British Journal of Anaesthesia, 118 (2): 167–81 (2017)

doi: 10.1093/bja/aew411
Review Article

Evidence basis for using perineural dexmedetomidine

to enhance the quality of brachial plexus nerve blocks:
a systematic review and meta-analysis of randomized
controlled trials
L. Vorobeichik1,2, R. Brull1,3 and F. W. Abdallah1,2,4,*
1
Department of Anaesthesia, University of Toronto, Toronto, Canada, 2Department of Anaesthesia, St.
Michael’s Hospital, University of Toronto, Toronto, Canada, 3Department of Anaesthesia, Women’s College
Hospital, Toronto, Canada and 4The Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada

*Corresponding author. E-mail: abdallahf@smh.ca

Abstract
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 expe-
dited 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 ¼ 0.0002)), and hypotension (5.4
[2.7, 11.0] (P < 0.0001)). A 50-60mg dexmedetomidine dose maximized sensory block duration while minimizing haemo-
dynamic side-effects. No patients experienced any neurologic sequelae. Evidence quality for sensory block was high accord-
ing 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.

Key words: adjunct; adjuvant; axillary; brachial plexus block; infraclavicular; interscalene; nerve block; perineural
dexmedetomidine; regional anaesthesia; sensory block; supraclavicular

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 168 | Vorobeichik et al.
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 mg.
• There is some uncertainty as to overall analgesic effect-
iveness and patient outcomes.
Anaesthetists have sought strategies to extend the benefits of
single-shot peripheral nerve blocks beyond the duration of com-
monly available local anaesthetics (LA).1 Perineural adjuncts are
one technically simple strategy that can be used for this pur-
pose.2 Dexmedetomidine, an alpha-2 agonist,3 has been pro-
posed as a safe4 and effective56 adjunct capable of extending the
duration of single-shot block.
Hyperpolarization-activated cation currents normally bring
neurons back to the resting potential and normal functional activ-
ity 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 animal56 and human7 studies that
have signaled efficacy, our quantitative systematic review of dex-
medetomidine as an adjunct to brachial plexus block (BPB), pub-
lished 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 add-
itional 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
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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 ad-
ministration were used (e.g. intra-articular injection);13 if surgeries
involved anatomical areas other than the upper extremity (e.g. ab-
dominal);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 manu-
script 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 as-
sessed 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 alloca-
tion), 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 au-
thor (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 an-
swering the question of interest. However, trials were excluded
if they had fewer than 10 subjects per group, to reduce the pos-
sibility 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
 Perineural dexmedetomidine for brachial plexus block
(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 out-
comes 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, ex-
pressed as oral morphine equivalents (mg);23 rest and dynamic
postoperative pain severity (visual analogue scale, VAS; 0 ¼ no
pain, 10 ¼ worst pain imaginable) at 12 and 24 h postoperatively;
patient satisfaction with postoperative pain relief, (VAS;
0 ¼ least satisfied, 10 ¼ 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: SD¼ Range/4 and
SD¼ IQR/1.35, respectively, as described by the Cochrane
Handbook for Systematic Reviews.25 Data reported as 95% confi-
dence 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 inter-
est 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 lev-
els of BPB will lead to different block characteristics and anal-
gesic 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 ex-
traction; when data were not presented in tables, we contacted
authors for additional information. Graphical data not other-
wise available in the text or from the authors were estimated
from figures. As a final resort, when SD values were not re-
ported 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
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| 169
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, re-
gardless of compliance or attrition, to estimate the influence on
treatment effect.31 Continuous data describing patient satisfac-
tion 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 ran-
dom 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 tri-
als 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 un-
likely to change the confidence in the estimate of effect; ii) mod-
erate 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 esti-
mate of effect and is likely to change the estimate; and iv) very
low quality: we are very uncertain about the estimate. For con-
sistency in specific, we resorted to examining the similarity of
point estimates, and the extent of overlap of confidence inter-
vals, 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 con-
tinuous outcomes. Differences were considered statistically sig-
nificant 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 as-
sociation with pre-specified confounders. The risk of publica-
tion 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
 170 | Vorobeichik et al.

Identification

Records identified through Additional records identified

database search through other sources
(n= 122) (n= 15)

Records after removing duplicates Records excluded

(n = 137) (n= 102)
4: Abstract, full text not available
Screening

1: Abstract, full text in different

record
30: Design: Reviews
Records screened 8: Population: Animal studies
(n = 137) 38: Intervention: Dex not
administered perineurally
9: Intervention: No Dex group
1: Intervention: Perineural Dex in
Full-text articles assessed other nerve blocks
for eligibility 2: Comparator: No control group
Eligibility

(n= 35) 1: Language (Chinese)

Studies included in Full-text articles excluded

qualitative synthesis (n= 1)
(n = 34) 1: Duplicated work
Included

Studies included in
quantitative synthesis
(meta-analysis)
(n = 34)

Fig 1 Preferred reporting items for systematic reviews and meta-analyses (PRISMA)12 flow diagram summarizing retrieved, included, and excluded randomized
trials.

