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Locoregional anaesthesia

Efficacy and safety of dexmedetomidine in peripheral nerve blocks

A meta-analysis and trial sequential analysis

Schnabel, Alexander*; Reichl, Sylvia U.*; Weibel, Stephanie; Kranke, Peter; Zahn, Peter K.; Pogatzki-Zahn, Esther M.; Meyer-Frießem, Christine H.

Author Information
European Journal of Anaesthesiology: October 2018 - Volume 35 - Issue 10 - p 745-758
doi: 10.1097/EJA.0000000000000870

Abstract

Introduction

Continuous improvements in peripheral nerve blockade (e.g. using ultrasound-guided techniques) and the advantages of regional blocks (such as reduced side effects) compared with administration of systemic opioids, have strengthened postoperative pain management over recent years.1,2 Furthermore, it has been shown that peripheral regional anaesthetic techniques are used increasingly, but only 25% of peripheral nerve blocks are continuous.3,4 However, the duration of analgesia provided by single-shot nerve blocks is limited to 6 to 8 h, even if only long-lasting local anaesthetic drugs (e.g. bupivacaine or ropivacaine) are used. Therefore, in recent years, research has focused on possible perineural or intravenous adjuvants (opioids,5 dexamethasone6–9 and α2-agonists).

Dexmedetomidine (DEX), an α2-agonist with more promising pharmacokinetic and pharmacodynamic characteristics than clonidine,10,11 has been proved to have a positive effect on postoperative pain intensity and to reduce opioid consumption compared with a placebo when administered intravenously.12,13 In rats, DEX blocks the hyperpolarisation-activated cation current,14 and it also causes more a2-selective vasoconstriction than clonidine.15 Thus DEX might enhance the duration of analgesia when used as an adjunct to local anaesthetics. A preclinical safety trial in rats showed no histopathological damage following a high dose of perineural DEX in addition to bupivacaine in sciatic nerve blocks.16 Recently, three meta-analyses investigated the efficacy and safety of perineural DEX in combination with local anaesthetics versus local anaesthetics alone in brachial plexus blocks.17–19 However, all three meta-analyses can be criticised because insufficient data were analysed, the influence of zero events was not investigated and no trial sequential analysis was performed.

The present meta-analysis investigated the efficacy and safety of perineural DEX in combination with local anaesthetics versus local anaesthetics alone or in combination with intravenous DEX in all peripheral nerve blocks. The latter comparison might be relevant, because perineural (compared with intravenous) administration of DEX in combination with local anaesthetics in a sciatic nerve block produced a longer sensory block.20

Materials and methods

Systematic review and meta-analysis were performed according to the criteria of the PRISMA statement21 and the current recommendations of the Cochrane Collaboration.22 The present review was registered within the PROSPERO database after the beginning of the literature search (CRD42016042486).

Search strategy and study selection

Randomised controlled trials (RCTs) were identified in a systematic search of the data sources MEDLINE, CENTRAL and EMBASE (to May 2017) combining indexed and free text terms (‘dexmedetomidine’ or ‘regional analgesia’ or ‘nerve block’). Search terms were modified to the conditions of each database. Additional articles were checked from references of selected studies and ongoing registered trials on ‘www.clinicaltrials.gov’. There were no restrictions due to language or year of publication. Two reviewers (A.S., S.R.) independently reviewed titles and abstracts in order to exclude irrelevant studies. Differences in literature inclusion/exclusion were decided by consensus or discussed with a third review author (C.M.F.).

Inclusion criteria

We included all RCTs investigating the efficacy and safety of perineural DEX combined with local anaesthesia compared with local anaesthetics alone or local anaesthetics in combination with systemic DEX in peripheral nerve blocks. The following criteria for inclusion were used: prospective RCT, and human studies that included adult men or women (≥18 years) undergoing surgery.

Data collection, extraction and quality analysis

Two review authors (S.R., C.M.F.) independently extracted the data using a self-developed standardised data extraction form. If different doses of perineural DEX were investigated, we always decided to extract the results following the highest perineural DEX dose. At each step of data extraction, differences were discussed within the reviewers’ group.

A critical evaluation of study quality was performed by two reviewers (A.S., S.R.) using the Cochrane Collaboration's recommended tool for assessing risk of bias (sequence generation, allocation sequence concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, other potential threats to validity).

