This was a prospective, observational parallel-cohort trial. The protocol was approved by the Institutional Review Board of Seoul St. Mary’s Hospital Ethics Committee (approval no. KC20OISI0124) on April 29, 2020. The study was performed in accordance with all relevant principles of the Declaration of Helsinki. The study protocol was prospectively registered on a publicly accessible clinical registration site recognized by the International Committee of Medical Journal Editors (Clinical Research Information Service, Republic of Korea; approval no. KCT0005040) on May 20, 2020. Written informed consent was obtained from all patients enrolled between May 2020 and July 2020. The study adhered to Strengthening the Reporting of Observational Studies in Epidemiology guidelines (Additional File 1); a study flow chart is shown in Figure 1.
The inclusion criteria for our study were: age 19–74 years, prostate cancer stage I or II , patients scheduled for elective RALP, and American Society of Anesthesiologists (ASA) physical status I or II. The exclusion criteria were: a history of allergy to a local anesthetic or opioid drug, coagulopathy (international normalized ratio [INR] > 1.5 for ITMB or INR > 2.0 for a single injection of ultrasound-guided RSB; and platelet count < 100.0 × 109/L) [11, 12], hemodynamic instability that required strong vasopressors (i.e., epinephrine or norepinephrine), hetastarch colloid infusion, or blood product transfusion (i.e., packed red blood cells ≥ 1 unit due to hemoglobin < 7.0 g/dL) , and refusal to participate.
The patients were divided into three groups based on their analgesia preference: IV-PCA alone (reference group), RSB and IV-PCA (RSB group), and ITMB and IV-PCA (ITMB group).
Patient management in the operating room
The RALP surgical technique and balanced anesthetic management were as described previously ; patient care was standardized apart from the analgesic treatments. Briefly, balanced anesthesia was performed by attending expert anesthesiologists. Induction of anesthesia was achieved using 1–2 mg/kg of propofol and 0.6 mg/kg of rocuronium; anesthesia was then maintained using 2.0–6.0% desflurane under medical air in oxygen. Remifentanil was continuously infused at a rate of 0.1–0.5 μg/kg/min, as appropriate. The Bispectral IndexTM instrument was set between 40 and 50 to ensure appropriate hypnotic depth. Rocuronium was repeatedly infused under train-of-four monitoring (> 1 twitch). End-tidal CO2 was set between 30 and 40 mmHg with adjustment of the ventilator mode. For fluid therapy, a baseline isotonic crystalloid was prepared based on the estimated fluid maintenance requirements, which were established in accordance with the patient’s weight and anticipated tissue trauma. Additional fluid boluses were infused according to blood loss; however, the total amount of fluid was restricted to a maximum of 1 L before vesicourethral anastomosis.
The attending anesthesiologists (whose subspecialty involved regional blocks) and nurses were aware of the group allocations, but were not involved in later patient care or data collection (other than the completion of medical records). RSB was established immediately after the induction of general anesthesia. An ultrasound probe was positioned transversely on the rectus abdominis muscle, above the umbilicus (Figure 2). Guided by real-time ultrasound, a sterile 22-G Tuohy-type epidural needle was cautiously advanced in-plane (to prevent injury to nearby vessels) from medially to laterally until the tip attained the plane between the lateral side of the rectus abdominis muscle and the posterior rectus sheath. After negative pressure aspiration, 20 mL of 0.25% (w/v) bupivacaine was administered and the block was repeated on the opposite side. ITMB was placed before the induction of general anesthesia. Each patient received 0.2 mg of intrathecal morphine sulfate and 7.5 mg of bupivacaine by means of a sterile 25-G Quincke-type spinal needle inserted between lumbar vertebrae 3 and 4. The drugs were administered through a single injection after collection of cerebrospinal fluid. All patients were allowed access to IV-PCA (1,000 μg of fentanyl, 90 mg of ketorolac, and 0.3 mg of ramosetron). The IV-PCA regimen featured a 2-mL bolus injection and 0.5 mL/h basal infusion with a lockout time of 10 min. If a patient experienced acute postoperative breakthrough pain (visual analog scale [VAS] score ≥ 7), 25 mg of pethidine (an IV rescue opioid) was administered based on the discretion of the attending physicians (in the postoperative acute care unit or ward), who were blinded to group assignment.
