LEGEND '=Abnormal, C=Cntical, A= Interpretive Data, c=Corrected, L=Low, H=High, !=Footnote, T =Textual Result

Result Comments 113: Glucose Level

Critical action: Notiiy physician Critical notiiy: dane mejas Read back: Yes Notiiy date: 04-12-2013 05.50

c&Hedt!>dtfote 4112\'2013 ... 411t/2ofs .. Cbller.:ted Time 05:00 POT . 1649 PDT

Procedure Units Sodium Level 137 ... mEq/L Potassium Level Chloride Lvl C02 Lvl Anion Gap Glucose Level BUN Crea1inine Estimated GFR.(Schwartz:.Bedside) Magnesium Serum

Phosphorus .se.ru.m ... Bilirubin Conjugated Bilirub1n Unconjugated AST(SGOT) ALT(SGPT) Alkaline Phosphatase,Serum Gamma Glutamyltransferase Ammonia,Blood Venous .La.ctic .. Acid .. Blood,Ve.nous .. Albumin Level

0.7

mEq/L mEq/L mEq/L mEq/L mg/dL mg/dL rngldL mL/min/1.73 m2 mg/dl

rng/dL mg/dL mg/dL IU/L IU/L IU/L IU/L mcmol/L MMOL!L g/dL

NAME: XIE, J IANHUA DRACO

Reference Range

[1,35.:.1.45J [3.5-5.5] [96-110] [18-27] [8 0-22 OJ [60-105] [6-20]

,,, 10 1:0 4:]

[1.8-2.4]

,,, [3 9:6 5.l [0.0-0.3] [0.0-1. 1]

[3-74] [6-45] [95-380],, [15-85] [9-33] [0.5:2 2J .. [2.9-5.5]

Seattle Children's Hospital

PO Box 5371 DOB: 9/16/2012

1275567

Print Date: 9/2312015 13:52 PDT

25788848 Seattle, Washington 98105-0371 MRN: RRID:

18 of 2081

LEGEND '=Abnormal, C=Cntical, A= Interpretive Data, c=Corrected, L=Low, H=High, !=Footnote, T =Textual Result

Result Comments 114: Glucose Level

Critical Glu called to Kylie Wontor and read back. 4/1212013 5:30 km 116: Estimated GFR (Schwartz Bedside)

Calculated by a Discern Rule Estima1ed GFR(Schwartz Bedside)= 0413 * Height(cm)/SCr(mg/dL)

Anion Gap BUN

Result Comments 116: Estimated GFR (Schwartz Bedside)

Calculated by a Discern Rule

> 120 116

2.4 J.7L

IU/L IUIL IU/L mcmol/L MMOL!L

mEqiL mEqiL mEqiL mg/dL mg/dl ml/min/1.73 m2 ing/dl mg/dl mg/dl

1Tigld.L

Estima1ed GFR(Schwartz Bedside)= 0413 ·• Height(cm)/SCr(mg/dL)

NAME: XIE, J IANHUA DRACO

-1 3]

[0,0-0.3] [0.0-1.1] [0.0-0.2]

[3:74] [6:45]

,,, [95-38()] [1585] [9-33]

... l0:5:2:?l [0.03-0.1 OJ [2.9-5.5J ..

... [1 8:2 4:] [3,9-6,5] [0.0-0.3]

... [0:°:1 1J

Seattle Children's Hospital PO Box 5371 DOB: 9/16/2012 Print Date: 9/2312015 13:52 PDT

25788848 Seat11e, Washington 98105-0371 MRN: 1275567 RRID:

19 of 2081

yxie

Rectangle

I

Pediatric Critical Care

Fourth Edition

Bradley P. Fuhrman, MD, FCCMProfessor of Pediatrics and Anesthesiology University at Buffalo School of Medicine Chief, Pediatric Critical Care Medicine Women and Children’s Hospital of Buffalo Buffalo, New York

Jerry J. Zimmerman, MD, PhD, FCCMProfessor of Pediatrics and AnesthesiologyDirector, Pediatric Critical Care MedicineSeattle Children’s HospitalSeattle, Washington

Joseph A. Carcillo, MDAssociate Professor of Critical Care Medicine

and Pediarics Children’s Hospital of Pittsburgh of UPMCUniversity of Pittsburgh School of MedicinePittsburgh, Pennsylvania

Robert S.B. Clark, MDChief, Division of Pediatric Critical Care

MedicineChildren’s Hospital of Pittsburgh of UPMCAssociate Director, Safar Center for

Resuscitation ResearchUniversity of PittsburghPittsburgh, Pennsylvania

Monica Relvas, MD, FAAPPediatric Critical Care MedicineFollowship DirectorVirginia Commonwealth UniversityRichmond, Virginia

Alexandre T. Rotta, MD, FCCM, FAAPDirector, Pediatric Cardiac Critical Care ProgramRiley Hospital for Children, Indiana UniversityAssociate Professor of Clinical PediatricsIndiana University School of MedicineIndianapolis, Indiana

Ann E. Thompson, MD, MHCPMProfessor and Vice Chair for Faculty DevelopmentDepartment of Critical Care MedicineAssociate Dean for Faculty AffairsUniversity of Pittsburgh School of MedicineMedical Director for Clinical Resource

ManagementChildren’s Hospital of PittsburghPittsburgh, Pennsylvania

Joseph D. Tobias, MDChief, Department of Anesthesiology &

Pain MedicineNationwide Children’s HospitalProfessor of Anesthesiology & PediatricsOhio State UniversityColumbus, Ohio

1089

Metabolism can be defined as the sum of all biochemical pro-cesses that convert food to smaller molecules and energy for the purposes of structure and function. An inborn error of metab-olism (IEM) is an inherited deficiency of any critical step in metabolism. Although genetic deficiency of catalytic enzymes in intermediary metabolic pathways is the classic paradigm for IEM, the pathophysiology of metabolic disorders may involve abnormalities of any number of cellular processes, includ-ing transmembrane transport, cell signaling, cell differentia-tion and development, energy production, and others. Many IEMs are individually rare, although a few, including phenyl-ketonuria (PKU) and medium-chain acyl-coenzyme A (acyl-CoA) dehydrogenase deficiency (MCADD), a defect in fatty acid oxidation, exhibit a population incidence approaching 1:10,000 live births.1,2 Specific IEMs may be more common in certain ethnic groups with a history of relative reproduc-tive isolation. Collectively, the population incidence of all IEMs may approach 1:1500 live births, depending upon how broadly IEM is defined. Many IEMs are associated with cata-strophic illness necessitating advanced life support. Although IEMs may present very rarely within the professional lifetime of the average medical practitioner, critically ill children with IEMs will not be uncommon visitors to the pediatric intensive care unit (ICU), especially in a tertiary care center.

The key to successful treatment of IEMs is the initial suspi-cion and timely diagnosis of the disorder. Certain features of the clinical history, physical signs and symptoms, and results of rou-tine laboratory studies often suggest the possibility of IEM. Sec-ond-tier screening metabolic studies provide further evidence for the presence of a disorder. The results of routine neonatal screening studies may suggest a specific disorder prior to devel-opment of any diagnostic suspicion on the part of the clinician or even prior to the onset of symptoms in the neonate. In the case of a critically ill child with a suspected metabolic disease or with an abnormal neonatal screening test result for a specific metabolic disorder, immediate consultation with a biochemical geneticist, even if only by telephone, is paramount. The genetic consultant helps direct the diagnostic laboratory evaluation and recommends nonspecific emergency treatment, if any is warranted, prior to the availability of the definitive diagnostic studies. Communication among the intensivist, genetic consul-tant, and biochemical genetic diagnostic laboratory is critical to achieving the timely and correct diagnosis of IEM. A satisfactory clinical outcome for the affected child is completely dependent upon the collaborative efforts of this tripartite team approach.

Other published textbooks on the diagnosis and treat-ment of IEM provide an exhaustive list of known disorders.3,4 Rather than recapitulate an encyclopedia of possible diseases, this chapter presents a diagnostic rationale based upon spe-cific clinical symptom complexes that are likely to occur in the critically ill child. Algorithms for the differential diagnosis of specific clinical scenarios are given in support of this rationale. Symptoms often begin during early infancy in the biochemi-cally most-severe IEMs; naturally, these IEMs with neonatal onset are the focus of our discussion in this chapter. However, “milder” or late-onset variants of virtually every IEM have been described, with onset of symptoms occurring at all ages, even during adulthood. Some IEMs uniformly present after the neo-natal period; age of symptom onset (late infancy, childhood, or adulthood) often is an important clue to the specific diagnosis. The clinical presentation, diagnostic workup, and treatment of neonatal onset disorders provide a paradigm for the evaluation and management of possible IEM in a child of any age.

Pathophysiology of Inborn Errors of MetabolismUnder the classic paradigm, an IEM is associated with defi-ciency of a specific protein, often a catalytic enzyme, involved in a critical metabolic pathway (Figure 76-1). This deficiency leads to a block in the pathway and the accumulation of the

Inborn Errors of MetabolismLaurie Smith and Cary O. Harding

Chapter 76

PEARLS• Unexpectedandunexplainedclinicaldeteriorationina

previouslyhealthyinfantorchildisanimportantcluetothepresenceofaninbornerrorofmetabolism(IEM).

• Lossofpreviouslyattaineddevelopmentalmilestonesduringchildhoodisanimportantcluetothepresenceofaneurodegenerativedisordersuchaslysosomalstoragedisease.

• Bloodglucoselessthan40mg/dLisdistinctlyunusualafterthefirst24hoursoflife,particularlyininfantswhohavestartedfeeding,andshouldbethoroughlyinvestigated.

• Laboratoryevaluationforinbornerrorsofmetabolismshouldbeundertakeninanychildwithasuggestiveclinicalhistoryregardlessoftheresultsofnewbornscreening.Anormalnewbornscreen,althoughperhapsreassuring,doesnotruleoutthepossibilityofanIEM.

• WithcatastrophicillnessinapreviouslywellchildwithoutsignsofanyparticularIEM,the“shotgun”diagnosticevaluationshouldminimallyincludeplasmaaminoacidanalysis,urineorganicacidanalysisbygaschromatography-massspectrometry,andaso-calledurine metabolic screen.

V

1090 Section V — Renal, Endocrine, and Gastrointestinal Systems

enzyme substrate. In this model, three distinct pathogenic mechanisms are possible proximate causes of the symptoms associated with an IEM. The specific pathogenic mechanism involved in any given IEM dictates the appropriate treatment strategy. First, accumulation of the substrate may lead to toxic effects at very high levels; successful therapy requires effec-tive elimination of the substrate or a method to block its toxic effects. An appropriate example for this mechanism is PKU, in which elevated phenylalanine levels adversely affect neuronal development, and the reduction of tissue phenylalanine con-tent through dietary phenylalanine restriction largely prevents the major clinical features of PKU.5 Second, deficiency of the reaction product, should it be a critically important metabo-lite, may lead to disease. Supplementation with the essen-tial metabolite, if possible, may cure the disease. Biotin is a required cofactor for four distinct carboxylase enzymes. Defi-ciency of free biotin develops in the face of genetic biotinidase deficiency and leads to symptoms of multiple carboxylase defi-ciency. Supplementation with oral biotin completely prevents the clinical manifestations of biotinidase deficiency.6 The final pathogenic mechanism involves the conversion of the enzyme substrate, through normally quiescent alternative pathways, to toxic secondary metabolites. Elimination or decreased pro-duction of these secondary metabolites may improve disease symptoms. For example, tyrosinemia type I (fumarylaceto-acetate hydrolase [FAH] deficiency) is associated with recur-rent attacks of abdominal pain and paresthesias reminiscent of acute intermittent porphyria. The accumulating substrate, fumarylacetoacetic acid, is converted through secondary path-ways to succinylacetone, and succinylacetone in turn inhibits the heme synthetic pathway and causes porphyria-like symp-toms. Pharmacologic inhibition of the tyrosine catabolic path-way proximal to the block at FAH decreases the production of fumarylacetoacetic acid and succinylacetone and alleviates the pathology associated with these toxic compounds.7

Inheritance of Inborn Errors of MetabolismIEMs are heritable disorders. The majority of diseases are inherited in an autosomal-recessive pattern, yielding a 25% recurrence risk in future offspring. The gene defects associated

with several IEMs are located on the X chromosome. These IEMs, such as ornithine transcarbamoylase deficiency and glycerol kinase deficiency, are inherited in an X-linked pat-tern. These IEMs are most severe in males, but carrier females may be symptomatic, although usually with less severe or late-onset disease as a result of skewed X-chromosome inactiva-tion. Mutations for several mitochondrial disorders are found on mitochondrial deoxyribonucleic acid (mtDNA). Because mtDNA is exclusively passed from mothers to their offspring, these IEMs exhibit a maternal inheritance pattern but often with variable penetrance and expressivity. Prenatal diagnosis is possible for many IEMs. In addition to allowing for appro-priate medical therapy, the timely diagnosis of an IEM in a sick infant or child is important for genetic counseling purposes.

Signs and Symptoms of Inborn Errors of MetabolismClinical signs and symptoms frequently associated with IEMs are listed in Box 76-1. The symptom repertoire of the criti-cally ill infant is limited, and the clinical presentation of meta-bolic disorders often is nonspecific. It is for this reason that the diagnosis of an IEM may be easily missed. To maintain maximum diagnostic sensitivity for IEMs, the clinician must maintain a high level of suspicion and be willing to initiate screening metabolic laboratory studies with little provoca-tion. As was true for appendectomies in the era prior to the advent of ultrasound-based diagnosis of appendicitis, a cer-tain number of nondiagnostic metabolic laboratory workups in sick children must be performed to ensure ascertainment of individuals with inherited metabolic disorders. In particular, IEM should be a strong diagnostic consideration in any neo-nate who has become catastrophically ill following a period of normalcy. This presentation may be clinically indistinguish-able from bacterial or viral sepsis, and the nonspecific sup-portive therapy provided to potentially septic infants (fluid and glucose administration) may alleviate the symptoms and

A B

C

BA

Figure 76–1. Inbornerrorofmetabolismparadigm.Normally,inagivenstepofintermediatemetabolismwithintactenzymaticactivity,thesub-strateAisefficientlyconvertedtotheproductB. Inaninbornerrorofmetabolism,deficiencyofenzymeactivitymayleadtoexcessiveaccumu-lationofthesubstrate;criticaldeficiencyoftheproduct;orproductionofanalternative,potentiallytoxicmetaboliteCthroughnormallyquiescentpathways.

BOX 76–1 Signs And Symptoms of Inborn Errors of Metabolism

Acuteillnessafterperiodofnormalbehaviorandfeeding(hourstoweeks)

Recurrentdecompensationwithfasting,intercurrentillness,orspecificfoodingestion

UnusualbodyodorPersistentorrecurrentvomitingFailuretothriveApneaortachypneaJaundiceHepatomegalyorliverdysfunctionLethargyorcomaSepsisUnexplainedhemorrhageorstrokesDevelopmentaldelaywithunknownetiologyDevelopmentalregressionSeizures,especiallyifseizuresareintractableHypotoniaChronicmovementdisorder(ataxia,dystonia,choreoathetosis)Familyhistoryofunexplaineddeathorrecurrentillnessin

siblings

Chapter 76 — Inborn Errors of Metabolism 1091

mask the presence of an IEM. Diagnostic metabolic labora-tory studies are most likely to provide definitive information if performed on clinical samples obtained at initial presentation and before any therapy is initiated. Failure to obtain the neces-sary specimens at this time may miss an important diagnostic window of opportunity. Many children with IEM have been saved initially by intensive but nonspecific treatment but then suffered clinical relapse or even death in the absence of the correct diagnosis. Certainly, the possibility of an IEM should be considered in any child for whom the clinical picture sug-gests sepsis but the laboratory evaluation for sepsis is negative. Unfortunately, bacterial sepsis is often a complicating factor in critically ill children with IEM. For example, Escherichia coli infection (including pyelonephritis, bacteremia, or men-ingitis) is frequently detected at presentation in infants with galactosemia. The astute clinician remains ever vigilant for the signs and symptoms that may suggest an inherited metabolic disorder.

Recurrent episodes of vomiting and dehydration in response to fasting or intercurrent illness are an important clue to IEM in older infants and children. Feeding difficulties and failure to thrive are common chronic complications. Children with unexplained hypotonia, developmental delay, or movement disorder should be evaluated for possible IEM. Inherited neurodegenerative disorders, such as the lysosomal storage diseases, stereotypically cause developmental regression, spe-cifically loss of previously attained developmental milestones. Several IEMs are associated with major physical anomalies (Table 76-1). When present, these anomalies are exceedingly valuable in suggesting a specific diagnosis and directing the diagnostic evaluation. More commonly, the child with IEM is morphologically normal, and the presenting symptoms are nonspecific. The clinician must then rely upon screening labo-ratory tests to evaluate the potential for IEM.

Laboratory Evaluation of Suspected Inborn Errors of MetabolismAbnormal results of routine laboratory studies may provide clues to the presence and type of IEM (Table 76-2). Highly informative but sometimes subtle laboratory abnormalities are often overlooked, especially in a busy ICU or hospital ward. For instance, a clinically relevant newborn screening result may have been sent to the primary care provider or birth hospital but not efficiently communicated to the ICU, in a different hospital, to which the now critically ill infant has been admitted. It is imperative to verify the infant’s screening results with the primary care provider or newborn screening laboratory (Box 76-2). Calculation of the anion gap, another example of a routine and highly informative result, is key to the differential diagnosis of metabolic acidosis. The absence of urine ketones in hypoglycemic children older than 2 weeks strongly suggests impaired ketogenesis as a consequence of either hyperinsulinism or fatty acid oxidation disorder. On the other hand, fatty acid oxidation and ketogenesis are incompletely developed in neonates. The presence of ketones in the urine of infants younger than 2 weeks is very unusual even during fasting or hypoglycemia and suggests the pres-ence of an unusual keto acid, such as those excreted in maple syrup disease or the organic acidemias. Keto acids, organic acids, and sugars such as galactose or fructose increase urine

specific gravity. Urine specific gravity greater than 1.020 in any neonate or in a well-hydrated older child suggests the unexpected presence of an osmotically active substance. Rou-tine urinalysis at many hospitals may not include use of the Clinitest to detect reducing substances. Urine Chemstrips uti-lize a colorimetric glucose oxidase-based method to specifi-cally detect glucose. This test does not react with any other sugar (galactose or fructose). However, some bedside glu-cose monitoring systems do react with galactose or fructose; inappropriately elevated capillary blood “glucose” accompa-nied by a normal venous glucose as measured by chemistry analyzer suggests the presence of a sugar other than glucose in the blood. A comatose infant with a blood urea nitrogen (BUN) level below the limits of detection may have an inher-ited defect in the urea cycle. Blood ammonia measurement is crucial to confirming that suspicion. Failure to check the blood ammonia level has caused missed diagnoses, failure to appropriately treat hyperammonemia, and further morbidity and mortality in comatose infants with urea cycle disorders

Table 76–1 Physical Anomalies Associated with Inborn Errors of Metabolism

Dysmorphic facial features

Peroxisomal disordersGlutaric aciduria type IISmith-Lemli-Opitz syndromeMenkes syndromeLysosomal storage disorders

Structural brain anomalies

Glutaric aciduria type II (cortical cysts)Pyruvate dehydrogenase deficiency

(cortical cysts, agenesis of the cor-pus callosum)

Glycosylation disorders (cerebellar agenesis)

Macrocephaly Glutaric aciduria type I (with subdural effusions)

Canavan diseaseAlexander disease

Cataracts GalactosemiaPeroxisomal disordersMitochondrial disordersLowe syndrome

Lens dislocation HomocystinuriaSulfite oxidase deficiencyMolybdenum cofactor deficiency

Pigmentary retinopathy

Peroxisomal disorders including cherry red spots

Lysosomal storage disordersLong chain 3-hydroxyacyl-CoA

dehydrogenase deficiency

Renal cysts Glutaric aciduria type II,Peroxisomal disordersMitochondrial disorders

Ambiguous genitalia Congenital adrenal hyperplasia Smith-Lemli-Opitz syndrome

Skeletal abnormalities Menkes diseaseHomocystinuriaPeroxisomal disordersLysosomal storage diseases

Hair or skin abnormalities

Menkes diseaseHolocarboxylase synthetase deficiencyBiotinidase deficiencyArgininosuccinic aciduriaPhenylketonuria

1092 Section V — Renal, Endocrine, and Gastrointestinal Systems

or organic acidemias. Finally, bacterial sepsis and menin-gitis are more common causes of severe lethargy and coma in infants than is IEM, but bacterial infection may also be a complicating feature in severely ill infants with IEM. Infants with galactosemia, for example, are particularly prone to

pyelonephritis, bacteremia, sepsis, or meningitis, often with E. coli, as noted above. Antibiotic therapy without diagnosis and specific treatment of the underlying disorder may be use-ful in the short term but does not mitigate long-term IEM-specific effects.

Suspicion of an IEM based upon clinical and routine labo-ratory findings should initiate specialized biochemical test-ing (Table 76–3). In the case of severely ill infants or when the clinical suspicion of IEM is very high, consultation with a biochemical geneticist, even if only by phone, is strongly advised to help direct the laboratory investigation and ini-tial therapy. When the clinical presentation is nonspecific, that is, catastrophic illness in a previously well child with-out signs of any particular IEM, the “shotgun” diagnostic evaluation should minimally include plasma amino acid analysis, urine organic acid analysis by gas chromatography-mass spectrometry, and a so-called urine metabolic screen. The battery of qualitative assays included in a urine meta-bolic screen differs among laboratories, and the ordering clinician should be aware of which tests and disorders are included in the repertoire of the diagnostic laboratory cho-sen. Furthermore, although diagnostic laboratories in the United States must meet Clinical Laboratory Improvement Amendments requirements and often are accredited by the College of American Pathologists, the testing methodolo-gies used, the quality of diagnostic testing for IEM, and more problematically, the availability of laboratory-associated consultants with experience in the diagnosis and treatment of IEM vary widely among laboratories. Although the ability of clinicians to direct clinical specimens toward specific diagnos-tic laboratories may be inhibited by contractual arrangements between the hospital and large referral laboratories, the criti-cally ill patient is best served by diagnostic evaluation carried out in a timely manner by an experienced biochemical genet-ics laboratory, with laboratory staff available by phone for expert consultation on interpretation of test results.