duplicated work.40 None of the remaining records involved less
than 10 subjects per group. A total of 34 full-text randomized tri-
als7 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.
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 out-
comes 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 de-
tails regarding the role of blocks. The mode of nerve block local-
ization was anatomical (landmark) in six trials,10 42 43 45–48 nerve
stimulation in 20 trials, ultrasound in three trials,8 55 63 a com-
bination 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 (ropiva-
caine, 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 ei-
ther weight-based doses (0.75 to 1.0 mg/kg) or flat doses (10 to
150 mg). A combination of perineural bolus and infusion of dex-
medetomidine 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

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Table 1 Trial characteristics and outcomes examined. Abbreviations: Dex, dexmedetomidine; Epi, epinephrine; kg, kilogram; ml, milliliter; ND, not defined; NS, normal saline; PONV, postopera-
tive nausea and vomiting; lg, microgram. (*) excluded from analysis

Author Surgery Block use N Groups (n) Local Anaesthetic Dex dose Block Primary outcome
Concentration – Total localization
volume, and Epi dose

Interscalene Block
Abdallah 201664 Shoulder, arthroscopic Analgesic 99 1. Ropivacaine þ NS (32) 0.5% - 15 ml epi 0.5 mg/kg Ultrasound Duration of analgesia
2. Ropivacaine þ Dex þ NS IV (33) 1:200,000
3. Ropivacaine þ NS þ Dex IV (34) *
Bengisun 201460 Shoulder, arthroscopic Analgesic 48 1. Levobupivacaine (25) 0.5% - 20 ml epi 50 mg 10 mg Stimulator Pain scores area
2. Levobupivacaine þ Dex (23) under the curve
Fritsch 201455 Shoulder, arthroscopic, Analgesic 61 1. Ropivacaine þ NS (30) 0.5% - 10 ml 150 mg Ultrasound Duration of sensory
open 2. Ropivacaine þ Dex (31)
Kumar 201443 Shoulder Surgical 90 1. Bupivacaine þ NS (30) 0.25% - 40 ml 50 mg Landmark N/D
2. Bupivacaine þ Dex (30)
3. Bupivacaine þ Dexamethasone (30) *
Rashmi 201652 Upper limb ND 60 1. Ropivacaine þ NS (30)2. Ropivacaine 0.75% - 30 ml 50 mg Stimulator Haemodynamic side-effects
þ Dex (30)
Supraclavicular Block
Agarwal 201456 Upper limb ND 50 1. Bupivacaine þ NS (25) 0.325% - 30 ml 100 mg Stimulator N/D
2. Bupivacaine þ Dex (25)
Bharti 201565 Upper limb Surgical 54 1. Ropivacaine þ lidocaine (27) Ropivacaine 0.325% 1 mg/kg Ultrasound Duration of analgesia
2. Ropivacaine þ lidocaine þ Dex (27) Lidocaine þ stimulator
1% 40 ml epi 1:200,000
Biswas 201457 Forearm, hand Surgical 60 1. Levobupivacaine þ NS (30) 0.5% - 35 ml 100 mg Stimulator N/D
2. Levobupivacaine þ Dex mg (30)
Das 201428 Distal arm, forearm, hand Surgical 84 1. Ropivacaine þ NS (42) 0.5% - 30 ml 100 mg Stimulator Duration of analgesia
2. Ropivacaine þ Dex (42)
Das 201667 Upper limb Surgical 80 1. Ropivacaine þ NS (40) 0.5% - 30 ml 1 mg/kg Stimulator Duration of analgesia
2. Ropivacaine þ Dex (40)
Dixit 201544 Upper limb Surgical 40 1. Levobupivacaine þ NS (20) 0.5% - 29 ml 1 mg/kg ND N/D
2. Levobupivacaine þ Dex (20)

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Gandhi 201210 Upper limb Surgical 70 1. Bupivacaine þ NS (35) 0.25% - 38 ml 30 mg Landmark Duration of analgesia
2. Bupivacaine þ Dex (35)
Gurajala 201562 Distal arm, forearm, hand Analgesic 36 1. Ropivacaine þ NS (18) 0.5% - 35 ml 50 mg Stimulator Onset of motor block
2. Ropivacaine þ Dex (18)
Kathuria 201563 Distal arm, forearm, hand Surgical 60 1. Ropivacaine (20) 0.5% - 30 ml 50 mg Ultrasound N/D
2. Ropivacaine þ Dex (20)
3. Ropivacaine þ Dex i.v. (20) *
Kaur 201545 Upper limb Surgical 92 1. Levobupivacaine þ lidocaine þ NS (45) Levobupivacaine 0.375% 1 mg/kg Landmark Onset of sensory block
2. Levobupivacaine þ lidocaine þ Dex (45) Lidocaine 0.25% 40 ml
Perineural dexmedetomidine for brachial plexus block

Khade 201346 Forearm ND 40 1. Bupivacaine þ lidocaine þ NS (20) Bupivacaine 0.33% 50 mg Stimulator N/D
|

2. Bupivacaine þ lidocaine þ Dex (20) Lidocaine 0.66% 30 ml

Kwon 201558 Forearm, hand Surgical 60 1. Ropivacaine þ NS (30) 0.5% - 40 ml 1 mg/kg Ultrasound Bispectral index changes
171

