This randomized controlled study was conducted at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China, between June 2017 and June 2018. This study was approved by the Obstetrics and Gynecology Hospital of Fudan University ethical committee (2017-22) and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment at clinicaltrials.gov (registration number: ChiCTR-IPR-17011658; principal investigator: Jia-wei Chen; date of registration: 2017/6/14).
This manuscript adheres to the applicable CONSORT guidelines.
Patients aged between 18-70 years with American Society of Anesthesiologists (ASA) physical status I-II who scheduled for laparoscopic radical hysterectomy under general anaesthesia were enrolled. Patients with opioid allergy, impaired kidney or liver function, history of abnormal anaesthesia, history of sedatives or antiemetic drug intake within 24 h of surgery, history of esophageal reflux disease, history of chronic obstructive pulmonary disease, shock, tumor involving the intestines, inability to understand the visual analogue scale (VAS) and inability to operate a patient-controlled intravenous analgesia (PCIA) device were excluded from the study. After a routine preanesthetic checkup, informed written consent was obtained from each patient.
Patients were randomly allocated to either the sufentanil (S) or the nalbuphine (N) group on the basis of drawing an opaque sealed envelope. Envelope randomization was performed with the use of a computer-generated code running a blocked randomization protocol. The anesthesiologists managing the intraoperative and postoperative courses as and the patients were blinded to any knowledge of the groups to which the patients belonged. The drug solution to be used intraoperatively was prepared by an assistant by dissolving 30 μg of sufentanil or 30 mg of nalbuphine in 10 ml of saline that was only labeled with a case number to keep the anesthesiologist “blind” from the patients assigned to each group. drug solution to be used postoperatively as PCIA was also prepared by the assistant by dissolving 2μg·kg-1 of sufentanil or 1mg·kg-1 of nalbuphine in 100ml of saline.
All anesthetic procedures were performed in a standardized fashion. Patients were transferred to the operating room and standard noninvasive monitoring was applied, including pulse oximetry, electrocardiography, and noninvasive blood pressure. The a right internal jugular vein catheter was inserted. General anaesthesia was intravenously induced with the unknown opioid in the dose of 0.1ml·kg-1 of the solution prepared, followed by propofol using target controlled infusion(TCI, the Marsh mode(12)) at Cpt of 6 μg·ml-1, and muscle relaxation was achieved by 0.2 mg·kg-1 of cis-atracurium. Endotracheal intubation was done after 3 minutes of bag and mask ventilation. Continuous monitoring of end tidal carbon dioxide was done after intubation. Anaesthesia was maintained with propofol using TCI at Cpt of 3 μg·ml-1 and continuous infusion of remifentanil in ntraoperatively. Mean arterial pressure and heart rate were maintained within ±20% of baseline values by adjusting the speed of remifentanil infusion. Mechanical ventilation was controlled using a ventilator and respiratory parameters were adjusted to keep end-tidal carbon dioxide at 35-45 mmHg. To maintain muscle relaxation, 4 mg of cis-atracurium were given every hour until an hour before the end of the operation.
Propofol was discontinued 10 minutes before the end of surgery and remifentanil was discontinued at the end of surgery. The neuromuscular blockade was reversed with neostigmine (0.02 mg·kg-1) and atropine (0.01 mg·kg-1). Clinicians were instructed to assess patients for adequacy of neuromuscular reversal using standard clinical criteria recommended by our department (5 s head lift or hand grip, eye opening on command, and negative inspiratory force more than -20 cm H2O). After extubation, the patients were transferred to the postanaesthesia care unit (PACU).
Patients in both groups were postoperatively treated with PCIA. One day before surgery, all patients were instructed on how to use the PCIA pump and rate pain intensity on a 10-cm visual analog scale, identifying 0 as “no pain” and 10 as “worst imaginable pain”. Once transferred to the PACU, a PCIA pump was attached and postoperative analgesia was started by administering a bolus of PCIA. Thereafter, patients were allowed to use PCIA themselves. The PCIA mode was set at a bolus of 2 ml with a lockout time of 10 minutes with basal infusing at 2 ml·h-1. At 24 hours after surgery, the basal infusion of the PCIA was reduced to 1 ml·h-1 to reduce the side effects.
On the day before surgery, patients received a clear liquid diet and bowel preparation with compound polyethylene glycol electrolytes (including NaCl 1.46 g, Na2SO2 5.68 g, KCl 0.74 g, NaHCO2 1.68 g, and polyethylene glycol 4000 59 g). To reduce the effects of other variables, the postoperative feeding regime was standardized for the patients: clear liquids were started beginning 8 hours after surgery if tolerated and a semiliquid diet was allowed beginning on the first day after surgery. Patients were allowed to progress to a solid diet in a patient-controlled fashion. Criteria for hospital discharge included stable vital signs with no fever for at least 24 h, ability to ambulate without assistance, ability to tolerate a semiliquid diet without vomiting, appearance of flatus and absence of other postoperative complications.
Our primary outcome measure was the time to the first passage of flatus after surgery. The secondary outcomes were the time to first defecation, the time to toleration of diet, pain intensity, the presence of nausea and vomiting, serum gastrin and length of hospital stay. Pain intensities were measured using a 100 mm VAS at 6, 12, 24 and 48 h after surgery. Opioid demand by patient-controlled analgesia (PCA) was monitored daily. The numbers of PCA events during postoperative 48 h was recorded. All patients were asked twice daily if first flatus and defecation had occurred. If defecation did not occur before hospital discharge, patients were asked every 2 days by telephone. Nausea and vomiting were noted by their presence. Once nausea and vomiting occurred, the gynecologist could administer 4 mg ondansetron. In the case of severe symptoms, after agreement with the patient, the PCIA pump was ceased and the case was noted. Any other side effect of opioids such as dizziness, pruritus and respiratory depression, defined as SpO2 <90%, was noted. 5mL of venous blood was taken for the serum gastrin immediately before the induction of anaesthesia and 24 hours after surgery. And the serum gastrin were measured by using a gastrin radioimmunoassay kit (Dainabot, Tokyo, Japan).
Our sample size was calculated based on the time to the first passage of flatus after surgery. According to our hospital, a sufentanil-PCIA just as Group S is routinely used in patient after laparoscopic surgery for gynecological malignancies. And the mean time to flatus was 29.0±9.27 h. A total of 41 patients needed to be recruited in each group for the results to identify a difference of 20% in the time to the first passage of flatus, with probabilities of two-side alpha and beta errors of 0.05 and 0.20, respectively. Sample size was increased to 100 patients to accommodate losses to follow-up and protocol violations.
Statistical analysis was performed using SPSS 19.0 for Windows (SPSS Inc., Chicago, IL). Whether variables were distributed normally was examined with the use of the Kolmogorov-Smirnov test. The χ2 and Fisher’s tests were used to compare categorical variables, the Student’s t test was used to compare normally distributed continuous variables, and the Mann-Whitney U test was used to compare variables that were not normally distributed. Data are presented as the mean ± standard deviation (SD), number (%) or median with interquartile range (IQR). We used an intention-to-treat protocol. A probability value of p <0.05 was considered significant.