Pediatric emergency medicine trisk 613

300 mg/kg/day IV or PO), which enhances secretion of organic acids, should be considered for patients
with isovaleric acidemia. Patients with holocarboxylase synthetase, biotinidase deficiency, or propionic
acidemia may improve with biotin (10 to 40 mg/day given PO or NG), those with maple syrup urine
disease may benefit from thiamine, and those with methylmalonic academia may benefit from
hydroxocobalamin (vitamin B12 ; 1 mg IM). It is usually not imperative that these cofactor therapies be
administered in the ED. Antibiotics should be administered as clinically indicated for infection.
Administration of an oral, broad-spectrum antibiotic to reduce gut flora, a significant source of organic
acids, may be beneficial but usually is not initiated in the ED. Efficacy of emergent treatment is
monitored by ongoing assessment of mental status, fluid and cardiovascular status, signs of bleeding, and
measurement of electrolytes, glucose, ammonia, and blood gas levels every 4 to 6 hours until the patient
is stabilized. Resolution of metabolic crisis usually takes days to weeks. The New England Consortium of
Metabolic Programs details treatment for specific organic acidemias on their website
.

UREA CYCLE DEFECTS
Goals of Treatment
For urea cycle defects, the specific goals of acute treatment are to eliminate protein intake, avoid protein
catabolism, remove ammonia, and treat any precipitating illness.

Current Understanding
Disorders of the urea cycle result in toxic accumulation of ammonia generated by the catabolism of
protein. Urea cycle disorders include carbamoyl phosphate synthetase 1 deficiency, ornithine
transcarbamylase deficiency, citrullinemia, argininosuccinate lyase deficiency, and arginase deficiency.
Ammonia, in excess, is a neurotoxin that results in cerebral edema as well as brainstem dysfunction.

Clinical Considerations
Assessment
Patients with severe enzyme deficiency present within the first few days of life, following consumption
of protein in breast milk or formula. Those with partial deficiency usually present within the first few
months of life, but may present even as adults, after intake of a quantity of protein that exceeds their
metabolic capacity. The most severe forms include carbamoyl phosphate synthetase 1 deficiency and

ornithine transcarbamylase deficiency, which is the most common urea cycle defect and the only one with
X-linked inheritance. Female carriers for ornithine transcarbamylase deficiency may manifest clinical
disease due to skewed inactivation of their X chromosomes, but usually present later, including during
adolescence. The other urea cycle defects affect males and females similarly. Arginase deficiency
typically presents later in life, ranging from infancy to adulthood, as a neurologic syndrome with
developmental delay and progressive neurologic abnormalities and usually less severe hyperammonemia.
Presentation even later in life can be acute, severe, and even life threatening.
Acute manifestations are anorexia, irritability, lethargy, vomiting, ataxia, seizures, progressing to
coma, and death without appropriate emergent treatment. Duration of coma is a better predictor of
outcome than is serum ammonia concentration. With late-onset forms, symptoms, although similar, are
usually episodic and/or less severe and may include subtle findings such as failure to thrive in infants and
learning and attention deficits, personality and behavioral disturbances, and migraine-like headaches in
school-age children and adolescents. Level of alertness and cardiorespiratory status must be assessed.
Potential precipitating factors, such as infection, should be investigated. Hyperammonemia is a brainstem
respiratory stimulant that results in tachypnea. Respiratory alkalosis is common, sometimes with
secondary metabolic acidosis. Increased intracranial pressure due to hyperammonemia may produce
bradycardia and elevated blood pressure. Electrolytes, blood gas, glucose, AST, ALT, alkaline


phosphatase, bilirubin, ammonia, plasma amino acid levels, CBC, and urinalysis should be obtained. All
labs except ammonia may be normal. Even patients who are not lethargic may have significant
hyperammonemia, masked by acclimatization to chronic elevations of ammonia.
Management
Immediate treatment of hyperammonemia is important to prevent morbidity and mortality ( Table 95.7 ).
Rapid consultation with an IEM specialist is crucial and central venous access may be needed. Protein
intake should be temporarily withheld (not longer than 36 to 48 hours). Although patients with urea cycle
defects are usually not hypoglycemic, dextrose should be provided in IV fluids (along with IV lipids at 1
to 3 g/kg/day) at typically 1.5 times the maintenance rate in order to maintain hydration and prevent
catabolism. IV Ammonul (sodium phenylacetate and sodium benzoate) is given via central line as a bolus
followed by 24-hour infusion in order to correct hyperammonemia. Arginine may also be used (except

