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\begin{document}

\title{Efficacy and Safety of Ciprofol versus Propofol for induction and
maintenance of general anesthesia in patients undergoing surgery. A
systematic Review and Meta-Analysis of Randomized Controlled Trials.}



\author[1]{Muhammad Hudaib}%
\author[2]{Hurais Malik}%
\author[3]{Syeda Javeria  Zakir }%
\author[3]{Samra Rabbani}%
\author[4]{Dhanushan Gnanendran }%
\author[3]{Abdul Rehman Shah Syed}%
\author[3]{Javeria  Khan}%
\author[3]{Noor Fatima Suri}%
\author[3]{Arham  Iqbal}%
\author[3]{Nowal Hussain}%
\author[5]{Muhammad Abdullah}%
\author[6]{Satesh Kumar}%
\author[3]{Mahima Khatri}%
\author[7]{Giustino Varrassi}%
\affil[1]{Fazaia Ruth Pfau Medical College }%
\affil[2]{Fazaia Ruth Pfau Medical College}%
\affil[3]{Dow University of Health Sciences}%
\affil[4]{York and Scarborough Teaching Hospitals NHS Foundation Trust}%
\affil[5]{CMH Lahore Medical College and Institute of Dentistry}%
\affil[6]{Shaheed Mohtarma Benazir Bhutto Medical College}%
\affil[7]{Paolo Procacci Foundation}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Background Propofol has been the gold standard for anesthesia induction
and maintenance due to its rapid onset and favourable pharmacokinetic
properties. However, the search for alternative agents with improved
safety and efficacy has led to the emergence of ciprofol (HSK3486), a
structural analog of propofol. This systematic review and meta-analysis
aims to comprehensively assess the safety and efficacy of ciprofol
compared to propofol for anaesthesia induction and maintenance in adult
patients undergoing surgical procedures. Methods This study included
only double-arm RCTs in which participants were aged eighteen or older
undergoing surgery. For the statistical analysis of the extracted data,
we employed RevMan 5.4.1. Results Ciprofol demonstrated a promising
trend of higher anesthesiologists' satisfaction during the induction
phase (MD: 0.14, 95\%, CI: -0.28 to 0.56, p = 0.51), whereas Propofol
was favored during maintenance. Propofol also exhibited advantages with
a shorter time to successful anesthesia induction (MD: 0.08 minutes,
95\% CI: 0.00 to 0.15, p = 0.04). and quicker attainment of full
alertness (MD: 0.11 minutes, 95\% CI: -1.29 to 1.52, p = 0.87),
suggesting its efficiency in clinical practice. Importantly, there were
no significant disparities in the success rate of anesthesia. Conclusion
Both ciprofol and propofol demonstrate comparable efficacy and safety
for anesthesia induction and maintenance in adult patients undergoing
surgery. While propofol provides a faster onset of induction, ciprofol
exhibits advantages in terms of pain management. Clinicians should
consider these findings when selecting anesthetic agents, tailoring
choices to individual patient needs and clinical scenarios.%
\end{abstract}%



\sloppy


\textbf{Title} : Efficacy and Safety of Ciprofol versus Propofol for
induction and maintenance of general anesthesia in patients undergoing
surgery. A systematic Review and Meta-Analysis of Randomized Controlled
Trials.

\textbf{Short title} : Effectiveness of Ciprofol for general anesthesia
in surgical patients.

\textbf{Authors:}

1 First Name: Muhammad

Last Name: Hudaib

Email : hudaibtajamal@gmail.com

Degree: MBBS

Institute : Fazaia Ruth Pfau Medical College , Karachi

ORCID : 0009-0000-9040-3345

2. First Name: Hurais

Last Name: Malik

Email: huraismalik38@gmail.com

Degree: 4th year MBBS

Institute: Fazaia Ruth Pfau Medical College, Karachi

ORCID: 0009-0005-0647-8181

3. First Name: Syeda Javeria

Last Name: Zakir

Email: sjaveriazakir@gmail.com

Degree: 5th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0009-0005-2230-6793

4. First Name: Samra

Last Name: Rabbani

Email: samrabbanikk@gmail.com

Degree: 5th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0009-0006-8938-9818

5. First Name: Abdul Rehman Shah

Last Name: Syed

Email: arshah321@gmail.com

Degree: 5th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0000-0001-9670-9011

6. First Name: Noor Fatima

Last Name: Suri

Email: noorfsuri@gmail.com

Degree: 4th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0000-0002-4416-482X

7. First Name: Javeria

Last Name: Khan

Email: javeriakhan0206@gmail.com

Degree: 4th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0009-0003-7866-099X

8. First Name: Arham

Last Name: Iqbal

Email: arhamarshadiqbal@gmail.com

Degree:5th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0000-0003-2075-673X

