Valproate Toxicity Clinical Presentation

  • Author: Timothy J Wiegand, MD; Chief Editor: Asim Tarabar, MD   more...
 
Updated: Nov 4, 2010
 

History

Few historical features are suggestive of valproic acid poisoning. As in most poisonings, a clinical history of the ingestion, including the amount and exact time of ingestion, are helpful. Adequate documentation of previous medical and psychiatric problems is essential.

Medical and psychiatric diagnoses and medications

Prescription and nonprescription medications (including over-the-counter drugs and drugs of abuse) may contribute or mask symptoms of overdose. Adequate documentation of all medications is necessary.

Consider herbal and natural remedies as co-ingestants.

Exact description of the type and amount of overdose

The formulation of valproic acid (eg, capsules, sprinkles, syrup, extended-release tablets) taken should be noted, as should the exact amount taken. In particular, Divalproex and the extended-release form may cause significant delays in peak concentration during overdose.

Count the remaining or unused portion in the prescription bottle. Subtract this count from the original amount dispensed from the pharmacy. A discrepancy between the number missing and the number that should be missing if the prescribed regimen was followed provides a rough estimate of the amount the patient may have taken.

Record the exact time of the overdose.

Previous suicide attempts

Previous suicidal attempts are important because they can lead the clinician to consider referring the patient to a psychiatrist.

If a patient continues to have suicidal ideation, holding the patient for psychiatric evaluation on legal grounds may be warranted.

Domestic violence

Remember to screen for domestic violence in all patients with valproic acid overdose.

Because domestic violence is widely underreported, be aware of other indications of such abuse, including assault, depression, or suicide attempts.

Next

Physical

Physical examination may provide clues to the nature of the poisoning. Physical findings may reveal the severity of the overdose, but they are not specific for valproic acid (VPA) overdose. GI upset with nausea and vomiting is the most common presentation of patients with valproic acid overdose, closely followed by CNS symptoms of decreased level of consciousness and confusion.

Vital signs

Vital signs are highly variable in patients with valproic acid poisoning.

Fever and hypothermia have been reported.

Hypotension has been reported with severe overdoses. Many case reports of severe valproic acid overdose discuss hypotension refractory to aggressive use of intravenous fluids and pressor agents. In a large multicenter review of 134 patients (80 of whom had VPA levels in the toxic range), 3% of patients had hypotension in association with acute valproic acid ingestion, and 25% of patients with levels greater than 850 mg/L had hypotension.[4] Levels greater than 1000 mg/L may be associated with refractory hypotension. (Despite that hypotension hemodialysis is often recommended for these patients to rapidly increase elimination as these levels are associated with severe morbidity and mortality. Hemodialysis is often effective and may produce dramatic improvements for these patients. (See elimination discussed in Emergency Department Care).

Cardiac arrest has been reported in severe valproic acid overdoses. The clinical condition of patients with valproic acid overdose can worsen dramatically as the drug is being absorbed. Patients with massive overdose can develop apnea and cardiac arrest.

Respiratory depression requiring intubation occurs with increasing frequency as valproic acid levels rise.

CNS

In a large multicenter review of 134 patients (80 with VPA levels in the toxic range), 71% of patients presented with lethargy, and 15% were comatose.[4] All patients with serum levels greater than 850 mg/L were comatose, and 63% of these patients needed intubation. CNS findings may include the following:

  • Coma
  • Confusion
  • Somnolence
  • Worsened seizure control
  • Dizziness
  • Hallucinations
  • Irritability
  • Headache
  • Ataxia
  • Cerebral edema: This well-documented manifestation usually occurs 48-72 hours after ingestion, even as serum levels are decreasing. It has been suggested that elevated serum ammonia (NH3) levels can produce encephalopathy via the inhibition of glutamate uptake by astrocytes, which may lead to potential neuronal injury and perhaps cerebral edema. It has also been suggested that hyperammonemia may lead to a disruption of the osmotic gradient, which is thought to precipitate the edema.

Dermatologic findings

Alopecia has been reported in severe and chronic overdose.

GI findings

Anorexia, nausea, and vomiting are the most common symptoms in acute toxicity.

Genitourinary (GU) findings

Renal failure is rare. Case reports describe renal failure in patients with serum levels of greater than 1000 mg/L. Anuria and enuresis may be noted.

Musculoskeletal findings

Patients may present with tremors and chorea.

Ocular findings

Miosis and nystagmus may be observed.

Previous
Next

Causes

  • Intentional ingestions in attempted suicide
  • Accidental ingestions
  • Intentional poisoning of another person
Previous
Proceed to Differential Diagnoses
 
 
Contributor Information and Disclosures
Author

Timothy J Wiegand, MD  Director, Ruth A Lawrence Poison and Drug Information Center, Associate Clinical Professor of Medicine and Emergency Medicine, University of Rochester Medical Center and Strong Memorial Hospital

Timothy J Wiegand, MD, is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, and American College of Physicians

Disclosure: Nothing to disclose.

