Patients
This randomized, double-blinded, placebo-controlled trial was performed following approval of the ethics committee of the Liaocheng People’s Hospital. The trial was registered with chictr.org before enrollment of the first participant (Trial registration: ChiCTR, ChiCTR2000029326. Registered 25 January 2020, http://www.chictr.org.cn), and written informed consent was obtained from all patients prior to enrollment. All findings are reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines.
All enrolled patients were scheduled to undergo laparoscopic radical resection (Dixon operation) following diagnosis of clinical stage I or II rectal cancer at the Liaocheng People’s Hospital between January 2020 and June 2020. The inclusion criteria were age between 35 and 70 years, ability to understand and use the pain assessment method, and physical status of I to III according to the American Society of Anesthesiologists (ASA). The exclusion criteria were history of allergy to local anesthetics, history of opioid abuse, history of treatment for another cancer, refusal to use patient-controlled analgesia (PCA), need for resection of another organ(s) in addition to the rectum, history of previous abdominal surgery, and preoperative intestinal obstruction requiring emergency surgery.
Randomization and blinding
Two days before surgery, a computerized random number generator was used to assign equal numbers of eligible participants to one of the three groups. The TR Group received US-guided bilateral posterior TAPB with 40 mL of 0.33% ropivacaine and RSB with 20 mL of 0.33% ropivacaine; the T Group received US-guided bilateral posterior TAPB with 40 mL of 0.33% ropivacaine and RSB with 20 mL of 0.9% normal saline; the Control Group received US-guided bilateral posterior TAPB with 40 mL of 0.9% normal saline and RSB with 20 mL of 0.9% normal saline. Patients in all groups also received postoperative patient controlled intravenous analgesia (PCIA) (see below for details). Randomized results were kept in a sealed envelope and relayed to an independent nurse anesthetist who prepared the drug or placebo on the morning of the operation. The remainder of the clinicians, the main anesthesiologist, and the anesthesiologist who administered the TAPB were all blinded to the group allocations.
General anesthesia and monitoring
All patients underwent regular fasting for 8 to 12 h without any preoperative medication. Before the induction of anesthesia, intravenous (IV) fluids were administered at a rate of 10 mL/kg/h, and the heart rate, continuous invasive arterial blood pressure, pulse oxygen saturation, bispectral index (BIS), and nasopharyngeal temperature were continuously monitored using a multifunction monitor (Philips IntelliVue MP50, Boeblingen, Germany). For all patients, anesthesia was induced with IV propofol (2.0 mg/kg), fentanyl (3 µg/kg), and cisatracurium (0.15 mg/kg), according to standard general anesthesia guidelines set by the institute. Tracheal intubation was performed after muscle relaxation. Anesthesia was maintained using inhalational sevoflurane and remifentanil. To maintain a BIS value of 40 to 60 and a mean arterial pressure within 20% of the baseline value, sevoflurane and remifentanil were continuously adjusted. Ephedrine was administrated if the intraoperative blood pressure was more than 20% below the baseline, and atropine was administered if the heart rate was lower than 50 bpm. IV cisatracurium (0.03 mg/kg) was added hourly until the end of the operation.
Surgery
Laparoscopic incision and trocar insertion were performed by adopting the five hole method. The five incisions were: (i) on the supraumbilical site; (ii) 2 finger widths inside the right anterior superior iliac spine; (iii) 3 to 4 cm above the cross point of the right clavicular midline and the umbilicus intersection; (iv) at the mid-point of the line between the left anterior superior iliac spine and umbilicus; and (v) 2 finger widths above the symphysis pubis, which could be expanded to 5 or 6 cm for specimen removal (Fig. 1). The pneumoperitoneum was established with carbon dioxide, and pressure was 12 to 14 mmHg (1.36 to 1.58 kpa). The operation was performed according to the specifications and principles of laparoscopic and radical resection of rectal cancer (i.e. total mesorectal resection (TEM), thorough lymphadenectomy, and tumor eradication). The Dixon operation was used based on tumor location.
