Valproic acid toxicity

Background

  • Peak concentration occurs within 4hr (12-18hr for controlled release forms)

Clinical Features

  • CNS depression
  • Hypotension
  • Respiratory depression

Evaluation

  • Level
    • Does not correlate well with toxicity
    • Adverse effects increase with level >150
  • Chemistry
  • LFT
    • Elevated transaminases
  • Hyperammonemia
    • Can be asymptomatic or cause Valproate associated Hepatic Encephalopathy (VPE)
    • Secondary to L-Carnitine and Acetyl-CoA depletion which inhibits urea cycle
    • Can be seen with therapeutic VPA levels and normal LFTs
    • Level does not correlate with severity of VPE

Management

Activated charcoal

Levo-carnitine

  • Increases valproate metabolism and recommended for patients with:
    • Lethargy, coma, VPA associated hyperammonemic encephalopathy, hepatic dysfunction
    • 100mg/kg IV bolus, followed by 50mg/kg Q8h or alternatively 50mg/kg/day IV in 3 divided doses[1][2]

Naloxone

  • May be effective in reversing CNS depression by unclear mechanism[3][4]

Dialysis

  • Effective but reserved for severe overdoses and refractory hemodynamic instability and metabolic acidosis that do not respond to fluid resuscitation[5]

Disposition

  • Consider discharge for patient with declining levels and patient is asymptomatic

References

  1. Ishikura H. et al. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol. 1996 Jan-Feb. 20(1):55-8.
  2. Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr. 2007 Apr. 19(2):206-10.
  3. Roberge R. et al. Use of naloxone in valproic acid overdose: case report and review. J Emerg Med. 2002 Jan;22(1):67-70.
  4. Thanacoody HK. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J. 2007 Sep. 24(9):677-8.
  5. Tank JE. et al. Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis. 1993 Aug. 22(2):341-4.