The specific clinical presentation or specific screening laboratory findings may direct the intensivist or biochemi-cal geneticist to order other more specialized metabolic tests (see Table 76-3). These analyses may provide diag-nostic confirmation for specific disorders and supportive evidence alone for others. For several IEMs, confirmation of diagnosis may require enzyme activity analysis in tissue (red blood cells, lymphocytes, cultured skin fibroblasts, liver, or skeletal muscle depending upon the specific dis-order in question) or molecular DNA testing for a spe-cific gene defect. In general, these tertiary tests, which are often difficult, labor-intensive, and expensive, should be ordered following consultation with a biochemical geneti-cist. In some instances, confirmatory diagnostic biochemi-cal or molecular tests are available only through specialized research laboratories.

Table 76–2 Initial Laboratory Evaluation of Suspected Inborn Errors of Metabolism

Laboratory Test Abnormality Disorder

Complete blood count

NeutropeniaMacrocytic anemiaPancytopenia

Organic acidemiasGlycogenosis type 1bCobalamin processing defectsCongenital lactic acidoses

Serum electrolytes

Metabolic acidosis GlycogenosesOrganic acidemiasFAO disordersMSUDCongenital lactic acidoses

Blood gas Metabolic acidosisMetabolic alkalosis

Same as aboveUrea cycle disorders

BUN Low or undetectable BUN(with hyperammonemia)

Urea cycle disorders

Transaminases (ALT, AST)

Liver dysfunction GalactosemiaFructosemiaTyrosinemiaα1-antitrypsin deficiencyFAO disordersOrganic acidemiasCongenital lactic acidosesCongenital disorders of glycosylation

Total and direct bili-rubin

Hyperbilirubinemia GalactosemiaFructosemiaTyrosinemiaα1-antitrypsin defi-ciencyCongenital lactic acidoses

Serum uric acid

Hyperuricemia GlycogenosesPurine disorders

Blood ammonia

Hyperammonemia Urea cycle disordersFAO disordersOrganic acidemias

Blood lactate Lactic acidemia Congenital lactic acidosesGlycogenosesFructosemiaGluconeogenesis disorders

UrinalysisOdorColorpHSpecific gravityKetonesReducing

substances

Unusual odorInappropriately high specific gravity due to metabolitesKetosisPositive reducing substances

PKU, MSUD, organic acidemiasOrganic acidemias, galactosemia, fructosemiaMSUD, organic acidemiasGalactosemia, fructosemia

BUN,Bloodureanitrogen;FAO,fattyacidoxidation;MSUD,maplesyrupurinedisease.

Box 76–2 Screening Metabolic Laboratory Studies for Children with Suspected Inborn Errors of Metabolism

• PlasmaaminoacidanalysisMinimum2mLbloodinaheparintube

• Urineorganicacidanalysis• Urinemetabolicscreen

Minimum10mLurine

Chapter 76 — Inborn Errors of Metabolism 1093

Postmortem Evaluation of a Child with Suspected Inborn Errors of MetabolismSome IEMs, particularly those exacerbated by fasting, may present as sudden infant death. For many IEMs, acute met-abolic compensation may be rapid and lethal despite inten-sive medical intervention. The time after clinical presentation but prior to death may be insufficient to execute an adequate metabolic evaluation. Disease diagnosis is still possible post-mortem and is important for fully understanding the cause of death and determining recurrence risk in the family. A pro-tocol for postmortem evaluation of an infant or child with suspected IEM is given in Box 76-3. Many of the biochemi-cal genetic analyses recommended for acutely ill children are still valid on postmortem specimens. Valuable information may be learned from amino acid, carnitine, and acylcarnitine analyses in blood and from metabolic screening and organic acid analysis in urine. However, collection of blood and urine

Table 76–3 Biochemical Genetic Laboratory Studies

Specimen Test Disorder

Blood Plasma amino acid analysis

Aminoacidopathies

Plasma carnitine Organic acidemiasFAO disorders

Plasma acylcarnitine profile

Organic acidemiasFAO disorders

Serum transferrin electrophoresis

Congenital disorders of glycosylation

Urine Metabolic screenKetonesReducing substances

Ferric chlorideDinitrophenylhydra-

zine2,4-nitrosonaphtholCyanide-nitroprusside

Mucopolysaccharide screen

Qualitative amino acid chromatography

Organic acidemiasGalactosemia,

fructosemiaPKUPKU, MSUD

TyrosinemiaSulfur-containing amino

acidsMucopolysaccharidoses

Multiple amino acid-urias

Organic acid analysis Organic acidemiasFAO disorders

Acylglycine profile Organic acidemiasFAO disorders

Quantitative muco-polysaccharide measurement and electrophoresis

Mucopolysaccharidoses

Qualitative sulfites (Sul-fitest) or quantitative sulfocysteine

Sulfite oxidase defi-ciency

Molybdenum cofactor deficiency

Quantitative succinylacetone

Tyrosinemia type 1

Quantitative purines Purine synthesis disorders

PKU,Phenylketonuria;FAO,fattyacidoxygenation;MSUD,maplesyrupurinedisease.

Box 76–3 Postmortem Biochemical Genetic Evaluation

Tobeperformedonanydeceasedinfant<1yearofageforwhomthecauseofdeathisnotapparentoranychildwithsuspectedIEM.

Analysesaremostreliableifobtainedwithin6hoursafterdeath.1. Contactnewbornscreeninglaboratoryforresultsofneonatal

screening.2. Obtaina3-mmpunchbiopsyofskinorAchillestendonfor

fibroblastculture. A. Prepareskinwithchlorhexidine(Hibiclens)oralcohol.Do

notuseBetadinebecauseitmayinhibitfibroblastgrowth. B. Usesteriletechnique. C. StorebiopsyspecimeninsterileRPMIculturemedia(if

available)atroomtemperature.Maybestoredinsterilenonbacteriostaticsalineforupto24hourspriortocultureifculturemediaisnotreadilyavailable.

D. Sendtocytogeneticsorbiochemicalgeneticslaboratoryforculture,possibleenzymeanalyses,andfrozenstorage.

3. Collectbloodviacardiacpuncture(~5mLpertube). A. Onered-toptubeatroomtemperature.Collectandstore

serumat70°C. i. Comprehensivemetabolicpanel(potassium,lipids,uric

acidmaynotbeaccuratepostmortem) ii. Ifhypoglycemic,insulin,growthhormone,andcortisol

levels B. Onegreen-top(sodiumheparin)tubeatroom

temperature.Collectandstoreplasmaat70°C. i. Plasmaaminoacidanalysis ii. Plasmacarnitinelevels iii. Plasmaacylcarnitineprofile C. Onegreen-top(sodiumheparin)tubeatroom

temperatureforcytogenetic(karyotype)analysis. D. Ifstoragedisordersuspected,onegreen-toptube

(sodiumheparin)at48°C(wetice)forleukocyteisolationanddiagnosticenzymeanalyses.

E. Onelavender-topp(EDTA)tubeatroomtemperatureforCBC.

F. Oneyellow-top(ACD)tubeforDNAisolationandpossiblemutationanalysis.

G. Ifinfantis<1yearold,spotwholebloodontonewbornscreeningfilterpapercardforrepeatscreen.

H. Bloodlactateandammoniamaynotbeaccuratepostmortem.

4. Collecturine(10–20mL)bysuprapubictaporbyswabbingthebladderinteriorwithcottonswab.

A. Urinalysis B. Urinereducingsubstances C. Urinemetabolicscreen D. Urineorganicacidanalysis E. Ifstoragedisordersuspected,quantitativeurine

mucopolysaccharideandoligosaccharideanalysis5. Ifurineisunobtainable,organicacidanalysismaybe

performedonvitreoushumorcollectedbyneedleaspirationfromaneye.Freezevitreoushumorat–70°C.

6. Ifbloodisunobtainable,collectbile(2–3mL)viapunctureofthegallbladderforacylcarnitineprofile.Storeat−20°C.

7. Collectseveralbiopsies(2geach)fromskeletalmuscle,cardiacmuscle,kidney,andliver.

A. Forroutinehistology,biopsiesshouldbesubmittedfreshtothepathologylaboratory.

B. Forenzymeanalyses,biopsiesshouldbewrappedinaluminumfoil,placedinalabeledsmallspecimencontainer,andimmediatelyfrozeninliquidnitrogen.Storeat–70°C.

ModifiedfromSteinerRD,CederbaumSD:Laboratoryevaluationofureacycledisorders.J Pediatr138(Suppl1):S21-29,2001.

1094 Section V — Renal, Endocrine, and Gastrointestinal Systems

may not be possible postmortem, especially if the autopsy is performed many hours after death. In these instances, meta-bolic testing may be obtained on alternative specimens such as vitreous humor or bile. In the event that screening biochemi-cal studies suggest a specific diagnosis, disease confirmation by enzyme analysis in tissue is highly desirable. Many enzymes can be assayed in cultured fibroblasts; viable fibroblasts may be cultured from skin or Achilles tendon samples obtained as late as 24 hours after death. Biopsies of other organs may be neces-sary for analysis of certain other enzymes. Muscle, liver, and kidney specimens may be obtained postmortem for enzymatic analysis, but most enzymatic activities in solid organs deterio-rate rapidly following death. Collection of specimens as soon as possible after death is critical for valid enzyme analyses.

Emergency Treatment of Children with Suspected Inborn Errors of MetabolismLaboratory investigation of suspected IEM may require several days to complete, given that the biochemical genetics labora-tory may be physically remote from the treating hospital and many of the tests involve complex specimen preparation and analysis. A general approach to the emergency treatment of children with suspected IEM, while awaiting diagnostic stud-ies, is given in Table 76-4. For many IEMs associated with acute catastrophic illness, elimination of the offending metabolite is the key to therapy. Immediate cessation of oral feedings, to stop protein or fat intake, will begin to limit toxin production in disorders of amino acid or fatty acid metabolism. Adequate energy intake as carbohydrate must be supplied, usually par-enterally, until a specific diagnosis and definitive treatment plan are available. Dextrose infusion at a high rate suppresses catabolism and reduces the consumption of endogenous pro-tein or fatty acid stores. In extremely recalcitrant cases, insulin infusion drives anabolism and further decreases toxin produc-tion. Acute metabolic decompensation in some IEMs (e.g., maple syrup disease) is associated with mild peripheral insulin resistance. Insulin administration (often as little as 0.01 to 0.05 units/kg/hour given by continuous intravenous [IV] infusion or subcutaneous bolus injection) overcomes this resistance and has an immediate impact upon metabolic control. Some clinicians also use anabolic agents such as growth hormone or testosterone to acutely suppress protein and fat catabolism. In certain types of congenital lactic acidosis, particularly defects of pyruvate metabolism, carbohydrate infusion worsens lac-tic acidosis. Replacement of some carbohydrate with fat as an intralipid infusion may partly reduce blood lactate levels, but infants with this degree of sensitivity to glucose infusion often are difficult to treat and suffer high mortality. Severe hyper-ammonemia that does not respond to dietary protein restric-tion and dextrose infusion must be treated by hemodialysis. Ammonia clearance with exchange transfusion or peritoneal dialysis is insufficient to adequately decrease blood ammonia levels. If the results of specialized biochemical genetic diag-nostic tests are expected within 2 to 3 days, then parenteral dextrose infusion alone should be adequate to maintain nutri-tion until a more definitive treatment plan is available. Beyond 3 days, developing essential amino acid and fatty acid deficien-cies may induce catabolism of endogenous protein and fat. To prevent this occurrence, enteral or parenteral nutrition with minimal amounts of protein (0.5 g/kg body weight/day)

and lipid (20% of total energy intake) should be considered. Empiric administration of cofactors such as the B vitamins is not harmful and may improve metabolite clearance, particu-larly in disorders caused by deficiency of enzymes that require specific cofactors. Carnitine is required for transport of long-chain fatty acids across the mitochondrial membrane and serves a secondary role in the disposal of excess and poten-tially toxic acyl-CoA species. Secondary carnitine deficiency is commonly associated with acute metabolic decompensation in organic acidemias and fatty acid oxidation defects. l-Car-nitine administration prevents secondary carnitine deficiency and may improve clearance of toxic metabolites; it is lifesaving in specific inherited dilated cardiomyopathies.

Classification of Inborn Errors of Metabolism by Clinical PresentationAs mentioned previously, the clinical presentation of IEM in neonates provides a paradigm for the suspicion and evalua-tion of potential IEM at all ages. The classification outlined

Table 76–4 Emergency Treatment of Suspected Inborn Error of Metabolism

Goal Action

Suppress toxic metabo-lite production

Discontinue oral feedings

Correct fluid imbalance and electrolyte abnormalities

Appropriate IV fluid management

Correct hypoglycemia IV dextrose-containing fluid infusion

Correct metabolic acidosis

Intravenous hydration if pH >7.2Add IV bicarbonate if pH <7.2Sodium bicarbonate (1 mEq/mL

solution), 1 mEq/kg IV push at <1 mEq/min

May repeat ×3 until pH >7.2; maximum dose 7 mEq/kg/24 hr

Correct hyperammonemia

Suppress protein catabolismHemodialysis

Treat infection Appropriate infectious disease laboratory evaluation and antibiotic therapy

Suppress protein and lipid catabolism

Infuse D101/2NS at 1.5-2 × maintenance rate

Add insulin infusion if hyperglycemicIf severe, unrelenting acidosis, con-

sider growth hormone or testoster-one therapy to promote anabolism

Empiric cofactor administration

l-carnitine, 25-50 mg/kg/every 6 hours IV if organic acidemia suspected or cardiomyopathy present

B vitamin complex, 100 mg each vitamin every day

Vitamin B12, 1 mg IM × 1 if macrocytic anemia

Maintain nutritional status (if without enteral feeds ×2 days and without diagno-sis of a specific IEM)

Enteral feeds or parenteral hyperali-mentation to include:

Protein, 0.5 gm/kg/day onlyLipid, 20% of total energy intakeCarbohydrate to provide at least the

minimum necessary energy intake

Chapter 76 — Inborn Errors of Metabolism 1095

here is adapted and expanded to include late-onset disorders from a neonatal IEM classification system first described by Jean-Marie Saudubray and colleagues.4,8

IEMs can be classified into one of three groups by patho-genic mechanism. In group 1 IEMs, the production or catabo-lism of complex molecules is disturbed. The lysosomal storage and peroxisomal disorders are included in this group. The symptoms of these disorders include permanent and progres-sive somatic and neurologic abnormalities that develop in utero, are often clinically apparent at birth, and are unaffected by food intake. This group is often distinguished by the pres-ence of somatic abnormalities such as dysmorphic features or hepatosplenomegaly. Typical clinical features, potential neo-natal and late-onset diagnoses, and confirmatory diagnostic tests are listed in Table 76-5.

In group 2 IEMs, the symptoms are caused by defects in the production or utilization of energy. This group includes the congenital lactic acidoses, glycogenoses, gluconeogenic defects, and fatty acid oxidation disorders. In group 3 IEMs, clinical symptoms are caused by progressive intoxication in a previously well infant because of accumulation of toxic metabolites proximal to a metabolic block. Often, neonatal onset IEM in groups 2 and 3 can be distinguished by the time of clinical onset relative to birth. The symptoms of a block in energy production or utilization (group 2) may present within hours after birth, whereas symptoms of intoxication (group 3) develop over the first week of life with increasing food intake and accumulation of toxic metabolites. However, variants of many of these disorders may not become clinically apparent for several months or even years after birth.

Group 2 Inborn Errors of MetabolismSystemic or tissue-specific impaired energy production from food substrates is the unifying feature of disorders classified in group 2. Generalized profound neurologic dysfunction, including severe central hypotonia, coma, and seizures, some-times with peripheral spasticity or abnormal movements, typ-ifies the clinical presentation. Children with these disorders

present with similar clinical phenotypes but are easily sepa-rated into four subgroups (A through D) based upon associ-ated results of routine laboratory studies (Table 76-6). Severe refractory generalized motor seizures, often beginning within the first hours after birth, sometimes even prenatally, are the hallmark of subgroup A. Routine laboratory studies (glucose, blood pH, electrolytes, ammonia) are generally normal unless the infant is near extremis, and secondary metabolic abnor-malities are present. Several inherited disorders are associated with this phenotype; diagnostic differentiation depends upon clinical evaluation by an experienced pediatric neurologist or geneticist and the judicious use of specialized diagnostic labo-ratory tests.

The amino acid glycine is an abundant neurotransmitter within the central nervous system (CNS). Inherited deficiency of the glycine cleavage system, which removes glycine from its receptor in the neuronal synapse, causes severe unrelenting generalized seizures and profound developmental arrest. The only ubiquitous laboratory finding is an elevated cerebrospinal fluid (CSF/plasma glycine ratio).9 Sulfite oxidase deficiency, either as a primary genetic defect or secondary to generalized deficiency of its molybdenum-containing cofactor, is another rare but important cause of neonatal-onset seizures. Recently, infantile-onset pyridoxine-dependent or folinic acid-depen-dent seizure disorders have both been found to be caused by recessively inherited deficiency of α-aminoadipic semialde-hyde (α-AASA) dehydrogenase, an intermediate enzyme in the metabolism of the amino acid lysine.10 Consequently, all neonates with refractory seizures should be screened for these treatable disorders either through measurement of α-AASA in urine or sequencing of the ALDH7A1 (antiquitin) gene. Pro-found neurologic dysfunction with seizures is one of many possible clinical presentations of infants with peroxisomal or respiratory chain disorders. Some subtypes of a still expand-ing list of congenital disorders of glycosylation present with seizures,11 as do disorders of sterol production such as Smith-Lemli-Opitz syndrome,12 but these diagnoses are often asso-ciated with stereotypic dysmorphic features and anomalies. Finally, disorders of neurotransmitter synthesis should be

Table 76–5 Features of Group 1 Inborn Errors of Metabolism

Clinical Features Laboratory Findings Possible Diagnoses Specialized Diagnostic Tests

HepatosplenomegalyCoarse faciesMacroglossiaFetal hydropsMacular cherry red spotsBone changesHypotonia or hypertoniaChronic rhinorrheaFailure to thrive

Liver dysfunctionNo acidosisNormal ammoniaNormal glucose

Neonatal onset:GM1 gangliosidosisIcell diseaseSialidosisGalactosialidosisNiemann-Pick type AMPS VIICDGLater onsetTay-Sachs diseaseKrabbe diseaseOther MPS syndromesNiemann-Pick B or C

Urine mucopolysaccharidesUrine oligosaccharidesSerum transferrin electrophoresisEnzyme analysis in serum, lympho-

cytes or fibroblasts

HepatomegalyDysmorphic faciesSevere hypotoniaLarge anterior fontanelleSeizuresEpiphyseal calcific stippling on

radiograph

Liver dysfunctionNo acidosisNormal ammoniaNormal glucoseAdrenal insufficiency

Peroxisomal disorders:Zellweger syndromeNeonatal adrenoleukodystrophyOthers

Plasma very long chain fatty acid analysis

Functional and genetic analysis of fibroblasts

MPS,Mucopolysaccharidosis;MPS VII,Slysyndrome;CDG,congenitaldisordersofglycosylation.

1096 Section V — Renal, Endocrine, and Gastrointestinal Systems

considered in any infant with idiopathic seizures and neu-rologic dysfunction, especially if a movement disorder, most commonly dystonia, is also present. Abnormal CSF neu-rotransmitter levels (5-methyltetrahydrofolate, 5-hydroxyin-doleacetic acid, homovanillic acid, 3-methyl-DOPA) are the only associated laboratory diagnostic clue in this latter cat-egory of disease.

Severe persistent lactic acidosis is the hallmark of the dis-orders in subgroup B of early-onset energy deficiency dis-eases. The presence of metabolic acidosis with an elevated anion gap suggests the possibility of lactic acidosis (sub-group B) or an organic acidemia (see group 3, intoxication types); these are differentiated by measurement of blood lactate and urine organic acid analysis. Blood lactate is most reliably measured on arterial blood or a free-flowing sample drawn from an indwelling central venous catheter. Artifac-tual elevation of lactate in peripheral venous blood samples

is nearly ubiquitous and should be confirmed by lactate mea-surement in a more appropriate sample. Secondary lactic acidosis resulting from asphyxia, poor tissue perfusion, or tissue necrosis is much more common and may be difficult to differentiate from the congenital lactic acidoses. Occult cardiac disease, intracranial hemorrhage, or bowel necro-sis must be considered and ruled out in infants with severe lactic acidosis. Congenital lactic acidosis generally persists despite adequate life support measures, including fluid resuscitation and ventilatory assistance. In certain enzyme deficiencies, the blood lactate level may further increase with IV dextrose infusion. Simultaneous measurements of blood and CSF lactate and amino acids are useful for differenti-ating primary from secondary lactic acidoses. In congeni-tal lactic acidosis, the CSF lactate level often is higher than the blood lactate level, while the CNS is relatively protected from systemic acidosis in secondary lactic acidemias. The

Table 76–6 Features of Group 2 Inborn Errors of Metabolism

Clinical Features Associated Laboratory Findings Possible Diagnoses Specialized Diagnostic Testing

SUBGROUP A

Profound neurologic dysfunction

Severe hypotoniaSeizures

No acidosisNormal ammoniaNormal glucose

Nonketotic hyperglycinemiaSulfite oxidase or molybdenum

cofactor deficiencyPyridoxine- or folinic acid-

responsive seizuresPeroxisomal disordersRespiratory chain disordersCDGCholesterol synthesis defectsNeurotransmitter synthesis

defects

Plasma and CSF amino acid analysisUrine sulfocysteineUrine oxypurinesUrine α-aminoadipic semialdehydeALDH7A1 gene sequencingPlasma very long chain fatty acid

analysisBlood and CSF lactatePlasma acylcarnitineUrine organic acidsSerum transferrin electrophoresisPlasma sterolsCSF neurotransmitters

SUBGROUP B

Neurologic dysfunctionHypotoniaSeizuresWith severe acidosis

± Liver dysfunction± Dilated cardiomyopathy

Severe acidosisLactic acidosis

± Ketosis± Hypoglycemia± Anemia

Congenital lactic acidosesPyruvate dehydrogenasePyruvate carboxylaseRespiratory chain disorders

Blood and CSF lactatePlasma and CSF amino acid analysisUrine organic acidsDiagnostic muscle biopsy to include

histology, enzyme analysis

SUBGROUP C

Neurologic dysfunctionVomitingDehydrationHypotoniaComa

± Hepatomegaly, liver dysfunction

± Dilated cardiomyopa-thy

Triggered by fasting or intercurrent illness

HypoglycemiaNo ketones in urineAcidosis

± Hyperammonemia± Lactic acidosis

Fatty acid oxidation defects:MCADLCHADVLCADCPT IICATMACDKetogenesis defects:HMG-CoA lyaseMCKATSCOT

Urine organic acidsPlasma carnitinePlasma acylcarnitine profileDiagnostic fasting studyFatty acid oxidation studies in cul-

tured skin fibroblastsGene-specific mutation analysis

SUBGROUP D

Neurologic dysfunction triggered by short fast

Hepatomegaly

Severe fasting hypoglycemiaLactic acidosisNormal ammonia

± Ketosis± Hyperuricemia± Hypophosphatemia

Glycogen storage:Glycogenosis 1Glycogenosis 3Fructose 1,6-bisphosphatase

deficiency

Diagnostic fasting studyEnzyme studies in liverGene-specific mutation analysis

CDG,Congenitaldisordersofglycosylation;MCAD,mediumchainacyl-CoAdehydrogenase;LCHAD,longchain3-hydroxyacyl-CoAdehydrogenase;VLCAD,verylongchainacyl-CoAdehydrogenase;CPT II,carnitinepalmitoyltransferaseII;CAT,carnitineacylcarnitinetranslocase;MACD,multipleacyl-CoAdehydrogenasedeficiency(alsoknownasglutaricaciduriatype2);HMG-CoA lyase,3-hydroxy-3-methylglutaryl-CoAlyase;MCKAT,mediumchainketoacyl-CoAthiolase;SCOT,succinyl-CoAoxaloacetatetransferase.

