- Email: [email protected]
Comparison of the effects of perineural or intravenous dexamethasone on low volume interscalene brachial plexus block: a randomised equivalence trial
British Journal of Anaesthesia, xxx (xxx): xxx (xxxx) doi: 10.1016/j.bja.2019.08.025 Advance Access Publication Date: xxx Clinical Investigation
CLINICAL INVESTIGATION
Comparison of the effects of perineural or intravenous dexamethasone on low volume interscalene brachial plexus block: a randomised equivalence trial Paul G. McHardy1, Oskar Singer1, Imad T. Awad1, Ben Safa1, Patrick D. G. Henry2, Alex Kiss3, Shelly K. Au1, Lilia Kaustov1 and Stephen Choi1,* 1
Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 2Division
of Orthopedic Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada and 3
Department of Research Design and Biostatistics, Sunnybrook Research Institute, Toronto, ON, Canada
*Corresponding author. E-mail: [email protected]
Abstract Background: Efforts to prolong interscalene block (ISB) analgesia include the use of local anaesthetic adjuvants such as dexamethasone. Previous work showing prolonged block duration suggests that both perineural and intravenous (i.v.) routes can both prolong analgesia. The superiority of either route is controversial given the design of previous studies. As perineural dexamethasone is an off-label use, anaesthesiologists should be fully informed of the clinical differences, if any, on block duration. This study was designed to test whether perineural vs i.v. dexamethasone administration are equivalent. Methods: We randomised 182 eligible patients scheduled for arthroscopic shoulder surgery to receive low-dose ISB (0.5% ropivacaine 5 ml) with perineural or i.v. dexamethasone 4 mg. Subjects, anaesthesiologists, and research personnel were blinded. All subjects also received a standardised general anaesthetic and multimodal analgesia. The primary outcome was duration of analgesia analysed as an equivalence outcome (2 h equivalency margin) using the two one-sided test (TOST) method. Results: For the primary outcome, duration of analgesia, and perineural and i.v. administration of dexamethasone were not equivalent. The upper and lower bounds of the 90% confidence interval were 1 h (P¼0.12) and e2.5 h (P¼0.01), respectively. The observed difference in mean block duration was not clinically relevant (0.75 h longer for i.v. dexamethasone). There were no other clinically significant differences between groups. Conclusion: In the context of low-volume ISB with ropivacaine, perineural and i.v. dexamethasone were not equivalent in terms of their effects on block duration. However, there were no clinically significant differences in outcomes, and there is no advantage of perineural over intravenous dexamethasone. www.clinicaltrials.gov registration: NCT02322242. Keywords: analgesia; dexamethasone; interscalene nerve block; local anaesthetic adjuvant; perineural; regional anaesthesia
Editorial decision: 01 August 2019; Accepted: 1 August 2019 © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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Editor’s key points Both perineural and i.v. dexamethasone can prolong analgesia after interscalene nerve block, but the superiority of either route is controversial. In a randomised, blinded equivalence design study, 182 eligible patients scheduled for arthroscopic shoulder surgery received low-dose interscalene block (0.5% ropivacaine 5 ml) with either perineural or i.v. dexamethasone 4 mg. Durations of analgesia were not equivalent, but the observed difference in mean block duration was not clinically relevant (0.75 h longer for i.v. dexamethasone). Given concerns over local perineural toxicity, there is little justification for perineural dexamethasone in lowvolume interscalene block.
Interscalene brachial plexus block (ISB) is the standard of care for analgesia after shoulder surgery in providing superior analgesia and reducing opioid consumption.1e6 ISB can have complications including ipsilateral phrenic nerve block resulting in diaphragmatic paralysis for the duration of the block. This can temporarily reduce ventilatory capacity, which has the potential for morbidity in patients with reduced respiratory reserve. Nonetheless, the analgesic and opioidsparing benefits usually outweigh the risks in the appropriate patient population. Patients undergoing shoulder surgery, once routinely admitted to hospital after surgery for analgesia, are now commonly managed on an ambulatory basis because of ISB analgesia. Single-injection ISB dissipates after several hours, unmasking the moderate to severe pain of the surgery and typically requires opioid analgesia.7 Efforts to prolong ISB by increasing local anaesthetic (LA) dose are limited by their narrow therapeutic window and volume/concentration considerations. Volumes of 10 ml or greater injected into the interscalene groove carry a high risk of ipsilateral hemi-diaphragmatic paresis. Recent data show that an extrafascial injection of 15 ml of LA (4 mm from the brachial plexus in the middle scalene muscle) produced similar analgesia but reduced hemi-diaphragmatic paresis.3e6,8 Several LA adjuvants have been studied to prolong ISB when continuous catheter techniques are not possible; the most common is the corticosteroid dexamethasone. Meta-analyses have shown that perineural dexamethasone, an off-label use, in conjunction with LA prolongs the duration of peripheral nerve blocks (PNB) with effect sizes ranging from 40% to 75% (or 6e10 h) using doses of 8e10 mg.9e12 Although the specific local mechanism of dexamethasone has not been elucidated, it is postulated to reduce ectopic neuronal discharge and inhibit potassium channel-mediated discharge of nociceptive C-fibres.13,14 Alternatively, it has been postulated that dexamethasone provides superior analgesia in the context of PNB through systemic antiinflammatory effects. Several current controversies warrant this trial to compare perineural vs i.v. dexamethasone. Previous trials investigating perineural dexamethasone used peripheral nerve stimulation and high LA volumes (30e40 ml).15e17 Although the total dose of LA delivered in close proximity to the target neural elements can impact block duration and efficacy, contemporary ultrasound-guided regional anaesthesia practice allows more accurate, targeted deposition of LA. Several studies have shown that ISB volumes ranging as low as 5e10 ml do not
affect block duration or efficacy, although the generalisability of lower volume ISB can be limited.3e6 Secondly, there are data suggesting that i.v. dexamethasone also prolongs block duration.16,18,19 Although these studies concluded that i.v. and perineural dexamethasone have equivalent block-prolonging effects, they were designed as superiority trials and therefore underpowered to determine equivalence. This trial was specifically designed and powered as an equivalence trial, with an a priori defined equivalence margin of 2 h, to test the hypothesis that perineural dexamethasome is not equivalent to i.v. dexamethasone on analgesic outcomes when combined with low-dose ISB using ropivacaine.