2. Ropivacaine þ Dex (30) þ stimulator

(continued)
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Table 1 Continued
Author Surgery Block use N Groups (n) Local Anaesthetic Dex dose Block Primary outcome

on 26 September 2017
Concentration – Total localization
172

volume, and Epi dose

|

Manohar 201522 Distal arm, forearm Surgical 90 1. Bupivacaine þ NS (30) 0.5% - 30 ml 50 mg Stimulator N/D
2. Bupivacaine þ Dex (30)
3. Bupivacaine þ Fentanyl 50 mg (30) *
Nema 201447 Forearm Surgical 60 1. Ropivacaine þ NS (30) 0.75% - 30 ml 50 mg Landmark N/D
2. Ropivacaine þ Dex (30)
Patki 201548 Forearm ND 60 1. Ropivacaine þ NS (30) 0.5% - 30 ml 1 mg/kg Landmark Duration of analgesia
2. Ropivacaine þ Dex (30)
Vorobeichik et al.

Saraf 201653 Upper limb ND 90 1. Ropivacaine þ NS (30) 0.75% - 20 ml 2. 25 mg Stimulator N/D

2. Ropivacaine þ Dex 25 mg (30) 3. 50 mg
3. Ropivacaine þ Dex 50 mg (30)
Singh 201649 Upper limb Surgical 60 1. Levobupivacaine þ NS (30) 0.5% - 30 ml 100 mg Stimulator Duration of analgesia
2. Levobupivacaine þ Dex (30)
Tanden 201651 Upper limb ND 90 1. Levobupivacaine þ NS (30) 0.5% - 30 ml 100 mg Stimulator N/D
2. Levobupivacaine þ Dex (30)
3. Levobupivacaine þ Clonidine 150 mg (30) *
Infraclavicular Block
Ammar 20129 Forearm, hand Surgical 60 1. Bupivacaine þ NS (30) 0.33% - 30 ml 0.75 m/kg Ultrasound þ Duration of analgesia
2. Bupivacaine þ Dex (30) Stimulator
Mirkheshti 201459 Distal arm, forearm Surgical 103 1. Lidocaine þ NS (34) 1.5% - 30 ml 100 mg Ultrasound þ N/D
2. Lidocaine þ Dex (34) stimulator
3. Lidocaine þ ketorolac 50 mg (35) *
Song 201466 Upper limb Surgical 30 1. Mepivacaine þ NS (10) 1% - 40 ml 1 mg/kg Stimulator Duration of sensory block
2. Mepivacaine þ Dex (10)
3. Mepivacaine þ epi 200 mg (30) *
Axillary block
Arun 201650 Forearm and hand ND 60 1. Ropivacaine þ NS (30) 0.75% - 25 ml 50 mg Stimulator N/D
2. Ropivacaine þ Dex (30)
Bangera 201661 Forearm and hand Surgical 80 1. Ropivacaine þ NS (40) 0.5% - 40 ml 100 mg Stimulator N/D
2. Ropivacaine þ Dex (40)
Esmaoglu 20107 Forearm and hand Surgical 60 1. Levobupivacaine þ NS (30) 0.25% - 40 ml 100 mg Stimulator Duration of sensory
2. Levobupivacaine þ Dex (30) and motor block
Hanoura 201341 Forearm and hand Surgical 48 1. Bupivacaine þ NS (24) 0.5% - 39 ml 100 mg Stimulator N/D

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2. Bupivacaine þ Dex (24)
Karthik 201542 Forearm and hand Surgical 100 1. Levobupivacaine þ NS (50) 0.375% - 39 ml 1 mg/kg Landmark N/D
2. Levobupivacaine þ Dex (50)
Kaygusuz 201211 Forearm and hand Surgical 60 1. Levobupivacaine þ NS (30) 0.5% - 39 ml 1 mg/kg Stimulator Duration Of sensory block
2. Levobupivacaine þ Dex (30)
Lee 201621 Forearm and hand Surgical 51 1. Ropivacaine þ NS (17) 0.5% - 22 ml 100 mg Stimulator Duration of sensory block
2. Ropivacaine þ Dex (17)
3. Ropivacaine þ dexamethasone 10 mg (17) *
Zhang 201454 Forearm and hand Surgical 45 1. Ropivacaine þ NS (15) 0.33% - 40 ml 2. 50 mg Stimulator Duration of analgesia
2. Ropivacaine þ Dex 50 lg (15) 3. 100 mg
3. Ropivacaine þ Dex 100 lg (15)
 Perineural dexmedetomidine for brachial plexus block | 173

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 out-
comes, and dexmedetomidine-related complications.
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

Blinding of participants and personnel (performance bias)

Risk of bias assessment

Blinding of outcome assessment (detection bias)

Some of the studies reviewed lacked sufficient details to permit

Random sequence generation (selection bias)

full evaluation of the risk of bias; in such cases, we were conser-

Incomplete outcome data (attrition bias)

Allocation concealment (selection bias)
vative in our risk of bias evaluation by tending to classify trials

Selective reporting (reporting bias)

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 general-
izations 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

