Eur J Anaesthesiol 2015; 32:751–758
ORIGINAL ARTICLE
Combination of dexamethasone and local anaesthetic solution in peripheral nerve blocks A meta-analysis of randomised controlled trials Thi Mum Huynh, Emmanuel Marret and Francis Bonnet BACKGROUND Dexamethasone decreases postoperative pain and prolongs the duration of local anaesthetic peripheral nerve blocks in studies including a limited number of patients. OBJECTIVE The objective of this study is to evaluate the effect of combining dexamethasone with local anaesthetic on sensory and motor peripheral nerve blockade in adults. DESIGN A systematic review with meta-analysis of randomised controlled trials. DATA SOURCES We systematically searched in Medline, Embase, Google Scholar and Cochrane Controlled Trials Register up to December 2013. ELIGIBILITY CRITERIA Randomised trials testing dexamethasone combined with local anaesthetic. RESULTS Twelve trials (1054 patients, 512 receiving perineural dexamethasone) were included. Ten studies evaluated dexamethasone for brachial plexus nerve block. Four to 10 mg dexamethasone-containing local anaesthetic solutions had a faster onset of action and resulted in a
significant increase in the duration of analgesia [weighted mean difference (WMD) 351 min, 95% confidence interval (95% CI) 288 to 413, P < 0.001] and motor blockade (WMD 277 min, 95% CI 167 to 387, P < 0.001) compared with local anaesthetic solutions alone. Time to onset of sensory and motor blocks was significantly reduced with dexamethasone (WMD 78 s, 95% CI 112 to 44, and 90 s, 95% CI 131 to 48, respectively). Dexamethasone significantly decreased postoperative nausea and vomiting (PONV, 9 vs. 27%, relative risk 0.36, 95% CI 0.19 to 0.70). Subgroup analyses showed that dexamethasone approximately doubled the duration of postoperative analgesia when it was combined with intermediate-acting (lidocaine, mepivacaine) or long-acting (bupivacaine, ropivacaine) local anaesthetics. CONCLUSION Combining dexamethasone with local anaesthetics results in a prolongation of the duration of peripheral nerve block. Published online 13 March 2015
Introduction Dexamethasone is commonly used in anaesthesia to prevent postoperative nausea and vomiting (PONV).1 Two recent meta-analyses have documented that dexamethasone also reduced postoperative pain and opioid requirement.2,3 Intravenous dexamethasone has also been shown to improve postoperative pain control in patients receiving spinal or epidural morphine.4 Hong et al.5 reported that intravenous dexamethasone in combination with a caudal block with ropivacaine prolonged the duration of postoperative analgesia without adverse effects in children undergoing orchidopexy. Experimentally, dexamethasone combined with local anaesthetic may also reinforce peripheral nerve block. In animals,
bupivacaine-dexamethasone microspheres prolonged the duration of rat sciatic nerve or sheep intercostal nerve blocks.6,7 In healthy volunteers, dexamethasone combined with bupivacaine in microspheres also prolonged the duration of analgesia after peripheral nerve block.8,9 In agreement with these results, several studies performed in a small series of patients have found an increase in the duration of sensory blockade when dexamethasone was used in combination with local anaesthetic in peripheral nerve blocks. Consequently, we sought to perform a meta-analysis of the published randomised trials assessing the clinical
From the Department of Anaesthesiology and Intensive Care, Tenon Hospital, Assistance Publique Hoˆpitaux de Paris, Pierre and Marie Curie University, Paris, France Correspondence to Dr Emmanuel Marret, MD, PhD, France American Hospital of Paris, 63 Bd Victor Hugo, 9220 Neuilly-sur-Seine, France E-mail: [email protected] 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000248
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
752 Huynh et al.
effect of combining dexamethasone with local anaesthetic on sensory and motor blockade, onset time and side effects for peripheral nerve blocks performed in adults.
Materials and methods This meta-analysis is reported according to PRISMA recommendations for meta-analysis. A protocol for this study was not registered. A wide search strategy was used to retrieve relevant reports in Embase, Medline, Cinhal, Biosis, Central and Google Scholar. The searching terms ‘dexamethasone’, ‘nerve block’, ‘local anaesthetic’, ‘lidocaine’ or ‘lignocaine’, ‘mepivacaine’, ‘bupivacaine’, ‘ropivacaine’, ‘levobupivacaine’, ‘chloroprocaine’, ‘articaine’, ‘prilocaine’ and ‘adjuvants’ were combined. Additional articles were retrieved through hyperlinks and by manually searching reference lists in original published articles, review articles and correspondence. We completed our research by consulting abstracts, published or not, presented at the American Society of Anesthesiologists, European Society of Anaesthesiology and Socie´te´ Francaise d’Anesthe´sie-Re´animation meetings from 2000 to 2012. The last electronic research was in December 2013. There was no language restriction. Authors were contacted for additional information on methods and results when required. The following inclusion criteria were applied: randomised treatment allocation; comparison of dexamethasone added to a local anaesthetic (experimental intervention) with the same local anaesthetic regimen without dexamethasone (control intervention); peripheral singleinjection nerve or plexus block; and adults undergoing surgery. When other adjuvants were added to local anaesthetic (for instance epinephrine), the data were considered if the comparison was strictly controlled (i.e. both experimental and control groups received the same regimen excepted for dexamethasone). Exclusion criteria were continuous local anaesthetic administration or repeated injection; intravenous regional anaesthesia (Bier’s block); dexamethasone administered only intravenously; local anaesthetics used in microspheres; healthy volunteers; children (younger than 18 years); and animal studies. To overcome random play of chance on estimation of treatment effects, we excluded studies with fewer than 10 participants per group. The primary evaluation criterion was the duration of analgesia defined as the delay before the first request for analgesics. Other endpoints were duration of motor blockade and onset time of sensory and motor blockades, postoperative pain scores at 24 and 48 h, PONV and dexamethasone-related side effects such as infection, neurological complications or haematoma.
One author (T.H.) extracted relevant information from original reports. A second author (E.M.) checked all extracted data. Discrepancies were resolved by discussion with the third author (F.B.). When continuous data were not reported as mean SD, we computed them whenever feasible. Quality of data reporting was assessed using the Cochrane Collaboration’s tool for assessing risk of bias in randomised trials evaluating selection, performance, detection, attrition and reporting bias. The risk of bias was classified as ‘low risk’, ‘high risk or ‘unclear risk’ according to the recommendations of Higgins et al.10 Each article was also scored using the Oxford Modified Scale, an eight-point (0 to 7) scale evaluating randomisation, blinding and completeness of patient follow-up. The lowest possible score was 1.11 Statistical analysis
When not reported in the article, we considered that an intention-to treat analysis was performed on the original data. For continuous data, mean differences with 95% confidence interval (95% CI) were first calculated for each individual study. A weighted mean difference (WMD) was computed to summarise the overall effect. A random effects model was used when the test for heterogeneity was significant (P < 0.10). To explore the effect of dexamethasone in different settings (subgroup analyses), we compared the degree of efficacy of dexamethasone in combination with intermediate and long-acting local anaesthetics. For dichotomous endpoints, the Mantel-Haenszel like procedure for relative risk (RR) was used to pool RRs of individual studies. For all pooled RRs reaching statistical significance, we computed the number needed to treat (NNT) as the inverse of the difference of the proportion of patients who had any event in the dexamethasone group and the control group. CIs of the NNT were constructed by inverting and exchanging the limits of the 95% CI for the RR. The NNT and 95% CI were calculated with the internetbased program Visual Rx (http://www.nntonline.net/). Analyses were performed using Review Manager (Computer program, version 5.1.6; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark, 2011).
