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Toxicity, Valproate: Differential Diagnoses & Workup

Author: Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Coauthor(s): Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; Medical Director, San Francisco Division, California Poison Control System; 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
Contributor Information and Disclosures

Updated: Jan 26, 2009

Differential Diagnoses

Alcohol and Substance Abuse Evaluation
Subdural Hematoma
Delirium Tremens
Toxicity, Acetaminophen
Delirium, Dementia, and Amnesia
Toxicity, Alcohols
Depression and Suicide
Toxicity, Ammonia
Diabetic Ketoacidosis
Toxicity, Antidepressant
Domestic Violence
Toxicity, Antidysrhythmic
Elder Abuse
Toxicity, Antihistamine
Hepatitis
Toxicity, Barbiturate
Hypothermia
Toxicity, Benzodiazepine
Hypothyroidism and Myxedema Coma
Toxicity, Carbamazepine
Metabolic Acidosis
Toxicity, Lithium
Pancreatitis
Toxicity, Narcotics
Pediatrics, Diabetic Ketoacidosis
Toxicity, Phenytoin
Pediatrics, Febrile Seizures
Toxicity, Salicylate
Pediatrics, Inborn Errors of Metabolism
Toxicity, Sedative-Hypnotics
Pediatrics, Meningitis and Encephalitis
Withdrawal Syndromes
Pediatrics, Reye Syndrome
Schizophrenia
Sexual Assault

Workup

Laboratory Studies

  • Valproate level and anticonvulsant screen
    • Determination of the valproic acid level is an obvious test. Because of reviews that have shown nearly 20% of valproic acid overdoses may present with initial valproic acid concentration in a therapeutic, or even nondetectable range, serial levels should be obtained until a peak level occurs and the levels are clearly trending down. Delayed absorption, in particular with Divalproex and the extended-release forms, has been frequently reported.
    • Patients taking valproic acid are frequently taking other anticonvulsants that they may not disclose.
    • Screening is preferably completed early and helps in determining if potentially complicating co-ingestion has occurred.
    • Consider screening for anticonvulsants, acetaminophen, and acetylsalicylic acid.
  • CBC count with differential
    • Thrombocytopenia
    • Agranulocytosis
  • Chemistries: Include a lithium level because of its use in mood stabilization (eg, in bipolar disorder).
  • Liver function studies
    • Fulminant hepatic failure is a potentially fatal but rare complication of both acute and chronic valproic acid toxicity.
    • Children younger than 3 years who are taking many anticonvulsants and who have medical comorbidities are at increased risk for this complication.
  • Coagulation studies
  • Measurement of the prothrombin time (PT) and international normalized ratio (INR)
  • Pregnancy testing in women of childbearing age
  • Arterial blood gas (ABG) analysis
  • Test for nonlactate metabolic acidosis: In one series, no patient with levels less than 450 mg/L developed acidosis.4
  • Test for respiratory depression with hypercapnia: This may reveal metabolic acidosis.
  • Lipase measurement
  • Assessment of the anion gap
    • Valproic acid can directly cause an anion gap. Conversion of valproic acid level to mmol/L has been shown to correspond with the anion gap in individuals with significantly elevated valproic acid levels.
    • In a large multicenter review of 134 patients (80 with toxic VPA levels), an elevated anion gap (>15) was seen in 26% of patients with valproic acid levels >450 mg/L.4
  • Assessment of the osmolar gap: Because of its small size, valproic acid may theoretically contribute to an elevated osmolar gap if the serum valproic acid level is very high (eg, >1000 mg/L).

Imaging Studies

  • Obtain a CT scan of the head to evaluate cerebral edema, which is well documented with acute overdose. 
  • Cerebral edema is usually associated with hyperammonemia and appears within 48-72 hours after acute ingestion.
  • Patients with encephalopathy and hyperammonemia due to chronic valproic acid therapy are at risk for cerebral edema.

Other Tests

  • An ECG should be obtained in all patients with overdose. 
    • Particular findings reported with valproic acid ingestion include atrial tachyarrhythmias (in particular sinus tachycardia). Nonspecific ST- and T-wave changes have been reported as well as drug-induced Brugada syndrome. 
    • Valproic acid has been studied as an antiarrhythmic, and, in normal doses, it may actually decrease the frequency of premature ventricular contractions.

More on Toxicity, Valproate

Overview: Toxicity, Valproate
Differential Diagnoses & Workup: Toxicity, Valproate
Treatment & Medication: Toxicity, Valproate
Follow-up: Toxicity, Valproate
References
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Further Reading

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Keywords

valproic acid, toxicity valproate, valproate overdose, valproate poisoning, VPA, valproic acid overdose, anticonvulsant, antiseizure, seizure treatment, valproate, divalproate, sodium valproate toxicity, dipropylacetic acid toxicity, divalproex sodium toxicity, valproate semisodium toxicity, 2-propylpentanoic acid toxicity, 2-propylvaleric acid toxicity, Depacon, Depakene, Depakote, Depakote ER, Epilim, Ergenyl, Leptilan, Valkote, Sprinkles

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Contributor Information and Disclosures

Author

Timothy Wiegand, MD, Clinical Assistant Professor of Medicine, University of Vermont College of Medicine and Maine Medical Center; Associate Medical Director, Northern New England Poison Center
Timothy Wiegand, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American College of Medical Toxicology, American College of Physicians, and Maine Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kent R Olson, MD, FACEP, Clinical Professor of Medicine and Pharmacy, University of California San Francisco; 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.

Medical Editor

Lance W Kreplick, MD, MMM, FAAEM, FACEP, 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, MMM, FAAEM, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physician Executives
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & 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.

Managing Editor

Fred Harchelroad, MD, FACMT, FAAEM, FACEP, Chair, Department of Emergency Medicine, Director of Medical Toxicology - Allegheny General Hospital, Associate Professor, Department of Emergency Medicine, Drexel University College of Medicine
Disclosure: Nothing to disclose.

CME Editor

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.

 
 
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