Unsuspected Neonatal Killers in Emergency Medicine

Emerg Med Clin N Am
22 (2004) 929–960
Unsuspected neonatal killers in

emergency medicine
James E. Colletti, MDa,b,c,d,*, James L. Homme, MDa,
Dale P. Woodridge, MD, PhDe,f
a
Department of Pediatric and Adolescent Medicine, Mayo Medical School,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
b
Department of Emergency Medicine, Mayo Medical School, Mayo Clinic,
200 First Street SW, Rochester, MN 55905, USA
c
Mayo Emergency Medicine Residency, Mayo Medical School, Mayo Clinic,
d
Department of Pediatrics, Mayo Medical School, Mayo Clinic,
e
Department of Pediatrics, University of Arizona,
1501 North Campbell Avenue, Tucson, AZ 85724, USA
f
Department of Emergency Medicine, University of Arizona,
1501 North Campbell Avenue, Tucson, AZ 85724, USA
Assessment of a neonate may prove challenging to the most experienced

clinician. Neonates present with a wide array of vague and nonspecific
symptoms, which often are not indicative of the diagnosis. Neonatal
respiratory distress may be caused by infectious, cardiac, metabolic, or
benign etiologies. Deadly conditions initially may appear benign. De-
veloping an awareness of subtle but fatal diagnoses is vital to emergency
physicians.
Because neonates present with few pathognomonic signs and symptoms,
a sepsis evaluation is often the primary consideration. It is important that
the emergency clinician is attuned to other neonatal deadly diagnoses
because early intervention can result in a drastic decline in morbidity and
mortality. The focus of this article is the atypical or subtle presentation of
four deceiving but devastating neonatal diagnoses: (1) neonatal herpes, a
disorder in which early recognition and therapy are crucial to the reduction
of morbidity and mortality; (2) pertussis, a disease wherein an atypical
* Corresponding author. Department of Emergency Medicine, Mayo Medical School,

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
E-mail address: colletti.james@mayo.edu (J.E. Colletti).
0733-8627/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved.
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%
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.
Polymerase chain reaction

Before the advent of PCR, a diagnosis of neonatal herpes depended on
viral isolation proven on skin or brain biopsy specimen and characteristic
findings on EEG and neuroimaging [24]. Since the introduction of PCR,
a diagnosis of neonatal herpes with or without skin lesions can be confirmed
within 24 hours. To increase diagnostic sensitivity of PCR testing for HSV
DNA, blood and CSF should be analyzed [24]. The sensitivity of CSF PCR
ranges from 71% to 100% [15,24]. A significant variability in PCR testing
exists among laboratories due to a lack of technique standardization and
the manner of sample collection and storage [15]. One small investigation
showed PCR of plasma and peripheral blood mononuclear cells to be
a useful diagnostic adjunct in the diagnosis of neonatal HSV, particularly in
the absence of skin manifestations [2]. Because sensitivity is not 100%,
a negative CSF or serum PCR does not exclude a diagnosis of neonatal
herpes. Viral cultures of skin vesicles, mouth, eyes, urine, blood, stool, and
CSF remain the gold standard [13,22].
Electroencephalogram and neuroimaging

An editorial advocated the combination of HSV PCR and a well-
performed EEG as a diagnostic strategy in the evaluation of HSV CNS in-
volvement [25]. This editorial stated that when interpreted by an experienced
pediatric epileptologist skilled in neonatal EEG interpretation, 80% to 90%
of children with documented HSV CNS disease could be detected [25].
Although utility of such a diagnostic strategy is limited in the emergency
department setting, EEG and neuroimaging should be obtained during the
patient’s inpatient evaluation [20].
Serum transaminase and chest radiograph

Given the propensity for HSV to involve the liver and lungs, screening for
serum transaminase elevations and a chest radiograph to detect pneumonitis
are recommended.
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
bacterial infections in infants 10 days to 2 months old [39]. Crowcroft et al

