A Randomized Controlled Trial Comparing the Effects of Different Anesthetic Sedatives on PONV in Laparoscopic Cholecystectomy

Background and rationale

Postoperative nausea and vomiting (PONV) is one of the most common complications following general anesthesia, occurring in 20-30% of the general surgical population and up to 53-72% in high-risk patients. PONV causes significant patient discomfort, prolongs post-anesthesia care unit stay, and may lead to complications including fluid and electrolyte imbalance, wound dehiscence, and aspiration pneumonia. Laparoscopic cholecystectomy (LC) is associated with a particularly high incidence of PONV (40-75%) due to the combined effects of pneumoperitoneum, carbon dioxide absorption, and vagal stimulation during visceral traction.

Propofol is the most widely used intravenous anesthetic agent and is known to possess direct antiemetic properties through suppression of the vomiting center and chemoreceptor trigger zone in the area postrema. However, propofol is associated with injection pain, hypotension, respiratory depression, and potential lipid metabolism disturbances. Two newer sedative agents have recently been approved for clinical use in China: ciprofol (HSK3486), a cyclopropyl structural analogue of propofol with approximately 5-fold greater affinity for GABAA receptors, offering reduced injection pain and improved hemodynamic stability; and remimazolam, an ultra-short-acting benzodiazepine acting on GABAA receptors with rapid onset, rapid recovery, minimal hemodynamic effects, and negligible respiratory depression. Its inactive metabolite and reversibility with flumazenil provide additional safety advantages.

To date, no prospective randomized controlled trial has directly compared the effects of propofol, ciprofol, and remimazolam on PONV in patients undergoing LC. This study aims to fill this evidence gap.

Study design

This is a prospective, randomized, controlled, single-blind clinical trial conducted in accordance with the CONSORT 2010 statement. The study will be conducted at Xi'an Aerospace Hospital. A total of 114 adult patients scheduled for elective LC under general anesthesia will be enrolled and randomly assigned in a 1:1:1 ratio to one of three groups (n=38 per group): propofol group, ciprofol group, or remimazolam group.

Sample size calculation

Sample size was estimated using PASS 21 software based on a pilot study of 33 patients (11 per group) who underwent LC at Xi'an Aerospace Hospital between June 1 and July 1, 2026. Using a chi-square test (Proportions → Contingency Table module) with α=0.05, power (1-β)=0.80, and df=2, the minimum required sample size was calculated as 91 patients. Accounting for an anticipated 20% dropout rate, the final planned sample size is 114 patients (38 per group).

Randomization and allocation concealment

A computer-generated block randomization sequence in a 1:1:1 ratio will be produced using SAS 9.0 software. Allocation assignments will be sealed in sequentially numbered opaque envelopes and opened in order by an anesthetic nurse not directly involved in the study, ensuring adequate concealment of the allocation sequence.

Anesthetic protocol

All enrolled patients will undergo preoperative assessment the day before surgery and provide written informed consent. On arrival in the operating room, standard monitoring will be established, including electrocardiography, non-invasive blood pressure, pulse oximetry (SpO2), nasopharyngeal temperature, and bispectral index (BIS) monitoring. All patients will receive intravenous ondansetron 8 mg and dexamethasone 10 mg as prophylactic antiemetic treatment.

Anesthesia induction: All patients will receive sufentanil citrate 0.5 μg/kg (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China) and cisatracurium 0.15 mg/kg. The sedative agent will be administered according to group assignment: propofol 2 mg/kg (Yangtze River Pharmaceutical Group, Taizhou, Jiangsu, China) intravenously over ≥30 s; ciprofol 0.4 mg/kg (Haisco Pharmaceutical Group, Shenyang, Liaoning, China) intravenously over ≥30 s; or remimazolam 0.3 mg/kg (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China) intravenously over ≥1 min. Once BIS reaches ≤60, preoxygenation via face mask will be performed for 3 min, followed by insertion of a supraglottic airway device and initiation of mechanical ventilation. After induction, bilateral subcostal and lateral transversus abdominis plane (TAP) blocks will be performed under ultrasound guidance using 0.3% ropivacaine 40 mL total (Shijiazhuang No.4 Pharmaceutical, Shijiazhuang, Hebei, China).

