What to do if a patient on valproate (valproic acid) has hyperammonemia?

Management of Valproate-Induced Hyperammonemia

Valproate-induced hyperammonemia requires immediate discontinuation of valproate therapy, with additional interventions based on ammonia levels and neurological status. 1, 2

Initial Assessment and Management

• Check ammonia level in any patient on valproate who presents with:

  • Unexplained lethargy or somnolence
  • Vomiting
  • Mental status changes
  • Confusion or altered consciousness
  • Hypothermia (body temperature <35°C) 2

• Immediate interventions based on ammonia levels:

  Ammonia Level	Clinical Status	Action
  Any elevation	Symptomatic	Discontinue valproate 2
  >150 μmol/L	Rapidly deteriorating neurological status	Discontinue valproate + initiate CKRT 1
  >400 μmol/L	Moderate/severe encephalopathy	Discontinue valproate + initiate CKRT 1
  >300 μmol/L	Rapid rise in levels	Discontinue valproate + initiate CKRT 1

Specific Treatment Modalities

1. Dialysis Options

• Continuous Kidney Replacement Therapy (CKRT): Preferred for hemodynamically unstable patients; prevents rebound hyperammonemia 1
• Intermittent Hemodialysis: For rapid ammonia clearance when immediate reduction is needed 1
• Peritoneal Dialysis: Only when other modalities unavailable (less efficient) 1

2. Pharmacological Interventions

• Nitrogen-scavenging agents:
  • Sodium benzoate: 250 mg/kg for weight <20 kg; 5.5 g/m² for weight >20 kg (max 12g daily)
  • Sodium phenylacetate: Same dosing as sodium benzoate 1
  • Continue these agents during dialysis to prevent rebound hyperammonemia

3. Nutritional Management

• Temporary protein restriction during acute phase
• Reintroduce protein within 48 hours after ammonia levels decrease to 80-100 μmol/L
• Gradual reintroduction: Start at 0.25 g/kg daily, increasing up to 1.5 g/kg daily 1
• Provide adequate calories: ≥100 kcal/kg daily as intravenous glucose and lipids 1

Monitoring and Follow-up

• Measure ammonia levels at 24 hours and 5-7 days 1
• Continuously assess neurological status using Glasgow Coma Scale 1
• Monitor for complications:
  • Cerebral edema
  • Increased intracranial pressure
  • Coma

Special Considerations

Risk Factors for Severe Hyperammonemia

• Concomitant topiramate use (can exacerbate hyperammonemia) 2, 3
• Undiagnosed urea cycle disorders 2, 4
• Prior history of unexplained encephalopathy 2

Common Pitfalls to Avoid

1. Failure to check ammonia levels in patients with altered mental status on valproate 5
2. Attributing lethargy solely to postictal state in seizure patients on valproate 5
3. Overlooking hyperammonemia when liver function tests are normal 6
4. Delaying treatment while waiting for genetic testing results 6

Important Caveats

• Hyperammonemic encephalopathy can occur with therapeutic valproate levels 5
• Normal liver function tests do not rule out valproate-induced hyperammonemia 2, 6
• Fatal cerebral edema can occur despite successful ammonia elimination if treatment is delayed 6
• Patients with undiagnosed urea cycle disorders are at particularly high risk 2, 4

Remember that valproate-induced hyperammonemic encephalopathy is potentially reversible if recognized early, but can be fatal if treatment is delayed 6.