Chapter 76 — Inborn Errors of Metabolism 1097

blood pyruvate level is elevated in some congenital lactic acidoses such as pyruvate dehydrogenase deficiency. How-ever, accurate measurement of blood pyruvate is difficult and fraught with false-positive elevations. Elevated plasma alanine (which is measured as part of a plasma amino acid analysis) is a more stable and reliable indicator of pyruvic acidosis, as alanine and pyruvate are in equilibrium. Enzy-matic analysis in cultured skin fibroblasts or mitochondria isolated from a fresh muscle biopsy often is necessary to confirm a specific enzyme deficiency.

Children with subgroup C defects present with hypoketotic hypoglycemia, triggered by fasting, metabolic stress, or inter-current illness. In these disorders, utilization of fatty acids as fuel is impaired. The most common of the fatty acid oxida-tion defects is MCADD, which occurs in up to 1:10,000 white births. Although fatty acid oxidation and ketogenesis defects may present in the newborn period, particularly in the setting of delayed maternal milk production for exclusively breastfed infants, the first clinically significant episode may not occur for weeks to months or even years after birth. With extended fast-ing or intercurrent illness where metabolic demand exceeds available energy supply, severe lethargy acutely develops and then progresses to coma. Recurrent vomiting and consequent dehydration may be associated. Sudden infant death after an overnight fast is an all-too-frequent initial presentation in up to one third of infants with fatty acid oxidation defects. Infants who survive may suffer recurrent episodes of fasting or illness-induced coma, leading to progressive CNS damage and permanent disability. Metabolic acidosis (resulting from accu-mulation of partially oxidized fatty acids or secondary lactic acidosis), hyperammonemia, hepatomegaly and liver dysfunc-tion, and hypertrophic cardiomyopathy may occur during acute metabolic decompensation episodes. Liver histology is typified by severe steatosis. Chronically affected children may exhibit recurrent vomiting, failure to thrive, develop-mental delay, and muscular hypotonia. Certain disorders that affect oxidation of long-chain fatty acids are frequently associated with recurrent rhabdomyolysis and myoglobinuria (long-chain 3-hydroxyacyl-CoA dehydrogenase [LCHAD] deficiency, trifunctional protein deficiency, very-long-chain acyl-CoA dehydrogenase [VLCAD] deficiency, or carnitine-palmitoyl transferase [CPT]-II deficiency) or pigmentary retinopathy and slowly progressive vision loss (LCHAD or trifunctional protein deficiency). Mothers of infants with fatty acid oxidation disorders (particularly LCHAD or trifunctional protein deficiency) may present with acute liver dysfunction during pregnancy with an affected fetus. This may manifest as acute fatty liver of pregnancy or maternal HELLP (hemo-lysis, elevated liver enzymes, low platelets) syndrome. In the affected infant, hypoglycemia (serum glucose <40 mg/dL) with inappropriately low or absent ketone production during a symptomatic episode is the key laboratory finding that leads to suspicion of a disorder in this subgroup. Differentiation of the specific defects requires analysis of urine organic acids and plasma acylcarnitine species. Between episodes, when the child is clinically well, the urine organic acid profile may be completely normal. Acylcarnitine profiles are more consis-tently abnormal, but both tests, if normal initially, should be repeated on samples obtained during a symptomatic period to absolutely rule out the possibility of a fatty acid oxidation defect. Carnitine is required for normal fatty acid oxidation; long-chain fatty acids are activated to fatty acyl-CoA, then

esterified to carnitine by CPT-I on the outer mitochondrial membrane. These acylcarnitine esters are then transported into mitochondria to complete the oxidation process. In fatty acid oxidation defects, the metabolic block leads to accumula-tion of the fatty acyl-CoA substrate specific to the deficient enzyme; these species appear in blood as acylcarnitine esters. Analysis of plasma acylcarnitine profiles by tandem mass spectrometry often suggests a specific enzyme deficiency in children with suspected fatty acid oxidation disorders.13 Diag-nostic confirmation may require enzyme analysis in liver tissue or radiometric evaluation of fatty acid oxidation in cultured skin fibroblasts. For certain defects, molecular DNA analysis is clinically available. Two disorders, namely, MCADD14 and LCHAD deficiency,15 are associated with relatively common disease-causing mutations. Treatment of all disorders in this subgroup is based upon the provision of adequate nonfat cal-ories and prevention of fasting. Generous IV glucose infusion is lifesaving and essential during acute episodes of metabolic decompensation. Chronic dietary therapy is tailored to the specific enzyme deficiency involved. Many practitioners pre-scribe carnitine supplementation, initially intravenously dur-ing an acute episode and later orally, but the efficacy of this intervention has not been formally investigated in any con-trolled clinical trial, and its use in disorders of long-chain fatty acid oxidation remains controversial.

Hypoglycemia following a short fast of only 4 to 6 hours is highly suggestive of a glycogen storage disease or a disor-der of gluconeogenesis such as fructose 1,6-bisphosphatase deficiency. These disorders of energy deficiency are classified in subgroup D. These infants appear healthy while fed but quickly become obtunded and hypotonic with fasting hypo-glycemia. Hepatomegaly is a prominent physical feature. Dur-ing acute hypoglycemia, other biochemical derangements, including lactic acidosis, hypophosphatemia, hyperuricemia, and hypertriglyceridemia, are frequently present. Confirma-tion of the diagnosis may require a provocative fast under controlled conditions with continuous monitoring and, sometimes, measurement of glycogen content or enzymatic analysis on a liver biopsy specimen. Molecular DNA analyses are increasingly available for a less invasive approach to diag-nostic confirmation in this class of diseases.

Group 3 Inborn Errors of MetabolismInfants with group 3 IEMs display symptoms and a progressive clinical course suggestive of intoxication. In these infants, who appear completely healthy at birth and for the first few days of life, neurologic dysfunction appears as toxic metabolites accumulate with increasing food intake. Initial symptoms may include vomiting and lethargy that progress, perhaps over only a few hours, to complete coma or shock. This specific clinical presentation in particular suggests the possibility of bacterial or viral sepsis; evaluation for infectious disease is entirely appro-priate. However, the clinician must remain alert to the possibil-ity of an underlying IEM in a previously healthy infant suffering catastrophic illness within the first days of life. Group 3 IEMs can be subdivided into four subgroups (A through D) based upon specific clinical and laboratory findings (Table 76-7).

Maple syrup urine disease (MSUD), or branched-chain keto acid dehydrogenase (BCKD) deficiency, affects the catab-olism of the branched-chain amino acids leucine, isoleucine, and valine and is the only disorder in subgroup A. Affected

1098 Section V — Renal, Endocrine, and Gastrointestinal Systems

infants present with coma; abnormal body movements including seizures; and, in contrast to many IEMs, hypertonia and opisthotonus. A severe burst-suppression pattern is the typical EEG abnormality. A sweet body odor, concentrated particularly in urine and cerumen, is often present. Mothers with previously affected children can often diagnose MSUD in a new infant by the presence of this odor. Routine labora-tory studies may document mild metabolic acidosis and mild ketosis, but normal lactate and ammonia. The branched-chain keto acids that accumulate in MSUD react only slightly with the urine dipstick test for ketones but readily form a flocculent white precipitate with 2,4-dinitrophenylhydrazine (DNPH) in a urine metabolic screen. The presence and specific identi-ties of branched-chain keto acids in urine are confirmed by urine organic acid analysis. Plasma amino acid analysis reveals tremendous elevation of leucine with lesser accumulations of valine and isoleucine. The neurologic symptoms associated with MSUD result entirely from leucine intoxication. Valine and isoleucine, which do not cross the blood-brain barrier as readily as leucine, seem to contribute little to the neurologic phenotype. Reduction of leucine levels in the body is the goal of MSUD treatment.16 Emergency therapy during the initial clinical episode includes dietary protein restriction and IV infusion of dextrose-containing fluids. Hyponatremia is a common associated feature; IV hydration with hypotonic flu-ids easily exacerbates this problem. Additionally, leucine accu-mulates in CSF and brain and is strongly osmotically active. Rapid IV infusion of hypotonic solutions in several instances

has led to acute cerebral edema and death. Dextrose solutions containing a minimum of 0.45% saline (one-half normal saline) are essential, but 10% dextrose with normal saline is preferred if the serum sodium concentration is greater than 135 mEq/L. With administration of IV dextrose, mild hyper-glycemia secondary to insulin resistance may occur; inclusion of regular insulin (often only 0.05 units/kg body weight/hour) by either IV infusion or subcutaneous injection promotes anabolism, suppresses endogenous protein catabolism, and accelerates leucine clearance. The vitamin thiamine is a cofac-tor for BCKD; some individuals with BCKD deficiency (usu-ally with a late rather than neonatal presentation) may respond clinically to thiamine supplementation. Oral thiamine (100 mg/day) is often given empirically to determine whether there is any effect on leucine levels. Once the diagnosis of MSUD is confirmed by plasma amino acid analysis, enteral feedings with a medical food that is free of branched-chain amino acids should be initiated, even if the infant is comatose and naso-gastric feedings are necessary. Parenteral hydration should continue until results of urine ketone and DNPH tests are neg-ative and full enteral feeds are reestablished. On this regimen, plasma valine and isoleucine levels plummet rapidly, but sev-eral days may be required before plasma leucine normalizes. The valine and isoleucine deficiencies that frequently develop on this regimen stimulate endogenous protein catabolism, which impairs reduction of blood leucine, prolongs neuro-logic impairment, and chronically may be associated with symptoms of protein insufficiency (hair loss, skin breakdown,

Table 76–7 Features of Group 3 Inborn Errors of Metabolism

Clinical Features Associated Laboratory Findings Possible Diagnoses Specialized Diagnostic Studies

Subgroup A

Neurologic deteriorationComaAbnormal movementsHypertoniaSweet odor

Mild acidosisNormal lactate

± KetonuriaNormal ammonia

+ urine DNPH test

Maple syrup disease (branched-chain keto acid dehydroge-nase deficiency)

Plasma amino acid analysisUrine organic acid analysis

Subgroup b

Neurologic deteriorationComaDehydration

Severe acidosisSevere ketonuria

± Hyperammonemia± Lactic acidosis± Hypoglycemia± Neutropenia

Negative urine DNPH test

Organic acidemias:Propionic acidemiaMethylmalonic acidemiaIsovaleric acidemiaMCD deficiencyOthers

Urine organic acid analysisPlasma carnitine levelsPlasma acylcarnitine profileUrine acylglycine profileMolecular DNA analysis

Subgroup C

Neurologic deteriorationComaSeizuresHypotonia

± Liver dysfunction

Severe hyperammonemiaNo acidosis

+ AlkalosisLow BUNNormal glucoseNormal lactate

Urea cycle disorders (CPS, OTC, ASS, ASL deficiencies)

Triple H syndrome (hyperorni-thinemia-hyperammonemia-homocitrullinuria)

Plasma amino acid analysisUrine organic acid analysisUrine orotic acidEnzyme studies in liver or fibroblastsMolecular DNA analysis

Subgroup D

Neurologic deteriorationHepatomegalyLiver dysfunctionCholestatic jaundice

Direct hyperbilirubinemia± Hypoglycemia± Acidosis± Lactic acidosis± Ketosis

GalactosemiaFructosemiaTyrosinemia type 1Neonatal hemochromatosisRespiratory chain disorders

Urine reducing substancesPlasma amino acid analysisUrine organic acid analysisUrine succinylacetoneEnzyme studiesMolecular DNA analysis

ASL,Argininosuccinatelyase;ASS,argininosuccinatesynthetase;BUN,bloodureanitrogen;CPS,carbamylphosphatesynthetase;DNPH,dinitrophenylhydrazine;MCD,multiplecarboxylasedeficiency;OTC,ornithinetranscarbamoylase.

Chapter 76 — Inborn Errors of Metabolism 1099

growth failure). Therefore valine and isoleucine supplemen-tation (50 to 100 mg/kg/day) is required. Chronic lifelong therapy involves dietary protein restriction and provision of sufficient energy and amino acids in a leucine-free synthetic medical food. Despite this, infants who suffered prolonged severe leucinosis as neonates often exhibit significant devel-opmental disability. Early diagnosis and appropriate therapy critically enhance neurodevelopmental outcome.

Severe ketoacidosis is the hallmark of IEMs in subgroup B, the organic acidemias. Methylmalonic, propionic, and isovale-ric acidemias are the most common disorders in this subgroup. Infants with organic acidemia present with catastrophic epi-sodes of vomiting, dehydration, and coma. Hypoglycemia, lac-tic acidosis, hyperammonemia, neutropenia, or pancytopenia may be associated findings depending upon the specific IEM. The urine dipstick test for ketones is strongly positive, but in contrast to MSUD, little precipitate forms following the addi-tion of DNPH reagent to the urine. Identification of the spe-cific offending organic acid is accomplished by urine organic acid analysis using gas chromatography-mass spectrometry. Diagnostic confirmation may require enzymatic analysis in tissues such as leukocytes, liver, or cultured skin fibroblasts. Molecular DNA analysis is increasingly available as a diag-nostic modality as well. Cessation of protein intake, vigorous rehydration with dextrose-containing fluid, and management of acidosis with sodium bicarbonate infusion are the mainstays of emergency management. In severely acidotic patients, espe-cially with associated hyperammonemia, hemodialysis may be useful for quickly removing both ammonia and the offend-ing organic acid with the goal of minimizing CNS damage. IV infusion of l-carnitine (100 to 300 mg/kg/day) assists with the removal of the offending organic acid and prevents second-ary carnitine deficiency. Oral l-glycine supplementation has a similar role in certain IEMs, most notably isovaleric acidemia. Chronic therapy is tailored to the specific enzyme deficiency but often involves dietary protein restriction and provision of a synthetic medical food supplying sufficient energy and amino acids. Recurrent episodes of life-threatening ketoacidosis and coma, generally triggered by fasting or intercurrent illness, are often the greatest long-term clinical difficulties.

Advancing dietary protein intake and normal protein catabolism during the first few days of life lead to severe hyperammonemia in infants with urea cycle and allied dis-orders (subgroup C). The clinical presentation is nonspe-cific, with progressive vomiting and neurologic dysfunction. Routine laboratory studies are generally deceptively normal, although the BUN often is below the limits of detection in infants who are unable to synthesize urea. No acidosis is pres-ent unless the infant is apneic or hypoperfused and secondary lactic acidosis has developed. Most severely hyperammone-mic infants demonstrate respiratory alkalosis secondary to Kussmaul-like hyperventilation triggered by cerebral edema. Detection of hyperammonemia is the critical diagnostic key. The blood ammonia level must be measured in any child with acute-onset obtundation without a clear etiology such as trauma. Determination of the specific IEM involved requires analysis of blood amino acids and urine organic acids. Diag-nostic confirmation is now often accomplished through molecular DNA analysis of specific genes involved in the urea cycle, but in rare instances, enzyme analysis in liver or for a few defects in cultured skin fibroblasts may yet be necessary if molecular testing is inconclusive. Provision of nonprotein

energy and suppression of protein catabolism through IV dex-trose infusion are essential, as in the organic acidemias, but emergency hemodialysis to rapidly decrease blood ammonia is absolutely required if any possibility of favorable neurode-velopmental outcome is to be preserved. Ammonia clearance by exchange transfusion or peritoneal dialysis is insufficient to accomplish this goal. Even with prompt hemodialysis, the metabolic derangement in some infants is so severe that little sustained decrease in blood ammonia is observed. Despite aggressive therapy, neonatal-onset urea cycle disorders are frequently lethal. The few infants exposed to hyperammone-mia for a prolonged period who, because of extraordinary life-support efforts, survive are often profoundly neurologically impaired. On the other hand, clinical outcome is favorable in cases where blood ammonia levels rapidly correct on hemo-dialysis. This dichotomy in outcome presents a considerable dilemma to the intensivist faced with these critical treatment decisions. In practice, hemodialysis should be attempted as soon as possible after the discovery of hyperammonemia unless clinical signs of severe permanent CNS damage are already present. Disorder-specific therapy should continue for infants whose blood ammonia levels immediately normalize with hemodialysis. Aggressive life support measures should be limited for those infants with recalcitrant hyperammone-mia. Following dialysis, generous IV hydration and provision of nonprotein calories should continue. The amino acid argi-nine, normally synthesized through the urea cycle, becomes an essential amino acid that must be provided exogenously in urea cycle disorders. l-Arginine hydrochloride is available for IV administration as 10% solution and should be added to the IV fluid bag to give 0.66 g arginine HCl/m2/day (6 mL/kg/day in infants). The ammonia scavenging agents sodium phenyl-acetate and sodium benzoate are available as a combined IV solution (Ammonul, Ucyclyd Pharma). Administration of this solution dramatically improves ammonia clearance and is indicated for the acute management of the proximal urea cycle disorders, but it is associated with severe adverse effects including metabolic acidosis and erosive gastritis if adminis-tered inappropriately. Ammonul should be used only in con-sultation with a provider experienced with its administration and with careful monitoring. Long-term therapy is based upon dietary protein restriction and oral l-arginine or l-citrulline supplementation. Oral administration of sodium benzoate or sodium phenylbutyrate (Buphenyl, Ucyclyd) as ammonia scavengers is often prescribed. Episodes of fasting- or illness-induced hyperammonemic coma frequently recur. Manage-ment of recurrent hyperammonemia in a patient known to have a urea cycle disorder is similar to that outlined earlier but can be tailored to the specific defect. Liver transplantation is a viable treatment option for individuals suffering recurrent hyperammonemia and chronic clinical and developmental difficulties despite adequate nutritional and medical therapy.

Hepatomegaly, liver dysfunction, and cholestatic jaundice in association with neurologic deterioration are the central presenting features of IEM in subgroup D. For all of these disorders, the accumulating toxin is particularly damaging to hepatocellular function. Hypoglycemia, acidosis, and mild ketosis may be present. Bacterial infection, particularly uri-nary tract infection, bacteremia, or meningitis, often caused by E. coli or other gram-negative enteral flora, is a frequent occurrence in infants with galactosemia. The specific diagno-sis is suggested by the clinical scenario and by the results of

1100 Section V — Renal, Endocrine, and Gastrointestinal Systems

screening laboratory studies. Infants with this clinical presen-tation who are breastfed or receiving cow’s milk-based infant formula are at risk for symptoms of galactosemia, given that lactose (milk sugar) is a disaccharide of galactose and glucose. Infants receiving exclusively soy milk-based formula ingest little galactose. The predominant dietary carbohydrates in soy formula are fructose and glucose, so infants fed soy formula who have this clinical presentation are likely to have fructo-semia rather than galactosemia. More typically, infants with fructosemia present clinically after the introduction of fruit to their diet. In either galactosemia or fructosemia, reducing sug-ars are detected in urine following ingestion of the offending sugar by the urine reducing substance test (Clinitest). Plasma tyrosine level is elevated, urine organic acid analysis displays metabolites from the tyrosine pathway, and succinylacetone is detected in the urine of children with tyrosinemia type I (fumarylacetoacetate hydrolase deficiency). Neonatal hemo-chromatosis can be diagnosed only on liver biopsy by staining for iron. Diagnostic confirmation differs for each disorder but may include further metabolite analyses, enzymatic analysis in tissue, or molecular DNA testing. Initial therapy is nonspe-cific: cessation of enteral feeding and IV infusion of dextrose-containing fluid. Once the exact diagnosis is known, a specific therapy plan can be developed. For the carbohydrate disor-ders, the offending sugar must be reduced or eliminated from the diet. Galactosemic infants are fed soy-milk based formu-las only. After weaning, ingestion of dairy products, includ-ing baked goods prepared with dairy products, is strictly avoided. Similarly, fructosemic individuals must strenuously avoid any fructose-containing foods. In prior eras, cirrho-sis and liver failure were the inevitable outcomes in children with tyrosinemia type I unless they received a liver transplant. Effective therapy that prevents liver degeneration in tyro-sinemia has now been developed. The oral drug 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) blocks tyrosine metabolism upstream from FAH and prevents accumulation of the intermediate metabolites that are toxic to hepatocytes.17 This medication was highly successful in pre-venting cirrhosis in two separate clinical trials and has been approved by the United States Food and Drug Administration for general use. The long-term efficacy of NTBC therapy, par-ticularly with regard to the incidence of hepatic adenoma, a common complication of tyrosinemia I, has yet to be proven.18

SummaryMost IEMs with symptom onset in the neonatal period emerge as one of the clinical presentations described. As mentioned previously, many of these IEMs have milder or late-onset forms that present with identical symptoms as described, but months or years after birth and often following the stress of fasting or intercurrent illness. These clinical scenarios provide a framework for the recognition, initial evaluation, and emer-gency treatment of infants with IEM. The remainder of this chapter focuses upon the differential diagnosis of select clini-cal situations encountered in the pediatric intensive care unit.

