Dose-Response Relationship of Single Intravenous Remimazolam on Bispectral Index and Cardiorespiratory Effects

The Bispectral Index (BIS) is a standardized, continuous measure of sedation depth. Studies have shown that remimazolam can induce a decrease in BIS, but the dose-response relationship between single-dose remimazolam and BIS remains unclear.

This study aimed to explore the correlation between single intravenous doses of remimazolam and BIS, and to observe its effects on respiration and circulation.

This was a prospective, randomized, double-blind, dose-finding study. One hundred patients scheduled for elective surgery under general anesthesia were randomly assigned to five groups and received intravenous remimazolam at 0.2, 0.3, 0.4, 0.5, or 0.6 mg/kg before anesthesia induction. BIS values at each time point, minimum BIS (BISmin), vital signs, adverse events, and interventions were recorded. Probit regression was used to calculate the ED₅₀ and ED₉₀ for the BIS ≤ 60 threshold (primary exploratory analysis), and a post hoc exploratory analysis was performed using the BIS ≤ 65 threshold.

BIS values decreased more significantly with increasing remimazolam doses, with a plateau effect observed above 0.4 mg/kg. The BISmin values for each group were 60.6 ± 10.4, 58.4 ± 9.2, 58.1 ± 6.2, 55.6 ± 7.9, and 55.0 ± 6.4, respectively. Using the BIS ≤ 60 threshold, the ED₅₀ and ED₉₀ were 0.317 mg/kg (95% CI: 0.187-0.415 mg/kg) and 1.172 mg/kg (95% CI: 0.704-13.959 mg/kg), respectively. The extremely wide confidence interval for the ED₉₀ reflects the statistical fact that the Probit model could not reliably extrapolate the dose-response relationship at higher doses within the studied range. Using the BIS ≤ 65 threshold in a post hoc exploratory analysis, the ED₅₀ and ED₉₀ were 0.147 mg/kg (95% CI: 0.024-0.216 mg/kg) and 0.436 mg/kg (95% CI: 0.334-0.958 mg/kg), respectively, with relatively narrower confidence intervals. Sensitivity analysis after excluding one patient who received ciprofol rescue was consistent with the primary analysis. There were no significant differences between groups in the incidence of tachycardia, bradycardia, hypoxemia, apnea, injection pain, body movement, diaphragmatic spasm, or cough, nor in the need for interventions. No serious adverse events occurred.

A dose-dependent relationship exists between single-dose remimazolam and BIS, with good respiratory and circulatory safety in the 0.2-0.6 mg/kg range and a plateau effect above 0.4 mg/kg. The extremely wide confidence interval for the ED₉₀ estimated using the BIS ≤ 60 threshold suggests that this endpoint may not be suitable for pharmacodynamic evaluation of single-dose remimazolam. The ED estimates obtained with the BIS ≤ 65 threshold are from a post hoc exploratory analysis and await prospective validation in future studies incorporating clinical sedation assessments, such as the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale.