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doi:10.1016/j.emc.2004.06.002
930 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
presentation is the norm, and infants account for the greatest risk of death
or severe complication; (3) congenital heart malformations, particularly
malformations with an initial asymptomatic period culminating in a rapidly
progressive and lethal course; and (4) inborn errors of metabolism (IEM),
which often are unsuspected and the diagnosis of which often is delayed
because of their heterogeneity and variability.
Neonatal herpes
Neonatal herpes simplex virus (HSV) infection is increasing. Concom-
itant with an increase in HSV infection among women of childbearing age is
the rate of fetal and neonatal acquisition. Each year in the United States,
nearly 2000 neonates contract HSV infection [1]. Prognosis is related to
disease extent and timing and efficacy of therapy, making early diagnosis
paramount. Diagnosis is difficult for the following reasons. (1) The neonate’s
symptoms are often subtle. (2) Most mothers at the time of delivery have
subclinical infection with asymptomatic viral shedding [2,3]. (3) Owing to
the incubation period of 5 to 21 days, a healthy-appearing neonate often is
taken home only to become unwell with vague nonspecific symptoms
between the first and third weeks of life [4]. The diagnosis of neonatal HSV
often is not entertained until the infant’s course is well advanced. A high
level of clinical suspicion is required for diagnosis and early initiation of
antiviral therapy [5]. Mortality in the preantiviral era was 90% for dis-
seminated disease and 50% for central nervous system (CNS) disease [6].
Institution of high-dose antiviral therapy with acyclovir has reduced
mortality to 31% for disseminated disease and 6% for CNS disease [7].
Although acyclovir has reduced mortality dramatically, the effects on
morbidity have been less impressive. Diagnosis relies on a high index of
suspicion because only a few mothers (20–35%) provide a history consistent
with genital herpes [8,9]. Most mothers (60–80%) have asymptomatic or
unrecognized infection [2,3,10,11]. The incidence of neonatal HSV is 33% to
50% in infants born vaginally to mothers with primary infection and
decreases to 3% to 5% in mothers with secondary infection [9,12–14]. This
incidence is believed to be due to the higher viral load and absence of
significant maternal antibodies in newborns [12]. Most infections (75–85%)
are caused by HSV-2, and 85% are acquired during the peripartum period.
Of the remainder, 5% to 10% are determined to be either congenital or
postnatal [15]. The following are associated with increased risk of neonatal
HSV: maternal primary infection, exposure to cervical viral shedding,
delivery before 38 weeks, fetal scalp monitoring, maternal age younger than
21, low-birth-weight infants, and rupture of membranes greater than 4 to 6
hours before delivery [10,14,16]. Cesarean delivery dramatically reduces the
risk of HSV transmission in mothers with recognized infection but does not
completely eliminate it [3,16,17].
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 931
Clinical manifestations
Neonatal HSV infections are categorized into one of three clinical entities:
disseminated disease; CNS disease; or localized disease to the skin, eyes, and
mouth (SEM) (Table 1). Clinical overlap and disease progression may occur
among the three clinical entities. Untreated, 70% of localized SEM disease
progresses to CNS and disseminated disease [18,19].
Disseminated disease shows a predilection for the liver and lungs but
can involve multiple organs, including CNS, adrenal gland, skin, eyes, and
mouth [20]. Disseminated disease accounts for 25% of neonatal HSV cases,
has one of the earliest onsets (occurring during the first week of life), and has
the highest mortality [13]. Mortality is correlated with aspartate trans-
aminase elevations of greater than 10 times the upper limits of normal and
lethargy at the time of initiation of acyclovir therapy.
CNS disease with or without skin involvement accounts for 35% of cases
of neonatal herpes. Presentation is the latest of the three, occurring between
the second and third weeks of life as cranial nerve abnormalities, irritability,
a bulging fontanelle, seizures, encephalitis, apnea, and bradycardia. Mor-
tality is associated with prematurity and seizures [20].
Localized SEM disease accounts for 40% of cases and has the lowest
mortality associated with it. SEM disease presents with vesicular lesions,
keratitis, or chorioretinitis. The most common involved site is the face and
scalp [21]. Localized disease tends to occur within the first week of life with
a mean presentation on day 5 or 6 of life [22].
Neonatal HSV should be considered in a neonate with fever, irritability,
and abnormal cerebrospinal fluid (CSF) findings, especially if seizures are
present [13]. Disseminated disease should be considered in neonates with
sepsis syndrome, negative bacterial cultures, and severe liver dysfunction.