Metabolic AcidosisThe key to the differential diagnosis of metabolic acidosis is calculating the serum anion gap (Na+ − [Cl− + HCO3

−]). This calculation, normally 10 to 15 mmol/L, represents the

unmeasured negative ions, predominantly albumin, in blood. Normal anion gap acidosis (low serum HCO3 but normal anion gap) is caused by excess bicarbonate loss from either the gut (diarrhea) or kidney (renal tubular acidosis). An elevated or so-called positive anion gap suggests the presence of another unmeasured anion. Incidentally, a low serum anion gap may be seen in extreme hypoalbuminemia, as occurs in nephrotic syndrome (see Chapters 68 and 71).

The differential diagnosis of positive anion gap metabolic acidosis in children is similar to that of adults (e.g., using a favorite mnemonic, such as MUDPILES or KETONES), but with the addition of another class of acidoses, the IEMs. Poi-soning with methanol, ethanol, paraldehyde, isoniazid, or salicylates can be readily ruled out by history or drug screen. Uremia is also easily discovered by laboratory evaluation. The most common etiologies of a positive anion gap acidosis in children are ketosis, lactic acidosis, or a combination of the two. Extreme dehydration can cause both ketosis and lactic acidosis; these abnormalities are readily corrected with vigor-ous parenteral rehydration with dextrose-containing fluids. Persistent lactic acidosis suggests ongoing tissue damage from hypoxemia, hypoperfusion, or, more rarely, an inborn error of mitochondrial metabolism. It should be remembered that several organic acids, such as propionic and methylmalonic acids, react with the urinary ketones dipstick. These pathologic organic acids can be differentiated only from the more typi-cal ketones, 3-hydroxybutyric and acetoacetic acids, by urine organic acid analysis. Severe positive anion gap metabolic aci-dosis that cannot be easily explained by the clinical context, especially if it occurs recurrently or is recalcitrant to parenteral fluid therapy, suggests an inborn error of organic acid metab-olism and should be evaluated with a battery of screening metabolic studies, including plasma amino acid analysis, urine organic acid analysis, and urine qualitative metabolic screen.

HypoglycemiaHypoglycemia can be defined as a blood glucose concentra-tion less than 40 mg/dL.19 Low blood glucose may be present within the first few hours after birth, especially in preterm or low-birth-weight infants, but the capacity for effective gluco-neogenesis and fatty acid oxidation is induced within the first day after birth. Therefore blood glucose less than 40 mg/dL is distinctly unusual after the first 24 hours of life, particu-larly in infants who have started feeding, and should be thor-oughly investigated (Fig. 76-2). A review of hypoglycemia in infants and children along with a useful diagnostic algorithm have been published.20 A detailed medical history and careful physical examination are essential to discovering the cause of hypoglycemia. The timing of hypoglycemia relative to feed-ing is a critical item of historical information. Persistent or postprandial hypoglycemia suggests hyperinsulinism. Hypo-glycemia after a short fast (3 to 6 hours) along with permanent hepatomegaly suggests a glycogen storage disorder. Hypogly-cemia following a longer fast (8 to 12 hours) suggests a defect in gluconeogenesis or a problem with utilization of fatty acids. The presence of ketones in urine (as measured qualitatively by urine dipstick) or in serum (quantitative measurement of 3-hydroxybutyrate or acetoacetate) is an important clue to the etiology of hypoglycemia. Ketosis during hypoglycemia demonstrates that insulin secretion is appropriately sup-pressed and that fatty acid mobilization and oxidation are

Chapter 76 — Inborn Errors of Metabolism 1101

intact. Glycogen storage disorders, gluconeogenic defects, and defects of ketone utilization all are associated with keto-sis. The absence of ketogenesis during hypoglycemia suggests that either insulin levels are inappropriately elevated or fatty acid oxidation is blocked. An important caveat to this rule is that infants younger than approximately 1 week cannot normally produce enough ketones during fasting to trigger a positive urine dipstick test for ketones. The absence of urine ketones in an infant younger than 1 week does not contrib-ute to the differential diagnosis of hypoglycemia. On the other hand, serum ketones increase with fasting even in neonates, and this test provides a valuable result in the investigation of hypoglycemia. In hypoketotic hypoglycemia, measurement of total serum free fatty acids provides further useful diagnos-tic information. During fasting, insulin secretion normally is suppressed, free fatty acids are mobilized into circulation from peripheral adipose tissues, and ketones are produced by oxidation of fatty acids in liver. A low serum total free fatty acid level during hypoketotic hypoglycemia strongly suggests inappropriate insulin secretion, even if insulin levels do not appear to be dramatically elevated. Hypoketotic hypoglycemia in association with elevated serum total free fatty acids sug-gests a defect in fatty acid oxidation.

The importance of treating hypoglycemia cannot be over-emphasized as affected individuals are at high risk for seizures and permanent brain damage.21 After appropriate diagnostic studies are obtained, hypoglycemia should be treated with IV glucose administration at the rate of normal hepatic glucose production, approximately 10 mg glucose/kg body weight

per minute or 150 mL/kg per day of a 10% solution until the underlying disorder is identified and more appropriate thera-pies can be initiated.

Hypoketotic hypoglycemia with low serum total free fatty acids suggests hyperinsulinism. Hyperinsulinism presenting in the newborn period may be caused by intrauterine exposure to elevated glucose levels (maternal diabetes mellitus), famil-ial hyperinsulinemic hypoglycemia (defect in the sulfonylurea receptor), or hyperammonemia/hyperinsulinism syndrome (abnormality in regulation of insulin secretion secondary to mutation in glutamate dehydrogenase). Infants with hyperin-sulinism often are obese and require glucose infusions greater than 10 mg/kg/min to maintain normoglycemia. Glucagon administration (0.03 mg/kg, up to 1 mg total dose) reverses hypoglycemia in hyperinsulinism. Oral diazoxide has not been shown to be efficacious in most neonatal cases; however, it can be effective in normalizing blood glucose levels in patients who have infantile forms of hyperinsulinism, including hyperam-monemia/hyperinsulinism syndrome.22 This usually is given at doses of 5 to 10 mg/kg/day divided into three doses. When initially administered, it is given along with glucose and glu-cagon. The efficacy of diazoxide is defined by demonstrating normal preprandial and postprandial glucose concentrations after overnight fasting and after having stopped IV glucose and any other medications for 5 consecutive days.

Hypoketotic hypoglycemia with elevated serum total free fatty acids, usually occurring following an extended fast (8 to 12 hours) or in association with an intercurrent illness, sug-gests a defect in fatty acid oxidation. The clinical presentation

Timing of hypoglycemia relative to feedingPostprandial?

Short (3–6 hour) fast?Long (>8 hr) fast?

Measure urine and serum ketones when hypoglycemic

Ketosis

Blood lactatePlasma amino acid analysisUrine organic acid analysis

Normal lactateNormal amino acids3-OHbutyrate and

acetoacetate in urine

Elevated lactateNormal amino acids3-OHbutyrate and

acetoacetate in urinepermanent hepatomegaly

No ketones

Defect in ketolysisGrowth hormone

deficiencyCortisol deficiency

Glycogenosis

Elevated insulinLow FFA

Hyperinsulinism

Elevated lactateElevated alanine

lactate and pyruvate in urine

Gluconeogenesisdefect

Serum insulinSerum free fatty acid analysis

Low insulinElevated FFA

Fatty acid oxidation defect

Urine organic acid analysisPlasma acylcarnitine profileFatty acid oxidation studies

in cultured fibroblasts

Figure 76–2. Algorithmforevaluationofhypoglycemiainchildren.FFA,Freefattyacid.

1102 Section V — Renal, Endocrine, and Gastrointestinal Systems

of fatty acid oxidation disorders has been described. Although inherited deficiency of at least nine different enzymatic steps in the mitochondrial β-oxidation pathway has been described, the clinical presentation of infants and children with these dis-eases is stereotypically similar and can be differentiated only by appropriate metabolic testing. In all cases, vigorous hydra-tion with dextrose-containing parenteral fluids is lifesaving. Fasting avoidance is key to long-term treatment and preven-tion of hypoglycemic episodes.

Infants and children with glycogen storage disorders pres-ent with hypoglycemia and permanent hepatomegaly. Hypo-glycemia in these disorders is poorly responsive to glucagon administration. Enzymatic defects affecting glycogen synthe-sis, including glycogen synthase deficiency (GSD-0), as well as defects in glycogen breakdown, such as debranching enzyme deficiency (GSD-III), result in hypoglycemia. Glycogen syn-thase deficiency usually presents as severe morning hypogly-cemia with hyperketonemia and low lactic acid and alanine. Debranching enzyme deficiency results in hypoglycemia sec-ondary to limitation of glucose release from the outer branches of the glycogen molecule. Ketosis is present in GSD-III as the body attempts to generate fuel by increased fatty acid oxida-tion. Furthermore, the gluconeogenesis pathway is intact; thus hypoglycemia is much milder. In glucose 6-phosphatase defi-ciency (GSD-1a) and glucose 6-phosphate translocase defi-ciency (GSD-1b), hypoglycemia usually is apparent 2.5 to 3 hours postprandially as these disorders not only affect glucose release from glycogen but also disrupt gluconeogenesis. Indi-viduals with these disorders have lactic acidosis, ketosis, and hyperuricemia in addition to hepatomegaly.

Hypoglycemia following a longer fast (8 to 12 hours) sug-gests a defect in gluconeogenesis, ketogenesis, ketolysis, or fatty acid oxidation. Fructose 1,6-bisphosphatase, a disorder of gluconeogenesis, presents as fasting hypoglycemia but also with metabolic decompensation following fructose ingestion. Ketonemia and lactic acidemia are major features, in addition to the hypoglycemia. The ketone synthesis defects that present with fasting hypoketotic hypoglycemia include 3-hydroxy-3-methylglutaryl-CoA synthase deficiency and 3-hydroxy-3-methylglutaryl CoA lyase deficiency. These patients have hypoglycemia in combination with normal blood lactate but no ketonuria. Infants with 3-hydroxy-3-methylglutaryl CoA lyase deficiency also are hyperammonemic. Defects in suc-cinyl-CoA oxoacid transferase and methylacetoacetyl-CoA thiolase represent ketolysis defects. Although the consistent biochemical abnormality is severe ketoacidosis, hypoglycemia also can be seen. Blood lactic acid and ammonia concentra-tions usually are normal.

Cardiomyopathy and Inborn Errors of MetabolismCardiomyopathies, as a rule, are rare. Studies undertaken by the Pediatric Cardiomyopathy Registry have determined that the overall annual incidence is 11.8 per 1 million patient-years and that the incidence was higher in children younger than 1 year than in those between 1 and 18 years old.23 In this regional study, 40% of cases were hypertrophic cardiomy-opathies, 49% of cases were dilated cardiomyopathies, 3% of cases were restrictive or other types, and 8% were unspeci-fied. Further study revealed that of cases of hypertrophic car-diomyopathy, 16% had an identifiable IEM as the underlying

cause. These causes included disorders of glycogen metabo-lism (5%), mucopolysaccharide metabolism (4%), oxidative phosphorylation (5%), and fatty acid metabolism (2%). In the cases of dilated cardiomyopathy, 5% were found to be of a metabolic etiology with disorders of glycogen metabolism (1%), mucopolysaccharide metabolism (2%), and oxidative phosphorylation (2%) as the recognizable underlying cause. Thus it is important to consider IEM in the differential diag-nosis of any child with dilated or hypertrophic cardiomyopa-thy. Because the prevalence of underlying metabolic disorders is so high, some authors have recommended that all children with cardiomyopathy undergo metabolic screening, includ-ing blood lactate, plasma amino acid analysis, urine organic acid analysis, urine metabolic screening (particularly for the detection of excessive urinary mucopolysaccharides), plasma carnitine levels, and plasma acylcarnitine profile (Box 76-4).24 Additionally, serum creatine kinase (CK) should be measured to exclude muscular dystrophy.

Autosomal dominant hypertrophic cardiomyopathy has an incidence of 1:500 but demonstrates extremely variable pen-etrance. Mutations in genes encoding structural sarcomeric proteins are frequent causes of dominant hypertrophic car-diomyopathy. More than 140 mutations in 15 different genes have been identified.25

Cardiomyopathy may be a complicating feature of several IEMs (Table 76-8), but with a few exceptions, other associ-ated symptoms or physical examination findings at the time of presentation point toward the appropriate diagnosis. Very broadly, the pathogenesis of cardiomyopathy in IEMs is either myocardial energy deficiency, as occurs in the dilated cardio-myopathy associated with several organic acidemias, or exces-sive storage of complex molecules in the heart, as occurs in the hypertrophic cardiomyopathy of mucopolysaccharidoses such as Hurler syndrome. Cardiomyopathy occurs as the sole initial clinical manifestation in a relatively restricted list of metabolic diseases, including autosomal recessively inherited deficiency of the cellular carnitine transporter, fatty acid oxi-dation disorders, glycogenosis types II and IX, and disorders of oxidative phosphorylation. The carnitine transporter defect is caused by deficiency of the sodium-dependent transporter OCTN2, which is responsible for transporting carnitine from the circulation into tissues including cardiac and skeletal mus-cle.26 Dilated cardiomyopathy with symptoms of heart failure generally presents within the first years of life and is associated with severely low plasma total carnitine levels. Cardiac func-tion improves dramatically after carnitine supplementation, and cardiomyopathy rarely recurs if carnitine is continued.

Hypertrophic cardiomyopathy resulting from myocar-dial steatosis may be an isolated presenting feature in several disorders of fatty acid oxidation, particularly those affecting

Box 76–4 Screening Laboratory Studies for Evaluation of Cardiomyopathy

BloodlactateSerumcreatinekinasePlasmaaminoacidanalysisUrineorganicacidanalysisUrinemetabolicscreeningPlasmacarnitinelevelsPlasmaacylcarnitineprofile

Chapter 76 — Inborn Errors of Metabolism 1103

long-chain fatty acid metabolism such as VLCAD or mito-chondrial trifunctional protein deficiencies. Saudubray et al.27 examined a series of 109 patients with fatty acid oxida-tion defects and found that cardiac involvement, including hypertrophic cardiomyopathy or arrhythmia, was apparent at presentation in 51% of cases. Fatty acid oxidation disorders are most reliably detected by analysis of plasma acylcarnitine profiles by tandem mass spectrometry. Long-chain fatty acids are activated to CoA derivatives and then esterified to carni-tine prior to transport into mitochondria for β-oxidation. In fatty acid oxidation disorders, especially during acute meta-bolic decompensation, acylcarnitine species accumulate in plasma and provide a diagnostic profile that is specific to a given enzyme deficiency. Confirmation of the diagnosis may require enzymatic analysis in cultured fibroblasts or mutation analysis. Once the diagnosis of a long-chain fatty acid oxida-tion disorder has been established, restriction of dietary long-chain fat intake and provision of medium-chain triglyceride oil as an alternative fuel source for the myocardium often reverses cardiomyopathy. Cardiac support measures, includ-ing extracorporeal membrane oxygenation, may be necessary for as long as 1 to 2 weeks after presentation before heart func-tion improves.

Glycogen storage disease type II (acid α-glucosidase defi-ciency; Pompe disease) is a disorder of lysosomal glycogen accumulation that frequently presents as hypertrophic car-diomyopathy, yielding the classic “boot-shaped” radiographic appearance of the cardiac silhouette. Skeletal myopathy manifesting as severe hypotonia may complicate the presen-tation. Confirmation of the diagnosis requires measurement

of enzyme activity in skeletal or cardiac muscle or cultured fibroblasts. In the past, treatment has only been supportive, but enzyme replacement therapy is now available. IV infusion of recombinant acid a-glucosidase every other week has led to improved cardiac function, neuromuscular development, and survival in infants with Pompe disease.28 However, antibody formation against the drug in some infants, with subsequently decreased treatment effectiveness, remains a clinical problem.

Myocardial function is highly dependent upon mitochon-drial oxidative phosphorylation; up to 30% of the total myo-cardial volume is composed of mitochondria.29 Dilated or hypertrophic cardiomyopathy is a frequent presenting fea-ture in infants with severe defects of mitochondrial oxidative phosphorylation. Skeletal muscle myopathy, liver dysfunc-tion, renal tubulopathy, bone marrow failure, or CNS abnor-malities may occur. Chronic lactic acidosis, if present, is an important indicator of mitochondrial dysfunction. Screening metabolic laboratory studies demonstrate nonspecific abnor-malities associated with chronic lactic acidosis. Definitive diagnosis requires histologic evaluation of skeletal muscle and measurement of respiratory chain enzyme activities. Isolated deficiency of cytochrome c oxidase (COX or complex IV) and reduced nicotinamide adenine dinucleotide (NADH)-ubiqui-none oxidoreductase (complex I) of the mitochondrial respi-ratory chain are the most common oxidative phosphorylation defects presenting with cardiomyopathy. Although some pro-tein subunits of complexes I and IV are encoded by mtDNA, most infant-onset isolated complex deficiencies probably are the result of autosomal-recessively inherited deficiency of nuclear-encoded respiratory chain subunits or of chaperone proteins that ensure proper assembly of functional complexes. For instance, hypertrophic cardiomyopathy caused by func-tional COX deficiency has been associated with mutations in nuclear COX subunit genes30,31 or nuclear genes for COX associated-proteins SCO1 and SCO2.32

Cardiomyopathy may be seen in several other IEMs, but in these disorders, other physical or biochemical features are generally apparent at initial clinical presentation. For instance, dilated cardiomyopathy may complicate propionic acide-mia during acute metabolic decompensation, but features of severe metabolic acidosis, vomiting, dehydration, coma, and possibly hyperammonemia are part of the initial clinical presentation.

Metabolic Myopathies and RhabdomyolysisRhabdomyolysis is a clinical syndrome resulting from skeletal muscle injury and release of potentially toxic substances into the circulatory system. Acute onset of severe muscle pain asso-ciated with increased serum CK levels is the hallmark of the disorder. In extreme cases, massive myoglobinuria may cause acute renal insufficiency. Although trauma and direct muscle injury are by far the most common causes of rhabdomyoly-sis, inborn errors of muscle metabolism should be considered in the differential diagnosis of rhabdomyolysis occurring at any age. In the absence of a history of trauma, the differen-tial diagnosis of acute rhabdomyolysis should include drug or toxin exposure, muscle hypoxia (often associated with sei-zures), temperature alterations, inflammatory diseases, and IEMs. Because muscle contraction depends upon adenosine triphosphate (ATP) generated by the mitochondrial electron

Table 76–8 Cardiomyopathy and Inborn Errors of Metabolism

Cardiomyopathy as the sole or key presenting feature

Carnitine transport defect

Fatty acid oxidation defects including:VLCAD deficiencyMitochondrial trifunctional protein

deficiencyCarnitine palmitoyltransferase

deficiency

Glycogen storage disease type II (Pompe disease)

Glycogen storage disease type IX (phosphorylase b kinase deficiency)

Disorders of oxidative phosphoryla-tion (mitochondrial myopathy)

Cardiomyopathy as a secondary feature

Organic acidemias, including:Propionic acidemiaMethylmalonic acidemia3-methylglutaconic aciduriaD-2-hydroxyglutaric aciduriaBiotinidase deficiency

Glycogen storage disease type III

Glycogen storage disease type IV

Mucopolysaccharidoses

Congenital disorders of glycosylation

Congenital myotonic dystrophy

Congenital muscular dystrophies

VLCAD,Verylongchainacyl-CoAdehydrogenase.

1104 Section V — Renal, Endocrine, and Gastrointestinal Systems

transport chain, it follows that any process that impairs mus-cle ATP synthesis or which results in energy expenditure that surpasses ATP production could lead to rhabdomyolysis. The clinical history should lead toward the appropriate diagnosis. A family history that includes rhabdomyolysis or a history in which more than one episode of exercise-induced rhabdomy-olysis has been observed should induce suspicion of a meta-bolic disorder. Along with muscular dystrophy and endocrine etiologies (hypothyroidism, hyperthyroidism, diabetic keto-acidosis, pheochromocytoma), glycolytic defects, fatty acid oxidation disorders, purine biosynthetic disorders, and dis-orders of mitochondrial oxidative phosphorylation should be considered if historical elements do not direct toward the more common etiologies. As described previously, the fatty acid oxi-dation disorders can be detected by urine organic acid analysis and plasma acylcarnitine profile. Chronic lactic acidosis may be a clue to a disorder of oxidative phosphorylation. Measure-ment of blood lactate level before and after an exercise tread-mill protocol may help detect a respiratory chain defect if the postexercise lactate level is severely elevated. Definitive diag-nosis of a mitochondrial disorder requires histologic and enzy-matic analysis of a fresh muscle biopsy. The glycolytic defects of phosphofructokinase and phosphoglycerate mutase deficien-cies along with myophosphorylase deficiency (glycogen stor-age disease type V or McArdle disease) cause severe recurrent rhabdomyolysis; their detection requires enzymatic analysis of muscle tissue. Likewise, myoadenylate deaminase deficiency, a defect in purine catabolism, and CPT-II deficiency are also diagnosed by measurement of the enzyme activities in muscle.

Neonatal Screening for Inborn Errors of MetabolismNewborn screening for IEMs was first introduced in the 1960s, with screening for phenylketonuria. Technological advances, most significantly the introduction of tandem mass spectrome-try to mass screening, have greatly increased the number of dis-orders that can be identified by analysis of a dried blood spot on a filter paper card.33 An expert review conducted by the Ameri-can College of Medical Genetics led to the recommendation

that 29 core conditions, including several aminoacidopathies, fatty acid oxidation defects, and organic acidurias detectable by tandem mass spectrometry, should be included in the panel of disorders screened.34 As of 2009, all states in the United States and most of Europe have now adopted this recommendation. The cost versus benefits of expanded screening, whether to include specific very rare or poorly treatable disorders in the screening panel, and the availability of adequate follow-up resources continue to be debated, but a general consensus has emerged that expanded newborn screening is an effective tool for identifying IEMs early in life, allowing for the initiation of therapy, often before the infant becomes symptomatic, and for preventing morbidity and mortality associated with IEMs.35 It must be remembered, however, that newborn screening is just that—a screen, and both false-positive and false-negative results are possible. Thus the astute clinician must remain cognizant of the fact that in an ill infant, a normal newborn screen is reassur-ing but should not be taken as absolute proof-positive that an IEM identifiable on newborn screen is not present. Appropri-ate screening laboratory evaluation and emergency treatment should be instituted if clinical signs and symptoms of an IEM are present in a sick child.