Cumulative IV-PCA drug consumption and the need for IV rescue opioids were primarily assessed during the first 24 h postoperatively. Peak pain scores at rest and with coughing were assessed using a VAS that ranged from 0 to 10, where “0” represented no pain and “10” represented the worst possible pain. Pain severity was classified as mild (VAS scores 0–3), moderate (4–6), or severe (7–10) . Pain was assessed using the VAS three times (i.e., at 1 h postoperatively in the post-anesthesia care unit [PACU], as well as at 6 and 24 h postoperatively in the ward). If a patient experienced acute postoperative breakthrough pain (VAS score ≥ 7), 25 mg of pethidine (an IV rescue opioid) was administered by attending physicians (anesthesiologists in the PACU and urologists in the ward) or nurses, none of whom were aware of the group allocations.
Preoperative demographic and laboratory parameters were recorded on the day before surgery by attending urologic physicians or nurses in the ward, who were not aware of the group allocations and were not involved in further data collection other than filling in medical record forms. Intraoperative findings, such as surgical duration, hypotension status (systolic blood pressure <90 mmHg for more than 10 min), total rescue ephedrine infusion, total remifentanil infusion, crystalloid fluid infusion, urine output, and hemorrhage status, were recorded by the attending anesthesiologists or nurses in the operating room, who were not involved in further patient care or data collection (other than filling in anesthetic record forms) and were not aware of the group allocations. Postoperative findings, such as the global quality-of-recovery score on a 15-item questionnaire (the QoR-15) ; the incidences of nausea, vomiting, and pruritus; the Clavien-Dindo grade ; and laboratory variables, were measured in the ward on the first day after surgery (between 6 and 8 pm). These findings were measured by anesthesiology residents (Y.J.C. and M.K.) who were not aware of the group allocations and were not involved in further patient care or data collection. Additionally, nausea and vomiting were assessed on a binary scale (yes/no). Patients were considered to have nausea, if they responded positively to the question, “are you or have you felt nauseated after surgery?”. Using similar questions, vomiting episodes were assessed . Pruritus was assessed using the following scale: 0 = no itch; 1 = itch with no need to scratch, just rubbing (mild); 2 = itch with need to scratch (moderate); 3 = itch with need to scratch and requiring treatment (severe) . We defined overt pruritus as a score ≥ 2. Therefore, nausea, vomiting, and pruritus were considered binary variables in our analysis.
The minimum sample size was based on the difference in cumulative IV-PCA drug consumption on POD 1 between patients who received RSB and those who received ITMB, calculated using electronic medical records. Mean cumulative IV-PCA drug consumption on POD 1 by patients who received RSB (n = 10) and those who received ITMB (n = 10) were 47.1 and 29.1 mL, respectively. The standard deviation (SD) among the 20 patients was 23.6 mL. Therefore, a minimum sample size of 27 patients/group was required to afford an α value of 0.05 and a power of 0.8. We recruited 30 patients for each group; we assumed a dropout rate of 10%.
Data are expressed as means ± standard deviations (SDs), medians with interquartile ranges (IQRs), or numbers with proportions (%), as appropriate. The normality of continuous data distributions was evaluated using the Shapiro–Wilk test. Continuous perioperative variables of the three groups were compared via one-way analysis of variance or the Kruskal–Wallis test; post hoc testing employed the unpaired t-test or the Mann–Whitney U test. Perioperative categorical variables were compared among the groups using the Pearson χ2 test or Fisher’s exact test, as appropriate. Trend testing employed a linear-by-linear association method. To determine the clinical analgesic efficacy of the treatments, logistic regression analysis was used to derive odds ratios with 95% confidence intervals of the risks (postoperative peak VAS score ≥ 7 at rest and with coughing) associated with IV-PCA alone (reference), and the RSB and ITMB, after adjusting for age, body mass index, and diabetes mellitus and hypertension statuses (these comorbidities may change in accordance with pain level) [20, 21], and intraoperative remifentanil consumption. Tests for linear trends among patients in terms of cumulative IV-PCA drug consumption on POD 1 were based on stepwise linear regression. All tests were two-sided and a p-value <0.017 was considered statistically significant (multiple comparisons were made). All statistical analyses were performed with the aid of SPSS for Windows (ver. 24.0; IBM Corp., Armonk, NY, USA) and MedCalc for Windows (ver. 11.0; MedCalc Software, Ostend, Belgium).