Abstract
Background
The aim of this study was to determine the optimal dose of butorphanol combined with ropivacaine for supraclavicular brachial plexus block in patients undergoing upper limb fracture surgery.
Methods
A total of 100 patients were randomly divided into five groups at a ratio of 1:1:1:1:1 to receive normal saline combined with 0.375% ropivacaine (NS group), 10 μg/kg (B10 group), 20 μg/kg (B20 group), 30 μg/kg (B30 group), and 40 μg/kg (B40 group) butorphanol combined with 0.375% ropivacaine for supraclavicular brachial plexus block with a volume of 20 mL under ultrasound guided, and intraoperative moderate sedation with target-controlled infusion (TCI) of propofol. The primary outcome was the onset time of sensory block, and the secondary outcomes were the onset time of motor block, duration of sensory and motor block, VAS scores at 30 minutes before surgery, 3 h, 8 h, 24 h, 48 h, and 72 h after surgery, QoR-15 scores at 1st, 2nd, and 3rd day after surgery, the time of first use of analgesic drugs after surgery, the intraoperative sedative dose of propofol, analgesic dose of dezocine within 72 hours after surgery, patient satisfaction, and adverse events.
Results
Compared to the NS group, the duration of sensory (352.7 ± 33.1 min vs 512.8 ± 36.2 min, and 538.7 ± 42.3 min) and motor blockade (307.6 ± 24.7 min vs 388.5 ± 37.8 min and 429.8 ± 36.9 min), time of first postoperative rescue analgesia (6.9 ± 0.6 h vs 9.2 ± 0.5 h, and 9.9 ± 0.7 h), and patient satisfaction score (1.1 ± 1.0 vs 2.4 ± 1.0 and 2.6 ± 0.9) were increased more significantly, and the onset time of sensory (16.4 ± 2.4 min vs 9.8 ± 2.6 min and 9.1 ± 2.9 min) and motor blockade (22.1 ± 3.5 min vs 16.8 ± 2.9 min and 16.2 ± 3.7 min), postoperative rescue analgesic dose of dezocine (38.2 ± 7.1 mg vs 24.0 ± 6.4 mg and 22.0 ± 6.2 mg), and dose of propofol (386.8 ± 55.8 mg vs 283.2 ± 42.1 mg, and 266.6 ± 43.0 mg) for intraoperative moderate sedation were lower in the B30 group and B40 group (all P < 0.005). The nerve block characteristics in B30group and B40 group were comparable (all P > 0.05). The QoR-15 scores at postoperative 24 h and 48 h in the B40 group (141.0 ± 6.6 and 141.9 ± 6.1) were higher than that in the NS group (122.6 ± 7.6 and 123.9 ± 6.9), B10 group (125.0 ± 8.0 and 127.1 ± 6.1), and B20 group (132.0 ± 7.2 and 133.9 ± 7.4, all P < 0.005), and comparable to those in the B30 group (139.4 ± 6.3 and 141.2 ± 6.6, P = 0.469 and 0.759). There was no difference in the incidence of adverse events between groups.
Conclusion
The optimal synergistic dose of butorphanol combined with ropivacaine for supraclavicular brachial plexus block under intraoperative moderate sedation with propofol was 30 μg/kg, without increasing the incidence of adverse events.
Keywords: supraclavicular brachial plexus block, butorphanol, ropivacaine, upper limb fracture
Introduction
In recent years, ultrasound-guided supraclavicular brachial plexus block has become increasingly popular in patients undergoing upper limb fracture surgery.1 This is because ultrasound guidance can clearly distinguish nerves and their surrounding tissue structures, control the direction of the puncture needle to enter the target nerve, accurately observe the diffusion of local anesthetics, improve nerve block anesthesia, and reduce the occurrence of complications.1,2 Ropivacaine is a pure S(-) enantiomer of bupivacaine with low toxicity to the central nervous system and cardiovascular system, and is used for various local anesthesia.3,4 However, the use of ropivacaine alone for single-shot nerve block in clinical practice often associates with a slower onset, short postoperative analgesia time, more opioid consumption after surgery, and delayed postoperative recovery.5,6 The combination of adjuvants can significantly improve the local anesthetic effect of ropivacaine with less cumulative opioid demand, delayed first analgesia demand after surgery, and enhanced recovery after surgery.6,7
Butorphanol is a synthetic opioid, which stimulates κ-opioid receptor and has agonistic and antagonistic effects on μ-opioid receptor.8 Clinical study has found that compared with nalbuphine, butorphanol as an adjuvant of ropivacaine can provide better postoperative analgesia, prolong postoperative analgesia time, and reduce complications.9 It is suggested that butorphanol is more suitable as an adjuvant of ropivacaine for local anesthesia. However, Bharathi et al found that compared with 1 mg of butorphanol, although 2 mg of butorphanol was able to significantly hasten the onset time of sensory and motor block, and prolong the analgesic duration when used as an adjuvant for supraclavicular nerve block with levobupivacaine, it also increased the incidence of sedation and adverse events.10 At present, the dosage of butorphanol as an adjuvant for local anesthetics varies from 1 to 2 mg.9,11 However, the optimal synergistic dose of butorphanol combined with ropivacaine for peripheral nerve block is unclear. Therefore, the aim of this study is to determine the optimal synergistic dose of butorphanol combined with ropivacaine for supraclavicular brachial plexus block.