ConclusionInborn errors of metabolism are individually rare but collec-tively will make not-infrequent appearances in a busy pediat-ric ICU. The signs and symptoms of IEMs may be nonspecific and often overlap extensively with more common disorders. When clinical suspicion of an IEM arises, screening biochemical genetic laboratory studies must be ordered. Further confirma-tory testing often is necessary if screening laboratory tests point toward a specific disease. Confirmatory testing and disease-spe-cific therapy should be instituted following consultation with a biochemical genetics specialist. If detected and treated early, the clinical outcome for many IEMs can be favorable.

References are available online at http://www.expertconsult. com.

TEXTBOOK OF CRITICAL CARE

JEAN-LOUIS VINCENT, MD, PhDProfessor of Intensive Care Medicine

Université Libre de BruxellesHead, Department of Intensive Care

Erasme University HospitalBrussels, Belgium

EDWARD ABRAHAM, MDProfessor and Chair

Spencer Chair in Medical Science LeadershipDepartment of Medicine

University of Alabama at BirminghamSchool of Medicine

Birmingham, Alabama

FREDERICK A. MOORE, MD, FACS, FCCMProfessor of Surgery

Head, Acute Care SurgeryCollege of MedicineUniversity of FloridaGainesville, Florida

PATRICK M. KOCHANEK, MD, FCCMProfessor and Vice Chairman

Department of Critical Care MedicineProfessor of Anesthesiology, Pediatrics, and Clinical and Translational Science

Director, Safar Center for Resuscitation ResearchUniversity of Pittsburgh School of Medicine

Pittsburgh, Pennsylvania

MITCHELL P. FINK, MDProfessor of Surgery and Anesthesiology

Vice Chair for Critical Care, Department of SurgeryDavid Geffen School of Medicine

University of California–Los AngelesLos Angeles, California

S i x t h E d i t i o n

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168168 Endocrine and Metabolic Crises in the Pediatric Intensive Care UnitANDREW C. ARGENT

Increasing numbers of endocrine and metabolic conditions are being recognized, and the number of children in treatment programs for them is increasing. Although improved screening programs and therapy may decrease the number of children requiring critical care for these conditions, it is likely they will be recognized in increasing numbers of critically ill children for the foreseeable future. There is also increasing awareness of the significance of metabolic changes such has hypo- and hyperglycemia in the pediatric intensive care unit (PICU).1 General principles of PICU management apply to patients with endocrine and metabolic crises (Table 168-1).2,3 Crises may cause damage with long-term sequelae for the child and family; however, they also present unique diagnostic opportunities. The intensivist has a particular responsibility to:

• Be aware of endocrine and metabolic problems.• Consider them in the differential diagnosis of particular clinical

syndromes.• Perform appropriate clinical and biochemical investigations.• Seek advice from specialists in the clinical and laboratory diagno-

sis and management of the conditions.• Consider the implications of metabolic and endocrine problems

for the family of the affected child.4

• Support the development of structures for the comprehensive management of metabolic problems from infancy through adulthood.5

Abnormalities of glucose control are relatively common in the PICU, but with the possible exception of diabetes mellitus, endocrine and metabolic crises are uncommon, and most intensivists do not see suf-ficient case numbers to become expert at managing these disorders. It is crucial to manage children with suspected or proven endocrine or metabolic crises in conjunction with specialist teams. The laboratory investigation of inborn errors of metabolism may be complex, and there are relatively few laboratories worldwide that have the capacity to fully elucidate most of the inborn errors of metabolism. Close cooperation with specialist laboratory centers is essential for accurate diagnosis and management.

A particular problem of endocrine and metabolic crises is that labo-ratory investigation of specific conditions may take time while patients require urgent therapeutic intervention. Because it may not always be possible to follow algorithms of investigation, a reasonable approach is to collect all relevant specimens immediately,6 store them appropri-ately, and liaise with laboratory services to use the specimens in a logical and cost-effective manner to confirm the diagnosis.

Endocrine CrisesEndocrine crises present in a limited number of ways that include abnormalities of glucose control, fluid and electrolyte balance, and blood pressure control. Management of these crises consists of identi-fying the problem, investigating the cause, and correcting the abnor-mality directly or managing the underlying problem. This section provides a clinical overview of pediatric endocrine crises; detailed pathophysiology is discussed in other chapters.

ABNORMALITIES OF GLUCOSE CONTROL

Abnormalities of glucose control, including diabetic ketoacidosis, are the most common endocrine crises encountered in the PICU. Hypo-glycemia and hyperglycemia are associated with increased mortality1,7 in sick children and may be part of a wide variety of disease processes. Measurement of blood glucose is part of the initial biochemical evalu-ation of any sick child, particularly if a depressed level of consciousness or shock is present. When an abnormal glucose level has been identi-fied, it must be addressed and levels be remeasured at appropriate intervals until the problem has been resolved. The situation is further complicated by technical issues in the measurement of blood glucose,8,9 with differences between blood and plasma glucose level (glucose con-centration in plasma is approximately 11% higher than whole blood because of the higher water content in plasma, but this may be affected by anemia or polycythemia); differences between arterial, venous, and capillary glucose levels (which may also vary depending on clinical context),8 and potentially significant differences between measurement techniques.9 A particular concern is that in general, inaccuracies increase at lower glucose levels.9 Generally, central laboratory devices are taken as the standard, although there is increasing utilization (and convenience) of point-of-care devices.

Hypoglycemia

Hypoglycemia may be associated with devastating damage to the brain and requires immediate attention. In general, a diagnosis of hypogly-cemia depends on the presence of symptoms and a low blood glucose level, and resolution of symptoms on correction of the low glucose level. Unfortunately, symptoms of hypoglycemia are relatively nonspe-cific, ranging from lethargy, poor feeding, hypotonia, and “jitteriness” to convulsions, apneic episodes, cardiovascular collapse, and sudden infant death syndrome (SIDS). Hypoglycemia may be hidden in the complex of critical illness, particularly if patients are deeply sedated and paralyzed. In addition, some diabetic patients have reduced aware-ness of hypoglycemia.10 Thus, regular monitoring of blood glucose is an important component of the management of any critically ill child.

Hypoglycemia immediately following birth may be common, but there are considerable controversies in the definition of hypoglycemia in this period.11-13 Table 168-2 lists an approach to hypoglycemia immediately following birth.

Symptomatic hypoglycemia occurs more frequently during the neo-natal period than in any other period of childhood. Infants at particu-lar risk include infants with poor hepatic glycogen stores (e.g., preterm or small-for-gestational-age infants); poor glucose intake (e.g., preterm or ill infants); and hyperinsulinism, either primary or secondary to high intrauterine glucose levels (e.g., infants of diabetic mothers).14 Hypoglycemia also may be a feature of perinatal illness including asphyxia, polycythemia, hypothermia, septicemia, and respiratory dis-tress syndrome. Much less common causes include growth hormone15 or adrenal insufficiency,16 inborn errors of metabolism, and glucagon insufficiency. Drugs administered to the mother during pregnancy, including oral hypoglycemic agents, also must be considered.

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1238 PART 10 Endocrine

The amount of glucose required to achieve normoglycemia and the duration of fast that can be endured without the development of hypoglycemia may assist in identifying a likely cause. Transient hypo-glycemia that can be reversed with normal infusion rates of glucose (4-6 mg/kg/min) and does not recur is unlikely to be associated with an endocrine problem. Hyperinsulinemia is associated with rapid development of hypoglycemia and high glucose requirements (>6-8 mg/kg/min to >15-20 mg/kg/min). Hypoglycemia associated with adrenal insufficiency, growth hormone deficiency, and hypothy-roidism tends to occur after several hours of fasting, is associated with ketosis, and can be reversed with normal infusion rates of glucose. Fatty acid oxidation defects are associated with hypoglycemia after a fast of some hours.

As soon as hypoglycemia is noted, specimens should be collected immediately for appropriate tests (Table 168-3). Treatment of hypo-glycemia with intravenous (IV) glucose should be initiated promptly. An initial bolus dose of 0.5 g/kg of glucose (may need 0.5-2 g/kg in neonates) should be given as a 10% or 25% (in older children) dextrose solution, followed by an ongoing infusion of glucose at a rate of 4 to 8 mg/kg/min. The concentration of the ongoing infusion depends on the fluid requirements of the child and the availability of central venous access (for higher concentrations). Glucagon may be given at a dose of 0.1 to 0.3 mg/kg (IV or intramuscularly [IM]) but is unlikely to be effective in patients with low glycogen stores, glycogen storage disorders, or hepatic dysfunction. Hydrocortisone at a dose of 5 mg/kg every 12 hours may be useful in some patients. Diazoxide and IV octreotide decrease insulin release and may be useful in the manage-ment of hyperinsulinemia.

If non–glucose-reducing substances are present in the urine, galac-tosemia, hereditary fructose intolerance, or tyrosinemia should be considered. In the absence of reducing substances, low urinary ketones with hypoglycemia suggest hyperinsulinism or defects of fatty acid oxidation. The latter can be distinguished from hyperinsulinemia by

In childhood, hypoglycemia may result from inadequate glucose intake (prolonged starvation, malabsorption); defects in glycogeno-lysis (glycogen storage disorders) or gluconeogenesis (fructose-1,6-diphosphatase deficiency, ethanol intoxication, Jamaican vomiting sickness, etc.), fatty acid oxidation disorders and defects in ketogenesis, deficiency of gluconeogenic hormones (e.g., adrenalin, corticosteroids, glucagons, growth hormone, thyroid hormone), excessive insulin secretion (hyperinsulinism), and a variety of specific disorders includ-ing abnormalities of amino acid metabolism.17

Principles of Management of Metabolic and Endocrine Crises

Principle Specifics of Conditions

Airway management Many patients have depressed level of consciousness, and airway management is essential to prevent complications.

Breathing support Acidotic patients may make huge respiratory effort; ventilatory support may help decrease the metabolic demands on these patients. Although administration of sodium bicarbonate may help to settle some of the acidosis-related symptoms such as hyperventilation, bicarbonate may aggravate some problems seen in conjunction with urea cycle defects. Give bicarbonate only if the plasma bicarbonate <10 mmol/L, and then only half correct deficits.

Circulatory support Ensure adequate circulating volume; this may be a particular issue if there has been excessive fluid loss from vomiting or diarrhea.

Disability Control seizures using anticonvulsant agents. Administer pyridoxine if possibility of pyridoxine dependency.

Dialysis to remove toxins where necessary

Hemodialysis is the most efficient means of removing toxins such as ammonia and leucine. Hemofiltration is less efficient but may be more applicable in critically ill children. Peritoneal dialysis is slower but has the advantage of ease of initiation.1 In some conditions, it may be possible to remove toxins by stimulating alternative pathways of metabolism.

Ensure that glucose is maintained in the normal range

A normal glucose level should be maintained at all times. Excessive administration of glucose in the mitochondrial energy chain problem may exacerbate lactic acidosis. Also, attempt to provide an adequate energy supply (may use medium-chain fatty acids where appropriate). Minimize energy demands on patient.

Fluids In general, provide 1.5× normal fluid maintenance requirements to accelerate excretion of water-soluble toxins. In the context of encephalopathy (MSUD or urea cycle defects), be careful to avoid overhydration, which may contribute to development of cerebral edema.

Feeds If there is accumulation of a product, this needs to be eliminated from the diet (e.g., fructose, galactose). Start with protein-free diet, but do not continue beyond 2 days, because the catabolic state also creates problems. If diagnosis not identified, need gradual reintroduction of feeds and nutrition. If there is deficiency of any nutrient (e.g., carnitine, which may have a primary or a secondary deficiency), supplement that nutrient. Ensure there is an adequate energy source along a metabolic route that is functional. Provide specific vitamin therapy where indicated.

Family support and information

The diagnosis of an inborn error of metabolism has major implications for families, and considerable support is required.2

Treat infection Infections are an important component of pediatric ICU presentation of inborn errors of metabolism. Some conditions such as galactosemia are related to specific infections such as Escherichia coli. Other conditions are related to pyogenic infections because of neutropenia. Children who are in a poor nutritional or metabolic state are more susceptible to infection. Intercurrent infections may be the precipitating factor for metabolic decompensation.

Investigations A wide variety of investigations are relevant to inborn errors of metabolism. Biochemical testing on a range of body fluids and on tissues is fundamental to accurate diagnosis of the problem. Biochemical tests may range from simple screening tests to more complex tests on tissue culture. Imaging techniques such as CT, MRI, magnetic resonance spectroscopy, and echocardiography may be relevant. Functional tests such as EEG, ECG, and EMG may be useful in diagnosis. Increasingly, genetic diagnosis is available if children have recognized genetic mutations.

Monitor response to therapy

Clinical monitoring is essential. Biochemical monitoring of the appropriate metabolites is essential to ensure that metabolic control is established.

CT, computed tomography; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; ICU, intensive care unit; MRI, magnetic resonance imaging.

TABLE 168-1

From Cornblath M, Hawdon JM, Williams AF et al. Controversies regarding definition of neonatal hypoglycemia: suggested operational thresholds. Pediatrics. 2000;105:1141-5.

At-Risk Infants for Whom Routine Monitoring of Blood Glucose Is Recommended

Associated with Changes in Maternal MetabolismIntrapartum administration of glucoseDrug treatment:

Terbutaline, ritodrine, propranololOral hypoglycemic agents

Diabetes in pregnancy/infant of diabetic mother

Associated with Neonatal ProblemsIdiopathic condition or failure to adaptPerinatal hypoxia-ischemiaInfectionHypothermiaHyperviscosityErythroblastosis fetalis, fetal hydropsOther:

Iatrogenic causesCongenital cardiac malformations

Intrauterine Growth RestrictionHyperinsulinismEndocrine DisordersInborn Errors of Metabolism

TABLE 168-2

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1239

hypoglycemia. Hepatic failure from infection, toxin ingestion, or drug reactions may be associated with severe hypoglycemia, and Reye syn-drome classically presents with hypoglycemia. Toxins such as salicylates and ethanol also may cause hypoglycemia. Hypoglycemia has been linked with increased mortality from malaria,23-26 gastroenteritis,27 and acute bacterial meningitis28 among other conditions. Hypoglycemia also has been described as a complication of therapy for leukemia with mercaptopurine and methotrexate.29,30 Although severe illness or sepsis may be an adequate explanation for hypoglycemia, a diagnosis of sepsis should not exclude the possibility of an endocrine or metabolic crisis.

Hyperinsulinemic  Hypoglycemia.  Hyperinsulinism is the most common cause of persistent or recurrent hypoglycemia in infancy.31-33 Hyperinsulinism may be secondary to risk factors in the perinatal period (associated with high maternal glucose levels,34 rhesus incom-patibility, intrauterine growth retardation,35 and perinatal asphyxia36) but may also be congenital37,38 or associated with Beckwith-Weidemann syndrome and some other developmental syndromes.33

Although most patients with hyperinsulinemic hypoglycemia present in the neonatal period, first presentation may be during infancy and occasionally during childhood,39 when the condition may be more likely to respond to medical therapy. Neonates with hypoglycemia may have the macrosomia typical of infants of diabetic mothers, but hyper-insulinemic hypoglycemia may occur in apparently normal infants of normal or low birth weight. Hypertrophic cardiomyopathy and hepatomegaly may be seen31 in affected infants. The characteristic fea-tures of hyperinsulinism include hypoglycemia with glucose require-ments of greater than 6 to 8 mg/kg/min to maintain normoglycemia, absence of ketonemia and ketonuria, low plasma free fatty acids and branch chain amino acids, detectable insulin at the time of hypoglyce-mia, and response to glucagon administration.31 The combination of hypoglycemia with low free fatty acids and absence of ketonemia is responsible for the potentially devastating effects of this condition on the brain, as it is deprived of both normal and alternate substrates.32

Hyperinsulinemic hypoglycemia with hyperammonemia (previ-ously called leucine-sensitive hypoglycemia) is well described40,41 and is attributed to mutations in the gene for glutamate dehydrogenase. Patients generally respond well to therapy with diazoxide, and con-sumption of extra carbohydrate before protein meals may help ame-liorate symptoms. Special low-leucine milks are available.

Congenital hyperinsulinemic hypoglycemia is caused by abnormali-ties in genes controlling the secretion of insulin by the beta cells of the pancreas, with abnormalities described in seven genes.32

Initial stabilization therapy consists of glucose infusions to achieve normoglycemia. Because there may be extremely high glucose require-ments and any cessation of infusion may be associated with severe hypoglycemia, it is essential to ensure that secure vascular access is always available, and central venous access may be required. Glucagon (0.5-1 mg/kg as an emergency dose IM or by IV bolus; alternatively, subcutaneously or as an IV infusion of 1-20 µg/kg/h) must always be available and can be used as short-term, emergency therapy to main-tain normoglycemia if there are problems with vascular access. Admin-istration of glucagon may be associated with rebound hypoglycemia, and frequent glucose monitoring must be continued. Octreotide (5-30 µg/kg/day subcutaneously or as an IV infusion) may also be given together with glucagon, but this drug may be associated with an increased risk of enterocolitis. As soon as normoglycemia has been achieved, the child should be transported to a center with specific expertise in the management of hyperinsulinemia. Great care must be taken to ensure that hypoglycemia does not occur during transport.

The aim of further management is to confirm the diagnosis and ensure normoglycemia (keep glucose levels > 3.5 mmol/L in view of low alternative sources of energy) without the ongoing use of glucose infusions. Glucose polymers can be added to the diet to provide an enteral source of glucose, but care must be taken to limit the osmolar load on the gut, particularly in premature infants.

Clinically, hyperinsulinemic hypoglycemic patients may be catego-rized by their response to diazoxide (5-20 mg/kg/d in 2-3 divided

Investigation of Hypoglycemia

Blood glucose Measurement of glucose using blood from capillary specimens and using test strips may be unreliable (particularly in poorly perfused patients or patients with high hematocrit); where possible, low glucose levels should be confirmed using laboratory assays on venous or arterial blood.

Actual glucose intake

Hypoglycemia in the presence of normal glucose intake or after brief fast suggests hyperinsulinism. Hypoglycemia after hours of fasting is associated with fatty acid oxidation defects and endocrine insufficiency.

Non–glucose-reducing substances in the urine

Particularly in neonates and probably not relevant in older children. If present in the urine, consider galactosemia, hereditary fructose intolerance, or tyrosinemia.

Serum and urinary ketones

Low ketones suggest hyperinsulinism or fatty acid oxidation problem.

Serum free fatty acids

Free fatty acids are low in hyperinsulinism but high in fatty acid oxidation defect.

Serum insulin (and C peptide), cortisol, glucagon, growth hormone, and thyroid levels

Normal serum insulin in the presence of hypoglycemia is evidence of hyperinsulinism. C peptide may be necessary to ascertain whether exogenous insulin was administered. Release of C peptide may not be as pulsatile as that of insulin.

Serum ammonia To recognize hyperinsulinism/hyperammonemia syndrome

Urinary organic acids and serum amino acids

To diagnose fatty acid oxidation defects (urinary organic acids). Aminoacidopathies such as MSUD, propionic acidemia, isovaleric acidemia, methylmalonic acidemia, and tyrosinemia may also present with hypoglycemia.

Total and free carnitine with acylcarnitine profile

To recognize primary and secondary deficiency of carnitine and fatty acid oxidation defects

TABLE 168-3

the presence of high serum free fatty acids. Assays of insulin levels can confirm the diagnosis of hyperinsulinism.

Abnormalities of growth hormone, cortisol, or thyroid hormone typically are associated with high urinary ketones, the absence of hepa-tomegaly, and increased lactate. Hypoglycemia also may occur as a complication of insulin therapy for diabetes mellitus. Patients with diabetes mellitus may have inadequate responses to hypoglycemia.

Neonates.  In the neonatal period, glucose is not the only energy source from oxidative metabolism in the brain, and alternative energy sources such as ketones may be used.11 In fact, breast-fed babies rou-tinely have lower glucose levels and higher ketone levels than formula-fed infants. Recent reviews have highlighted that “there is inadequate information in the literature to define any one value of glucose below which irreparable hypoglycemic injury to the central nervous system occurs, at any one time or for any defined period of time, in a popula-tion of infants or in any given infant.”18 However, there is evidence that hypoglycemic injury is more likely to occur at very low levels of glucose (20-25 mg/dL [1.1-1.4 mmol/L]) and if hypoglycemia is prolonged, is the consequence of hyperinsulinemia (when alternative energy sources for the brain may be very limited), and in the presence of other poten-tial injuries.18,19

A suggested approach to hypoglycemia in the neonatal period is shown in Figure 168-1. Although the threshold for treatment in the asymptomatic neonate is 25 to 30 mg/dL (1.1-1.4 mmol/L), the rec-ommended levels during treatment are above 45 mg/dL (2.5 mmol/L).

Although the exact definition of hypoglycemia in children is con-troversial, a minimal level of 2.6 mmol/L or greater should be main-tained to ensure normal neural function.12,20,21 It probably is safer to maintain a level of greater than 3.5 mmol/L. Because there are multiple causes for hypoglycemia, and symptoms may not be due to the hypo-glycemia alone, it is essential to identify the cause.

Hypoglycemia is associated with severe illness. A wide range of ill-nesses including infections,22 cyanotic and acyanotic congenital heart disease, and cardiomyopathy/myocarditis have been associated with

1240 PART 10 Endocrine

Ketotic Hypoglycemia.  Although ketotic hypoglycemia (“accelerated starvation”) is probably the most common cause of hypoglycemia in previously healthy children,50 it is unlikely to present in the PICU. This condition usually affects children aged 6 months to 8 years, and the clinical features include ketosis, severe nausea, and hypoglycemia, usually occurring in the morning after a moderate fast. Treatment consists of ensuring that there is an adequate and regular intake of glucose, particularly during intercurrent infections. Urinary ketones may act as a warning signal, because the ketosis usually precedes the onset of hypoglycemia by several hours.