Other bias
considered to be at a high risk for selective reporting. The re-
viewers’ consensus assessment of the risk is detailed in Table 2.
Considering our conservative approach, and the fact that the Abdallah 2016 (64) + + + + + + +
main outcomes of interest, namely block characteristics, were
Agarwal 2014 (56) + ? ? + + + ?
less likely to be affected by the aforementioned biases, we con-
sidered the methodological quality for the majority of the 34 tri- Ammar 2012 (9) + + + ? + + +
als included to be acceptable, and rated the overall risk of bias
Arun 2016 (50) + ? ? ? ? – +
across the studies as moderate. Most of trials had low risk for
Bangera 2016 (61) + ? ? + ? + +
selection bias, attrition bias, and other biases; moreover, the
majority of trials were assigned unclear risk of selection and Bengisun 2014 (60) ? ? ? + + – +
performance bias, because authors did not provide sufficient Bharti 2015 (65) + + ? + + + +
details regarding blinding and concealment of sequence
Biswas 2014 (57) + ? + + + – +
allocation. Bias as a result of selective reporting was classified
as high in most of the trials, because of the aforementioned Das 2014 (28) + ? ? + + – ?
conservative approach in assessing the reporting of the Das 2016 (67) ? ? ? + + + +
dexmedetomidine-related haemodynamic side-effects. None of
Dixit 2015 (44) ? ? – – ? + +
the trials were quasi-randomized.
Esmaoglu 2010 (7) + ? ? ? + – +

Fritsch 2014 (55) + + + + + ? ?

Sensory block duration
Ghandi 2012 (10) ? ? ? + + – +
Data describing the primary outcome, sensory block duration
(time to full recovery from sensory block), were available from Gurajala 2015 (62) + ? + + + + –
all trials (910 patients in Dex group) except two,8 60 and are pre- Hanoura 2013 (41) – – – – – + ?
sented in Figure 2. Administering perineural dexmedetomidine
Karthik 2015 (42) – – ? ? + – –
as an LA adjunct to BPB prolonged sensory block duration com-
pared with Control. Expressed as lower CI [point estimate], the Kathuria 2015 (63) + ? ? + ? + +
prolongation was at least 44% [57%], (P < 0.0001, I2 ¼ 99%) for ISB; Kaur 2015 (45) + ? ? + + – +
54% [82%], (P < 0.0001, I2 ¼ 100%) for SCB; 21% [37%], (P < 0.0001,
Kaygusuz 2012 (11) + ? ? ? + ? +
I2 ¼ 75%) for ICB; and 34% [37%], (P < 0.0001, I2 ¼ 92%) for AXB. The
overall treatment effect for all levels of BPB suggested that dex- Khade 2013 (46) ? ? ? ? ? – ?

medetomidine prolonged sensory block duration by at least 57%
[65%], (P < 0.0001, I2 ¼ 100%), or by 3.8 h (from 7.7 h to 11.5 h).
The primary outcome results were characterized by signifi-
cant heterogeneity for all four subgroups. Performing meta-
Kumar 2014 (43) ? ? – – ? – ?
Kwon 2015 (58) + + ? ? + ? +
Lee 2016 (21) + ? ? ? + + +

regression analysis using the a priori pre-specified confounders,
namely the LA dose, dexmedetomidine dose, epinephrine dose,
Mirkheshti 2014 (59)
block localization technique, and nature of surgical anaesthetic,
yielded omnibus P-values of 0.047, 0.948, 0.37, 0.09, and 0.215, re-
spectively, 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
Manohar 2015 (22) ? ? ? ? ? ? ?
+ ? ? ? ? + +
Nema 2014 (47) ? ? ? ? + – ?
Patki 2015 (48) ? ? – – + – –
Rashmi 2016 (52) + ? ? ? + – ?
Saraf 2016 (53) ? ? ? ? ? – ?

analysis to assess the influence of potential selection bias intro- Singh 2016 (49) + ? ? ? + – ?
duced by including non-indexed trials. This analysis indicated
Song 2014 (66) ? – – – + – ?
that dexmedetomidine prolonged sensory block duration by at
least 46% [60], (P < 0.0001, I2 ¼ 99%) and 58% [70], (P < 0.0001, Tandon 2016 (51) ? ? ? ? + – +
I2 ¼ 100%) for the indexed and non-indexed trials, respectively. Zhang 2014 (54) + ? ? ? ? – ?
There was no difference between the two subgroups (P ¼ 0.3),

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 174 | Vorobeichik et al.

