eMedicine Specialties > Neurology > Neurotoxicology

Hyperammonemia: Treatment & Medication

Author: Elena Crisan, MD, Consulting Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital
Coauthor(s): Jasvinder Chawla, MBBS, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Associate Professor and Director, Neurology Residency Training Program, Loyola University Medical Center
Contributor Information and Disclosures

Updated: Aug 20, 2009

Treatment

Medical Care

The aims 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 Later, phenylacetate was used, which has now been replaced by phenylbutyrate.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 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.
    • Intravenous 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.
  • 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.15

Surgical Care

  • Liver transplantation: The main goal of liver transplantation is to correct the metabolic error. In one recent 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.16

Consultations

  • 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

Diet

  • Dietary management consists of the following:
    • 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, 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.
    • Providing enough calories to meet energy requirements

Activity

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

Medication

The medical management of urea cycle disorders used to be limited to dietary modifications, which were not sufficient in many patients. Introduction of compounds that promote alternate pathways for nitrogen excretion was a big breakthrough. As nitrogen is converted to compounds other than urea, the load on the urea cycle is reduced.

Urea cycle disorder treatment agents

This group consists of sodium benzoate, sodium phenylacetate, and sodium phenylbutyrate. These drugs lower blood ammonia concentrations by conjugation reactions involving acylation of amino acids. Sodium phenylbutyrate is a prodrug and is metabolized to phenylacetate. Phenylacetate then conjugates with glutamine to form phenylacetylglutamine, which is then excreted by the kidneys. On a molar basis, 1 mole of phenylacetate removes 2 moles of nitrogen.

Animal studies have demonstrated that L ornithine, which is used as a substrate for glutamine synthesis, combined with phenylacetate, acted synergistically and produced a sustained reduction in ammonia and brain water in cirrhotic rats.17


Sodium benzoate and sodium phenylacetate (Ucephan)

Benzoate combines with glycine to form hippurate, which is excreted in urine. One mole of benzoate removes 1 mole of nitrogen.

Adult

250 mg/kg/d PO in 3-6 equally divided doses; not to exceed 10 g/d each of sodium benzoate and sodium phenylacetate
Alternatively, 250 mg/kg/dose IV given over 90 min in 25-35 mL/kg of 10% glucose solution; continue IV administration at 250 mg/kg/d; to be infused over 24 h

Pediatric

Administer as in adults

Penicillin may decrease effects; probenecid may inhibit renal excretion of products; valproate may antagonize efficacy

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution when administering to patients with neonatal hyperbilirubinemia (competes for bilirubin binding sites on albumin); due to sodium content, caution when giving to patients with congestive heart failure, severe renal dysfunction, or sodium retention with edema; common adverse effects include nausea, vomiting, tinnitus, and visual disturbance


Sodium phenylbutyrate (Buphenyl)

Phenylacetate was introduced after benzoate but now has been replaced by phenylbutyrate because former has bad odor. Adverse effects include menstrual disturbances (23% of patients), anorexia, pH disturbance, hypoalbuminemia, disturbance in phosphate metabolism, Fanconi syndrome, bad taste, and offensive body odor. Available in powder and tablet forms.

Adult

450-600 mg/kg/d PO or 9.9-13 g/m2/d given in divided doses 4-6 times/d with meals; not to exceed 20 g/d

Pediatric

<20 kg: 250-600 mg/kg/d PO
>20 kg: 9.9-13 g/m2/d PO in divided doses 4-6 times/d with meals; not to exceed 20 g

Corticosteroids may decrease effectiveness by inducing catabolic state; valproate and haloperidol may increase ammonia levels, thus administer these combinations with caution

Documented hypersensitivity; acute hyperammonemic episodes

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Due to sodium content, avoid in congestive heart failure, severe renal dysfunction, or sodium retention with edema

Antiemetic

These agents control nausea and vomiting associated with IV administration of sodium benzoate and phenylacetate.


Ondansetron hydrochloride (Zofran)

Selective 5-HT3-receptor antagonist that blocks serotonin both peripherally and centrally. Prevents nausea and vomiting associated with emetogenic cancer chemotherapy (eg, high-dose cisplatin) and complete body radiotherapy as well as sodium benzoate and phenylacetate.

Adult

32 mg IV infused over 15 min beginning 30 min before start of IV sodium benzoate and phenylacetate infusion

Pediatric

0.15 mg/kg IV

Although potential for cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) to change half-life and clearance, dosage adjustment not usually required

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Commonly observed adverse effects in children include local reactions, anxiety, agitation, headache, drowsiness; medication to be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

More on Hyperammonemia

Overview: Hyperammonemia
Differential Diagnoses & Workup: Hyperammonemia
Treatment & Medication: Hyperammonemia
Follow-up: Hyperammonemia
References
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References

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Further Reading

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Keywords

hyperammonemia, urea cycle disorders, urea cycle enzyme deficiencies, hepatic encephalopathies, Reye syndrome, toxic encephalopathies, metabolic disorders, ornithine transcarbamoylase deficiency, OTC deficiency, N -acetylglutamate synthetase deficiency, NAGS deficiency, carbamoyl phosphate synthetase I deficiency, carbamyl phosphate synthetase I deficiency, CPS I deficiency, argininosuccinic acid synthetase deficiency, AS deficiency, argininosuccinic lyase deficiency, AL deficiency, arginase deficiency, isovaleric acidemia, propionic acidemia, methylmalonic acidemia, glutaric acidemia type II, multiple carboxylase deficiency, beta-ketothiolase deficiency, congenital lactic acidosis, pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, mitochondrial disorders, acyl CoA dehydrogenase deficiency, systemic carnitine deficiency, hyperammonemia-hyperornithinemia-homocitrullinuria, HHH

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Contributor Information and Disclosures

Author

Elena Crisan, MD, Consulting Staff, Department of Neurology, Edwards Hines Veterans Affairs Hospital
Elena Crisan, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Jasvinder Chawla, MBBS, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Associate Professor and Director, Neurology Residency Training Program, Loyola University Medical Center
Jasvinder Chawla, MBBS, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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