Changes in Free and Total Remimazolam Concentrations During Cardiopulmonary Bypass: A Randomized Dose-Comparison Trial

Objectives: Remimazolam is increasingly used in cardiac surgery for hemodynamic stability; however, during cardiopulmonary bypass (CPB), hemodilution and hypoalbuminemia may increase its pharmacologically active free fraction, raising concern about unrecognized overexposure under constant infusion. Yet, the temporal profile of free remimazolam during CPB has not been fully elucidated. We investigated whether a pragmatic dose adjustment could maintain free remimazolam concentrations within a stable range. Design: Randomized, controlled, parallel-group trial. Setting: A university hospital. Participants: Thirty-six adults undergoing cardiac surgery with CPB. Interventions: Patients were assigned to a normal-dose group (1 mg/kg/h) or a low-dose group in which the infusion rate of remimazolam was reduced to 70% at CPB initiation (0.7 mg/kg/h). Measurements and Main Results: The primary outcome was free remimazolam concentration. Secondary outcomes included total remimazolam concentration, protein binding, and associations between bispectral index values and drug concentrations. Baseline-adjusted analysis of free remimazolam concentrations showed a significant time-by-group interaction (pinteraction = 0.001), increasing over time in the normal-dose group but remaining stable in the low-dose group. The largest adjusted between-group difference was observed 30 minutes after CPB termination (mean difference [95% CI], 89 [58-120] ng/mL; p < 0.001). No linear association was observed between bispectral index values and free or total remimazolam concentrations. Conclusion: During CPB, free remimazolam concentrations increased over time under constant infusion without corresponding changes in bispectral index values, whereas reducing the infusion rate to 70% at CPB initiation maintained free remimazolam concentrations within a stable range. © 2026 Elsevier Inc.