Introduction
The safe and efficient management of anesthesia during surgical procedures is essential. Despite the availability of excellent anesthetic agents such as propofol, dexmedetomidine, and midazolam, each has its limitations, and efforts to find ideal hypnotic and sedative agents are ongoing.
Recently introduced to the medical field, remimazolam is increasingly used in both general anesthesia and procedural sedation [1]. It exhibits many characteristics of an ideal anesthetic, including rapid onset, a short half-life, minimal effects on respiratory or cardiovascular function, and pharmacological reversibility [1]. Ongoing research on the efficacy and safety of remimazolam as an anesthetic further amplifies its promising expectations as an ideal hypnotic and sedative agent [2–4].
Postoperative delirium is a serious complication that occurs after surgery. It not only extends the hospital stay and increases healthcare costs but also has long-term effects on cognitive function (i.e., dementia) [5,6], making it a critical issue to address. Anesthesia can influence the development of postoperative delirium, and research on the effects of different anesthetic methods and agents is ongoing [7]. Given these considerations, investigating the impact of remimazolam on postoperative delirium and cognitive function is particularly relevant. Benzodiazepines are known risk factors for delirium [8]. Although remimazolam is a novel benzodiazepine, its effects on postoperative delirium and cognitive function remain controversial.
Based on the hypothesis that remimazolam does not increase the risk of postoperative cognitive decline, this study aimed to compare the incidence of postoperative delirium and cognitive function between patients administered remimazolam and propofol under general anesthesia or procedural sedation.
Materials and Methods
This meta-analysis was conducted and documented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [9]. We registered a detailed, predefined protocol for this study in the International Prospective Register of Systematic Reviews (PROSPERO; identifier: CRD42024566651).
Eligible criteria
The following population, intervention, comparison, outcomes, and study design (PICOS) were used to define the inclusion criteria: (1) participants undergoing surgeries or procedures, (2) performing general anesthesia sedation using remimazolam and propofol, (3) studies that compared the incidence of postoperative delirium or cognitive function, and (4) randomized controlled trials (RCTs) reporting at least one of the outcomes of interest. Exclusion criteria were retrospective cohort studies, meta-analyses, review articles, editorials, letters to the editor, case reports, observational studies, study protocols, conference abstracts, and animal studies.
Search strategy
To identify suitable RCTs for this study, we searched electronic databases, including PubMed, CENTRAL, Embase, Scopus and Web of Science, from their inception to July 04, 2024, without any restrictions on language, region, publication year, or journal. The search terms included ‘remimazolam,’ ‘Byfavo,’ ‘Anerem,’ ‘Aptimyda,’ ‘Ruima,’ ‘delirium,’ ‘cognitive dysfunction,’ ‘cognitive impairment,’ and ‘cognition.’ The detailed literature search strategies are listed in Supplementary Table 1.
Study selection and data extraction
Two independent reviewers (JIP and HJS) selected appropriate RCTs for data synthesis based on predetermined inclusion and exclusion criteria. The non-English article [10] was translated using Google Translate [11] and ChatGPT-4 [12], both of which have established accuracy. Relevant studies from each electronic database were selected by reviewing titles and abstracts, followed by a full-text review, to determine the final studies to be included in the analysis. Any disagreements were resolved by a third reviewer (HSN).
Following the evaluation of the final RCTs by two independent reviewers (JIP and HJS), key variables were extracted and documented in a data collection form for synthesis. The collected data included information such as authors, publication year, sample size, mean age of participants, American Society of Anesthesiologists Physical Status (ASA-PS), and details regarding remimazolam and propofol (including induction and maintenance doses). Additionally, data on the occurrence of postoperative delirium and hypotension were recorded. Postoperative cognitive function status (Mini-Mental State Examination [MMSE] score) was also assessed. Median values with interquartile ranges were converted to means with standard deviations (SDs) using Wan’s formula [13]. For graphically represented data, values were extracted using WebPlotDigitizer (version 4.8; Ankit Rohatgi; Available at https://automeris.io/WebPlotDigitizer).
