Medications for Hyperammonemia Treatment
Immediate pharmacological treatment of hyperammonemia requires intravenous nitrogen-scavenging agents (sodium benzoate and sodium phenylacetate) combined with L-arginine hydrochloride, while simultaneously stopping all protein intake and providing adequate calories through IV glucose and lipids. 1
Initial Stabilization and Nutritional Management
Stop all protein intake immediately to reduce nitrogen load and prevent further ammonia production. 1, 2
Provide adequate caloric support to prevent catabolism, which drives additional ammonia generation:
- IV glucose infusion at 8-10 mg/kg/min 1, 3
- IV lipids starting at 0.5 g/kg daily, up to 3 g/kg daily 1, 3
- Total caloric intake ≥100 kcal/kg daily 1, 3
Reintroduce protein gradually by 0.25 g/kg daily up to 1.5 g/kg daily within 48 hours once ammonia levels stabilize to 80-100 μmol/L, as prolonged protein restriction paradoxically promotes catabolism. 1, 2
Nitrogen-Scavenging Agents (Primary Pharmacotherapy)
Sodium Benzoate
Dosing based on body weight: 1
- <20 kg: 250 mg/kg IV
- >20 kg: 5.5 g/m² IV
- Administration: Give over 90 minutes as bolus, then continue as maintenance infusion over 24 hours
- Maximum dose: 12 g daily (high-dose benzoate can be toxic and lethal within 1 hour) 1
Mechanism: Benzoate conjugates with glycine to generate hippurate, providing an alternative pathway for nitrogen excretion. 1
Sodium Phenylacetate
Dosing based on body weight: 1
- <20 kg: 250 mg/kg IV
- >20 kg: 5.5 g/m² IV
- Administration: Give over 90 minutes as bolus, then continue as maintenance infusion over 24 hours
Mechanism: Phenylacetate conjugates with glutamine to generate phenylacetylglutamine, removing nitrogen through an alternative route. 1
Combined Sodium Benzoate and Sodium Phenylacetate
When used together: 1
- Same weight-based dosing as individual agents
- Give over 90-120 minutes as bolus, then as maintenance over 24 hours
- This combination has demonstrated 84% overall survival and 96% episode survival in 299 patients with 1181 hyperammonemic episodes. 4
Urea Cycle Intermediates
L-Arginine Hydrochloride
Dosing depends on the specific enzyme deficiency: 1, 5
For OTC and CPS deficiencies:
- <20 kg: 200 mg/kg IV
- >20 kg: 4 g/m² IV
For ASS and ASL deficiencies:
- <20 kg: 600 mg/kg IV
- >20 kg: 12 g/m² IV
Administration: Give over 90 minutes as bolus, then continue as maintenance infusion over 24 hours. 1
Important caveat: L-arginine is a precursor to nitric oxide (a potent vasodilator), so intravenous administration could lead to hypotension. The dose may need titration or reduction, especially if the patient is simultaneously receiving hemodialysis. 1
L-Carnitine
Dosing: 1
- Loading dose: 50 mg/kg IV over 90 minutes
- Maintenance: 100-300 mg/kg daily
Indication: Required for organic acidurias but not needed for urea cycle disorders. 1
L-Citrulline
Alternative urea cycle primer that can be supplemented to aid ammonia removal, with choice depending on which enzyme deficiency is present. 1
Additional Supportive Medications
Vitamins: 1
- Vitamin B12: 1 mg
- Biotin: 5-15 mg
Oral phenylbutyrate (sodium phenylbutyrate or glycerol phenylbutyrate) can be initiated after urea cycle disorder diagnosis is confirmed for long-term management. 1
Treatment Algorithm Based on Ammonia Levels
Ammonia >150 μmol/L (255 μg/dl)
Initiate nitrogen-scavenging agents (sodium benzoate and sodium phenylacetate) with L-arginine at the dosages above. 1
Ammonia 301-499 μmol/L (513-850 μg/dl) with moderate to severe encephalopathy
Start scavenger treatment immediately while preparing for dialysis. 1
Ammonia >400-500 μmol/L or refractory to medical therapy
Urgent hemodialysis or continuous kidney replacement therapy is indicated, as pharmacological therapy alone may be insufficient. 6, 7 Nitrogen-scavenging agents can be continued during dialysis, though they will be dialyzed along with other small molecules. 1
Critical Monitoring Parameters
Check plasma ammonia levels every 3 hours until normalized, using free-flowing venous or arterial blood collected into lithium heparin or EDTA tubes, transported on ice, and processed within 15 minutes. 1, 3, 6
Assess neurological status continuously for signs of encephalopathy improvement or deterioration. 3, 2
Monitor electrolytes closely, especially during kidney replacement therapy. 3, 2
Common Pitfalls to Avoid
Do not delay treatment while awaiting diagnostic confirmation—the duration of hyperammonemic coma is the most important prognostic factor for neurological outcomes, not the rate of ammonia clearance. 1, 3
Do not restrict protein beyond 48 hours without reintroduction, as this paradoxically promotes catabolism and further ammonia production. 1, 2
Do not rely solely on ammonia thresholds—the evolving clinical status of the patient should be the primary determinant of treatment escalation. 1, 2
Recognize that ammonia levels >1,000 μmol/L (1,703 μg/dl) or hyperammonemic coma lasting >3 days are adverse prognostic factors associated with irreversible neurological damage. 1