9. First Name: Nowal

Last Name: Hussain

Email: nhussain1124@gmail.com

Degree: 4th year MBBS

Institute: Dow University of Health Sciences

ORCID: 0000-0002-9613-1077

10. First Name: Dhanushan (Corresponding Author)

Last Name: Gnanendran

Email : gdhanush01@gmail.com

Degree: MBBS

Institute : York and Scarborough Teaching Hospital NHS Foundation Trust

ORCID : 0000-0001-8534-6622

11. First Name: Muhammad

Last Name: Abdullah

Email: muhammadabdullahtahir99@gmail.com

Degree: 4th year MBBS

Institute: CMH Lahore Medical College and Institute of Dentistry

ORCID: 0009-0002-1900-2543

12.~ ~ ~First name: Satesh

Last Name: Kumar

Shaheed Mohtarma Benazir Bhutto Medical College, Karachi

Email: {Kewlanisatish@gmail.com}

13.~ First Name: Mahima

Last Name: Khatri~~

~Dow University of Health Sciences, Karachi

Email: {Mahimakhatri12333@gmail.com}

14. First Name: Giustino

Last Name: Varrassi~ ~ ~

Paolo Procacci Foundation (PPF), Rome

Email: {giuvarr@gmail.com}

ORCID: 0000-0002-3822-2923



\textbf{Abstract}

\textbf{Background}

Propofol has been the gold standard for anesthesia induction and
maintenance due to its rapid onset and favourable pharmacokinetic
properties. However, the search for alternative agents with improved
safety and efficacy has led to the emergence of ciprofol (HSK3486), a
structural analog of propofol. This systematic review and meta-analysis
aims to comprehensively assess the safety and efficacy of ciprofol
compared to propofol for anesthesia induction and maintenance in adult
patients undergoing surgical procedures.

\textbf{Methods}

This study included only double-arm RCTs in which participants were aged
eighteen or older undergoing surgery. For the statistical analysis of
the extracted data, we employed RevMan 5.4.1.

\textbf{Results}

Ciprofol demonstrated a promising trend of higher anesthesiologists'
satisfaction during the induction phase (MD: 0.14, 95\%, CI: -0.28 to
0.56, p = 0.51), whereas Propofol was favored during maintenance.
Propofol also exhibited advantages with a shorter time to successful
anesthesia induction (MD: 0.08 minutes, 95\% CI: 0.00 to 0.15, p =
0.04). and quicker attainment of full alertness (MD: 0.11 minutes, 95\%
CI: -1.29 to 1.52, p = 0.87), suggesting its efficiency in clinical
practice. Importantly, there were no significant disparities in the
success rate of anesthesia.

\textbf{Conclusion}

Both ciprofol and propofol demonstrate comparable efficacy and safety
for anesthesia induction and maintenance in adult patients undergoing
surgery. While propofol provides a faster onset of induction, ciprofol
exhibits advantages in terms of pain management. Clinicians should
consider these findings when selecting anesthetic agents, tailoring
choices to individual patient needs and clinical scenarios.

\textbf{Keywords:} Analgesia, Anesthesia induction, Ciprofol, General
Anesthesia\textbf{,} Propofol.

\textbf{Word count: 5585}

\textbf{Table count: 4 tables}

\textbf{Figure count: 8 figures}

\textbf{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.

\textbf{What this study adds}

\begin{itemize}
\tightlist
\item
  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.
\item
  Propofol and Ciprofol exhibited similar efficacy and safety profiles.
  Nevertheless, Propofol achieved general anesthesia induction more
  rapidly.
\item
  With Ciprofol there was a reduced incidence of pain at injection site.
\end{itemize}

\textbf{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 \selectlanguage{greek}γ-\selectlanguage{english}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 {[}5-7{]}. It
continues to serve as the gold standard against which newer agents are
benchmarked, one of these agents being 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.

\textbf{Methods}

\textbf{Data Sources and Search Strategy}Cochrane and Preferred
Reporting Items for Systematic Review and Meta-Analyses (PRISMA)
guidelines were implemented while executing and publishing 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 the supplementary material. \textbf{Figure 1}.
Information about the search strategy is given in \textbf{supplementary
table 1.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 compromised
individuals aged eighteen or over. The intervention involved 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. This rigorous selection process aimed to ensure the quality and
relevance of the studies included in our systematic review and
meta-analysis.

\textbf{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,
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), ASA score, mean operation time, subgroups of dosage
of drug). The baseline characteristics are given in

\textbf{supplementary table 3.}

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),
CTCAE severity scale (grade 1) (induction), CTCAE severity scale (grade
2) (induction), bradycardia (induction), any treatment-emergent adverse
event, 0.4 mg number of patients who maintained BIS between 40-60 (min)
and 0.4 mg elevated AST (induction and maintenance). This is shown in

\textbf{supplementary table 4.}

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 exposure, selective reporting
of outcomes, and missing data.

\textbf{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
Ratio's (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
I\textsuperscript{2}statistics and was reported as a percentage for
every outcome. For an I\textsuperscript{2} value of less than 50\%, low
heterogeneity was indicated, moderate heterogeneity was considered when
the I\textsuperscript{2} value was less than 75\%, and high
heterogeneity was observed with an I\textsuperscript{2} value of greater
than 75\%. Outcomes, if reporting an I\textsuperscript{2} 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.