Anesthesia maintenance: All patients will receive continuous remifentanil infusion at 0.1-0.2 μg/kg/min for analgesia (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China). Maintenance sedation will be administered per group: propofol 4-12 mg/kg/h; ciprofol 0.8-1.2 mg/kg/h; or remimazolam 0.2-1.0 mg/kg/h. Infusion rates will be titrated to maintain BIS values between 40 and 60. Cisatracurium besylate will be administered intermittently as needed for neuromuscular blockade. Ketorolac tromethamine 30 mg (Shandong New Time Pharmaceutical, Linyi, Shandong, China) will be given intravenously 5 min before surgery completion, after which all maintenance agents will be discontinued.

Postoperative analgesia: All patients will receive multimodal analgesia via patient-controlled intravenous analgesia (PCIA) pump. The PCIA formulation will comprise nalbuphine hydrochloride 1.5 mg/kg, ketorolac tromethamine 2 mg/kg, and ondansetron 16 mg diluted with normal saline to a total volume of 100 mL; background infusion rate 2 mL/h, bolus dose 2 mL, lockout interval 15 min, for 48 h. Intravenous ondansetron 8 mg will be administered as rescue antiemetic therapy for moderate-to-severe PONV.

Outcome measures

The primary outcome is the incidence of PONV (defined as nausea and/or vomiting) within 24 h postoperatively. PONV severity will be graded according to World Health Organization (WHO) criteria: Grade I, no nausea or retching; Grade II, mild nausea with abdominal discomfort but no vomiting; Grade III, nausea with retching but no expulsion of gastric contents; Grade IV, severe vomiting with expulsion of gastric contents requiring pharmacological intervention.

Secondary outcomes include: (1) incidence of vomiting within 24 h; (2) incidence of nausea within 24 h; (3) frequency of nausea, vomiting, and PONV episodes within 24 h; (4) visual analog scale (VAS) pain scores at 0, 6, 12, and 24 h postoperatively; and (5) peak VAS pain score within 24 h. Pain intensity will be assessed using a 0-10 VAS, where 0 = no pain and 10 = worst imaginable pain.

Statistical analysis

All statistical analyses will be performed using SPSS 27.0 software. Continuous variables will be assessed for normality. Normally distributed data will be presented as mean ± standard deviation (SD) and compared using one-way ANOVA with LSD post-hoc test for pairwise comparisons. Non-normally distributed data will be presented as median (interquartile range) and compared using the Kruskal-Wallis test. Categorical variables will be expressed as frequency (percentage) and compared using the chi-square test or Fisher's exact test as appropriate. Repeated measures data will be analyzed using repeated measures ANOVA. A multivariable logistic regression model will be constructed adjusting for age, sex, ASA classification, body mass index (BMI), and operation time to evaluate the independent associations between sedative agents and postoperative PONV outcomes. Spearman's rank correlation will be used to assess the relationship between postoperative pain scores and PONV frequency. All tests will be two-sided, with p \< 0.05 considered statistically significant.

Participants in this arm will receive propofol for anesthesia induction and maintenance during elective laparoscopic cholecystectomy. All participants will also receive standardized perioperative care, including prophylactic antiemetics (ondansetron 8 mg and dexamethasone 10 mg), intraoperative analgesia with sufentanil and remifentanil, cisatracurium for neuromuscular blockade, ultrasound-guided transversus abdominis plane (TAP) block with 0.3% ropivacaine, and postoperative patient-controlled intravenous analgesia (PCIA). The primary and secondary outcomes will be assessed within 24 hours after surgery.

