Introduction
After its first approval for use in general anesthesia in Japan in 2020, remimazolam has been used in various types of surgery as a hypnotic, showing favorable safety and efficacy [1,2]. Subsequently, it has been approved worldwide, including in the US, EU, and South Korea, with ongoing research exploring broader applications and establishing its role in various clinical settings [3].
Remimazolam is a novel short-acting benzodiazepine developed for anesthetic/sedative use, and its applications are expanding worldwide [4]. The key features of remimazolam include rapid onset and short duration of pharmacological action, enabling rapid recovery from anesthesia and clinical hemodynamic stability and promoting patient safety in anesthetic management during surgery [3].
Recently, studies comparing remimazolam with other hypnotics such as propofol and volatile agents for general anesthesia have aimed to expand its use and understand its safety profile. In a meta-analysis by Huang et al. [5], the risk of total adverse events (i.e., hypotension, bradycardia, or hypoxemia) was lower in the remimazolam group than in the propofol group. Similarly, Peng et al. [6] reported that remimazolam provided more stable hemodynamics and caused fewer adverse events than propofol when used as the main general anesthetic. However, although clinical investigations have been conducted to identify differences in the safety or efficacy profiles between remimazolam and volatile agents that are commonly used as hypnotics, inconsistent results have been observed, necessitating evidence assessment [7,8]. For example, Song et al. [8] reported that the administration of remimazolam did not reduce the incidence of hypotension compared to desflurane but increased the extubation time. Conversely, Lee et al. [7] showed that remimazolam decreased the occurrence of intraoperative hypotension and resulted in shorter extubation times than sevoflurane.
This study analyzed and compared the safety and efficacy of remimazolam-based total intravenous anesthesia (TIVA), assuming that remimazolam is non-inferior to volatile agents in terms of safety and efficacy. Specifically, in adult patients undergoing general anesthesia, a meta-analysis was conducted focusing on the incidence of intraoperative hypotension for safety and extubation time for efficacy.
Materials and Methods
This systematic review and meta-analysis was conducted and reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement [9]. The predefined protocol for the present study was registered with the International Prospective Register of Systematic Reviews (PROSPERO; identifier: CRD42024551647).
Eligible criteria
The inclusion criteria were established based on the following population, intervention, comparison, outcomes, and study design: (1) participants undergoing surgery under general anesthesia, (2) studies that compared the safety or efficacy of remimazolam with volatile agents, and (3) randomized controlled trials (RCTs) reporting at least one of the outcomes of interest. The exclusion criteria included meta-analyses, case reports, letters to the editor, editorials, observational studies, retrospective cohort studies, review articles, trial protocols, conference abstracts, and animal studies.
Search strategy
Eligible trials were searched using electronic databases, including PubMed, Embase, CENTRAL, and Scopus, from inception to May 20, 2024, without any limitations on language, publication year, region, or journal. The search terms included ‘Remimazolam,’ ‘Byfavo,’ ‘CNS-7056,’ ‘Volatile,’ ‘Inhalation,’ ‘gas,’ ‘sevoflurane,’ ‘desflurane,’ ‘isoflurane,’ ‘balanced anesthesia,’ ‘balanced anaesthesia,’ ‘General,’ ‘General Anesthesia,’ ‘General anaesthesia,’ ‘general an*,’ ‘Intubation,’ and ‘intubat*.’ The detailed literature search strategies are listed in Supplementary Table 1.
Study selection and data extraction
In accordance with the inclusion and exclusion criteria, two independent reviewers (JIP and HJS) identified studies eligible for data synthesis. Relevant studies were selected from each database based on titles and abstracts. After a full-text review, the RCTs were finalized for analysis. Any disagreements between reviewers were resolved through a consultation with a third reviewer (HSN).
