Comparing the safety and efficacy of propofol, ciprofol, and remimazolam in general anesthesia

To the Editor: The concept of comfortable medical care has advanced significantly, focusing on minimizing psychological and physiological stress during medical procedures. Although propofol is a widely used anesthetic, it has notable limitations, including hypotension, respiratory depression, and injection pain.[1] In response, newer alternatives such as ciprofol and remimazolam have emerged, promisingly improved safety and efficacy. Ciprofol (HSK3486; Haisco Pharmaceutical Group, Chengdu, Sichuan, China), a domestically developed intravenous anesthetic, acts as a gamma-aminobutyric acid type A (GABAA) receptor agonist. It offers rapid onset, quick recovery, minimal injection pain, and reduced cardiovascular and respiratory complications compared with propofol.[2] Remimazolam, an ultrashort-acting benzodiazepine, also acts on GABA receptors and features rapid metabolism, minimal accumulation, and reversibility with flumazenil. Both agents aim to enhance safety and comfort during anesthesia.[3] Although ciprofol and remimazolam have been studied, direct comparisons between them are lacking. This study addresses that gap by evaluating the safety and efficacy of propofol, ciprofol, and remimazolam through a network meta-analysis to guide clinicians’ choices in anesthesia induction. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was formally registered at https://www.crd.york.ac.uk/PROSPERO (No. CRD42023415735). A comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Library was conducted up to July 7, 2024, with the search strategy detailed in Supplementary Table 1, https://links.lww.com/CM9/C649. Two reviewers independently screened abstracts and full texts to identify randomized controlled trials (RCTs) comparing ciprofol or remimazolam with propofol for anesthetic induction in adult patients (age ≥18 years) undergoing elective, nonemergency, noncardiothoracic, and nonbrain surgeries under general anesthesia with tracheal intubation. Exclusions included studies with regional analgesia (e.g., epidural or nerve block), no propofol control group, sedated surgical patients, incomplete outcomes, or non-full-length publications (e.g., letters, abstracts, reviews, case reports). The primary focus of the research was on safety parameters, assessed through treatment-emergent adverse events (TEAEs) such as injection pain, post-induction hypotension (systolic blood pressure <90 mmHg), bradycardia (as defined by individual studies), and postoperative nausea and vomiting (PONV) occurring within 24 h post-surgery. Secondary endpoints, representing efficacy parameters, included the success rate of general anesthesia induction (defined as induction without recall, no rescue sedation, and minimal supplemental drug use), time to loss of consciousness (LOC) from the first drug administration, anesthetic depth immediately after induction (measured using the bispectral index [BIS]), and time to full alertness (measured from drug discontinuation to full recovery). A Bayesian network meta-analysis with random-effects models was conducted to estimate odds ratios (ORs), mean differences (MDs), and 95% confidence intervals (CIs). The surface under the cumulative ranking curve (SUCRA) was calculated, with higher values (0–100%) indicating better treatment performance. Heterogeneity was evaluated using I2 tests, the risk of bias was assessed with the RoB 2 tool (Cochrane Methods, Cochrane, London, UK), and the certainty of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. Analyses were performed using R (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria) with the “gemtc” package in RStudio, and network plots were generated using Stata (version 14.0; StataCorp, College Station, TX, USA). Based on our inclusion criteria, we identified 28 RCTs involving 3528 patients. The study selection process is detailed in the flowchart [Supplementary Figure 1, https://links.lww.com/CM9/C649]. Participants’ mean ages ranged from 34 to 76 years, with sample sizes ranging from 46 to 375. Detailed study characteristics are provided in Supplementary Table 2, https://links.lww.com/CM9/C649. Of these, 21 studies compared remimazolam with propofol, whereas the remaining 7 studies compared ciprofol with propofol [Supplementary Figure 2, https://links.lww.com/CM9/C649]. The risk of bias for the included RCTs was assessed using the RoB 2 tool, with three studies identified as having a “high risk” due to deviations from intended interventions [Supplementary Figure 3, https://links.lww.com/CM9/C649]. The network meta-analysis showed that remimazolam had the lowest likelihood of TEAEs (odds ratio [OR] = 0.31, 95% confidence interval [CI]: 0.19–0.50) with moderate-certainty evidence. Compared with propofol, remimazolam also demonstrated the lowest odds of hypotension (OR = 0.31, 95% CI: 0.22–0.41), injection pain (OR = 0, 95% CI: 0–0.01), and bradycardia (OR = 0.30, 95% CI: 0.10–0.78), with no statistically significant differences in PONV occurence [Table 1]. Based on SUCRA rankings, remimazolam had an 82% probability of being associated with fewest TEAEs, showing superior hemodynamic stability and minimal injection pain. Ciprofol ranked second in safety (SUCRA 80%), with fewer adverse events than propofol and benefits such as reduced injection pain and fewer cardiovascular complications [Supplementary Figure 