Clinical Consequences of Occult Free Valproate Toxicity in Critically Ill Adult Patients: A Multicenter Retrospective Cohort Study

Background and Objectives: Valproate has wide pharmacokinetic variability and a narrow therapeutic index. Its protein binding is unpredictable, particularly among critically ill patients who may experience unexpectedly elevated free concentrations. We sought to identify the clinical consequences and determinants of occult free valproate toxicity in critically ill adults. Methods: We conducted a multicenter retrospective cohort study of adult patients admitted to an intensive care unit (ICU) who were receiving valproate and had concurrent total and free valproate concentrations measured. We examined whether valproate concentrations were independently associated with adverse drug effects (ADEs) including thrombocytopenia, hepatotoxicity, hyperammonemia, and pancreatic injury. Determinants of occult toxicity were also identified using logistic mixed-effects models, adjusting for age, weight, albumin, propofol and aspirin use, and blood urea nitrogen (BUN). Occult toxicity was defined as a free valproate concentration that was discordant with total concentration (e.g., supratherapeutic free concentration associated with therapeutic total concentration). Results: 311 unique patients (mean age 58 [±17] years, 36% female, 31% non-white, and 29% on valproate prior to admission) with 550 concurrent free and total valproate concentration pairs met inclusion criteria. The median (IQR) total valproate concentration was 46 mcg/mL (34-63) and the median free valproate concentration was 17 mcg/ml (11-23); median free fraction was 35% (25-63%). Eighty-four percent of total valproate concentrations represented occult free toxicity; a therapeutic total with a supratherapeutic free valproate concentration was the most common pattern (32% of concentration pairs). Each 2.5 mcg/mL increase in free valproate concentration was associated with thrombocytopenia (adjusted unit odds 1.15, 95% CI 1.05-1.26) and hepatotoxicity (adjusted unit odds 1.11, 95% CI 1.05-1.18). Albumin concentration (adjusted odds; aOR 0.17, 95% CI 0.08-0.36), BUN (aOR 1.36, 95% CI 1.09-1.70), and propofol exposure (aOR 3.06, 95% CI 1.38-6.79) were associated with occult toxicity. Conclusion: Free valproate concentrations should be measured in critically ill patients because it is associated with ADEs and is often underrepresented by total concentrations. Most critically ill patients are at risk, especially those with hypoalbuminemia, uremia, and lipid exposure. ### Competing Interest Statement A.J. Webb has received consulting fees from Acasti Pharma Inc. D.J. Gagnon is a clinical specialist in neurosciences for Lexicomp and is supported by NIGMS grant 1P20GM139745. C.S. Brown has received consulting fees from Trevena Pharmceuticals and grant funding from Astra Zeneca. R.R. Riker is supported by NIH-NIGMS grant 1P20GM139745. S.F. Zafar is supported by NIH-NINDS grants (1R01NS131347, 5K23NS114201, 1R01AG082693, and 1R21NS137117). E.S Rosenthal has received consulting fees from UCB, Inc. and Ceribell, Inc. and is supported by DoD grants (W81XWH-18-DMRDP-PTCRA) and NIH-NINDS and NIH-OD grants (R01NS117904, K23NS105950, R01NS113541, U54NS100064, OT2OD032701). ### Funding Statement D.J. Gagnon is supported by NIGMS grant 1P20GM139745. R.R. Riker is supported by NIH-NIGMS grant 1P20GM139745. S.F. Zafar is supported by NIH-NINDS grants (1R01NS131347, 5K23NS114201, 1R01AG082693, and 1R21NS137117). E.S Rosenthal is supported by DoD grants (W81XWH-18-DMRDP-PTCRA) and NIH-NINDS and NIH-OD grants (R01NS117904, K23NS105950, R01NS113541, U54NS100064, OT2OD032701). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was deemed exempt by the Massachusetts General Brigham Institutional Review Board and the need for informed consent was waived (2023P000131). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Anonymized data not published within this article will be made available upon reasonable request from any qualified investigator after completion of a data use agreement.