The efficacy and safety of remimazolam versus propofol for endoscopy in Chinese patients: A meta-analysis of randomized controlled trials with trial sequential analysis

doi:10.21203/rs.3.rs-1867021/v1

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The efficacy and safety of remimazolam versus propofol for endoscopy in Chinese patients: A meta-analysis of randomized controlled trials with trial sequential analysis

https://doi.org/10.21203/rs.3.rs-1867021/v1

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Background

Several trials have been designed to assess the efficacy and safety of remimazolam for endoscopy in Chinese patients. However, the results were not powerful with the small number of patients. Therefore, we performed this meta-analysis to investigate the efficacy and safety of remimazolam compared with propofol for endoscopy.

Materials and Methods

We searched PubMed, EMBASE, the Cochrane Library, China Wan Fang, CNKI, and ClinicalTrials.gov (up to 6 November 2021). Eligible randomized controlled trials (RCT) comparing I.V. propofol versus remimazolam for endoscopy were included. The primary outcome was sedation success rate. The trial sequential analysis (TSA) and GRADE assessment were performed to evaluate the level of evidence.

Results

Nine RCTs with 1321 patients were included. Although the success rate in the remimazolam group (97.6%) was lower than that in the propofol group (98.9%), the difference was not statistically significant (RR 0.98, 95% Confidence Interval (CI) 0.97 to 1.00; I2 = 16%, P = 0.09; high-quality). Moreover, I.V. remimazolam led to a significant reduction in the incidence of injection pain (RR 0.03, 95% CI 0.01 to 0.08; I2 = 0%; P < 0.001; high-quality), intraoperative hypotension (RR 0.37, 95% CI 0.23 to 0.60; I2 = 78%; P < 0.001; low-quality), and respiratory depression (RR 0.17, 95% CI 0.10 to 0.28; I2 = 0%; P < 0.001; high-quality). TSA showed that the cumulative Z curve crossed the monitoring boundary for all outcomes.

Conclusion

There is high-quality evidence to support that compared with propofol for Chinese patients undergoing endoscopy, remimazolam has similar high sedation success rates, with less injection pain and respiratory depression; there is low-quality evidence to support the benefit of low incidence of hypotension of remimazolam.

remimazolam

propofol

endoscopy

meta-analysis

Commonly used drugs in procedural sedation for endoscopy include midazolam and propofol. [1, 2] In China, the number of patients requiring endoscopy has increased in recent years and ranked first around the world. [3, 4] Although propofol is popular with a fast onset of action and short duration, [5, 6] some challenges are faced when used in procedural sedation, including injection pain, [7] respiratory depression, [8, 9] increasing the risk of intraoperative hypotension and even causing cardiac arrest. [10] Therefore, similar sedatives with fewer adverse reactions were much anticipated.

Remimazolam, an intravenously administered benzodiazepine sedative, produces sedative effects by binding to the benzodiazepine binding site on γ-aminobutyric acid (GABA) receptors in the brain and has organ-independent metabolic effects. [11, 12] With the pharmacologic effect of a fast onset, rapid recovery, mild effects on liver and kidney function, fewer cardiovascular side effects, and quick reversal by flumazenil, remimazolam was considered an ideal sedative in theory. [13–15]

Several studies have focused on remimazolam for endoscopy in Chinese patients. However, the results were not powerful due to the small number of patients, and no meta-analysis focused on remimazolam compared with propofol for endoscopy. Therefore, we performed this meta-analysis of randomized controlled trials (RCTs) to investigate the efficacy and safety of remimazolam compared with propofol for endoscopy. Meanwhile, the trial sequential analysis (TSA) and GRADE assessment were performed to evaluate the level of evidence.

2.1 Registers and Protocols

We have registered this review on PROSPERO (CRD42021288896) and described the protocol in detail. This review was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 2020. [16] and in accordance with the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines. [17]

2.2. Search strategy

Two researchers (LXX, HYR) searched PubMed, EMBASE, the Cochrane Library, China Wan Fang, CNKI, and ClinicalTrials.gov from inception to 6 November 2021 without language restriction. The search terms were based on a combination of "remimazolam" or "CNS 7056" with "propofol", "sedation", and "randomized controlled trial". The search strategies for all databases and websites are listed in Appendix 1. Moreover, the reference lists of the included studies were screened to identify more eligible studies.