Assessment of risk of bias and evidence quality
Two independent reviewers assessed the risk of bias for each outcome of the included studies using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2) [14]. This evaluation addressed five domains: 1) bias arising from the randomization process, 2) bias due to deviations from intended interventions, 3) bias due to missing outcome data, 4) bias in outcome measurement, and 5) bias in the selection of reported results. The risk of bias was categorized as ‘low risk,’ ‘some concerns,’ or ‘high risk.’
The certainty of the evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system that considers five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias [15].
Outcome measures
The incidence of postoperative delirium or cognitive function was considered as the primary outcome. Secondary outcomes included the incidence of hypotension, as it is known to be related to changes in cognitive function after surgery [16].
Statistical analysis
The effect size for each trial was calculated using Stata SETM (version 17.0; Stata Corp.) to describe the effects of the interventions. Odds ratios (OR) with 95% CI for dichotomous variables and mean differences (MD) with 95% CI for continuous variables were adopted as effect sizes. A random-effects model was adopted for all statistical analyses to provide a robust estimation of the effect size considering the variability between studies. Statistical significance was set at P < 0.05.
The level of heterogeneity among the pooled effect sizes was evaluated using Cochran’s Q test and I2 statistics and classified as none (I2 < 25%), low (I2 = 26%‒49%), moderate (I2 = 50%‒74%), or high (I2 > 76%) [17]. When the heterogeneity was reported to be high, we performed a meta-regression analysis to explore the potential sources of heterogeneity, including publication year, sample size, age, type of anesthesia, ASA-PS, and dose of remimazolam for induction as covariates. Furthermore, a leave-one-out sensitivity analysis was conducted to detect small study effects to determine whether any single study could influence the robustness of the pooled effect size. Subgroup analyses were conducted according to the type of anesthesia (general anesthesia and procedural sedation).
Considering Cochrane’s guidelines [18], as the number of included studies for each outcome was less than 10, we did not assess publication bias either visually (funnel plot) or statistically (Egger’s test).
In a meta-analysis, the potential non-independence of results from studies with multiple intervention arms was addressed by splitting the shared group into two distinct groups [19]. This decision was guided by the recommendations of the Cochrane Handbook for handling multiple comparisons [18]. Pre-specified criteria were established based on similarities in the intervention type, population characteristics, and outcome measures. Separate effect sizes were calculated for each group, and the robustness of the findings was confirmed through sensitivity analyses.
Results
Study selection
Initially, 333 articles were identified using electronic databases. After removing 125 duplicates, screening based on titles and abstracts led to the exclusion of 63 and 124 articles, respectively. After excluding two studies for which the full manuscripts could not be retrieved from either the database or the authors, the full texts of 17 eligible studies were thoroughly reviewed, and 11 were included in the final analysis [10,19–28]. The following reasons were identified for excluding studies during the review process: the primary outcome was not measured [29,30]; propofol was used only as an adjuvant agent [31,32]; the study was a protocol rather than a completed study [33]; and the study design was retrospective [34]. A flow diagram is shown in Fig. 1.
Characteristics of study and participant
The characteristics of the RCTs included in the final analysis are summarized in Table 1. A total of 1,295 adult participants were included, with 664 and 631 assigned to the remimazolam and propofol groups, respectively. In nine studies [10,19,22–28], the participants received general anesthesia, while the remaining two studies [20,21] involved participants undergoing bronchoscopy and hip fracture surgery after sedation. The assessment tools for detecting postoperative delirium include the Confusion Assessment Method (CAM) [20,24,25,27], the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) [22], and the Postoperative Quality of Recovery Scale (PQRS) [19,28]. The MMSE was used to determine the status of postoperative cognitive function [10,19–21,23,26]. Various regimens were applied for total intravenous anesthesia induction and maintenance with remimazolam and propofol perioperatively, except in one study [25] that added desflurane to remimazolam and propofol for anesthesia maintenance.
Incidence of postoperative delirium
The incidence of postoperative delirium was reported in eight RCTs [19–22,24,25,27,28] with nine comparisons (two different comparisons were made in one study [19]). The incidence of postoperative delirium was 8.0% (44 cases out of 552) in the remimazolam group and 10.4% (54 cases out of 520) in the propofol group. The overall pooled effect size revealed that remimazolam administration did not increase the incidence of postoperative delirium (OR: 0.74, 95% CI [0.39–1.42], P = 0.369, I2 = 32%; Fig. 2).