Results Of 1568 retrieved titles, 17 were potentially relevant (Fig. 1). We excluded five studies. One was performed in healthy volunteers. The second study evaluated chronic pain. Three abstracts were excluded because of missing relevant information. We eventually analysed data from 12 randomised trials including 13 comparisons (1054 patients, 512 receiving dexamethasone). Ten studies evaluated dexamethasone in brachial plexus nerve blocks (five supraclavicular block, four interscalene block and one axillary block)12–21 and two in other peripheral nerve blocks (perineal block and transversus
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Dexamethasone and peripheral nerve block 753
Fig. 1
Embase
Medline
Cinhal
Biosis
Central
Google scholar
ASA/SFAR abstracts
1568 hits Inadequate reference (n = 1551) Potentially relevant RCTs (n = 17) Healthy volunteers (n = 1) Chronic pain (n = 1) Lack of information (n = 3) Valid RCTs (1054 patients, 512 received perineural dexamethasone) (n = 12)
Bupivacaine (n = 6)
Ropivacaine (n = 2)
Lidocaine (n = 3)
Mepivacaine (n = 1)
Lidocaine + Bupivacaine (n = 1)
Flowchart of process selection. RCT, randomised controlled trial; n, number of manuscripts. One trial had four arms: bupivacaine and placebo, bupivacaine and dexamethasone, ropivacaine and placebo, ropivacaine and dexamethasone.
abdominis plane block).22,23 All the nerve blocks were performed as a single injection in patients undergoing upper limb surgery (10 trials, four performed in patients scheduled for shoulder surgery), haemorrhoidectomy or abdominal hysterectomy. General anaesthesia was combined with regional anaesthesia in seven trials (shoulder surgery, haemorrhoidectomy and hysterectomy). Dexamethasone was combined with intermediate-acting local anaesthetic [lidocaine alone (three studies), mepivacaine (one study)] or long-acting local anaesthetics [ropivacaine (two studies), bupivacaine (six studies), combination of lidocaine and bupivacaine (one study)]. Eleven trials evaluated a single dose of dexamethasone (8 mg in nine studies; 10 or 4 mg in one study each). One trial compared two doses of dexamethasone (8 vs. 4 mg). Two trials had three arms comparing intravenous dexamethasone, perineural dexamethasone and placebo (Table 1). Dexamethasone was compared with tramadol in one trial and with epinephrine in another.19,21 Some patients had a failed block and data were not reported for some outcomes. The procedure of randomisation was adequately described in 10 trials (83%). Concealment of treatment allocation was described in 10 trials (83%) (Table 2). Nine studies were double-blinded (75%). Follow-up was completed in 11 trials. The median quality score was six (range 2 to 7). Duration of postoperative analgesia
Duration of analgesia, defined as the time before the first analgesic administration, was reported in all studies
(n ¼ 874 patients; Fig. 2). All comparisons were significantly in favour of dexamethasone. In controls, the median time to first postoperative analgesic administration was 325 min (range 98 to 888 min). Dexamethasone significantly increased the duration of analgesia to about 351 min (95% CI 288 to 413, P < 0.001). This result remained statistically significant when only studies using upper extremity nerve blocks were pooled (WMD 420 min, 95% CI 326 to 511, P < 0.001). Duration of motor blockade
Duration of motor blockade was reported in five trials.12,15,17,18,21 Four comparisons were significantly in favour of dexamethasone, and the difference was not significant in one trial. In controls, the median duration of motor blockade was 202 min (range 130 to 1500 min). Dexamethasone significantly increased the duration of motor blockade (WMD 278 min, 95% CI 168 to 389, P < 0.001) (Fig. 3). Subgroup analyses
Subgroup analyses were performed to test the impact of adding dexamethasone to intermediate-acting (four trials, n ¼ 207) and long-acting (eight trials, n ¼ 667) local anaesthetics (Fig. 2). Median duration of analgesia in the control groups was 167 min (range 98 to 228 min) with intermediate-acting local anaesthetic solutions and 708 min (range 162 to 888 min) with long-acting local anaesthetic solutions. Dexamethasone approximately doubled (Fig. 2) the duration of postoperative analgesia in combination with all tested local anaesthetic solutions. Similarly, dexamethasone increased the duration of motor block of
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
754 Huynh et al.
Table 1
Characteristics of clinical trials included in the meta-analysis Number of Quality patients scorea Nerve block
Author Abdelmonem and Rizk23
a
60
2/1/2/1
Dose of dexamethasone Local anaesthetics
Perianal
8 mg
Ammar and Mahmoud22
60
2/1/3/1
Transversus 8 mg abdominis plane
Biradar et al.12
60
2/0/3/1
Supraclavicular
8 mg
Cummings et al.14
218
2/1/3/1
Interscalene
8 mg
Desmet et al.13
150
2/1/3/1
Interscalene
10 mg
Golwala et al.20
60
1/0/0/1
Supraclavicular
8 mg
Movafegh et al.15
60
2/1/3/0
Axillary
8 mg
Parrington et al.16
58
2/1/3/1
Supraclavicular
8 mg
Shrestha et al.21
60
2/1/3/1
Supraclavicular
8 mg
Tandoc et al.17
90
2/1/3/1
Interscalene
4 and 8 mg
Vieira et al.18
88
2/1/3/1
Interscalene
8 mg
Yadav et al.19
90
1/1/2/1
Supraclavicular
4 mg
(1) Bupivacaine 100 mg and perineural dexamethasone 8 mg (20) (2) Bupivacaine 100 mg and 0.9% saline (20) (3) Bupivacaine 100 mg and intravenous dexamethasone 8 mg (20) (1) Bupivacaine 50 mg and dexamethasone 8 mg (30) (2) Bupivacaine 50 mg and saline (30) (1) Lidocaine 1.5% (7 ml kg1), epinephrine 1 : 200 000 and dexamethasone 8 mg (30) (2) Lidocaine1.5% (7 ml kg1), epinephrine 1 : 200 000 and 0.9% saline (30) (1) Ropivacaine 150 mg and dexamethasone 8 mg (54) (2) Ropivacaine 150 mg and 0.9% saline (54) (3) Bupivacaine 150 mg and dexamethasone 8 mg (54) (4) Bupivacaine 150 mg and 0.9% saline (56) (1) Ropivacaine 150 mg and perineural dexamethasone10 mg (50) (2) Ropivacaine 150 mg and intravenous dexamethasone 10 mg (50) (3) Ropivacaine 150 mg and 0.9% saline (50) (1) Lidocaine 300 mg, bupivacaine 75 mg and epinephrine 1 : 200 000 þ dexamethasone 8 mg (30) (2) Lidocaine 300 mg, bupivacaine 75 mg and epinephrine1 : 200 000 þ 0.9% saline (30) (1) Lidocaine 510 mg and dexamethasone 8 mg (30) (2) Lidocaine 510 mg and 0.9% saline (30) (1) Mepivacaine 450 mg and dexamethasone 8 mg (30) (2) Mepivacaine 450 mg and saline (28) (1) Bupivacaine 0.5% 2 mg kg1 and tramadol 2 mg kg1 (30) (2) Bupivacaine 0.5% 2 mg kg1 and dexamethasone 8 mg (30) (1) Bupivacaine 200 mg, epinephrine 1 : 200 000 and dexamethasone 8 mg (30) (2) Bupivacaine 200 mg, epinephrine 1 : 200 000 and 0.9% saline (30) (3) Bupivacaine 200 mg, epinephrine 1 : 200 000 and dexamethasone 4 mg (30) (1) Bupivacaine 100 mg, epinephrine 1 : 200 000 and clonidine 75 mg þ dexamethasone 8 mg (44) (2) Bupivacaine 100 mg, epinephrine 1 : 200 000 and clonidine 75 mg þ 0.9% saline (44) (1) Lidocaine 360 mg and dexamethasone 4 mg (30) (2) Lidocaine 360 mg and epinephrine 1 : 200 000 (30) (3) Lidocaine 360 mg and neostigmine 500 mg (30)
Oxford Modified Scale: randomisation (0 to 2)/concealment of treatment allocation (0 to 1)/blinding (0 to 3)/description of withdrawals (0 to 1).
intermediate and long-acting local anaesthetics (Fig. 3). Pain intensity at 24 h after surgery was reported in three trials14,16,22 (n ¼ 366) evaluating dexamethasone combined with long-acting local anaesthetics. The median Table 2
pain score at 24 h was 55 (range 24 to 70). Dexamethasone-containing solutions decreased visual analogue scale (VAS) scores compared with plain local anaesthetic solutions (WMD 16.05, 95% CI 30.19 to 1.91).
