Possessed? No Bored

LEBOWSKI-491

Wrapping up your secret interpretive dance class, you realize that the teacher is looking awfully slow. You approach him, and before he falls into your hands in his sweaty silver spandex, he tells you that his dancing is inspired by his seizure disorder. He then tells you that he thinks that he may have unintentionally taken too many of his pills, confusing them with his “dance vitamins”.

You are left with a nearly comatose patient who smells like ammonia. In the ED you find a transaminitis, elevated ammonia and lactic acidosis.

Which anticonvulsant did your spandexed hero likely take?

Valproic acid.

– Valproic acid is a GABA agonist, NMDA antagonist, decreases sodium channel

excitation.

– Standard preparations reach peak levels serum concentrations in 4h; extended

release preparations in 12-17h. The half life is 8-21h.

– It is metabolized in the liver in the mitochondria using L-carnitine as a cofactor.

– Valproic acid blocks the metabolism of ammonia in liver and increases production

in kidneys.

What are the symptoms of said anticonvulsant toxicity?

– Severe poisoning is also called valproate-related hyperammonemic encephalopathy

(VHE). This includes:

CNS depression and respiratory depression
Hypotension
Hypocalcemia
Hypernatremia
Hypoglycemia
Hypophosphatemia
Hyperammonemia
Transaminitis
Lactic acidosis
Pancreatitis
Thrombocytopenia

Over 50% of patients with chronic Valproate toxicity will have elevated liver enzymes and normalize after reduction of dose or discontinuation.
Fulminant dose-independent hepatotoxicity may occur.

How do you evaluate and treat such a patient?

Evaluation:

– Obtain serum drug concentrations: Therapeutic range is 50-100 (mcg/ml)

– Serum ammonia, comprehensive metabolic panel (including liver function

tests), blood gas including lactate, urinalysis, complete blood count.

Treatment:

– Boards answer: L-Carnitine: This will increase valproate metabolism through

oxidation and help achieve resolution of symptoms more rapidly.

– Mostly supportive care should be initiated such as, respiratory support, IV hydration, and repletion of electrolytes.

– GI decontamination: One dose of activated charcoal is typically sufficient, but

for extended release formulations, whole bowel irrigation may be needed.

– High-dose naloxone has been shown in case studies to decrease CNS depression (possibly through antagonism of intrinsic opiates).

– Hemodialysis: Although valproate is mostly protein bound, removal of the

unbound molecules will reduce half-life substantially.

– All fulminant liver failure should be evaluated for acetaminophen toxicity and empiric NAC therapy should be considered.

References:

Tintinalli, Judith E., Gabor D. Kelen, and J. Stephan. Stapczynski. Emergency Medicine: A Comprehensive Study Guide. Chapter 191. New York: McGraw-Hill, Medical Pub. Division, 2004. Print.

Written by Itamar

Special thanks to Dr’s. deSouza, Willis, and Wiener.