Ratio of means Ratio of means

Study or subgroup Ratio of means SE Weight IV, random, 95% CI IV, random, 95% CI
1.3.1 ISB
Fritsch 2014 (55) 1.2857 0.0085 3.3% 1.29 [1.27, 1.30]
Kumar 2014 (43) 2.2466 0.0689 3.0% 2.25 [2.11, 2.38]
Rashmi 2016 (52) 1.3673 0.0048 3.3% 1.37 [1.36, 1.38]
Subtotal (95% CI) 9.6% 1.57 [1.44, 1.69]
Heterogeneity: Tau2=0.01; χ2=239.51, df=2 (P<0.00001); I2=99%
Test for overall effect: Z=24.35 (P<0.00001)

1.3.2 SCB
Agarwal 2014 (56) 3.2181 0.0528 3.1% 3.22 [3.11, 3.32]
Bharti 2015 (65) 1.3636 0.0388 3.2% 1.36 [1.29, 1.44]
Biswas 2014 (57) 1.3922 0.0209 3.3% 1.39 [1.35, 1.43]
Das 2014 (28) 1.793 0.0425 3.2% 1.79 [1.71, 1.88]
Das 2016 (67) 1.5562 0.025 3.3% 1.56 [1.51, 1.61]
Dixit 2015 (44) 1.4009 0.029 3.2% 1.40 [1.34, 1.46]
Ghandi 2012 (10) 4.9993 0.0435 3.2% 5.00 [4.91, 5.08]
Gurajala 2015 (62) 2.119 0.0807 2.9% 2.12 [1.96, 2.28]
Kathuria 2015 (63) 1.7481 0.0773 2.9% 1.75 [1.60, 1.90]
Kaur 2015 (45) 1 0.0219 3.3% 1.00 [0.96, 1.04]
Khade 2013 (46) 2.0025 0.0453 3.2% 2.00 [1.91, 2.09]
Kwon 2015 (58) 1.4334 0.0528 3.1% 1.43 [1.33, 1.54]
Manohar 2015 (22) 1 0.0154 3.3% 1.00 [0.97, 1.03]
Nema 2014 (47) 1.4044 0.058 3.1% 1.40 [1.29, 1.52]
Patki 2015 (48) 1.2862 0.0084 3.3% 1.29 [1.27, 1.30]
Saraf 2016 (53) 1.5323 0.0319 3.2% 1.53 [1.47, 1.59]
Singh 2016 (49) 2.0937 0.057 3.1% 2.09 [1.98, 2.21]
Tandon 2016 (51) 1.4097 0.0155 3.3% 1.41 [1.38, 1.44]
Subtotal (95% CI) 57.1% 1.82 [1.54, 2.10]
Heterogeneity: Tau2=0.36; χ2=9789.54, df=17 (P<0.00001); I2=100%
Test for overall effect: Z=12.85 (P<0.00001)

1.3.3 ICB
Ammar 2012 (9) 1.4621 0.0269 3.2% 1.46 [1.41, 1.51]
Mirkheshti 2014 (59) 1.3139 0.135 2.4% 1.31 [1.05, 1.58]
Song 2014 (66) 1.2699 0.0654 3.0% 1.27 [1.14, 1.40]
Subtotal (95% CI) 8.7% 1.37 [1.21, 1.52]
Heterogeneity: Tau2=0.01; χ2=8.16, df=2 (P=0.02); I2=75%
Test for overall effect: Z=17.69 (P<0.00001)

1.3.4 AXB
Arun 2016 (50) 1.4236 0.0053 3.3% 1.42 [1.41, 1.43]
Bangera 2016 (61) 1.3699 0.0324 3.2% 1.37 [1.31, 1.43]
Esmaoglu 2010 (7) 1.318 0.0242 3.3% 1.32 [1.27, 1.37]
Hanoura 2013 (41) 1.0885 0.0456 3.2% 1.09 [1.00, 1.18]
Karthik 2015 (42) 1.4004 0.0024 3.3% 1.40 [1.40, 1.41]
Kaygusuz 2012 (11) 1.3905 0.0229 3.3% 1.39 [1.35, 1.44]
Lee 2016 (21) 1.8031 0.1171 2.6% 1.80 [1.57, 2.03]
Zhang 2014 (54) 1.447 0.1292 2.5% 1.45 [1.19, 1.70]
Subtotal (95% CI) 24.6% 1.37 [1.34, 1.40]
Heterogeneity: Tau2=0.00; χ2=89.31, df=7 (P<0.00001); I2=92%
Test for overall effect: Z=82.48 (P<0.00001)

Total (95% CI) 100.0% 1.65 [1.57, 1.73]

Heterogeneity: Tau2=0.05; χ2=10251.31, df=31 (P<0.00001); I2=100%
–2 –1 0 1 2
Test for overall effect: Z=40.09 (P<0.00001)
Favours control Favours dexmedetomidine
Test for subgroup differences: χ2=18.23, df=3 (P =0.0004); I2=83.5%

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.