Risk of bias and methodological quality assessment of included trials
Abdelmonem and Rizk23 Ammar and Mahmoud22 Biradar et al.12 Cummings et al.14 Desmet et al.13 Golwala et al.20 Movafegh et al.15 Parrington et al.16 Shrestha et al.21 Tandoc et al.17 Vieira et al.18 Yadav et al.19
Randomisation
Concealment of allocation
Blinding patient
Blinding provider of the intervention
Blinding observer
Follow-up
þ þ þ þ þ þ þ þ þ þ þ þ
þ þ ? þ þ ? þ þ þ þ þ þ
þ þ þ þ þ ? þ þ þ þ þ þ
? þ þ þ þ ? þ þ þ þ þ þ
þ þ þ þ þ ? þ þ þ þ þ ?
þ þ þ þ þ ? þ þ þ þ þ þ
þ, low risk of bias; ?, unclear.
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Dexamethasone and peripheral nerve block 755
Fig. 2
Experimental Control Study or subgroup Mean SD Total Mean SD Total Weight Duration of analgesia with intermediate-acting LAs Biradar 326 58.6 29 159 20.1 29 9.4% Movafegh 242 76 24 98 33 20 9.2% Parrington 332 17 24 228 41 21 9.4% Yadav 454.2 110.7 30 176.5 53.5 30 9.1% Subtotal (95% CI) 107 100 37.1% Heterogeneity: Tau2 = 3411.69; Chi2 = 56.85, df= 3 (P < 0.00001); I2 = 95% Test for overall effect: Z = 5.64 (P < 0.00001) Duration of analgesia with long-acting LAs Abdelmonem 21 18 162.3 16.9 19 287.7 9.5% 75.3 30 325.4 63.6 30 Ammar 459.8 9.2% Cummings Bupivacaine 54 888 280.21 52 6.8% 1344 391.4 Cummings Ropivacaine 52 51 6.5% 1332 476.46 708 182.36 1433 Desmet 4.2% 619 49 824 510 46 265 30 300 88.8 30 Golwala 900 7.6% 30 453.17 72.81 30 8.4% Shrestha 1028.17 194.51 30 28 4.6% Tandoc 530 780 240 1500 1457 434 44 833 267 44 6.1% Vieira Subtotal (95% CI) 337 330 62.9% Heterogeneity: Tau2 = 41253.75; Chi2 = 367.40, df= 8 (P < 0.00001); I2 = 98% Test for overall effect: Z = 6.77 (P < 0.00001) Total (95% CI) 444 430 100.0% Heterogeneity: Tau2 = 10756.57; Chi2 = 425.58, df= 12 (P < 0.00001); I2 = 97% Test for overall effect: Z = 10.97 (P < 0.00001) Test for subgroup differences: Chi2 = 16.25, df= 1 (P < 0.0001); I2 = 93.8%
Mean difference IV, Random, 95% CI
Mean difference IV, Random, 95% CI
167.00 [144.45, 189.55] 144.00 [110.33, 177.67] 104.00 [85.19, 122.81] 277.70 [233.70, 321.70] 170.74 [111.45, 230.03]
125.40 [113.08, 137.72] 134.40 [99.13, 169.67] 456.00 [326.78, 585.22] 624.00 [485.16, 762.84] 609.00 [381.49, 836.51] 600.00 [499.99, 700.01] 575.00 [500.68, 649.32] 720.00 [510.55, 929.45] 624.00 [473.44, 774.56] 483.13 [343.31, 622.95]
350.58 [287.94, 413.22] –500 –250 0 250 500 Favours control Favours dexamethasone
Meta-analysis of the duration of postoperative analgesia (min). Subgroup analysis comparing the efficacy of dexamethasone added to intermediateacting and long-acting local anaesthetics. Duration of postoperative analgesia was defined as time until the first analgesic request. Meta-analyses were performed using a random effect model. Symbols and horizontal lines are mean differences (single trials) or WMDs (combined data) with 95% CIs. CI, confidence interval; IV, inverse variance; LA, local anaesthetic; SD, standard deviation; WMD, weighted mean difference.
Other outcomes
The time to onset of sensory blockade was documented in seven trials (n ¼ 356; (Supplemental Data File, http://links.lww.com/EJA/A67)).12,15,16,19 – 21,23 Six comparisons were significantly in favour of dexamethasone.
In controls, median time to onset of sensory blockade was 10 min (range 4.6 to 18.5 min). Dexamethasone significantly shortened onset time when studies were pooled (WMD 78 s, 95% CI 112 to 44, P < 0.001).
Fig. 3 Control Experimental Study or subgroup Mean SD Total Mean SD Total Weight 3.1.1 Duration of motor block with intermediate-acting LAs Biradar 290.6 52.7 29 29 32.9% 135.5 20.3 24 8.4% 310 817 20 130 31 Movafegh 53 49 41.3% Subtotal (95% CI)
Mean difference IV, Random, 95% CI
Mean difference IV, Random, 95% CI
155.10 [134.55, 175.65] 180.00 [–147.14, 507.14] 155.20 [134.68, 175.71]
Heterogeneity: Tau2 = 0.00; Chi2 = 0.02, df= 1 (P = 0.88); I2 = 0% Test for overall effect: Z = 14.83 (P < 0.00001) 3.1.2 Duration of motor block with long-acting LAs 393.03 98.96 30 202.93 30.55 Shrestha 30 32.1% 30 28 1.8% 900 2340 2040 1500 Tandoc 44 44 24.8% 292 827 239 1374 Vieira 102 58.7% Subtotal (95% CI) 104 Heterogeneity: Tau2 = 62907.82; Chi2 = 37.69, df= 2 (P < 0.00001); I2 = 95% Test for overall effect: Z = 2.51 (P < 0.01) Total (95% CI) 157 151 100.0% Heterogeneity: Tau2 = 9425.35; Chi2 = 49.61, df= 4 (P < 0.00001); I2 = 92% Test for overall effect: Z = 4.96 (P < 0.00001) Test for subgroup differences: Chi2 = 2.52, df= 1 (P < 0.11); I2 = 60.3%
190.10 [153.04, 227.16] 840.00 [37.49, 1642.51] 547.00 [435.51, 658.49] 423.06 [93.00, 753.12]
277.7 [167.92, 387.56] –500 –250 0 250 500 Favours experimental Favours control
Meta-analysis of the duration of motor block (min). Subgroup analysis comparing the efficacy of dexamethasone added to intermediate-acting and long-acting local anaesthetics. Meta-analyses were performed using a random effect model. Symbols and horizontal lines are mean differences (single trials) or WMDs (combined data) with 95% CIs. CI, confidence interval; IV, inverse variance; LA, local anaesthetic; SD, standard deviation; WMD, weighted mean difference.