Definition of primary and secondary outcome parameters

The following parameters were defined as primary outcome parameters: duration of analgesia (h), number of patients with intraoperative bradycardia, number of patients with hypotension. Secondary outcomes were postoperative pain intensity (<2 h, 2 to 24 h, 24 to 48 h after surgery), onset of motor block or sensory block (min), duration of motor block (h), number of patients with opioid-related adverse events (nausea, vomiting, or nausea and vomiting), respiratory depression, pruritus, sedation or urinary retention.

Statistics

All statistical analyses were performed with the Review Manager (RevMan; Computer program; version 5.3.5; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) or as otherwise indicated.

Measures of treatment effects

For dichotomous data, we calculated the risk ratio with 95% confidence intervals (95% CIs), while for continuous endpoints, we calculated the mean difference with 95% CI. For the outcome ‘postoperative pain’, all results reported on different scales used to measure pain intensity were pooled. We used the standardised mean difference (SMD) as a summary statistic for pain intensity. For dichotomous and continuous data, we used the inverse variance fixed-effect or random-effects model. A number-needed-to-harm (NNH) was calculated for dichotomous outcomes, if more than at least two trials reported patients suffering from that adverse event and the result was significant.

Zero event handling

Computational problems can occur when no events are observed in one or both groups in an individual study.22 We performed a constant continuity correction of 1.0 (0.5 to each cell) for zero total event trials23 (TSA software v0.9.5.10 Beta; Copenhagen Trial Unit) and presented these results as sensitivity analysis.

Trial sequential analysis

For the primary outcomes, we performed a trial sequential analysis on the basis of all ‘low-risk of bias’ trials to calculate the required information size (RIS).24–27 The following assumptions (as defined in the protocol; a priori) were used to calculate the (heterogeneity-adjusted, D2) RIS and to construct the trial sequential monitoring boundaries by using the TSA software v.0.9.5.10 Beta (Copenhagen Trial Unit)28: a risk for a type I error of 5% and for a type II error of 10% (90% power), mean difference = 4 h with SD = 0.5 h (for duration of anaesthesia), RRR (relative risk reduction) = 10% and control event rate (CER) = 18% (for rate of intraoperative bradycardia) and CER = 60% (for rate of intraoperative hypotension). In a posthoc TSA, we calculated the RIS based on the empirical data from the meta-analyses for the outcome ‘intraoperative bradycardia’ (RRR = −115%, CER = 3.65%) and ‘intraoperative hypotension’ (RRR = −173%, CER = 16.05%), as the empirical data deviated strongly from the a-priori assumptions.

Heterogeneity, subgroup and sensitivity analyses

If data appeared to be clinically and statistically heterogeneous, we used a random-effect model. For all primary outcomes with significant summary treatment effect (95% CI) in random-effects meta-analysis, we additionally calculated the 95% prediction interval, which is an index of dispersion (based on the standard deviation) that tells us how widely the effects vary across the population.29,30 Furthermore, statistical heterogeneity was assessed with the I2 statistic and was rated as substantial if an I2 value higher than 50% was observed.31 To explore the effects of heterogeneity, the following subgroup analyses were performed for the primary outcome ‘duration of analgesia’, if more than five trials were included for the outcome: doses of perineural DEX (25, 50, 75, 100, 150 μg), type of local anaesthetics used (long-lasting versus short-lasting or mixture of local anaesthetics), addition of perineural adrenaline (1 : 200 000), location of nerve block, guiding method (landmark, nerve stimulation, ultrasound), anaesthetic technique (general anaesthesia combined with regional anaesthesia versus regional anaesthesia alone). If weight-based doses of DEX were used, we calculated the approximate dose according to the average weight mentioned in the trials and rounded up or down. In addition, sensitivity analyses were performed to detect the influence of study quality [high-quality trials (study quality rated as ‘low risk’ or ‘unclear risk’) versus low-quality trials (study quality rated as ‘high risk’)] and the impact of zero total event trials.

Assessment of reporting biases

We created funnel plots for outcomes including more than 10 trials by plotting effect estimates of included trials versus their precision (inverse of the standard error of point estimate). If asymmetry was suggested by visual assessment, we investigated funnel plot asymmetry by performing exploratory analyses (e.g. arcsine test for binary data, Egger's test for continuous data). To adjust for small-study effects, we used Duval and Tweedie's trim and fill method. We performed all statistical tests for publication bias using the R package.