US-guided TAPB and RSB
After removal of the tracheal tube, TAPB was performed immediately by a qualified anesthesiologist using US guidance (SonoSite S-Nerve Ultrasound System) and a broadband (4 to 13 MHz) linear array ultrasound probe. For the posterior approach, the probe was placed transversely in the midaxillary line between the iliac crest and the costal margin [8]. Then, the probe was moved outward and the needle was inserted when the TAP was identified. When the tip of the needle was in the TAP, 2 mL of normal saline was injected to adjust its position. Then, 40 mL of 0.33% ropivacaine was administered to the TR Group and T Group, and 40 mL of 0.9% normal saline was administered to the Control Group (Fig. 2). Next, RSB was performed on both sides of the linea alba under US-guidance [7]. For the RSB, the probe was placed transversely on the rectus abdominis and the needle was inserted using US guidance until the tip was in the plane between the rectus abdominis and the posterior sheath of the rectus abdominis [9]. Patients in the TR Group received 20 mL of 0.33% ropivacaine, and patients in the T Group and Control Group received 20 mL of 0.9% normal saline. The procedure was divided into 3 or 4 injection sites on the left and right sides of the surgical site (Fig. 3).
Postoperative care
Sufentanil was used for PCIA, which was initiated in the post-anesthesia care unit (PACU). The PCIA regimen consisted of 300 mL of 0.8 µg/mL sufentanil, with a bolus dose of 2 mL, a lockout time of 5 min with no background infusion, and a 4-h maximum limit of 30 mL (24 µg). The aim of PCIA was to control pain intensity based on a numerical rating scale (NRS) at rest of 4 or less. The NRS is an objective pain intensity assessment tool that has a scale of 0 to 10, in which 0 indicates no pain and 10 indicates the worst pain possible. Any patient whose NRS value at rest was above 4 was given a loading dose of 4 mL (3.2 µg) sufentanil, and had a 4 h maximum limit of 40 mL. For patients with insufficient analgesia or sufentanil intolerance, additional rescue analgesia was given (30 mg IV ketorolac).
Data Collection
Sufentanil-based PCIA was used in all groups with the same regimen for 72 h after surgery. The cumulative PCA usage during three time period after the operation (0 to 24 h, 24 to 48 h, and 48 to 72 h) was the primary outcome, and was recorded by a blinded member of the acute pain service (APS) team. The secondary outcomes were postoperative pain intensity on the NRS and functional activity score (FAS) at rest and during coughing after 24, 48, and 72 h [10]. The FAS is a subjective pain intensity assessment tool that uses grades A, B, and C. Grade A indicates that functional activity is not limited by pain; grade B indicates that functional activity is moderately limited because of pain; and grade C indicates that functional activity is severely limited because of pain. Use of intraoperative medications and rescue analgesia were recorded. In addition, the time to first flatus, defecation, oral intake, and discharge were recorded. All adverse effects possibly due to sufentanil, such as nausea, vomiting, pruritus, respiratory depression, and dizziness, were recorded.
Statistical Analysis
The sample size was based on the initial pilot data, in which the means ± standard deviations of sufentanil use during the 24 h period after surgery were recorded. (Control Group: 84 ± 47 µg, T Group: 80 ± 37 µg, TR Group: 41 ± 16 µg). Based on a power of 95% and a significance level of 5%, 20 patients per group were necessary. Assuming a 30% dropout rate, a minimum of 26 patients per group were enrolled.
Statistical analysis was performed using SPSS 16.0 (SPSS Inc. Chicago, IL). The Kolmogorov-Smirnov test was used to assess the distributions of variables, and homogeneity of variance was determined using Levene’s test. Data with normal distributions are presented as means and standard deviations and data with non-normal distributions are presented as medians and interquartile ranges. Categorical data are presented as number (n) and percentage (%). Non-parametric tests were used to compare data with non-normal distributions; the Kruskal-Wallis H method was used for overall comparisons, and the Mann-Whitney U method was used to compare differences between groups. Categorical variables were analyzed using the χ2 test or Fisher’s exact test. P values below .05 were considered significant.