Methods This study was conducted at Sunnybrook Health Sciences Centre (SHSC), a tertiary care academic health sciences centre fully affiliated with the University of Toronto. The study was approved by Research Ethics Board of SHSC in October 2014 (REB ID# 437-2013) and registered with www.clinicaltrials.gov (December 2014, NCT02322242). Regulatory approval was sought and received (May 2014, Control #174415) from Health Canada for the off-label perineural use of dexamethasone sodium phosphate (multi-dose vial 4 mg ml1, benzyl alcohol free, and sodium metabisulphite preservative, sourced from Sandoz Canada). Adults (18e80 yr old) with ASA physical status 1e3, scheduled to undergo arthroscopic shoulder surgery (subacromial decompression or rotator cuff repair), were eligible for enrolment and recruited by research assistants in the preoperative anaesthesia clinic. Exclusion criteria were as follows: allergy or intolerance to study medications; BMI 35 kg m2; contraindication to low dose dexamethasone based on product monograph (peptic ulcer disease, systemic infection, glaucoma, active varicella/herpetic infections, diabetes mellitus); contraindication to ISB (severe Chronic Obstructive Pulmonary Disease, coagulopathy, pre-existing neurologic deficit in ipsilateral upper extremity, localised infection), pregnant or nursing females, or chronic opioid use (>30 mg oral morphine equivalents [OME] day1). Research assistants recruited patients from the preoperative anaesthesia clinic. Patients providing informed consent and meeting all eligibility criteria were randomised (1:1) in blocks of 10 to perineural dexamethasone (Dex-PN) or i.v. dexamethasone (Dex-IV) (treatment arms described below). The computer-generated randomisation sequence and sequentially numbered, sealed, opaque envelopes were prepared by an individual not otherwise involved in study conduct to maintain blinding and allocation concealment. Eligible participants were randomised on the day of surgery using the next numbered envelope in sequence. The randomisation list was kept in a secure location inaccessible to investigators or study personnel. Participants were premedicated with oral paracetamol 1000 mg (650 mg if <60 kg body weight), and oral celecoxib 400 mg (200 mg if <60 kg body weight) 1 h before surgery. After establishing i.v. access, applying standard monitors (ECG, noninvasive blood pressure cuff, continuous oxygen saturation), participants received sedation with midazolam (1e2 mg i.v.). The lateral aspect of the neck including the supraclavicular fossa ipsilateral to the surgical site was cleansed with an isopropyl alcohol/chlorhexidine gluconate solution. The ultrasound-guided low volume ISB (0.5% ropivacaine 5 ml) was performed under sterile conditions by a staff regional anaesthesiologist, or supervised regional anaesthesia fellow with a 13e6 MHz 38 mm linear probe (MTurbo®; SonoSite Inc., Bothell, WA, USA) at the C6 nerve root
Perineural vs systemic dexamethasone
level via posterior approach with a 22 gauge insulated 50 mm regional needle (Stimuplex®; B.Braun Medical, Bethlehem, PA, USA). After satisfactory position of the needle tip was achieved and with negative aspiration, the LA (±dexamethasone 4 mg) was injected. General anaesthesia was induced with a standardised technique using fentanyl 1 mg kg1 and propofol 1e3 mg kg1. Tracheal intubation was facilitated with rocuronium 0.6 mg kg1. Anaesthesia was maintained using sevoflurane at an end-tidal concentration of 1.4e2 vol%. The posterior arthroscopic port site was injected with 10 ml of bupivacaine 0.25% (1:200 000 epinephrine). The study infusion of 0.9% saline 50 ml (±dexamethasone 4 mg) was commenced after induction of anaesthesia and securing of the airway. Intraoperatively, aliquots of fentanyl (25 mg) were administered when blood pressure or heart increased more than 20% of preoperative baseline values. Muscle relaxation was reversed using neostigmine (0.04 mg kg1) and glycopyrrolate (0.007 mg kg1). Standard antiemetic prophylaxis with the serotonin antagonist ondansetron 4 mg i.v. was administered before emergence. Upon arrival to the recovery room, pain (Numeric Rating Scale [NRS] 4 or patient request for analgesia) was treated with oral analgesics if deemed necessary (hydromorphone or combination acetaminophen (325mg) oxycodone (5mg) tablet). Postoperative nausea was managed with haloperidol (1 mg) or dimenhydrinate (25 mg) i.v. if necessary. Subjects were instructed to self-administer paracetamol 500 mg every 6 h and ibuprofen (200 mg every 8 h) PO for 3 days after discharge. Additional oral analgesics (oxycodone or hydromorphone) were prescribed at the discretion of the surgical team, and patients were instructed to take them if the NRS was 4. Participants completed a home diary with outcomes described below. These data were collected by telephone at two time points, 2 days and 1 week after operation. Follow-up attempts were until 30 days after operation.
Assigned interventions Perineural dexamethasone ISB injectate mixturedropivacaine 1% (3 ml) þ dexamethasone 0.4% (1 ml), 0.9%, saline (2 ml); final ropivacaine concentration 0.5%, dexamethasone 667 mg ml1. IV infusiond0.9% saline (50 ml infusion bag).
Intravenous dexamethasone ISB injectate mixturedropivacaine 1% (3 ml) þ 0.9% saline (3 ml); final ropivacaine concentration 0.5%. IV infusiond0.9% saline (50 ml infusion bag) þ dexamethasone 0.4% 1 ml. The ISB injectate was made to a total volume of 6 ml to account for dead space in the block needle tubing, of which 5 ml was injected for the ISB. The perineural dexamethasone dose was set at 4 mg (final concentration 667 mg ml1) based on an a priori study.20 This dexamethasone concentration of 667 mg ml1 combined with ropivacaine was the maximal concentration that did not induce neurotoxicity compared with ropivacaine alone.
Blinding All study materials were prepared immediately before use by trained anaesthesia assistants/nurses who were aware of group allocation but took no further part in study procedures or assessments. The ISB injectate was prepared in a syringe
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labelled ‘ropivacaine 0.5% (±dexamethasone 4 mg)’. Meanwhile, the 50 ml 0.9% saline infusion was labelled as ‘saline or dexamethasone 4 mg’. All other personnel including subjects, anaesthesiologists performing the ISB and anaesthetising in the operating theatre, surgeons, research assistants performing outcome measures, and statistician were blinded until data analysis was completed.
Outcomes The primary outcome was duration of sensory block defined as the time from the end of injection to the first sensation of pain at the surgical site. The secondary outcomes were: (a) painrelated outcomesdtime to first opioid consumption, Numeric Rating Scale (NRS) for pain, and cumulative opioid consumption (in OME) at 12 h, 24 h, and 1 week; (b) blockrelated outcomesdduration of motor block (end of injection to baseline motor function); (c) block-related complicationsdpostoperative room air oxygen saturation, localised infection at block site, postoperative blood glucose, postoperative block-related nerve palsy at 1 week; and (d) other complicationsdpostoperative nausea and vomiting. Opioid doses were converted to OME according to the general monograph for opioids in the Canadian Pharmacists’ Association Compendium of Pharmaceuticals and Specialties (oral oxycodone/oral morphine sulphate¼1:2, oral hydromorphone/oral morphine sulphate¼1:5, and oral codeine/oral morphine sulphate¼6.6:1).
Sample size calculation Based on our clinical experience with low-dose ultrasoundguided ISB (0.5% ropivacaine 5 ml) and previously published work, we expected a mean sensory block duration of 12 h with a standard deviation of 4 h. Based on previous literature, we expected a mean prolongation of block time associated with perineural dexamethasone to be ~50% thereby increasing block duration to 18 h. Defining an equivalency margin of 2 h, we estimated that 87 individuals per group (174 total) were required to be randomised to reliably test our hypothesis given a¼0.05 and 90% power. The specific sample size calculation is based on the typical analysis used for equivalence studies, the two onesided test (TOST) methodology.21,22 To account for incomplete data or loss to follow-up, we planned to randomise 90 subjects per group (180 total). As the recruitment and consent process was conducted by research assistants in the preoperative clinic before evaluation by anaesthesiologists, it was expected that there would be consenting individuals who would ultimately be ineligible. Final eligibility was confirmed by the investigators (PM and SC), and only those who met all inclusion/exclusion criteria proceeded to be randomised on the day of surgery.
