and common coagulation pathways.
Activated partial thromboplastin time (aPTT) The aPTT is prolonged in 50 to 60 percent of

cases. A prolonged aPTT reflects a reduction in the activity of the intrinsic and common
coagulation pathways.
Factor V and VIII levels Both Factor V (common coagulation pathway) and factor VIII
(intrinsic pathway) are decreased.
Some patients with DIC will have a normal PT and aPTT as noted above. This may be due to
circulating activated clotting factors such as thrombin and factor Xa.
Fibrin formation Studies indicative of fibrin formation include:
Fibrinogen When the fibrinogen concentration is low, it is consistent with a diagnosis of DIC
due to its consumption in the formation of fibrin. However, fibrinogen is not a sensitive test for
DIC because it is also an acute phase reactant. When the concentration is normal, it may
represent a significant decrease in a patient whose fibrinogen level should be higher because of
the inflammation from his/her underlying disease.
Thrombin time Thrombin time is prolonged when the fibrinogen concentration is low. FDPs
also impair fibrin formation, thereby prolonging the thrombin time.
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Microangiopathic hemolytic anemia Microangiopathic changes on the peripheral smear are
suggestive of DIC and are due to mechanical shearing of red blood cells by intravascular fibrin
strands.
Fibrinolysis DIC is unlikely if there is no evidence of fibrinolysis as indicated by the following:
Fibrin degradation products (FDPs) FDPs are products of plasmin degradation of fibrinogen
and fibrin. They are present in 85 to 100 percent of patients with DIC. However FDPs are not a
specific test, since they are also present in patients who have systemic lupus erythematous,
necrotizing enterocolitis, thrombotic events from causes other than DIC, and in some
individuals taking oral contraceptives.
D-dimer D-dimer is a neoantigen produced when cross-linked fibrin is degraded by plasmin.

It is elevated in 90 percent of patients with DIC and is more specific than FDPs.
Other studies DIC is also characterized by decreased levels of antithrombin, and protein C
and S, which lead to impairment of the anticoagulant pathway. Despite the decreased
concentration of these anticoagulants, their measurement generally is not helpful in clinical
management.
There are several other tests for DIC that may prove to be helpful but are not widely available
or used.
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Procoagulant activation Commercial assays are available to measure markers of
procoagulant activation such as prothrombin fragment 1.2, fibrinopeptide A and fibrinopeptide
B, and thrombin-antithrombin (TAT) complexes.
Fibrinolysis Fibrinolysis can be detected by elevated levels of plasmin and plasmin-

antiplasmin (PAP) complex.
DIAGNOSIS The diagnosis of overt DIC is based upon clinical findings of hemorrhage and
microthrombi in patients with predisposing medical conditions and abnormal coagulation
studies.
Laboratory evaluation Although laboratory studies are used to support the diagnosis, there
is no single test that is sensitive or specific enough to assure a definite diagnosis. A reasonable
panel of coagulation studies to establish the diagnosis includes:
Complete blood count (CBC).
Prothrombin time (PT).
Activated partial thromboplastin time (aPTT).
D-dimer level.
Fibrinogen level.
Factor V and VIII levels.
The most helpful tests clinically are those that indicate the presence of fibrinolysis (e.g., FDPs
and D-dimers). D-dimer is a more specific test for DIC than FDPs. The latex agglutination assay
for D-dimer is commonly used and is one of the more reliable tests. In addition, decreased levels
of factors V and VIII help substantiate the diagnosis of DIC.
Serial measurements of coagulation parameters are more informative than laboratory

measurements performed at a single timepoint. As an example, a prothrombin time, which is in
the upper normal range but is significantly longer than an earlier measurement, reflects the
consumptive process of DIC and not a normal hemostatic state. Serial measurements of platelet
counts that document a downward trend are a sensitive but not specific sign for DIC.
Scoring system A scoring system to simplify the diagnosis of DIC has been developed by the
DIC subcommittee of the International Society on Thrombosis and Haemostasis (ISTH). This
scoring system is based upon:
Patients having a medical condition known to be associated with DIC.
Readily available global coagulation tests that include platelet count, FDPs, PT, and fibrinogen
concentration.
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Scores are dependent on the degree of abnormality measured by each test. As an example, a
platelet count <50,000/microL is scored higher than one that is <100,000/microL.
A preliminary study in critically ill adults with DIC reported a 91 percent sensitivity and 97
percent specificity for the ISTH scoring system compared to clinical expert opinion. A review of
the literature demonstrated several studies that have reported accurate prediction of mortality
with the use of this scoring system. The system score also correlated with other markers of DIC
including decreased antithrombin and protein C activity, and increased TAT complexes and
soluble fibrin levels. The DIC subcommittee of the ISTH is developing a similar template for
children and infants.
Neonates Similar to older patients, the diagnosis of DIC in the neonate relies on abnormal
global coagulation tests in the appropriate clinical setting. However, it is more difficult to
establish the diagnosis of DIC in these patients. Testing is limited because the volume of blood
required may be difficult to attain in the neonate. In addition, the interpretation of these studies
in the neonate is challenging as the hemostatic system is still in a state of flux at birth with
physiologic alterations of coagulation and fibrinolysis. As a result, the diagnosis of DIC in the
neonate may rely more heavily on the patient's clinical manifestations than on laboratory
studies. The recognition of the underlying condition rather than establishing the diagnosis of DIC
is more important as the most important therapeutic intervention is to treat the underlying
disorder.
DIFFERENTIAL DIAGNOSIS The clinical differential diagnosis for DIC is broad and includes
those diseases that present with bleeding. The laboratory evaluation, however, usually
differentiates DIC from these other diseases.
1. Thrombocytopenia and normal coagulation tests In children, the main cause of

destructive thrombocytopenia is idiopathic thrombocytopenic purpura (ITP). It is differentiated
from DIC as patients with ITP have normal coagulation tests. In contrast to patients with DIC
who appear sickly, the vast majority of patients with ITP are well appearing besides findings of
petechiae and ecchymoses.
Hemolytic uremic syndrome (HUS), like DIC, presents with thrombocytopenia and
microangiopathic hemolytic anemia. Although in most patients with HUS, PT and aPTT are
normal, severe cases may have abnormal coagulation tests. In these patients, the history and
clinical setting are important to differentiate between the two conditions.
Neonate In the neonate, causes of consumptive thrombocytopenia without evidence of

other coagulation abnormalities include:
Alloimmune neonatal thrombocytopenia.
Maternal idiopathic thrombocytopenia.
Renal vein thrombosis.
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Bacterial and viral infections.
2. Abnormal coagulation tests and normal platelet count There are many conditions that
present with bleeding and have abnormal PT and aPTT but a normal platelet count. These
include genetic disorders of specific clotting factor deficiency (e.g., Hemophilia due to factors
VIII and IX deficiency), and are discussed elsewhere.
Hepatic failure and vitamin K deficiency have similar clinical findings as those with DIC but
have normal platelet counts. Bleeding from the latter is often seen in neonates who do not
receive prophylactic vitamin K at birth.
3. Normal coagulation tests and platelet count Children with disorders of platelet function
(eg, Glanzmann thrombasthenia), factor XIII deficiency, and fibrinolytic pathway defects (e.g.,
plasminogen activator inhibitor, PAI-1, deficiency) can present with bleeding diathesis but their
screening coagulation tests and platelet counts will be normal.
TREATMENT DIC is a serious complication of the underlying primary disease. As a result,

successful treatment of DIC is dependent on identifying and treating the underlying cause,
263
thereby removing the triggering factors implicated in the DIC process. In some cases, successful
treatment of the underlying cause will lead to resolution of DIC. In others, despite vigorous
therapy directed towards the primary disease, coagulation abnormalities persist resulting in
significant hemorrhage and/or thrombosis with organ damage. These patients have a high rate
of mortality, and as a result, commonly receive DIC supportive therapy.
There is no consensus on how supportive therapy should be used due to the paucity of data. In
general, supportive care is divided into component replacement and anticoagulation therapy.
Treatment is individualized based upon a patient's age, severity of clinical symptoms, underlying
primary disorder, and overall clinical status.
Replacement therapy There have been no randomized controlled trials to study the efficacy
of platelet, fresh frozen plasma (FFP), or cryoprecipitate transfusions in children or adults with
DIC. Nevertheless, the use of these agents seems rational in patients with significant bleeding
due to thrombocytopenia and clotting factor consumption.
Our approach for replacement therapy in patients with DIC is as follows:
Replacement therapy should not be routinely given to correct coagulation tests or in children
with mild clinical signs of bleeding (e.g., a few petechiae or positive guaiac test).
Replacement therapy is indicated in patients with significant bleeding symptoms (e.g., melena
or prolonged bleeding from venipuncture sites) or who are at high risk for bleeding because of
an impending invasive procedure.
The goal of replacement therapy is to reduce or stop significant bleeding. Although

replacement therapy should not be used to normalize laboratory tests (which often is
impossible), a reasonable guide for the judicious use of blood components in the setting of
significant bleeding includes maintaining platelet counts >50,000 per mm3 and fibrinogen
concentration >100 mg/dL (1 mol/L).
Clotting factors can be replaced by either FFP or cryoprecipitate. FFP provides both
procoagulant and anticoagulant proteins and is administered every 12 to 24 hours at a dose of
10 to 15 mL/kg per infusion. Cryoprecipitate has higher concentrations of factor VIII and
fibrinogen, and can be used to correct hypofibrinogenemia. It is administered every 6 hours as
needed at a dose of 10 mL/kg per infusion. Platelet transfusions are administered with a goal of
maintaining the platelet counts >50,000 per mm3.
Repeat transfusions may be necessary. The theoretical concern of replacement therapy

increasing thrombotic risk by "adding fuel to the fire" has not been demonstrated, and should
not dissuade the clinician from administering replacement therapy to control significant
bleeding.
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Anticoagulation Anticoagulation therapy can be divided into administration of extrinsic
anticoagulants (i.e., heparin) or restoration of endogenous anticoagulant proteins (i.e.,
antithrombin).
Heparin Although the administration of heparin to interrupt the underlying coagulopathy

would appear to be a logical therapeutic approach, there are no controlled trials that
demonstrate a benefit in children or adults with DIC. A major concern regarding the use of
heparin is its potential to aggravate bleeding. It is contraindicated in patients with CNS injury or
liver failure.
Heparin had been routinely used in patients with clinically overt thrombosis and potential end-
organ failure. However, there is little evidence that its use improved organ dysfunction. In most
cases of DIC, heparin infusion is not indicated. It is our practice to administer heparin only to
patients with life-threatening or symptomatic thrombi without clinical bleeding.
Once the decision is made to administer heparin, the dose of unfractionated heparin is 5 to 10
U/kg per hour by constant intravenous infusions. Low-molecular weight heparin (LMWH) has
been used in adults but there are no data to assess its effectiveness in children. Another note of
caution in using LMWH in children is the need to monitor Anti-Xa levels due to increased
metabolism of the medication.
Anticoagulant restoration The levels of both antithrombin and protein C are decreased in
DIC. It is reasonable to think that administration of these anticoagulants may have a beneficial
effect in management as restoration of these proteins may reduce microthrombus formation. In
addition to fresh frozen plasma, which provides anticoagulant and procoagulant factors, there
are specific protein C and antithrombin concentrates.
Protein C Protein C concentrate has been effective in the treatment of children with purpura
fulminans associated with congenital homozygous protein C.
Investigational therapy Recombinant human soluble thrombomodulin (ART-123), a new

agent which inactivates coagulation by binding to thrombin and activates protein C, is being
investigated in patients with DIC. A phase III clinical trial in Japanese patients greater than 15
years of age with DIC from infection or malignancy, showed promising results in comparison to
heparin therapy.
265
Treatment of hemophilia
W Keith Hoots, MD - Amy D Shapiro, MD
The optimal management of patients with hemophilia is complex, and requires the provision of
preventive care, the use of replacement therapy during acute bleeding episodes as well as for
prophylaxis, and the treatment of the complications of the disease and its therapy.
PREVENTIVE AND COMPREHENSIVE CARE Patients with hemophilia should receive

integrated care as soon as the diagnosis is made. Most children with severe disease present with
bleeding episodes within the first two years of life, although a few do not bleed before the age
of four.
Circumcision Approximately 50 percent of undiagnosed hemophilics bleed in association

with circumcision. For this reason, male infants born to known or suspected carrier mothers
should not be circumcised until hemophilia has been excluded. Assays can be performed on cord
blood; if it is not available, a sample can be obtained by venipuncture from a superficial limb
vein. Femoral, arterial, and jugular sites should be avoided.
Whether or not hemophilic children should be circumcised is an important social and

controversial problem for these families. The use of fibrin glue is safe, lessens the need for
factor substitution after circumcision, and markedly reduces the high cost of treatment.
Routine immunizations Routine immunizations, such as diphtheria-tetanus-pertussis or

measles-mumps-rubella, may be given in the deep subcutaneous tissue or via the usual route.
The smallest gauge needle should be used and pressure and ice applied to the site for three to
five minutes post injection.
Hepatitis B vaccine should be given to all infants with hemophilia as soon after birth as
possible, while hepatitis A vaccine is given after the age of one year. The live oral polio
attenuated vaccine is contraindicated in an infant when there is an immunocompromised
household member (e.g., HIV-infected hemophilic). In these instances, the Salk vaccine is
utilized.
Dental care Dental care is essential for individuals with congenital bleeding diatheses. Early
infant dental intervention is recommended to teach proper tooth brushing and ensure adequate
household water fluoridation. The teeth should be cleaned routinely, and anticipated problem
areas for causing bleeding should be discussed.
266
Counseling and education Genetic and psychosocial counseling is important for the family
with a newborn with hemophilia, especially for the approximately 30 percent for whom no
previous family experience with the disease exists.
REPLACEMENT THERAPY Clotting factor concentrates are given to prevent bleeding and to
limit existing hemorrhage. Dosing is reasonably standard, but the choice of product and the use
of primary and secondary prophylaxis require expert intervention.
Available products The initial strategy for improving replacement therapy for hemophilia
was to increase the concentration and purity of clotting factor concentrates, which permitted
home infusion therapy for bleeding episodes. With plasma fractionation, similar proteins
copurify.
Commercial fractionation of cryoprecipitate yielded the first generation of lyophilized factor

VIII concentrates. They resulted in an approximate 100-fold increase in concentration of factor
VIII over fresh frozen plasma, which contains a concentration similar to that in normal plasma.
However, plasma-derived concentrate therapy in the 1970s and 1980s was associated with
serious viral complications. Most patients became infected with hepatitis C virus (HCV), and HIV
infection occurred in up to 50 percent; coinfection with HCV and HIV is a concern because the
liver disease may have an accelerated course that typically does not respond well to treatment.
Factor VIII products Factor VIII products can be stratified based upon purity. Although
solvent-detergent-treated fresh frozen plasma is now safe from the viewpoint of viral
transmission, its main use now is in situations and countries in which appropriate concentrates
are unavailable.
Intermediate purity concentrates typically contain 6 to 10 U/mg protein.
High purity products are those with at least 50 U/mg protein (range 50 to 150 U/mg protein),
excluding albumin for stabilization.
Ultrahigh purity products are the monoclonal antibody affinity-purified plasma-derived factor
concentrates and the recombinant products. The specific activity of the monoclonal
preparations (prior to the addition of human serum albumin) is 3000 U of factor VIII per mg
protein. This concentration is essentially identical to the purity of the licensed recombinant
products, which should provide the means for the ultimate pure and safe products.
Plasma-derived concentrates Current production of plasma-derived clotting factor

concentrates requires a large starting pool of carefully screened donor plasma that is processed
to produce a clotting factor concentrate that is as pure as practical. Affinity chromatography
using monoclonal antibodies currently provides very pure plasma-derived products. Viral
inactivation procedures (pasteurization, solvent-detergent treatment, chemical disruption with
sodium thiocyanate, or ultrafiltration) are effective against HIV and hepatitis viruses.
267
Recombinant human factor VIII Collaborative clinical trials have demonstrated excellent
efficacy with the recombinant human factor VIII concentrates produced by two companies,
Baxter-Hyland-Immuno (Recombinate) and Aventis Bayer (Kogenate). In one multicenter trial,
for example, 92 percent of bleeding episodes responded as expected to Recombinate.
Second-generation recombinant factor VIII concentrates are without added albumin

(Kogenate-FS and Advate, Plasma/Albumin-free method), including a mutated protein lacking
the B domain (B-domain deleted recombinant human factor VIII, BDDrFVIII, r-VIII SQ, ReFacto)
in an albumin-free concentrate that is stabilized with sucrose. These products may provide a
higher level of confidence against any future microbiologic contamination.
Presently, the only available third-generation recombinant product (no added human or
animal proteins in the manufacturing process or final preparation) is Advate, Plasma/Albumin-
free method manufactured by Baxter. In one study, the mean half-life of this preparation in
individuals with hemophilia A 10 years of age was 12 hours, with a significant degree of
individual variation (range: 6.7 to 25 hours).
Choice of product The choice of factor VIII product usually is based upon safety, purity, and
cost. There is marked increase in the average wholesale price between cryoprecipitate and
recombinant concentrates, with the unit price increasing in proportion to the final product
purity.
Factor IX products As noted above, the use of prothrombin complex concentrates, which
contains factors II, VII, and X as well IX, are associated with a significant thrombogenic risk. For
this reason and with the advent of highly purified products, PCCs no longer are the preparation
of choice for patients with hemophilia B. Either a monoclonal or recombinant product is
preferred; these preparations are obligatory when high-dose recurrent infusion therapy is
required.
Purified factor IX Chromatographic partitioning and monoclonal antibody affinity

purification have been used to purify factor IX. Both of these products are further subjected to
viral inactivation processes, such as solvent-detergent, thiocyanate, and ultrafiltration. The
product produced by chromatographic partitioning contains minor residual plasma proteins,
whereas the monoclonal product is free of other plasma proteins. Viral attenuation to remove
HIV and hepatitis is effective for both processes. However, studies using surrogate viruses may
imply greater safety from hepatitis C or similar viruses with the monoclonal factor IX
concentrate.
Recombinant factor IX Recombinant factor IX has been genetically engineered by insertion

of the human factor IX gene into a Chinese hamster ovary cell line. It has been proven to be safe
and effective in the treatment of patients with previously treated and previously untreated
hemophilia B, with a half-life of 16 to 17 hours. The product has no added albumin, giving it a
theoretical advantage over plasma-derived concentrates. The volume of distribution of
268
recombinant FIX is larger than that for plasma-derived FIX, with a more pronounced increase in
infants and children.
Dosing Early treatment of bleeding episodes with appropriate dosing decreases the duration
of required therapy and the predisposition to rebleeding, and improves the quality of life.
One international unit (IU) of clotting factor is that amount present in 1 mL of pooled normal
plasma. Thus, on average, a normal individual with a plasma volume of 3000 mL would have
3000 IU of each clotting factor in his or her circulation. Provided all of the infused dose of the
clotting factor is delivered to the plasma, a dose of 3000 IU of factor VIII would be required to
raise the plasma level to normal (i.e., 100 percent = 1 IU/mL) in a patient with severe disease
and baseline levels of less than 1 percent of the normal concentration of factor VIII.
In practice, however, the number of units required depends upon body weight (kg), the volume
of distribution, and the desired factor level. The volume of distribution for factor VIII is
approximately 0.5; in comparison, recombinant human factor IX (ie, monoclonal factor IX) has a
volume of distribution that is approximately 1.0 to 1.2, which is larger than the value of 1.0 for
the native protein. The difference in volume of distribution is primarily caused by a difference in
charge conferred by decreased or absent phosphorylation and sulfation at two sites compared
to the plasma species.
Desired factor levels The desired factor level is a function of severity and location of the
bleeding episode.
Early joint or muscle bleeding episodes are treated to achieve factor levels of 30 to 40
percent. The usual hemarthrosis typically responds to a single injection if treated early.
Patients with more severe muscle hematomas and those undergoing dental surgery usually
are treated to achieve levels of 50 percent. Oral antifibrinolytic therapy is used to reduce the
use of concentrates in patients undergoing dental procedures or those with oral mucous
membrane bleeding. Desmopressin also can be used in combination with antifibrinolytic
agents to raise plasma concentrations of von Willebrand factor and factor VIII in patients with
mild hemophilia.
Severe or potentially serious episodes such as intracranial or intraabdominal hemorrhage or

bleeding in areas such as the face, neck, and hip require correction to 80 to 100 percent for
longer periods of time, usually until the hemorrhage has resolved.
Most orthopedic surgery can be managed with initial levels of 80 to 100 percent followed in a
few days by minimum levels of at least 30 percent; an exception occurs at times of wound or
joint manipulation when a level of at least 50 percent is necessary.
To achieve hemostasis for major surgical procedures, an initial level of 60 to 100 percent is
achieved. This level is followed by a prophylactic level of 30 to 50 percent until the wound is
healed, typically 10 to 14 days.
269
Factor levels should be checked to ensure the effectiveness of the calculated dose. The half-life
of recombinant human factor VIII is approximately 8 to 12 hours. For this reason, doses are
repeated on a 12-hour basis and assays are performed near the end of the 12-hour period.
Recombinant factor IX has a half-life of about 16 to 17 hours, the same as the native protein.
Concentrates also can be given by continuous infusion. A continuous infusion of factor VIII
concentrate at a dose of 2 to 4 U/kg per hour will often maintain the level initially achieved by
bolus infusion. This method offers the advantage of consistent levels, less frequent monitoring,
and decreased factor utilization. A similar effect has been noted with factor IX concentrates.
Patients undergoing major surgery or those with major hemorrhage at risk of rebleed may
benefit from such continuous therapy.
Calculating the required dose
Factor VIII replacement As noted above, it has been found that, on average, IV
administration of 0.5 international units (IU)/kg of body weight of factor VIII will increase
circulating factor VIII levels by ~1 IU/dL (i.e., 1 percent). Although dosing should be
individualized for each patient and for each product employed, one can estimate the dose
required to raise the factor VIII concentration by a specified amount according to the following
formula:
Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5
As an example, if it is desired to increase the factor VIII level by 30 percent (eg, from zero to 30
percent or from 10 percent to 40 percent) in a patient weighing 50 kg, the required IV dose is
750 IU.
Factor IX replacement IV administration of 1.0 to 1.2 IU/kg of body weight of factor IX will
increase circulating factor IX levels by 1 percent. Although dosing should be individualized for
each patient and differs for each preparation used, one can estimate the dose required to raise
the factor IX concentration by a specified amount according to the following formula:
Dose of F IX (IU) = Weight (kg) x (Desired % increase) x F
(F = 1.0 for AlphaNine and Mononine; F= 1.2 for BeneFix in adults and 1.4 in children)
As an example, if it is desired to increase the factor IX level by 80 percent (e.g., from zero to 80
percent or from 20 percent to 100 percent) in an adult patient weighing 70 kg, the required IV
dose is 5600 IU for AlphaNine or Mononine or 6720 IU when using BeneFix.
Prophylactic therapy The regular administration of replacement therapy with the aim of
reducing spontaneous bleeding is a logical approach to the treatment of severe hemophilia. The
goal of such an approach is to maintain the factor VIII or IX level above 1 percent, which should
270
convert the patient to a moderate phenotype. This level can be achieved by factor concentrate
administration two to three times per week.
Several studies have shown that primary prophylaxis starting during the early years of life can
markedly reduce the risk of subsequent arthropathy. This approach has been used extensively in
parts of Europe, particularly in Sweden and has been accepted by the Medical and Scientific
Advisory Council of the National Hemophilia Foundation as the optimal treatment modality for
patients with severe hemophilia.
THERAPIES OTHER THAN FACTOR REPLACEMENT The two therapeutic options in addition to
factor replacement are desmopressin and antifibrinolytic agents.
Desmopressin Patients with mild hemophilia A can often be treated with desmopressin
(dDAVP), a synthetic analogue of vasopressin (antidiuretic hormone) that lacks pressor activity.
In such patients, desmopressin increases circulating factor VIII levels two to four times above
baseline, via release from endothelial storage sites, and as much as four to six times above
baseline in those who begin with factor VIII levels more than 9 percent of normal. In another
report, factor VIII levels adequate for hemostasis were attained in 82 percent of patients with
mild hemophilia or hemophilia A carriers. As a result, it is the treatment of choice for mild to
moderate bleeding in most individuals with mild hemophilia A, similar to certain types of von
Willebrand disease.
Desmopressin can be administered intravenously, by subcutaneous injection, or by intranasal

spray. When given intravenously for prophylaxis before invasive procedures or for acute
bleeding episodes, a dose of 0.3 g/kg (maximum 20 g) is diluted in 50 mL of normal saline and
infused over 20 to 30 minutes; the same dose is given with subcutaneous therapy with no single
injection exceeding a dose of 1.5 mL. An increase in factor VIII levels is expected to occur at
approximately 30 to 60 minutes after the infusion, and the response persists for 6 to 12 hours. A
repeat dose may be given at 12 hours, and subsequent doses often are switched to once daily
dosing.
The response to 300 g of intranasal spray (150 g/mL) is approximately equivalent to that
seen with an intravenous dose of 0.2 g/kg [74] . The usual dose is one puff (150 g) in patients
weighing less than 50 kg and two puffs in heavier patients.
Side effects of desmopressin include vasodilatation that causes facial flushing, headache (which
can often be controlled by decreasing the rate of infusion), and occasional tingling. Both
hypotension and hypertension have been reported but are not common and usually are mild.
Tachyphylaxis occurs after repeated administration because of depletion of endothelial stores.
Thus, the response should be monitored in individuals who require repeated dosing (e.g., daily
or more often). Another problem is that the persistent antidiuretic activity can lead to water
271
retention and possibly serious hyponatremia. As a result, doses often are limited to once daily
after the first day, water intake is restricted, and the serum sodium concentration is monitored.
Antifibrinolytic therapy Tranexamic acid and epsilon aminocaproic acid (EACA) inhibit
fibrinolysis by inhibiting plasminogen activation in the fibrin clot, thereby enhancing clot
stability. They are useful therapeutic adjuncts to stabilize clots in areas of increased fibrinolysis,
such as the oral cavity, and in patients with difficult episodes of epistaxis and menorrhagia.
The usual dose of tranexamic acids is 25 mg/kg per dose every six to eight hours, whereas the
usual dose of EACA is 75 to 100 mg/kg per dose every six hours (maximum single dose 3 to 4 g).
Both drugs can be administered orally or intravenously. When given orally, they must be given
three or four times over a 24-hour period because of their short half-lives.
Treatment with these drugs may be required for 7 to 14 days after initial infusion therapy,
depending upon the amount of tissue injury. In patients with hemophilia B, a purified factor IX
preparation should be used when antifibrinolytic therapy is given to avoid the additive
thrombotic risks of these drugs with prothrombin complex concentrates.
Other adjunctive therapies include the use of microfibrillar collagen, especially for bleeding in
the oral cavity, and fibrin glue, which, as noted above, has been used for bleeding following
circumcision.
ACUTE THERAPY ACCORDING TO SITE OF BLEEDING Acute therapy varies in part with the
site of bleeding. Treatment of such episodes also may require pain management, less often the
use of corticosteroids, and surgery.
Hemarthrosis of peripheral joints Patients with hemarthroses of peripheral joints (knees,

elbows, ankles) often can be treated at home, and home infusion training should be begun as
soon as possible after diagnosis to permit the benefits of early factor replacement with acute
episodes. At the first indication of bleeding, the patient or parent should infuse clotting factor at
a dose that achieves a level of 40 to 50 percent.
When a joint undergoes repeated hemorrhage, it is called a target joint. A short course of
corticosteroids can be used to reduce the pain and swelling associated with synovial
inflammation in a target joint. Prednisone or its equivalent is given for a three to five day period
at a dose of up to 60 to 80 mg/day for three days and 40 mg/day for two days. Joint aspiration is
used infrequently to remove blood and relieve pain. Clotting factors should be raised to at least
50 percent of normal before aspiration.
Enforced rest and splinting are used early. They should be followed by a program of active
range of motion and strengthening exercises with resolution of acute symptoms. Aspirin and
other nonsteroidal antiinflammatory drugs are contraindicated in patients with hemophilia.
Pain should be treated with acetaminophen, propoxyphene, and codeine.
272
In addition to these acute approaches to a target joint, the patient should be placed upon
short-term prophylaxis with factor administration three to four times per week for several
weeks to months.
Hemarthrosis of the hip and iliopsoas bleeds Hip joint or acetabular hemorrhages may
result in increased intraarticular pressure and osteonecrosis (aseptic necrosis) of the femoral
head. Twice-daily infusion therapy designed to sustain a factor level above a minimum of 20
percent for at least three days should be given, along with enforced bed rest.
Compartment syndrome Closed compartment muscle and soft tissue hemorrhages, often in
the upper arm, forearm, wrist, volar hand, and anterior or posterior tibial compartment, may
result in impingement on the neurovascular bundle. Swelling and pain precede tingling,
numbness, and loss of distal arterial pulses. Surgical decompression is undertaken only if
medical therapy fails to forestall progression, and in consultation with a Comprehensive
Hemophilia Treatment Center.
Severe hemorrhage and head trauma An acutely hemorrhaging hemophilic patient should
be transported, if possible, to an emergency center that stocks appropriate replacement
products. For life-threatening bleeding, the factor level should be maintained at levels greater
than 50 percent of normal. All head injuries must be considered nontrivial unless proved
otherwise by observation and CT/MRI imaging.
Late bleeding after head trauma can occur up to three to four weeks following the event. For
this reason, patients with head and neck injuries should be infused immediately unless the
injury is clearly insignificant. Nonhospitalized patients and their families should be instructed
about the neurologic signs and symptoms of central nervous system bleeding so that repeat
infusion, clinical and radiological assessment, and hospitalization occur at the earliest
manifestation of bleeding.
LONG-TERM COMPLICATIONS The major long-term complications of hemophilia are chronic

hemarthrosis with joint destruction and infections transmitted by clotting factor concentrates.
Chronic hemarthrosis As mentioned previously, short-term prophylaxis three to four times

per week for several weeks to months in patients with target joints can slow the rate of joint
deterioration.
Synovectomy is another treatment modality for selected patients. Synovectomy can be

achieved through an open procedure, arthroscopically, or by injection of a radioactive material
into the joint. Radioactive synovectomy is indicated in patients with inhibitors to the clotting
factor, advanced HIV infection or hepatitis, or multiple joint involvement.
Hepatitis C virus and end stage liver disease Most hemophilic patients treated with older
factor VIII and factor IX concentrates were infected with hepatitis C virus (HCV), and HIV
infection occurred in up to 65 percent. The continued high prevalence of anti-HCV in this
273
population is because of past exposure, because new cases related to factor administration are
rare with the new preparations.
GENE THERAPY A number of approaches are possible in attempting to employ gene therapy
for the hemophilias.
Ex vivo gene therapy in which cells from the intended recipients are explanted, genetically
modified to secrete factor VIII or IX, and reimplanted into the donor.
In vivo injection of factor VIII or IX encoding vectors into the recipient. Vectors incorporating
factor VIIa, a protein to which factor VIII-deficient and factor IX-deficient subjects have
immunologic tolerance, have also been employed.
Nonautologous therapy in which universal cell lines are enclosed in immunoprotective devices
before implantation into the recipient.
The goal of therapy does not have to be restoration of normal factor levels; conversion from a
severe (factor VIII <1 percent) to a mild phenotype (factor VIII >5 percent) would be sufficient to
produce dramatic improvement. However, issues of sustained levels of factor delivery,
neutralizing antibody response, T-cell response to the viral insertion vector, safety, and cost
remain to be resolved for all of these approaches.
274
Treatment and prognosis of immune (idiopathic)
thrombocytopenic purpura in children
C Philip Steuber, MD
Immune (idiopathic) thrombocytopenic purpura (ITP) of childhood is characterized by

acquired thrombocytopenia and is a generally benign disorder of unknown cause. ITP is also
referred to as autoimmune thrombocytopenic purpura or isoimmune thrombocytopenic
purpura.
The management of children with ITP is the subject of much debate because it is unclear
whether "watchful waiting" or pharmacologic intervention provides the most appropriate care
for affected children.
INITIAL MANAGEMENT
Supportive care Regardless of whether pharmacologic therapy is used, restriction of activity

(especially contact sports) should be recommended in all children with ITP. In addition,
medications with antiplatelet activity (including aspirin-containing preparations, ibuprofen and
other non-steroidal anti-inflammatory drugs) or those with anticoagulant activity should be
avoided.
Pharmacologic intervention As previously noted, there are limited data on the use of
pharmacologic intervention in children with ITP.
The presence of one or more of the following factors is used as an indication for pharmacologic
intervention:
1. Presence of severe or life-threatening bleeding.

2. Risk of significant bleeding, such as a child undergoing a procedure that is likely to induce
blood loss.
3. Any concomitant or preexisting condition that increases the risk of thrombocytopenia or
bleeding (e.g., hemophilia).
In randomized trials of children with ITP, prednisone therapy has been shown to more rapidly
increase platelet counts than placebo.
A variety of dose regimens have been used ranging from prednisone at a dose of 2 mg/kg per
day for two to four weeks, to high pulse doses of intravenous or oral methylprednisolone (50
mg/kg per day) for three to seven days. Some evidence suggests that time of response and rate
of response are dose-related, but comparative studies among the multiple regimens are few and
involve only small numbers of patients.
The following three steroid regimens are commonly used:
275
1. Prednisone 1 to 2 mg/kg (maximum dose 60 mg) per day in 3 divided doses for 14 days
followed by a week of tapering
2. Prednisone 4 mg/kg per day divided into 3 doses for four days .
3. Methylprednisolone 30 mg/kg per day intravenously for 3 days.
Repeat courses may be given for patients with persistent, recurrent, or chronic disease.
IVIG Steroids were the only therapy used for children presenting with acute ITP until
1981,when the successful use of intravenous immunoglobulin (IVIG) in children with ITP was
first published.
The exact mechanism of action is unknown and is likely multifactorial, and could involve the
following:
1. Competitive inhibition or steric hindrance of autoantibody adsorption to the patient's

platelets.
2. Prevention of reticuloendothelial uptake of autoantibody-coated platelets directly
through blockade of macrophage Fc-receptors, or indirectly by activating Fc-receptors
on dendritic cells.
3. Interaction of the autoantibodies with anti-idiotype antibodies in the IGIV.
Regardless of its mechanism of action, IVIG appears to more reliably improve platelet
numbers in patients with ITP than corticosteroids or no treatment
Reported dose regimens for children with ITP range from 400 mg/kg per day for five days to a
single dose of 1000 mg/kg. A single dose regimen appears to be preferable.
Side effects of IVIG include flu-like symptoms, such as nausea and vomiting (63 percent),
headache (56 percent), or fever (19 percent). Adverse effects tend to be more pronounced in
older patients. Neutropenia (absolute neutrophil count less than1500/microL) develops in about
30 percent of patients.
Anti-Rho(D) immune globulin Based upon the premise that IVIG acts in part by producing
antibody-coated red cells that block antibody-coated platelets sequestration by the
reticuloendothelial system, trials were conducted to study the effect of anti-Rho(D)
immunoglobulin [anti-Rho(D) Ig] in patients with ITP who were Rho(D)-positive.
Anti-Rho(D) Ig has been shown to be effective in the treatment of children with ITP and with
higher doses appears to have comparable results to IVIG. However, anti-Rho(D) Ig is associated
with an increased incidence of significant hemolysis.
Platelet transfusions The only indication for platelet transfusions is life-threatening

hemorrhage, such as intracranial hemorrhage. Larger-than-normal doses are required because
normal doses are ineffective due to platelet destruction.
276
Life-threatening bleeding Life-threatening bleeding is rare. Although intracranial
hemorrhage (ICH) has an incidence of only 0.1 to 0.5 percent, it is the most serious consequence
of ITP. The presence of significant headache should prompt careful evaluation for any other
neurologic signs, and early diagnostic imaging should be considered to identify ICH.
If ICH or any other life-threatening hemorrhage occurs, immediate intervention should be

given to the affected patient. In our institution this includes the following;
Platelet transfusions.
IVIG 1000 mg/kg per day for two days.
Methylprednisolone 30 mg/kg per day administered intravenously for three days.
For ITP patients with unstable or progressive ICH, emergency craniotomy may be necessary.
Emergency splenectomy may be considered in selected clinical situations but only as a last
resort.
CHRONIC ITP Approximately 20 to 30 percent of children who present with ITP will have
chronic ITP, defined as persistent thrombocytopenia (platelet count less than 150,000/microL)
beyond six months from the time of presentation.
Individuals with chronic ITP should undergo evaluation to exclude other causes of
thrombocytopenia, such as chronic infections (including HIV), bone marrow failure, collagen
vascular disorders, and other autoimmune or immunodeficiency disorders. Studies should
include viral antibody titers, bone marrow examination, and studies for collagen vascular
disorders (eg, antinuclear antibody test).
Management In up to one-third of children with chronic ITP, spontaneous remission will

occur months or even years later. Children younger than 10 years of age are more likely to
remit than older patients and treatment is usually not necessary. Children older than 10 years of
age, especially adolescent females, have a disease course more like that seen in adults with ITP
and should be treated in a similar manner.
In chronic ITP, platelet counts tend to range between 20,000 and 75,000/microL; consequently,
many patients will require no treatment. It is very uncommon for an individual with chronic ITP
to have a platelet count less than 10,000/microl.
Pharmacologic therapy In children with chronic ITP, pharmacologic therapy usually is used
when patients have significant bleeding, or require surgery or dental extraction. Adolescent girls
may have excessive bleeding during their menses and may require therapeutic intervention.
Therapy generally raises the platelet count temporarily.
Pharmacologic options are similar to those used in the initial management of patients with ITP
at presentation.
277
Splenectomy A small percentage of patients with chronic ITP will have persistent significant
hemorrhagic symptoms and require repeated, sometimes almost continuous, pharmacologic
interventions. For such patients, the risks and benefits of splenectomy must be considered.
Splenectomy is effective in improving the platelet count and reducing the associated risk of
bleeding in 60 to 90 percent of children with chronic ITP. No universally accepted standards for
the timing of splenectomy in chronic ITP exist, but the American Society of Hematology
guidelines recommend waiting until at least 12 months after diagnosis, if possible. When
possible, surgery should be performed using laparoscopic techniques.
The anticipated improvement in hemostasis and platelet count must be balanced with the
small risk of overwhelming post-splenectomy infection, which may be life-threatening. Because
of the high infection rates in younger asplenic individuals, temporizing therapies are especially
important for patients younger than 4 to 5 years of age with chronic ITP. Presplenectomy
immunizations and subsequent penicillin prophylaxis are necessary for all age groups.
Treatment of refractory chronic ITP Approximately 25 to 30 percent of children with chronic

ITP have ongoing hemorrhagic problems after splenectomy. In these cases, evaluation should
identify any possible accessory spleen, which should be removed, if present.
Rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, may be useful in

treating both primary and secondary refractory chronic ITP in children
278
Nephrology
Nephrotic syndrome in children

Patrick Niaudet, MD
The nephrotic syndrome is caused by renal diseases that increase the permeability across the
glomerular filtration barrier. It is classically characterized by four clinical features, but the first
two are used diagnostically because the last two may not be seen in all patients:
Nephrotic range proteinuria Urinary protein excretion greater than 50 mg/kg per day
Hypoalbuminemia Serum albumin concentration less than 3 g/dL (30 g/L)
Edema
Hyperlipidemia
DIAGNOSIS
The diagnosis of nephrotic syndrome is made by fulfilling the following two defining
characteristics:
Urinary protein excretion greater than 50 mg/kg per day
Hypoalbuminemia
Although, edema is generally the presenting sign of nephrotic syndrome, the diagnosis is
confirmed by the presence of nephrotic range proteinuria and hypoalbuminemia.
Urine tests
Urine protein excretion Nephrotic range proteinuria in children is defined as urinary protein
excretion greater than 50 mg/kg per day or 40 mg/m2 per hour.
However, it is difficult to obtain accurately timed urine collections in young children.
An alternative method of quantitative assessment of urine protein excretion is measurement

of the total protein/creatinine ratio on a spot urine sample.
The ratio that is indicative of nephrotic range proteinuria is greater than 0.2 mg protein/mg
creatinine (20 mg protein/mmol creatinine).
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Urinalysis The urinary dipstick measures albumin concentration via a colorimetric reaction
between albumin and tetrabromophenol blue. It measures protein concentration rather than
the rate of protein excretion and therefore cannot be used to make the diagnosis of nephrotic
syndrome. However, in most patients with nephrotic syndrome, the urinary dipstick
demonstrates a high albumin concentration (3+ to 4 +, 300 to >1000 mg/dL). Thus, it is often
used as a screening test while awaiting confirmation by quantitative protein excretion studies.
Patients with idiopathic nephrotic syndrome have relatively inactive urine sediment (i.e., oval
fat bodies and hyaline casts but few red cells and no red cell or other cellular casts). Hematuria
is commonly seen in patients with glomerulonephritis but does occur in focal segmental
sclerosis (FSGS) and, less often, minimal change disease (MCD).
Blood tests
Serum proteins Hypoalbuminemia is one of the criteria that defines nephrotic syndrome.
The serum albumin is typically below 3 g/dL (30 g/L) and can be as low as 1 g/dL (10 g/L).
Lipids Hyperlipidemia is a characteristic feature of nephrotic syndrome. Serum total

cholesterol, triglycerides, and total lipids are elevated. The increase in cholesterol is inversely
correlated to the serum albumin concentration.
Estimation of GFR In stable patients, the glomerular filtration rate (GFR) is estimated from
the serum creatinine. The serum creatinine is elevated in 30 to 40 percent of patients with MCD
at presentation, due at least in part to hypovolemia.
Other studies
Complete blood count Hemoglobin and hematocrit may be increased in children with
nephrotic syndrome, particularly MCD, as a result of plasma volume contraction.
Thrombocytosis is common and platelet counts may reach 500,000 to 1 million counts/microL.
Hemoconcentration and thrombocytosis may contribute to hypercoagulability and thrombotic
complications.
Complement studies Serum complement testing can be useful in the diagnosis of a specific
renal or systemic disease that presents with nephrotic syndrome. Low C3 levels are typically
seen in patients with membranoproliferative glomerulonephritis (MPGN) and postinfectious
glomerulonephritis, while both low C3 and C4 are seen in patients with lupus nephritis. Serum
complement is normal in patients with idiopathic nephrotic syndrome.
Hyponatremia can be present due to decreased free water excretion, resulting from
hypovolemic stimulation of the release of antidiuretic hormone (ADH).
Clinical experience has demonstrated that the response to steroid therapy rather than the
histologic features seen on renal biopsy is better at predicting long-term prognosis.
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Patients who respond to steroids have an excellent prognosis and rarely develop end stage
renal failure. As a result, patients with NS can be defined by their response to steroid therapy as
follows:
Steroid-sensitive NS More than 90 percent of patients who respond to steroid therapy have
MCD, and FSGS is seen in the remaining patients.
Steroid-resistant NS One-fourth of patients who fail to respond to steroids will have MCD.
Patients who fail an initial course of steroid should undergo renal biopsy to determine the
underlying diagnosis to guide further therapeutic choices.
INITIAL PHARMACOLOGIC THERAPY Empiric steroid therapy can be initiated in patients with
a high probability of having minimal change (MCD) without confirmation of the diagnosis by
renal biopsy because more than 90 percent of patients with MCD will respond to corticosteroid
therapy within eight weeks. Initial steroid therapy is given to patients who fulfill all of the
following criteria.
Age older than 1 year and younger than 10 years of age
None of the following findings: hypertension, gross hematuria, and a marked elevation in serum
creatinine
Normal complement levels
No extra-renal symptoms such as malar rash or purpura
Although steroid therapy is often started immediately following the diagnosis of NS, it should
be stressed that spontaneous remission occurs in 5 percent of cases within one or two weeks.
Therefore, the initiation of steroid therapy may be delayed for a few days or a week.
Steroid response Idiopathic NS is steroid-responsive in most children. Approximately 30

percent of treated patients will not have a relapse and are therefore cured after the initial
course of therapy. Ten to 20 percent will relapse several months after steroid treatment is
discontinued, but will have less than four steroid-responsive episodes before permanent
remission occurs. However, 30 to 40 percent of patients will have frequent relapses, defined as
four or more relapses per year, and some patients will relapse while on steroid therapy
(referred to as steroid dependent).
Based upon the currently available data, we initially treat children with idiopathic NS who are
likely to have minimal change disease with oral prednisone at a dose of 60 mg/m2 per day
(maximum of 60 mg/day). When proteinuria disappears, prednisone is continued at the same
dose for 30 days and the patient is then switched to alternate day therapy (at the same daily
dose) for two months. Thereafter, the alternate day dose is decreased every two weeks by 15
mg/m2. The net effect is that the total duration of initial therapy is 4.5 months.
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Time to response In a report from the International Society of Kidney Disease in Children
(ISKDC), approximately 90 percent of patients who will respond to steroids do so within four
weeks after starting steroids, with the remaining 10 percent going into remission after two to
four more weeks of a daily steroid therapy.
In our practice, among patients who are not in remission after four weeks of daily steroid
therapy, we administer three pulses of methylprednisolone (1000 mg/1.73 m2) every other day.
Patients who have persistence of proteinuria one week after this treatment are considered
steroid resistant. A renal biopsy is performed in these patients with steroid resistant NS, as
there is increased likelihood that they have another glomerular disease. No additional steroid
therapy is administered until a histologic diagnosis is made, which aids in making therapeutic
choices.
Other options in those who are not in remission after four weeks of daily steroid therapy
include the following:
Biopsy patients without administering the three pulses of methylprednisolone, as there is an

increased likelihood that they have another glomerular disease that may not be responsive to
additional steroid therapy.
Continue daily steroid therapy for another four weeks because an additional 10 percent of
steroid responsive patients will respond after four weeks of therapy. However, prolongation of
daily steroid treatment beyond an initial four to five weeks to a maximum of eight weeks
increases the risk of side effects from steroid therapy. Patients who fail to respond to a
maximum eight weeks of daily steroid therapy are considered steroid resistant and require a
renal biopsy to determine the underlying glomerular disease.
Monitoring Once a patient responds to steroid therapy, monitoring for proteinuria is

required to detect relapses early and initiate therapy to prevent significant fluid accumulation
(edema) and minimize the complications associated with childhood idiopathic NS.
Patients and their parents are taught to frequently measure body weight and monitor urine
protein levels by urine dipstick. Increased urinary protein concentration typically provides the
first indication of a relapse. When this occurs, the family should call their health care provider
for instructions regarding management.
Initial relapse With the first few relapses, steroid therapy is typically administered at a dose
of 60 mg/m2 per day (maximum of 60 mg/day). The length of steroid therapy varies among
pediatric nephrologists. In our practice, daily prednisone is given until proteinuria has
disappeared for four to five days. Alternate day therapy is then begun and the dose tapered to
15 to 20 mg/m2 every other day according to the patient's steroid threshold.
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Frequent relapsing/steroid dependent nephrotic syndrome Two different steroid regimens
have been used to treat patients with frequent relapses and/or are steroid dependent:
The International Study of Kidney Disease in Children (ISKDC) recommends a prednisone dose
of 60 mg/m2 per day (maximum of 60 mg/day) be initiated when a patient has relapsed and is
continued for three days after the urine has become protein free; thereafter, alternate day
prednisone, 40 mg/m2, is given for four weeks.
Another approach recommends treatment of relapses with daily prednisone, 40 to 60 mg/m2,

until proteinuria has disappeared for four to five days. Alternate day therapy is then begun and
the dose tapered to 15 to 20 mg/m2 every other day according to the patient's steroid threshold
(i.e., the dose at which the relapse has occurred). This regimen is continued for 12 to 18 months.
The first regimen allows better definition in terms of relapses, but is associated with more
relapses because of the shorter duration of therapy resulting in larger cumulative steroid dose.
We recommend the second approach, which is associated with fewer steroid side effects, as the
duration of high-dose therapy is shorter.
Alkylating agents Alkylating agents, such as cyclophosphamide and chlorambucil, can induce
longer lasting remissions than prednisone alone in patients who are frequent relapsers or
steroid dependent.
We administer a 12-week course of oral cyclophosphamide at a dose of 2 mg/kg per day

