Valproate Toxicity

Valproate (valproic acid, sodium valproate, divalproex) has a therapeutic range of 50 to 100 mg/L (350 to 700 micromol/L). It is highly protein bound at therapeutic levels, but binding saturates in overdose, so the free fraction rises and the drug enters the brain. Ingestion of over 200 mg/kg causes significant central nervous system depression, and over 400 mg/kg is potentially life-threatening.

Mechanisms

• GABA enhancement and sodium channel blockade (sedation)
• Inhibition of the urea cycle (carbamoyl phosphate synthetase) by valproyl-CoA and carnitine depletion, causing hyperammonemia
• Inhibition of mitochondrial beta oxidation
• Anion gap metabolic acidosis from valproate and its metabolites

Toxicity patterns:

• acute overdose: coma, cerebral edema, hypernatremia, hypocalcemia, thrombocytopenia
• chronic toxicity: tremor, ataxia, encephalopathy with hyperammonemia and normal levels, hepatotoxicity, pancreatitis
• idiosyncratic hepatotoxicity: mitochondrial disease, particularly POLG mutations, and children under 2 years

Peak levels are delayed for 12 to 24 hours with enteric-coated and sustained-release products, so early levels underestimate risk.

Complications: cerebral edema, hepatic failure, pancreatitis, bone marrow suppression, respiratory depression and hypotension.

• Drowsiness, confusion, ataxia, tremor, nystagmus and miosis (early)
• Coma with respiratory depression, hypotension and tachycardia
• Hyperammonemic encephalopathy (confusion, vomiting, asterixis, seizures)
• Cerebral edema 12 to 72 hours after a large overdose
• Metabolic acidosis, hypernatremia, hypocalcemia, hypoglycemia
• Red flags: coma, unstable breathing, hypotension, seizures and a rising ammonia

1. Serum valproate level at presentation and every 4 to 6 hours until falling on two samples (a delayed peak is common).
2. Ammonia (arterial or venous, on ice, processed within 15 minutes), arterial blood gas, lactate, anion gap, sodium, calcium, phosphate, glucose and osmolality.
3. Liver tests, lipase, full blood count (thrombocytopenia), coagulation, creatinine.
4. Paracetamol and salicylate levels, ECG, and toxicology screen for coingestants.
5. CT head for severe obtundation or suspected cerebral edema.

Differentials: other sedative overdose, hepatic encephalopathy, Reye-like syndromes, urea cycle disorders, Wernicke encephalopathy, central nervous system infection.

1. Airway protection and supportive care: intubate for falling consciousness, with IV crystalloid for hypotension.
2. Gut decontamination: activated charcoal 50 g orally (children 1 g/kg, maximum 50 g) within 1 to 2 hours for a large acute ingestion.
3. L-carnitine for hyperammonemia, hepatotoxicity or large overdose: 100 mg/kg IV (maximum 6 g) over 30 minutes, followed by 15 mg/kg IV every 4 hours until ammonia and clinical status normalize.
4. Hyperammonemia: lactulose 30 mL orally every 6 to 8 hours titrated to 2 to 3 soft stools a day, and haemodialysis when ammonia is above 150 micromol/L with encephalopathy.
5. Extracorporeal removal (intermittent haemodialysis): recommended for valproate over 1300 mg/L (9000 micromol/L), cerebral edema, shock, or pH 7.10 or below. Suggested when the level is over 900 mg/L (6250 micromol/L) or there is acute hepatic or respiratory failure. Stop when the level is under 100 mg/L (700 micromol/L) or clinical improvement is evident.
6. Cerebral edema: head up 30 degrees, hypertonic saline 3% 2 to 5 mL/kg IV over 10 to 20 minutes or mannitol 0.5 to 1 g/kg IV, and intubation with controlled ventilation.
7. Seizures: lorazepam 4 mg IV (children 0.1 mg/kg, maximum 4 mg).
8. Hypotension: crystalloid 20 mL/kg and norepinephrine 0.05 to 0.5 micrograms/kg/min.
9. Correct hypocalcemia, hypernatremia, hypoglycemia and acidosis. Give sodium bicarbonate only for severe acidosis.

Prevention: avoid valproate in women of childbearing potential unless other drugs have failed, because of neural tube defects (1 to 2%) and neurodevelopmental effects, and use effective contraception. Check liver tests and blood count at baseline and during treatment. Avoid in suspected mitochondrial disease.