The Ethics Committee of The Affiliated Hospital of Xuzhou Medical University has authorized the prospective, randomized controlled trial (XYFY2022-KL037-02). The trial was registered on the Chinese Clinical Trial Registry prior to initiation (ChiCTR2200066138). The study was in accordance with the Declaration of Helsinki and its later amendments. All patients provided their written informed consent. The trial report complies with the Consolidated Standards of Reporting Trials (CONSORT) checklist (Supplementary Material, Table S1).

Patients were between 18 and 65 years old, with Body Mass Index (BMI) over 30 kg/m2, American Society of Anesthesiologists (ASA) classification II–III, and were scheduled for LBS. The study’s exclusion criteria included: (a) allergy to any medication used in the study, (b) known hyperthyroidism or pheochromocytoma, grade III hypertension (very high risk), severe arrhythmias, severe cardio-cerebrovascular disease, or hemodynamic instability, (c) severe hepatorenal insufficiency, (d) recent use of any tricyclic antidepressants, sedatives, opioids, monoamine oxidase inhibitors, or sleep-inducing medications within the past month, (e) anemia with hemoglobin levels less than 9.0 mg/dL, and (f) refusal to provide informed consent or inability to cooperate with the researcher.

Each individual was randomly assigned on the basis of a random table from http://www.randomization.com in a 1:1 ratio to either the esketamine group (group E) or the control group (group C). The patient’s allocation was placed in an opaque and sealed envelope. Upon admission to the surgical center, the envelope was opened by a separate anesthetist who had no involvement in patient care or data collection. This anesthetist was responsible for preparing 20 mL syringes of 0.9% normal saline with or without 50 mg esketamine, which run at a rate of 0.2 mL/kg/h during surgery. Besides, emergency envelopes containing the case medication number and drug name were prepared to enable the unblinding and resuscitation if necessary. Other staff members could not identify the group of preparation in light of its appearance. Surgical team members, anesthetists, data collectors, and statisticians were blinded to the group allocation. The trial’s surgical procedures were conducted exclusively by a single surgical team.

All patients were required to fast for 8 h before surgery. After they were admitted to the operating room, electrocardiography, heart rate, invasive blood pressure, blood oxygen saturation (SpO2), anesthesia index (Ai), and train-of-four stimulation (TOF) were routinely monitored. Ai with a range from 0 to 100, was monitored by Pearlcare Anesthesia Depth Monitor (Conview YY-105). A low value indicated deeper anesthesia. After preoxygenation for 5 min, anesthesia was induced with 0.05 mg/kg midazolam, 0.5 µg/kg sufentanil, 0.3 mg/kg etomidate, rocuronium 0.8 mg/kg, and dezocine 5 mg. All drug dosage calculations were based on lean body weight (LBW). The patient was intubated using an endotracheal tube upon a TOF of 0 and an Ai of 60. After intubation, the ventilation mode was changed to pressure-control-volume-guaranteed (PCV-VG) mode: oxygen concentration 60%, oxygen flow 2 L/min, positive end-expiratory pressure 5 cmH2O, partial pressure of end-tidal carbon dioxide (PetCO2) 35–40 mmHg. All patients received transverse abdominal plane (TAP) blocks with 20 mL of 0.25% ropivacaine on each side under ultrasound guidance.

General anesthesia was maintained with 1% sevoflurane, propofol at 4–6 mg/kg/h, and remifentanil at 0.1–0.3 μg/kg/min. Infusions of the study medications were followed by endotracheal intubation. Group E received 0.5 mg/kg/h esketamine (i.e., 0.2 mL/kg/h) infusion. Group C received 0.2 mL/kg/h normal saline. The infusions were stopped 20 min before the end of the procedure. During surgery, the infusion rate of propofol or remifentanil was adjusted by an experienced anesthesiologist to maintain mean arterial pressure (MAP) within ± 20% of baseline values and an Ai value within 40–60. In case of mean blood pressure (MBP) below 30% of baseline values, injections of 3 mg ephedrine [heart rate (HR) < 50 beats/min] or 40 μg phenylephrine (HR ≥ 50 beats/min) were given; when MBP was above 30% of baseline values, 5 mg urapidil was injected. In case of bradycardia (HR < 50 beats/min), 0.5 mg atropine was administered. These measures would be repeated as necessary. Rocuronium or cisatracurium was titrated on the basis of TOF, surgeon demand, or post-tetanic count over 15. Pneumoperitoneum inflation pressure ranged from 12 to 15 mmHg.

