Neonatal Hyperammonemia and Continuous Renal Replacement Therapy

Neonatal hyperammonemia (NH) is a life-threatening medical emergency. NH should be suspected if the plasma ammonium level is greater than 150 umol/L in a neonate. Disorders leading to hyperammonemia result from the inability of the body to excrete nitrogenous waste, as seen with inborn errors of metabolism involving urea cycle or organic acidemias. The initial diagnosis of such disorders may be delayed as a result of the nonspecificity of presenting signs and symptoms, such as poor feeding, vomiting, hypotonia, irritability, and somnolence ( Fig. 207.1 ). For many disorders, newborn screening tests have little impact on management or prognosis at time of initial presentation, because results may be yet unavailable. Eight identified inborn errors of ureagenesis (seven autosomal recessive and one X-linked) have a combined estimated prevalence of 1 in 30,000 live births, and together constitute the most common causes of neonatal hyperammonemia ( Fig. 207.2 ). These disorders typically manifest within 12 to 72 hours of birth. The main goals of therapeutic interventions for the treatable inborn errors of metabolism are early recognition and prompt treatment of hyperammonemia, with the aim of preventing progressive neurologic damage and limiting morbidity and mortality. Data suggest that a lower presenting serum ammonia concentration (less than 150–200 µmol/L) is associated with improved survival with fewer or milder neurologic sequelae, whereas higher presenting plasma ammonia concentration (greater than 200 µmol/L) is associated with decreased survival and more severe neurologic deficits. Thus patient outcome is highly dependent on the speed with which the diagnosis is made (or suggestive abnormalities are detected) and treatment initiated.

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Flow diagram for the causes of hyperammonemia. Urea cycle defects: AS, argininosuccinate synthetase; CPS, carbamoylphosphate synthetase; OTC, ornithine transcarbamylase; THN, transient hyperammonemia of the newborn.

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Urea cycle pathway. Thin arrows indicate primary pathway. Thick arrows show alternative pathways used to eliminate nitrogen in patients with urea cycle defects. Enzymes are in boxes . Acetyl-CoA, Acetyl-coenzyme A; AL, argininosuccinate lyase; ARG, arginase; AS, argininosuccinate synthetase; CPS, carbamoylphosphate synthetase; NAGS, N -acetylglutamate synthase; OTC, ornithine transcarbamoylase.

To prevent permanent neurologic sequelae and/or death secondary to the extensive neurotoxicity of increased levels of ammonia, current recommended guidelines for initial treatment include (1) restriction of nitrogen supply (e.g., removal of protein intake); (2) subsequent supply of adequate glucose-based calories to inhibit of endogenous catabolism; (3) substitution of missing metabolites such as carnitine, thiamine, biotin, B12; (4) increased clearance of toxic compounds; and (5) in patients not responsive to medical therapy alone, extracorporeal removal of metabolites through renal replacement therapy (RRT). The use of dialysis for treatment of neonatal hyperammonemia has become standard practice when dietary and medical interventions fail. RRT should be initiated within 6 hours in patients who do not respond to medical therapy with continuation of medical therapy, as noted above, while on RRT.