[40] concluded that deaths from pertussis are underestimated and revealed
that 88% of pertussis mortality occurred in infants younger than 4 months
old. The classic signs and symptoms of pertussis are often lacking in the
nonimmunized neonate, delaying the diagnosis [41]. Often a systemically ill-
appearing neonate is treated for sepsis with broad-spectrum antibiotics [34].
The atypical nature of the presentation and its potential for morbidity and
mortality make awareness of this disease crucial. Despite the success of the
immunization program, neonates remain susceptible to pertussis infection.
Pertussis is caused by Bordetella pertussis, a gram-negative bacillus, for
which the only known host is humans. Transmission occurs by intimate
contact with respiratory secretions. In close contacts, the transmission rate
of B. pertussis approaches 100%, with the most contagious period being the
catarrhal stage [31,42,43]. A reservoir of susceptible adolescents and adults
has developed because immunity provided by vaccination is limited (\12
years). Most neonatal infection is obtained from this reservoir of older
siblings or adults with mild or atypical illness [32,36,44]. The lack of
placentally transferred passive immunity increases the infant’s vulnerability
to pertussis when exposed [36]. Pertussis is endemic, with 3- to 5-year
epidemic cycles [45,46]. Most cases occur between June and September [30].
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
believed to be secondary to hypoxia or cerebral hemorrhage resulting from

prolonged coughing spells.
The final or third stage is the convalescent stage in which the intensity of
the cough wanes and eventually disappears over 2 to 3 weeks. Feeding
difficulty often continues through this stage leading to inadequate caloric
intake and susceptibility to secondary infections.
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.
Complete blood count and blood cultures

A white blood cell count of 15,000/mm3 or greater with a predominance
of lymphocytes may be observed but is not reliably present in infants
younger than 3 months old [47]. The presence of a leukocytosis with a
lymphocytosis may be present in neonates with other infections [46].
Extreme leukocytosis (white blood cell count [100,000/mm3) and throm-
bocytosis have been associated with increased morbidity and mortality
[45,48]. Blood cultures are typically negative.
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.
Direct immunofluorescent assay

DFA of nasopharyngeal specimens is a rapid test (results available within
approximately 1 day) that can provide a presumptive diagnosis [50]. It also
may be useful for patients on antibiotics. DFA has been fraught with
multiple difficulties, however. DFA has a low and varying sensitivity and
specificity and a high false-positive rate (85%), and a positive DFA is not
confirmatory of a diagnosis [46,50]. Laboratory personnel experienced in

DFA preparation and interpretation are required. Because of these limiting
factors, DFA always should be preformed in conjunction with nasopha-
ryngeal culture [50].
Polymerase chain reaction

The likely successor to DFA is the PCR test. PCR provides a more rapid,
sensitive, and specific technique than culture. PCR results can be obtained
in 2.5 hours to 2 days and have a greater sensitivity [50,51]. PCR allows
detection over a longer time period and later into the illness than cultures do
and may yield findings in patients who have been administered antibiotics
[43,50,52]. To date, preliminary data on use of PCR is promising but not
definitive. Culture still should be obtained for confirmation, epidemiology,
and antibiotic sensitivity [44,53,54]. Serologic testing has been useful for
clinical studies and is available from microbiology reference laboratories but
is not readily available for clinical diagnosis.
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].
Antimicrobials are most effective during the catarrhal stage. Efficacy

