Introduction
The use of sedatives in patients is a critical aspect of modern anesthesia and procedural medicine, particularly in non-operating room settings. Among the agents available, dexmedetomidine and remimazolam have emerged as prominent choices due to their unique pharmacological profiles and efficacy in achieving sedation with minimal adverse effects (1).
Dexmedetomidine, an α-2 adrenergic agonist, is known for its sedative and analgesic properties and is often utilized in various procedures including, orthopedic surgeries, cardiovascular surgeries and neurosurgery procedures (2). Dexmedetomidine offers advantages such as reduced opioid requirements and minimal respiratory depression, making it suitable for use in patients undergoing sedation outside the operating room (3,4). However, its use is not without challenges; higher doses can lead to bradycardia and hypotension, necessitating careful monitoring and dosage adjustments (5,6).
By contrast, remimazolam, a newer benzodiazepine, has gained attention for its rapid onset and short duration of action, which may be particularly beneficial when quick recovery from sedation is often desired (7). Studies have indicated that remimazolam provides comparable hemodynamic stability to dexmedetomidine, with a lower incidence of adverse cardiovascular events (8,9). This characteristic is crucial in patients who may be more susceptible to the hemodynamic fluctuations associated with sedation (8). Furthermore, remimazolam has been associated with a reduced incidence of postoperative delirium compared with traditional sedatives (9,10).
Despite the promising profiles of both agents, the existing literature reveals a gap in large-scale comparative studies. Most studies to date have been limited in scope, often involving small sample sizes and heterogeneous populations, which complicates the generalizability of their findings (8,9). A systematic review and meta-analysis focusing on the comparative efficacy of dexmedetomidine and remimazolam in sedation is warranted to synthesize the available evidence and provide clearer insights into their relative advantages and disadvantages. Moreover, the safety profiles of these agents must be carefully evaluated. While dexmedetomidine is generally well-tolerated, its potential for inducing bradycardia and hypotension raises concerns, particularly in vulnerable patients (5,6). Additionally, remimazolam, despite its rapid metabolism and favorable recovery profile, has been associated with rare but serious adverse events, including anaphylaxis (11). Understanding these risks is essential for clinicians when selecting the appropriate sedative for patients. In conclusion, the comparative efficacy of dexmedetomidine and remimazolam in sedation represents a critical area of inquiry. The present systematic review and meta-analysis aims to elucidate the relative safety and efficacy of these two agents, providing evidence-based guidance for clinicians involved in sedation practices. By addressing the existing gaps in the literature, the present study seeks to enhance the understanding of sedation strategies, ultimately improving patient outcomes and safety.
Discussion
The present study evaluated the efficacy and safety profiles of remimazolam and dexmedetomidine across 9 studies, comprising 4 RCTs and 5 observational studies. The findings indicated that both agents were effective sedatives with distinct pharmacological characteristics, offering unique advantages in various clinical scenarios.
In the present study, the pooled analysis of the time to fully alert outcome revealed that remimazolam consistently demonstrated a significantly shorter time to full alertness compared with dexmedetomidine. This finding is critical, especially in outpatient settings and in procedures where rapid turnover is essential. For example, Kim et al (15) reported that patients receiving remimazolam achieved full alertness notably faster, a finding that is reinforced by the meta-analysis data of the present study, which showed a robust effect size favoring remimazolam (P<0.001). These results corroborate those of previous studies that have highlighted the rapid onset of remimazolam and offset of sedation, a property largely attributable to its metabolism by ubiquitous tissue esterases and the availability of a specific antagonist (flumazenil) for rapid reversal. By contrast, dexmedetomidine is well known for its slower onset (19,23). The pharmacodynamic profile of dexmedetomidine, characterized by a gradual titration to achieve adequate sedation, may be beneficial in scenarios requiring cooperative sedation (such as awake tracheal intubation) but is less suited for procedures that demand swift sedation and quick recovery. Hong et al (20) demonstrated that while dexmedetomidine maintains a state of arousable sedation, its longer half-life may contribute to a delayed recovery, which can be a drawback in high-turnover clinical environments.
