Pharmacodynamic analysis of intravenous bolus remimazolam for loss of consciousness in patients undergoing general anaesthesia: a randomised, prospective, double-blind study

Remimazolam is a new rapid offset benzodiazepine used for procedural sedation and general anaesthesia. This study evaluated the efficacy and safety of i.v. bolus remimazolam during induction of anaesthesia. A total of 120 patients undergoing general anaesthesia were randomly allocated into six dose groups (n=20) of i.v. bolus remimazolam (0.02–0.27 mg kg−1). Loss of consciousness, respiratory depression, patient state index (PSI), and haemodynamic variables were evaluated during anaesthetic induction. Parametric time-to-event models were used to identify the 50% effective dose (ED50)/95% effective dose (ED95) associated with loss of consciousness and respiratory depression. Non-linear mixed-effect models analysed the PSI and haemodynamic changes after i.v. bolus remimazolam. Loss of consciousness and respiratory depression onset showed steep dose-responses with ED50/ED95 of 0.11/0.19 and 0.14/0.27 mg kg−1 and Hill coefficients of 5.3 and 4.6, respectively. Older age was significantly associated with lower ED50/ED95 for both endpoints. ED50/ED95 and the Hill coefficient of PSI decline were 0.12/0.68 mg kg−1 and 1.7, respectively. We propose optimal doses of 0.25–0.33, 0.19–0.25, and 0.14–0.19 mg kg−1 in patients aged 80 yr, respectively, based on the ED95 estimates for the corresponding age groups. The maximum percentage reduction of MAP was 27.8% and the ED50/ED95 were 0.14/2.60 mg kg−1. The effect of remimazolam on heart rate was insignificant. The ED50/ED95s of i.v. bolus remimazolam were successfully estimated from the time to loss of consciousness and respiratory depression. No serious adverse events occurred within the range of tested doses. NCT04901871.