unsuspected neonatal killers in emergency medicine

Emerg Med Clin N Am

22 (2004) 929–960

Unsuspected neonatal killers inemergency medicine

James E. Colletti, MDa,b,c,d,*, James L. Homme, MDa,Dale P. Woodridge, MD, PhDe,f

aDepartment of Pediatric and Adolescent Medicine, Mayo Medical School,

Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USAbDepartment of Emergency Medicine, Mayo Medical School, Mayo Clinic,

200 First Street SW, Rochester, MN 55905, USAcMayo Emergency Medicine Residency, Mayo Medical School, Mayo Clinic,

200 First Street SW, Rochester, MN 55905, USAdDepartment of Pediatrics, Mayo Medical School, Mayo Clinic,

200 First Street SW, Rochester, MN 55905, USAeDepartment of Pediatrics, University of Arizona,

1501 North Campbell Avenue, Tucson, AZ 85724, USAfDepartment of Emergency Medicine, University of Arizona,

1501 North Campbell Avenue, Tucson, AZ 85724, USA

Assessment of a neonate may prove challenging to the most experiencedclinician. Neonates present with a wide array of vague and nonspecificsymptoms, which often are not indicative of the diagnosis. Neonatalrespiratory distress may be caused by infectious, cardiac, metabolic, orbenign etiologies. Deadly conditions initially may appear benign. De-veloping an awareness of subtle but fatal diagnoses is vital to emergencyphysicians.

Because neonates present with few pathognomonic signs and symptoms,a sepsis evaluation is often the primary consideration. It is important thatthe emergency clinician is attuned to other neonatal deadly diagnosesbecause early intervention can result in a drastic decline in morbidity andmortality. The focus of this article is the atypical or subtle presentation offour deceiving but devastating neonatal diagnoses: (1) neonatal herpes, adisorder in which early recognition and therapy are crucial to the reductionof 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: [email protected] (J.E. Colletti).

0733-8627/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.emc.2004.06.002

mailto:[email protected]

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 deathor severe complication; (3) congenital heart malformations, particularlymalformations with an initial asymptomatic period culminating in a rapidlyprogressive and lethal course; and (4) inborn errors of metabolism (IEM),which often are unsuspected and the diagnosis of which often is delayedbecause 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 isthe rate of fetal and neonatal acquisition. Each year in the United States,nearly 2000 neonates contract HSV infection [1]. Prognosis is related todisease extent and timing and efficacy of therapy, making early diagnosisparamount. Diagnosis is difficult for the following reasons. (1) The neonate’ssymptoms are often subtle. (2) Most mothers at the time of delivery havesubclinical infection with asymptomatic viral shedding [2,3]. (3) Owing tothe incubation period of 5 to 21 days, a healthy-appearing neonate often istaken home only to become unwell with vague nonspecific symptomsbetween the first and third weeks of life [4]. The diagnosis of neonatal HSVoften is not entertained until the infant’s course is well advanced. A highlevel of clinical suspicion is required for diagnosis and early initiation ofantiviral 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 reducedmortality to 31% for disseminated disease and 6% for CNS disease [7].Although acyclovir has reduced mortality dramatically, the effects onmorbidity have been less impressive. Diagnosis relies on a high index ofsuspicion because only a few mothers (20–35%) provide a history consistentwith genital herpes [8,9]. Most mothers (60–80%) have asymptomatic orunrecognized infection [2,3,10,11]. The incidence of neonatal HSV is 33% to50% in infants born vaginally to mothers with primary infection anddecreases to 3% to 5% in mothers with secondary infection [9,12–14]. Thisincidence is believed to be due to the higher viral load and absence ofsignificant 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 orpostnatal [15]. The following are associated with increased risk of neonatalHSV: maternal primary infection, exposure to cervical viral shedding,delivery before 38 weeks, fetal scalp monitoring, maternal age younger than21, low-birth-weight infants, and rupture of membranes greater than 4 to 6hours before delivery [10,14,16]. Cesarean delivery dramatically reduces therisk of HSV transmission in mothers with recognized infection but does notcompletely eliminate it [3,16,17].

931J.E. Colletti et al / Emerg Med Clin N Am 22 (2004) 929–960

Clinical manifestations

Neonatal HSV infections are categorized into one of three clinical entities:disseminated disease; CNS disease; or localized disease to the skin, eyes, andmouth (SEM) (Table 1). Clinical overlap and disease progression may occuramong the three clinical entities. Untreated, 70% of localized SEM diseaseprogresses to CNS and disseminated disease [18,19].

Disseminated disease shows a predilection for the liver and lungs butcan involve multiple organs, including CNS, adrenal gland, skin, eyes, andmouth [20]. Disseminated disease accounts for 25% of neonatal HSV cases,has one of the earliest onsets (occurring during the first week of life), and hasthe highest mortality [13]. Mortality is correlated with aspartate trans-aminase elevations of greater than 10 times the upper limits of normal andlethargy at the time of initiation of acyclovir therapy.

CNS disease with or without skin involvement accounts for 35% of casesof neonatal herpes. Presentation is the latest of the three, occurring betweenthe 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 lowestmortality associated with it. SEM disease presents with vesicular lesions,keratitis, or chorioretinitis. The most common involved site is the face andscalp [21]. Localized disease tends to occur within the first week of life witha 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 arepresent [13]. Disseminated disease should be considered in neonates withsepsis syndrome, negative bacterial cultures, and severe liver dysfunction.Although no single sign or symptom has been shown to be pathognomonicfor 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

prematurity and

seizures

Bulging fontanelle

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 highlysuggestive of neonatal herpes but, their absence should not exclude thediagnosis because 17% to 39% of neonatal HSV cases never manifest skinlesions during the course of illness [20]. A study concluded that the pro-portion of infants presenting with fever alone was comparable betweeninfants with HSV and infants with bacterial meningitis. The results advo-cated routine testing and empirical therapy for neonatal HSV in febrileinfants with negative bacterial cultures [23].

Diagnostic evaluation

Diagnostic evaluation includes HSV polymerase chain reaction (PCR),viral culture, electroencephalogram (EEG), and liver transaminases.