(cumulative dose 168 mg) to patients with steroid dependency who have evidence of steroid
toxicity. The maximum daily dose should not exceed 2.5 mg/kg.
Similar efficacy can be achieved with chlorambucil. The recommended dose is 0.2 mg/kg for
two months. Higher daily doses give similar results but have a greater risk of side effects. As with
cyclophosphamide, the likelihood of long-lasting remission is greater in frequent relapsers than
in steroid-dependent children.
Side effects Complications associated with the use of alkylating agents include the following:
Neutropenia and infection Bone marrow suppression by alkylating agents requires

monitoring complete blood cell counts (CBC). If the white cell count falls below 3000/mm3, the
drug should be withdrawn until the count rises. Treatment also should be discontinued if
infection develops. There are reported cases of significant morbidity and mortality associated
with varicella and the administration of cyclophosphamide. If varicella infection occurs, acyclovir
should be administered immediately and the alkylating agent discontinued.
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Gonadal toxicity The development of gonadal toxicity resulting in infertility generally
requires a total dose greater than 200 to 300 mg/kg for cyclophosphamide, which exceeds the
recommended cumulative dose (168 mg/kg for cyclophosphamide). The gonadal toxicity
threshold for chlorambucil is 8 to 10 mg/kg.
Malignancy There is a single reported case of malignancy (acute lymphoblastic leukemia)

associated with cyclophosphamide administered in a child with NS using the above
recommended regimen. The extensive use of this regimen of cyclophosphamide in children with
NS and only a single reported associated case of malignancy suggest that there is not a clinically
significant increased risk of malignancy compared to the general pediatric population with
cyclophosphamide at the recommended dosage for treatment of childhood NS.
Alopecia and hemorrhagic cystitis rarely occur at the recommended doses used to treat
children with NS.
Seizures Chlorambucil has been associated with an increase risk of seizures in children with
NS.
Other therapies Other drugs, such as levamisole, cyclosporine, and mycophenolate mofetil,
have been tried in frequently relapsing or steroid-dependent children with idiopathic NS.
Levamisole Levamisole, which stimulates the immune system, has been shown to have a
steroid-sparing effect in children with steroid-sensitive NS. The British Association for Paediatric
Nephrology performed a multicenter study in which 61 children received either levamisole (2.5
mg/kg on alternate days to a maximum dose of 150 mg) or placebo. Fourteen patients in the
levamisole group and four in the control group were still in remission after four months despite
prednisone withdrawal. However, most patients relapsed within three months after cessation of
treatment.
Regular blood counts should be performed, as the most serious side effect of levamisole is
reversible neutropenia, which occurred in 3 of 140 patients.
Cyclosporine Cyclosporine is effective in inducing or maintaining remission in patients with

frequently relapsing or steroid-dependent NS.. The recommended dose is 150 mg/m2 per day in
two oral doses. The dose may be adjusted to maintain trough whole blood levels between 100
and 200 ng/mL, but the level should not exceed 200 mg/m2.
STEROID-RESISTANT NEPHROTIC SYNDROME Some children fail to respond to initial

steroid treatment. A renal biopsy and screening for genetic disorders should be performed in
this setting, as the underlying pathology or a detection of a genetic disorder may affect
therapeutic choices.
Screening and treatment Because immunosuppressive therapy has not been shown to be
effective in treating children with SRNS due to NPHS2, NPHS1, or WTI mutations, identifying
these patients can avoid unnecessary exposure to these medications and their side effects.
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Thus, screening for such mutations should be performed in those with a familial history of SRNS
and children with steroid-resistant disease.
Alkylating agents There are no data showing a beneficial effect of alkylating agents in
children with SRNS. Partial or complete remissions have been reported in 20 percent of cases
following a course of cyclophosphamide, but this is similar to the remission rate of nontreated
patients or those who continue to receive steroid therapy alone.
In patients with SRNS caused by genetic disorders, we do not administer additional

immunosuppressive therapy because it is not effective and has significant adverse effects.
Although data are lacking in children, we treat these patients with persistent proteinuria with
ACE inhibitors or ARBs.
The optimal approach to SRNS not associated with a genetic disorder is uncertain. We initially
use a combination of cyclosporine and prednisone in children with steroid-resistant minimal
change disease or FSGS, provided they have normal glomerular filtration rate. In addition, we
treat children with refractory NS and persistent proteinuria with ACE inhibitors or ARBs, and
symptomatic therapy.
SYMPTOMATIC TREATMENT Symptomatic treatment is used in conjunction with

pharmacologic therapy. It is important in the early course of therapy as response to steroid
therapy may take several weeks. Symptomatic treatment also becomes the mainstay of therapy
in children who fail to respond to steroids, especially those with genetic mutations that cause
their NS.
Edema
Salt restriction Edema is treated by salt restriction because renal retention of sodium is one
of two principal mechanisms that leads to edema in the NS.
Diuretics Although diuretics are commonly used in adults with NS, their role in often
severely hypoalbuminemic children is less clear. Affected children may be intravascularly
volume depleted and aggressive diuresis may lead to further volume depletion, thereby possibly
precipitating acute renal failure and increasing the risk of thrombosis in this already susceptible
group of patients. Rarely, diuretics can contribute to severe volume depletion that results in
hypovolemic shock.
Diuretics should only be given in cases of severe edema and only if there is not significant
intravascular volume depletion. Patients with anasarca may be treated with furosemide (1 to 2
mg/kg per dose) in combination with salt-poor albumin (0.5 to 1 g/kg infused over four hours).
Albumin raises the intravascular oncotic pressure and thereby protects the intravascular
compartment against volume contraction. Albumin infusion also increases protein-binding of
furosemide, which improves the rate of delivery to the kidney resulting in increased renal salt
excretion
285
In a retrospective study, albumin and furosemide therapy in children with NS effectively
removed fluid with a mean loss of 0.4 kg (1.2 percent of body weight) per infusion.However, the
effect is transient and can be associated with complications resulting from increased vascular
volume including hypertension and respiratory distress. As a result, aggressive diuresis with
albumin and furosemide therapy should be reserved for patients with anasarca who have
respiratory compromised due to ascites and/or pleural effusions, severe scrotal edema
sufficient to threaten perforation, peritonitis, or severe tissue breakdown.
Fluid restriction Although there is debate on the role of fluid restriction, initial restriction of
fluid intake to an equivalent volume of the patient's insensible losses plus his/her urine output
will result in stabilizing the patient's weight without further accumulation of edema.
Hypercoagulability Nephrotic patients with severe hypoalbuminemia are at risk for

thromboembolic complications. Preventative measures include mobilization, avoidance of
hemoconcentration resulting from hypovolemia, and early treatment of sepsis or volume
depletion.
Infection
Bacterial Nephrotic children are at increased risk of developing infection (e.g., peritonitis,
pneumonia, and sepsis) due to encapsulated bacteria, in part due to reduced serum
concentrations of immunoglobulin, decreased cellular immunity, and the administration of
immunosuppressive therapy. The most common agent is streptococcus pneumoniae followed
by Escherichia coli.
Varicella Children with NS who require immunosuppressive therapy are at increased risk for
developing varicella.
Acyclovir, a synthetic nucleoside analog which inhibits replication of human herpesviruses, is

effective therapy for primary varicella infection. It should be instituted promptly in any patient
who is receiving immunosuppressive therapy and exhibits any sign of varicella infection.
Acyclovir has also been used prophylactically in children exposed to varicella while receiving
immunosuppressive therapy.
Other dietary measures
Caloric intake Increased caloric consumption as a result of appetite stimulation of

corticosteroid therapy can lead to excessive weight gain. Dietary measures that limit excessive
caloric consumption, including a low-fat diet, will help children avoid large weight gains.
Calcium and vitamin D Abnormalities in bone histology can be seen in patients with NS,
calcium (500 mg/day) and vitamin D (2000 to 4000 units) supplements often are prescribed
especially when there are documented low calcium and/or vitamin D concentrations,
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Hyperlipidemia The lipid abnormalities induced by the NS reverse with remission.
The optimal treatment of hyperlipidemia in children with persistent NS is unknown.
Treat children who remain persistently nephrotic and have hyperlipidemia with statin therapy
based upon the adult data.
Hyponatremia Fluid restriction is recommended in children with moderate to severe

hyponatremia (plasma sodium concentration less than 125 meq/L), because hyponatremia is
believed to be a result of excess water retention due to the hypovolemic stimulation of the
release of antidiuretic hormone.
Hypertension Children with NS and persistent hypertension are more likely to have chronic
kidney disease with poor outcome. As a result, in patients with hypertension, angiotensin
converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) are the preferred
antihypertensive agents because of their potential additive antiproteinuric benefit and ability to
slow progression of renal impairment. ACE inhibitor and ARBs should be terminated if
hyperkalemia cannot be controlled or the plasma creatinine concentration increases more than
30 percent above the baseline value.
287
Urinary tract infections in children
Nader Shaikh, MD - Alejandro Hoberman, MD
Urinary tract infections (UTI) are a common and important clinical problem in childhood. Upper
urinary tract infections (i.e., acute pyelonephritis) may lead to renal scarring, hypertension, and
end-stage renal dysfunction. Although children with pyelonephritis tend to present with fever,
it is often difficult on clinical grounds to distinguish cystitis from pyelonephritis, particularly in
young children (those younger than two years).
LABORATORY EVALUATION The laboratory evaluation for the child with suspected UTI
includes obtaining a urine sample for a dipstick and/or microscopic evaluation and urine culture.
How to obtain Catheterization or suprapubic aspiration are the preferred methods of urine
collection for dipstick, microscopic examination, and culture of the urine in infants and young
children who are not toilet-trained. Clean catch is the preferred method of collection in toilet-
trained children.
All urine specimens should be examined as soon as possible after collection. A delay of even a
few hours increases both the false-positive and false-negative rates substantially.
We recommend that urine obtained in a sterile bag not be used for culture. Up to 85 percent
of positive cultures from bag urine specimens represent false-positive results; results of urine
cultures from bag specimens are useful only if they are negative.
Dipstick analysis Dipstick tests are convenient, inexpensive, and require little training for
proper usage; they may be the only test available in some settings. However, they will likely miss
some children with UTI (at best they are 88 percent sensitive). Because the sensitivity of
dipstick analysis is less than 100 percent, we suggest that a urine culture be obtained in
children with suspected UTI who have a negative dipstick test.
Leukocyte esterase The presence of leukocyte esterase on dipstick analysis is suggestive of

UTI. However, a positive leukocyte esterase test does not always signal a true UTI.
Nitrite A child with a positive nitrite test is likely to have a UTI. The nitrite test is highly
specific, with a low false-positive rate. However, false-negative tests are common because urine
needs to remain in the bladder for at least four hours to accumulate a detectable amount of
nitrite. Thus, a negative nitrite test does not exclude a UTI.
Microscopic exam Microscopic examination requires more equipment and training than
dipstick tests. In standard microscopy, a centrifuged sample of unstained urine is examined for
white blood cells (WBC) and bacteria. When performed in this way, pyuria is defined as 5
WBC/high power field (hpf) and bacteriuria as the presence of any bacteria per hpf. Because
the sensitivity of the standard microscopic examination conducted using a centrifuged urine
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specimen is at best 81 percent, we suggest that a urine culture be obtained in children with
suspected UTI who have a negative standard microscopic examination.
Urine culture Urine culture is the gold standard for the diagnosis of UTI. We suggest that
urine culture be performed in the following groups, even if the dipstick and microscopic analysis
are negative:
1. Girls and uncircumcised boys younger than two years with at least one risk factor for UTI
(history of UTI, temperature >39C, fever without apparent source, ill appearance, suprapubic
tenderness, fever >24 hours or nonblack race).
2. Circumcised boys younger than two years with suprapubic tenderness or at least two risk
factors for UTI.
3. Girls and uncircumcised boys older than two years with any of the following urinary or
abdominal symptoms (abdominal pain, back pain, dysuria, frequency, high fever, or new-onset
incontinence).
4. Circumcised boys older than two years with multiple urinary symptoms (abdominal pain, back
pain, dysuria, frequency, high fever, or new-onset incontinence).
5. Febrile infants and children with abnormalities of the urinary tract, or family history of
urinary tract disease.
Urine obtained for culture should be processed as soon as possible after collection. A delay of
even a few hours increases both the false-positive and false-negative rates substantially.
Serum creatinine Measurement of serum creatinine is not routinely necessary in children

with suspected UTI. However, we suggest that serum creatinine be measured in children with a
history of multiple UTI and suspected renal involvement.
DIAGNOSIS OF UTI Quantitative urine culture is the standard test for the diagnosis of UTI.
UTI is best defined as significant bacteriuria in a patient with an inflammatory response (ie,
pyuria on dipstick or microscopic analysis).
DIFFERENTIAL DIAGNOSIS
Asymptomatic bacteriuria Asymptomatic bacteriuria (eg, colonization of the urinary tract

with bacteria in the absence of inflammation) occurs in 1 to 3 percent of infants and preschool
age children, and approximately 1 percent of older children. The bacteria tend to be of low
virulence and are easily eliminated by antibiotics. In most children, asymptomatic bacteriuria
resolves spontaneously without causing renal scarring, decreased filtration rate, or interfering
with renal growth. Although sterilization of the urine can be achieved with prophylactic
antibiotic therapy, such therapy is not recommended because it appears to increase the risk of
pyelonephritis.
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Other considerations The differential diagnosis in a child with suspected UTI depends upon
the presenting symptoms and signs.
The differential diagnosis of a well-appearing infant who has fever without a definite source is
extensive, but most commonly includes UTI and occult bacteremia. In children vaccinated
against Haemophilus influenzae and Streptococcus pneumoniae, the probability of UTI (7
percent) is much higher than the probability of occult bacteremia (<1 percent).
Urinary symptoms (e.g., urgency, frequency, dysuria) and bacteriuria may be caused by
nonspecific vulvovaginitis, urinary calculi, urethritis secondary to an STD (particularly
Chlamydia), and vaginal foreign body.
Patients with group A streptococcal infection, appendicitis, and Kawasaki disease may present
with fever, abdominal pain, and pyuria.
Dysfunctional elimination is a frequently overlooked diagnosis in children with urinary

symptoms and a negative urine culture.
TREATMENT
Goals The goals of treatment for UTI include:
1. Elimination of infection and prevention of urosepsis
2. Prevention of recurrence and long-term complications including hypertension, renal scarring,

and impaired renal growth and function
3. Relief of acute symptoms (e.g., fever, dysuria, frequency)
Decision to hospitalize Most infants older than two months with UTI can be safely managed
as outpatients as long as close follow-up is possible.
Usual indications for hospitalization include:
1. Age <2 months Clinical urosepsis or potential bacteremia Immunocompromised patient
2. Vomiting or inability to tolerate oral medication
3. Lack of adequate outpatient follow-up (e.g., no telephone, live far from hospital, etc.)
4. Failure to respond to outpatient therapy.
290
ANTIBIOTIC THERAPY The effectiveness of antimicrobial therapy for UTI is demonstrated by
the change in mortality between the pre- and post-antibiotic eras. The mortality of UTI was as
high as 20 percent in the preantibiotic era. In contrast, when UTI are appropriately treated with
antibiotics, acute complications, including death, are uncommon.
Antimicrobial therapy for children with presumed UTI depends upon a number of factors,
including the age of the child, severity of illness, presence of vomiting, duration of fever before
presentation, underlying medical and/or urologic problems, and the antimicrobial resistance
patterns in the community.
Empiric therapy Early and aggressive antibiotic therapy (e.g., within 72 hours of
presentation) is necessary to prevent renal damage. Delayed therapy has been associated with
increased severity of infection and greater likelihood of renal damage in experimental,
retrospective, and small prospective studies.
We suggest that empiric antimicrobial therapy be initiated while awaiting culture results in
infants and young children who are at increased risk for UTI on the basis of demographic and
clinical factors and children with underlying urologic abnormalities. In children who are not at
increased risk for UTI, we suggest that empiric antibiotic therapy be initiated if the results of
urine dipstick or microscopic examination indicate a high likelihood of UTI .
Choice of agent Gram staining of the urine, if readily available, can help guide decisions
regarding empiric therapy. The ultimate choice of antimicrobial therapy is based upon the
sensitivities of the patient's urine culture isolate.
Escherichia coli is the most common bacterial cause of UTI; it accounts for approximately 80
percent of UTI in children. Other gram-negative bacterial pathogens include Klebsiella, Proteus,
Enterobacter, and Citrobacter. Gram-positive bacterial pathogens include Staphylococcus
saprophyticus, Enterococcus, and, rarely, Staphylococcus aureus. We recommend that empiric
therapy for UTI in children include an antibiotic that provides adequate coverage for E. coli. The
agent of choice should be guided by local resistance patterns.
Approximately 50 percent of E. coli are resistant to amoxicillin or ampicillin . In addition,

increasing rates of E. coli resistance to first-generation cephalosporins (eg, cephalexin),
amoxicillin-clavulanate or ampicillin-sulbactam, and trimethoprim-sulfamethoxazole (TMP-SMX)
have been reported in some communities. Increased resistance to extended-spectrum
cephalosporins has been reported in children receiving prophylactic antibiotics.
Second- and third-generation cephalosporins (eg, cefprozil, cefpodoxime, cefixime,

cefotaxime, ceftriaxone) and aminoglycosides (eg, gentamicin, amikacin) are appropriate first-
line agents for empiric treatment of UTI in children. However, these drugs are not effective in
treating Enterococcus and should not be used for patients in whom enterococcal UTI are
suspected (e.g., those with a urinary catheter in place, instrumentation of the urinary tract, or
an anatomical abnormality). In such patients, amoxicillin or ampicillin should be added.
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Oral therapy
We suggest cefixime or another oral third generation cephalosporin (e.g., cefdinir, ceftibuten)
as the first-line oral agent in the treatment of UTI in children. In a randomized, controlled trial of
306 children 1 to 24 months of age with a febrile UTI, oral therapy with cefixime for 14 days was
as effective as intravenous therapy with cefotaxime for three days followed by oral therapy with
cefixime. The rates of symptom resolution, sterilization of the urine, reinfection, and renal
scarring did not differ between groups.
Cefixime, cefdinir, and ceftibuten are dosed as follows:
Cefixime (16 mg/kg per day by mouth in two divided doses on the first day, followed by 8
mg/kg once per day to complete therapy).
Cefdinir (14 mg/kg per day by mouth divided in two doses).
Ceftibuten (9 mg/kg by mouth once per day)
Amoxicillin and ampicillin are not routinely recommended for empiric therapy because of the
high rate of resistance of E. coli. Similarly, amoxicillin-clavulanate, first-generation
cephalosporins (eg, cephalexin), and TMP-SMX should be used with caution because of the
increasing rates of resistance to these drugs.
Fluoroquinolones (e.g., ciprofloxacin) are effective for E. coli and resistance is rare.
Ciprofloxacin is licensed by the United States Food and Drug Administration for use in
complicated UTI and pyelonephritis in children. However, the safety of quinolones in children is
still under study.
Ciprofloxacin should not be used as a first-line agent. The American Academy of Pediatrics
(AAP) Committee on Infectious Diseases recommends that the use of ciprofloxacin for UTI in
children be limited to UTI caused by Pseudomonas aeruginosa or other multi-drug resistant,
gram-negative bacteria.
Oral agents that are excreted in the urine but do not achieve therapeutic serum (e.g.,
nalidixic acid, nitrofurantoin) should not be used to treat UTI in febrile infants and young
children in whom renal involvement is likely.
Parenteral therapy
Third- or fourth-generation cephalosporins (eg, cefotaxime, ceftriaxone, cefepime) and

aminoglycosides (e.g., gentamicin) are appropriate first-line parenteral agents for empiric
treatment of UTI in children.
Definitive therapy is based upon the results of urine culture and sensitivities.
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Acceptable inpatient treatment regimens include the combination of ampicillin and
gentamicin, gentamicin alone, or a third- or fourth-generation cephalosporin . Ampicillin
should be included if enterococcal UTI is suspected.
The doses are as follows:
Ampicillin (100 mg/kg/day IV divided in four doses)
Gentamicin (7.5 mg/kg/day divided in three doses)
Cefotaxime (150 mg/kg per day IV divided in three doses)
Ceftriaxone (50 to 100 mg/kg per day IV)
Cefepime (100 mg/kg per day divided in two doses for children weighing 40 kg, maximum
daily dose 1 g; 500 mg twice per day for children weighing >40 kg)
Outpatient parenteral therapy Once-daily parenteral administration of gentamicin or

ceftriaxone in a day treatment center may avoid the need for hospital admission in select
patients (e.g., children who are 3 months old who are unable to tolerate oral therapy and are
nontoxic appearing, well-hydrated, without urologic abnormalities, and whose caretakers will be
able adhere to the outpatient regimen).
In children receiving antibiotic prophylaxis Whether the child has been receiving antibiotic
prophylaxis (for urinary tract infection or other medical problems) is another factor to consider
in the choice of empiric antibiotics. This was illustrated in a review of antibiotic resistance
patterns among 361 children hospitalized for UTI at a tertiary care children's hospital between
1997 and 2001. E.coli was the causative organism in 87 percent of cases overall, but was less
frequent among children receiving prophylactic antibiotics (58 percent) and in children with a
history of previous UTI (47 percent).
Antibiotic resistance patterns of isolated organisms differed according to whether the child was
receiving prophylactic antibiotics. Among the isolates from 26 children receiving prophylaxis
(with amoxicillin, TMP-SMX, penicillin, or nitrofurantoin), the following findings were noted:
Resistance to cefotaxime was 27 percent, compared to 4 percent overall
Resistance to ceftazidime and cefepime were 19 and 16 percent, respectively (compared to 4

and 2 percent overall)
Sensitivity to aminoglycosides remained high (98 and 95 percent for amikacin and gentamicin,
respectively)
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It is not clear whether the increased resistance to third- and fourth-generation cephalosporins
among patients receiving prophylaxis is caused by altered bacterial flora, a predisposition to
acquisition of resistant organisms, and/or previous exposure to third-generation cephalosporins.
Duration of therapy The total duration of therapy depends upon the age of the child and
the clinical scenario.
Children younger than 2 years and children with febrile or recurrent UTI are usually treated
for 10 days.
We suggest that prophylactic antibiotics (e.g., TMP-SMX, nitrofurantoin) be initiated after

completion of treatment and continued until the results of the imaging tests are available,
unless images are obtained immediately following therapy.
Children older than 2 years who are afebrile, and without abnormalities of the urinary tract or
previous episodes of UTI are usually treated for five days; such children have a low risk of
recurrence or complications.
Response to therapy
Clinical response The clinical condition of most patients improves within 24 to 48 hours of
initiation of appropriate antimicrobial therapy.
In children whose clinical condition (other than persistent fever) worsens or fails to improve as
expected within 24 to 48 hours of initiation of antimicrobial therapy, broadening antimicrobial
therapy may be indicated if the culture and sensitivity results are not yet available. Most of the
empiric regimens suggested above do not provide adequate coverage for enterococcus.
In addition, renal ultrasonography (RUS) or computed tomography should be performed as

soon as possible (to evaluate the presence of renal abscess, urinary calculi, or surgically
correctable anatomic abnormalities or obstruction); voiding cystourethrogram (VCUG) or
radionuclide cystogram (RNC) should be performed at the earliest convenient time.
It is not necessary to routinely obtain repeat urine cultures during antimicrobial therapy to
document sterilization of the urine provided that the child has had the expected clinical
response and the uropathogen is susceptible to the antibiotic that is used for treatment.
However, urine cultures should be repeated after 48 hours of therapy if the uropathogen is not
susceptible (intermediate or resistant) to the antibiotic that is being used for treatment or if
susceptibility testing is not performed.
IMAGING The rationale for imaging in young children with UTI is to identify abnormalities of
the genitourinary tract, including VUR and obstructive uropathies. If such abnormalities are
detected, steps can be taken to modify the risk of subsequent renal damage (e.g., surgical
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intervention or antibiotic prophylaxis to prevent recurrent UTI). Urinary tract anomalies are
more frequent among children with UTI caused by pathogens other than Escherichia coli.
We suggest routine imaging (RUS and VCUG) for:
1. Girls younger than 3 years of age with a first UTI (children older than 3 years are more reliably
able to verbalize urinary symptoms)
2. Boys of any age with a first UTI
3. Children of any age with a febrile UTI
4. Children with recurrent UTI (if they have not been imaged previously)
5. First UTI in a child of any age with a family history of renal disease, abnormal voiding pattern,
poor growth, hypertension, or abnormalities of the urinary tract.
Ultrasonography Renal ultrasonography (RUS) is a non-invasive test that can demonstrate

the size and shape of the kidneys, the presence of duplication and dilatation of the ureters, and
the existence of gross anatomic abnormalities. It is not reliable in detecting renal scarring or
VUR.
Voiding cystourethrogram Approximately 40 percent of young children with a first febrile

UTI have VUR on VCUG . The VCUG is the test of choice to establish the presence and degree of
VUR. The procedure involves catheterization to fill the bladder with a radioopaque or
radioactive liquid and recording of VUR during voiding.
Two tests are available to detect VUR:
The fluoroscopic contrast voiding cystourethrogram (VCUG) and
radionuclide cystogram (RNC).
The RNC is more sensitive than the contrast VCUG (sensitivity 45 to 47 percent versus 78 to 91
percent, respectively) and is less expensive. However, contrast VCUG provides better anatomic
resolution, which makes it more suited to grading VUR. The radiation exposure depends upon
the technique and equipment used.
Although VCUG is often scheduled several weeks after UTI, it may be performed as soon as the
patient is asymptomatic. Early imaging (as early as the first week) does not appear to falsely
increase the detection of VUR.
Renal scintigraphy Renal scintigraphy using dimercaptosuccinic acid (DMSA) can be used to
detect acute pyelonephritis and renal scarring in the acute and chronic settings, respectively.
DMSA is injected intravenously, and uptake by the kidney is measured two to four hours later.
Areas of decreased uptake represent pyelonephritis or scarring.
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PROGNOSIS
Recurrent UTI Approximately 14 percent of children younger than 6 years with UTI have a
subsequent UTI.
A large retrospective study found that white race (hazard ratio [HR], 2.0), age 3 to 5 years (HR
~2.5), and VUR of grade IV to V (HR, 4.38, 95% CI 1.3 to 15.3) were associated with a higher risk
of UTI recurrence. Importantly, treatment with antimicrobial prophylaxis was not associated
with a lower risk of UTI recurrence. Furthermore, children treated with antimicrobial prophylaxis
had a higher risk of resistant organisms with their subsequent UTI (odds ratio 7.5, 95% CI 1.6 to
35.2).
Long-term sequelae The effects of UTI in young children were identified in a prospective
study evaluating various imaging modalities after a first febrile urinary tract infection in children
who underwent RUS, DMSA scan within 72 hours of diagnosis, VCUG one month later, and
follow-up DMSA scan six months later:
Approximately 40 percent had VUR (identified with VCUG); among children with VUR, 96
percent had VUR of grade I, II, or III, which typically resolves spontaneously over time.
Renal scars (identified by DMSA scan) developed in approximately 8 percent of patients overall,
15 percent of those who had abnormal DMSA scan at the time of diagnosis, and none of the
children who had normal renal scans at the time of diagnosis. The long-term significance of
scarring, as identified by DMSA, remains to be determined.
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Hemolytic uremic syndrome in children
Patrick Niaudet, MD
The hemolytic-uremic syndrome (HUS) is defined by the simultaneous occurrence of the clinical
triad:
1. Microangiopathic hemolytic anemia
2. Thrombocytopenia
3. Acute renal injury
HUS is one of the main causes of acute renal injury in children. This disorder is divided by
whether or not there is an association with bacteria that produce a shiga-like toxin and clinical
presentation.
Shiga-like toxin associated HUS Shiga-like toxin (Stx) associated HUS is the most common
form of HUS in children accounting for 90 percent of all cases. It usually occurs after a prodromal
episode of diarrhea that is frequently bloody. In the majority of cases, Stx HUS is associated with
strains of Escherichia coli that produce a Shiga toxin. This form is also referred to as typical,
classical, or diarrhea-associated HUS, D+ HUS, or Shiga toxin-associated HUS.
Non-shiga toxin associated HUS Non-shiga toxin (NStx) associated HUS is a heterogeneous
group of disorders distinguished clinically by the absence of diarrhea or Shiga toxin-producing E.
coli infection. This disorder is also referred to as atypical, nondiarrhea-associated HUS, D- HUS,
or sporadic HUS.
SYMPTOMATIC THERAPY The prognosis of HUS has improved in part because of the early
institution of supportive therapy and improvements in intensive care and renal replacement
therapy. Appropriate care should be given for the following:
Anemia
Thrombocytopenia
Fluid and electrolyte disturbances
Acute renal failure
Hypertension
Neurologic dysfunction
Other organ involvement including colon, heart, pancreas, and lung
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Anemia Children with HUS can become profoundly and rapidly anemic. Based upon clinical
experience, packed red blood cells (RBC) should be transfused when the hemoglobin (Hgb) level
is <6 g/dL or hematocrit <18 percent to avoid cardiovascular and pulmonary compromise. About
80 percent of patients with Stx HUS require PRBC transfusions.
A post-transfusion goal of an Hgb level between 8 to 9 g/dL is recommended to prevent cardiac

and pulmonary complications resulting from high output cardiac failure. The goal is not to
restore the Hgb level to normal because the increased volume may cause heart failure,
pulmonary edema, and hypertension.
Most patients do not require iron therapy, as iron from hemolyzed blood is available for
erythropoiesis. In addition, there is no indication for the use of erythropoietin.
Thrombocytopenia Platelet transfusion is reserved for patients with HUS who have
significant clinical bleeding or if an invasive procedure is required
Fluid and electrolyte management
Fluid management is based upon the intravascular fluid status of the patient and renal function.
Patients with decreased intravascular volume are repleted to an euvolemic state. Those with
increased volume and diminished urine output are fluid restricted. They also may require
dialysis treatment to remove fluid, especially if there is cardiac and pulmonary compromise.
Once the patient is in an euvolemic state, administration of fluids should be given as insensible
losses plus urine output until renal function returns to normal.
Frequent monitoring of fluid balance, weight, and vital signs is imperative. At the first sign of
hypertension or cardiopulmonary overload, fluids should be restricted. Diuretics rarely avert
anuria but a trial of furosemide (2 to 5 mg/kg per dose) may be attempted to induce a diuresis,
particularly in patients with cardiopulmonary compromise. Diuretics should not be continued in
the child who fails to respond. Dialysis therapy is required if fluid restriction and/or diuretic
therapy fail to improve the compromised cardiorespiratory status of the patient in a timely
manner.
Electrolyte disturbances are common usually due to acute renal insufficiency or failure. They
include hyperkalemia, hyperphosphatemia, and metabolic acidosis.
Acute renal failure In patients with HUS who develop renal insufficiency or renal failure,
nephrotoxic medications should be stopped. The dosing of drugs that are excreted by the kidney
also must be readjusted for renal dysfunction.
Dialysis There is no evidence that early dialysis effects clinical outcome. As a result, the
indications for dialysis in children with HUS are similar to those in children with other forms of
acute renal failure. These include the following:
1. Signs and symptoms of uremia
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2. Azotemia defined as BUN 80 to 100 mg/dL (29 to 36 mmol/L)
3. Severe fluid overload (e.g., cardiopulmonary compromise and/or hypertension) that is

refractory to medical therapy
4. Severe electrolyte abnormalities (eg, hyperkalemia and acidosis) that are refractory to
medical therapy
5. Need for nutritional support in a child with oliguria or anuria
The choice of renal replacement modalities varies among pediatric nephrologists and medical
centers. However, if there is a severe abdominal complication requiring surgical intervention,
peritoneal dialysis is contraindicated. Earlier studies had preferentially recommended peritoneal
dialysis because it more effectively removed the procoagulant, plasminogen-activator inhibitor
type 1, which was thought to play a role in the pathogenesis of HUS .
Hypertension In patients with HUS, hypertension is caused by overexpansion of

intravascular volume and/or ischemia-induced activation of the renin-angiotensin system .
Management is directed toward correcting the fluid status and the use of antihypertensive
agents.
We suggest the use of calcium channel blockers (such as nifedipine or nicardipine) as the initial
choice of antihypertensive agents because of the concern of reduced renal perfusion with ACE
inhibitors. After the acute phase of HUS, we suggest that antihypertensive therapy is changed to
ACE inhibitors in patients who appear to have long-term renal sequelae.
Neurologic dysfunction Serious complications of the central nervous system (CNS), such as
seizures and strokes, are predictors of poor outcome. In any patient with HUS who presents
with serious neurologic dysfunction (e.g., seizure and coma), radiological imaging should be
performed to assess for CNS infarction. Seizures also may be secondary to severe hypertension.
Seizures are treated with parenteral antiepileptic agents. These include diazepam, phenytoin,
and fos-phenytoin.
Other organ involvement
Gastrointestinal complications Severe colitis may progress to necrosis and in some cases
intestinal perforation. Management includes serial abdominal examinations, guaiac testing of
the stool, and the use of parenteral nutrition. Surgical intervention may be required.
Cardiac dysfunction Cardiac dysfunction can be a result of cardiac ischemia and fluid
overload. Pericarditis may be associated with uremia. Appropriate therapy should be directed to
the underlying pathology and may include inotropic agents, fluid restriction, and/or dialysis.
Pancreatitis Clinically significant pancreatitis can occur resulting in insulin deficiency. Insulin
therapy may be required for hyperglycemia.
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Pulmonary complications Pulmonary edema and effusions may result from intravascular
fluid overload. Management may include fluid restriction, diuretics, dialysis, and/or ventilatory
support.
SPECIFIC THERAPY Multiple modalities and/or agents have been utilized that are directed
against the underlying or presumed pathogenic mechanisms of Stx HUS. These include
antithrombotic agents, plasma exchange and/or plasma infusion, tissue-type plasminogen
activator, and oral Shiga toxin-binding agent.
Plasma infusion and plasma exchange The use of plasma infusion (to supply a missing
anticoagulant factor) or plasma exchange (to supply a missing anticoagulant factor and/or
remove procoagulant factor) has been successful in many adults with thrombotic
thrombocytopenic purpura (TTP).
Plasma exchange can be used in children with Stx HUS and severe CNS involvement (eg, stroke)
based upon reported benefits with plasma exchange in adults with TTP and severe neurologic
dysfunction.
The volume of exchange is 40 to 60 mL/kg, and FFP is generally used as the replacement fluid.
PROGNOSIS The hematologic manifestations of Stx HUS completely resolve usually within one
to two weeks. The prognosis for recovery of renal function is generally favorable, with
resolution beginning after hematologic improvement. The mortality rate is less than 5 percent
but another 5 percent of patients have significant sequelae (e.g., stroke or end-stage renal
disease) .
Children who have long-term complications from HUS often have one or more of the following
risk factors during the acute phase of the disease:
1. A white blood cell count >20,000 per mm3 at presentation. The leukocytosis in part reflects
neutrophil activation resulting from monocytes release of the neutrophil chemoattractant
interleukin-8; these neutrophils may then contribute to tissue damage.
2. Initial oliguria/anuria that is persistent (>5 days of anuria and >10 days of oliguria).
3. Renal histology showing a glomerular microangiopathy affecting >50 percent of glomeruli,

arterial microangiopathy, and/or cortical necrosis.
Permanent and serious renal sequelae are reported in 5 to 25 percent of patients with Stx HUS.
Long-term follow-up often reveals evidence of irreversible injury during the acute phase of the
disease. These include an increased incidence of the following:
Hypertension
Mild proteinuria (usually less than 1000 mg per day)
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Subclinical decline in GFR with plasma creatinine concentration remaining in the normal range
Recurrence after renal transplantation In patients with Stx HUS who progress to end-stage
renal failure and undergo renal transplantation, recurrence of HUS in the transplanted kidney is
rare (zero to 10 percent) .
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Acute renal failure in children
Abubakr Imam, MD, FAAP
Acute renal failure (ARF) is defined by a rapid decline in glomerular filtration rate, resulting in
the disturbance of renal physiological functions including:
1. Impairment of nitrogenous waste product excretion
2. Loss of water and electrolyte regulation
3. Loss of acid-base regulation
MANAGEMENT OF ARF The basic principles of the general management of the child with
acute renal failure (ARF) include:
Maintenance of electrolyte and fluid balance
Adequate nutritional support
Avoidance of life-threatening complications
Treatment of the underlying cause
Hyperkalemia Depending upon the severity and the rate of onset, hyperkalemia can be
asymptomatic or severe enough to constitute a medical emergency. Electrocardiographic
findings associated with hyperkalemia consist of peaked T waves, flattened P waves, increased
PR interval, and widening of the QRS. Bradycardia, supraventricular or ventricular tachycardia,
and ventricular fibrillation may occur.
Although severe symptoms of hyperkalemia usually do not occur until the plasma potassium
concentration is above 7.0 mEq/L (unless the rise has been very rapid), there is substantial
interpatient variability. Severe life-threatening hyperkalemia requires immediate treatment.
The following modalities are listed by both their rapidity and mode of action and address the
immediate consequences of severe hyperkalemia:
Stabilization of the cardiac membrane with the intravenous calcium (calcium gluconate 10
percent solution in a dose 0.5 to 1.0 mL per kilogram intravenously over 5 to 15 minutes).
Promotion of potassium movement from the extracellular fluid (ECF) into the cells via three
different therapies:
1. Administration of intravenous glucose and insulin (0.5 to 1.0 g of glucose per kilogram over
30 minutes and 0.1 unit of insulin per kilogram intravenously or subcutaneously).
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2. Administration of intravenous sodium bicarbonate (in a dose of 1 to 2 milliequivalent per
kilogram over 30 to 60 minutes); and
3. Administration of beta agonists, such as albuterol, via nebulization (2.5 mg if the child
weighs less than 25 kilogram or 5 mg if the child weighs more). Albuterol can be
administered intravenously at 4 to 5 microgram per kg over 15 minutes, but nebulization is
the preferred treatment route.
The above modalities only transiently lower the plasma potassium concentration; as a result,
additional therapy is required to remove potassium from the body. Thus, kayexalate, an ion
exchange resin, can be used to effect a net elimination of potassium, at a dose of 1 gram per
kilogram orally or rectally.
Acidosis In children with ARF, not only is acid excretion impaired, acid production frequently
is increased on account of underlying comorbid conditions such as shock and sepsis. Respiratory
compensation provides some correction of the acidosis and in some cases may be sufficient.
Administration of sodium bicarbonate should be done only in life-threatening situations in

which maximal respiratory compensation is inadequate, and/or the acidosis is contributing to
hyperkalemia. In cases of severe or progressive acidosis following shock, serious infections or
other hypercatabolic states, supplemental bicarbonate may be required to correct and maintain
arterial pH above 7.2 until the underlying disease is controlled. Patients with serum bicarbonate
levels that are above 14 mEq/L or with arterial pH greater than 7.2 do not require intervention.
We administer 1 mEq of intravenous sodium bicarbonate/kg of body weight, and monitor

arterial pH and bicarbonate levels to determine further therapy.
Intravascular volume Appropriate immediate fluid management is crucial in children with