2.3 Selection criteria

Two researchers (LXX, CP) independently performed the literature screening. First, duplicate articles were identified and removed using Endnote X9 software. Then, by scanning the title and abstract and then reading the full text, ineligible studies were excluded. The inclusion criteria were as follows: (1) RCTs; (2) Chinese patients undergoing hysteroscopy, bronchoscopy, gastrointestinal endoscopy, etc.; (3) age ≥ 18 years old; (4) American Society of Anesthesiologists (ASA) classification I-III; (5) patients in the experimental group treated intravenously with remimazolam and in the control group treated with propofol. The exclusion criteria were as follows: (1) studies focused on patients suffering hepatic impairment; and (2) studies for which the full text was unavailable. Disagreements in study selection were discussed to reach consensus.

2.4 Data collection

The researcher (LXX) designed a custom Excel spreadsheet containing the first author name, publication year, number of patients, type of surgery, detailed methods of drug administration, and outcome parameters. Two researchers (HYR, CP) independently performed data extraction according to the custom Excel spreadsheet. Discrepancies in data extraction were resolved by discussion to reach consensus.

2.5 Outcomes

The primary outcome was the sedation success rate, which was defined as follows [18]: (1) completing the endoscopy; (2) no requirement for rescue therapy; and (3) a maximum of 5 supplementary doses within 15 minutes of the initial dose. The secondary outcomes included injection pain, intraoperative hypotension, and respiratory depression.

2.6 Risk of bias within studies

Two researchers (HYR, CP) assessed the risk of bias among studies according to the Cochrane Handbook for Systematic Reviews of Interventions [19] on the following domains: randomization sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data reporting, selective reporting, and other bias. We classified the bias of each domain into low risk, unclear risk, and high risk.

2.7 Statistical methods

The median and interquartile range data were converted into the mean and standard deviation according to Hozo’s formula. [20] For zero events, we added 0.5 to zero in both groups for calculation. [21]

We reported risk ratios (RRs) with 95% Confidence Interval (CI) for dichotomous data using the Mantel-Haenszel method. Heterogeneity was quantified by the I2 statistic. The fixed-effect model was applied to calculate the pooled effect size when I2 < 40%; otherwise, the random-effect model would be used and subgroup analysis by surgery types would be performed to explore possible causes of heterogeneity. All tests were two-tailed, and P < 0.05 was considered to be statistically significant. Review Manager 5.4.1 software was used for data analysis.

Moreover, publication bias was assessed by Egger's funnel plot; sensitivity analysis was performed by omitting one study in turn. Publication bias and sensitivity analyses were performed by STATA15.1 software. We also performed TSA to evaluate the power of the conclusions with TSA software. The quality level of each outcome was evaluated with the guidelines of the Recommendations Assessment, Development, and Evaluation (GRADE) system with GRADEpro version 3.6 software.

3.1. Eligible studies and the characteristics

We identified 149 records, and 9 RCTs [18, 22–29] with 1321 patients (673 in the remimazolam group and 648 in the propofol group) proved eligible. (Fig. 1) The types of surgery were gastroscopy (n = 2), colonoscopy (n = 1), hysteroscopy (n = 2), fiberoptic bronchoscopy (n = 1), and gastroenteroscopy (n = 1). Two studies [23, 27] assessed two dosage groups of remimazolam, and we only selected the one similar to other trials for analysis to reduce heterogeneity (Guo’s: I.V. 0.3 mg/kg for induction, then I.V. 1/4 of initial dose per time for maintenance; Zhang’s: I.V. 0.25 mg/kg for induction and then infused at a rate of 0.6 mg/kg/h). Moreover, patients in all studies were treated intravenously with analgesics before induction, including fentanyl (n = 2), remifentanil (n = 3), sufentanil (n = 2), alfentanil (n = 1), and butorphanol (n = 1). The characteristics of the included studies are summarized in Table 1.