Adrenal Insufficiency.  Adrenal insufficiency after high-dose inhaled corticosteroid therapy has presented with hypoglycemia51-54 and should be considered if there is a past history of inhaled steroid use (particu-larly fluticasone).53,55 Adrenal insufficiency also may occur after adrenal bleeds (e.g., after meningococcal septicemia or difficult delivery), as part of adrenal disease (e.g., congenital adrenal hyperplasia or hypo-plasia) in which ambiguous genitalia may (or may not) be a pointer in females, or as part of hypopituitarism (e.g., congenital, after cranio-pharyngioma, or after cranial irradiation56). Some patients with primary adrenal insufficiency may present with hypoglycemia, particu-larly during acute illnesses.16,57 Adrenoleukodystrophy should be con-sidered as part of the etiologic diagnosis in any male patient with Addison’s disease (pigmentation may be a clue) and should be tested for by measurement of very-long-chain fatty acids.58,57

There has been considerable interest in adrenocorticoid deficiency in children with critical illness and particularly acute severe sepsis (see Chapter 131).59-63 Currently, supplementary steroids are recommended for children with acute severe sepsis and catecholamine resistant

doses), with most responding. Exceptions include those with congeni-tal hyperinsulinemia related to focal hyperinsulinemia and those with diffuse hyperinsulinemia related to inactivating mutations in ABCC8 and KCNJ11. Unfortunately, diazoxide may predispose to fluid reten-tion, and use must be carefully monitored. Chlorothiazide (7-10 mg/kg/day in 2 divided doses) may be added (particularly in neonates).32 Nifedipine (0.25-2.5 mg/kg/d in 3 divided doses) may also be useful in some patients.42

A suggested approach to ongoing diagnosis and management is outlined in Figure 168-2, showing a marked change from previous practice. In those patients who are responsive to diazoxide, that will remain the basis of therapy. In those with no response to diazoxide, genetic testing (for homozygous or compound heterozygous muta-tions in ABCC8 and KCNJ11), followed by fluorine-18 (18F)-dopa posi-tron emission tomography (PET) scanning for those with potentially focal pancreatic lesions will enable identification of those who may benefit from resection of the pancreas. Pancreatic islets cells take up L-3, 4-dihydroxyphenylalanine (L-dopa), where it is converted to dopamine by dopa-decarboxylase. Uptake of the positron-emitting tracer 18F-dopa PET is increased in beta cells with a high rate of insulin synthesis and secretion provides visualization of the focal lesion.43-46 Patients with focal lesions should respond to partial pancreatectomy, which may be done laparoscopically.47,48 Diffuse disease that is unre-sponsive to diazoxide therapy will require a near-total pancreatectomy and may be associated with a high incidence of both endocrine and exocrine problems.49

Close long-term follow up will be required in all these patients, and there may be significant neurologic and psychological problems to be dealt with.49

Figure 168-1  A suggested approach to management of the neonate with low glucose.  (From Rozance PJ, Hay WW. Hypoglycemia in newborn infants: features associated with adverse outcomes. Biol Neonate 2006;90:74-86.)

Check glucose level(reagent strip glucometer

or laboratory)

High risk or symptomatic neonate

<40–50 mg/dL* Asymptomatic

Begin feedingRecheck serum glucose

within 30 min

Symptomatic and/or glucose<25–30 mg/dL*

>40–50 mg/dL*

Begin feeding

Follow clinicallyOther evaluation as indicated

IV bolus 2 mL/kg D10WInfuse D10W at 4–8 mg/kg/min

Recheck serum glucosewithin 30 min

Serum glucose>40–45 mg/dL*

Continue glucose infusionRecheck serum glucose

every 1–2 hours

Serum glucose<40–45 mg/dL*

Serum glucose>40–45 mg/dL*

Continue feeding every 3 hRecheck serum glucose

every 1–2 hours

Serum glucose<40–45 mg/dL*or not tolerating

feeding

Repeat D10W bolusIncrease infusion rate

D10W 10%–15%Recheck serum glucose

within 30 min

If symptomspersist, consider IV

glucose therapy

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1241

These authors postulated that continuous infusion of hydrocortisone may be more appropriate in critical illness.

Growth  Hormone  Deficiency.  In the neonatal period, growth hormone deficiency presents with hypoglycemia (possibly with sei-zures), prolonged jaundice, and in boys, micropenis and undescended testes. Growth failure becomes apparent only toward the end of the first year of life. In later childhood, growth failure is a more common presentation, and hypoglycemia rarely occurs56 unless associated with adrenocorticotropic hormone deficiency.

Hyperglycemia Other Than Diabetes Mellitus

Hyperglycemia is relatively common in the PICU.70 In a retrospective study of 948 nondiabetic patients admitted to the PICU, there was a high prevalence of hyperglycemia, with 70.4% of patients having a glucose value above 120 mg/dL, 44.5% above 150 mg/dL, and 22.3% above 200 mg/dL within 10 days of admission. A 2.5-fold increased risk of dying was seen if the maximum glucose obtained within 24 hours of admission was over 150 mg/dL and a 5.68-fold increased risk if the maximum glucose obtained within 10 days of admission to the PICU was over 120 mg/dL.71 However, that study was retrospective and not corrected for severity of illness. In addition, ascertainment bias was present,72 so the study could not really provide insight in terms of causality or the potential impact of therapy.73

Hyperglycemia is common in a wide variety of conditions including bronchiolitis,74 sepsis, hemolytic uremic syndrome,75 tetanus,76 and

shock,64,65 but there are not clear definitions for either adrenal insuf-ficiency or catecholamine resistance, nor are there firm recommenda-tions for the dose of adrenal replacement therapy.

Adrenocorticoid deficiency also has been shown in preterm infants.66 A randomized controlled study of “stress” dose hydrocortisone therapy in hypotensive very low-birthweight infants showed that steroids were effective in treating refractory hypotension.67

Congenital adrenal hyperplasia is associated rarely with hypoglyce-mia. Female patients are usually diagnosed early in life as a result of virilization, whereas male patients tend to present later. Patients with the salt-losing form of congenital adrenal hyperplasia present with hyponatremic dehydration and shock, usually associated with hyper-kalemia. Because patients with salt-wasting 21-hydroxylase deficiency also may have catecholamine deficiency, shock may be a significant feature. Diagnosis is based on the clinical picture, typical electrolyte pattern, hypoaldosteronism, and hyperreninemia.68 Long-term treat-ment consists of hydrocortisone (to suppress excess secretion of corticotropin-releasing hormone and corticotropin), 10 to 20 mg/m2 of body surface area per day in three divided doses, although larger doses may be required during adrenal crises, together with mineralo-corticoid replacement (0.1-0.2 mg of fludrocortisone daily) and sodium chloride supplementation. Little is known about the dose of hydrocortisone required during critical illness, although Charmandari et al.69 showed that when 6-hourly bolus doses of 15 mg/m2 of hydro-cortisone are given, high immediate serum levels are achieved, followed by rapid decline to undetectable levels by 4 hours after administration.

Figure 168-2  Flow chart outlining the management cascade of neonates with hyperinsulinemic hypoglycemia (HH). Clinically, HH can be classified into diazoxide-responsive and diazoxide-unresponsive disease. A fluorine-18 L-3, 4-dihydroxyphenylalanine positron emission tomography (18F-dopa PET) scan is currently only indicated in neonates who are unresponsive to diazoxide and do not have genetically confirmed diffuse disease. (From Kapoor RR, Flanagan SE, James C, Shield J, Ellard S, Hussain K. Hyperinsulinaemic hypoglycaemia. Arch Dis Child 2009;94:450-7.)

Diazoxide responsive Diazoxide unresponsive

No Yes

Assess fasting toleranceand discharge

Rapid genetic analysis of theABCC8 and KCNJ11 genes

Genetically confirmed diffuse disease(homozygous/compound heterozygous

for ABCC8/KCNJ11 mutations)

High calorie diet/frequent feedsOctreotide therapy

Near-total pancreatectomy

Established diagnosis of HH

18F-DOPA PET/CT scan

Resection offocal lesion

Focal disease Diffuse disease

Follow-up:Request genetic analysis onthe basis of the phenotype

Consider trial off diazoxide inhospital when dose of diazoxide

falls below 5 mg/kg/day

Regular monitoring of growth/development and neurology

Follow-up:Regular monitoring ofgrowth, development

and neurology

Follow-up:Growth and development

Neurologic genetic counseling

Post near total pancreatectomy:Diabetes mellitus management

Pancreatic exocrine function

1242 PART 10 Endocrine

In the context of major burns there is also some evidence that insulin therapy to maintain lower blood glucose levels may be associ-ated with improvements in metabolism.95

A recent review96 concluded:

Hence, efficacy and safety of intensive insulin therapy may be affected by patient-related and ICU setting-related variables. Therefore, no single optimal blood glucose target range for ICU patients can be advocated. It appears safe not to embark on targeting “age-normal” levels in PICUs that are not equipped to accurately and frequently measure blood glucose, and have not acquired extensive experience with intravenous insulin administration using a customized guideline. A simple fallback position could be to control blood glucose levels as close to normal as possible without evoking unacceptable blood glucose fluctuations, hypoglycemia, and hypokalemia.

Pediatricians have been reluctant to implement tight glucose control in PICU because of concerns about the deleterious effects of hypoglycemia.97,98

A recent review of hyperglycemia in the preterm infant99 suggested the following pragmatic approach to management: confirm hypergly-cemia with laboratory test; treat any underlying problem such as sepsis, stress, etc.; calculate glucose infusion rates, and if above 12 mg/kg/min, reduce infusion rate; treat with insulin if glucose is over 10 mmol/L (or other symptoms such as polyuria), but start cautiously with very low doses; finally, if hyperglycemia persists, consider other diagnoses such as diabetes.

Diabetes Mellitus

Children with diabetes mellitus have a higher mortality than healthy children,100,101 with standardized mortality ratios of 2.15102 to 4.2,103 although some deaths are not directly related to diabetes. The highest mortality is in children aged 1 to 4 years, in whom the standardized mortality ratios may be 9.2104 to 13.7.105 Most deaths attributable to diabetes mellitus occur as a consequence of diabetic ketoacidosis (DKA) or hyperglycemia, with the remainder attributable to hypogly-cemia.104 Diabetic ketoacidosis is relatively common at the time of first presentation, particularly in younger children,106 in whom diagnosis may be delayed. Although the incidence of type 1 diabetes mellitus has been increasing in many parts of the world, the hospitalization rate for DKA in established and new cases of type 1 diabetes mellitus has not increased in Canada and Europe since the 1990s107,108 because of earlier diagnosis and safer ambulatory management with the help of a mul-tidisciplinary team.

The mortality rate in the developed world for DKA ranges from 0.15% to 0.31%109 but may be far higher in other settings.110 The most common cause of death among patients with DKA is cerebral edema. Other causes of death in DKA include electrolyte disturbances, hypo-glycemia, pulmonary edema, rhabdomyolysis, infections (including mucormycosis), and thrombosis. The management of DKA in child-hood has been extensively reviewed elsewhere,109,111,112 with current recommendations.

Cerebral  Edema  in  Diabetic  Ketoacidosis.  In affluent countries, symptomatic cerebral edema occurs in 0.5% to 1% of pediatric DKA episodes,113 with risks being higher in young children and previously undiagnosed diabetics. Mortality is high (21%-24%), and 15% to 26% of survivors will have permanent morbidity (including pituitary insufficiency).113

The exact mechanisms of cerebral edema in DKA are not clear,114 although some imaging studies suggest that cerebral edema may be related to vasogenic factors rather than osmotic factors.115 Cerebral hyperemia has also been demonstrated as part of abnormal autoregu-lation.116,117 Factors that have been associated with the development of cerebral edema include the administration of bicarbonate, a higher plasma urea, arterial partial pressure of carbon dioxide (Pco2),118,119 and a smaller increase in plasma sodium concentration during

toxin ingestion (e.g., theophylline poisoning77). Other studies have confirmed that high glucose levels are not only common in the PICU population but are associated with increased mortality and/or morbid-ity in a wide variety of conditions.78-81

Iatrogenic causes of hyperglycemia in the PICU include resuscita-tion using glucose-containing fluids, parenteral nutrition or high load of administered glucose, and high-dose corticosteroid therapy. Con-tinuing hyperglycemia may also be an indication of ongoing stress or undiagnosed type 1 diabetes and should prompt the clinician to inves-tigate further.

An initial report from an adult surgical unit (predominantly cardiac)82 provided evidence that “tight” control of glucose levels was associated with a significant improvement in patient outcomes. The same group studied a cohort of patients in a medical ICU, and there was no difference in mortality between groups.83 There have been numerous studies in a variety of adult critical care populations since that time, with positive effects of tight glucose control noted on cho-lestasis,84 renal function,85 neurologic and neuromuscular complica-tions,86,87 and endothelial function.88 Unfortunately, there have also been increased reports of iatrogenic hypoglycemia, and a recent meta-analysis of studies in adults89 concluded that tight glucose control was not associated with an improvement in hospital mortality and was associated with an increased incidence of hypoglycemia. Subsequently, a large randomized controlled trial (RCT) of adult patients compared “tight” (81-108 mg/dL or 4.5-6.0 mmol/L) with “conventional” glucose control (target of ≤180 mg/dL or ≤10.0 mmol/L). The 90-day mortal-ity was higher in the group on tight glucose control, and subgroup analysis showed that the outcomes favored conventional control in all groups except trauma patients and patients on steroids.

Pediatricians have been more cautious in their approach to control of hyperglycemia, but a number of protocols for PICU management of hyperglycemia have been implemented and reported.90,91 An RCT of protocols for tight glucose control in the PICU showed no difference between a paper-based protocol and a computerized decision support tool.92

In a study of glycemic control in 177 postoperative cardiac patients,93 there was no difference in glucose levels on day 1 between survivors and nonsurvivors, but the 5-day mean peak glucose levels were signifi-cantly higher in nonsurvivors. Insulin usage was higher in the nonsur-vivors, and nonsurvivors had more hypoglycemic events. The authors speculated that targeting a more permissive glucose level of 90-140 mg/dL (5-7.7 mmol/L) might be associated with both improved outcomes and reduced risk of hypoglycemia. In a retrospective review of 100 postoperative cardiac patients, there was high incidence of hypergly-cemia (and an association with higher severity of illness), and imple-mentation of a pediatric glycemic control protocol had a low incidence of hypoglycemia.79

A prospective RCT of 700 critically ill children (317 infants and 383 children) admitted to PICU94 randomized patients to targeted blood glucose levels (throughout PICU stay) of 2.8 to 4.4 mmol/L in infants and 3.9 to 5.6 mmol/L in children, with insulin infusion throughout PICU stay (intensive group [n=349]) or to insulin infusion only to prevent blood glucose from exceeding 11.9 mmol/L (conventional group [n=351]). Mean blood glucose concentrations were lower in the intensive group than in the conventional group, and hypoglycemia (glucose ≤2.2 mmol/L) occurred in 87 (25%) patients in the intensive group (P < 0.0001) versus 5 (1%) patients in the conventional group. Severe hypoglycemia (blood glucose less than 117 mmol/L) occurred in 17 (5%) of the intensive group versus 3 (1%) of the conventional group (P=0.001). Duration of PICU stay was reduced in the intensively treated group (5.51 days [95% CI, 4.65-6.37] versus 6.15 days [95% CI, 5.25-7.05]; P=0.017). The number of patients with stay in PICU longer than the median was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (P=0.013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conven-tional group (P = 0.038). There is ongoing debate about appropriate targets for glucose, optimization of protocols, balance of nutrient and glucose intake versus insulin therapy, and the like.

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1243

using aliquots of 5 to 10 mL/kg until an acceptable blood pressure is obtained.141 Typically, 10 to 20 mL/kg needs to be infused over 1 to 2 hours.109 Ringer’s lactate may be a reasonable alternative, because administration of large volumes of 0.9% saline has been associated with the development of hyperchloremic acidosis. There is no evidence to support the use of colloid solutions.

Thereafter the acceptable principles are that hypovolemia, rapid changes in plasma osmolality, and large volumes of sodium uptake should be avoided. Fluid therapy should be calculated to achieve rehy-dration over 48 hours.109,112,113 Careful monitoring of fluid balance is essential to ensure that patients are neither losing excessive fluid (via osmotic diuresis) nor gaining excessive fluid. Fluid with a tonicity less than that of 0.45% saline should not be used, and a positive balance of around 6 mmol of sodium chloride per kilogram over 24 hours should be regarded as the upper limit.141 The rate of fluid infusion rarely exceeds 1.5 to 2 times the usual daily requirement.

Despite the fact that almost all patients with DKA are potassium depleted, serum potassium levels frequently are increased at presenta-tion. With initiation of insulin therapy and correction of acidosis, there is rapid intracellular movement of potassium, and careful monitoring of potassium levels is essential. As soon as potassium levels are less than 5.5 mEq/L, 30 to 40 mEq/L of potassium should be added to the fluid infusions, and 0.5 to 1 mEq/kg/h of potassium may be required to correct potassium deficits. Potassium may be given as chloride or phos-phate. Although severe hypophosphatemia is relatively common,142 and symptomatic hypophosphatemia has been reported,143 there is no evidence that phosphate administration is routinely necessary in the management of DKA, and the clinical effects of severe hypophospha-temia rarely are seen in DKA. Theoretically, phosphate administration may reduce insulin resistance and depletion of adenosine triphosphate and have positive effects on 2,3-diphosphoglycerate.144 Administration of potassium phosphate helps decrease the chloride load given to patients with DKA. Potassium phosphate may be used safely,145 pro-vided that calcium levels are monitored carefully.146,147 Glucose must be added to the infusion of fluids when the glucose levels are 14 to 17 mmol/L to avoid hypoglycemia.

Bicarbonate. The use of bicarbonate in DKA is extremely limited. Many studies have shown no clinical benefit from its administration.148-150 More recently, bicarbonate administration has been associated with the development of cerebral edema. It should not be given routinely, not in bolus form, and possibly only in patients who have a pH of less than 6.9 despite appropriate correction of intravascular volume and ongoing adequate insulin therapy.

Insulin Therapy. Intravenous insulin should be provided as a con-tinuous low-dose infusion starting at 0.1 unit/kg/h about 1 to 2 hours after starting fluid replacement. If there is no response to insulin therapy, the infusion should be reviewed for technical problems (incor-rect preparation, adhesion of insulin to infusion tubing), and the patient should be reviewed for ongoing hypovolemia or uncontrolled sepsis. There is no place for a bolus of IV insulin or an initial loading dose, other than in the management of life-threatening hyperkalemia. The insulin infusion should be continued until ketoacidosis is resolved and the patient is fully conscious and retaining solid food.

Treat Underlying Cause. In previously undiagnosed patients, the cause of DKA is insulin deficiency. Even in previously diagnosed patients, most episodes of DKA probably are related to insulin omis-sion or treatment error, although children 3 years old or younger are more likely to have a bacterial infection.151 If infection is suspected as the precipitating cause of DKA, aggressive therapy with antibiotics and drainage of any pus should be instituted. Routine prophylactic antibi-otic therapy is not indicated in DKA.

Monitoring. Although some patients are hypovolemic on presenta-tion, there is little evidence that invasive hemodynamic monitoring is necessary. Careful monitoring of sodium levels is essential because smaller changes in serum sodium with therapy have been associated with development of cerebral edema.118 Hyperlipidemia may decrease the aqueous phase of serum and artificially reduce sodium levels; this can be corrected using the following formula152:

therapy.120 However, a recent systematic review121 of the literature con-cluded that there was no clear evidence that treatment was related to the development of cerebral edema. Cerebral ischemia and reperfusion injury have also been considered.122 Cerebral edema may be present before therapy for DKA in 5% of cases, although most cases develop 4 to 12 hours after initiation of therapy.118,123 The clinical signs of cerebral edema in DKA are variable and include headache, deteriora-tion in level of consciousness, inappropriate slowing of pulse rate, and increased blood pressure. However, children with no clinical signs of cerebral edema have been documented to have brain swelling,124 and a significant proportion of children have disrupted memory function following episodes of DKA.125

Adverse outcomes have been associated with greater neurologic depression at the time of diagnosis, high initial serum urea nitro-gen,118,126 and intubation with hyperventilation to a Pco2 less than 22 mm Hg.126,127

Although the biochemical derangements of hyperglycemia, meta-bolic acidosis with ketosis, and electrolyte abnormalities are the most obvious problems in DKA, significant derangements in other systems have been documented, including plasma tryptophan levels,128 thia-mine levels,129 cytokine130 and lymphocyte responses,130 and coagula-tion abnormalities.130 There is little doubt that DKA is associated with a thrombotic state131 and an increased incidence of cerebrovascular accidents, and care should be taken about the use of femoral central venous access because this may have a higher than usual complication rate in these patients.132 A reported case of myocardial infarction related to DKA133 may be a complication of the thrombotic state. Although myocardial function is generally normal in DKA, myocardi-tis134 has been noted in occasional case reports, whereas pulmonary edema may be more common than previously recognized.135 Prolonga-tion of the QTc interval may be common in DKA (it correlates with ketosis), and careful cardiac monitoring is essential.136

Principles of Management. Management of DKA should be coor-dinated by an experienced diabetes team. The biochemical criteria for the diagnosis of DKA include a serum glucose concentration above 11 mmol/L (~200 mg/dL), ketonemia and ketonuria, and acidosis with venous pH below 7.3, or serum bicarbonate level below 15 mEq/L.112 The severity of DKA is defined by the level of acidosis, with mild having venous pH less than 7.3 (or bicar-bonate <15 mmol/L); moderate, pH less than 7.2 (or bicarbonate <10 mmol/L); and severe, pH less than 7.1 (or bicarbonate <5 mmol/L).112 Children with severe DKA should be managed in a specialized diabetic unit or in the PICU.

Baseline Assessment. An admission weight should be obtained if at all possible, and future therapy should be based on this weight. Blood samples should be taken for the following investigations: serum or plasma glucose, electrolytes (including bicarbonate or total carbon dioxide), blood urea nitrogen, creatinine, osmolality, venous (or arte-rial in critically ill patient) pH, Pco2, calcium, phosphorus, and mag-nesium concentrations (if possible), HbA1c, hemoglobin and hematocrit or complete blood count. Measurement of blood β-hydroxybutyrate concentration, if available, is useful to confirm ketoacidosis and may be used to monitor the response to treatment.137-140 Urine specimens should be analyzed for ketones. Electrocardiograms may be useful if delays are expected in getting potassium results.