Statistical analysis Patient data are summarised and expressed using appropriate measures of central tendency and dispersion or counts and percentages for categorical data. The primary outcome, time to first sensation of pain at the surgical site, was assessed for equivalence using the TOST method. Specifically, if the upper and lower boundaries of the 90% confidence interval (CI) were both less than the defined equivalence margin, the criteria for equivalence between groups is met. The equivalence margin was specified as 2 h based on what we considered a clinically important difference in block duration given the established
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Subjects approached n=892 Refused par cipa on • Not interested in research (n=289) • Not interested in study interven on (n=330) Subjects consen ng n= 273
Subjects randomised n=182
Allocated to dex-PN n=92 • Protocol devia ons n=1 • Repeat ISB prior to surgery due to primary block failure (ropivacaine 0.5% 10ml)
Analyzed for primary outcome n=92
Analyzed for all secondary outcomes n=90 • 2 lost to follow-up
Not randomised (n=91) • Withdrew consent before surgery (n=17) • Study staff not available (n=5) • Surgery cancelled (n=7) • Exclusion criteria • Diabe c (n=3) • BMI (n=44) • Chronic opioid use (n=8) • Pre-exis ng neuropathy (n=7)
Allocated to dex-IV n=90 • Protocol devia ons n=2 • Second 4mg dose of IV-dexamethasone • Repeat ISB prior to surgery due to primary block failure (ropivacaine 0.5% 10ml)
Analyzed for primary outcome n=90
Analyzed for all secondary outcomes n=89 • 1 lost to follow-up
Fig 1. CONSORT flow diagram of screened, enrolled, randomised, and analysed participants. CONSORT, Consolidated Standards of Reporting Trials.
analgesic duration of ISB and the reported prolongation associated with dexamethasone. Secondary outcomes were evaluated with conventional inferential tests assessing superiority. Continuous secondary outcomes (time to first analgesic request, duration of motor block opioid consumption, NRS) were assessed with the t-test. Categorical outcomes (paresthesia, infection) were compared with the c2 or Fisher’s exact test for the case of low expected cell counts. Secondary outcomes were considered exploratory in nature, and thus no correction for multiple comparisons was made. All data were analysed on an intention-to-treat principle. The funding agency (Physicians’ Services Incorporated Foundation) had no role in the design, conduct, or analysis of the study. This manuscript adheres to applicable CONSORT guidelines.
Results The Consolidated Standards of Reporting Trials (CONSORT) flow diagram details the number of participants that received the
allocated intervention (Fig. 1). Of the 892 patients approached, 273 provided written and informed consent to participate in the study between February 2015 and September 2018; 289 declined participation in any research activity and 330 declined the study specifically. Whereas 82 of the 273 patients who provided consent were not randomised because of exclusion criteria, 182 subjects without any exclusion criteria were randomised with 92 allocated to the Dex-PN group and 90 to the Dex-IV group (Table 1). There were three protocol deviations. One subject in the Dex-IV group inadvertently received a second 4 mg dose of i.v. dexamethasone in addition to the study drug infusion. One participant in each group received a second preoperative ISB with ropivacaine 0.5% 10 ml because of primary block failure (no sensory loss in the C5e6 dermatomes). Subjects remained in the study and were analysed in the groups to which they were randomised. The primary outcome was recorded for all 182 subjects randomised. Despite repeated attempts, three participants (two Dex-PN, one Dex-IV) were lost to follow-up at the 1 week interval and secondary outcome data for these were not recorded.
Perineural vs systemic dexamethasone
Table 1 Subject characteristics. *American Society of Anesthesiologists physical status classification. OME, oral morphine equivalent in mg. Data are presented as mean (standard deviation) or n [%].
Age (yr) Sex M:F BMI (kg m2) ASA physical status* 1/2/3 Preoperative opioid usage (OME)
Perineural dexamethasone (Dex-PN)
Intravenous dexamethasone (Dex-IV)
51.6 (18e73) 67 [73]:25 [27] 28.2 (4.1) 25/49/18 [27/53/20]
52.8 (22e76) 69 [77]:21 [23] 28.4 (3.8) 18/57/15 [20/73/17] 2.4 (6.6)
1.8 (5.8)
Analysis of the primary outcome with TOST indicates that block duration between the Dex-PN and Dex-IV groups are not equivalent (Fig. 2). The upper and lower bounds of the 90% CI were 1 h (P¼0.12) and e2.5 h (P¼0.01), respectively. Because the lower bound of the 90% CI crossed 2 h, conditions for
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establishing equivalency were not met. The mean difference in block duration between groups was 0.75 h (Dex-IV longer than Dex-PN). The observed mean (standard deviation) analgesic duration in the Dex-PN group was 8.7 (7.4) h and 9.4 (7.1) h in the Dex-IV group. Among the secondary outcomes, the only observed difference was a higher mean postoperative blood glucose in the Dex-PN group that was not clinically relevant (mean difference 0.34; 95% CI, 0.03e0.07; P¼0.02). There were no other observed differences in other secondary outcomes. There were no important adverse events or sideeffects in either group (Table 2).
Discussion This randomised trial compared the effects of perineural vs i.v. dexamethasone on block duration and analgesia-related outcomes in the context of low-volume ISB in patients undergoing arthroscopic shoulder surgery. It is the first trial designed specifically to test the hypothesis of equivalence between the two routes of administration and the largest sample size examining the issue. This trial also used the highest perineural
90% Equivalence margin Lower bound
90% Equivalence margin Upper bound
-2.53. P=0.01
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-0.75
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-1
1.02, P=0.12
0
1
2
Difference (h)
Perineural dexamethasone
Intravenous dexamethasone
Fig 2. Ninety percent confidence interval of mean interscalene block (ISB) duration.
Table 2 Secondary outcomes. Data are presented as mean (standard deviation) or n [%].