ARF. Based upon the underlying cause, comorbid conditions, and possible previous therapy, the
child with ARF may be hypovolemic, euvolemic, or hypervolemic (including pulmonary edema
and heart failure).
A child with a clinical history and physical exam consistent with fluid loss, and/or oliguria
requires immediate intravenous fluid therapy in an attempt to restore renal function and
perhaps prevent ischemic renal injury. Commonly used fluids are crystalloid solutions, such as
normal saline (20 mL/kg) administered over 20 to 30 minutes, which may be repeated. If urine
output does not increase and renal function fails to improve with the restoration of
intravascular volume, invasive monitoring may be required to adequately assess the child's fluid
status and help guide further therapy.
Once euvolemia has been obtained, the clinician must pay careful attention to ongoing fluid
losses (insensible water loss of approximately 300 to 500 mL/m2 per day in addition to
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replacement of urine and gastrointestinal losses) and gains (fluid administered for nutritional
and medical requirements).
Hyperphosphatemia and hypocalcemia Oral phosphate binders and dietary restriction of

phosphorus are commonly used to decrease intestinal absorption of phosphorus. Intravenous
administration of calcium gluconate should be considered if hypocalcemia is severe and/or if
bicarbonate therapy is required for severe acidosis and hyperkalemia.
Hypertension Although peripheral vasoconstriction can be a contributing factor,

hypertension in ARF is most likely secondary to fluid overload. The absolute degree of
hypertension, clinical presentation, and response to initial therapy (such as diuretics) will
determine the choice of antihypertensive therapy.
Nutrition ARF is associated with marked catabolism, and inadequate nutrition can delay
recovery of the patient's renal function. Infants should receive at least maintenance calories
(120 Kcal/kg per day) and older children should be administered appropriate maintenance
calories or higher. Hyperalimentation can be considered if enteral feeding is not possible. If the
child is oliguric or anuric, and sufficient calories cannot be achieved while maintaining
appropriate fluid balance, renal replacement therapy should be started.
Renal replacement therapy Renal replacement therapy in children with ARF should be
initiated for the following:
1. Signs and symptoms of uremia symptoms that include pericarditis, neuropathy or an

otherwise unexplained decline in mental status regardless of the serum BUN or
creatinine concentration.
2. Azotemia (BUN greater than 80 to 100 mg/dL [29 to 36 mmol/L]).
3. Severe fluid overload as manifested by hypertension, pulmonary edema or heart failure

that is refractory to supportive medical therapy.
4. Severe electrolyte abnormalities including hyperkalemia, hypernatremia,

hyponatremia, and acidosis that are refractory to supportive medical therapy.
5. Need for intensive nutritional support in a child with oliguria or anuria.
Available renal replacement modalities for the management of acute renal failure include the
following:
Hemodialysis Hemodialysis is the intervention that most rapidly changes plasma solute
composition and removes excessive body water compared to the other modalities. However,
this may not be tolerated by hemodynamically unstable patients.
Peritoneal dialysis Although peritoneal dialysis is less efficient in altering blood solute
composition and fluid removal, it can be applied continuously. It is therefore well tolerated by
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hemodynamically unstable patients. It is the simplest of the modalities to apply and hence is the
one most frequently used.
Continuous renal replacement therapy (CRRT) The use of continuous replacement therapy
(also referred to as hemofiltration) is increasing in children and includes several modalities
(continuous arteriovenous hemofiltration, continuous venovenous hemofiltration, continuous
arteriovenous hemodialysis, and continuous venovenous hemodialysis). In patients treated with
CRRT, the rate of fluid and solute removal is slow and continuous. As a result, CRRT is better
tolerated than hemodialysis in patients who are hemodynamically unstable. The removal of
solutes over the course of 24 to 48 hours is as efficient as conventional hemodialysis. In
addition, some prefer this technique in patients with sepsis or multiorgan system failure, as it
may enhance the removal of cytokines.
Outcome of renal replacement therapy Outcomes among children with acute renal failure
who require renal replacement therapy also vary with disease severity, underlying renal process,
extra-renal organ involvement, and other factors. In a retrospective report of 226 children, the
variables associated with survival among patients with acute renal failure were evaluated .
Renal replacement therapies included hemofiltration, hemodialysis, and peritoneal dialysis.
Significant factors influencing patient survival included:
Blood pressure at onset of renal replacement therapy (33, 61, and 100 percent survival with
low, normal, and high blood pressure, respectively).
Use of pressors during renal replacement therapy (35 and 89 percent survival in those requiring
and not requiring pressors, respectively).
Renal replacement modality (40, 49, and 81 percent survival with hemofiltration, peritoneal
dialysis, and hemodialysis, respectively). However, pressor use was significantly less in patients
on hemodialysis (33 percent) compared to those who received hemofiltration and peritoneal
dialysis (74 and 81 percent, respectively).
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Management of chronic kidney disease in children
Tarak Srivastava, MD - Bradley A Warady, MD
INTRODUCTION Chronic kidney disease (CKD) refers to a state of irreversible kidney damage
and/or reduction of kidney function, which can be progressive. CKD is now the accepted term in
the pediatric nephrology community, replacing the clinical terms of chronic renal failure (CRF)
and chronic renal insufficiency (CRI), which describe kidney dysfunction of varying degrees from
severe to mild in nature. CKD more clearly defines renal dysfunction as a continuum, rather than
a discrete change in renal function.
DEFINITIONS The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality
Initiative (K/DOQI) has defined CKD as a disorder lasting three or more months with either
kidney damage defined by structural or functional renal abnormalities, or an estimated
glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m2.
Chronic kidney disease is defined as either kidney damage or GFR <60 mL/min/1.73 m2 for 3
months.
Kidney damage is defined as pathologic abnormalities or markers of damage, including

abnormalities in blood or urine tests or imaging studies.
Normal levels of GFR vary with age, gender, and body size. GFR increases with maturation from
infancy and approaches adult mean values by two years of age.
GENERAL PRINCIPLES The general management of the patient with CKD includes the
following components:
1. Treat reversible renal dysfunction
2. Prevent or slow the progression of renal disease
3. Treat the complications of CKD
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4. Identify and adequately prepare the child/family in whom renal replacement therapy will be
required
REVERSIBLE RENAL DYSFUNCTION
The most common conditions with potentially recoverable renal function are primarily due to
decreased renal perfusion or the administration of nephrotoxic agents.
Decreased renal perfusion Renal hypoperfusion is produced by hypotension (e.g., septic

shock), volume depletion from vomiting, diarrhea, diuretic use, or bleeding, and the
administration of drugs that lower the renal perfusion (such as nonsteroidal anti-inflammatory
drugs, angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARBs].
Administration of nephrotoxic drugs Common nephrotoxic drugs include nonsteroidal anti-

inflammatory agents, diagnostic agents (e.g., radiographic contrast materials), and others (e.g.,
aminoglycosides, amphotericin B, cyclosporine, and tacrolimus). The administration of such
drugs, therefore, should be avoided or used with caution in patients with underlying CKD, with
the assistance of therapeutic drug level monitoring.
Certain drugs, such as cimetidine, trimethoprim, ciprofloxacin, and flucytosine, lead to an

elevation in serum creatinine but not blood urea nitrogen (BUN), as they interfere with either
the tubular secretion of creatinine or the laboratory assay for creatinine.
SLOWING CKD PROGRESSION
Despite the lack of data in children, we recommend that hypertension be strictly controlled
with antihypertensive therapy in children with CKD based upon the beneficial effect that blood
pressure control has in reducing the progression of CKD in adults. We suggest that patients with
hypertension and proteinuria be treated with an ACE inhibitor or an ARB as there is evidence in
adult studies that these agents appear to be more protective than other antihypertensive drugs
in this clinical setting.
The current consensus by pediatric nephrology experts is to provide children with CKD the age
appropriate recommended daily allowance for protein.
CKD COMPLICATIONS A wide range of complications result as a consequence of the loss of

renal function. These include disorders of fluid and electrolyte balance, renal osteodystrophy,
hypertension, anemia, dyslipidemia, growth impairment, malnutrition and risk of poor
neurodevelopmental outcome.
Sodium and intravascular volume As GFR becomes severely decreased (i.e., stages 4 and 5
disease), water and sodium retention may result in volume overload. In general, a combination
of dietary sodium restriction and diuretic therapy may correct the increased water balance and
prevent water retention from recurring.
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In our practice, we work with the child and family to decrease the sodium intake to 2 to 3 g/day.
This is often a difficult task given the sodium content of the current favorite foods of children.
Diuretic therapy includes either loop diuretics such as furosemide given at a dose of 0.5 to 2
mg/kg per day or thiazide diuretics such as hydrochlorothiazide at 1 to 3 mg/kg per day.
Hyperkalemia Hyperkalemia develops primarily because of inadequate potassium excretion

due to a reduced GFR. Other factors that can contribute to elevated potassium levels include a
high dietary potassium intake, increased tissue breakdown, metabolic acidosis,
hypoaldosteronism (due in some cases to administration of an ACE inhibitor or an ARB), or an
impaired cellular uptake of potassium.
Management to prevent hyperkalemia in children with CKD consists of the following:
1. Low potassium diet.
2. Administration of a loop diuretic (eg, furosemide) to increase urinary potassium loss.
3. If there is metabolic acidosis, oral sodium bicarbonate to correct acidosis.
4. In infants under selected circumstances, formula can be mixed with kayexalate and decanted
externally to decrease the potassium content of the formula prior to feeding. The use of
kayexalate in this manner is a common practice in many pediatric nephrology centers.
Hypokalemia is uncommon in children with CKD. However, it can be observed in children in the
early stages of CKD associated with Fanconi syndrome, renal tubular acidosis, or from excessive
diuretic therapy.
Metabolic acidosis In children, overt acidosis is characteristically present when the

estimated GFR is less than 30 mL/min per 1.73 m2 (i.e., stage 4 disease). Acidosis is associated
with growth impairment because the body utilizes bone buffering to bind some of the excess
hydrogen ions.
Current guidelines by the K/DOQI working group are to maintain the serum bicarbonate level
at or above 22 mEq/L [10] . We suggest sodium bicarbonate therapy in patients with metabolic
acidosis to achieve this targeted goal. Sodium bicarbonate therapy is started at 1 to 2 mEq/kg
per day in two to three divided doses, and the dose is titrated to the clinical target. Citrate
preparations should, on the other hand, be used with caution in children with CKD, as these
preparations enhance aluminum absorption from the intestine and increase the risk of
aluminum toxicity.
Bone metabolism and bone disease Changes in mineral metabolism and bone structure are
an almost universal finding with progressive CKD due to abnormalities in the metabolism of
calcium, phosphate, vitamin D, and parathyroid hormone (PTH) levels. If these abnormalities are
not addressed, these changes result in renal bone disease, referred to as renal osteodystrophy.
Significant morbidity may be associated with renal osteodystrophy, including growth failure,
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avascular necrosis, and skeletal fractures and deformities. Renal osteodystrophy and its
complications can be prevented with ongoing monitoring of bone metabolism (measurement of
serum concentrations of calcium, phosphorus, and parathyroid hormone levels) and appropriate
therapeutic interventions such as dietary phosphate restriction, use of phosphate binding
agents, and vitamin D replacement therapy.
Hypertension The prevalence of hypertension in children with CKD is high, even when the
GFR is only mildly reduced, and increases with further declines in GFR.
Treatment of hypertension should include specification of target blood pressure levels,

nonpharmacologic therapy, and antihypertensive therapy.
Therapeutic interventions Therapy includes both nonpharmacologic and pharmacologic

interventions:
Nonpharmacologic therapy Treatment should be initiated with conservative measures such

as weight reduction, exercise, and dietary salt reduction. The current recommendation for
adequate daily sodium intake is only 1.2 g/day for four to eight year olds and 1.5 g/day for older
children. This amount is substantially lower than the average current intake of a child. We work
with the child and family to decrease the sodium intake to 2 to 3 g/day, which is often difficult
given the sodium content of current favorite foods of children.
Pharmacologic therapy A diuretic is often recommended in the early stages of CKD. The
thiazide diuretics, such as hydrochlorothiazide (1 to 3 mg/kg per day to a maximum of 50
mg/day), become less effective as monotherapy as the GFR declines. Thus, a loop diuretic is
recommended for the treatment of hypertension and edema in patients with more severe CKD.
In our practice, we use the loop diuretic furosemide at a dose of 0.5 to 2 mg/kg per day in one to
two divided doses.
In our practice, we prefer to initiate therapy with an ACE inhibitor as there are more data on the
safety and efficacy of this class of drugs compared to ARBs in children. We often start with an
initial dose of enalapril of 0.08 mg/kg per day (maximum of 5 mg/day), which is titrated to a
maximum dose of 0.6 mg/kg per day (maximum of 40 mg/day) based upon the response of the
patient's blood pressure and results of lab tests (eg, serum potassium). We use enalapril
because its long half-life allows once a day dosing. An alternative, long-acting ACE inhibitor
commonly used in children is lisinopril, which is also administered once a day.
Anemia Anemia due to reduced renal erythropoietin production generally develops when
the GFR is below 30 mL/min per 1.73 m2. At the onset of dialysis, the presence of anemia in
children is very common and has been associated with excessive morbidity and an increased
mortality risk.
Screening and evaluation of anemia Annual testing of either hemoglobin (Hgb) or

hematocrit (Hct) should be performed in children with CKD, regardless of stage or cause.
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A diagnosis of anemia is made when the observed Hgb (Hct) result is below the fifth percentile
of normal adjusted for age and sex. Once anemia is detected in a child with CKD, the following
evaluation, which is focused upon eliminating causes of anemia other than CKD and determining
the iron status of the patient, is recommended.
Red blood cell indices
Reticulocyte count
Iron parameters (serum iron, total iron binding capacity, percent transferrin saturation [TSAT]
and serum ferritin)
Test for occult blood in stool
Treatment of anemia The treatment of anemia in children with CKD often includes iron
supplementation and erythropoietin replacement therapy.
Iron therapy (elemental iron 3 to 4 mg/kg per day) should be initiated if iron deficiency is
detected. Iron supplementation is targeted to maintain a TSAT 20 percent and serum ferritin
100 ng/dL in children with CKD. All patients receiving therapy with an erythropoiesis stimulating
agent (ESA) such as recombinant human erythropoietin (rHuEPO) require iron supplementation
to prevent the development of iron deficiency. Once iron status is normal, it should be
monitored at least every three months, or monthly following the initiation of and/or increase in
ESA dosing.
Limited data suggest that children with CKD and a Hgb less than 9.9 g/dL are at increased risk
for mortality, left ventricular hypertrophy, and/or decreased exercise capacity compared to
those with greater than 9.9 g/dL [17] . In addition, quality of life and neurocognitive function has
improved in patients treated with rHuEPO who experienced a significant increase in Hgb
compared to baseline Hgb, which was below 9 g/dL.
The initial rHuEPO dose in older children not receiving dialysis is 80 to 120 u/kg per week,
administered in two to three divided doses. Children younger than five years of age or children
receiving dialysis frequently require higher doses (300 u/kg per week). In predialysis patients
and in those who receive peritoneal dialysis, rHuEPO should preferably be administered by the
subcutaneous route and the site of injection should be rotated. In patients who receive
hemodialysis, erythropoietin is typically administered intravenously through their vascular
access.
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The most common cause of an incomplete response to an ESA is iron deficiency. However,
other conditions in the iron replete patient may cause an inadequate response to an ESA as
well and include:
1. Infection or inflammation .
2. Chronic blood loss .
3. Osteitis fibrosa .
4. Aluminum toxicity .
5. Folate or vitamin B12 deficiency .
6. Malnutrition.
7. Hemoglobinopathies .
8. Hemolysis .
9. Carnitine deficiency (rare).
10. Copper deficiency (rare).
Dyslipidemia Abnormal lipid metabolism is common in patients with CKD and adds to the
risk for cardiovascular disease (CVD) in children with CKD. Evaluation is performed by obtaining
a fasting lipid profile that includes total cholesterol, low-density lipoprotein cholesterol (LDL-C),
high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) at presentation, and annually
thereafter or two to three months following a change in treatment or subsequent to the
presentation of another condition known to cause dyslipidemia.
Although of unproven benefit in children with CKD, the following treatment guidelines have
been suggested by the AHA and the AAP for children with CKD and dyslipidemia based upon a
literature review by an expert panel:
Fasting TG >150 mg/dL Interventions initially include therapeutic lifestyle changes, such as
a decreased intake of simple sugars; in patients with TG >700 mg/dL consider administration of
a fibric acid, such as gemfibrozil or fenofibrate.
HDL < 35 mg/dL Therapeutic lifestyle changes, such as vigorous daily physical activity of
greater than 60 minutes, weight loss, and dietary substitution of monounsaturated for saturated
fatty acids.
LDL 100 mg/dL Therapeutic lifestyle changes including a low-saturated-fat, low-cholesterol

diet and a daily exercise regimen. In children greater than 10 years of age, the use of statin
therapy can be considered.
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Nutrition Malnutrition is common in children with CKD because of poor appetite, decreased
intestinal absorption of nutrients, and metabolic acidosis. Attention to nutrition is critical as it
affects both the physical growth and neurocognitive development of children.
The K/DOQI pediatric guidelines for nutrition recommend that the nutritional status of children
with CKD should be monitored on a monthly basis for children younger than two years and
every three to four months for children older than two years of age. The measures for
monitoring should include the following:
1. Dietary interview.
2. Weight.
3. Height or length.
4. Weight/height index.
5. Mid-arm circumference and muscle circumference or area Skin folds thickness.
6. Head circumference for patients younger than three years of age.
Children with CKD should be provided with 100 percent of the RDA for protein based upon age
and gender, as these diets are safe and palatable for the child and avoid the problems
associated with an excessive protein intake. Protein restriction is not recommended in children
as it has not been shown to influence the decrease in renal function in children with CKD.
Children with CKD should receive 100 percent of the dietary reference intakes for water-soluble
vitamins such as thiamine (B1), riboflavin (B2), pyridoxine (B6), vitamin B12, and folic acid. An
intake of 100 percent of the RDA should be the goal for vitamins A, C, E, K, and the minerals,
copper and zinc. In children with advanced CKD (i.e. stage 5), the loss of renal clearance of
vitamin A metabolites places these children at risk for developing hypervitaminosis A. This
should be considered when selecting a multivitamin that contains a combination of water- and
fat-soluble vitamins.
Growth Growth failure has been long recognized in children with CKD. While the institution
of recombinant human growth hormone rHuGH therapy can have a profound effect on the
height velocity of children with CKD who are growing poorly, early recognition and management
of malnutrition, renal osteodystrophy, acid-base abnormalities and electrolyte disturbances
should take place prior to considering the institution of rHuGH.
The criteria for initiating rHuGH in children with CKD include all of the following:
1. Height SDS that is more negative than -1.88 and/or a height velocity SDS that is more
negative than -2.
2. Growth potential that is documented by open epiphyses.
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3. There are no contraindications for rHuGH.
The use of rHuGH is continued until the child reaches the 50th percentile for mid-parental
height, achieves a final adult height with closed epiphyses, or receives a kidney transplant.
Neurodevelopment Uremia is associated with alterations in cognition and may impact

neurodevelopment in children. Neurologic findings can range from seizures and severe mental
retardation to subtle deficits resulting in poor school performance.
Uremic bleeding An increased tendency for bleeding is present in patients with severe CKD
due primarily to abnormalities in platelet adhesion and aggregation properties. In asymptomatic
patients, no specific therapy is required.
However, in patients who are actively bleeding or who are about to undergo a surgical or
invasive procedure (such as renal biopsy), the platelet abnormality should be addressed. A
number of different treatment options can be considered in this setting. These include the
following:
1.Desmopressin (dDAVP), an analog of antidiuretic hormone than is the simplest and least toxic
acute treatment. It is administered intravenously or subcutaneously at a dose of 0.3 mcg/kg
with an onset of effect within one hour of administration; the effect lasts for six to eight hours.
2. Cryoprecipitate (1 to 2 units/10 kg); the effect lasts for 24 to 36 hours, but there is an
increased risk of transmitted infectious diseases.
3. Estrogen (0.6 mg/kg per day for 5 days); the onset of effect is over 6 to 24 hours, but the
effect lasts for two to three weeks.
4. Correction of anemia; as an improved hemoglobin (hematocrit) is believed to facilitate

increased interaction between platelets and blood vessels.
Uremic pericarditis Uremic pericardial disease (pericarditis and pericardial effusion) is seen
only in the late stages of CKD and is an indication to institute dialysis. Most patients with uremic
pericarditis respond rapidly to dialysis with resolution of chest pain as well as a decrease in the
size of the pericardial effusion.
RENAL REPLACEMENT THERAPY Once the estimated GFR declines to less than 30 mL/min
per 1.73 m2 (stage 4 CKD), it is time to start preparing the child and the family for renal
replacement therapy.
Choice of renal replacement therapy The choice of replacement therapy in children is

variable. The registry of the North American Pediatric Renal Trials and Collaborative Studies
(NAPRTCS) reports that of patients initiating renal replacement therapy in pediatric centers:
One quarter of children underwent preemptive renal transplantation
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One half were started on peritoneal dialysis
One quarter were started on hemodialysis
PSYCHOLOGICAL IMPACT ON THE CHILD AND FAMILY CKD, as is true for any chronic
condition, may result in severe psychological and social stresses for both the child and family.
The normal progression of the child to independence is impeded, and concerns about body
composition and image are greatly magnified in children whose growth and pubertal
development are delayed or altered. The prospect of a lifetime with renal replacement therapy
(dialysis and/or transplant) and the potential for catastrophic complications and/or death makes
it difficult to achieve normal childhood and adolescent developmental goals .
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The Endocrine System
Epidemiology, presentation, and diagnosis of type 1 diabetes

mellitus in children and adolescents
Lynne L Levitsky, MD - Madhusmita Misra, MD, MPH
Type 1 diabetes mellitus, one of the most common chronic diseases in childhood, is caused by
insulin deficiency following destruction of the insulin-producing pancreatic beta cells. It most
commonly presents in childhood but one-fourth of cases are diagnosed in adults.
Geographical variation The incidence of childhood type 1 diabetes varies worldwide. In

general, the risk appears to rise as the geographical latitude increases (distance from the
equator).
Age and gender The age of presentation of childhood onset type 1 diabetes has a bimodal
distribution with one peak at 4 to 6 years of age and a second in early puberty (10 to 14 years of
age)
Although most autoimmune diseases are more common in females, there appears to be no
gender difference in the overall incidence of childhood type 1 diabetes.
Genetic susceptibility The risk of type 1 diabetes is significantly increased in close relatives
of a patient with type 1 diabetes:
No family history 0.4 percent.
Offspring of an affected mother 2 to 4 percent.
Offspring of an affected father 5 to 8 percent.
Offspring with both parents affected reported as high as 30 percent.
Non-twin sibling of affected patient 5 percent.
Dizygotic twin 8 percent.
Monozygotic twin 50 percent lifetime risk, 30 percent within 10 years of diagnosis of the first
twin.
Environmental factors In genetically susceptible individuals, exposure to one or more

environmental agents appears to trigger an immune response that ultimately causes destruction
of the insulin-producing pancreatic beta cells. Identification of these environmental factors
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should lead to a better understanding of the pathogenesis of the disease and aid in developing
strategies to prevent type 1 diabetes.
Reports have linked several environmental factors to an increased risk of type 1 diabetes;
however, none of these have associations have been verified and many have been contradicted
by other studies. They include:
Viral infections.
Immunizations.
Diet especially exposure to cow's milk at an early age.
Perinatal factors such as maternal age, history of preeclampsia, and neonatal jaundice. Low
birth weight decreases the risk of developing type 1 diabetes.
CLINICAL PRESENTATION Childhood type 1 diabetes can present in several different ways.
1. Classic new onset.

2. Diabetic ketoacidosis.
3. Silent (asymptomatic) incidental discovery.
Classic new onset Hyperglycemia without acidosis is the most common presentation of
childhood type 1 diabetes. Symptoms are caused by hyperglycemia and include polyuria,
polydipsia, weight loss despite increased appetite initially (polyphagia), and lethargy.
Polyuria Polyuria occurs when the serum glucose concentration rises above 180 mg/dL (10
mmol/L), exceeding the renal threshold for glucose, which leads to increased urinary glucose
excretion. Glycosuria causes osmotic diuresis (ie, polyuria) and hypovolemia. Polyuria may
present as nocturia, bedwetting, or daytime incontinence in a previously continent child. In
children who are not toilet trained, parents may note an increased frequency of wet diapers
and/or diapers that are unusually heavy (wet).
Polydipsia Polydipsia is due to enhanced thirst because of increased serum osmolality from
hyperglycemia and hypovolemia.
Weight loss Weight loss is a result of hypovolemia and increased catabolism. Insulin
deficiency in diabetic children impairs glucose utilization in skeletal muscle and increases fat and
muscle breakdown. Initially, appetite is increased, but over time, children may become anorexic,
contributing to weight loss.
Diabetic ketoacidosis Children with type 1 diabetes often present with diabetic ketoacidosis
(hyperglycemia and ketoacidosis). Symptoms are similar but usually more severe than those of
patients without acidosis. The reported frequency of diabetic ketoacidosis (DKA) as the initial
presentation for childhood type 1 diabetes varies from 15 to 67 percent. Young children (<6
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years of age) or from a low socioeconomic background are more likely to have DKA as their
initial presentation of type 1 diabetes.
Silent presentation Some children will be diagnosed with type 1 diabetes before the onset
of clinical symptoms. This presentation is least common and typically occurs in children who
have another close family member with type 1 diabetes and are being closely monitored. The
diagnosis is made based upon an elevated blood glucose concentration.
The diagnosis of diabetes mellitus is based upon one of three detected abnormalities of
glucose metabolism. These diagnostic criteria based upon the guidelines of the American
Diabetes Association (ADA) are similar to those used in adults with diabetes.
1. Fasting plasma glucose 126 mg/dL (7 mmol/L) on two occasions.

2. Symptoms of hyperglycemia and a random venous plasma glucose 200 mg/dL (11.1
mmol/L).
3. Abnormal oral glucose tolerance test (OGTT) defined as a plasma glucose 200 mg/dL
(11.1 mmol/L) measured two hours after a glucose load of 1.75 g/kg (maximum dose of
75 g).
Most children and adolescents are symptomatic and have plasma glucose concentrations well
above 200 mg/dL (11.1 mmol/L); thus, OGTT is seldom necessary to diagnose type 1 diabetes.
Glycosuria is suggestive of diabetes, but not diagnostic. For example, patients with renal
glucosuria or Fanconi syndrome will present with glycosuria but have normal plasma glucose
concentration.
Glycosylated hemoglobin (A1C) measures the percent of hemoglobin bound to glucose in a

non-enzymatic reaction, and is an indication of average blood sugar levels for 10 to 12 weeks
prior to the time of measurement. A1C is invariably high at the time of diagnosis of type 1
diabetes. Values >6.5 percent suggest the presence of diabetes, however, levels <6.5 percent do
not exclude diabetes.
Type 1 versus type 2 diabetes As the incidence of type 2 diabetes (characterized by variable
degrees of insulin resistance and deficiency) increases in children and adolescents, it becomes
increasingly important for long-term management to distinguish type 1 from type 2 disease.
Differentiating between the two is based upon clinical presentation, history, and laboratory
studies.
Body habitus Patients with type 2 diabetes are generally overweight with body mass index
>85th percentile for age and gender. In contrast, children with type 1 diabetes are usually not
overweight and often have a recent history of weight loss.
Age Patients with type 2 diabetes generally present after the onset of puberty, whereas
those with type 1 disease often present at an earlier age. Age of presentation of type 1 disease
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is bimodal, with a peak between 4 and 6 years of age and a second at prepuberty or early
puberty, between 10 and 14 years of age.
Insulin resistance Patients with type 2 diabetes frequently have acanthosis nigricans (a sign
of insulin resistance), hypertension, dyslipidemia, and polycystic ovary syndrome, which are less
likely in children with type 1 disease.
Family history Patients with either type 1 or type 2 diabetes can have an affected close
relative.
Although there is no diagnostic test, type 1 diabetes is suggested by the presence of serum
islet-specific pancreatic autoantibodies, glutamic acid decarboxylase (GAD), the 40K fragment of
tyrosine phosphatase (IA2), and/or insulin. However, the absence of pancreatic autoantibodies
does not rule out the possibility of type 1 diabetes. In addition, up to 30 percent of individuals
with the classical appearance and presentation of type 2 diabetes have positive autoantibodies.
Other causes of diabetes Type 1 diabetes is distinguished from other diseases that cause
diabetes by patient characteristics, history, and laboratory studies. This approach is similar to
that used to differentiate type 1 from type 2 diabetes discussed above.
Diseases of the exocrine system Cystic fibrosis, hereditary hemochromatosis, and chronic
pancreatitis.
Endocrine abnormalities in glucose regulation Cushing's syndrome, growth-hormone

excess, glucagon-secreting tumors, catecholamine excess in pheochromocytoma. With the
exception of Cushing's syndrome, these are all extremely rare.
Drug-induced diabetes A number of drugs (eg, glucocorticosteroids, HIV protease

inhibitors, cyclosporine, L-asparaginase, and tacrolimus) and atypical antipsychotic agents can
impair glucose tolerance by inhibiting insulin secretion, increasing hepatic glucose production,
or causing insulin resistance.
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Management of type 1 diabetes mellitus in children and
adolescents
Successful management of children with diabetes includes the following:
1. Balancing strict glycemic control, which reduces the risk of long-term sequelae, and
avoidance of severe hypoglycemia, which is more likely with stricter control. In children,
targeted glycemic goals define what is thought to be the best balance between these long-
and short-term complications.
2. Setting realistic goals for each child and family. The patient's age and developmental status,
and the level of family involvement are important factors in establishing a practical
management plan that can be implemented by the patient and family.
3. Maintaining normal growth, development, and emotional maturation. Increasing self-
independent management as the child grows is an ongoing goal.
4. Training the patient and family to provide appropriate daily diabetes care in order to attain
glucose control within the range of predetermined goals, and to recognize and treat
hypoglycemia.
Initial management The initial phase begins at the time of diagnosis. In these first few days,
the family begins to understand the disease process and is trained to successfully administer
insulin, check blood glucose concentrations, check for ketonuria, and recognize and treat
hypoglycemia.
Basic understanding The diabetes team teaches the patient and family the cause and
treatment of type 1 diabetes, how to maintain a daily schedule and record of blood glucose
testing, insulin administration, and the timing and carbohydrate content of meals and snacks.
Insulin administration Training includes teaching the family about the different types of
prescribed insulin, how to measure and inject insulin, and how to rotate injection sites. Family
members and caretakers must learn about the duration and action of the various types of
insulin prescribed to their child. They must also understand how to adjust the insulin dose based
upon blood glucose concentrations and carbohydrate intake.
In our practice, we encourage the parents to administer the first injection. We also find it
useful to have the parents administer a saline injection to themselves, so that they realize the
discomfort is minimal.
Blood glucose testing Families must master blood glucose testing using a meter that is easy
to use. They are instructed on the frequency and timing of monitoring depending upon the
needs of their child
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Ketonuria Families are taught to check urine for ketones at times of illness and/or if the
blood glucose concentration is greater than 250 mg/dL (13.9 mmol/L) for two consecutive
readings.
Hypoglycemia Families are instructed to recognize the signs and symptoms of

hypoglycemia. This is particularly difficult in the non-verbal young child and infant in whom the
signs of hypoglycemia are nonspecific. Parents are trained to check a blood glucose level and, if
this is too low, to intervene with dietary measures and/or glucagon.
Ongoing management After the initial phase, the diabetes team continues to provide care,
teaching, and support to the child and family. Sessions with individual team members
(endocrinologist, nurse educator, dietitian, and a mental health professional) allow more in-
depth education and care directed toward the goal of maintaining excellent glucose control.
Infants Infants (younger than 1 year of age) with diabetes have the highest risk of severe
hypoglycemia. Hypoglycemia is difficult to detect because infants are unable to communicate
their symptoms and clinical signs are nonspecific (eg, poor feeding, lethargy, jitteriness,
hypotonia).
Hypoglycemia can also lead to neurologic complications. Infants with severe hypoglycemia can
present with seizures or coma, which may have permanent neurologic sequelae. In addition,
repeated episodes of hypoglycemia may have deleterious effects on brain development and
learning, especially in children younger than five years of age.
Toddlers The issues surrounding the care of toddlers (1 to 3 years of age) are similar to
those in infants. The parents must learn and be responsible for the daily care of the patient and
also learn to recognize episodes of hypoglycemia. Hypoglycemia is a constant concern because
of the erratic food intake and activity levels of toddlers. It also can be difficult to distinguish
developmentally normal episodes of oppositional behavior and temper tantrums from altered
behavior caused by hypoglycemia. The parents must learn to measure blood glucose before
ignoring a temper tantrum.
Preschool and early school-aged children For the most part, parents still provide daily care
for preschool and early school-aged children (3 to 7 years of age). However, some of these
patients can begin to participate in their own care by testing their blood glucose or preparing
materials. Often, such mastery behaviors are short-lived, as the children rapidly become bored
and wish to forgo such responsibilities. The parents must be counseled that this behavior is
normal and age appropriate. As these children enter daycare or school, childcare providers and
school nurses must be involved in their diabetes care.
School-aged children School-aged children (8 to 11 years of age) can assume more of the
daily management of their diabetes with adult supervision and support. They can learn to
administer insulin injections on a routine basis, but still need significant assistance and
supervision for nonroutine management decisions. All glucose testing and insulin
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administration should be under adult supervision. Early independent self-management in this
age group with minimal or no adult supervision results in poorer glycemic control. Shared
responsibility with appropriate adult supervision needs to be established for optimal care.
The diagnosis of diabetes has a psychological impact on these children, which may be
manifested by depression and anxiety. Children may also have difficulty with social interactions
because of the perception of being different from their peers. The parents and the diabetes
team need to ensure that children attend school regularly and encourage participation in school
activities to develop normal peer relationships.
GLYCEMIC CONTROL Daily blood glucose levels are used to monitor glycemic control and
adjust management. The most widely used clinical test to evaluate long-term glycemic control is
blood glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin, or glycosylated
hemoglobin).
In adults, based upon data from controlled studies, an A1C value of 7 percent or less is the
targeted goal that best balances the risks of long-term sequelae and hypoglycemia.
Long-term complications The relationship between glycemic control and significant long-
term sequelae has been firmly established in randomized controlled trials in adolescents and
adults. This was illustrated in the Diabetes Control and Complications Trial (DCCT), which
demonstrated that strict glycemic control delayed the onset of microvascular disease
(retinopathy, nephropathy, and neuropathy), slowed progression of already-present
microvascular disease, and decreased the incidence of cardiovascular disease. As A1C
decreased, so did the risk of long-term sequelae, such as diabetic retinopathy .
Hypoglycemia The DCCT demonstrated that as A1C decreased, the incidence of severe
hypoglycemic episodes increased.
Although there is a continued relative risk reduction of retinopathy and other complications at
A1C values below 7 percent, the absolute risk of developing these complications is low if the
A1C value is kept below this threshold. Conversely, the absolute risk of severe hypoglycemia
increases progressively. In adults, an A1C goal of 7 percent has been recommended as a goal
that balances the long- and short-term risks.
Age-specific goals In children and adolescents, there are not comparable data to determine
the optimal target goal for A1C levels. The intensity of glycemic control needs to be balanced
against the increased risk of recurrent hypoglycemia and the consequences of severe
hypoglycemia. This was illustrated in a retrospective review of 709 children with type 1 diabetes.
In this cohort, as the A1C fell from 10.2 to 8.8, there was an increase in the episodes of
hypoglycemia (4.8 to 15.6 episodes per 100 patient years). The increase in episodes of
hypoglycemia was greatest in children younger than 6 years of age (14.0 to 42.1 episodes per
100 patient years).
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Targeted goals for A1C and blood glucose have been defined by a committee of the American
Diabetes Association (ADA) based upon the risk of hypoglycemia, with the highest target values
set for young children and infants because they have the greatest risk for hypoglycemia .
Age-specific ADA A1C goals are:
<6 years of age 7.5 to 8.5 percent
6 to 12 years of age 8 percent
13 to 19 years of age 7.5 percent
Age-specific ADA blood glucose goals are: Bedtime
<6 years of age: 110 to 200 mg/dL (6.1 to 11.1 mmol/L)
6 to 12 years of age: 100 to 180 mg/dL (5.6 to 10 mmol/L)
13 to 19 years of age: 90 to 150 mg/dL (5 to 8.3 mmol/L)
Before meals
<6 years of age: 100 to 180 mg/dL (5.6 to 10 mmol/L)
6 to 12 years of age: 90 to 180 mg/dL (5 to 10 mmol/L)
13 to 19 years of age: 90 to 130 mg/dL (5 to 7.2 mmol/L)
BLOOD GLUCOSE MONITORING Optimal glycemic control is dependent upon monitoring

blood glucose and appropriate adjustment of insulin dose. Ongoing monitoring allows the child
and family to become familiar with the patient's metabolic response to different types and
amount of foods, exercise, and stress.
Frequent monitoring has been shown to improve glycemic control in children and decrease the
frequency of severe hypoglycemic episodes. Children and their parents show poor ability to
detect high or low blood glucose levels based on symptoms alone.
Although the ADA recommends testing of blood glucose at least four times a day, more
frequent monitoring may be required. This is especially true in very young children who are at
increased risk for severe hypoglycemia, and in patients who are treated with intensive therapy
who have multiple meals/snacks during the day and require blood glucose checks prior to
administration of a premeal bolus of insulin. To safeguard against hypoglycemia, monitoring at
anticipated peaks of insulin action and during periods of increased physical activity may be
necessary.
In children, blood glucose meters, which require a small sample of blood (0.3 to 1 microliters)
obtained by fingerstick, are used to intermittently monitor blood glucose concentrations. Newer
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devices that use interstitial fluid or subcutaneous electrodes to measure continuous glucose
levels are now available and approved for use in children.
INSULIN Exogenous administration of insulin is designed to replace the deficient hormone

and to attain normoglycemia. However, this goal remains elusive because of the difficulty in
replicating the minute-to-minute variations of physiologic insulin secretion and the difference in
delivery of exogenous insulin action either subcutaneously or intravenously compared to normal
secretion of endogenous insulin directly to the portal bed. The failure of exogenous insulin to
completely mimic physiologic insulin secretion results in acute and chronic complications of
diabetes.
There are many different insulins and delivery systems available. The selected regimen is
individualized for the child and family to fit their lifestyle and optimize compliance while
providing glycemic control that meets age-specific goals. Input from the patient, if age
appropriate, and the family (eg, timing of meals and snacks, school/daycare, physical activity) is
important to ensure optimal glycemic control and minimize episodes of hypoglycemia. As a
result, the types of insulin used and regimens will vary among children and can change for an
individual child over time.
Preparations Insulin types can be classified by their onset and duration of action.
Rapid-acting (e.g., lispro, aspart, glulisine) and short-acting types (eg, regular insulin) are
typically administered as a premeal bolus (typically 5 to 10 minutes before the meal for the
rapid-acting insulins, and 20 to 30 minutes before meals for the short-acting type) based on (i)
carbohydrate content of food to cover the extra requirements after food is absorbed, and (ii)
the blood glucose level. These can be administered post meal in younger children for whom
intake is unpredictable. Rapid- and short-acting insulins delivered by continuous subcutaneous
infusion via an insulin pump provide basal insulin levels.
Intermediate NPH insulin is usually given two to three times a day, but may be given in a
targeted manner in combination with longer-acting insulins. Intermediate-acting insulin thus
provides some coverage for meals (NPH insulin given before breakfast will cover lunch).
Long-acting types (e.g., insulin glargine and insulin detemir) are given once or twice a day.
They provide a basal insulin level that suppresses hepatic glucose production and maintains
near-normal glucose levels in the fasting state.
Insulin is administered by needle and syringe, pen, or pump.
Needle and syringe An advantage of needle and syringe is that NPH and rapid-, or very-
rapid-acting insulins can be mixed in a single injection, thereby reducing the number of
injections. However, insulin glargine cannot be mixed with any other form of insulin and must
be administered separately. The smallest needle available is 31 gauge and 5/16 inches in length.
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Syringes are available in 30 (0.3 mL), 50 (0.5 mL), and 100 (1 mL) unit sizes. Thirty unit syringes
marked to administer half units are available.
Pens Pens, which are more commonly used in Europe, are supplied pre-filled with insulin
and may be either disposable or reusable. The ease of use and portability of pens are appealing
to many patients. The smallest needle available is 31 gauge and 3/16 inches in length. Although
mixed insulin preparations are available in pens, these are not tailored for the needs of children.
Mixed insulin pens are usually reserved for individuals who are limited in their ability to make
dosing decisions and, as a result, glycemia is not usually as strictly controlled. Aspart insulin-
filled pens can be obtained that offer the flexibility of half-unit delivery.
Regimen choices A number of insulin regimens are available to children with diabetes and
their families:
Conventional regimen This traditional therapy includes administration of an intermediate-

acting insulin (NPH) at least twice a day (at breakfast with a second dose either at dinner or
bedtime), with a rapid-acting (ie, lispro or aspart) or short-acting ("regular") insulin two or three
times a day. The rapid- or short-acting insulin would be given at breakfast and dinner, and
sometimes at lunch or the afternoon snack depending on blood glucose concentrations. This
regimen is fixed and the patient and family must adjust their lifestyles so that meals and
vigorous physical activity occur on a relatively fixed daily schedule. Two-thirds of the total daily
dose is administered before breakfast (2/3 as NPH and 1/3 as rapid- or short-acting insulin)
and one-third before dinner and at bedtime (1/3 to 1/2 as rapid- or short-acting insulin before
dinner and 2/3 to 1/2 as NPH at bedtime). The dose of NPH can be split such that a portion is
delivered before dinner and the remainder at bedtime.
Intensive regimens The intensive regimen provides insulin dosing that more closely
approaches physiologic insulin secretion than does conventional therapy. It includes
administration of a form of insulin that will maintain a basal insulin level and suppress lipolysis
and hepatic glucose production, with additional premeal and presnack boluses of rapid- or
short-acting insulin to minimize postprandial elevation of blood glucose. These boluses are
adjusted to the carbohydrate content of meals as well as the current blood glucose level. This
approach allows greater flexibility than the conventional regimen in terms of timing and
carbohydrate content of meals.
In adults, controlled studies, such as the Diabetes Control and Complications Trial (DCCT), have
demonstrated that intensive compared to conventional insulin therapy, which utilized one or
two fixed insulin injections (including mixtures of insulin), achieved better glycemic control and
reduced the incidence of long-term sequelae.
Controlled studies in adolescents show similar improved glycemic control with intensive
compared to conventional therapy. As an example, a sub-set analysis of 195 adolescents (13 to
17 years of age), who participated in DCCT, demonstrated that intensive compared to
conventional therapy improved glycemic control and decreased the risk of retinopathy.
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Results are as follows:
Intensive compared to conventional therapy decreased the mean daily blood glucose level (177
31 versus 260 52 mg/dL).
Median A1C levels throughout the study were significantly lower with intensive therapy.
Intensive therapy decreased the risk of retinopathy (RR 0.53, 95% CI 0.1 to 0.78).
Although the choice of regimen depends upon patient, family, and clinician preference, we
recommend that an intensive regimen be selected whenever possible based upon the above
data.
An intensive regimen is delivered either by multiple daily injections, or by continuous insulin

infusion (pump). The choice of intensive regimen is based upon patient, family, and clinician
preferences.
Multiple daily injections The multiple daily injections (MDI) regimen combines a baseline
level of insulin using a long-acting insulin analog (insulin glargine or detemir) with
premeal/snack boluses of rapid- or short-acting insulin. This approach results in more stable
glycemic control and fewer episodes of hypoglycemia than the conventional approach in
children.
Insulin glargine is the long-acting analog most commonly used in pediatric patients. It usually
has a duration of action of 20 to 24 hours, but the half-life is shorter in some patients, requiring
division of the daily dose into two injections per day.
Although the Food and Drug Administration (FDA) has only approved insulin glargine in
children 6 years of age, the use of insulin glargine appears to be beneficial in younger children
as well. Observational studies in children <6 years of age have shown that the use of insulin
glargine reduced the incidence of severe hypoglycemic episodes and improved glycemic control.
These results are probably due to the increased flexibility of this regimen in young children who
have unpredictable patterns of meal intake and variable levels of physical exercise. MDI using
glargine in this age group should be carried out under the supervision of an experienced
pediatric diabetes team.
Although many families chose this regimen because of its increased flexibility, MDI requires
increased blood glucose monitoring and increased frequency of insulin administration. The
patient and family also are required to count dietary carbohydrates and accurately judge the
impact of exercise on insulin requirements. Without this increased involvement and
patient/family education, the benefits of this regimen are not attained. Prior to initiation of
MDI, the patient and family must be informed and accept the increased commitment, the need
for increased frequency of blood monitoring, and insulin injections required by this therapeutic
approach.
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Insulin pump The insulin pump (continuous subcutaneous insulin infusion) is increasingly
used in the pediatric population. In 2006, there were more than 35,000 patients younger than
the age of 21 years who received insulin therapy through a pump system. A position statement
of the ADA, European Society for Pediatric Endocrinology and others recommends that insulin
pump therapy should be considered for patients with one or more of the following
characteristics:
1. Recurrent severe hypoglycemia.

