This prospective, randomized, double-blinded trial was approved by the Biomedical Research Ethics Committee of Peking University First Hospital (2017-1398). It was registered at http://www.chictr.org.cn with an identification number of ChiCTR-INR-17013244. Written informed consent was obtained from each patient. The study adhered to the CONSORT guidelines.
Potential participants were screened the day before surgery. Patients aged between 18 and 70 years and scheduled to undergo elective laparoscopic radical or partial nephrectomy through the retroperitoneal approach were included. Patients who met any of the following criteria were excluded: (1) chronic opioid addiction and/or use of other kinds of analgesic drugs for more than 3 months; (2) inability to communicate due to severe dementia, language barrier, or end-stage disease; (3) allergic to local anaesthetics; (4) nerve block contraindication such as an infection in the puncture site or severe coagulation dysfunction; and (5) refusal to participate in the study. Patients who were enrolled for this trial were taught how to evaluate pain intensity by using the numeric rating scale (NRS, an 11-point scale where 0 indicates no pain and 10 indicates the worst pain) and how to use a patient-controlled analgesia (PCA) device.
Anaesthesia management and surgical technique
All patients were managed according to a standardized anaesthetic protocol. Anaesthesia was induced with sufentanil, propofol and etomidate. Endotracheal intubation was facilitated with cisatracurium or rocuronium. Anaesthesia was maintained with continuous infusion of propofol, remifentanil (and intermittent sufentanil) or sufentanil, with or without dexmedetomidine; the aim was to maintain the BIS values between 40 and 60, and the mean arterial pressure and heart rate within 20% of the preoperative values. At 30 minutes before the end of surgery, 50 mg of flurbiprofen axetil and 5 mg of tropisetron were administered intravenously. After emergence from anaesthesia, all patients were monitored in the post-anaesthesia care unit (PACU) for at least 1 hour before transferred to the general ward.
The retroperitoneal laparoscopic procedure was usually performed through three ports. The primary port was invariably placed through the incision made for the creation of the working space, which was just below the tip of the 12th rib on the posterior axillary line. The secondary port was placed 2 cm above the iliac crest on the midaxillary line. The third port was placed under the costal margin on the anterior axillary line. In case of radical nephrectomy, the initial incision was extended ventrally for kidney removal. The pneumoperitoneum was maintained at approximately 12-14 mmHg throughout the procedure (Figure 1).
For all patients, a standard postoperative pain management was provided, i.e., a PCA pump, which was established with 1.25 µg/ml sufentanil and programmed to administer a background rate of 0.5 ml/h and an on-demand bolus of 4 ml every 10 minutes, together with a rigorous rescue analgesia plan. The target was to maintain the NRS pain score below 4. In the PACU, regular pain evaluation was performed every 30 minutes. If the NRS score was higher than 4, a PCA bolus of 4 ml was administered first, and pain was evaluated 5 min later. If the NRS score remained higher than 4, another 3-5 µg sufentanil was administered intravenously according to the patient’s body weight. No more rescue analgesics were administered if the NRS score decreased to 4 or less. In the general ward, pain evaluation was performed at 2, 6, 12, and 24 hours after surgery; in addition, patients were instructed to request additional analgesia in case of breakthrough pain. Pain control measures were similar to those in the PACU, except that morphine (3-5 mg) was administered instead of sufentanil. NSAIDS or other analgesics could also be administered according to the surgeons’ prescription.
Randomization and intervention
Stratified randomization with a block size of 4 was performed using the SAS statistical package version 9.3 (SAS Institute, Cary, NC, USA) by a biostatistician (XLN) who was not involved in the data management and statistical analyses. Stratification was performed according to the planned type of surgery, i.e., radical or partial nephrectomy. The randomization results were then sealed in sequentially numbered envelopes, transferred to a study coordinator (TTJ) with the Good Clinical Practice (GCP) certification and stored at the site of the investigation until the end of the study.