of antimicrobial therapy during the paroxysmal stage is controversial.
Historically, it was thought that antimicrobials did little to alter disease
course but that they limited infectivity. Some more recent reports suggest
antimicrobial therapy may reduce the severity and duration of illness even
after the catarrhal stage [43,55,57].
The efficacy of b-agonist therapy in pertussis is mixed. A few small
investigations suggested that b-agonist therapy may be beneficial, whereas
others have not shown this benefit. To date, no controlled randomized trial
of sufficient size and power has evaluated definitively the clinical efficacy of
b-agonist therapy, and further evaluation is required [60–63].
In the 1930s and 1940s, hyperimmune serum obtained from adults con-
valescing from pertussis was widely used [45]. A multicenter investigation
of pertussis hyperimmune serum is currently under way, and preliminary
data suggest that early initiation of immunoglobulin therapy with hyper-
immune serum may reduce the severity and duration of illness, especially
in high-risk infants [43,64].
The routine use of corticosteroids is not supported by the literature.
Although a few small studies have shown a benefit, a controlled investiga-
tion of adequate size has not been performed. The use of corticosteroids
(betamethasone, 0.075 mg/kg/24 h orally, or hydrocortisone succinate, 30
mg/kg/24 h intramuscularly) is not recommended routinely, and cortico-
steroids should be reserved for infants with life-threatening pertussis
[32,43,65,66]. Anecdotal reports of nebulized corticosteroids reducing the
severity and frequency of cough exist, but to date a controlled investigation
has not been undertaken [43].
In addition to antimicrobial therapy directed at B. pertussis, it is
imperative that close attention be given to airway management because
intubation and ventilation are often necessary owing to apnea, respiratory
failure, or seizures. In a neonate requiring intubation, particular attention
should be given to bradycardia, secondary pulmonary infections, and pul-
monary toilet. In a neonate presenting with respiratory distress or failure,
broad-spectrum antibiotics should be initiated in addition to erythromycin.
Congenital heart defects

Cardiac malformations account for approximately 10% of infant
mortality and almost all pediatric cardiac-related deaths [67]. Congenital
heart disease (CHD) has an incidence of 4 to 6 cases per 1000 live births
[68–73]. The most common lethal heart defect in the neonatal period is
hypoplastic left heart syndrome (HLHS), a ductal-dependent lesion that
if untreated is uniformly fatal. Although other lesions presenting in the
neonatal period are discussed briefly, the focus of this section is on ductal-
dependent lesions, especially HLHS.
The transition from fetal circulation consists of a conversion from a

right-sided circulation (oxygenation occurs in placenta) to a left-sided
circulation (oxygenation occurs in the lungs). This progression is the result
of a decrease in pulmonary vascular resistance (PVR) and closure of ductal
shunts (ie, the ductus arteriosus, ductus venosus, and foramen ovale). The
hemodynamics of each individual congenital heart defect may create
dependence or an incompatibility with the fetal or adult circulation. During
this transitional phase, especially when components of left-sided and right-
sided circulation coexist, the neonate may not be overtly symptomatic at
birth, and the diagnosis may be overlooked in the nursery [70,71,74].
Depending on the defect, patients can present in extremis with cyanosis,
respiratory failure, or shock. One of the most deadly diagnoses, left
ventricular outflow obstruction, has an initial period of compensation that
culminates in a rapidly progressive and fatal course over hours. Distinguish-
ing congenital malformations from sepsis in a critically ill neonate is
challenging given shared features of their systemic effects. Often the
emergency physician approaches these patients assuming the more common
causes without considering a primary cardiac etiology. A high index of
suspicion can alert the provider to initiate lifesaving therapies.
Lesions that present precipitously at birth or during the immediate
postnatal period tend to be due to incompatibilities in transitioning from
fetal to adult circulation. Most depend on flow through the ductus arteriosus
and are collectively referred to as ductal-dependent lesions. Ductal-dependent
lesions present with either cyanosis (right-to-left shunt lesions) or shock
(left ventricular outflow obstruction).
Left ventricular outflow tract obstructions are the most common subset of
ductal-dependent lesions and categorically include HLHS, interrupted
aortic arch, coarctation of the aorta, and aortic valve stenosis. A summary
of the pathophysiology of ductal-dependent lesions using HLHS as an
example is provided here. Oxygen-rich pulmonary venous blood returns to
the left atrium but is unable to flow into the left ventricle due to hypoplasia
of the left ventricle or mitral valve atresia. The blood crosses the atrial
septum into the right atrium, where the oxygen-rich blood from the left
atrium is encountered creating a mixture with systemic venous return. From
the right ventricle, blood flows to the pulmonary artery, then may empty
into the lungs or, if it crosses the patent ductus arteriosus (PDA), enter the
systemic circulation. In the presence of a complete left ventricular outflow
tract obstruction, all systemic perfusion depends on flow across the PDA
(Fig. 1). After birth, as the ductus constricts, blood is increasingly less able
to cross from the pulmonary to the systemic circuit. Eventually with PDA
closure, overload of the pulmonary circulation and systemic hypoperfusion
result.
Left ventricular outflow tract obstruction is a major source of neonatal
morbidity and mortality from CHD and accounts for 12.4% of congenital
cardiac disease in infancy [67,70,74,75]. Of neonates with a left heart
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].
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].
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
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
physician should be highly suspicious of any murmur that is louder than