those with arginase deficiency) and citrulline is used in CPS1 and OTC deficiencies to correct
hyperammonemia. Sodium chloride (not Ringer lactate) can be used to correct dehydration but should be
used with extreme caution when giving Ammonul, which is high in sodium and/or arginine, which is high
in chloride. Although patients with urea cycle defects have low levels of carnitine and may be taking L carnitine as a routine medication, patients should not receive L -carnitine while being treated with
Ammonul because it conjugates and inactivates sodium benzoate. For treatment of seizures, valproic acid
should be avoided because it decreases urea cycle activity and may therefore worsen hyperammonemia.
The New England Consortium of Metabolic Programs details treatment for specific urea cycle defects on
their
website
.

FATTY ACID OXIDATION DEFECTS
Goals of Treatment
Goals specific for the treatment of the patient with a fatty acid oxidation defect are to correct acidosis and
hypoglycemia which should correct hyperammonemia, if present.

Clinical Understanding
Disorders include enzyme deficiencies involving metabolism of short, medium, long, and very long-chain
fatty acids and carnitine transport defects. Medium-chain acyl-CoA dehydrogenase deficiency is not only
the most common fatty acid oxidation defect but also one of the most common IEMs with an incidence of
approximately 1/10,000. Patients with a fatty acid oxidation defect usually present in infancy between
ages 3 months and 2 years due to longer overnight fasts as the infant begins sleeping through the night or
due to increased metabolic demand caused by intercurrent illness, often gastroenteritis, recent surgery, or,
particularly in children and adolescents, vigorous exercise. Normally in these scenarios, inadequate
glucose availability to meet caloric demands results in catabolism of fatty acids, which are oxidized in the
mitochondria to acetyl CoA, which is used to produce ketones to meet energy needs. In fatty acid
oxidation defects, accumulation of fatty acid metabolites inhibits gluconeogenesis, causes metabolic
acidosis and has hepatotoxic effects. Inadequate energy leads to impairment of skeletal and cardiac
muscle.

Current Considerations
Assessment
Early manifestations of decompensation may include lethargy, dehydration, vomiting and/or diarrhea,
hepatomegaly, and usually hypoglycemia with absent or inappropriately low ketones (except in patients
with short-chain acyl-CoA deficiency who often produce ketones). Decompensation may progress within
hours to encephalopathy, coma, cardiac dysfunction (heart failure or pericardial effusion), liver


dysfunction, hypotonia, seizures, metabolic acidosis, and hyperammonemia. Patients with very longchain acyl-CoA dehydrogenase deficiency or long-chain L -3-hydroxyacyl-CoA dehydrogenase
deficiency may have exercise-induced rhabdomyolysis. Patients may be normal between episodes of
decompensation or may have chronic manifestations of disease that can include failure to thrive,
developmental delay, chronic peripheral neuropathy, motor deficits (with long-chain L -3-hydroxyacylCoA dehydrogenase deficiency), retinitis pigmentosa (with glutaric acidemia type II), cardiac
dysfunction, and dysmorphic facial features. Patients with a fatty acid oxidation defect are at risk for
SIDS and cardiac arrest due to hypertrophic cardiomyopathy and/or cardiac arrhythmia. Women who are
pregnant with a fetus affected with long-chain L -3-hydroxyacyl-CoA dehydrogenase deficiency are, as
carriers, at risk for HELLP syndrome.
During decompensation, laboratory assessment should include electrolytes, BUN, creatinine, blood
gas, glucose, AST, ALT, alkaline phosphatase, PT, PTT, bilirubin, ammonia, carnitine, and creatinine
phosphokinase.
Management
After administration of bolus fluid and correction of any hypoglycemia, D10 in ½ normal saline should be
continued at 1 to 1.5 times maintenance, along with insulin, if needed, to maintain serum glucose level at
120 to 170 mg/dL. Sodium bicarbonate should be administered for bicarbonate less than 16 mg/dL. In
patients with fatty acid oxidation defects, correction of acidosis and hypoglycemia usually corrects
hyperammonemia. Administration of L -carnitine is controversial because in excess, long-chain
acylcarnitine may produce cardiac arrhythmias; therefore, L -carnitine should be administered only after
consulting a metabolism specialist. Drugs that induce hypoglycemia and epinephrine, which stimulates
lipolysis, should be avoided, and if they must be given, glucose concentration should be maintained with
dextrose. Medium chain triglyceride (MCT) oil is beneficial for children with Very Long Chain Acyl
Dehydrogenase (VLCADD) Deficiency but it is dangerous for other fatty acid oxidation defects. Clinical

and laboratory parameters should be monitored until the patient is stabilized and tolerating fluid well.
Long-term patients may be on a high-carbohydrate, low-fat diet that includes a complex carbohydrate
such as cornstarch to avoid hypoglycemia. Asymptomatic siblings and parents should be tested. The New
England Consortium of Metabolic Programs details treatment for specific fatty acid oxidation defects on
their
website
.