Although no single sign or symptom has been shown to be pathognomonic
for neonatal HSV infection, the presence of skin lesions (which may occur in
Table 1
Clinical classifications of neonatal herpes simplex virus
Clinical entity Presentation Onset Case % Mortality
SEM Vesicular lesions Week 1 40 Lowest
Keratitis
Chorioretinits
CNS Encephalitis Week 2 and 3 35 Untreated 50%
Cranial nerve deficit Treated 6%
Irritability Associated with
Bulging fontanelle prematurity and
Seizures seizures
Apnea
Bradycardia
Disseminated Atypical sepsis Week 1 25 Highest
Liver dysfunction Untreated 90%
Treated 31%
932 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
any disease category) and seizures (especially patients with CNS disease)
seems to suggest HSV infection [20]. The presence of skin lesions is highly
suggestive of neonatal herpes but, their absence should not exclude the
diagnosis because 17% to 39% of neonatal HSV cases never manifest skin
lesions during the course of illness [20]. A study concluded that the pro-
portion of infants presenting with fever alone was comparable between
infants with HSV and infants with bacterial meningitis. The results advo-
cated routine testing and empirical therapy for neonatal HSV in febrile
infants with negative bacterial cultures [23].
Diagnostic evaluation
Diagnostic evaluation includes HSV polymerase chain reaction (PCR),
viral culture, electroencephalogram (EEG), and liver transaminases.
Management
For maximal benefit, acyclovir must be initiated before widespread viral
dissemination or significant CNS replication occurs. Since the 1980s, little
progress has been made in decreasing the time to initiation of therapy [20].
In most neonates, a relatively short window of opportunity exists to initiate
antiviral therapy effectively [15]. Although every neonate presenting with
suspected sepsis need not be evaluated for HSV, particular consideration
should be given to neonates with atypical sepsis presentations, HSV risk
factors, unexplained acute hepatitis, or focal seizure activity [22,26]. When
considering initiating antiviral therapy, it is important to consider that 17%
to 39% of patients may not have skin lesions at the time of presentation [20].
High-dose acyclovir (60 mg/kg in three divided doses) has been shown to
improve outcomes in patients with disseminated disease or CNS manifes-
tations [1]. The main toxicities of high-dose acyclovir are transient neutro-
penia (which to date has not been associated with adverse sequelae) and
nephrotoxicity. Adequate hydration is crucial in preventing the latter. Pre-
vious guidelines for acyclovir in neonates with impaired renal function also
apply to high-dose acyclovir (Table 2) [7,27]. In addition to systemic
acyclovir, ocular involvement requires a topical ophthalmic solution (1–2%
trifluridine, 1% iododeoxyuridine, or 3% vidarabine) [13].
Pertussis
The introduction of pertussis immunization in the 1940s led to a sig-
nificant decline in morbidity and mortality. Awareness and reporting of this
disease have declined along with morbidity [28]. Despite the success of
vaccination, pertussis has continued to cause serious illness and death in the
United States [29]. Since the early 1980s, the reported incidence of pertussis
has been increasing, with peaks occurring at 3- to 5-year intervals [30–32].
Between 1990 and 1996, infants younger than 2 months of age accounted for
35% of cases [30]. Between 1994 and 1996, the rate of pertussis increased
by 11% among infants [33]. In 2000, infants younger than 4 months old
accounted for all cases of pertussis-associated mortality [34]. Infants have
the highest risk of death or a severe complication from pertussis and often
present in an atypical manner [33,35–38]. Preterm infants and infants born
to adolescent mothers are at particular risk [29,31]. Pertussis was found to
be the number one cause of death resulting from community-acquired
Table 2
Renal dose acyclovir
Creatinine (mg/dL) Dose (mg/kg/dose) Frequency
0.8–1.1 10 bid
1.2–1.5 10 qd
>1.5 5 qd
934 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Clinical manifestations
Classically, pertussis consists of three stages: catarrhal, paroxysmal, and
convalescent. Incubation lasts 7 to 10 days and is followed by the catarrhal
stage, which typically lasts 2 to 7 days. Symptoms of the catarrhal stage
include rhinorrhea, low-grade fever, and mild but increasing cough. Because
the symptoms during the catarrhal stage are mild and nonspecific, the
diagnosis of pertussis is rarely considered. During the catarrhal stage,
the rate of positive cultures and infectivity is highest. In the neonate, the
catarrhal stage can last only a few days or may not occur at all [31].
The catarrhal stage is followed by the paroxysmal stage, which may last 4
to 6 weeks and is characterized by coughing paroxysms, often provoked by
feeding [32]. Unless a secondary bacterial pneumonia is present, the infant
appears normal between paroxysms [45]. Infants may become dehydrated
from frequent episodes of posttussive emesis. In neonates, classic gasp or
whoop and coughing paroxysms may be absent, and as such these parox-
ysms should not be considered pathognomonic during infancy [28,31,36].
More common symptoms include hypoxia, feeding difficulties, apnea, and
seizures. Fever is often low grade or may be absent. Apnea or cyanosis is
a clue to the diagnosis of pertussis in infants younger than 3 months old [45].
Pneumonia, seizures, and encephalopathy are present in 22%, 3%, and 1%
of infantile cases of pertussis [46]. The most commonly recognized immediate
cause of mortality is respiratory insufficiency, which can progress to failure
[34]. Seizures primarily affect infants younger than 6 months old and are
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 935
Diagnostic evaluation
Diagnosis is problematic because isolation of the organism is time-
consuming and has a low sensitivity. Diagnostic evaluation may include a
complete blood count, nasopharyngeal culture, direct immunofluorescent
assay (DFA) or PCR of nasopharyngeal secretions, and chest radiograph.
