What is already known about this subject?

Propofol has been the gold standard for anesthesia induction and maintenance due to its rapid onset and favorable pharmacokinetic properties.

What this study adds

  • This systematic review and meta-analysis comprehensively assessed the safety and efficacy of ciprofol compared to propofol for anesthesia induction and maintenance in adult patients undergoing surgical procedures.

  • Propofol and Ciprofol exhibited similar efficacy and safety profiles. Nevertheless, Propofol achieved general anesthesia induction more rapidly.

  • With Ciprofol there was a reduced incidence of pain at the injection site.

Introduction

General anesthesia is a cornerstone of modern medical practice, designed to achieve the vital goals of amnesia, unconsciousness (hypnosis), and immobilization during surgical procedures. These objectives are met through the use of general anesthetics, which exhibit the remarkable ability to reversibly induce these therapeutic effects [1, 2]. Among the diverse classes of anesthetic agents, both volatile and intravenous anesthetics play pivotal roles in ensuring reliable and effective anesthesia.

Propofol, a potent γ-aminobutyric acid (GABA) receptor agonist, stands as a testament to the success of intravenous anesthetics over the past three decades [3, 4]. Its favorable pharmacokinetic (PK) and pharmacodynamic (PD) properties have propelled it to the forefront of anesthesia practice. Known for its rapid and consistent induction, minimal excitation phenomena, short context-sensitive time, rapid terminal half-life, and low incidence of postoperative nausea and vomiting, propofol has become a cornerstone of anesthesia induction and maintenance [3]. Nevertheless, even with its exceptional attributes, propofol is not without limitations, which include injection pain, hypotension, respiratory depression leading to apnea, and the potential for the development of intensive care unit (ICU) syndrome [5,6,7]. It continues to serve as the gold standard against which newer agents are benchmarked. One of these agents is ciprofol (HSK3486).

In recent years, the field of anesthesiology has experienced a surge in the exploration of novel agents for both induction and maintenance of general anesthesia. Among these, ciprofol has emerged as a promising contender, boasting claims of enhanced safety and efficacy when compared to traditional agents. First reported in 2017, ciprofol represents a structural analog of propofol, incorporating an R-chiral center and a cyclopropyl group that imparts improved pharmacological and physicochemical properties. These enhancements render ciprofol more potent than propofol and, notably, less painful upon injection [8, 9]. A phase 1 trial demonstrated the safety of ciprofol at doses ranging from 0.15 to 0.90 mg/kg, with most adverse events being of mild to moderate intensity [10]. Given its increased potency relative to propofol, ciprofol necessitates a lower drug volume for achieving anesthesia, which not only reduces the required solvent volume but may also mitigate side effects, particularly those associated with injection site pain.

The primary objective of this comprehensive meta-analysis is to systematically review and synthesize the existing body of literature pertaining to the safety and efficacy of ciprofol compared to propofol in the context of induction and maintenance of general anesthesia in adult patients undergoing surgical procedures. Through the amalgamation of data from multiple studies, we aspire to offer an extensive evaluation of the relative merits of these two agents. By doing so, we aim to provide valuable insights for both researchers and clinicians in the field of anesthesiology, ultimately contributing to the enhancement of anesthesia practices and patient care.

Methods

Data sources and search strategy

Cochrane and Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines were implemented while preparing this meta-analysis [11]. A comprehensive electronic search performed using Medline, Google Scholar, Embase, and Cochrane Central was conducted to identify relevant randomized controlled trials (RCTs). The search strategy was composed of the following keywords and their MeSH terms “Propofol” OR “2,6-Diisopropylphenol” OR “2,6 Diisopropylphenol” OR “2,6-Bis(1-methyl ethyl)phenol” OR “Disoprofol” OR “Diprivan” OR “Disoprivan” OR “Fresofol” OR “ICI-35,868” OR “ICI 35,868” OR “ICI35,868” OR “ICI-35868” OR “ICI 35868” OR “ICI35868” OR “Ivofol” OR “Propofol Fresenius” OR “Propofol MCT” OR “Propofol Rovi” OR “Propofol-Lipuro” OR “Recofol” OR “Aquafol” OR “Propofol Abbott” AND “ciprofol OR HSK3486” AND “anesthesia OR sedation”. The PRISMA diagram of the studies used can be found in the PRISMA flow chart in Fig. 1. Information about the search strategy is given in Supplementary Table S1.

Fig. 1
figure 1

Prisma flow chart

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Eligibility criteria

The study selection process was conducted in accordance with predetermined eligibility criteria and specific outcome measures. Only double-arm, randomized controlled trials (RCTs) were included in our analysis. The target demographic comprised individuals aged eighteen or over. The intervention involved the utilization of ciprofol, which was compared with the administration of propofol. The primary outcome assessed was the induction and maintenance of general anesthesia. Some studies were omitted based on the exclusion criteria. Studies in which ciprofol was utilized for screening and diagnostic procedures were not included. Articles published in languages other than English or any other specified language were excluded from consideration. Furthermore, all types of reviews (systematic and non-systematic), case reports, case series, cross-sectional, editorials, commentaries, and animal studies were excluded to maintain the integrity and focus of our study. Details of the studies that were selected are given in Supplementary Table S2. This rigorous selection process aimed to ensure the quality and relevance of the studies included in our systematic review and meta-analysis.

