This study was designed to be a double-blind parallel randomized controlled trial and applied the opioid-reduced anesthesia program to gynecological day surgery to observe the effects on patients’ hemodynamics, PONV, postoperative pain and other adverse reactions. Ethics approval was obtained from the Ethics Committee of the Weifang People’s Hospital (2021-030) on November 11, 2021. The study was registered in Chinese Clinical Trial Registry (November 13, 2021; Chinese Clinical Trial registry, No. ChiCTR2100053153). Written informed consent was obtained from all participants. The trial report complies with the Consolidated Standards of Reporting Trials (CONSORT) checklist.

Eligible patients were adult women scheduled for hysteroscopy and cervical conization day surgery at Weifang People’s Hospital. The exclusion criteria were: 1) morbid obesity, body mass index (BMI) > 30 kg/m2; 2) coronary artery disease, liver and kidney dysfunction, and neuromuscular and psychiatric disorders; 3) a history of cerebral infarction, myocardial infarction, and severe arrhythmia; 4) a history of chronic pain or use of any sedatives or analgesics; and 5) allergies to any drug involved in the study. All patients enrolled in this study were evaluated by anesthesiologists above the attending doctor before anesthesia and signed informed consent forms. If the patient refused to participate in the study or the surgical method was changed, the study was stopped. The study protocol had no important harmful or unintended effects on participants.

The primary endpoint was the incidence of postoperative nausea within 24 h after surgery. The secondary endpoints included the incidence of postoperative vomiting, pain scores evaluated by the VAS, length of stay in the PACU until discharge criteria according to the Aldrete’s modified postanesthetic recovery score [13], adverse hemodynamic events during the perioperative period, postoperative length of hospital stay and other adverse reactions.

Patients were randomly allocated to the two interventions or the control group. The computer-generated random allocation sequence was randomly created by an independent investigator using Excel 2016 with a 1:1:1 allocation randomly. Participants and outcome evaluators were blinded to group assignments. Because of the significant differences between anesthetic techniques, the anesthesia providers could not be blinded.

The tow opioid-reduced groups were based on previously reported approaches [14,15,16,17] and the instructions and were assessed for feasibility in a pilot series preceding this study.

After verifying the patient’s information, routine monitoring was established, and baseline values were obtained. Then, venous access was obtained, and a crystalloid solution was started. All patients received flurbiprofen axetil 50 mg to relieve inflammatory pain and then dexamethasone 5 mg for PONV prophylaxis based on preoperative risk stratification with Apfel’s simplified PONV risk score [18].

All patients received preoxygenation after verification. For anesthesia induction, all patients received propofol at a loading dose of 2 mg/kg intravenous injection in one minute. Patients in Group C and Group MO received 20 μg/kg alfentanil, and patients in Group LO received alfentanil 10 μg/kg mixed with 0.2 mg/kg esketamine. Then, the patients in the three groups received 0.2 mg/kg mivacurium chloride, followed by laryngeal mask insertion for three minutes. The ventilator settings were adjusted to maintain normoxia (SpO2 > 97%) and normocapnia (35 < PETCO2 < 45 mmHg). Body temperature management was initiated to maintain normothermia. For maintenance of anesthesia, all patients in there groups received 0.5 mg/kg/h propofol. The patients in Group C received 40 μg/kg/h alfentanil, and those in Group MO and Group LO received 0.5 mg/kg/h esketamine. Bradycardia was defined as a heart rate (HR) below 50 beats per minute [19] and hypotension was defined as a mean arterial pressure (MAP) below 65 mmHg [20]. Hypotension or bradycardia occurring at each intraoperative time point was recorded as a hemodynamic adverse event, and summarized after operation as the frequency of adverse events in the perioperative period. Patients with bradycardia and hypotension were given 0.5 mg atropine or 0.6 mg ephedrine by intravenous injection. Considering the specific pharmacokinetics of the drugs used in each arm of the trial, all anesthetic agents were stopped after the end of surgery.

After tracheal extubation, patients were transferred to the PACU and assessed for nausea, vomiting, pain and other adverse reactions. For the remedial treatment of postoperative pain, we recommended oral ibuprofen (0.4 g, bid) for three days after discharge. For antiemetic rescue treatment, patients received drinking water, chewing gum or 5 mg tropisetron intravenous injection. Postoperative pain and antiemetic therapy were standardized according to institutional regulations. Patients were assessed for discharge readiness in accordance with the criteria of Aldrete’s Modified Postanesthetic Recovery Score, and the length of stay in the PACU was defined from the time of admission until these criteria were met.

There were nine time points in the whole operation, including the patient entering the operating room (T0), before anesthesia induction (T1), after anesthesia induction but before laryngeal mask insertion (T2), laryngeal mask fixation (T3), the beginning of the surgery (T4), 5 minutes into surgery (T5), 10 minutes into surgery (T6), 15 minutes into surgery (T7),stopping of the anesthesia (T8) and 1 minute after extubation (T9). The MAP and HR of patients at each time point were recorded. If the MAP or HR reached the standard we set, an adverse hemodynamic event was considered to have occurred. The total frequence of hemodynamic adverse events during the operation was recorded. We also recorded the drug dosage, total anesthesia time, extubation time, length of stay in the PACU and in the hospital, postoperative pain and other perioperative adverse reactions (vertigo, excessive oral secretion, etc.) of all patients. Excessive oral secretion was defined as excessive secretion that patients could not remove by themselves, and that needed to be removed by an aspirator after extubation. Patients were followed up at two postoperative time points (within the PACU and on the first day of discharge) to evaluate the incidence of PONV.

According to the pretest results, we calculated the sample size with PASS 15.0 software using the incidence of nausea within 24 hours as the primary study endpoint. Sample size calculations resulted in n = 41 patients per group to achieve a power of 90% with a type 1 error of 0.05 to reject the primary null hypothesis that there would be no difference in the primary outcome between all three treatment arms. With an estimated sample loss rate of 15% estimated, we finally decided to include 150 patients.

Data are summarized as the mean (standard deviation), median (interquartile range [IQR]), or number (%). Categorical data were analyzed with Fisher’s exact test or the X2 test. One-way ANOVA was used for normally distributed data assessed by the Shapiro–Wilk test. The least-significant difference test (LSD) was used for post hoc testing. Continuous variables that did not conform to a normal distribution were assessed with the Kruskal-Wallis test. Bonferroni correction was performed in paired comparisons. Two-sided p values < 0.05 were considered significant. All statistical analyses were performed by SPSS Statistics 25.0. The statistical analysis plan was approved by the authors before the analyses began.