2. Wide fluctuations in blood glucose levels (regardless of A1C).
3. Suboptimal diabetes control (A1C exceeds target range for age).
4. Microvascular complications and/or risk factors for macrovascular complications.
5. Good metabolic control, but insulin regimen that compromises lifestyle.
Other situations in which the insulin pump may be helpful include young children and infants,
adolescents with eating disorders, pregnant adolescents, ketosis-prone individuals, and
competitive athletes.
Insulin pumps deliver a basal rate (small aliquots every few minutes, evenly spaced over an
hour) of either rapid- or short-acting insulin subcutaneously. The rate of insulin administration
can be transiently increased to give mealtime or glucose correction boluses. Most insulin pump
therapy is now started with a rapid-acting insulin, rather than short-acting insulin.
Premeal/snack boluses are administered to minimize increases in postprandial glucose
concentrations. Insulin is delivered through a subcutaneously inserted catheter that is replaced
at two- to three-day intervals. Information on insulin administration, frequency of catheter site
changes, and frequency and timing of premeal insulin boluses can be downloaded from a
memory chip within the pump. Insulin pumps have not yet incorporated a "closed loop" system
in which blood glucose values are determined and automatically used to reprogram the insulin
pump. Therefore, insulin pump therapy relies on frequent blood glucose monitoring and
appropriate readjustment of insulin infusion rates either by the patient or parent.
Data from adult controlled studies demonstrate the superiority of intensive therapy compared
to conventional therapy in achieving glycemic control and reducing the incidence of long-term
sequelae. In addition, one meta-analysis has reported that continuous insulin infusion (pump
therapy) appears to provide slightly better glycemic control and decreased hypoglycemia than
MDI.
Insulin pump therapy is often preferred by children and their families. MDI regimens can
require as many as six to seven injections per day, which may be a barrier for some patients and
families. In these children, an insulin pump can be an attractive option for intensive therapy at
any age, and appears to improve quality of life. Of note, most families with young children who
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participated in clinical studies decided to continue with pump therapy even after the study was
completed.
Dose Insulin requirement is based upon the body weight, age, and pubertal stage of the
child. In general, the newly diagnosed child requires an initial total daily insulin dose of 0.5 to
1.0 units/kg. Prepubertal children usually require lower doses. Higher doses are needed in
pubertal children, patients in ketoacidosis, or in patients receiving glucocorticoid therapy.
In infants and toddlers who receive their insulin by syringe, the insulin dose may be so small
that dilution is required to allow for easier and more precise administration. The smallest dose
of insulin that can be accurately administered without dilution using a syringe is 0.5 units. Many
insulins can be diluted either at a specialized pharmacy or at home with proper training. Diluting
fluid for many insulin preparations is available from the insulin manufacturer. The insulin pump
can deliver much smaller doses of insulin, in the order of 0.05 units at a time and often obviates
this problem.
Follow-up visits at least every three months are required to adjust for the increasing insulin
requirement with continued growth of the child and increasing insulin deficiency with duration
of diabetes. Interim adjustments can be taught to the family with telephone consultation. As a
child enters puberty, daily insulin requirements may increase to more than 1 unit/kg because
puberty increases insulin resistance.
Intensive therapy To use the different types of insulin in intensive therapy, the various
functions of exogenous insulin need to be considered.
Basal insulin In children, the basal insulin requirement (e.g., insulin glargine or basal rate of
pump) is approximately 40 to 50 percent of the total daily dose.
Correction of elevated blood glucose An insulin correction factor can be used to adjust
insulin dose for hyperglycemia before meals or between meals. For rapid-acting insulin, divide
1500 by the total daily insulin dose. This calculation estimates the decrease in blood glucose
from one unit of a rapid-acting insulin. As an example, if the total daily insulin dose is 30 units,
then 1 unit of rapid-acting insulin will decrease the blood glucose approximately by 50 mg/dL.
Utilization of ingested carbohydrate A premeal or presnack rapid-acting agent is used to

cover the insulin requirements for the anticipated consumption of carbohydrates. The amount
of ingested carbohydrate covered by one unit of rapid-acting insulin is roughly calculated based
upon the total daily insulin dose and dividing this into 500. As an example, if the total daily
insulin dose is 50 units, then 1 unit of rapid-acting insulin will cover 10 gms of carbohydrate. For
short-acting (regular) insulin (rarely used in MDI or pump regimens), divide 450 by the total daily
insulin dose.
On average, 1 unit of insulin is required to cover:
20 grams of carbohydrates in most young children (1 to 6 years of age).
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10 to 12 grams of carbohydrates in older prepubertal children..
8 to 10 grams in pubertal adolescents.
The initial dose administered by insulin pump when converting a patient from MDI or
conventional therapy is dependent on diabetes control and total daily insulin dose. If control has
been excellent, the initial daily insulin pump dose is 10 to 20 percent less than the previous
dose. If control has been poor, the same total previous daily dose should be used.
Honeymoon phase A few weeks after the diagnosis and initiation of insulin therapy, a
period of decreasing exogenous insulin requirement occurs, popularly known as the
"honeymoon" or remission phase of diabetes. During this period, the remaining functional beta
cells secrete some endogenous insulin resulting in reduced exogenous requirement. Close
monitoring of blood glucose is mandatory as hypoglycemic episodes are likely if the insulin dose
is not appropriately adjusted. The duration of this phase is variable and may last several months
to several years. The end of this phase is indicated by rising blood glucose, A1C, and increasing
exogenous insulin need.
OTHER MANAGEMENT ISSUES Other issues that need to be addressed in the management
of children and adolescents with type 1 diabetes include nutrition, exercise, and psychosocial
factors that impact on glycemic control.
Nutrition Prescriptive nutritional therapy depends in large part on the choice of insulin
regimen. Ideally, meal planning should provide a consistent carbohydrate intake. This is
especially true for children on a conventional fixed insulin regimen who require a nutritional
prescription. Meal planning must be individualized to accommodate the child's food preference
and cultural eating patterns and schedules.
At the time of diagnosis, many patients have lost weight that is restored with the initiation of
insulin therapy, hydration, and adequate energy intake. During this time of increased
consumption, children often require large amounts of insulin to control their blood glucose
levels. After correction of weight loss in a few weeks, ongoing assessment of growth (e.g.,
weight, height, body mass index [BMI]) is necessary to monitor adequacy of dietary intake and
glycemic control. Excellent glycemic control is necessary for normal growth and development.
Excess insulin administration, or failure to reduce insulin dose post puberty or after initial regain
of weight, may lead to excessive weight gain as the child attempts to treat hypoglycemia by
overeating. If the child becomes overweight, caloric intake or insulin administration may need to
be reduced.
It is desirable for the patient and family to consult with a registered dietitian with experience in
pediatric nutrition and diabetes. The dietitian provides instruction regarding the effect of food
on blood glucose concentration, a diet that ensures adequate nutritional intake, and
information regarding carbohydrate counting. Mastery of carbohydrate counting and
understanding the glycemic effects of different kinds of carbohydrates is especially important in
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patients on an intensive regimen, who need to adjust premeal boluses insulin based upon the
anticipated glycemic effect of consumed carbohydrates.
Exercise In patients with diabetes, the physiologic response to exercise depends upon the
plasma insulin concentration at the time of exercise. This variable response increases the risk of
hypoglycemia in patients when they engage in physical activity that is greater than the intensity,
duration or frequency of normal activity.
Children who participate in sport activities require increased monitoring of blood glucose
(before, after, and hourly during prolonged strenuous activity) and appropriate adjustment of
insulin dosing.
In children on fixed-dose insulin regimens, snacks should be administered before sports. Some
children may require additional carbohydrates after sports because intense physical exertion
can result in high blood glucose during sports, likely from increased catecholamine release, but
will usually result in hypoglycemia if not treated following the game.
In children on insulin pump therapy, the basal insulin infusion rate is reduced by 30 to 70
percent during sports activities to prevent hypoglycemia.
School personnel and coaches need to recognize hypoglycemic symptoms and know how to
treat hypoglycemia. At the onset of a new sports season, frequent blood glucose monitoring
during the 12 hours after physical activity should be performed to guide insulin dose adjustment
as insulin requirements will decrease during this period.
Psychosocial issues Diabetes, as with other chronic diseases, has a psychological impact on
the patient and family. Depression and anxiety are commonly seen in parents, older children,
and adolescents with diabetes. In older children and adolescents, family conflict arises over the
level of adult involvement in the care of the patient during a normal developmental period of
increasing independence and self-assertiveness. These psychological issues lead to poorer
glycemic control and an increased risk of hospitalization and episodes of diabetic ketoacidosis.
FOLLOW-UP Frequency of follow-up visits is tailored to the needs of the child and family.
Visits are more frequent during the initial educational phase with intensive training for the
family and during periods when adjustment of glycemic control and insulin dose are
problematic.
Once the family is well trained and a management plan is established and stable, we
recommend follow-up at least every three months to review glycemic control and adjust
management as needed. However, families must be trained to perform interim adjustments and
to contact the diabetes team for assistance in adjustment of insulin dosing between visits.
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Screening A complete physical examination should be performed at least twice a year and
includes the following:
Height and weight Monitor for adequate growth.
Blood pressure Screen for hypertension.
Pubertal assessment Because puberty increases insulin resistance, increased insulin

requirement can be anticipated by identifying early signs of puberty.
Thyroid examination Check for thyroid enlargement to screen for autoimmune

hypothyroidism, an associated condition of type 1 diabetes.
Examination of injection sites for evidences of lipohypertrophy or atrophy that can alter insulin
absorption rates.
Fundoscopic examination Screen for retinopathy. However, interpretation is limited in an

endocrine office setting without dilatation of the pupil.
As the disease duration increases, extremity examination for evidence of sclerodactyly (joint or
finger stiffness) or peripheral neuropathy (feet).
Laboratory evaluation includes evaluation of glycemic control and screening for long-term
sequelae. A1C, every three months Evaluate glycemic control.
Annual screening for microalbuminuria for children 10 years of age and five-year duration of
diabetes Screen for nephropathy.
Annual ophthalmologic examination for children 10 years of age and three- to five-year
duration of diabetes Screen for retinopathy.
Annual foot examination Evaluate foot health and screen for neuropathy in children 10
years of age.
Celiac disease screening at diagnosis and every other year
Lipid profile Screen for dyslipidemia once puberty begins, and if normal, repeat the screen
every five years. If abnormal, screen yearly as recommended in the ADA guidelines. However,
children who are in poor glycemic control may manifest new lipid abnormalities. Therefore, we
also suggest rescreening at the time of a prolonged episode of poor glycemic control.
Thyroid function testing Screening for autoimmune hypothyroidism every one or two years
or if features of hypothyroidism or if an enlarged thyroid are evident.
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Referrals include:
Nutrition therapy by registered dietitian.
Mental health evaluation including screening for depression for children 10 years of age.
Dilated ophthalmologic evaluation for retinopathy yearly for children 10 years of age or after
five-year duration of diabetes .
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Clinical features and diagnosis of diabetic ketoacidosis in
children
George S Jeha, MD - Morey W Haymond, MD
Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type
1 diabetes mellitus (DM). DKA also can occur children with type 2 DM, particularly in obese
African-American adolescents.
In recent years, the incidence and prevalence of type 2 diabetes mellitus have increased across
all ethnic groups. This has been coupled with an increasing awareness that children with type 2
DM can present with ketosis or DKA, particularly obese African American adolescents.
DEFINITION Consensus statements from the European Society for Paediatric

Endocrinology/Lawson Wilkins Pediatric Endocrine Society (ESPE/LWPES) and from the
American Diabetes Association defined two biochemical criteria for the diagnosis of DKA:
Hyperglycemia, blood glucose of >200 mg/dL (11 mmol/L) AND
Metabolic acidosis, defined as a venous pH <7.3 and/or plasma bicarbonate <15 meq/L (15
mmol/L).
These abnormalities are accompanied by hyperketosis (concentration of total ketone bodies >5
mmol/L) and hyperosmolality. The clinical manifestations of DKA are related to the degree of
hyperosmolality, volume depletion, and acidosis.
EPIDEMIOLOGY DKA is frequently the initial presentation of children with new onset type 1
DM. In a surveillance study of almost 3000 episodes of DKA in the United Kingdom, 38 percent
occurred in patients at the time of initial diagnosis of DM. In other studies from Europe and
North America, the frequency of DKA as the initial presentation for type 1 DM is approximately
25 percent (range from 15 to 67 percent).
Children who are young (<6 years of age) or from a low socioeconomic background are at
increased risk for DKA at initial presentation
Risk factors for recurrent DKA included:
Higher A1C levels and higher reported insulin requirements.
Female adolescents, with the highest risk in female adolescents over 13 years of age.
Children over 13 years of age, regardless of gender, who are underinsured and/or have a
history of psychiatric disorders.
Longer duration of DM.
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Type 2 diabetes mellitus Although less common, ketosis and DKA can occur in children with
type 2 DM, particularly in African-American children. In a retrospective review of 69 patients
(between 9 and 18 years of age) who presented with DKA at a tertiary center, 13 percent had
type 2 DM. At presentation, there was no difference in the serum pH level but patients with
type 2 DM compared to those with type 1 DM had higher blood glucose levels.
PRECIPITATING FACTORS Recurrent episodes of DKA with established type 1 DM are

primarily the result of underlying poor metabolic control and frequently missed insulin
injections. Omission of insulin injections is particularly common among adolescents.
Stress is also an important precipitating factor. Stress increases the secretion of

catecholamines, cortisol, and glucagon, which promote both glucose and ketoacid production.
As an example, infection can precede an episode of DKA.
In addition, medications such as corticosteroids, atypical antipsychotics, diazoxide, and high

dose thiazides, have precipitated DKA in individuals not previously diagnosed with type 1 DM.
DIAGNOSTIC EVALUATION The clinical diagnosis of diabetes in a previously healthy child

requires a high index of suspicion. Signs and symptoms of DKA are related to the degree of
hyperosmolality, volume depletion, and acidosis.
Signs and symptoms The earliest symptoms are related to hyperglycemia. Older children
and adolescents typically present with polyuria (due to the glucose osmotic diuresis), polydipsia
(due to the increased urinary losses), and fatigue. Other findings include weight loss, nocturia
(with or without secondary enuresis), daytime enuresis, and vaginal or cutaneous moniliasis.
Hypovolemia may be severe if the urinary losses are not replaced.
Polyphagia usually occurs early in the course of the illness. However, once insulin deficiency
and ketoacidosis become significant, appetite is suppressed. Some patients present with
anorexia, vomiting, and abdominal pain, which at times can mimic appendicitis or
gastroenteritis.
Hyperventilation and deep (Kussmaul) respirations represent the respiratory compensation to

metabolic acidosis. Hyperpnea results from an increase in minute volume (rate x tidal volume)
and can be increased by tidal volume alone without an increase in respiratory rate. As a result,
the patient's chest excursion as well as respiratory rate should be carefully observed. In infants,
the hyperpnea may be manifested only by tachypnea. Patients may also have a fruity breath
secondary to exhaled acetone.
Although children with DKA are volume depleted, they are less likely to show the classic signs
of hypovolemia such as dry oral mucous membranes and decreased skin turgor than patients
with vomiting or diarrhea with the same degree of weight loss. This important distinction is a
reflection of water loss in excess of sodium with a glucosuria-induced osmotic diuresis and
water loss from hyperventilation. Water is freely distributed between the extracellular and
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intracellular fluids. As a result, water loss produces less extracellular fluid volume depletion than
salt and water loss. Water loss also is largely responsible for the often marked rise in plasma
osmolality.
Neurologic findings, ranging from drowsiness, lethargy, and obtundation to coma, are related
to the severity of hyperosmolality. Cerebral edema occurs in 0.5 to 1 percent of cases of DKA in
children, and is the leading cause of mortality. The clinician should be vigilant for early signs of
cerebral edema and should treat aggressively if cerebral edema is suspected.
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Laboratory findings Initial laboratory testing should include serum testing for glucose,
electrolytes, creatinine and urea nitrogen, blood gases, and hematocrit. The diagnosis of DKA is
confirmed by the findings of hyperglycemia, a high anion gap acidosis, ketonuria, and
ketonemia.
Serum glucose The serum glucose is, by definition, greater than 200 mg/dL (11 mmol/L).
This degree of hyperglycemia exceeds the renal tubular threshold for glucose reabsorption,
resulting in an osmotic diuresis with polyuria and subsequent volume depletion. Glucosuria also
predisposes to candidal infections in diapered children and adolescent girls.
Acid-base status The second criterion for the diagnosis of DKA is a serum bicarbonate <15
meq/L or a venous pH <7.3. Both insulin deficiency and glucagon excess contribute to the
development of both the hyperglycemia and the ketoacidosis. Acetoacetic acid is the initial
ketone formed and it may be reduced to beta-hydroxybutyric acid (another organic acid) or
decarboxylated to acetone, which will be detected as a ketone but does not contribute to the
acidosis.
The severity of metabolic acidosis is dependent upon three factors:
1. The rate of ketoacid production.
2. The duration of increased ketoacid production; the acidosis will be less severe in patients
who present early due, for example, to abdominal pain or an underlying infection that
precipitated the DKA.
3. The rate of acid excretion in the urine. Patients with relatively normal renal function can
markedly increase acid excretion, thereby minimizing the severity of the acidosis
Conventional urine screening tests for ketones are performed with nitroprusside impregnated
strips or tablets (Acetest). Nitroprusside reacts with acetoacetate and acetone but not beta-
hydroxybutyrate. In DKA, beta-hydroxybutyrate makes up 75 percent of the circulating ketones.
Thus, clinical testing with nitroprusside may underestimate the severity of ketoacidosis and
ketonuria. On the other hand, during recovery beta-hydroxybutyrate is converted to
acetoacetate and acetone persists for a longer period. As a result, urine testing may give a false
impression of persistent ketoacidosis. Therefore, direct measurement of beta-hydroxybutyrate
should be used whenever possible.
When insulin is given to patients with diabetic ketoacidosis, metabolism of the ketoacid anions
results in the regeneration of HCO3- and correction of the metabolic acidosis. For this reason,
ketoacid anions have been called "potential bicarbonate," and their loss in the urine represents
the loss of HCO3-. As a result, a normal AG acidosis is typically seen during the treatment phase
of diabetic ketoacidosis due to the urinary loss of these bicarbonate precursors.
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The serum anion gap is calculated from the following formula in units of meq/L or mmol/L:
Serum anion gap = Serum sodium (Serum chloride + bicarbonate)
The normal value in children is 122 mmol/L.
Serum sodium The serum sodium concentration is affected by hyperglycemia. The

magnitude of this effect is determined by two major factors.
Hyperglycemia will raise the plasma osmolality, resulting in osmotic water movement out of
the cells which lowers the serum sodium by dilution. Physiologic calculations suggest that the
serum sodium should be lowered by 1.6 meq/L for every 100 mg/dL (5.5 mmol/L) elevation in
serum glucose. However, experimental data in adults suggest that a better overall estimate is a
reduction in serum sodium of 2.4 meq/L for every 100 mg/dL (5.5 mmol/L) elevation of plasma
glucose.
The direct effect of hyperglycemia to lower the serum sodium is counteracted to a variable
degree by the glucosuria-induced osmotic diuresis. The diuresis results in water loss in excess of
sodium and potassium, which will tend to raise the serum sodium concentration and plasma
osmolality. Inadequate water intake, which may be a particular problem in hot weather and in
infants and young children who cannot independently access water, prevents partial correction
of the hyperosmolality and can even lead to hypernatremia despite the presence of
hyperglycemia. On the other hand, consumption of large volumes of dilute fluid, since thirst is
stimulated by hyperosmolality, can contribute to hyponatremia.
A third factor that can affect the serum sodium concentration represents a laboratory artifact.
Hyperlipidemia can cause a form of pseudohyponatremia by reducing the fraction of plasma
that is water. As a result, the amount of sodium in the specimen is reduced and the measured
plasma sodium concentration will be lower, even though the physiologically important plasma
water sodium concentration and plasma osmolality are not affected. Ion-selective electrodes
have been used to directly measure the plasma water sodium concentration in this setting, but
they have been shown to have variable accuracy and are not routinely used.
Serum potassium The osmotic diuresis and increased ketoacid excretion promote urinary
potassium loss, while vomiting and diarrhea, if present, increase gastrointestinal potassium
losses. In adults, average potassium losses during DKA are 3 to 5 meq/kg; the estimated
potassium loss in children has been less well studied but average losses appear to be 6 to 7
meq/kg.
The potassium losses will tend to produce hypokalemia. However, the combination of insulin
deficiency, which impairs potassium entry into the cells, and hyperosmolality, which pulls water
and potassium out of the cells, tends to raise the serum potassium. Ketoacidosis itself appears
to have little effect on transcellular potassium movement.
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Because of these counteracting effects, the serum potassium at the time of presentation can
be normal, increased, or decreased. Regardless of the initial level, therapy with insulin and fluids
will predictably lower the serum potassium concentration, which needs to be monitored
carefully.
Serum phosphate Children with DKA are typically in negative phosphate balance because of
decreased phosphate intake and phosphaturia caused by the glucosuria-induced osmotic
diuresis. Despite the presence of phosphate depletion, the serum phosphate concentration at
presentation is usually normal or even high because both insulin deficiency and metabolic
acidosis cause a shift of phosphate out of the cells. This transcellular shift is reversed and the
true state of phosphate balance is unmasked after treatment with insulin.
Blood urea nitrogen Patients with severe hypovolemia often have elevations in blood urea
nitrogen. This finding at presentation may have predictive value since it is a risk factor for
cerebral edema during therapy.
Assessment of severity At presentation, the following clinical and laboratory findings may
be used to estimate the severity of DKA:
Acid-base status The venous pH and serum bicarbonate concentration directly reflect the
severity of the acidosis. The respiratory rate also may be helpful, since the magnitude of the
respiratory compensation is directly related to the severity of the acidosis.
The degree of elevation in the anion gap is another measure of the severity of the ketosis and
can be a helpful estimate of acidosis. Marked elevations may also reflect decreased renal
perfusion, which limits ketoacid excretion. Alternatively, measurement of plasma beta-
hydroxybutyrate is now widely available and is a direct method for monitoring the degree of
ketoacidemia.
Neurologic status Severe neurologic compromise at presentation is a poor prognostic

indicator, in part because such patients are at increased risk for developing cerebral edema
during therapy. This was illustrated in a retrospective multicenter study of 61 children with DKA
and cerebral edema; all patients who either died or survived in a persistent vegetative state
presented with Glasgow coma score 7 (score of 6 to 7 includes an abnormal or absent
purposeful response to pain). Because of the high morbidity and mortality of cerebral edema, it
is important to recognize and treat at the earliest signs of neurologic compromise.
Estimation of volume status, (generally 5-10% fluid deficit).
Duration of symptoms A long duration of symptoms, as well as depressed level of

consciousness or compromised circulation, is evidence of severe DKA and should prompt close
monitoring for potential complications of DKA, such as cerebral edema. Symptoms of cerebral
edema typically occur several hours after the initiation of treatment for DKA. The presence of
such symptoms at presentation indicates a poor neurologic prognosis.
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Treatment and complications of diabetic ketoacidosis in children
The approach and principles of management are the same for all children with DKA regardless
of the severity of DKA.
The clinician must individualize the treatment plan based on the child's physical and laboratory
findings, and treatment will need to be adjusted over time for each child. No protocol or
formula should be blindly used in the management of DKA.
Moderate and severe DKA The underlying principles of management are to administer
insulin and to correct the fluid and electrolyte abnormalities of metabolic acidosis, hypovolemia,
potassium, and perhaps phosphate depletion. During initial therapy, the patient should be
carefully monitored for signs of cerebral edema. At the time of presentation, clinical estimates
of the extracellular fluid volume deficit in moderate to severe DKA are usually in the range of 7
to 10 percent. Hypovolemic shock is a rare occurrence in DKA. The patient in shock should be
evaluated for other causes of shock.
Evaluation of the degree of dehydration in the child with DKA is difficult even for the
experienced clinician. Many of the clinical findings used to assess volume status are unusable,
such as the condition of the patient's oropharynx, which is almost always dry because of
hyperventilation and mouth breathing. Skin turgor is also frequently unreliable because the fluid
losses are from both the extracellular and intracellular spaces.
In addition, the degree of extracellular fluid loss is in part masked because hyperglycemia results
in a shift of water from the intracellular to the extracellular fluid compartment. This effect is
rapidly reversed with insulin therapy.
The goals of initial volume expansion are:
To restore the effective circulating volume by replacing sodium and water loss.
To restore glomerular filtration rate to enhance clearance of ketones and glucose from the
blood.
Fluid repletion in moderate to severe DKA is usually begun with an infusion of 10 to 20 mL/kg
over one hour. If and only if the effective circulating volume is still compromised, an additional
infusion of 10 mL/kg can be given over the next hour. We generally do not give more than 20
mL/kg in total boluses unless the patient's cardiovascular status is compromised.
After the first four to six hours, we usually switch to one-half isotonic saline. The rate of fluid
administration should be calculated to fully replete the patient over 48 hours. However, the rate
over the first 24 hours should not exceed 1.5 to 2 times the usual rate of administration of
maintenance fluid. Based upon body surface area, the volume should be no greater than 2500
mL/m2 for 24 hours, which includes the initial fluid bolus as well as any oral intake. Urinary
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losses should not be added to the calculated total volume of fluids. Higher rates of fluid
administration might increase the risk for cerebral edema
Insulin After the initial fluid bolus is complete, an insulin infusion is begun at a rate of 0.1
unit/kg per hour. A lower dose of 0.05 unit/kg per hour may be used initially in younger children
who may be more sensitive to insulin. An insulin bolus should NOT be given. A study with a
case-control design suggests that the risk of cerebral edema is decreased by delaying insulin
administration for one hour or more after initiation of fluid therapy.
The insulin can be mixed in one-half isotonic saline and administered in a syringe infusion
pump to control the rate of insulin administration. The solution should be concentrated as much
as possible, because the tubing and syringe can bind insulin, and should be flushed through the
tubing of the insulin infusion syringe. As an example, 50 units of short-acting ("regular") insulin
are added to 50 mL of one-half isotonic saline, providing 1 unit per mL of infusate. The syringe is
then "piggybacked" into the patient's indwelling intravenous catheter as close as possible to the
venous site.
A frequent mistake is to follow the glucose concentration as a measure of improvement of

DKA. The insulin infusion rate should only be reduced when the ketoacidosis is corrected. If
the ketoacidosis persists, the patient should be reassessed. Possible explanations are severe
insulin resistance due to infection, incorrect preparation of the insulin infusion, and decreased
insulin delivery due to adhesion of insulin to tubing. We recommend preparing a new insulin
syringe for the pump to rule out the possibility of an erroneous dilution of insulin. The insulin
dose in such patients usually needs to be increased.
In most patients, the hyperglycemia corrects before the ketoacidosis. The saline infusion
should be changed to 5 percent dextrose in isotonic saline or lactated Ringer's solution when
the serum glucose concentration decreases to 250 to 300 mg/dL (13.9 to 16.7 mmol/L). This
allows continued administration of insulin, which is often necessary to correct the residual
ketoacidosis. If the serum glucose falls below 250 mg/dL (13.9 mmol/L) before complete
resolution of the ketoacidosis, the concentration of dextrose in the intravenous solution should
be increased to up to 10 to 12.5 percent.
The purpose of adding dextrose to the intravenous solution is to prevent hypoglycemia while
continuing to administer insulin to correct ketoacidosis. In our practice, we establish steady
rates of insulin and intravenous fluids during the first six to eight hours of insulin therapy, which
allows for a gradual decrease in serum glucose concentrations (about 50 to 100 mg/dL per hour
or 3 to 5 mmol/L per hour). Once the serum glucose reaches 200 to 300 mg/dL, dextrose is
added to the IV solution (usually as 5 percent dextrose) to permit the continued insulin
administration necessary to clear the ketoacidosis while minimizing the risk of hypoglycemia. In
younger patients with increased insulin sensitivity it may be necessary to decrease the insulin
infusion rate to 0.05 u/kg/hour as long as the ketoacidosis continues to improve. For patient
safety reasons, it is advisable to keep serum glucose concentrations around 150 to 200 mg/dL
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(8.3 to 11.1 mmol/L) for younger children; or 100 to 150 mg/dL in older children (5.5 to 8.3
mmol/L), before switching to subcutaneous insulin.
In unusual circumstances, and especially if facilities to administer intravenous insulin are not
readily available, subcutaneous or intramuscular insulin can be used as initial therapy. However,
with subcutaneous administration, the absorption of insulin may be inconsistent, particularly in
the setting of volume depletion and secondary sympathetic activation which can decrease local
perfusion
Serum potassium Both renal and gastrointestinal losses can contribute to an often marked
degree of potassium depletion in DKA. These losses will tend to produce hypokalemia. On the
other hand, the combination of insulin deficiency, which impairs potassium entry into the cells,
and hyperosmolality, which pulls water and potassium out of the cells, tend to raise the serum
potassium.
Because of these counteracting effects, the serum potassium at the time of presentation can
be normal, increased, or decreased. Regardless of the initial level, insulin therapy drives
potassium into cells, resulting in a fall in the serum potassium concentration. Thus, potassium
replacement will almost always be required within one to two hours of the initiation of fluid
and insulin therapy in children with DKA who do not have renal failure.
Optimal therapy varies with the initial serum potassium. Regardless of the regimen, the serum
potassium should be carefully monitored during therapy. In addition, electrocardiographic
monitoring is recommended in patients with either hypokalemia or hyperkalemia.
If the patient is normokalemic, potassium replacement should be given with the start of insulin
therapy (e.g., adding 40 meq/L of potassium to the saline solution), as insulin will reduce the
serum potassium.
If the patient is markedly hypokalemic, potassium replacement should be started immediately,

using an initial potassium concentration of 40 meq/L, concurrent with volume expansion. The
serum potassium levels should be monitored hourly and the replacement adjusted as needed.
The insulin infusion should be delayed and/or given at a reduced rate until the serum potassium
is in the normal range.
If the patient is hyperkalemic, potassium replacement should be initiated when the serum
potassium falls to normal and after verifying urine production.
Potassium replacement is usually given as potassium chloride. Potassium phosphate and

potassium acetate also have been used. Potassium replacement therapy should continue with
intravenous insulin and fluid therapy and the serum potassium should be carefully monitored.
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The main indication for phosphate therapy is a serum phosphate concentration less than 1.0
mg/dL (0.32 mmol/L). When phosphate is given, careful monitoring of the serum calcium and
magnesium is required
Hourly monitoring of blood glucose is needed with the initiation of fluid and insulin therapy to
avoid hypoglycemia. If capillary samples are obtained, they should initially be compared to a
venous measurement.
Electrolytes and venous pH should be initially evaluated hourly for the first three to four hours
and then every two hours, to assess the anticipated changes of sodium, potassium, bicarbonate,
and anion gap described above. When clinically appropriate, the frequency of measurement can
be reduced to every four to six hours.
Clinical parameters including heart rate, respiratory rate, blood pressure, oxygen saturation,
and neurologic status need to be monitored continuously. In patients with severe DKA or altered
mental status, frequent neurologic examinations are recommended. It is particularly important
to monitor for warning signs and symptoms of cerebral edema (headache, inappropriate
decrease in heart rate, recurrence of vomiting, changes in neurologic status, rising blood
pressure, and decreased oxygen saturation).
Electrocardiographic monitoring, especially in severe DKA, for evidence of changes characteristic

of hyperkalemia or hypokalemia.
Accurate measurement of fluid input and output. If the patient is neurologically impaired or it is
difficult to ascertain urine output, a urine catheter should be placed.
Discontinuing the insulin infusion The insulin infusion should continue at 0.05 to 0.1
units/kg per hour until the following conditions are met:
1. Serum anion gap reduced to normal (12 2 meq/L).

2. Venous pH is >7.30 or serum HCO3 is >15 meq/L.
3. Plasma glucose <200 mg/dL (11.1 mmol/L).
4. Tolerating oral intake.
The first subcutaneous injection should be given at an appropriate interval to allow for
absorption prior to stopping insulin infusion. The onset of rapid-acting insulin (i.e., insulin lispro)
is approximately 15 minutes, whereas that of short-acting (regular) insulin is 30 to 60 minutes.
COMPLICATIONS AND MORTALITY Reported mortality rates for DKA are consistent in
developed countries, ranging from 0.15 to 0.51 percent in national population studies in
Canada, the United Kingdom, and the United States. Cerebral edema accounts for the majority
of deaths (60 to 90 percent). Other causes include aspiration pneumonia, multiple organ failure,
gastric perforation, and traumatic hydrothorax.
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Cerebral edema in children with diabetic ketoacidosis
It is generally believed that cerebral edema is related to the management of DKA. Numerous
factors have been implicated, but none has been proven. Cerebral edema may be present
before treatment has begun, but more commonly occurs 4 to 12 hours after the initiation of
therapy. Thus, therapy may exacerbate but not initiate the pathologic process(es) that lead to
cerebral edema.
The mechanisms responsible for cerebral edema remain poorly understood. Ischemic,
vasogenic, osmotic, or cytotoxic processes have been proposed.
Several risk factors for developing cerebral edema in children with DKA have been identified.
Some of these risk factors may merely reflect a longer period of symptoms prior to diagnosis
with a greater likelihood of presenting with severe DKA.
Younger children.
Children with newly diagnosed diabetes.
Failure of the serum sodium to rise as predicted following insulin therapy and fluid repletion,
indicating a greater fall in plasma osmolality .
Increased blood urea nitrogen at presentation of DKA, which may represent a greater degree of
hypovolemia .
The severity of acidosis at presentation.
The use of bicarbonate therapy for correction of the acidosis in DKA.
After adjusting for the severity of acidosis, a lower initial partial pressure of arterial carbon
dioxide.
SIGNS AND SYMPTOMS The presentation of cerebral edema varies but the onset of
headache is usually the earliest symptom. Altered level of consciousness, sustained heart rate
deceleration, or age-inappropriate incontinence are important early signs of impending
neurologic collapse. These symptoms often occur prior to notable changes in head computed
tomography. Frequent monitoring at the bedside for early symptoms of cerebral edema may
identify these children sufficiently early for intervention to prevent brain damage.
Bedside evaluation The following criteria may be helpful in identifying children who may
progress to severe, life-threatening cerebral edema.
Major criteria
1. Altered mentation/fluctuating level of consciousness.
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2. Sustained heart rate deceleration (decline more than 20 beats per minute) not
attributable to improved intravascular volume or sleep state.
3. Age-inappropriate incontinence.
Minor criteria
1. Vomiting.
2. Headache.
3. Lethargy or not easily aroused from sleep.
4. Diastolic blood pressure >90 mmHg.
5. Age <5 years.
Diagnostic criteria
1. Abnormal motor or verbal response to pain.

2. Decorticate or decerebrate posture.
3. Cranial nerve palsy (especially III, IV, and VI).
4. Abnormal neurogenic respiratory pattern (eg, grunting, tachypnea, Cheyne-Stokes
respiration, apneusis).
TREATMENT An essential part of therapy in DKA is careful monitoring for changes in

mental or neurologic status that would permit early identification and therapy of cerebral
edema. As soon as cerebral edema is suspected, treatment should be initiated. The 2004
ESPE/LWPES consensus statement recommends the following:
The rate of fluid administration should be reduced.
Mannitol should be given at 0.25 to 1.0 g/kg intravenously over 20 minutes. The mannitol dose
may be repeated in two hours, if there is no initial response.
3 percent saline (5 to 10 mL/kg over 30 minutes), has been used as an alternative hypertonic
agent, but clinical experience is limited.
Intubation and mechanical ventilation may be required. However, hyperventilation should be

avoided and has been associated with a poor outcome in patients whose pCO2 was driven
below 22 mmHg. Aggressive hyperventilation (beyond the baseline hyperventilation present in
most patients with DKA) may decrease cerebral blood flow enough to cause cerebral ischemia
and actually increase the extent of brain injury in any form of cerebral edema.
OUTCOME The mortality rate among children with DKA who develop cerebral edema is
approximately 20 to 25 percent; among survivors, approximately 15 to 35 percent have
permanent sequelae.
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Venous thrombosis Children with DKA appear to be at increased risk for deep venous
thrombosis, particularly in association with femoral central venous catheter placement. It has
been suggested that this may in part be due to a prothrombotic state associated with DKA.
Aspiration Children with DKA who present with an altered state of consciousness and
vomiting are at increased risk for aspiration. Placement of a nasogastric tube should be
performed and stomach contents emptied. If necessary, intubation also should be performed to
protect the airway.
Cardiac arrhythmia Cardiac arrhythmias may be seen with either hypokalemia or

hyperkalemia.
Pancreatic enzyme elevations Mild elevations in serum amylase and lipase are seen in
about 40 percent of children with DKA, and are also common in adults with DKA. In most cases,
this does not reflect acute pancreatitis. The diagnosis of acute pancreatitis should be based on
clinical findings and confirmed by CT scan.
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Clinical features and detection of congenital hypothyroidism
Stephen LaFranchi, MD
Congenital hypothyroidism, occurring in approximately 1:4000 newborns, is the most common

treatable cause of mental retardation. There is an inverse relationship between age at
diagnosis and intelligence quotient (IQ) later in life, so that the longer the condition goes
undetected, the lower the IQ.
Most newborn babies with congenital hypothyroidism have few or no clinical manifestations of
thyroid deficiency, and the majority of cases are sporadic. As a result, it is not possible to predict
which infants are likely to be affected. For these reasons, newborn screening programs in which
either thyroxine (T4) or thyrotropin (TSH) are measured in heel-stick blood specimens were
developed in the mid-1970s to detect this condition as early as possible. These screening efforts
have been largely successful, but more severely affected infants may still have a slightly reduced
IQ and other neurologic deficits despite prompt diagnosis and initiation of therapy.
ETIOLOGY Approximately 85 percent of cases of congenital hypothyroidism are sporadic

and 15 percent are hereditary (most of which are because of one of the inborn errors of thyroid
hormone synthesis).
Thyroid dysgenesis The most common cause of congenital hypothyroidism is some form of
thyroid dysgenesis, eg, agenesis, hypoplasia, or ectopy. Thyroid ectopy accounts for two-thirds
of the cases worldwide.
Disorders of thyroid hormone synthesis and secretion Hereditary defects in virtually all
steps in thyroid hormone biosynthesis and secretion have been described; all are characterized
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by autosomal recessive inheritance. Among them, the most common is a defect in thyroid
peroxidase activity that results in impaired iodide oxidation and organification.
Defects in thyroid hormone transport Passage of thyroid hormone into the cell is facilitated
by plasma membrane transporters. A mutation in one such transporter gene, monocarboxylase
transporter 8 (MCT8), located on the X chromosome, has been reported in five boys with X-
linked mental retardation. The defective transporter appears to impair passage of T3 into
neurons; this syndrome is characterized by elevated serum T3 levels and psychomotor
retardation.
Central hypothyroidism Those screening programs that use the initial T4-back-up TSH
approach detect infants who have central (hypothalamic or pituitary) hypothyroidism, whereas
screening programs based only on TSH screening do not. Central hypothyroidism occurs in
1:25,000 to 1:100,000 newborns. It may be associated with other congenital syndromes,
particularly mid-line defects such as septo-optic dysplasia or mid-line cleft lip and palate defects,
and may follow birth trauma or asphyxia. Rare genetic causes result from mutations in the
genes for the thyrotropin-releasing hormone receptor, or for TSH or its receptor.
Transient congenital hypothyroidism Transient congenital hypothyroidism is more common

in Europe (1:100) than in North America (1:50,000). In a 20-year study from a French newborn
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screening program, 40 percent of patients had transient hypothyroidism. The causes of transient
hypothyroidism in newborn infants are:
1. Iodine deficiency Iodine deficiency, particularly in preterm infants, accounts for many
cases in Europe, where maternal dietary iodine intake is less than in the United States.
2. Transfer of blocking antibodies or antithyroid drugs Transplacental transfer of TSH-
receptor blocking antibodies (TRB-Ab) can occur in infants of mothers with autoimmune
thyroid disease. Studies using newborn screening specimens shows TRB-Ab in
approximately 1:100,000 newborns. This form of hypothyroidism subsides in one to
three months as the maternal antibodies are cleared.
3. Antithyroid drugs Antithyroid drugs given to mothers with hyperthyroidism also can
cross the placenta. These drugs are cleared in days; as a result, many of these infants
are euthyroid when restudied a few weeks after delivery.
4. Iodine exposure Exposure of the fetus or newborn to high doses of iodine can cause
hypothyroidism. This can occur in infants of mothers with cardiac arrhythmias treated
with amiodarone, when iodine-containing antiseptic compounds are used in mothers or
infants, or after amniofetography with a radiographic contrast agent. The risk is
probably related to the type and duration of iodine exposure.
CLINICAL MANIFESTATIONS More than 95 percent of newborn infants with congenital

hypothyroidism have few if any clinical manifestations of hypothyroidism. This is because
some maternal T4 crosses the placenta, so that even in infants who cannot make any thyroid
hormone umbilical cord serum T4 concentrations are about 25 to 50 percent of those of normal
infants. In addition, many infants with congenital hypothyroidism have some, albeit inadequate,
functioning thyroid tissue.
Birth length and weight typically are within the normal range although birth weight can be
increased; head circumference also may be increased. The absence of knee epiphyses are
more likely to occur in males than females (40 versus 28 percent, respectively).
Symptoms and signs that may be present include lethargy, slow movement, hoarse cry,
feeding problems, constipation, macroglossia, umbilical hernia, large fontanels, hypotonia, dry
skin, hypothermia, and prolonged jaundice. A few newborn infants with thyroid
dyshormonogenesis have a palpable goiter, but it usually appears later.
Congenital malformations Congenital hypothyroidism appears to be associated with an