Duration of motor block (h) Time to first analgesic request (h) Numeric rating scale for pain 12 h 24 h 7 days Opioid consumption 12 h 24 h 7 days Postoperative oxygen saturation Postoperative blood glucose Postoperative nausea/vomiting Persistent nerve palsy
Perineural dexamethasone
Intravenous dexamethasone
P-value
18.5 (13.8) 9.1 (6.9)
20.3 (22.3) 9.6 (10.8)
0.99 0.78
3.3 (3.0) 4.9 (2.6) 3.1 (2.3)
3.3 (2.9) 4.7 (2.6) 3.4 (2.4)
0.88 0.62 0.37
12.2 (17.1) 24.3 (14.6) 148.8 (117.9) 96.6 (2.3) 6.8 (1.0) 32 [35] 0
12.9 (13.2) 25.6 (18.5) 167.2 (140.0) 97.0 (2.4) 6.5 (1.1) 32 [36] 0
0.39 0.95 0.52 0.24 0.02 0.96 e
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dexamethasone concentration (667 mg ml1) shown to be safe to maximise perineural effects. This is important given that there is a perineural doseeresponse relationship.23 Although there was statistically significant evidence that i.v. administration was not equivalent to perineural, the observed difference in block duration (0.75 h) may be of limited clinical significance. We did not observe any significant differences in pain scores, opioid consumption, or block-related safety outcomes. Our study suggests that perineural dexamethasone does not provide any significant block-related analgesic advantages over the i.v. route commonly used for antiemetic prophylaxis. Earlier studies comparing only perineural dexamethasone and placebo consistently showed longer block duration with dexamethasone. More contemporary literature comparing perineural and systemic dexamethasone showed that both routes are associated with prolonged block duration. Albrecht and colleagues9 concluded in a meta-analysis that perineural dexamethasone had a greater effect than systemic dexamethasone when used in conjunction with bupivacaine (4 h) vs ropivacaine alone (2 h). Similarly, a Cochrane review concluded that perineural dexamethasone prolonged block duration by 3 h over i.v. dexamethasone in upper and lower extremity PNB.24 Individual studies have had varied results (ISB and other blocks). Whereas some studies have concluded that perineural dexamethasone provides superior analgesia,25,26 others have determined statistically significant but clinically insignificant differences,27 and yet others have found no statistically significant differences between groups thereby concluding equivalence.16,18,28 There are potential explanations for the contrasting results between these studies and our results identifying minimal differences. Our study was predicated on the assumption that dexamethasone, regardless of route, prolongs PNB duration. If dexamethasone exerts PNB prolongation through a systemic anti-inflammatory effect, a doseeresponse relationship would be evident. Alternatively, if local perineural effects were the primary factor, dexamethasone concentration should also be contributory. The concentration of dexamethasone in previous studies ranged from 50 to 500 mg ml1 compared with 667 mg ml1 in our study. Given that higher block volumes (>10 ml) result in greater cranial/caudad spread along the plexus, but also increase spread away from the plexus across the anterior and middle scalene, less perineural dexamethasone. The dexamethasone dose in direct proximity to the plexus may be higher in our study because of less ‘wasted’ LA spread. Together, this suggests that if block duration was not appreciably different between groups, and that higher amounts of dexamethasone were in close proximity to neural elements, the analgesic effects of dexamethasone are mediated systemically. Alternatively, in the context of lower ISB volume (5 ml), one could speculate that there was accelerated block regression potentially obscuring any effects. Even though there was a higher concentration of dexamethasone in close proximity to neural elements, the lack of a depot in surrounding tissue could possibly have resulted in a reduced effect. Our study is the first trial specifically powered and designed as an equivalency trial with defined time margins (2 h) and the largest (182 subjects). Previous trials have been powered as superiority trials and are therefore underpowered to determine equivalence. Furthermore, this is the first trial to examine dexamethasone in low volume (<10 ml) ISB. Other strengths of this trial stem from efforts to minimise bias with methodological rigour (blinding, allocation concealment,
intention-to-treat analysis) and a multimodal analgesic regimen reflecting contemporary practice. There are several limitations or weaknesses in our study design. Firstly, we cannot discount that our measure of analgesic duration was shortened because patients reported surgical site pain from the posterior port site, not covered by the ISB. Secondly, although participants were instructed to use multimodal analgesia after discharge from hospital (paracetamol 500 mg every 6 h/ibuprofen 200 mg every 8 h), there was no ability to verify compliance. Moreover, opioid analgesia was prescribed at the discretion of the surgical team. Thirdly, the majority of outcomes were from participant recorded home diaries. It would be ideal to conduct sensory testing in hospital to evaluate regression, however, it is not feasible in the context of ambulatory surgery. Although potentially affecting outcomes, these weaknesses are unlikely to systematically favour one group over another. With effective blinding, randomisation, and allocation concealment, we expect these effects would be evenly distributed across treatment arms nullifying any systematic bias. A final note of caution is required regarding combining ropivacaine and dexamethasone in that in the context of alkalinised ropivacaine and high concentrations of dexamethasone (>2000 mg ml1), precipitation of dexamethasone can occur, and this could potentially cause morbidity with inadvertent intravascular injection.29 This effect has not been observed with bupivacaine. Multiple LA adjuvants have been investigated for off-label use to prolong the analgesic duration of PNB. They would be helpful when continuous catheter techniques are not possible because of a paucity of technical training or inability to arrange out-patient support. This equivalency trial demonstrates that any difference between perineural or systemic administration of dexamethasone is of limited clinical significance. Indeed, recent editorials have called for caution in the use of perineural dexamethasone based on a lack of understanding of its local effects (both beneficial and deleterious) and multiple studies producing equivocal results.30,31 This study demonstrates that perineural dexamethasone has no analgesic advantage compared with i.v. dexamethasone commonly used for postoperative nausea prophylaxis.
Authors’ contributions Study concept: PGM, SC Study design: PGM, SC, AK Conduct: PGM, SC, OS, ITA, BS, PGH, SKA, LK Data interpretation: PGM, SC Data analysis: AK Drafting of the manuscript: PGM, SC Editing and approval of the manuscript: OS, ITA, BS, PGH, SKA, LK, AK
Acknowledgements PGM and SC received dedicated academic time from the Sunnybrook Anesthesia Academic Partnership. Brendan Flynn, Research Coordinator (Department of Anesthesia) for data collection and maintenance of trial database.
Declarations of interest The authors declare that they have no conflicts of interest.
Perineural vs systemic dexamethasone
Funding Health Services Research Grant from The Physicians’ Services Incorporated Foundation to PM and SC (Grant ID 14-39).
