Abstract
Objective
Remimazolam besylate is a novel ultra-short-acting benzodiazepine sedative. This study aimed to evaluate its hemodynamics profiles during sedation in mechanically ventilated patients in the intensive care unit (ICU), compared with propofol.
Methods
We conducted a single-center, retrospective, propensity score–matched observational study including patients who underwent mechanical ventilation and received either remimazolam or propofol for sedation. The primary outcome was change in mean arterial pressure (MAP) during sedation. Secondary outcomes included the incidence of hypotension and hypertension, norepinephrine requirements, bradycardia, tachycardia, volume of fluid resuscitation, post-sedation nausea and vomiting, duration of mechanical ventilation, ICU and hospital length of stay, and 28-day mortality.
Results
After matching, 366 patients (183 pairs) were analyzed. The median (IQR) age was 55.0 (43.3–67.0) years, and 64.2% were male. Compared with propofol, the remimazolam group had a smaller change in MAP [13 (9–17) vs. 14 (11–18) mmHg, p < 0.05], along with a lower incidence of hypotension and reduced need for high-dose norepinephrine (p < 0.05). No significant differences were observed in change in heart rate, hypertension, bradycardia, tachycardia, fluid resuscitation, nausea or vomiting, or major clinical outcomes including duration of mechanical ventilation, ICU and hospital stay, and 28-day mortality.
Conclusions
In this retrospective matched analysis, remimazolam was associated with fewer blood pressure fluctuations and less hypotension compared with propofol, while overall clinical outcomes were similar. Prospective multicenter studies are needed to further confirm these findings.
Trial registration
Chinese Clinical Trial Registry (ChiCTR2200063981).
Keywords: Remimazolam besylate, Propofol, Sedation, Hemodynamics, Mechanical ventilation
Introduction
Mechanical ventilation is an essential intervention for patients with refractory hypoxemia, ventilatory failure, or airway compromise. In the United States, between 2 and 3 million critically ill adults receive invasive mechanical ventilation annually [1]. To reduce discomfort, anxiety, and agitation associated with endotracheal intubation and ventilation, most patients require continuous intravenous sedatives combined with analgesics. While sedation improves tolerance to mechanical ventilation and reduces metabolic demands, currently available agents often have undesirable hemodynamic effects that may complicate clinical management [2, 3]. Thus, the selection of an appropriate sedative agent and dosing strategy is crucial for patient safety and clinical outcomes.
Benzodiazepines, propofol, and dexmedetomidine are among the most frequently used ICU sedatives [4]. However, each has notable limitations. Benzodiazepines are associated with tachycardia, hypotension, prolonged duration of ventilation and extubation, and have been linked to higher mortality and an increased risk of delirium [5–7]. Propofol provides rapid onset and offset but can lead to respiratory depression, hypotension, and bradycardia, particularly at higher doses or during rapid administration; prolonged use is further complicated by the risk of propofol infusion syndrome (PRIS) [8, 9]. Dexmedetomidine reduces delirium, duration of ventilation, and ICU length of stay compared with conventional sedation regimens (often including benzodiazepines), yet its use is often limited by clinically significant bradycardia and hypotension [10]. Moreover, in critically ill patients with hepatic or renal dysfunction, the risk of drug accumulation and sustained hemodynamic compromise with prolonged or high-dose benzodiazepine or propofol administration is a concern [11]. To date, no single sedative has proven ideal in providing effective sedation while preserving stable hemodynamics.
Remimazolam is a novel ultra–short-acting benzodiazepine, structurally derived from midazolam with the addition of a metabolizable ester moiety. Unlike traditional benzodiazepines, which are primarily metabolized by hepatic or renal pathways, remimazolam is rapidly hydrolyzed by ubiquitous tissue esterases into an inactive carboxylic acid metabolite (CNS7054) [12]. This unique metabolism confers predictable pharmacokinetics with minimal accumulation, even during prolonged infusion, suggesting it may offer a favorable recovery profile with a potentially reduced risk of delirium [13], a hypothesis that warrants testing in the ICU setting. Remimazolam provides rapid onset and offset of action, with controllable depth and duration of sedation via positive allosteric modulation of the Gamma-Aminobutyric Acid A (GABA𝐴) receptor [14, 15]. Early studies have demonstrated its efficacy and favorable safety profile for short-term deep sedation, and emerging data suggest potential utility in the ICU [16].
