Valproic acid toxicity
The case
A 50-year-old woman on chronic valproic acid (VPA) therapy for mania is brought to the Emergency Department for drowsiness. She was recently switched from tablets to a liquid formulation of her medication. The night before presenting to the ED, she "winged it" and took a large gulp of the syrup approximating her usual dose. She denied suicidal intent or other ingestions. The caregiver, on seeing the patient the next morning, brought her in about 18 hours after the ingestion. She determined that there were about 50 mL missing from the bottle between last night and now, corresponding to 2500 mg.
Vital signs are normal. Exam is notable for somnolence and dysarthria. She responds to verbal stimuli but quickly falls asleep. Her respiratory effort is normal. She is fully oriented, and her neurologic exam is otherwise normal. There are no external signs of trauma.
The brush up
Remember that VPA is GABA-ergic, so the clinical effects are largely due to central nervous system depression. Occasionally, an acute VPA overdose can mimic an opioid toxidrome. With chronic toxicity, signs and symptoms of hepatic failure may be present. Without getting into too much detail, VPA can decrease serum carnitine levels (by complexing with carnitine and increasing renal excretion), as well as increase ammonia levels (by reducing fatty acid metabolism, causing a shift toward amino acid oxidation and thus increased nitrogenous waste production). This becomes important for treatment.
As with many acute ingestions, activated charcoal administration may help prevent worsening toxicity after VPA overdose (as long as there are no contraindications and it can be given within about 1 hour). Remember that with sustained-release preparations (such as Depakote and Depakote ER), repeated dose charcoal or even whole-bowel irrigation may help.
Of course, we can't *really* talk toxicology without mentioning a few numbers:
As a general rule, drugs amenable to removal by extracorporeal methods have a low volume of distribution (Vd) and low protein binding (or higher free serum levels). VPA does have a low Vd but is highly protein-bound, which in theory doesn't make it the best candidate for HD or CRRT. However, with a massive overdose, protein-binding sites will become saturated and thus the serum level of free VPA will increase. In these cases, consider involving a nephrologist early.
Treatment of VPA toxicity is largely supportive. While there is no true antidote, there may be a role for L-carnitine supplementation (for both prevention and treatment of toxicity). The IV formulation has been associated with better outcomes, but use caution as it can precipitate tachyarrhythmias and seizures.
The conclusion
EKG showed a normal QTc. Initial laboratory findings include a normal CBC, normal electrolytes, undetectable ammonia level, and VPA level of 175 mg/L. Serial VPA levels were consistently lower. The patient became more alert during her ED course and was discharged home to hold her valproic acid for 24 hours.
References:
Olson KR & California Poison Control System. (2012). Poisoning & drug overdose. New York: Lange Medical Books/McGraw-Hill.
Wadzinski J, Franks R et al. Valproate-associated Hyperammonemic Encephalopathy. J Am Board Fam Med Sept-Oct 2007;20(5):499-502.