Background. Dexmedetomidine has been proposed as a perineural local anaesthetic (LA) adjunct to prolong peripheral nerve block duration; however, results from our previous meta-analysis in the setting of brachial plexus block (BPB) did not support its use. Many additional randomized trials have since been published. We thus conducted an updated meta-analysis.

Methods. Randomized trials investigating the addition of dexmedetomidine to LA compared with LA alone (Control) in BPB for upper extremity surgery were sought. Sensory and motor block duration, onset times, duration of analgesia, analgesic consumption, pain severity, patient satisfaction, and dexmedetomidine-related side-effects were analysed using random-effects modeling. We used ratio-of-means (lower confidence interval [point estimate]) for continuous outcomes.

Results. We identified 32 trials (2007 patients), and found that dexmedetomidine prolonged sensory block (at least 57%, P < 0.0001), motor block (at least 58%, P < 0.0001), and analgesia (at least 63%, P < 0.0001) duration. Dexmedetomidine expedited onset for both sensory (at least 40%, P < 0.0001) and motor (at least 39%, P < 0.0001) blocks. Dexmedetomidine also reduced postoperative oral morphine consumption by 10.2mg [-15.3, -5.2] (P < 0.0001), improved pain control, and enhanced satisfaction. In contrast, dexmedetomidine increased odds of bradycardia (3.3 [0.8, 13.5](P = 0.0002)), and hypotension (5.4 [2.7, 11.0] (P < 0.0001)). A 50-60µg dexmedetomidine dose maximized sensory block duration while minimizing haemodynamic side-effects. No patients experienced any neurologic sequelae. Evidence quality for sensory block was high according to the GRADE system.

Conclusions. New evidence now indicates that perineural dexmedetomidine improves BPB onset, quality, and analgesia. However, these benefits should be weighed against increased risks of motor block prolongation and transient bradycardia and hypotension.

Anaesthetists have sought strategies to extend the benefits of single-shot peripheral nerve blocks beyond the duration of commonly available local anaesthetics (LA).1 Perineural adjuncts are one technically simple strategy that can be used for this purpose.2 Dexmedetomidine, an alpha-2 agonist,3 has been proposed as a safe4 and effective5,6 adjunct capable of extending the duration of single-shot block.

Editor’s key points

  • Dexmedetomidine, an alpha-2 agonist, can be expected to extend the duration of local anaesthetic blocks but it has been unclear whether this has clinical benefit.

  • This systematic review provides sufficient evidence to properly test this concept, finding enhanced onset and longer duration of block with minimal side-effects.

  • The optimal local anaesthetic adjunct dose for brachial plexus block seems to be 50-60 µg.

  • There is some uncertainty as to overall analgesic effectiveness and patient outcomes.

Hyperpolarization-activated cation currents normally bring neurons back to the resting potential and normal functional activity during the refractory phase in an action potential. By blocking these currents, dexmedetomidine can accentuate inhibition of neuronal conduction and produce analgesia.6 However, despite early promising evidence from animal5,6 and human7 studies that have signaled efficacy, our quantitative systematic review of dexmedetomidine as an adjunct to brachial plexus block (BPB), published in 2013,8 was unable to demonstrate any clinically important benefits. Some of the trials7,9–11 were marked by substantial clinical and statistical heterogeneities that may have undermined a precise estimation of the dexmedetomidine treatment effect. Many additional trials of dexmedetomidine as a BPB adjunct have been since published, thus prompting a re-examination specifically to assess the role of dexmedetomidine in prolonging sensory block duration.

Methods

We followed PRISMA statement guidelines12 in the preparation of this manuscript. Randomized trials examining the effect of dexmedetomidine on the duration of sensory block after single-shot BPB were evaluated using a predefined protocol, but this was not previously published.

Literature search

Two of the authors (LV and FWA) independently sought and retrieved relevant studies from electronic databases including the US National Library of Medicine database, MEDLINE; the Excerpta Medica database, EMBASE; the Cochrane Databases of systematic reviews; the Cochrane central register of controlled clinical trials; Cumulative Index of Nursing and Allied Health Literature (CINAHL); Scopus; Web of Science; MEDLINE In-Process; and other non-indexed citations. The medical subject headings (MeSH), text words, and controlled vocabulary terms relating to Dexmedetomidine and Medetomidine were sought. Results were combined using the Boolean operator “AND” with the search terms analgesia, anaesthesia, adjunct, adjuvant, anaesthetics local, nerve block, perineural, regional anaesthesia and terms designating upper extremity such as arm, brachial plexus, forearm, elbow, hand, humerus, radius, shoulder, and wrist. Additional non-indexed articles were retrieved using Google Scholar; and the bibliographies of retrieved trials were hand-searched for additional relevant studies. Our search was limited to randomized trials published in the English language. Only trials including adults (age > 18 yr) published in full-manuscript form between January 1985 and February 2016 were considered. Abstracts were excluded.

Inclusion criteria

We included randomized trials with parallel group design examining the effects of adding perineural dexmedetomidine as an adjunct to LA (Dex group), compared with LA alone (Control group) on BPB characteristics, postoperative analgesia and dexmedetomidine-related side-effects, in patients undergoing upper extremity surgery with BPB. Specifically, interscalene (ISB), supraclavicular (SCB), infraclavicular (ICB) and axillary (AXB) level blocks of the brachial plexus performed for either anaesthesia or postoperative analgesia were considered. Randomized and quasi-randomized, and single- and double-blinded trials were included. Randomized trials without a control group were excluded. We also excluded trials if non-perineural routes of dexmedetomidine administration were used (e.g. intra-articular injection);13 if surgeries involved anatomical areas other than the upper extremity (e.g. abdominal);14 and if blocks other than BPB were performed.15 Studies of i.v. regional anaesthesia16,17 and distal peripheral nerve blocks (e.g. medial, radial or ulnar blocks)18,19 were also excluded.

Trial selection and methodological assessment

The two authors (LV and FWA) independently evaluated the identified abstracts. Inclusion of qualifying studies in the review was taken by consensus between the two authors. Disagreements were resolved by re-evaluating the full manuscript of the source studies and consulting with the third author (RB). Trials that failed to meet the inclusion criteria were excluded.

The quality of the reviewed trials was independently assessed using the Cochrane Collaboration Risk of Bias tool20 by two of the authors (LV and FWA). The tool evaluates trials for biases, among which are selection (randomization and allocation), performance and detection (blinding), attrition, reporting, and other forms of bias. A score was assigned to each trial by consensus; if an agreement could not be reached, the third author (RB) was consulted. Considering the limited number of studies and that our earlier meta-analysis failed to demonstrate the effects of dexmedetomidine on nerve blocks, we decided not to exclude studies based on the quality scores, but rather to take an inclusive approach towards studies with a view towards answering the question of interest. However, trials were excluded if they had fewer than 10 subjects per group, to reduce the possibility of chance in estimating a treatment effect.

Data extraction

The authors independently extracted relevant data using a standardized data sheet; discrepancies were resolved by re-examining the source data as a first resort, then consulting with the third author. Data extracted included primary author, yr of publication, comparative groups, sample size, nature of primary outcome, surgical site, nature of surgical anaesthetic, level of BPB, nerve localization technique, type and dose of LA, dose of perineural dexmedetomidine, block characteristics, analgesic effects, and dexmedetomidine-related side-effects. Data on additional study arms examining other perineural additives (e.g. dexamethasone21, fentanyl22) were extracted but excluded from the final analysis.