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 Perineural dexmedetomidine for brachial plexus block
and heterogeneity remained high. Finally, the funnel plot did
not suggest significant publication bias (P ¼ 0.08) for our primary
outcome.
When the strength of the synthesized evidence was eval-
uated using the GRADE guidelines, there was high evidence that
mixing dexmedetomidine with long-acting LA used in a BPB, re-
gardless of the level, prolongs the duration of sensory block dur-
ation 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.
Block characteristics
The effect of perineural dexmedetomidine on motor block dur-
ation 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 dur-
ation by at least 26% [50%], (P < 0.0001, I2 ¼ 100%) for ISB; 61%
[90%], (P < 0.0001, I2 ¼ 100%) for SCB; 19% [38%], (P < 0.0001,
I2 ¼ 85%) for ICB; and 11% [35%], (P < 0.0001, I2 ¼ 100%) for AXB
(Fig. 3). The overall treatment effect for all levels of BPB sug-
gested that dexmedetomidine prolongs motor block duration by
at least 58% [68%], (P < 0.0001, I2 ¼ 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.
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 ¼ 0.003, I2 ¼ 99%) for ISB; 44%
[33%], (P < 0.0001, I2 ¼ 94%) for SCB; 38% [31%], (P < 0.0001, I2 ¼ 0%)
for ICB; and 24% [18%], (P < 0.0001, I2 ¼ 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 ¼ 98%), or from 20.0 min to
10.8 min. The level of evidence for this finding was rated as
moderate. (Table 3, Supplementary Fig. S1) The overall quality
assessment was downgraded by quality and consistency limita-
tions; 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 ¼ 96%) for SCB; 40% [31%], (P < 0.0001, I2 ¼ 0%)
for ICB; and 17% [15%], (P < 0.0001, I2 ¼ 26%) for AXB (Table 3).
Though both trials52 55 examining the effect of dexmedetomi-
dine 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 lev-
els of BPB suggested that dexmedetomidine shortened motor
block onset time by at least 39% [27%], (P < 0.00001, I2 ¼ 99%), or
from 21.2 min to 13.4 min. The level of evidence for this finding
was rated as moderate. (Table 3, Supplementary Fig. S2) The
overall quality assessment was downgraded by quality and con-
sistency limitations; but was also upgraded by the large treat-
ment effect.
Analgesic outcomes
The effect of perineural dexmedetomidine on duration of post-
operative 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
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| 175
was not defined in six trials.45 46 48 51–53 Dexmedetomidine pro-
longed the duration of analgesia by at least 60% [74%],
(P < 0.0001, I2 ¼ 100%) for ISB; 69% [91%], (P < 0.0001, I2 ¼ 100%) for
SCB; 0% [39%], (P < 0.0001, I2 ¼ 97%) for ICB; and 12% [33%],
(P < 0.0001, I2 ¼ 99%) for AXB (Table 3). The overall treatment ef-
fect for all levels of BPB suggested that dexmedetomidine pro-
longed the duration of analgesia by at least 63% [72%],
(P < 0.0001, I2 ¼ 100%), or from 7.5 h to 11.9 h. The level of evi-
dence for this finding was rated as moderate. (Table 3,
Supplementary Fig. S3) 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 re-
ported 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 ¼ 0.05, I2 ¼ 92%) and -11.6 mg [-15.6, -
7.6], (P < 0.0001, I2 ¼ 30%) for the ISB and SCB subgroups, respect-
ively. The overall treatment effect for these two levels of BPB
suggested that dexmedetomidine reduced postoperative anal-
gesic consumption by -10.2 mg [-15.3, -5.2], (P< 0.0001, I2 ¼ 83%)
of oral morphine equivalents. The level of evidence for this find-
ing 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 ¼ 0.03, I2 ¼ 0%) and 0.8 cm [1.6, 0.0], (P ¼ 0.04, I2 ¼ 0) for SCB
and AXB subgroups, respectively but there were no differences
in the ISB and ICB subgroups. The level of evidence for this find-
ing 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 re-
ported 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 fu-
ture was assessed in six trials.8 22 41 45 52 60 The proportion of pa-
tients with high satisfaction was greater among those who
received dexmedetomidine, with an OR [95% CI] of 2.5 [1.2, 5.3],
(P ¼ 0.02, I2 ¼ 49%), compared with Control. The level of evidence
for this finding was rated as very low. (Table 3) The overall qual-
ity 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 ¼ 0.0002,
I2 ¼ 70%); it also increased the odds of hypotension by an OR of
5.4 [2.7, 11.0], (P < 0.0001, I2 ¼ 0%). The level of evidence for these
findings was rated as moderate. (Table 3) The overall quality as-
sessment was downgraded by quality and consistency limita-
tions. 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 mg maximizes sensory
block duration (by at least 52% [61%], P < 0.0001), while minimiz-
ing the haemodynamic side-effects to none [i.e. by an OR of 1.7
by guest
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

on 26 September 2017
Time-to-event Number of References of studies Dex N Dex Control Control Ratio of Means P-Value for P-Value for I2 Test for Quality of
176

outcomes studies included Mean N Mean [95% Confidence statistical heterogeneity heterogeneity evidence
|

included Interval] significance (GRADE)

Sensory block 31 7, 9, 10, 11, 21, 22, 28, 41, 953 10.8 909 20.0 0.7 [0.6, 0.8] < 0.00001 < 0.00001 98% 丣丣丣両, Moderate
onset (min) 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55,
56, 58, 59, 60, 61, 62, 65,
67, 63
Sensory block 32 7, 9, 10, 11, 21, 22, 28, 41, 970 691.8 924 460.6 1.7 [1.6, 1.7] < 0.00001 < 0.00001 100% 丣丣丣丣, High
Vorobeichik et al.

