Background and objectives This multicenter, randomized trial compared 2, 5, and 8 mg of perineural dexamethasone for ultrasound-guided infraclavicular brachial plexus block. Our research hypothesis was that all three doses of dexamethasone would result in equivalent durations of motor block (equivalence margin=3.0 hours).
Methods Three hundred and sixty patients undergoing upper limb surgery with ultrasound-guided infraclavicular block were randomly allocated to receive 2, 5, or 8 mg of preservative-free perineural dexamethasone. The local anesthetic agent (35 mL of lidocaine 1%-bupivacaine 0.25% with epinephrine 5 µg/mL) was identical in all subjects. Patients and operators were blinded to the dose of dexamethasone. During the performance of the block, the performance time, number of needle passes, procedural pain, and complications (vascular puncture, paresthesia) were recorded. Subsequently a blinded observer assessed the success rate (defined as a minimal sensorimotor composite score of 14 out of 16 points at 30 min), onset time as well as the incidence of surgical anesthesia (defined as the ability to complete surgery without local infiltration, supplemental blocks, intravenous opioids, or general anesthesia). Postoperatively, the blinded observer contacted patients with successful blocks to inquire about the duration of motor block, sensory block, and postoperative analgesia. The main outcome variable was the duration of motor block.
Results No intergroup differences were observed in terms of technical execution (performance time/number of needle passes/procedural pain complications), onset time, success rate, and surgical anesthesia. Furthermore, all three doses of dexamethasone provided similar durations of motor block (14.9–16.1 hours) and sensory block. Although 5 mg provided a longer analgesic duration than 2 mg, the difference (2.7 hours) fell within our pre-established equivalence margin (3.0 hours).
Conclusions 2, 5, and 8 mg of dexamethasone provide clinically equivalent sensorimotor and analgesic durations for ultrasound-guided infraclavicular block. Further trials are required to compare low (ie, 2 mg) and ultra-low (eg, 0.5–1 mg) doses of perineural dexamethasone for brachial plexus blocks.
Trial registration number TCTR20150624001.
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Intravenous and perineural (PN) dexamethasone have been previously shown to prolong the duration of brachial plexus blocks.1–17 Postulated mechanisms of action include inhibition of nociceptive C fibers, suppression of ectopic neural discharge, peripheral/central anti-inflammatory effects, and suppression of the neuropeptide immune response to injury.15 In two recent trials (combined n=300), our research team has demonstrated that PN dexamethasone outperforms its intravenous counterpart for infraclavicular and axillary brachial plexus blocks.18 19 At present time, the optimal dose of PN dexamethasone remains controversial. While some authors advocate “low” doses (ie, 2 mg),20 others have employed “intermediate” doses (ie, 4–5 mg).2 4 6 12 18 In contrast, the majority of published studies have favored a “high” dose (ie, 8–10 mg) of PN dexamethasone.1–3 7–11 13–17 19 21
In this multicenter, randomized trial, we set out to compare low (2 mg), intermediate (5 mg), and high (8 mg) doses of PN dexamethasone for ultrasound (US)-guided infraclavicular brachial plexus block (ICB). Because the most recent evidence pertaining to intravenous dexamethasone suggests minimal differences between 4 and 10 mg,22 we hypothesized that all three PN doses would also result in similar block durations, and consequently designed the study as an equivalence trial. Since analgesic and sensory duration can be influenced by postoperative analgesic regimen and surgical trauma to small cutaneous nerves, respectively, we selected the duration of motor block as the primary outcome.18 19
Materials and methods
The current trial was registered at www.clinicaltrials.in.th (trial registration number: TCTR20170720001) on July 20, 2017. After obtaining ethics committee approval and written informed consent, we enrolled 360 patients undergoing surgery of the forearm, wrist, or hand. Inclusion criteria were age between 18 and 80 years, American Society of Anesthesiologists physical status I–III, and body mass index between 18 and 35 kg/m2. Exclusion criteria were inability to consent to the study, coagulopathy, sepsis, hepatic or renal failure, allergy to local anesthetic (LA), pre-existing muculocutaneous/median/radial/ulnar neuropathy, and prior surgery in the infraclavicular fossa.