However, evidence on the hemodynamic effects of remimazolam during long-term ICU sedation remains limited. In particular, whether remimazolam offers more stable hemodynamics compared with propofol during sedation of mechanically ventilated patients has not been fully elucidated. Therefore, we conducted a propensity score–matched, retrospective observational study to compare the hemodynamic profiles of remimazolam besylate and propofol in critically ill patients requiring mechanical ventilation in the ICU.
Patients and methods
Study population
This single-center, retrospective, propensity score–matched observational study was conducted in the Department of Critical Care Medicine, Renmin Hospital of Wuhan University. The study protocol was approved by the institutional ethics committee (WDRY2021-K179). As this study involved only the secondary analysis of fully anonymized clinical data from past medical records, with no additional interventions or risks to patients, the requirement for prospective written informed consent was waived by the ethics committee. All procedures complied with the principles of the Declaration of Helsinki (2013 revision).
Eligible patients were adults who underwent invasive mechanical ventilation and received continuous sedation with either remimazolam besylate or propofol for more than 24 h between December 2021 and December 2022. For the purpose of this retrospective analysis, the index sedation episode was defined as the period of continuous sedation initiated in the ICU with one of the study drugs. Patients who were transferred from other units (e.g., operating room, emergency department) while already under sedation were included only if the sedation regimen was continued or switched to one of the study drugs within the ICU for the specified duration. The exclusion criteria were as follows: (1) prior tracheostomy; (2) received sedation with agents other than remimazolam or propofol, or analgesics other than remifentanil, during the index ICU admission prior to meeting the inclusion criteria; (3) history of alcoholism or drug abuse within the preceding 3 months; (4) pregnancy or lactation; (5) incomplete medical records; (6) patients who were receiving extracorporeal membrane oxygenation (ECMO) at the initiation of the study sedation (to avoid confounding from drug adsorption in the extracorporeal circuit). The sex of participants was determined from the legal designation documented in the electronic health record, with options recorded as male or female.
Procedures
Endotracheal intubation and initiation of mechanical ventilation were performed by board-certified anesthesiologists, emergency physicians, or intensivists. Sedative administration: (1) A total of 446 patients who received either propofol or remimazolam for sedation during mechanical ventilation between December 2021 and December 2022 were screened. After applying inclusion and exclusion criteria and propensity score matching, 183 pairs (366 patients) were included in the final analysis. (2) In the propofol group, induction was achieved with an intravenous bolus of 0.6 mg/kg (0.06 mL/kg, 1% w/v, 20 mL:0.2 g; Xi’an Lipont Enterprise Union Management Co., Ltd., China) administered within 60 s, followed by a continuous infusion of 0.5–2 mg/kg/h. (3) In the remimazolam group, induction was performed with an intravenous bolus of 0.04–0.1 mg/kg (Remimazolam besylate for injection; Yichang Humanwell Pharmaceutical Co., Ltd., China) administered within 60 s, followed by a continuous infusion titrated between 0.2 and 1 mg/kg/h. Sedation target: The Richmond Agitation-Sedation Scale (RASS) was maintained between − 2 and 0. Analgesia protocol: Remifentanil was infused at 0.05–0.15 µg/kg/min, with the goal of maintaining a Critical-Care Pain Observation Tool (CPOT) score < 3. Sedation and analgesia adjustments: (1) If the RASS score remained > 0 at the maximum infusion rate of remimazolam (1 mg/kg/h) or propofol (2 mg/kg/h) for 3 min, an additional bolus of propofol (0.2 mg/kg) was administered intravenously. (2) If the RASS score dropped below − 3, the infusion rate was decreased by 0.1 mg/kg/h for remimazolam or 0.5 mg/kg/h for propofol. (3) If the CPOT score exceeded 3, the remifentanil infusion was increased by 0.025 µg/kg/min each time. Hemodynamic management:
In the event of hemodynamic instability (e.g., MAP < 60 mmHg or a decrease ≥ 20% from baseline), a standardized protocol was followed to to maintain a mean arterial pressure (MAP) between 60 and 100 mmHg and heart rate between 50 and 120 beats/min. The priority of interventions was as follows: First, ensure adequate intravascular volume with a fluid challenge (e.g., 250–500 mL crystalloid), unless contraindicated (e.g., fluid overload). Second, titrate vasoactive medications (primarily norepinephrine) to restore perfusion pressure. Third, consider reducing the dose of the sedative or analgesic infusion if hypotension persisted despite the above measures, with the goal of minimizing sedation-related vasodilation or myocardial depression while avoiding patient distress or ventilator asynchrony. Weaning protocol: Daily sedative interruption and spontaneous breathing trials were performed to evaluate readiness for weaning from mechanical ventilation.