grade 3, associated with a thrill, or associated with a hyperdynamic
precordium [83]. Likewise, diastolic murmurs are always abnormal [84].
Other physical findings include the presence or absence of hepatomegaly
and extremity pulses. In neonates, hepatomegaly as a sign of CHF is much
more likely than that of jugular venous distention and isolated lower
extremity edema. Detecting differences in peripheral pulses also can be
helpful. In general, any lesion with an interrupted aortic arch or stenosis
along the aortic arch causes a varied pulse pressure between extremities.
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.
Arterial blood gas

Blood gas values are essential for the evaluation of any critically ill neonate
who presents in respiratory distress or shock. Important values include PCO2,
PO2, and pH. The PO2 value is useful in distinguishing cyanotic from acyanotic
lesions during the 100% oxygen test. The presence of acidosis suggests
inadequate oxygenation in cyanotic lesions or inadequate perfusion in
acyanotic lesions. The PCO2 value indicates the patient’s ventilatory state.
Patients with CHD in the absence of respiratory failure are unlikely to be
hypercarbic (PCO2 [40 mm Hg). Most often these patients have increased
ventilation at baseline shown by a PCO2 of 25 to 40 mm Hg [86].
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
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
CHD typically is noted by changes consistent with ventricular hypertrophy.

These changes can be a result of ventricular dilation, hypertrophy, or
opposing hypoplasia.
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
that it be identified and corrected. In the neonatal period, treatment is with

10 mL/kg of 10% glucose solution.
As with any patient, maintaining the airway is a priority. The decision
to intubate is made on an individual basis. Positive-pressure ventilation
helps with pulmonary edema but may antagonize hypotension. Consulting
with a pediatric cardiologist and intensivist is of utmost importance. The
definitive diagnosis requires echocardiography or cardiac catheterization.
Inborn errors of metabolism

The diagnosis of IEM often is missed or delayed because it is unsuspected
and considered only after the exclusion of more common conditions. Timely
recognition is crucial to the reduction of morbidity and mortality. It is vital
for the emergency clinician to become familiar with the presentation and
management of IEM. Recognition of IEM does not require extensive
knowledge of metabolic pathways or even characteristics of specific dis-
orders, but rather requires a heightened index of suspicion. When an IEM
is suspected, the clinician is able to pursue a diagnosis and promptly initiate
straightforward, lifesaving treatment strategies. Failure to consider IEM in
a critically ill neonate can be catastrophic.
The focus of this section is purposefully limited to an overview of the
presentation, initial diagnostic evaluation, and management of IEM that
present in the neonatal period with the potential for life-threatening con-
sequences. Detailed discussions of the various IEM seen in the newborn
period are beyond the scope of this section and have been well described
elsewhere [95–110].
IEM are a diverse group of disorders typically involving a single gene
defect that results in diminished or absent enzyme activity, transport protein
abnormalities, or altered binding of cofactor molecules. As such, a partial or
complete interruption occurs in a metabolic pathway leading to either
accumulation of a metabolic substance or a deficiency in a metabolic end
product.
More than 400 IEM have been identified and characterized with new
disorders identified yearly [102,103]. Individually, these disorders are rare,
but collectively they cause a substantial proportion of childhood morbidity
or mortality [95,97,98,104,105]. Most IEM are inherited in an autosomal
recessive pattern, affecting boys and girls. Autosomal dominant and X-
linked dominant modes of inheritance exist as well.
Newborn screening for IEM was implemented with the recognition that
many disorders had significantly improved outcomes when treatment was
initiated early. Currently, all 50 states test newborns for phenylketonuria,
congenital hypothyroidism, and galactosemia [110,111]. With these three
exceptions, no parity exists in the number or types of disorders screened for
by state. At present, the range is 4 to 36 different disorders tested in
newborns [111]. Some other, more commonly tested metabolic disorders
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].
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
blocks in the pathways for energy production [95,96,99–102,105,108–110,