Data extraction and quality assessment

Articles retrieved from the systematic search were exported to EndNote Reference Library software, and any duplicates found were discarded. The remaining articles were initially screened based on abstract and title, and then a review of the entire text was conducted to assess relevance. Screening of the articles was distributed amongst two reviewers, (M.H, H.M), and any inconsistencies were resolved by discussion till consensus or by the third reviewer (A.R.S.S). The following baseline characteristics were extracted onto an online Microsoft Excel Spreadsheet: study characteristics (first author’s name along with publication year, study design, number of patients) population characteristics (patient age in years, male gender percentage, body mass index (BMI) (kg/m2), American Society of Anesthesiologists (ASA) score, mean operation time, subgroups of dosage of drug). The baseline characteristics are given in Supplementary Table S3.

Primary outcomes included efficacy of ciprofol (satisfaction evaluation for anesthesiologists, time to full alertness, time to successful anesthesia induction, time to loss of eyelash reflex, success rate of anesthesia, time required for patients to leave the post-anesthesia care unit - PACU, time to respiratory recovery) on anesthesia induction and maintenance in comparison to propofol.

Secondary outcomes included the safety profile of ciprofol (total adverse events, tachycardia, rash, prolonged QT interval, pain on injection (induction), hypoxia, hypotension, hypertension (induction), Common Terminology Criteria for Adverse Events (CTCAE) severity scale (grade 1) (induction), CTCAE severity scale (grade 2) (induction), bradycardia (induction), any treatment-emergent adverse event, number of patients who maintained BIS between 40 and 60 min at 0.4 mg/kg and elevated AST (induction and maintenance) at 0.4 mg/kg. This is shown in Supplementary Table S4.

The revised Cochrane Risk of Bias (RoB) tool was used independently by the two researchers (H.M, N.F.S) to examine the quality of the included RCTs [12]. Reports were analyzed for the generation of allocation sequence, randomization of participants to ciprofol (intervention group) or propofol (control group), selective reporting of outcomes, and missing data.

Statistical analysis

For the statistical analysis of the extracted data, we employed RevMan 5.4.1. In instances where raw data was available, we calculated risk ratios (RR) and mean difference (MD) along with their corresponding 95% confidence intervals (CIs). These calculations were performed using a random-effects model, allowing us to create forest plots that visually represented the dichotomous and continuous outcomes respectively.

Heterogeneity was measured using the Higgins I2 statistics and was reported as a percentage for every outcome. For an I2 value of less than 50%, low heterogeneity was indicated, moderate heterogeneity was considered when the I2 value was less than 75%, and high heterogeneity was observed with an I2 value greater than 75%. Outcomes, if reporting an I2 greater than 75%, were subjected to sensitivity analysis. Following the high heterogeneity leave one out sensitivity analysis was performed for only one outcome time to successful anesthesia induction.

In all statistical analyses, a p value of ≤ 0.05 was established as the threshold for statistical significance. This criterion was applied across the board to determine the significance of our findings.

Publication bias

To assess for publication bias, we generated funnel plots for all outcomes using the random effects model. Funnel plots for the primary outcomes are available in the supplementary material (Supplementary Figures S2–S8).

Results

Eligible studies

In adherence to predetermined eligibility criteria and specific outcome measures, our meta-analysis considered six double-arm, RCTs [13,14,15,16,22].

Interestingly, in this study, no statistically significant difference between both drugs for alertness were detected. However, these results are inconsistent with other existing literature on the subject. For instance, a recent systematic review [19] in the context of painless gastroenteroscopy found that propofol consistently leads to faster alertness compared to ciprofol. This inconsistency in results could be attributed to the fact that our study exclusively focused on invasive surgeries, which encompassed a diversity of surgical types. Propofol is well-known for its characteristics of rapid onset and swift recovery, which results from its pharmacokinetic property of fast elimination [3, 23]. Thus, it is an important option to induce and maintain anesthesia, particularly for short-duration procedures. The rapid elimination of propofol minimizes the risk of residual sedation, making it a valuable drug also for cesarean delivery [24]. Anesthesiologists value propofol for its ability to induce and reverse anesthesia swiftly, providing a significant advantage in various clinical scenarios. However, it's crucial to recognize that this advantage comes with the caveat of a relatively narrow therapeutic window and potential concentration-dependent effects on cardiovascular and respiratory systems, especially in elderly and frail patients [9]. These considerations underscore the importance of a nuanced approach when selecting anesthetic agents, taking into account the specific characteristics and vulnerabilities of the patient population.