\textbf{Publication Bias}

For all the outcomes, funnel plots were also formulated using the
random-effects model. \textbf{(Supplementary figure 2-8)}

\textbf{Results}

\textbf{Eligible Studies}

In adherence to predetermined eligibility criteria and specific outcome
measures, our meta-analysis considered six double-arm, randomized
controlled trials (RCTs) {[}13-18{]}. These trials investigated the use
of ciprofol versus propofol for the induction and maintenance of general
anesthesia. Our comprehensive search strategy is illustrated in the
PRISMA diagram in \textbf{Figure 1} , encompassing articles published
between 2022 and 2023.

\textbf{Baseline Characteristics}

Our thorough analysis encompassed six randomized controlled trials,
involving a total of 714 participants. Among them, 348 patients received
propofol, while 417 patients were administered ciprofol (HSK3486). The
average age of the study population was just under 40 years,
representing a diverse range of adult patients. Gender distribution data
revealed that approximately 2/3\textsuperscript{rd} of the participants
were females. The majority of participants exhibited an American Society
of Anesthesiologists (ASA) score of 2, indicating an adequate state of
general health. A comprehensive summary of the baseline characteristics
of the included patients can be found in \textbf{supplementary table 3.}

\textbf{Primary Outcomes:~~}

\textbf{Satisfaction Evaluation for Anesthesiologists:}

Our analysis on satisfaction evaluation for anesthesiologists
incorporated data from two studies, {[}13-14{]} and we observed that, on
average, no significant difference was observed in terms of the
anesthesiologist satisfaction levels when using 0.4mg ciprofol compared
to propofol for anesthesia induction and maintenance (MD: 0.14; 95\% CI:
-0.28 to 0.5; p = 0.51; I2 = 9\%). Subgroup analysis unveiled a similar
trend, with no significant difference in preference for either ciprofol
or propofol during the induction phase (MD: 0.40; 95\% CI: -0.56 to
1.36; p = 0.42; I2 = 47\%), or the maintenance phase (MD: -0.10, 95\%
CI: -1.00 to 0.80).

\textbf{Time to Full Alertness:}

In our review of two studies, {[}14,15{]} we found that there were no
statistically significant differences in patients who received either
drug with regards to achieving full alertness. The MD: 0.11 minutes;
95\% CI: -1.29 to 1.52; p = 0.87; I2 = 0\%).

\textbf{Time to Successful Anesthesia Induction:}

Our comprehensive analysis, drawing data from five out of six studies,
{[}13-17{]} highlighted a significant advantage of propofol. The time
required for a successful anesthesia induction was significantly shorter
with propofol compared to ciprofol, with a mean difference of 0.08
minutes (95\% CI: 0.00 to 0.15, p = 0.04, I2 = 77\%). Subgroup analyses
however showed us that there was a statistically significant difference
with 0.5 mg resulting in a shorter time to induction for propofol and no
difference in the 0.4 mg group. Interestingly, a leave-one-out
sensitivity analysis highlighted the study ''Wang X 2022'' as a source
of substantial heterogeneity within the subgroup receiving 0.4 mg of
treatment. Upon its removal, subgroup-specific heterogeneity
significantly decreased to 0\%, and overall heterogeneity saw a minor
reduction to 73\%.

\textbf{Time to Loss of Eyelash Reflex:}

Our analysis, based on data from two studies, {[}13,16{]} revealed that
there was no difference observed between the two drugs in terms of time
to loss of eyelash reflex (95\% CI: -0.05 to 0.14; p = 0.38; I2 = 92\%).
Unfortunately, due to the pronounced heterogeneity and limited data, a
leave-one-out analysis was not feasible.

\textbf{Success Rate of Anesthesia:}

Across all six studies, {[}13-18{]} our combined analysis demonstrated
no discernible differences between ciprofol and propofol in terms of the
success rate of anesthesia induction and maintenance. The risk ratio
(RR) was 1.00, with a 95\% CI of 0.99 to 1.01 (p = 1.00, I2 = 0\%).
Subgroup analysis further reinforced these findings, revealing no
significant differences at different dosage levels (0.4mg and 0.5mg) for
both the induction and maintenance phases.

\textbf{Time Required for Patients to Leave the Post-Anesthesia Care
Unit (PACU):}

Based on data from two studies, {[}14,15{]} our pooled analysis
indicated that there were no differences with regards to time required
to leave the PACU between patients who received propofol than those
administered ciprofol (95\% CI: -1.45 to 2.34, p = 0.64, I2 = 0\%).

\textbf{Time to Respiratory Recovery:}Analyzing data from two studies
{[}14,15{]} regarding 0.4mg time to respiratory recovery, we found that
there was no statistically significant difference in recovery time for
respiratory functions following both induction and maintenance phases
with propofol compared to ciprofol (p = 0.40).

\textbf{Secondary outcomes:}

\textbf{Secondary outcomes}

Upon performing the analysis, no significant difference was found in all
of the outcomes except pain on the injection site in which ciprofol
performed notably better in reducing pain. (P=0.0003). Insignificant
differences between the two drugs were revealed in terms of total
adverse events , tachycardia, rash, prolonged QT interval, hypoxia,
hypotension, hypertension, CTCAE severity grading (grade 1), CTCAE
Severity Grading (Grade 2), bradycardia, any treatment-emergent adverse
events, elevated AST, number of patients who maintained Bispectral index
(BIS) between 40 -- 60 (min).