Methods
Study Design and Population
This randomized, double-blind, controlled clinical study was approved by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College (Ethical Approval No.: 2021ER021-1) and registered in the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?Proj=128419, registration number: ChiCTR2100050566, registration date: 28/08/2021). From August 2021 to June 2022, a total of 100 patients aged 18–60 years, ASA (American Society of Anesthesiologists) scores of I or II, scheduled for upper limb surgery under nerve block anesthesia at the Affiliated Hospital of North Sichuan Medical College were enrolled in the study. Exclusion criteria: Allergies to butorphanol or ropivacaine, suffering from cardiovascular diseases (arrhythmia, sinus bradycardia, atrioventricular block, aortic stenosis, ischemic heart disease, severe hypertension, heart failure, ejection fraction <30%), preoperative coagulation dysfunction, individuals with infected or damaged skin at the puncture site, suffering from liver and kidney diseases, recent use of sedatives or opioid drugs, sleep apnea syndrome, drug or alcohol addiction, surgery involving more than the affected arm, participated in other clinical trials. Withdrawal criteria: incomplete data collection, patients voluntarily withdraw from this clinical trial, events that seriously affect the patient’s life occur during the surgery, failed blockade, surgery time >4 hours. All procedures conducted in this study followed research ethical standards and the Helsinki Declaration.12,13 Participants received oral and written information about the observational study and signed informed consent forms prior to inclusion.
Patients were randomly divided into 5 groups at a ratio of 1:1:1:1:1 by an anesthesiologist who was not involved in this trial using the random number table method. One hundred three-digit numbers are randomly selected from the random number table and serialized in ascending order. The anesthesiologist set the serial number 1–20 as NS group, 21–40 as B10 group, 41–60 as B20 group, 61–80 as B30 group, and 81–100 as B40 group. The cards marked with the patient grouping information were placed in the same sealed envelope and stored in a closed box. When the patient arrived at the operating room, the anesthesia nurse randomly drew an envelope from the box and prepared the local anesthetic drugs according to the information on the card. NS group: 0.375% ropivacaine + equal volume normal saline as placebo; B10group: 0.375% ropivacaine + butorphanol (10 μg/kg); B20group: 0.375% ropivacaine + butorphanol (20 μg/kg); B30group: 0.375% ropivacaine + butorphanol (30 μg/kg); B40 group: 0.375% ropivacaine + butorphanol (40 μg/kg), all diluted to 20 mL with normal saline. All the supraclavicular brachial plexus block was performed by an anesthesiologist who was skilled in these procedures under ultrasound guidance. All the surgeries for upper limb fractures were performed by the same group of orthopedic surgeons. The patients, anesthesiologist in charge of anesthesia, surgeons, operating nurses, and ward nurses were all unaware of the grouping. The primary outcome was the onset time of sensory block, and the secondary outcomes were the onset time of motor block, the duration of sensory and motor block, VAS scores at 30 minutes before surgery, 3 h, 8 h, 24 h, 48 h, and 72 h after surgery, the time of first use of analgesic drugs after surgery, the intraoperative sedative dose of propofol, analgesic dose of dezocine within 72 hours after surgery, and patient satisfaction.
Anesthesia Management
Patients were preoperatively abstained from drinking for 4 h and fasted for 8 h. After the patient entered the operating room, the upper limb venous channel was established, and the lactated Ringer’s solution was intravenously infused at 10 mL/kg·h. Non-invasive blood pressure (NIBP), electrocardiogram, and oxygen saturation (SpO2) were routinely monitored, and mask oxygen inhalation (4 L/min) was performed. Supraclavicular brachial plexus block: The patient was placed in a supine position, with the head turned to the non-surgical side. After local anesthesia with 1% lidocaine at the puncture site, the brachial plexus and its branches were blocked under aseptic technique by using the long-axis plane technique under ultrasound guidance, and slowly inserted the needle into the upper part of the subclavian artery in the ultrasound plane, with the needle tip close to the brachial plexus. After prior negative blood or air aspiration, a total of 0.375% ropivacaine 20 mL with or without butorphanol was administered for supraclavicular brachial plexus block. 20 min after the completion of the nerve block procedure, the pain sensation of the skin in the operation area was evaluated with pinprick. Patients with inadequate block or failed block were converted to general anesthesia.
Anesthesia Maintenance
The surgery was started after complete analgesia in the surgical area or 20 minutes after the completion of the block procedure.14 The patients were maintained intraoperative moderate sedation by target-controlled infusion (TCI) of propofol in the Marsh model with an initial plasma target concentration of propofolat 2 μg/mL.15 During surgery, the modified observational alertness/sedation assessment scale (MOAA/S) (5 = responds readily to name spoken in normal tone, 4 = lethargic response to name spoken in normal tone, 3 = responds only after the name is called loud or repeatedly, 2 = responds only after mild prodding or shaking, 1 = does not respond to mild prodding or shaking, 0 = does not respond to deep stimuli) was used to evaluate the sedation level, and the intraoperative MOAA/S 2–4 was maintained by adjusting the plasma target concentration of propofol. The TCI of propofol for sedation was stopped at the end of surgery. Patients were transferred to the postanesthesia care unit (PACU) for monitoring vital signs when MOAA/S > 4, and a nasal cannula oxygen inhalation was performed at a rate of 5 L/min. When the Steward score >4, patients were discharged to the surgical ward.16 When the patient had bradycardia (heart rate <50 beats/min), atropine 0.5 mg was administered intravenously. When patients suffered from hypotension (SBP < 90 mmHg, or MAP < 60 mmHg), intravenous injection of ephedrine 6 mg was administered.