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
756 Huynh et al.
Time to onset of motor blockade was described in seven trials (n ¼ 356).12,15,16,19–21,23 Four comparisons were significantly in favour of dexamethasone; the difference was not significant in three trials. In controls, the median time to onset of motor blockade was 8 min (range 5.4 to 22). Dexamethasone significantly shortened this time duration (WMD 90 s, 95% CI 131 to 49, P < 0.001; P < 0.001 for test of heterogeneity). Postoperative pain scores were reported in seven trials but at different times. Pain scores measured by VAS graded from 0 to 100 were evaluated at 24 h in four trials (403 patients). Decrease in pain intensity did not reach statistical significance (WMD 13, 95% CI 25 to 0.4, P ¼ 0.06).14,16,18,22 At 48 h, there was no difference (three trials, WMD 3, 95% CI 9 to 2).14,18,22 PONV were reported in four trials.16,20,22,23 Dexamethasone significantly decreased the incidence of PONV (9 vs. 27%, RR 0.36, 95% CI 0.19 to 0.70, P ¼ 0.003; P ¼ 0.88 for test of heterogeneity, NNT 6, 95% CI 5 to 13). Incomplete block, or block failure, defined as a need for additional intravenous sedative or analgesic medication, additional nerve block or wound infiltration during surgery were reported in five trials.14,16,18,20,23 In controls, the risk of incomplete block was 7.7% with local anaesthetic alone and 5.9% with dexamethasone, a difference that was not statistically significant (RR 0.77, 95% CI 0.43 to 1.38, P ¼ 0.38; P ¼ 0.95 for test of heterogeneity). No adverse effects of dexamethasone were reported. A neurological complication was described in one trial. One patient in the dexamethasone group complained of hypoaesthesia after interscalene block.13 Exploration revealed spinal disc herniation. No haematoma was reported.
Discussion This meta-analysis of 12 randomised controlled trials documents that the combination of dexamethasone with local anaesthetic solutions in peripheral nerve blocks prolongs the durations of analgesia and motor blockade. These effects were documented with both intermediate and long-acting local anaesthetics. In addition, perineural administration of dexamethasone decreased the incidence of PONV. This meta-analysis included 512 patients who had received perineural dexamethasone. Upper limb blocks were performed in most of the studies. All the studies demonstrated separately and collectively the superiority of dexamethasone-containing local anaesthetic solutions over plain solutions in terms of durations of analgesia and motor blockade. As the quality of most of the studies was adequate, supported by an Oxford Modified Score value of more than 5, the results of this meta-analysis can be considered to have a low risk of bias. Three doses of dexamethasone were studied (4, 8 and 10 mg), making the results more heterogeneous. However, no dose effect
could be evaluated. Only one study by Tandocet et al.17 compared 4 and 8 mg of dexamethasone combined with bupivacaine. No difference was found between the two groups. The minimal effective dose of dexamethasone is also unknown. The definition of the duration of sensory blockade was the same in all the studies. It was considered as the delay between local anaesthetic administration and the first analgesic administration. This time accounts for the duration of analgesia, which is not, strictly speaking, the duration of the anaesthetic blockade. The aim of the administration of an adjuvant to a local anaesthetic solution is either to prolong anaesthesia or to prolong analgesia induced by local anaesthetic, or both. In the case of dexamethasone, the mean gain in the duration of analgesia is more than 6 h, which compares favourably with the prolongation achieved with other adjuvants such as neostigmine or clonidine.19,24 Unfortunately, the duration of motor blockade is also dramatically increased, which makes it less easy to manage in patients scheduled for ambulatory surgery or when a rapid recovery of motor function is required. In addition, in some patients, an extremely long duration of motor blockade could increase nerve block complications, necessitating prolonged monitoring until recovery of motor function, and increasing anxiety of patients. Finally, the benefit of adding dexamethasone to local analgesia with infiltration may be interesting to investigate for cases in which motor block may be problematic.9 The mechanism of action of dexamethasone is not documented. A drawback of the studies’ designs is that a third arm corresponding to intravenous administration of dexamethasone was included in only two trials.13,23 A comparable increase in the duration of analgesia was documented by the perineural and intravenous routes of administration in these two trials. In addition, intravenous dexamethasone increases the duration of analgesia after caudal block with ropivacaine in children.5 It is consequently difficult to consider that the local effect of dexamethasone is stronger than the systemic one, and this point needs to be clarified. No drug-related adverse effects, especially peripheral neuropathy, were reported in patients who received dexamethasone-containing local anaesthetic solution. However, the number of patients is not sufficient to permit definitive conclusions to be reached regarding the lack of neurotoxicity of dexamethasone. Epidemiological studies suggest that complications after regional anaesthesia affect about one in 8000 patients.25,26 These complications are drug-specific, and dose and timedependent.27 The safety of dexamethasone is controversial. In isolated nerve cells (dorsal root ganglia), Williams et al.28 found that ropivacaine-induced neurotoxicity was increased by large doses of dexamethasone (time and concentrationdependent). The mechanisms include an increase in the
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Dexamethasone and peripheral nerve block 757
intracellular calcium flow (inducing cell apoptosis) and activation of induced apoptosis factors and caspase 3. Some studies have shown that dexamethasone activated apoptosis genes coding for the mRNA of tumour necrosis factor (TNF) a and b, and interleukin-1.29 Tissue injury depends on the injection site. After intrafascicular neural injection, direct injury to myelin and axons has been induced by hydrocortisone and triamcinolone. Similar injuries have been observed with dexamethasone, but to a lesser extent. Eventually, the neurotoxicity of dexamethasone may depend on the solvent associated with the active agent (propylene glycol).30 This meta-analysis has several limitations. First, peripheral nerve blocks were not ultrasound-guided in most cases. Second, the volume of injection was usually more than 20 ml. Utrasonography is now used commonly in regional anaesthesia and may increase the efficacy and the reliability of blocks. The benefit of dexamethasone needs further investigation when small volumes of local anaesthetic are used. Third, the current meta-analysis does not allow determination of whether perineural administration of dexamethasone is more effective than intravenous administration to prolong the duration of peripheral nerve blocks. Fourth, two trials included in the meta-analysis were not strictly controlled.19,21 Dexamethasone was compared with two other adjuvants (tramadol, epinephrine). However, the duration of postoperative analgesia was longer with dexamethasone. Fifth, only positive trials have been published. The possibility of publication bias cannot be ruled out completely. All trials included in this meta-analysis were positive with regard to the duration of postoperative analgesia with dexamethasone. Small doses of perineural dexamethasone, that is less than 4 mg, were not studied. The dose– response effect of adding dexamethasone to local anaesthetics remains unclear and needs further investigation. Others adjuvants such as a2-agonists prolong the duration of postoperative analgesia after peripheral nerve block but increase the risk of hypotension, fainting or sedation.24 Multimodal analgesia is frequently used for relieving postoperative pain. It combines several analgesics to provide equivalent or better analgesia with reduced analgesic side effects. This concept may be tested in the context of peripheral nerve block. High doses of dexamethasone increase the neurotoxicity induced by ropivacaine.28 Small doses of adjuvants (dexamethasone, clonidine) added to small volumes and/or low concentrations of local anaesthetics for nerve blocks need evaluation.
Conclusion This meta-analysis supports a significant prolongation of the peripheral nerve block by combining dexamethasone with local anaesthetic solution. Questions remain concerning the mechanism of action, the optimal dose, the
lack of toxicity and the comparison with intravenous administration.
Acknowledgements relating to this article Assistance with the study: none. Funding and sponsorship: this work was funded by departmental resources only. This work should be attributed to Department of Anaesthesiology and Intensive Care, Tenon Hospital, Assistance Publique Hpitaux de Paris, Pierre and Marie Curie University, Paris VI. Conflicts of interest: none. Presentation: this work was presented in part at the September 2012 annual meeting of the French Society of Anaesthesiology and Intensive Care (SFAR) in Paris, France.
