Analgesic Ecacy of Rectus Sheath Bupivacaine and Intrathecal Morphine With Bupivacaine Compared to Intravenous Patient-controlled Analgesia in Males Undergoing Robot-Assisted Laparoscopic Prostatectomy: A Prospective, Observational Parallel-Cohort Study

Background: We explored the analgesic outcomes on postoperative day (POD) 1 of males undergoing robot-assisted laparoscopic prostatectomy (RALP) who received intravenous (IV) patient-controlled analgesia (PCA), a rectus sheath bupivacaine block (RSB), or an intrathecal morphine with bupivacaine (ITMB) block. Methods: This was a prospective, observational parallel-cohort trial. Patients were divided into three groups: IV-PCA (n = 30), RSB (n = 30), and ITMB block (n = 30). Peak pain scores at rest and when coughing, cumulative IV-PCA drug consumption, the need for IV rescue opioids, and Quality of Recovery-15 (QoR-15) questionnaire scores collected on POD 1 were compared among the groups. Results: The preoperative and intraoperative ndings were comparable among the groups; the ITMB block group required the least remifentanil of all groups. During POD 1, the ITMB block group reported lower levels of pain at rest and when coughing than did the other two groups. After adjustment for age, body mass index, comorbidities, and intraoperative remifentanil infusion, severe pain at rest was 0.167-fold less common in the ITMB block than in the IV-PCA group, and pain when coughing was 0.1-fold lower in the ITMB block group and 0.306-fold lower in the RSB group compared to the IV-PCA group. The ITMB block group required lower cumulative IV-PCA drug infusions and less IV rescue opioids, and exhibited a better QoR-15 global score than did the other two groups. Conclusion: An ITMB block seems to provide appropriate analgesia with tolerable complications and enhances early patient recovery after RALP.


Background
Robot-assisted laparoscopic prostatectomy (RALP) is a technically advanced, minimally invasive surgical method affording a much better surgical view and greater maneuverability than open or laparoscopic prostatectomy [1]. Previous studies found that RALP was associated with better oncological and functional outcomes than open or laparoscopic radical prostatectomy [2,3]. However, RALP patients frequently experience considerable pain, particularly on the day after surgery, re ecting the skin-port incisions, multiple dissections of prostate-involved and surrounding tissues, bladder spasm, and transurethral catheter irritation [4]. Various central and/or peripheral pain-relief methods have been used to attenuate the severe pain that develops immediately after RALP [5,6]. A rectus sheath block (RSB) afforded peri-umbilical incision site analgesia superior to that achieved via local anesthetic in ltration; this site is the principal source of pain immediately after laparoscopy-based surgery [7]. Compared to a transversus abdominis plane (TAP) block, a RSB may afford better analgesia when a midline incision is created and more prolonged blockade of noxious input from that site [8]. An intrathecal morphine and bupivacaine (ITMB) block afforded pain relief for 20-48 h postoperatively and reduced bladder spasmrelated discomfort (a common complication associated with urinary catheter insertion after prostate surgery) [9]. However, no ideal analgesic method affording maximal bene ts with minimal side effects has been described; this would improve the quality of early postoperative recovery after RALP.
Here, we measured the analgesic outcomes on postoperative day (POD) 1 of males undergoing RALP who received an RSB or ITMB block compared to those on intravenous patient-controlled analgesia (IV-PCA) alone. We also compared postoperative complications, including patient satisfaction.

Ethical considerations
This was a prospective, observational parallel-cohort trial.  Figure 1.

Study population
The inclusion criteria for our study were: male sex, age 19-74 years, prostate cancer stage I or II [10], 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] >2.0 and platelet count <100.0 × 10 9 /L), hemodynamic instability that required strong vasopressors or a blood product transfusion, and refusal to participate.
We divided the patients into three groups based on patient preference: IV-PCA only (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 [11]; patient care was standardized apart from the analgesic treatments. The attending anesthesiologist 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). The 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 repeated on the opposite side. The ITMB block was placed before the induction of general anesthesia. Each patient received 0.2 mg of intrathecal morphine sulfate and 7.5 mg of bupivacaine via a sterile 25 G Quincke type spinal needle inserted between lumbar vertebrae 3 and 4. The drugs were given via a single injection after cerebrospinal uid was collected. 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 program featured a 2-mL bolus injection and 0.5-mL basal infusion with a lockout time of 10 min. If a patient suffered 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.