Furthermore, after conducting a subgroup analysis it was discovered that
a significant reduction in total adverse events occurred when 0.5 mg
ciprofol was used for induction (P \textless{} 0.0001). Similarly,
ciprofol fared significantly better in terms of reducing the incidence
of tachycardia when 0.5mg ciprofol was utilized for both induction and
maintenance of general anesthesia (P = 0.01). Propofol performed
significantly worse compared to 0.4mg ciprofol during the induction
phase according to the CTCAE severity grading scale (grade 1) (P =
0.005).

\textbf{Quality Assessment and Publication Bias:}

We conducted a rigorous quality assessment of the included trials using
the Cochrane risk of bias tool, identifying trials of moderate-to-high
quality. Notably, our results remained unaffected by any potential
publication bias, as demonstrated by the symmetrical distribution of
studies on each side of the vertical axis in the funnel plots of the
primary outcomes.

\textbf{Discussion}

The influence of anesthesiologists' satisfaction is pivotal in selecting
anesthetic agents. Their trust in a drug's effectiveness and safety
profoundly impacts patient care. Our meta-analysis hints at a slightly
stronger preference for Ciprofol, particularly during the induction
phase. It's essential to note, though, that these preferences don't
quite reach the threshold of statistical significance thus emphasizing
that ciprofol and propofol exhibit similar satisfaction levels among
anesthesiologists during both induction and maintenance phases of
anesthesia. This aligns with existing literature, suggesting that
Ciprofol could be a compelling alternative to Propofol in clinical
anesthesia. {[}19{]} These consistent results strengthen the evidence
that ciprofol can be a viable alternative to propofol in anesthesia
practice, offering similar satisfaction levels for anesthesiologists
while providing potential benefits such as safety and effectiveness
{[}20,21{]} However, the absence of statistical significance highlights
the multifaceted nature of this preference. Various factors, including
individual preferences, patient-specific characteristics, surgical
requirements, and the collective experiences of the anesthesia team, all
play a role in shaping satisfaction levels. Furthermore, variations in
satisfaction at different phases of anesthesia administration emphasize
the need for tailored approaches to match the unique demands of each
surgical step, ensuring the best possible patient outcomes and overall
satisfaction {[}22{]}

Interestingly, we observed no statistically significant difference
between both drugs for alertness. However, our results are inconsistent
with 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
making it a promising option to induce and maintain anesthesia,
particularly for short-duration procedures. The rapid elimination of
propofol minimizes the risk of residual sedation, promoting patient
safety and reducing the need for extended post-anesthesia
monitoring.{[}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 and Propofol is an
intriguing finding. It suggests that, at this lower dosage, Ciprofol can
achieve induction times similar to Propofol {[}15{]}. This implies that
Propofol may have a slightly faster onset of action for inducing
anesthesia than Ciprofol {[}19{]}, which could be advantageous in
specific clinical scenarios. Heterogeneity is observed in Wang X's study
for several reasons. Firstly, Wang X 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. Furthermore, variations in patient age, BMI, and ASA
score distribution in Wang X's 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 our analysis of time to loss of eye reflex,
which suggests substantial variability among the included studies. This
heterogeneity, coupled with the limitation of limited data availability
resulted in a trend not favoring either of the drugs, especially
propofol.

Our 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 our subgroup analysis, which demonstrates that
even with different Ciprofol dosages (0.4mg and 0.5mg), 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 {[}25{]}. 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 Post-Anesthesia Care Unit
(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
{[}26{]}. Nevertheless, these findings have significant clinical
relevance, as quicker recovery and discharge from the PACU can enhance
patient throughput and optimize resource utilization {[}27{]}.

Managing pain at the injection site, a factor that can induce anxiety
and discomfort among patients during intravenous (IV) infusion, is a
critical consideration. Propofol has been known to cause pain at the
injection site. {[}28{]} To address this concern, pretreatment with
local anesthetics like lidocaine before IV administration of Propofol
has been employed. Additionally, using a more diluted dose of Propofol
has been explored to alleviate pain at the injection site {[}29{]}. In
support of the current literature, our meta-analysis collectively shows
that Ciprofol is less likely to cause pain at the injection site. This
can be explained by the hydrophobic nature of Ciprofol, resulting in
relatively lower plasma concentrations compared to Propofol {[}30{]}.

In our comprehensive meta-analysis comparing ciprofol and propofol in
the context of anesthesia, we conducted a thorough evaluation of various
adverse events to assess the safety profiles of these two agents. Our
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.{[}25{]} In contrast, others have
noted that propofol remains a standard and safe choice for anesthesia
induction. {[}31{]}

Our study does have its limitations. We only included double-arm
randomized control trials, limiting our dataset to six studies.
Additionally, our study exclusively focused on invasive surgeries, which
encompassed a diversity of surgical types. 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 {[}32{]}. 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 gastrointestinal sedation, can shed light on the
advantages concerning patient comfort and recovery. {[}33{]} Moreover,
investigating long-term outcomes and cost-effectiveness can offer
valuable guidance for clinical decision-making.