Polymerase chain reactionBefore the advent of PCR, a diagnosis of neonatal herpes depended on

viral isolation proven on skin or brain biopsy specimen and characteristicfindings on EEG and neuroimaging [24]. Since the introduction of PCR,a diagnosis of neonatal herpes with or without skin lesions can be confirmedwithin 24 hours. To increase diagnostic sensitivity of PCR testing for HSVDNA, blood and CSF should be analyzed [24]. The sensitivity of CSF PCRranges from 71% to 100% [15,24]. A significant variability in PCR testingexists among laboratories due to a lack of technique standardization andthe manner of sample collection and storage [15]. One small investigationshowed PCR of plasma and peripheral blood mononuclear cells to bea useful diagnostic adjunct in the diagnosis of neonatal HSV, particularly inthe absence of skin manifestations [2]. Because sensitivity is not 100%,a negative CSF or serum PCR does not exclude a diagnosis of neonatalherpes. Viral cultures of skin vesicles, mouth, eyes, urine, blood, stool, andCSF remain the gold standard [13,22].

Electroencephalogram and neuroimagingAn 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 experiencedpediatric 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 emergencydepartment setting, EEG and neuroimaging should be obtained during thepatient’s inpatient evaluation [20].

Serum transaminase and chest radiographGiven the propensity for HSV to involve the liver and lungs, screening for

serum transaminase elevations and a chest radiograph to detect pneumonitisare recommended.


Management

For maximal benefit, acyclovir must be initiated before widespread viraldissemination or significant CNS replication occurs. Since the 1980s, littleprogress has been made in decreasing the time to initiation of therapy [20].In most neonates, a relatively short window of opportunity exists to initiateantiviral therapy effectively [15]. Although every neonate presenting withsuspected sepsis need not be evaluated for HSV, particular considerationshould be given to neonates with atypical sepsis presentations, HSV riskfactors, unexplained acute hepatitis, or focal seizure activity [22,26]. Whenconsidering 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 toimprove 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) andnephrotoxicity. Adequate hydration is crucial in preventing the latter. Pre-vious guidelines for acyclovir in neonates with impaired renal function alsoapply to high-dose acyclovir (Table 2) [7,27]. In addition to systemicacyclovir, 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 thisdisease have declined along with morbidity [28]. Despite the success ofvaccination, pertussis has continued to cause serious illness and death in theUnited States [29]. Since the early 1980s, the reported incidence of pertussishas 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 for35% of cases [30]. Between 1994 and 1996, the rate of pertussis increasedby 11% among infants [33]. In 2000, infants younger than 4 months oldaccounted for all cases of pertussis-associated mortality [34]. Infants havethe highest risk of death or a severe complication from pertussis and oftenpresent in an atypical manner [33,35–38]. Preterm infants and infants bornto adolescent mothers are at particular risk [29,31]. Pertussis was found tobe 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 revealedthat 88% of pertussis mortality occurred in infants younger than 4 monthsold. The classic signs and symptoms of pertussis are often lacking in thenonimmunized 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 andmortality make awareness of this disease crucial. Despite the success of theimmunization program, neonates remain susceptible to pertussis infection.

Pertussis is caused by Bordetella pertussis, a gram-negative bacillus, forwhich the only known host is humans. Transmission occurs by intimatecontact with respiratory secretions. In close contacts, the transmission rateof B. pertussis approaches 100%, with the most contagious period being thecatarrhal stage [31,42,43]. A reservoir of susceptible adolescents and adultshas developed because immunity provided by vaccination is limited (\12years). Most neonatal infection is obtained from this reservoir of oldersiblings or adults with mild or atypical illness [32,36,44]. The lack ofplacentally transferred passive immunity increases the infant’s vulnerabilityto pertussis when exposed [36]. Pertussis is endemic, with 3- to 5-yearepidemic cycles [45,46]. Most cases occur between June and September [30].


Classically, pertussis consists of three stages: catarrhal, paroxysmal, andconvalescent. Incubation lasts 7 to 10 days and is followed by the catarrhalstage, which typically lasts 2 to 7 days. Symptoms of the catarrhal stageinclude rhinorrhea, low-grade fever, and mild but increasing cough. Becausethe symptoms during the catarrhal stage are mild and nonspecific, thediagnosis of pertussis is rarely considered. During the catarrhal stage,the rate of positive cultures and infectivity is highest. In the neonate, thecatarrhal 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 4to 6 weeks and is characterized by coughing paroxysms, often provoked byfeeding [32]. Unless a secondary bacterial pneumonia is present, the infantappears normal between paroxysms [45]. Infants may become dehydratedfrom frequent episodes of posttussive emesis. In neonates, classic gasp orwhoop 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, andseizures. Fever is often low grade or may be absent. Apnea or cyanosis isa 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 immediatecause 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 fromprolonged coughing spells.

The final or third stage is the convalescent stage in which the intensity ofthe cough wanes and eventually disappears over 2 to 3 weeks. Feedingdifficulty often continues through this stage leading to inadequate caloricintake 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 acomplete blood count, nasopharyngeal culture, direct immunofluorescentassay (DFA) or PCR of nasopharyngeal secretions, and chest radiograph.

Complete blood count and blood culturesA white blood cell count of 15,000/mm3 or greater with a predominance

of lymphocytes may be observed but is not reliably present in infantsyounger than 3 months old [47]. The presence of a leukocytosis with alymphocytosis 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 cultureThe long-held gold standard has been nasopharyngeal culture. Specimens

should be obtained by aspiration or a flexible swab held in the posteriornasopharynx for 15 to 30 seconds (dacron or calcium alginate), then platedon a specialized agar (Bordet-Gengou or Regan-Lowe). Culture of B.pertussis by this means requires an incubation period of 10 to 14 days. Thebenefit of nasopharyngeal cultures for diagnosis is limited because the rateof recovery and the likelihood of positive culture are highest during thecatarrhal stage, when illness is least suspected. Cultures are 80% sensitiveduring 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 toculture is the increased possibility of false-negative cultures in infantsalready on antimicrobials. To increase diagnostic capture throughout thecourse of illness, culture should be combined with a nasopharyngeal secre-tion assay.