Summary of findings

We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to rate the quality of evidence,32–39 associated with the primary outcomes in our review. The exact description can be found within the supplementary file (Supplemental Digital Content 1, http://links.lww.com/EJA/A169).

Results

The literature search identified 273 potential studies at the first stage but only 60 RCTs appeared to satisfied the inclusion criteria according to their title and abstract. Fourteen of these were subsequently excluded (Fig. 1).40–53

Fig. 1
Fig. 1:
Flow diagram of included and excluded randomised controlled trials (RCTs).

All 46 remaining studies were parallel group RCTs (Table 1). 54–99 All studies (3149 patients) investigated the efficacy of perineural administration of DEX and local anaesthetics in comparison with placebo and local anaesthetics. The DEX doses were 25,54–58 50,43,54,55,58–69 75,54,70 10071–80 or 150 μg.81 The other studies administrated DEX according to body weight (0.5, 0.75 or 1 μg kg−1).17,82–97 Two trials (107 patients) investigated the comparison of perineural DEX combined with local anaesthetics versus systemic DEX combined with local anaesthetics.63,98 In two studies, adrenaline (1 : 200 000) was given with the local anaesthetics.86,98 Although patients underwent surgery only under regional anaesthesia in 37 studies, nine studies used a combination of general and regional anaesthesia.54,60,62,81,82,87,95,96,98 Different nonopioid analgesics (paracetamol, traditional NSAIDs) were given in 18 out of 46 trials for rescue analgesia.55,56,60,61,63,64,66,67,72,74,75,78,84,86,89–92 In addition, five trials combined nonopioid analgesics with opioids57,65,83,88,98 and 13 trials reported that patients received only opioids for rescue analgesia.54,62,68,69,71,73,76,77,81,85,87,95,96 Nine authors reported no details about rescue analgesics.43,58,59,70,79,82,93,97,99 Finally, five of the included trials reported the use of a prophylactic drug for postoperative nausea and vomiting (PONV) (serotonin antagonists, steroid or droperidol).2,60,66,81,87

Table 1
Table 1:
Characteristics of included randomised controlled trials
Table 1
Table 1:
(Continued) Characteristics of included randomised controlled trials

The Cochrane Handbook for Systematic Review of Interventions was consulted to assess risk of bias among RCTs. All RCTs provided clear inclusion and exclusion criteria. The methodological quality assessment is summarised in Supplemental Digital Content 2, http://links.lww.com/EJA/A169. Most trials (29 out of 46) used an adequate randomisation method.54,55,59,62,63,68,69,73,74,76–78,80–83,85–90,92,93,95–99 Two trials reported no details about the randomisation method58,67; they were assessed as being at high risk of bias. Only 17 trials specified explicitly the method of allocation concealment (mainly via sealed envelopes).54,60,65,71,73,78,81–83,85,86,88,90,92,94,98,99 Double blinding (participants and personnel) was used in most RCTs (36 out of 46). Five of the included trials were assessed as having an unclear risk of bias.58,67,87,90,97 Five trials were rated as being at a high risk of detection bias because only participants were blinded91,99 or blinding was unclear.65,66,70 Only 22 trials describe the blinding of outcome assessment. Two trials were rated at a high risk, because blinding was unclear or missing.66,91 Twenty RCTs provided complete outcome data.54,57,60,62,66,67,69,74,76,77,79,81,83,86,88,89,92,94,97,99

Comparison of perineural dexmedetomidine combined with local anaesthetics versus local anaesthetics alone

Primary outcomes

Thirty-two trials investigated the outcome ‘duration of analgesia’.54–56,58,59,61,63–75,77–79,83,85,87,88,91,92,95–98 Eight of these 32 trials were not included in the meta-analysis,65–67,70–72,74,96 because they did not state that data were reported as mean and standard deviation. The exact definitions of duration of analgesia can be seen in Supplemental Digital Content 3, http://links.lww.com/EJA/A169. Three trials did not define the duration of analgesia explicitly.64,68,78 The random-effects meta-analysis of 24 trials with 1510 participants demonstrated that participants receiving 25 to 100 μg of perineural DEX in combination with local anaesthetics had a 4.87 hours longer duration of analgesia than those treated only with local anaesthetics (95% CI 4.02 to 5.73; P < 0.00001, Fig. 2).