\textbf{Conclusion}

In conclusion, this systematic review and meta-analysis have illuminated
the comparative effectiveness and safety of Ciprofol and Propofol in the
context of general anesthesia. Both agents exhibited similar overall
efficacy and safety, indicating their potential interchangeability for
anesthesia induction and maintenance. Propofol had a faster onset of
anesthesia during the induction phase. Conversely, Ciprofol resulted in
reduced incidence of pain at injection site. Clinicians should consider
these findings while tailoring their choice of anesthetic agents to
individual patient characteristics and preferences.

\textbf{Acknowledgment:}

None

\textbf{Declaration of interests:}

The authors report no conflicts with any product mentioned or concepts
discussed in this article.

\textbf{Funding:}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

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\textbf{Supplementary Table 1}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\textbf{DATABASE} & \textbf{SEARCH STRATEGY} &
\textbf{RESULTS}\tabularnewline
\midrule
\endhead
Medline & (((((((((((((((((((((Propofol) OR (2,6-Diisopropylphenol)) OR
(2,6 Diisopropylphenol)) OR (2,6-Bis(1-methylethyl)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)) & 30\tabularnewline
Google Scholar & (((((((((((((((((((((Propofol) OR
(2,6-Diisopropylphenol)) OR (2,6 Diisopropylphenol)) OR
(2,6-Bis(1-methylethyl)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)) &
97\tabularnewline
Embase & (((((((((((((((((((((Propofol) OR (2,6-Diisopropylphenol)) OR
(2,6 Diisopropylphenol)) OR (2,6-Bis(1-methylethyl)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)) & 67\tabularnewline
\bottomrule
\end{longtable}

