How to manage encephalopathy caused by non-cirrhotic hyperammonemia?

Management of Non-Cirrhotic Hyperammonemic Encephalopathy

Immediately initiate ammonia-scavenging therapy with intravenous sodium benzoate and sodium phenylacetate while simultaneously stopping all protein intake and providing adequate calories through IV glucose and lipids; if ammonia levels exceed 300 μmol/L or the patient shows severe encephalopathy, prepare for urgent hemodialysis or continuous kidney replacement therapy. 1, 2

Immediate Initial Management

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

Provide adequate caloric support to prevent catabolism, which drives further ammonia generation:

• IV glucose infusion at 8-10 mg/kg/min 1, 2
• IV lipids: 0.5 g/kg daily, up to 3 g/kg daily 1, 2
• Target caloric intake ≥100 kcal/kg daily 1, 2

Reintroduce protein gradually within 48 hours once ammonia levels decrease to 80-100 μmol/L, starting at 0.25 g/kg daily and increasing up to 1.5 g/kg daily to prevent ongoing catabolism. 2, 3

Pharmacological Ammonia-Scavenging Therapy

Initiate nitrogen-scavenging agents immediately for ammonia levels >150 μmol/L (255 μg/dL) or any patient with encephalopathy: 1, 2, 4

Sodium Benzoate Dosing:

• Weight <20 kg: 250 mg/kg IV given over 90 minutes as bolus, then as continuous maintenance over 24 hours 1
• Weight >20 kg: 5.5 g/m² IV given over 90 minutes as bolus, then as continuous maintenance over 24 hours 1
• Maximum dose: 12 g daily (high-dose benzoate can be toxic and lethal within 1 hour) 1

Sodium Phenylacetate Dosing:

• Weight <20 kg: 250 mg/kg IV given over 90 minutes as bolus, then as continuous maintenance over 24 hours 1
• Weight >20 kg: 5.5 g/m² IV given over 90 minutes as bolus, then as continuous maintenance over 24 hours 1

The combination of sodium phenylacetate and sodium benzoate is FDA-approved for acute hyperammonemia and associated encephalopathy, providing alternative pathways for nitrogen disposal when the urea cycle is impaired. 4

Additional Pharmacological Agents:

L-arginine hydrochloride (dosing depends on specific enzyme deficiency if known): 1, 2

• For OTC and CPS deficiencies: 200 mg/kg (weight <20 kg) or 4 g/m² (weight >20 kg)
• For ASS and ASL deficiencies: 600 mg/kg (weight <20 kg) or 12 g/m² (weight >20 kg)
• Given over 90 minutes as bolus, then as maintenance over 24 hours
• Caution: May cause hypotension, especially with concurrent hemodialysis 1

L-carnitine (primarily for organic acidemias, not urea cycle disorders): 1

• 50 mg/kg loading dose over 90 minutes
• Then 100-300 mg/kg daily

Vitamins: Vitamin B12 1 mg and biotin 5-15 mg 1

Kidney Replacement Therapy (KRT)

The clinical status of the patient should be the primary determinant for initiating KRT, not rigid ammonia thresholds alone. 1

Indications for KRT:

Consider dialysis urgently if: 1, 2

• Ammonia levels 301-499 μmol/L (513-850 μg/dL) with moderate to severe encephalopathy or seizures
• Ammonia levels >300-400 μmol/L despite medical therapy 2, 3
• Severe encephalopathy/seizures with indeterminate response to ammonia-scavenging agents after 2 hours 1
• Rapid neurological deterioration 2, 3

Choice of Dialysis Modality:

High-dose continuous venovenous hemodialysis (CVVHD) is first-line when available for severe hyperammonemia: 2

• Blood flow rate (Qb): 30-50 mL/min
• Target dialysis fluid flow rate (Qd)/Qb ratio >1.5

Intermittent hemodialysis (HD) is most effective for rapid ammonia clearance: 1, 2

• Achieves 50% reduction in ammonia levels within 1-3 hours 2
• More efficient than CVVHD or peritoneal dialysis for rapid reduction 1
• Ammonia clearance: 3.95-5.37 mL/min/kg body weight 1
• Filtration fraction: 95-96% 1

Peritoneal dialysis is least effective and should be avoided when HD or CVVHD are available, as it has limited efficacy in reducing ammonia levels. 1

Hybrid or sequential therapy (combination of HD and CVVHD) can gradually reduce ammonia while controlling rebound effect, particularly useful in hemodynamically unstable neonates. 2

Monitoring During Treatment

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

Assess neurological status regularly for signs of encephalopathy improvement or deterioration. 2, 3

Monitor electrolytes closely, especially during CKRT, to prevent complications. 2

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

Common Pitfalls and Caveats

Delayed recognition and treatment can lead to irreversible neurological damage. 2, 3 The duration of hyperammonemic coma prior to dialysis initiation is the most important prognostic factor, not the rate of ammonia clearance. 2

Do not rigidly apply numerical ammonia thresholds for treatment decisions; the evolving clinical status should guide therapy. 1

Avoid prolonged protein restriction beyond 48 hours, as this paradoxically promotes catabolism and further ammonia production. 2, 3

High-dose sodium benzoate carries significant toxicity risk and can be lethal within 1 hour if maximum doses are exceeded. 1

Arginine administration may cause hypotension, particularly when combined with hemodialysis; dose titration may be necessary. 1

Neonates with peak ammonia >1000 μmol/L have poorest prognosis (38% survival), requiring aggressive early dialysis. 5

Multidisciplinary decision-making involving nephrology, critical care, and metabolism teams is essential for optimal dialysis modality selection based on institutional resources, patient age, hemodynamic stability, and ammonia trends. 1