Direct immunofluorescent assayDFA of nasopharyngeal specimens is a rapid test (results available within

approximately 1 day) that can provide a presumptive diagnosis [50]. It alsomay be useful for patients on antibiotics. DFA has been fraught withmultiple difficulties, however. DFA has a low and varying sensitivity andspecificity and a high false-positive rate (85%), and a positive DFA is not


confirmatory of a diagnosis [46,50]. Laboratory personnel experienced inDFA preparation and interpretation are required. Because of these limitingfactors, DFA always should be preformed in conjunction with nasopha-ryngeal culture [50].

Polymerase chain reactionThe likely successor to DFA is the PCR test. PCR provides a more rapid,

sensitive, and specific technique than culture. PCR results can be obtainedin 2.5 hours to 2 days and have a greater sensitivity [50,51]. PCR allowsdetection over a longer time period and later into the illness than cultures doand may yield findings in patients who have been administered antibiotics[43,50,52]. To date, preliminary data on use of PCR is promising but notdefinitive. Culture still should be obtained for confirmation, epidemiology,and antibiotic sensitivity [44,53,54]. Serologic testing has been useful forclinical studies and is available from microbiology reference laboratories butis not readily available for clinical diagnosis.

Chest radiographChest 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. Othermacrolides and trimethoprim-sulfamethoxazole are possible alternatives.Some experts have preferred the estolate preparation of erythromycinbecause of its pharmacokinetic superiority [31,32,43,55]. An association be-tween the administration of erythromycin and development of hypertrophicpyloric stenosis has been described in neonates. As such, clinicians pre-scribing erythromycin to a neonate should inform the parents regarding thepossibility 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 lessthan 1% of cases [58].

Clarithromycin and azithromycin are possible alternatives to erythro-mycin, although large studies of these agents during the neonatal periodhave not been performed [59]. Trimethoprim-sulfamethoxazole is an effec-tive alternative for patients unable to tolerate the macrolides or in casesof erythromycin-resistant B. pertussis. Because of the associated risk ofhyperbilirubinemia in neonates, trimethoprim-sulfamethoxazole should beavoided during the neonatal period if possible [31].


Antimicrobials are most effective during the catarrhal stage. Efficacyof antimicrobial therapy during the paroxysmal stage is controversial.Historically, it was thought that antimicrobials did little to alter diseasecourse but that they limited infectivity. Some more recent reports suggestantimicrobial therapy may reduce the severity and duration of illness evenafter the catarrhal stage [43,55,57].

The efficacy of b-agonist therapy in pertussis is mixed. A few smallinvestigations suggested that b-agonist therapy may be beneficial, whereasothers have not shown this benefit. To date, no controlled randomized trialof sufficient size and power has evaluated definitively the clinical efficacy ofb-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 investigationof pertussis hyperimmune serum is currently under way, and preliminarydata suggest that early initiation of immunoglobulin therapy with hyper-immune serum may reduce the severity and duration of illness, especiallyin 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, 30mg/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 theseverity and frequency of cough exist, but to date a controlled investigationhas not been undertaken [43].

In addition to antimicrobial therapy directed at B. pertussis, it isimperative that close attention be given to airway management becauseintubation and ventilation are often necessary owing to apnea, respiratoryfailure, or seizures. In a neonate requiring intubation, particular attentionshould 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 infantmortality and almost all pediatric cardiac-related deaths [67]. Congenitalheart 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 ishypoplastic left heart syndrome (HLHS), a ductal-dependent lesion thatif untreated is uniformly fatal. Although other lesions presenting in theneonatal 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 aright-sided circulation (oxygenation occurs in placenta) to a left-sidedcirculation (oxygenation occurs in the lungs). This progression is the resultof a decrease in pulmonary vascular resistance (PVR) and closure of ductalshunts (ie, the ductus arteriosus, ductus venosus, and foramen ovale). Thehemodynamics of each individual congenital heart defect may createdependence or an incompatibility with the fetal or adult circulation. Duringthis transitional phase, especially when components of left-sided and right-sided circulation coexist, the neonate may not be overtly symptomatic atbirth, 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, leftventricular outflow obstruction, has an initial period of compensation thatculminates in a rapidly progressive and fatal course over hours. Distinguish-ing congenital malformations from sepsis in a critically ill neonate ischallenging given shared features of their systemic effects. Often theemergency physician approaches these patients assuming the more commoncauses without considering a primary cardiac etiology. A high index ofsuspicion can alert the provider to initiate lifesaving therapies.

Lesions that present precipitously at birth or during the immediatepostnatal period tend to be due to incompatibilities in transitioning fromfetal to adult circulation. Most depend on flow through the ductus arteriosusand are collectively referred to as ductal-dependent lesions. Ductal-dependentlesions 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 ofductal-dependent lesions and categorically include HLHS, interruptedaortic arch, coarctation of the aorta, and aortic valve stenosis. A summaryof the pathophysiology of ductal-dependent lesions using HLHS as anexample is provided here. Oxygen-rich pulmonary venous blood returns tothe left atrium but is unable to flow into the left ventricle due to hypoplasiaof the left ventricle or mitral valve atresia. The blood crosses the atrialseptum into the right atrium, where the oxygen-rich blood from the leftatrium is encountered creating a mixture with systemic venous return. Fromthe right ventricle, blood flows to the pulmonary artery, then may emptyinto the lungs or, if it crosses the patent ductus arteriosus (PDA), enter thesystemic circulation. In the presence of a complete left ventricular outflowtract obstruction, all systemic perfusion depends on flow across the PDA(Fig. 1). After birth, as the ductus constricts, blood is increasingly less ableto cross from the pulmonary to the systemic circuit. Eventually with PDAclosure, overload of the pulmonary circulation and systemic hypoperfusionresult.

Left ventricular outflow tract obstruction is a major source of neonatalmorbidity and mortality from CHD and accounts for 12.4% of congenitalcardiac disease in infancy [67,70,74,75]. Of neonates with a left heart


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 obstructioncould be made, and 96% developed symptoms by 3 weeks of life [70,74].

