This single-center, prospective, randomized, controlled pilot study was approved by the Ethics Committee of Union Hospital (2021-0069-01). Written informed consent was obtained from all patients or their legal representatives. The study was registered before enrollment at clinicaltrials.gov (NCT04790734).
The inclusion criteria were age ≥ 18 years and ≤ 75 years, intubated and mechanically ventilated ≤ 96 h before enrollment, expected to require continuous invasive ventilation and sedation ≥ 24 h with a target sedation depth between 0 and − 3 on the Richmond Agitation and Sedation Scale (RASS) . The exclusion criteria are provided in Additional file 1: Table S1.
Randomization and intervention
Eligible patients were randomized to receive remimazolam besylate (intervention) or propofol (control) in a 1:1 ratio using sequentially numbered opaque envelopes. Patients were blinded to allocation, but medical staff were not.
Analgesics and sedatives used before study enrollment were discontinued. Remifentanil at 4.0–9.0 μg/kg/h was administered for analgesia. Study drug was given when patients had a RASS score of − 3 or above. Patients in the remimazolam group received remimazolam besylate (Yichang Humanwell Pharmaceutical Co., Ltd., China) intravenously at an initial infusion rate of 0.15 mg/kg/h and adjusted (maximum of 0.3 mg/kg/h) to maintain a RASS score between − 3 and 0. Patients in the propofol group received propofol (Fresenius Kabi China Co., Ltd.) intravenously at an initial infusion rate of 2.0 mg/kg/h and adjusted (maximum of 4.0 mg/kg/h) to maintain a RASS score between − 3 and 0. Assessment of RASS score was performed every 4 h by a clinician and a nurse, and disagreements were resolved by consultation with a third medical staff. If the maximum dose of study drug was insufficient to sedate, rescue dexmedetomidine at 0.2–1.0 μg/kg/h was administered. The stopping criteria included extubation, discharge from our ICU, discontinuation of study drugs for 24 h by treating physicians and 7 days after enrollment, whichever came first. Patients were followed up for 28 days.
The primary outcome was the percentage of time in the target sedation range without rescue sedation. The secondary outcomes included ventilator-free days at day 7, length of ICU stay and 28-day mortality after enrollment. Adverse events were defined if any of the following lasted for no less than 5 min: systolic blood pressure below 80 or over 180 mmHg, diastolic blood pressure below 50 or over 100 mmHg, or heart rate below 50 or over 120 bpm.
Sample estimation was not conducted because of the absence of hypothesis. Continuous data were presented as means with standard deviations or medians with interquartile ranges (IQRs), and categorical data as frequencies and proportions. To examine between-group differences, continuous data were analyzed using the Student’s t test or the Mann–Whitney U test based on the distribution, and categorical data were analyzed using the chi-square test or the Fisher exact test. The length of ICU stay was calculated using log-rank test, and Kaplan–Meier survival plot was generated. Statistical analyses were performed using SPSS 26.0 software (IBM SPSS Statistics, Armonk, NY) and GraphPad Prism 5.0 (GraphPad Software, San Diego, CA, USA). A p value less than 0.05 was considered statistically significant.