118–121].
Relevant family history includes consanguinity, siblings with IEM, prior
unexplained neonatal demise, neurologic disability, developmental delay,
mental retardation, and problems during pregnancy such as acute fatty liver
of pregnancy or hemolysis, elevated liver enzymes, and low platelets
(HELLP) syndrome [96,103,110]. Although this history should be sought, it
is frequently absent and should be considered significant only when positive.
Physical examination findings in the neonate are typically nonspecific
because the characteristic phenotypes associated with certain IEM have not
fully developed. When present, dysmorphic features (lysosomal and per-
oxisomal disorders) or unusual odors (‘‘sweaty feet’’ for isovaleric acidemia
or glutaric aciduria II; ‘‘maple syrup’’ for maple syrup urine disease) may
indicate an underlying IEM. These are uncommon, however, and seldom
useful in the acute decision analysis for diagnosis and treatment. Most
infants with seemingly dysmorphic features or abnormal odor do not have
an IEM.
The relationship of onset of symptoms to feeding often provides diag-
nostic clues. In certain disorders of intermediary metabolism, toxic meta-
bolites accumulate only after introduction of feedings. Illness worsens with
repeated exposures and may improve with dietary restriction. Alternatively,
disorders of energy production often are precipitated by fasting or increased
catabolism owing to stress or intercurrent illness [100].
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
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.
and usually is controlled easily by enteral or parenteral dextrose supple-

mentation. Although most neonates with hypoglycemia do not have a
primary metabolic or endocrine disorder, any unexplained, severe, or per-
sistent hypoglycemia should serve as a red flag for IEM and prompt fur-
ther investigation [102]. The definition of hypoglycemia in a neonate is
debatable. Typically a plasma glucose less than 40 to 45 mg/dL in a term
newborn more than 24 hours old is considered hypoglycemic, especially
when the infant is symptomatic (irritable, jittery, feeding difficulties,
tachycardia, or tachypnea). If these symptoms are the result of cerebral
glycopenia, complete resolution occurs within hours after normalization of
the plasma glucose. Persistence of symptoms with euglycemia suggests an
alternate etiology [122].
Hypoglycemia is a common manifestation of disorders of carbohydrate
metabolism (hepatic forms of glycogen storage diseases, disorders of
gluconeogenesis, and galactosemia) and fatty acid oxidation [98]. Disorders
of fat oxidation probably represent the largest group of IEM currently
identified. Medium-chain acyl-CoA dehydrogenase deficiency, the most
common of these disorders, has been estimated to occur in 1:10,000
newborns. A large percentage of patients with fatty acid oxidation defects
present within the first 48 to 72 hours of life with profound hypoglycemia
[95,118]. In addition, many of these disorders have been associated to
varying degrees with sudden death, most commonly on first presentation in
previously well infants [118]. Presence or absence of blood or urine ketone
bodies is necessary to classify hypoglycemia as ketotic or hypoketotic.
Although neonates are poor producers of ketone bodies, they are able to
generate detectable levels through lipolysis in response to hypoglycemia.
Hypoketotic hypoglycemia is highly suggestive of a fatty acid oxidation

disorder [95,105,109,118]. Occasionally, hypoglycemia is seen as a secondary
metabolic abnormality in the disorders of amino acid metabolism.
Symptomatic hypoglycemia associated with another metabolic derange-
ment, such as an anion gap metabolic acidosis or ketosis, should prompt
consideration of an IEM [101].
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
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].
Complete blood count

Obtaining a complete blood count with differential analysis is often part
of the evaluation of a critically ill neonate. Certain metabolic disorders,
most notably methylmalonic and propionic acidemia, can produce isolated
neutropenia or pancytopenia secondary to bone marrow suppression; this
not only mimics sepsis, but also may predispose to overwhelming infections.
Galactosemia is another IEM that predisposes to infection (Escherichia coli
sepsis) [97,98,107,124].
Liver function tests