Clinical data collection
Baseline demographic and clinical data, including age, sex, body mass index (BMI), Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, primary diagnosis, and treatments, were extracted from the hospital information system (HIS).
Physiological variables, fluid intake and output, RASS scores, and vital signs were recorded at baseline (T0), 30 min (T1), 60 min (T2), 4 h (T3), and 24 h (T4) after the initial sedative bolus. During the observation period, all patients were continuously monitored by electrocardiography, pulse oximetry (SpO₂), non-invasive blood pressure (NIBP), and ventilator parameters, with recordings obtained at 30-minute intervals.
Daily laboratory tests, including hematology, biochemistry, urinalysis, and arterial blood gas analyses, were retrieved from the laboratory information system. Mechanical ventilation parameters, including respiratory rate (RR) and fraction of inspired oxygen (FiO₂), were collected directly from the ventilator system.
Outcomes
The primary outcome of the study was hemodynamic fluctuation during sedation. Changes in mean arterial pressure (∆MAP) were defined as the difference between the maximum or minimum MAP and the baseline value, while changes in heart rate (∆HR) were defined as the difference between the maximum or minimum HR and baseline.
The secondary outcomes included the incidence of hypotension, hypertension, bradycardia, tachycardia, norepinephrine dose requirements, total volume of fluid resuscitation, post-sedation nausea and vomiting, duration of mechanical ventilation, length of stay in the ICU and hospital, and 28-day mortality. Norepinephrine dosage was recorded at predefined time points (T0–T4) during the first 24 h after initiation of sedation. For analysis, both the median cumulative dose and the peak dose within 24 h were assessed. High-dose norepinephrine use was defined as a peak infusion rate exceeding 1 mg/h during this period. This unit (mg/h) corresponds directly to the infusion rate as recorded in our electronic medical record system and used for bedside titration. For clinical context, this threshold is equivalent to approximately 0.14 µg/kg/min for a 70-kg patient. This threshold was chosen based on common clinical practice in our institution and aligns with previous literature that uses rates above 0.1 µg/kg/min to define significant vasopressor support [17]. The dose is expressed as norepinephrine base (the active moiety), as is standard for reporting vasopressor dosing in critical care.
Hemodynamic events were defined as follows: (1) Hypotension: a decrease in MAP ≥ 20% from baseline or MAP < 60 mmHg lasting at least 1 min. (2) Hypertension: MAP > 105 mmHg. (3) Bradycardia: HR < 50 beats/min. (4) Tachycardia: HR > 120 beats/min.
Identification and Duration of Events: These thresholds are consistent with common clinical definitions. In our ICU, patients with hemodynamic instability or requiring vasoactive agents typically undergo invasive arterial pressure monitoring, providing continuous, real-time data that allows precise identification of sustained events. For all patients, events are flagged in real-time by monitor alarms and documented by nursing staff when clinically significant.
For this retrospective study, an event was considered present if it was either: (a) recorded in the nursing flow sheet or progress notes as a sustained episode meeting the above criteria, or (b) captured by two consecutive scheduled non-invasive blood pressure measurements (30 min apart) both meeting the criteria (applied primarily to patients without continuous invasive monitoring). The “lasting at least 1 minute” criterion formalizes the requirement for a sustained, clinically relevant change rather than a transient artifact.
Bias and confounding
To reduce confounding, we applied propensity score matching (PSM). The covariates included in the propensity score model were selected a priori based on clinical relevance and prior evidence, encompassing demographics, baseline disease severity, physiological status, primary diagnosis, and critical care support at sedation initiation (as detailed in Table 1). Data on specific comorbidities and chronic medications were not uniformly available; therefore, we utilized composite scores (APACHE II, SOFA) and organ support therapies as proxies. Multicollinearity was assessed using variance inflation factors (VIF < 5), and correlated variables were reviewed to retain the most clinically relevant one.
Table 1.