\textbf{Supplementary Table 2}\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Author name}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{ZENG}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{LIANG}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{MAN}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{CHEN}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{QIN}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Wang}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Trial name}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Efficacy and safety of HSK3486 for the induction and maintenance of
general anesthesia in elective surgical patients: a multicenter,
randomized, open-label, propofol-controlled phase 2 clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Efficacy and safety of ciprofol vs. propofol for the induction and
maintenance of general anesthesia A multicenter, single-blind,
randomized, parallel-group, phase 3 clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Study on the effectiveness and safety of ciprofol in anesthesia in
gynecological day surgery: a randomized double-blind controlled
study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
The efficacy and safety of ciprofol use for the induction of general
anesthesia in patients undergoing gynecological surgery: a prospective
randomized controlled study\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Effect of ciprofol on induction and maintenance of general anesthesia in
patients undergoing kidney transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Effects of ciprofol for the induction of general anesthesia in patients
scheduled for elective surgery compared to propofol: a phase 3,
multicenter, randomized, double-blind, comparative study\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Patient no.}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
129\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
128\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
120\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
120\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
176\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Year of publication}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2022\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2023\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2023\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2022\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2022\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
2022\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Trial type}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
a multicenter, randomized, open-label, propofol-controlled phase 2
clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
A multicenter, single-blind, randomized, parallel-group, phase 3
clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
a randomized double-blind controlled study\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
a prospective randomized controlled study\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
prospective, randomized, single-blind study\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
A multi-center, randomized, propofol-controlled, double-blind
trial\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Trial number}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT04048811\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
~NCT04511728.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ChiCTR2100053444\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ChiCTR2100045211\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
ChiCTR2200058826\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
NCT03808844\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Inclusion criteria}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age 18 -65 years old. An American Society of Anesthesiologists (ASA)
rating of Class I-III, endotracheally intubated under GA, and a blood
loss of [?] 1,000 mL were included.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(American Society of Anesthesiologists (ASA) classes I to II); age
[?]18 years and [?]65 years;\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age (18 \textasciitilde{} 64years), with American Society of
Anesthesiologists physical classification status I or II, BMI 18 to
28~kg/m2.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Adult females between the ages of 18 to 60 (ASA physical status: I or
II) who were scheduled to undergo elective gynecological surgery under
GA.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Patients who had a kidney transplant under GA with tracheal intubation.
Age 18-65 years, (BMI) of 18-30 kg/m2 American Society of Anesthesiology
(ASA) physical status of III-IV.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age 18-64 years (BMI) between 18 and 30 kg/m2, American Society of
Anesthesiologists physical status of I or II scheduled to undergo
elective surgery under HA\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Exclusion criteria}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Scheduled to receive emergency, surgical procedures with
contraindications to GA or with a history of previous anesthesia
incidents were excluded.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Contraindications to GA; a history of anesthesia incidents; a disease
history of diseases or issues in any systems that could increase the
risk of sedation/anesthesia.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Patients were excluded if they suffered from propofol allergies, had
significant diseases in various systems Women who were pregnant, or
planning to become pregnant were excluded.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
morbid obesity, egg/soy allergies, had significant diseases in various
systems. Women who were pregnant, lactating, or planning to become
pregnant within 1~month after the trial were excluded.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
patients with liver, mental, nervous system diseases, coagulation
dysfunctions, heart failure, respiratory failure, long-term use of
sedatives or antidepressants, pregnant or lactating women, and unable to
communicate or cooperate.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
a history of allergy or hypersensitivity. Those who had clinically
significant systemic diseases; pregnant or had a pregnancy plan within 1
month postoperatively; a family history of malignant hyperthermia; those
who had surgery under GA within 4 weeks perioperatively; who had
previously received sedative/narcotic agents within 3 days of screening
and had alcohol or drug abuse within 3 months perioperatively; who had
previously received drugs that could have affected the QT interval or
induced/inhibited P450 or CYP2B6 within 2 weeks perioperatively.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Treatment}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Randomly assigned to HSK3486 or propofol dosage groups in a ratio of
3:1. Drugs were administered as a bolus injection of 0.4 mg/kg (HSK3486)
or 2.0 mg/ kg (propofol) for induction, followed by maintenance
infusion.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Patients were given midazolam 0.04 mg kg-1~and sufentanil 0.3 \selectlanguage{greek}μ\selectlanguage{english}g kg-1~as
preanesthetic medication. Anesthesia induction was then initiated with
either HSK3486 or propofol. After successful induction, the muscle
relaxant rocuronium bromide was administered at 0.6 mg kg-1, and
endotracheal intubation was performed. HSK3486 or propofol was given at
appropriate doses to maintain anesthesia. Remifentanil was administered
at 0.1--0.3 \selectlanguage{greek}μ\selectlanguage{english}g/kg-1~min-1~for analgesia, and sufentanil and a muscle
relaxant were added. bromide.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
During anesthesia induction, the ciprofol group was infused at a time
limit of 0.5~mg/kg for one minute, and the propofol group was infused at
a time limit of 2~mg/kg for 1~min.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Intravenous midazolam (0.03~mg/kg) and sufentanil (0.3~\selectlanguage{greek}μ\selectlanguage{english}g/kg) were used
to start general anesthesia induction, followed 2~min later by the
manual injection of ciprofol (0.4~mg/kg) or medium-and long-chain
triglyceride (MCT/LCT) propofol (2~mg/kg). Patients started receiving
preoxygenation after intravenous midazolam and sufentanil being
administrated. When spontaneous breathing disappeared, it switched to
manual controlled breathing. i\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The patients were randomized into a ciprofol group (group C) and a
propofol group (group P). Anesthesia induction: group C had injected IV
with ciprofol 0.4 mg/kg, group P had injected IV with propofol 2.0
mg/kg, while both groups had injected IV with sufentanil 0.4-0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg
and cisatracurium 0.2 mg/kg. Anesthesia maintenance: ciprofol was
injected IV with 0.8-2.4 mg*kg-1*h-1 in group C, propofol was injected
IV with 4-12 mg*kg-1*h-1 in group P, while remifentanil was injected IV
with 8-15 \selectlanguage{greek}μ\selectlanguage{english}g*kg-1 *h-1 and cisatracurium was injected IV with
0.1-0.2mg*kg-1*h-1, with the bispectral index\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Optimal injected doses of 0.4 mg/kg of ciprofol and 2.0 mg/kg of
propofol\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Primary efficacy outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The success rate of anesthesia maintenance.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Noninferiority between the drugs was evaluated as the lower limit of the
95\% confidence interval (CI) for the group difference.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
(1) bradycardia (HR \textless{} 50 beats/min, \textgreater{} 30s); (2)
Tachycardia (HR \textgreater{} 100 beats/min, \textgreater{} 30s) (3)
Hypotension (30\% reduction in SBP compared to baseline value); (4)
Hypertension (SBP is 20\% higher than baseline value); (5) injection
pain at the site. (6) Intraoperative body movements\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
Safety and efficacy of ciprofol. Evaluation The success rate of general
anesthesia induction was the primary outcome for the present
study.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The success rate of sedation.\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
The anesthesia induction success.\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Secondary Efficacy outcome}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Times from discontinuation of HSK3486 or propofol maintenance to full
alertness, respiratory recovery, extubation and reaching the goal of the
Aldrete score.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Successful anesthetic induction, full alertness and spontaneous
breathing recovery, time until leaving the postanesthetic care.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(1) success rate of induction of anesthesia, (2) the time of loss of
consciousness (time of initiation of study drug infusion to MOAA/S [?] 1),
(3) time of awakening (time of drug discontinuation to extubation), (4)
study drug top-up doses, (5) rescue drug use.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
(1) the time to onset of successful induction; (2) the incidence of