Nasopharyngeal culture
The long-held gold standard has been nasopharyngeal culture. Specimens
should be obtained by aspiration or a flexible swab held in the posterior
nasopharynx for 15 to 30 seconds (dacron or calcium alginate), then plated
on a specialized agar (Bordet-Gengou or Regan-Lowe). Culture of B.
pertussis by this means requires an incubation period of 10 to 14 days. The
benefit of nasopharyngeal cultures for diagnosis is limited because the rate
of recovery and the likelihood of positive culture are highest during the
catarrhal stage, when illness is least suspected. Cultures are 80% sensitive
during the first 2 weeks of infection, insensitive at 4 weeks (14% sensitivity),
and ineffective after 5 weeks (0 sensitivity) [32,36,49]. A further limitation to
culture is the increased possibility of false-negative cultures in infants
already on antimicrobials. To increase diagnostic capture throughout the
course of illness, culture should be combined with a nasopharyngeal secre-
tion assay.
Chest radiograph
Chest radiographs should be obtained in conjunction with laboratory
data, nasopharyngeal samples, and culture in the evaluation of pertussis.
Although often normal, typical radiographic findings include focal atelecta-
sis or infiltrates, peribronchial cuffing, perihilar infiltrate, or perihilar edema.
Management
The management of neonatal pertussis should include hospitalization
(with respiratory isolation) with cardiopulmonary monitoring, antibiotics,
and supportive care. The antibiotic of choice is erythromycin. Other
macrolides and trimethoprim-sulfamethoxazole are possible alternatives.
Some experts have preferred the estolate preparation of erythromycin
because of its pharmacokinetic superiority [31,32,43,55]. An association be-
tween the administration of erythromycin and development of hypertrophic
pyloric stenosis has been described in neonates. As such, clinicians pre-
scribing erythromycin to a neonate should inform the parents regarding the
possibility of pyloric stenosis [56]. Before more recent reports, erythromy-
cin-resistant B. pertussis was essentially nonexistent [57]. Although erythro-
mycin resistance is rare, clinicians should be aware that it does exist in less
than 1% of cases [58].
Clarithromycin and azithromycin are possible alternatives to erythro-
mycin, although large studies of these agents during the neonatal period
have not been performed [59]. Trimethoprim-sulfamethoxazole is an effec-
tive alternative for patients unable to tolerate the macrolides or in cases
of erythromycin-resistant B. pertussis. Because of the associated risk of
hyperbilirubinemia in neonates, trimethoprim-sulfamethoxazole should be
avoided during the neonatal period if possible [31].
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 937
Fig. 1. In hypoplastic left heart syndrome, oxygenated blood is unable to enter the hypoplastic
left ventricle (LV) and cross the atrial septum into the right atrium (RA) where it mixes with
deoxygenated blood. From the right ventricle (RV), it enters the pulmonary artery, where via
the patent ductus arteriosus it can reach the systemic circulation. IVC, inferior vena cava; LA,
left atrium; SVC, superior vena cava.
obstructive lesion, 78% were discharged from the hospital without a diag-
nosis, and 69% of infants had a normal newborn screening examination
[70,74]. Approximately, 6% died before a diagnosis of left heart obstruction
could be made, and 96% developed symptoms by 3 weeks of life [70,74].
Most right-to-left shunting lesions are also ductal-dependent lesions (total
anomalous pulmonary venous return [TAPVR] is a right-to-left shunting
lesion and cyanotic but in the presence of a large ventricular septal defect or
atrial septal defect is not ductal dependent). In these malformations,
admixtures of deoxygenated and oxygenated blood are delivered to the
systemic circulation, requiring a significant portion of deoxygenated blood
to bypass the pulmonary circuit. In patients with tetralogy of Fallot and
associated pulmonary atresia, the combination of right-to-left shunting
pulmonary blood flow depends on a PDA, and secondary to pulmonary
atresia, a significant portion of deoxygenated blood is capable of bypassing
the pulmonary circuit. These patients present with rapidly progressive
central cyanosis, respiratory distress, and tachycardia as the ductus
arteriosus begins to close [76].
940 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Left-to-right shunting lesions are not ductal dependent but still can result
in equally acute presentation. In these lesions, oxygenated blood from the
left ventricle flows into the right, where it mixes with deoxygenated blood.
As PVR decreases, right-sided pressures decline, and shunting increases.
This mixed blood is delivered to the pulmonary system and results in
pulmonary overcirculation. These patients often develop signs and
symptoms of congestive heart failure in the first year of life but may
present during the neonatal period. An infant with a ventricular septal
defect may present with pulmonary overload, right heart failure, poor
peripheral perfusion, and peripheral cyanosis [77].
Clinical manifestations
Often the clinical findings of CHD mimic other disease processes, such as
sepsis. Common presenting complaints are often nonspecific and may
include fussiness, tachypnea, or inadequate weight gain. Patients may have
a low-grade fever due to their hypermetabolic state. Because feeding for the
infant is equivalent to exercise in adults, often feeding intolerance may be
the only indication of underlying heart disease [78]. Questions regarding
length of feedings, sweating during feeding, the need for frequent breaks,
and refusal of feedings are often helpful. Any child who takes longer than 30
minutes per feeding warrants suspicion [79].