Measurement of transaminases and bilirubin levels can be useful in
identifying the group of IEM with primary features of hepatic injury and
dysfunction. Disorders that are associated more commonly with prominent
hepatic abnormalities include galactosemia, tyrosinemia, and some fatty
acid oxidation defects. Many other IEM manifest varying degrees of liver
involvement [102,107].
Other laboratory tests

Expanded evaluation of a patient with a suspected IEM includes measure-
ment of plasma carnitine, acylcarnitine and quantitative amino acid profiles,
biotinidase, and urine for organic acid and acylglycine profiles. Acquisition
and interpretation of these tests is not of practical utility for guiding acute
therapy. Measurement of urine organic acids requires only a few milliliters
of urine and can aid in identification of 200 distinct disorders [103,108].
In the event the patient dies, there is a window of opportunity to obtain
selected samples for a ‘‘metabolic autopsy.’’ Coordination of postmortem
evaluation should include a specialist in the area of metabolic diseases to
assist in ordering appropriate testing and to review pertinent results with the
family. Box 1 describes samples and storage of postmortem specimens
[96,99,102,118].
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
Box 1. Suggested metabolic autopsy samples

Plasma: 3–10 mL (frozen)
Whole blood: 3–10 mL in ethylenediamine tetraacetic acid tube
for DNA analysis (refrigerated at 4 C)
Blood spots on filter paper for tandem mass spectrometry
Urine: 5–10 mL* (frozen)
Cerebrospinal fluid: 1–3 mL (frozen)
Skin biopsy for fibroblast culture (store in tissue culture medium
or sterile saline at 4 C)
Muscle biopsy and liver biopsyy (flash frozen in liquid nitrogen or
on dry ice for electron microscopy, histopathology, and
enzyme and DNA analysis)
* Preferred volume. Testing can be performed on microvolumes.

y
Collect within 2–4 hours after death.
airway. A secure airway is especially important when transport is anti-

cipated. Additionally, even brief periods of hypoxia could potentiate
neurotoxicity from toxic metabolites and should be avoided. Continuous
cardiorespiratory monitoring is indicated even in patients who are not
ventilated to watch for evidence of arrhythmias secondary to cardiotoxic
metabolites or cardiomyopathy. Fluid boluses to correct hypovolemia or to
counteract cardiovascular collapse may be necessary along with inotropic
support of cardiac output and blood pressure.
Acidosis and hyperkalemia

Sodium bicarbonate and calcium gluconate administration for correction
of acidosis and cardiac myocyte stabilization in the setting of hyperkalemia
is often necessary. Some organic acidemias may require large doses of
sodium bicarbonate (20–30 mmol/kg) for correction of the severe acidosis.
Judicious use of isotonic saline may be necessary to avoid sodium and water
overload.
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.
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].
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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Emerg Med Clin N Am

Unsuspected neonatal killers in

Assessment of a neonate may prove challenging to the most experienced

* Corresponding author. Department of Emergency Medicine, Mayo Medical School,

Polymerase chain reaction

Electroencephalogram and neuroimaging

Serum transaminase and chest radiograph

bacterial infections in infants 10 days to 2 months old [39]. Crowcroft et al

believed to be secondary to hypoxia or cerebral hemorrhage resulting from

Complete blood count and blood cultures

Direct immunoﬂuorescent assay

conﬁrmatory of a diagnosis [46,50]. Laboratory personnel experienced in

Polymerase chain reaction

Antimicrobials are most eﬀective during the catarrhal stage. Eﬃcacy

Congenital heart defects

The transition from fetal circulation consists of a conversion from a

physician should be highly suspicious of any murmur that is louder than

Arterial blood gas

CHD typically is noted by changes consistent with ventricular hypertrophy.

that it be identiﬁed and corrected. In the neonatal period, treatment is with

Inborn errors of metabolism

blocks in the pathways for energy production [95,96,99–102,105,108–110,

and usually is controlled easily by enteral or parenteral dextrose supple-

Hypoketotic hypoglycemia is highly suggestive of a fatty acid oxidation

Complete blood count

Liver function tests

Other laboratory tests

Box 1. Suggested metabolic autopsy samples

* Preferred volume. Testing can be performed on microvolumes.

airway. A secure airway is especially important when transport is anti-

Acidosis and hyperkalemia

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