After the final RCTs were evaluated by two independent reviewers (JIP and HJS), the key variables were extracted and recorded in a data collection form for synthesis. The collected data included the following details: authors; publication year; sample size; age range of participants; American Society of Anesthesiologists physical status (ASA-PS); specifics of remimazolam and volatile agent usage (including doses for induction and maintenance of anesthesia); and occurrence of hypotension, bradycardia, and postoperative nausea and/or vomiting (PONV). Additional variables included extubation time, duration of post-anesthesia care unit (PACU) stay, and overall length of hospital stay. Median values with interquartile ranges were converted to means with standard deviations using Wan’s formula [10]. For the data shown in the graphs, values were extracted using WebPlot Digitizer (https://apps.automeris.io/wpd/).
Assessment of risk of bias and evidence quality
Two independent reviewers examined the risk of bias for each outcome of the included studies using the revised Cochrane risk-of-bias tool for randomized trial 2 (RoB 2) [11]. This assessment covers five areas: 1) bias originating from the randomization process, 2) bias due to deviations from the intended interventions, 3) bias resulting from incomplete outcome data, 4) bias in the outcome measurement, and 5) bias in the selection of the reported results. The risk of bias was rated as ‘low risk,’ ‘some concerns,’ or ‘high risk.’
The certainty of evidence for each outcome was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system that assesses five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias [12].
Outcome measures
We considered the incidence of hypotension as the primary outcome. Secondary outcomes included the incidence of bradycardia, extubation time, occurrence of PONV, and lengths of stay in the PACU and hospital.
The values used to evaluate the safety of remimazolam included the incidence of hypotension, bradycardia, and PONV, whereas the efficacy profile was examined in terms of the time required for extubation, duration of stay in the PACU, and length of hospital stay.
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. Relative risk (RR) with a 95% CI for dichotomous variables and mean difference (MD) with a 95% CI for continuous variables were adopted as the effect size. 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 low (I2 = 0%‒25%), moderate (I2 = 26%‒75%), or high (I2 = 76%‒100%). When heterogeneity was reported to be high, we conducted a meta-regression analysis, assuming the publication year, type of surgery, ASA-PS, drug for induction, dose of remimazolam for maintenance, and type of volatile agent for maintenance. Furthermore, to detect small study effects, a leave-one-out sensitivity analysis was conducted to determine whether any single study could influence the robustness of the pooled effect size.
Considering Cochrane’s guidelines [13], 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).
Results
Study selection
Initially, 215 articles were identified using electronic databases. Following the removal of 58 duplicates, screening of titles and abstracts led to the exclusion of 85 and 60 articles, respectively. The full texts of the 12 eligible studies were thoroughly reviewed, and all 12 were included in the final analysis [7,8,14–23] (Fig. 1).
Characteristics of the study and participants
The characteristics of the RCTs included in the final analysis are summarized in Table 1. A total of 969 adult participants were included, with 468 and 501 assigned to the remimazolam and volatile agent groups, respectively. Sevoflurane was used as the control agent in seven studies [7,15–18,20,22], whereas desflurane was used in the remaining five studies [8,14,19,21,23]. Various regimens have been used for induction, with a combination of hypnotics and opioids, including remimazolam (continuous infusion or bolus), propofol, etomidate, remifentanil (continuous infusion or bolus), and fentanyl. Except in one study [19] that used nitrous oxide, remifentanil was administered with remimazolam or other volatile agents during surgery.
Incidence of hypotension
Various definitions of hypotension were used in each study (Supplementary Table 2).
The incidence of hypotension was reported in eight studies [7,8,15–18,21,23] with nine comparisons made (two different comparisons were made in one study [21]). The incidence of hypotension was 14% (47 of 344 participants) in the remimazolam group and 34% (128 of 377 participants) in the volatile agent group. The pooled effect size showed that remimazolam use significantly lowered the incidence of hypotension in participants undergoing surgery under general anesthesia (eight studies [7,8,15–18,21,23]; RR: 0.43, 95% CI [0.29–0.63], P = 0.0000, I2 = 26%; Fig. 2).