References 1. Borgeat A, Tewes E, Biasca N, Gerber C. Patient-controlled interscalene analgesia with ropivacaine after major shoulder surgery: PCIA vs PCA. Br J Anaesth 1998; 81: 603e5 2. Fredrickson MJ, Krishnan S, Chen CY. Postoperative analgesia for shoulder surgery: a critical appraisal and review of current techniques. Anaesthesia 2010; 65: 608e24 3. Lee JH, Cho SH, Kim SH, et al. Ropivacaine for ultrasoundguided interscalene block: 5 mL provides similar analgesia but less phrenic nerve paralysis than 10 mL. Can J Anaesth 2011; 58: 1001e6 4. Renes SH, Rettig HC, Gielen MJ, Wilder-Smith OH, van Geffen GJ. Ultrasound-guided low-dose interscalene brachial plexus block reduces the incidence of hemidiaphragmatic paresis. Reg Anesth Pain Med 2009; 34: 498e502 5. Riazi S, Carmichael N, Awad I, Holtby RM, McCartney CJ. Effect of local anaesthetic volume (20 vs 5 ml) on the efficacy and respiratory consequences of ultrasound-guided interscalene brachial plexus block. Br J Anaesth 2008; 101: 549e56 6. Sinha SK, Abrams JH, Barnett JT, et al. Decreasing the local anesthetic volume from 20 to 10 mL for ultrasound-guided interscalene block at the cricoid level does not reduce the incidence of hemidiaphragmatic paresis. Reg Anesth Pain Med 2011; 36: 17e20 7. Abdallah FW, Halpern SH, Aoyama K, Brull R. Will the real benefits of single-shot interscalene block please stand up? A systematic review and meta-analysis. Anesth Analg 2015; 120: 1114e29 8. Palhais N, Brull R, Kern C, et al. Extrafascial injection for interscalene brachial plexus block reduces respiratory complications compared with a conventional intrafascial injection: a randomized, controlled, double-blind trial. Br J Anaesth 2016; 116: 531e7 9. Albrecht E, Kern C, Kirkham KR. A systematic review and meta-analysis of perineural dexamethasone for peripheral nerve blocks. Anaesthesia 2015; 70: 71e83 10. Baeriswyl M, Kirkham KR, Jacot-Guillarmod A, Albrecht E. Efficacy of perineural vs systemic dexamethasone to prolong analgesia after peripheral nerve block: a systematic review and meta-analysis. Br J Anaesth 2017; 119: 183e91 11. Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: a systematic review and meta-analysis of randomized trials. Br J Anaesth 2014; 112: 427e39 12. Heesen M, Klimek M, Imberger G, Hoeks SE, Rossaint R, Straube S. Co-administration of dexamethasone with peripheral nerve block: intravenous vs perineural application: systematic review, meta-analysis, metaregression and trial-sequential analysis. Br J Anaesth 2018; 120: 212e27
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13. Attardi B, Takimoto K, Gealy R, Severns C, Levitan ES. Glucocorticoid induced up-regulation of a pituitary Kþ channel mRNA in vitro and in vivo. Recept Channels 1993; 1: 287e93 14. Johansson A, Hao J, Sjolund B. Local corticosteroid application blocks transmission in normal nociceptive C-fibres. Acta Anaesthesiol Scand 1990; 34: 335e8 15. Cummings 3rd KC, Napierkowski DE, Parra-Sanchez I, et al. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth 2011; 107: 446e53 16. Desmet M, Braems H, Reynvoet M, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth 2013; 111: 445e52 17. Tandoc MN, Fan L, Kolesnikov S, Kruglov A, Nader ND. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth 2011; 25: 704e9 18. Abdallah FW, Johnson J, Chan V, et al. Intravenous dexamethasone and perineural dexamethasone similarly prolong the duration of analgesia after supraclavicular brachial plexus block: a randomized, triple-arm, doubleblind, placebo-controlled trial. Reg Anesth Pain Med 2015; 40: 125e32 19. Desmet M, Vanneste B, Reynvoet M, et al. A randomised controlled trial of intravenous dexamethasone combined with interscalene brachial plexus blockade for shoulder surgery. Anaesthesia 2015; 70: 1180e5 20. Williams BA, Hough KA, Tsui BY, Ibinson JW, Gold MS, Gebhart GF. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med 2011; 36: 225e30 21. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm 1987; 15: 657e80 22. Flight L, Julious SA. Practical guide to sample size calculations: non-inferiority and equivalence trials. Pharm Stat 2016; 15: 80e9 23. Albrecht E, Reynvoet M, Fournier N, Desmet M. Doseeresponse relationship of perineural dexamethasone for interscalene brachial plexus block: a randomised, controlled, triple-blind trial. Anaesthesia 2019; 74: 1001e8 24. Pehora C, Pearson AM, Kaushal A, Crawford MW, Johnston B. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev 2017; 11: CD011770 25. Aliste J, Leurcharusmee P, Engsusophon P, et al. A randomized comparison between intravenous and perineural dexamethasone for ultrasound-guided axillary block. Can J Anaesth 2017; 64: 29e36 26. Holland D, Amadeo RJJ, Wolfe S, et al. Effect of dexamethasone dose and route on the duration of interscalene brachial plexus block for outpatient arthroscopic shoulder surgery: a randomized controlled trial. Can J Anaesth 2018; 65: 34e45 27. Kahn RL, Cheng J, Gadulov Y, Fields KG, YaDeau JT, Gulotta LV. Perineural low-dose dexamethasone prolongs
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interscalene block analgesia with bupivacaine compared with systemic dexamethasone: a randomized trial. Reg Anesth Pain Med 2018; 43: 572e9 28. Rosenfeld DM, Ivancic MG, Hattrup SJ, et al. Perineural versus intravenous dexamethasone as adjuncts to local anaesthetic brachial plexus block for shoulder surgery. Anaesthesia 2016; 71: 380e8 29. Watkins TW, Dupre S, Coucher JR. Ropivacaine and dexamethasone: a potentially dangerous combination for
therapeutic pain injections. J Med Imaging Radiat Oncol 2015; 59: 571e7 30. Hewson D, Bedforth N, McCartney C, Hardman J. Dexamethasone and peripheral nerve blocks: back to basic (science). Br J Anaesth 2019; 122: 411e2 31. Marhofer P, Columb M, Hopkins PM. Perineural dexamethasone: the dilemma of systematic reviews and metaanalyses. Br J Anaesth 2018; 120: 201e3
Handling editor: H.C. Hemmings Jr
CLINICAL INVESTIGATION
Comparison of the effects of perineural or intravenous dexamethasone on low volume interscalene brachial plexus block: a randomised equivalence trial Paul G. McHardy1, Oskar Singer1, Imad T. Awad1, Ben Safa1, Patrick D. G. Henry2, Alex Kiss3, Shelly K. Au1, Lilia Kaustov1 and Stephen Choi1,* 1
Department of Anesthesia, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada, 2Division
of Orthopedic Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada and 3
Department of Research Design and Biostatistics, Sunnybrook Research Institute, Toronto, ON, Canada
*Corresponding author. E-mail: [email protected]
Abstract Background: Efforts to prolong interscalene block (ISB) analgesia include the use of local anaesthetic adjuvants such as dexamethasone. Previous work showing prolonged block duration suggests that both perineural and intravenous (i.v.) routes can both prolong analgesia. The superiority of either route is controversial given the design of previous studies. As perineural dexamethasone is an off-label use, anaesthesiologists should be fully informed of the clinical differences, if any, on block duration. This study was designed to test whether perineural vs i.v. dexamethasone administration are equivalent. Methods: We randomised 182 eligible patients scheduled for arthroscopic shoulder surgery to receive low-dose ISB (0.5% ropivacaine 5 ml) with perineural or i.v. dexamethasone 4 mg. Subjects, anaesthesiologists, and research personnel were blinded. All subjects also received a standardised general anaesthetic and multimodal analgesia. The primary outcome was duration of analgesia analysed as an equivalence outcome (2 h equivalency margin) using the two one-sided test (TOST) method. Results: For the primary outcome, duration of analgesia, and perineural and i.v. administration of dexamethasone were not equivalent. The upper and lower bounds of the 90% confidence interval were 1 h (P¼0.12) and e2.5 h (P¼0.01), respectively. The observed difference in mean block duration was not clinically relevant (0.75 h longer for i.v. dexamethasone). There were no other clinically significant differences between groups. Conclusion: In the context of low-volume ISB with ropivacaine, perineural and i.v. dexamethasone were not equivalent in terms of their effects on block duration. However, there were no clinically significant differences in outcomes, and there is no advantage of perineural over intravenous dexamethasone. www.clinicaltrials.gov registration: NCT02322242. Keywords: analgesia; dexamethasone; interscalene nerve block; local anaesthetic adjuvant; perineural; regional anaesthesia
Editorial decision: 01 August 2019; Accepted: 1 August 2019 © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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Editor’s key points Both perineural and i.v. dexamethasone can prolong analgesia after interscalene nerve block, but the superiority of either route is controversial. In a randomised, blinded equivalence design study, 182 eligible patients scheduled for arthroscopic shoulder surgery received low-dose interscalene block (0.5% ropivacaine 5 ml) with either perineural or i.v. dexamethasone 4 mg. Durations of analgesia were not equivalent, but the observed difference in mean block duration was not clinically relevant (0.75 h longer for i.v. dexamethasone). Given concerns over local perineural toxicity, there is little justification for perineural dexamethasone in lowvolume interscalene block.
