TOXCard: Valproic Acid Toxicity

Author: Kathleen Yip, MD (Harbor-UCLA Medical Center) // Edited by: David Tanen, MD (Harbor-UCLA Medical Center), Cynthia Santos, MD (@CynthiaSantosMD, Rutgers New Jersey Medical School), Alex Koyfman, MD (@EMHighAK, UTSW / Parkland Memorial Hospital), and Brit Long, MD (@long_brit)

Case:

A 28-year-old male with a history of bipolar disorder is brought in by ambulance for altered mental status. His mother discovered him lying on the ground at home with an empty bottle of immediate-release valproic acid near him and a suicide note; he was last seen well 6 hours prior. He had started the valproic acid for bipolar disorder a couple days ago, and the bottle had contained 60 500 mg tabs. Vitals are T 37.2C, HR 88, BP 118/72, RR 16, SpO2 99%. Exam reveals a young adult male who appears somnolent with a Glasgow Coma Scale 3-4-6 (one point off for opening eyes to command and one point off for slurred speech) and an otherwise unremarkable neurologic exam. He mentions feeling nauseated.

Questions:

• What are the symptoms of valproic acid (VPA) toxicity?
• At what level is valproic acid toxic?
• Is there anything to consider for massive delayed- versus immediate-release valproic acid ingestions?
• Should L-carnitine be given, and if so, what are the indications?

Epidemiology

• U.S. Poison Control Centers recorded over 3,000 single exposures to VPA in 2016, two-thirds of which were treated in a healthcare facility. (1)
• Anticonvulsants are in the top 10 substance categories with the greatest rate of exposure increase. (1)

Pharmacology

• Besides seizures, VPA is also used to treat certain psychiatric disorders as well as for migraine prophylaxis. (2)
• Exerts its effects on seizure control by increasing γ-aminobutyric acid (GABA) synthesis and release, attenuating N-methyl-D-aspartate (NMDA)-type glutamate receptors, and acting directly on excitable membranes. (2)
• May cause hyperammonemia and hepatic enzyme abnormalities in both chronic, therapeutic use as well as acute overdoses. (2)
  • VPA directly and indirectly interferes with fatty acid metabolism, β-oxidation, and the urea cycle, leading to depletion of carnitine stores, the formation of organic acids, and hyperammonemia. (3)
• Mostly metabolized by the liver, with a half-life of 5-20 hours (longer at toxic levels). (2)

Figure 1: The ‘Carnitine’ Shuttle

Clinical presentation

• Most cases are asymptomatic.
• CNS effects: lethargy, confusion, and coma.
  • At levels >850 mg/L, patients are likely to be in a coma.
  • Valproic acid induced hyperammonemia encephalopathy may occur with or without hepatotoxicity or elevated VPA levels.
  • May also show increased seizure frequency and focal or bilateral neurologic signs.
  • Cerebral edema
    • Some metabolites of VPA have been implicated in the development of cerebral edema. (2)
• Cardiovascular effects: tachycardia, hypotension.
• GI effects: nausea, vomiting, and abdominal pain.
• Hepatotoxicity and pancreatitis are rare.

Diagnostic testing

• Electrolytes
  • Hypernatremia may be seen in divalproex sodium.
  • Hypocalcemia.
• Obtain blood gas due to anion gap metabolic acidosis (secondary to organic acid production from hepatic metabolism of VPA).
• Valproic acid level
  • Check levels every 4-6 hours to ensure they are downtrending, especially for overdoses with delayed release formulations; levels may peak 24 hours after ingestion.
  • Therapeutic level: 50-100 ug/mL
    • Eliminated by first-order kinetics at therapeutic ranges.
    • VPA is highly protein bound at therapeutic ranges, but at higher concentrations, an increasing percentage exists as free drug. (3)
  • Toxic level
    • <450 mg/L: limited toxicity.
    • 450-850 mg/L: moderate to severe toxicity.
    • >850 mg/L: coma, metabolic acidosis, respiratory depression (majority of whom required intubation). (4, 5)
• Ammonia level
  • VPA metabolites precipitate hyperammonemia due to their interference with the urea cycle.
  • Can be elevated in patients who have taken it chronically at a therapeutic dose, and patients may be asymptomatic.

