Abstract
Remimazolam, an ultra-short-acting benzodiazepine rapidly metabolized by carboxylesterase-1, was developed as a promising alternative for ICU sedation. It was anticipated to overcome the unpredictable accumulation associated with midazolam and the hemodynamic/metabolic risks of propofol, offering superior hemodynamic stability and potential benefits in reducing postoperative delirium. Its ultra-short, predictable half-life positioned it as an ideal candidate for facile titration in critically ill patients. However, the trajectory of remimazolam's development for long-term ICU sedation faced a critical setback in Japan. Based on results from the ONO-2745-04 Phase II trial conducted on mechanically ventilated postoperative patients, the development program for the ICU indication was halted in 2013. The central safety concern was the unexpected pharmacokinetic failure observed in a subset of patients receiving continuous infusion for 24 h or longer. Specifically, this subgroup exhibited plasma concentrations of the parent drug far exceeding predicted levels, resulting in significantly delayed awakening and recover. This observation directly challenged the fundamental non-accumulating advantage of the drug. The mechanism is hypothesized to be compromised carboxylesterase-1 activity due to severe critical illness, systemic inflammation, or organ dysfunction-conditions that impair the very non-organ-dependent clearance pathway the drug relies upon. While international experience continues to validate the safe and effective use of remimazolam for short-to-medium-term ICU sedation, the Japanese experience serves as a critical clinical warning. It underscores that even drugs with inherently favorable pharmacokinetic profiles are susceptible to unpredictable parent drug accumulation in the highly heterogeneous and physiologically compromised ICU population during prolonged infusion. Therefore, extreme caution and individualized dosing strategies are warranted for remimazolam use in critically ill patients, especially those with severe systemic dysfunction.