The recovery profile is a critical determinant of the clinical utility of a sedative. This was evident from the pooled estimates where discharge times, though variable across studies, trended towards faster recovery with remimazolam. Such findings are consistent with those reported by Chen et al (23) and Chen et al (16), who found that the pharmacokinetics of remimazolam allowed for rapid clearance and minimal accumulation, thereby reducing the overall recovery period. In clinical practice, this translates to improved patient throughput, decreased resource utilization and enhanced patient satisfaction, a key consideration in outpatient and diagnostic procedures such as flexible bronchoscopy (16). Conversely, the prolonged duration of action of dexmedetomidine may be advantageous in settings where sustained sedation is necessary, such as during procedures that require extended patient cooperation or in intensive care units where gradual weaning from sedation is preferred. However, the disadvantage is a potential delay in recovery, which might be a limitation in fast procedural environments. Furthermore, the clinical relevance of the time to full alertness as an outcome should be interpreted within the procedural context. For outpatient or diagnostic procedures where rapid turnover is essential (such as flexible bronchoscopy and endoscopy), the shorter recovery time of remimazolam represents a clear advantage (24). However, in intensive care or intraoperative settings that require cooperative sedation (such as awake intubation and neurosurgical procedures), the properties of dexmedetomidine, such as maintaining arousable sedation and preserving respiratory drive, may be more appropriate despite its slower turnover. Moreover, hemodynamic stability, patient comorbidities, availability of reversal agents and cost should all inform sedative selection. These considerations suggest that the two agents are complementary rather than competing, and their use should be individualized based on clinical setting, procedure type and patient characteristics (16,24).
Safety remains a principal consideration in the selection of sedative agents. In the present study, the analysis of safety outcomes revealed that while both remimazolam and dexmedetomidine are generally safe, there are distinct differences in their hemodynamic profiles. Remimazolam was associated with fewer incidences of arrhythmia and hypotension compared with dexmedetomidine. For instance, Kim et al (15) and Deng et al (21) reported that remimazolam-treated patients experienced a more stable heart rate and blood pressure profile both during and after sedation. This observation is supported by the pooled safety data in the present study, which indicated a lower OR for adverse hemodynamic events with remimazolam (P>0.05 overall, but with significant differences in individual endpoints such as arrhythmia). These results align with but also extend the safety insights reported in the scoping review by Kempenaers et al (8), which evaluated remimazolam-related safety signals across 6,740 patients from case series and observational studies. This review identified 911 instances of hypotension, 68 of delayed emergence, 10 cases of anaphylaxis and 8 of re-sedation, underscoring the importance of post-market vigilance. Unlike the meta-analysis performed in the present study, which compared remimazolam directly with dexmedetomidine in controlled clinical trials, Kempenaers et al (8) focused on aggregated signal detection across heterogeneous settings without a comparator arm. The findings of the present study suggest that remimazolam, when compared head-to-head with dexmedetomidine, does not increase the risk of hypotension and significantly reduces the risk of arrhythmia. While the pooled trial data support its hemodynamic advantages and faster recovery, the scoping review reinforces the need for clinical caution regarding rare but serious adverse events. Together, these studies provide complementary perspectives: The present study quantifies comparative safety and efficacy, while the study by Kempenaers et al (8) outlines broad pharmacovigilance considerations.
Dexmedetomidine, while beneficial for preserving respiratory function, has a well-documented propensity to cause arrhythmia and hypotension. Studies by Hong et al (20) and Lee et al (18) highlighted these concerns, noting a higher incidence of such events in patients sedated with dexmedetomidine. This increased arrhythmia risk is consistent with the pharmacological action of dexmedetomidine as a highly selective α2-adrenergic agonist, which suppresses central sympathetic tone and norepinephrine release, leading to decreased heart rate and potential atrioventricular conduction effects (25). Although these side effects can be managed with vigilant monitoring and dose titration, they remain a significant consideration, particularly in patients with underlying cardiovascular risk factors. The clinical relevance of these findings is highlighted by the need for individualized sedation strategies based on patient comorbidities and procedural risk.