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Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines for the management of postoperative nausea and vomiting. Anesth Analg 2007; 105:1615–1628. De Oliveira GS Jr, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a metaanalysis of randomized controlled trials. Anesthesiology 2011; 115:575– 588. Waldron NH, Jones CA, Gan TJ, et al. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth 2013; 110:191–200. Allen TK, Jones CA, Habib AS. Dexamethasone for the prophylaxis of postoperative nausea and vomiting associated with neuraxial morphine administration: a systematic review and meta-analysis. Anesth Analg 2012; 114:813–822. Hong JY, Han SW, Kim WO, et al. Effect of dexamethasone in combination with caudal analgesia on postoperative pain control in day-case paediatric orchidopexy. Br J Anaesth 2010; 105:506–510. Drager C, Benziger D, Gao F, Berde CB. Prolonged intercostal nerve blockade in sheep using controlled-release of bupivacaine and dexamethasone from polymer microspheres. Anesthesiology 1998; 89:969–979. Castillo J, Curley J, Hotz J, et al. Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres. Anesthesiology 1996; 85:1157–1166. Kopacz DJ, Lacouture PG, Wu D, et al. The dose response and effects of dexamethasone on bupivacaine microcapsules for intercostal blockade (T9 to T11) in healthy volunteers. Anesth Analg 2003; 96:576–582. Holte K, Werner MU, Lacouture PG, Kehlet H. Dexamethasone prolongs local analgesia after subcutaneous infiltration of bupivacaine microcapsules in human volunteers. Anesthesiology 2002; 96:1331– 1335. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343:d5928. Elia N, Tramer MR. Ketamine and postoperative pain – a quantitative systematic review of randomised trials. Pain 2005; 113:61–70. Biradar PA, Kaimar P, Gopalakrishna K. Effect of dexamethasone added to lidocaine in supraclavicular brachial plexus block: a prospective, randomised, double-blind study. Indian J Anaesth 2013; 57:180–184. Desmet M, Braems H, Reynvoet M, et al. I.V. and perineural dexamethasone are equivalent in increasing the analgesic duration of a single-shot interscalene block with ropivacaine for shoulder surgery: a prospective, randomized, placebo-controlled study. Br J Anaesth 2013; 111:445– 452. Cummings KC 3rd, Napierkowski DE, Parra-Sanchez I, et al. Effect of dexamethasone on the duration of interscalene nerve blocks with ropivacaine or bupivacaine. Br J Anaesth 2011; 107:446–453. Movafegh A, Razazian M, Hajimaohamadi F, Meysamie A. Dexamethasone added to lidocaine prolongs axillary brachial plexus blockade. Anesth Analg 2006; 102:263–267. Parrington SJ, O’Donnell D, Chan VW, et al. Dexamethasone added to mepivacaine prolongs the duration of analgesia after supraclavicular brachial plexus blockade. Reg Anesth Pain Med 2010; 35:422–426. Tandoc MN, Fan L, Kolesnikov S, et al. Adjuvant dexamethasone with bupivacaine prolongs the duration of interscalene block: a prospective randomized trial. J Anesth 2011; 25:704–709.
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21
22
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Vieira PA, Pulai I, Tsao GC, et al. Dexamethasone with bupivacaine increases duration of analgesia in ultrasound-guided interscalene brachial plexus blockade. Eur J Anaesthesiol 2010; 27:285–288. Yadav RK, Sah BP, Kumar P, Singh SN. Effectiveness of addition of neostigmine or dexamethasone to local anaesthetic in providing perioperative analgesia for brachial plexus block: a prospective, randomized, double blinded, controlled study. Kathmandu Univ Med J (KUMJ) 2008; 6:302–309. Golwala M, Swadia V, Dhimar A, Sridhar N. Pain relief by dexamethasone as an adjuvant to local anaesthetics in supraclavicular brachial plexus block. J Anaesth Clin Pharmacol 2009; 25:284–288. Shrestha BR, Maharjan SK, Shrestha S, et al. Comparative study between tramadol and dexamethasone as an admixture to bupivacaine in supraclavicular brachial plexus block. JNMA J Nepal Med Assoc 2007; 46:158–164. Ammar AS, Mahmoud KM. Effect of adding dexamethasone to bupivacaine on transversus abdominis plane block for abdominal hysterectomy: a prospective randomized controlled trial. Saudi J Anaesth 2012; 6:229–233. Abdelmonem A, Rizk S. Comparative study between intravenous and local dexamethasone as adjuvant to bupivacaine in perianal block. Egypt J Anaesth 2011; 27:163–168.
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Popping DM, Elia N, Marret E, et al. Clonidine as an adjuvant to local anesthetics for peripheral nerve and plexus blocks: a meta-analysis of randomized trials. Anesthesiology 2009; 111:406–415. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France: the SOS Regional Anesthesia Hotline Service. Anesthesiology 2002; 97:1274–1280. Auroy Y, Narchi P, Messiah A, et al. Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology 1997; 87:479–486. Perez-Castro R, Patel S, Garavito-Aguilar ZV, et al. Cytotoxicity of local anesthetics in human neuronal cells. Anesth Analg 2009; 108:997–1007. Williams BA, Hough KA, Tsui BY, et al. Neurotoxicity of adjuvants used in perineural anesthesia and analgesia in comparison with ropivacaine. Reg Anesth Pain Med 2011; 36:225–230. Bruccoleri A, Pennypacker KR, Harry GJ. Effect of dexamethasone on elevated cytokine mRNA levels in chemical-induced hippocampal injury. J Neurosci Res 1999; 57:916–926. Benzon HT, Chew TL, McCarthy RJ, et al. Comparison of the particle sizes of different steroids and the effect of dilution: a review of the relative neurotoxicities of the steroids. Anesthesiology 2007; 106:331–338.
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ORIGINAL ARTICLE
Combination of dexamethasone and local anaesthetic solution in peripheral nerve blocks A meta-analysis of randomised controlled trials Thi Mum Huynh, Emmanuel Marret and Francis Bonnet BACKGROUND Dexamethasone decreases postoperative pain and prolongs the duration of local anaesthetic peripheral nerve blocks in studies including a limited number of patients. OBJECTIVE The objective of this study is to evaluate the effect of combining dexamethasone with local anaesthetic on sensory and motor peripheral nerve blockade in adults. DESIGN A systematic review with meta-analysis of randomised controlled trials. DATA SOURCES We systematically searched in Medline, Embase, Google Scholar and Cochrane Controlled Trials Register up to December 2013. ELIGIBILITY CRITERIA Randomised trials testing dexamethasone combined with local anaesthetic. RESULTS Twelve trials (1054 patients, 512 receiving perineural dexamethasone) were included. Ten studies evaluated dexamethasone for brachial plexus nerve block. Four to 10 mg dexamethasone-containing local anaesthetic solutions had a faster onset of action and resulted in a
significant increase in the duration of analgesia [weighted mean difference (WMD) 351 min, 95% confidence interval (95% CI) 288 to 413, P < 0.001] and motor blockade (WMD 277 min, 95% CI 167 to 387, P < 0.001) compared with local anaesthetic solutions alone. Time to onset of sensory and motor blocks was significantly reduced with dexamethasone (WMD 78 s, 95% CI 112 to 44, and 90 s, 95% CI 131 to 48, respectively). Dexamethasone significantly decreased postoperative nausea and vomiting (PONV, 9 vs. 27%, relative risk 0.36, 95% CI 0.19 to 0.70). Subgroup analyses showed that dexamethasone approximately doubled the duration of postoperative analgesia when it was combined with intermediate-acting (lidocaine, mepivacaine) or long-acting (bupivacaine, ropivacaine) local anaesthetics. CONCLUSION Combining dexamethasone with local anaesthetics results in a prolongation of the duration of peripheral nerve block. Published online 13 March 2015
Introduction Dexamethasone is commonly used in anaesthesia to prevent postoperative nausea and vomiting (PONV).1 Two recent meta-analyses have documented that dexamethasone also reduced postoperative pain and opioid requirement.2,3 Intravenous dexamethasone has also been shown to improve postoperative pain control in patients receiving spinal or epidural morphine.4 Hong et al.5 reported that intravenous dexamethasone in combination with a caudal block with ropivacaine prolonged the duration of postoperative analgesia without adverse effects in children undergoing orchidopexy. Experimentally, dexamethasone combined with local anaesthetic may also reinforce peripheral nerve block. In animals,
bupivacaine-dexamethasone microspheres prolonged the duration of rat sciatic nerve or sheep intercostal nerve blocks.6,7 In healthy volunteers, dexamethasone combined with bupivacaine in microspheres also prolonged the duration of analgesia after peripheral nerve block.8,9 In agreement with these results, several studies performed in a small series of patients have found an increase in the duration of sensory blockade when dexamethasone was used in combination with local anaesthetic in peripheral nerve blocks. Consequently, we sought to perform a meta-analysis of the published randomised trials assessing the clinical
From the Department of Anaesthesiology and Intensive Care, Tenon Hospital, Assistance Publique Hoˆpitaux de Paris, Pierre and Marie Curie University, Paris, France Correspondence to Dr Emmanuel Marret, MD, PhD, France American Hospital of Paris, 63 Bd Victor Hugo, 9220 Neuilly-sur-Seine, France E-mail: [email protected] 0265-0215 Copyright ß 2015 European Society of Anaesthesiology. All rights reserved.
