Efficacy of ultrasound-guided rectus sheath block, butorphanol for single-incision laparoscopic cholecystectomy: A prospective, randomized, clinical trial

Background: Whether rectus sheath block (RSB) combined with butorphanol can relieve incision pain and visceral pain in patients undergoing single-incision laparoscopic cholecystectomy (SILC) remains unknown. The goal of this study was to assess the efficacy of ultrasound-guided bilateral RSB, butorphanol on postoperative analgesia in patients undergoing SILC. Methods: All 116 patients who met the criteria were randomly divided into four groups: (Ⅰ) (n=29) general anesthesia combined with patient controlled intravenous analgesia (PCIA) (sufentanil 100ug); (Ⅱ) (n=29) general anesthesia combined with PCIA (butorphanol 8mg); (Ⅲ) (n=29) ultrasound-guided RSB combined with PCIA (sufentanil 100ug). (Ⅳ) (n=29) RSB combined with PCIA (butorphanol 8mg). Outcomes included visual analog scale (VAS) scores of incisional and visceral pain at rest and cough at 2,6,12 and 24h postoperatively, if a patient’s pain score3, then butorphanol 2mg was administered intravenously. the dose of butorphanol and opioids, the pressing numbers of PCIA, the length of hospital stay and the incidence of postoperative adverse events. Results: Both rest and cough pain scores were lower during first 2,6 hours in group Ⅲ than groupⅠ, similarly, group Ⅳwas significantly lower than groupⅡ. GroupⅠneeded more butorphanol as rescue analgesic for pain relief than group Ⅲ, group Ⅳ was better than group Ⅱ. In the above pairwise comparisons, it was clear that group Ⅲ and group Ⅳ had lower VAS scores. VAS scores of visceral pain was lower in groupⅡ at 2, 6 and 12 h after surgery compared with the groupⅠ. In the both groups Ⅲ and Ⅳ, the group Ⅳ was also lower than groupⅢ. Overall, RSB combined with PCIA (butorphanol 8mg) is the best match. Conclusions: Ultrasound-guided RSB combined with butorphanol can provide sufficient pain treatment after SILC. Trial registration: The study was registered prospectively with

the spread of local anaesthetics can be seen, which may decrease accidental puncture.
RSB is mainly used for postoperative analgesia after abdominal surgery. Studies have shown that 10 ml of 0.5% ropivacaine is usually appropriate [10,11]. Recently, an increasing number of studies have emphasized the clinical value of RSB for pain relief related to midline abdominal incisions and laparoscopic and umbilical surgery [12].
Visceral pain is a complex disorder, that can be caused by mechanical traction, dilation, spasm, inflammation and chemical stimulation. Some studies have suggested that butorphanol, a κ-agonist, produces profound visceral analgesia [13].
The efficacy of RSB has been reported for postoperative analgesia after SILC [14], but the study did not thoroughly examine postoperative pain by distinguishing between incisional pain and visceral pain. Accordingly, we decided to assess the efficiency of ultrasoundguided RSB with butorphanol for incisional pain and visceral pain in patients undergoing SILC .

Patients and study design
A total of 128 patients undergoing elective SILC were enrolled in this study from February 2019 to April 2019 at the Affiliated Hospital of Nantong University. The inclusion criteria were as follows: male and female patients between 18 and 59 years of age with an American Society of Anesthesiology (ASA) score of I or II and a body mass index(BMI) of 18-30 kg/ . Patients with preexisting neuropathy, coagulopathy, local skin infection, hepatic, renal or cardiorespiratory failure, local anaesthetic allergy, pregnancy, complications of gallstones with gallbladder perforation, diffuse peritonitis or acute pyogenic cholangitis were excluded.
The study was registered prospectively with the Chinese Clinical Trial Registry reg no.ChiCTR1900020738) and approved by the ethics committee of Affiliated Hospital of Nantong University (approval number: 2018-K067), and written informed consent was obtained.

Randomization and blinding
All 116 patients, 64 males, 52 females, scheduled for elective, SILC were randomly divided into four groups using a computer-generated random sequence concealed in consecutively numbered, opaque, sealed envelopes, which were opened on the morning of surgery.

Anaesthesia
In a total of 116 patients, anaesthesia was induced with intravenous midazolam 0.1 mg/kg, propofol 2 mg/kg, sufentanil 0.5 µg/kg and cisatracurium 0.15 mg/kg. Anaesthesia was maintained with the infusion of propofol 10 mg/ml at 4 mg/kg/h and remifentanil 50 µg/ml at 0.2 µg/kg/min. To ensure adequate depth of anaesthesia, response entropy indexes were kept between 40 and 60 during the entire anaesthesia period by adjusting the rate of infusion of sufentanil and propofol.
After systemic anaesthesia was induced, in groups III and IV, the probe was transversely placed at the lateral level of the umbilicus. Using the in-plane technique, the needle was advanced until the posterior aspect of the rectus muscle was penetrated. No blood and no gas were drawn back, furthermore, a small volume of saline ( 2 ml) was initially injected to ensure that the needle tip was correctly positioned. When the needle was located between the posterior rectus muscle and posterior sheath, 20 ml of 0.5% ropivacaine was injected bilaterally (Figure 1).
Patients in groups II and IV received an intravenous infusion of 1 mg of butorphanol 30 minutes before the end of surgery. Those in groups I and III received an intravenous infusion of 10 µg of sufentanil 30 minutes before the end of surgery.
Vital signs, such as blood pressure, heart rate, oxygen saturation, and electrocardiogram pattern, were recorded during the operation. The operative duration, haemorrhage volume and consumption of remifentanil and propofol were also recorded.
PCIA with a bolus dose of 2 µg of sufentanil, a lock-out interval of 15 min and a maximum dose of 2 µg/h was used for routine analgesia in groups I and III. In groups II and IV, all patients received butorphanol PCIA at a background rate of 170 µg/h and a demand dose of 170 µg every 15 min as rescue analgesia for postoperative pain management. During a preoperative visit, patients were adequately informed about the concept of the VAS and trained how to use PCIA.
All patients were treated by the same experienced anaesthesiologist, who specialized in ultrasound-guided regional anaesthesia and did not participate in the postoperative data collection.

