Valproic acid is used as an anticonvulsant, a mood stabilizer, for the treatment of chronic pain and as prophylaxis for migraine headaches.
Valproic acid inhibits GABA transaminase, increasing GABA concentrations in the brain. Valproic acid also depletes coenzyme A (CoA) stores in the liver by trapping CoA in the mitochondria. Depletion of CoA affects the activation of the carbamyl phosphate synthetase I, leading to disruption of the urea cycle, which may cause hyperammonemia. Valproic acid depletes carnitine levels resulting in decreased transport of fatty acids and their accumulation in the cytoplasm. This process may result in development of fatty liver.
The most common effects of valproic acid overdose are vomiting, tachycardia, and CNS depression. With severe poisoning, patients may develop coma, miotic pupils, tachycardia, hypotension, QTc prolongation, and respiratory depression. Paradoxic seizures and cerebral edema may occur. Laboratory abnormalities may include hypernatremia, hypocalcemia, elevation of transaminases, and bone marrow suppression. Hyperammonemic encephalopathy can develop after overdose or therapeutic use.
Valproic acid concentration should be measured and repeated every 4 to 6 hours until the level is decreasing. The therapeutic serum concentration is generally considered to be 50 to 100 μg/mL. Values greater than 450 μg/mL are associated with drowsiness and obtundation; those greater than 850 μg/mL are associated with coma. Useful studies may include complete blood count, liver enzymes, ammonia concentration, lactic acid, electrolytes, blood sugar, renal function, and ECG. Consider obtaining a CT scan of the head if cerebral edema is suspected.
Provide meticulous supportive care with attention to the airway, breathing, and circulation.
Consider activated charcoal in patients who have ingested a potentially toxic dose and have presented within 1 hour of ingestion.4
Hemodialysis10 or charcoal hemoperfusion11 should be considered in patients with severe symptoms, severe metabolic disturbance or serum valproic acid concentration greater than 1000 μg/mL.
L-carnitine may be considered for patients with coma, hepatotoxicity, hyperammonemia, or serum valproic acid concentration greater than 450 μg/mL.12 Although there are no controlled studies to support its use after acute overdose, reports suggest it lowers serum ammonia concentrations, and it is associated with few adverse effects.
Patients should be observed for at least 6 hours after immediate-release valproic acid ingestions, and for 12 hours following ingestion of delayed-release preparations. Patients may be medically cleared if valproic acid concentrations are declining, and symptoms are resolved. Patients with persistent altered mental status, abnormal vital signs, acidosis, renal or hepatic involvement should be admitted to the hospital.