What is the treatment for hyperammonemia?

Treatment of Hyperammonemia

Immediately discontinue all oral protein intake, provide intravenous glucose at 8-10 mg/kg/min with lipid supplementation, and initiate nitrogen-scavenging agents (sodium benzoate and sodium phenylacetate) for ammonia levels >150 μmol/L, while preparing for kidney replacement therapy if levels exceed 300-400 μmol/L or if neurological deterioration occurs. 1, 2, 3

Immediate Initial Management

Stop all protein intake immediately to reduce nitrogen load and prevent further ammonia production. 1, 2

Provide adequate non-protein calories:

• Maintain glucose infusion rate of 8-10 mg/kg/min 1, 2, 4
• Target ≥100 kcal/kg daily (or >80 kcal/kg/day minimum) 1, 2, 4
• Add intravenous lipids starting at 0.5 g/kg daily, up to 3 g/kg daily for caloric support 1, 2

Critical timing: Reintroduce protein within 48 hours once ammonia levels decrease to 80-100 μmol/L (136-170 μg/dl), starting at 0.25 g/kg daily and advancing to 1.5 g/kg daily to prevent catabolism. 5, 1, 2

Pharmacological Therapy with Nitrogen Scavengers

Initiate nitrogen-scavenging agents when ammonia levels exceed 150 μmol/L (255 μg/dl). 5, 3

Intravenous sodium benzoate dosing: 1, 2, 4

• Body weight <20 kg: 250 mg/kg
• Body weight >20 kg: 5.5 g/m²
• Administer as loading dose over 90-120 minutes, followed by maintenance infusion over 24 hours

Intravenous sodium phenylacetate dosing: 1, 2, 4

• Body weight <20 kg: 250 mg/kg
• Body weight >20 kg: 5.5 g/m²
• Same administration schedule as benzoate

L-arginine hydrochloride supplementation (for urea cycle disorders): 1, 2, 4

• For OTC and CPS deficiencies:
  • Weight <20 kg: 200 mg/kg
  • Weight >20 kg: 4 g/m²
• For ASS and ASL deficiencies:
  • Weight <20 kg: 600 mg/kg
  • Weight >20 kg: 12 g/m²

For organic acidemias: Add L-carnitine 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily. 2

Kidney Replacement Therapy (KRT)

Indications for urgent KRT: 1, 2, 3

• Ammonia levels >300-400 μmol/L despite medical therapy
• Rapidly deteriorating neurological status or coma
• Moderate to severe encephalopathy
• Increased intracranial pressure

First-line modality: High-dose continuous venovenous hemodialysis (CVVHD) 1, 3

• Blood flow rate (Qb): 30-50 ml/min
• Target dialysis fluid flow rate (Qd)/Qb ratio >1.5
• Most effective when available and patient is hemodynamically stable

Alternative: Intermittent hemodialysis (HD) 1, 2, 3

• Most effective for rapid ammonia reduction (95-96% filtration fraction)
• Achieves 50% reduction in ammonia levels within 1-3 hours
• Preferred when rapid clearance is critical

Hybrid/sequential therapy (HD followed by CKRT): Recommended for neonates who are hemodynamically unstable, as it provides rapid initial clearance while controlling ammonia rebound. 1

Peritoneal dialysis: Only use when other KRT modalities are unavailable, as it is significantly less effective. 2, 3

Important caveat: Nitrogen scavengers will be dialyzed during KRT but should be continued concurrently as they remain effective. 5, 3

Monitoring During Treatment

Plasma ammonia levels: Check every 3-4 hours until normalized. 1, 2

Neurological assessment: Continuously monitor for signs of encephalopathy, Glasgow Coma Scale changes, and cerebral edema. 2, 4

Laboratory monitoring during treatment: 4

• Electrolytes (especially during CKRT)
• Blood glucose
• Venous or arterial blood gases
• AST and ALT
• Quantitative plasma amino acids and glutamine

Sample collection critical detail: Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid false elevations. 1, 2, 3

Prognostic Factors and Treatment Urgency

The duration of hyperammonemic coma is the most critical prognostic factor, not the rate of ammonia clearance. 5, 3

Poor prognostic indicators: 5, 3

• Hyperammonemic coma lasting >3 days
• Plasma ammonia levels >1,000 μmol/l (1,703 μg/dl)
• Increased intracranial pressure

Early management and reduced duration of coma prevent irreversible neurological damage, including permanent cognitive impairment. 5, 3

Critical Pitfalls to Avoid

Do not prolong protein restriction beyond 48 hours as this will induce catabolism and paradoxically increase ammonia production. 5, 1, 2, 3

Do not delay KRT initiation in patients with severe hyperammonemia or neurological deterioration, as delayed treatment leads to irreversible brain damage. 5, 3

Avoid repeat loading doses of sodium phenylacetate and sodium benzoate due to prolonged plasma levels; continue with maintenance infusions only. 4

Watch for drug interactions: Valproic acid can induce hyperammonemia and should be avoided; penicillin and probenecid may compete with nitrogen scavenger excretion. 4

Overdose risk: Ambiguous prescriptions and inadequate cross-checking have resulted in fatal overdoses causing cardiorespiratory failure, cerebral edema, and metabolic acidosis. 6

Adjunctive Considerations

Antiemetic administration: Consider during nitrogen scavenger infusion to control nausea and vomiting. 4

For hemodynamically unstable patients: CKRT with ECMO support may be considered for rapid ammonia clearance. 2

Therapeutic hypothermia: May be considered in conjunction with KRT, as each 1°C decrease in body temperature reduces basal metabolic rate by 8%, slowing ammonia production. 2