Outcome Measurements
The onset time of sensory blockade, which is defined as the time from the completion of local anesthetic injection to the absence of skin pain in the surgical area, was recorded. Sensory blockade was tested by pinprick every minute until the absence of skin pain in the surgical area. The duration of sensory blockade which is defined as the time from the absence of skin pain in the surgical area to the recovery of pain sensation in the surgical upper limb, was recorded. Motor blockade of the surgical upper limb was assessed using the modified Bromage score (Bromage 0 = no motion; Bromage 1 = finger movement; Bromage 2 = wrist flexion against gravity force; Bromage3 = elbow flexion against gravity force).17 The onset time of motor blockade was defined as the time from the completion of injection of local anesthetics to the time when the modified Bromage score reached 2. The duration of motor blockade was defined as the time from the modified Bromage score reached 2 to the time when the modified Bromage score reached 3. Postoperative pain was evaluated using visual analogue scale (VAS) (assessment of pain severity on a 100-mm linear scale with the left end of the line marked as 0representingpainlessness, and the right end marked as 100 representing severe pain)18 at 30 minutes before surgery, 3 h, 8 h, 24 h, 48 h, and 72 h after surgery. If the patient received remedial analgesia before evaluation, the highest VAS score before administration of remedial analgesia was recorded. When the postoperative VAS ≥ 4, an intravenous injection of dezocine 5 mg for rescue analgesia, and the dosage of dezocine for rescue analgesia was recorded. The Bruggrmann comfort scale (BCS) (4 no pain during coughing, 3 no pain during deep breathing, 2 no pain when lying at rest and slight pain during deep breathing or coughing, 1 no pain at rest and severe pain during deep breathing or coughing, 0 continuous pain)19 was used to evaluate the patient’s satisfaction 24 h after surgery. The recovery quality of the patients was evaluated by using the QoR-15 scoring scale20 on the 1st, 2nd, and 3rd day after surgery. The incidence of adverse events (such as dizziness, nausea and vomiting, respiratory depression, pruritus) was recorded.
Sample Size
The sample size was calculated using PASS 15 software based on a pilot study with 10 patients undergoing supraclavicular brachial plexus block in each group, and the onset time of sensory blockade in the NS, B10, B20, B30, and B40groups was14.73 ± 2.6 min, 12.8 ± 4.2 min, 11.8 ± 3.6 min, 10.2 ± 2.3 min, and 9.8 ± 2.5 min, respectively. Assuming a type II error of 0.10 (a power of 0.90), and a two-sided type I error of 0.05, the sample size of each group was calculated to be 18. Considering a 20% dropout rate, 23 patients were included in each group.
Statistical Analysis
SPSS 23.0 program was used to perform the statistical analyses. Quantitative variables with normal distribution were expressed as the mean ± standard deviation (SD), and quantitative variables of non-normal distribution were expressed as median (interquartile range). The enumeration data was presented as frequencies. The demographic data and clinical characteristic data with normal distribution data were analyzed with one-way ANOVA, and the Bonferroni correction test was used for further comparisons between groups. Repeated measures analysis of variance was used for VAS scores and QoR-15 scores to observe the potential variation over the time, and post-hoc analysis was performed using the SNK post hoc test to detect pairwise differences with Bonferroni correction. The gender composition, types of fractures and incidence of adverse events were compared by using the chi-square test or Fisher’s exact tests. A P value of <0.05 or Bonferroni corrected P value <0.005 was considered statistically significant.
Results
A total of 115 patients were screened for eligibility, three patients with cardiovascular diseases, four patients who had moderate or severe anemia, and three patients with chronic obstructive pulmonary disease were excluded. One hundred and five patients were subsequently allocated to five groups. No patients in the five groups suffered from incomplete or failed block. One patient with surgery time >4 hours in the NS group, one patient voluntarily withdrew from this clinical trial in the B10 group, one patient with incomplete data collection in the B20 group, one patient with surgery time >4 hours in the B30 group, and one patient voluntarily withdrew from this clinical trial in the B40 group, were withdrawn from this clinical trial. A total of 100 patients completed the study (Figure 1).
Figure 1.
Participant flow diagram.
The demographic profiles of the patients in all groups are shown in Table 1. There was no difference in the demographic data according to age, height, weight, sex, ASA class, types of upper limb fractures, surgery time, and duration of hospital stay between groups (P = 0.901, 0.128, 0.890, 0.658, 0.615, 0.999, 0.852, and 0.289, respectively).
Table 1.