injection site pain as detected by a withdrawal response or a numeric
rating. (3) time to eyelash reflex disappearance. (4) changes in the
bispectral index (BIS) during the 10-min interval.\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
. HR showed no significant difference between the two groups
(p\textgreater{}0.05). MAP decreased more significantly in group P at T6
(p0.05)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
The average time to successful anesthesia and loss of the eyelash
reflex. The pattern of BIS changes. The incidence of injection
pain/\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Follow up}\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
N/A\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Supplementary Table 3}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{STUDY}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{STUDY DESIGN}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{TOTAL NO OF PATIENTS}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{MALE (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{MALE (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Age} \selectlanguage{ngerman}\textbf{Mean (±SD)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{Age} \selectlanguage{ngerman}\textbf{Mean (±SD)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{BMI (kg/m2) Mean (±SD)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\selectlanguage{ngerman}\textbf{BMI (kg/m2) Mean (±SD)}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{ASA Score} \textbf{1/2/3/4}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{ASA Score} \textbf{1/2/3/4}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{OPERATION TIME, MEAN SD}\strut
\end{minipage} & \begin{minipage}[b]{0.07\columnwidth}\raggedright\strut
\textbf{OPERATION TIME, MEAN SD}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{CIPROFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{PROPOFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{CIPROFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{PROPOFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{CIPROFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{PROPOFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{CIPROFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{PROPOFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{CIPROFOL}\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\textbf{PROPOFOL}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Zeng Y 2022\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
multicenter, randomized, open-label, propofol-controlled phase 2
clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
11 (36.7)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
3 (30.0)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
42.5 \selectlanguage{ngerman}± 10.3\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
46.4 \selectlanguage{ngerman}± 11.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.7 \selectlanguage{ngerman}± 3.0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.6 \selectlanguage{ngerman}± 3.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
16/14/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
4/6/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
105.3 \selectlanguage{ngerman}± 62.6\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Wang X 2022\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
phase 3, multicenter, randomized, double-blind, comparative study\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
176\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
32\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
31\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
38.5 (12.1)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
41.1 (11.1)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.3 (2.9)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.3 (3.1)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
51/37/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48/40/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Qin K 2022\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
prospective, randomized, single-blind study\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
105\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
18 (34.6)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
18 (34.0)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
39.00\selectlanguage{ngerman}±10.10\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
41.25\selectlanguage{ngerman}±10.63\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.38\selectlanguage{ngerman}±3.33\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22.63\selectlanguage{ngerman}±2.38\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0/0/42/10\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
0/0/44/9\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
175.88\selectlanguage{ngerman}±42.22\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Chen-Ben Zhen 2022\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
prospective, double-blind, single-center study\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
120\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
33.9\selectlanguage{ngerman}±9.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
33.8\selectlanguage{ngerman}±9.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22.2\selectlanguage{ngerman}±3.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
21.4\selectlanguage{ngerman}±2.8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
32/28/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
34/26/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
55.2\selectlanguage{ngerman}±20.5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Liang Peng 2023\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
multicenter, single-blinded, propofol-controlled, randomized, phase 3
trial\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
128\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23 (26.7)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
10 (23.8)\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
38.5 \selectlanguage{ngerman}± 10.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
40.5 \selectlanguage{ngerman}± 10.1\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.3 \selectlanguage{ngerman}± 2.8\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.3 \selectlanguage{ngerman}± 3.0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
48/38/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22/20/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
94.6 \selectlanguage{ngerman}± 39.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
Zhu Qianmei 2023\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
phase 2a, 7-center, open-labeled, non-randomized and positive controlled
clinical trial\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
68\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
0.4mg 0.5mg\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
4 13\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
53.5 \selectlanguage{ngerman}± 8.3 46.6 ± 12.4\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
44.8 \selectlanguage{ngerman}± 12.4\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
24.4 \selectlanguage{ngerman}± 2.5 23.8 ± 2.6\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
24.4 \selectlanguage{ngerman}± 3.0\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
6/2/0/0 7/22/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
14/17/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.07\columnwidth}\raggedright\strut
102.6 \selectlanguage{ngerman}± 44.4 81.8 ± 47.9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
Man Yan 2023\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
randomized double-blind controlled study\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
128\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
42.2\selectlanguage{ngerman}±9.46\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
44.1\selectlanguage{ngerman}±9.4\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
22.8\selectlanguage{ngerman}±2.2\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
23.3\selectlanguage{ngerman}±2.6\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
18/46/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
14/50/0/0\strut
\end{minipage} & \begin{minipage}[t]{0.05\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Supplementary table 4}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
OUTCOME & EFFECT SIZE (RR OR WMD) & 95\% CI & p-VALUE\tabularnewline
\midrule
\endhead
\textbf{Total adverse events (induction)} 0.4mg ciprofol 0.5 mg ciprofol
& \textbf{RR: 0.76} 0.93 0.61 & \textbf{0.46,1.25} 0.85,1.01 0.49,1.25 &
\textbf{0.28} 0.10 \textless{}0.0001\tabularnewline
\textbf{Tachycardia} 0.4mg cipro vs propo (induction) 0.5mg cipro vs
propo (induction) o.4mg ciprofol (induction and maintenance) &
\textbf{RR: 0.24} 0.24 3.00 0.03 & \textbf{0.0040.04,1.51} 0.04,1.45
0.12,72.29 0.00,0.45 & \textbf{0.13} 0.12 0.50 0.01\tabularnewline
\textbf{Rash} 0.4mg cipro vs propo (induction) 0.4mg ciprofol (induction
and maintenance) & \textbf{RR: 1.33} 1.48 1.26 & \textbf{0.22,8.25}
0.06,35.64 0.14,11.68 & \textbf{0.76} 0.81 0.84\tabularnewline
\textbf{Prolonged QT interval} & \textbf{RR: 0.43} & \textbf{0.05,3.95}
& \textbf{0.45}\tabularnewline
\textbf{Pain on injection site (induction)} 0.4mg ciprofol 0.5mg
ciprofol & \textbf{RR: 0.16} 0.26 0.02 & \textbf{0.06,0.44} 0.13,0.52
0.00,0.14 & \textbf{0.0003} 0.09 \textless{}0.0001\tabularnewline
\textbf{Hypoxia} 0.4mg cipro vs propo (induction) 0.4mg cipro vs propo
(indcution and maintenance) & \textbf{RR: 1.56} 1.80 1.06 &
\textbf{0.31,7.94} 0.27,12.09 0.05,24.25 & \textbf{0.59} 0.55
0.97\tabularnewline
\textbf{Hypotension} 0.4mg cipro vs propo (induction) 0.5mg cipro vs
propo (induction) 0.4mg (induction and maintenance) & \textbf{RR: 0.74}
0.67 0.69 0.71 & \textbf{0.53,1.02} 0.35,1.29 0.48,1.01 0.35,1.46 &
\textbf{0.06} 0.23 0.06 0.35\tabularnewline
\textbf{Hypertension (induction)} 0.4mg cipro vs propo 0.5mg cipro vs
propo & \textbf{RR: 1.61} 1.36 2.00 & \textbf{0.54,4.86} 0.31,5.95
0.38,10.54 & \textbf{0.39} 0.68 0.41\tabularnewline
\textbf{CTCAE Severity Grading (grade 1)} 0.4mg cipro vs propo
(induction) 0.mg cipro vs propo (induction and maintenance) &
\textbf{RR: 1.21} 1.37 1.00 & \textbf{0.89} 1.10,1.70 0.70,1.43 &
\textbf{0.23} 0.005 1.00\tabularnewline
CTCAE Severity Grading (Grade 2) 0.4mg cipro vs propo (induction) 0.4mg
cipro vs propo (induction and maintenance) & \textbf{RR: 0.95} 0.94 0.96
& \textbf{0.80,1.14} 0.73,1.22 0.75,1.24 & \textbf{0.60} 0.65
0.77\tabularnewline
\textbf{Bradycardia} 0.4mg cipro vs propo (induction) 0.5mg cipro vs
propo (induction) 0.4mg cipro vs propo (induction and maintenance) &
\textbf{RR: 0.81} 0.89 1.17 0.74 & \textbf{0.58,1.14} 0.47,1,70
0.41,3.28 0.45,1.22 & \textbf{0.23} 0.72 0.77 0.24\tabularnewline
Any treatment-emergent adverse events 0.4mg cipro vs propo (induction)
0.4mg cipro vs propo (induction and maintenance) & \textbf{RR: 1.07}
1.05 1.14 & \textbf{0.96,1.19} 0.94,1.19 0.90,1.45 & \textbf{0.21} 0.38
0.29\tabularnewline
0.4 mg Number of patients who maintained BIS between at 40 - 60 (min) &
\textbf{RR: 1.31} & \textbf{0.59,2.90} & \textbf{0.51}\tabularnewline
0.4 mg elevated AST (induction and Maintenance) & \textbf{RR: 0.69} &
\textbf{0.09,5.40} & \textbf{0.72}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Legends to Figures:}