Outcomes assessed

We designated sensory block duration (min), defined as time from completion of LA injection to full recovery from sensory block, as a primary outcome. Secondary outcomes included block characteristics, namely motor block duration (min), and sensory and motor block onset times (min), defined as time from completion of LA injection to achieving full sensory and motor block, respectively. We also evaluated analgesic outcomes comprising duration of analgesia (min), defined as time to first analgesic request, or as defined by authors; cumulative analgesic consumption during the first 24 h postoperatively, expressed as oral morphine equivalents (mg);23 rest and dynamic postoperative pain severity (visual analogue scale, VAS; 0 = no pain, 10 = worst pain imaginable) at 12 and 24 h postoperatively; patient satisfaction with postoperative pain relief, (VAS; 0 = least satisfied, 10 = most satisfied); and length of hospital stay. Also included were frequency of dexmedetomidine-related adverse effects (bradycardia, hypotension, excessive sedation, hypoxemia)24 and postoperative nausea and vomiting (PONV), as defined by authors, and block-related complications.

For the purpose of this review, trials reporting the range or interquartile range (IQR) were included using an estimate of the standard deviation (SD), using the formulas: SD= Range/4 and SD= IQR/1.35, respectively, as described by the Cochrane Handbook for Systematic Reviews.25 Data reported as 95% confidence intervals (CI) were similarly used to estimate the range, and were converted to SD. The median was used to estimate the mean if its value was not provided.26 Postoperative pain severity reported as numerical rating scale scores or verbal rating scale scores was converted to VAS scores.27

Predefined sources of heterogeneity

To explore potential causes of heterogeneity in our results, we pre-identified the clinical characteristics of individual trials and known confounders that may lead to variations in our primary outcome results (sensory block duration). The variables of interest included i) level of BPB, ii) LA dose, iii) dexmedetomidine dose, iv) epinephrine dose, v) block localization technique, and vi) nature of surgical anaesthetic used (general anaesthesia vs nerve block). Based on the clinical assumption that different levels of BPB will lead to different block characteristics and analgesic effects, we planned to separately analyse outcomes according to the type of BPB performed (interscalene, supraclavicular, infraclavicular, and axillary). The degree to which the remaining factors can predict the duration of sensory block (primary outcome) was evaluated using meta-regression analysis.

Statistical analysis

We used data presented in tables as the primary source for extraction; when data were not presented in tables, we contacted authors for additional information. Graphical data not otherwise available in the text or from the authors were estimated from figures. As a final resort, when SD values were not reported for an outcome (e.g. postoperative pain),9,28 these values were imputed.29,30 Dichotomous data relating to side-effects were converted to incidence (n/N) during a given time interval; and the single highest incidence was used to capture the proportion of patients who experienced a certain side-effect at least once.

Data from trials with more than two intervention groups receiving different doses of perineural dexmedetomidine were combined into a single group as per the Cochrane Handbook.30 We analysed results on an intention-to-treat basis by analysing the data available from all participants in each study group, regardless of compliance or attrition, to estimate the influence on treatment effect.31 Continuous data describing patient satisfaction were converted to odds ratios (OR) to facilitate quantitative analysis.32

Meta-analysis

Data entry was performed by one author (LV) and checked by another (FWA). Meta-analytic techniques (Revman 5.3, Cochrane Library, Oxford, UK, and OpenMeta[Analyst] software version: Beta 3.13, Tufts Medical Centre)33 were used to combine the data where possible. As a variety of BPB and upper extremity procedures were examined, we selected the DerSimonian random effect modeling to pool the results.34

The strength of evidence pooled from the trials reviewed was assessed using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) guidelines.35 In contrast to other assessment tools that evaluate quality across outcomes within a given trial, the GRADE tool evaluates quality across trials for each outcome. Based on key elements including study quality, consistency, directness, precision, and publication bias, the GRADE tool classifies the strength of synthesized evidence into four categories: i) high quality: further research is very unlikely to change the confidence in the estimate of effect; ii) moderate quality: further research is likely to have an important impact on the confidence in the estimate of effect and may change the estimate; iii) low quality: further research is very likely to have an important impact on the confidence in the estimate of effect and is likely to change the estimate; and iv) very low quality: we are very uncertain about the estimate. For consistency in specific, we resorted to examining the similarity of point estimates, and the extent of overlap of confidence intervals, in addition to testing heterogeneity using the I2 statistic.

All time-to-event outcomes, including block characteristics (sensory and motor block onset and duration), and the duration of analgesia, the ratio of means, standard error, and 95% CIs were calculated for all continuous outcomes that examined change from baseline.36,37 For the remaining outcomes, the OR and 95% CIs were reported for dichotomous outcomes, while the weighted mean difference and 95% CI were reported for continuous outcomes. Differences were considered statistically significant when the P-value was < 0.05 and the 95% CI did not include 1 for OR and 0 for the standardized mean difference.

Heterogeneity of the pooled results was assessed using the I2 statistic.38 When heterogeneity was significant (I2 >50%), we planned to explore the sources of heterogeneity of the primary outcome data (i.e. sensory block duration), by examining the association with pre-specified confounders. The risk of publication bias was evaluated by checking for asymmetry of the funnel plots, as described in the Egger regression test.39

Results

Our database search strategy retrieved 137 potentially relevant records published between 2010 and 2016, including 15 from non-indexed citations. Of these, 102 records were excluded after initial screening; and another record was excluded for duplicated work.40 None of the remaining records involved less than 10 subjects per group. A total of 34 full-text randomized trials7,9–11, 21,22,28,41–67 were included in the final analysis. Figure 1 represents the preferred reporting items for systematic reviews and meta-analyses (PRISMA)12 flow diagram, and summarizes the reasons for exclusion of records.

Fig 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA)12 flow diagram summarizing retrieved, included, and excluded randomized trials.

Fig 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA)12 flow diagram summarizing retrieved, included, and excluded randomized trials.

Trial characteristics

Data from a total of 2007 patients, including 1026 in the Dex group and 981 in the Control group, were available for analysis. Details of the 34 trials, intervention arms, sample size, and outcomes assessed are summarized in Table 1. These 34 trials examined single-shot nerve blocks at all levels of brachial plexus, with five trials at the interscalene level,43,52,55,60,64 18 at the supraclavicular level,10,22,28,44–49, 51,53,56–58, 62,63,65,67 three at the infraclavicular level,9,59,66 and eight at the axillary level.7,11,21,41,42,50,54,61 The blocks were used to provide surgical anaesthesia in 23 trials, postoperative analgesia in four trials,55,60,62,64 and seven trials46,48,50–53, 56 did not provide sufficient details regarding the role of blocks. The mode of nerve block localization was anatomical (landmark) in six trials,10,42,43,45–48 nerve stimulation in 20 trials, ultrasound in three trials,8, 55,63 a combination of nerve stimulation and ultrasound in four trials,9,58,59,65 and not defined in one trial.44 With the exception of one trial that used mepivacaine,66 all trials used long-acting LAs (ropivacaine, bupivacaine, or levobupivacaine) alone or in conjunction with short acting LAs; and three trials used epinephrine in all study arms.60,64,65 Perineural dexmedetomidine was used in either weight-based doses (0.75 to 1.0 µg/kg) or flat doses (10 to 150 µg). A combination of perineural bolus and infusion of dexmedetomidine was used in one study; in this case, we excluded all outcomes influenced by the infusion.60 Eight trials examined adjuncts other than perineural dexmedetomidine;8, 21,43,51,59 these study arms were excluded from the analysis as they did not meet the inclusion criteria. Two trials included two perineural dexmedetomidine arms54 with different doses, which were combined into a single group for the purpose of this analysis. All trials reported block characteristics, analgesic outcomes, and dexmedetomidine-related complications.