Demographic Data
| NS Group (n = 20) |
B10 Group (n = 20) |
B20 Group (n = 20) |
B30 Group (n = 20) |
B40 Group (n = 20) |
F/X2 values |
P values |
|
|---|---|---|---|---|---|---|---|
| Age, mean ± SD (y) | 41.6 ± 10.3 | 42.7 ± 12.0 | 40.4 ± 11.4 | 43.6 ± 13.3 | 40.9 ± 9.6 | 0.264 | 0.901 |
| Height, mean ± SD (cm) | 163.9 ± 6.5 | 165.1 ± 8.1 | 167.3 ± 7.6 | 160.5 ± 8.8 | 164.5 ± 9.0 | 1.837 | 0.128 |
| Weight, mean ± SD (Kg) | 65.4 ± 7.2 | 64.4 ± 9.2 | 66.1 ± 6.9 | 65.8 ± 7.7 | 67.0 ± 9.3 | 0.280 | 0.890 |
| Sex, n (%) | |||||||
| Female | 13 (65.0) | 11 (55.0) | 8 (40.0) | 11 (55.0) | 12 (60.0) | 2.828 | 0.658 |
| Male | 7 (35.0) | 9 (45.0) | 12 (60.0) | 9 (45.0) | 8 (40.0) | ||
| ASA class, n (%) | |||||||
| I | 11 (55.0) | 8 (40.0) | 13 (65.0) | 10 (50.0) | 9 (45.0) | 2.961 | 0.615 |
| II | 9 (45.0) | 12 (60.0) | 7 (35.0) | 10 (50.0) | 11 (55.0) | ||
| Types of upper limb fractures, n (%) | |||||||
| Humeral fracture | 4 (20.0) | 5 (25.0) | 3 (15.0) | 5 (25.0) | 4 (20.0) | 4.012 | 0.999 |
| Only radial fracture | 4 (20.0) | 2 (10.0) | 3 (15.0) | 4 (20.0) | 2 (10.0) | ||
| Only ulna fractures | 3 (15.0) | 5 (25.0) | 4 (20.0) | 3 (15.0) | 4 (20.0) | ||
| Fracture of radius and ulna | 3 (15.0) | 3 (15.0) | 4 (20.0) | 4 (20.0) | 5 (25.0) | ||
| Hand fracture | 6 (30.0) | 5 (25.0) | 6 (30.0) | 4 (20.0) | 5 (25.0) | ||
| Surgery time, mean ± SD (min) | 108.5 ± 14.9 | 107.2 ± 14.2 | 104.2 ± 14.5 | 106.2 ± 15.8 | 109.3 ± 16.7 | 0.337 | 0.852 |
| Duration of hospital stay, mean ± SD (d) | 8.0 ± 1.3 | 7.6 ± 1.5 | 7.4 ± 1.1 | 7.3 ± 1.2 | 7.2 ± 1.0 | 1.265 | 0.289 |
Notes: Values are mean ± SD and number of patients. Differences in age, height, weight, surgery time, and duration of hospital stay among groups were analyzed using one-way ANOVA, and in ASA, sex, and type of upper limb fractures among groups were analyzed using chi-square test or Fisher’s exact tests.
Abbreviations: ASA, American Society of Anesthesiologists; SD, standard deviation, NS group, normal saline combined with ropivacaine; B10 group, 10 μg/kg butorphanol combined with ropivacaine; B20 group, 20 μg/kg butorphanol combined with ropivacaine; B30 group, 30 μg/kg butorphanol combined with ropivacaine; B40 group, 40 μg/kg butorphanol combined with ropivacaine.
Compared to the NS group, the duration of motor blockade and patient satisfaction score were increased more significantly ([307.6 ± 24.7 min vs 388.5 ± 37.8 min and 429.8 ± 36.9 min] and [1.1 ± 1.0 vs 2.4 ± 1.0 and 2.6 ± 0.9], P < 0.001, < 0.001, = 0.001, and < 0.001, respectively), and the onset time of sensory and motor blockade were decreased more significantly ([16.4 ± 2.4 min vs 9.8 ± 2.6 min and 9.1 ± 2.9 min] and [22.1 ± 3.5 min vs 16.8 ± 2.9 min and 16.2 ± 3.7 min], all P < 0.001) in the B30 group and B40 group, the duration of sensory blockade, and time of first postoperative rescue analgesia were increased more significantly in the B20 group, B30 group, and B40 group ([352.7 ± 33.1 min vs 422.0 ± 37.3 min, 512.8 ± 36.2 min, and 538.7 ± 42.3 min] and [6.9 ± 0.6 h vs 7.7 ± 0.6 h, 9.2 ± 0.5 h, and 9.9 ± 0.7 h], P < 0.001, < 0.001, < 0.001, = 0.001, < 0.001, and < 0.001, respectively). The postoperative rescue analgesic dose of dezocine and dose of propofol for intraoperative moderate sedation were higher in the NS group than in the B20 group, B30 group, and B40 group ([38.2 ± 7.1 mg vs 27.5 ± 7.6 mg, 24.0 ± 6.4 mg, and 22.0 ± 6.2 mg] and [386.8 ± 55.8 mg vs 315.3 ± 41.0 mg, 283.2 ± 42.1 mg, and 266.6 ± 43.0 mg], all P < 0.001). The onset time of sensory and motor were lower in the B40 group than in the B10 group and B20 group ([9.1 ± 2.9 min vs 14.1 ± 3.2 min and 13.2 ± 3.8 min] and [16.2 ± 3.7 min vs 21.2 ± 4.1 min and 20.6 ± 4.5 min], P < 0.001, < 0.001, = 0.001, and = 0.004, respectively). The duration of sensory blockade was increased more significantly in the B40 group than in the B10 group and B20 group (538.7 ± 42.3 min vs 371.6 ± 30.8 min and 422.0 ± 37.3 min, all P < 0.001). The postoperative rescue analgesic dose of dezocine was lower in the B40 group than in the B10 group (22.0 ± 6.2 mg vs 33.3 ± 6.9 mg, P < 0.001). The time of first postoperative rescue analgesia in the B40 group was prolonged more significantly than that in the B10 group, B20 group, and B30 group (9.9 ± 0.7 h vs 7.2 ± 0.5 h, 7.7 ± 0.6 h, and 9.2 ± 0.5 h, all P < 0.001). Although the difference in the duration of PACU among groups was statistically significant (P = 0.037), there was no difference between the groups after further comparisons between groups using Bonferroni correction test, as shown in Table 2.