In the present study, the precision analysis demonstrated a relatively wide 95% prediction interval (-1.43 to 3.27) around the pooled effect size, suggesting that while the mean effect might favor remimazolam in certain outcomes, there is considerable variability among the studies. Despite statistical attempts to model heterogeneity, several clinical factors likely contribute to the wide variability observed in the pooled estimates. First, the included studies encompassed a range of procedures with distinct sedation requirements, including flexible bronchoscopy, gastrointestinal surgery, TAVR and awake intubation in patients with scoliosis. These procedures differ in duration, invasiveness and sedation goals, which may influence both drug performance and recovery time. Second, sedation protocols were not standardized across studies. Some used bolus dosing (7,16,22) while others relied on continuous infusions (19,20), and only certain remimazolam-treated patients received flumazenil to reverse sedation. Third, the use of adjunctive opioids (such as remifentanil and alfentanil) varied or was not reported, introducing potential confounding in both efficacy and safety outcomes. Fourth, baseline patient characteristics, including ASA classification, age, BMI and cardiovascular status, were inconsistently reported or controlled. Finally, definitions of sedation success and procedure completion varied or were implicit, and observer-based assessments may introduce measurement bias. These clinical inconsistencies, coupled with methodological diversity, likely account for the high I² and wide prediction intervals observed in the present analysis. Future meta-analyses would benefit from individual patient data or standardized outcome frameworks to better resolve these sources of heterogeneity. Nonetheless, the overall meta-analytic findings remain robust, as evidenced by the sensitivity analysis, which confirmed that no single study significantly altered the pooled estimates. Publication bias assessments indicated a reasonably symmetric funnel plot and non-significant Begg-Mazumdar rank correlation test (Kendall's τ=0.20; P=0.53). Egger's regression test was also conducted, which did not reveal significant small-study effects (intercept=-1.87; P=0.337). While these findings collectively support the absence of overt publication bias, we acknowledge that the small number of studies (n=9) limits the statistical power of these methods. Moreover, the classic fail-safe N analysis indicated that no additional ‘null’ studies would be required to render the observed effects non-significant; however, this test may be less informative for niche topics with few studies. Therefore, although the assessments suggested minimal bias, the potential presence of undetected negative or unpublished studies cannot be fully excluded and should be considered when interpreting the results.
One of the primary strengths of the present study is the inclusion of a comprehensive set of high-quality RCTs and observational studies, as confirmed by the ROBINS-I and RoB assessments. The use of rigorous methodological criteria minimizes bias and enhances the reliability of the findings. Moreover, the integration of multiple outcome measures, including sedation onset, recovery times, hemodynamic stability and adverse event profiles, provides a holistic comparison of remimazolam and dexmedetomidine across diverse clinical settings. Another strength is the application of several meta-analytic techniques, such as sensitivity analysis, precision analysis and publication bias assessments. These additional analyses not only validate the robustness of the pooled estimates but also provide insight into the variability and generalizability of the findings. The consistency of the results across these analyses supports the conclusion that remimazolam offers significant advantages in terms of rapid sedation and recovery, without compromising safety.
Despite the overall neutral pooled effect (SMD=0.049; P=0.523), notable heterogeneity was observed across the included studies, as reflected by a high I² value (93.9%) and a wide 95% prediction interval (-1.43 to 3.27). To explore potential sources of this variability, a random-effects meta-regression was performed including age and dosing parameters for both remimazolam and dexmedetomidine as moderators. However, none of these covariates significantly predicted the treatment effect (all P>0.23), and the model explained negligible between-study variance (R² analog=0.00). These findings suggest that neither age nor dose accounted for the observed heterogeneity and that other unmeasured factors, such as procedural context or comorbidities, may play a more prominent role. Due to the limited number of studies per procedural category and overlapping clinical contexts (such as bronchoscopy, gastrointestinal surgery, TAVR and spinal anesthesia), formal subgroup analyses by procedure type were not feasible in the present meta-analysis, a limitation that likely contributed to the notable residual heterogeneity. While age and dosage were explored as moderators via meta-regression, their effects were non-significant and the procedure type could not be formally tested. Future studies should prospectively stratify by procedure type during protocol development and aim to include at least 5 studies per subgroup, enabling meaningful comparisons using subgroup-specific τ² models and interaction tests. Visual inspection through stratified forest plots and potential use of mixed-effects models or individual-patient-data meta-analysis could also help clarify whether the observed faster recovery and hemodynamic advantages of remimazolam are consistent across different procedural settings.