Table 1

Trial characteristics and outcomes examined. Abbreviations: Dex, dexmedetomidine; Epi, epinephrine; kg, kilogram; ml, milliliter; ND, not defined; NS, normal saline; PONV, postoperative nausea and vomiting; μg, microgram. (*) excluded from analysis

Author Surgery Block use Groups (n) Local Anaesthetic Concentration – Total volume, and Epi dose Dex dose Block localization Primary outcome 
Interscalene Block 
Abdallah 201664 Shoulder, arthroscopic Analgesic 99 1. Ropivacaine + NS (32) 0.5% - 15 ml epi 1:200,000 0.5 µg/kg Ultrasound Duration of analgesia 
2. Ropivacaine + Dex + NS IV (33) 
3. Ropivacaine + NS + Dex IV (34) * 
Bengisun 201460 Shoulder, arthroscopic Analgesic 48 1. Levobupivacaine (25) 0.5% - 20 ml epi 50 µg 10 µg Stimulator Pain scores area under the curve 
2. Levobupivacaine + Dex (23) 
Fritsch 201455 Shoulder, arthroscopic, open Analgesic 61 1. Ropivacaine + NS (30) 0.5% - 10 ml 150 µg Ultrasound Duration of sensory 
2. Ropivacaine + Dex (31) 
Kumar 201443 Shoulder Surgical 90 1. Bupivacaine + NS (30) 0.25% - 40 ml 50 µg Landmark N/D 
2. Bupivacaine + Dex (30) 
3. Bupivacaine + Dexamethasone (30) * 
Rashmi 201652 Upper limb ND 60 1. Ropivacaine + NS (30)2. Ropivacaine + Dex (30) 0.75% - 30 ml 50 µg Stimulator Haemodynamic side-effects 
Supraclavicular Block 
Agarwal 201456 Upper limb ND 50 1. Bupivacaine + NS (25) 0.325% - 30 ml 100 µg Stimulator N/D 
2. Bupivacaine + Dex (25) 
Bharti 201565 Upper limb Surgical 54 1. Ropivacaine + lidocaine (27) Ropivacaine 0.325% Lidocaine 1% 40 ml epi 1:200,000 1 µg/kg Ultrasound + stimulator Duration of analgesia 
2. Ropivacaine + lidocaine + Dex (27) 
Biswas 201457 Forearm, hand Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 35 ml 100 µg Stimulator N/D 
2. Levobupivacaine + Dex µg (30) 
Das 201428 Distal arm, forearm, hand Surgical 84 1. Ropivacaine + NS (42) 0.5% - 30 ml 100 µg Stimulator Duration of analgesia 
2. Ropivacaine + Dex (42) 
Das 201667 Upper limb Surgical 80 1. Ropivacaine + NS (40) 0.5% - 30 ml 1 µg/kg Stimulator Duration of analgesia 
2. Ropivacaine + Dex (40) 
Dixit 201544 Upper limb Surgical 40 1. Levobupivacaine + NS (20) 0.5% - 29 ml 1 µg/kg ND N/D 
2. Levobupivacaine + Dex (20) 
Gandhi 201210 Upper limb Surgical 70 1. Bupivacaine + NS (35) 0.25% - 38 ml 30 µg Landmark Duration of analgesia 
2. Bupivacaine + Dex (35) 
Gurajala 201562 Distal arm, forearm, hand Analgesic 36 1. Ropivacaine + NS (18) 0.5% - 35 ml 50 µg Stimulator Onset of motor block 
2. Ropivacaine + Dex (18) 
Kathuria 201563 Distal arm, forearm, hand Surgical 60 1. Ropivacaine (20) 0.5% - 30 ml 50 µg Ultrasound N/D 
2. Ropivacaine + Dex (20) 
3. Ropivacaine + Dex i.v. (20) * 
Kaur 201545 Upper limb Surgical 92 1. Levobupivacaine + lidocaine + NS (45) Levobupivacaine 0.375% Lidocaine 0.25% 40 ml 1 µg/kg Landmark Onset of sensory block 
2. Levobupivacaine + lidocaine + Dex (45) 
Khade 201346 Forearm ND 40 1. Bupivacaine + lidocaine + NS (20) Bupivacaine 0.33% Lidocaine 0.66% 30 ml 50 µg Stimulator N/D 
2. Bupivacaine + lidocaine + Dex (20) 
Kwon 201558 Forearm, hand Surgical 60 1. Ropivacaine + NS (30) 0.5% - 40 ml 1 µg/kg Ultrasound + stimulator Bispectral index changes 
2. Ropivacaine + Dex (30) 
Manohar 201522 Distal arm, forearm Surgical 90 1. Bupivacaine + NS (30) 0.5% - 30 ml 50 µg Stimulator N/D 
2. Bupivacaine + Dex (30) 
3. Bupivacaine + Fentanyl 50 µg (30) * 
Nema 201447 Forearm Surgical 60 1. Ropivacaine + NS (30) 0.75% - 30 ml 50 µg Landmark N/D 
2. Ropivacaine + Dex (30) 
Patki 201548 Forearm ND 60 1. Ropivacaine + NS (30) 0.5% - 30 ml 1 µg/kg Landmark Duration of analgesia 
2. Ropivacaine + Dex (30) 
Saraf 201653 Upper limb ND 90 1. Ropivacaine + NS (30) 0.75% - 20 ml 2. 25 µg 3. 50 µg Stimulator N/D 
2. Ropivacaine + Dex 25 µg (30) 
3. Ropivacaine + Dex 50 µg (30) 
Singh 201649 Upper limb Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 30 ml 100 µg Stimulator Duration of analgesia 
2. Levobupivacaine + Dex (30) 
Tanden 201651 Upper limb ND 90 1. Levobupivacaine + NS (30) 0.5% - 30 ml 100 µg Stimulator N/D 
2. Levobupivacaine + Dex (30) 
3. Levobupivacaine + Clonidine 150 µg (30) * 
Infraclavicular Block 
Ammar 20129 Forearm, hand Surgical 60 1. Bupivacaine + NS (30) 0.33% - 30 ml 0.75 µ/kg Ultrasound + Stimulator Duration of analgesia 
2. Bupivacaine + Dex (30) 
Mirkheshti 201459 Distal arm, forearm Surgical 103 1. Lidocaine + NS (34) 1.5% - 30 ml 100 µg Ultrasound + stimulator N/D 
2. Lidocaine + Dex (34) 
3. Lidocaine + ketorolac 50 mg (35) * 
Song 201466 Upper limb Surgical 30 1. Mepivacaine + NS (10) 1% - 40 ml 1 µg/kg Stimulator Duration of sensory block 
2. Mepivacaine + Dex (10) 
3. Mepivacaine + epi 200 µg (30) * 
Axillary block 
Arun 201650 Forearm and hand ND 60 1. Ropivacaine + NS (30) 0.75% - 25 ml 50 µg Stimulator N/D 
2. Ropivacaine + Dex (30) 
Bangera 201661 Forearm and hand Surgical 80 1. Ropivacaine + NS (40) 0.5% - 40 ml 100 µg Stimulator N/D 
2. Ropivacaine + Dex (40) 
Esmaoglu 20107 Forearm and hand Surgical 60 1. Levobupivacaine + NS (30) 0.25% - 40 ml 100 µg Stimulator Duration of sensory and motor block 
2. Levobupivacaine + Dex (30) 
Hanoura 201341 Forearm and hand Surgical 48 1. Bupivacaine + NS (24) 0.5% - 39 ml 100 µg Stimulator N/D 
2. Bupivacaine + Dex (24) 
Karthik 201542 Forearm and hand Surgical 100 1. Levobupivacaine + NS (50) 0.375% - 39 ml 1 µg/kg Landmark N/D 
2. Levobupivacaine + Dex (50) 
Kaygusuz 201211 Forearm and hand Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 39 ml 1 µg/kg Stimulator Duration Of sensory block 
2. Levobupivacaine + Dex (30) 
Lee 201621 Forearm and hand Surgical 51 1. Ropivacaine + NS (17) 0.5% - 22 ml 100 µg Stimulator Duration of sensory block 
2. Ropivacaine + Dex (17) 
3. Ropivacaine + dexamethasone 10 mg (17) * 
Zhang 201454 Forearm and hand Surgical 45 1. Ropivacaine + NS (15) 0.33% - 40 ml 2. 50 µg 3. 100 µg Stimulator Duration of analgesia 
