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[...]a sufficient dose of sugammadex would not result in recurarization. [...]modified effect-site concentrations of remimazolam and flumazenil were determined with corresponding equilibration rate constant, ke0, using standard effect compartment model [9, 12], with which modified effect-site concentration equal is the same as free plasma concentration at steady state. With the assumption of modified effect-site concentration, conventional effect-site concentration, which is used in medical devices such as target-controlled infusion pump or pharmacokinetic simulator in anesthesia information management system, can be calculated as modified effect-site concentration divided by (1 − plasma protein binding ratio). All pharmacokinetic parameters and ke0 are applied from published articles [8, 9, 12] When it is difficult to understand the influence of the change in receptor occupancy rate, the time courses of remimazolam equivalent effect-site concentration (Fig. 1C and D) would help to more simply understand the potential risk of the re-sedation and respiratory depression.

The emergence profiles in patients undergoing total intravenous anesthesia with either propofol or remimazolam with flumazenil reversal were compared. A prospective, double-blind, randomized trial. An operating room and a post-anesthesia care unit (PACU). Adult patients (n = 100) having American Society of Anesthesiologists (ASA) physical status of I-III undergoing general anesthesia were enrolled and randomly assigned to the propofol or the remimazolam group. The propofol group received target-controlled infusion of propofol, and the remimazolam group received continuous infusion of remimazolam. Continuous infusion of remifentanil was used in both groups. For emergence, flumazenil was used in increments of 0.2 mg in the remimazolam group. The primary outcome was the time required for the patient to obey verbal commands. The secondary outcomes included the time to bispectral index (BIS) over 80, the time to laryngeal mask airway (LMA) removal, the Richmond Agitation-Sedation Scale (RASS) scores in the PACU, and adverse events throughout the study period. The time taken to obey verbal commands was significantly longer in the propofol group than the remimazolam group (14 [9, 19]) vs. 5 [3, 7]) minutes, P < 0.001; median difference -9, 95% confidence interval -11 to -6). The times to BIS over 80 and to LMA removal were also significantly longer in the propofol group. In addition, the RASS score upon arrival to the PACU differed significantly between the two groups (P = 0.006). Re-sedation in the PACU was observed in 11 (22%) of the patients in the remimazolam group. Remimazolam-based total intravenous anesthesia with flumazenil reversal may be effective in reducing emergence time, but a significant incidence of re-sedation was observed in the PACU. Further studies are needed to determine adequate dose and timing of routine flumazenil use and minimize the risk of re-sedation. •Remimazolam is a novel ‘ultra-short-acting’ benzodiazepine.•Remimazolam has a short history of use in total intravenous anesthesia.•Remimazolam's effect can be reversed by flumazenil.•Propofol has no specific antagonist.•Remimazolam can provide accelerated emergence after continuous infusion.

We report a case of post-awakening recurrent episodes of spontaneous re-sedation and apnea with severe desaturation after procedural sedation with dexmedetomidine and propofol in a leukemic adolescent with an ionic channel variant. The mutation is located in the 3′-UTR regulatory region of SCN9A. We speculate that this variant may affect the stability of the mRNA, making the patient more susceptible to the combined effects of propofol and dexmedetomidine. This is the first pediatric report of late onset re-sedation with apnoea after combined sedation with propofol and dexmedetomidine highlighting the risk of adverse events in selected patients with a genetic increased susceptibility. If validated by further studies, pharmacogenetic testing may be implemented to provide personalized therapies in patients needing anesthesia.

Remimazolam combined with flumazenil can shorten recovery time, but the occurrence of re-sedation may put the patient at risk. Herein, we report a case of a 50-year-old woman who underwent general anesthesia using remimazolam. During emergence from general anesthesia, she briefly regained consciousness after receiving 0.4 mg of flumazenil and then fell unconscious again. The disturbance of consciousness lasted for 75 min. We diagnosed re-sedation after ruling out other possible causes. We simulated anesthetic concentration changes using TIVA trainer software, further confirming re-sedation through mechanistic analysis. Additionally, we reviewed the literature and analyzed the potential reasons for the occurrence of re-sedation under various conditions. The occurrence of re-sedation is not only related to the administration of flumazenil but also to individual differences in the effect-site concentration of remimazolam and the phenomenon of rapid tolerance. In clinical practice, flumazenil should be used cautiously, avoiding single high-dose administration, and considering delayed administration when appropriate. For critically ill patients, clinicians should closely monitor and guard against the occurrence of re-sedation. Further research is needed to determine the optimal time to administer flumazenil and to identify the demographic and clinical characteristics of patients who experience re-sedation, thereby guiding patient safety.