Fig. 2
Fig. 2:
Forest plot for the outcome ‘duration of analgesia’ in patients treated with perineural dexmedetomidine (Dex) combined with local anaesthetic versus local anaesthetic alone.

Significant heterogeneity influenced this result (I2 = 100%). However, the 95% prediction interval did not include the line of equality (95% prediction interval 0.52 to 9.23) indicating that perineural DEX will be beneficial and prolong analgesia when applied in at least 95% of individual study settings (Supplemental Digital Content 4, http://links.lww.com/EJA/A169). In consideration of the high statistical heterogeneity (I2 = 100%), we performed subgroup analyses. Heterogeneity was not reduced below an I2 of 50% in any of the subgroups with more than two trials (Supplemental Digital Content 5, http://links.lww.com/EJA/A169). The test for subgroup differences reached statistical significance in case of type of local anaesthetics (P < 0.001), nerve block location (P < 0.00001) and guiding technique (P = 0.02) (Supplemental Digital Content 5, http://links.lww.com/EJA/A169).

The effect estimate remained robust in a sensitivity analysis excluding high risk of bias trials56,58,59,61,64,68,73,78,79,91 (mean difference 4.29 h, 95% CI 3.19 to 5.40, 14 trials, 923 patients).54,55,63,69,75,77,83,85,87,88,92,95,97,98 However, the effect estimate changed when the fixed effect model was applied (mean difference 2.32 h, 95% CI 2.28 to 2.36) (Supplemental Digital Content 4, http://links.lww.com/EJA/A169).

Trial sequential analysis for duration of analgesia with a-priori defined assumptions (which were similar to the empirical result of the meta-analysis) and with only low risk of bias trials (14 trials, n = 923) revealed a RIS of 571 participants, indicating that firm evidence was reached with respect to the sample size (Supplemental Digital Content 6, http://links.lww.com/EJA/A169).

There was a discrepancy between funnel plots using random-effects and fixed-effect models. The linear regression test suggested funnel plot asymmetry (P = 0.0059) and the adjusted effect estimate with trim and fill analysis (with 12 studies added) suggested a smaller mean difference in the duration of analgesia (mean difference 2.02 h, 95% CI 1.15 to 2.88).

We graded the quality of the evidence for the outcome ‘duration of analgesia’ as ‘moderate’ (downgrade for inconsistency).

The other primary outcomes, the most common adverse events following DEX administration, intraoperative bradycardia and hypotension, were reported by 30 (1729 patients)54–56,59–64,66,69,70,72,74–76,78–80,83–86,88,92–95,97,98 and 25 (1369 patients)54,56,59–64,66,69,70,72,73,75,76,78,80,83–86,88,92,97,98 of the included trials, respectively. The meta-analysis showed an approximately three times higher risk of intraoperative bradycardia (risk ratio 2.83; 95% CI 1.50 to 5.33; P = 0.035; I2 = 40%; NNH = 12.5; Fig. 3) and hypotension (risk ratio 3.42; 95% CI 1.24 to 9.48; P = 0.002; I2 = 65% NNH = 25; Fig. 4) with perineural DEX. Meta-analyses including all trials with double zero cell frequencies (continuity correction of 0.5) revealed a relative risk of bradycardia of 2.01 (95% CI 1.27 to 3.19) and for hypotension of 1.49 (95% CI 0.94 to 2.38) with perineural DEX.

Fig. 3
Fig. 3:
Forest plot for the outcome ‘number of patients with intraoperative bradycardia’ in patients treated with perineural dexmedetomidine combined with local anaesthetic versus local anaesthetic alone.
Fig. 4
Fig. 4:
Forest plot for the outcome ‘number of patients with intraoperative hypotension’ in patients treated with perineural dexmedetomidine combined with local anaesthetic versus local anaesthetic alone.

The meta-analysis for intraoperative hypotension (without double zero event trials) was influenced by heterogeneity (I2 = 40%; I2 = 65%), which was reduced by inclusion of double zero event trials to 11 and 6%, respectively. The 95% prediction interval crossed the line of equality and the range of effects ranged from benefit to harm for bradycardia (95% prediction interval 0.47 to 17.07) and for hypotension (95% prediction interval 0.19 to 62.95). The subgroup analyses investigating possible reasons for the heterogeneity of intraoperative hypotension showed that the addition of perineural adrenaline might have influenced the result (P < 0.001; I2 = 94.8%) (Supplemental Digital Content 7, http://links.lww.com/EJA/A169).