2. Ropivacaine + Dex 50 μg (15) 
3. Ropivacaine + Dex 100 μg (15) 
Author Surgery Block use Groups (n) Local Anaesthetic Concentration – Total volume, and Epi dose Dex dose Block localization Primary outcome 
Interscalene Block 
Abdallah 201664 Shoulder, arthroscopic Analgesic 99 1. Ropivacaine + NS (32) 0.5% - 15 ml epi 1:200,000 0.5 µg/kg Ultrasound Duration of analgesia 
2. Ropivacaine + Dex + NS IV (33) 
3. Ropivacaine + NS + Dex IV (34) * 
Bengisun 201460 Shoulder, arthroscopic Analgesic 48 1. Levobupivacaine (25) 0.5% - 20 ml epi 50 µg 10 µg Stimulator Pain scores area under the curve 
2. Levobupivacaine + Dex (23) 
Fritsch 201455 Shoulder, arthroscopic, open Analgesic 61 1. Ropivacaine + NS (30) 0.5% - 10 ml 150 µg Ultrasound Duration of sensory 
2. Ropivacaine + Dex (31) 
Kumar 201443 Shoulder Surgical 90 1. Bupivacaine + NS (30) 0.25% - 40 ml 50 µg Landmark N/D 
2. Bupivacaine + Dex (30) 
3. Bupivacaine + Dexamethasone (30) * 
Rashmi 201652 Upper limb ND 60 1. Ropivacaine + NS (30)2. Ropivacaine + Dex (30) 0.75% - 30 ml 50 µg Stimulator Haemodynamic side-effects 
Supraclavicular Block 
Agarwal 201456 Upper limb ND 50 1. Bupivacaine + NS (25) 0.325% - 30 ml 100 µg Stimulator N/D 
2. Bupivacaine + Dex (25) 
Bharti 201565 Upper limb Surgical 54 1. Ropivacaine + lidocaine (27) Ropivacaine 0.325% Lidocaine 1% 40 ml epi 1:200,000 1 µg/kg Ultrasound + stimulator Duration of analgesia 
2. Ropivacaine + lidocaine + Dex (27) 
Biswas 201457 Forearm, hand Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 35 ml 100 µg Stimulator N/D 
2. Levobupivacaine + Dex µg (30) 
Das 201428 Distal arm, forearm, hand Surgical 84 1. Ropivacaine + NS (42) 0.5% - 30 ml 100 µg Stimulator Duration of analgesia 
2. Ropivacaine + Dex (42) 
Das 201667 Upper limb Surgical 80 1. Ropivacaine + NS (40) 0.5% - 30 ml 1 µg/kg Stimulator Duration of analgesia 
2. Ropivacaine + Dex (40) 
Dixit 201544 Upper limb Surgical 40 1. Levobupivacaine + NS (20) 0.5% - 29 ml 1 µg/kg ND N/D 
2. Levobupivacaine + Dex (20) 
Gandhi 201210 Upper limb Surgical 70 1. Bupivacaine + NS (35) 0.25% - 38 ml 30 µg Landmark Duration of analgesia 
2. Bupivacaine + Dex (35) 
Gurajala 201562 Distal arm, forearm, hand Analgesic 36 1. Ropivacaine + NS (18) 0.5% - 35 ml 50 µg Stimulator Onset of motor block 
2. Ropivacaine + Dex (18) 
Kathuria 201563 Distal arm, forearm, hand Surgical 60 1. Ropivacaine (20) 0.5% - 30 ml 50 µg Ultrasound N/D 
2. Ropivacaine + Dex (20) 
3. Ropivacaine + Dex i.v. (20) * 
Kaur 201545 Upper limb Surgical 92 1. Levobupivacaine + lidocaine + NS (45) Levobupivacaine 0.375% Lidocaine 0.25% 40 ml 1 µg/kg Landmark Onset of sensory block 
2. Levobupivacaine + lidocaine + Dex (45) 
Khade 201346 Forearm ND 40 1. Bupivacaine + lidocaine + NS (20) Bupivacaine 0.33% Lidocaine 0.66% 30 ml 50 µg Stimulator N/D 
2. Bupivacaine + lidocaine + Dex (20) 
Kwon 201558 Forearm, hand Surgical 60 1. Ropivacaine + NS (30) 0.5% - 40 ml 1 µg/kg Ultrasound + stimulator Bispectral index changes 
2. Ropivacaine + Dex (30) 
Manohar 201522 Distal arm, forearm Surgical 90 1. Bupivacaine + NS (30) 0.5% - 30 ml 50 µg Stimulator N/D 
2. Bupivacaine + Dex (30) 
3. Bupivacaine + Fentanyl 50 µg (30) * 
Nema 201447 Forearm Surgical 60 1. Ropivacaine + NS (30) 0.75% - 30 ml 50 µg Landmark N/D 
2. Ropivacaine + Dex (30) 
Patki 201548 Forearm ND 60 1. Ropivacaine + NS (30) 0.5% - 30 ml 1 µg/kg Landmark Duration of analgesia 
2. Ropivacaine + Dex (30) 
Saraf 201653 Upper limb ND 90 1. Ropivacaine + NS (30) 0.75% - 20 ml 2. 25 µg 3. 50 µg Stimulator N/D 
2. Ropivacaine + Dex 25 µg (30) 
3. Ropivacaine + Dex 50 µg (30) 
Singh 201649 Upper limb Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 30 ml 100 µg Stimulator Duration of analgesia 
2. Levobupivacaine + Dex (30) 
Tanden 201651 Upper limb ND 90 1. Levobupivacaine + NS (30) 0.5% - 30 ml 100 µg Stimulator N/D 
2. Levobupivacaine + Dex (30) 
3. Levobupivacaine + Clonidine 150 µg (30) * 
Infraclavicular Block 
Ammar 20129 Forearm, hand Surgical 60 1. Bupivacaine + NS (30) 0.33% - 30 ml 0.75 µ/kg Ultrasound + Stimulator Duration of analgesia 
2. Bupivacaine + Dex (30) 
Mirkheshti 201459 Distal arm, forearm Surgical 103 1. Lidocaine + NS (34) 1.5% - 30 ml 100 µg Ultrasound + stimulator N/D 
2. Lidocaine + Dex (34) 
3. Lidocaine + ketorolac 50 mg (35) * 
Song 201466 Upper limb Surgical 30 1. Mepivacaine + NS (10) 1% - 40 ml 1 µg/kg Stimulator Duration of sensory block 
2. Mepivacaine + Dex (10) 
3. Mepivacaine + epi 200 µg (30) * 
Axillary block 
Arun 201650 Forearm and hand ND 60 1. Ropivacaine + NS (30) 0.75% - 25 ml 50 µg Stimulator N/D 
2. Ropivacaine + Dex (30) 
Bangera 201661 Forearm and hand Surgical 80 1. Ropivacaine + NS (40) 0.5% - 40 ml 100 µg Stimulator N/D 
2. Ropivacaine + Dex (40) 
Esmaoglu 20107 Forearm and hand Surgical 60 1. Levobupivacaine + NS (30) 0.25% - 40 ml 100 µg Stimulator Duration of sensory and motor block 
2. Levobupivacaine + Dex (30) 
Hanoura 201341 Forearm and hand Surgical 48 1. Bupivacaine + NS (24) 0.5% - 39 ml 100 µg Stimulator N/D 
2. Bupivacaine + Dex (24) 
Karthik 201542 Forearm and hand Surgical 100 1. Levobupivacaine + NS (50) 0.375% - 39 ml 1 µg/kg Landmark N/D 
2. Levobupivacaine + Dex (50) 
Kaygusuz 201211 Forearm and hand Surgical 60 1. Levobupivacaine + NS (30) 0.5% - 39 ml 1 µg/kg Stimulator Duration Of sensory block 
2. Levobupivacaine + Dex (30) 
Lee 201621 Forearm and hand Surgical 51 1. Ropivacaine + NS (17) 0.5% - 22 ml 100 µg Stimulator Duration of sensory block 
2. Ropivacaine + Dex (17) 
3. Ropivacaine + dexamethasone 10 mg (17) * 
Zhang 201454 Forearm and hand Surgical 45 1. Ropivacaine + NS (15) 0.33% - 40 ml 2. 50 µg 3. 100 µg Stimulator Duration of analgesia 
2. Ropivacaine + Dex 50 μg (15) 
3. Ropivacaine + Dex 100 μg (15) 

