Efficacy and Safety of Remimazolam Tosylate versus Propofol for Sedation of Postoperative Mechanically Ventilated Patients in Intensive Care Units: A Multicenter, Randomized, Single-blind, Noninferiority, Phase 3 Trial

BACKGROUND: Remimazolam tosylate, a novel short-acting benzodiazepine, has shown effective and safe sedation in mechanically ventilated patients in intensive care units in a phase 2 trial. The authors conducted a multicenter, randomized, single-blind, actively controlled, phase 3 trial (NCT06222294) for further evaluation. METHODS: Mechanically ventilated patients, requiring sedation for 6 h or longer with a target Richmond Agitation-Sedation Scale (RASS) of -2 to +1, were randomized (1:1) to receive intravenous remimazolam tosylate (loading dose, 0.08 mg/kg; maintenance, 0 to 2.0 mg · kg -1 · h -1 ) or propofol (loading dose, 0.3 to 0.5 mg/kg; maintenance, 0.3 to 4.0 mg · kg -1 · h -1 ). Both allowed for adjusted infusion rates or additional doses to maintain target RASS. Maximum treatment duration was 24 h. The primary endpoint was the proportion of patients achieving sedation success, defined as maintaining target sedation range for 70% or more of drug administration time without rescue sedation. Noninferiority margin was -8%. RESULTS: Between March 12, 2024, and September 24, 2024, a total of 211 patients (mean age, 61.1 yr; 63.5% male; 99.1% postoperative) received remimazolam tosylate (n = 106) or propofol (n = 105). Mean ± SD treatment duration was 11.5 ± 3.6 h for remimazolam tosylate and 11.1 ± 3.1 h for propofol; mean ± SD total dose was 187.1 ± 134.4 mg and 593.7 ± 530.9 mg, respectively. Sedation success rate was 98.1% with remimazolam tosylate and 96.2% with propofol (difference, 1.9%; 95% CI, -3.3 to 7.8%); mean ± SD percentage of time in RASS target range was 95.1% ± 13.8% versus 95.0% ± 12.9%, and the proportion of patients receiving rescue sedation was 0.0% (0 of 106) versus 1.0% (1 of 105). Mean ± SD additional doses required totaled 0.03 ± 0.17 for remimazolam tosylate and 0.18 ± 0.77 for propofol. Adverse event occurred in 81 (76.4%) patients with remimazolam tosylate and 77 (73.3%) with propofol; all were mild-moderate, except one severe with propofol. Mean ± SD terminal half-life of remimazolam tosylate was 1.97 ± 1.62 h. CONCLUSIONS: Remimazolam tosylate demonstrated noninferior efficacy and good tolerability compared with propofol for short-term sedation in postoperative mechanically ventilated intensive care unit patients.