\textbf{Figure 1:} Prisma Flow Chart

\textbf{Figure 2:} Satisfaction Evaluation for Anesthesiologists (forest
plot)

\textbf{Figure 3:} Time to Full Alertness (forest plot)

\textbf{Figure 4:} Time to Successful Anesthesia Induction (forest plot)

\textbf{Figure 5:} Time to loss of Eyelash Reflex (forest plot)

\textbf{Figure 6:} Success Rate of Anesthesia (forest plot)

\textbf{Figure 7:} Time Required for Patients to Leave the
Post-Anesthesia Care Unit (PACU) (forest plot)

\textbf{Figure 8:} Time to Respiratory Recovery (forest plot)

\textbf{Supplementary materials:}

\textbf{Supplementary Figure 1:} Cochrane Risk of Bias

\textbf{Supplementary Figure 2:} Satisfaction Evaluation for
Anesthesiologists (funnel plot)

\textbf{Supplementary Figure 3:} Time to Full Alertness (funnel plot)

\textbf{Supplementary Figure 4:} Time to Successful Anesthesia Induction
(funnel plot)

\textbf{Supplementary Figure 5:} Time to loss of Eyelash Reflex (funnel
plot)

\textbf{Supplementary Figure 6:} Success Rate of Anesthesia (funnel
plot)

\textbf{Supplementary Figure 7:} Time Required for Patients to Leave the
Post-Anesthesia Care Unit (PACU) (funnel plot)

\textbf{Supplementary Figure 8:} Time to Respiratory recovery (funnel
plot)

\textbf{Hosted file}

\verb`Figures.docx`  available at \url{https://authorea.com/users/672371/articles/671468-efficacy-and-safety-of-ciprofol-versus-propofol-for-induction-and-maintenance-of-general-anesthesia-in-patients-undergoing-surgery-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials}

\selectlanguage{english}
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\end{document}