Risk of bias assessment

Some of the studies reviewed lacked sufficient details to permit full evaluation of the risk of bias; in such cases, we were conservative in our risk of bias evaluation by tending to classify trials as having an “unclear risk of bias” when the complete details that allow the exclusion of selection, performance and detection biases were not reported. Furthermore, trials that used generalizations such as “similar side-effects between study groups”, or presented haemodynamic outcomes data in a graphical format that precluded determining the actual risk of side-effects, were considered to be at a high risk for selective reporting. The reviewers’ consensus assessment of the risk is detailed in Table 2. Considering our conservative approach, and the fact that the main outcomes of interest, namely block characteristics, were less likely to be affected by the aforementioned biases, we considered the methodological quality for the majority of the 34 trials included to be acceptable, and rated the overall risk of bias across the studies as moderate. Most of trials had low risk for selection bias, attrition bias, and other biases; moreover, the majority of trials were assigned unclear risk of selection and performance bias, because authors did not provide sufficient details regarding blinding and concealment of sequence allocation. Bias as a result of selective reporting was classified as high in most of the trials, because of the aforementioned conservative approach in assessing the reporting of the dexmedetomidine-related haemodynamic side-effects. None of the trials were quasi-randomized.

Table 2

Risk of bias summary: review authors’ judgements about each risk of bias item for each included study. Green circle, low risk of bias; orange circle, high risk of bias; yellow circle, unclear risk of bias

graphic 
graphic 

Sensory block duration

Data describing the primary outcome, sensory block duration (time to full recovery from sensory block), were available from all trials (910 patients in Dex group) except two,8,60 and are presented in Figure 2. Administering perineural dexmedetomidine as an LA adjunct to BPB prolonged sensory block duration compared with Control. Expressed as lower CI [point estimate], the prolongation was at least 44% [57%], (P < 0.0001, I2 =99%) for ISB; 54% [82%], (P < 0.0001, I2 =100%) for SCB; 21% [37%], (P < 0.0001, I2 =75%) for ICB; and 34% [37%], (P < 0.0001, I2 =92%) for AXB. The overall treatment effect for all levels of BPB suggested that dexmedetomidine prolonged sensory block duration by at least 57% [65%], (P < 0.0001, I2 =100%), or by 3.8 h (from 7.7 h to 11.5 h).

Fig 2

Forest plot depicting sensory block duration. The individual trials’ ratio of means, standard error, and the pooled estimates of the ratio of means are shown. The 95% confidence intervals are shown as lines for individual studies and as diamonds for pooled estimates. Abbreviations: AXB, axillary block; CI, confidence interval; ICB, infraclavicular block; ISB, interscalene block; SCB, supraclavicular block; SE, standard error.

Fig 2

Forest plot depicting sensory block duration. The individual trials’ ratio of means, standard error, and the pooled estimates of the ratio of means are shown. The 95% confidence intervals are shown as lines for individual studies and as diamonds for pooled estimates. Abbreviations: AXB, axillary block; CI, confidence interval; ICB, infraclavicular block; ISB, interscalene block; SCB, supraclavicular block; SE, standard error.

The primary outcome results were characterized by significant heterogeneity for all four subgroups. Performing meta-regression analysis using the a priori pre-specified confounders, namely the LA dose, dexmedetomidine dose, epinephrine dose, block localization technique, and nature of surgical anaesthetic, yielded omnibus P-values of 0.047, 0.948, 0.37, 0.09, and 0.215, respectively, suggesting that the total LA dose is a predictor of sensory block prolongation.

Based on the fact that 15 trials were contributed by non-indexed citations, we elected to perform an additional subgroup analysis to assess the influence of potential selection bias introduced by including non-indexed trials. This analysis indicated that dexmedetomidine prolonged sensory block duration by at least 46% [60], (P < 0.0001, I2 =99%) and 58% [70], (P < 0.0001, I2 =100%) for the indexed and non-indexed trials, respectively. There was no difference between the two subgroups (P = 0.3), and heterogeneity remained high. Finally, the funnel plot did not suggest significant publication bias (P = 0.08) for our primary outcome.

When the strength of the synthesized evidence was evaluated using the GRADE guidelines, there was high evidence that mixing dexmedetomidine with long-acting LA used in a BPB, regardless of the level, prolongs the duration of sensory block duration compared with LA alone, in patients undergoing upper extremity surgery (Table 3). The overall quality assessment was downgraded by quality limitations; but was also upgraded by the large treatment effect and presence of a dose response.