Drug: Propofol

Participants in this arm will receive ciprofol, a novel cyclopropyl analogue of propofol, for anesthesia induction and maintenance during elective laparoscopic cholecystectomy. All participants will also receive standardized perioperative care, including prophylactic antiemetics (ondansetron 8 mg and dexamethasone 10 mg), intraoperative analgesia with sufentanil and remifentanil, cisatracurium for neuromuscular blockade, ultrasound-guided transversus abdominis plane (TAP) block with 0.3% ropivacaine, and postoperative patient-controlled intravenous analgesia (PCIA). The primary and secondary outcomes will be assessed within 24 hours after surgery.

Drug: Ciprofol

Participants in this arm will receive remimazolam, an ultra-short-acting benzodiazepine, for anesthesia induction and maintenance during elective laparoscopic cholecystectomy. All participants will also receive standardized perioperative care, including prophylactic antiemetics (ondansetron 8 mg and dexamethasone 10 mg), intraoperative analgesia with sufentanil and remifentanil, cisatracurium for neuromuscular blockade, ultrasound-guided transversus abdominis plane (TAP) block with 0.3% ropivacaine, and postoperative patient-controlled intravenous analgesia (PCIA). The primary and secondary outcomes will be assessed within 24 hours after surgery.

Drug: Remimazolam

Drug: Propofol (Yangtze River Pharmaceutical Group, Taizhou, Jiangsu, China) Induction: 2 mg/kg intravenously over ≥ 30 seconds Maintenance: 4-12 mg/kg/h by continuous intravenous infusion, titrated to maintain BIS between 40 and 60

Drug: Ciprofol (HSK3486; Haisco Pharmaceutical Group, Shenyang, Liaoning, China) Induction: 0.4 mg/kg intravenously over ≥ 30 seconds Maintenance: 0.8-1.2 mg/kg/h by continuous intravenous infusion, titrated to maintain BIS between 40 and 60

Drug: Remimazolam besylate (Yichang Humanwell Pharmaceutical, Yichang, Hubei, China) Induction: 0.3 mg/kg intravenously over ≥ 1 minute Maintenance: 0.3-1.0 mg/kg/h by continuous intravenous infusion, titrated to maintain BIS between 40 and 60

Plazo: 24 hours after surgery

The proportion of patients who experience nausea and/or vomiting within the first 24 hours after surgery. Postoperative nausea and vomiting (PONV) is defined as nausea and/or vomiting occurring within 24 hours postoperatively. Severity will be graded according to World Health Organization (WHO) criteria: Grade I, no nausea or retching; Grade II, mild nausea with abdominal discomfort but no vomiting; Grade III, nausea with retching but no expulsion of gastric contents; Grade IV, severe vomiting with expulsion of gastric contents requiring pharmacological intervention. Overall PONV incidence = (Grade II + Grade III + Grade IV cases) / total cases × 100%.

Plazo: 24 hours postoperatively

The proportion of patients who experience nausea (a subjective unpleasant sensation associated with the urge to vomit) within the first 24 hours after surgery.

Plazo: 24 hours postoperatively

The proportion of patients who experience vomiting (expulsion of gastric contents) within the first 24 hours after surgery.

Plazo: 24 hours postoperatively

The total number of discrete nausea episodes experienced by each patient during the first 24 hours after surgery. An episode is defined as a distinct period of nausea separated from other episodes by at least 5 minutes of no nausea.

Plazo: 24 hours postoperatively

The total number of discrete vomiting episodes (forceful expulsion of gastric contents) experienced by each patient during the first 24 hours after surgery. An episode is defined as a distinct vomiting event separated from other vomiting events by at least 5 minutes.

Plazo: 24 hours postoperatively

The highest pain intensity score recorded within the first 24 hours after surgery, assessed using a 0-10 visual analog scale (VAS), where 0 represents no pain and 10 represents the worst imaginable pain. Pain scores are evaluated at 0, 6, 12, and 24 hours postoperatively; the peak score is the maximum of these four measurements for each patient.

A Prospective, Randomized, Controlled, Single-Blind Clinical Trial Comparing the Effects of Propofol, Ciprofol, and Remimazolam on Postoperative Nausea and Vomiting in Patients Undergoing Laparoscopic Cholecystectomy