duration (min) 42, 43, 44, 45, 46, 47, 48,

49, 50, 51, 52, 53, 54, 55,
56, 57, 58, 59, 61, 62, 63,
65, 66, 67
Motor block 27 7, 9, 10, 11, 22, 28, 42, 44, 860 13.4 815 21.2 0.7 [0.6, 0.9] < 0.00001 < 0.00001 99% 丣丣丣両, Moderate
onset (min) 45, 46, 47, 48, 49, 50, 51,
52, 53, 54, 55, 56, 58, 59,
61, 62, 63, 65, 67
Motor block 31 9, 7, 10, 11, 22, 28, 41, 42, 957 605.9 909 412.9 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% 丣丣丣丣, High
duration (min) 43, 44, 45, 46, 47, 48, 49,
50, 51, 52, 53, 54, 56, 57,
58, 59, 61, 62, 63, 64, 65,
66, 67
Duration of 26 7, 9, 10, 11, 22, 28, 41, 43, 787 716.5 754 452.4 1.7 [1.6, 1.8] < 0.00001 < 0.00001 100% 丣丣丣両, Moderate
analgesia (min) 45, 46, 47, 48, 49, 50, 51,
52, 53, 56, 57, 59, 61, 62,
63, 64, 65, 66
Analgesic Number of References of studies Dex N Dex Control Control Odds Ratio or P-Value for P-Value for I2 Test for Quality of
outcomes studies included (Mean N (Mean Weighed Mean[95% statistical heterogeneity heterogeneity evidence
included or n/N) or n/N) Confidence Interval) significance (GRADE)
Analgesic 8 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% 丣丣両両, Low
consumption
Rest pain scores 7 9, 28, 41, 55, 60, 64, 65 207 3.4 206 3.9 0.6 [-0.9, -0.3] 0.0002 0.5 0% 丣丣両両, Low
at 24 h (cm)
Dynamic pain 1 55 31 3.9 30 3.5 0.5 [-0.9, 1.8] 0.48 NA NA N/A
scores at 24 h (cm)

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Patient satisfaction 6 22, 41, 45, 52, 60, 64 183 151/183 186 124/186 2.5 [1.2, 5.3] 0.02 0.08 49% 丣両両両, Very low
Dex-related Number of References of studies Dex N Dex Control Control Odds Ratio or Weighed P-Value for P-Value for I2 Test for Quality of
adverse effects studies included (Mean N (Mean Mean[95% Confidence statistical heterogeneity heterogeneity evidence
included or n/N) or n/N) Interval) significance (GRADE)
Bradycardia 19 7, 10, 11, 21, 22, 42, 45, 49, 540 69/540 525 10/525 4.8 [1.2, 19.2] 0.03 0.001 66% 丣丣丣両, Moderate
51, 54, 56, 57, 58, 60, 61,
62, 63, 64, 65
Hypotension 14 7, 10, 11, 21, 42, 49, 54, 57, 410 50/410 395 15/395 5.4 [2.7, 11.0] < 0.00001 0.99 0% 丣丣丣両, Moderate
60, 61, 62, 63, 64, 65
Excessive sedation 8 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% 丣両両両, Very low
Hypoxemia 11 7, 11, 21, 22, 42, 49, 56, 57, 328 0/328 327 0/327 NA NA NA NA NA
61, 63, 65
PONV 15 7, 9, 11, 21, 22, 43, 51, 55, 386 19/386 386 43/386 0.4 [0.2, 1.0] 0.06 0.08 49% 丣丣両両, Low
56, 57, 60, 63, 64, 65
 Perineural dexmedetomidine for brachial plexus block | 177

Ratio of means Ratio of means

Study or subgroup Ratio of means SE Weight IV, random, 95% CI IV, random, 95% CI
1.4.1 ISB
Abdallah 2016 (64) 1.0649 0.0015 3.3% 1.06 [1.06, 1.07]
Kumar 2014 (43) 2.1685 0.0684 3.2% 2.17 [2.03, 2.30]
Rashmi 2016 (52) 1.3371 0.0068 3.3% 1.34 [1.32, 1.35]
Subtotal (95% CI) 9.9% 1.50 [1.26, 1.74]
Heterogeneity: Tau2=0.04; χ2=1782.28, df=2 (P<0.00001); I2=100%
Test for overall effect: Z=12.37 (P<0.00001)