The age at which symptoms develop can serve as a valuable tool in
discerning the underlying cardiac defect. Patients who develop symptoms in
the first week of life tend to have ductal-dependent lesions because this is the
period during which the ductus typically closes. The next crucial period is
marked by the decline in PVR and progressively increasing left-to-right
shunting (2–6 weeks of life). Patients who present at this time have lesions
that allow shunting in the face of unrestricted pulmonary blood flow.
Examples include transposition of the great arteries (TGA), TAPVR, and
truncus arteriosus. In each of these lesions, as PVR decreases, left-to-right
shunting increases resulting in progressively increased pulmonary perfusion,
leading to congestive heart failure. Patients with left-to-right shunts are
more susceptible to respiratory infections. Often an underlying infection tips
the patient into a decompensated state that requires medical care [80].
Patients with CHD should be approached systematically. If symptom
development has progressed over days, there is a degree of dehydration or
muscle wasting due to inadequate oral intake. The infant manifests tachy-
cardia and tachypnea. Patients with hemodynamically significant lesions
have some degree of increased work of breathing. Hypotension is a late and
more ominous finding. Blood pressures should be measured in the upper
and lower extremities to elicit clues suggesting a coarctation of the aorta or
an interrupted aortic arch. The hallmark of these lesions is diminished lower
extremity blood pressure. Blood pressures that are equal throughout do not
exclude the possibility of a congenital heart defect. TGA has normal blood
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 941
pressures. HLHS (which derives all systemic perfusion from across the
PDA) in the presence of a widely patent PDA also may have normal blood
pressures (contributing to the possibility of infants with this lesion being
discharged from the nursery). No rule is foolproof in that all lesions
eventually show diminished blood pressure as dehydration and heart failure
ensue. Even a classic coarctation of the aorta develops diminished upper
extremity blood pressures as symptoms progress and heart failure develops.
Differential blood pressures also should be correlated with preductal (right
upper extremity) and postductal (lower extremity) pulse oximetry measure-
ments. TGA is cyanotic throughout. Right-to-left shunting across the PDA
in the presence of normal left ventricular outflow (coarctation of the aorta)
is cyanotic in the lower extremities.
Cyanosis may not be present by visual inspection, requiring a 3 to 5 g/dL
reduction in hemoglobin to be detected [77,81]. The presence of central
cyanosis is a pathologic finding and is not to be confused with peripheral
cyanosis. The distinction between these two is crucial for the emergency
physician. Peripheral cyanosis, a manifestation of inadequate peripheral
perfusion, is common in the neonate and generally does not indicate a
serious illness. Peripheral cyanosis involves the hands and feet as opposed
to central cyanosis, which involves the trunk, extremities, and mucous
membranes. Central cyanosis is a manifestation of hypoxia and may be
secondary to a cardiac, pulmonary, or CNS etiology [77,81]. Any neonate
with central cyanosis should be admitted to a monitored setting and
undergo an evaluation to determine the etiology. Evaluation should include
a chest radiograph, electrocardiogram (ECG), preductal and postductal
oxygen saturations, and a 100% oxygen test (also called a hyperoxia test).
A critically ill neonate with an underlying cardiac malformation may present
with peripheral and central cyanosis because the neonate is hypoxic and has
poor peripheral perfusion [77]. In an acutely ill infant, it may prove difficult
to distinguish between the two forms of cyanosis. Transient cyanosis
associated with crying may suggest pulmonary disease or a cardiac defect
allowing right-to-left shunting. Often one sees the patient with a cyanotic
heart defect to be ‘‘comfortably blue’’ at rest only to worsen with agitation.
Patients with primary pulmonary processes show cyanosis that improves
with crying because the underlying defect is ventilatory in nature.
A thorough cardiopulmonary examination is essential for the evaluation
of a patient with suspected CHD. Features that should be scrutinized
include the presence and location of a precordial thrill or impulse, nature of
S1 and S2 heart sounds, the presence of associated clicks or gallops, and the
characteristics and timing of audible murmurs. Murmurs are a common
finding in pediatric patients. In addition, an ill or anxious infant often has
a more pronounced murmur. Differentiating benign murmurs, such as Still’s
murmur or a pulmonary flow murmur, from a pathologic murmur can be
difficult. Key indicators of a pathologic murmur are based on the harshness
or character of the murmur [82]. In general, the emergency department
942 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Diagnostic evaluation
Diagnostic evaluation that may be helpful includes pulse oximetry, blood
gases, the 100% oxygen test, ECG, glucose and chest radiography.
Pulse oximetry
Specific roles for pulse oximetry include the initial patient evaluation,
assessment of response to therapies, and monitoring when the patient has
been stabilized. Pulse oximetry may serve as the first indicator that an
oxygenation problem exists prompting the emergency physician to obtain
further diagnostic tests [75]. One investigation found pulse oximetry to be
100% sensitive and nearly 100% specific for detecting cyanotic CHD [85].