Clinical variables
Preoperative demographic and laboratory parameters were recorded. Intraoperative ndings included surgical duration, hypotension status (systolic blood pressure <90 mmHg for more than 10 min), total rescue ephedrine infusion, total remifentanil infusion, crystalloid uid infusion, urine output, and hemorrhage status. Postoperative ndings included the global quality-of-recovery score on a 15-item questionnaire (the QoR-15) [12]; the incidences of nausea, vomiting, and pruritus; the Clavien-Dindo classi cation [13]; and laboratory variables.

Statistical analyses
The minimum sample size was based on the difference in cumulative IV opioid consumption on POD 1 between patients who received the RSB and ITMB block, calculated using electronic medical records. A minimum sample size of 27 patients/group was required to afford an α = 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 a 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 χ 2 test or Fisher exact test, as appropriate. Trend testing employed a linear-by-linear association method. Logistic regression analysis was used to derive odds ratios with 95% con dence intervals of the risks (postoperative VAS score peaks ≥7 at rest and when coughing) associated with IV-PCA alone (reference), and the RSB and ITMB block, after adjusting for age, body mass index, diabetes mellitus and hypertension status, and intraoperative remifentanil consumption. All tests were two-sided and a p-value <0.017 was considered signi cant (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).

Study population
A total of 103 patients were assessed in terms of eligibility. Thirteen aged >74 years (n = 6), of ASA physical status III (n = 5), or who refused to participate (n = 2) were excluded. Thus, 90 patients were enrolled and divided into 30 in each of the IV-PCA, RSB, and ITMB block groups.

Preoperative and intraoperative ndings
Of all patients (n = 90), the median age was 65 (62-71) years and the median body mass index 24.0 (22.5-26.5) kg/m 2 . In total, 15 patients (16.7%) had diabetes mellitus and 35 (38.9%) hypertension. Table  1 shows that the preoperative and intraoperative ndings were comparable among the three groups.
However, during surgery, the ITMB block group exhibited the lowest remifentanil consumption, and the RSB group required less remifentanil than the IV-PCA alone group.

Postoperative pain
During POD 1, the ITMB block group reported lower pain levels at rest and when coughing than did the RSB and IV-PCA groups ( Figure 3). After adjustment for age, body mass index, comorbidity status, and intraoperative remifentanil infusion, the severe pain level at rest was 0.167-fold lower in the ITMB block group than in the IV-PCA group, and that during coughing was 0.1-fold lower in the ITMB and 0.306-fold lower in the RSB group compared to the IV-PCA alone group ( Table 2). The ITMB block group required less IV-PCA drug infusion and IV rescue opioids than did the RSB and IV-PCA groups (Table 3).

Postoperative clinical ndings
The global QoR-15 questionnaire score was higher in the ITMB block than the RSB and IV-PCA groups (Table 3). Complications (nausea and pruritus) were marginally more common in the ITMB block group than the other two groups; however, we noted no ITMB block-or RSB-related surgical complication (Clavien-Dindo class I or II) (respiration depression, post-dural headache, nerve injury, or puncture site hematoma or infection) during the hospital stay.