increased risk of additional congenital malformations. As an example, in a population-based
study of 1420 infants with congenital hypothyroidism, the prevalence of other congenital
malformations (mostly cardiac) was fourfold higher (8.4 percent) than in the control infant
population (1 to 2 percent).
NEWBORN SCREENING PROGRAMS Screening of all newborns is now routine in all 50 states
of the United States, Canada, Europe, Israel, Japan, Australia and New Zealand, and is under
development in Eastern Europe, South America, Asia, and Africa. In the United States, for
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example, more than 4 million infants are screened annually, leading to the detection of 1000
infants with congenital hypothyroidism. Worldwide, it is estimated 12 million infants are
screened and 3000 with hypothyroidism are detected annually.
Blood for screening is collected onto filter paper cards after heel prick, usually two to five days
after delivery. Some programs also routinely obtain a second specimen between two and six
weeks after delivery. The cards are then sent to a centralized laboratory for testing.
Two major screening strategies have evolved:
1. Initial blood T4 assay, with follow-up TSH assay if the blood T4 value is below a certain
concentration.
2. Initial blood TSH assay.
DIAGNOSTIC STUDIES At recall, the infant is examined and a blood sample is obtained by
venipuncture to confirm the diagnosis of hypothyroidism. If the diagnosis of hypothyroidism is
confirmed, other studies (such as thyroid radionuclide uptake and imaging), ultrasonography,
serum thyroglobulin assay, tests for thyroid autoantibodies, or urinary iodine excretion, may be
performed to identify the cause. These tests usually do not alter treatment; thus, we
recommend they be done only in special circumstances.
Serum tests of thyroid function The findings of low serum T4 or free T4 and high serum TSH
values confirm the diagnosis of primary hypothyroidism. One must keep in mind that serum T4
concentrations are higher in the first few weeks of life in normal infants than in adults on
account of the surge in TSH secretion that occurs soon after birth.
Between one and four days of life, the normal range for serum total T4 concentrations is about
10 to 22 mcg/dL (129 to 283 nmol/L) and the normal range for serum free T4 concentrations is
about 2 to 5 ng/dL (25 to 64 pmol/L).
Between one and four weeks of life, the normal range for serum total T4 concentrations is 7 to
16 mcg/dL (90 to 206 nmol/L) and the normal range for serum free T4 concentrations is 0.8 to
2.0 ng/dL (10 to 26 pmol/L).
A normal serum total or free T4 concentration and a high serum TSH concentration define
subclinical hypothyroidism. Because of the critical dependence of the developing central
nervous system on adequate amounts of T4, we recommend that infants with subclinical
hypothyroidism be treated.
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In those programs that follow infants with low blood T4 screening results alone, low serum
total and free T4 concentrations in the presence of low or normal serum TSH concentrations
indicate the presence of central hypothyroidism. Rare infants who are ultimately proven to have
primary hypothyroidism also may have low serum T4 and TSH values when recalled, because the
expected rise in serum TSH is delayed. Infants with either of these findings should be treated.
Premature infants and infants with nonthyroidal illness also may have low serum total and free
T4 and normal serum TSH concentrations. We do not recommend treatment for these infants
unless there is other evidence of hypothalamic or pituitary disease.
The combination of a low serum total T4 concentration and normal serum free T4 and TSH
concentrations indicates the presence of thyroxine-binding globulin (TBG) deficiency, an X-
linked recessive disorder that occurs in approximately 1:4000 newborns, predominantly males.
These infants are euthyroid and do not require treatment.
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Treatment and prognosis of congenital hypothyroidism
The overall goals of treatment are to assure normal growth and development and
psychometric outcome similar to genetic potential, by restoring the serum T4 concentration
rapidly to the normal range followed by continued clinical and biochemical euthyroidism.
Oral T4 is the treatment of choice. Although triiodothyronine (T3) is the more biologically
active hormone, the majority of brain T3 is derived from local deiodination of T4; thus, it is not
necessary to use T3. Treatment should be initiated in any infant with a positive screening test
as soon as confirmatory blood samples have been drawn, but before test results are available
Dose of T4 Both the timing and dose of thyroid hormone replacement are important. The
initial goal of treatment should be to restore the serum T4 concentration to >10 mcg/dL (>129
nmol/L) as rapidly as possible. In one study, patients who took longer than two weeks to
normalize their thyroid function had lower cognitive, attention, and achievement scores than
those who achieved normal function within two weeks after therapy was started.
There is an inverse correlation between the starting T4 dose and the time to achieve the goal
T4 concentration. The American Academy of Pediatrics (AAP) recommends an initial dose of 10
to 15 mcg/kg per day, which usually amounts to 37.5 or 50 mcg per day. However, in the above
study, full-scale IQ scores were 11 points higher in those started on 50 mcg per day versus 37.5
mcg per day. As a result, we recommend the higher dose (50 mcg per day) in term and full-size
infants. In preterm and other low-birth weight infants, we recommend using 10 to 15 mcg/kg
per day. For infants with low T4 levels ( 5 ug/dL or 65 nmol/L), we would recommend using a
dose closer to the higher end of the initial AAP recommended dose (ie, 15 mcg/kg per day).
Infants with congenital hypothyroidism who are fed soy formula should be monitored closely
with serum T4 and TSH. Their dose of T4 should be increased as necessary to achieve normal
thyroid function tests, as the time to normalization of thyroid function is critical to preservation
of cognitive abilities.
Treatment goals The aim of treatment is to keep the serum T4 or free T4 concentration in
the upper half of the normal range. In the first year of life, the values should be 10 to 16 mcg/dL
(130 to 206 nmol/L) for serum T4 and 1.4 to 2.3 ng/dL (18 to 30 pmol/L) for serum free T4. The
serum TSH concentration should be less than 5 mU/L.
Infants who have serum T4 concentrations below 10 mcg/dL (129 nmol/L) in the first year of
life, particularly if accompanied by serum TSH concentrations above 15 mU/L, will have lower
IQs than infants whose serum T4 concentrations are above 10 mcg/dL (129 nmol/L).
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On the other hand, overtreatment also can lead to complications and should be avoided.
Persistently high serum T4 concentrations for age, especially if above 16 mcg/dL (206 nmol/L),
may adversely affect the tempo of brain development, result in disorders of temperament or
attention span] , and cause premature craniosynostosis.
In studies in which the starting dose was 10 to 15 mcg/kg per day, there were no harmful
effects on linear growth or skeletal maturation in the first two years of life.
Recommended follow-up Clinical evaluation should be performed every few months during
the first three years of life. Laboratory evaluation should be carried out more often to ensure
optimal T4 dose. The American Academy of Pediatrics recommends measurement of serum T4
or free T4 and TSH according to the following schedule:
At 2 and 4 weeks after the initiation of T4 treatment.
Every 1 to 2 months during the first 6 months of life.
Every 3 to 4 months between 6 months and 3 years of age.
Every 6 to 12 months thereafter until growth is complete.
Two weeks after any change in dose.
At more frequent intervals when compliance is questioned or abnormal results are obtained.
The serum T4 concentration should become normal within one to two weeks, and serum TSH
should be normal in most infants after one month of treatment. Some infants may have a high
serum TSH concentration (10 to 20 mU/L) despite serum T4 values in the upper half of the
normal range. Conversely, when serum TSH is normal, some infants will have elevated serum
free T4 above the reference range for age. This appears to be the result of resetting of the
pituitary-thyroid feedback threshold because of intrauterine hypothyroidism. In a study of 42
patients with congenital hypothyroidism, this mild to moderate thyroid hormone resistance was
more common in infants (less than one year of age) than in older children (43 versus 10 percent,
respectively) [19] . These data suggest the resistance improves with age, but can persist.
Assessment of permanent versus transient hypothyroidism Some patients with congenital

hypothyroidism, perhaps 10 to 20 percent, have transient hypothyroidism. Although
radionuclide imaging and ultrasonography of the thyroid gland in infants with congenital
hypothyroidism are considered optional, as in most cases these test results are not required for
management decisions, some clinicians elect to routinely perform these studies. However, if
they are performed, permanent hypothyroidism can be assumed if:
1. Thyroid radionuclide imaging shows an ectopic gland or absent thyroid tissue, confirmed
by ultrasonography.
2. Studies confirm dyshormonogenesis .
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3. Permanent hypothyroidism also can be assumed if the serum TSH concentration rises to
above 20 mU/L after the first year of life on account of insufficient T4 replacement.
If permanent hypothyroidism has not been established, T4 therapy can be discontinued for 30
days after age 3 years. If a low serum T4 or free T4 and high TSH concentration are found,
permanent hypothyroidism is confirmed and treatment should be restarted. If the serum T4 or
free T4 and TSH values remain normal, transient hypothyroidism is presumed. These children
should still be examined periodically, and if they have any suspicious clinical features of
hypothyroidism, such as slowing of growth, laboratory assessment of thyroid status should be
performed. If the results are inconclusive, careful follow-up and subsequent retesting are
indicated.
In addition, some clinicians undertake imaging studies to determine a definitive etiology. In a

report of 33 children with congenital hypothyroidism who were investigated at three years of
age, 27 percent had an absent or ectopic thyroid, 36 percent had dyshormonogenesis, and 36
percent had transient hypothyroidism. The percentage with transient hypothyroidism was
higher than in other studies. The average dose of T4 at the time of discontinuation was lower
among children with transient hypothyroidism than those with permanent hypothyroidism (2.0
versus 2.9 mcg/kg per day).
A potential novel approach is the use of rhTSH to make the diagnosis of congenital
hypothyroidism without requiring withdrawal of thyroid hormone therapy. In one study, the
results of thyroid scintography after thyroid hormone withdrawal versus rhTSH administration
was identical in eight children with congenital hypothyroidism, identifying those patients with
agenesis, lingual thyroids, or TSH receptor mutations and potentially avoiding the need to
withdraw thyroid hormone.
PROGNOSIS Several programs in North America, Europe, and Australia have now reported
long-term follow-up of infants detected through newborn screening. In general, these infants
grow and develop normally. The psychometric outcome is much improved over the
prescreening era, but some severely affected infants or those who are inadequately treated in
the first two or three years of life have IQs below those of normal children.
Psychometric outcome In general, infants treated early (two to six weeks of life) and
appropriately through the first three years of life have global IQs similar to normal infants.
Even when there are no differences in global IQ scores, there may be differences in subtest
components. A screening program in Toronto reported language deficits at age three years,
which diminished with age, along with poor visual-spatial and verbal skills at age five years.
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Severely affected infants Some screening programs report that more severely affected
infants, as judged by a lower serum T4 concentration or immature skeletal maturation at
diagnosis, have lower IQ scores later in life.
Other neurologic sequelae A small proportion of infants, including those with normal IQ
scores, can have other neurologic problems, such as gross and fine motor incoordination,
ataxia, increased or decreased muscle tone, short attention span, speech defects, and
strabismus. Studies before the initiation of newborn screening reported that up to 20 percent of
children had sensorineural hearing loss.
Effect of noncompliance The New England Collaborative found that noncompliance beyond
the first three years of life can affect cognitive performance.
Maternal hypothyroidism Neurologic development may be adversely affected in children

born to mothers with hypothyroidism, even in the absence of neonatal hypothyroidism.
Low maternal serum T4 concentrations early in pregnancy (before the time the fetus begins to
produce its own T4) may be a risk factor for impaired infant development. In a consensus
statement, the American Thyroid Association (ATA) does not recommend routine maternal
screening of thyroid function during pregnancy. The ATA does recommend that women who are
at risk for thyroid disease based on personal or family history, symptoms or physical
examination findings, or a history of other autoimmune disorders should undergo thyroid
testing early in pregnancy.
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Genetics and clinical presentation of classic congenital adrenal
hyperplasia due to CYP21A2 (21-hydroxylase) deficiency
Deborah P Merke, MD, MS
INTRODUCTION Defective conversion of 17-hydroxyprogesterone to 11-deoxycortisol

accounts for more than 90 percent of cases of congenital adrenal hyperplasia. This conversion is
mediated by 21-hydroxylase, or in current terminology, CYP21A2.
Patients with "classic" or the most severe form of congenital adrenal hyperplasia due to
CYP21A2 deficiency present during the neonatal period and early infancy with adrenal
insufficiency with or without salt losing, or as toddlers with virilization. Females have genital
ambiguity.
"Nonclassic", or late-onset CYP21A2 deficiency, presents later in life with signs of androgen
excess, and without neonatal genital ambiguity. Clinical features in childhood may include
premature pubarche, and accelerated bone age; adolescent and adult females may present with
hirsutism, menstrual irregularity, infertility, and acne. Some patients with nonclassic CAH remain
asymptomatic.
PREVALENCE Based upon neonatal screening studies that detect classic congenital adrenal
hyperplasia, CYP21A2 deficiency is one of the more common inherited disorders. Data from
approximately 6.5 million newborn infants screened worldwide shows an estimate of
approximately one in 15,000 livebirths.
Approximately 67 percent of classic patients are classified as "salt-losing", while 33 percent of

classic patients have "non-salt-losing" or the "simple-virilizing" form, reflecting the degree of
aldosterone deficiency.
PATHOPHYSIOLOGY The defective conversion of 17-hydroxyprogesterone to 11-

deoxycortisol in patients with CYP21A2 deficiency results in decreased cortisol synthesis and
therefore increased corticotropin (ACTH) secretion. The resulting adrenal stimulation leads to
increased production of androgens. The severity of disease relates to the degree to which the
mutations compromise enzyme activity.
CLINICAL PRESENTATION The clinical spectrum of disease ranges from the most severe to
mild forms, depending on the degree of CYP21A2 deficiency. Three main clinical phenotypes
have been described: classic salt-losing, classic non-salt-losing (simple-virilizing) and nonclassic
(late-onset):
Females with the classic form (salt-losing and non-salt-losing) present with genital ambiguity.
Males with the salt-losing form present with failure to thrive, dehydration, hyponatremia, and
hyperkalemia typically at 7 to 14 days of life.
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Males with the classic non-salt-losing form who are not identified by neonatal screening,
typically present at two to four years of age with early virilization (pubic hair, growth spurt,
adult body odor).
Nonclassic or late-onset CYP21A2 deficiency may present as hirsutism and menstrual

irregularity in young women, early pubarche or sexual precocity in school age children, or there
may be no symptoms.
Infants/children
Ambiguous genitalia Female infants with classic CYP21A2 deficiency are born with
ambiguous genitalia. Female newborns have clitoral enlargement, labial fusion and formation of
a urogenital sinus caused by the effects of androgen excess on development of the external
genitalia in utero. Rarely, genital ambiguity may be so profound that inappropriate sex
assignment is made at birth.
Affected males are normal appearing at birth, but may have subtle findings such as
hyperpigmentation of the scrotum or an enlarged phallus.
The surgical management of children born with ambiguous genitalia is complex. The Lawson
Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology
recommend that surgery should be done in virilized girls with classic CAH at age two to six
months because it is technically easier than at a later age.
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Growth Children with CAH are at risk for early puberty and adult short stature. Exposure to
high levels of sex hormones can induce early puberty and premature epiphyseal closure. Excess
glucocorticoid exposure secondary to treatment may also suppress growth and contribute to
adult short stature.
Sexual behavior Studies of female patients with classic congenital adrenal hyperplasia
suggest that exposure to excess androgens during prenatal development may influence the
brain as evidenced by the following:
Female patients with classic congenital adrenal hyperplasia have more male-typical childhood
play than unaffected girls and have more interest in male-typical activities and careers.
Adolescent and adult women with congenital adrenal hyperplasia may have greater aggressive
tendencies than unaffected healthy women.
Overall, patients with CAH have favorable quality-of-life and good psychological health.
Cognitive function The effect of CYP21A2 deficiency on cognitive function is uncertain.

Some studies suggest that patients with the most severe form of CYP21A2 deficiency and those
who have experienced salt-losing adrenal crises with abnormal electrolytes and/or
hypoglycemia as neonates are at risk for cognitive impairment.
Female reproduction Fertility rates in women with classic forms of CYP21A2 deficiency are
low.
Male reproduction Reproductive function may be impaired in men with CYP21A2 deficiency.
Affected boys or young men may have no symptoms or signs of androgen excess. However, they
may have testicular masses composed of adrenal tissue.
Infertility Most men with CYP21A2 deficiency are fertile as adults, but others have evidence
of Leydig cell failure or impaired spermatogenesis . As note above, testicular adrenal rests may
be associated with seminiferous tubule obstruction, gonadal dysfunction and infertility.
Epinephrine deficiency Adrenomedullary function is compromised in patients with classic

congenital adrenal hyperplasia, as illustrated in a study of 38 children with classic CYP21A2
deficiency. Plasma epinephrine and metanephrine concentrations, and urinary epinephrine
excretion were 40 to 80 percent lower than in normal subjects.
Other findings Other clinical findings that have been described include adrenal
incidentalomas, pituitary adenomas, insulin resistance and hyperleptinemia.
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Diagnosis of classic congenital adrenal hyperplasia due to
CYP21A2 (21-hydroxylase) deficiency
Classic CYP21A2 deficiency The characteristic biochemical abnormality in patients with

CYP21A2 deficiency is a high serum concentration of 17-hydroxyprogesterone, the normal
substrate for CYP21A2. Most affected neonates have concentrations greater than 3500 ng/dL
(105 nmol/L).
A very high concentration of 17-hydroxyprogesterone in a randomly timed blood sample is

diagnostic of classic CYP21A. False positive results from neonatal screening are common with
premature infants, and many screening programs have established reference ranges that are
based upon weight and gestational age. To define the metabolic defect in infants, serum
concentrations of cortisol, 11-deoxycortisol, 17-hydroxypregnenolone, and androstenedione
also should be measured.
The simple virilizing form of CYP21A2 deficiency cannot be distinguished from the salt-wasting
form on the basis of serum 17-hydroxyprogesterone values . To assess borderline cases, the
standard high-dose (250 mcg cosyntropin) test, not the low-dose (1 mcg) test, should be used.
Patients with the salt-losing form of CYP21A2 deficiency have low serum concentrations of
aldosterone and 11-deoxycorticosterone and increased plasma renin activity. As noted above,
the mineralocorticoid deficiency can lead to volume depletion, hyponatremia, and
hyperkalemia. Patients are also at risk for hypoglycemia during an adrenal crisis.
Other abnormalities that may be present include high serum concentrations of

androstenedione, 3-alpha-androstanediol glucuronide, testosterone, 21-deoxycortisol, and
progesterone, and increased urinary excretion of metabolites of cortisol precursors, particularly
pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids. (Pregnanetriol and its
glucuronide are the major metabolites of 17-hydroxyprogesterone, and 17-ketosteroids are
metabolites of androgens).
Nonclassic CYP21A2 deficiency The biochemical findings are less severe in patients with the
nonclassic form of the disorder.
PRENATAL DIAGNOSIS Prenatal diagnosis may be considered when a fetus is known to be at

risk because of an affected sibling, or when both partners are known to be heterozygous for one
of the severe mutations, thus predicting a one-in-eight chance of female genital ambiguity.
Measurements of amniotic fluid 17-hydroxyprogesterone, HLA typing of fetal cells, and direct
analysis of fetal CYP21 genes in amniocytes or chorionic villus samples have all been used as
screening methods, although the molecular analysis of CYP21A2 genes is now the method of
choice.
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NEONATAL SCREENING AND GENOTYPING Neonatal screening for 21-hydroxylase
deficiency can be performed on Guthrie cards (filter paper on which samples of blood are
collected, dried, and transported). Neonatal screening for 21-hydroxylase deficiency is available
worldwide in 13 countries (including the majority of US states).
Conventional screening is done by measuring 17-hydroxyprogesterone in the dried blood. The

positive predictive value of the screening test may be improved by stratifying by birth weight
and age at screening. The sensitivity of newborn screening may be lower in females compared
to male infants.
Administration of antenatal corticosteroids, particularly multiple courses (administered to

induce pulmonary maturation in pregnancies with expected preterm delivery), may decrease 17-
hydroxyprogesterone levels in filter-paper blood, increasing the risk of false-negative results.
Repeat screening for CAH at one to two weeks of age should be considered in infants who have
received multiple courses of antenatal corticosteroids; salt-loss should be carefully monitored in
the interim between screening samples.
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Treatment of classic congenital adrenal hyperplasia due to
CYP21A2 (21-hydroxylase) deficiency in infants and children
MANAGEMENT IN NEONATES Newborn infants with CAH may be identified through
prenatal diagnosis, neonatal screening programs, because they are noted to have ambiguous
genitalia on physical examination (females), or because of an adrenal crisis (hyponatremia,
hyperkalemia, dehydration) at one to two weeks of life (males). Every newborn with ambiguous
genitalia or a suspected diagnosis of CAH should be evaluated by a pediatric endocrinologist.
Ambiguous genitalia Infants with ambiguous genitalia require urgent medical attention. The
initial evaluation should include history, physical examination, ultrasonography of the internal
genitalia (uterus) and possibly adrenals, possibly karyotype or fluorescence in situ hybridization
for sex chromosome material (if not available from prenatal testing), and rapid and reliable
measurement of 17-hydroxyprogesterone.
Adrenal crisis Urgent medical therapy is necessary for infants who present in adrenal crisis.
The initial goals are treatment of hypotension and dehydration, reversal of electrolyte
abnormalities, and correction of cortisol deficiency. Normal (0.9 percent) saline solution or 5
percent dextrose in normal saline should be infused intravenously as quickly as possible. An
intravenous bolus of 10 to 20 mL/kg of normal saline should be administered. An intravenous
bolus of 2 to 4 mg/kg of 10 percent dextrose should be considered if there is significant
hypoglycemia. Hypotonic saline should not be used because it can worsen the hyponatremia;
the same is true of 5 percent dextrose without the addition of normal saline. Hyperkalemia
should be corrected with the administration of glucose and insulin if necessary.
Once a blood sample is obtained for steroid hormone measurements (most importantly 17-
OH-progesterone), stress doses of hydrocortisone should be administered. An initial dose of
hydrocortisone 50 to 100 mg/m2 should be administered as an IV bolus (typical neonatal dose
is 25 mg), followed by hydrocortisone 50 to100 mg/m2 IV per day divided every four hours.
Stress doses of hydrocortisone should be continued until the patient is stable and feeding
normally.
During treatment with stress doses of hydrocortisone, mineralocorticoid replacement is

unnecessary. If the diagnosis of salt-losing CAH is confirmed, infants should receive
glucocorticoid and mineralocorticoid therapy and salt supplementation.
Positive newborn screen A positive newborn screening test for CAH needs to be confirmed
by a second serum/plasma sample. The urgent medical issue is identification of infants with the
salt-losing form before they develop adrenal crisis. Symptoms of salt-losing, including vomiting,
poor feeding with failure to thrive, lethargy, hypovolemia, dehydration, hyponatremia with
hyperkalemia, hypoglycemia, and cardiovascular collapse can occur within the first few days to
weeks of life if CAH is not treated .
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As soon as CAH is suspected on the basis of a positive newborn screen, a sample of blood should
be obtained for confirmatory steroid hormone measurements (most importantly, 17-OH
progesterone), and serum electrolytes should be measured. After the confirmatory blood
sample is obtained, treatment doses of glucocorticoid and mineralocorticoid should be initiated
in all infants in whom CAH is a consideration, to prevent the potentially life-threatening
manifestations of adrenal crisis. If the physician chooses not to initiate treatment while awaiting
confirmatory steroid hormone measurements, serum electrolytes should be measured daily.
These patients should be managed by a pediatric endocrinologist.
MANAGEMENT IN CHILDREN
Glucocorticoid Glucocorticoid replacement is necessary in children who have classic

CYP21A2 deficiency and in symptomatic patients with nonclassic CYP21A2 deficiency. The goal
of therapy is to replace deficient steroids while minimizing adrenal sex hormone and
glucocorticoid excess.
Glucocorticoid is usually administered as hydrocortisone (cortisol) in a dose of 12 to 18 mg/m2

body surface area per day. In the early phase of treatment, infants may require up to 25
mg/m2/day of hydrocortisone to reduce markedly elevated adrenal hormones. This dose range
exceeds the daily cortisol secretory rate of normal infants and children, which is estimated to be
7 to 9 mg/m2 body surface area in neonates and 6 to 7 mg/m2 body surface area in children and
adolescents.
For older adolescents and adults, long-acting glucocorticoids such as dexamethasone or

prednisone are the preferred treatment. When given at bedtime, these drugs effectively
suppresses ACTH secretion for much of the next day. However, the longer duration of action and
greater potency of dexamethasone may increase the risk of overtreatment, restricting linear
growth if given prior to epiphyseal closure. Dexamethasone is given as a bedtime dose of 0.25 to
0.50 mg. A glucocorticoid that does not cross the placenta (eg prednisone) is preferred in
sexually active women.
Because the results of therapy are frequently suboptimal in terms of eventual adult height and
fertility and because excessive doses can be detrimental, several other regimens have been
evaluated.
Long-acting glucocorticoids such as dexamethasone and prednisone have been used to treat
children with CAH in a few studies. As discussed above, these drugs may be more growth
suppressive than shorter-acting forms of corticosteroids. However, one study of 26 children
treated with dexamethasone (average dose 0.27 mg/m2 every morning) for an average of seven
demonstrated normal growth and control of androgen secretion with normal sexual maturation.
Similarly, nine children with adrenal insufficiency had normal short-term (six months) growth
velocity when receiving prednisolone at a dose of 15 to one relative potency to hydrocortisone.
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The growth suppressive effects of longer-acting glucocorticoid preparations could be dose
related. However, hydrocortisone remains the glucocorticoid of choice and the standard of
care during childhood.
Mineralocorticoid Mineralocorticoid replacement is necessary in patients who have the

classic form of CAH, whether or not it is the salt-losing form. Mineralocorticoid is given as
fludrocortisone, in a dose sufficient to restore normal serum sodium and potassium
concentrations. Excessive dosing can induce hypertension, hypokalemia, and possibly, impaired
growth, while underdosing also can lead to poor growth with failure-to-thrive. This may be in
part because inadequate mineralocorticoid replacement increases the glucocorticoid
replacement requirement, impairing growth. In addition, inadequate mineralocorticoid
replacement may lead to increased adrenal androgen production. This is because patients may
be chronically volume depleted, which is clinically inapparent but results in persistent
overproduction of renin and angiotensin II. Angiotensin II can stimulate early steps in the
steroidogenic pathway, leading to higher adrenal androgen synthesis. For all of these reasons,
mineralocorticoid therapy may benefit patients with either the classic salt-losing form or the
classic non-salt-losing (simple virilizing) form of CYP21A2 deficiency.
The usual pediatric dose of fludrocortisone is 0.05 to 0.20 mg per day. Infants with the salt-
losing form of CYP21A2 deficiency may require higher doses of fludrocortisone (occasionally up
to 0.30 mg per day) and also require sodium chloride supplementation of 1 to 3 g per day (about
17 to 51 mEq per day) distributed in several feedings. Fludrocortisone doses may be decreased
after 6 to 12 months of age because sensitivity to mineralocorticoid increases as the kidneys
mature in the first year of life. Salt tablets can be discontinued as the child begins to eat table
food and the taste for salty food increases. Additional salt intake may be needed with exposure
to hot weather or with intense exercise.
Monitoring therapy The response to therapy should be evaluated every three months in
the neonate and infant, and every 4 to 12 months thereafter. More frequent monitoring is
sometimes clinically indicated. Response to therapy is monitored by measuring serum 17-
hydroxyprogesterone, androstenedione, plasma renin activity or direct renin, as well as
growth velocity and the rate of skeletal maturation. Blood samples for monitoring therapy
should be obtained at a consistent time in relation to glucocorticoid dosing, optimally in the
morning to reflect peak concentrations. In addition, normative laboratory data for age and
sexual maturation should be used in the interpretation of all laboratory tests; normative data
may vary depending upon the laboratory.
A serum 17-hydroxyprogesterone concentration of 400 to 1200 ng/dL (12-36 nmol/L) with

serum androstenedione concentrations appropriate for the patient's age and sex, measured in
the morning before the glucocorticoid is taken, is a reasonable target. The serum tests serve as
markers of the adequacy of treatment and of patient adherence to it, and along with the growth
record provide the basis for adjustments in the doses of hydrocortisone. Simply adjusting the
glucocorticoid dose to normalize the serum 17-hydroxyprogesterone value is insufficient
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because of the risk of iatrogenic Cushing syndrome and since androgen excess may persist
because of avid adrenal conversion of 17-hydroxyprogesterone to androgens. Plasma renin
activity should be in the normal range for age. In patients with salt-losing and continued
androgen excess, fludrocortisone and salt tablets dose should be adjusted to normalize renin
before increasing the glucocorticoid dose.
Patients with significant elevations of androstenedione levels due to poor compliance may
respond more rapidly to a limited 7- to 10-day course of dexamethasone administered in
supraphysiologic doses, followed by the standard replacement doses. It is essential that the
high-dose course be brief to avoid compromising growth and increasing weight.
The measurements of bone age, which should be obtained every six months, and growth rate
reflect long-term control. Ideally, treatment should be modified well before there is evidence of
reduced growth rate or advanced bone age. In practice, however, this may not be a simple
matter. In a randomized trial in 26 children, for example, hydrocortisone at a dose of 25 mg/m2
per day caused significant slowing of growth compared with 15 mg/m2 per day over the course
of one year. However, at the lower dose there was often incomplete suppression of androgen
secretion. Thus, the patient's symptoms and signs of androgen excess, steroid measurements,
and growth and development all need to be considered. Patients with CAH are at risk for early
central puberty. Central precocious puberty is most likely to develop when the diagnosis of CAH
is delayed or when adrenal androgen secretion is poorly controlled; such patients may benefit
from treatment with gonadotropin-releasing hormone analog. In boys with CAH, the onset of
central puberty has been closely linked to a bone age of 12 years to 12 years 6 months, but no
clear association has been identified in girls.
Adrenal crisis Routine illnesses may become life-threatening in children with CAH unless
their glucocorticoid regimen is appropriately modified. Treatment of mild illnesses in children
who have adequate oral intake requires doubling or tripling the dose of glucocorticoids for the
duration of illness; changes in fludrocortisone dose are not usually required. If a patient is
unable to tolerate oral medication, hydrocortisone should be given intramuscularly, and medical
advice should be promptly sought.
Illnesses that are associated with diarrhea or vomiting and impaired oral intake require
assessment by a medical team, and possibly the administration of intravenous glucocorticoids,
saline, and glucose until resumption of adequate oral intake. Patients with CAH and febrile
illnesses are at risk for hypoglycemia, especially if oral intake is impaired.
Parents should be instructed in the techniques for IM administration of glucocorticoids and not
rely solely on rapid access to an emergency center. Patients with nausea and vomiting who are
unable to take oral medications should receive IM hydrocortisone sodium succinate (Solucortef).
The optimal IM dose and frequency depends upon the patient's size and the severity of the
intercurrent illness. As a general rule, 100 mg/m2/dose or triple the patient's usual daily dose
362
with a maximum dose of 100 mg may be used. The parents' knowledge of indications for and
techniques of emergency treatment should be assessed at each clinic visit.
Patients who have severe illness or major surgery should receive intravenous glucocorticoids as
indicated below. The recommended bolus is followed by a continuous intravenous infusion at
stress doses for children of various ages as follows:
3 years Hydrocortisone (25 mg IV x one dose, followed by 25 to 30 mg per day)
>3 years and <12 years Hydrocortisone (50 mg IV x one dose, followed by 50 to 60 mg per
day)
12 years of age Hydrocortisone (100 mg IV x one dose, followed by 100 mg per day)
Stress doses of hydrocortisone should be tapered rapidly according to the clinical

improvement, generally by reducing the dose by 50 percent each day.
Every patient should wear a medical alert (MedicAlert) bracelet or necklace and carry the
Emergency Medical Information Card that is supplied with it. Both should indicate the diagnosis
"adrenal insufficiency" (not CAH), and the clinician to call in the event of an emergency. Patients
can enroll in MedicAlert by calling (800) 432-5372 or through the internet at
www.medicalert.org (United States) and www.medicalert.ca/ (Canada).
OUTCOME OF THERAPY The outcome of therapy for CYP21A2 deficiency can be measured
by evaluating growth, bone density, and, in women, menstrual function. In addition, children
with CYP21A2 are at risk for obesity in part due to therapy.
Growth The adult height achieved in treated patients is usually less than that in reference
groups.
Retrospective studies have shown that final height of patients with CAH is independent of the
degree of control of adrenal androgen concentrations, suggesting that both hyperandrogenism
and hypercortisolism contribute to the observed short stature. Several studies have suggested
that treatment during the first two years of life and during puberty are the most important
factors influencing height outcome.
Bone density The effect on bone mineral density depends upon the age of the patient
studied. In 30 younger patients (mean age 17.5 years) in one study, for example, those treated
with glucocorticoid therapy for a mean of 15 years did not have decreased bone mineral
density, as compared with age, sex, and weight-matched normal subjects. However, another
report of 32 older adults who had been treated since childhood found significantly lower bone
density compared with a reference population, most likely because of overtreatment with
glucocorticoids.
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Menstrual cycle One study found that among 16 adult women (mean age 22 years),
menarche had occurred at a mean age of 13 years. However, only 10 of 24 had reasonably
regular menses, while eight had irregular menses.
Testicular function Ectopic adrenal tissue located in the testes (testicular adrenal rest) is
commonly found in males with CAH and can interfere with testicular function.
Obesity Obesity is a complication in glucocorticoid-treated patients with CYP21A2. In the

largest review of 89 children from Germany with CYP21A2 (ages between 0.2 and 17.9 years), 17
percent of patients were obese as defined by a body mass index (BMI) that was >2 SD from the
mean BMI for age. There was no difference in incidence of obesity based upon either gender or
clinical form of CYP21A2 (simple virilizing and salt-losing forms). All patients received
glucocorticoid therapy and there was a positive correlation between BMI and the dose of
medication prescribed. The BMI of normally growing children with CAH has been found to
increase throughout childhood more than the expected age-related increase. Children with an
obese parent were at increased risk for developing obesity. In a second study, elevated blood
pressure was associated with increased BMI. These results show that obesity is common in
children and adolescents with CYP21A2 and is associated with higher glucocorticoid dose and
parental obesity. In addition, elevated blood pressure is also seen in obese patients. These
children and their families should be closely monitored and participate in weight management
programs if appropriate.
Mortality Mortality is increased threefold in patients aged 1 to 4 years, often because of

adrenal crisis after an infection; improved parent education about congenital adrenal
hyperplasia and its treatment, especially during episodes of acute illness (e.g., infection), may
reduce mortality. Mortality in older patients is unknown.
EXPERIMENTAL MEDICAL THERAPY An alternative therapeutic approach designed to

minimize the effects of excess androgens while reducing the glucocorticoid dose was evaluated
in a randomized trial of 28 children with classic CYP21A2 deficiency [72]. A four-drug regimen of
flutamide (an antiandrogen), testolactone (to inhibit aromatization of androgen to estrogen,
which stimulates premature epiphyseal closure), reduced-dose hydrocortisone (average 8.3
mg/day per m2), and fludrocortisone was compared with a control regimen of hydrocortisone
(average dose 13.3 mg/day per m2) and fludrocortisone. Although serum androgen
concentrations remained high in the experimental group because of the lower glucocorticoid
dose, these children had a normal linear growth rate and bone maturation after two years of
therapy.
Because short stature commonly occurs in spite of good adrenal hormonal control during
childhood and puberty, exogenous growth hormone therapy has been given to improve final
adult height in these patients. In some cases, GnRH agonist therapy has been added to block
excess androgen activity that exacerbates premature epiphyseal fusion.
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SURGICAL ADRENALECTOMY There have been some reports of total bilateral
adrenalectomy for severe CYP21A2 deficiency. The major potential benefit of this procedure lies
in obviating the need to administer glucocorticoids to suppress adrenal androgen secretion.
Reported long-term (average of five years) follow-up of 18 patients with CAH who underwent
bilateral adrenalectomy revealed improved signs and symptoms of hyperandrogenism and less
obesity after surgery. A minimum dose of hydrocortisone of 11 mg/m2/day was necessary in
most patients to prevent hyperpigmentation and the activation of ectopic adrenal tissue. A
possible increase in susceptibility to adrenal crisis and sudden death must be considered for
patients considering this controversial surgical option.
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Diagnosis and treatment of nonclassic (late-onset) congenital
adrenal hyperplasia due to CYP21A2 (21-hydroxylase) deficiency
Lynnette K Nieman, MD
"Nonclassic", or late-onset CYP21A2 deficiency, does not manifest with neonatal genital
ambiguity; rather, it presents later in life with signs of androgen excess. Clinical features in late
childhood include premature pubarche, acne and accelerated bone age; adolescent and adult
females present with acne, hirsutism and menstrual irregularity.
DIAGNOSIS
Classic CYP21A2 deficiency The characteristic biochemical abnormality in patients with

CYP21A2 deficiency is a high serum concentration of 17-hydroxyprogesterone, the normal
substrate for CYP21A2. Most affected neonates (with the classic form) have concentrations
greater than 3500 ng/dL (105 nmol/L), with most exceeding 10,000 ng/dL (300 nmol/L), whereas
the levels in normal newborns are below 100 ng/dL (3 nmol/L). Patients with this disorder also
have an exaggerated serum 17-hydroxyprogesterone response to ACTH stimulation with values
more than 10,000 ng/dL (300 nmol/L), providing good diagnostic separation from patients with
nonclassic CYP21A2 deficiency.
Nonclassic CYP21A2 deficiency The biochemical findings are less severe in patients with the
late-onset form of the disorder. Basal serum 17-hydroxyprogesterone concentrations (during
the follicular phase of the menstrual cycle) may be only slightly high, especially late in the day,
but are always greater than 200 ng/dL (6 nmol/L) in adult women and greater than 82 ng/dL (2.5
nmol/L) in children. A morning value greater than 200 ng/dL (6 nmol/L) in the early follicular
phase or greater than 82 ng/dL in children strongly suggests the diagnosis, which may be
confirmed by a high dose (250 mcg) ACTH stimulation test. The response to ACTH is
exaggerated, and most patients have values exceeding 1500 ng/dL (43 nmol/L) after ACTH
stimulation. Stimulated values of serum 17-hydroxyprogesterone concentrations at 60 minutes
range between 1000 ng/dL (30 nmol/L) and 10,000 ng/dl (300 nmol/L).
Other abnormalities that may be present include high serum concentrations of 17-
hydroxypregnenolone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate
(DHEA-S), androstenedione, 3-alpha-androstanediol glucuronide, testosterone, 21-
deoxycortisol, and progesterone, and increased urinary excretion of metabolites of cortisol
precursors, particularly pregnanetriol, pregnanetriol glucuronide, and 17-ketosteroids
(pregnanetriol and its glucuronide are the major metabolites of 17-hydroxyprogesterone, and
17-ketosteroids are metabolites of androgens, especially DHEA and DHEA-S).
Heterozygote carriers Heterozygote carriers have the same pattern of abnormalities, but
they have smaller responses to ACTH that may overlap the responses of normal subjects.
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There is no clear consensus as to whether heterozygote carriers are at increased risk of
developing hyperandrogenic symptoms.
If it is important to document the presence of a carrier state, CYP21A2 genotyping should be

performed in patients with borderline responses to ACTH stimulation to avoid a false diagnosis
of late-onset CYP21A2 deficiency.
When to test Testing for CYP21A2 deficiency should be considered in women with an early
onset of hirsutism (including those with premature adrenarche), a family history of congenital
adrenal hyperplasia, or a strong desire to know a specific etiologic diagnosis.
TREATMENT
Indications for treatment of nonclassic CYP21A2 deficiency include:
1. Children Children with precocious pubarche or severe acne.

2. Women Hirsutism and acne in women Antiandrogen therapy, including cyproterone
acetate may be superior to glucocorticoids for the treatment of hirsutism.
Oral contraceptives, which suppress ovarian androgens, also suppress ACTH and adrenal
androgens. Given the potential risks and side effects of glucocorticoids, and the fact that
hirsutism typically requires long-term therapy, oral contraceptives and/or antiandrogens are
reasonable options for first-line therapy.
3. Oligomenorrhea If fertility is not desired, we suggest oral contraceptive agents rather

than glucocorticoid therapy for menstrual cycle management. Although glucocorticoids
may restore ovulation and regular cycles, they do not provide contraception, and are
associated with important risks and side effects.
4. Anovulatory infertility Dexamethasone is generally the initial treatment for ovulation
induction; clomiphene citrate and other assisted reproduction techniques may be added
if glucocorticoid therapy alone is ineffective.
Treatment may be discontinued when an adult woman no longer seeks fertility.