Interscalene brachial plexus block (ISB) is the standard of care for analgesia after shoulder surgery in providing superior analgesia and reducing opioid consumption.1e6 ISB can have complications including ipsilateral phrenic nerve block resulting in diaphragmatic paralysis for the duration of the block. This can temporarily reduce ventilatory capacity, which has the potential for morbidity in patients with reduced respiratory reserve. Nonetheless, the analgesic and opioidsparing benefits usually outweigh the risks in the appropriate patient population. Patients undergoing shoulder surgery, once routinely admitted to hospital after surgery for analgesia, are now commonly managed on an ambulatory basis because of ISB analgesia. Single-injection ISB dissipates after several hours, unmasking the moderate to severe pain of the surgery and typically requires opioid analgesia.7 Efforts to prolong ISB by increasing local anaesthetic (LA) dose are limited by their narrow therapeutic window and volume/concentration considerations. Volumes of 10 ml or greater injected into the interscalene groove carry a high risk of ipsilateral hemi-diaphragmatic paresis. Recent data show that an extrafascial injection of 15 ml of LA (4 mm from the brachial plexus in the middle scalene muscle) produced similar analgesia but reduced hemi-diaphragmatic paresis.3e6,8 Several LA adjuvants have been studied to prolong ISB when continuous catheter techniques are not possible; the most common is the corticosteroid dexamethasone. Meta-analyses have shown that perineural dexamethasone, an off-label use, in conjunction with LA prolongs the duration of peripheral nerve blocks (PNB) with effect sizes ranging from 40% to 75% (or 6e10 h) using doses of 8e10 mg.9e12 Although the specific local mechanism of dexamethasone has not been elucidated, it is postulated to reduce ectopic neuronal discharge and inhibit potassium channel-mediated discharge of nociceptive C-fibres.13,14 Alternatively, it has been postulated that dexamethasone provides superior analgesia in the context of PNB through systemic antiinflammatory effects. Several current controversies warrant this trial to compare perineural vs i.v. dexamethasone. Previous trials investigating perineural dexamethasone used peripheral nerve stimulation and high LA volumes (30e40 ml).15e17 Although the total dose of LA delivered in close proximity to the target neural elements can impact block duration and efficacy, contemporary ultrasound-guided regional anaesthesia practice allows more accurate, targeted deposition of LA. Several studies have shown that ISB volumes ranging as low as 5e10 ml do not
affect block duration or efficacy, although the generalisability of lower volume ISB can be limited.3e6 Secondly, there are data suggesting that i.v. dexamethasone also prolongs block duration.16,18,19 Although these studies concluded that i.v. and perineural dexamethasone have equivalent block-prolonging effects, they were designed as superiority trials and therefore underpowered to determine equivalence. This trial was specifically designed and powered as an equivalence trial, with an a priori defined equivalence margin of 2 h, to test the hypothesis that perineural dexamethasome is not equivalent to i.v. dexamethasone on analgesic outcomes when combined with low-dose ISB using ropivacaine.
Methods This study was conducted at Sunnybrook Health Sciences Centre (SHSC), a tertiary care academic health sciences centre fully affiliated with the University of Toronto. The study was approved by Research Ethics Board of SHSC in October 2014 (REB ID# 437-2013) and registered with www.clinicaltrials.gov (December 2014, NCT02322242). Regulatory approval was sought and received (May 2014, Control #174415) from Health Canada for the off-label perineural use of dexamethasone sodium phosphate (multi-dose vial 4 mg ml1, benzyl alcohol free, and sodium metabisulphite preservative, sourced from Sandoz Canada). Adults (18e80 yr old) with ASA physical status 1e3, scheduled to undergo arthroscopic shoulder surgery (subacromial decompression or rotator cuff repair), were eligible for enrolment and recruited by research assistants in the preoperative anaesthesia clinic. Exclusion criteria were as follows: allergy or intolerance to study medications; BMI 35 kg m2; contraindication to low dose dexamethasone based on product monograph (peptic ulcer disease, systemic infection, glaucoma, active varicella/herpetic infections, diabetes mellitus); contraindication to ISB (severe Chronic Obstructive Pulmonary Disease, coagulopathy, pre-existing neurologic deficit in ipsilateral upper extremity, localised infection), pregnant or nursing females, or chronic opioid use (>30 mg oral morphine equivalents [OME] day1). Research assistants recruited patients from the preoperative anaesthesia clinic. Patients providing informed consent and meeting all eligibility criteria were randomised (1:1) in blocks of 10 to perineural dexamethasone (Dex-PN) or i.v. dexamethasone (Dex-IV) (treatment arms described below). The computer-generated randomisation sequence and sequentially numbered, sealed, opaque envelopes were prepared by an individual not otherwise involved in study conduct to maintain blinding and allocation concealment. Eligible participants were randomised on the day of surgery using the next numbered envelope in sequence. The randomisation list was kept in a secure location inaccessible to investigators or study personnel. Participants were premedicated with oral paracetamol 1000 mg (650 mg if <60 kg body weight), and oral celecoxib 400 mg (200 mg if <60 kg body weight) 1 h before surgery. After establishing i.v. access, applying standard monitors (ECG, noninvasive blood pressure cuff, continuous oxygen saturation), participants received sedation with midazolam (1e2 mg i.v.). The lateral aspect of the neck including the supraclavicular fossa ipsilateral to the surgical site was cleansed with an isopropyl alcohol/chlorhexidine gluconate solution. The ultrasound-guided low volume ISB (0.5% ropivacaine 5 ml) was performed under sterile conditions by a staff regional anaesthesiologist, or supervised regional anaesthesia fellow with a 13e6 MHz 38 mm linear probe (MTurbo®; SonoSite Inc., Bothell, WA, USA) at the C6 nerve root
Perineural vs systemic dexamethasone
level via posterior approach with a 22 gauge insulated 50 mm regional needle (Stimuplex®; B.Braun Medical, Bethlehem, PA, USA). After satisfactory position of the needle tip was achieved and with negative aspiration, the LA (±dexamethasone 4 mg) was injected. General anaesthesia was induced with a standardised technique using fentanyl 1 mg kg1 and propofol 1e3 mg kg1. Tracheal intubation was facilitated with rocuronium 0.6 mg kg1. Anaesthesia was maintained using sevoflurane at an end-tidal concentration of 1.4e2 vol%. The posterior arthroscopic port site was injected with 10 ml of bupivacaine 0.25% (1:200 000 epinephrine). The study infusion of 0.9% saline 50 ml (±dexamethasone 4 mg) was commenced after induction of anaesthesia and securing of the airway. Intraoperatively, aliquots of fentanyl (25 mg) were administered when blood pressure or heart increased more than 20% of preoperative baseline values. Muscle relaxation was reversed using neostigmine (0.04 mg kg1) and glycopyrrolate (0.007 mg kg1). Standard antiemetic prophylaxis with the serotonin antagonist ondansetron 4 mg i.v. was administered before emergence. Upon arrival to the recovery room, pain (Numeric Rating Scale [NRS] 4 or patient request for analgesia) was treated with oral analgesics if deemed necessary (hydromorphone or combination acetaminophen (325mg) oxycodone (5mg) tablet). Postoperative nausea was managed with haloperidol (1 mg) or dimenhydrinate (25 mg) i.v. if necessary. Subjects were instructed to self-administer paracetamol 500 mg every 6 h and ibuprofen (200 mg every 8 h) PO for 3 days after discharge. Additional oral analgesics (oxycodone or hydromorphone) were prescribed at the discretion of the surgical team, and patients were instructed to take them if the NRS was 4. Participants completed a home diary with outcomes described below. These data were collected by telephone at two time points, 2 days and 1 week after operation. Follow-up attempts were until 30 days after operation.
Assigned interventions Perineural dexamethasone ISB injectate mixturedropivacaine 1% (3 ml) þ dexamethasone 0.4% (1 ml), 0.9%, saline (2 ml); final ropivacaine concentration 0.5%, dexamethasone 667 mg ml1. IV infusiond0.9% saline (50 ml infusion bag).
Intravenous dexamethasone ISB injectate mixturedropivacaine 1% (3 ml) þ 0.9% saline (3 ml); final ropivacaine concentration 0.5%. IV infusiond0.9% saline (50 ml infusion bag) þ dexamethasone 0.4% 1 ml. The ISB injectate was made to a total volume of 6 ml to account for dead space in the block needle tubing, of which 5 ml was injected for the ISB. The perineural dexamethasone dose was set at 4 mg (final concentration 667 mg ml1) based on an a priori study.20 This dexamethasone concentration of 667 mg ml1 combined with ropivacaine was the maximal concentration that did not induce neurotoxicity compared with ropivacaine alone.