DOI:10.1097/EJA.0000000000000248
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
752 Huynh et al.
effect of combining dexamethasone with local anaesthetic on sensory and motor blockade, onset time and side effects for peripheral nerve blocks performed in adults.
Materials and methods This meta-analysis is reported according to PRISMA recommendations for meta-analysis. A protocol for this study was not registered. A wide search strategy was used to retrieve relevant reports in Embase, Medline, Cinhal, Biosis, Central and Google Scholar. The searching terms ‘dexamethasone’, ‘nerve block’, ‘local anaesthetic’, ‘lidocaine’ or ‘lignocaine’, ‘mepivacaine’, ‘bupivacaine’, ‘ropivacaine’, ‘levobupivacaine’, ‘chloroprocaine’, ‘articaine’, ‘prilocaine’ and ‘adjuvants’ were combined. Additional articles were retrieved through hyperlinks and by manually searching reference lists in original published articles, review articles and correspondence. We completed our research by consulting abstracts, published or not, presented at the American Society of Anesthesiologists, European Society of Anaesthesiology and Socie´te´ Francaise d’Anesthe´sie-Re´animation meetings from 2000 to 2012. The last electronic research was in December 2013. There was no language restriction. Authors were contacted for additional information on methods and results when required. The following inclusion criteria were applied: randomised treatment allocation; comparison of dexamethasone added to a local anaesthetic (experimental intervention) with the same local anaesthetic regimen without dexamethasone (control intervention); peripheral singleinjection nerve or plexus block; and adults undergoing surgery. When other adjuvants were added to local anaesthetic (for instance epinephrine), the data were considered if the comparison was strictly controlled (i.e. both experimental and control groups received the same regimen excepted for dexamethasone). Exclusion criteria were continuous local anaesthetic administration or repeated injection; intravenous regional anaesthesia (Bier’s block); dexamethasone administered only intravenously; local anaesthetics used in microspheres; healthy volunteers; children (younger than 18 years); and animal studies. To overcome random play of chance on estimation of treatment effects, we excluded studies with fewer than 10 participants per group. The primary evaluation criterion was the duration of analgesia defined as the delay before the first request for analgesics. Other endpoints were duration of motor blockade and onset time of sensory and motor blockades, postoperative pain scores at 24 and 48 h, PONV and dexamethasone-related side effects such as infection, neurological complications or haematoma.
One author (T.H.) extracted relevant information from original reports. A second author (E.M.) checked all extracted data. Discrepancies were resolved by discussion with the third author (F.B.). When continuous data were not reported as mean SD, we computed them whenever feasible. Quality of data reporting was assessed using the Cochrane Collaboration’s tool for assessing risk of bias in randomised trials evaluating selection, performance, detection, attrition and reporting bias. The risk of bias was classified as ‘low risk’, ‘high risk or ‘unclear risk’ according to the recommendations of Higgins et al.10 Each article was also scored using the Oxford Modified Scale, an eight-point (0 to 7) scale evaluating randomisation, blinding and completeness of patient follow-up. The lowest possible score was 1.11 Statistical analysis
When not reported in the article, we considered that an intention-to treat analysis was performed on the original data. For continuous data, mean differences with 95% confidence interval (95% CI) were first calculated for each individual study. A weighted mean difference (WMD) was computed to summarise the overall effect. A random effects model was used when the test for heterogeneity was significant (P < 0.10). To explore the effect of dexamethasone in different settings (subgroup analyses), we compared the degree of efficacy of dexamethasone in combination with intermediate and long-acting local anaesthetics. For dichotomous endpoints, the Mantel-Haenszel like procedure for relative risk (RR) was used to pool RRs of individual studies. For all pooled RRs reaching statistical significance, we computed the number needed to treat (NNT) as the inverse of the difference of the proportion of patients who had any event in the dexamethasone group and the control group. CIs of the NNT were constructed by inverting and exchanging the limits of the 95% CI for the RR. The NNT and 95% CI were calculated with the internetbased program Visual Rx (http://www.nntonline.net/). Analyses were performed using Review Manager (Computer program, version 5.1.6; The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark, 2011).
Results Of 1568 retrieved titles, 17 were potentially relevant (Fig. 1). We excluded five studies. One was performed in healthy volunteers. The second study evaluated chronic pain. Three abstracts were excluded because of missing relevant information. We eventually analysed data from 12 randomised trials including 13 comparisons (1054 patients, 512 receiving dexamethasone). Ten studies evaluated dexamethasone in brachial plexus nerve blocks (five supraclavicular block, four interscalene block and one axillary block)12–21 and two in other peripheral nerve blocks (perineal block and transversus
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Dexamethasone and peripheral nerve block 753
Fig. 1
Embase
Medline
Cinhal
Biosis
Central
Google scholar
ASA/SFAR abstracts
1568 hits Inadequate reference (n = 1551) Potentially relevant RCTs (n = 17) Healthy volunteers (n = 1) Chronic pain (n = 1) Lack of information (n = 3) Valid RCTs (1054 patients, 512 received perineural dexamethasone) (n = 12)
Bupivacaine (n = 6)
Ropivacaine (n = 2)
Lidocaine (n = 3)
Mepivacaine (n = 1)
Lidocaine + Bupivacaine (n = 1)
Flowchart of process selection. RCT, randomised controlled trial; n, number of manuscripts. One trial had four arms: bupivacaine and placebo, bupivacaine and dexamethasone, ropivacaine and placebo, ropivacaine and dexamethasone.