Hyperandrogenic symptoms persist, and require ongoing therapy, although not necessarily with
glucocorticoids.
Men Treatment is not necessary for men unless there are testicular masses (testicular
adrenal rest tumors) or oligospermia (in a man desiring fertility). The few studies reporting
treatment of testicular rest tumors or infertility in men initially used dexamethasone (0.75
mg/day), a dose which was often reduced later because of the development of Cushingoid
features. Surgical extirpation of the masses in eight men with classic CAH did not normalize
sperm count in one study. Further studies are needed to evaluate the optimal timing of surgery
in men with classic and nonclassic CAH and the timing of initiation of glucocorticoid treatment in
men with non-classic CAH.
367
Treatment may be discontinued when the symptoms resolve, e.g., when a boy with precocious
pubarche becomes an adult or an adult male no longer seeks fertility.
Choice of glucocorticoid Dexamethasone, given as a bedtime dose of 0.25 to 0.75 mg, is the
preferred treatment for older adolescents and adults after epiphyseal closure is complete. The
lowest dose that ameliorates the sign or symptom being treated should be used.
Prednisone (5 to 7.5 mg) also may be given at bedtime.
Monitoring treatment in adults Standards have not been established for monitoring
glucocorticoid therapy in adults with CYP21A2 deficiency. In general, the same principles apply
as in treating children. Serum concentrations of 17-hydroxyprogesterone, DHEA sulfate,
androstenedione, and testosterone should be measured in women, with the goal of normalizing
testosterone levels. In men, reduction of serum 17-hydroxyprogesterone levels to slightly above
normal provides a good index of therapeutic efficacy. However, the primary endpoint is
normalization of symptoms (eg, acne, hirsutism).
One should be alert to symptoms and signs of Cushing's syndrome. Patients should have
measurements of bone mineral density periodically to look for bone loss. The lowest dose that
ameliorates symptoms should be used.
Patients with nonclassic CYP21A2 deficiency do not require higher glucocorticoid

doses during stress.
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The Nervous System
Clinical features and diagnosis of cerebral palsy

Geoffrey Miller, MD
Cerebral palsy (CP) consists of a heterogeneous group of nonprogressive clinical

syndromes that are characterized by motor and postural dysfunction. These
conditions, which range in severity, are due to abnormalities of the developing brain
resulting from a variety of causes. Although the disorder itself is not progressive, the
appearance of neuropathologic lesions and their clinical expression may change over time
as the brain matures.
CLINICAL FEATURES The CP syndromes are characterized by abnormalities of

motor activity and posture. In affected patients, a voluntary movement that should be
complex, coordinated, and varied is instead uncoordinated, stereotypic, and limited.
Simple actions that are performed unconsciously by unaffected individuals require
marked effort and concentration and often fail in patients with CP. In severely affected
individuals, an attempted voluntary movement may evoke a primitive reflex, co-
contraction of agonist and antagonist muscles, and mass movements. For example,
attempts at flexion may involve all segments of a limb, and extension of all the fingers
may accompany extension of the wrist. Discrete movements, such as that of an individual
finger, may be impossible.
Classification of CP syndromes is based upon the type and distribution of motor

abnormalities. However, there may be substantial overlap among the clinical features. For
example, patients with spastic syndromes may have involuntary abnormal movements,
and those with dyskinetic and ataxic syndromes may have pyramidal signs.
Spastic syndromes The spastic syndromes have variable expression. They may be
symmetric or asymmetric and may involve one or more extremities. These variations are
important in identifying etiology, associated findings, and prognosis.
Patients with spastic CP have features of an upper motor neuron syndrome, which
include positive and negative signs. A positive sign is an abnormality that can be seen or
felt by the observer. A negative sign is felt by the observer and reflects an inability to
function in some way. These differ from signs of upper motor neuron syndrome with
adult onset because the developing nervous system may respond differently to insults.
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Positive signs of spastic CP include:
Spastic hypertonia.
Hyperreflexia caused by hyperexcitability of the stretch reflex.
Extensor plantar responses.
Clonus.
Negative signs of spastic CP include:
Slow effortful voluntary movements.
Impaired fine-motor function.
Difficulty in isolating individual movements.
Fatiguability.
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Spastic diplegia Spastic diplegia affects both term and preterm infants. Spastic
diplegia in preterm infants often is associated with periventricular leukomalacia
(PVL), and the risk is greater with increasing prematurity. The lower limbs are affected
predominantly. Patients with mild PVL may have relatively good hand function and
fewer associated disabilities. In more severely affected patients, upper limb function also
may be compromised, depending upon the degree of spasticity, presence of contractures,
sensory loss, associated involuntary movements, and intelligence.
Spastic hemiplegia Spastic hemiplegia typically affects term infants of normal

birth weight. Most cases in term infants result from maldevelopment, prenatal
circulatory disturbances, or neonatal stroke. Prenatal causes include hypercoagulable
states, vasculopathies, abnormal development of blood vessels, and emboli secondary to
disorders affecting the placenta or fetus. Causes of strokes that occur during early infancy
include sepsis, disseminated intravascular coagulation, venous sinus thrombosis, emboli,
and congenital heart disease. Some cases are caused by periventricular atrophy or
cerebral dysgenesis. Affected patients with nondiagnostic neuroimaging may have
maldevelopment at a microscopic level.
The presentation of congenital spastic hemiplegia is variable. It is usually caused by a

cortical lesion. Thus, the arm typically is more affected than the leg. The condition
may be missed during the newborn period and become evident during a later
examination. It may be detected when an infant's caregiver notices hand dominance,
reduced movement, or abnormal posturing on one side. The disorder sometimes is
detected after a seizure occurs.
Spastic quadriplegia Spastic quadriplegia is the most severe form of spastic CP. It
usually affects term infants who are small for gestational age, consistent with a prenatal
origin, such as cerebral dysgenesis or infection. Other cases result from perinatal or
postnatal events or a combination of prenatal and perinatal causes. This disorder also is
seen in extremely low birth weight infants.
Dyskinetic syndromes Dyskinetic CP typically affects term infants. In most cases,

it results from severe, acute perinatal asphyxia. The disorder is associated with status
marmoratus (lesions in the basal ganglia and thalamus with a marbled appearance) that
may appear as high-intensity areas on T2-weighted MRI.
Athetosis Athetosis consists of slow, smooth, writhing movements that involve distal
muscles. There is dyssynergia (antagonistic action) of opposing muscle groups, such as
flexion and extension or pronation and supination. Emotion, change in posture, or
intended movement may accentuate or induce the abnormal movements. Athetosis is
most apparent during reaching, as the fingers extend and abduct. Primitive reflexes often
are retained. Oropharyngeal difficulties may result from facial grimacing.
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Chorea Chorea consists of rapid, irregular, unpredictable contractions of individual
muscles or small muscle groups that involve the face, bulbar muscles, proximal
extremities, and fingers and toes. Stress, excitement, or fever may exacerbate the chorea.
In some cases, fever may result in ballismus, a form of severe, coarse chorea.
Dystonia The second category of dyskinetic CP is characterized by dystonia,

although tension, and persistent neonatal reflex patterns often occur. Dystonia consists of
repetitive, patterned, twisting, and sustained movements of the trunk and limbs that may
be either slow or rapid. Affected patients usually are severely disabled in all four limbs,
the trunk, and pharyngeal muscles.
Ataxic syndromes Although ataxia indicates an incoordination of cerebellar or

sensory origin, ataxic CP represents a widespread disorder of motor function. Affected
patients usually are born at term.
The etiology of ataxic cerebral palsy is heterogeneous. Most cases are caused by early
prenatal events. Some cases have genetic causes. Autosomal recessive conditions include
cerebellar hypoplasia, granule cell deficiency, and Joubert syndrome. An autosomal
dominant form of nonprogressive ataxia has been described. Congenital hypoplasia of the
cerebellum and pure ataxia occur rarely.
Atonic syndromes Atonic syndromes comprise another form of CP. Although first
described in 1910, atonic CP often is absent from contemporary classifications.
Affected infants usually are born at term with severe hypotonia. Many have cerebral
dysgenesis, microcephaly, and profound mental retardation. Development is extremely
delayed, and affected children never stand or walk.
ASSOCIATED DISORDERS CP often is accompanied by other disorders of

cerebral function. In a population-based study in Atlanta, 75 percent of 204 10-year-old
children with CP had another disability. Mental retardation, epilepsy, and sensory
impairment occurred in 65, 46, and 15 percent, respectively. In another report of 784
cases from Northern Ireland, 49 percent had at least one other impairment (active seizures
or intellectual or sensory impairment).
Associated abnormalities may affect cognition, vision, hearing, language, cortical

sensation, attention, vigilance, and behavior. Some children have epilepsy and many
have disturbed gastrointestinal function and growth. Dyspraxias and agnosias may
interfere with skilled tasks, regardless of the severity of motor deficit. In a child with
relatively mild CP, for example, disorders of higher cortical function may interfere with
activities of daily living, such as dressing or managing buttons.
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Mental retardation Mental retardation occurs in approximately 65 percent of
patients with CP. The severity of mental retardation often correlates with the extent of
motor handicap. However, substantial variability in cognitive ability occurs among
affected individuals. Cognitive function usually is better with dyskinetic CP that is
mainly athetoid than with bilateral spastic syndromes. Children with spastic
quadriplegia usually are the most severely affected.
Language development in hemiplegia is related to cognitive ability rather than to the

side of the lesion. As a group, children born at term do better with congenital than
postnatally acquired hemiplegia. In patients without frank mental retardation, learning
disabilities may affect educational potential.
Psychiatric disorders Behavioral and emotional disorders commonly are associated

with CP. Psychiatric disorders also occur frequently. These may be related to the primary
neurologic signs, including emotional lability, poor attention and vigilance, and
obsessive-compulsive traits. The secondary effects of dependency, frustration, and low
self-esteem also may play a role.
Epilepsy Epilepsy occurs in approximately one-third to one-half of patients with

CP. Patients with spastic quadriplegia and acquired hemiplegia are affected most often.
Seizures are less common in mild symmetric spastic diplegia and CP that is mainly
athetoid.
The onset of seizures is typically during the first two years after birth. Partial seizures
with secondary generalization are the most common type. Infantile spasms occur in some
infants; those with microcephaly and spastic quadriplegic or atonic CP are at the greatest
risk.
Mental retardation is more common in CP patients with than without seizures. Severe
retardation is more likely in those with multiple seizure types. Epilepsy can impose an
additional handicap when it is difficult to control, or if anticonvulsant drug doses cause
sedation that further impairs learning and socialization.
Visual disorders Ocular and visual disorders are common in CP. In one study of 120
school age children with CP, for example, strabismus and significant refractive errors
occurred in 52.5 and 50 percent, respectively. Amblyopia (15 percent) and visual field
defects (11 percent) were common. Eyes or ocular adnexae were normal in only 20
percent.
Low visual acuity may be due to cortical impairment. This was illustrated by a study
of visual acuity in children with CP. In 36 of 43 patients (84 percent) with low visual
acuity not explained by ophthalmological examination, cerebral visual disturbance was
considered a likely cause. Severe dyskinetic eye movements also can result in slow,
variable, and highly inefficient visual function.
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Speech impairment Patients with CP frequently have disorders of speech and
language, including aphasia and dysarthria. Some have complex disorders. Hearing
impairment may be an important cause. In one series of 75 children with spastic CP,
brainstem auditory evoked potentials were abnormal in 23 percent. Abnormal function of
oropharyngeal muscles and lack of coordination of breathing patterns contribute to
speech disorders in some patients. Low intelligence also plays a role.
Growth failure Patients with CP often have growth failure primarily due to poor
nutrition.
Poor nutritional status is caused by inadequate intake and gastrointestinal

abnormalities. In one series of 58 children with CP ages six months to 12 years, 92
percent had clinically significant gastrointestinal symptoms. These included swallowing
disorders, chronic constipation, regurgitation and/or vomiting, chronic aspiration, and
abdominal pain in 60, 74, 32, 41, and 32 percent, respectively.
Gastroesophageal reflux and palatopharyngeal incoordination contribute to chronic

respiratory disease in patients with severe CP. This may be exacerbated by poor
coordination of respiratory muscles and chest deformity. Reflux also contributes to dental
abnormalities, such as tooth erosion.
Orthopedic disorders Orthopedic disorders common in children with CP include

subluxation, dislocation, and progressive dysplasia of the hip. Adults with CP frequently
report back, neck, and joint pain.
Osteopenia Osteopenia, resulting in frequent fractures, develops as a result of

multiple factors including lack of mobility, feeding dysfunction and nutritional status.
Osteopenia in children with CP appears to be related to diminished rate of bone growth
rather than bone loss. Treatment with intravenous pamidronate for 12 months increased
bone mineral density in an open label trial, but the effect on fracture rates is unknown.
Urinary disorders Approximately one-third of children with CP have dysfunctional

voiding symptoms, including enuresis, frequency, urgency, and stress incontinence.
These are caused by urodynamic abnormalities, such as bladder hyperreflexia, detrusor
sphincter dyssynergia, bladder hypertonia with leakage, and periodic relaxation of the
distal sphincter during filling.
Neurologic deterioration Although the primary lesion in CP is static, neurologic

signs may change or worsen with increasing age. In some cases, neurologic deterioration
is due to cervical spondylotic myelopathy resulting from exaggerated neck flexion or
extension.
Dystonia and other progressive movement disorders (eg, tremor, parkinsonism,

myoclonus, chorea) may develop in patients with CP.
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DIAGNOSIS The diagnosis of CP depends upon a combination of findings including
motor delay, neurologic signs, persistence of primitive reflexes, and abnormal
postural reactions. A diagnosis rarely is made on the basis of an isolated abnormality.
Infants with normal functional development and behavior who have mild hypertonia or
hyperreflexia should be observed. If these abnormalities remain isolated, they will
resolve progressively after the child reaches nine months of age in most cases.
Infants with an abnormal obstetric or perinatal history may be at increased risk to

develop CP and should be monitored closely. Clues to an early diagnosis include
abnormal behavior, psychomotor delay, and abnormal oromotor or oculomotor patterns.
The infant may be hypotonic or have increased tendon reflexes and clonus.
Developmental (primitive) reflexes may be asymmetric or persistent, and postural
reactions may be delayed. In many cases, spasticity may not be identified until six
months of age. Dyskinetic patterns are not typically apparent until approximately
18 months. Ataxia may not become obvious until even later.
Although the lesion in CP is static, clinical signs evolve as the nervous system
matures. Thus, a definitive diagnosis usually requires serial examinations and often
is not possible until later infancy, especially in preterm infants.
Neurobehavioral signs Neurobehavioral signs suspicious for CP are excessive

docility or irritability. A typical history includes poor feeding in the neonatal period. The
baby often is irritable, sleeps poorly, vomits frequently, is difficult to handle and cuddle,
and has poor visual attention.
Motor abnormalities Tone in the extremities may be normal or increased. Persistent

or asymmetric fisting may be present. Abnormal oromotor patterns include tongue
retraction and thrust, tonic bite, oral hypersensitivity, and grimacing. Poor head control
may be an early motor sign. However, increased neck extensor and axial tone may make
head control appear better than it actually is.
In addition to the neurologic examination, achievement of motor milestones should be

evaluated. The infant should be observed in the prone and supine positions. Posture
and tone are assessed on pulling to sit, supported sitting, and vertical and ventral
suspension. The infant should be able to support himself or herself on arms and
hands and rotate within the body axis at the appropriate ages. The emergence and
quality of protective postural reactions should be noted.
Serial examination using motor milestones can be an effective screening process for CP.
In one study, six motor milestones (roll prone to supine, roll supine to prone, sit with
support, sit without support, crawl, and cruise) were sequentially evaluated for at least 18
months in 173 infants born at <33 weeks gestational age, of whom 31 (18 percent)
developed CP. Serial screening of these milestones predicted the development of CP
better than did any individual milestone. Delays in more than four milestones were
especially worrisome. In another report, signs present at four months of age that indicated
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increased risk of CP were failure to support weight on the forearms in a prone position,
sit supported with head erect, or show interest in surroundings or respond socially.
Developmental reflexes In normal infants, most developmental reflexes related to

posture (tonic labyrinthine, tonic neck, and neck-righting and body-righting reflexes)
disappear when the infants are between three and six months of age. These reflexes often
are not appropriately integrated or inhibited in children with CP. Thus, delay in the
disappearance or exaggeration of a developmental reflex may be an early indication of
motor disability.
. The tonic labyrinthine response is tested in the supine position. Extension of the neck
results in shoulder retraction, leg extension, and either elbow flexion or extension and
pronation of the arms. Flexion of the neck results in flexion of the extremities. Infants
with an exaggerated tonic labyrinthine response may have opisthotonic posturing or roll
over at an age that is earlier than appropriate.
Other abnormal signs can be elicited when the infant is held in vertical suspension.
During the first few months, the appropriate response is for the baby to assume a sitting
position ("sit in the air"). An abnormal response is persistent extension of the legs. This
may be followed by or associated with an abnormal positive support reaction. The latter
is tested by placing the anteromedial areas of the soles on a firm surface, which should
result in a few seconds of plantar flexion then return of the feet to a neutral position. An
abnormal response is plantar flexion that is obligate or maintained for more than 30
seconds, especially if accompanied by equinus posturing.
Specific syndromes The specific CP syndromes are best recognized after five years
of age. Earlier diagnosis may be difficult.
Spastic diplegia Infants with spastic diplegia often have hypotonia of the lower
limbs with delayed functional maturation for several months. Spasticity that involves
ankle plantar flexors and hip adductors usually is detected at approximately six months of
age. This often results in contractures of the hip flexors and hamstring muscles.
Spastic hemiplegia Hemiplegia is characterized by the early appearance of motor

asymmetry, often with some retraction of the shoulder on the affected side. The fingers
tend to be held in flexion, and with adduction of the thumb. Spasticity initially may be
minimal, but usually develops later with decreased abduction at the hip, plantar flexion at
the ankle, clawing of the toes, and a flexion-pronation pattern that affects the upper limb.
Other early signs are the inability to use both hands in the midline or to reach out with
the affected limb. When the infant is placed in the prone position, the affected upper limb
provides decreased support, and movement of the affected leg is diminished. When the
child is pulled to a sitting position, the affected leg tends to extend. The protective
reactions that appear at five to eight months of age are asymmetric.
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Spastic quadriplegia Patients with spastic quadriplegia typically have moderate or
severe psychomotor delay and poor head control. Spasticity may begin by two to three
months of age and involves the antigravity muscles, especially the biceps, forearm
pronators, wrist flexors, thumb adductors, and finger flexors. Adduction of the thighs and
flexion of the hips and knees occur, with equinus of the feet and adduction of the
forefoot. Marked adduction of the thighs results in typical scissoring of the legs.
Diagnosis of spastic CP usually is easier in the older infant. At approximately 9 to 10

months of age, affected infants who are pulled to sitting are unable to flex the legs and
have poor truncal balance. They cannot form a pincer grasp when reaching for an object.
Instead, the hand splays and they may achieve an ulnar grasp.
Dyskinetic CP In early infancy, patients with dyskinetic CP may have reduced

spontaneous movement and oromotor incoordination. They may be hypotonic at rest, but
tone may be variable with movement or emotion. Primitive reflexes typically persist.
Patients typically have extension patterns in the supine position, and flexion with
shoulder retraction in the prone position; the head usually is persistently turned to one
side.
Laboratory studies No specific tests confirm the diagnosis of CP. Children with
unusual features in the history or abnormalities on physical or neurologic examination
should be thoroughly evaluated for other conditions. Laboratory studies including serum
concentrations of glucose, ammonia, lactate and pyruvate, plasma amino acid analysis,
urine organic acid analysis, and arterial acid-base status should be obtained to exclude a
metabolic disorder.
Neuroimaging Magnetic resonance imaging (MRI) of the brain can identify a

lesion in the majority of cases of CP and may provide information regarding the
timing of the insult. In a systematic review and practice parameter from the American
Academy of Neurology and the Child Neurology Society, abnormalities on MRI were
noted in 89 percent of children with CP (range 68 to 100 percent). The yield of MRI
depended upon the type of CP (mixed > quadriplegic > hemiplegic > diplegic > ataxic >
dyskinetic > hypotonic) and the timing of birth; scans were abnormal in 99 percent of
preterm infants, 92 percent of term infants, and 79 percent of infants older than one
month of age. MRI, in combination with the clinical history, also helped determine
whether the injury was prenatal, perinatal, or postnatal in onset.
While the practice parameter cited above also found that CT scans can identify
abnormalities in a large number of children with CP, MRI is preferred because it
generally has a higher yield of suggesting both an etiology and the timing of insult
leading to CP.
Placenta Examination of the placenta may indicate infection or chronic pathologic

changes due to ischemia. Lesions associated with asphyxia include chronic ischemic
change, meconium staining, nucleated red blood cells, intravillous hemorrhages and
chronic ischemic changes.
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Metabolic and genetic testing Children with CP may have congenital brain
malformations such as lissencephaly, schizencephaly, or pachygyria, and these
malformations are increasingly associated with specific genetic disorders.
As a result, the practice parameter from the American Academy of Neurology and the
Child Neurology Society recommends that metabolic and genetic testing be considered
only if the clinical history or findings on neuroimaging do not determine a specific
structural abnormality or if there are suggestive or atypical features in the history or
clinical examination. Detection of a brain malformation in a child with CP also warrants
consideration of a genetic or metabolic etiology.
Recommendations The practice parameter from the American Academy of

Neurology and the Child Neurology Society recommends the following approach to the
evaluation of the child with CP, recognizing that there is insufficient evidence to
determine the optimal sequence of tests to determine the etiology:
All children should undergo a detailed history and physical examination. It is particularly
important to determine that the condition is static rather than progressive or degenerative.
It is also important to classify the type of CP.
Screening for mental retardation, ophthalmologic abnormalities, hearing impairment,

speech and language disorders, and disorders of oral-motor function are warranted as part
of the initial assessment because these problems are commonly associated with CP.
An EEG is recommended when there are features suggestive of epilepsy.
Neuroimaging is recommended to both establish an etiology and for prognostic

purposes. MRI is preferred to CT scan.
Metabolic and genetic testing are considered if the clinical history or findings on
neuroimaging do not determine a specific structural abnormality or if there are additional
and atypical features in the history or clinical examination.
DIFFERENTIAL DIAGNOSIS CP is a diagnosis of exclusion. Typical symptoms

and signs of CP, such as early hypotonia, spasticity, and dystonia and/or choreoathetosis,
may be present in other conditions. These include neurodegenerative diseases, inborn
errors of metabolism, developmental or traumatic lesions of the brain or spinal cord,
neuromuscular or movement disorders, and neoplasm.
Some conditions, especially those that are slowly progressive, may be misdiagnosed as
CP. Thus, all children with manifestations of CP should be evaluated for a possible
underlying cause. Situations in which another diagnosis, such as a neurodegenerative
disease or metabolic disorder, is likely include:
Positive family history of the neurologic condition.
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Loss of developmental milestones.
Ataxia, involuntary movements, oculomotor abnormalities, muscle atrophy, or sensory

loss.
Hypotonia associated with weakness.
Rapid deterioration of neurologic signs.
Marked worsening during periods of catabolism.
Signs and symptoms associated with other conditions that may be initially diagnosed as
CP are described below.
Muscle weakness Conditions with muscle weakness as well as central nervous

system involvement include degenerative disorders, such as metachromatic
leukodystrophy and pontocerebellar atrophies.
Diplegia or quadriplegia Conditions that may present with diplegia or quadriplegia

include metabolic disorders such as arginase deficiency. Holocarboxylase synthetase
deficiency, a rare and treatable disorder of biotin metabolism, presents with generalized
hypertonia and developmental delay, which may be mistaken for CP; patients also have
scaly skin eruptions and episodes of metabolic acidosis. Other degenerative diseases with
diplegia or quadriplegia include adrenoleukodystrophy and hereditary progressive spastic
paraplegia.
Dystonia and choreoathetosis Glutaric aciduria type 1, caused by deficiency of

riboflavin dependent glutaryl-CoA dehydrogenase, often presents with an episode of
metabolic decompensation with ketoacidosis, hyperammonemia, hypoglycemia, and
encephalopathy during the first year or later, often accompanied by infection and fever.
Affected patients also develop a dystonic movement disorder with preserved cognitive
function.
Dopa-responsive dystonia, an unusual form of hereditary progressive dystonia that

presents in childhood, may mimic dyskinetic CP. The dystonia usually starts in the legs
and becomes generalized. Some patients also have hyperreflexia, rigidity, tremor, and
other parkinsonian features..
Dystonia and/or choreoathetosis also occur in other disorders including Lesch-Nyhan

disease, pyruvate dehydrogenase complex deficiency, and Rett syndrome.
Ataxia Ataxia may occur in a number of disorders that could be mistaken for CP.
These include ataxia telangiectasia, X-linked spinocerebellar ataxia, and Niemann-
Pick disease.
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Bulbar and oromotor dysfunction Bulbar and oromotor dysfunction occur in
children with CP and result in difficulty with feeding and speech. However, these
conditions usually are less prominent than are other motor findings. Thus, other
diagnoses should be considered in patients with profound bulbar and oromotor
abnormalities. One example is bilateral perisylvian syndrome (also known as opercular
syndrome).
Management and prognosis of cerebral palsy

TREATMENT GOALS Psychological development, communication, and education
are priorities in the management of CP. Longitudinal social, language, and psychometric
assessment provides a rational basis for training in communication and activities of daily
living and allows the child to derive the maximum benefit from school.
Multidisciplinary team Management of the child with CP requires a

multidisciplinary team to address the multiple medical, social, psychological,
educational, and therapeutic needs. Team members should have a goal-oriented approach
that is based upon an adequate knowledge base and an understanding and appreciation of
contributions from all the disciplines. Management should be directed at promoting the
child's
Social and emotional development
Communication
Education
Nutrition
Mobility
Maximal independence in activities of daily living
Appearance as nearly normal as possible
SPASTICITY Medications and/or surgery may help to reduce spasticity,

hyperreflexia, and clonus, although they do not improve weakness and incoordination.
For medical therapy of spasticity, I have found botulinum toxin to be more effective
than oral antispastic drugs.
Botulinum toxin Injection of botulinum toxin A (BTX) into affected muscles blocks
the presynaptic release of acetylcholine from motor endplates of the lower motor neuron
at the myoneural junction and decreases tone by limiting muscle contraction.
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Indications The appropriate use of BTX in children with CP has been described in a
treatment protocol. BTX is indicated in patients who have increased muscle tone that
interferes with function or is likely to lead to joint contracture with growth; the best
evidence is for equinus varus. Patients younger than four years old and without fixed
contractures are expected to have the most favorable response. Ideally, only two or three
muscles will require treatment at one time.
In general, BTX should not be used in children younger than 18 months old because
no data are available on the long-term use of this therapy. BTX is not appropriate for
patients with diffuse hypertonia, although it might be used to treat focal aspects of
generalized spasticity. Fixed contractures are not amenable to BTX therapy, although
BTX injections may facilitate serial casting.
Treatment Prior to therapy, a complete baseline assessment should be performed by

a multidisciplinary team. The evaluation should include range of motion, strength,
assessment of selective motor control, muscle tone, and function.
Complications Complications are rare and include fever, which may last for one to
three days, and transient pain, local irritation, and bruising. Weakness and temporary
(less than two weeks) loss of function in the injected area may follow a dose that is too
high, and may indicate previously undiagnosed muscle weakness.
Oral antispastic drugs Dantrolene, benzodiazepines, and baclofen have been

used by some clinicians to treat spasticity in CP, although I do not find these as useful as
botulinum toxin.
Dantrolene Dantrolene sodium reduces muscle contraction by inhibiting release of

calcium ions from the sarcoplasmic reticulum. Treatment may decrease tone, tendon
reflexes, and scissoring and may improve range of motion, but objective functional
improvement is limited. Side effects, which are common, include weakness, drowsiness,
lethargy, paresthesias, nausea, and diarrhea.
Benzodiazepines Benzodiazepines, such as diazepam, may reduce spasticity. The

mechanism is increased presynaptic inhibition due to binding to benzodiazepine receptors
that are linked to receptors for the inhibitory neurotransmitter gamma-aminobutyric acid
(GABA) located on the terminals of primary afferent fibers; there is subsequent increased
affinity for GABA at the receptor site and increased flux of chloride ions across the
terminal membrane. The tranquilizer effect makes benzodiazepines useful in dyskinetic
CP. However, they may produce sedation, weakness, ataxia, memory disturbances, and
dependence after prolonged use.
Baclofen Baclofen, an analog of GABA, binds to the GABA-B receptors on the

terminals of primary afferent fibers. Activation of these receptors inhibits the influx of
calcium ions into presynaptic terminals and suppresses release of excitatory
neurotransmitters. Side effects include confusion, sedation, hypotonia, ataxia,
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paresthesias, and nausea. Seizures and hallucination may occur if the drug is discontinued
abruptly.
Intrathecal baclofen The effect of oral baclofen is limited because poor lipid
solubility results in low cerebrospinal fluid (CSF) levels. Intrathecal baclofen
(administered via a pump) achieves higher CSF drug levels. Side effects include
confusion and lethargy and appear to be related to the dose. This treatment is restricted to
severely affected patients.
Surgical treatment Surgical treatment of spasticity includes selective dorsal

rhizotomy and stereotactic encephalotomy.
Selective dorsal rhizotomy Selective dorsal rhizotomy (SDR) is a surgical

procedure that selectively divides parts of the dorsal lumbosacral roots of the spinal cord.
This interrupts the afferent limb of the reflex arc on the sensory side, thus reducing
spasticity without causing paralysis.
Which children are most likely to benefit from SDR is uncertain. I recommend the
procedure in severely affected nonambulatory patients with contractures. In these
children, SDR aids in cleanliness and dressing.
Stereotactic encephalotomy Stereotactic encephalotomy on the basal ganglia

(cutting specific tracts) has been performed in patients with hyperkinesia or dystonia. In a
retrospective study, improvement was seen in eight of 18 patients (initial sample was 28
patients) evaluated at an average of 21 years after the procedure. Outcomes were better in
patients with hyperkinesia, tremor, and predominantly unilateral dystonia. This procedure
may be considered in children with very severe dystonia.
ORTHOPEDIC INTERVENTIONS Orthopedic interventions are directed at relief

and prevention of deformity and maximizing function. Gait analysis, using physical
examination, electromyography, and videotaping of limb motion, is often used to identify
which muscles might benefit from lengthening procedures and to evaluate the effects of
surgery. This should be performed when the gait is mature, usually between six and
ten years of age.
Muscle-tendon surgery Release or recession of limb muscles and tendons (muscle-

tendon surgery) is sometimes performed to reduce restricted joint motion or
malalignment. They are recommended when fixed contractures interfere with possible
function or care.
Hip disorders Disorders of the hip, including subluxation, dislocation, and

dislocation with degeneration and pain are common complications of spastic CP.
Although the hip is initially normal, progressive dysplasia results from a combination of
bony deformity and muscle imbalance, usually involving the adductor and iliopsoas
muscles.
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Diagnosis is made by an anteroposterior radiograph of the pelvis because physical
examination is unreliable. Because earlier surgical intervention is associated with better
outcomes, some clinicians recommend screening radiographic examination in all
nonambulant children with bilateral CP, beginning at 18 months of age and repeated
every six to 12 months.Postural management may have a role in prevention of hip
dysplasia.
PHYSICAL THERAPY Physical therapy is an established part of treatment

programs for CP, although the effectiveness of this approach is uncertain. Physical
therapy is typically started early and continued by the parents at home.
CONSTRAINT THERAPY Constraint-induced movement therapy (CIMT) has

been used as a treatment for children with hemiplegic cerebral palsy. Children with
hemiplegia avoid using the affected limb, in a process termed "developmental disregard".
CIMT aims to promote function of the affected limb by encouraging its use through
intermittent restraint of the unaffected limb during therapeutic tasks. The method of
restraint varies from holding a child's hand to casting, and the length of time in the
restraint varies from 1 to 24 hours a day. "Forced use" is a variation of CIMT in which
the limb's use is encouraged only by placement of the contralateral restraint; no additional
therapeutic tasks are assigned to the affected limb.
ELECTRICAL STIMULATION Electrical stimulation has been used in an effort

to increase muscle strength in children with cerebral palsy. In neuromuscular electrical
stimulation (NMES), electrical impulses of high intensity and short duration generate
muscle contraction. In threshold electrical stimulation (TES), the stimulus is of lower
intensity and does not generate muscle contraction; it is typically applied during sleep.
FEEDING DISORDERS Feeding problems and oromotor dysfunction are common

in children with CP. In a review of 49 children with CP, ages 12 to 72 months, more than
90 percent had clinically significant oromotor dysfunction. Problems with sucking and
swallowing occurred during the first year after birth in 57 and 38 percent, respectively.
These difficulties require caregivers to devote substantial time to oral feeding. Some
children may not achieve sufficient intake if the time available for feeding is limited.
Gastrostomy feeding improves nutritional status in children with CP and growth failure.
This intervention also reduces aspiration and provides a reliable route for medication. It
improves the quality of life for both the child and family in the majority of cases.
However, it is unknown whether gastrostomy placement prior to the development of
malnutrition or aspiration pneumonia would improve long-term outcome in these
patients.
DROOLING Oromotor dysfunction in children with CP often leads to drooling,

which is a significant impediment to social acceptance. In one study, the mechanisms of
drooling were evaluated in children with CP by measuring intraoral pressure during the
suction and propulsion stages of swallowing small amounts of liquid. Drooling was
associated with abnormal suction of liquid onto the tongue caused by incomplete lip
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closure during swallowing, low suction pressure, and prolonged delay between suction
and propelling stages.
Approaches to improve drooling include medication, behavior therapy, and surgery.

Anticholinergic agents, such as benzhexol hydrochloride (trihexyphenidyl
hydrochloride), scopolamine, or glycopyrrolate may be effective by decreasing the flow
of saliva. Another possible approach is injection of botulinum toxin A (BTX) into the
salivary glands.
Surgical treatment of drooling is directed at reducing salivary production.

Techniques include repositioning of the submandibular ducts and unilateral ligation of a
parotid duct. Although surgery reduced drooling frequency and severity, complications
such as ranula formation, dry mouth, difficulty with swallowing, and changes in the
consistency of oral secretions occurred often (39 percent in one series), limiting the
acceptance of this intervention.
SOCIAL AND PSYCHOLOGICAL SUPPORT Similar to any family with a child

with a chronic medical condition, social and psychological support is essential. Parents of
a child with CP may have chronic grief, as well as guilt, frustration, denial, anger,
resentment, and embarrassment. They may limit themselves socially and strain
relationships with their spouse and other children. Some express dissatisfaction with
health care professionals.
Technological support Technological aids provide important support for patients

with CP, especially those with severe motor impairment. Equipment such as motorized
wheelchairs, switching devices used to activate communication systems, voice-activated
computers, and other environmental control systems can improve quality of life by
enhancing functional abilities and social interactions.
PROGNOSIS
Survival The majority of children with CP survive to adulthood. In a regional

analysis of children with CP who were born in various regions of the UK between 1980
and 1996, 20-year survival ranged from 87 to 94 percent.
The mortality rate in patients with severe multiple handicaps is partly affected by the
aggressiveness and quality of care. In one study, children with CP who were immobile,
had no toilet skills, and required tube feedings typically died by five years of age, and
only 20 percent survived to 10 years. Respiratory disease, often aspiration pneumonia,
is the most common cause of death.
Motor impairment The extent of motor impairment is difficult to predict in young

children, except at the extremes of mild or severe involvement. In general, prognosis for
motor function depends upon the type of CP, rate of motor development, presence of
developmental reflexes, intellectual ability, sensory impairment, and emotional-social
adjustment. Significant intellectual impairment often, although not always, accompanies
384
severe motor deficit. Patients with CP who walk before age two years typically have
normal or borderline normal IQs.
Nearly all children with hemiplegic CP will walk, as will many with athetosis or
ataxia. The prognosis for walking is poor in children who do not achieve head
balance by 20 months, retain primitive reflexes or have no postural reactions by 24
months, or do not crawl by approximately five years of age. The prognosis for
walking is good in children who sit by two years and crawl before 30 months of age.
Some children who sit between three and four years of age eventually walk, but most
require aids or braces or have restricted functional ambulation. In general, children who
walk independently do so by approximately three years of age; those who walk only
with support may take up to nine years. A child who does not walk by nine years of age is
unlikely to ever walk, even with support.
Although these curves provide important prognostic information, parents should

understand that considerable variability occurs within each severity group. In addition,
functional outcome in CP depends on multiple factors besides motor function. These
include intelligence, physical function, ability to communicate, and personality attributes.
Social (eg, family support) and environmental factors and the availability of specialist
medical care play an important role. Adjustment is facilitated by the availability of
training, independent or sheltered employment, and counseling.
385
Febrile Seizures
Micheal V. Johnson
Febrile convulsions, the most common seizure disorder during childhood. Febrile
seizures are age dependent and are rare before 9 mo and after 5 yr of age. The peak age of
onset is 1418 mo of age, and the incidence approaches 34% of young children.
A simple febrile convulsion is usually associated with a core temperature that increases
rapidly to 39C. It is initially generalized and tonic-clonic in nature, lasts a few seconds
and rarely up to 15 min, is followed by a brief postictal period of drowsiness, and occurs
only once in 24 hr. A febrile seizure is described as complex or complicated when the
duration is >15 min, when repeated convulsions occur within 24 hr, or when focal seizure
activity or focal findings are present during the postictal period.
Approximately 3050% of children have recurrent seizures with later episodes of

fever and a small minority has numerous recurrent febrile seizures. Factors associated
with increased recurrence risk include age <12 mo, lower temperature before seizure
onset, a positive family history of febrile seizures, and complex features.
During the acute evaluation, a physician's most important responsibility is to determine

the cause of the fever and to rule out meningitis or encephalitis. If any doubt exists about
the possibility of meningitis, a lumbar puncture with examination of the cerebrospinal
fluid (CSF) is indicated. A lumbar puncture should be strongly considered in
children <12 mo of age and considered in those 1218 mo of age, especially if
seizures are complex or sensorium remains clouded after a short postictal period.
An electroencephalogram (EEG) is not warranted after a simple febrile seizure but may
be useful for evaluating patients with complex or atypical features or with other risk
factors for later epilepsy. Similarly, neuroimaging is also not useful for children with
simple febrile convulsions, but may be considered for children with atypical features,
including focal neurologic signs or pre-existing neurologic deficits.
TREATMENT.
Routine management of a normal infant with simple brief febrile convulsions includes a careful
search for the cause of the fever and reassurance and education of the parents. Although
antipyretics have not been shown to prevent seizure recurrences, active measures to control the
fever, including the use of antipyretics, may reduce discomfort and are reassuring. In a setting
where support for ventilation can be provided, consideration should be given to treating
seizures lasting >5 min with a benzodiazepine as a first-line therapy. Prolonged anticonvulsant
prophylaxis for preventing recurrent febrile convulsions is controversial and no longer
recommended for most children. Antiepileptics such as phenytoin and carbamazepine do not
prevent febrile seizures. Phenobarbital prevents recurrent febrile seizures but may also
decrease cognitive function in treated children compared with untreated children. Sodium
386
valproate is also effective for prevention of febrile seizures, but the potential risks of the drug
do not justify its use in a disorder with an excellent prognosis regardless of treatment. The
incidence of fatal valproate-induced hepatotoxicity is highest in children <2 yr of age.
If parental anxiety is very high, oral diazepam may be used as an effective and safe
method of reducing the risk of recurrence of febrile seizures. At the onset of each febrile
illness, oral diazepam, 0.3 mg/kg q8h (1 mg/kg/24 hr), is administered for the duration of
the illness (usually 23 days). The side effects are usually minor, but symptoms of
lethargy, irritability, and ataxia may be reduced by adjusting the dose. Another approach
for selected patients with recurrent complex febrile seizures is to prescribe diazepam in
the form of a gel that can be given rectally at the time of a seizure in a dose of
approximately 0.5 mg/kg for children aged 25 yr. This will usually terminate the seizure
and prevent recurrence over 12 hr.
Preventive anticonvulsant treatment or treatment after the seizure has not been shown to
reduce the risk of later epilepsy in higher risk patients.
387
Acute bacterial meningitis in children
Sheldon L Kaplan, MD
Suspected bacterial meningitis is a medical emergency, and immediate diagnostic steps

must be taken to establish the specific cause so that appropriate antimicrobial therapy can
be initiated. The mortality rate of untreated bacterial meningitis approaches 100 percent
and, even with optimal therapy, morbidity and mortality may occur. Neurologic sequelae
are common among survivors.
GENERAL PRINCIPLES There are a number of general principles of antibiotic

therapy in patients with bacterial meningitis. The most important initial issues are
avoidance of delay in administering therapy and the choice of drug regimen.
Avoidance of delay Antibiotic therapy should be initiated immediately after lumbar

puncture (LP) is performed if the clinical suspicion for meningitis is high. Delay in the
administration of appropriate antibiotics can have a deleterious effect on outcome for
patients who are deteriorating rapidly.
If computed tomography (CT) scan is to be performed before LP, antibiotic therapy

should be initiated immediately after blood cultures are obtained. Although the
administration of antimicrobial therapy before LP may affect the yield of CSF Gram stain
and culture, pathogens other than meningococcus usually can be identified in the CSF up
to several hours after the administration of antibiotics.
Antibiotic regimen There are two general principles of antibiotic therapy for
bacterial meningitis:
The agent(s) used must be bactericidal against the infecting organism.
The agent(s) used must be able to penetrate past the blood brain barrier to enter the CSF.
PRETREATMENT EVALUATION If possible, the pretreatment evaluation of

children with suspected bacterial meningitis should include a complete history and
physical examination, cerebrospinal fluid (CSF) examination (cell count and differential,
glucose, protein, Gram stain and culture), complete blood count with differential and
platelet count, two aerobic blood cultures, serum electrolytes, glucose, blood urea
nitrogen, and creatinine; evaluation of clotting function is especially indicated if
petechiae or purpuric lesions are noted.
IMMEDIATE MANAGEMENT Immediate management of children with

suspected bacterial meningitis includes:
1. Assurance of adequate ventilation and cardiac perfusion.

