Hyperammonemia Treatment & Management

Updated: Sep 30, 2021
  • Author: Jasvinder Chawla, MD, MBA; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
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Treatment

Medical Care

The aims of treatment for hyperammonemia are to correct biochemical abnormalities and ensure adequate nutritional intake. Treatment involves compounds that increase the removal of nitrogen waste. These compounds convert nitrogen into products other than urea, which are then excreted; hence, the load on the urea cycle is reduced. The first compounds to be used were sodium benzoate and arginine. Later, phenylacetate was used, which has now been replaced by phenylbutyrate.

  • Treatment of neonatal hyperammonemic coma

    • Protein intake should be stopped.

    • Calories should be supplied by giving hypertonic 10% glucose.

    • Hemodialysis should be started promptly in all comatose neonates with plasma ammonium levels greater than 10 times reference range. Plasma ammonium levels are reduced quickly and the total dialysis time is shorter with hemodialysis than with peritoneal dialysis. Continuous arteriovenous or venovenous hemofiltration may be used as an alternative method. [29]

    • Intravenous sodium benzoate and phenylacetate should be started once the plasma ammonium level falls to 3-4 times the upper limit of the reference range.

    • Intravenous arginine should be provided.

    • Corticosteroids are not indicated for the management of increased intracranial pressure in hyperammonemia because they induce negative nitrogen balance. Mannitol is not effective in treating cerebral edema induced by hyperammonemia.

    • Valproic acid should not be used to treat seizures as it decreases urea cycle function and increases serum ammonia levels.

  • Treatment of intercurrent hyperammonemia
    • Patients with urea cycle defects may present with episodes of hyperammonemia secondary to increased protein intake, increased catabolism, or noncompliance with therapy. This should be recognized early and treated as an emergency.

    • Treatment should be started if the plasma ammonium level is 3 times the reference level.

    • All nitrogen intake should be stopped.

    • High parenteral intake of calories from 10-15% glucose and intralipids should be provided.

    • Intravenous infusion of sodium benzoate and phenylacetate should be started.

    • Plasma ammonium levels should be checked at the end of the infusion and every 8 hours.

    • Once the ammonia level is near normal, oral medication should be started.

    • If the level does not decrease in 8 hours, hemodialysis should be started.

    • Osmotic demyelination syndrome has been reported as a potential serious complication of standard therapy for hyperammonemia in patients with ornithine transcarbamylase deficiency. [30]

Patients usually can go back to their dietary regimen and oral medications in 3-4 days. They should be admitted to an intensive care unit initially, and their neurologic status should be monitored carefully.

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Surgical Care

Liver transplantation

The main goal of liver transplantation in hyperammonemia is to correct the metabolic error. In one study of liver transplantation in patients with defects causing hyperammonemia, metabolic errors were corrected in all patients, and requirements for medication and dietary restriction were eliminated. Neurologic outcomes correlated closely with status prior to transplantation. Thus, liver transplantation is a good option for patients with urea cycle defects who have not suffered major brain injury.

Liver cell transplantation, administered as multiple intraportal infusions of cryopreserved hepatocytes, has been reported as a potentially less invasive alternative or bridging to liver transplantation. [3, 4]

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Consultations

Consultation with the following may prove helpful:

  • Nephrologist for hemodialysis

  • Dietitian to help with the dietary management and education of the family

  • Geneticist for possible testing of family members and to provide genetic counseling

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Diet

Dietary management of hyperammonemia consists of

  • Low protein intake: Current recommendation is 0.7 g/kg/day of protein and 0.7 g/kg/day of essential amino acid mixture. During the first 6 months, an infant may tolerate 1.5-2 g/kg/day of protein.

  • Arginine supplementation: Arginine is an essential amino acid in patients with urea cycle defects. In neonates and in OTC and CPSI deficiencies, citrulline can be given as a source of arginine as it gives one less nitrogen atom; in late-onset cases, however, arginine is acceptable because of increased nitrogen tolerance. Citrulline levels are elevated in ASS and ASL deficiencies and citrulline should not be administered in patients with unknown enzyme deficiency.

  • Providing enough calories to meet energy requirements

  • A tube feeding may be needed to provide a stable feeding route. A gastrostomy tube is the most reliable way to administer medications and fluids during illness and helps provide adequate nutritional support to prevent catabolism. [2]

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Activity

Restricting physical activity of children with hyperammonemia is not necessary; however, caloric intake should be sufficient to avoid protein breakdown.

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Prevention

Parents should be educated to take the symptoms of hyperammonemia (ie, lethargy, vomiting, changes in behavior) very seriously. They should contact their physician immediately at the onset of these symptoms. Following dietary recommendations and compliance with medications decreases the frequency of hyperammonemic episodes.

Antenatal diagnosis of urea cycle disorders can be made using several laboratory techniques. Families should be informed about the availability of these tests if they have had an affected infant or if the mother is a carrier of OTC mutation.

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Long-Term Monitoring

Outpatient care involves monitoring growth and development of the child that would indicate the adequacy of treatment. Additionally, periodic fasting levels of the following should be determined:

  • Plasma ammonium

  • Plasma glutamine (should be maintained at < 1000 µmol/L)

  • Arginine

  • Total protein

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