The study was a prospective, randomized, observer-blinded, interventional, single-center trial, conducted in accordance with the current Declaration of Helsinki. Ethics approval was obtained from the institutional review board of the Hakodate Central Hospital, Hakodate, Japan (April 22, 2016, No. 2016-2). This trial was registered with the UMIN Clinical Trial Registry (UMIN 000023647).
Between August 2016 and February 2017, we enrolled 88 consecutive patients aged 20–60 years, who were scheduled to undergo elective laparoscopic gynecological surgery under combined general/epidural anesthesia. Written informed consent was obtained from all the patients before randomization. The exclusion criteria were patients with ASA physical status ≥ III, with pregnancy or cognitive dysfunction. Patients for whom surgical procedure was changed to laparotomy, epidural anesthesia was ineffective, or follow-up data were lost were also excluded.
After providing patients with an explanation of this study, to evaluate the PONV risk score, patients were asked three questions to ascertain whether they had a history of smoking, motion sickness, or PONV [14]. An affirmative answer for each question was scored 1 point. Subsequently, patients were randomly assigned to two groups using computer-generated random numbers (JMP, version 12.0.1; SAS Institute, Cary, NC, USA). The patient allocation was revealed to each anesthesiologist via a sealed envelope on the day of the surgery. The surgeons, anesthesiologists, statistical analysts, and medical staff in the operating room were not blinded to the treatment group, while the patients, ward staff, and observers were blinded.
No preoperative sedatives or analgesics were administered. After placing the peripheral vein and epidural catheters at the Th12/L1 level, an electrocardiogram, pulse oximetry, noninvasive arterial pressure, muscle relaxant, and end-tidal CO2 (EtCO2) monitors were used. Propofol was administrated via a target-controlled infusion (TCI) device (Cardinal Health, Basingstoke, UK), using a three-compartment model that was proposed by Schnider et al. [15]. Anesthesia induction was performed using propofol TCI (3–5 μg/ml), remifentanil (0.1–0.5 μg/kg/min), fentanyl (0.2–2 μg/kg), and rocuronium (0.6–0.9 mg/kg). Following tracheal intubation, the lungs were ventilated so as to maintain EtCO2 between 35 and 45 mmHg in 50% oxygen at a total flow of 1 L/min. Patients received either propofol alone (group P) or 0.8% sevoflurane and propofol (group SP) for maintenance of anesthesia. In addition to propofol with an infusion rate adjusted to maintain bispectral index (BIS; A-2000TM SP, Aspect Medical System, Norwood, MA, USA) between 40 and 60, i.v. remifentanil 0.05–0.25 g/kg/min and epidural ropivacaine (0.75%, 4–5 ml/h) were administered to all patients. Fentanyl, antiemetics, or nonsteroidal anti-inflammatory drugs were not administered during surgery. Rocuronium 10 mg was administered when train-of-four (TOF) count was > 1. Hypotension (MAP < 60 mmHg) was treated with intravenous phenylephrine or ephedrine.
The administration of propofol, remifentanil, and sevoflurane was stopped upon completion of the surgery. Sugammadex 2 mg/kg (when the TOF count was ≥ 2) or 4 mg/kg (when the TOF count was ≤ 1) was administered. Subsequently, patients were observed without being awoken until they naturally aroused. Tracheal extubation was performed when spontaneous breathing recovered sufficiently with a TOF count of > 0.9, and the patients were able to follow verbal commands.
After operation, 4 ml/h of 0.25% levobupivacaine was administrated via an epidural catheter for postoperative analgesia. Pain assessment was conducted by ward nurses every 3 h, and flurbiprofen or acetaminophen was administered for additional analgesia.
The primary outcome of this study was the incidence of PONV. We also scored the severity of the PONV (0 = no nausea, 1 = mild nausea recovered without antiemetics, 2 = severe nausea requiring antiemetics, and 3 = retching, vomiting, or both) every 3 h until up to 12 h post-surgery and then evaluated the maximum PONV score. We defined patients with a PONV risk score of 1 or less as low risk, and a PONV risk score of 2 or more as high risk, which was used to evaluate the max PONV score. Other factors that were evaluated included the following: level of agitation evaluated using the Ricker sedation scale (1–7 points); amount of coughing at two time points, immediately after extubation and on leaving the operation room [16]; pain scale (0–10) [17]; scores assigned to the quality of recovery assessed via a questionnaire [18]; and perioperative patient satisfaction scores (1 = very unsatisfied, 2 = somewhat unsatisfied, 3 = not satisfied or unsatisfied, 4 = somewhat satisfied, and 5 = very satisfied). These were recorded 24–30 h following the day of surgery.
The sample size was calculated by power analysis while designing the study. We included independent cases and controls, with 1 control per case. A previous study [19] indicated that the incidence of PONV after TIVA was 0.125 and that when using an inhalation agent was 0.415. On applying these results to the sample size calculation, a total of 36 experimental and 36 control subjects were required to reject the null hypothesis, and such that the failure rates for experimental and control subjects are equal with a power of 0.8. The probability of type I error associated with the testing of this null hypothesis was 0.05 with an uncorrected chi-squared test (PS: Power and Sample Size Calculation version 3.1.2, 2014, Vanderbilt University, Nashville, TN, USA).
The values were either expressed as median (interquartile range [IQR]) or by percentage of patients (%). Statistical analyses were performed using commercially available software (JMP, version 12.0.1; SAS Institute, Cary, NC, USA). An independent t test was used to analyze parametric data, and nonparametric data were analyzed by the Mann–Whitney U test. Categorical variables were evaluated by the Fisher exact test. P < 0.05 was considered statistically significant.