1.4.2 SCB
Agarwal 2014 (56) 3.375 0.0386 3.3% 3.38 [3.30, 3.45]
Bharti 2015 (65) 1.3 0.0539 3.2% 1.30 [1.19, 1.41]
Biswas 2014 (57) 1.6406 0.0241 3.3% 1.64 [1.59, 1.69]
Das 2014 (28) 1.6892 0.0404 3.3% 1.69 [1.61, 1.77]
Das 2016 (67) 1.2078 0.0697 3.2% 1.21 [1.07, 1.34]
Dixit 2015 (44) 1.522 0.0282 3.3% 1.52 [1.47, 1.58]
Ghandi 2012 (10) 6.5561 0.0825 3.1% 6.56 [6.39, 6.72]
Gurajala 2015 (62) 2.1538 0.1221 2.9% 2.15 [1.91, 2.39]
Kathuria 2015 (63) 1.9456 0.0918 3.1% 1.95 [1.77, 2.13]
Kaur 2015 (45) 0.6627 0.0271 3.3% 0.66 [0.61, 0.72]
Khade 2013 (46) 1.9993 0.0452 3.3% 2.00 [1.91, 2.09]
Kwon 2015 (58) 1.2679 0.0587 3.2% 1.27 [1.15, 1.38]
Manohar 2015 (22) 1.2408 0.0293 3.3% 1.24 [1.18, 1.30]
Nema 2014 (47) 1.402 0.0668 3.2% 1.40 [1.27, 1.53]
Patki 2015 (48) 1.3144 0.0067 3.3% 1.31 [1.30, 1.33]
Saraf 2016 (53) 1.6442 0.0359 3.3% 1.64 [1.57, 1.71]
Singh 2016 (49) 1.9085 0.1034 3.0% 1.91 [1.71, 2.11]
Tandon 2016 (51) 1.5165 0.0209 3.3% 1.52 [1.48, 1.56]
Subtotal (95% CI) 58.0% 1.90 [1.61, 2.20]
Heterogeneity: Tau2=0.42; χ2=7985.11, df=17 (P<0.00001); I2=100%
Test for overall effect: Z=12.46 (P<0.00001)

1.4.3 ICB
Ammar 2012 (9) 1.4711 0.0336 3.3% 1.47 [1.41, 1.54]
Mirkheshti 2014 (59) 1.453 0.1482 2.7% 1.45 [1.16, 1.74]
Song 2014 (66) 1.2333 0.0551 3.2% 1.23 [1.13, 1.34]
Subtotal (95% CI) 9.2% 1.38 [1.19, 1.56]
Heterogeneity: Tau2=0.02; χ2=13.67, df=2 (P=0.001); I2=85%
Test for overall effect: Z=14.40 (P<0.00001)

1.4.4 AXB
Arun 2016 (50) 1.0065 0.0065 3.3% 1.01 [0.99, 1.02]
Bangera 2016 (61) 1.3546 0.0289 3.3% 1.35 [1.30, 1.41]
Esmaoglu 2010 (7) 1.3443 0.0274 3.3% 1.34 [1.29, 1.40]
Hanoura 2013 (41) 1.0519 0.0375 3.3% 1.05 [0.98, 1.13]
Karthik 2015 (42) 1.4849 0.003 3.3% 1.48 [1.48, 1.49]
Kaygusuz 2012 (11) 1.489 0.0245 3.3% 1.49 [1.44, 1.54]
Zhang 2014 (54) 1.7305 0.1021 3.0% 1.73 [1.53, 1.93]
Subtotal (95% CI) 22.9% 1.35 [1.11, 1.58]
Heterogeneity: Tau2=0.10; χ2=4582.20, df=6 (P<0.00001); I2=100%
Test for overall effect: Z=11.36 (P<0.00001)

Total (95% CI) 100.0% 1.68 [1.58, 1.79]

Heterogeneity: Tau2=0.09; χ2=27788.77, df=30 (P<0.00001); I2=100%
–2 –1 0 1 2
Test for overall effect: Z=30.83 (P<0.00001)
Favours control Favours dexmedetomidine
Test for subgroup differences: χ2=10.17, df=3 (P=0.02); I2=70.5%

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.

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 178 | Vorobeichik et al.
(0.3, 9.6), P ¼ 0.5 and OR of 6.9 (0.8, 60.8), P ¼ 0.08 for bradycardia
and hypotension, respectively]. (Supplementary Fig. S4)
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 un-
defined 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 ¼ 0.05,
I2 ¼ 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 sug-
gested that there was no statistically significant difference in
the incidence of PONV between the two groups. The level of evi-
dence for this finding was rated as low. The overall quality as-
sessment 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 dexmedeto-
midine as peripheral nerve block adjunct. Our updated review
demonstrates that using perineural dexmedetomidine as a BPB
adjunct is associated with important facilitatory effects regard-
less 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 dexmedetomi-
dine was also associated with increased risk of transient hypo-
tension, bradycardia, and postoperative sedation. The levels of
evidence relating to sensory block duration and duration of an-
algesia were high and moderate, respectively.
The observed differences in the magnitude of dexmedetomi-
dine effects on the various BPB levels may be attributed to in-
trinsic 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 find-
ings 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 desir-
able 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
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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 peri-
neural 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 perineu-
ral 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 haemo-
dynamic 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 pre-
cluded 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 sam-
ple sizes of 10-50 patients/group, which increases the chances
of type I error and publication bias. Fourth, only two trials origi-
nated from North America64 and Europe,55 which may represent
another source of publication bias.7778 Fifth, while a variety of
doses of dexmedetomidine were used, we could not detect a
dose-response, although evidence suggests that dexmedetomi-
dine 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 methodo-
logical shortcomings of studies and inconsistencies in the defin-
ition 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 out-
comes indicative of dexmedetomidine effectiveness (i.e. dur-
ations 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 ef-
fect, 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 lit-
erature 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
 Perineural dexmedetomidine for brachial plexus block
heterogeneity. These factors underscore the validity of our
findings.
Conclusion
Our study provides strong evidence that using perineural dex-
medetomidine 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
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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