Blinding All study materials were prepared immediately before use by trained anaesthesia assistants/nurses who were aware of group allocation but took no further part in study procedures or assessments. The ISB injectate was prepared in a syringe
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labelled ‘ropivacaine 0.5% (±dexamethasone 4 mg)’. Meanwhile, the 50 ml 0.9% saline infusion was labelled as ‘saline or dexamethasone 4 mg’. All other personnel including subjects, anaesthesiologists performing the ISB and anaesthetising in the operating theatre, surgeons, research assistants performing outcome measures, and statistician were blinded until data analysis was completed.
Outcomes The primary outcome was duration of sensory block defined as the time from the end of injection to the first sensation of pain at the surgical site. The secondary outcomes were: (a) painrelated outcomesdtime to first opioid consumption, Numeric Rating Scale (NRS) for pain, and cumulative opioid consumption (in OME) at 12 h, 24 h, and 1 week; (b) blockrelated outcomesdduration of motor block (end of injection to baseline motor function); (c) block-related complicationsdpostoperative room air oxygen saturation, localised infection at block site, postoperative blood glucose, postoperative block-related nerve palsy at 1 week; and (d) other complicationsdpostoperative nausea and vomiting. Opioid doses were converted to OME according to the general monograph for opioids in the Canadian Pharmacists’ Association Compendium of Pharmaceuticals and Specialties (oral oxycodone/oral morphine sulphate¼1:2, oral hydromorphone/oral morphine sulphate¼1:5, and oral codeine/oral morphine sulphate¼6.6:1).
Sample size calculation Based on our clinical experience with low-dose ultrasoundguided ISB (0.5% ropivacaine 5 ml) and previously published work, we expected a mean sensory block duration of 12 h with a standard deviation of 4 h. Based on previous literature, we expected a mean prolongation of block time associated with perineural dexamethasone to be ~50% thereby increasing block duration to 18 h. Defining an equivalency margin of 2 h, we estimated that 87 individuals per group (174 total) were required to be randomised to reliably test our hypothesis given a¼0.05 and 90% power. The specific sample size calculation is based on the typical analysis used for equivalence studies, the two onesided test (TOST) methodology.21,22 To account for incomplete data or loss to follow-up, we planned to randomise 90 subjects per group (180 total). As the recruitment and consent process was conducted by research assistants in the preoperative clinic before evaluation by anaesthesiologists, it was expected that there would be consenting individuals who would ultimately be ineligible. Final eligibility was confirmed by the investigators (PM and SC), and only those who met all inclusion/exclusion criteria proceeded to be randomised on the day of surgery.
Statistical analysis Patient data are summarised and expressed using appropriate measures of central tendency and dispersion or counts and percentages for categorical data. The primary outcome, time to first sensation of pain at the surgical site, was assessed for equivalence using the TOST method. Specifically, if the upper and lower boundaries of the 90% confidence interval (CI) were both less than the defined equivalence margin, the criteria for equivalence between groups is met. The equivalence margin was specified as 2 h based on what we considered a clinically important difference in block duration given the established
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Subjects approached n=892 Refused par cipa on • Not interested in research (n=289) • Not interested in study interven on (n=330) Subjects consen ng n= 273
Subjects randomised n=182
Allocated to dex-PN n=92 • Protocol devia ons n=1 • Repeat ISB prior to surgery due to primary block failure (ropivacaine 0.5% 10ml)
Analyzed for primary outcome n=92
Analyzed for all secondary outcomes n=90 • 2 lost to follow-up
Not randomised (n=91) • Withdrew consent before surgery (n=17) • Study staff not available (n=5) • Surgery cancelled (n=7) • Exclusion criteria • Diabe c (n=3) • BMI (n=44) • Chronic opioid use (n=8) • Pre-exis ng neuropathy (n=7)
Allocated to dex-IV n=90 • Protocol devia ons n=2 • Second 4mg dose of IV-dexamethasone • Repeat ISB prior to surgery due to primary block failure (ropivacaine 0.5% 10ml)
Analyzed for primary outcome n=90
Analyzed for all secondary outcomes n=89 • 1 lost to follow-up
Fig 1. CONSORT flow diagram of screened, enrolled, randomised, and analysed participants. CONSORT, Consolidated Standards of Reporting Trials.
analgesic duration of ISB and the reported prolongation associated with dexamethasone. Secondary outcomes were evaluated with conventional inferential tests assessing superiority. Continuous secondary outcomes (time to first analgesic request, duration of motor block opioid consumption, NRS) were assessed with the t-test. Categorical outcomes (paresthesia, infection) were compared with the c2 or Fisher’s exact test for the case of low expected cell counts. Secondary outcomes were considered exploratory in nature, and thus no correction for multiple comparisons was made. All data were analysed on an intention-to-treat principle. The funding agency (Physicians’ Services Incorporated Foundation) had no role in the design, conduct, or analysis of the study. This manuscript adheres to applicable CONSORT guidelines.
Results The Consolidated Standards of Reporting Trials (CONSORT) flow diagram details the number of participants that received the
allocated intervention (Fig. 1). Of the 892 patients approached, 273 provided written and informed consent to participate in the study between February 2015 and September 2018; 289 declined participation in any research activity and 330 declined the study specifically. Whereas 82 of the 273 patients who provided consent were not randomised because of exclusion criteria, 182 subjects without any exclusion criteria were randomised with 92 allocated to the Dex-PN group and 90 to the Dex-IV group (Table 1). There were three protocol deviations. One subject in the Dex-IV group inadvertently received a second 4 mg dose of i.v. dexamethasone in addition to the study drug infusion. One participant in each group received a second preoperative ISB with ropivacaine 0.5% 10 ml because of primary block failure (no sensory loss in the C5e6 dermatomes). Subjects remained in the study and were analysed in the groups to which they were randomised. The primary outcome was recorded for all 182 subjects randomised. Despite repeated attempts, three participants (two Dex-PN, one Dex-IV) were lost to follow-up at the 1 week interval and secondary outcome data for these were not recorded.
Perineural vs systemic dexamethasone
Table 1 Subject characteristics. *American Society of Anesthesiologists physical status classification. OME, oral morphine equivalent in mg. Data are presented as mean (standard deviation) or n [%].
Age (yr) Sex M:F BMI (kg m2) ASA physical status* 1/2/3 Preoperative opioid usage (OME)
Perineural dexamethasone (Dex-PN)
Intravenous dexamethasone (Dex-IV)
51.6 (18e73) 67 [73]:25 [27] 28.2 (4.1) 25/49/18 [27/53/20]
52.8 (22e76) 69 [77]:21 [23] 28.4 (3.8) 18/57/15 [20/73/17] 2.4 (6.6)
1.8 (5.8)
Analysis of the primary outcome with TOST indicates that block duration between the Dex-PN and Dex-IV groups are not equivalent (Fig. 2). The upper and lower bounds of the 90% CI were 1 h (P¼0.12) and e2.5 h (P¼0.01), respectively. Because the lower bound of the 90% CI crossed 2 h, conditions for
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establishing equivalency were not met. The mean difference in block duration between groups was 0.75 h (Dex-IV longer than Dex-PN). The observed mean (standard deviation) analgesic duration in the Dex-PN group was 8.7 (7.4) h and 9.4 (7.1) h in the Dex-IV group. Among the secondary outcomes, the only observed difference was a higher mean postoperative blood glucose in the Dex-PN group that was not clinically relevant (mean difference 0.34; 95% CI, 0.03e0.07; P¼0.02). There were no other observed differences in other secondary outcomes. There were no important adverse events or sideeffects in either group (Table 2).