Most right-to-left shunting lesions are also ductal-dependent lesions (totalanomalous pulmonary venous return [TAPVR] is a right-to-left shuntinglesion and cyanotic but in the presence of a large ventricular septal defect oratrial septal defect is not ductal dependent). In these malformations,admixtures of deoxygenated and oxygenated blood are delivered to thesystemic circulation, requiring a significant portion of deoxygenated bloodto bypass the pulmonary circuit. In patients with tetralogy of Fallot andassociated pulmonary atresia, the combination of right-to-left shuntingpulmonary blood flow depends on a PDA, and secondary to pulmonaryatresia, a significant portion of deoxygenated blood is capable of bypassingthe pulmonary circuit. These patients present with rapidly progressivecentral cyanosis, respiratory distress, and tachycardia as the ductusarteriosus begins to close [76].

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.


Left-to-right shunting lesions are not ductal dependent but still can resultin equally acute presentation. In these lesions, oxygenated blood from theleft 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 inpulmonary overcirculation. These patients often develop signs andsymptoms of congestive heart failure in the first year of life but maypresent during the neonatal period. An infant with a ventricular septaldefect may present with pulmonary overload, right heart failure, poorperipheral perfusion, and peripheral cyanosis [77].


Often the clinical findings of CHD mimic other disease processes, such assepsis. Common presenting complaints are often nonspecific and mayinclude fussiness, tachypnea, or inadequate weight gain. Patients may havea low-grade fever due to their hypermetabolic state. Because feeding for theinfant is equivalent to exercise in adults, often feeding intolerance may bethe only indication of underlying heart disease [78]. Questions regardinglength of feedings, sweating during feeding, the need for frequent breaks,and refusal of feedings are often helpful. Any child who takes longer than 30minutes per feeding warrants suspicion [79].

The age at which symptoms develop can serve as a valuable tool indiscerning the underlying cardiac defect. Patients who develop symptoms inthe first week of life tend to have ductal-dependent lesions because this is theperiod during which the ductus typically closes. The next crucial period ismarked by the decline in PVR and progressively increasing left-to-rightshunting (2–6 weeks of life). Patients who present at this time have lesionsthat allow shunting in the face of unrestricted pulmonary blood flow.Examples include transposition of the great arteries (TGA), TAPVR, andtruncus arteriosus. In each of these lesions, as PVR decreases, left-to-rightshunting increases resulting in progressively increased pulmonary perfusion,leading to congestive heart failure. Patients with left-to-right shunts aremore susceptible to respiratory infections. Often an underlying infection tipsthe patient into a decompensated state that requires medical care [80].

Patients with CHD should be approached systematically. If symptomdevelopment has progressed over days, there is a degree of dehydration ormuscle wasting due to inadequate oral intake. The infant manifests tachy-cardia and tachypnea. Patients with hemodynamically significant lesionshave some degree of increased work of breathing. Hypotension is a late andmore ominous finding. Blood pressures should be measured in the upperand lower extremities to elicit clues suggesting a coarctation of the aorta oran interrupted aortic arch. The hallmark of these lesions is diminished lowerextremity blood pressure. Blood pressures that are equal throughout do notexclude the possibility of a congenital heart defect. TGA has normal blood


pressures. HLHS (which derives all systemic perfusion from across thePDA) in the presence of a widely patent PDA also may have normal bloodpressures (contributing to the possibility of infants with this lesion beingdischarged from the nursery). No rule is foolproof in that all lesionseventually show diminished blood pressure as dehydration and heart failureensue. Even a classic coarctation of the aorta develops diminished upperextremity blood pressures as symptoms progress and heart failure develops.Differential blood pressures also should be correlated with preductal (rightupper extremity) and postductal (lower extremity) pulse oximetry measure-ments. TGA is cyanotic throughout. Right-to-left shunting across the PDAin 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/dLreduction in hemoglobin to be detected [77,81]. The presence of centralcyanosis is a pathologic finding and is not to be confused with peripheralcyanosis. The distinction between these two is crucial for the emergencyphysician. Peripheral cyanosis, a manifestation of inadequate peripheralperfusion, is common in the neonate and generally does not indicate aserious illness. Peripheral cyanosis involves the hands and feet as opposedto central cyanosis, which involves the trunk, extremities, and mucousmembranes. Central cyanosis is a manifestation of hypoxia and may besecondary to a cardiac, pulmonary, or CNS etiology [77,81]. Any neonatewith central cyanosis should be admitted to a monitored setting andundergo an evaluation to determine the etiology. Evaluation should includea chest radiograph, electrocardiogram (ECG), preductal and postductaloxygen saturations, and a 100% oxygen test (also called a hyperoxia test).A critically ill neonate with an underlying cardiac malformation may presentwith peripheral and central cyanosis because the neonate is hypoxic and haspoor peripheral perfusion [77]. In an acutely ill infant, it may prove difficultto distinguish between the two forms of cyanosis. Transient cyanosisassociated with crying may suggest pulmonary disease or a cardiac defectallowing right-to-left shunting. Often one sees the patient with a cyanoticheart defect to be ‘‘comfortably blue’’ at rest only to worsen with agitation.Patients with primary pulmonary processes show cyanosis that improveswith crying because the underlying defect is ventilatory in nature.

A thorough cardiopulmonary examination is essential for the evaluationof a patient with suspected CHD. Features that should be scrutinizedinclude the presence and location of a precordial thrill or impulse, nature ofS1 and S2 heart sounds, the presence of associated clicks or gallops, and thecharacteristics and timing of audible murmurs. Murmurs are a commonfinding in pediatric patients. In addition, an ill or anxious infant often hasa more pronounced murmur. Differentiating benign murmurs, such as Still’smurmur or a pulmonary flow murmur, from a pathologic murmur can bedifficult. Key indicators of a pathologic murmur are based on the harshnessor character of the murmur [82]. In general, the emergency department


physician should be highly suspicious of any murmur that is louder thangrade 3, associated with a thrill, or associated with a hyperdynamicprecordium [83]. Likewise, diastolic murmurs are always abnormal [84].