The use of adjunctive opioids, particularly remifentanil, notably varied across studies, with some studies explicitly excluding additional sedatives [Chen et al (16), Chen et al (23), Kim et al (15), Kitaura et al (7), Xu et al (19)] and others lacking detailed reporting [Deng et al (21), Hong et al (20), Lee et al (18) and Zhou et al (22)]. This inconsistency introduces potential confounding in the evaluation of cardiovascular adverse events, given the independent hemodynamic effects of opioids on heart rate and blood pressure. Such variability in analgesic co-administration, along with differences in procedural context and patient selection, likely contributes to the observed heterogeneity in safety outcomes reported in the present meta-analysis (26).
Nevertheless, there are several limitations to the present analysis. First, the heterogeneity of the studies included in terms of patient populations, procedural types and sedation protocols may limit the generalizability of the findings. For example, the outcomes reported in studies involving flexible bronchoscopy may not be directly applicable to those involving gastrointestinal or cardiac procedures. Second, while the present meta-analysis includes 4 RCTs, the majority of included studies remain observational in nature. Although observational studies were rated as high quality using ROBINS-I, they are inherently limited by the potential for unmeasured confounding such as differences in adjunctive medications (such as remifentanil), sedation protocols or patient selection. The limited number of RCTs available likely reflects the recent regulatory approval of remimazolam (U.S. in 2020; EU in 2021) and the challenges of conducting blinded, protocol-standardized trials in acute procedural settings. Although the meta-regression and sensitivity analyses performed in the present study attempted to address some of this variability, they cannot fully eliminate bias. RCTs remain the gold standard for establishing causal relationships and future meta-analyses should aim to incorporate additional randomized data and perform subgroup analyses stratified by study design to improve inference strength and clinical applicability. Third, differences in adjunctive medication use (such as remifentanil and alfentanil) and dosing regimens across studies could have influenced the outcomes. Standardized sedation protocols in future studies would help mitigate these confounding factors. Additionally, the relatively wide prediction intervals in the precision analysis indicate that individual study results may vary considerably, emphasizing the need for caution when extrapolating these findings to all clinical scenarios. Another limitation relates to the variability and incomplete reporting of patient comorbidities across the included studies. Although several studies provided baseline data on hypertension, diabetes, cardiovascular or respiratory conditions, others either excluded patients with significant comorbidities or did not report them in detail. This heterogeneity in health status and the lack of standardized comorbidity reporting may confound the observed safety outcomes, particularly regarding hemodynamic events such as arrhythmia and hypotension. The predominance of relatively healthy patients (ASA I-II) in most cohorts may also limit the generalizability of the findings to higher-risk populations, such as those with unstable cardiovascular disease, chronic respiratory conditions or complex ICU cases. Furthermore, the present study was not preregistered on PROSPERO or a similar platform, which limits external verification of the protocol and introduces a potential risk of post hoc modifications to the inclusion criteria or analytical plan. Although the PRISMA guidelines were followed and the methods were predefined prior to data extraction and analysis, future meta-analyses should incorporate protocol preregistration to enhance transparency and reproducibility. Finally, while the search remained limited to English-language publications, the absence of additional studies in broader databases suggests that the risk of significant publication or language bias is low. Nevertheless, future studies may benefit from a fully multilingual and gray literature-inclusive strategy to further minimize this risk.
In conclusion, the present meta-analysis provides evidence that remimazolam is an effective and safe sedative with distinct advantages over dexmedetomidine in terms of rapid onset, shorter recovery times and improved hemodynamic stability. These properties make remimazolam particularly well-suited for outpatient procedures and high-turnover clinical settings. Conversely, dexmedetomidine retains its value in scenarios where cooperative sedation and preservation of airway reflexes are paramount, despite its slower recovery profile and higher risk of arrhythmia and hypotension. Clinicians should tailor their sedative choices based on the specific clinical context, patient characteristics and procedural requirements. The favorable profile of remimazolam, as demonstrated by the pooled data analysis and supported by recent literature, suggests that it may become the preferred agent in settings that demand rapid patient recovery and minimal hemodynamic disruption. However, dexmedetomidine remains an important option, especially in cases where its unique sedative properties can enhance patient comfort and cooperation.