• Also helpful
  • Liver function tests
  • Coagulation panel (PT/INR, PTT)
  • Acetaminophen level
  • Salicylate level
  • Urine toxicology screen

Management

• Resuscitation
  • Airway management.
  • Fluids and pressors if hypotensive.
• GI decontamination
  • Activated charcoal may be useful, especially for patients with delayed-release VPA overdoses. (6)
• L-Carnitine
  • IV L-carnitine is recommended in symptomatic patients and those with valproic acid concentrations above 450 mg/L. (3)
    • 100 mg/kg (up to 6 g) administered over 30 minutes, followed by 15 mg/kg every 6 hours over 10 to 30 minutes.
  • For asymptomatic acute overdoses without hepatic enzyme abnormalities, PO carnitine can be considered prophylactically. (7)
    • 100 mg/kg/day divided every 8 hours (up to 3 g/day).
  • Overall there is insufficient evidence for routine use of carnitine.
    • Current evidence suggests that it does not appear to be harmful and could be helpful, regardless of whether the overdose is acute, chronic, or acute on chronic. (2)
• Hemodialysis
  • VPA is a relatively small molecule that is easily dialyzed.
  • One case study of two similar patients demonstrated that in severe VPA overdose, immediate dialysis and hemodiafiltration rapidly reduces VPA and ammonia levels with clinical improvement, which was not seen with supportive care alone. (8)
  • Recommended in patients with severe clinical symptoms (e.g. coma, hemodynamic compromise) and levels exceeding 850 mg/L. (9)

Take home points

• Check serial valproic acid levels to make sure it is downtrending.
• CNS effects (e.g. somnolence, confusion) are most common.
• Valproic acid induced hyperammonemia encephalopathy may be seen even without hepatotoxicity or elevated VPA levels.
• Supportive care is key, though L-carnitine may be helpful.

Case Conclusion:

The patient’s valproic acid level returns at 562 mg/L, and the ammonia is 68 μmol/L. The remaining labs are unremarkable. Since the patient is responding appropriately to voice and has stable vitals, you hold off on intubation and dialysis, but since he appears somnolent and is complaining of nausea, you do not provide activated charcoal. You order IV carnitine, place him on a psychiatric hold, and admit him to medicine. A repeat valproic acid level four hours later revealed it came down to 350 mg/L.

References/Further Reading:

1. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila) 2017;55:1072-252.
2. Lheureux PE, Penaloza A, Zahir S, Gris M. Science review: carnitine in the treatment of valproic acid-induced toxicity – what is the evidence? Crit Care 2005;9:431-40.
3. Doyon S. Antiepileptics. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank’s Toxicologic Emergencies, 10e. New York, NY: McGraw-Hill; 2015.
4. Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol 2000;38:755-60.
5. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002;40:789-801.
6. van der Wouden EA, Dekkers A, Kruis HM, van Geijlswijk IM, Tjan DH, Feith GW. Extracorporeal elimination in acute valproate intoxication. BMJ Case Rep 2009.
7. Ginsburg BY. Anticonvulsant Poisoning. In: Hoffman RJ, Wang VJ, Scarfone RJ. eds. Fleisher and Ludwig’s 5-Minute Pediatric Emergency Medicine Consult, 1e. Philadelphia, PA: Lippincott Williams & Wilkins; 2012
8. Licari E, Calzavacca P, Warrillow SJ, Bellomo R. Life-threatening sodium valproate overdose: a comparison of two approaches to treatment. Crit Care Med 2009;37:3161-4.
9. Borek HA LD. Valproic Acid. In: Kazzi ZN, Shih R. eds. AAEM Toxicology Handbook, 2e. AAEM; 2011.