Fluid Management. The objectives of fluid and electrolyte replace-ment therapy are restoration of circulating volume, replacement of sodium and body fluid deficit, improved renal function with enhanced clearance of glucose and ketones from the blood, and minimization of risk of cerebral edema.112 There is a wide range in the amount and rate of fluid and electrolyte loss in patients presenting with DKA (depend-ing on the rate of onset and duration of symptoms, the severity of vomiting or diarrhea or both, and the fluid ingested by the patient).112 There is a wide range of intravascular status ranging from normovole-mia to severe hypovolemia (uncommon). Clinical assessment of dehy-dration is notoriously inaccurate, and there is an unpredictable rate of ongoing fluid loss related to the osmotic diuresis. In the (unusual) presence of hypovolemic shock, it is reasonable to infuse 0.9% saline

1244 PART 10 Endocrine

per 100,000 live births in other countries.178 In addition, some condi-tions have a particularly high incidence in particular population groups (e.g., maple syrup urine disease has an incidence of 568 per 100,000 births in the Mennonite community in Pennsylvania). Inborn errors of metabolism have a diverse presentation and are part of the differential diagnosis of many children admitted to the PICU with acute illness. Until more recently, only conditions such as phenylke-tonuria and galactosemia had been identified at birth using screening programs. With increasing availability of technology such as tandem mass spectrometry, screening of other inborn errors of metabolism (including fatty acid oxidation abnormalities and aminoacidopathies) has been introduced in some parts of the world,179-182 and this poten-tially may decrease the number of children presenting with acute meta-bolic decompensation.

There is evidence that SIDS may be related to inborn errors of metabolism in at least 1% of cases,183,184 and inborn errors of metabo-lism must be considered as part of the differential diagnosis of any infant who presents to the PICU or neonatal ICU after a near-SIDS episode. A family history of SIDS also should raise the possibility of inborn errors of metabolism in siblings presenting to the PICU with acute illness.

Although there are a bewildering number of inborn errors of metab-olism, many are amenable to therapy, and screening may be performed using relatively simple tests. Patients with incurable conditions may derive considerable relief of suffering from diagnosis and appropriate therapy. Even when a condition is not amenable to therapy, it is impor-tant to make a diagnosis to facilitate counseling for the family involved and prevent unnecessary suffering in future children. Long-term man-agement of most inborn errors of metabolism requires a team approach including metabolic experts, dietitians, geneticists, biochemists, and social workers to elucidate the exact nature of the problem, provide appropriate therapy and therapeutic plans, and give genetic and family counseling. Although many screening tests for inborn errors of metab-olism can be done in most diagnostic laboratories, the specialized tests required to identify the exact nature of an inborn error of metabolism can be done at relatively few laboratories. Despite the complexity of inborn errors of metabolism, there are principles germane to the man-agement of all children who are admitted to a PICU, and these should apply (see Table 168-1).

WHEN TO CONSIDER AN INBORN ERROR OF METABOLISM IN THE PEDIATRIC INTENSIVE CARE UNIT

Inborn errors of metabolism may be classified into diagnostically useful groups185: (1) disorders that give rise to intoxication (e.g., organic acidemias and urea cycle defects); (2) disorders involving energy metabolism (e.g., fatty acid oxidation defects and respiratory chain defects); (3) disorders involving complex molecules in which symptoms are permanent, progressive, and independent of intercur-rent events (e.g., peroxisomal disorders, lysosomal disorders, and con-genital defects of glycosylation); and (4) those disorders that present with seizures (particularly in the neonatal period). The conditions most likely to present acutely in the PICU are conditions involving intoxication and energy metabolism. There is overlap, however, between all of these groups in terms of clinical presentation. There also may be considerable variation in the clinical presentation of conditions that have the same underlying genetic abnormality; this may apply even within families.

Although the clinical features of an inborn error of metabolism may be related primarily to the accumulation of a toxic metabolite, the condition may be complicated by the relative deficiency of another compound or increased stress put on other metabolic pathways by the primary problem.186 Management may involve limiting the intake of potentially toxic substances, increasing the removal of toxic substances, supplementation of deficient substances, and supplementation of other metabolic pathways that are being stressed.

Inborn errors of metabolism should be considered as part of the differential diagnosis of any child or infant who presents with a severe

True sodium mEq L reported sodium mEq Ltriglyc

[ ] ( ) = ( )[ ]××0 021. eerides mg dL( )[ ]+[ ])0 994.

The osmotic load of glucose also decreases serum sodium levels, with a decrease in sodium concentration of approximately 1.6 to 1.8 mEq/L per 100 mg/dL increase in glucose153 (alternatively, Cor-rected sodium = measured Na + 2([plasma glucose − 5.6]/5.6) (mmol/L). The expectation is that with decreasing levels of hypergly-cemia and hyperlipidemia, sodium levels should increase. This increase may be offset, however, by urinary losses of sodium secondary to osmotic diuresis. Careful and frequent monitoring of potassium and glucose levels is essential. If phosphate is being administered, calcium levels should be monitored. Regular acid-base monitoring is required.

Monitoring of end-tidal Pco2154 or transcutaneous Pco2

155 could be used as a noninvasive method for continuous monitoring of response to therapy for DKA. The only proviso (as pointed out by the authors and in an accompanying editorial156) is that any changes in respiratory drive or efficiency of the respiratory system may mask changes in acid-base that otherwise might be reflected by capnometry.

Investigations for Possible Cerebral Edema in Diabetic Ketoacido-sis. Although cerebral edema is the most common cause of depressed level of consciousness in DKA, there are other causes that are amenable to alternative therapy, including cerebral venous thrombosis157 and acute hydrocephalus.158 Other abnormalities such as brain infarction159 and extrapontine myelinolysis160 have been shown. Computed tomog-raphy (CT) of patients with a depressed level of consciousness may be recommended to exclude other treatable pathology. Because the risks are relatively low, however, excluding other pathology must be bal-anced against the risks associated with moving ill patients to the radiol-ogy suite.

Mannitol has been used for the management of cerebral edema161 (0.25-1 g/kg over 20 minutes), although there are no controlled studies. Hypertonic saline (5-10 mL/kg of 3% saline) may be an alternative to mannitol.162 Hyperventilation after intubation for cerebral edema may be associated with worse outcomes.126

Despite improvements in the management of DKA, it remains a serious illness with significant morbidity and mortality. In addition to improving management of the condition, strong focus must be brought to ensure that the condition is avoided where possible and diagnosed and treated promptly when it occurs.

Thyroid Insufficiency

Neonates exposed to large amounts of iodine in iodine-containing antiseptics may develop transient hypothyroidism163-167 (also called the Wolff-Chaikoff effect) as a result of transcutaneous absorption of iodine. This condition also has been shown in infants undergoing cardiac cath-eterization and cardiac surgery.168 Care should be taken to limit the exposure of infants to iodine-containing agents. Triiodothyronine sup-plementation may be considered in children who have been exposed to significant amounts of iodine before or during a critical illness.

The sick euthyroid syndrome has been well documented in the PICU, particularly in patients undergoing cardiac surgery. The subject has been reviewed elsewhere.169 Although there may be benefit to some children from triiodothyronine supplementation after cardiac surgery,170-172 there is no established role for triiodothyronine supple-mentation after cardiac surgery.173

Children with Down syndrome have a high incidence of hypothy-roidism.174,175 Attention should be paid to the possible need for triio-dothyronine supplementation in critically ill children with Down syndrome.

Metabolic CrisesEPIDEMIOLOGY

Population data on inborn errors of metabolism suggest that there is a minimal incidence of 35 to 40 per 100,000 live births176,177 in coun-tries such as Canada or Italy, while the incidence may be as high as 150

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1245

is dependent on continuous pharmacologic doses of pyridoxine or pyridoxal-5′-phosphate, respectively. However, it has recently been shown that detection of elevated levels of α-amino-adipic semialde-hyde in blood, urine, or cerebrospinal fluid (CSF), along with the demonstration of mutations in the ALDH7A1 (antiquitin) gene, confirm a diagnosis of PDE189; whereas an abnormal pattern of CSF catecholamine and indole amine metabolite levels, together with ele-vated CSF and plasma glycine and threonine concentrations and urinary vanillactic acid excretion are characteristic but not uniformly present in PNPO.190,191 It has also been shown that patients with folinic acid–dependent seizures have the same mutation in the antiquitin gene.188 There is a considerable range in clinical presentation, and pyridoxine-dependent seizures probably should be considered in any infant up to age 18 months presenting with seizures.

Patients with defects in transport of glucose across the blood-brain barrier associated with mutations in the GLUT1 gene may present with seizures. The only clue is the presence of low CSF glucose in the pres-ence of normal blood glucose. Patients may improve on a ketogenic diet.192

Inborn errors of metabolism that may present with seizures associ-ated with lactic acidosis include biotinidase deficiency, disorders of mitochondrial energy metabolism (including pyruvate dehydrogenase deficiency and mitochondrial electron transport chain defects), and peroxisomal and storage disorders.

Biotinidase deficiency (an autosomal recessively inherited disorder of biotin recycling—estimated incidence of biotinidase deficiency is about 1 in 60,000193) can be ameliorated or prevented by administering pharmacologic doses of the vitamin biotin (5-20 mg daily independent of age). A large proportion of cases present with seizures and hypoto-nia, associated with failure to thrive, and rash or alopecia. Some 50% of cases have ataxia, developmental delay, and eye problems (conjunc-tivitis and optic atrophy), with more than 75% developing hearing loss. There is a considerable variation in clinical presentation, even within affected families,194 with features ranging from mild episodes of seizure and ataxia to severe metabolic failure and death. Onset of symptoms may occur at any time from the neonatal period through to adulthood. Untreated individuals may have ketoacidosis, lactic acidosis, and/or hyperammonemia, with a wide range of other metabolic anomalies.194 Diagnosis can be made from analysis of organic acids in urine, whereas an enzyme assay can be done on blood. Guidelines for testing have recently been published.194

Intractable tonic/clonic seizures also may be a feature of molybde-num cofactor deficiency.195,196 This condition presents in early infancy with seizures, encephalopathy in the absence of metabolic acidosis, hypoglycemia or hyperammonemia, and failure to thrive. Imaging of the brain initially shows cerebral edema, which may progress to cere-bral atrophy. There are typical imaging findings.197 Clinical features, CT findings, and neuropathology may be similar to that seen in severe hypoxic-ischemic brain injury.198,199 Lens dislocation may be a clinical feature.200 Uric acid levels are low, whereas urinary amino acid analysis shows increased S-sulfocysteine. Sulfite may be demonstrated on fresh urine specimens. Electrospray tandem mass spectrometry of urine or urine-soaked filter paper may facilitate rapid diagnosis.201 Seizures may be part of the clinical presentation of many other disorders, including seizures with lactic acidosis (Leigh disease; mitochondrial encepha-lopathy lactic acidosis and strokelike episodes [MELAS]; mito chondrial encephalopathy with ragged red fibers [MERRF]), GM2 gangliosidosis, and peroxisomal disorders. Other clinical features predominate in these conditions and should direct investigation.

Investigation and Management.  In infants presenting primarily with intractable seizures, investigations should include measurement of blood glucose, blood acid-base status, blood lactic acid (in association with pyruvate levels), CSF glucose, lactic acid and pyruvic acid levels, urinary organic acids, and sulfite. CT and magnetic resonance imaging (MRI) help diagnose disorders of abnormal accumulation of metabo-lites and exclude structural brain problems that are responsible for symptoms. Treatment focuses on control of the airway and respiration,

illness, particularly during the neonatal period.185 Acute symptoms that are particularly associated with inborn errors of metabolism include encephalopathy (acute or acute on chronic), intractable seizures, hepatic failure, cardiomyopathy, metabolic acidosis, and hypoglycemia (Table 168-4). Family history of SIDS or of previous childhood deaths may suggest an inborn error of metabolism. Particular attention should be paid to the identification of specific risk factors for the dif-ferential diagnoses, including drug exposure, prolonged rupture of membranes, and perinatal asphyxial episodes.

CLINICAL PRESENTATIONS OF INBORN ERRORS OF METABOLISM

Intractable Seizures

Seizures (in isolation) are an uncommon presentation of inborn errors of metabolism and, with the exception of the pyridoxine-dependent seizures, tend to be associated with other clinical and metabolic abnor-malities. In neonates or some infants presenting with intractable seizures, (particularly if associated with grimacing and abnormal eye movements), pyridoxine-dependent seizures (PDS),187 pyridoxine phosphate oxidase deficiency (PNPO) hypophosphatasia, and folinic acid–responsive seizures188 should be considered. The clinical diagnosis of both PDS and PNPO depends on demonstration that seizure control

Factors That Should Alert the Intensivist to the Possibility of an Inborn Error of Metabolism

HistoryGeneral Population group with high incidence of inborn errors of

metabolismConsanguinity of parentsPrevious history of apparent SIDS or childhood deaths in the

familyPresence of dysmorphic features associated with inborn error

of metabolismDuring

pregnancyPrevious history multiple spontaneous abortionsHyperemesis may be associated with fat oxidation disorders,240

as may frank hepatic symptoms such as acute fatty liver of pregnancy or the more severe HELLP syndrome (hemolysis, liver enzymes, low platelets).

In neonatal period

Deterioration after apparently being normal at birth, particularly if Apgar scores and early neonatal period were normal

Earliest signs of inborn error of metabolism in the neonatal period may include lethargy and poor feeding, which may progress rapidly to obvious depressed level of consciousness.

Depressed level of consciousness without obvious explanationVomiting is an unusual clinical feature of illness in neonates

and is strongly associated with inborn errors of metabolism.

Strange odorsIn childhood Previous history of being “sickly” with episodes of

intermittent vomitingPrevious hospital admissions (even for apparent respiratory

symptoms as this may be acidosis)Unusual dietary preferences by the childOnset of virtually any organ dysfunction (liver, heart, renal,

etc.) may be related to inborn error.

ExaminationGeneral in

neonatal period

Dysmorphic features that may be associated with inborn errors of metabolism

Strange odorsNeurologic signs in inborn errors of metabolism tend to

include increased tone and abnormal movements, in contrast to the features of sepsis, which usually is associated with decreased tone.

In childhood Acute or intermittent ataxia is a common feature of inborn errors of metabolism in children.

SIDS, sudden infant death syndrome.

TABLE 168-4

1246 PART 10 Endocrine

of presentation, because this may provide the best opportunity for diagnosis (Table 168-5).

Blood Glucose Levels. The reader is referred to the earlier discus-sion of the approach to hypoglycemia. Hypoglycemia may be a par-ticular feature of fatty acid oxidation defects and organic acidurias. Immediate correction of hypoglycemia is an essential element of treatment.

Plasma Ammonia Levels. Plasma ammonia levels should be checked in all children, especially neonates with unexplained depressed level of consciousness, particularly if there is hypotonia and apnea (see section on hyperammonemia for management and investigation). Treatment of severe hyperammonemia is an emergency.

Liver Function Tests. Reye syndrome is part of the differential diag-nosis of acute encephalopathy, but fatty acid oxidation defects such as medium-chain acyl-CoA dehydrogenase deficiency, carnitine defi-ciency (usually with associated myopathy), and far less frequently, long-chain acyl-CoA dehydrogenase deficiency and short-chain acyl-CoA dehydrogenase deficiency, may present with encephalopathy (usually in the neonatal period).

Blood Gas Analysis. Arterial blood gas analysis should be per-formed, with particular attention to the presence of metabolic acidosis and calculation of the anion gap (this should be corrected for the pres-ence of hypoalbuminemia).203-205

Blood Lactate Levels. Blood lactate levels may be increased in many situations but typically are very elevated in mitochondrial electron transport chain defects.

Plasma Carnitine. Levels of carnitine may be substantially decreased in organic acidurias and fatty acid oxidation defects. Analysis of acyl-carnitine and amino acid profile may help to make the diagnosis of isovaleric aciduria, methylmalonic aciduria, and propionic acidemia.

Quantitative Amino Acid Analysis. Quantitative amino acid analy-sis is necessary to identify the aminoacidopathies. This test is not

together with control of seizures. Pyridoxine or biotin should be administered early in appropriate doses if indicated.

Encephalopathy

The onset of acute encephalopathy always constitutes a medical emergency, and the cause must be elucidated as rapidly as possible. The differential diagnosis includes trauma, infection, intracranial space-occupying lesions, toxin ingestion, acute hepatic failure or Reye syndrome, intracranial vascular problems (including thrombosis, hemorrhage, and embolic phenomena), and seizure disorders. There is often a strong tendency to attribute neurologic symptoms to hypo-glycemia or hypocalcemia, but because these may be associated with inborn errors of metabolism, it is vital to consider an inborn error of metabolism as part of the cause of the hypoglycemia.

The inborn errors of metabolism that present with acute encepha-lopathy vary with age. In the neonatal period, the common inborn errors of metabolism include urea cycle defects (with hyperammone-mia), maple syrup urine disease, nonketotic hyperglycinemia, and organic acidopathies.202 All of these conditions, with the exception of nonketotic hyperglycinemia, also may present during childhood. During childhood, the common inborn errors of metabolism present-ing with acute encephalopathy include fatty acid oxidation defects and maple syrup urine disease.

Investigation.  The specimens that normally would be collected for diagnosis of sepsis should be collected, including blood culture, hemo-globin, white blood cell count (including differential), and platelets. Serum electrolytes should be checked, including sodium, potassium, calcium, phosphate, and magnesium. Liver function tests are essential because acute hepatic failure may cause acute encephalopathy, and the liver may be affected by inborn errors of metabolism. Specimens for testing for inborn errors of metabolism must be collected at the time

Specimen Collection for Inborn Errors of Metabolism

Substance Tests Comments on Technique Conditions Identified

Urine Detecting odors Urine odors are best identified from urine drying on filter papers or from urine that has been kept in a closed container at room temperature for a while.

MSUD (smell of maple syrup; some describe this as burnt sugar133)

Isovaleric acidemia (sweaty feet odor) 3-methylcrotonyl glycinuria (catlike)

Urine (screening tests)

Ketones Urinary ketones are rare in neonates and are almost diagnostic of an inborn error of metabolism in a neonate.

Dinitrophenylhydrazine Strongly positive with MSUD, PKU, or in ketoacidosisFerric chloride Green color with PKU; other colors may occur with

other conditions.Merckoquant 10013 Sulfit test Urine specimen must be fresh because

sulfite oxidizes rapidly at room temperature.

Molybdenum cofactor deficiency

Reducing substances Galactosemia

Urine Measurement of organic acids and amino acids

Specimen collected and frozen at −20°C All aminoacidemias and organic acidurias

Measurement of acylcarnitines and acylglycines

Can increase the sensitivity of these tests by the use of loading dose of levocarnitine,100 mg/kg orally

Many fatty acid oxidation defects

Blood Anion gap Correct for hypoalbuminemia Screen to identify generally unmeasured anionsTandem mass spectrometry Collected as blood on filter paper All fatty acid oxidation defects, many of the

aminoacidemiasAbnormalities of the carnitine pathways

Galactose-1-phosphate uridyltransferase Collected as blood on filter paper GalactosemiaEstimation of ammonia, lactate,

pyruvate, and ketoacidsAll of these substances may be unstable;

must collect on ice and transport immediately to laboratory

Aminoacidopathies, urea cycle defects

Genetic studies Before blood transfusion All problems with identified genetic abnormalitiesEnzyme defects, organelle defects

Skin, liver, muscle, and endocardial biopsy

Fibroblast culture, enzyme identification, identification of abnormal collections and organelles

MSUD, maple syrup urine disease; PKU, phenylketonuria.

TABLE 168-5

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1247

renal concentrating ability. One-third of patients may present later in life.

Strokelike episodes are a feature of isovaleric aciduria, methylmalo-nic aciduria, and propionic acidemia in later life, although there may be a wide range of neurologic presentations including hypotonia and developmental delay. Extrapyramidal signs related to infarction of the basal ganglia may be a feature of methylmalonic aciduria and propionic acidemia. Neutropenia, thrombocytopenia, and anemia are common in the neonatal presentation, whereas neutropenia also may be a feature of a later presentation. Sepsis may be a significant compo-nent of clinical exacerbations, particularly in propionic acidemia. Pan-creatitis has been reported to be associated with these disorders.209 Cardiomyopathy also may develop, particularly during metabolic decompensation.210 Isovaleric aciduria, propionic acidemia, and meth-ylmalonic aciduria are diagnosed by the organic acid profiles, and tandem mass spectroscopy may be useful by looking at the acylcarni-tine profiles.

Patients presenting in the neonatal period with encephalopathy require treatment with limitation of protein intake (this requires varied adjustment to a diet with appropriate amino acid profile), removal of toxin (exchange transfusion may be useful; methylmalonic aciduria can be cleared renally if adequate fluid volumes are given), ensuring normal glucose levels, promoting anabolism, and manage-ment of sepsis. Some patients with methylmalonic aciduria may respond to therapy with hydroxycobalamin, and this should be given for several days to assess response. Supplemental glycine should be given to patients with isovaleric aciduria, and carnitine supplementa-tion is useful for all. Some patients with propionic acidemia may benefit from metronidazole to decrease propionate metabolites from the bowel.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia presents in early infancy with severe encephalopathy in the absence of acidosis, ketosis, hypoglycemia, hyperammonemia, or any other clinical abnormalities. Although the outcome is almost invariably poor, there have been more recent descriptions of transient neonatal hyperglycinemia.211 There also is an association of abnormality of the corpus callosum with nonketotic hyperglycinemia.212 Diagnosis is confirmed by the presence of high CSF glycine. The enzyme defect can be confirmed on a liver biopsy specimen.213,214 Sodium benzoate may be helpful in therapy, possibly in combination with imipramine.215

HYPOGLYCEMIA AND INBORN ERRORS OF METABOLISM

The reader is referred to the section on endocrine crises for an approach to hypoglycemia. In hyperinsulinemia, the hypoglycemia typically develops soon after the intake of a feed, whereas patients with defects in fatty acid oxidation tend to be able to tolerate fasts of 4 to 8 hours. In hyperinsulinemia, it often is difficult to provide adequate amounts of glucose to correct the hypoglycemia (may require >12 mg/kg/min together with glucagon to control the hypoglycemia). In defects of gluconeogenesis, the hypoglycemia is relatively easy to control but usually does not respond to glucagon administration. In hereditary fructose intolerance, the onset of hypoglycemia is concurrent with the introduction of sucrose (source of fructose) into the diet. Although hypoglycemia may occur in association with sepsis, many inborn errors of metabolism are associated with sepsis (e.g., direct association with Escherichia coli and galactosemia, sepsis as precipitant of crisis, or ill health from inborn error of metabolism causing increased risk of sepsis) and should be considered diagnostically even if sepsis is proven.

