Patrick D. Brophy
Individual inborn errors of metabolism are rare, but with emerging diagnostic capabilities, many specific disorders can now be identified. The neonatal period is a critical time for detection as well as treatment of a significant proportion of disorders due to inborn errors of metabolism. The initial diagnosis of such disorders often is delayed as a result of the nonspecificity of presenting signs and symptoms, which may include poor feeding, vomiting, hypotonia, irritability, and somnolence. Inborn errors of metabolism are strongly suggested, however, by findings of hyperglycemia or hypoglycemia and hyperammonemia or ketoacidosis on common blood chemistry studies, including comprehensive metabolic panels. The clinical presentation of urea cycle disorders may be that of a severely ill child with hyperammonemia and a low blood urea nitrogen (BUN) concentration with respiratory alkalosis, whereas patients with organic acidemias or congenital lactic acidosis commonly demonstrate laboratory results consistent with metabolic acidosis or ketoacidosis with hyperammonemia. For many disorders, screening tests have little impact on management or prognosis, because results are unavailable at the time of presentation. Many abnormalities are acutely treatable, particularly hyperammonemia; therefore, any delay in initiating treatment can lead to permanent neurological damage.
The main goals of therapeutic interventions for the treatable inborn errors of metabolism are early recognition and prompt treatment, with the aim of preventing progressive neurological damage and limiting morbidity and mor-tality. Along with appropriate clinical examination and correction of dehydration (which almost always is present in these patients) or any electrolyte abnormalities, the use of continuous renal replacement therapy (CRRT) for treatment of inborn errors of metabolism (such as urea cycle defects) (Fig. 298-1) has become standard practice when dietary and medical interventions fail to produce improvement.
Hyperammonemia results from the inability of the body to excrete nitrogenous waste, as seen during inborn errors of metabolism involving the urea cycle or organic acidemias (Fig. 298-2). Both ammonia, levels of which are elevated in urea cycle defects and some organic acidemias, and branched-chain amino acids, levels of which are elevated in maple syrup urine disease, have been shown to be effectively cleared by CRRT, demonstrating this to be an efficient adjuvant therapy for acute management of inborn errors of metabolism.[3–6]
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 cause of neonatal hyperammonemia. These disorders typically manifest within 12 to 72 hours of birth. To prevent permanent brain damage and death secondary to the extensive neurotoxicity of increased levels of ammonia, the current recommended guidelines for initial treatment include (1) restriction of nitrogen supply; (2) inhibition of endogenous catabolism by providing adequate calories; (3) substitution of missing metabolites; (4) increased clearance of toxic compounds; and (5) in patients not responsive to medical therapy alone, extracorporeal removal of metabolites through dialysis.
Treatment of severe hyperammonemia (serum ammonia levels greater than 1000 μmol/L) should begin with hemodialysis when medically appropriate and tolerated, because CRRT has an efficacy of only 5% to 15% of that achieved with hemodialysis. Once serum ammonia levels are less than 200 μmol/L, transition to CRRT is appropriate. This combined use of initial hemodialysis followed by CRRT has been shown to result in improved control of hyperammonemia and prevents the rebound of serum ammonia levels seen with intermittent therapy alone. CRRT alone may be used as an initial therapy in patients with less severe hyperammonemia (serum ammonia levels less than 500 μmol/L), but in the event that levels increase during CRRT, use of hemodialysis must be considered. Peritoneal dialysis has little role in the treatment of these disorders.
Because the goal of any treatment in patients with inborn errors of metabolism is rapid removal of toxic metabolites (such as ammonia or branched-chain amino acids), appropriate pharmacological therapy needs to be initiated as soon as possible to control the primary disease, in addition to the initiation of hemodialysis or CRRT, or both. CRRT prescriptions should be altered to maximize clearance of the toxic molecules. Recommendations are for blood flow rates to increase by 100% from 4 to 5 mL/kg per minute to 8 to 10 mL/kg per minute and for dialysate flow rates to increase by 50% to 100% from 2000 mL/1.73 m2 to 3000 to 4000 mL/1.73 m2, when possible. With increased flow rates effectively increasing clearance, electrolytes should be monitored frequently (every 6 hours), and care must be taken to prevent the development of any abnormalities, particularly hypophosphatemia. Patients with inborn errors of metabolism who do not have acute oliguric or anuric renal failure will routinely require potassium- and phosphate-containing dialysate during renal replacement therapy (hemodialysis or CRRT).
Studies continue to demonstrate that a lower presenting serum ammonia concentration (less than 200 μmol/L) is associated with improved survival and fewer or milder neurological sequelae, and a high presenting plasma ammonia concentration (greater than 200 μmol/L) demonstrates a trend toward decreased survival and more severe neurological deficits. Deodato and colleagues, with limited data, showed short-term prognosis to be related to the duration of hyperammonemic coma. With the very young age at presentation for most inborn errors of metabolism involving hyperammonemia, the outcome is highly dependent on the speed with which the diagnosis is made (or suggestive abnormalities are detected) and treatment initiated.
Complications related to CRRT in the treatment of inborn errors of metabolism can be associated with cardiovascular compromise (hypotension or arrhythmias) or hypothermia. McBryde and associates observed that the most common complication was hypotension. The high risk of hypothermia in patients with inborn errors of metabolism and severe hyperammonemia is a result of the combination of small patient size (generally these patients are infants), low blood volumes, and increased blood flow rates required for adequate toxic metabolite clearance. Implementation of preventive measures such as use of heat lamps or warming blankets, warming of the circuit tubing, or use of an in-line blood warmer should be considered with the initiation of CRRT.
CRRT has been shown to clear pharmacologically created substrates that provide alternative pathways of nitrogen removal, such as glutamine and glycine.[13–14] It also has been demonstrated that pharmacological agents (e.g., sodium benzoate, sodium phenylacetate or phenylbutyrate, arginine hydrochloride) used to treat metabolic disorders are substantially cleared with these therapies, and the administration of increased doses of these agents should be considered when they are used with CRRT or hemodialysis.
Unlike the management of acute renal failure, in which nutritional supplementation is required, the treatment of inborn errors of metabolism often requires that protein be significantly restricted at presentation. Depending on the duration of CRRT, long-term protein intake may range anywhere from 0.5 to 2 g/kg per day, to prevent development of a catabolic state. Increased clearance of glucose and amino acids in supplemented intravenous fluids, total parenteral nutrition solutions, or enteral feedings that occurs with CRRT needs to be taken into account. This consideration, along with the fact that many of these infants and children have otherwise appropriate renal function, necessitates careful attention to composition of the dialysate or filter replacement fluid composition in order to provide homeostatic electrolytes.