Trial Design and Participants
Before patient enrollment, the trial was approved by the Ethical Committee of Henan University (registration no. 2018LW012) on October 20, 2018. The trial was conducted in accordance with the Declaration of Helsinki and registered at the Chinese Clinical Trial Registry (registration no. ChiCTR1800019209, chictr.org.cn). The actual research start date was November 15, 2018, and the main actual completion date was December 31, 2019. A data and safety monitoring board (DSMB) was established to oversee the safety of the study and check the integrity of data.
This LWINK trial was a single-center, prospective, randomized, double-blind study. Patients with American Society of Anesthesiologists (ASA) physical status classes I–III, aged 28–80 years and scheduled for open colorectal surgery were considered eligible to participate in the study after providing written informed consent. Major exclusion criteria included allergy to the study drugs (local anesthetics, opioids and NSAIDs); chronic pain treatment or chronic steroid therapy ; psychiatric disorders; neuromuscular or endocrine diseases; diabetes mellitus; coagulopathy; cardiac, liver or renal diseases; and pregnant and lactating women. Those who underwent laparoscopic surgery, were sent to the intensive care unit after the operation, presented severe postoperative infection, or refused to participate in the study were also excluded from the study.
Randomization and Blinding
A computer-generated simple randomization list was used to classify the patients into three groups at a 1:1:1 ratio using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp. Armonk, NY, USA). The three groups were as follows: group R (n = 41): 10 mL of ropivacaine 0.75% + 20 mL normal saline; group RN (n = 42): 10 mL of ropivacaine 0.75% + 19 mL normal saline + subcutaneous injection of nalbuphine (10 mg) in 1 mL; and group RK (n = 41): 10 mL of ropivacaine 0.75% + 19.2 mL normal saline + subcutaneous ketorolac (25 mg) in 0.8 mL.
Intravenous nalbuphine or ketorolac was not administered to all patients perioperatively. Before the operation, an anesthesiologist, blind to the groups, evaluated the preoperative status of the patients to determine whether they met the inclusion criteria of the study. All patients were taught how to use patient-controlled intravenous analgesia (PCIA) and the numerical rating scale (NRS, with 0: no pain, to 10: the worst imaginable pain). The randomization numbers were stored in a locked container in the operating room. A nurse who did not participate in the trial opened the appropriate numbered envelope and prepared the drugs. The syringe cylinder was covered using the same opaque material for uniformity. Incision length was measured before skin closure, and the group of surgeons who were not involved in the study performed the LWI.
All patients were instructed to fast for 8 h and refrain from intake of water for 4 h. In the operating room, peripheral venous access was established, and an infusion of a lactated Ringer’s solution was initiated. Five-lead electrocardiogram (ECG), heart rate (HR), noninvasive blood pressure (BP), respiratory rate (RR), and pulse oxygen saturation (SpO2) were continuously monitored. Radial artery catheterization was performed to measure mean arterial pressure (MAP). Catheterization was conducted via the right internal jugular vein or right subclavian vein to monitor central venous pressure (CVP).
General anesthesia was induced with 0.5 μg/kg of sufentanil, 0.15–0.30 mg/kg of etomidate, and 0.2 mg/kg of cisatracurium. Etomidate, sevoflurane, remifentanil and cisatracurium were used to maintain the bispectral index (BIS) at 40–60, thereby maintaining anesthesia. After the operation, all patients were connected to the prepared PCIA pump and sent to the post-anesthesia care unit (PACU) for further observation.
Standardized analgesia was used in patients as follows: (1) The drug was infiltrated into the tissues around the entire incision, including the muscles and subcutaneous tissue, with 1 mL of drug per 1 cm incision. (2) For postoperative analgesia, all patients received PCIA. PCIA was administered for NRS ≥ 4 or upon patient request. The analgesic pump configuration was as follows: 2.0 μg/ kg sufentanil diluted to 100 mL (0.5 mL bolus, a lockout time interval of 15 min and 1 h of 2 mL without any baseline infusion). (3) During early recovery in the PACU, rescue intramuscular morphine was given as needed when NRS was ≥ 4; tropisetron 5 mg was injected intravenously when nausea and vomiting occurred. (4) In the ward, additional rescue analgesia measures (intravenous morphine 5 mg) were taken whenever the PCIA analgesic effect was still unsatisfactory.