2. Initiation of hemodynamic monitoring and support at the same time as obtaining
appropriate laboratory studies (blood and CSF).
388
3. Establishment of venous access.
4. Administration of fluids as necessary to treat septic shock, if present.
5. Administration of dexamethasone if warranted after assessment of potential benefits
and risks before or immediately after the first dose of antimicrobial therapy.
6. Administration of the first dose of empiric antibiotics (cefotaxime [100 mg/kg] or
ceftriaxone [50 mg/kg] plus vancomycin [15 mg/kg].
7. Administration of glucose (0.25 g/kg) for documented hypoglycemia (serum glucose
concentration less than 40 mg/dL [2.2 mmol/L]).
8. Treatment of acidosis and coagulopathy if present.
SUPPORTIVE CARE
Fluid management Careful management of fluid and electrolyte balance is an

important aspect of supportive therapy. Both over- and under-hydration are associated
with adverse outcomes.
Children who are in shock should receive sufficient quantities of isotonic fluid to
maintain blood pressure and cerebral perfusion.
Children who are hypovolemic, but not in shock, should be rehydrated with careful and
frequent attention to fluid status. Body weight, urine volume and specific gravity, and
serum electrolytes should be monitored regularly.
For children who are neither in shock nor hypovolemic, we suggest moderate fluid
restriction (1200 mL/m2 per day) initially, especially if the serum sodium is less than 130
meq/L, until evidence of inappropriate secretion of antidiuretic hormone can be excluded.
Body weight, urine volume and specific gravity, serum electrolytes, and if indicated,
serum and urine osmolalities should be carefully monitored. Fluid administration can be
liberalized gradually as the serum sodium reaches 135 meq/L. Most children can receive
maintenance fluid intake within 24 hours of hospitalization.
Monitoring Children who are being treated for bacterial meningitis should be
monitored carefully for complications (eg, increased intracranial pressure, seizure
activity, development of infected subdural effusions), particularly during the first two to
three days of treatment, when complications are most likely to occur.
Heart rate, blood pressure, and respiratory rate should be monitored regularly with a
frequency appropriate to the care setting.
A complete neurologic examination should be performed daily; rapid assessment of

neurologic function should be performed several times per day for the first several days
of treatment.
Head circumference should be measured daily in children younger than 18 months.
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EMPIRIC THERAPY The organism causing bacterial meningitis seldom is known
at the outset of therapy; as a result, an empiric treatment plan usually needs to be
formulated.
Major pathogens The two most common causes of bacterial meningitis in infants
and children who have received a full series of Hib conjugate vaccines are S.
pneumoniae and N. meningitidis. Among S. pneumoniae isolates, antibiotic resistance
remains a concern. In developing countries that do not routinely immunize against Hib,
Hib continues to be a frequent cause of meningitis.
Group B streptococcus, Escherichia coli, and L. monocytogenes are important

causes in infants younger than three months.
An appropriate empiric regimen (ie, one that covers antibiotic resistant S. pneumoniae,
N. meningitidis, and Hib) includes high doses of a third generation cephalosporin (eg,
cefotaxime, ceftriaxone) and vancomycin: Cefotaxime (300 mg/kg per day
intravenously [IV], maximum dose 12 g/day, in 3 or 4 divided doses), or ceftriaxone (100
mg/kg per day IV, maximum dose 4 g/day, in 1 or 2 divided doses), plus: Vancomycin
(60 mg/kg per day IV, maximum dose 2 g/day, in 4 divided doses)
If ceftriaxone is used, we suggest twice daily dosing to avoid the possibility of

inadequate treatment in the event of dosing errors, delayed doses, or missed doses. Some
experts suggest the addition of rifampin to the empiric regimen if dexamethasone is
administered.
Consultation with an expert in pediatric infectious diseases is recommended for children

in whom cephalosporins or vancomycin are contraindicated.
Use of dexamethasone
The American Academy of Pediatrics (AAP) Committee on Infectious Diseases

suggests that dexamethasone therapy may be beneficial in children with Hib meningitis if
given before or at the same time as the first dose of antimicrobial therapy, but is probably
of no benefit if given more than one hour later. The AAP Committee on Infectious
Diseases suggests that dexamethasone therapy be considered for infants and children
older than six weeks with pneumococcal meningitis after weighing the potential risks
and benefits.
Regimen If the decision is made to use dexamethasone, dexamethasone should be

given before or concurrently with the first dose of the antimicrobial agent(s); it is
probably of no benefit if given more than one hour later . The regimen for
dexamethasone is: Dexamethasone (0.15 mg/kg per dose) every 6 hours for 2 to 4
days. Two days of dexamethasone appear to be as effective and less toxic than longer
courses.
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If a gram-negative rod is observed on Gram stain of the CSF, the addition of an
aminoglycoside (eg, gentamicin, amikacin) to these two agents is recommended.
- Gentamicin (7.5 mg/kg per day IV in 3 divided doses), or
- Amikacin (15 to 22. 5 mg/kg per day IV, maximum dose 1.5 g/day, in 3 divided
doses)
Recent neurosurgery In addition to the usual nosocomial pathogens that may

complicate any surgical procedure, coagulase-negative staphylococci (such as S.
epidermidis) and S. aureus are important causes of meningitis in patients who have had
recent neurosurgery. Patients who undergo operations that involve a prosthetic device,
such as a ventricular shunt or drain, are notoriously at risk for developing infection.
Patients who have undergone recent neurosurgery also are at increased risk for
meningitis with enteric gram-negative rods, such as Escherichia coli and Klebsiella
species, as well as Pseudomonas aeruginosa.
Empiric therapy in this setting usually consists of a combination of a third-generation

cephalosporin and vancomycin. In addition, an aminoglycoside (eg, gentamicin,
amikacin) should be added if Gram-negative bacilli are noted on CSF Gram stain.
Alternative regimens include:
Vancomycin (60 mg/kg per day IV, maximum dose 2 g/day, in 4 divided doses), plus
Cefepime (150 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses), or
ceftazidime (150 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses), or
meropenem (120 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses)
Penetrating head trauma Patients with penetrating head trauma are at risk for
meningitis with S. aureus, coagulase negative staphylococci (such as S. epidermidis), and
aerobic Gram-negative bacilli, including Pseudomonas aeruginosa.
Empiric therapy in this setting usually consists of a combination of vancomycin plus an

extended spectrum cephalosporin (cefepime or ceftazidime) or meropenem, plus an
aminoglycoside:
Vancomycin (60 mg/kg per day IV, maximum dose 2 g/day, in 4 divided doses), plus
Cefepime (150 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses), or
ceftazidime (150 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses), or
meropenem (120 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses), plus
Gentamicin (7.5 mg/kg per day IV in 3 divided doses) or amikacin (15 to 22.5 mg/kg per
day IV, maximum dose 1.5 g/day, in 3 divided doses)
391
CSF leak Patients with a CSF leak (CSF rhinorrhea or otorrhea) should be treated
for presumed pneumococcal meningitis since S. pneumoniae is the most likely organism
in this setting. Pneumococcal meningitis in these patients is usually less severe than that
caused by hematogenous invasion and the prognosis is somewhat better. Nevertheless,
because of the possibility of an isolate highly resistant to penicillin, such patients should
be treated with a third-generation cephalosporin plus vancomycin until culture results
return. This regimen also will cover H. influenzae, which rarely causes meningitis in
patients with dural defects.
SPECIFIC THERAPY Once the causative agent and its in vitro antimicrobial
susceptibility pattern are known, empiric antimicrobial therapy can be altered
accordingly.
Antimicrobial therapy for bacterial meningitis caused by Streptococcus

pneumoniae based upon susceptibility test results in patients begun on cefotaxime or
ceftriaxone plus vancomycin.
The usual duration of therapy in uncomplicated cases of S. pneumoniae meningitis is 10

to 14 days.
N. meningitidis Meningococcal meningitis is best treated with penicillin:
Penicillin G (250,000 to 300,000 U/kg per day IV, maximum 24 million U/day, in 4
or 6 divided doses)
A third-generation cephalosporin is an effective alternative to penicillin for children

with penicillin allergy that is not characterized by anaphylaxis.
Possible regimens include:
Cefotaxime (225 to 300 mg/kg per day IV, maximum dose 12 g/day, in 3 or 4 divided
doses), or Ceftriaxone (100 mg/kg per day IV, maximum dose 4 g/day, in 1 or 2
divided doses)
For patients with penicillin allergy characterized by anaphylaxis, chloramphenicol is a

recommended alternative. Desensitizing the patient to the third generation cephalosporin
is another option. Chloramphenicol (75 to 100 mg/kg per day IV, maximum dose 2 to 4 g
per day, in 4 divided doses).
Although scattered cases of N. meningitidis resistant to penicillin have been reported,

such strains are rare. Relative resistance to penicillin occurs more commonly but does not
have an impact on the response to penicillin or cephalosporin therapy.
A five- to seven-day duration of therapy is adequate for meningococcal meningitis

and eradication of the organism from the CSF. However, neither penicillin nor
chloramphenicol therapy reliably eradicates nasopharyngeal carriage of N. meningitidis.
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Patients treated with penicillin or chloramphenicol should receive antimicrobial therapy
to eradicate nasopharyngeal carriage before hospital discharge to prevent transmission of
the organism to contacts.
H. influenzae type b Ceftriaxone or cefotaxime is the treatment of choice for

ampicillin-resistant Hib meningitis. Cefotaxime (200 mg/kg per day IV, maximum
dose 12 g/day, in 3 or 4 divided doses), or Ceftriaxone (100 mg/kg per day IV, maximum
dose 4 g/day, in 1 or 2 divided doses).
Ampicillin is effective for susceptible strains: Ampicillin (300 to 400 mg/kg per day IV,
maximum dose 10 to 12 g/day, in 4 to 6 divided doses).
For patients with penicillin allergy characterized by anaphylaxis, desensitizing the

patient is one option. Chloramphenicol is another: Chloramphenicol (100 mg/kg per day
IV, maximum dose 2 to 4 g per day, in 4 divided doses).
Patients with Hib meningitis should be treated for 7 to 10 days. Pharyngeal

colonization persists after curative therapy with agents other than ceftriaxone and
cefotaxime.
Patients who are not treated with ceftriaxone or cefotaxime should receive rifampin
before hospital discharge to prevent transmission of the organism to contacts.
For patients who are treated with chloramphenicol, rifampin therapy should be delayed
until chloramphenicol is discontinued since concomitant administration of rifampin may
reduce serum concentrations of chloramphenicol.
L. monocytogenes Listeria meningitis traditionally has been treated with

ampicillin and gentamicin, because resistance to these drugs is quite rare. Although
gentamicin has poor CSF penetration, it is used for synergy. Ampicillin (300 mg/kg per
day IV, maximum dose 10 to 12 g/day, in 4 to 6 divided doses), plus Gentamicin (7.5
mg/kg per day IV in 3 divided doses)..
Trimethoprim-sulfamethoxazole (TMP-SMX) is an alternative for penicillin-allergic

patients. The dose for TMP-SMX is as follows: TMP-SMX (10 to 12 mg/kg of the TMP
component and 50 to 60 mg/kg of the SMX component per day in 4 divided doses).
Meropenem, a carbapenem approved for the treatment of pediatric meningitis, has

excellent in vitro activity against L. monocytogenes. It may prove to be useful for listeria
infections but has not yet been approved for this indication. Other antibiotics are less
effective against L. monocytogenes.
The usual duration of therapy for Listeria meningitis is 14 to 21 days.
Gram-negative rods Meningitis caused by enteric Gram-negative rods is usually

treated with an extended-spectrum cephalosporin and an aminoglycoside. The
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aminoglycoside often can be discontinued after the first week, once the CSF cultures
have been documented to be sterile. Consultation with an expert in pediatric infectious
diseases is recommended for children with meningitis caused by a Gram-negative rod.
One suggested regimen is as follows:
Cefotaxime (200 to 300 mg/kg per day IV, maximum dose 12 g/day, in 4 divided doses)
or ceftriaxone (100 mg/kg per day IV, maximum dose 4 g/day, in 2 divided doses), plus
Gentamicin (7.5 mg/kg per day IV in 3 divided doses)
Organisms such as Pseudomonas aeruginosa often are resistant to many

commonly used antibiotics. Ceftazidime has been the most consistently effective
cephalosporin in the treatment of P. aeruginosa infections, including meningitis:
Ceftazidime (150 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses).
Meropenem is an effective drug in the treatment of meningitis, and is approved by the

United States Food and Drug Administration (FDA) for the treatment of bacterial
meningitis in children and adolescents. It may be used in patients with ceftazidime-
resistant strains of various Gram-negative rods and is the agent of choice in the
treatment of meningitis caused by extended-spectrum beta-lactamase producing
Gram-negative enteric organisms. It is dosed as follows:
Meropenem (120 mg/kg per day IV, maximum dose 6 g/day, in 3 divided doses)
A repeat CSF sample should be obtained for culture two to three days into therapy to help
assess the efficacy of treatment.
In addition, we suggest repeating the CSF analysis near the end of therapy, particularly
in young infants, to determine whether treatment may be discontinued.
CSF findings suggestive of the need for continued therapy include:
Percentage of neutrophils >30 percent, or
CSF glucose concentration <20 mg/dL
Occasionally, intraventricular administration of an antibiotic (generally an

aminoglycoside) for several days is necessary to sterilize the CSF. Intraventricular
therapy should be undertaken in consultation with specialists in pediatric infectious
diseases and neurosurgery.
DURATION OF THERAPY The duration of antimicrobial therapy depends upon

the causative organism and the clinical course.
Positive CSF culture We suggest the following durations of therapy for

uncomplicated meningitis caused by the following organisms:
394
S. pneumoniae 10 to 14 days N.
meningitidis 5 to 7 days
Hib 7 to 10 days
L. monocytogenes 14 to 21 days
Gram-negative bacilli 3 weeks or a minimum of 2 weeks beyond the first sterile

culture, whichever is longer.
Outpatient therapy In highly selected patients, a portion of antibiotic therapy may

be administered in the outpatient setting. Advantages of completion of therapy in the
outpatient setting include: decreased risk of nosocomial infection, improved quality of
life, and decreased cost of therapy.
One group of investigators used the following criteria for outpatient antimicrobial
therapy in children:
Completion of at least 6 days of inpatient therapy; serious adverse complications of

meningitis are exceedingly rare after 3 or 4 days of therapy, particularly in children who
are clinically well and afebrile.
Afebrile for at least 24 to 48 hours before initiation of outpatient therapy.
No significant neurologic dysfunction or focal findings.
No seizure activity.
Clinical stability.
Ability to take fluids by mouth.
First dose of outpatient antibiotic is administered in the hospital.
Outpatient antibiotic therapy is administered in the office or emergency department

setting or by qualified home health nursing.
Daily examination is performed by a physician.
Parents are reliable and have transportation and a telephone
Negative CSF culture For children with negative CSF cultures at 48 to 72 hours, the
duration of antibiotic therapy is individualized depending upon the remainder of the CSF
evaluation, blood culture result, and clinical status:
395
For those who have a normal CSF profile, and negative blood and CSF culture, we
usually discontinue antimicrobial therapy if cultures remain sterile after 48 to 72 hours of
incubation.
For those who have a CSF pleocytosis and positive blood culture, but negative CSF
culture, treat for meningitis caused by the organism isolated from the blood culture (ie,
management is the same as if the CSF culture was positive for the same organism).
For those who have a CSF pleocytosis, negative blood culture, and negative CSF culture,
we individualize the duration of meningitic doses of antimicrobial therapy based on
clinical parameters.
RESPONSE TO THERAPY The response to therapy is monitored clinically (eg,

fever curve, resolution of symptoms and signs). Repeat examination of the spinal fluid
and neuroimaging may be necessary in some patients. In children who had a positive
blood cultures at initial evaluation, blood cultures should be repeated to document
sterility of the blood stream. The follow-up blood culture is usually obtained when it is
known that the initial blood culture is positive.
In patients with prolonged obtundation, irritability, seizures, focal neurologic

abnormalities, or increased head circumference, neurologic complications (eg, subdural
empyema, cerebral vascular thrombosis, ventricular dilation, brain abscess) should be
considered, and neuroimaging may be warranted.
Duration of fever The duration of fever is typically four to six days after the initiation
of adequate therapy. Fever lasts longer than five days in approximately 13 percent of
patients; secondary fever (eg, recurrence of fever after being afebrile for at least 24
hours) occurs in approximately 16 percent.
Persistence of fever beyond 8 days and secondary fever have a number of causes,
including:
1. Inadequate treatment.
2. Development of nosocomial infection (eg, infected intravenous catheters, urinary
tract infection, viral infection); nosocomial infection is more often associated with
secondary fever than with persistent fever.
3. Discontinuation of dexamethasone.
4. Development of a suppurative complication (pericarditis, pneumonia, arthritis,
subdural empyema).
5. Drug fever (a diagnosis of exclusion).
Repeat CSF analysis Reexamination of the CSF is recommended for patients who
have a poor clinical response despite 24 to 36 hour of appropriate antimicrobial therapy.
This is particularly true for children with cephalosporin-resistant pneumococcal
meningitis and for children with pneumococcal meningitis who were treated with
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dexamethasone (since dexamethasone may interfere with the ability of the physician to
assess clinical response such as resolution of fever).
Reexamination of the CSF also may be indicated in children with persistent or recurrent
fever.
In addition, reexamination of the CSF is necessary after two to three days of treatment for
Gram-negative bacillary meningitis to determine appropriate duration of therapy.
Repeat CSF cultures should be sterile.
Extension of the duration of therapy is indicated
1. If organisms are seen on Gram stain or isolated from CSF cultures of the repeat CSF
examination.
2. If CSF examination at the conclusion of the standard duration of treatment shows
>30 percent neutrophils, CSF glucose of 20 mg/dL, or CSF to blood glucose
ratio of <20 percent, respectively.
Neuroimaging Neuroimaging (with CT or MRI) may be indicated during the course

of treatment for acute bacterial meningitis in the following circumstances:
Focal neurologic signs, increasing head circumference, or prolonged obtundation,

irritability, or seizures (>72 hours after the start of treatment);
Persistently positive CSF cultures despite appropriate antibiotic therapy
Persistent elevation of CSF neutrophils at the completion of standard duration of therapy

(more than 30 to 40 percent)
Recurrent meningitis (to evaluate the possibility of a communication between the nasal
passage or ear and the meninges.
In addition, neuroimaging of infants with Gram-negative meningitis sometime during

their treatment is recommended to detect hydrocephalus or other complications of the
meningitis. This is particularly true for infants with Citrobacter or Enterobacter sakazakii
(also known as Cronobacter) meningitis.
PROGNOSIS
A meta-analysis of prospectively enrolled cohorts of 4920 children from 1955 to 1993
found a mortality rate of 4.8 percent in developed countries and 8.1 percent in developing
countries. The mortality rate in developed countries varied by organism, ranging from 3.8
percent for Hib to 7.5 percent for N. meningitidis to 15.3 percent for S. pneumoniae. In
the more recent multicenter pneumococcal meningitis surveillance study (1993-1996),
mortality for pneumococcal meningitis was 7.7 percent in the United States.
397
Neurologic sequelae Persistent neurologic sequelae are not uncommon in children
who survive an episode of bacterial meningitis.
In the meta-analysis of 4520 children from 1955 to 1993 cited above, 84 percent of the
surviving children in developed countries and 74 percent in developing countries
appeared to have complete recovery. The most common sequelae present after hospital
discharge in the remaining children were:
Deafness 11 percent, including bilateral severe or profound deafness in 5 percent
Mental retardation 4 percent
Spasticity and/or paresis 4 percent
Seizures 4 percent
FOLLOW-UP
Hearing evaluation Hearing evaluation should be performed at the time of or

shortly after discharge from the hospital. Hearing may be assessed by pure tone
audiometry; evoked response audiometry may be used in young children or those who
cannot cooperate with pure tone audiometry.
Development Young children who have been treated for meningitis are at risk for
developmental delay.
PREVENTION
Isolation All patients admitted to the hospital with meningitis should be placed on
standard precautions.
In addition, droplet precautions are recommended for patients with N. meningitidis and
Hib meningitis until they have received 24 hours of effective therapy. Patients should be
in private rooms and hospital personnel should wear a face mask when they are within
three feet (one meter) of the patient.
Chemoprophylaxis Chemoprophylaxis should be administered to close contacts as

early as possible after the primary case has been identified (ideally within 24 hours of
identification of the index patient), but is of little value if administered more than two
weeks after the index case.
Close contacts include:
Household members or other close contacts, such as child-care center contacts,

coworkers in the same office, young adults in dormitories, recruits in training centers,
398
and, for travelers, direct contact with respiratory secretions from an index patient or
sitting next to an index patient for more than eight hours.
Exposure to oral secretions (eg, intimate kissing, mouth-to-mouth resuscitation,

endotracheal intubation or endotracheal tube management).
Antimicrobial chemoprophylaxis regimens for meningococcal infection
Rifampin (oral) Children <1 month 5 mg/kg every 12 hours Two days
Children 1 month 10 mg/kg every 12 hours Two days
Adults 600 mg every 12 hours Two days
Ciprofloxacin (oral) Adults 500 mg Single oral dose
Ceftriaxone (intramuscular) Children <15 years 125 mg Single IM dose
Older children and adults 250 mg Single IM dose
Azithromycin Children <15 years 10 mg/kg Single oral dose
Children >15 years 500 mg Single oral dose
Antimicrobial prophylaxis
Chemoprophylaxis of close contacts eradicates nasopharyngeal carriage of Hib, thereby

reducing the risk of developing invasive disease, and/or transmission.
To prevent invasive disease in susceptible children, we recommend chemoprophylaxis

for close contacts of patients with invasive Hib disease who live in a household with
a child who is younger than 4 years of age and has not received an age-appropriate
number of doses of HbCV or an immunocompromised child.
We recommend chemoprophylaxis for child-care and preschool contacts when

unimmunized or incompletely immunized children attend the facility and two or
more cases of Hib invasive disease have occurred among attendees within 60 days.
We recommend chemoprophylaxis for the index patient if he or she was treated

with an agent other than cefotaxime or ceftriaxone and is younger than 2 years of
age or lives in a household with a child <4 years of age who has not received an age-
appropriate number of HbCV doses or an immunocompromised child. We
recommend rifampin for Hib chemoprophylaxis. The dose is 20 mg/kg (maximum dose
600 mg) once per day for four days.
399
Viral meningitis: Clinical features and diagnosis in children
Cecilia Di Pentima, MD
Meningitis Meningitis is inflammation of the meninges, manifest by cerebrospinal

fluid (CSF) pleocytosis (ie, an increased number of white blood cells [WBC]).
Aseptic meningitis is the clinical syndrome of meningeal inflammation with negative

cultures for routine bacterial pathogens in a patient who did not receive antibiotics before
lumbar puncture. Aseptic meningitis has a number of infectious and noninfectious causes.
Viruses (usually enteroviruses) are the most common cause. Because viruses are the most
common cause of aseptic meningitis, the terms aseptic meningitis and viral meningitis are
sometimes used synonymously.
Encephalitis Encephalitis is inflammation of the brain parenchyma, manifest by

neurologic dysfunction (eg, altered mental status, behavior, or personality; motor or
sensory deficits; speech or movement disorders; hemiparesis; and paresthesias).
Encephalitis may occur during or after a viral infection.
Myelitis Myelitis is inflammation of the spinal cord, manifest by flaccid paralysis

and reduced or absent reflexes.
The presence or absence of normal brain function distinguishes meningitis from

encephalitis. Certain viruses usually cause isolated meningitis or isolated encephalitis.
Others cause less discrete manifestations of CNS infection, described as
meningoencephalitis or encephalomyelitis. Although the distinction between meningitis
and encephalitis is sometimes blurred, it is important to try to distinguish between them
because the likely causes differ.
CLINICAL FEATURES Clinical features of viral meningitis in children vary with

age, immune status, and etiologic agent.
Common features The manifestations of viral meningitis are generally similar to

those of bacterial meningitis, but often are less severe.
Neonates may have an abrupt onset of fever accompanied by nonspecific symptoms

(eg, poor feeding, vomiting, diarrhea, rash, respiratory symptoms). Neurologic
manifestations may be minimal, ranging from no symptoms, to irritability and lethargy,
to frank nuchal rigidity or bulging fontanelle. CNS disease may progress to encephalitis
with seizures and/or focal neurologic findings. Neonates are at increased risk for severe
systemic disease, particularly with herpes simplex virus (HSV). Systemic manifestations
may include pneumonia, hepatitis with necrosis, myocarditis, and necrotizing
enterocolitis. Disseminated intravascular coagulation and other findings of sepsis can
mimic overwhelming bacterial infection.
400
Older children may present with acute onset of fever, headache, nausea, vomiting, stiff
neck, and photophobia.
Physical findings in neonates and older children are variable. Nuchal rigidity, bulging
fontanelle, and manifestations of particular viruses (eg, rash, conjunctivitis, pharyngitis,
diarrhea) tend to be the most prevalent findings.
Features associated with specific viruses
Enteroviruses Enteroviruses (EV) include poliovirus, coxsackievirus, echovirus, and

the numbered enteroviruses. Meningitis due to enteroviruses is associated with the acute
onset of fever that ranges from 38 to 40C in more than 50 percent of cases and is
sometimes biphasic. Fever is generally accompanied by nonspecific constitutional
symptoms such as anorexia, nausea, vomiting, exanthem, myalgias, and upper and lower
respiratory symptoms.
Older children typically complain of fever, headaches (usually retroorbital or frontal),

and photophobia. More than one-half of adults and children older than 1 to 2 years
present with nuchal rigidity.
Clinical features suggestive of EV include conjunctivitis, pharyngitis, rash, herpangina

and hand-foot-mouth disease. EV71, which usually causes hand-foot-mouth disease, also
may cause more severe illness, including cranial nerve palsies, flaccid paralysis, and
pulmonary edema.
Herpesviruses HSV infections of the CNS in neonates manifest primarily as

encephalitis with or without multiorgan involvement; however, meningitis in this age
401
group also can present with fever as the only manifestation. The long-term prognosis for
infants with disseminated HSV and/or HSV encephalitis is poor.
Older children, teenagers, and adults with primary HSV infection who develop
encephalitis generally present with fever, altered mental status, focal neurologic deficits,
and seizures. Those with meningitis generally present with fever and classic symptoms of
meningitis (eg, fever, stiff neck, headache, photophobia). HSV and other herpesvirus
meningitis may be complicated by sacral radiculopathy (manifest by urinary retention,
constipation, paresthesia, and motor weakness).
Arboviruses Arboviruses are spread by arthropod or insect vectors (eg, mosquitoes,

ticks, sand flies). The clinical manifestations of meningitis caused by arboviruses are
similar to those of other viral pathogens. Most cases are characterized by the acute onset
of fever, chills, headaches, nausea, vomiting, and nuchal rigidity in the absence of focal
neurologic findings.
The manifestations of St. Louis encephalitis (SLE) virus range from a mild "flu-like"
illness to fatal encephalitis. The manifestations of La Crosse (California) encephalitis,
which primarily occurs in children, include fever, focal neurologic signs, and focal
seizures that mimic HSV encephalitis.
West Nile virus (WNV) is characterized by fever, headache, malaise, back pain,
myalgias, and anorexia. A maculopapular rash appears in approximately one-half of
patients. Some manifestations seen in adults (eg, weakness, peripheral neuropathy,
diffuse paralysis) are rare in children.
Western equine encephalitis (WEE) virus infection is characterized by headache,

vomiting, stiff neck, and backache; restlessness, irritability, and seizures are common in
children. Neurologic sequelae are relatively common in infants.
Lymphocytic choriomeningitis virus Most lymphocytic choriomeningitis virus

(LCMV) infections are asymptomatic or associated with mild constitutional symptoms.
Symptomatic infection manifests as a biphasic illness with an initial phase characterized
by fever, malaise, photophobia, headache, nausea, vomiting, sore throat, and adenopathy.
Signs and symptoms of CNS disease develop in the second phase, which follows
resolution of fever.
Congenital infection is characterized by chorioretinitis (affecting more than 90 percent

of infants in reported cases), micro- or macrocephaly, and neurologic sequelae including
seizures, mental retardation, and cerebral palsy.
Meningitis develops in approximately 15 percent of confirmed cases of LCMV.

Encephalitis and meningoencephalitis are rare complications of LCMV [1] . Other
complications include transverse myelitis, Guillain-Barr syndrome, myocarditis,
pneumonitis, and parotiti
402
Rabies Rabies infection, which is more commonly associated with
encephalomyelitis, is heralded by a prodrome of 2 to 10 days of nonspecific symptoms
such as fever, headache, malaise, myalgias, cough, sore throat, nausea, and vomiting.
Anxiety, hallucinations, nightmares, and insomnia may occur during this early stage.
Rapid and progressive neurologic deterioration occurs in one to two weeks, leading to
coma and death, usually by the third week of illness.
403
Influenza Influenza A and B infections of the CNS are preceded by the classic
symptoms of typical influenza infection: fever, coryza, cough, vomiting, headaches, and
diarrhea. Neurologic manifestations develop within one to four days after the onset of
symptoms.
Mumps Mumps infection is frequently accompanied by a nonspecific prodrome

consisting of low-grade fever, malaise, headache, myalgias, and anorexia. These
symptoms are generally followed within 48 hours by the development of painful parotitis,
the hallmark of mumps infection.
Meningitis occurs in approximately 1 to 10 percent of mumps infections. CNS infection

usually manifests about five days after parotitis, but it may occur as much as two weeks
later or one week earlier. Mumps meningitis generally has a benign course with full
neurologic recovery.
DIAGNOSTIC APPROACH
Overview The diagnostic approach to suspected aseptic meningitis focuses on

identification of conditions and pathogens that require specific therapy.
Children who are suspected of having meningitis should be treated as if they have
bacterial meningitis until bacterial meningitis has been excluded or a specific viral
diagnosis has been made. This includes rapid evaluation and stabilization of
cardiorespiratory and hemodynamic status and obtaining initial laboratory studies as soon
as is possible.
Viral meningitis may be suspected on the basis of epidemiologic data, clinical features,
and initial CSF studies, but clinical features cannot reliably differentiate viral from
bacterial meningitis; the CSF profiles of bacterial and viral meningitis overlap,
particularly during the earliest stages of bacterial meningitis.
History Information from the history helps prioritize among the possible causes of
meningitis and aseptic meningitis. Important aspects of the history in a child with
suspected viral meningitis include:
The presence of classic symptoms (fever, stiff neck, headache, photophobia) but without
the presence of severe systemic disease (except for the neonate).
Symptoms of encephalitis (eg, altered mental status, behavior, or personality; motor or

sensory deficits; speech or movement disorders; hemiparesis; and paresthesias).
Symptoms associated with specific viruses (eg, rash, sore throat, vomiting, diarrhea,
genitourinary symptoms).
Preceding illness (pneumonia or respiratory illness may indicate M. pneumoniae).
404
Exposure in preceding two to three weeks to: ill contacts; ticks, mosquitoes, or animals,
including pet rodents; water potentially contaminated with rodent droppings or urine;
uncooked meat; swimming in hot springs (associated with primary amebic
meningoencephalitis).
Prenatal and perinatal history in the neonate and young infant (<3 months), particularly
related to congenital infection..
Previous episodes (consider HSV-2, epidermoid cyst).
Sexual history and risk factors for human immunodeficiency virus (HIV) infection.
Immunization history.
Recent injections and/or medications including antibiotics, NSAIDS, immunoglobulin.
Outbreaks of human or animal disease in the community, particularly by season (eg,

EV, influenza, WNV, measles, rabies, WEE, etc).
Examination The examination of the patient with suspected aseptic meningitis

centers on assessment of meningeal inflammation, brain function (to exclude
encephalitis), and clues to specific viral etiologies. Important aspects of the examination
include:
Signs of meningeal inflammation (nuchal rigidity, Kernig and Brudzinsky's signs).
Assessment of mental status (Glasgow coma scale) and presence of focal neurologic
signs (suggestive of encephalitis or EV71).
Findings associated with EV infection (eg, conjunctivitis, pharyngitis, rash, herpangina,

hand-foot-mouth disease).
Findings associated with other potential causes of viral meningitis (eg, generalized
lymphadenopathy, suggestive of Epstein-Barr or HIV infection; oral or genital ulcers,
suggestive of HSV infection; rash suggestive of chicken pox; parotid swelling, suggestive
of mumps or LCMV).
Weakness or paralysis, which may occur with poliovirus or EV71.
Dermal sinus track in midline from coccyx to nose (associated with epidermoid cysts
and direct connection with CNS).
405
Imaging Computed tomography (CT) of the head is necessary before lumbar puncture
in patients with signs or symptoms of increased intracranial pressure. Indications for
head CT may include:
1. Altered mental status (GCS <12 or drop in GCS of 2).

2. Immune deficiency.
3. Papilledema.
4. Focal neurologic deficit (excluding palsy of cranial nerves VI [abducens] or VII
[facial]).
5. CSF shunt.
6. Hydrocephalus.
7. CNS trauma.
8. History of neurosurgery or a space-occupying lesions.
9. Signs or symptoms of parameningeal infection or tumor.
Neuroimaging with nuclear magnetic resonance (MRI) and/or

electroencephalography may be helpful in assessing brain inflammation and making
the distinction between meningitis and encephalitis.
Additional imaging studies may be necessary in select patients (eg, chest radiograph in
children with a history of exposure to M. tuberculosis)
406
Laboratory evaluation Viral meningitis may be suspected on the clinical and
epidemiologic features, but the diagnosis requires a positive identification of a viral
pathogen, most often in the context of a negative CSF culture for routine bacterial
pathogens.
The initial laboratory evaluation of a child with suspected meningitis includes blood
tests and lumbar puncture. For children in whom viral meningitis is suspected, CSF
studies, discussed below, are essential. Stool and throat swabs may be sent for viral
culture. Further testing may be necessary to exclude nonviral causes of aseptic meningitis
that require specific therapy, particularly in patients with an atypical presentation (eg,
immunodeficiency, structural heart disease or hardware) or specific exposures (eg,
tuberculosis, ticks, rodents).
Additional evaluation (including urinalysis, urine culture, and/or chest radiograph) is

necessary for febrile infants younger than 3 months.
Blood tests Initial blood tests for a child with suspected meningitis should include:
1. Blood cultures.
2. CBC with differential and platelet count.
3. PT, PTT (particularly in patients with petechiae or purpura).
4. Serum electrolytes,BUN, creatinine, and glucose.
Additional studies may be indicated if there are clinical clues suggestive of particular
infections. These may include serologic testing for measles, mumps, arboviruses,
varicella, EBV, LCMV, HIV, syphilis, and Lyme disease.
CSF studies Examination of the CSF is necessary to establish a diagnosis of

meningitis and to make a provisional diagnosis of bacterial, viral, or unclear etiology.
Lumbar puncture also may provide symptom relief in patients with viral meningitis.
CSF should be sent for Gram stain and bacterial culture, cell count, glucose, and protein.
Viral studies (viral culture, polymerase chain reaction [PCR]) should be sent if the
clinical picture suggests viral meningitis.
Additional antigen detection tests (enzyme immunoassay, fluorescent antibody),

pathogen-specific antibody tests, and/or cultures for bacteria, mycobacteria, fungi, and
parasites may be necessary in special circumstances (eg, in immunocompromised hosts).
It is helpful to reserve a tube of CSF for further testing, which may be necessary if the
patient fails to improve as expected.
Interpretation of CSF The CSF findings in bacterial meningitis typically include:

WBC count of >1000 cells/microL with a predominance of neutrophils
(polymorphonuclear leukocytes, PMN); glucose <40 mg/dL (2.2 mmol/L); and protein
between 100 and 500 mg/dL.
407
The characteristic findings of viral meningitis are summarized below:
Cell count and differential WBC ranges from 10 to 500 cells/microL (higher values
can be seen with some viruses,). Normal CSF WBC counts can be seen in EV meningitis
and, more rarely, with HSV meningoencephalitis early in the course of infection.
There is a predominance of mononuclear cells in most cases of viral meningitis, although

a PMN predominance has been described early (the first 24 to 48 hours) in the course of
EV meningitis caused by the most common serotypes.
Glucose Normal or slightly reduced, but usually 40 percent of the serum value.
Protein Normal to slightly elevated, but usually less than 150 mg/dL (may be as high
as 900 mg/dL in WNV)
Analysis of the CSF is not always predictive of viral or bacterial infection since there is
considerable overlap in the respective CSF findings. In addition, wide variations in CSF
findings can occur during an outbreak of a single EV serotype.
408
Virology Samples of CSF should be sent for PCR analysis for EV and, in the
appropriate patients, HSV and WNV. Stool (or rectal swab) and throat swabs may be sent
for viral culture to confirm PCR results for EV. Serologies may be obtained for the less
common etiologies of viral meningitis; for some pathogens (eg, WNV), specific antibody
determinations for IgG and IgM also may be performed on CSF. In addition, samples of
blood and urine should be sent for viral studies when viral meningitis is suspected in
immunocompromised children.
PCR has largely replaced viral culture and serologic diagnosis of viral meningitis,
improving diagnostic accuracy. PCR results are available sooner than viral culture results
(5 to 24 hours compared to 4 to 8 days) and are available from several reference
laboratories. Earlier identification of EV or human parechovirus may reduce unnecessary
days of hospitalization, intravenous antibiotic therapy, and additional diagnostic testing.
It also may help inform prognosis.
Diagnosis Pending CSF culture results, clinical features and initial CSF results can
be used to make a provisional diagnosis of suspected viral meningitis. The diagnosis of
viral meningitis is confirmed by negative bacterial cultures and identification of a virus
through PCR, culture, antigen detection, or serology.
Features supportive of a provisional diagnosis of viral meningitis include:
CSF WBC of <500 cells/microL with a mononuclear predominance.
Normal CSF glucose.
CSF protein <100 mg/dL.
Negative CSF Gram stain.
Enterovirus disease in the community or close contact with an individual with an

enterovirus-compatible disease process.
Improvement in symptoms following lumbar puncture.
DIFFERENTIAL DIAGNOSIS It is particularly important to consider causes of

aseptic meningitis that require specific therapy and affect prognosis.
Among nonviral conditions that may cause CSF pleocytosis with a predominance of
mononuclear cells, the CSF glucose concentration helps narrow the differential diagnosis:
Normal CSF glucose concentration Syphilis, Lyme disease, leptospirosis, Rocky

Mountain Spotted fever, ehrlichiosis, Kawasaki disease, postinfectious
encephalomyelitis, and drugs (NSAIDS, trimethoprim-sulfamethoxazole).
409
Decreased CSF glucose concentration Partially treated bacterial meningitis,
Listeria monocytogenes, M. tuberculosis, fungal infections, primary amebic
meningoencephalitis.
Bacterial infections Bacterial infections can cause a clinical picture that overlaps
with that of viral meningitis for a variety of reasons, including:
Early in the disease process, bacteria do not always elicit a marked polymorphonuclear
response.
Pathogens with unusual growth requirements may not grow in routine bacterial cultures
(eg, Mycobacteria, spirochetes, rickettsii).
Subtherapeutic concentrations of antibiotics administered for other reasons (eg, to treat

otitis media) may inhibit bacterial growth.
Bacteria may be sequestered in pockets adjacent to, but not directly communicating with
the CSF (eg, sinuses, epidural abscess, subdural abscess).
The Bacterial Meningitis Score (BMS) is a clinical prediction rule for children with CSF
pleocytosis (CSF WBC 10 cells/microL) that classifies children at very low risk of
bacterial meningitis if they lack all of the following:
- Positive CSF Gram stain
- CSF absolute neutrophil count 1000 cells/microL
- CSF protein 80 mg/dL
- Peripheral blood ANC 10,000 cells/microL
- History of seizure before or at the time of presentation
The BMS should not be applied to children who are immunocompromised; who were
treated with antibiotics before lumbar puncture; or who have critical illness, purpura,
ventriculoperitoneal shunt, or recent history of neurosurgery.
Lyme meningitis Lyme disease, which may cause meningitis, occurs during the
same season as EV infection, the most common cause of culture-negative aseptic
meningitis. Lyme disease usually occurs in older children and has a longer duration of
symptoms than EV infection. Additional features suggestive of Lyme meningitis include
erythema migrans, cranial neuropathy, papilledema, and CSF neutrophil count <10
percent.
410
411
Parameningeal infection Parameningeal infections include brain abscess, epidural
or subdural abscess, and infections of the sinuses or ear that can occasionally extend to
involve the CNS. Parameningeal infections can be diagnosed through neuroimaging.
Viral encephalitis Viral encephalitis is a febrile illness in which signs and symptoms
of neurologic dysfunction indicate parenchymal brain involvement. Manifestations of
encephalitis include: altered mental status, behavior, or personality; motor or sensory
deficits; speech or movement disorders; hemiparesis; and paresthesias. The prognosis for
viral encephalitis is usually worse than that for viral meningitis.
412
Viral meningitis: Management, prognosis, and prevention in
children
Cecilia Di Pentima, MD
Indications for hospitalization may include:
1. Ill-appearance or signs of encephalitis (eg, altered mental status, behavior, or

personality; motor or sensory deficits; speech or movement disorders;
hemiparesis; flaccid paralysis; paresthesias; seizures).
2. Need for empiric antimicrobial therapy.
3. Need for intravenous hydration or aggressive pain control.
4. Immunocompromised host.
5. Age younger than one year.
Suspected bacterial meningitis Children with positive Gram stain, CSF white blood
cell (WBC) count >1000/microL with a predominance of neutrophils
(polymorphonuclear leukocytes, PMN), and CSF glucose concentration <40 mg/dL (2.2
mmol/L), are likely to have bacterial meningitis.
Suspected viral meningitis Children with CSF WBC count<500/microL with >50
percent mononuclear cells, CSF protein <80 to 100 mg/dL, normal CSF glucose, and
negative Gram stain are likely to have viral meningitis. Epidemiologic and clinical data
that support the provisional diagnosis of viral meningitis include associated herpangina,
enterovirus disease in the community in the summer or fall, and improvement in clinical
illness after lumbar puncture (LP).
Unclear etiology The etiology is unclear when the clinical and laboratory features of
bacterial and viral infections overlap. We suggest that such children be treated with
empiric therapy pending additional information (eg, results of culture, PCR, or repeat
lumbar puncture).
SUPPORTIVE CARE Supportive care for children with viral meningitis may
include:
Rest in a quiet, dimly lit room.
Acetaminophen for headache, pain, and fever; aspirin should be avoided because of its
association with Reye syndrome.
Intravenous fluid therapy if prolonged emesis has resulted in hypovolemia. Careful

attention to fluid balance is an important aspect of supportive care. The need for fluid
repletion must be balanced against the risk of inappropriate secretion of antidiuretic
hormone.
413
Neonates and immunocompromised hosts may require aggressive supportive care for
disseminated disease (eg, myocarditis, pericarditis, hepatitis, coagulopathy), particularly
with enterovirus or herpes simplex virus (HSV) infection.
EMPIRIC THERAPY While awaiting the results of bacterial cultures, empiric

antimicrobial therapy should be provided to patients in whom bacterial meningitis
is suspected or cannot be excluded. Empiric treatment for HSV, tuberculosis, and
various other infections also may be warranted in patients who are severely ill or have
clinical features suggestive of these infections.
We recommend empiric antibiotic therapy while awaiting bacterial culture results in the
following patients with suspected viral meningitis:
Those who are younger than three months of age.
Those who are severely ill or immunocompromised.
Choice of agent Empiric antibiotics should be chosen to cover the most likely
bacterial pathogens in the individual host. In severely ill patients, empiric therapy for
unusual bacterial pathogens also may be warranted. Glucocorticoids, when administered
initially to children who were ultimately diagnosed with aseptic meningitis, were not
shown to produce detectable adverse outcomes.
Duration of therapy In patients who improve symptomatically, empiric antibiotic

therapy is usually discontinued when the bacterial culture is negative after 24 to 48 hours
and/or an alternative diagnosis is made (eg, by viral polymerase chain reaction [PCR]). In
patients with persistent symptoms, additional evaluation may be necessary.
Empiric antivirals Depending upon the clinical scenario and severity of illness,
empiric treatment with antiviral therapy may be warranted for certain patients.
We recommend empiric therapy with acyclovir for children with CSF pleocytosis
who have encephalitis, or focal findings on examination, imaging, or
electroencephalography. Acyclovir also may be warranted when HSV is a possible
etiology in an immunocompromised patient.
Decisions regarding the use of empiric acyclovir in infants with CSF pleocytosis who
are younger than 28 days must be made on a case-by-case basis. Clinical features
suggestive of HSV infection include: mucocutaneous vesicles, seizures, lethargy,
respiratory distress, thrombocytopenia, hypothermia, hepatitis, sepsis-like illness, and
elevated transaminases.
Duration In patients who are clinically improved, empiric acyclovir may be

discontinued when HSV PCR and cultures are negative or an alternative diagnosis
is made (eg, by enteroviral PCR). Viral isolates usually grow in tissue culture by four to
eight days.
414
In patients with persistent symptoms, continuation of empiric acyclovir and/or additional
evaluation may be necessary.
SPECIFIC THERAPY Most cases of viral meningitis are treated symptomatically.
Selected antiviral agents have been tried against some of the viral pathogens.
Herpesviruses Although the outcome of HSV meningitis without encephalitis is

usually excellent even without antiviral therapy, acyclovir can be used to hasten recovery.
Acyclovir is dosed as follows:
For neonatal HSV, 60 mg/kg per day in three divided doses for 21 days.
For CNS infections in children aged 3 months to <12 years, 60 mg/kg per day, in three
divided doses for a minimum of 14 to 21 days.
For CNS infections in children 12 years old, 30 mg/kg per day, in three divided doses
for a minimum of 14 to 21 days.
PERSISTENT SYMPTOMS When symptoms persist or worsen in patients with

bacterial culture-negative aseptic meningitis, nonviral causes must be considered.
Additional evaluation may include:
Repeat lumbar puncture with removal of 3 to 5 mL of CSF (if possible) for fungal and
mycobacterial cultures.
Imaging of the CNS and sinuses with MRI or CT to look for parameningeal infection and
acute disseminated encephalomyelitis.
Evaluation for Lyme disease, ehrlichiosis, rickettsial infection.
PROGNOSIS Most children with viral meningitis recover spontaneously. Some

patients complain of fatigue, irritability, decreased concentration, muscle weakness and
spasm, and incoordination for several weeks after the acute illness.
Prognosis depends upon the age of the child and the etiologic agent. Enteroviral
meningitis typically has a benign clinical course, which by definition, lacks the
neurologic abnormalities that characterize encephalitis or myelitis.
Children with EV meningitis generally recover without neurologic sequelae.