Table 2.
The Clinical Characteristics in All Groups
| NS Group (n = 20) |
B10 Group (n = 20) |
B20 Group (n = 20) |
B30 Group (n = 20) |
B40 Group (n = 20) |
F values |
Pvalues | |
|---|---|---|---|---|---|---|---|
| Onset time of sensory blockade, Mean ± SD (min) | 16.4 ± 2.4# | 14.1 ± 3.2# | 13.2 ± 3.8# | 9.8 ± 2.6* | 9.1 ± 2.9* | 20.545 | < 0.001 |
| Onset time of motor blockade, Mean ± SD (min) | 22.1 ± 3.5# | 21.2 ± 4.1# | 20.6 ± 4.5# | 16.8 ± 2.9* | 16.2 ± 3.7* | 9.985 | < 0.001 |
| Duration of sensory blockade, Mean ± SD (min) | 352.7 ± 33.1# | 371.6 ± 30.8# | 422.0 ± 37.3*# | 512.8 ± 36.2* | 538.7 ± 42.3* | 105.806 | < 0.001 |
| Duration of motor blockade, Mean ± SD (min) | 307.6 ± 24.7# | 322.0 ± 34.4# | 341.8 ± 32.0# | 388.5 ± 37.8*# | 429.8 ± 36.9* | 45.447 | < 0.001 |
| Time of first postoperative rescue analgesia, Mean ± SD (h) | 6.9 ± 0.6# | 7.2 ± 0.5# | 7.7 ± 0.6*# | 9.2 ± 0.5*# | 9.9 ± 0.7* | 102.660 | < 0.001 |
| Postoperative rescue analgesic dose of dezocine, Mean ± SD (mg) | 38.2 ± 7.1# | 33.3 ± 6.9# | 27.5 ± 7.6* | 24.0 ± 6.4* | 22.0 ± 6.2* | 18.976 | < 0.001 |
| Dose of propofol for intraoperative sedation, mean ± SD (mg) | 386.8 ± 55.8# | 357.2 ± 47.3# | 315.3 ± 41.0* | 283.2 ± 42.1* | 266.6 ± 43.0* | 23.586 | < 0.001 |
| Patient satisfaction score, mean ± SD | 1.1 ± 1.0# | 1.6 ± 1.2 | 2.0 ± 1.1 | 2.4 ± 1.0* | 2.6 ± 0.9* | 7.418 | < 0.001 |
| Duration of PACU, mean ± SD (min) | 35.7 ± 6.8 | 37.1 ± 7.3 | 38.5 ± 8.1 | 40.9 ± 7.6 | 42.5 ± 7.9 | 2.674 | 0.037 |
Notes: Values are mean ± SD. Differences in the onset time of sensory and motor blockade, duration of sensory and motor blockade, time of first postoperative rescue analgesia, postoperative rescue analgesic dose of dezocine, dose of propofol for intraoperative sedation, patient satisfaction score, and duration of PACU among groups were analyzed using one-way ANOVA. Bonferroni correction test was used for further statistical comparison between groups.*P < 0.005 vs NS group,#P < 0.005 vs B40 group.
Abbreviations: PACU, postanesthesia care unit; SD, standard deviation; NS group, normal saline combined with ropivacaine; B10 group, 10 μg/kg butorphanol combined with ropivacaine; B20 group, 20 μg/kg butorphanol combined with ropivacaine; B30 group, 30 μg/kg butorphanol combined with ropivacaine; B40 group, 40 μg/kg butorphanol combined with ropivacaine.
As data of VAS scores violated sphericity (P < 0.001), a two-way repeated measures analysis of variance with Greenhouse–Geisser correction was used. There was no difference in VAS scores between the groups 30 minutes before surgery (2.2 ± 0.6, 1.9 ± 0.7, 2.0 ± 0.7, 1.9 ± 06, and 2.1 ± 0.8, P = 0.758), postoperative 3 h (1.7 ± 0.7, 1.5 ± 0.6, 1.4 ± 05, 1.3 ± 0.7, and 1.1 ± 0.5, P = 0.128) and 72 h (2.4 ± 0.7, 2.2 ± 0.6, 2.1 ± 0.5, 2.0 ± 0.7, and 1.9 ± 0.6, P = 0.155). The VAS scores were decreased more significantly postoperative 3 h, increased gradually from 8 h to 48 h after surgery, and returned to the preoperative level at 72 h after surgery in all groups (all P < 0.001).