Other physical findings include the presence or absence of hepatomegalyand extremity pulses. In neonates, hepatomegaly as a sign of CHF is muchmore likely than that of jugular venous distention and isolated lowerextremity edema. Detecting differences in peripheral pulses also can behelpful. In general, any lesion with an interrupted aortic arch or stenosisalong the aortic arch causes a varied pulse pressure between extremities.


Diagnostic evaluation that may be helpful includes pulse oximetry, bloodgases, the 100% oxygen test, ECG, glucose and chest radiography.

Pulse oximetrySpecific roles for pulse oximetry include the initial patient evaluation,

assessment of response to therapies, and monitoring when the patient hasbeen stabilized. Pulse oximetry may serve as the first indicator that anoxygenation problem exists prompting the emergency physician to obtainfurther diagnostic tests [75]. One investigation found pulse oximetry to be100% sensitive and nearly 100% specific for detecting cyanotic CHD [85].A specific diagnostic role for pulse oximetry is in testing preductal andpostductal oxygen saturation.

Arterial blood gasBlood 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 acyanoticlesions during the 100% oxygen test. The presence of acidosis suggestsinadequate oxygenation in cyanotic lesions or inadequate perfusion inacyanotic lesions. The PCO2 value indicates the patient’s ventilatory state.Patients with CHD in the absence of respiratory failure are unlikely to behypercarbic (PCO2 [40 mm Hg). Most often these patients have increasedventilation at baseline shown by a PCO2 of 25 to 40 mm Hg [86].

Hyperoxia testThe 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. Hypoxiasecondary to pulmonary disease or hypoventilation typically is overcomewith 100% oxygen. In these cases, PO2 values often increase to greater than200 mm Hg unless severe pulmonary disease is present. With a cyanoticcardiac 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 Hgdespite 100% oxygen is highly suggestive of a cardiac etiology for cyanosis[81].

Chest radiographFeatures of the chest radiograph that should be evaluated include the size

and shape of the cardiac silhouette, associated bone abnormalities, and theappearance of the pulmonary lung fields. Almost all CHD, excludingTAPVR, results in cardiomegaly. The absence of cardiomegaly can helpdifferentiate a congenital obstructive lesion, such as a left heart obstruc-tion, from a systemic illness, such as sepsis, in an acutely ill neonate. Aretrospective review found the presence of cardiomegaly to predict a con-genital obstructive lesion with a sensitivity of 85%, a specificity of 95%, anda positive predictive value of 0.95 [87]. The overall shape of the cardiacsilhouette may be characteristic of specific defects but often is nonspecific.Classic descriptions include ‘‘boot-shaped’’ in tetralogy of Fallot, ‘‘egg ona string’’ in TGA, and ‘‘figure-eight’’ in TAPVR. An additional featurecharacteristic of specific lesions is a right-sided aortic arch in tetralogy ofFallot and TGA. In a normal radiograph, the airway deviates slightly to theright above the carina. In a right-sided aortic arch, the airway is eitherstraight or deviates to the left. The pulmonary lung fields should beevaluated for signs of effusions or infiltrates. These signs are important forthe differentiation of cardiac and pulmonary disease. Caution should beexercised when the possibility of CHD is discounted based on the presenceof an infiltrate because many patients with CHD are more susceptible tolower respiratory tract infections, which may be the source of theirdecompensation. One also should identify the side of the stomach bubblebecause abnormal abdominal situs often is associated with complex heartdefects. Increased or decreased pulmonary vascular markings suggest thedegree of pulmonary perfusion and may help to differentiate betweencardiac defects [88]. In general, increased pulmonary vascular markingssuggest pulmonary overperfusion, and decreased pulmonary vascularmarkings suggest right heart obstructive lesions.

ElectrocardiogramThe 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�). Thisconverts by approximately 3 to 4 weeks of life to the axis more often seen inadults (approximately 0–90�). Deviation from this normal transition shouldbe considered suspicious. An upright T wave in V1 is normal at birth, butpersistence beyond 3 days of age should prompt careful interrogation [90].ECG findings suggestive of individual chamber hypertrophy are based onage. Most comprehensive pediatric textbooks have reference tables listingpopulation-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, oropposing hypoplasia.

Management

Therapy is directed toward the presenting condition and always startswith the ABCs of resuscitation (airway, breathing, circulation). Congenitalheart defects that present to the emergency department in the first week oflife are almost exclusively ductal-dependent lesions [91]. Stabilization inthese patients requires maintaining ductal patency. This section providesa generalized initial treatment plan for a neonate presenting in suspectedcardiogenic 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) tomaintain ductal patency. The dosage of PGE1 is a continuous infusion at0.05 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 isstable [76]. Justifiable hesitance to start prostaglandins may be due to anunclear diagnosis because side effects may antagonize hypotension secondaryto sepsis. Intravenous prostaglandins are lifesaving, however, in the presenceof a ductal-dependent lesion. If a physician strongly suspects the presence ofan underlying ductal-dependent defect in this age group, he or she shouldnot hesitate to start prostaglandins. The three most common side effects ofprostaglandins are hyperpyrexia (14%), apnea (9–12%), and flushing (10%)[76,92,93]. Of these, apnea is the most concerning major complication andseems 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]. Lesscommon 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 correcthypotension with an initial fluid bolus because the diagnosis is not alwaysclear initially and most often is misconceived as sepsis. Complications mayarise because many patients have a degree of pulmonary edema secondary toabnormal hemodynamics. A poor response to crystalloid bolus in a neonateshould increase suspicion of an underlying congenital heart defect. Afterfluid bolus, inotropic agents, such as dobutamine or dopamine, may be used[94]. The foundation to managing an acutely ill neonate with CHD is use ofPGE1. If the patient is decompensating as a result of a ductal-dependentlesion, agents other than PGE1 are likely to be of limited value.