Coauthor(s)

Kent R Olson, MD, FACEP  Clinical Professor of Medicine and Pharmacy, University of California, San Francisco, School of Medicine; Medical Director, San Francisco Division, California Poison Control System

Kent R Olson, MD, FACEP is a member of the following medical societies: American Academy of Clinical Toxicology and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Herbert E Hern Jr, MD  Assistant Clinical Professor, Department of Emergency Medicine, University of California, San Francisco; Residency Director, Department of Emergency Medicine, Highland General Hospital

Herbert E Hern Jr, MD is a member of the following medical societies: American College of Emergency Physicians and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Specialty Editor Board

Lance W Kreplick, MD, FAAEM, MMM  Medical Director of Hyperbaric Medicine, Fawcett Wound Management and Hyperbaric Medicine; Consulting Staff in Occupational Health and Rehabilitation, Company Care Occupational Health Services; President and Chief Executive Officer, QED Medical Solutions, LLC

Lance W Kreplick, MD, FAAEM, MMM, is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives

Disclosure: Nothing to disclose.

John T VanDeVoort, PharmD  Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists

Disclosure: Nothing to disclose.

Fred Harchelroad, MD, FACMT, FAAEM, FACEP  Director of Medical Toxicology, Allegheny General Hospital

Disclosure: Nothing to disclose.

John D Halamka, MD, MS  Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD  Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital

Disclosure: Nothing to disclose.

Additional Contributors

The staff, faculty, and fellows of the San Francisco Bay Area Regional Poison Control Center contributed insight, review, and encouragement for this review.

References

  1. Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose--treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol. 1996;34(3):335-41. [Medline].

  2. Flomenbaum N, Goldfrank L, Hoffman R, Howland MA, Lewin N, Nelson L, et al. Goldfrank's Toxicologic Emergencies. 8th ed. New York: McGraw-Hill Companies; 2006.

  3. Lai MW, Klein-Schwartz W, Rodgers GC, Abrams JY, Haber DA, Bronstein AC, et al. 2005 Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database. Clin Toxicol (Phila). 2006;44(6-7):803-932. [Medline]. [Full Text].

  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(7):755-60. [Medline].

  5. Tank JE, Palmer BF. Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis. Aug 1993;22(2):341-4. [Medline].

  6. Kane SL, Constantiner M, Staubus AE, Meinecke CD, Sedor JR. High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose. Ann Pharmacother. Oct 2000;34(10):1146-51. [Medline].

  7. Kay TD, Playford HR, Johnson DW. Hemodialysis versus continuous veno-venous hemodiafiltration in the management of severe valproate overdose. Clin Nephrol. Jan 2003;59(1):56-8. [Medline].

  8. Thanacoody HK. Chronic valproic acid intoxication: reversal by naloxone. Emerg Med J. Sep 2007;24(9):677-8. [Medline].

  9. Ishikura H, Matsuo N, Matsubara M, Ishihara T, Takeyama N, Tanaka T. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol. Jan-Feb 1996;20(1):55-8. [Medline].

  10. LoVecchio F, Shriki J, Samaddar R. L-carnitine was safely administered in the setting of valproate toxicity. Am J Emerg Med. May 2005;23(3):321-2. [Medline].

  11. Russell S. Carnitine as an antidote for acute valproate toxicity in children. Curr Opin Pediatr. Apr 2007;19(2):206-10. [Medline].

  12. Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol. 1992;30(2):209-14. [Medline].

  13. Alberto G, Erickson T, Popiel R, Narayanan M, Hryhorczuk D. Central nervous system manifestations of a valproic acid overdose responsive to naloxone. Ann Emerg Med. Aug 1989;18(8):889-91. [Medline].

  14. Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol. 1995;33(3):279-84. [Medline].

  15. Bigler D. Neurological sequelae after intoxication with sodium valproate. Acta Neurol Scand. Sep 1985;72(3):351-2. [Medline].

  16. Caraccio TR, Mofenson HC. Carnitine. J Toxicol Clin Toxicol. 2003;41(6):897; author reply 901-2. [Medline].

  17. Chicharro AV, de Marinis AJ, Kanner AM. The measurement of ammonia blood levels in patients taking valproic acid: looking for problems where they do not exist?. Epilepsy Behav. Nov 2007;11(3):361-6. [Medline].

  18. Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J. Jun 1987;32(3):85-6. [Medline].

  19. Dart RC, ed. Medical Toxicology. 3rd ed. Lippincott Wiliams and Wilkins; 2004.

  20. Doyon S. Anticonvulsants. In: Goldfrank L, ed. Goldfrank's Toxicologic Emergencies. 7th ed. New York, NY: McGraw Hill; 2002:614-30.

  21. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf. Jan-Feb 1990;5(1):65-71. [Medline].