Demographic and Baseline Characteristics of Patients before and after Propensity Score Matching
| Variable | Before PSM | After PSM | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Total (n = 446) |
Remimazolam (n = 247) |
Propofol (n = 199) |
p | SMD | Total (n = 366) |
Remimazolam (n = 183) |
Propofol (n = 183) |
p | SMD | |
| Age, years, median (IQR) | 56.0 (44.0, 68.0) | 59.0 (45.5, 68.5) | 54.0 (41.0, 66.0) | 0.028* | -0.208 | 55.0 (43.3, 67.0) | 55.0 (44.0, 67.0) | 54.0 (42.0, 67.0) | 0.563 | -0.060 |
| Male sex, n (%) | 290 (65.0) | 160 (64.8) | 130 (65.3) | 0.904 | 0.012 | 235 (64.2) | 115 (62.8) | 120 (65.6) | 0.586 | 0.058 |
| BMI, kg/m2, median (IQR) | 22.4 (21.0, 23.8) | 22.5 (21.1, 24.1) | 22.3 (20.8, 23.6) | 0.036* | -0.301 | 22.4 (20.9, 23.7) | 22.3 (21.0, 23.7) | 22.4 (20.9, 23.8) | 0.915 | -0.028 |
| APACHE II, median (IQR) | 16.0 (13.0, 20.0) | 17.0 (12.5, 21.0) | 16.0 (13.0, 18.0) | 0.041* | -0.438 | 16.0 (12.0, 19.0) | 15.0 (12.0, 19.5) | 16.0 (13.0, 19.0) | 0.409 | 0.059 |
| SOFA, median (IQR) | 7.0 (5.0, 9.0) | 8.0 (5.0, 9.0) | 7.0 (5.0, 9.0) | 0.620 | -0.023 | 7.0 (5.0, 9.0) | 7.0 (5.0, 9.0) | 7.0 (5.0, 9.0) | 0.844 | 0.021 |
| pH, median (IQR) | 7.40 (7.35, 7.44) | 7.40 (7.36, 7.44) | 7.40 (7.35, 7.44) | 0.399 | -0.057 | 40 (7.35, 7.44) | 7.40 (7.34, 7.44) | 7.40 (7.35, 7.44) | 0.751 | 0.032 |
| PaO2, mmHg, median (IQR) | 117.0 (80.0, 150.0) | 118.0 (81.5, 150.5) | 117.0 (79.0, 148.5) | 0.720 | -0.033 | 118.0 (80.0, 150.0) | 118.0 (80.0, 150.0) | 118.0 (80.5, 150.5) | 0.704 | 0.042 |
| PCO2, mmHg, median (IQR) | 46.0 (41.0, 53.8) | 46.0 (41.0, 54.0) | 46.0 (41.0, 53.0) | 0.438 | -0.071 | 46.0 (41.0, 53.0) | 46.0 (41.0, 52.5) | 46.0 (41.0, 54.0) | 0.974 | 0.010 |
| MAP, mmHg, median (IQR) | 98.0 (85.0, 105.0) | 98.0 (87.0, 104.5) | 98.0 (81.5, 105.0) | 0.804 | -0.060 | 8.0 (84.3, 104.8) | 99.0 (85.0, 105.0) | 98.0 (81.5, 104.0) | 0.743 | -0.050 |
| HR, bpm, median (IQR) | 80.0 (69.3, 95.0) | 79.0 (69.5, 93.0) | 81.0 (69.5, 97.0) | 0.400 | 0.086 | 80.0 (69.3, 95.0) | 80.0 (69.5, 96.0) | 81.0 (69.5, 95.0) | 0.970 | -0.026 |
| Vasopressors&, n (%) | 131 (29.37) | 66 (26.72) | 65 (32.66) | 0.171 | 0.127 | 109 (29.8) | 51 (27.9) | 58 (31.7) | 0.424 | 0.082 |
| PaO2/FiO2 ratio, mmHg, median (IQR) | 174.0 (110.0, 251.0) | 172.0 (113.0, 248.5) | 176.0 (107.5, 253.5) | 0.872 | 0.010 | 177.0 (123.0, 257.8) | 174.0 (131.5, 257.5) | 177.0 (113.5, 257.0) | 0.948 | -0.013 |
| GCS, median (IQR) | 12.0 (10.0, 14.0) | 12.0 (10.0, 14.0) | 11.0 (10.0, 14.0) | 0.350 | -0.105 | 12.0 (10.0, 14.0) | 12.0 (10.0, 13.0) | 12.0 (10.0, 14.0) | 0.784 | -0.002 |
| Reasons for mechanical ventilation, n (%) | 0.784 | 0.980 | ||||||||
| Sepsis | 145 (32.5) | 81 (32.8) | 64 (32.2) | -0.014 | 121 (33.1) | 62 (33.9) | 59 (32.2) | -0.035 | ||
| ARDS | 113 (25.3) | 62 (25.1) | 51 (25.6) | 0.012 | 93 (25.4) | 46 (25.1) | 47 (25.7) | 0.013 | ||
| Heart failure | 76 (17.0) | 37 (15.0) | 39 (19.6) | 0.116 | 69 (18.9) | 32 (17.5) | 37 (20.2) | 0.068 | ||
| Trauma | 54 (12.1) | 32 (13.0) | 22 (11.1) | -0.061 | 43 (11.8) | 23 (12.6) | 20 (10.9) | -0.053 | ||
| Post-surgery | 37 (8.3) | 23 (9.3) | 14 (7.0) | -0.089 | 23 (6.3) | 12 (6.6) | 11 (6.0) | -0.023 | ||