The VAS scores at postoperative 8 h in the B20 group, B30 group, and B40 group decreased more significantly than that in the NS group (3.7 ± 1.1 vs 2.1 ± 1.0, 1.8 ± 0.7, and 1.6 ± 0.7, all P < 0.001). Compared to the NS group, the VAS scores at postoperative 24 h and 48 h were decreased more significantly in the B30 group and B40 group ([3.9 ± 1.0 vs 2.7 ± 0.9 and 2.5 ± 1.0] and [3.5 ± 0.8 vs 2.5 ± 0.6 and 2.3 ± 0.7], P = 0.001,< 0.001,< 0.001, and < 0.001, respectively). Compared to preoperative 30 min, the VAS scores from postoperative 8 h to postoperative 48 h in the NS group and B10 group increased significantly ([2.2 ± 0.6 vs 3.7 ± 1.1, 3.9 ± 1.0, and 3.5 ± 0.8] and [1.9 ± 0.7 vs 3.1 ± 1.4, 3.7 ± 1.0, and 3.3 ± 0.6], all P < 0.001), the VAS scores at postoperative 24 h and 48 h were significantly increased in the B20 group (2.0 ± 0.7 vs 3.1 ± 0.8 and 2.9 ± 0.7, all P < 0.001), and the VAS scores at postoperative 24 h was increased in the B30 group (1.9 ± 0.6 vs 2.7 ± 0.9, P < 0.001), as shown in Table 3.
Table 3.
The Perioperative VAS Scores of Patients in All Groups
| Time points | NS group (n = 20) |
B10 Group (n = 20) |
B20 Group (n = 20) |
B30 Group (n = 20) |
B40 Group (n = 20) |
F values | P values |
|---|---|---|---|---|---|---|---|
| Preoperative 30 min | 2.2 ± 0.6 | 1.9 ± 0.7 | 2.0 ± 0.7 | 1.9 ± 0.6 | 2.1 ± 0.8 | 0.469 | 0.758 |
| Postoperative 3 h | 1.7 ± 0.7 | 1.5 ± 0.6 | 1.4 ± 0.5 | 1.3 ± 0.7 | 1.1 ± 0.5 | 1.839 | 0.128 |
| Postoperative 8 h | 3.7 ± 1.1#$ | 3.1 ± 1.4#$ | 2.1 ± 1.0* | 1.8 ± 0.7* | 1.6 ± 0.7* | 15.617 | <0.001 |
| Postoperative 24 h | 3.9 ± 1.0#$ | 3.7 ± 1.0#$ | 3.1 ± 0.8$ | 2.7 ± 0.9*$ | 2.5 ± 1.0* | 8.608 | <0.001 |
| Postoperative 48 h | 3.5 ± 0.8#$ | 3.3 ± 0.6#$ | 2.9 ± 0.7$ | 2.4 ± 0.6* | 2.3 ± 0.7* | 11.274 | <0.001 |
| Postoperative 72 h | 2.4 ± 0.7 | 2.2 ± 0.6 | 2.1 ± 0.5 | 2.0 ± 0.7 | 1.9 ± 0.6 | 1.706 | 0.155 |
| F values | 24.362 | 19.124 | 13.263 | 9.979 | 8.875 | – | – |
| P values | <0.001 | <0.001 | <0.001 | < 0.001 | < 0.001 | – | – |
Notes: Values are mean ± SD. Differences in the VAS scores among groups were analyzed using one-way ANOVA. Bonferroni correction test was used for further statistical comparison between groups. *P < 0.005 vs NS group, #P < 0.005 vs B40 group, $ P < 0.004 vs preoperative 30 min.
Abbreviations: VAS, visual analogue scale; NS group, normal saline combined with ropivacaine; B10 group, 10 μg/kg butorphanol combined with ropivacaine; B20 group, 20 μg/kg butorphanol combined with ropivacaine; B30 group, 30 μg/kg butorphanol combined with ropivacaine; B40 group, 40 μg/kg butorphanol combined with ropivacaine.
As data of QoR-15 scores violated sphericity (P < 0.001), a two-way repeated measures analysis of variance with Greenhouse–Geisser correction was used. From 24 to 72 hours after surgery, the QoR-15 scores gradually increased in the NS group, B10 group, and B20 group (all P < 0.001), while there was no significant change in the QoR-15 scores in the B30 and B40 groups (P = 0.335 and 0.637). The QoR-15 scores at postoperative 24 h and 48 h were higher in the B20 group, B30 group, and B40 group than that in the NS group ([122.6 ± 7.6 vs 132.0 ± 7.2, 139.4 ± 6.3, and 141.0 ± 6.6] and [123.9 ± 6.9 vs 133.9 ± 7.4, 141.2 ± 6.6, and 141.9 ± 6.1]) (P = 0.001, < 0.001, < 0.001, < 0.001, < 0.001, and < 0.001, respectively). Compared to the B40 group, the QoR-15 scores at postoperative 24 h and 48 h were lower in the NS group, B10 group, and B20 group ([141.0 ± 6.6 vs 122.6 ± 7.6, 125.0 ± 8.0, and 132.0 ± 7.2] and [141.9 ± 6.1 vs 123.9 ± 6.9, 127.1 ± 6.1, and 133.9 ± 7.4], P < 0.001, < 0.001, = 0.001, < 0.001, < 0.001, and = 0.002, respectively), as shown in Table 4.
Table 4.