Discussion This randomised trial compared the effects of perineural vs i.v. dexamethasone on block duration and analgesia-related outcomes in the context of low-volume ISB in patients undergoing arthroscopic shoulder surgery. It is the first trial designed specifically to test the hypothesis of equivalence between the two routes of administration and the largest sample size examining the issue. This trial also used the highest perineural
90% Equivalence margin Lower bound
90% Equivalence margin Upper bound
-2.53. P=0.01
-3
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-0.75
-2
-1
1.02, P=0.12
0
1
2
Difference (h)
Perineural dexamethasone
Intravenous dexamethasone
Fig 2. Ninety percent confidence interval of mean interscalene block (ISB) duration.
Table 2 Secondary outcomes. Data are presented as mean (standard deviation) or n [%].
Duration of motor block (h) Time to first analgesic request (h) Numeric rating scale for pain 12 h 24 h 7 days Opioid consumption 12 h 24 h 7 days Postoperative oxygen saturation Postoperative blood glucose Postoperative nausea/vomiting Persistent nerve palsy
Perineural dexamethasone
Intravenous dexamethasone
P-value
18.5 (13.8) 9.1 (6.9)
20.3 (22.3) 9.6 (10.8)
0.99 0.78
3.3 (3.0) 4.9 (2.6) 3.1 (2.3)
3.3 (2.9) 4.7 (2.6) 3.4 (2.4)
0.88 0.62 0.37
12.2 (17.1) 24.3 (14.6) 148.8 (117.9) 96.6 (2.3) 6.8 (1.0) 32 [35] 0
12.9 (13.2) 25.6 (18.5) 167.2 (140.0) 97.0 (2.4) 6.5 (1.1) 32 [36] 0
0.39 0.95 0.52 0.24 0.02 0.96 e
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dexamethasone concentration (667 mg ml1) shown to be safe to maximise perineural effects. This is important given that there is a perineural doseeresponse relationship.23 Although there was statistically significant evidence that i.v. administration was not equivalent to perineural, the observed difference in block duration (0.75 h) may be of limited clinical significance. We did not observe any significant differences in pain scores, opioid consumption, or block-related safety outcomes. Our study suggests that perineural dexamethasone does not provide any significant block-related analgesic advantages over the i.v. route commonly used for antiemetic prophylaxis. Earlier studies comparing only perineural dexamethasone and placebo consistently showed longer block duration with dexamethasone. More contemporary literature comparing perineural and systemic dexamethasone showed that both routes are associated with prolonged block duration. Albrecht and colleagues9 concluded in a meta-analysis that perineural dexamethasone had a greater effect than systemic dexamethasone when used in conjunction with bupivacaine (4 h) vs ropivacaine alone (2 h). Similarly, a Cochrane review concluded that perineural dexamethasone prolonged block duration by 3 h over i.v. dexamethasone in upper and lower extremity PNB.24 Individual studies have had varied results (ISB and other blocks). Whereas some studies have concluded that perineural dexamethasone provides superior analgesia,25,26 others have determined statistically significant but clinically insignificant differences,27 and yet others have found no statistically significant differences between groups thereby concluding equivalence.16,18,28 There are potential explanations for the contrasting results between these studies and our results identifying minimal differences. Our study was predicated on the assumption that dexamethasone, regardless of route, prolongs PNB duration. If dexamethasone exerts PNB prolongation through a systemic anti-inflammatory effect, a doseeresponse relationship would be evident. Alternatively, if local perineural effects were the primary factor, dexamethasone concentration should also be contributory. The concentration of dexamethasone in previous studies ranged from 50 to 500 mg ml1 compared with 667 mg ml1 in our study. Given that higher block volumes (>10 ml) result in greater cranial/caudad spread along the plexus, but also increase spread away from the plexus across the anterior and middle scalene, less perineural dexamethasone. The dexamethasone dose in direct proximity to the plexus may be higher in our study because of less ‘wasted’ LA spread. Together, this suggests that if block duration was not appreciably different between groups, and that higher amounts of dexamethasone were in close proximity to neural elements, the analgesic effects of dexamethasone are mediated systemically. Alternatively, in the context of lower ISB volume (5 ml), one could speculate that there was accelerated block regression potentially obscuring any effects. Even though there was a higher concentration of dexamethasone in close proximity to neural elements, the lack of a depot in surrounding tissue could possibly have resulted in a reduced effect. Our study is the first trial specifically powered and designed as an equivalency trial with defined time margins (2 h) and the largest (182 subjects). Previous trials have been powered as superiority trials and are therefore underpowered to determine equivalence. Furthermore, this is the first trial to examine dexamethasone in low volume (<10 ml) ISB. Other strengths of this trial stem from efforts to minimise bias with methodological rigour (blinding, allocation concealment,
intention-to-treat analysis) and a multimodal analgesic regimen reflecting contemporary practice. There are several limitations or weaknesses in our study design. Firstly, we cannot discount that our measure of analgesic duration was shortened because patients reported surgical site pain from the posterior port site, not covered by the ISB. Secondly, although participants were instructed to use multimodal analgesia after discharge from hospital (paracetamol 500 mg every 6 h/ibuprofen 200 mg every 8 h), there was no ability to verify compliance. Moreover, opioid analgesia was prescribed at the discretion of the surgical team. Thirdly, the majority of outcomes were from participant recorded home diaries. It would be ideal to conduct sensory testing in hospital to evaluate regression, however, it is not feasible in the context of ambulatory surgery. Although potentially affecting outcomes, these weaknesses are unlikely to systematically favour one group over another. With effective blinding, randomisation, and allocation concealment, we expect these effects would be evenly distributed across treatment arms nullifying any systematic bias. A final note of caution is required regarding combining ropivacaine and dexamethasone in that in the context of alkalinised ropivacaine and high concentrations of dexamethasone (>2000 mg ml1), precipitation of dexamethasone can occur, and this could potentially cause morbidity with inadvertent intravascular injection.29 This effect has not been observed with bupivacaine. Multiple LA adjuvants have been investigated for off-label use to prolong the analgesic duration of PNB. They would be helpful when continuous catheter techniques are not possible because of a paucity of technical training or inability to arrange out-patient support. This equivalency trial demonstrates that any difference between perineural or systemic administration of dexamethasone is of limited clinical significance. Indeed, recent editorials have called for caution in the use of perineural dexamethasone based on a lack of understanding of its local effects (both beneficial and deleterious) and multiple studies producing equivocal results.30,31 This study demonstrates that perineural dexamethasone has no analgesic advantage compared with i.v. dexamethasone commonly used for postoperative nausea prophylaxis.
Authors’ contributions Study concept: PGM, SC Study design: PGM, SC, AK Conduct: PGM, SC, OS, ITA, BS, PGH, SKA, LK Data interpretation: PGM, SC Data analysis: AK Drafting of the manuscript: PGM, SC Editing and approval of the manuscript: OS, ITA, BS, PGH, SKA, LK, AK
Acknowledgements PGM and SC received dedicated academic time from the Sunnybrook Anesthesia Academic Partnership. Brendan Flynn, Research Coordinator (Department of Anesthesia) for data collection and maintenance of trial database.
Declarations of interest The authors declare that they have no conflicts of interest.
Perineural vs systemic dexamethasone
Funding Health Services Research Grant from The Physicians’ Services Incorporated Foundation to PM and SC (Grant ID 14-39).
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Handling editor: H.C. Hemmings Jr