The subgroup analysis showed that remimazolam significantly reduced the incidence of hypotension compared to desflurane (three studies [8,21,23] with four comparisons; RR: 0.57, 95% CI [0.39–0.83], P = 0.0029, I2 = 0%; Fig. 2) and sevoflurane (five studies [7,15–18]; RR: 0.29, 95% CI [0.17–0.50], P = 0.0000, I2 = 8%; Fig. 2).
In the leave-one-out sensitivity analysis, no study skewed the effect size, supporting the robustness of the results (Supplementary Fig. 1).
Incidence of bradycardia
Three RCTs (four comparisons) [15,17,21] were included in the meta-analysis of the incidence of bradycardia between the remimazolam and volatile agent groups. In all three studies, bradycardia was defined as a heart rate < 50 beats/min. Participants in the remimazolam group had a similar incidence of bradycardia to those in the volatile agent group (three studies [15,17,21] with four comparisons; RR: 1.06, 95% CI [0.59–1.90], P = 0.8502, I2 = 42%; Fig. 3).
In the subgroup analysis, consistent results were noted compared to the overall pooled effect size, showing no differences between remimazolam and desflurane (one study [21] with two comparisons; RR: 1.28, 95% CI [0.22–7.40], P = 0.7840, I2 = 79%; Fig. 3) or sevoflurane (two studies [15,17]; RR: 1.03, 95% CI [0.94–1.13], P = 0.5569, I2 = 0%; Fig. 3). Considering that the heterogeneity changed through subgrouping, the moderate heterogeneity (I2 = 42%) in the overall effect size might be due to the type of volatile agent used. Furthermore, the high heterogeneity (I2 = 79%) observed in the desflurane subgroup might be attributed to the difference in the remifentanil dose (low vs. high) during surgery.
The sensitivity analysis did not show any changes in the significance of the pooled effect size, indicating that no single study significantly skewed the results (Supplementary Fig. 2).
Extubation time
Extubation times were evaluated in eight RCTs [7,8,15,16,18–20,23], and no significant difference was observed between the two groups (MD: 1.10, 95% CI [0.92–3.11], P = 0.3269, I2 = 95%; Fig. 4).
Subgroup analysis based on the type of volatile agent in the control group revealed no significant differences in the extubation time between remimazolam and desflurane (three studies [8,19,23]; MD: 3.53, 95% CI [–0.16 to 7.21], P = 0.0606; I2 = 96%; Fig. 4) or sevoflurane (five studies [7,15,16,18,20]; MD: –0.42, 95% CI [–1.67 to 0.83], P = 0.5086; I2 = 79%; Fig. 4) groups. Despite subgrouping, the heterogeneity remained high. To identify the potential source of this heterogeneity, additional meta-regression was conducted, including publication year, type of surgery, ASA-PS, drug for induction, dose of remimazolam for maintenance, and type of volatile agent for maintenance. No covariates significantly influenced the heterogeneity, suggesting the presence of other hidden factors (Supplementary Table 3).
Leave-one-out sensitivity analysis did not reveal any changes in the pooled effect size of extubation time (Supplementary Fig. 3).
PONV
Nine studies [7,8,14,15,17–19,22,23] evaluated the occurrence of PONV. The remimazolam group exhibited a pooled estimated incidence of PONV of 13% (48 of 363 participants), whereas the volatile group had an incidence of 28% (102 of 366 participants), showing a significant difference between the two groups (nine studies [7,8,14,15,17–19,22,23]; RR: 0.51, 95% CI [0.37–0.72], P = 0.0001, I2 = 15%; Fig. 5).
The subgroup analysis showed that the incidence of PONV was significantly lower in the remimazolam group than in the desflurane (four studies [8,14,19,23]; RR: 0.35, 95% CI [0.20–0.61], P = 0.0002, I2 = 2%; Fig. 5) or sevoflurane (five studies [7,15,16,18,22]; RR: 0.63, 95% CI [0.45–0.88], P = 0.0065, I2 = 0%; Fig. 5) groups.