We analysed only trials that reported patients with intraoperative bradycardia or hypotension requiring active treatment. The pooled analysis of 13 trials55,61,64,68,69,72,74,76,80,92–94,98 revealed a two times higher risk of intraoperative bradycardia requiring treatment following perineural DEX administration in combination with local anaesthetics compared with local anaesthetics alone (risk ratio 2.46; 95% CI 1.22 to 4.96; P = 0.01; I2 = 9%; NNH = 20). In contrast, the pooled risk of six trials62–64,66,88,98 for intraoperative hypotension with the need for active treatment was not significantly different between DEX and local anaesthetics compared with local anaesthetics alone (risk ratio 2.54; 95% CI 0.64 to 10.16; P = 0.19; I2 = 50%, NNH = 16.7).

The effect estimates for bradycardia and hypotension did not remain robust in a sensitivity analysis excluding high-risk trials, with risk ratio 2.16 (95% CI 1.00 to 4.67)54,55,69,72,74–76,80,88,93,94,98 and risk ratio 2.73 (95% CI 0.75 to 10.00),54,63,80,88,98 respectively.

Trial sequential analysis for bradycardia with both a-priori defined assumptions and assumptions based on the empirical meta-analysis (including only low risk of bias trials with events in at least one arm) revealed RIS of 80 032 and 5139 participants, respectively, indicating that insufficient evidence was reached with respect to the sample size. Trial sequential analysis for hypotension resulted in a RIS of 31 510 and 4584 participants with a-priori and empirical assumptions, respectively. In this case, evidence was also insufficient.

Funnel plots and explorative analyses for bradycardia and hypotension did not reveal funnel plot asymmetry.

We graded the quality of the evidence for the outcomes ‘bradycardia’ and ‘hypotension’ as ‘very low’ (downgrade for risk of bias, inconsistency and imprecision).

Secondary outcomes

Seven trials investigated the postoperative pain intensity at the earliest time point (<2 h) (474 patients).57,58,60,89,90,95,98 The meta-analysis showed no significant differences between participants treated with perineural DEX combined with local anaesthetics compared with local anaesthetics alone (SMD −0.16 points; 95% CI −1.73 to 1.41; P = 0.84; I2 = 97%). The same holds true for the other time point reported in six included trials (429 patients)57,60,81,87,90,95 (SMD2–24 h −0.42 points; 95% CI −1.01 to 0.18; P = 0.17; I2 = 87%). Only one trial (60 patients) reported data for the last time point (24 to 48 h) and again showed no significant differences between patients treated with perineural DEX combined with local anaesthetics compared with local anaesthetics alone.83

In all, 34 trials (2058 patients)54–61,63–70,72–75,77–80,83–85,88,89,91–93,97,98 investigated the duration of motor blockade defined as the time interval between the end of the injection and complete recovery of motor function (Supplemental Digital Content 3, http://links.lww.com/EJA/A169). Patients receiving perineural DEX combined with local anaesthetics reported a longer duration of motor blockade than patients treated with local anaesthetics only (mean difference 3.92 h; 95% CI 3.17 to 4.67; P < 0.00001; I2 = 100%). Results of the meta-analyses ‘onset of motor or sensory blockade’ can be found in Supplemental Digital Content 8, http://links.lww.com/EJA/A169.

The most common adverse events were postoperative nausea (PON), postoperative vomiting (POV), PONV and respiratory depression. No patient with respiratory depression was reported in 18 trials (1095 patients),54,59,63,64,66,69,73,75,76,78,79,83–86,88,92,93 but the meta-analyses focusing on PON (13 trials; 785 patients),59–61,63,72,73,75,78,79,82,92,95,96 POV (12 trials; 734 patients)59–61,63,72,73,75,78,79,92,95,96 and PONV (11 trials; 586 patients)64,66,70,71,76,78,82,83,86,88,98 showed no significant difference between patients treated with perineural DEX combined with local anaesthetics versus local anaesthetics (Supplemental Digital Content 9, http://links.lww.com/EJA/A169). The same holds true for the other meta-analyses investigating the risk for pruritus (six trials; 323 patients)66,70–72,78,83 and sedation (nine trials; 591 patients64,66,69,70,78,79,83,86,89 (Supplemental Digital Content 9, http://links.lww.com/EJA/A169). No patient with urinary retention was reported within three trials including 167 participants.72,78,96