Discussion
Our principal ndings are that the ITMB block afforded superior analgesia and better patient satisfaction (in terms of early postoperative recovery) compared to the RSB in males undergoing RALP. The analgesic e cacy of the ITMB block was approximately three-fold better (in terms of reducing severe pain during the early postoperative period) than that of the RSB. Although the ITMB block was associated with more nausea and pruritus than the RSB, we noted no ITMB block-related, postoperative adverse event (respiration depression, lower leg numbness, or post-dural puncture headache).
One retrospective study comparing intrathecal and peripheral postoperative blocks for patients, including those undergoing robotic pancreatoduodenectomy, suggested that intrathecal morphine administration was signi cantly associated with a lower pain score and a lower opioid requirement soon after surgery than were a tap block and a quadratus lumborum nerve block [14]. In an orthopedic study, intrathecal morphine seemed to be more reliable in terms of analgesic e cacy and opioid-sparing than a femoral nerve block [15]. In a gynecological study, the addition of intrathecal bupivacaine to intrathecal morphine signi cantly improved postoperative pain relief, but the addition of rectus sheath bupivacaine to intrathecal morphine did not afford additional analgesia [16]. A urological study suggested that multimodal pain control via intrathecal bupivacaine/morphine may optimally improve the quality of early recovery and reduce postoperative pain, being associated with less pain during exertion and fewer bladder spasms (compared to a control group) [5]. Our ITMB block data are similar to those of previous laparoscopic or open surgery reports [5,[14][15][16]; the ITMB block was a feasible and practicable form of pain relief, not associated with serious complications (such as nerve injury) during or after surgery, and was better than the RSB or IV-PCA alone.
The differences between intrathecal and peripheral blocks include the sites affected by the analgesic drugs and later drug actions. Intrathecally injected morphine and bupivacaine become widely dispersed in cerebrospinal uid, thus more reliably (than the RSB) preventing nociceptive inputs from multiple somatic dermatomic levels of patients undergoing RALP [16,17]. The principal skin wound created during laparoscopy-based surgery lies in the peri-umbilical area; the ori ce is used for camera insertion and specimen (prostate mass) removal. In the past, an RSB effectively countered pain caused by injury to the peri-umbilical dermatomes [18,19]. However, as surgery advanced from open surgery to human-executed laparoscopic surgery to RALP (reducing the operation time and numbers of painful stimuli delivered by surgical wounds in sites such as the umbilicus) [20], the analgesic effect of an RSB seems to have gradually decreased as surgical wound care techniques also improved. Also, an ITMB block may deliver visceral analgesia by interacting with spinal µ-and ĸ-opioid receptors and voltage-gated sodium channels that contain binding sites for local anesthetics. It is now possible to totally (and simultaneously) avoid the surgical stress and pain imparted by intra-abdominal wounds (created when prostate-adjacent tissues are dissected and retracted) and skin wounds (created when the skin is incised, punctured, and retracted) [21,22]. However, the RSB blocks only somatic, afferent nerve pain, and thus cannot deliver comprehensive analgesia; pain from the visceral origins is not dulled [18].
Turning to complications, postoperative nausea/vomiting and pruritus compromise the quality of patient recovery [23]. Previous studies suggested that the incidence of such complications was higher in patients who received intrathecal morphine than in those receiving local anesthetic-based analgesia [24][25][26]. Our ITMB block regimen included bupivacaine (7.5 mg); this allowed us to reduce the morphine dose to 0.2 mg, in turn reducing nausea/vomiting and pruritus but with maintenance of appropriate analgesia. We found no signi cant difference in the incidences of nausea and vomiting among patients who received the ITMB block, the RSB, and IV-PCA alone. Nguyen et al. [27] suggested that the addition of bupivacaine (15 mg) to intrathecal morphine (0.4 mg) improved pain relief and reduced the incidence of adverse events (such as hypotension) in patients undergoing laparoscopic liver resection. Girgin et al. [28] found that the incidence of pruritus increased as the dose of intrathecal morphine rose from 0.1 to 0.4 mg; however, when morphine was combined with low-dose bupivacaine (7.5 mg), the complication rate was reduced but analgesia remained stable in women undergoing Cesarean sections. The good analgesia, and the tolerable complication rate, afforded by the ITMB block may enhance early postoperative recovery compared to that of patients treated via the RSB and IV-PCA alone.
Our work has certain limitations. First, we (obviously) included only males. As opioid-related analgesia and side effects vary by sex [29], further work is required to investigate the quality of postoperative recovery, including pain, afforded by the various analgesic methods in both males and females. Second, we delivered single bupivacaine injections to the rectus sheath when comparing the outcomes of the three pain relief methods. However, no ideal regional analgesic technique for RALP has yet been established; other regional analgesic models, including catheter-delivered continuous blockade, may be even better than the ITMB block [30].

Conclusions
The ITMB block may usefully reduce postoperative pain and aid recovery in males undergoing RALP. Although robot-assisted surgery is more advanced and less invasive than open or laparoscopic surgery, analgesic care must counter both parietal and visceral pain associated with multi-level skin wounds and intra-abdominal tissue injuries. Our ITMB block regimen (a low dose of morphine combined with bupivacaine) seems to deliver appropriate analgesia with a tolerable level of complications, and to enhance early patient recovery.     The peri-umbilical wound site (arrow) that is the principal analgesic target of the RSB.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.