The pooled effect size remained consistent in the sensitivity analysis, supporting the robustness of our results (Supplementary Fig. 4).
PACU stay time
In six trials [7,8,15,16,18,20], the PACU stay time was evaluated, and the pooled effect size did not show a significant difference between the remimazolam and volatile agent groups (six studies [7,8,15,16,18,20]; MD: 0.42, 95% CI [–1.08 to 1.92], P = 0.8138, I2 = 46%; Fig. 6).
The subgroup analysis indicated that participants in the remimazolam group stayed longer in the PACU compared to those in the desflurane group (one study [8]; MD: 1.80, 95% CI [0.98–2.62], P = 0.0000, I2 = not applicable; Fig. 6), whereas no significant differences were observed between remimazolam and sevoflurane (five studies [7,15,16,18,20]; MD: –0.12, 95% CI [–1.60 to 1.35], P = 0.8700; I2 = 1%; Fig. 6). The MD of 1.8 min observed in the comparison between remimazolam and desflurane may be considered clinically insignificant, given the relatively short duration.
The leave-one-out sensitivity analysis did not reveal any changes in the effect size after omitting these studies (Supplementary Fig. 5).
Length of hospital stay
In four studies [7,15,16,20] that compared remimazolam and sevoflurane, the length of hospital stay was investigated. However, this outcome has not been reported in previous studies comparing remimazolam and desflurane. Regardless of whether remimazolam or sevoflurane was administered, participants had similar lengths of hospital stay (four studies [7,15,16,20]; MD: –0.07, 95% CI [–0.29 to 0.16], P = 0.5591, I2 = 0%; Fig. 7).
In the sensitivity analysis, no small study effects were detected and the effect size remained stable (Supplementary Fig. 6).
Risk of bias
The results of the overall risk-of-bias assessment are demonstrated in Supplementary Figs. 7A and B. The RoB 2 tool assesses studies differently based on the data analysis methods used, namely intention-to-treat (ITT) and per-protocol (PP). The included studies were then evaluated and classified using this approach. Eight studies [7,14–16,19,20,22,23] used the ITT method, whereas four studies [8,17,18,21] used the PP method. Nine RCTs [7,14–16,18–20,22,23] were classified as ‘low,’ and three RCTs [8,17,21] that had some concerns regarding deviations from intended intervention were classified as ‘some concerns.’
Certainty of the evidence
As shown in Supplementary Table 4, the certainty of evidence was high for the four outcome variables (incidence of bradycardia and PONV, duration of PACU stay, and length of hospital stay). In the assessment of the incidence of hypotension and extubation time, the evidence level was downgraded to moderate owing to the diversity of definitions for hypotension and high heterogeneity, respectively.
Discussion
In the present meta-analysis, remimazolam-based TIVA demonstrated a favorable hemodynamic effect, demonstrating a lower incidence of hypotension and similar bradycardia events compared to volatile agent-based anesthesia in patients undergoing surgery under general anesthesia. Furthermore, the reduction in PONV without delaying extubation time and discharge from the PACU and hospital supports the consideration of remimazolam-based TIVA as a valuable method for general anesthesia.
Maintaining hemodynamic stability during surgery is crucial and cannot be overemphasized. General anesthesia is primarily achieved using propofol-based TIVA and volatile agent-based anesthesia. However, both methods can cause a decrease in blood pressure owing to vasodilation effects during the induction and maintenance of anesthesia. Therefore, it is natural that efforts continue to find appropriate agents that can minimize this effect in patients in whom maintaining hemodynamic stability is particularly important. To date, several studies have compared the safety and efficacy of remimazolam and propofol under general anesthesia, and meta-analyses have revealed that remimazolam provides a more stable blood pressure maintenance than propofol [5,6,24]. The present study revealed that remimazolam reduced the incidence of hypotension by 57% (RR, 0.43) compared to volatile agents, which has significant clinical implications. Our results confirmed that remimazolam induced a smaller decrease in blood pressure than volatile agents and did not increase the risk of bradycardia. These characteristics support the suggestion that remimazolam can be used effectively and safely as a general anesthetic, particularly in vulnerable patients who require extreme hemodynamic stability. However, further research on this topic is required.