abdominis plane block).22,23 All the nerve blocks were performed as a single injection in patients undergoing upper limb surgery (10 trials, four performed in patients scheduled for shoulder surgery), haemorrhoidectomy or abdominal hysterectomy. General anaesthesia was combined with regional anaesthesia in seven trials (shoulder surgery, haemorrhoidectomy and hysterectomy). Dexamethasone was combined with intermediate-acting local anaesthetic [lidocaine alone (three studies), mepivacaine (one study)] or long-acting local anaesthetics [ropivacaine (two studies), bupivacaine (six studies), combination of lidocaine and bupivacaine (one study)]. Eleven trials evaluated a single dose of dexamethasone (8 mg in nine studies; 10 or 4 mg in one study each). One trial compared two doses of dexamethasone (8 vs. 4 mg). Two trials had three arms comparing intravenous dexamethasone, perineural dexamethasone and placebo (Table 1). Dexamethasone was compared with tramadol in one trial and with epinephrine in another.19,21 Some patients had a failed block and data were not reported for some outcomes. The procedure of randomisation was adequately described in 10 trials (83%). Concealment of treatment allocation was described in 10 trials (83%) (Table 2). Nine studies were double-blinded (75%). Follow-up was completed in 11 trials. The median quality score was six (range 2 to 7). Duration of postoperative analgesia
Duration of analgesia, defined as the time before the first analgesic administration, was reported in all studies
(n ¼ 874 patients; Fig. 2). All comparisons were significantly in favour of dexamethasone. In controls, the median time to first postoperative analgesic administration was 325 min (range 98 to 888 min). Dexamethasone significantly increased the duration of analgesia to about 351 min (95% CI 288 to 413, P < 0.001). This result remained statistically significant when only studies using upper extremity nerve blocks were pooled (WMD 420 min, 95% CI 326 to 511, P < 0.001). Duration of motor blockade
Duration of motor blockade was reported in five trials.12,15,17,18,21 Four comparisons were significantly in favour of dexamethasone, and the difference was not significant in one trial. In controls, the median duration of motor blockade was 202 min (range 130 to 1500 min). Dexamethasone significantly increased the duration of motor blockade (WMD 278 min, 95% CI 168 to 389, P < 0.001) (Fig. 3). Subgroup analyses
Subgroup analyses were performed to test the impact of adding dexamethasone to intermediate-acting (four trials, n ¼ 207) and long-acting (eight trials, n ¼ 667) local anaesthetics (Fig. 2). Median duration of analgesia in the control groups was 167 min (range 98 to 228 min) with intermediate-acting local anaesthetic solutions and 708 min (range 162 to 888 min) with long-acting local anaesthetic solutions. Dexamethasone approximately doubled (Fig. 2) the duration of postoperative analgesia in combination with all tested local anaesthetic solutions. Similarly, dexamethasone increased the duration of motor block of
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754 Huynh et al.
Table 1
Characteristics of clinical trials included in the meta-analysis Number of Quality patients scorea Nerve block
Author Abdelmonem and Rizk23
a
60
2/1/2/1
Dose of dexamethasone Local anaesthetics
Perianal
8 mg
Ammar and Mahmoud22
60
2/1/3/1
Transversus 8 mg abdominis plane
Biradar et al.12
60
2/0/3/1
Supraclavicular
8 mg
Cummings et al.14
218
2/1/3/1
Interscalene
8 mg
Desmet et al.13
150
2/1/3/1
Interscalene
10 mg
Golwala et al.20
60
1/0/0/1
Supraclavicular
8 mg
Movafegh et al.15
60
2/1/3/0
Axillary
8 mg
Parrington et al.16
58
2/1/3/1
Supraclavicular
8 mg
Shrestha et al.21
60
2/1/3/1
Supraclavicular
8 mg
Tandoc et al.17
90
2/1/3/1
Interscalene
4 and 8 mg
Vieira et al.18
88
2/1/3/1
Interscalene
8 mg
Yadav et al.19
90
1/1/2/1
Supraclavicular
4 mg
(1) Bupivacaine 100 mg and perineural dexamethasone 8 mg (20) (2) Bupivacaine 100 mg and 0.9% saline (20) (3) Bupivacaine 100 mg and intravenous dexamethasone 8 mg (20) (1) Bupivacaine 50 mg and dexamethasone 8 mg (30) (2) Bupivacaine 50 mg and saline (30) (1) Lidocaine 1.5% (7 ml kg1), epinephrine 1 : 200 000 and dexamethasone 8 mg (30) (2) Lidocaine1.5% (7 ml kg1), epinephrine 1 : 200 000 and 0.9% saline (30) (1) Ropivacaine 150 mg and dexamethasone 8 mg (54) (2) Ropivacaine 150 mg and 0.9% saline (54) (3) Bupivacaine 150 mg and dexamethasone 8 mg (54) (4) Bupivacaine 150 mg and 0.9% saline (56) (1) Ropivacaine 150 mg and perineural dexamethasone10 mg (50) (2) Ropivacaine 150 mg and intravenous dexamethasone 10 mg (50) (3) Ropivacaine 150 mg and 0.9% saline (50) (1) Lidocaine 300 mg, bupivacaine 75 mg and epinephrine 1 : 200 000 þ dexamethasone 8 mg (30) (2) Lidocaine 300 mg, bupivacaine 75 mg and epinephrine1 : 200 000 þ 0.9% saline (30) (1) Lidocaine 510 mg and dexamethasone 8 mg (30) (2) Lidocaine 510 mg and 0.9% saline (30) (1) Mepivacaine 450 mg and dexamethasone 8 mg (30) (2) Mepivacaine 450 mg and saline (28) (1) Bupivacaine 0.5% 2 mg kg1 and tramadol 2 mg kg1 (30) (2) Bupivacaine 0.5% 2 mg kg1 and dexamethasone 8 mg (30) (1) Bupivacaine 200 mg, epinephrine 1 : 200 000 and dexamethasone 8 mg (30) (2) Bupivacaine 200 mg, epinephrine 1 : 200 000 and 0.9% saline (30) (3) Bupivacaine 200 mg, epinephrine 1 : 200 000 and dexamethasone 4 mg (30) (1) Bupivacaine 100 mg, epinephrine 1 : 200 000 and clonidine 75 mg þ dexamethasone 8 mg (44) (2) Bupivacaine 100 mg, epinephrine 1 : 200 000 and clonidine 75 mg þ 0.9% saline (44) (1) Lidocaine 360 mg and dexamethasone 4 mg (30) (2) Lidocaine 360 mg and epinephrine 1 : 200 000 (30) (3) Lidocaine 360 mg and neostigmine 500 mg (30)
Oxford Modified Scale: randomisation (0 to 2)/concealment of treatment allocation (0 to 1)/blinding (0 to 3)/description of withdrawals (0 to 1).
intermediate and long-acting local anaesthetics (Fig. 3). Pain intensity at 24 h after surgery was reported in three trials14,16,22 (n ¼ 366) evaluating dexamethasone combined with long-acting local anaesthetics. The median Table 2
pain score at 24 h was 55 (range 24 to 70). Dexamethasone-containing solutions decreased visual analogue scale (VAS) scores compared with plain local anaesthetic solutions (WMD 16.05, 95% CI 30.19 to 1.91).
Risk of bias and methodological quality assessment of included trials
Abdelmonem and Rizk23 Ammar and Mahmoud22 Biradar et al.12 Cummings et al.14 Desmet et al.13 Golwala et al.20 Movafegh et al.15 Parrington et al.16 Shrestha et al.21 Tandoc et al.17 Vieira et al.18 Yadav et al.19
Randomisation
Concealment of allocation
Blinding patient
Blinding provider of the intervention
Blinding observer
Follow-up
þ þ þ þ þ þ þ þ þ þ þ þ
þ þ ? þ þ ? þ þ þ þ þ þ
þ þ þ þ þ ? þ þ þ þ þ þ
? þ þ þ þ ? þ þ þ þ þ þ
þ þ þ þ þ ? þ þ þ þ þ ?
þ þ þ þ þ ? þ þ þ þ þ þ
þ, low risk of bias; ?, unclear.
