UMEM Educational Pearls

Inborn errors of metabolism (IEM) are rare, each typically affecting 1 in 5000 to 1 in 100,000 children, BUT collectively these disorders are more common because there are so many. If you are lucky…when they present to the ED they come with a letter from Dr. Greene (our world renowned metabolic geneticist) detailing exactly what to do. The rest of the time…you are on your own. Think about IEM in any neonate or child with history of feeding difficulties, failure to thrive, recurrent vomiting, unexplained altered mental status and/or acidosis. Pay particular attention to feeding difficulties that appear with changes in diet: switch from soy to cow’s milk formula (galactose), addition of juice or fruit or certain soy formulas (fructose), switch from breast milk to formula or foods (increased protein load), and longer fasting periods from sleeping or illness.

For this pearl, we will focus on primary hyperammonemia from an enzymatic block in ammonia metabolism within the urea cycle. It is important to remember that secondary hyperammonemia can result from metabolic defects such as organic acid disorders, fatty acid oxidation disorders, drugs that interfere with urea cycle, or severe liver disease. Amino acids liberated from excess protein breakdown (stress of newborn period, infection, injury, dehydration, surgery, or increased intake) release nitrogen which circulates as ammonia. Ammonia is then converted to urea via the urea cycle and excreted in the urine. With urea cycle defects (UCD) there is an enzymatic block in the cycle that results in accumulation of ammonia which has toxic effects on the CNS especially cerebral edema. The most common UCD is ornithine transcarbamylase deficiency followed by argininosuccinic academia, and citrullinemia.

Clinical presentation includes poor feeding, lethargy, tachypnea, hypothermia, irritability, vomiting, ataxia, seizures, hepatomegaly, and coma. Hyperammonemic crises in neonates mimic sepsis! If you think about an IEM in your differential, send plasma ammonia (1.5 mL sodium-heparin tube on ice STAT), plasma amino acids, and urine organic acids. Other helpful labs include blood gas, CMP, urinalysis (looking at ketones), lactate, plasma acylcarnitines, and newborn screen if not already sent. Plasma ammonia is a direct index of CNS toxicity and important to follow for acute management. Serum level > 150 in sick neonate or > 100 in sick infant/child is concerning for IEM. The presence of hyperammonemia and respiratory alkalosis suggest urea cycle defect. The presence of metabolic acidosis and hyperammonemia suggests organic acid disorder.

Immediate treatment of hyperammonemia is critical to prevent neurologic damage. Cognitive outcome is inversely related to the number of days of neonatal coma caused by the cerebral edema.

1. Stop all protein intake! You need to stop catabolism.

2. Start D10 at 1.5 times maintenance rate with GIR at least 6-8. Start intralipids 1-3g/kg/day when able (typically in the ICU after central line placed).

3. Give ammonia scavenger medications sodium benzoate and sodium phenylacetate. These are available commercially as Ammonul.

     a. 0-20kg: 2.5mL/kg IV bolus over 90 min followed by same dose as 24 hr infusion

     b. >20kg: 55 mL/m2 IV bolus over 90 min followed by same dose as 24 hr infusion

4. HEMODIALYSIS! Dialysis is the most effective way to remove ammonia and should be done when level > 300. The decision to hemodialyze is crucial in preventing irreversible CNS damage; when in doubt in the face of elevated ammonia, HEMODIALYZE!