A specific diagnostic role for pulse oximetry is in testing preductal and
postductal oxygen saturation.
Hyperoxia test
The 100% oxygen test is used to differentiate pulmonary and cardiac
causes of cyanosis. The hyperoxia test is performed by administering 100%
oxygen, then assessing the increase in arterial oxygenation. Hypoxia
secondary to pulmonary disease or hypoventilation typically is overcome
with 100% oxygen. In these cases, PO2 values often increase to greater than
200 mm Hg unless severe pulmonary disease is present. With a cyanotic
cardiac defect, there is central mixing of saturated and desaturated blood.
Because the admixture always contains desaturated blood, there is a blunted
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 943
response to 100% oxygen. A PO2 value that does not exceed 100 mm Hg
despite 100% oxygen is highly suggestive of a cardiac etiology for cyanosis
[81].
Chest radiograph
Features of the chest radiograph that should be evaluated include the size
and shape of the cardiac silhouette, associated bone abnormalities, and the
appearance of the pulmonary lung fields. Almost all CHD, excluding
TAPVR, results in cardiomegaly. The absence of cardiomegaly can help
differentiate a congenital obstructive lesion, such as a left heart obstruc-
tion, from a systemic illness, such as sepsis, in an acutely ill neonate. A
retrospective review found the presence of cardiomegaly to predict a con-
genital obstructive lesion with a sensitivity of 85%, a specificity of 95%, and
a positive predictive value of 0.95 [87]. The overall shape of the cardiac
silhouette may be characteristic of specific defects but often is nonspecific.
Classic descriptions include ‘‘boot-shaped’’ in tetralogy of Fallot, ‘‘egg on
a string’’ in TGA, and ‘‘figure-eight’’ in TAPVR. An additional feature
characteristic of specific lesions is a right-sided aortic arch in tetralogy of
Fallot and TGA. In a normal radiograph, the airway deviates slightly to the
right above the carina. In a right-sided aortic arch, the airway is either
straight or deviates to the left. The pulmonary lung fields should be
evaluated for signs of effusions or infiltrates. These signs are important for
the differentiation of cardiac and pulmonary disease. Caution should be
exercised when the possibility of CHD is discounted based on the presence
of an infiltrate because many patients with CHD are more susceptible to
lower respiratory tract infections, which may be the source of their
decompensation. One also should identify the side of the stomach bubble
because abnormal abdominal situs often is associated with complex heart
defects. Increased or decreased pulmonary vascular markings suggest the
degree of pulmonary perfusion and may help to differentiate between
cardiac defects [88]. In general, increased pulmonary vascular markings
suggest pulmonary overperfusion, and decreased pulmonary vascular
markings suggest right heart obstructive lesions.
Electrocardiogram
The normal ECG findings in newborns and infants differ from findings in
adults [89]. As a result of the hemodynamic influence of the fetal circulation,
most infants are born with a rightward axis (approximately 90–180 ). This
converts by approximately 3 to 4 weeks of life to the axis more often seen in
adults (approximately 0–90 ). Deviation from this normal transition should
be considered suspicious. An upright T wave in V1 is normal at birth, but
persistence beyond 3 days of age should prompt careful interrogation [90].
ECG findings suggestive of individual chamber hypertrophy are based on
age. Most comprehensive pediatric textbooks have reference tables listing
population-based ECG findings in different age groups. ECG evidence of
944 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Management
Therapy is directed toward the presenting condition and always starts
with the ABCs of resuscitation (airway, breathing, circulation). Congenital
heart defects that present to the emergency department in the first week of
life are almost exclusively ductal-dependent lesions [91]. Stabilization in
these patients requires maintaining ductal patency. This section provides
a generalized initial treatment plan for a neonate presenting in suspected
cardiogenic shock with a focus on ductal-dependent lesions.
The mainstay of medical therapy for patients with a suspected ductal-
dependent lesion entails the use of intravenous prostaglandin E1 (PGE1) to
maintain ductal patency. The dosage of PGE1 is a continuous infusion at
0.05 to 0.1 lg/kg/min. Typically a constant infusion is initiated at 0.1 lg/kg/
min; this may be decreased gradually to 0.05 lg/kg/min when the patient is
stable [76]. Justifiable hesitance to start prostaglandins may be due to an
unclear diagnosis because side effects may antagonize hypotension secondary
to sepsis. Intravenous prostaglandins are lifesaving, however, in the presence
of a ductal-dependent lesion. If a physician strongly suspects the presence of
an underlying ductal-dependent defect in this age group, he or she should
not hesitate to start prostaglandins. The three most common side effects of
prostaglandins are hyperpyrexia (14%), apnea (9–12%), and flushing (10%)
[76,92,93]. Of these, apnea is the most concerning major complication and
seems to occur at higher doses. Close monitoring is essential when PGE1
is administered, and strong consideration should be given to intubation,
particularly in neonates requiring prolonged transport [76,92,93]. Less
common complications include tachycardia, bradycardia, hypotension,
cardiac arrest, necrotizing enterocolitis, and jitteriness [92,93].