Hypoglycemia and profound acidosis should be corrected (inotropes areoften ineffective in an acidic milieu) [94]. Treatment of profound acidosisshould begin with 1 to 2 mEq/kg of sodium bicarbonate. Hypoglycemiacan be present secondary to increased metabolic stress, and it is essential


that it be identified and corrected. In the neonatal period, treatment is with10 mL/kg of 10% glucose solution.

As with any patient, maintaining the airway is a priority. The decisionto intubate is made on an individual basis. Positive-pressure ventilationhelps with pulmonary edema but may antagonize hypotension. Consultingwith a pediatric cardiologist and intensivist is of utmost importance. Thedefinitive diagnosis requires echocardiography or cardiac catheterization.

Inborn errors of metabolism

The diagnosis of IEM often is missed or delayed because it is unsuspectedand considered only after the exclusion of more common conditions. Timelyrecognition is crucial to the reduction of morbidity and mortality. It is vitalfor the emergency clinician to become familiar with the presentation andmanagement of IEM. Recognition of IEM does not require extensiveknowledge of metabolic pathways or even characteristics of specific dis-orders, but rather requires a heightened index of suspicion. When an IEMis suspected, the clinician is able to pursue a diagnosis and promptly initiatestraightforward, lifesaving treatment strategies. Failure to consider IEM ina critically ill neonate can be catastrophic.

The focus of this section is purposefully limited to an overview of thepresentation, initial diagnostic evaluation, and management of IEM thatpresent in the neonatal period with the potential for life-threatening con-sequences. Detailed discussions of the various IEM seen in the newbornperiod are beyond the scope of this section and have been well describedelsewhere [95–110].

IEM are a diverse group of disorders typically involving a single genedefect that results in diminished or absent enzyme activity, transport proteinabnormalities, or altered binding of cofactor molecules. As such, a partial orcomplete interruption occurs in a metabolic pathway leading to eitheraccumulation of a metabolic substance or a deficiency in a metabolic endproduct.

More than 400 IEM have been identified and characterized with newdisorders identified yearly [102,103]. Individually, these disorders are rare,but collectively they cause a substantial proportion of childhood morbidityor mortality [95,97,98,104,105]. Most IEM are inherited in an autosomalrecessive 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 thatmany disorders had significantly improved outcomes when treatment wasinitiated early. Currently, all 50 states test newborns for phenylketonuria,congenital hypothyroidism, and galactosemia [110,111]. With these threeexceptions, no parity exists in the number or types of disorders screened forby state. At present, the range is 4 to 36 different disorders tested innewborns [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-CoAdehydrogenase (21 states), and homocystinuria (17 states) [111]. Improvingtechniques, availability, and expertise in the use of tools such as tandemmass spectrometry are increasing rapidly the availability of ‘‘expanded’’newborn screening programs [111–113].


Neonates have a limited spectrum of responses to severe, overwhelmingillness, which results in considerable overlap in the presenting signs andsymptoms of widely varied disease processes [95–110,114–116]. For thesereasons, the differential diagnosis of a sick neonate is broad and mustinclude IEM; this is especially true when the history is that of a previouslywell infant with no obvious risk factors for sepsis who shows a rapidlyprogressive decline after a period of nonspecific symptoms. Table 3 listssubtle and overt signs and symptoms consistent with possible IEM. Height-ened clinical suspicion is paramount to recognizing these subtle signs asheralds of a potential IEM. Suspicion of an IEM may be heightened in thefollowing presentations: intractable seizures, seizures and hypotonia, per-sistent or recurrent vomiting, lethargy, coma, unexplained hemorrhage, andfamily history indicating an IEM [104].

Clinical manifestations of IEM typically are the primary result of eitheran 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 progressiveintoxication secondary to the accumulation of endogenous intermediatecompounds [99,102,108,117]. Metabolic derangements found in fatty acidoxidation 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, priorunexplained neonatal demise, neurologic disability, developmental delay,mental retardation, and problems during pregnancy such as acute fatty liverof pregnancy or hemolysis, elevated liver enzymes, and low platelets(HELLP) syndrome [96,103,110]. Although this history should be sought, itis frequently absent and should be considered significant only when positive.

Physical examination findings in the neonate are typically nonspecificbecause the characteristic phenotypes associated with certain IEM have notfully developed. When present, dysmorphic features (lysosomal and per-oxisomal disorders) or unusual odors (‘‘sweaty feet’’ for isovaleric acidemiaor glutaric aciduria II; ‘‘maple syrup’’ for maple syrup urine disease) mayindicate an underlying IEM. These are uncommon, however, and seldomuseful in the acute decision analysis for diagnosis and treatment. Mostinfants with seemingly dysmorphic features or abnormal odor do not havean 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 withrepeated exposures and may improve with dietary restriction. Alternatively,disorders of energy production often are precipitated by fasting or increasedcatabolism owing to stress or intercurrent illness [100].


Early detection and initiation of appropriate therapy is essential toreduce morbidity and mortality from IEM. For the clinician, the crucialfactor in fulfilling this goal is not detailed knowledge of specific IEM butrather consideration of one of these disorders. The initial approach to anysuspected IEM is based on application and correct interpretation of a selectfew commonly used laboratory tests rather than administration of ametabolic panel. Table 4 presents recommendations for a staged evaluationbased on the overall index of suspicion of an IEM.

In the current era of expansion of newborn screening programs, manyneonates from selected locations already may have undergone a limited‘‘metabolic evaluation’’ by virtue of these screens [111,113,119]. Familiaritywith regional testing and how to access this information may help to focusa clinician’s investigation. Parental recall of test results should not be reliedon.

Serum glucoseNeonates 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


and usually is controlled easily by enteral or parenteral dextrose supple-mentation. Although most neonates with hypoglycemia do not have aprimary 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 isdebatable. Typically a plasma glucose less than 40 to 45 mg/dL in a termnewborn more than 24 hours old is considered hypoglycemic, especiallywhen the infant is symptomatic (irritable, jittery, feeding difficulties,tachycardia, or tachypnea). If these symptoms are the result of cerebralglycopenia, complete resolution occurs within hours after normalization ofthe plasma glucose. Persistence of symptoms with euglycemia suggests analternate etiology [122].