The primary outcome was analgesia duration, defined as the time in minutes to the first press of the analgesia pump. The total morphine-equivalent consumption over the 48-h postoperative period and the additional rescue analgesia rates for the three groups were recorded within 2 days after surgery as key secondary outcomes. The total morphine-equivalent consumption included both sufentanil dose in the PCIA pump and rescue morphine dose. We employed a published equivalence formula, cumulative opioid consumption with opioid drugs other than morphine converted to morphine-equivalent doses, where 10 mg intravenous (i.v.) morphine = 0.01 mg i.v. sufentanil. Other secondary outcomes were NRS (score range, 0 [no pain] to 10 [worst imaginable pain]) scores on resting and moving (taking a deep breath) at 2, 4, 8, 12, 24, 48, and 72 h postoperatively. Adverse events (nausea, vomiting, local anesthetic toxicity, hypotension, bradycardia, gastrointestinal bleeding, pruritus and wound infection) from 0 to 48 h were also recorded as exploratory outcomes.
We conducted a preliminary study of 15 patients (five per group) and calculated the sample size according to the primary outcome. The calculation of sample size and power of the test were performed using PASS software version 15 (NCSS, Kaysville, UT, USA). One-way analysis of variance (ANOVA) was selected and grouped into three groups; the group allocation ratio was 1:1:1, with hypothesized means of 381.3, 607.5 and 620.9 and SD of 107.5, 133.1, and 142.7, respectively. The required sample size for each group was calculated to be 36 at a power (1 − β) of 0.90, and a Bonferroni-corrected alpha error of 0.01 . It was estimated to be at least 40 per group considering 10% dropouts and incomplete follow-up.
Statistical analysis was performed by an independent statistician (CGN) with IBM SPSS v25.0 and R software (Version 3.5.3, R Foundation for Statistical Computing). The modified intention-to-treat data were used for analysis with no planned interim analysis. We did not address the missing data because the data for postoperative assessments were less than 5%. All reported P values are two-tailed.
All data were checked for normal distribution with the Kolmogorov–Smirnov test. Continuous data are presented as mean with a confidence interval (CI) or standard deviation (SD) for normally distributed variables and medians with CI for non-normally distributed data. Categorical variables are summarized using numbers (proportions) or proportions with CI.
The main analysis of the primary outcome of duration of analgesia employed pairwise comparisons between groups using the Kruskal–Wallis test followed by Dunn-Bonferroni post hoc comparison for non-normally distributed data. Changes between groups are presented as median differences and CIs. The threshold for type I errors was adjusted to 0.05/3 = 0.017 for the pairwise comparisons between the three groups (three comparisons) for the primary outcome of analgesia duration . For time-to-event outcomes (duration of analgesia), we analyzed the data using the Kaplan–Meier survival method and compared the groups using the log-rank test, with adjustment for multiple comparisons to ensure the reliability of results .
Generalized estimating equations (GEE) with robust standard error estimates were used to account for repeated measures of NRS data [18, 19]. The level of significance and corresponding CI were 0.001 and 99.9% for other secondary outcomes of NRS scores. Because all patients reported pain, sensitivity analyses were not performed to evaluate the statistical nature of the missing data (NRS = 0 was considered as missing data) .
Categorical data (rescue analgesia rates and the incidence of side effects) were analyzed using the Pearson χ2 test or Fisher exact test, as appropriate. P < 0.017 (Bonferroni adjusted) was considered statistically significant for comparisons of rescue analgesia rates between groups, and the differences between groups were calculated using relative risk (RR) with 98.3% CI using the mean difference. The level of significance and corresponding confidence interval were set at 0.05 and 95% for the incidence of side effects .
Additionally, secondary analyses included adjusted analyses (for sex, age, wound length, and type of surgery) for the primary outcome and the key secondary outcomes. The adjusted analyses were tested for interaction with three groups by the GEE approach using the gee package in R software . The results of the secondary analysis were interpreted as exploratory only.