When an infant presents in shock, initial attempts may be made to correct
hypotension with an initial fluid bolus because the diagnosis is not always
clear initially and most often is misconceived as sepsis. Complications may
arise because many patients have a degree of pulmonary edema secondary to
abnormal hemodynamics. A poor response to crystalloid bolus in a neonate
should increase suspicion of an underlying congenital heart defect. After
fluid bolus, inotropic agents, such as dobutamine or dopamine, may be used
[94]. The foundation to managing an acutely ill neonate with CHD is use of
PGE1. If the patient is decompensating as a result of a ductal-dependent
lesion, agents other than PGE1 are likely to be of limited value.
Hypoglycemia and profound acidosis should be corrected (inotropes are
often ineffective in an acidic milieu) [94]. Treatment of profound acidosis
should begin with 1 to 2 mEq/kg of sodium bicarbonate. Hypoglycemia
can be present secondary to increased metabolic stress, and it is essential
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 945
include congenital adrenal hyperplasia (32 states), maple syrup urine disease
(24 states), biotinidase deficiency (24 states), medium-chain acyl-CoA
dehydrogenase (21 states), and homocystinuria (17 states) [111]. Improving
techniques, availability, and expertise in the use of tools such as tandem
mass spectrometry are increasing rapidly the availability of ‘‘expanded’’
newborn screening programs [111–113].
Clinical manifestations
Neonates have a limited spectrum of responses to severe, overwhelming
illness, which results in considerable overlap in the presenting signs and
symptoms of widely varied disease processes [95–110,114–116]. For these
reasons, the differential diagnosis of a sick neonate is broad and must
include IEM; this is especially true when the history is that of a previously
well infant with no obvious risk factors for sepsis who shows a rapidly
progressive decline after a period of nonspecific symptoms. Table 3 lists
subtle and overt signs and symptoms consistent with possible IEM. Height-
ened clinical suspicion is paramount to recognizing these subtle signs as
heralds of a potential IEM. Suspicion of an IEM may be heightened in the
following presentations: intractable seizures, seizures and hypotonia, per-
sistent or recurrent vomiting, lethargy, coma, unexplained hemorrhage, and
family history indicating an IEM [104].
Clinical manifestations of IEM typically are the primary result of either
an accumulation of toxic metabolites or the interference with energy pro-
duction. Defects of intermediary metabolism, such as aminoacidopathies,
organic acidemias, and urea cycle defects, lead to an acute or progressive
intoxication secondary to the accumulation of endogenous intermediate
compounds [99,102,108,117]. Metabolic derangements found in fatty acid
oxidation disorders, lactic acidosis, defects in glycogenolysis, gluconeogen-
esis, and respiratory chain complexes result in insufficient substrate or
Table 3
Nonspecific clinical signs and symptoms of inborn errors of metabolism
Subtle Overt
Poor feeding/feeding refusal Persistent hypoglycemia
Irritability Acidosis
Somnolence Dehydration
Vomiting Poor perfusion/hypotension
Poor weight gain Apnea
Abnormal tone Seizures
Tachypnea Lethargy or coma
Tachycardia Altered thermoregulation
Arrhythmia
Cardiomyopathy
Sudden unexplained death
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 947
Diagnostic evaluation
Early detection and initiation of appropriate therapy is essential to
reduce morbidity and mortality from IEM. For the clinician, the crucial
factor in fulfilling this goal is not detailed knowledge of specific IEM but
rather consideration of one of these disorders. The initial approach to any
suspected IEM is based on application and correct interpretation of a select
few commonly used laboratory tests rather than administration of a
metabolic panel. Table 4 presents recommendations for a staged evaluation
based on the overall index of suspicion of an IEM.
In the current era of expansion of newborn screening programs, many
neonates from selected locations already may have undergone a limited
‘‘metabolic evaluation’’ by virtue of these screens [111,113,119]. Familiarity
with regional testing and how to access this information may help to focus
a clinician’s investigation. Parental recall of test results should not be relied
on.
Serum glucose
Neonates are particularly vulnerable to hypoglycemia owing to in-
sufficient glycogen stores and high glucose use by the brain [110,122,123].
Hypoglycemia is a common complication of many acute neonatal illnesses
948 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Table 4
Laboratory investigation for possible inborn errors of metabolism
Primary evaluation Secondary evaluation
Blood Blood
Glucose Primary evaluation laboratory tests plus
Electrolytes (Naþ, Kþ, Cl, HCO3, anion gap) Plasma carnitine, acylcarnitine profile
Creatinine, BUN Amino acid profile (quantitative)
CBC with differential Biotinidase
ABG Urine
Ammonia Primary evaluation laboratory tests plus
Lactate, pyruvate Organic and amino acids
Hepatic transaminases, bilirubin Acylglycines
(if jaundiced)
Urine
Ketones
Reducing substances
pH
Abbreviations: ABG, arterial blood glucose; BUN, blood urea nitrogen; CBC, Complete
blood count.