Table 3

Summary of results and GRADE35 of evidence. Abbreviations: cm, centimetre; Dex, Dexmedetomidine; h, hours; min, minute; NA, not applicable; PONV, postoperative nausea and vomiting

Time-to-event outcomes Number of studies included References of studies included Dex N Dex Mean Control N Control Mean Ratio of Means [95% Confidence Interval] P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Sensory block onset (min) 31 7, 9, 10, 11, 21, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 65, 67, 63 953 10.8 909 20.0 0.7 [0.6, 0.8] < 0.00001 < 0.00001 98% ⊕⊕⊕⊝, Moderate 
Sensory block duration (min) 32 7, 9, 10, 11, 21, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 65, 66, 67 970 691.8 924 460.6 1.7 [1.6, 1.7] < 0.00001 < 0.00001 100% ⊕⊕⊕⊕, High 
Motor block onset (min) 27 7, 9, 10, 11, 22, 28, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 63, 65, 67 860 13.4 815 21.2 0.7 [0.6, 0.9] < 0.00001 < 0.00001 99% ⊕⊕⊕⊝, Moderate 
Motor block duration (min) 31 9, 7, 10, 11, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67 957 605.9 909 412.9 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% ⊕⊕⊕⊕, High 
Duration of analgesia (min) 26 7, 9, 10, 11, 22, 28, 41, 43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 56, 57, 59, 61, 62, 63, 64, 65, 66 787 716.5 754 452.4 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% ⊕⊕⊕⊝, Moderate 
Analgesic outcomes Number of studies included References of studies included Dex N Dex (Mean or n/N) Control N Control (Mean or n/N) Odds Ratio or Weighed Mean[95% Confidence Interval) P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Analgesic consumption 28, 43, 48, 55, 60, 63, 64, 65 234 26.7 234 36.0 −10.2 [-15.3, -5.2] < 0.0001 < 0.00001 83% ⊕⊕⊝⊝, Low 
Rest pain scores at 24 h (cm) 9, 28, 41, 55, 60, 64, 65 207 3.4 206 3.9 −0.6 [-0.9, -0.3] 0.0002 0.5 0% ⊕⊕⊝⊝, Low 
Dynamic pain scores at 24 h (cm) 55 31 3.9 30 3.5 0.5 [-0.9, 1.8] 0.48 NA NA N/A 
Patient satisfaction 22, 41, 45, 52, 60, 64 183 151/183 186 124/186 2.5 [1.2, 5.3] 0.02 0.08 49% ⊕⊝⊝⊝, Very low 
Dex-related adverse effects Number of studies included References of studies included Dex N Dex (Mean or n/N) Control N Control (Mean or n/N) Odds Ratio or Weighed Mean[95% Confidence Interval) P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Bradycardia 19 7, 10, 11, 21, 22, 42, 45, 49, 51, 54, 56, 57, 58, 60, 61, 62, 63, 64, 65 540 69/540 525 10/525 4.8 [1.2, 19.2] 0.03 0.001 66% ⊕⊕⊕⊝, Moderate 
Hypotension 14 7, 10, 11, 21, 42, 49, 54, 57, 60, 61, 62, 63, 64, 65 410 50/410 395 15/395 5.4 [2.7, 11.0] < 0.00001 0.99 0% ⊕⊕⊕⊝, Moderate 
Excessive sedation 9, 28, 44, 46, 49, 55, 56, 65 222 53/222 220 4/220 17.2 [1.0, 286.5] 0.05 0.001 78% ⊕⊝⊝⊝, Very low 
Hypoxemia 11 7, 11, 21, 22, 42, 49, 56, 57, 61, 63, 65 328 0/328 327 0/327 NA NA NA NA NA 
PONV 15 7, 9, 11, 21, 22, 43, 51, 55, 56, 57, 60, 63, 64, 65 386 19/386 386 43/386 0.4 [0.2, 1.0] 0.06 0.08 49% ⊕⊕⊝⊝, Low 
Time-to-event outcomes Number of studies included References of studies included Dex N Dex Mean Control N Control Mean Ratio of Means [95% Confidence Interval] P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Sensory block onset (min) 31 7, 9, 10, 11, 21, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 65, 67, 63 953 10.8 909 20.0 0.7 [0.6, 0.8] < 0.00001 < 0.00001 98% ⊕⊕⊕⊝, Moderate 
Sensory block duration (min) 32 7, 9, 10, 11, 21, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 65, 66, 67 970 691.8 924 460.6 1.7 [1.6, 1.7] < 0.00001 < 0.00001 100% ⊕⊕⊕⊕, High 
Motor block onset (min) 27 7, 9, 10, 11, 22, 28, 42, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 63, 65, 67 860 13.4 815 21.2 0.7 [0.6, 0.9] < 0.00001 < 0.00001 99% ⊕⊕⊕⊝, Moderate 
Motor block duration (min) 31 9, 7, 10, 11, 22, 28, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67 957 605.9 909 412.9 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% ⊕⊕⊕⊕, High 
Duration of analgesia (min) 26 7, 9, 10, 11, 22, 28, 41, 43, 45, 46, 47, 48, 49, 50, 51, 52, 53, 56, 57, 59, 61, 62, 63, 64, 65, 66 787 716.5 754 452.4 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% ⊕⊕⊕⊝, Moderate 
Analgesic outcomes Number of studies included References of studies included Dex N Dex (Mean or n/N) Control N Control (Mean or n/N) Odds Ratio or Weighed Mean[95% Confidence Interval) P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Analgesic consumption 28, 43, 48, 55, 60, 63, 64, 65 234 26.7 234 36.0 −10.2 [-15.3, -5.2] < 0.0001 < 0.00001 83% ⊕⊕⊝⊝, Low 
Rest pain scores at 24 h (cm) 9, 28, 41, 55, 60, 64, 65 207 3.4 206 3.9 −0.6 [-0.9, -0.3] 0.0002 0.5 0% ⊕⊕⊝⊝, Low 
Dynamic pain scores at 24 h (cm) 55 31 3.9 30 3.5 0.5 [-0.9, 1.8] 0.48 NA NA N/A 
Patient satisfaction 22, 41, 45, 52, 60, 64 183 151/183 186 124/186 2.5 [1.2, 5.3] 0.02 0.08 49% ⊕⊝⊝⊝, Very low 
Dex-related adverse effects Number of studies included References of studies included Dex N Dex (Mean or n/N) Control N Control (Mean or n/N) Odds Ratio or Weighed Mean[95% Confidence Interval) P-Value for statistical significance P-Value for heterogeneity I2 Test for heterogeneity Quality of evidence (GRADE) 
Bradycardia 19 7, 10, 11, 21, 22, 42, 45, 49, 51, 54, 56, 57, 58, 60, 61, 62, 63, 64, 65 540 69/540 525 10/525 4.8 [1.2, 19.2] 0.03 0.001 66% ⊕⊕⊕⊝, Moderate 
Hypotension 14 7, 10, 11, 21, 42, 49, 54, 57, 60, 61, 62, 63, 64, 65 410 50/410 395 15/395 5.4 [2.7, 11.0] < 0.00001 0.99 0% ⊕⊕⊕⊝, Moderate 
Excessive sedation 9, 28, 44, 46, 49, 55, 56, 65 222 53/222 220 4/220 17.2 [1.0, 286.5] 0.05 0.001 78% ⊕⊝⊝⊝, Very low 
Hypoxemia 11 7, 11, 21, 22, 42, 49, 56, 57, 61, 63, 65 328 0/328 327 0/327 NA NA NA NA NA 
PONV 15 7, 9, 11, 21, 22, 43, 51, 55, 56, 57, 60, 63, 64, 65 386 19/386 386 43/386 0.4 [0.2, 1.0] 0.06 0.08 49% ⊕⊕⊝⊝, Low 

Block characteristics

The effect of perineural dexmedetomidine on motor block duration was evaluated in 31 trials.7,9–11, 21,22,28,41–54,56–59,61–63,65–67 Adding dexmedetomidine to BPB prolonged motor block duration by at least 26% [50%], (P < 0.0001, I2 =100%) for ISB; 61% [90%], (P < 0.0001, I2 =100%) for SCB; 19% [38%], (P < 0.0001, I2 =85%) for ICB; and 11% [35%], (P < 0.0001, I2 =100%) for AXB (Fig. 3). The overall treatment effect for all levels of BPB suggested that dexmedetomidine prolongs motor block duration by at least 58% [68%], (P < 0.0001, I2 =100%), or from 6.9 h to 10.1 h. The level of evidence for this finding was rated as high. (Table 3) The overall quality assessment was downgraded by quality limitations; but was also upgraded by the large treatment effect.