Table 1

The characteristics of included randomized controlled trials
Study	No. of patients	Participants	Remimazolam administration	Propofol administration	Adjuvant drugs	Main Outcomes
Chen SH 2020 ^[18]	Group R = 196 Group P = 192	(1) undergoing colonoscopy; (2) aged 18–65 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. 5.0 mg and titrated with 2.5 mg per time for induction, then I.V. 2.5 mg per time for maintenance	I.V. 1.5 mg/kg for induction, then I.V. 0.5 mg/kg per time for maintenance	I.V. fentanyl before induction	Sedation success rate, injection pain, intraoperative hypotension, respiratory depression
Chen SH 2021 ^[22]	Group R = 188 Group P = 189	(1) undergoing upper gastrointestinal endoscopy (2) aged 18–60 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. 5.0 mg for induction, then I.V. 2.5 mg per time for maintenance	I.V. 1.5 mg/kg for induction, then I.V. 0.5 mg/kg per time for maintenance	Oral lidocaine and I.V. fentanyl before induction	Sedation success rate, injection pain, intraoperative hypotension, respiratory depression
Guo M 2021 ^[23]	Group R1 = 48 Group R2 = 33 Group P = 43	(1) undergoing gastroscopy (2) aged 18–64 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. 0.3 mg/kg (R1) or 12mg (R2) for induction, then I.V. 1/4 of initial dose (R1), or 2.5mg (R2) per time for maintenance	I.V. 1.5 mg/kg, and for induction, then I.V. 1/4 of initial dose per time for maintenance	Oral lidocaine and I.V. remifentanil before induction	Sedation success rate, injection pain, intraoperative hypotension, respiratory depression
Li WY 2021 ^[24]	Group R = 40 Group P = 40	(1) undergoing gastroscopy; (2) aged 65–75 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. slowly until adequate sedation for induction, then I.V. 1 mg/kg/h for maintenance	I.V. slowly until adequate sedation for induction, then I.V. 6 mg/kg/h for maintenance	I.V. remifentanil before induction	Sedation success rate, injection pain, intraoperative hypotension, respiratory depression
Qu MC 2021 ^[25]	Group R = 50 Group P = 50	(1) undergoing fiberoptic bronchoscopy; (2) aged 18–64 years old; (3) ASA I-III; (4) BMI 18.5–28.0 kg/m²	I.V. 0.2 mg/kg for induction, then I.V. 1 mg/kg/h for maintenance	I.V. 1.5-2.0 mg/kg for induction, then I.V. 6 mg/kg/h for maintenance	I.V. alfentanil before induction, mivacurium for muscular relaxation	Intraoperative hypotension
Zhang X 2021 ^[26]	Group R = 41 Group P = 41	(1) undergoing hysteroscopy; (2) aged 18–65 years old; (3) ASA I-II; (4) BMI 19–30 kg/m²	I.V. 0.2 mg/kg for induction, then I.V. 1 mg/kg/h for maintenance	I.V. 1.5-2.0 mg/kg for induction, then I.V. 3 mg/kg/h for maintenance	I.V. remifentanil before induction	Injection pain, Intraoperative hypotension
Zhang S 2021 ^[27]	Group R1 = 30 Group R2 = 30 Group P = 30	(1) undergoing hysteroscopy; (2) aged 18–55 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. 0.25 mg/kg for induction, then I.V. 0.48 mg/kg/h (R1), or 0.6 mg/kg/h (R2) for maintenance	I.V. 2.0 mg/kg, and for induction, then I.V. 5 mg/kg/h for maintenance	I.V. sufentanil before induction	Sedation success rate, injection pain, respiratory depression
Zhao YY 2021 ^[28]	Group R = 35 Group P = 35	(1) undergoing gastroenteroscopy; (2) aged 30–65 years old; (3) ASA I-II; (4) BMI 18–30 kg/m²	I.V. 0.2 mg/kg for induction, then I.V. 0.05 mg/kg per time for maintenance	I.V. 1.5-2.0 mg/kg for induction, then I.V. 0.5 mg per time for maintenance	I.V. butorphanol before induction	Sedation success rate, injection pain, intraoperative hypotension, respiratory depression
Zhao J 2021 ^[29]	Group R = 30 Group P = 30	(1) undergoing gastroscopy (2) aged 18–65 years old; (3) ASA I-II; (4) BMI 18–28 kg/m²	I.V. 0.2 mg/kg for induction, then I.V. 2.5 mg per time for maintenance	I.V. 1.5-2.0 mg/kg for induction, then I.V. 0.5 mg per time for maintenance	I.V. sufentanil before induction	Sedation success rate, respiratory depression

Note: Group R: Patients injected intravenously with remimazolam; Group P: Patients injected intravenously with propofol; ASA: American Society of Anesthesiologists; BMI: Body Mass Index.

