Valproate Dose Associated With Therapeutic Free Valproate Concentrations in the Critically Ill

Introduction: Valproate (VPA) has altered protein binding in the critically ill and thus patients in the ICU may be exposed to disproportionately elevated free VPA concentrations at standard doses. We sought to identify what VPA dose was most likely to achieve a therapeutic free VPA concentration.


Methods: This retrospective cohort study was conducted at two centers in Boston, MA from 04/2016-04/2024 including patients who received VPA and had concurrent free and total VPA concentrations measured while admitted to any ICU. All free and total VPA concentrations collected in the ICU per patient were included. The primary outcome was the median VPA dose (mg/kg/day) that led to an in-goal free VPA concentration, defined as 5-15 mg/L. VPA dose was calculated as the mg/kg dose administered within 24 hours of the concentration measurement using ideal body weight for obese (BMI >30) patients and actual body weight for non-obese patients. Secondary outcomes included differences in dosing between in-goal free and total (defined as 50-100 mg/L) VPA concentrations.


Results: A total of 338 patients and 618 free/total VPA pairs were included. Mean (±SD) age was 58 (±17) years, 225 (67%) were female, 101 (29%) were non-White, and the mean weight was 81 (±21) kg. The median (IQR) total and free VPA concentrations were 46 (34-63) mg/L and 17 (11-24) mg/L with a median free fraction of 35% (25-53%). The median VPA doses were 1500 (1000-2500) mg/day and 25 (18-40) mg/kg/day. Overall, 252 (41%) and 243 (39%) of total and free VPA concentrations were in-goal, 15 (2%) and 343 (56%) were above goal, and 351 (57%) and 32 (5%) were below goal; only 101 (16%) had concordant interpretations (i.e., both in-goal). The VPA dose needed to attain in-goal free VPA concentrations was 22 (15-35) mg/kg/day, lower than the estimated VPA dose to attain therapeutic total concentrations (28 [21-44] mg/kg/day, p< 0.001).


Conclusions: A VPA dose of ~20 mg/kg/day is required to achieve an in-goal free VPA concentration in critically ill adults and is lower than what is required to achieve an in-goal total VPA concentration. Increasing doses to target a therapeutic total concentration may overexpose critically ill adults to unbound VPA which could lead to adverse effects.