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

Background: 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. Methods: 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. Results: 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. Conclusions: 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. Clinical trial registration: NCT04901871.restrictio