Measurements
Primary outcome: In both groups, a blinded investigator who was not involved in patient recruitment or the anaesthesia procedure recorded the incisional pain at rest using a 10cm visual analogue scale (0 cm=no pain; 10 cm=worst pain) at 6 h after the operation.
Secondary outcomes: Incisional and visceral pain at rest and during cough at 2, 12 and 24 h after the operation, incisional and visceral pain during cough at 6 h after the operation, postoperative nausea and vomiting (PONV), somnolence, constipation, uroschesis, pruritus, and respiratory depression were assessed by a blinded observer separately.
Butorphanol 1 mg was administered intravenously as rescue analgesia in patients with a VAS score 3 in all groups. The blinded observer recorded the doses of butorphanol and sufentanil and the number of PCIA presses.

Statistical analyses
Statistical analysis was performed using IBM SPSS 21

Patients
The study flow diagram is presented in Figure 2. A total of 128 participants were recruited into the study, eleven of them were excluded from the study, including six patients due to complications of gallstones with gallbladder perforation during surgery, three patients due to BMI 30 kg/ , and two patients due to age 59. Other patients met the inclusion criteria.
Individual characteristics of patients are expressed in Table 1. There were no significant differences. The four groups showed no statistically significant differences in patients' characteristics.
BMI indicates body mass index; ASA, American Society of Anesthesiologists.

Postoperative pain
There were no significant differences in the time needed for the block procedure or the quality of ultrasound images. At rest and during cough, the VAS score of incisional pain was lower during the first 2 and 6 hours in group III than in group I (  All date are expressed as mean±SD.  Date are expressed as mean±SD.  Discussion SILC involves only a 2-cm incision into the umbilicus between the T7 and T11 intercostal nerves [15]. RSB mainly blocks the sheath nerve plexus between the rectus abdominis and posterior sheath of the rectus muscles, which is dominated by the ventral rami of the 6th to 11th intercostal nerves, providing analgesia for the peritoneum, muscle and skin involved in anterior abdominal wall incisions [9]. In the PACU, we found that the range of sensory blockade was measured as a circular area with a radius of 5 cm centered on the umbilicus. RSB covers all the nerves that innervate the umbilicus, provides pre-emptive analgesia and avoids central sensitization caused by nociceptive stimuli before surgery [16,17]. According to our data, RSB in these patients resulted in low incisional pain scores at rest and during movement at 2 and 6 h after surgery, which shows that RSB can effectively relieve incisional pain in patients. The sufentanil consumption and number of PCIA presses in group III were lower than those in the group I. There were no marked differences at 12 or 24 h after SILC among the three groups, perhaps because the efficacy of ropivacaine wears off after 12 h. Theoretically, RSB block should provide excellent analgesia for the abdominal wall, but unfortunately, visceral pain was still evident in groups I and III. By limiting postoperative opioid use in groups II and IV, patients have fewer adverse biological reactions, but with a poor effect on visceral pain.
Visceral pain is mainly transmitted by unmyelinated C fibres, which is a complex sensory experience caused by trauma and inflammation, generally described as dull, diffuse and poorly localized [8]. Visceral pain is difficult to manage effectively, largely because visceral sensory mechanisms and factors that contribute to the pathogenesis of visceral pain are poorly understood [18]. Visceral hyperalgesia and central sensitization have been suggested to be part of the pathophysiology [19]. At present, some studies have shown that the management of visceral pain can be achieved by activating κ-receptors [20,21].
Opioids have been reported to have a small effect on visceral pain [8], which agrees with our data: the VAS scores of visceral pain were lower in group II at 2, 6 and 12 h after surgery than in group I and lower in group IV than in group III. Butorphanol, a mixed agonist-antagonist opioid, induce analgesia by opioid pathways [13]. Some studies have shown that butorphanol relieves visceral pain by indirectly suppressing cyclooxygenase activity and thus preventing prostaglandin formation in response to injury [8,16]. In addition, the main metabolite of butorphanol activates K-receptors and has dual effects of excitation and antagonism on u-receptors. In contrast to u-receptor agonists, such as sufentanil, which cause side effects, such as respiratory depression, nausea and vomiting, pruritus was alleviated and the incidence of side effects was low with the use of butorphanol [13].
Compared with other methods, RSB and butorphanol are useful for multimodal postoperative pain management in SILC patients. This combination also facilitates earlier mobilization and discharge and follows the trend of enhanced recovery after surgery (ERAS). Analgesia management has a far-reaching impact on the perioperative period.
There are a number of limitations to this study. First, this study did not examine whether prolonged postoperative analgesia could be achieved with continuous infusion through rectus sheath catheter placement, Second, we did not study the optimal volume or dose for RSB as a postoperative analgesic method for SILC patients.

Conclusions
Our results suggest that ultrasound-guided RSB combined with butorphanol can relieve postoperative incisional and visceral pain significantly in patients undergoing SILC. Adding adjuvants to prolong the duration of local anaesthesia should be considered for in-depth study.

Authors' contributions
HMF carried out the studies, and drafted the manuscript. CCZ performed the statistical analysis and helped to collect the data. XGX and YTG helped to revise the manuscript. All authors read and approved the final manuscript.

Availability of data and materials
All necessary data supporting our findings has been presented within the manuscript. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.