After arrival in the induction room, an 18-gauge or 20-gauge intravenous catheter was placed in the upper limb contralateral to the surgical site, and intravenous premedication (0.015–0.03 mg/kg of midazolam and 0.6 µg/kg of fentanyl) was administered to patients if necessary. Supplemental oxygen (nasal cannulae at 4 L/min) and pulse oximetry were applied throughout the procedure.
The ICB was performed according to a previously described technique (add references 18, 23).⇓ A 6–13 MHz linear US transducer (SonoSite M-Turbo, SonoSite, Bothell, Washington, USA; or General Electric LOGIC E, General Electric Healthcare, Wauwatosa, Wisconsin, USA) was applied in a sterile fashion in the infraclavicular fossa, medially to the coracoid process, to obtain a short axis view of the axillary artery. A skin weal was raised with 3 mL of 1.0% lidocaine. Using an inplane technique and a cephalad to caudad direction, a 21-gauge or 22-gauge, 90–100 mm block needle (StimuQuik Echo, Arrow International, Reading, Pennsylvania, USA; UniPlex NanoLine, Pajunk, Geisingen, Germany; Stimuplex Ultra 360, B Braun Medical AG, Melsungen, Germany; or Stimuplex A, B Braun Medical AG) was advanced until its tip was located dorsal to the axillary artery. Thirty-five milliliters of lidocaine 1.0%-bupivacaine 0.25% (obtained by mixing equal parts of lidocaine 2% and bupivacaine 0.5%) with epinephrine 5 µg/mL were incrementally injected. Using a computer-generated sequence of random numbers and a sealed envelope technique, patients were randomly allocated to receive 2, 5, or 8 mg of preservative-free PN dexamethasone. Subjects were randomized in blocks of 15 to ensure equal distribution of the three study groups. Based on anticipated surgical volume, the Santiago, Montreal, Chiang Mai, and Bangkok centers were assigned 10, 5, 5, and 4 blocks of 15 patients, respectively. Randomization was independently carried out in each of the four centers. The study solutions were prepared by an investigator not involved in clinical care; thus, patients, operators, and outcome assessors remained blinded to the dose of PN dexamethasone.
All blocks were performed by residents, fellows, or staff anesthesiologists. Independently of their status, operators were considered experts for a given approach if, prior to the start of the study, they possessed an experience level equal or superior to 60 ICBs. Otherwise they were considered trainees.24 For both groups, the imaging time was defined as the time interval between contact of the US probe with the patient and the acquisition of a satisfactory picture. The needling time (defined as the temporal interval between the start of the skin weal and the end of LA injection through the block needle) was also recorded. Thus, performance time was defined as the sum of imaging and needling times. The number of needle passes was also recorded. The initial needle insertion counted as the first pass. Any subsequent needle advancement that was preceded by a retraction of at least 10 mm counted as an additional pass.25 Furthermore, the level of procedural pain (0=no pain; 10=worst imaginable pain) as well as the incidence of vascular puncture and paresthesia were recorded.
After LA injection through the block needle, measurements of brachial plexus blockade were carried out every 5 min until 30 min by a blinded observer. Sensory blockade of the musculocutaneous, median, radial, and ulnar nerves was graded according to a 3-point scale using a cold test: 0=no block, 1=analgesia (patient can feel touch, not cold), and 2=anesthesia (patient cannot feel touch).18 19 Sensory blockade of the musculocutaneous, median, radial, and ulnar nerves was assessed on the lateral aspect of the forearm, the volar aspect of the thumb, the lateral aspect of the dorsum of the hand, and the volar aspect of the fifth finger, respectively.18 19 Motor blockade was also graded on a 3-point scale: 0=no block, 1=paresis, and 2=paralysis.18 19 Motor blockade of the musculocutaneous, radial, median, and ulnar nerves was evaluated by elbow flexion, thumb abduction, thumb opposition, and thumb adduction, respectively. 18 19 Overall the maximal composite score was 16 points. We considered the block a success and the patient ready for surgery when a minimal composite score of 14 points was achieved, provided the sensory block score was equal or superior to 7 out of 8 points. This scale has been used in previous studies. 18 19 The onset time was defined as the time required to obtain 14 points. If after 30 min the composite score was inferior to 14 points, the patient was transferred to the operating room for the start of the surgery. For these patients, we did not record an onset time. Surgical anesthesia was recorded by the same blinded observer and defined as the ability to proceed with surgery without the need for intravenous narcotics, general anesthesia, rescue blocks, or LA infiltration by the surgeon (add references 18 and 23). ⇓ However, in case of anxiety (as voiced by patients or determined by the treating anesthesiologists), subjects could receive a propofol infusion (25–80 µg/kg/min) intraoperatively, provided response to verbal stimulus was maintained. The blinded observer also recorded the patient’s anthropometric data.