Subgroup analysis showed that remimazolam significantly reduced the incidence of postoperative delirium compared with propofol after sedation (OR: 0.24, 95% CI [0.08–0.73], P = 0.012, I2 = 0%; Fig. 2), whereas no significant differences were observed between remimazolam and propofol after general anesthesia (OR: 1.04, 95% CI [0.65–1.66], P = 0.886, I2 = 0%; Fig. 2). Considering that the heterogeneity changed through subgrouping, the low heterogeneity (I2 = 32%) in the overall effect size may be due to the type of anesthesia.
Sensitivity analysis showed that the pooled OR did not change significantly after omitting each study, supporting the robustness of our results (Supplementary Fig. 1).
Postoperative cognitive function
Postoperative cognitive function was assessed in six RCTs [10,19–21,23,26] with eight comparisons (two different comparisons were made in two studies [10,19]), using the MMSE as the assessment tool. A significant difference was observed between the two groups (MD: 1.06, 95% CI [0.32–1.80], P = 0.005, I2 = 89%; Fig. 3).
In the subgroup analysis, postoperative cognitive function was higher in the remimazolam group than in the propofol group after general anesthesia (MD: 1.30, 95% CI [0.53–2.06], P = 0.001, I2 = 90%; Fig. 3), but not after sedation (MD: –0.13, 95% CI [–2.18 to 1.91], P = 0.898, I2 = 63%; Fig. 3). Despite subgrouping, the heterogeneity remained high. To identify the potential source of this heterogeneity, additional meta-regression was conducted, including publication year, type of anesthesia, ASA-PS, sample size, induction dose of remimazolam (induction dose of propofol, maintenance dose of remimazolam, and propofol were omitted due to collinearity), and age. No covariates significantly influenced the heterogeneity, suggesting the presence of other hidden factors (Supplementary Table 2).
The leave-one-out sensitivity analysis did not reveal any changes in the pooled effect size of postoperative cognitive function (Supplementary Fig. 2).
Incidence of hypotension
The incidence of hypotension was reported in seven studies [7,8,15–17,20,21,23] with eight comparisons (one study included two different comparisons [19]). The incidence of hypotension was 23.2% in the remimazolam group and 49.9% in the propofol group. The overall pooled effect size indicated that remimazolam significantly lowered the incidence of hypotension in participants undergoing surgery or procedure (OR: 0.28, 95 CI [0.21–0.37], P = 0.000, I2 = 0%; Fig. 4).
Subgroup analysis demonstrated that remimazolam significantly decreased the incidence of hypotension compared to propofol in both general anesthesia (OR: 0.28, 95 CI [0.20–0.39], P = 0.000, I2 = 0%; Fig. 4) and sedation settings (OR: 0.26, 95 CI [0.13–0.52], P = 0.0002, I2 = 0%; Fig. 4).
In the leave-one-out sensitivity analysis, no study skewed the effect size, supporting the robustness of our results (Supplementary Fig. 3).
Risk of bias
The overall risk-of-bias assessment results are shown in Supplementary Fig. 4 and Supplementary Fig. 5. The RoB 2 tool assesses studies based on intention-to-treat (ITT) and per-protocol (PP) analyses. The included studies were then evaluated and classified using this approach. Six studies [10,20,24–27] used the ITT method, while five studies [19,21–23,28] used the PP method. Four RCTs [23–25,27] were classified as ‘Low,’ and seven RCTs [7,16,20] had ‘Some concerns’ regarding the randomization process [10,20–22,26,28] or deviations from intended interventions [19,22].
Certainty of the evidence
As shown in Supplementary Table 3, the certainty of the evidence was moderate for the four outcome variables (incidence of postoperative delirium and hypotension). However, the assessment of postoperative cognitive function resulted in a decrease in the evidence level owing to concerns regarding the risk of bias and high heterogeneity.
Discussion
Our meta-analysis showed that remimazolam, when used under general anesthesia or sedation, did not increase the risk of postoperative delirium, and resulted in better postoperative cognitive function than propofol. Furthermore, the lower incidence of intraoperative hypotension and bradycardia compared to propofol supports the favorable hemodynamic effects of remimazolam. The similar incidence of postoperative nausea and vomiting (PONV) with remimazolam and propofol further strengthens the notion that remimazolam is a valuable anesthetic agent.
