What is the treatment for hyperammonemia?

Treatment of Hyperammonemia

High-dose continuous venovenous hemodialysis (CVVHD) is the first-line treatment for severe hyperammonemia when available, combined with immediate initiation of nitrogen-scavenging agents, caloric support, and protein restriction. 1, 2

Immediate Initial Management

Stop all oral feeds immediately to reduce nitrogen load and prevent further ammonia production. 2, 3

Provide aggressive caloric support to prevent catabolism, which drives further ammonia production:

• Maintain glucose infusion rate of 8-10 mg/kg/min 2, 3, 4
• Provide ≥100 kcal/kg daily as intravenous glucose and lipids 2, 3
• Start intravenous lipids at 0.5 g/kg daily, increasing up to 3 g/kg daily 2, 3
• Gradually reintroduce protein by 0.25 g/kg daily (up to 1.5 g/kg daily) within 48 hours to prevent ongoing catabolism 2, 3

Critical pitfall: Protein restriction should not be prolonged beyond 48 hours, as this paradoxically worsens catabolism and ammonia production. 3, 5

Pharmacological Therapy

Initiate nitrogen-scavenging agents immediately without waiting for dialysis availability:

Sodium benzoate and sodium phenylacetate dosing (must be diluted in D10W and given via central line): 4

• For patients <20 kg: 250 mg/kg of each agent
• For patients >20 kg: 5.5 g/m² of each agent
• Administer as loading dose over 90-120 minutes, then same dose as continuous infusion over 24 hours 4

L-arginine hydrochloride dosing (varies by specific urea cycle disorder): 2, 3, 4

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

For organic acidemias specifically, add L-carnitine: 50 mg/kg loading dose over 90 minutes, then 100-300 mg/kg daily. 3

Important caveat: These nitrogen scavengers will be dialyzed during kidney replacement therapy but remain effective when used concurrently. 3

Kidney Replacement Therapy (KRT)

Initiate CVVHD immediately in the following situations: 1, 2

• Rapidly deteriorating neurological status, coma, or cerebral edema
• Ammonia levels >300-400 μmol/L despite medical therapy
• Persistent ammonia >400 μmol/L (681 μg/dl) refractory to medical measures
• Rapid rise in ammonia >300 μmol/L (511 μg/dl) within hours

CVVHD parameters: 2

• Blood flow rate (Qb): 30-50 ml/min
• Dialysis fluid flow rate (Qd)/Qb ratio: >1.5
• Use warmed dialysate in neonates for hemodynamic stability 1

Alternative KRT modalities when CVVHD unavailable:

Intermittent hemodialysis (HD) is more effective for rapid ammonia reduction, achieving 50% reduction within 1-3 hours, but carries higher risk of rebound hyperammonemia and hemodynamic instability. 2, 3, 6

Hybrid/sequential therapy (HD followed by CVVHD) is recommended for neonates who are hemodynamically unstable, as it provides rapid initial clearance while controlling rebound effect. 2

Peritoneal dialysis (PD) should only be used when HD or CKRT are completely unavailable, with the same clinical indications as above. Avoid rigid peritoneal catheters due to increased complications. 1

Critical prognostic factor: The duration of hyperammonemic coma prior to dialysis initiation is the most important determinant of survival—not the rate of ammonia clearance. Early dialysis is paramount. 1, 2, 7

Monitoring During Treatment

Check plasma ammonia levels every 3-4 hours until normalized. 2, 3, 5

Critical sampling technique: Ammonia samples must be collected from free-flowing venous or arterial blood, transported on ice, and processed within 15 minutes to avoid false elevations. 2, 3, 5

Monitor continuously: 4

• Neurological status and Glasgow Coma Scale
• Electrolytes (especially during CKRT to prevent complications)
• Blood glucose, venous/arterial blood gases
• AST, ALT, plasma glutamine, quantitative amino acids

Special Considerations and Drug Interactions

Avoid valproic acid, as it induces hyperammonemia by inhibiting N-acetylglutamate synthesis, a cofactor for carbamyl phosphate synthetase. 4

Use corticosteroids cautiously, as they create a protein catabolic state that increases ammonia production. 4

Penicillin antibiotics may compete with phenylacetylglutamine for renal tubular secretion, potentially affecting drug clearance. 4

For hemodynamically unstable patients, consider CKRT with ECMO support, which enables use of larger cannulas and more rapid ammonia clearance. 3

Therapeutic hypothermia may be considered as adjunctive therapy, as each 1°C decrease in body temperature reduces basal metabolic rate by 8%, slowing ammonia production. 3