https://doi.org/10.4081/ecj.2026.15627
Early clinical features associated with severe valproic acid poisoning: a toxicology investigators consortium core registry study
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Published: 4 September 2026
Severe acute Valproic Acid (VPA) ingestions may require intensive care, intubation, or Extracorporeal Treatments (ECTRs), but early predictors are poorly defined. In this study we aimed to identify presentation features associated with Intensive Care Unit (ICU)-level care, intubation, and ECTRs after VPA exposure. We analyzed 164 VPA cases reported to the Toxicology Investigators Consortium Core Registry from January 1, 2012, through December 31, 2025. Candidate predictors were selected a priori from severe VPA toxicity features. Associations were assessed using Fisher exact tests and Odds Ratios (ORs). Median age was 34.5 years; 144/164 exposures (87.8%) were intentional. ICU-level care occurred in 49/164 cases (29.9%), intubation in 23/164 (14.0%), and ECTRs in 5/164 (3.0%). ICU-level care was associated with respiratory depression (OR 30.0), metabolic acidosis (OR 15.9), hypotension (OR 4.63), central nervous system depression (OR 4.23), and co-ingestion (OR 3.25). Therapeutic-use cases were less likely to require ICU-level care or intubation. Respiratory depression, metabolic acidosis, hypotension, central nervous system depression, and co-ingestion identify VPA exposures at higher risk for ICU-level care.
Downloads
1. Isbister GK, Balit CR, Whyte IM, Dawson A. Valproate overdose: a comparative cohort study of self poisonings. Br J Clin Pharmacol 2003;55:398-404. DOI: https://doi.org/10.1046/j.1365-2125.2003.01772.x
2. Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol 2002;40:789-801. Erratum in: J Toxicol Clin Toxicol 2003;41:215. DOI: https://doi.org/10.1081/CLT-120014645
3. Greene SC, Wyatt K, Cates AL, Weiss S. Anticonvulsant fatalities reported to the American Association of Poison Control Centers 2000 - 2019. Seizure 2023;106:1-6. DOI: https://doi.org/10.1016/j.seizure.2023.01.010
4. Chadwick DW. Concentration-effect relationships of valproic acid. Clin Pharmacokinet 1985;10:155-63. DOI: https://doi.org/10.2165/00003088-198510020-00003
5. Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf 1990;5:65-71. DOI: https://doi.org/10.2165/00002018-199005010-00006
6. Shnayder NA, Grechkina VV, Khasanova AK, et al. Therapeutic and toxic effects of valproic acid metabolites. Metabolites 2023;13:134. DOI: https://doi.org/10.3390/metabo13010134
7. Lheureux PE, Hantson P. Carnitine in the treatment of valproic acid-induced toxicity. Clin Toxicol (Phila) 2009;47:101-11. DOI: https://doi.org/10.1080/15563650902752376
8. Schrettl V, Felgenhauer N, Rabe C, et al. L-Arginine in the treatment of valproate overdose - five clinical cases. Clin Toxicol (Phila) 2017;55:260-6. DOI: https://doi.org/10.1080/15563650.2017.1284333
9. 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. DOI: https://doi.org/10.1081/CLT-100102388
10. Ingels M, Beauchamp J, Clark RF, Williams SR. Delayed valproic acid toxicity: a retrospective case series. Ann Emerg Med 2002;39:616-21. DOI: https://doi.org/10.1067/mem.2002.124443
11. Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol 1995;33:279-84. DOI: https://doi.org/10.3109/15563659509018000
12. Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol 1992;30:209-14. DOI: https://doi.org/10.3109/15563659209038632
13. Triggs WJ, Gilmore RL, Millington DS, et al. Valproate-associated carnitine deficiency and malignant cerebral edema in the absence of hepatic failure. Int J Clin Pharmacol Ther 1997;35:353-6.
14. Juurlink DN. Carbapenems in the management of valproic acid overdose. Br J Clin Pharmacol 2025;91:648-53. DOI: https://doi.org/10.1111/bcp.16376
15. Vannaprasaht S, Tiamkao S, Sirivongs D, Piyavhatkul N. Acute valproic acid overdose: enhance elimination with multiple-doses activated charcoal. J Med Assoc Thai 2009;92:1113-5.