Investigation and Management

If the glucose level is low, a venous specimen of blood should be col-lected immediately for laboratory glucose estimation (because bedside measuring techniques may be inaccurate at low levels of glucose). The clinician should give 0.5 g/kg of 10% to 25% dextrose in water (diluted with water for injection) promptly as a bolus IV followed by

always available, and results may take some time. Screening tests on the urine may point in the direction of certain conditions.

Urinary and Blood Ketones. Ketones are unusual in the neonatal period but tend to be a feature of maple syrup urine disease and pro-pionic, isovaleric, and methylmalonic acidemia. Quantitative determi-nation of blood ketones (acetoacetate using urine ketone strips or β-hydroxybutyrate by specific blood strip) may be a useful bedside screen.

Urinary Organic Acids. Urinary organic acids are abnormal in maple syrup urine disease, organic aciduria, and fatty acid oxidation defects.

Management.  The principles of therapy are as follows:1. Maintain airway control and breathing.2. Maintain circulation.3. Treat underlying or associated sepsis.4. Remove toxic compounds.5. Ensure an appropriate energy source for the body.6. Provide any specific therapy that is available.

The toxic compounds that potentially can be removed include ammonia and leucine (see details subsequently).

SPECIFIC INBORN ERRORS OF METABOLISM

Maple Syrup Urine Disease

If there is no acidosis and the ammonia is not increased, maple syrup urine disease (MSUD) should be considered. Patients typically are not dehydrated, are not acidotic, have no hyperammonemia, and have no hematologic abnormalities. Cerebral edema is a feature of maple syrup urine disease within the neonatal period and during later presentations.

The urine may smell like maple syrup, but the smell is also similar to that of burned sugar.202 The urine smell may be difficult to detect in the first few days of life, then may be detected on diapers that have been allowed to dry.206 Urine tests for ketones are usually strongly posi-tive, and dinitrophenylhydrazine is usually positive, although both tests may be negative before 3 days of age.206 Tandem mass spectrometry is the quickest and most efficient screening test in neonates. Leucine levels can be checked rapidly on whole-blood filter paper specimens, or quantitative amino acid analysis should be done on plasma or serum. Principles of management have been to remove leucine using dialysis and to reduce the production of leucine by dietary manipula-tion. Hemodialysis has been shown to decrease leucine levels rapidly,207 particularly if used in conjunction with dietary therapy. Previously, exchange transfusion, peritoneal dialysis, and hemofiltration were reported to decrease leucine levels. Morton and colleagues206 have used a protocol consisting of total caloric intake of 120 to 140 kcal/kg/d, with lipid forming 40% to 50% of calories; 3 to 4 g/kg/d of protein as essential and nonessential amino acids, with 80 to 120 mg/kg/d each of isoleucine and valine and 250 mg/kg/d each of glutamine and alanine, with tyrosine, histidine, and threonine supplemented to nor-malize plasma amino acid ratios; careful attention to sodium balance to ensure that serum sodium is kept at greater than 140 mEq/L; and hyperosmolar therapy if cerebral edema develops. This protocol pro-duces decreases in leucine equal to that seen after dialysis. Recent studies suggest that norleucine may have a place in reducing brain injury in patients with MSUD.208

Isovaleric Aciduria, Methylmalonic Aciduria, and Propionic Acidemia

Isovaleric aciduria, methylmalonic aciduria, and propionic acidemia may present in the neonatal period with encephalopathy hyperam-monemia, ketoacidosis (occasionally hyperammonemia may induce a respiratory alkalosis), moderate lactic acidosis, and hypocalcemia. The smell associated with isovaleric aciduria may be distinctive (“sweaty feet”). Blood glucose levels may be variable from hypoglycemia to hyperglycemia. Dehydration is a feature of the clinical presentation, partly related to vomiting and poor intake and partly related to poor

1248 PART 10 Endocrine

Diagnosis is based on the clinical features described earlier: tolerance of 8 to 24 hours of fasting, high plasma free fatty acid levels, normal to low ketone levels, increased urinary organic acids (C-6 to C-10 dicar-boxylic acids), and low plasma carnitine levels. The abnormal findings may not be present between acute exacerbations, and it is crucial to collect specimens during the acute illness. Urine specimens must be collected; blood can be collected on filter paper for tandem mass spec-trometry (these assays may be abnormal while the child is well). Specific mutation analysis is available for the most common medium-chain acyl-CoA deficiency. Treatment consists of supplying adequate glucose, supplementing carnitine, and providing symptomatic support.

HYPERAMMONEMIA

Transient hyperammonemia may occur in preterm infants in so-called transient hyperammonemia of the newborn, which is not associated with an inborn error of metabolism. Aggressive therapy may be associ-ated with completely normal outcome. Hyperammonemia results in a marked encephalopathy, although patients typically are more hypo-tonic than in other metabolic encephalopathies and may develop a respiratory alkalosis, which is uncommon in other encephalopathies.

Primary hyperammonemia occurs in the urea cycle defects, but a secondary hyperammonemia may occur in defects of fatty acid oxida-tion or organic acidemia. Hyperammonemia also may be a conse-quence of acute hepatic failure (e.g., with acute viral infection; toxin ingestion; and drug reactions, particularly antituberculosis drugs).

Investigation

Ammonia is potentially toxic, and therapy must be instituted urgently to remove ammonia. It is crucial to collect appropriate diagnostic specimens at the time of presentation because it may be difficult to establish a diagnosis when dialysis and other therapy have been insti-tuted. The following tests enable an approach to diagnosis.218

Plasma Ammonium Levels.  Hyperammonemia with levels of greater than 250 µmol/L typically are associated with urea cycle defects or transient hyperammonemia of the newborn.

Arterial  Blood  Gas  Analysis.  Hyperammonemia with urea cycle defects and transient hyperammonemia of the newborn are not associ-ated with acidosis. Patients often may have a respiratory alkalosis. A metabolic acidosis is more likely to be associated with organic acidopathies.

Tests of the Urea Cycle.  Tests of the urea cycle include plasma citrul-line, urinary argininosuccinic acid synthetase, and urinary orotic acid.

Amino Acids.  Quantitative amino acids may be difficult to interpret but help with diagnosis of conditions such as methylmalonic aciduria, isovaleric aciduria, and propionic acidemia.

Carnitine Levels and Acylcarnitine Analysis.  Carnitine and the acyl-carnitines may be affected as part of the aminoacidemias.

Management

Principles of management for hyperammonemia consist of the following:

1. Provide IV glucose and lipid to decrease ammonia production from endogenous protein breakdown.

2. Administer arginine (l-arginine hydrochloride, 600 mg/kg IV over 1 hour, followed by 2 to 4 mmol/kg/24 h in 4 divided doses).

3. Administer sodium benzoate (250 mg/kg IV followed by 250 mg/kg/d in 4 divided doses) and sodium phenylacetate (250 mg/kg IV immediately followed by 250 mg/kg/24 h in 4 divided doses).

4. Dialyze to remove excessive ammonia. Hemodialysis is the most efficient means to remove ammonia, hemofiltration is the next option (and may be particularly useful in neonates who are too unstable to tolerate hemodialysis), and finally peritoneal dialysis

administration of 4 to 8 mg/kg/min of glucose. The glucose level should be reviewed within 30 minutes. The rate of glucose infusion may need to be increased, and high requirements suggest hyperinsulinemia.

Urine for Reducing Substances.  Glucose should be excluded, but in the setting of hypoglycemia, this is unlikely unless there have been substantial doses of glucose given. If reducing substances are positive, this suggests galactosemia, hereditary fructosemia, or tyrosinemia.

Urinary Ketones.  If urinary ketones are positive, the clinician should assess for urinary and plasma organic acids and quantitative amino acids. High urinary ketones in the presence of hepatomegaly suggest glycogen storage disease type 1, fructose-1,6-diphosphatase (FDPase) deficiency, or β-ketothiolase deficiency.216 In the last-mentioned condi-tion, lactate levels are normal, whereas they are increased in glycogen storage disease type 1 and FDPase deficiency. In the absence of hepa-tomegaly, high ketones suggest ketotic hypoglycemia or deficiencies of growth hormone or glucocorticoids.

Plasma Free Fatty Acids.  If plasma free fatty acids are elevated, the patient is likely to have a fatty acid oxidation defect, but if they are low, hyperinsulinemia is more likely.

Lactate  Levels.  Lactic acidosis in association with hypoglycemia is characteristic of defects of gluconeogenesis such as glycogen storage diseases.

Urinary  Organic  Acids,  Plasma  Amino  Acids,  and  Ammonia Levels.  Urinary organic acids, plasma amino acids, and ammonia levels should be measured, because hypoglycemia may be a feature of abnormalities of all these systems.

Specific Conditions Associated with Hypoglycemia

Galactosemia.  Please see the section on hepatitis. Hypoglycemia may be a prominent feature of galactosemia, whereas hepatitis may be a more common presentation.

Hereditary Fructose Intolerance.  Hereditary fructose intolerance is characterized by the onset of severe vomiting and hypoglycemia after the ingestion of fructose or sucrose.

Glycogen  Storage  Disease  Type  1.  Glycogen storage disease type 1 may present in the neonatal period with hypoglycemia which may be mild or easily controlled. However, the patients present later with hepatomegaly and lactic acidosis. Characteristically, the hypoglycemia does not respond to therapy with glucagon.

Fatty Acid Oxidation Defects.  Fatty acids are metabolized primarily via β-oxidation in the mitochondria and to a lesser extent in the per-oxisomes (β-oxidation) and the microsomes (ω-oxidation). Defects in the mitochondrial oxidation of free fatty acid result in the accumula-tion of fatty acid oxidation products, which may be responsible for encephalopathy, hepatocellular dysfunction, and cardiac arrhythmias, which are a potentially fatal complication of fatty acid oxidation defects. Defects in fatty acid oxidation also may result in failure to meet the energy requirements of tissues such as skeletal muscles or cardiac muscles, resulting in myopathy or cardiomyopathy.

Many studies have suggested that fatty acid oxidation defects may be an important cause of SIDS. Fatty acid oxidation defects are an important cause of cardiomyopathy.217

Medium-chain acyl-CoA deficiency is the most common of the fatty acid oxidation defects and most frequently presents with a Reye-like episode, with acute or recurrent Reye-like episodes with vomiting, encephalopathy hypoglycemia, and hyperammonemia. Cardiomyopa-thy never occurs in medium-chain acyl-CoA deficiency. Cardiomyopa-thy is a more common presentation of carnitine deficiency and long-chain acyl-CoA dehydrogenase deficiency.

168  Endocrine and Metabolic Crises in the Pediatric Intensive Care Unit 1249

in which thiamine was associated with clinical improvement, although high levels may be required.223

Lactic acidosis occurs in all of the conditions affecting the metabo-lism of pyruvate through the tricarboxylic acid cycle. Abnormalities include pyruvate dehydrogenase deficiency and mitochondrial energy cycle defects. The mitochondrial energy cycle problems frequently are associated with persistent lactic acidosis, myopathy, failure to thrive, psychomotor retardation, and seizures. Other symptoms that may be present in mitochondrial energy conditions in children include ante-natal problems,224 cardiomyopathy225-227 and cardiac arrhythmias,225 sensorineural hearing loss,228 stroke and abnormalities of central respi-ratory drive,229 and diabetes mellitus.230

Acquired defects in mitochondrial function have been associated with severe lactic acidosis in adults and children on antiretroviral therapy.231 Lactic acidosis also may be a secondary phenomenon of defects of organic acid metabolism, including 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, propionic acidemia, and methyl-malonic acidemia.

Ketoacidosis

Primary defects in ketone use are rare but include β-ketothiolase defi-ciency, which may respond rapidly to administration of IV glucose. Ketoacidosis is a common feature of many of the organic acidemias, including MSUD, methylmalonic acidemia, propionic acidemia, and isovaleric aciduria. Investigation of patients with ketoacidosis should include measurement of urinary organic acids.

CARDIOMYOPATHY

A wide variety of inborn errors of metabolism may present with car-diomyopathy or cardiac arrhythmias. In most of these conditions, other clinical problems and symptoms predominate (e.g., in glycogen storage disease, organic acidopathies), and the cardiomyopathy is just part of an overall picture. In these situations, the diagnosis is assisted by the associations.

A few conditions may present with cardiac problems apparently in isolation. In the differential diagnosis of myocarditis/cardiomyopathy, many conditions need to be excluded, including carnitine deficiency, trifunctional protein defects, or isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. In the latter two conditions, urinary organic acid analysis at the time of the acute illness shows the presence of medium-chain and long-chain dicarboxylic acids. At least one form of very-long-chain acyl-CoA dehydrogenase deficiency can present as an acute cardiomyopathy. For all these conditions, measurement of acyl-carnitines using tandem mass spectrometry allows diagnosis. Diagnosis is confirmed using enzyme activity in cultured fibroblasts. At least one case report232 shows that substantial clinical improvement can be achieved by elimination of long-chain fatty acids from the diet (replac-ing with medium-chain fatty acids). Many of the disorders of the mito-chondrial energy chain have poor myocardial function as a component of their multiple symptoms, but echocardiography may be needed to show more subtle features of poor contractility.

HEPATOPATHOLOGY

Inborn errors of metabolism can affect the liver in a variety of ways. Patients may present with symptoms ranging from acute hepatic failure to hepatomegaly to chronic hepatitis to cirrhosis. The hepatic dysfunction may present in apparent isolation or in association with cardiac, cerebral, muscle, and renal disease. The presentations of “hep-atitis” may be virtually indistinguishable from the presentation of acute viral hepatitis or toxin ingestion.

In one study of infants presenting to a transplant service in acute hepatic failure, inborn errors of metabolism were responsible for the hepatic failure in 42.5% of the patients. Of these patients, 35% had hepatorenal tyrosinemia, whereas 50% had mitochondrial abnormali-ties. Hereditary fructose intolerance and galactosemia together were present in less than 9% of patients.233

may be used. Exchange transfusion has been performed but is relatively inefficient at removal of ammonia.

METABOLIC ACIDOSIS

Metabolic acidosis can occur in many ways. It may be related to inad-equate excretion of acid via the kidneys (e.g., proximal and distal renal tubular acidosis) or excessive production of acid in the body. In the case of inadequate excretion of acid from the kidneys, the pH of the urine almost always is inappropriately high. In addition, there is no anion gap. In the context of excessive acid production, there is an excessive anion gap.

The most common acids related to an increased anion gap are lactic acid and ketoacids, such as acetoacetate and 3-butyrobutyrate. All the organic acidopathies and aminoacidopathies may be associated with an increased anion gap, however. A variety of inborn errors of metabo-lism may be associated with proximal renal tubular acidosis, particu-larly cystinosis and Lowe syndrome.

Acid also may be produced by bacterial overgrowth in the bowel and absorbed, as occurs in d-lactic acidosis.219 d-Lactic acid is not detected by routine blood tests for lactic acid, which employ a lactic dehydro-genase, but is detected by urinary assays for organic acids. These patients present with acidosis with increased anion gap.

Patients with organic acidemias rarely present with metabolic aci-dosis as a primary feature of the illness, and the rest of the clinical presentation frequently provides clues as to the appropriate line of investigation. Investigation of organic acids remains an important component of the investigation of any patient, however, with unex-plained metabolic acidosis.

Lactic Acidosis

Lactic acidosis is associated with inadequate oxygenation of tissues, as occurs in hypoxemia or in shock. In this situation, treatment consists of ensuring adequate oxygen content of blood and appropriate cardiac output.

So-called primary lactic acidosis occurs in the absence of hypoxemia and shock. Lactate accumulates either as a consequence of increased production of lactate or because of inadequate clearance and metabo-lism of lactate (primarily in the liver). Accumulation of lactate may occur without the development of acidosis, depending on the compen-satory mechanisms. Many patients with congenital lactic acidosis have increased lactate levels with no acidosis between episodes of exacerba-tion, although episodes of exacerbation usually are associated with severe lactic acidosis.

Congenital lactic acidoses are variable in presentation, ranging from severe neonatal lactic acidosis with generally poor prognosis to chil-dren with milder defects and other children with syndromes such as the MELAS and MERRF syndromes and Leigh disease. In many of these conditions, the lactic acidosis is completely or partially overshad-owed by the other clinical features of the conditions. Not all children with defects of mitochondrial energy metabolism have elevated levels.

Lactate production may be caused by increased glycolysis (e.g., gly-cogen storage disease type 1, hereditary fructose intolerance) or by decreased oxidation of pyruvate. Oxidation of pyruvate can be limited by many conditions, including the following:

1. Pyruvate dehydrogenase complex deficiency2. Primary pyruvate carboxylase or holocarboxylase deficiency (this

is related to biotin/biotinidase deficiency)3. Electron transport chain defects (associated with increased

lactate pyruvate ratios in blood and CSF)The clinical course of pyruvate dehydrogenase deficiency may be

extremely variable, and diagnosis is confirmed by studies of enzyme activity in cultured fibroblasts. The lactic acidosis in pyruvate dehy-drogenase deficiency can be ameliorated by a ketogenic diet,220 although many factors must be considered before embarking on this diet, including its protein content, particularly if there is associated renal failure, and the long-term problems of ketogenic diets.221 Dichloroace-tic acid may be helpful in some cases.222 Many cases have been reported

1250 PART 10 Endocrine

Boles RG, Buck EA, Blitzer MG, et al. Retrospective biochemical screening of fatty acid oxidation disorders in post-mortem livers of 418 cases of sudden death in the first year of life. J Pediatr 1998;132:924-33.The authors devised a biochemical protocol for evaluation of frozen postmortem liver specimens for defects of fatty acid oxidation. On review of specimens from 418 cases of sudden death in the first year of life, the authors were able to identify 14 cases that closely matched the biochemical profiles seen in fatty acid oxida-tion defects. No cases of death due to abuse or accidents tested positive. Of deaths that had been classified as infectious, 20% showed multiple abnormalities in the liver specimens, suggesting that fatty acid oxidation defects should be considered as part of the differential diagnosis of sudden or unexpected death, even when an infectious agent has been identified.

Dunger DB, Sperling MA, Acerini CL, et al. ESPE/LWPES consensus statement on DKA in children and adolescents. Arch Dis Child 2004;89:188-94.This is an extensive evidence-based review of acute DKA in children and adolescents. Consensus guidelines are presented with appropriate references for the management of acute DKA in children and adolescents.

Durand P, Debray D, Mandel R, et al. Acute liver failure in infancy: A 14-year experience of a pediatric liver transplantation center. J Pediatr 2001;139:871-6.This article presents a 14-year review of 80 infants (children <1 year old) admitted to the pediatric hepatol-ogy unit or ICU of a French hospital with acute liver failure (defined as prothrombin time >17 seconds and factor V plasma levels <50% of normal). Acute liver failure was a result of inherited metabolic disorders in

Hepatorenal tyrosinemia may present in the neonatal period as acute hepatic failure. It is difficult to distinguish from acute viral hepatitis, because plasma amino acid levels may be similar in both situations. Alpha-fetoprotein levels may be substantially elevated in hepatorenal tyrosinemia and may be a distinguishing feature. The coagulopathy tends to be relatively severe in hepatorenal tyrosinemia, and coagulopathy may be the only presenting feature of hepatorenal tyrosinemia.234 Patients tend to have moderate to severe anemia. The response to treatment with 2-(2-nitro-4-triflu-oromethylbenzoyl)-1,3-cyclohexandion (NTBC) may be dramatic.235-238

Galactosemia is characterized by the development of hypoglycemia in the neonatal period in association with jaundice (initially unconju-gated, but subsequently conjugated), marked increase in transaminase levels, some abnormality of coagulation, and moderate hypoalbumin-emia. Severe cerebral edema occasionally may be a dominant feature. Management has been reviewed elsewhere.239 There is a close associa-tion with Escherichia coli septicemia, and any infant presenting with E. coli septicemia should be investigated for galactosemia. Galactosuria clears rapidly if feeds are stopped. A screening test is available on blood collected on filter paper (semiquantitative measure of galactose-1-phosphate uridyltransferase). The diagnosis can be confirmed on a quantitative measurement of galactose-1-phosphate uridyltransferase. Wilson’s disease may present as acute hepatitis, but rarely before age 5 years.

KEY POINTS1. Although endocrine and metabolic conditions are individually

rare,collectivelytheyconstituteasignificantcauseofpathologyinthepediatricintensivecareunit(PICU).

2. PICU admission is a crucial opportunity to identify endocrineproblemsandinbornerrorsofmetabolism.

3. Hyperglycemia and hypoglycemia are important metabolicabnormalitiesandrequirebothanetiologicdiagnosisandman-agement. A cause for hypoglycemia or hyperglycemia alwaysmustbeidentified.

4. Inbornerrorsofmetabolismalwaysmustbeconsideredaspartof the differential diagnosis of critical illness, particularly inyounginfants.

5. Appropriatespecimensshouldbecollectedat thetimeof theacute illness,andthereafter theclinicianshouldconsultwithaspecialistlaboratoryfordiagnosticroutes.

6. Specialistteamsshouldbeconsultedearlyinthecourseoftheillness,because few intensivistsdevelopexpertise in theman-agementofinbornerrorsofmetabolism.

7. Amultidisciplinaryteamapproachisessentialtosuccessfulcareforaffectedchildren.

ANNOTATED REFERENCES42.5% of cases, including mitochondrial respiratory chain disorders, type 1 hereditary tyrosinemia, and urea cycle defects.

Marcin JP, Glaser N, Barnett P, et al. Factors associated with adverse outcomes in children with DKA-related cerebral edema. J Pediatr 2002;141:793-7.This is a retrospective study of 61 children (≤18 years old) from 10 U.S. pediatric centers admitted between 1982 and 1997 with DKA and cerebral edema. Only 59% survived without neurologic sequelae, and 28% died or survived in a vegetative state. Intubation with hyperventilation was associated with adverse outcome after adjustment for confounding variables. Poor outcome also was associated with greater neurologic depression at the time of diagnosis and a higher initial serum urea nitrogen concentration.

Morton DH, Strauss KA, Robinson DL, et al. Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 2002;109:999-1008.This article evaluates an approach to the diagnosis and treatment of MSUD. Eighteen neonates were diagnosed as having MSUD between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. No infant identified before 3 days of age and treated with the protocol became ill during the neonatal period. A further 18 neonates who were intoxicated at the time of diagnosis responded rapidly to the management protocol without the need for dialysis or hemoperfusion. Follow-up of the 36 infants over more than 219 patient-years showed generally good metabolic control, with good developmental outcome. A management protocol is presented.

REFERENCES

Access the complete reference list online at http://www.expertconsult.com.