Clinical Consequences of Disproportionate Free Valproate Elevation in Critically Ill Adult Patients: A Multicenter Retrospective Cohort Study.

Background: Valproate has a narrow therapeutic index and unpredictable protein binding, and critically ill patients may experience unexpectedly elevated free concentrations. We sought to identify the clinical consequences and determinants of disproportionate free valproate concentration elevation in critically ill adults.

Methods: This was a retrospective observational cohort study conducted at two academic medical centers from December 2015 to December 2023. Adult patients admitted to an intensive care unit who were receiving valproate and had concurrent total and free valproate concentrations measured were eligible for inclusion. We examined whether valproate concentrations were independently associated with adverse effects (AEs), including thrombocytopenia, hepatotoxicity, hyperammonemia, and pancreatic injury. Secondarily, determinants of disproportionate free valproate elevation, defined as a free valproate concentration that was greater than expected and out of proportion to the total concentration (e.g., free valproate above reference range but total valproate below reference range), were also identified.

Results: A total of 311 patients (mean age 58 [SD ± 17] years, 36% female, 31% non-White, and 29% on valproate prior to admission) with 550 concurrent free valproate and total valproate pairs were included. The median total valproate concentration was 46 μg/mL (interquartile range [IQR] 34-63), and the median free valproate concentration was 17 μg/mL (IQR 11-23); the median free fraction was 35% (IQR 25-63%). Disproportionate free valproate elevation was observed in 462 (84%) samples. Each 2.5-μg/mL increase in free valproate concentration was associated with thrombocytopenia (adjusted odds ratio [aOR] 1.15, 95% confidence interval [CI] 1.05-1.26) and hepatotoxicity (aOR 1.11, 95% CI 1.05-1.18). Albumin concentration (aOR 0.17, 95% CI 0.08-0.36), blood urea nitrogen (aOR 1.36, 95% CI 1.09-1.70), and propofol exposure (aOR 3.06, 95% CI 1.38-6.79) were associated with disproportionate free valproate elevation.

Conclusions: Elevated free valproate concentrations were associated with hepatotoxicity and thrombocytopenia; free valproate concentrations should be directly measured in critically ill patients because it is underrepresented by total valproate. Most critically ill patients are at risk, especially those with hypoalbuminemia, uremia, and propofol exposure.