CARBOHYDRATE DISORDERS
Disorders of Carbohydrate Intolerance
Galactosemia. Classic galactosemia, characterized by less than 1% galactose-1-phosphate
uridyltransferase activity, results in clinical symptoms usually within the first week of life, often within
the first 2 to 3 days, and may be rapidly fatal.

Goals of Treatment
Treatment goals specific for galactosemia are to eliminate galactose from the diet and recognizing and
treating possible sepsis.

Clinical Considerations
Assessment
Manifestations include poor feeding, vomiting, diarrhea, failure to thrive, bulging fontanelle lethargy that
may progress to coma, jaundice and coagulopathy due to liver disease, and/or sepsis, classically with E.
coli, which may be the initial manifestation. Most newborns will have cataracts although they may only
be appreciated by slit lamp examination.


Urine dip will be positive for non–glucose-reducing substances, that is, positive Clinitest, and have
negative or trace of glucose with glucose oxidase strip, that is, Clinistix or Glucostix. CBC will reveal
hemolysis. Electrolytes may be remarkable for hyperchloremic metabolic acidosis due to renal tubular
dysfunction. LFTs are expected to reveal markedly elevated bilirubin level, initially indirect and after 1 to

2 weeks direct, alkaline phosphate and mild to moderately elevated AST and ALT, and markedly elevated
PT and PTT. Given that most patients present as neonates, those with a known diagnosis will likely have
received the diagnosis based on NBS. Definitive diagnosis requires measurement of erythrocyte enzyme
activity, and particularly in patients with less severe presentation, it may reveal more benign forms.
Management
In addition to correction of dehydration, metabolic derangements, and infection, treatment requires
complete lifelong exclusion of galactose from the diet. In neonates, breast milk and cow milk must be
replaced with lactose-free soy formula, (e.g., Nutramigen, Pregestimil). Even when galactose-free diet is
initiated early, those who survive the neonatal period often have developmental delay or learning
disabilities.

Disorders of Carbohydrate Production or Utilization
Glycogen Storage Disorders
Goals of Treatment. Treatment goals specific for glycogen storage disorders are to correct hypoglycemia
if present and provide supportive care for organ dysfunction or failure most notably for GSD II heart and
liver, GSD IV liver, GSD V renal.
Current Understanding. Glycogen storage disorders are due to defects in glycogen synthesis, degradation,
or regulation. GSD 0, I, III, IV, VI, IX, which primarily involve liver, and GSD II, which involves
skeletal and cardiac muscle, account for the vast majority of cases in the United States and Europe.
Clinical Considerations
Assessment. GSD 0 is the most likely to result in acute decompensation, usually due to hypoglycemia
during intercurrent illness when patients are unable to take cornstarch, the mainstay of therapy.
Presentation is similar to that for fatty acid oxidation defects. Patients with GSD I, III, VI, IX may also
present with symptoms of hypoglycemia. Hepatomegaly is seen with GSD 0, I, III, IV, VI, IX.
Manifestations of skeletal muscle involvement include weakness and potentially renal failure due to
rhabdomyolysis. Depending on type, other findings can include cardiomyopathy, cardiac arrhythmias,
hemolysis, and jaundice.
Laboratory findings, depending on the organ systems involved, may include hypoglycemia, elevated
liver transaminases, ketosis, elevated CPK, myoglobinuria, elevated BUN, creatinine, anemia,
neutropenia, coagulopathy, elevated LDH and bilirubin. EKG may reveal arrhythmia or findings

consistent with cardiomegaly.
Management. Correction of hypoglycemia with glucose and glucose-containing fluids is the same as for
fatty acid oxidation defects. Enzyme replacement therapy is now available for a subset of GSDs.

NEONATE WITH POSITIVE NEWBORN SCREEN
CLINICAL PEARLS AND PITFALLS