PONV remains a significant factor that causes discomfort in postoperative patients and plays a major role in determining patient satisfaction [25]. Typically, 30% of surgical patients experience PONV, with reports reaching as high as 80% in high-risk groups [26]. The risk of PONV varies depending on the anesthetic agent used during general anesthesia, with propofol known to have antiemetic effects, thus reducing the incidence of PONV compared to volatile agents [27]. Studies comparing the effects of the intravenous agents remimazolam and propofol on PONV have shown no significant differences between the two drugs [5,6]. Our study investigated the incidence of PONV between remimazolam and volatile agents and found that it reduced the incidence by approximately 49% (RR, 0.51) compared to volatile agents. When analyzed separately, remimazolam decreased the incidence of PONV by 65% (RR, 0.35) compared to desflurane, and by 37% (RR, 0.63) compared to sevoflurane. Overall, these findings indicate that while remimazolam is similar to propofol, when used as the main drug in TIVA, it significantly lowers the risk of PONV compared with volatile agents. Therefore, remimazolam-based TIVA is recommended because of its positive impact on patient recovery.
Rapid emergence and recovery from general anesthesia are important factors to consider when selecting an appropriate anesthetic agent. In this study, remimazolam did not delay extubation time or length of stay in the recovery room compared with volatile agents. This can be attributed to the pharmacological properties of remimazolam. It has a rapid onset of action and is metabolized by a tissue esterase into an inactive metabolite (CNS 7054), bypassing the need for hepatic metabolism that reduces variability in patients with liver impairment [28]. Moreover, its elimination half-life is short that contributes to its rapid recovery [28]. With respect to continuous infusion, a short context half time allows the use of remimazolam for long-duration surgery, minimizing the risk of delayed awakening from general anesthesia [29]. The presence of flumazenil, a benzodiazepine reversal drug, can be considered a strength in terms of the efficient use of remimazolam.
Careful interpretation of the results of the present study is necessary owing to several limitations. First, the studies included in the meta-analysis used three definitions of hypotension. Currently, there is no standardized definition of intraoperative hypotension; however, all three definitions are commonly used. Therefore, it is unlikely that clinically significant hypotension has been overlooked [30]. Second, the optimal dose of remimazolam for induction and maintenance under general anesthesia has not yet been established. This variation in remimazolam dosing regimens may have contributed to heterogeneity in the meta-analyses. However, most of the heterogeneity was mild to moderate that was mitigated by subgrouping according to the type of volatile agent used. The high heterogeneity noted in the extubation time was not attributable to the drug regimen, as confirmed by meta-regression. Third, this study included various types of surgeries, differing in the location and intensity of the stimuli applied to the patients. Nonetheless, all studies monitored the depth of anesthesia and adjusted drug dosages according to a predetermined protocol. The diversity in surgical types did not result in high heterogeneity, indicating that remimazolam can be effectively used in a range of surgeries. Fourth, most included studies were conducted in South Korea. This indicates that remimazolam was approved relatively recently and is being actively used in East Asia. Thus, it is important to consider that generalizing the current results may be challenging owing to this limitation. Finally, hidden factors may have contributed to the heterogeneity observed in this meta-analysis, and the potential impact of unmeasured confounding variables should be considered.
In conclusion, remimazolam-based TIVA effectively reduced the incidence of hypotension and PONV without delaying extubation time or discharge from the PACU and hospital in patients undergoing general anesthesia after surgery. Although the safety and efficacy of remimazolam were elucidated in this meta-analysis, we deem that well-planned large clinical trials using standardized regimens for remimazolam administration, while minimizing confounders as much as possible, are needed to clarify the role of remimazolam in general anesthesia.
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