Fig 3

Forest plot depicting motor block duration. The individual trials’ ratio of means, standard error, and the pooled estimates of the ratio of means are shown. The 95% confidence intervals are shown as lines for individual studies and as diamonds for pooled estimates. Abbreviations: AXB, axillary block; CI, confidence interval; ICB, infraclavicular block; ISB, interscalene block; SCB, supraclavicular block; SE, standard error.

Fig 3

Forest plot depicting motor block duration. The individual trials’ ratio of means, standard error, and the pooled estimates of the ratio of means are shown. The 95% confidence intervals are shown as lines for individual studies and as diamonds for pooled estimates. Abbreviations: AXB, axillary block; CI, confidence interval; ICB, infraclavicular block; ISB, interscalene block; SCB, supraclavicular block; SE, standard error.

The effect of perineural dexmedetomidine as a LA adjunct o n the sensory block onset was evaluated in 31 trials.7,9–11, 21,22,28,41,42,44–56,58–63, 65,67,68 Dexmedetomidine hastened sensory block onset by at least 77% [32%], (P = 0.003, I2 =99%) for ISB; 44% [33%], (P < 0.0001, I2 =94%) for SCB; 38% [31%], (P < 0.0001, I2 =0%) for ICB; and 24% [18%], (P < 0.0001, I2 =64%) for AXB (Table 3). The overall treatment effect for all levels of BPB suggested that dexmedetomidine shortened sensory block onset time by at least 40% [28%], (P < 0.0001, I2 =98%), or from 20.0 min to 10.8 min. The level of evidence for this finding was rated as moderate. (Table 3,

) The overall quality assessment was downgraded by quality and consistency limitations; but was also upgraded by the large treatment effect.

The effect of perineural dexmedetomidine on motor block onset was assessed in 27 trials.7,9–11, 22,28,42,44–56, 58,59,61–63, 65,67 Dexmedetomidine hastened motor block onset by at least 35% [26%], (P < 0.0001, I2 =96%) for SCB; 40% [31%], (P < 0.0001, I2 =0%) for ICB; and 17% [15%], (P < 0.0001, I2 =26%) for AXB (Table 3). Though both trials52,55 examining the effect of dexmedetomidine on motor block onset time in ISB showed faster motor block onset, the pooled results for this specific brachial plexus level was not significant. The overall treatment effect for all levels of BPB suggested that dexmedetomidine shortened motor block onset time by at least 39% [27%], (P < 0.00001, I2 =99%), or from 21.2 min to 13.4 min. The level of evidence for this finding was rated as moderate. (Table 3,

) The overall quality assessment was downgraded by quality and consistency limitations; but was also upgraded by the large treatment effect.

Analgesic outcomes

The effect of perineural dexmedetomidine on duration of postoperative analgesia was evaluated in 26 trials.7,9–11, 22,41,43,45–53, 56,57,59,61–67 The definition of duration of analgesia in these trials varied to include time to first analgesic request,7,9,11,41,47,49,50,56,57,61,63,65,67 to attain a pain VAS score> 359 or> 4,22,43,62 or to first patient report of postoperative pain at surgical site,10,64,66 and was not defined in six trials.45,46,48,51–53 Dexmedetomidine prolonged the duration of analgesia by at least 60% [74%], (P < 0.0001, I2 =100%) for ISB; 69% [91%], (P < 0.0001, I2 =100%) for SCB; 0% [39%], (P < 0.0001, I2 =97%) for ICB; and 12% [33%], (P < 0.0001, I2 =99%) for AXB (Table 3). The overall treatment effect for all levels of BPB suggested that dexmedetomidine prolonged the duration of analgesia by at least 63% [72%], (P< 0.0001, I2 =100%), or from 7.5 h to 11.9 h. The level of evidence for this finding was rated as moderate. (Table 3,

) The overall quality assessment was downgraded by quality, consistency, and directness limitations; but was also upgraded by the large treatment effect and dose-response.

Cumulative 24-h postoperative analgesic consumption was reported in eight trials belonging to the ISB43,55,60,64 and SCB28,48,63,65 subgroups; and none of the trials examining ICB or AXB reported this outcome. Combining dexmedetomidine with LA reduced oral morphine equivalent consumption by a mean [95% CI] of -9.6 mg [-19.4, 0.1], (P = 0.05, I2 =92%) and -11.6 mg [-15.6, -7.6], (P < 0.0001, I2 =30%) for the ISB and SCB subgroups, respectively. The overall treatment effect for these two levels of BPB suggested that dexmedetomidine reduced postoperative analgesic consumption by -10.2 mg [-15.3, -5.2], (P< 0.0001, I2 =83%) of oral morphine equivalents. The level of evidence for this finding was rated as low. (Table 3) The overall quality assessment was downgraded by quality and sparse data limitations.

The effect of perineural dexmedetomidine on posto perative rest pain scores at 24 h was reported in seven trials.28,41,43,55,60,64,65 Dexmedetomidine reduced pain scores by -0.5 cm [−0.9, −0.0], (P = 0.03, I2 =0%) and −0.8 cm [−1.6, −0.0], (P = 0.04, I2 =0) for SCB and AXB subgroups, respectively but there were no differences in the ISB and ICB subgroups. The level of evidence for this finding was rated as low. (Table 3) The overall quality assessment was downgraded by quality and sparse data limitations. Rest pain at 12 h and length of hospital stay time were inconsistently assessed in the reviewed trials; while dynamic pain was reported in one trial only,55 precluding any conclusions regarding these outcomes.

Patient satisfaction with the pain management received and/or willingness to receive the same management in the future was assessed in six trials.8, 22,41,45,52,60 The proportion of patients with high satisfaction was greater among those who received dexmedetomidine, with an OR [95% CI] of 2.5 [1.2, 5.3], (P = 0.02, I2 =49%), compared with Control. The level of evidence for this finding was rated as very low. (Table 3) The overall quality assessment was downgraded by quality, consistency and sparse data limitations.