  22. Eeg-Olofsson O, Lindskog U. Acute intoxication with valproate. Lancet. Jun 5 1982;1(8284):1306. [Medline].

  23. Eyer F, Felgenhauer N, Gempel K, Steimer W, Gerbitz KD, Zilker T. Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy. J Clin Psychopharmacol. Aug 2005;25(4):376-80. [Medline].

  24. Farrar HC, Herold DA, Reed MD. Acute valproic acid intoxication: enhanced drug clearance with oral-activated charcoal. Crit Care Med. Feb 1993;21(2):299-301. [Medline].

  25. Fernandez MC, Walter FG, Kloster JC, et al. Hemodialysis and hemoperfusion for treatment of valproic acid and gabapentin poisoning. Vet Hum Toxicol. Dec 1996;38(6):438-43. [Medline].

  26. Franssen EJ, van Essen GG, Portman AT, et al. Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion. Ther Drug Monit. Jun 1999;21(3):289-92. [Medline].

  27. Gourru J. Intoxication aigue massive par le valproate de sodium: a propos d'une observation d1intoxication voluntaire mortelle [medical thesis]. Lyons, France: University of Lyons; 1981.

  28. Haller C. L-Carnitine. In: Olson K, ed. Poisoning and Drug Overdose. 7. 4th ed. New York, NY: McGraw-Hill; 2004:426.

  29. Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med. Jun 2002;39(6):616-21. [Medline].

  30. Janssen F, Rambeck B, Schnabel R. Acute valproate intoxication with fatal outcome in an infant. Neuropediatrics. Nov 1985;16(4):235-8. [Medline].

  31. Karlsen RL, Kett K, Henriksen O. Intoxication with sodium valproate. A case report. Acta Med Scand. 1983;213(5):405-6. [Medline].

  32. Kearney TE. Valproic acid. In: Olson K, ed. Poisoning and Drug Overdose. 5th ed. New York, NY: McGraw-Hill Medical; 2005.

  33. Lakhani M, McMurdo ME. Survival after severe self poisoning with sodium valproate. Postgrad Med J. May 1986;62(727):409-10. [Medline].

  34. Leggio L, Kenna GA, Swift RM. New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry. Jul 1 2008;32(5):1106-17. [Medline].

  35. 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. Oct 5 2005;9(5):431-40. [Medline].

  36. LoVecchio F, Thole D, Bagnasco T. Delayed absorption of valproic acid, resulting in coma. Acad Emerg Med. Dec 2002;9(12):1464. [Medline].

  37. Marklund N, Enblad P, Ronne-Engstrom E. Neurointensive care management of raised intracranial pressure caused by severe valproic acid intoxication. Neurocrit Care. 2007;7(2):160-4. [Medline].

  38. Meek MF, Broekroelofs J, Yska JP, et al. Valproic acid intoxication: sense and non-sense of haemodialysis. Neth J Med. Oct 2004;62(9):333-6. [Medline].

  39. Mortensen PB, Hansen HE, Pedersen B, Hartmann-Andersen F, Husted SE. Acute valproate intoxication: biochemical investigations and hemodialysis treatment. Int J Clin Pharmacol Ther Toxicol. Feb 1983;21(2):64-8. [Medline].

  40. Olson K, ed. Poisoning and Drug Overdose. 4th ed. New York: McGraw-Hill Companies; 2004:362-64, 426-27.

  41. Palatnik W, Hoorcharik N, Roberts D, et al. Coma anion gap and metabolic derangements associated with massive valproic acid ingestion. Vet Hum Toxicol. 1989;31:368.

  42. Perez A, McKay CA. Role of carnitine in valproic acid toxicity. J Toxicol Clin Toxicol. 2003;41(6):899; author reply 901-2. [Medline].

  43. Roodhooft AM, Van Dam K, Haentjens D, Verpooten GA, Van Acker KJ. Acute sodium valproate intoxication: occurrence of renal failure and treatment with haemoperfusion-haemodialysis. Eur J Pediatr. Feb 1990;149(5):363-4. [Medline].

  44. Seger DL. Anticonvulsant medications. In: Dart R, ed. Medical Toxicology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:798-801.

  45. Singh SM, McCormick BB, Mustata S, Thompson M, Prasad GV. Extracorporeal management of valproic acid overdose: a large regional experience. J Nephrol. Jan-Feb 2004;17(1):43-9. [Medline].

  46. Snodgrass WR. Valproic acid. In: Brent J, Wallace K, Burkhart K, et al, eds. Critical Care Toxicology. St Louis, MO: Mosby; 2005:565-9.

  47. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002;40(6):789-801. [Medline].

  48. Unal E, Kaya U, Aydin K. Fatal valproate overdose in a newborn baby. Hum Exp Toxicol. May 2007;26(5):453-6. [Medline].

  49. Wadzinski J, Franks R, Roane D, Bayard M. Valproate-associated hyperammonemic encephalopathy. J Am Board Fam Med. Sep-Oct 2007;20(5):499-502. [Medline].

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.