4, https://links.lww.com/CM9/C649]. Propofol, although effective, had the highest adverse event rates, particularly for injection pain and hypotension. Table 1 - Summary of the network meta-analysis and GRADE quality of evidence assessment for the primary outcomes of studies comparing safety and efficacy of propofol, ciprofol, and remimazolam in general anesthesia. Outcomes Participants in direct comparisons, (n of RCTs) Network OR (95% CI) Network certainty of evidence (GRADE) Treatment-emergent adverse events Ciprofol vs. propofol 3413 (7) 0.46 (0.22, 0.96) Moderate* Remimazolam vs. propofol 7413 (21) 0.31 (0.19, 0.50) Moderate* Remimazolam vs. ciprofol – 0.67 (0.28, 1.61) Very low*,†,‡ Hypotension Ciprofol vs. propofol 948 (7) 0.63 (0.40, 0.95) Moderate§ Remimazolam vs. propofol 1707 (13) 0.31 (0.22, 0.41) Moderate§ Remimazolam vs. ciprofol – 0.48 (0.28, 0.82) Low†,§ Injection pain Ciprofol vs. propofol 780 (5) 0.10 (0, 2.60) Low*,‡ Remimazolam vs. propofol 1296 (9) 0 (0, 0.01) Moderate* Remimazolam vs. ciprofol – 0 (0, 0.21) Low*,† Bradycardia Ciprofol vs. propofol 697 (6) 0.95 (0.33, 2.91) Low‡,§ Remimazolam vs. propofol 1143 (10) 0.30 (0.10, 0.78) Moderate§ Remimazolam vs. ciprofol – 0.32 (0.06, 1.28) Very low†,‡,§ Postoperative nausea and vomiting Ciprofol vs. propofol 532 (3) 1.73 (0.31, 12.84) Low‡,§ Remimazolam vs. propofol 1728 (13) 0.95 (0.55, 1.53) Low‡,§ Remimazolam vs. ciprofol – 0.54 (0.07, 3.06) Very low†,‡,§ *Downgraded by 1 level due to concerns about inconsistency (such as heterogeneity of estimates of effects across trials). †Downgraded by 1 level due to significant concerns about indirectness in effects across studies ‡Downgraded by 1 level due to significant concerns about imprecision; the confidence interval suggests the possibility of a null effect or benefit for either intervention. §Downgraded by 1 level due to significant concerns about methodological considerations, including a lack of blinding and, in some cases, other sources of bias. CI: Confidence interval; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; OR: Odds ratio; RCT: Randomized controlled trial. –: Not available. Regarding secondary outcomes, remimazolam showed a slightly longer time to LOC (MD = 24.73 s, 95% CI: 11.22–38.28 s) compared with propofol, with low-quality evidence [Supplementary Table 3, https://links.lww.com/CM9/C649]. No statistically significant differences were noted in the success rate of general anesthesia induction, anesthetic depth post-induction, or time to full alertness among the three drugs. Propofol had the highest probability of success in anesthesia induction (SUCRA 62%), the shortest LOC time (SUCRA 68%), and the deepest anesthesia upon induction (SUCRA 73%) [Supplementary Figure 5, https://links.lww.com/CM9/C649]. Subgroup and sensitivity analyses confirmed the robustness of these findings [Supplementary Table 4, https://links.lww.com/CM9/C649]. For TEAEs, remimazolam’s risk reduction remained consistent across subgroups. The comparison-adjusted funnel plot and Egger’s test showed no significant publication bias (P = 0.250) [Supplementary Figure 6, https://links.lww.com/CM9/C649]. Heterogeneity among individual studies was minimal for all outcomes. Remimazolam’s hemodynamic stability and reversibility with flumazenil provide unique advantages, especially for patients with cardiovascular risks. Its minimal injection pain and rapid metabolism enhance patient comfort.[4] Ciprofol, with its structural modifications and higher binding affinity to GABAA receptors, achieves effective sedation with a wide safety margin.[5] Although propofol remains the standard choice due to its established use and rapid action, the findings highlight the clinical potential of remimazolam and ciprofol as safer alternatives. Limitations of this study include variability in drug dosages and administration techniques, as well as heterogeneity in study populations and interventions. Factors such as patient age, comorbidities, and American Society of Anesthesiologists (ASA) classification, along with differences in surgical procedures, may influence safety and efficacy outcomes, thereby constraining the generalizability of the findings. The absence of direct comparisons between ciprofol and remimazolam limits the ability to evaluate their relative benefits comprehensively. Furthermore, publication and selection biases represent significant concerns, especially considering the small sample sizes in certain studies and the predominance of research originating from China. This geographical concentration may introduce regional biases and limit the wider applicability of the results. To confirm these findings and evaluate long-term effects, high-quality, multicenter RCTs involving diverse populations are essential. In conclusion, remimazolam was associated with a more favorable safety profile, exhibiting fewer reported adverse events compared with both ciprofol and propofol. Ciprofol, on the other hand, was superior to propofol in minimizing injection pain and cardiovascular adverse effects. These insights offer valuable guidance for clinicians in selecting the most suitable anesthetic agents to enhance patient safety and improve perioperative outcomes. Funding This study was supported by grants from the Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2023ZD0501801), and 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (No. ZYJC21008). Conflicts of interest None.