Hypoglycemia is a common manifestation of disorders of carbohydratemetabolism (hepatic forms of glycogen storage diseases, disorders ofgluconeogenesis, and galactosemia) and fatty acid oxidation [98]. Disordersof fat oxidation probably represent the largest group of IEM currentlyidentified. Medium-chain acyl-CoA dehydrogenase deficiency, the mostcommon of these disorders, has been estimated to occur in 1:10,000newborns. A large percentage of patients with fatty acid oxidation defectspresent within the first 48 to 72 hours of life with profound hypoglycemia[95,118]. In addition, many of these disorders have been associated tovarying degrees with sudden death, most commonly on first presentation inpreviously well infants [118]. Presence or absence of blood or urine ketonebodies is necessary to classify hypoglycemia as ketotic or hypoketotic.Although neonates are poor producers of ketone bodies, they are able togenerate detectable levels through lipolysis in response to hypoglycemia.

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

(if jaundiced)

Acylglycines

Urine

Ketones

Reducing substances

pH

Abbreviations: ABG, arterial blood glucose; BUN, blood urea nitrogen; CBC, Complete

blood count.


Hypoketotic hypoglycemia is highly suggestive of a fatty acid oxidationdisorder [95,105,109,118]. Occasionally, hypoglycemia is seen as a secondarymetabolic 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 promptconsideration of an IEM [101].

Acid-base statusSerum electrolytes and arterial or venous pH measurement provide

crucial diagnostic information and help guide therapeutic interventions. Inan infant who was apparently well at birth, development of an anion gapacidosis greater than 20 mmol/L is highly suggestive of an IEM. This isespecially true when the clinical presentation is one of recurrent vomitingwith rapidly progressive neurologic deterioration as seen in the morecommon organic acidemias [95,98]. Disorders of pyruvate oxidation or therespiratory chain (ie, primary lactic acidoses) may manifest immediatelyafter birth or gradually over the first days to weeks of life with an anion gapacidosis. In contrast to many of the IEM clinically apparent in the newbornperiod, manifestation of these disorders is unrelated to dietary proteinexposure [98]. Causes of metabolic acidosis with a normal anion gap areessentially restricted to bicarbonate losses from the gastrointestinal tract orrenal losses seen in renal tubular acidosis or the ‘‘salt wasting’’ form ofcongenital adrenal hyperplasia [99,110].

LactateMeasurement of a serum lactate level can be crucial for proper

interpretation of a metabolic acidosis or diagnostic evaluation of any acuteunexplained illness. Elevated lactate levels often are misinterpreted assecondary 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 orhypoxic insult, are consistent with a metabolic etiology. Lactate levelsgreater than 10 mmol/L are frequently the result of perinatal hypoxia orischemic injury and not the result of an IEM. The finding of a neutral bloodpH or normal anion gap does not exclude the possibility of lactic or organicacidemia [107]. Natural buffering capabilities typically maintain a neutralpH until blood lactate levels are greater than 5 mmol/L [108]. Additionallythe anion gap may be normal to an excess of 6 mmol/L of lactate [102]. Evenin the absence of acidosis or increased anion gap, lactate measurement isindicated for a neonate with a suspected IEM.

PyruvateMeasurement 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), suggestinga 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 ofoxidative phosphorylation or pyruvate carboxylase or alternatively hypox-emia [95,100].

UrinalysisUrinalysis for ketones, reducing substances, and pH can provide im-

mediate and compelling evidence for an IEM. Ketonuria is highly suggestiveof an IEM because most neonates are inefficient producers of ketone bodies,even in response to significant hypoglycemia [95,99]. In methylmalonic andpropionic acidemia, the two most commonly diagnosed organic acidemias,specific ketoacid metabolites are detectable in the urine [108]. The presenceof urine-reducing substances must be investigated to rule out disorders suchas galactosemia. Infants with this disorder may present before the results ofthe newborn screening test are available. Careful attention to urine pH alsocan provide the initial diagnostic clue of an organic acidemia or lacticacidosis. With significantly elevated blood levels, filtered lactate or organicacids exceed tubular reabsorptive capabilities and result in decreased urinepH (often\5.5). This finding may be present with a normal or near-normalblood pH.

AmmoniaAn 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 respiratorystimulant, and one of the earliest clinical clues of hyperammonemia ishyperventilation and respiratory alkalosis on blood gas analysis. Elevatedplasma ammonia levels may indicate a primary defect in nitrogen processing(ie, urea cycle defect) or secondary effects of other IEM, liver disease, orother illness on the efficiency of this pathway [101,103,109]. Interpretation ofammonia levels depends not only on the magnitude of elevation, but also thepresence or absence of other metabolic abnormalities. A normal ammonialevel in a neonate is less than 65 lmol/L. Mild elevations (1.5–2 timesnormal) can be seen in neonates with a wide variety of illnesses or simply asthe result of improper handling of the sample. When the level reaches 2.5to 3 times normal (>150 lmol/L), the likelihood of an underlying IEMincreases significantly [96]. Laboratory findings of an elevated anion gapmetabolic acidosis, ketosis, and hyperammonemia point toward an organicacademia [109]. Markedly elevated ammonia levels, associated with a normalanion gap and normal blood glucose, is highly suggestive of a urea cycledefect [96,99,102,105,109,117,125–127].


Complete blood countObtaining 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 isolatedneutropenia or pancytopenia secondary to bone marrow suppression; thisnot only mimics sepsis, but also may predispose to overwhelming infections.Galactosemia is another IEM that predisposes to infection (Escherichia colisepsis) [97,98,107,124].

Liver function testsMeasurement of transaminases and bilirubin levels can be useful in

identifying the group of IEM with primary features of hepatic injury anddysfunction. Disorders that are associated more commonly with prominenthepatic abnormalities include galactosemia, tyrosinemia, and some fattyacid oxidation defects. Many other IEM manifest varying degrees of liverinvolvement [102,107].