| Other | 21 (4.7) | 12 (4.9) | 9 (4.5) | -0.016 | 17 (4.6) | 8 (4.4) | 9 (4.9) | 0.025 | ||
| Monitoring or Treatment, n (%) | ||||||||||
| PICCO | 34 (7.6) | 19 (7.7) | 15 (7.5) | 0.951 | -0.006 | 26 (7.1) | 12 (6.6) | 14 (7.7) | 0.684 | 0.041 |
| IABP | 21 (4.7) | 12 (4.9) | 9 (4.5) | 0.868 | -0.016 | 18 (4.9) | 10 (5.5) | 8 (4.4) | 0.629 | -0.053 |
| PCI | 15 (3.4) | 11 (4.5) | 4 (2.0) | 0.155 | 0.174 | 7 (1.9) | 3 (1.6) | 4 (2.2) | 1.000 | 0.037 |
| CRRT | 85 (19.1) | 45 (18.2) | 40 (20.1) | 0.615 | 0.047 | 75 (20.5) | 38 (20.8) | 37 (20.2) | 0.897 | -0.014 |
Values are presented as median (interquartile range, IQR) or number (%). PSM propensity score matching, SMD standardized mean difference, BMI body mass index, APACHE II acute physiology and chronic health evaluation II, SOFA sequential organ failure assessment, MAP mean arterial pressure, HR heart rate, GCS Glasgow coma scale, ARDS Acute respiratory distress syndrome, PICCO pulse indicator continuous cardiac output, IABP intra-aortic balloon pump, PCI percutaneous coronary intervention, CRRT continuous renal replacement therapy. *p < 0.05. &Vasopressors: Use of any vasoactive drug (norepinephrine, epinephrine, vasopressin, or dopamine) at baseline (sedation initiation)
All covariates were anchored to a baseline time point (T0), defined as the moment before the first sedative bolus. Arterial blood gases were the last values within 1 h pre-T0. APACHE II scores were based on the worst values in the first 24 h of ICU admission, while SOFA scores and hemodynamics were values at T0.
Propensity scores were estimated using logistic regression models incorporating demographic variables (e.g., age, sex, body mass index), baseline clinical characteristics (e.g., APACHE II score, SOFA score, pH, PaO₂, PaCO₂, MAP, HR), primary diagnoses (e.g., sepsis, heart failure, trauma, post-surgery, other), and key concurrent interventions or monitoring with potential hemodynamic impact-such as Pulse index Continuous Cardiac Output (PiCCO), Intra-aortic balloon pumping (IABP), Percutaneous coronary intervention (PCI), and Continuous renal replacement therapy (CRRT). This was done to balance major non-sedative determinants of hemodynamics between groups. Patients were matched in a 1:1 ratio using the nearest-neighbor method without replacement and a caliper width of 0.2 of the standard deviation of the logit of the propensity score. Balance between groups was assessed using standardized mean differences (SMDs), with values < 0.1 indicating adequate balance.
Statistical analysis
Continuous variables were expressed as median with interquartile range (IQR, 25th–75th percentile), depending on the distribution. Categorical variables were presented as absolute numbers and percentages. Between-group comparisons of continuous variables were performed using Student’s t-test or analysis of variance (ANOVA) for normally distributed data, and Mann–Whitney U test or Kruskal–Wallis test for non-normally distributed data, with Bonferroni correction applied for multiple comparisons where appropriate. Categorical variables were compared using the chi-square test or Fisher’s exact test as appropriate.