Several studies have suggested possible long-term neurologic, cognitive, developmental,
and language abnormalities in young children following EV meningitis; however, these
observations have been inconsistent. EV71 CNS infection with cardiopulmonary
involvement has been associated with neurologic sequelae, including delayed
development and reduced cognitive function.
415
FOLLOW-UP Assessment for muscular weakness should be performed several
weeks after the symptoms of viral meningitis have improved.
PREVENTION
Hygiene Simple hygienic measures, such as hand washing, particularly after diaper
changing, are important to prevent the spread of enteroviruses.
Vaccines Vaccines are available to prevent poliovirus, influenza, rabies, and some
arboviruses (eg, Japanese encephalitis virus, Tick-borne encephalitis).
Personal protection Personal protection measures to avoid mosquito and tick

exposure is a mainstay of prevention. A variety of insect repellants are available.
Infection control When children are hospitalized with aseptic meningitis, contact
precautions are indicated for the duration of illness.
416
Treatment of seizures and epileptic syndromes in children
Angus Wilfong, MD
INTRODUCTION Children with epilepsy, particularly infants, differ from adults

not only in the clinical manifestations of their seizures, but also in the presence of unique
electroencephalogram (EEG) patterns, etiologies, and response to antiepileptic drugs
(AEDs).
The long-term prognosis for seizure cessation tends to be better in children, particularly
those who are neurologically intact. On the other hand, status epilepticus is more
common in children, as are severely abnormal EEG patterns, including hypsarrhythmia
(West syndrome) and slow spike and slow wave discharges (Lennox-Gastaut syndrome).
The detrimental effects of AEDs are probably also greater in the immature and rapidly
developing child's brain.
THE FIRST SEIZURE A child's first seizure may be caused by an acute illness,
such as a metabolic derangement or infectious disorder, and be nonrecurrent, or may
represent the beginning of epilepsy. A decision must be made about initiating chronic
antiepileptic drug (AED) treatment if a potentially reversible acute cause is not found
during the evaluation.
Prognosis after a first seizure The child who is neurologically normal, has no
history of a prior neurologic illness, and has an unprovoked seizure with no evident acute
cause has a 24 percent risk of having another seizure in the next year, and a 45 percent
risk over the next 14 years .
The one year recurrence risk increases to 37 percent in children with a prior neurologic
insult (remote symptomatic), such as cerebral palsy, and increases to 70 percent in
patients who have had two seizures that are separated by at least 24 hours.
Withholding treatment until after the second seizure does not alter the long-term
prognosis of epilepsy.
Predictors of recurrence In children with an unprovoked seizure, the

electroencephalogram (EEG) is the most valuable predictor of recurrence. In one study,
the recurrence risk was 41 percent in the first 12 months after the initial seizure if the
EEG was abnormal (epileptiform activity, focal or generalized slowing) compared with
15 percent in children with a normal EEG .
Long-term remission Children with idiopathic generalized epilepsy and age of onset
between five and nine years were more likely to have remission. Those with a remote
symptomatic etiology, family history of epilepsy, frequent seizures, and slowing on the
initial EEG were less likely to have remission. Approximately one-half of relapses
417
occurred in children who had stopped or were tapering medication, while one-fourth
occurred while on medication.
Recommendations The decision whether to treat a child after an initial unprovoked

seizure is an individualized one.
Treatment with AEDs is not indicated for the prevention of the development of
epilepsy.
Treatment with AEDs may be considered when the benefits of reducing the risk of
a second seizure are greater than the risks of pharmacologic and psychosocial side
effects.
BASIC PRINCIPLES OF ANTIEPILEPTIC DRUG THERAPY
Choice of drug
The AED chosen for initial therapy should be one that is highly effective for a particular
seizure type or syndrome and that is safe and well tolerated (table 1).
(Table 1)
418
CBZ: carbamazepine; CRZ: clorazepate; CNZ: clonazepam; ESM: ethosuximide;
FBM: felbamate; GBP: gabapentin; LEV: levetiracetam; LTG: lamotrigine; OXC:
oxcarbazepine; PHT: phenytoin; PB: phenobarbital; PRM: primidone; TPM:
topiramate; TGB: tiagabine; VPA: valproic acid (divalproex sodium).
1: first line drugs.
2: second line drugs.
Adapted from Tharp, BR, Epilepsy in Infants and Children. In: Conn's Current
Therapy, Rakel, RE (Ed), W.B. Saunders 1998; p.883.
Drug dose
The AED dose should be increased until seizures stop, unremitting adverse effects occur,
or serum levels reach a high or supratherapeutic range without a significant impact upon
seizure frequency. The recommended upper therapeutic serum levels of most of the
AEDs can be exceeded if side effects are absent. This should be done with particular
caution with phenytoin because of its nonlinear pharmacokinetics and with valproate
because of dose-related thrombocytopenia (show table 2A-2B). If side effects appear but
are tolerable, the dose should remain stable for several weeks to determine if the
symptoms remit. Dose increases can continue at a slower rate if side effects remit and
seizures continue.
Adding a second AED A second AED is added when seizures are resistant to the
initial drug. If the initial drug was partially effective, it should be continued until
reasonable levels of the new AED are achieved. Tapering the first drug can then be
attempted if seizures are controlled. If the initial AED is ineffective, it can be tapered
earlier, as the dose of the second drug is increased.
Monotherapy versus polytherapy Single-drug therapy is the goal of epilepsy

treatment. Monotherapy is associated with better compliance, fewer adverse effects, less
potential for teratogenicity, and lower cost than is polytherapy.
Most of the AEDs have been reported to increase seizure frequency in a small
percentage of patients and, in some instances, induce new seizure types. These seizures
may occur at low or therapeutic doses of some drugs and at toxic doses in others.
Carbamazepine, for example, can precipitate atonic seizures, particularly in children
with Lennox-Gastaut syndrome. Phenytoin can worsen absence seizures at therapeutic
doses and cause generalized seizures at toxic doses.
419
The initial approach to the child with intractable seizures on polytherapy is to
slowly decrease the AED that the family feels has been the least effective.
However, there are instances when the synergistic interaction of two AEDs improves
seizure control. Children with certain generalized epilepsy syndromes occasionally
require a combination of valproate and ethosuximide or lamotrigine. A second AED may
also be considered in children with several different seizure types when monotherapy is
not effective. Virtually every combination of AEDs has been used. Certain combinations
should be avoided when mechanisms of action overlap and toxicities are additive, such as
any combinations of phenobarbital, primidone, and benzodiazepines, all of which are
central nervous system depressants. Phenytoin and carbamazepine also have overlapping
mechanisms of action and are usually not given together.
Laboratory monitoring and adverse effects of AEDs Routine laboratory screening

of hematologic and hepatic function is commonly done in children receiving AEDs.
However, the cost for every patient in the United States with epilepsy to be tested three
times per year with blood counts and serum transaminase levels was estimated in 1989 to
be over $400 million annually. Evidence is convincing that this routine laboratory
testing is not cost effective or necessary. With the exception of felbamate, which is
associated with a relatively high risk of aplastic anemia and requires close laboratory
monitoring.
Valproic acid Valproate is associated with a relatively high incidence of minor and
usually insignificant elevations of one or more liver enzymes and serum ammonia.
Hepatic enzyme elevations that are less than three times normal in an asymptomatic
child are unlikely to be significant. Higher levels should be repeated in a few weeks and
the medications stopped if levels are increasing rapidly or if the child becomes
symptomatic.
Carbamazepine Leukopenia is not uncommon with carbamazepine, often appearing

in the first two to three months of therapy. Severe aplastic anemia or agranulocytosis is
reported but rare, occurring in 2 per 575,000 exposures. I obtain a CBC after the first
month of carbamazepine therapy. If the white blood count (WBC) is significantly
decreased, I repeat every three to four weeks until the counts stabilize. If the ANC falls
below 800 to 1000, the medication should be stopped
Recommendations Most clinicians obtain screening laboratory tests before initiating

AED therapy with a CBC and platelet count, liver and renal function tests, glucose,
electrolytes, total protein, albumin, and globulin. In children under the age of three or
those who might have a neurometabolic disorder, one should consider obtaining serum
ammonia, pyruvate, lactate, and carnitine levels and serum amino acid and urine organic
acid analyses before initiating valproic acid. Valproate should be avoided if there is
clinical suspicion that the child's illness is progressive when no etiology has been
determined
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421
422
TRANSMUCOSAL AED ADMINISTRATION Antiepileptic drugs (AEDs) can
be administered intravenously for control of prolonged seizures in children, but this often
entails treatment delays related to transportation to a hospital emergency department and
difficulty establishing intravenous access. Such problems have led to increased use of
transmucosal routes of AED delivery, such as rectal, buccal, intranasal, and sublingual
administration. Transmucosal routes allow for more rapid seizure control and permit the
initial use of AEDs at home or in the field, allowing for earlier treatment. The largest
experience is with rectal diazepam, although accumulating evidence suggests that buccal
midazolam is also safe and effective.
Rectal therapy Rectal benzodiazepines are an effective and relatively safe

emergency treatment, particularly for patients who live at some distance from a medical
facility, those requiring emergency therapy while traveling, and those whose seizures
occur in clusters. Diazepam is available in a rectal gel (Diastat ) that is obtained from
the pharmacy in prefilled ready-to-use syringes that are set to deliver a specific dose.
These have a long shelf life (years) and do not require refrigeration. The rates of
absorption and response are slower than those of intravenous diazepam but faster than
with oral administration. Respiratory depression is extremely rare, although if concerns
about this possible complication exist, particularly in a handicapped child, a test dose can
be given under physician supervision.
Many AEDs can be given as a rectal suppository for short periods (eg, postoperatively)
and occasionally as chronic treatment for patients unable to take oral medications. Any
AED available as an oral suspension (clonazepam, carbamazepine, valproate,
oxcarbazepine, levetiracetam) can be given rectally for short periods. Carbamazepine
has a significant cathartic effect.
Buccal therapy Buccal midazolam therapy uses the intravenous formulation of

midazolam hydrochloride delivered into the buccal cavity between the gum and cheek.
Buccal midazolam is effective for the emergency treatment of seizures in children, as

demonstrated by at least two randomized clinical trials. In the earlier and smaller trial that
evaluated 79 seizures in 28 children with severe epilepsy, buccal midazolam was as
effective as rectal diazepam at stopping seizures.
Recommendations Rectal diazepam remains first-line therapy for emergency

treatment of prolonged or closely-clustered seizures in settings where intravenous access
is not readily available. This includes at home treatment of prolonged or recurrent febrile
seizures.
Buccal midazolam appears to be more effective than rectal diazepam, and is suggested
as primary hospital emergency department treatment of prolonged seizures prior to
establishment of intravenous access.
STOPPING ANTIEPILEPTIC DRUG THERAPY Withdrawal of antiepileptic

drug (AED) therapy should be considered in most children after two years without
423
seizures regardless of the etiology of the seizures. The likelihood of recurrence after a
two-year period without seizures is approximately 30 to 40 percent. Longer seizure-free
periods are associated with only a slightly lower incidence of recurrence and therefore
longer observation periods are not warranted.
AEDs should be tapered rather than halted abruptly. There are limited data to guide
an AED tapering schedule. Rapid changes (over days to a few weeks) in drug treatment
increase the risk of seizures. Slower rates of AED taper, over several weeks to a few
months, are generally recommended. In particular, benzodiazepines and barbiturates are
associated with withdrawal seizures and should be discontinued very gradually.
EPILEPSY SURGERY Surgical interventions should be considered, regardless of

age, in children who have persistent, frequent seizures that are having an adverse impact
upon their lives or are interfering with their cognitive and psychosocial development.
Surgical approaches can be divided into relatively less invasive procedures, such as vagus
nerve stimulation, and surgeries such as focal resections, lobar or multilobar resections,
corpus callosotomy, hemispherectomy, and multiple subpial transections.
424
Treatment of neonatal seizures
Eli M Mizrahi, MD
The occurrence of neonatal seizures may be the first, and perhaps the only, clinical sign
of a central nervous system (CNS) disorder in the newborn infant. As such, seizures may
indicate the presence of a potentially treatable etiology and should prompt an immediate
evaluation to determine cause and to institute etiology-specific therapy. In addition,
seizures themselves may require emergent therapy, since they can adversely affect the
infant's homeostasis or they may contribute to further brain injury. Some types of
neonatal seizures are associated with a relatively high incidence of early death and, in
survivors, a high incidence of neurologic impairment, developmental delay, and
postneonatal epilepsy.
ETIOLOGIC-SPECIFIC THERAPY Etiologic specific therapy is critical since it

may prevent further brain injury. This is particularly true for seizures associated with
some metabolic disorders (eg, hypoglycemia, hypocalcemia, and hypomagnesemia) and
with central nervous system (CNS) or systemic infections. Furthermore, neonatal seizures
may not be effectively controlled with antiepileptic drugs (AEDs) unless their underlying
cause is treated.
425
Neonatal encephalopathy Neonatal encephalopathy (and associated hypoxic-
ischemic encephalopathy) is the most common cause of neonatal seizures.
CNS infection Infection of the central nervous system is a relatively common cause
of neonatal seizures and should be treated with broad spectrum antibiotics at doses
sufficient to treat meningitis.
Metabolic disturbances Metabolic disturbance are a treatable common cause of

neonatal seizures.
Hypoglycemia Hypoglycemia should be corrected immediately with a 10 percent

glucose solution given intravenously at 2 mL/kg. Maintenance glucose infusion can be
given to a maximum of 8 mg/kg per minute.
Hypocalcemia Hypocalcemia associated with severe neuromuscular irritability or

seizures is treated with 10 percent calcium gluconate (100 mg/kg or 1 mL/kg IV). The
solution is infused over 5 to 10 minutes while the heart rate and infusion site are
monitored. The dose can be repeated in 10 minutes if no response occurs. Alternatively,
calcium chloride (20 mg/kg or 0.2 ml/kg) can be given. After acute treatment,
maintenance calcium gluconate should be added to the intravenous solution.
Hypomagnesemia Neonatal hypomagnesemia is often associated with

hypocalcemia, although it can occur alone. The treatment is 50 percent solution of
magnesium sulfate given by intramuscular injection at 0.25 mL/kg. The same dose (0.25
mL/kg IM) can be repeated every 12 hours until normomagnesemia is achieved.
Pyridoxine dependency Pyridoxine (100 mg/kg intravenously) is often used

empirically during EEG monitoring in infants with refractory seizures, and can have a
dramatic beneficial effect in those with pyridoxine dependency.
ANTIEPILEPTIC THERAPY The use of antiepileptic (AED) drug therapy in

neonates will be reviewed. Initiating therapy, selecting appropriate agents, and stopping
or continuing therapy are the main decisions involved. Evidence of effectiveness is
limited.
Decision to institute AED therapy After initial management of airway and

cardiovascular support and the identification and institution of etiologic-specific therapy,
the physician must decide whether to initiate antiepileptic drug therapy and then decide
what AEDs to use. Factors that must be considered in deciding whether to initiate AED
therapy include seizure type (epileptic versus nonepileptic in origin) and, if epileptic in
origin, seizure duration and severity.
Antiepileptic drugs are utilized to treat neonatal seizures of epileptic origin but not those
of nonepileptic origin.
426
It is not necessary to treat all neonatal seizures of epileptic origin, since some are brief,
infrequent, and self-limited (occurring only in reaction to an acute CNS insult). In these
instances, no AEDs may be warranted, and the infant need not be exposed to acute and
chronic AED therapy.
On the other hand, some neonatal epileptic seizures are long in duration, frequent,
and are not self-limited. These are treated acutely and vigorously with AEDs.
The main clinical difficulty arises in the management of those infants whose seizures
have characteristics that fall between these two extremes. Currently, almost all neonatal
epileptic seizures within this intermediate category are treated with AEDs.
Selection and administration of AEDs The traditional strategy is to acutely treat

seizures with an AED that can be subsequently given as maintenance therapy.
Phenobarbital is most frequently used as the initial drug. The next most frequently
used is phenytoin. However, neither agent appears to be more effective than the other,
and neither is as effective as previously thought.
As an alternative to phenytoin, fosphenytoin is often used because of reports of reduced

adverse effects with acute administration. An alternative strategy of seizure management
is acute treatment with repeated doses of short acting benzodiazepines until seizures are
controlled, thus avoiding chronic AED therapy.
Phenobarbital Phenobarbital is eliminated by the liver and kidney; thus, infants with
impaired hepatic or renal function, such as those with HIE, will have a reduced rate of
elimination and potential for toxicity with standard dosing. There half-life of
phenobarbital is greater in premature compared with term infants, and longer in the first
month of life compared with older ages in term infants.Thus, standard phenobarbital
dosing in premature infants has the potential for higher serum levels and resultant
toxicity. As the infant becomes older, identical daily maintenance doses may result in
lower serum levels and create the potential for breakthrough seizures with no other
change in the infant's clinical condition. Overall, monitoring trends of serum levels rather
than day-to-day fluctuations are more useful in management of phenobarbital therapy.
Phenytoin Pharmacologic characteristics of phenytoin include its nonlinear

pharmacokinetics, variable rate of hepatic metabolism, a decrease in elimination rates
during the first weeks of life, and a variable bioavailability of the drug with various
generic preparations [10,11] . In addition, redistribution of phenytoin that results in a
drop in brain concentrations after the first dose. Thus, phenytoin use requires
individualization of dosing after initiation of therapy.
Other AEDs Some studies have reported limited success with second line,
alternative, or adjuvant AEDs for the control of medically refractory neonatal seizures. A
number of intravenous AEDs have been used including clonazepam, lidocaine,
midazolam, and paraldehyde. Oral AEDs have also been employed including
carbamazepine, primidone, valproate, vigabatrin, and lamotrigine
427
Effectiveness There are little data from high quality clinical trials regarding the
effectiveness of AEDs for the treatment of neonatal seizures. A systematic review
published in 2004 identified only two randomized controlled trials, and the results of
these are summarized as follows:
Phenobarbital and phenytoin appear to have comparable but limited efficacy. In a trial of
59 infants with neonatal seizures, both drugs controlled seizures in less than half of the
infants. Seizure severity was a better predictor of treatment success of treatment than the
assigned treatment.
Neonatal seizures refractory to phenobarbital appear to respond poorly to second

line AEDs.
Chronic AED therapy There are no well-defined criteria to determine which

neonates require chronic AED therapy after acute seizures are controlled or the duration
of such treatment. When chronic therapy is considered, maintenance doses of either
phenobarbital or phenytoin are given (3 to 4 mg/kg per day for both drugs), and serum
levels are monitored. Reported schedules for chronic AED treatment range from one
week up to 12 months after the last seizure, although a currently utilized schedule is
to withdraw AEDs two weeks after the infant's last seizure. This is often done just
prior to the recording of an EEG that demonstrates no electrical seizure activity.
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Overview of Guillain-Barr syndrome in children
Robert P Cruse, DO
The acute immune-mediated polyneuropathies are classified under the eponym Guillain-
Barr syndrome (GBS), after the authors of early descriptions of the disease. Historically,
GBS was considered a single disorder, but it is now known to be a heterogeneous
syndrome with several variant forms. Most often, GBS presents as an acute
monophasic paralyzing illness provoked by a preceding infection. In addition to the
demyelinating form, which is the most common type, axonal forms of GBS are well-
recognized.
EPIDEMIOLOGY Guillain-Barr syndrome is the most common cause of acute

flaccid paralysis in healthy infants and children. It has an annual incidence of 0.6 to 2.4
cases per 100,000 population and occurs at all ages and in both sexes. GBS occurs rarely
in children younger than two years of age, but can occur in infants. Males are affected
approximately 1.5 times more often than females in all age groups.
PATHOPHYSIOLOGY GBS is really a group of disorders rather than a single

disease. It is now considered to be a syndrome with a number of variants. Peripheral
nerve demyelination in the demyelinating form is believed to be immunologically
mediated.
Approximately two-thirds of patients have a history of an antecedent respiratory tract

or gastrointestinal infection. A variety of infectious agents have been associated with
GBS, although Campylobacter is the most frequent. Other organisms that commonly
precede GBS include cytomegalovirus, Epstein-Barr virus, Haemophilus influenzae
mycoplasma pneumoniae, the enteroviruses, hepatitis A and B, herpes simplex, and
Chlamydophila (formerly Chlamydia) pneumoniae.
The main lesions of GBS are acute inflammatory demyelinating

polyradiculoneuropathy and, particularly in patients with Campylobacter-
associated disease, acute axonal degeneration.
The GBS variant known as Miller Fisher syndrome, in which the cranial nerves are
affected, also is associated with Campylobacter infection. Most of these patients have
cross-reacting antibodies to GQ1b ganglioside, which is present in cranial nerve myelin.
CLINICAL FEATURES In patients with acute inflammatory demyelinating

polyradiculopathy (AIDP), the most common form of Guillain-Barr syndrome (GBS),
two-thirds develop the neurologic symptoms two to four weeks after having what appears
to be a benign febrile respiratory or gastrointestinal infection.
The classic presentation is fine paresthesias in the toes and fingertips, followed by lower
extremity symmetric weakness that may ascend over hours to days to involve the arms
and (in severe cases) the muscles of respiration.
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By the peak of the illness, the frequency of symptoms was as follows:
79 percent had neuropathic pain.
60 percent could not walk.
51 percent had autonomic dysfunction.
46 percent had cranial nerve involvement.
24 percent could not use their arms.
13 percent required mechanical ventilation.
In those with cranial neuropathy, the facial nerve is most commonly affected,
resulting in bilateral facial weakness. Pain typically involves the back and the legs.
Autonomic dysfunction occurs in approximately one-half of children with GBS, and

may include the following:
A variety of cardiac dysrhythmias (asystole, bradycardia, persistent sinus tachycardia,

and atrial and ventricular tachyarrhythmias).
Orthostatic hypotension.
Transient or persistent hypertension.
Paralytic ileus.
Bladder dysfunction.
Abnormal sweating.
Rare patients have central nervous system involvement.
Physical examination Physical examination reveals symmetric weakness with

diminished or absent reflexes. Minimal loss of sensation occurs, despite paresthesias.
Variable initial physical findings can render making an early diagnosis difficult.
Examples of less common signs include predominant proximal weakness, hyperreflexia
with extensor plantar response, and sphincter disturbances that raise concerns about a
spinal cord lesion. Papilledema can occur with or without increased intracranial pressure.
Clinical course More than 90 percent of patients reach the nadir of their function
within two to four weeks, with return of function occurring slowly over the course of
weeks to months. A chronic (extending beyond two months), slowly progressive or
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relapsing inflammatory demyelinating polyneuropathy generally is considered a distinct
entity from acute GBS.
The clinical course of GBS in children is shorter than in adults and recovery is more
complete. In patients who did not require mechanical ventilation, the median time to
recovery of independent walking was 43 to 52 days in children compared to 85 days
in adults.
GBS FORMS
Acute inflammatory demyelinating polyneuropathy Acute inflammatory

demyelinating polyneuropathy (AIDP) is the prototype of GBS, and is the most common
form in North America, Europe and most of the developed world, where it accounts for
about 85 to 90 percent of cases.
Acute motor axonal neuropathy Acute motor axonal neuropathy (AMAN) is a pure
motor form of GBS. This disorder is distinguished from AIDP by its involvement of
predominantly motor nerves and an electrophysiologic pattern suggesting axonal damage.
AMAN occurs mainly in northern China, but is also a common form of GBS in other
locations, including Japan, Mexico, and South America.
The presenting clinical features and recovery are similar to those of AIDP. However,
more patients have respiratory failure requiring assisted ventilation.
Acute motor-sensory axonal neuropathy Acute motor-sensory axonal neuropathy

(AMSAN) resembles the motor axonal variant but has more sensory symptoms. The
course tends to be prolonged. The pathology is predominantly axonal lesions of both
motor and sensory nerve fibers. This form of GBS is recognized infrequently in children.
The infrequent diagnosis may be caused in part by the difficulty of performing sensory
testing in children and because electrophysiologic studies often are not done.
Miller Fisher syndrome Patients with Miller Fisher syndrome (MFS) have external
ophthalmoplegia, ataxia, and muscle weakness with areflexia. CSF and
electrophysiologic features are similar to those in AIDP. Brainstem auditory evoked
potentials demonstrate peripheral and central conduction defects.
Polyneuritis cranialis Patients with polyneuritis cranialis develop acute bilateral

multiple cranial nerve involvement and severe peripheral sensory loss. They typically
have bilateral facial weakness, dysphagia, and dysphonia with optic nerve sparing.
Patients tend to be younger than those with other types. This variant is associated with
preceding cytomegalovirus infections.
DIAGNOSIS Electrophysiologic studies are the most specific and sensitive tests
for diagnosis of the disease. They demonstrate a variety of abnormalities indicating
evolving multifocal demyelination, including:
431
Partial motor conduction block
Slowed nerve conduction velocities
Abnormal temporal dispersion
Prolonged distal latencies
Electromyogram abnormalities typically are delayed for two to three weeks. The motor
units show denervation potentials, reflecting secondary axonal degeneration.
In the motor and motor-sensory variants, nerve conduction velocities are normal. In both
forms, motor amplitudes in nerve conduction studies are less than 10 percent of normal,
with severe denervation evident on follow-up needle examination. In the motor-sensory
variant, sensory amplitudes also are decreased.
Cerebrospinal fluid After the first week of symptoms, analysis of the CSF typically
reveals normal pressures, fewer than 10 cells (typically mononuclear), and an elevated
protein concentration (greater than 45 mg/dL). These findings may be delayed and a
repeat lumbar puncture may be required.
The protein may not rise for one to two weeks, but only rarely does it remain
persistently normal. Maximum protein values may not be seen for four to five weeks. An
initial pleocytosis of less than 100 lymphocytes may occur. If this is noted, other diseases
associated with GBS (such as HIV infection, Lyme disease, and malignancy) should be
considered. In addition, other diseases, including inflammatory (infectious or
autoimmune disorders) and demyelinating diseases, may be associated with leg weakness
and CSF pleocytosis.
Differential diagnosis Disorders of the central nervous system, peripheral nerve,

neuromuscular junction, and muscle may have features that initially resemble GBS.
However, consideration of the neurologic examination, clinical course, CSF profile, and
electrophysiologic findings usually establish the diagnosis of GBS.
PROGNOSIS The severity of GBS in children does not correlate with long-term
outcome. As many as 85 percent of children can be expected to have an excellent
recovery. Approximately one-half of patients are ambulatory by six months, and 70
percent walk within a year after onset. A better prognosis is associated with a gradual
evolution of weakness. Mortality is approximately 3 to 4 percent, and usually is
secondary to respiratory failure or cardiac complications.
432
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Treatment of Guillain-Barr syndrome in children
The main modalities of therapy for Guillain-Barr syndrome (GBS) include
plasmapheresis and administration of intravenous immune globulin. Even before
initiating specific therapy, common problems are when and whether to admit the patient
to the intensive care unit (ICU) and when to consider mechanical ventilation.
MONITORING AND SUPPORTIVE CARE During the initial phase of GBS, all
patients require close monitoring of motor, autonomic (blood pressure, heart rate and
sphincter function), and respiratory function. Any patient admitted with GBS should be
evaluated frequently, and serial lung function testing should be performed in those at
highest risk for developing respiratory failure.
Need for intensive care Children with the following should be admitted to a
pediatric intensive care unit.
1. Flaccid quadriparesis.
2. Rapidly progressive weakness.
3. Reduced vital capacity ( 20 mL/kg).
4. Bulbar palsy.
5. Autonomic cardiovascular instability.
Hospitalization is continued until the child's condition has clearly stabilized.
Need for assisted ventilation Approximately 20 percent of children with GBS

require mechanical ventilation for respiratory failure. The need for tracheal intubation
should be anticipated so that it can be performed as an elective procedure.
Children with vital capacity approximately one half the normal value for age or 20
mL/kg body weight generally progress to require ventilatory support.
Progression to the need for mechanical ventilation was likely to occur in patients with
rapid disease progression, bulbar dysfunction, bilateral facial weakness, or
dysautonomia.
The following parameters warn of impending respiratory arrest and are an indication
for intubation:
1. Vital capacity 20 mL/kg.

2. Maximum inspiratory pressure 30 cm.
3. H2O Maximum expiratory pressure 40 cm.
4. H2O Tidal volume <5 mL/kg.
Pulmonary testing and measuring vital capacity is difficult in children who cannot
cooperate, typically those younger than 6 years of age. These patients should be closely
434
monitored and observed for fatigue and other clinical signs of impending respiratory
muscle failure. These signs include the following:
A sustained increase of pCO2 to 50 mmHg (normally 35 to 40 mmHg).
An increasing respiratory rate.
Increasing oxygen requirement and increasing alveolar to arterial oxygen difference

(normally 5 to 10 mmHg).
An increased use of accessory muscles (eg, sternocleidomastoid use, flaring of the ala
nasae, intercostal retractions) and decreased or paradoxical diaphragm movements; these
reflect restrictive lung-chest wall movement and low lung volumes.
Sweating about the head and neck, wide pulse pressure, and bounding pulses portend
CO2 retention.
Children have less metabolic and muscle reserve than adults. They can deteriorate quite
rapidly and become apneic or develop alveolar hypoventilation "right under your
nose." Generally, it is wise to have a pediatric pulmonologist involved early in the
clinical course.
Sedation and neuromuscular blockade should be avoided in ventilated patients

because they obscure the course of the illness. Providing scrupulous airway care and
chest physiotherapy reduce the risk of pneumonia. Tracheostomy may need to be
performed if prolonged ventilation is required.
Autonomic dysfunction Autonomic dysfunction is a well-recognized feature of

GBS and is a significant source of mortality. Consequently, close monitoring of blood
pressure, fluid status, and cardiac rhythm are essential to the management of these
patients. Care must also be taken when vasoactive or sedative drugs are used, because the
dysautonomia may exaggerate the hypotensive responses to these drugs.
Other supportive measures Nutritional needs should be addressed early in the

disease course. Orogastric tube feeding, gastrostomy, or parental nutrition often are
necessary.
The patient's position should be changed frequently for comfort and to avoid skin
breakdown. Intermittent pressure leg boots and subcutaneous heparin treatment should be
initiated to prevent deep vein thrombosis. Physical therapy, occupational therapy, and
social service should be involved early. Provide the patient with a method of
communication is important if normal speech is not possible. Pencil and paper, a "magic
slate," or a communication board can be given to those old enough to write.
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INTRAVENOUS IMMUNE GLOBULIN (IVIG) Reports of the use of IVIG in
children with GBS are limited, as no large randomized controlled trials exist.
Nevertheless, data from the few available small open randomized trials in children
suggest that IVIG shortens the time to recovery compared with supportive care alone.
While these studies in children are not definitive because of design limitations, their
results are consistent with the larger randomized trials in adults that show a beneficial
effect for IVIG treatment of GBS.
Similarly, most observational studies show that IVIG hastens recovery in children,
although one study found that IVIG may not be effective in children with EMG evidence
of axon involvement.
The mechanism of improvement with IVIG is uncertain, but the antibodies are thought
to block the immune cascade that leads to nerve damage. This block may occur through
competition by IgG for receptors in the reticuloendothelial cell system, disassociation of
antibodies from target cells, impaired binding of immune complexes to target cells,
immune modulation of T cell and B cell function, inhibition of complement dependent
tissue injury, or inhibition of cytokine activity.
Methodologic differences between reports make it difficult to generalize about when

children with GBS begin to improve after IVIG treatment. Nevertheless, strength
generally begins to improve in most children within 14 days after initiation of IVIG
therapy and most are walking within three months.
The total dose of IVIG for the treatment of GBS in children is 2 g/kg, given as 1 g/kg
for two days or 400 mg/kg for five days.
PLASMA EXCHANGE Large, multicenter trials have established the effectiveness

of plasma exchange in adult patients with severe GBS. The mechanism is thought to be
removal of antibodies directed against nerves from the circulation. Increased muscle
strength, earlier improvement, and a lower requirement for mechanical ventilation have
been demonstrated.
Plasma exchange generally is considered more effective if begun within three weeks of
initial symptoms. Approximately 10 percent of these patients will have a relapse within
10 days after treatment.
The procedure usually consists of four double-volume exchanges performed on

alternate days over one week. Immunoglobulin levels may be decreased by 30 to 40
percent after plasma exchange.
Plasma exchange is recommended for those patients who have rapidly progressing
weakness, worsening respiratory status, are unable to walk unaided, require
mechanical ventilation, or have significant bulbar weakness. As a result of the cost,
risk, and discomfort to the patient, plasma exchange generally is not used for ambulatory
patients with mild disease or for patients whose symptoms have stabilized.
436
We use plasma exchange in children who have had a previous adverse reaction to
intravenous immune globulin (IVIG) treatment and in those who do not respond to
IVIG.
OTHER THERAPIES Corticosteroids, once the mainstay of therapy for GBS, have
not been shown to be beneficial and no longer have a role. Interferon- has been reported
to be beneficial in individual cases, but its safety and efficacy have not been established
in clinical trials.
RECOMMENDATIONS The American Academy of Neurology (AAN) issued a

practice parameter regarding immunotherapy for GBS in September 2003. While
acknowledging the limitations of data for children, the AAN concluded that IVIG and
plasma exchange are options for children with severe GBS. IVIG and plasma exchange
are not recommended for ambulatory children with GBS who have mild disease or
for children whose symptoms have stabilized.
IVIG and plasma exchange for children with GBS should be reserved for those with:
1. Rapidly progressing weakness.

2. Worsening respiratory status or need for mechanical ventilation.
3. Significant bulbar weakness.
4. Inability to walk unaided.
Time to treatment onset may be important in children although data are lacking. In
adults, IVIG is recommended by the AAN for patients who are unable to walk unaided if
treatment is started within two or possibly four weeks of onset. Similarly, plasma
exchange is recommended for adult patients who are unable to walk unaided if treatment
is started within four weeks of symptom onset.
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What's new in pediatrics
ALLERGY AND IMMUNOLOGY
Food allergy In an observational study, 75 percent of children with cow's milk allergy
tolerated cow's milk in baked goods and waffles. However, because the quantity of allergen may
vary from batch to batch, the food might be tolerated on one occasion and not another
Hyper IgE syndrome Failure of production of IL-17 producing CD4+ T cells may explain the
susceptibility to particular infections in patients with hyperimmunoglobulin E syndrome.
CARDIOLOGY
Atherosclerosis In 2008, the American Academy of Pediatrics revised guidelines for the
screening and prevention of dyslipidemia and early cardiovascular disease (CVD).
Recommendations include screening at-risk children (eg, positive family history of early CVD)
with a fasting lipid profile, and management of the pediatric patient with dyslipidemia and/or
other atherosclerotic risk factors using nonpharmacologic and pharmacologic interventions.
CRITICAL CARE MEDICINE
Early goal-directed therapy A randomized trial of 102 children and adolescents with severe
sepsis or fluid refractory septic shock evaluated the impact of goal-directed therapy during the
first six hours of care. Children who received care guided by pediatric advanced life support
(PALS) principles and goal-directed resuscitation based on central venous oxygen saturation
measurement had a 27 percent lower 28-day mortality than patients who received PALS care
alone.
EMERGENCY MEDICINE
Appendicitis The pediatric appendicitis score (PAS) is a tool that utilizes history (anorexia,
nausea/vomiting, migration of pain), physical examination (right lower quadrant tenderness,
peritoneal signs), and laboratory results (white blood cell count, polymorphonuclear cell count)
to categorize risk of appendicitis in children with abdominal pain. Prospective validation of the
score in 849 children (age 1 to 17 years) coming to a children's hospital with abdominal pain
found it to be useful in discriminating appendicitis from other causes of abdominal pain. The
PAS also appeared useful in deciding disposition and diagnostic approach.
GENERAL PEDIATRICS
Autism A case-control study found no evidence of increased measles virus RNA in the bowel
tissue of children with autism spectrum disorders (ASD) and gastrointestinal (GI) disturbances.
Measles virus RNA was assayed in three laboratories, including the one from which the
438
hypothetical association between measles vaccination and ASD was originally reported. The
timing of measles/mumps/rubella (MMR) vaccination, onset of GI disturbances, and onset of
autism were not consistent with MMR vaccine as a trigger of GI disturbances or ASD.
Obesity Mild elevations of liver function tests are common among children and adolescents
with obesity; in most cases this is caused by non-alcoholic fatty liver disease (NAFLD). Increasing
evidence points to associations between NAFLD and elements of the metabolic syndrome,
including insulin resistance, dyslipidemia, and hypertension, independent of the degree of
obesity.
Toilet training A small randomized trial demonstrated the efficacy of using a daytime
wetting alarm compared to timed potty training for toilet training in children aged 20 to 36
months. Neither of these parent-oriented approaches to toilet training have been compared to
the more frequently used child-oriented approach: allowing the child to master each step at his
or her own pace.
GASTROENTEROLOGY
Crohns disease The United States Food and Drug Administration (FDA) has issued a warning
about the risk for pulmonary and disseminated histoplasmosis and other invasive fungal
infections in patients undergoing treatment with infliximab or other TNF inhibitors. Clinicians
should have a high index of suspicion for invasive fungal infections, particularly in patients who
live in or have traveled to endemic regions, and investigate and treat promptly.
GENETIC DISEASES
Pompe disease In a pilot study, newborns screened for Pompe disease with enzyme analysis
in dried blood spots were identified earlier than those who were not screened (<1 month versus
3 to 6 months of age). Repeat samples and additional evaluation were required for fewer than 1
percent of screened newborns. Although these findings are preliminary, they demonstrate the
feasibility of universal newborn screening for Pompe disease for which enzyme replacement
therapy is now available. (
HEPATOLOGY
Biliary atresia The presence of acholic (very light-colored) stools is one of the earliest
presenting signs of biliary atresia. In Taiwan, a universal screening protocol employs stool color
cards to facilitate early identification of acholic stools. The screening protocol was effective in
promptly identifying affected infants, thus facilitating earlier surgical intervention and improving
outcomes.
Neonatal hemochromatosis Neonatal hemochromatosis, which causes hepatic failure in

neonates, recurs in more than 90 percent of subsequent pregnancies. The disorder is now
understood to have an autoimmune mechanism. For pregnant women with a previous
439
pregnancy that resulted in an infant with neonatal hemochromatosis, treatment with high-dose
intravenous immunoglobulin (IVIG) dramatically reduces the risk for severe disease in the fetus.
HEMATOLOGY
Sickle cell disease and moyamoya Patients with sickle cell disease (SCD) and moyamoya
disease (characterized by areas of brain ischemia due to stenosis or occlusion of cerebral
arteries) have a significant risk for ischemic stroke. In a case series, neurosurgical intervention
restored circulation to ischemic brain areas in patients with moyamoya disease. Short-term
evaluation suggests a reduction in significant cerebrovascular events in this high-risk population;
however, long-term follow-up and a larger number of cases are needed to demonstrate the
benefit of surgical intervention.
INFECTIOUS DISEASES
Bacterial meningitis Although the incidence of pneumococcal meningitis has declined in the
post-pneumococcal conjugate vaccine era, Streptococcus pneumoniae remains the most
frequent cause of bacterial meningitis in children ( 1 month to 18 years of age) in the United
States.
Cerebrospinal fluid (CSF) chemistry results in children who receive antibiotics before lumbar
puncture (LP) should be interpreted with caution. In a retrospective review of 85 children who
were pretreated with antibiotics, receipt of antibiotics for 12 hours before LP was associated
with increased median CSF glucose concentration (48 versus 29 mg/dL [2.66 versus 1.6 mmol/L])
and decreased median CSF protein concentration (121 versus 178 mg/dL [1.21 versus 1.78 g/L]).
Herpes simplex virus In a five-year, single-institution case series of 5817 hospitalized

neonates ( 28 days), the prevalence of herpes simplex virus (HSV) infection was not statistically
different than that of bacterial meningitis (0.2 and 0.4 percent, respectively). All of the neonates
with HSV infection in this series had clinical features suggestive of HSV (eg, rash, elevated liver
transaminases, sepsis-like picture). However, others describe more subtle presentations of
neonatal HSV.
Palivizumab Data from the Palivizumab Outcomes Registry indicate that infants at risk for
respiratory syncytial virus who received the second through fifth doses of palivizumab within 35
days of the previous dose had a lower risk of hospitalization than those who had longer intervals
between doses.
NEONATOLOGY
Barriers to breastfeeding A survey by the Centers for Disease Control and Prevention
demonstrated a substantial prevalence of practices that interfered with breastfeeding. These
included distribution of gift bags containing infant formula, limiting duration of suckling at
breastfeeding, pacifier use, and non-breast milk supplementation. Because a higher prevalence
440
of these practices correlated with a lower rate of breastfeeding, these results suggest that
eliminating these practices would improve the rate of breastfeeding.
Maternal smoke exposure Prenatal maternal smoking is a well-established risk factor of low
birth weight. A systematic review of the literature reported that smoke exposure may also be
associated with an increased risk of delivering a low birth weight infant.
Neonatal analgesia A French population-based study demonstrated that prolonged

neonatal sedation and/or analgesia for more than seven days did not affect five-year neurologic
outcome.
Neonatal pain A large prospective French study found that neonates admitted to tertiary
neonatal intensive care units (NICU) experienced a median of 115 procedures during a two-
week time period, of which 75 were painful. Of the painful procedures, only about 20 percent of
infants received specific analgesic therapy. The results of this study underscore the need to
provide better analgesic therapy to neonates admitted to the NICU.
Newborn hearing screening In a 2008 statement, the United States Preventive Services Task
Force (USPSTF) recommended universal screening for hearing loss in newborn infants. The
recommendation was based upon evidence that currently available inexpensive screening tests
can accurately identify newborns with permanent hearing loss, and early detection improved
language outcomes.
NEPHROLOGY
Ambulatory blood pressure monitoring Ambulatory blood pressure monitoring (ABPM) is

being increasingly used in the evaluation and management of children with hypertension. The
American Heart Association (AHA) has published a scientific statement outlining the indications
for 24-hour ABPM and the necessary criteria for accurate and valid ABPM in children and
adolescents.
Prehypertension An analysis of longitudinal data from the National Childhood Blood

Pressure database demonstrated 12 and 14 percent of female and male prehypertensive
adolescents, respectively, became hypertensive over a two-year time period.
Prehypertension was defined as a systolic and/or diastolic blood pressure 90th percentile
but <95th percentile for age, gender, and height, or blood pressure exceeding 120/80 mmHg.
VACCINES
Combination vaccines The United States Food and Drug Administration has approved two
new combination vaccines: Diphtheria, tetanus, acellular pertussis (DTaP), inactivated poliovirus
(IPV), and Haemophilus influenzae type b: Pentacel, approved for use in infants and children at
2, 4, 6, and 15 through 18 months of age. DTaP and IPV: Kinrix , approved for the fifth dose of
441
DTaP and the fourth dose of IPV at four to six years in children whose previous DTaP doses were
with Infanrix or Pediarix or a combination of the two.
HPV vaccine safety Although there have been case reports of Guillain-Barr syndrome (GBS)
after receipt of the quadrivalent human papillomavirus (HPV) vaccine, there is no evidence that
the rate of GBS after HPV vaccination is increased compared to the rate of GBS in the general
population.
Influenza vaccine The Centers for Disease Control and Prevention (CDC) Advisory Committee
on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) recommend
annual influenza vaccination for all children aged 6 months to 18 years. This represents an
expansion of the target group to include children age 5 to 18 years. Children in high-risk groups
should continue to be a priority.
In a randomized trial, immunization of pregnant women with inactivated influenza vaccine

during the third trimester of pregnancy was associated with fewer cases of laboratory-
confirmed influenza infection in infants (efficacy of 63 percent).
Rotavirus vaccines The ACIP provisional recommendations for the prevention of rotavirus
gastroenteritis include modifications to the rotavirus vaccine schedule in the United States:
The first dose may be given to infants as old as 14 weeks and 6 days (rather than 12 weeks and
6 days). The final dose may be administered until eight months of age (rather than 32 weeks).
The two rotavirus vaccines that are licensed in the United States have different doses and
schedules of administration.
442
Referrences
1. 2008 Up To Date DESKTOP 16.3.
2. NELSON TEXTBOOK OF PEDIATRICS , 18Th EDITION , SAUNDERS ELSEVIER , 2008
443

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UP TO DATE

1st edition printed in Kerbala , Iraq 2009

This book is dedicated to my family, the souls of my uncle Ismail

Part I Psychological Disorders

BREATH HOLDING SPELLS 5

Part III Neonatology

RESPIRATORY DISTRESS SYNDROME 44

Part IV Infectious Diseases

TOXIC SHOCK SYNDROME 70

MYCOPLASMA PNEUMONIA INFECTION 87

Part V The Digestive System

ACUTE GASTROENTERITIS 106

PERSISTENT DIARRHOEA 117

CELIAC DISEASE 120

NEONATAL CHOLESTASIS 125

FULMINANT HEPATIC FAILURE 129

Part VI Respiratory System

HYDROCARBON ASPIRATION 162

SUDDEN INFANT DEATH SYNDROME 165

Part VII The Cardiovascular System

KAWASAKI DISEASE 195

SICKLE CELL DISEASE 227

G6PD DEFICIENCY 235

VON WILLEBRAND DISEASE 240

URINARY TRACT INFECTION 288

HEMOLYTIC UREMIC SYNDROME 297

ACUTE RENAL FAILURE 302

CHRONIC KIDNEY DISEASE 306

Part X The Endocrine System

DIABETIC KETOACIDOSIS 332

CONGENITAL HYPOTHYROIDISM 345

CONGENITAL ADRENAL HYPERPLASIA 354

Part XI The Nervous System

FEBRILE SEIZURE 386

VIRAL MENINGITIS 399

EPILEPTIC SYNDROMES 416

NEONATAL SEIZURES 424

GUILLAIN BARRE SYNDROME 429

Part XII What is new in Pediatrics

Management of nocturnal enuresis in children

Urinary incontinence is a common problem in children. At 5 years of age, 15 percent of children

Treatment may involve one or a combination of the following nonpharmacologic and

Motivational therapy leads to significant improvement (decrease in enuretic events by 80

Nonetheless, a trial of bladder training exercises is recommended before alarms and

PHARMACOLOGIC THERAPY Two pharmacological agents have been shown to be effective

To prevent dilutional hyponatremia with oral desmopressin, it is recommended that fluid

Tricyclic antidepressants The tricyclic antidepressants (e.g., imipramine, amitriptyline, and

Other drugs, including phenmetrazine, amphetamine sulfate, ephedrine, atropine,

Iron supplementation in anemic or iron-deficient patients appears to reduce the frequency of

Etiology and evaluation of failure to thrive (undernutrition) in

PATTERNS OF GROWTH The trajectory of growth in weight, length, and head

Deceleration of head circumference before deceleration in weight or length is suggestive of a

Evaluation of proportionality can be helpful in determining contributing factors to diminished

Decreased weight in proportion to length ("wasting") reflects inadequate nutritional intake.

Decreased length in proportion to weight is suggestive of an endocrinologic abnormality.

Prenatal Intrauterine growth restriction; prematurity; prenatal infection, congenital

3 to 6 months Underfeeding (possibly associated with poverty); improper formula

7 to 12 months Feeding problems (e.g., autonomy struggles, particularly if the parent is a

Medical history Important aspects of the history include:

Specific areas of inquiry include:

Deficient protein or vitamin intake in some vegetarian diets.

Important aspects of the feeding observation include:

Is the child adaptively positioned to eat (e.g., in a high-chair)?

Are the child's cues of hunger and satiety clear?