Postoperatively, patients with successful blocks (minimal composite score of 14 points at 30 min) were provided a datasheet to record the exact time when they first regained sensation in the fingers (duration of sensory block), moved the fingers (duration of motor block), and experienced pain at the surgical site (analgesic duration). We did not seek sensation or movement of specific digits but only of those whose tips were not covered by the cast. The blinded observer contacted study subjects at 24 hours for data collection. In the event that patients could not be reached or that ICBs had receded during sleep, we did not record any data for the duration of sensorimotor block and postoperative analgesia. However data pertaining to technical execution/onset/success/surgical anesthesia were retained for analysis (figure 1).
One week after the surgery, patients were contacted by the blinded investigator to inquire about complications such as persistent numbness/paresthesia or motor deficit.
Our previous experience with PN dexamethasone (5 mg) for US-guided ICB revealed a motor block duration of 15.7±6.2 hours.18 For the current study, we speculated equivalency between 2, 5, and 8 mg of PN dexamethasone and thus designed the protocol as an equivalence trial. We deemed that a 20% difference in motor block duration (3 hours) carries minimal clinical significance, and therefore set our equivalence margin at ±3 hours. A calculated sample size of 270 patients was required to provide a statistical power of 0.90 and a type I error of 0.025 (one-way analysis of variance [ANOVA]). Since block duration can only be calculated for successful blocks and since we anticipated a 90% success rate with a 35 mL volume,23 300 subjects needed to be enrolled to account for block failure. Furthermore, since the duration of motor block cannot be accurately measured if the blocks wear off during the patient’s sleep (approximately 20% of cases), a total of 360 patients were recruited to account for potential dropout. Equivalence was assessed by comparing 95% CIs, and the significance of intergroup differences was assessed by planned post-hoc comparisons (ie, each group was compared with its adjacent dose group).
Statistical analysis was performed using SPSS Statistics for Windows V.21. Continuous variables were analyzed with the one-way ANOVA followed by Sidak’s test. Ordinal variables as well as continuous data that did not follow a normal distribution were examined with the Kruskal-Wallis one-way ANOVA. Nominal variables were analyzed with χ2 or Fisher’s exact test as appropriate. All p values were corrected for multiple comparisons and those inferior to 0.05 were considered significant.
The 360 subjects were recruited over a period of approximately 10.5 months (August 2017 to mid-June 2018) (figure 1). As planned, 150, 75, 75, and 60 patients were initially enrolled in Santiago, Montreal, Chiang Mai, and Bangkok, respectively. However, one subject (2 mg group) rescinded his consent immediately after the performance of the block. Thus his data were not included in any subsequent analysis. Therefore demographic characteristics (table 1) and block performance data (table 2) are presented for a total of 359 patients.
Patients in the 8 mg group displayed a higher body mass index compared with their 2 mg and 5 mg counterparts. However there were no other intergroup differences in terms of demographic data and surgical intervention (table 1).
Technical execution (performance time/number of needle passes/procedural pain/complications) was comparable between the three groups (table 2). No intergroup differences were recorded in terms of onset time, success rate, and surgical anesthesia (table 2; figure 2). Furthermore, all three doses of dexamethasone provided similar durations of motor block and sensory block. However, compared with its 2 mg counterpart, the 5 mg group resulted in longer postoperative analgesia (22.7±6.0 vs 20.0±5.7 hours; p=0.006) (table 2; figures 3–5).
Patient follow-up at 1 week revealed sensory deficits in only one patient. However all symptoms spontaneously resolved by 2 weeks.
In this randomized trial, we compared 2, 5, and 8 mg of PN dexamethasone for US-guided ICB. Our findings suggest that all three doses provide similar durations of sensorimotor block. Although 5 mg provided a longer analgesic duration than 2 mg, the difference (2.7 hours) fell within our pre-established equivalence margin (3.0 hours).