3.2 Primary outcome

Sedation success rate

Seven RCTs [18, 22–24, 27–29] (n = 1122) reported the outcome of the sedation success rate, and the heterogeneity among studies was low (I2 = 16%). Although the success rate in the remimazolam group (552/565; 97.6%) was lower than that in the propofol group (551/557; 98.9%), the difference was not statistically significant (RR 0.98, 95% CI 0.97 to 1.00; P = 0.09). (Fig. 2)

3.3 Secondary outcomes

3.3.1 Injection pain

Seven RCTs [18, 22–24, 26–28] (n = 1144) were included, and the results demonstrated that I.V. remimazolam led to a significant reduction in the incidence of injection pain (RR 0.03, 95% CI 0.01 to 0.08; I2 = 0%; P < 0.001). (Fig. 3)

3.3.2 Intraoperative hypotension

Seven RCTs [18, 22–26, 28] (n = 1184) reported that a significant reduction was detected in patients who received remimazolam (RR 0.37, 95% CI 0.23 to 0.60; I2 = 78%; P < 0.001). (Fig. 3)

3.3.3 Respiratory depression

Seven RCTs [18, 22–24, 26–28] (n = 1144) were included, and we found that compared with 16.9% (96/568) in the propofol group, the incidence of respiratory depression was 2.7% (16/576) in the remimazolam group (RR 0.17, 95% CI 0.10 to 0.28; I2 = 0%; P < 0.001). (Fig. 3)

3.4 Additional analysis – assessment of the evidence

Most included studies had a low risk of bias in all domains. (Appendix 2) For all outcomes, the publication bias analysis detected little bias because of the basically symmetric scatter point distributions in Egger's funnel plots, and the P values were all more than 0.05. (Fig. 4) In addition, the sensitivity analysis showed that the pooled analysis results were similar after eliminating one single study in turn. (Fig. 5)

For all outcomes, the cumulative Z curve crossed both the conventional boundary and TSA monitoring boundary. Moreover, the sample size of the sedation success rate and injection pain were over the required information size. (Fig. 6)

The GRADE assessment showed that for sedation success rate, injection pain, and respiratory depression, the quality of evidence was high, while for intraoperative hypotension, the quality evidence was low.

The meta-analysis showed high-quality evidence to support the benefit of remimazolam compared with propofol on a high sedation success rate, reducing injection pain and respiratory depression, and low-quality evidence on decreasing the incidence of intraoperative hypotension. TSA confirmed that the conclusions were reliable. This was the first meta-analysis to compare remimazolam with propofol in Chinese patients undergoing endoscopy.

The sedation success rate was critical to assess the sedation efficacy of remimazolam, of which Chen and his colleagues concluded that a reduction of less than 8% was considered not inferior to propofol. [23] In fact, the pooled result was as high as 97.6%, indicating that remimazolam was efficacious in patients requiring endoscopies. A possible explanation might be that remimazolam produces a similar high affinity to the γ-aminobutyric acid (GABA) receptors in the brain as propofol. [19] In our study, the criterion of successful sedation was composite of completing the endoscopy, no requirement for rescue therapy, and a maximum of 5 supplementary doses within 15 minutes of the initial dose, which was comprehensive and consistent with the recommended definition. However, dosing regimens were different across the trials, which may account for the heterogeneity among studies. The induction dosage varied from 5.0 mg, or 0.2 to 0.3 mg/kg, and the maintenance dosage varied from 1/4 of the initial dose or 2.5 mg per time, or 0.6 to 1 mg/kg/h. The optimal dosage has not been determined. While in the USA and the EU, the dosage of remimazolam for procedural sedation was recommended to be individualised and titrated to the desired clinical response. [30, 31] Many trials have found that remimazolam could present different sedation levels by using different dosages. [22, 32, 33], which may significantly influence the sedation success rate. However, we did not compare the sedation levels due to missing relevant data in the original studies.