The QoR-15 Scores of Patients in All Groups
| Time points | NS group (n = 20) |
B10 Group (n = 20) |
B20 Group (n = 20) |
B30 Group (n = 20) |
B40 Group (n = 20) |
F values | P values |
|---|---|---|---|---|---|---|---|
| Postoperative 24 h | 122.6 ± 7.6# | 125.0 ± 8.0# | 132.0 ± 7.2*# | 139.4 ± 6.3* | 141.0 ± 6.6* | 26.425 | <0.001 |
| Postoperative 48 h | 123.9 ± 6.9# | 127.1 ± 6.1# | 133.9 ± 7.4*# | 141.2 ± 6.6* | 141.9 ± 6.1* | 29.613 | <0.001 |
| Postoperative 72 h | 137.4 ± 8.7 | 140.4 ± 9.7 | 141.6 ± 6.9 | 142.3 ± 6.0 | 142.9 ± 6.2 | 1.621 | 0.175 |
| F values | 22.175 | 21.207 | 10.004 | 1.115 | 0.455 | – | – |
| P values | <0.001 | <0.001 | <0.001 | 0.335 | 0.637 | – | – |
Notes: Values are mean ± SD. Differences in the VAS scores among groups were analyzed using one-way ANOVA. Bonferroni correction test was used for further statistical comparison between groups. *P < 0.005 vs NS group, #P < 0.005 vs B40 group.
Abbreviations: QoR-15, Quality of Recovery-15 score; NS group, normal saline combined with ropivacaine; B10 group, 10 μg/kg butorphanol combined with ropivacaine; B20 group, 20 μg/kg butorphanol combined with ropivacaine; B30 group, 30 μg/kg butorphanol combined with ropivacaine; B40 group, 40 μg/kg butorphanol combined with ropivacaine.
There were no differences in the incidences of dizziness, nausea and vomiting, respiratory depression, and pruritus among groups (P = 0.101, 0.982, 1, and 0.930, respectively), as shown in Table 5.
Table 5.
The Incidence of Adverse Events
| NS group (n = 20) |
B10 Group (n = 20) |
B20 Group (n = 20) |
B30 Group (n = 20) |
B40 Group (n = 20) |
χ2 | P | |
|---|---|---|---|---|---|---|---|
| Dizziness, n (%) | 0 (0) | 1 (5) | 3 (15) | 4 (20) | 5 (25) | 7.655 | 0.101 |
| Nausea and vomiting, n (%) | 4 (20) | 4 (20%) | 5 (25) | 5 (25) | 6 (30) | 0.880 | 0.982 |
| Respiratory depression, n (%) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 | 1 |
| Pruritus, n (%) | 1 (5) | 1 (5) | 2 (10) | 2 (10) | 2 (10) | 1.145 | 0.930 |
Notes: Values are number of patients. Differences in the incidences of dizziness, nausea and vomiting, respiratory depression, and pruritus among groups were analyzed using Fisher’s exact tests.
Abbreviations: NS group, normal saline combined with ropivacaine; B10 group, 10 μg/kg butorphanol combined with ropivacaine; B20 group, 20 μg/kg butorphanol combined with ropivacaine; B30 group, 30 μg/kg butorphanol combined with ropivacaine; B40 group, 40 μg/kg butorphanol combined with ropivacaine.
Discussion
In the present study, we found that the combination of ropivacaine and butorphanol could significantly accelerate the onset time of sensory and motor blockade, prolong the duration of sensory and motor blockade, and the time of the first postoperative rescue analgesia, and improve patient satisfaction. The rescue analgesic dose of dezocine after surgery and the dose of propofol for intraoperative sedation were both significantly reduced. The time of the first postoperative rescue, analgesia was prolonged the most in B40 group. The QoR-15 scores in the B40 group at 24 and 48 hours after surgery were higher than those in the NS group, B10 group, and B20 group, and were comparable to those in the B30 group.
Brachial plexus block is more popular than general anesthesia in upper limb fracture surgery, with faster postoperative recovery, lower incidence of postoperative nausea and vomiting, and faster discharge time.20 However, the use of local anesthetics alone for nerve block may lead to imperfect nerve block anesthesia, and the duration of single-injection nerve block anesthesia is relatively short.21 In previous study, we found that the combination of ropivacaine and adjuvant can not only reduce the dose of ropivacaine, but also improve postoperative analgesia and promote postoperative recovery.5,22 It indicated that the combination of adjuvants and local anesthetics is crucial in nerve block anesthesia. Butorphanol is an opioid analgesic with strong analgesic effects. As a local anesthetic adjuvant, it can significantly improve local anesthesia.23 Some studies have found that the improvement of nerve block by local anesthetic adjuvants was varied with the dosage.24–26 Bharathi et al reported that patients received 0.375% levobupivacaine combined with 2 mg of butorphanol had a faster onset time and longer duration of nerve blockade compared to patients received 0.375% levobupivacaine combined with 1 mg of butorphanol.10 In the present study, compared with normal saline, 10ug/kg butorphanol did not improve the nerve block with ropivacaine, 20, 30, and 40 ug/kg butorphanol could significantly shorten the onset time of nerve block, prolong the duration of nerve block and the time of first rescue analgesia after surgery. Further intergroup analysis showed that the combination of 30 and 40 ug/kg butorphanol was significantly better than the combination of 10 and 20 ug/kg butorphanol in improving nerve block and postoperative analgesia with ropivacaine. It indicated that the potential of butorphanol to improve the anesthetic efficacy of ropivacaine nerve block is dose-dependent, which was consistent with the results of above study. Moreover, 30 and 40 ug/kg butorphanol combined with ropivacaine had similar nerve block characteristics, indicating that the potential of 30 and 40 ug/kg butorphanol in improving ropivacaine nerve block anesthesia is comparable.