Benzodiazepines have long been known to increase the risk of delirium [8]. However, recent questions about the actual impact of benzodiazepines on delirium incidence have led to criticism of the existing guidelines that classify all benzodiazepines as risk factors, regardless of their duration of action [35]. Additionally, a meta-analysis examining the use of benzodiazepines during the perioperative period found that benzodiazepines did not increase the risk of delirium, highlighting the need for further research [36]. The results of the present study support this hypothesis. Although remimazolam is a benzodiazepine, it is short-acting and does not impair cognitive function compared with propofol when used for general anesthesia or sedation. In fact, participants who received remimazolam showed better cognitive function than those who received propofol postoperatively. Therefore, we believe that there is little reason to hesitate in using remimazolam to reduce the risk of postoperative delirium. However, well-designed studies are required to confirm this conclusion.
Maintaining hemodynamic stability during surgery is arguably the most crucial aspect of anesthesia management. Unfortunately, the currently used hypnotics tend to cause some degree of blood pressure reduction, necessitating careful monitoring and management. In our study, remimazolam reduced the incidence of hypotension by 72% compared to propofol and decreased the incidence of bradycardia by 54%. These clinically significant reductions suggest that remimazolam can be safely used in critically ill patients for whom maintaining blood pressure is of paramount importance.
One factor contributing to remimazolam causing fewer postoperative cognitive function impairments than propofol is its ability to provide hemodynamic stability. Various studies have examined the correlation between intraoperative blood pressure and postoperative delirium, showing that hypotension is associated with an increased incidence of delirium. Wachtendorf et al. [16] reported an association between mean arterial pressure < 55 mmHg and postoperative delirium in participants undergoing noncardiac surgery. Duan et al. [37] identified that intraoperative hypotension (mean arterial pressure ≤ 65 mmHg) maintained for over 5 min increased the incidence of postoperative delirium in older adults after thoracic and orthopedic surgery. Moreover, studies have indicated that blood pressure fluctuations rather than absolute levels of hypotension can predict the occurrence of postoperative delirium [38]. Considering this, the hemodynamic stability demonstrated by remimazolam in our study likely contributed to the maintenance of cognitive function and did not increase the incidence of postoperative delirium. However, further research on this topic is required.
Several aspects should be considered when interpreting the results of this study. First, three tools were used to assess postoperative delirium. However, the CAM [39], DSM-V [40], and PQRS [41] are all validated methods for assessing cognitive function, and as long as researchers follow their planned protocols, the evaluation of postoperative delirium is likely to be accurate. Secondly, anesthetic drugs are administered in various regimens. Currently, the optimal dose of remimazolam has not been established; therefore, drugs are administered based on anesthesia depth to achieve the intended anesthetic effects within a safe range. This variability may have contributed to some degree of heterogeneity in the meta-analysis. However, most outcome variables showed no or low heterogeneity. The meta-regression analysis confirmed that regimen variability did not contribute to the degree of postoperative cognitive function that showed high heterogeneity. Third, the heterogeneity in the anesthesia methods among the included studies may have influenced the generalizability of our findings. Although we performed a subgroup analysis differentiating between general anesthesia and sedation, the results may still be affected by variations in administration techniques and protocols. Furthermore, the diversity in surgical types across studies poses a challenge in conducting meaningful subgroup analyses. Given the range of surgeries included, from minor outpatient procedures to major surgeries, it was deemed inappropriate to attempt to further categorize the interventions. This limitation underscores the need for caution when interpreting the results, and emphasizes the complexity of anesthesia practice in various clinical contexts. Future studies should strive for greater homogeneity in surgical procedures to allow for more nuanced comparisons. Finally, the confounding variables and sources of heterogeneity were not identified.
In conclusion, when used for general anesthesia or sedation, remimazolam did not increase the incidence of postoperative delirium and provided better hemodynamic stability during surgery than propofol. Importantly, this was associated with improved postoperative cognitive function. Furthermore, it does not increase the incidence of PONV. These findings suggest that remimazolam is a safe and valuable anesthetic agent with the potential to significantly enhance patient recovery, particularly in terms of cognitive outcomes. Further clinical studies are required to confirm these findings.
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