Abstract
BACKGROUND: Although pharmacokinetic and pharmacodynamic models of remimazolam have been developed, their clinical application remains limited. This study aimed to administer a target-controlled infusion (TCI) of remimazolam at the effect-site concentration (Ce) in patients undergoing general anesthesia and to investigate the relationship of the remimazolam Ce with sedative effects and with recovery from general anesthesia. METHODS: Fifty patients aged 20-75 years, scheduled for minimally invasive surgery under general anesthesia for less than 2 h, were enrolled. Anesthesia was induced and maintained using Schüttler's model for effect-site TCI of remimazolam. During induction, the remimazolam Ce was increased stepwise, and sedation levels were assessed using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and bispectral index (BIS). Following attainment of MOAA/S scale 1, continuous infusion of remifentanil was commenced, and rocuronium (0.6 mg/kg) was administered for endotracheal intubation. The target Ce of remimazolam and the remifentanil infusion rate were adjusted to maintain a BIS between 40 and 70 and a heart rate within 20% of the baseline value. Approximately 5 min before surgery completion, the target Ce of remimazolam was reduced by 20-30%, and anesthetic infusion ceased at the end of surgery. Nonlinear mixed-effects modeling was employed to develop pharmacodynamic models for each sedation level as well as emergence from anesthesia. RESULTS: The remimazolam Ces associated with 50% probability (Ce(50)) of reaching MOAA/S scale ≤4, 3, 2, and 1 were 0.302, 0.397, 0.483, and 0.654 μg/mL, respectively. The Ce(50) values for recovery of responsiveness (ROR) and endotracheal extubation were 0.368 and 0.345 μg/mL, respectively. The prediction probabilities of Ce and BIS for detecting changes in sedation level were 0.797 and 0.756, respectively. The sedation scale significantly correlated with remimazolam Ce (r = -0.793, P < 0.0001) and BIS (r = 0.914, P < 0.0001). Age significantly correlated with Ce at MOAA/S1 and ROR. CONCLUSION: Effect-site TCI of remimazolam was successfully performed in patients undergoing general anesthesia. The remimazolam Ce significantly correlated with sedation depth. The Ce(50) for MOAA/S scale ≤1 and ROR were determined to be 0.654 and 0.368 μg/mL, respectively.