Intraoperative sedation can promote better tolerance of patients to surgery under regional anesthesia.27 Previous studies have found that intravenous infusion of propofol and dexmedetomidine during surgery can induce moderate sedation in patients. However, compared with dexmedetomidine, propofol did not reduce opioid consumption within 24 hours after surgery and prolong the first postoperative rescue analgesia time.28 In our study, compared with different doses of butorphanol, propofol could not reduce the dose of dezocine for postoperative rescue analgesia and prolong the time of postoperative rescue analgesia. It indicated that propofol does not improve the effect of local anesthesia like dexmedetomidine and butorphanol. The sedative effect of butorphanol is induced by stimulating the kappa opioid receptors in the central nervous system. Clinical study has shown that butorphanol induces a dose-dependent sedative effect with minimal circulation and respiratory depression.29 In our study, we administered intravenous infusion of propofol to maintain the intraoperative MOAA/S sedation level of 2–4 in patients, and found that the dosage of propofol in the B20, B30, and B40 groups during the surgery was significantly lower than that in the NS group and the B10 group. It indicated that the intraoperative sedation of butorphanol is dose-dependent, which was consistent with the above studies. Moreover, although butorphanol has a dose-dependent sedative effect, the duration of PACU of patients in the butorphanol groups was not significantly prolonged.
In our study, the time of first postoperative rescue analgesia was significantly prolonged with less postoperative rescue analgesic dose of dezocine, and the QOR-15 scores was higher in patients received butorphanol as an adjuvant for ropivacaine. It indicated that the delay in the first rescue analgesic opioid time after surgery and the reduction in opioid consumption for postoperative analgesia are associated with higher QOR-15 scores.30 Somnolence, dizziness, and nausea or vomiting were the most frequently adverse effects of butorphanol.31 In the present study, no patients who received butorphanol suffered from respiratory depression, indicating that butorphanol had no effect on spontaneous breathing within the dose range of 10 to 40 μg/kg. Although there was no statistically significant difference in the incidence of dizziness and itching between the butorphanol group and the saline group, the incidence of drowsiness gradually increased with the increase of butorphanol dose. It is suggested that lower-dose butorphanol should be used while ensuring the clinical efficacy.
There are limitations in our study. Currently, the dosage of butorphanol as an adjuvant for local anesthetics varies from 1 to 2 mg.9,11 Therefore, we only observed the potential improvement of local anesthesia with 10–40 ug/kg butorphanol as an adjuvant of ropivacaine in this study, and the improvement effect of higher doses of butorphanol on nerve block was not investigated. Given that the incidence of drowsiness gradually increased with the increase of butorphanol dose.10 It is suggested that lower-dose butorphanol should be used while ensuring the clinical efficacy. Although propofol cannot improve the effectiveness of local anesthesia like dexmedetomidine and butorphanol. However, it is unclear whether intraoperative propofol sedation affects the improvement effect of butorphanol on ropivacaine supraclavicular nerve block. This study is a single-center small-sample clinical trial, the results of this study need to be verified in multi-center clinical trials with large sample size in the future. Finally, we only observed the improvement of butorphanol as an adjuvant to ropivacaine for supraclavicular brachial plexus block. The effect of butorphanol as an adjuvant to other local anesthetics on nerve block anesthesia is unclear.
Conclusion
In conclusion, butorphanol as an adjuvant of ropivacaine for supraclavicular brachial plexus block under intraoperative moderate sedation with TCI of propofol can significantly shorten the onset time of nerve block, prolong the duration of nerve block and the first postoperative remedial analgesia time, reduce the dosages of intraoperative sedative drug and postoperative remedial analgesic drug, and improve the satisfaction of patients after surgery. The optimal synergistic dose of butorphanol combined with ropivacaine for supraclavicular brachial plexus block was 30 μg/kg, with no effect on the incidence of adverse events.
Acknowledgments
The authors thank the participants for their enthusiastic collaboration, and the orthopedic surgeons and nurses who assisted with clinical data collection.
Funding Statement
This study was supported by the Primary Health Development Research Center of Sichuan Province Program (SWFZ24-Y-28). The funder only provided financial support for this study and did not participate in the design, implementation, data collection, analysis, result interpretation, or document writing process of the study.
Data Sharing Statement
Due to ethical reasons, to protect the integrity of the participants, the study data are not publicly available. The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.
Ethics Approval and Consent to Participate
This observational clinical study was approved by the ethics committee of Affiliated Hospital of North Sichuan Medical College Ethical Approval No.: 2021ER021-1) and registered with the Chinese Clinical Trial Registry (https://www.chictr.org.cn/showproj.html?Proj=128419, registration number: ChiCTR2100050566, registration date: 28/08/2021) prior to patient enrolment. Participants received oral and written information about the observational study prior to inclusion and signed informed consent. All procedures performed in this study followed ethical standards of research and the Declaration of Helsinki.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors declare that they have no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Due to ethical reasons, to protect the integrity of the participants, the study data are not publicly available. The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.