In the literature, randomized trials investigating intermediate (4–5 mg) and high (7.5–8 mg) doses of PN dexamethasone in the setting of brachial plexus blocks have reported mixed results. For interscalene blocks, studies by Tandoc et al,2 Woo et al,26 and Holland et al 27 have found no intergroup differences in terms of block duration or time to first analgesia. In contrast, for supraclavicular blocks, Patel et al 28 detected longer motor blockade and postoperative analgesia with 8 mg compared with 4 mg of PN dexamethasone. To date, only Woo et al 26 have compared low (2.5 mg) and intermediate (5 mg) doses of PN dexamethasone. These authors reported no differences in the time to first analgesia between the two doses.26 Therefore the cumulative results derived from the current trial as well as most previously published studies2 26 27 seem to suggest that high doses of PN dexamethasone provide no significant benefits compared with their intermediate counterparts. Furthermore, intermediate and low doses of PN dexamethasone also appear to result in similar durations of sensorimotor block and postoperative analgesia.26
The rationale of the current trial requires discussion. In light of the conflicting results stemming from previous studies by Tandoc et al,2 Woo et al,26 Holland et al,27 and Patel et al,28 a practical argument could be made to systematically administer 8 mg of PN dexamethasone for brachial plexus blocks, thereby increasing the odds of maximizing postoperative analgesia. However, despite its increasing popularity,1–21 PN remains an off-label adjuvant. Theoretical concerns of neurotoxicity may persist, as no human study has been carried out to analyze neural injury caused by LA combined with PN dexamethasone.29 Therefore, during the inception phase of our trial, we reasoned that if 2 mg of PN dexamethasone can be equivalent to 5 mg or 8 mg, it would provide clinicians with a non-negligible 60%–75% decrease in commonly used doses of PN dexamethasone. Furthermore, 2 mg would also mirror the dosing recommended by Williams et al 30 31 based on extrapolation of doses that are least likely to be associated with LA-induced worsening of cytotoxicity in cultured neurons.
The fact that we only used patients with 14-point minimal composite scores to tabulate block duration also deserves special mention. In our trial, 92.5%–97.5% of subjects reached 14 points (or more) at 30 min. In contrast, up to 95.8%–99.2% of patients achieved surgical anesthesia. In theory, one could have a sensory block with minimal motor blockade and still display surgical anesthesia. However, since our primary outcome was motor block duration, we elected to retain only subjects with minimal composite scores of 14 points. This strategy mirrors the one employed in our two previous trials investigating intravenous and PN dexamethasone.18 19
Our protocol contains some limitations. First, the durations of sensorimotor block and postoperative analgesia inherently depend on patient recall. Therefore, in order to minimize subjectivity, we selected motor block as the primary outcome and discarded patients whose blocks receded during their sleep. Second, our findings are specific to the adrenalized lidocaine 1%-bupivacaine 0.25% mixture, 35 mL injectate, and infraclavicular approach used in the current study. Further randomized investigation is required for other LAs, different injectates, as well as other approaches for brachial plexus block and other types of nerve block. Finally, we did not record postoperative pain scores, breakthrough opioid consumption, and opioid-related side effects. Because the trial was carried out in four centers (across three countries), we reasoned that different patterns of opioid prescription/consumption might have constituted a confounding variable.
In conclusion, 2, 5 and 8 mg of PN dexamethasone provide clinically equivalent sensorimotor and analgesic durations for US-guided ICB. Further trials are required to compare low (ie, 2 mg) and ultra-low (eg, 0.5–1 mg) doses of PN dexamethasone for brachial plexus blocks.
The authors thank Derek Mitchell and Andrew Owen for their assistance with patient recruitment at the Montreal General Hospital; Alejandra Castillo, Verónica Salinas, Ma Mercedes Aguirre and Estela Maulén for their assistance with patient recruitment at the Hospital Clínico Universidad de Chile; as well as Theerawat Chalachewa and Thepparat Kanchanathepsak for their assistance with patient recruitment at Ramathibodi Hospital.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethics committee approval was obtained from Hospital Clínico Universidad de Chile, Santiago, Chile; McGill University Health Centre, Montreal, Canada; Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand; and Ramathibodi Hospital, Bangkok, Thailand.
Provenance and peer review Not commissioned; externally peer reviewed
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