One of the most commonly reported adverse reactions of propofol was injection pain, which was mainly caused by lipid emulsions. The incidence of injection pain after I.V. propofol was up to 64%,[34] and the incidence of moderate to severe pain was as high as 38.1%. [35] Many studies have explored methods to solve this problem, such as pretreatment with other drugs (including lidocaine, etc.) [36] or dilution with saline. [37] The pooled results of our meta-analysis indicated a low incidence of injection pain of I.V. remimazolam (0.3%). Moreover, other previous studies found that remimazolam administration was not associated with clinically meaningful injection pain in colonoscopy trials 1 and 2, [38, 39] which would greatly improve the comfort level of patients.

Hypotension is a worrisome problem when propofol is used for procedural sedation. Studies have shown that propofol can cause vasodilation in a dose-dependent manner, resulting in a decrease in blood pressure. [40] Similarly, one of the adverse reactions to remimazolam was hypotension. [41] In our meta-analysis, we found that the incidence of intraoperative hypotension in remimazolam recipients was significantly lower. However, the heterogeneity across studies was high, which made the quality of the evidence low. The reason for the high heterogeneity may be the different blood pressure management strategies during procedures. In most trials, the patient's vital signs were often checked to maintain the target blood pressure level. [42] Although remimazolam does not present significant hypotension, vital signs of patients should still be continuously monitored during the whole sedation period.

Propofol can also bring respiratory depression to patients. Compared with other sedative drugs, the severity and frequency of respiratory depression caused by propofol were significantly higher. [43] Propofol may even lead to severe hypoxia, especially when administered rapidly into the body to inhibit sudden vigorous movement or cough reactions, which often require emergency endotracheal intubation. The pooled results showed that the incidence of respiratory depression in the remimazolam-treated patients was far less than that in the propofol group (2.7% vs 16.9%).

The ideal properties of sedatives for procedural sedation include quick recovery and minimal residual sedation. [44] Unlike propofol, sedation with remimazolam can be reversed with flumazenil. [45] One study suggested that the time of remimazolam to full recovery from anesthesia was only 1.64 minutes after I.V. flumazenil, which was much less than that of propofol [25] and met the requirement of good control for procedural sedation. However, reversal of sedation with flumazenil was not required routinely. [41] This characteristic indeed increased the potential of remimazolam to be a safe sedative agent for endoscopy.

Our study also has some limitations. First, in the initial protocol, we planned to perform the subgroup analysis according to surgery types. However, there are few studies other than gastroscopy; therefore, subgroup analysis could not be performed. Second, the dosage varied across studies. However, there is no consensus on the recommended dosage of remimazolam for endoscopy, and several clinical trials have been designed to explore the optimal dosage. Third, this study only focuses on Chinese patients, and further studies should be performed to investigate the efficacy and safety of remimazolam in patients from other countries.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no conflict of interest.

Funding

None

Authors' contributions

Xiaoxiao Li, Yurong Han, Pan Chang collected the data and drafted the manuscript. Xiaoxiao Li and Yurong Han performed statistical analyses. Wensheng Zhang contributed to study conception. All the authors read the manuscript and approved the final submission.

Acknowledgements

We are deeply grateful to Professor Hong Xie (West China Hospital, Sichuan University) and her team for their guidance on this study.

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No competing interests reported.

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The efficacy and safety of remimazolam versus propofol for endoscopy in Chinese patients: A meta-analysis of randomized controlled trials with trial sequential analysis

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Abstract

Background

Materials and Methods

Results

Conclusion

Figures

1. Introduction

2. Methods

2.1 Registers and Protocols

2.2. Search strategy

2.3 Selection criteria

2.4 Data collection

2.5 Outcomes

2.6 Risk of bias within studies

2.7 Statistical methods

3. Results

3.1. Eligible studies and the characteristics

3.2 Primary outcome

3.3 Secondary outcomes

3.3.1 Injection pain

3.3.2 Intraoperative hypotension

3.3.3 Respiratory depression

3.4 Additional analysis – assessment of the evidence

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

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