The day before surgery, an investigator (ZML) screened potential participants and recruited patients after obtaining written informed consents. On the day of surgery, the study coordinator opened the envelopes consecutively according to the recruitment sequence and prepared the study drugs for each patient, but did not participate in the rest of the trial. All study drugs were provided as clear aqueous solutions in the same 20 ml syringes for TAP block. In this way patients were randomly assigned into two groups: patients in Group T received 30 ml of 0.4% ropivacaine, while those in Group C received an equivalent amount of normal saline. Apart from the study drugs used for TAP block, other perioperative management was identical in both groups. All health-care team members, investigators, and patients themselves were fully blinded to the group assignments throughout the study period.
Ultrasound-guided TAP block was performed by two experienced anaesthetists (DH and HK) immediately after the induction of anaesthesia and approximately 15 minutes before skin incision. With the patient in the supine position, the ultrasound probe was placed at the midaxillary line between the lower costal margin and the iliac crest. At this point, the plane between the internal oblique and transverse abdominal muscles was identified (Figure 2A). A special needle used for nerve block (80 mm or 100 mm, Stimuplex D, Germany) was inserted using an in-plane technique in the anteroposterior direction. After aspiration, to avoid inadvertent intravascular injection and abdominal paracentesis, an injection with 2 ml of normal saline was used to ensure correct positioning of the needle. The prepared study drug was then injected into this plane. Successful study drug injection was defined as the appearance of a hypoechoic ellipsoid with well-defined margins on ultrasonic imaging (Figure 2B).
Follow-up schedule and outcomes
Investigators (XL, ZZX, and ZML) who were blinded to the study group assignment were in charge of the perioperative data collection. Patients were followed-up at several time points in the first 24 hours after surgery. In addition, the electronic medical record was reviewed to obtain necessary data.
The primary outcomes were opioid consumption (intravenous morphine equivalent dose) during surgery and within the first 24 hours after surgery. The secondary outcomes included the following: (1) the NRS pain scores both at rest and with coughing immediately awakening from anaesthesia and at 0.5, 1, 2, 6, 12 and 24 hours after surgery; (2) time to the first bolus demand in the PCA system, as well as the numbers of required and administered bolus; (3) time to the first rescue analgesic, as well as its use and frequency in addition to the PCA system; (4) the incidence of postoperative nausea and vomiting (PONV) within 24 hours after surgery and the use of antiemetics; (5) subjective sleep quality on the night of surgery evaluated by the NRS (an 11-point scale where 0 indicates the best sleep quality and 10 indicates the worst sleep experience); (6) time to the first ambulation after surgery; (7) drainage during the first 24 hours after surgery; and (8) the length of hospital stay after surgery.
Safety outcomes were monitored from the beginning of anaesthesia until 24 hours after surgery. The adverse events associated with TAP block included but not limited to the following: numbness in the lower extremities, haematoma and bleeding in the needle trajectory, visceral organ injury, anaphylaxis, local anaesthetic toxicity. Other perioperative adverse events were also documented.
Sample size estimation
According to previous studies [10,12, 13], the use of TAP block decreased opioid consumption by 13.5%-45.3% compared with the placebo during the first 24 hours after surgery. We conservatively assumed that opioid consumption would be reduced by 10% in the TAP block group. Sample size calculation was performed based on the previous data obtained from our clinical follow-up system, which showed that the total consumption of sufentanil (within 24 hours after surgery) in patients who underwent RLRS without TAP block was 36.5 ± 5.4 μg. With the significance and power set at 0.05 (two-sided) and 90%, respectively, the sample size required to detect differences was 94 patients. Taking into account a drop-out rate of approximately 10%, we planned to enrol 104 patients. Sample size calculation was performed with the PASS 11.0 software (Stata Corp. LP, College Station, TX).
Normally distributed continuous variables are expressed as the mean ± standard deviation and were compared using a two-tailed Student’s t-test. Non-normally distributed continuous variables and ordinal data are expressed as medians (interquartile range) and were compared using the Mann-Whitney U test. Categorical variables are expressed as numbers (percentages) and were compared with Chi-squared analysis or Fischer’s exact test. Time-to-event data were analysed by the Kaplan-Meier estimator, with the difference between groups compared by the log-rank test. Per-protocol analysis was performed. Two-sided P values of less than 0.05 were regarded as statistically significant. All statistical analyses were performed with the SPSS statistical package version 25.0 (IBM SPSS Inc., Chicago, IL, USA).