Two Bupivacaine Concentrations for Recto-Intercostal Fascial Plane Block After Laparoscopic Cholecystectomy

Design. This is a prospective, randomized, double-blind (participant and outcomes assessor), controlled, three-arm, parallel-group, single-centre trial to be conducted at Istanbul Medipol University Mega Hospital Complex. The trial will start only after approval by the Istanbul Medipol University Clinical Research Ethics Committee and authorization by the Turkish Medicines and Medical Devices Agency (TİTCK), and will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Bupivacaine, licensed in Turkey, is used within its approved indication. Written informed consent will be obtained from all participants before any study procedure.

Randomization and blinding. Before transfer to the operating room, patients will be allocated in a 1:1:1 ratio to one of three groups using a balanced sequence generated with the Research Randomizer program (www.randomizer.org). The allocation list will be kept by an anesthesiologist not otherwise involved in the conduct or assessment of the trial, who will prepare the study solutions under sterile conditions immediately before use (Group Y: 25 mL of 0.5% bupivacaine + 25 mL of 0.9% saline; Group D: 12.5 mL of 0.5% bupivacaine + 37.5 mL of 0.9% saline) and supply them in identical, indistinguishable 25 mL syringes for each side, labelled only with the randomization number. As both solutions are clear and colourless, the anesthesiologist performing the block is also blinded to the concentration. All procedures are performed under general anesthesia, so participants are unaware of their allocation. All postoperative assessments will be performed by an anesthesiologist blinded to group allocation who takes no part in the intervention, and statistical analysis will be performed on a dataset with masked group codes. If knowledge of the allocation is required for patient safety (e.g., suspected local anesthetic systemic toxicity), it can be obtained immediately from the anesthesiologist who prepared the solution.

Groups. Group Y receives bilateral recto-intercostal fascial plane block (RIFPB) with 25 mL of 0.25% bupivacaine per side (50 mL, 125 mg in total). Group D receives bilateral RIFPB with 25 mL of 0.125% bupivacaine per side (50 mL, 62.5 mg in total). Group K (control) receives no block and is managed with the institution's routine analgesic protocol, including port-site infiltration with 25 mL of 0.25% bupivacaine (62.5 mg) performed by the surgical team. The injected volume is identical in both block groups; only the concentration, and therefore the administered dose, differs. The investigators' previous trial used 30 mL per side for the block and 30 mL for port-site infiltration; in this trial the volume has been set at 25 mL to reduce the total local anesthetic dose. To allow the isolated effect of the block to be assessed, port-site infiltration is not performed in the block groups. The total single dose of bupivacaine (at most 125 mg) will not exceed the maximum single adult dose stated in the product information (150 mg) in any patient, and patients weighing 60 kg or less are not included.

Anesthesia and surgery. Standard monitoring (electrocardiography, non-invasive blood pressure and pulse oximetry) will be applied. After premedication with 2 mg of intravenous midazolam, general anesthesia will be induced with propofol (2-2.5 mg/kg), fentanyl (1-1.5 mcg/kg) and rocuronium (0.6 mg/kg), and maintained with sevoflurane in an oxygen-air mixture and a remifentanil infusion (0.05-2 mcg/kg/min). All patients will receive 4 mg of intravenous ondansetron for nausea prophylaxis, and 400 mg of intravenous ibuprofen and 100 mg of intravenous tramadol approximately 20 minutes before skin closure. Surgery will be performed by the same team using the conventional four-port technique.

Block technique. The block will be performed bilaterally at the end of surgery, before extubation, with the patient supine and under general anesthesia. Using a high-frequency linear ultrasound probe (11-12 MHz) and a 22-gauge, 80 mm block needle, the probe will be placed in a sagittal orientation 3-4 cm lateral and caudal to the epigastrium to visualize the rectus abdominis muscle and the 6th and 7th costal cartilages. With an in-plane technique in a caudal-to-cranial direction, hydrodissection with 5 mL of saline will be performed, 25 mL of the study solution will be injected on each side, and spread will be confirmed with ultrasound. Aspiration will be performed before injection and after every 5 mL, the drug will be given in fractionated doses, patients will be continuously monitored, and 20% lipid emulsion will be immediately available in the operating room.

Postoperative analgesia and assessment. All patients will receive 400 mg of intravenous ibuprofen every 8 hours. Pain will be assessed by the blinded assessor with the numeric rating scale (NRS; 0 = no pain, 10 = worst imaginable pain) at rest and on movement (coughing) at 1, 3, 6, 12, 18 and 24 hours postoperatively. Rescue analgesia with 0.5-1 mg/kg of intravenous tramadol will be given whenever the NRS score is 4 or higher, up to a maximum daily tramadol dose of 400 mg. The standard 100 mg of tramadol given to all patients at the end of surgery is not included in the primary outcome. Patients with inadequate analgesia despite rescue tramadol will receive additional analgesic treatment at the discretion of the responsible physician, and this will be recorded. Nausea and vomiting will be treated according to routine clinical practice.

Withdrawal. Patients will be withdrawn if they are converted to open surgery after randomization, withdraw consent, or require postoperative mechanical ventilation or intensive care because of a serious surgical or anesthetic complication; if the study solution or intervention cannot be administered according to the protocol; or if the responsible investigator considers withdrawal necessary for patient safety. Withdrawn patients will continue to receive standard care.

Sample size. The sample size was calculated with G*Power 3.1, assuming that the primary outcome would be compared among the three groups with one-way analysis of variance. Considering the marked difference in rescue analgesic requirement between RIFPB and control in the investigators' previous trial (17.9% versus 55.3%), a medium-to-large effect size (f = 0.35), an alpha of 0.05 and 80% power yielded 84 patients (28 per group). Allowing for approximately 7% data loss, 30 patients per group (90 in total) will be enrolled.

Statistical analysis. Data will be analysed with SPSS 25.0 (IBM Corp., Armonk, NY, USA). Normality will be assessed with the Shapiro-Wilk test; normally distributed variables will be presented as mean ± standard deviation and non-normally distributed variables as median (interquartile range). Normally distributed variables will be compared among the three groups using one-way analysis of variance (ANOVA) with post hoc Bonferroni tests, and non-normally distributed variables, including 24-hour rescue tramadol consumption, using the Kruskal-Wallis test followed by Bonferroni-corrected Mann-Whitney U tests. Categorical variables will be presented as number (%) and compared with the chi-square test or, when any expected cell count is below 5, the Fisher-Freeman-Halton exact test. NRS scores will be compared among groups at each time point with the Kruskal-Wallis test, and time to first rescue analgesia will be analysed with the Kaplan-Meier method and the log-rank test. Between-group differences in the primary outcome will be reported with 95% confidence intervals. Bonferroni correction will be applied to pairwise comparisons; otherwise a p value below 0.05 will be considered statistically significant. Analyses will include randomized patients who complete the 24-hour follow-up; withdrawn patients will be reported with reasons in the CONSORT flow diagram.

Ethical considerations. Patients in the control group will not be deprived of analgesic treatment; they will receive the institution's routine port-site infiltration and standard multimodal analgesia protocol, and rescue analgesia whenever the NRS score is 4 or higher. All drugs used are licensed in Turkey and used in routine clinical practice. Patient data will be stored in coded form. The study has no external funding and the investigators declare no conflict of interest.