Highlights
The SHOSREB trial establishes remimazolam besylate as a viable non-inferior alternative to propofol for short-term light sedation in mechanically ventilated ICU patients. Both agents achieved remarkable success rates of 97.5%, with comparable time spent within target Richmond Agitation-Sedation Scale (RASS) ranges. The median maintenance doses were 0.20 mg·kg⁻¹·h⁻¹ for remimazolam and 0.61 mg·kg⁻¹·h⁻¹ for propofol, suggesting distinct pharmacodynamic profiles that merit further investigation for optimizing ICU sedation protocols.
Background
Sedation management represents one of the cornerstone therapies in modern intensive care, particularly for mechanically ventilated patients who require comfort, anxiolysis, and synchronization with mechanical ventilation. Since its introduction, propofol has become a standard agent for ICU sedation due to its favorable pharmacokinetic profile, rapid onset, and quick recovery characteristics. However, propofol carries notable limitations including hemodynamic instability, propofol infusion syndrome with prolonged use, and potential lipid load from the formulation vehicle.
Remimazolam besylate is an ultrashort-acting benzodiazepine recently approved for procedural sedation. Its unique ester-based metabolism results in organ-independent clearance, potentially offering advantages in critically ill patients with hepatic or renal dysfunction. The SHOSREB trial addresses a critical evidence gap by systematically comparing remimazolam to propofol specifically for ICU sedation applications, evaluating whether its pharmacological properties translate into comparable clinical performance in the intensive care setting.
Study Design
The SHOSREB trial (Short-term light sedation with remimazolam besylate versus propofol in the ICU) was conducted as a multicenter, randomized, single-blind, controlled non-inferiority trial. The study enrolled 164 mechanically ventilated patients requiring light sedation, defined as RASS scores between -2 and +1.
Participants were equally randomized to receive either remimazolam besylate or propofol as continuous intravenous infusion. The primary outcome measure was “successful sedation,” operationalized as the absence of rescue sedative administration during the study drug infusion period combined with maintenance of RASS scores within the target range for at least 70% of the total infusion duration. Secondary analyses included comparisons of the percentage of time with target RASS scores, infusion duration, and maintenance dosing requirements.
The predefined non-inferiority margin was set at -8%, meaning remimazolam would be considered non-inferior if the lower bound of the 95% confidence interval for the difference in success rates exceeded this threshold. The trial was registered prospectively on ClinicalTrials.gov (NCT05782894) prior to enrollment initiation.
Key Findings
The trial demonstrated unequivocal non-inferiority of remimazolam besylate compared to propofol for the primary endpoint. Both groups achieved identical successful sedation rates of 97.5% (80 out of 82 patients in each group), yielding a difference of 0% with a 95% confidence interval of -6.5% to 6.4%. This confidence interval comfortably exceeded the predefined non-inferiority margin of -8%, establishing remimazolam as a non-inferior alternative to propofol for short-term ICU sedation.
The median infusion duration was comparable between groups: 10.5 hours (interquartile range 8.1-14.7) for remimazolam versus 11.0 hours (interquartile range 7.0-14.3) for propofol, with no statistically significant difference (p = 0.534). This similarity in treatment duration suggests that the comparison was conducted under clinically equivalent conditions.
Regarding maintenance dosing, remimazolam demonstrated a lower median maintenance dose of 0.20 mg·kg⁻¹·h⁻¹ (interquartile range 0.19-0.30) compared to propofol at 0.61 mg·kg⁻¹·h⁻¹ (interquartile range 0.30-1.17). While direct dose comparisons between agents with different mechanisms are inherently limited, this fourfold difference in dosing requirements reflects fundamental pharmacological distinctions between benzodiazepines and sedative-hypnotic agents.
The percentage of time spent within target RASS scores showed no significant difference between groups. The remimazolam group maintained target sedation 88.6% of the time (95% CI: 84.2%-92.9%), while the propofol group achieved 89.4% (95% CI: 85.0%-93.8%) (p = 0.543). The overlapping confidence intervals and non-significant p-value confirm equivalent sedation quality between the two agents.
Expert Commentary
The SHOSREB trial represents a significant contribution to critical care pharmacology by providing rigorous comparative evidence for a novel sedative agent in the ICU environment. Several aspects warrant consideration when interpreting these findings and their potential implications for clinical practice.
The single-blind design, while methodologically acceptable for non-inferiority trials, introduces potential assessment bias, particularly for subjective endpoints. However, the objective nature of the primary endpoint—combining rescue medication use with quantified time-in-range—mitigates this concern substantially. The multicenter structure enhances generalizability, though the exclusion of patients with severe hemodynamic instability or specific organ failures may limit applicability to the most critically ill populations.
The 97.5% success rates in both arms substantially exceed typical real-world sedation outcomes, suggesting careful patient selection and optimized protocol implementation. This high success rate may reflect the relatively straightforward nature of light sedation targets (RASS -2 to +1) compared to deeper sedation strategies that have dominated historical ICU sedation research.
The pharmacokinetic advantages of remimazolam’s organ-independent metabolism hold particular appeal for ICU patients with compromised hepatic or renal function, populations typically underrepresented in sedation trials. The absence of lipid vehicle in remimazolam formulations may also benefit patients requiring prolonged nutritional support or those at risk for hypertriglyceridemia.
Further investigation is needed to characterize remimazolam’s performance in specific ICU subpopulations, including patients requiring deeper sedation, those with sepsis-associated encephalopathy, and individuals with documented benzodiazepine tolerance. Comparative data on long-term outcomes including delirium incidence, cognitive recovery, and ICU-acquired weakness would substantially enhance the clinical utility of these findings.
Conclusion
The SHOSREB trial establishes remimazolam besylate as non-inferior to propofol for achieving successful short-term light sedation in mechanically ventilated ICU patients. With both agents achieving identical 97.5% success rates and comparable time within target RASS ranges, remimazolam emerges as a viable alternative that may offer pharmacological advantages in specific patient populations. These findings support the expansion of remimazolam’s clinical indications beyond procedural sedation to encompass critical care applications, while acknowledging that further studies are needed to define optimal positioning within ICU sedation algorithms.
The availability of effective non-inferior alternatives to established agents provides clinicians with valuable flexibility for individualizing sedation strategies based on patient characteristics, institutional resources, and anticipated treatment duration. As the paradigm of ICU sedation continues to evolve toward lighter sedation protocols and daily interruption strategies, agents with favorable pharmacokinetic profiles and safety margins assume increasing importance in achieving the dual goals of patient comfort and neurological recovery.
Funding and Clinical Trial Registration
ClinicalTrials.gov Identifier: NCT05782894 (registered February 18th, 2023)
References
Yang X, Pan J, Gong X, Lv A, Liang F, Liu J, Li D, Fu S, Pan A, Yu L, Zhang L, Chen T, Zhan L, Qin B, Lin F, Xiong X, Zhu Y, He Z, Sun R, Sun T, Qian S, Wen D, Zou X, Qi H, Shu H, Song L, Wang C, Shang Y. Short-term light sedation with remimazolam besylate versus propofol in the ICU (SHOSREB): a multicentre, randomized, single-blind, controlled trial. Intensive Care Med. 2026 Mar 31. PMID: 41915173.