Dexmedetomidine-related adverse effects

The definitions of dexmedetomidine-related adverse effects in the reviewed trials were diverse; therefore, we reported these outcomes as ‘standardized units’. Dexmedetomidine increased the odds of bradycardia by an OR of 3.3 [0.8, 13.5], (P = 0.0002, I2 =70%); it also increased the odds of hypotension by an OR of 5.4 [2.7, 11.0], (P < 0.0001, I2 =0%). The level of evidence for these findings was rated as moderate. (Table 3) The overall quality assessment was downgraded by quality and consistency limitations. Notably, these side-effects were transient, reversible, did not require any intervention, and did not cause any long-term consequence in any of the patients. Our additional subgroup analysis suggested that a dose of 50-60 µg maximizes sensory block duration (by at least 52% [61%], P < 0.0001), while minimizing the haemodynamic side-effects to none [i.e. by an OR of 1.7 (0.3, 9.6), P = 0.5 and OR of 6.9 (0.8, 60.8), P = 0.08 for bradycardia and hypotension, respectively]. (

)

Excessive postoperative sedation was reported using various scales, including Richmond,49,56 Modified Wilson,46 University of Michigan,44 and four-point sedation scales;65 it was undefined in three trials.9,55,67 Patients who received perineural dexmedetomidine had greater odds of experiencing excessive postoperative sedation, with an OR of 17.2 [1.04, 286.5], (P = 0.05, I2 =78%). The level of evidence for this finding was rated as very low. (Table 3) The overall quality assessment was downgraded by quality, consistency and sparse data limitations.

Hypoxaemia was defined as oxygen saturation below 90%7,11,21,42,49,56,65, 93%61 or was not defined.22,57,63 None of the patients in the reviewed trials experienced hypoxemic events. Furthermore, data from 15 trials7,9,11 21,22,43,44,51,55–57, 60,63–65 suggested that there was no statistically significant difference in the incidence of PONV between the two groups. The level of evidence for this finding was rated as low. The overall quality assessment was downgraded by quality and sparse data limitations.

Finally, none of the patients reported any block-related complications.

Discussion

This is the first study to provide a high level of evidence from clinical trials supporting the efficacy of perineural dexmedetomidine as peripheral nerve block adjunct. Our updated review demonstrates that using perineural dexmedetomidine as a BPB adjunct is associated with important facilitatory effects regardless of the BPB level, specifically prolonged sensory and motor block durations, and faster sensory and motor block onset. The analgesic benefits of using dexmedetomidine include prolonged duration of analgesia, reduced cumulative 24 h postoperative analgesic consumption, improved pain control and enhanced satisfaction with pain relief. However, perineural dexmedetomidine was also associated with increased risk of transient hypotension, bradycardia, and postoperative sedation. The levels of evidence relating to sensory block duration and duration of analgesia were high and moderate, respectively.

The observed differences in the magnitude of dexmedetomidine effects on the various BPB levels may be attributed to intrinsic differences in the systemic uptake69 and neuraxial spread70 between these levels. This updated systematic review and meta-analysis overcomes the limitations of our earlier meta-analysis8 of a small number of trials that had suggested lack of efficacy of dexmedetomidine in prolonging sensory block duration or expediting block onset. However, the present results are similarly characterized by high heterogeneity, and while LA dose-response account for some of this heterogeneity, our findings should still be interpreted with caution.

The benefits of dexmedetomidine should be carefully weighed against prolonged motor block duration and the increased risks of sedation, bradycardia and hypotension. Practically, while extended motor block duration may be desirable in certain populations, using dexmedetomidine in lower extremity blocks may delay recovery after ambulatory surgery and increase the risk of falls.71,72 Additionally, sedation may interfere with fast-tracking, recovery room bypass, or other pathways aimed to expedite discharge. The potential for haemodynamic side-effects may limit the administration of blocks inclusive of dexmedetomidine to monitored settings, where bradycardia and hypotension can be readily identified and treated. Furthermore, these side-effects may preclude use in higher risk patients and in procedures inherently associated with changes in heart rate and bp, such as surgery in the sitting position.73

This meta-analysis has positive safety implications. While our previous meta-analysis8 could not draw conclusions about the safety of the clinical use of dexmedetomidine, the present review incorporates data from 1026 patients who received perineural dexmedetomidine for the BPB, and none developed any neurotoxicity symptoms, or any other neurologic sequalae. In fact, there is further evidence from in vitro and animal studies suggesting that the perineural application of dexmedetomidine may be neuroprotective against the LA-induced inflammatory response.5, 74,75 While this has also been shown for clonidine,76 the latter may carry a risk of neurotoxicity when combined with local anaesthetics.4 Nonetheless, recent evidence suggesting that systemic dexmedetomidine may be as effective as perineural dexmedetomidine in prolonging the duration of analgesia after BPB, is a promising new area of research,8 though the underlying mechanisms and the comparative risk of haemodynamic side-effects have yet to be explored.

Limitations

Our review has several limitations. First, clinical heterogeneity characterized the data reviewed as it originated from different surgical, anaesthetic, and analgesic settings. While we stratified studies according to the level of BPB, considerable variability may persist within each subgroup. For example, postoperative pain after shoulder rotator cuff repair is likely more severe than simple shoulder arthroscopy; but lack of sufficient data precluded any further stratification by surgical procedure. Second, definitions of some outcomes of interest, such as postoperative analgesia duration, hypoxaemia, and excessive sedation varied between trials, which may have contributed to the observed heterogeneity. Third, the trials reviewed were small, with sample sizes of 10-50 patients/group, which increases the chances of type I error and publication bias. Fourth, only two trials originated from North America64 and Europe,55 which may represent another source of publication bias.77,78 Fifth, while a variety of doses of dexmedetomidine were used, we could not detect a dose-response, although evidence suggests that dexmedetomidine produces a dose-dependent prolongation in sensory block duration.19 This may be as a result of the clinical heterogeneity of nerve block techniques and LA doses used. We also did not seek abstracts from meeting and trial results from clinical trial registries, and we restricted our search to trials published in the English language. Lastly, it is noteworthy that the methodological shortcomings of studies and inconsistencies in the definition and assessment of outcomes were main reasons why the strength of evidence was down-graded for some outcomes. Despite these inconsistencies, the methods of assessing outcomes indicative of dexmedetomidine effectiveness (i.e. durations of sensory block, motor block, and postoperative analgesia), were marked by good internal and external validity. Furthermore, factors such as the strength of the treatment effect, presence of a dose-response, and successful identification of confounders served to offset these limitations for some outcomes.

In contrast, our review has several points of strength. The literature review we conducted was exhaustive and included all relevant databases. Our inclusion criteria were limited to randomized trials. The primary outcome results maintained their robustness despite our attempt to explore statistical heterogeneity. These factors underscore the validity of our findings.

Conclusion

Our study provides strong evidence that using perineural dexmedetomidine improves BPB onset, quality, and analgesia. These results differ considerably from our earlier meta-analysis that did not support the use of perineural dexmedetomidine. There is now strong evidence to support its effect in prolonging sensory block duration, and moderate evidence to supports its effect in hastening block onset and extending the duration of analgesia. However, these benefits should be weighed against the increased risks of motor block prolongation and transient bradycardia and hypotension.

Authors’ contributions

Study design/planning: F.W.A.

Study conduct: L.V., F.W.A.

Data analysis: L.V., R.B., F.W.A.

Writing paper: L.V., R.B., F.W.A.

Revising paper: all authors

Supplementary material

is available at British Journal of Anaesthesia online.

Declaration of interest

None declared.

Funding

This work was supported by departmental funding. Both F.W.A.and R.B. are supported by the Merit Award Program, Department of Anaesthesia, University of Toronto.

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