For both groups, all patients received an intravenous infusion of crystalloid and colloid solution in a 2:1 ratio. All subjects received systematic prophylaxis for nausea and vomiting, including dexamethasone 5 mg and phencyclidine hydrochloride 10 mg before the operation and palonosetron 0.25 mg at the end of the operation. Ketorolac 60 mg was given intravenously 20 min before the end of surgery. Upon skin closure, inhaled drugs ceased, and oxygen flow was increased to 8 L/min to hasten sevoflurane washout. Once closure has been completed, propofol and remifentanil were discontinued, and 0.5 mg flumazenil was injected intravenously. The residual neuromuscular block was antagonized by 0.04 mg/kg neostigmine and 0.02 mg/kg atropine. All patients were extubated in the operating room when T4/T1 was > 90% and tidal volume was > 5 mL/kg and then transported to the postanesthesia care unit (PACU).

In PACU, patients received standard postoperative monitoring and 2–3 L/min oxygen by nasal cannula. If the NRS score exceeded 4 points, 5 mg of dezocine would be injected intravenously. If SpO2 ≤ 90%, patients were alerted by waking them up and asking them to breathe deeply. Supplemental oxygen of the mask was initiated at 2 L/min if the respiratory rate was less than 8. The patients were transferred to the ward upon Modified Aldrete Score (MAS) above 9 points. On the surgical ward, ketorolac 30 mg was routinely administered intravenously every 8 h and use of dezocine depended on the patient’s needs. Patients were encouraged to early ambulation and to take a deep breath on the POD 1.

The primary outcome was the QoR-40 score assessed on postoperative day 1 (POD 1). The questionnaire evaluates five components of patient recovery: physical comfort (12 questions), physical independence (5 questions), emotional state (9 questions), psychological support (7 questions), and pain (10 questions). The QoR-40 questionnaire is scored on a scale of 40–200. Each patient was provided with a detailed explanation of all questions in the QoR-40 questionnaire on the day prior to surgery.

The secondary outcomes included time to extubation, additional postoperative analgesic use, QoR-40 on PODs 2 and 7, Numeric Rating Scale (NRS) on PODs 1, 2 and 7, length of hospital stay, and time to first exhaust (the interval between the end of surgery and the first flatulence). Patients who were discharged prior to POD 7 were contacted by mail or telephone by a team member to complete the QoR-40 and NRS questionnaires.

The safety indices were the utilization of vasoactive drugs or urapidil and the incidence of side effects (PONV, urinary retention, itching, or adverse central nervous system events). In addition, MAP, HR, and Ai were recorded at baseline (T0), 5 min (T1), 10 min (T2), 15 min (T3) and 30 min (T4) after intubation, at extubation (T5), and 5 min after extubation (T6).

The sample size was calculated based on the results of the pilot study (unpublished data, n = 20) using PASS version 15.0. The mean QoR-40 scores in the ketamine and control groups were 175.0 and 168.7, the standard deviations (SDs) were 7.46 and 6.99, respectively. Assuming an α of 0.05, β of 0.1, and a dropout rate of 20%, with a two-tailed analysis, each group required 37 patients in this trial. Eventually, 74 cases were needed to be recruited for this study.

We performed the data analysis with Statistical Package for Social Sciences (SPSS) software version 26.0 and GraphPad Prism version 8.0. A two-sided p < 0.05 was considered statistically significant. The statistical analysis was performed per protocol. For continuous data, the Shapiro–Wilk test, combined with histograms, was used to determine the normality of data. Normally distributed data were reported as mean ± SD and evaluated using a two-sided t-test for equal variances. Non-normally distributed interval and ordinal data were presented as median (interquartile range) and evaluated using the Mann–Whiney U test. Categorical variables were summarized as absolute numbers (%) and assessed using a chi-squared test (χ2) and Fisher’s exact test.

Repeated normally distributed variables with a confounding variable (HR, MAP, Ai) were assessed by analysis of covariance (ANCOVA). The covariates were the baseline measurement. The sphericity was assessed with Mauchly’s test, and if the assumption of sphericity was violated, the Greenhouse–Geisser correction would be used for correcting the degrees of freedom. For repeated abnormally distributed variables (NRS, QoR-40), a generalized estimating equation (GEE) was used for comparison.

We conducted multiple linear regression analyses to assess the association between QoR-40 scores on POD 1 and various factors. We checked for multicollinearity among the independent variables using variance inflation factor (VIF), and considered a VIF > 10 to indicate statistically significant multicollinearity. Our independent variables included age, BMI, patient sex, ASA status, surgery type, surgery time, intraoperative sevoflurane and remifentanil doses, preoperative QoR-40 score, and group allocation. We performed univariate linear regression to identify variables with p < 0.1, which were then included in subsequent multivariate linear regression analyses.

Post hoc exploratory subgroup analyses of the primary endpoint were also performed according to age, sex, BMI, surgical type, and ASA grade. The subgroup results were presented in the form of mean ± SD and interaction p values.