Comparison of perineural dexmedetomidine combined with local anaesthetics versus systemic DEX combined with local anaesthetics

Because only two trials (107 patients) investigated the comparison ‘perineural DEX combined with LA versus systemic DEX combined with LA’, meta-analyses could be performed only for a low number of outcomes.63,98

Primary outcomes

The included trials defined the duration of analgesia as ‘time to first analgesic request’63 or ‘time to first pain’.98 The pooled analysis showed that there was a significant difference between the duration of analgesia between 53 participants treated with less than 0.05 mg of perineural DEX combined with local anaesthetics compared with 54 patients receiving local anaesthetics only (mean difference 0.98 h; 95% CI −0.12 to - 2.08; P = 0.08; I2 = 0%). Due to the limited number of included trials, sensitivity analyses and funnel plot analysis were not performed.

Both trials reported data for bradycardia and hypotension, but there were no differences between the risk for intraoperative bradycardia (risk ratio 0.47; 95% CI 0.11 to 1.97; P = 0.3; I2 = 0%) or hypotension (risk ratio 0.77; 95% CI 0.5 to 1.18; P = 0.23; I2 = 0%) between groups.63,98 Only one trial reported the more specific outcome ‘number of patients with intraoperative bradycardia, respectively hypotension requiring treatment’ and again showed no significant difference between the groups.98

Secondary outcomes

The two included trials investigated only the outcome duration of motor blockade, defined as return to normal or presurgical strength in the arm,98 and the recovery of complete motor power of the hand and forearm.63 The meta-analysis showed a significantly longer duration of motor blockade in patients receiving perineural DEX combined with local anaesthetics compared with systemic DEX combined with local anaesthetics (mean difference 2.19 h; 95% CI 0.67 to 03.7; P = 0.005; I2 = 0%).

Discussion

The present meta-analysis indicates that use of DEX as an adjuvant to long-lasting local anaesthetics significantly prolongs the duration of analgesia by around 5 h following peripheral regional anaesthesia, but is associated with three times higher risks of intraoperative bradycardia and hypotension. However, the meta-analysis demonstrated that the duration of analgesia and the risks of intraoperative bradycardia or hypotension might not differ between patients treated with perineural or systemic DEX combined with local anaesthetics.

Efficacy of perineural dexmedetomidine in peripheral nerve blocks

The present meta-analysis demonstrated that the duration of analgesia is prolonged by around 5 h, if 25 to 150 μg DEX is added perineurally. In contrast to other meta-analyses,17–19 we excluded trials if data were not explicitly reported as mean and SD or 95% CI. However, we showed for the first time within the TSA (accounting for heterogeneity) that the evidence is powered sufficiently by a large number of trials so that RCTs should not investigate the duration of analgesia following perineural DEX combined with local anaesthetics compared with local anaesthetics alone in the future.

The subgroup analyses demonstrated that the duration of analgesia might be longer if DEX is used in combination with long-lasting local anaesthetics (instead of short-lasting local anaesthetics or a local anaesthetic mixture), for supraclavicular or femoral nerve blocks (compared with interscalene, infraclavicular, axillary nerve blocks, transversus abdominis plane blocks and eye blocks) or blocks that were performed guided by ultrasound (compared with nerve stimulation or a landmark technique). We could not demonstrate a DEX dose-related difference for the duration of analgesia, in contrast to another meta-analysis.17 However, a RCT in volunteers not only showed a significant dose-dependent increase in mean duration of sensory block but also dose-dependent prolonged sedation following perineural DEX use combined with ropivacaine 0.2%.92,100 These authors concluded that 100 μg of perineural DEX might offer the best risk–benefit profile. Another clinical study showed that the addition of perineural DEX decreased the median effective dose of lignocaine required for an obturator nerve block in patients undergoing resection of bladder tumours.42,50 However, the latter results should be confirmed in more common nerve blocks (e.g. femoral or axillary nerve blocks).

We showed a significant prolongation of motor blockade following the perineural administration of DEX. This difference (∼4 h) might be clinically relevant if it delays discharge following outpatient surgery. Nevertheless, those results were influenced by significant heterogeneity and should be viewed with caution.

