Research ethics
The present prospective, double-blind, single-center study was conducted at Sichuan Provincial Women’s and Children’s Hospital. The Medical Ethics Committee of Sichuan Provincial Women’s and Children’s Hospital approved the present study (review board number: 20201113–114), which was registered in the Chinese Clinical Trial Registry in 08/04/2021(Registration number: ChiCTR2100045211). Written informed consent was obtained from all participants. This manuscript adheres to the applicable EQUATOR guidelines.
Study design
This study was a non-inferiority design, and the primary endpoint was the success rate of induction of general anesthesia. In type I error (false positive), 0.025 (unilateral), Power of test is 80%. The success rate of general anesthesia induction for both cyprofol and propofol positive control drugs was set to be 98%, the non-inferiority margin was defined as 8%, and a total of 120 hospitalized subjects undergoing elective surgery in our hospital from June 2021 to March 2022 were included in this study. They were equally assigned to the ciprofol group and the propofol group, with 60 subjects in each group. Consecutive adult females between the ages of 18 and 60 (ASA physical status: I or II) who were scheduled to undergo elective gynecological surgery under general anesthesia were recruited for the present study. The CONSORT Flow Diagram was listed in Fig. 1. Patients were excluded if they suffered from morbid obesity, egg/soy allergies, diabetes mellitus, gastroesophageal reflux, or symptomatic neurological, respiratory, or cardiovascular disease in this study. In addition, women who were pregnant, lactating, or planning to become pregnant within 1 month after the trial were excluded. After assessing patient eligibility, they were informed regarding the study by members of the study team, with written informed consent then being obtained.
Randomisation, blinding, and general anesthesia induction
Patients were randomly assigned to two equally sized groups using a computer-generated random number table, with this list being maintained in a locked cabinet to which only nursing staff members without any direct involvement in patient care or the study as a whole had access. These nurses prepared study medications in a closes room without observation based on patient group assignments.
Patients in this study were fasted for a minimum of 6 h without premedication. Following arrival in the operating room, patients were monitored via electrocardiography, respiratory rate, pulse oximetry, bispectral index (BIS), and continuous noninvasive arterial blood pressure (CNAP). An 18-Gauge intravenous cannula was inserted into a vein in the dorsum of the right hand.
Intravenous midazolam (0.03 mg/kg) and sufentanil (0.3 μg/kg) were used to start general anesthesia induction, followed 2 min later by the manual injection for 30 s of ciprofol (0.4 mg/kg; Haisco Pharmaceutical Group Co. Ltd, China) or medium-and long-chain triglyceride (MCT/LCT) propofol (2 mg/kg; Fresenius Kabi Deutschland GMBH) as appropriate. Patients started receiving preoxygenation (breath spontaneous using a closed mask with 100% oxygen) after intravenous midazolam and sufentanil being administrated. When spontaneous breathing disappeared, it switched to manual controlled breathing. The patient's respiratory rate remained between 12 and 20 during induction before the administration of rocuronium and the SPO2 remained 100%. Patient responses were then monitored until there was clinical evidence that anesthetization was effective. Sedation levels in subjects were assessed using the Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) scale [11,12,13]. The patients’ baseline MOAA/S were measured before administering midazolam. Time to eyelash reflex disappearance from the beginning of study drug administration were assessed every 5 s through touch the eyelashes with a sterile cottom swab gently. The following two conditions should be met for successful induction of anesthesia: 1) MOAA/S ≤ 1; 2) No alternative hypnotics were used. If successful induction was not achieved within 1 min, the addition of an additional dose of ciprofol (0.2 mg/kg) or MCT/LCT propofol (1 mg/kg) was allowed for patients in the corresponding treatment groups. When induction remained unsuccessful following the administration of two additional study drug doses, propofol was administered to complete the induction. Once induction was successful, rocuronium (0.6 mg/kg) was administered, and endotracheal intubation was conducted after the muscle relaxant took effect, the intubation time point was uniformly defined as 4 min after the beginning of induction(administration of study drug). 2 min after intubation, anesthesia was maintained with sevoflurane in oxygen 50% and/or other intravenous anesthetics depending on the need for surgery or the personal habits of the anesthesiologist.
Outcomes
The present study was conducted to assess the safety and efficacy of ciprofol. Evaluation was performed every 30 s after administering midazolam, and the evaluation interval was shortened to 5 s at the beginning of study drug administration until the MOAA/S score was ≤ 1, and the longest evaluation time was no more than 3 min after the beginning of study drug administration. The success rate of general anesthesia induction was the primary outcome for the present study, and was defined as the percentage of successful induction cases in each group(the lack of any need for an alternative sedative/anesthetic drug or the need for > 2 top-up study drug doses following the start of study drug administration).
Secondary study outcomes included: (1) the time to onset of successful induction from the initiation of study drug treatment to a MOAA/S score ≤ 1; (2) the incidence of injection site pain as detected by a withdrawal response or a numeric rating scale value ≥ 3, Subjects were asked “Do you feel pain in the arm where the drug was injected?” during the injection. If the answer was “yes”, Subjects were asked to describe the intensity of the pain (0 to10 points indicated “no pain” to “unbearable pain”). Evaluation was performed at least once during the study drug injection until the successful induction of the subjects (MOAA/S ≤ 1); (3) time to eyelash reflex disappearance from the beginning of study drug administration; (4) changes in the bispectral index (BIS) during the 10-min interval following the start of study drug administration; and (5) the utilization of study drug top-up doses and/or rescue/remediation drugs.
Statistical analysis
SPSS v26.0 (SPSS, Inc., IL, USA) was used for all statistical analyses. Data were compared between groups using unpaired t-tests, chi-squared tests, Fisher’s exact test, or Kruskal–Wallis one-way ANOVAs with Dunn’s multiple comparison test as appropriate. P < 0.05 was the significance threshold.