All statistical analyses were conducted using SPSS version 22.0 (SPSS Inc., Chicago, IL, USA), R version 4.3.0 (R Foundation for Statistical Computing, Vienna, Austria), and the Storm Statistical Platform (www.medsta.cn/software). A two-tailed p value < 0.05 was considered statistically significant.
Reporting guidelines and handling of missing data
The reporting of this study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for observational research.
Regarding missing data: This retrospective study utilized data routinely entered into the hospital’s electronic health record system for clinical care. The rate of missing values for key analytical variables was low (< 5%). Specifically, the demographic, severity score (APACHE II, SOFA), and baseline physiological variables used for propensity score matching and primary analysis were required fields or derived from mandatory assessments, and were thus complete for all included patients. For sporadic missing values in secondary variables (e.g., a single scheduled blood pressure measurement), the case was excluded only from the specific analysis involving that variable (i.e., complete-case analysis was applied per analysis).
Results
A total of 639 patients who underwent mechanical ventilation and sedation were identified from the hospital information system. After applying the inclusion and exclusion criteria, 446 patients were eligible for analysis. Propensity score matching was performed using the nearest-neighbor method without replacement and a caliper width of 0.2, yielding 183 matched pairs (Fig. 1).
Fig. 1.
Flow chart of the study
In the matched cohort, the median (IQR) age was 55.0 (43.3–67.0) years, and 235 patients (64.2%) were male. Demographic and baseline clinical characteristics before and after matching are presented in Table 1. Prior to matching, several variables showed significant imbalances between the two groups, including BMI, APACHE II score, age, Glasgow Coma Scale (GCS) score, the presence of acute respiratory distress syndrome (ARDS), PCI performed during the current hospitalization, and the use of vasopressors. Notably, ‘Vasopressors’ in Table 1 refers to the use of any vasoactive drug (e.g., norepinephrine, epinephrine, vasopressin, dopamine) at the initiation of study sedation, serving as a marker of baseline hemodynamic instability. After matching, all covariates were well balanced, with standardized mean differences (SMDs) less than 0.1. Crucially, the use of interventions with major hemodynamic effects, such as IABP, CRRT, and PCI, was equally distributed between the remimazolam and propofol groups after matching (e.g., IABP: 5.5% vs. 4.4%; CRRT: 20.8% vs. 20.2%; PCI: 1.6% vs. 2.2%). This balance supports the comparability of the two groups regarding these potent confounders.
The median ΔMAP was significantly smaller in the remimazolam group compared with the propofol group [13 (9–17) vs. 14 (11–18) mmHg, p < 0.05] (Table 2). Both groups exhibited a decrease in MAP within 30 min after initiation of sedation, with a greater reduction observed in the propofol group (Fig. 2). The incidence of hypotension was significantly lower in the remimazolam group compared with the propofol group (p < 0.05, Table 2). While the proportion of patients receiving any vasopressor at baseline was similar between groups (Table 1), the remimazolam group required high-dose norepinephrine (peak rate > 1 mg/h) significantly less frequently during the first 24 h of sedation (Table 2). This suggests that despite comparable baseline needs for hemodynamic support, propofol sedation was associated with a greater subsequent requirement for intensified vasopressor therapy.
Table 2.
Study outcomes in the remimazolam and propofol groups
| Variable | Remimazolam (n = 183) | Propofol (n = 183) | p value |
|---|---|---|---|
| Primary outcome | |||
| ΔMAP, mmHg, median (IQR) | 13 (9, 17) | 14 (11, 18) | 0.001* |
| ΔHR, bpm, median (IQR) | 9 (7, 12) | 9 (7, 12) | 0.491 |
| Secondary outcomes | |||
| Hypotension, n (%) | 25 (13.7) | 41 (22.4) | 0.041* |
| Hypertension, n (%) | 22 (12.0) | 27 (14.8) | 0.540 |
| Norepinephrine doses >1 mg/h, n (%) | 11 (6.0) | 23 (12.6) | 0.046* |
| Bradycardia, n (%) | 9 (4.9) | 7 (3.8) | 0.799 |
| Tachycardia, n (%) | 1 (0.5) | 2 (1.1) | 1.000 |
| Fluid resuscitation volume > 500mL, n (%) | 28 (15.3) | 35 (19.1) | 0.406 |
| Nausea and vomiting, n (%) | 3 (1.6) | 11 (6.0) | 0.053 |
| Mechanical ventilation duration, days, median (IQR) | 5 (3,8) | 5 (4,9) | 0.236 |
| Length of ICU stay, days, median (IQR) | 19 (12,26) | 18 (13,25) | 0.921 |
| Length of hospital stay, days, median (IQR) | 23 (18,31) | 23 (17,31) | 0.756 |
| 28-day mortality, n (%) | 23 (12.6) | 28 (15.3) | 0.546 |
Variables are presented as median (interquartile range, IQR) or number (%). MAP mean arterial pressure, HR heart rate, ICU intensive care unit. *p < 0.05
Fig. 2.