Acid-base status
Serum electrolytes and arterial or venous pH measurement provide
crucial diagnostic information and help guide therapeutic interventions. In
an infant who was apparently well at birth, development of an anion gap
acidosis greater than 20 mmol/L is highly suggestive of an IEM. This is
especially true when the clinical presentation is one of recurrent vomiting
with rapidly progressive neurologic deterioration as seen in the more
common organic acidemias [95,98]. Disorders of pyruvate oxidation or the
respiratory chain (ie, primary lactic acidoses) may manifest immediately
after birth or gradually over the first days to weeks of life with an anion gap
acidosis. In contrast to many of the IEM clinically apparent in the newborn
period, manifestation of these disorders is unrelated to dietary protein
exposure [98]. Causes of metabolic acidosis with a normal anion gap are
essentially restricted to bicarbonate losses from the gastrointestinal tract or
renal losses seen in renal tubular acidosis or the ‘‘salt wasting’’ form of
congenital adrenal hyperplasia [99,110].
Lactate
Measurement of a serum lactate level can be crucial for proper
interpretation of a metabolic acidosis or diagnostic evaluation of any acute
unexplained illness. Elevated lactate levels often are misinterpreted as
secondary to sampling error (difficult blood draw) or tissue hypoxia/necrosis
[95,109,124]. Lactate levels persistently elevated in the 3 to 6 mmol/L range
(normal \2 mmol/L), particularly in the absence of evidence of infection or
hypoxic insult, are consistent with a metabolic etiology. Lactate levels
greater than 10 mmol/L are frequently the result of perinatal hypoxia or
ischemic injury and not the result of an IEM. The finding of a neutral blood
pH or normal anion gap does not exclude the possibility of lactic or organic
acidemia [107]. Natural buffering capabilities typically maintain a neutral
pH until blood lactate levels are greater than 5 mmol/L [108]. Additionally
the anion gap may be normal to an excess of 6 mmol/L of lactate [102]. Even
in the absence of acidosis or increased anion gap, lactate measurement is
indicated for a neonate with a suspected IEM.
Pyruvate
Measurement of plasma pyruvate and calculation of the lactate-to-
pyruvate ratio may help differentiate the etiology of a lactic acidemia. When
950 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
pyruvate levels are increased at the same time as lactate, the lactate-to-
pyruvate ratio remains in the normal to low range (10–25), suggesting
a disorder of pyruvate oxidation (pyruvate dehydrogenase complex dis-
order) or gluconeogenesis. A normal or low pyruvate, producing an in-
creased lactate-to-pyruvate ratio (50–100), may suggest a disorder of
oxidative phosphorylation or pyruvate carboxylase or alternatively hypox-
emia [95,100].
Urinalysis
Urinalysis for ketones, reducing substances, and pH can provide im-
mediate and compelling evidence for an IEM. Ketonuria is highly suggestive
of an IEM because most neonates are inefficient producers of ketone bodies,
even in response to significant hypoglycemia [95,99]. In methylmalonic and
propionic acidemia, the two most commonly diagnosed organic acidemias,
specific ketoacid metabolites are detectable in the urine [108]. The presence
of urine-reducing substances must be investigated to rule out disorders such
as galactosemia. Infants with this disorder may present before the results of
the newborn screening test are available. Careful attention to urine pH also
can provide the initial diagnostic clue of an organic acidemia or lactic
acidosis. With significantly elevated blood levels, filtered lactate or organic
acids exceed tubular reabsorptive capabilities and result in decreased urine
pH (often \5.5). This finding may be present with a normal or near-normal
blood pH.
Ammonia
An ammonia level should be obtained in all neonates presenting with an
altered level of consciousness, poor feeding, persistent emesis, or an acute,
progressive unexplained illness [98]. Ammonia is a potent respiratory
stimulant, and one of the earliest clinical clues of hyperammonemia is
hyperventilation and respiratory alkalosis on blood gas analysis. Elevated
plasma ammonia levels may indicate a primary defect in nitrogen processing
(ie, urea cycle defect) or secondary effects of other IEM, liver disease, or
other illness on the efficiency of this pathway [101,103,109]. Interpretation of
ammonia levels depends not only on the magnitude of elevation, but also the
presence or absence of other metabolic abnormalities. A normal ammonia
level in a neonate is less than 65 lmol/L. Mild elevations (1.5–2 times
normal) can be seen in neonates with a wide variety of illnesses or simply as
the result of improper handling of the sample. When the level reaches 2.5
to 3 times normal (>150 lmol/L), the likelihood of an underlying IEM
increases significantly [96]. Laboratory findings of an elevated anion gap
metabolic acidosis, ketosis, and hyperammonemia point toward an organic
academia [109]. Markedly elevated ammonia levels, associated with a normal
anion gap and normal blood glucose, is highly suggestive of a urea cycle
defect [96,99,102,105,109,117,125–127].
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 951
Management
In contrast to the heterogeneity and complexity of IEM, the initial
approach to treatment of these disorders is relatively straightforward. The
primary goals are attention to airway, breathing, and circulation; preven-
tion of catabolism; and correction of acidosis and hyperammonemia. Any
suspected or known associated condition, such as sepsis, seizures, or co-
agulopathy, requires appropriate evaluation and management.