Propofol's superior induction speed, consistent with previous research, highlights its status as the preferred choice for anesthesia induction in clinical practice [19]. The absence of a substantial difference in induction time between ciprofol at 0.4 mg/kg and propofol is an intriguing finding. It suggests that ciprofol can achieve induction times similar to propofol at 0.4 mg/kg [15]. Heterogeneity is observed in a study for several reasons [13]. Firstly, the researchers conducted a phase 3, multicenter, randomized, double-blind, comparative study, which introduced differences in study design, data collection, and interpretation compared to studies in the same analysis. Additionally, the study had a larger sample size with a higher percentage of male patients, potentially introducing gender-related variations in anesthesia induction times, due to differences in drug responses and pharmacokinetics. Hormonal fluctuations, such as those associated with the menstrual cycle in females, can impact drug metabolism and distribution. This can result in variations in anesthesia induction times between male and female patients [25]. Furthermore, variations in patient age, BMI, and ASA score distribution in that study could impact how individuals respond to anesthesia, leading to differences in induction times.

Contrary to the above-mentioned findings, our focus on the loss of eyelash reflex specifically revealed no divergences between the two agents. However, it is essential to acknowledge the presence of pronounced heterogeneity in the analysis of this parameter, which suggests substantial variability among the included studies in this meta-analysis. This heterogeneity, coupled with the limitation of limited data availability resulted in a trend not favoring either of the drugs, especially propofol.

This meta-analysis provides valuable insights, affirming that both ciprofol and propofol can effectively serve for anesthesia induction and maintenance, with no significant differences observed. This conclusion gains strength through the subgroup analysis, which demonstrates that even with different ciprofol dosages (0.4 mg/kg or 0.5 mg/kg), there are no significant differences in the success rate of anesthesia induction compared to propofol. This suggests that the choice of ciprofol dosage doesn't significantly affect induction success rates [26]. These findings hold practical implications for anesthesiologists, indicating that both ciprofol and propofol are valid choices for anesthesia induction and maintenance. Clinicians can make their choices based on patient-specific factors and individual preferences.

The observation of a faster exit from the PACU and improved recovery of respiratory functions with propofol aligns with its established characteristics of rapid onset and short duration of action. This can be attributed to propofol's favorable pharmacokinetic profile. However, the absence of statistical significance in these findings could be due to inherent variability in patient responses and the specific criteria used for assessment [27]. Nevertheless, these findings have significant clinical relevance, as quicker recovery and discharge from the PACU can enhance patient throughput and optimize resource utilization [28].

Pain at the injection site, a factor that can induce anxiety and discomfort among patients during intravenous infusion, is a critical consideration. Propofol has been known to cause pain at the injection site [29]. To mitigate this side effect, injection of local anesthetics such as lidocaine before intravenous propofol administration, as well as the use of a more diluted propofol, have been considered for pain reduction at the injection site [30]. In support of the current literature, this meta-analysis collectively shows that ciprofol is less likely to cause pain at the injection site. This can be explained by its hydrophobic nature, resulting in relatively lower plasma concentrations compared to propofol [31].

In this comprehensive meta-analysis comparing ciprofol and propofol for anesthesia, the safety profiles of these two drugs were assessed with a thorough evaluation of various adverse events. The findings indicate that, in general, there was no statistically significant difference observed between ciprofol and propofol in terms of overall adverse events. This suggests that both agents are generally well-tolerated and safe for use in anesthesia induction. Comparing our results to the existing literature, studies have reported varying safety profiles for both ciprofol and propofol. Some have highlighted the safety and effectiveness of ciprofol in anesthesia induction, with a lower incidence of adverse events [26]. In contrast, others have noted that propofol remains a standard and safe choice for anesthesia induction [32].

This study has some limitations. In order to increase the quality of the extracted data, we only included double-arm randomized control trials, limiting our dataset to six studies. Additionally, it exclusively focused on invasive surgeries, which encompassed a diversity of surgical types. Since some studies focused on induction of anesthesia while others studied both induction and maintenance of sedation through ciprofol, our choice of primary safety outcomes was limited. Though most studies affirm the safety of both drugs for clinical practice, it is worth noting that the existing literature on the comparison between these two drugs is relatively limited. Looking ahead, future research should delve into optimized ciprofol dosing strategies aimed at achieving the desired depth of anesthesia while minimizing side effects [33]. Exploring patient-centered outcomes and integrating advanced monitoring technologies could also provide deeper insights into the comparative strengths and weaknesses of these agents. Large-scale studies spanning diverse patient groups and clinical scenarios, including specific procedures like sedation for gastrointestinal endoscopy or other procedures, can shed light on the advantages concerning patient comfort and recovery [34]. Moreover, investigating long-term outcomes and cost-effectiveness can offer valuable guidance for clinical decision-making.

Conclusion

In conclusion, this systematic review and meta-analysis have highlighted the comparative effectiveness and safety of ciprofol and propofol in the context of general anesthesia. Propofol had a faster onset of anesthesia during the induction phase. Conversely, ciprofol resulted in a reduced incidence of pain at the injection site. Clinicians should consider these findings while tailoring their choice of anesthetic agents to individual patient characteristics and preferences.