16. Alrazooqi MK, Abumuaileq L, Zia S, Kazim S. Massive valproic acid overdose with confirmed pharmacobezoar formation and neuromuscular toxicity: a case report and literature review. Cureus 2025;17:e96884. DOI: https://doi.org/10.7759/cureus.96884
17. Ghannoum M, Laliberté M, Nolin TD, et al. Extracorporeal treatment for valproic acid poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila) 2015;53:454-65. DOI: https://doi.org/10.3109/15563650.2015.1035441
18. Aldy K, Li S, Costantini M, et al. The Toxicology Investigators Consortium 2024 Annual Report. J Med Toxicol 2026;22:2-28. DOI: https://doi.org/10.1007/s13181-025-01099-0
19. Nguyen P, Chevillard L, Gouda AS, et al. L-carnitine does not improve valproic acid poisoning management: a cohort study with toxicokinetics and concentration/effect relationships. Ann Intensive Care 2022;12:7. DOI: https://doi.org/10.1186/s13613-022-00984-z
20. Beauchamp J, Olson K. Valproic acid overdoses: A retrospective study comparing serum drug levels and the incidence of adverse outcomes. J Toxicol Clin Toxicol 1999;37:637–8.
21. Connacher AA, Macnab MS, Moody JP, Jung RT. Fatality due to massive overdose of sodium valproate. Scott Med J 1987;32:85-6. DOI: https://doi.org/10.1177/003693308703200312
22. Katiyar A, Aaron C. Case files of the Children's Hospital of Michigan Regional Poison Control Center: the use of carnitine for the management of acute valproic acid toxicity. J Med Toxicol 2007;3:129-38. DOI: https://doi.org/10.1007/BF03160923
23. Franssen EJ, van Essen GG, Portman AT, et al. Valproic acid toxicokinetics: serial hemodialysis and hemoperfusion. Ther Drug Monit 1999;21:289-92. DOI: https://doi.org/10.1097/00007691-199906000-00005
24. Carroll D, Darling A, Vohra V, et al. Correlation between metabolic derangements and serum valproate concentrations in critically ill poisoned patients. Clin Toxicol 2025;63:129.
25. National Center for Biotechnology Information. PubChem Compound Summary for CID 23663956, Divalproex Sodium. PubChem March 23, 2026; Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Divalproex-Sodium
26. Bischof MCM, Stadelmann MIE, Janett S, et al. Valproic acid-associated acute pancreatitis: systematic literature review. J Clin Med 2023;12:6044. DOI: https://doi.org/10.3390/jcm12186044
27. Ezhilarasan D, Mani U. Valproic acid induced liver injury: An insight into molecular toxicological mechanism. Environ Toxicol Pharmacol 2022;95:103967. DOI: https://doi.org/10.1016/j.etap.2022.103967
28. Buoli M, Serati M, Botturi A, Altamura AC. The risk of thrombocytopenia during valproic acid therapy: a critical summary of available clinical data. Drugs R D 2018;18:1-5. DOI: https://doi.org/10.1007/s40268-017-0224-6
29. Rahman A, Mican LM, Fischer C, Campbell AH. Evaluating the incidence of leukopenia and neutropenia with valproate, quetiapine, or the combination in children and adolescents. Ann Pharmacother 2009;43:822-30. DOI: https://doi.org/10.1345/aph.1L617
30. Oluboka OJ, Haslam D, Gardner DM. Pancytopenia and valproic acid: a dose-related association. J Am Geriatr Soc 2000;48:349–50. DOI: https://doi.org/10.1111/j.1532-5415.2000.tb02668.x
CRediT authorship contribution
David K. Carroll, conceptualization, methodology, investigation, data curation, formal analysis, visualization, project administration, writing – original draft, and writing – review & editing. Andrew M. King, methodology, validation, supervision, and writing – review & editing. Brandtly Yakey: investigation, data curation, validation, and writing – review & editing. Aria Darling, investigation, validation, and writing – review & editing. Jennifer Thompson, investigation, data curation, and writing – review & editing. Bram A. Dolcourt, methodology, supervision, and writing – review & editing. Varun Vohra, methodology, validation, resources, and writing – review & editing. The Toxicology Investigators Consortium (ToxIC), resources, investigation, and data curation. All named authors critically reviewed the manuscript, approved the final version, and agreed to be accountable for the work.
Supporting Agencies
Data Availability Statement
The data underlying this study are not publicly available because they are derived from the Toxicology Investigators Consortium Core Registry and are subject to registry data-use restrictions.
How to Cite
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