Resuscitation
The presence of encephalopathy, associated compromise of airway pro-
tective reflexes, and frequent apnea or hypopnea and the possibility of rapid
or relentless decompensation should prompt the establishment of a secure
952 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Hypoglycemia
Prevention of catabolism through the use of 8 to 10 mg/kg/min of
intravenous dextrose is achieved by administering a 10% dextrose solution
in quarter normal saline with or without potassium chloride at 1.5 times
the maintenance rate. Higher dextrose concentrations occasionally may be
necessary. Rarely a patient may develop a worsening acidosis with dextrose
administration (ie, pyruvate dehydrogenase complex deficiency) [95]. Most
IEM respond favorably, however, to empirical dextrose administration.
J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960 953
Feeding
Temporary discontinuation of feeds is often necessary pending clinical
and metabolic stabilization. This is particularly important in the setting
where symptoms are thought to be secondary to accumulation of toxic
metabolites.
Hyperammonemia
In the presence of hyperammonemia, early initiation of treatment is
imperative and is directed at rapid reduction of ammonia levels. Ammonia is
a potent neurotoxin and a diffusable small molecule that causes cerebral
edema. The urea cycle is the only effective clearance system for ammonia,
and any disruption results in rapid clinical progression [128]. It is well
known that the degree of neurologic impairment is related directly to
duration and severity of hyperammonemia and cerebral edema [129,130].
Hemodialysis has been shown to be the most rapid and effective means
of reducing ammonia levels [128]. In addition to the previously mentioned
therapies, the emergency department should anticipate the need for dialysis
with placement of appropriate lines and mobilization of the dialysis team
[131]. Administration of ammonia scavenging agents and repletion of
arginine should be considered for emergency department management of
these disorders. A loading dose of arginine hydrochloride (600 mg/kg)
combined with sodium benzoate and sodium phenylacetate (250 mg/kg
each) in a volume of 25 to 35 mL/kg of a 10% dextrose solution is infused
over 90 minutes [130]. Scavenging agents increase renal excretion of nitrogen
and are effective only if urine output is adequate. Certain enzymatic defects
in the urea cycle result in decreased arginine synthesis, making it an essential
amino acid.
Feeding
Temporary discontinuation of feeds is often necessary pending clinical
and metabolic stabilization. This discontinuation is particularly important
when symptoms may be attributed to accumulation of toxic metabolites.
Glucocorticoids
In the case of congenital adrenal hyperplasia, glucocorticoid administra-
tion (hydrocortisone, 50 mg/M2/d intravenously divided every 8 hours) may
be lifesaving in the setting of a neonate presenting in shock during the first
week of life. Congenital adrenal hyperplasia should be suspected with
a history of poor feeding; emesis; dehydration; and laboratory abnormalities
of hyponatremia, hypochloremia, and hyperkalemia. Defects in cholesterol
biosynthesis, most commonly 21-hydroxylase deficiency, can present as
a ‘‘salt wasting crisis’’ and refractory hypoglycemia in male neonates (or
gender misassigned females with ambiguous genitalia) [132].
954 J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960
Summary
A neonate presenting to the emergency department can present a chal-
lenge to even the most experienced clinician. This article has focused on four
deceiving and potentially devastating neonatal diseases.
1. Neonatal herpes is a potentially devastating illness without pathogno-
monic signs or symptoms. Early recognition and therapy can reduce
mortality markedly. Although no specific sign or symptom is diagnostic,
the diagnosis should be strongly considered in the presence of HSV risk
factors, atypical sepsis, unexplained acute hepatitis, or focal seizure
activity. Acyclovir therapy should be initiated before viral dissemination
or significant CNS replication occurs.
2. Pertussis is a disease in which infants are at greatest risk of death or
severe complication. Neonatal pertussis often presents in an atypical
manner, lacking the classic signs and symptoms such as the ‘‘whoop.’’
More common signs and symptoms include cough, feeding difficulty,
low-grade fever, emesis, increasing respiratory distress, apnea, cyanosis,
and seizures. Management should include hospitalization, supportive
care, and antibiotics.
3. Congenital heart defects, particularly ductal-dependent lesions, may
have an initial asymptomatic period that culminates in a rapidly
progressive and fatal course. A neonate with CHD presents with shock
refractory to volume resuscitation or pressor support. Resuscitative
efforts are ineffective unless PGE1 is administered.
4. Inborn errors of metabolism often are unsuspected because of their
protean and heterogeneous nature. Signs and symptoms are subtle,
are nonspecific, and often mimic other, more common diseases.
An elevated index of suspicion, along with application and correct
interpretation of a select few laboratory tests, is the key to making
a diagnosis. Therapy is relatively straightforward and focused on
resuscitation followed by prevention of catabolism and correction of
specifically identified abnormalities.
Although these disorders are relatively uncommon, prompt diagnosis and
therapy can lead to a decrease in morbidity and mortality. The key is to
maintain a high index of suspicion.
Acknowledgments
The authors acknowledge Raquel M. Schears, MD, Matthew D.
Sztajnkrycer, MD, and Judith A. Roberson.
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