Line graphs showing mean arterial pressure (MAP, A) and heart rate (HR, B) at different time points in the remimazolam and propofol groups. *P < 0.05
No significant differences were observed between the two groups in ΔHR, heart rate at individual time points, the incidence of hypertension, bradycardia, tachycardia, fluid resuscitation volumes, or post-sedation nausea and vomiting (Fig. 2; Table 2). Likewise, clinical outcomes, including duration of mechanical ventilation, ICU length of stay, hospital length of stay, and 28-day mortality, were comparable between groups (Table 2).
Discussion
Remimazolam is a novel ultra–short-acting benzodiazepine characterized by rapid onset and recovery. In this study, we found that among mechanically ventilated ICU patients, remimazolam was associated with smaller MAP fluctuations, a lower incidence of hypotension, and reduced need for high-dose norepinephrine compared with propofol. However, the absolute difference in ∆MAP between the two groups was small, suggesting that while statistically significant, the clinical impact of this finding may be limited. Other hemodynamic parameters, adverse events, and clinical outcomes—including mechanical ventilation duration, ICU and hospital length of stay, and 28-day mortality—were comparable between groups.
Previous studies have shown that remimazolam is a safe and effective sedative with favorable recovery profiles in procedural settings such as bronchoscopy, gastrointestinal endoscopy, and anesthesia, as well as in pediatric populations [18–20]. In a single-session study of colonoscopy sedation, remimazolam achieved higher success rates compared with midazolam (92% vs. 75%, p = 0.007) [21]. Both Remimazolam besylate is a novel ultra-short-acting benzodia and remimazolam tosylate are currently available, and their sedative effects appear comparable to propofol when used in mechanically ventilated patients [14, 18]. A previous study suggested that remimazolam tosylate provided sedation equivalent to propofol or midazolam, but with less heart rate variability in ICU patients receiving prolonged ventilation [19]. Dose-finding studies indicate that continuous infusion of 0.15–0.3 mg/kg/h can maintain target sedation levels (RASS − 3 to 0) [22], and an induction dose of 0.02–0.05 mg/kg followed by 0.20–0.35 mg/kg/h is effective [23]. The regimen applied in our study (0.04–0.1 mg/kg induction, 0.2–1.0 mg/kg/h maintenance) was within this reported effective range.
Adverse effects remain the primary concern in ICU sedation. Reported side effects of remimazolam include hypotension, bradycardia, and respiratory depression, although these are generally less frequent than with propofol [18, 24]. A key pharmacokinetic advantage of remimazolam is its metabolism by tissue esterases into an inactive metabolite (CNS7054), independent of hepatic and renal function, which reduces the risk of drug accumulation even with prolonged infusion [25]. Fechner et al. demonstrated fewer episodes of hypotension and vasopressor use with remimazolam compared to propofol in anesthetized patients [26], consistent with our findings in the ICU population. Similarly, studies in endoscopic sedation reported a lower incidence of respiratory depression and cardiovascular instability with remimazolam [18]. Limited research has been conducted on the negative impacts of sedation, specifically prolonged use of sedative drugs, on mechanically ventilated patients in ICU. Nevertheless, evidence from ICU settings remains limited. A pilot study of 30 deeply sedated patients reported comparable rates of hypotension in remimazolam and propofol groups (53.3% vs. 60.0%) and no bradycardia events [16]. Our results expand on these findings by showing that remimazolam may reduce hemodynamic fluctuations without compromising sedative efficacy during prolonged mechanical ventilation.