Other laboratory testsExpanded 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. Acquisitionand interpretation of these tests is not of practical utility for guiding acutetherapy. Measurement of urine organic acids requires only a few millilitersof 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 obtainselected samples for a ‘‘metabolic autopsy.’’ Coordination of postmortemevaluation should include a specialist in the area of metabolic diseases toassist in ordering appropriate testing and to review pertinent results with thefamily. Box 1 describes samples and storage of postmortem specimens[96,99,102,118].

Management

In contrast to the heterogeneity and complexity of IEM, the initialapproach to treatment of these disorders is relatively straightforward. Theprimary goals are attention to airway, breathing, and circulation; preven-tion of catabolism; and correction of acidosis and hyperammonemia. Anysuspected or known associated condition, such as sepsis, seizures, or co-agulopathy, requires appropriate evaluation and management.

ResuscitationThe presence of encephalopathy, associated compromise of airway pro-

tective reflexes, and frequent apnea or hypopnea and the possibility of rapidor relentless decompensation should prompt the establishment of a secure


airway. A secure airway is especially important when transport is anti-cipated. Additionally, even brief periods of hypoxia could potentiateneurotoxicity from toxic metabolites and should be avoided. Continuouscardiorespiratory monitoring is indicated even in patients who are notventilated to watch for evidence of arrhythmias secondary to cardiotoxicmetabolites or cardiomyopathy. Fluid boluses to correct hypovolemia or tocounteract cardiovascular collapse may be necessary along with inotropicsupport of cardiac output and blood pressure.

Acidosis and hyperkalemiaSodium bicarbonate and calcium gluconate administration for correction

of acidosis and cardiac myocyte stabilization in the setting of hyperkalemiais often necessary. Some organic acidemias may require large doses ofsodium bicarbonate (20–30 mmol/kg) for correction of the severe acidosis.Judicious use of isotonic saline may be necessary to avoid sodium and wateroverload.

HypoglycemiaPrevention of catabolism through the use of 8 to 10 mg/kg/min of

intravenous dextrose is achieved by administering a 10% dextrose solutionin quarter normal saline with or without potassium chloride at 1.5 timesthe maintenance rate. Higher dextrose concentrations occasionally may benecessary. Rarely a patient may develop a worsening acidosis with dextroseadministration (ie, pyruvate dehydrogenase complex deficiency) [95]. MostIEM respond favorably, however, to empirical dextrose administration.

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 spectrometryUrine: 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, andenzyme and DNA analysis)

* Preferred volume. Testing can be performed on microvolumes.y Collect within 2–4 hours after death.


FeedingTemporary discontinuation of feeds is often necessary pending clinical

and metabolic stabilization. This is particularly important in the settingwhere symptoms are thought to be secondary to accumulation of toxicmetabolites.

HyperammonemiaIn the presence of hyperammonemia, early initiation of treatment is

imperative and is directed at rapid reduction of ammonia levels. Ammonia isa potent neurotoxin and a diffusable small molecule that causes cerebraledema. The urea cycle is the only effective clearance system for ammonia,and any disruption results in rapid clinical progression [128]. It is wellknown that the degree of neurologic impairment is related directly toduration and severity of hyperammonemia and cerebral edema [129,130].Hemodialysis has been shown to be the most rapid and effective meansof reducing ammonia levels [128]. In addition to the previously mentionedtherapies, the emergency department should anticipate the need for dialysiswith placement of appropriate lines and mobilization of the dialysis team[131]. Administration of ammonia scavenging agents and repletion ofarginine should be considered for emergency department management ofthese disorders. A loading dose of arginine hydrochloride (600 mg/kg)combined with sodium benzoate and sodium phenylacetate (250 mg/kgeach) in a volume of 25 to 35 mL/kg of a 10% dextrose solution is infusedover 90 minutes [130]. Scavenging agents increase renal excretion of nitrogenand are effective only if urine output is adequate. Certain enzymatic defectsin the urea cycle result in decreased arginine synthesis, making it an essentialamino acid.

FeedingTemporary discontinuation of feeds is often necessary pending clinical

and metabolic stabilization. This discontinuation is particularly importantwhen symptoms may be attributed to accumulation of toxic metabolites.

GlucocorticoidsIn the case of congenital adrenal hyperplasia, glucocorticoid administra-

tion (hydrocortisone, 50 mg/M2/d intravenously divided every 8 hours) maybe lifesaving in the setting of a neonate presenting in shock during the firstweek of life. Congenital adrenal hyperplasia should be suspected witha history of poor feeding; emesis; dehydration; and laboratory abnormalitiesof hyponatremia, hypochloremia, and hyperkalemia. Defects in cholesterolbiosynthesis, most commonly 21-hydroxylase deficiency, can present asa ‘‘salt wasting crisis’’ and refractory hypoglycemia in male neonates (orgender 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 fourdeceiving and potentially devastating neonatal diseases.

1. Neonatal herpes is a potentially devastating illness without pathogno-monic signs or symptoms. Early recognition and therapy can reducemortality markedly. Although no specific sign or symptom is diagnostic,the diagnosis should be strongly considered in the presence of HSV riskfactors, atypical sepsis, unexplained acute hepatitis, or focal seizureactivity. Acyclovir therapy should be initiated before viral disseminationor significant CNS replication occurs.

2. Pertussis is a disease in which infants are at greatest risk of death orsevere complication. Neonatal pertussis often presents in an atypicalmanner, 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, supportivecare, and antibiotics.

3. Congenital heart defects, particularly ductal-dependent lesions, mayhave an initial asymptomatic period that culminates in a rapidlyprogressive and fatal course. A neonate with CHD presents with shockrefractory to volume resuscitation or pressor support. Resuscitativeefforts are ineffective unless PGE1 is administered.

4. Inborn errors of metabolism often are unsuspected because of theirprotean 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 correctinterpretation of a select few laboratory tests, is the key to makinga diagnosis. Therapy is relatively straightforward and focused onresuscitation followed by prevention of catabolism and correction ofspecifically identified abnormalities.

Although these disorders are relatively uncommon, prompt diagnosis andtherapy can lead to a decrease in morbidity and mortality. The key is tomaintain 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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