We investigated for the first time the comparison of perineural versus intravenous DEX administration in combination with local anaesthetics, but there was no significant difference for the duration of analgesia. This is confirmed by a recent RCT in volunteers,20 which showed that DEX as an adjuvant might have a peripheral action, but the observed difference might show no clinical relevance. However, our results were limited by the small number of trials, and there is a need for more RCTs investigating this aspect in the future.

Safety of perineural dexmedetomidine in peripheral nerve blocks

Because perineural administration of DEX is an off-label use, reporting of possible adverse events and an appropriate risk–benefit analysis are crucial before using DEX as an adjuvant in everyday regional anaesthesia. We showed that the risk for intraoperative hypotension or bradycardia is around three times higher in patients treated with perineural DEX compared with placebo. The results for intraoperative bradycardia were comparable with other systematic reviews.17,19

However, because one-third of the included trials reported zero events in treatment and control groups, we investigated this fact in a specific sensitivity analysis and revealed only around a two times higher risk of intraoperative bradycardia, while the risk for intraoperative hypotension was not significantly different between treatment and control groups. This result was confirmed in the sensitivity analysis, including only trials that specifically stated the number of patients with intraoperative bradycardia and hypotension with the need for active treatment. However, the TSA clearly showed that the overall number of patients analysed is too low to obtain a clear view of the evidence.

Interestingly, there was no significant difference in the risks of intraoperative bradycardia or hypotension in the meta-analyses of the two trials which compared perineural versus systemic DEX in combination with local anaesthetics for peripheral nerve blockade.

Taken together, according to the GRADE approach, the overall quality of evidence for the risk of intraoperative bradycardia or hypotension was rated as very low (Supplemental Digital Content 10, http://links.lww.com/EJA/A169). There is an urgent need for large RCTs focusing on these adverse events before perineural DEX is used in every patient receiving regional anaesthesia.

Other adverse events were reported in only a small number of included trials and there were no significant differences in the risks of PON, POV, PONV, respiratory depression, pruritus, sedation and urinary retention between patients treated with perineural DEX or placebo.

Finally, an important issue of perineural adjuvants is the risk of neurotoxicity. After an injection at the sciatic nerves of rats, several preclinical studies suggested that the combination of perineural DEX with bupivacaine or ropivacaine did not cause more significant histopathological changes compared with administration of ropivacaine93,101 or bupivacaine16,94,95,102,103 alone. Moreover, these studies revealed that perineural DEX reduced the local anaesthetic induced inflammatory effects.94,102 Therefore, the use of perineural DEX might be protective against local anaesthetics induced nerve damage. Within our meta-analysis, no trial reported any case of possible nerve damage, but the duration of the follow-up was no longer than 2 weeks.

The most important limitation is the large heterogeneity of the meta-analysis investigating the primary outcomes ‘duration of analgesia’ and ‘intraoperative hypotension’ for the comparison of perineural DEX in combination with local anaesthetics versus local anaesthetics alone. Accordingly, we performed a number of subgroup and sensitivity analyses and identified a number of possible influencing factors (e.g. nerve block location), which should be studied more closely in the future. In contrast to the previously published meta-analyses,17–19 we calculated the 95% prediction interval for all primary outcomes, in order to obtain a better view of treatment effects, and showed less pronounced effects. Finally, we cannot exclude that different definitions describing primary and secondary outcomes might have influenced our results, but there is currently no ‘gold standard’ for the description of regional anaesthesia outcomes.96,104

In conclusion, the present meta-analysis of 46 RCTs demonstrated that perineural DEX in combination with local anaesthetics led to a longer duration of analgesia compared with the use of local anaesthetics alone (moderate quality evidence). However, it was associated with increased risks of intraoperative bradycardia or hypotension (both very low quality evidence). In contrast, there was no significant difference between perineural or systemic application of DEX in combination with local anaesthetics. As the perineural injection of DEX is currently off-label in peripheral regional anaesthesia, there is a need for trials focusing on adverse events following perineural DEX to better define patients at a high risk of intraoperative bradycardia or hypotension.

Acknowledgements relating to this article

Assistance with the study: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Presentation: preliminary data from this study were presented as a poster presentation at the Congress of the German Society of Anaesthesiology and Intensive Care Medicine ‘DAC 2017’, 3 to 5 May 2017, Nürnberg, Germany.

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* Both Alexander Schnabel and Sylvia U. Reichl contributed equally to this study.

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