This study has several limitations. First, despite the use of propensity score matching, residual confounding cannot be excluded, as certain variables such as liver and kidney function and cumulative sedative exposure were not available. Second, the study was conducted in a single center with a limited sample size, which may restrict generalizability. Third, only remimazolam and propofol were compared; further studies directly comparing remimazolam with midazolam and dexmedetomidine are warranted. Fourth, our assessment of vasoactive support relied primarily on norepinephrine requirements, as it was the first-line and predominant agent in our cohort. While this provides a consistent and quantifiable metric, it may not fully capture the complexity of hemodynamic management. Other vasopressors, such as vasopressin, dopamine, or epinephrine, were used sporadically, typically as adjuncts in specific clinical contexts (e.g., refractory shock). Consequently, our analysis might not reflect the total intensity or nuances of vasopressor therapy, particularly in the most unstable patients. However, the balanced use of any vasopressors at baseline between the matched groups (Table 1) suggests that this limitation likely affected both groups equally. Fifth, although we included interventions such as IABP, CRRT, and PCI as covariates in the propensity score model and achieved post-matching balance (Table 1), their profound and dynamic hemodynamic effects may not be entirely eliminated by statistical adjustment. Their presence could attenuate observed differences between sedatives, though including these patients enhances the real-world generalizability of our findings. Sixth, as a retrospective study using aggregated data, we could not perform a time‑series or dose–response analysis linking real‑time sedative adjustments to immediate hemodynamic changes. Our results thus reflect the net hemodynamic effect over the sedation period rather than the dynamic pharmacodynamic interaction. Seventh, we did not assess delirium, a critical neurocognitive outcome. While preliminary evidence suggests remimazolam may pose a lower delirium risk than traditional benzodiazepines and be comparable to propofol, this requires prospective validation in mechanically ventilated patients using tools such as the CAM‑ICU. Eighth, the external validity of our findings should be interpreted in context. The study was conducted during the SARS‑CoV‑2 pandemic (December 2021–December 2022), when patients often required deep sedation for hypoxemia but might have exhibited less distributive shock compared with classic bacterial sepsis. Therefore, our observations—particularly the hemodynamic advantage of remimazolam—need confirmation in broader ICU populations (e.g., bacterial sepsis, trauma, postoperative) where sedation needs and hemodynamic profiles may differ. Finally, plasma drug concentrations were not measured, and the optimal dosing regimen for prolonged ICU sedation remains to be determined.
Conclusions
In conclusion, this propensity score-matched study in mechanically ventilated ICU patients found that compared with propofol, remimazolam for sedation was associated with a more favorable hemodynamic profile, which was our primary outcome of interest. Specifically, remimazolam use resulted in: (1) A smaller reduction in mean arterial pressure (ΔMAP). (2) A lower incidence of hypotension. (3) A reduced need for high-dose norepinephrine support. Regarding secondary outcomes, no significant differences were observed in heart rate changes, fluid resuscitation volume, or the incidence of hypertension, bradycardia, or tachycardia. Importantly, key clinical outcomes such as the duration of mechanical ventilation, lengths of ICU and hospital stay, and 28-day mortality were comparable between the two groups.
These findings suggest that for mechanically ventilated ICU patients where hemodynamic stability is a concern, remimazolam may be a preferable sedative to propofol, providing equivalent sedation and clinical recovery while exerting less depressant effect on blood pressure. Prospective trials are warranted to confirm these observations.
Acknowledgements
The authors sincerely thank all the patients who participated in this study, the staff of the participating departments, and the research coordinators for their support and assistance in conducting this study.
Authors’ contributions
WJX, LW, and LYZ conceived and designed the study. WJX drafted the manuscript. XYF, ZKS, WW, MW, HDZ, SSW, HFW, GL, WFX, WWG, ZWL, ZL, LXQ and GJJ contributed to study implementation and data collection. LW performed the statistical analysis. All authors contributed to the interpretation of the data. LW and LYZ revised the manuscript. All authors read and approved the final version of the manuscript.
Funding
This study received no external funding.
Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki Declaration-2013. The study was approved by the ethics boards of Renmin Hospital of Wuhan University (WDRY2021-K179). Due to the retrospective nature of the study, which involved only the secondary analysis of fully anonymized clinical data from past medical records with no additional interventions or risks to patients, the requirement for written informed consent was waived by the ethics committee.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Lu Wang, Email: wanglu@whu.edu.cn.
Liying Zhan, Email: zhanliying@whu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.