S-ketamine promotes postoperative recovery of gastrointestinal function and reduces postoperative pain in gynecological abdominal surgery patients: a randomized controlled trial

The double-blind, prospective randomized controlled trial was conducted in a tertiary hospital in Beijing, China. This study was approved by the Institutional Review Board at Peking University Cancer Hospital’s Ethics Committee (No.2021YJZ109) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry (No. ChiCTR2200055180, Principal investigator: Hongyu Tan, Date of registration: January 02, 2022). This article adheres to applicable Consolidated Standards of Reporting Trials (CONSORT) guidelines.

Eligible patients were recruited at the Peking University Cancer Hospital from January 2022 to July 2022 if they (1) were aged 18–65 years, with body mass index (BMI, in kg/m²) between 18 and 30, were diagnosed with gynecological cancers, and underwent elective open abdominal gynecological surgery, (2) were stratified by the American Society of Anesthesiologists (ASA) grade into I-II, (3) were expected to be hospitalized for over 4 days, and (4) had the operation finished before 20:00 of the day.

All eligible patients were randomly assigned to the S-ketamine group (group S) or placebo (0.9% saline) group (group C) in a 1:1 ratio. The randomization was performed by a data manager who was not involved in determining eligibility or assessment of outcomes. The participants were randomized using random number tables. A research nurse who was independent of the recruitment process opened each patient’s envelope containing the random numbers upon completion of the baseline assessment. Patients with the following conditions were excluded from the study: (1) refusal to participate in the study; (2) tumor recurrence; (3) multiple primary malignant tumors; (4) current and chronic use of analgesics, psychotropic medications, hormones, or non-steroidal anti-inflammatories; (5) a history of chronic pain, schizophrenia, epilepsy, dementia; (6) a history of diabetes with uncontrolled hypertension or blood glucose; (7) hepatorenal dysfunction; (8) any contraindications to the anesthetic agents used during surgery; (9) any of the gynecologic disease such as pelvic inflammatory disease, endometriosis ovarian cyst rupture with hemoperitoneum. The enrolled patients’ age, BMI, ASA physical status, preoperative comorbidity, and type of gynecological cancer were recorded.

Patient monitoring in the operating room was performed using electrocardiography, pulse oximetry, end-tidal carbon dioxide, invasive arterial pressure, urine output, and the bispectral index (BIS). All patients received general anesthesia induced by intravenous administration of 2 mg/kg of propofol, 0.4 μg/kg of sufentanil, and a single dose of 0.2 mg/kg cisatracurium to facilitate endotracheal intubation. In group C, general anesthesia was maintained by inhalation of 1% sevoflurane and intravenous administration of 2–4 ng/ml (plasma concentration) remifentanil and 1–3 μg/ml (plasma concentration) propofol. In group S, general anesthesia was maintained by the same doses of sevoflurane, remifentanil, and propofol, and an additional target-controlled infusion (CP-600TCI; SLGO, Beijing, China) of 0.2 mg/kg/h S-ketamine (Hengrui Medicine Co., Ltd., Jiangsu, China). The oxygen inhalation flow rate was 50% during anesthesia, and the ventilator was adjusted to maintain the end-tidal carbon dioxide at 35 to 45 mmHg. Sevoflurane and propofol concentrations were adjusted to maintain an adequate depth of anesthesia according to theBIS (spectral entropy value of 40 to 60). Remifentanil concentrations were adjusted by hemodynamic changes. Intravenous sufentanil (10 μg) and ketorolac tromethamine (15 mg) were administered 30 min before the end of the surgery. Tropisetron (5 mg) was administered 15 min before the end of the surgery.

S-ketamine was discontinued 30 min before the end of the surgery. Following surgery, patients were connected to PCIA pump containing 120 ml of 2 μg/kg of sufentanil, 90 mg ketorolac tromethamine, and 20 mg tropisetron in 0.9% sodium chloride solution in group C. An additional 50 mg S-ketamine was added in group S. The PCIA pump was programmed to deliver a loading dose of 2 ml, a 1 ml/h basal infusion, a 2 ml bolus dose with a lockout interval of 10 min, and a maximum dose of 13 ml/h. At the end of the operation, the patient was transferred to the post-anesthesia care unit and then transferred to the ward after extubation. The dose of S-ketamine infusion during surgery, total intraoperative infusion, red blood cell transfusion requirement, blood loss, total urine output, and general anesthesia time were recorded.

Postoperative pain at rest was assessed using the VAS (ranging from 0 to 10, 0 = no pain, 10 = the worst imaginable pain). Patients received 0.1 μg/kg of sufentanil administered by an anesthesiologist to achieve a VAS score ≤ 3 before discharge from the post-anesthesia care unit. If the VAS score > 3, 0.1 μg/kg sufentanil was given repeatedly in intervals of at least 15 min until the VAS score ≤ 3. Postoperative visits were performed by a nurse anesthetist who was independent of the research process. Additional analgesic drugs (primarily intravenous morphine) were given by surgeon whenever the VAS score was > 3 after pressing the PCIA pump frequently. The S-ketamine consumption of PCIA, first postoperative flatus time of patients, VAS scores at 24 h and 48 h after surgery, the additional requirement of analgesic drugs, and sufentanil consumption of PCIA in the first postoperative 24 h were recorded from the time when the patient was discharged from the post-anesthesia care unit. All adverse events such as dizziness, nausea, and vomiting were documented.

In a preliminary trial that we conducted, the mean of first postoperative flatus time in patients who accepted additional use of S-ketamine was 2.01 days, the standard deviation (SD) was 0.736. The mean of first postoperative flatus time in patients without S-ketamine was 2.54 days, the SD was 0.694. According to PASS 15 power analysis and sample size software (NCSS, LCC. Kaysville, Utah, USA, ncss.com/software/pass.) using a test for two sample T-tests allowing unequal variance with a randomization ratio of 1:1, sample size was 40 patients per group was calculated to provide 90% power to detect this difference based on a two-tailed significance level of 0.05. Considering a dropout rate of about 20%, we intended to enroll 50 patients in each group.

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 20.0 software (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). Continuous variables with normal distribution are presented as mean ± SD. Non-normal variables are presented as median (interquartile range), and categorical data are presented as percentages (%). Continuous variables were analyzed using the independent-sample t-test or the Mann–Whitney U test, with differences expressed as 95% confidence interval (CI). Categorical variables were analyzed using the χ² test. A two-sided P value of < 0.05 was the statistical significance level.