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Dexamethasone and peripheral nerve block 755
Fig. 2
Experimental Control Study or subgroup Mean SD Total Mean SD Total Weight Duration of analgesia with intermediate-acting LAs Biradar 326 58.6 29 159 20.1 29 9.4% Movafegh 242 76 24 98 33 20 9.2% Parrington 332 17 24 228 41 21 9.4% Yadav 454.2 110.7 30 176.5 53.5 30 9.1% Subtotal (95% CI) 107 100 37.1% Heterogeneity: Tau2 = 3411.69; Chi2 = 56.85, df= 3 (P < 0.00001); I2 = 95% Test for overall effect: Z = 5.64 (P < 0.00001) Duration of analgesia with long-acting LAs Abdelmonem 21 18 162.3 16.9 19 287.7 9.5% 75.3 30 325.4 63.6 30 Ammar 459.8 9.2% Cummings Bupivacaine 54 888 280.21 52 6.8% 1344 391.4 Cummings Ropivacaine 52 51 6.5% 1332 476.46 708 182.36 1433 Desmet 4.2% 619 49 824 510 46 265 30 300 88.8 30 Golwala 900 7.6% 30 453.17 72.81 30 8.4% Shrestha 1028.17 194.51 30 28 4.6% Tandoc 530 780 240 1500 1457 434 44 833 267 44 6.1% Vieira Subtotal (95% CI) 337 330 62.9% Heterogeneity: Tau2 = 41253.75; Chi2 = 367.40, df= 8 (P < 0.00001); I2 = 98% Test for overall effect: Z = 6.77 (P < 0.00001) Total (95% CI) 444 430 100.0% Heterogeneity: Tau2 = 10756.57; Chi2 = 425.58, df= 12 (P < 0.00001); I2 = 97% Test for overall effect: Z = 10.97 (P < 0.00001) Test for subgroup differences: Chi2 = 16.25, df= 1 (P < 0.0001); I2 = 93.8%
Mean difference IV, Random, 95% CI
Mean difference IV, Random, 95% CI
167.00 [144.45, 189.55] 144.00 [110.33, 177.67] 104.00 [85.19, 122.81] 277.70 [233.70, 321.70] 170.74 [111.45, 230.03]
125.40 [113.08, 137.72] 134.40 [99.13, 169.67] 456.00 [326.78, 585.22] 624.00 [485.16, 762.84] 609.00 [381.49, 836.51] 600.00 [499.99, 700.01] 575.00 [500.68, 649.32] 720.00 [510.55, 929.45] 624.00 [473.44, 774.56] 483.13 [343.31, 622.95]
350.58 [287.94, 413.22] –500 –250 0 250 500 Favours control Favours dexamethasone
Meta-analysis of the duration of postoperative analgesia (min). Subgroup analysis comparing the efficacy of dexamethasone added to intermediateacting and long-acting local anaesthetics. Duration of postoperative analgesia was defined as time until the first analgesic request. Meta-analyses were performed using a random effect model. Symbols and horizontal lines are mean differences (single trials) or WMDs (combined data) with 95% CIs. CI, confidence interval; IV, inverse variance; LA, local anaesthetic; SD, standard deviation; WMD, weighted mean difference.
Other outcomes
The time to onset of sensory blockade was documented in seven trials (n ¼ 356; (Supplemental Data File, http://links.lww.com/EJA/A67)).12,15,16,19 – 21,23 Six comparisons were significantly in favour of dexamethasone.
In controls, median time to onset of sensory blockade was 10 min (range 4.6 to 18.5 min). Dexamethasone significantly shortened onset time when studies were pooled (WMD 78 s, 95% CI 112 to 44, P < 0.001).
Fig. 3 Control Experimental Study or subgroup Mean SD Total Mean SD Total Weight 3.1.1 Duration of motor block with intermediate-acting LAs Biradar 290.6 52.7 29 29 32.9% 135.5 20.3 24 8.4% 310 817 20 130 31 Movafegh 53 49 41.3% Subtotal (95% CI)
Mean difference IV, Random, 95% CI
Mean difference IV, Random, 95% CI
155.10 [134.55, 175.65] 180.00 [–147.14, 507.14] 155.20 [134.68, 175.71]
Heterogeneity: Tau2 = 0.00; Chi2 = 0.02, df= 1 (P = 0.88); I2 = 0% Test for overall effect: Z = 14.83 (P < 0.00001) 3.1.2 Duration of motor block with long-acting LAs 393.03 98.96 30 202.93 30.55 Shrestha 30 32.1% 30 28 1.8% 900 2340 2040 1500 Tandoc 44 44 24.8% 292 827 239 1374 Vieira 102 58.7% Subtotal (95% CI) 104 Heterogeneity: Tau2 = 62907.82; Chi2 = 37.69, df= 2 (P < 0.00001); I2 = 95% Test for overall effect: Z = 2.51 (P < 0.01) Total (95% CI) 157 151 100.0% Heterogeneity: Tau2 = 9425.35; Chi2 = 49.61, df= 4 (P < 0.00001); I2 = 92% Test for overall effect: Z = 4.96 (P < 0.00001) Test for subgroup differences: Chi2 = 2.52, df= 1 (P < 0.11); I2 = 60.3%
190.10 [153.04, 227.16] 840.00 [37.49, 1642.51] 547.00 [435.51, 658.49] 423.06 [93.00, 753.12]
277.7 [167.92, 387.56] –500 –250 0 250 500 Favours experimental Favours control
Meta-analysis of the duration of motor block (min). Subgroup analysis comparing the efficacy of dexamethasone added to intermediate-acting and long-acting local anaesthetics. Meta-analyses were performed using a random effect model. Symbols and horizontal lines are mean differences (single trials) or WMDs (combined data) with 95% CIs. CI, confidence interval; IV, inverse variance; LA, local anaesthetic; SD, standard deviation; WMD, weighted mean difference.
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Time to onset of motor blockade was described in seven trials (n ¼ 356).12,15,16,19–21,23 Four comparisons were significantly in favour of dexamethasone; the difference was not significant in three trials. In controls, the median time to onset of motor blockade was 8 min (range 5.4 to 22). Dexamethasone significantly shortened this time duration (WMD 90 s, 95% CI 131 to 49, P < 0.001; P < 0.001 for test of heterogeneity). Postoperative pain scores were reported in seven trials but at different times. Pain scores measured by VAS graded from 0 to 100 were evaluated at 24 h in four trials (403 patients). Decrease in pain intensity did not reach statistical significance (WMD 13, 95% CI 25 to 0.4, P ¼ 0.06).14,16,18,22 At 48 h, there was no difference (three trials, WMD 3, 95% CI 9 to 2).14,18,22 PONV were reported in four trials.16,20,22,23 Dexamethasone significantly decreased the incidence of PONV (9 vs. 27%, RR 0.36, 95% CI 0.19 to 0.70, P ¼ 0.003; P ¼ 0.88 for test of heterogeneity, NNT 6, 95% CI 5 to 13). Incomplete block, or block failure, defined as a need for additional intravenous sedative or analgesic medication, additional nerve block or wound infiltration during surgery were reported in five trials.14,16,18,20,23 In controls, the risk of incomplete block was 7.7% with local anaesthetic alone and 5.9% with dexamethasone, a difference that was not statistically significant (RR 0.77, 95% CI 0.43 to 1.38, P ¼ 0.38; P ¼ 0.95 for test of heterogeneity). No adverse effects of dexamethasone were reported. A neurological complication was described in one trial. One patient in the dexamethasone group complained of hypoaesthesia after interscalene block.13 Exploration revealed spinal disc herniation. No haematoma was reported.
Discussion This meta-analysis of 12 randomised controlled trials documents that the combination of dexamethasone with local anaesthetic solutions in peripheral nerve blocks prolongs the durations of analgesia and motor blockade. These effects were documented with both intermediate and long-acting local anaesthetics. In addition, perineural administration of dexamethasone decreased the incidence of PONV. This meta-analysis included 512 patients who had received perineural dexamethasone. Upper limb blocks were performed in most of the studies. All the studies demonstrated separately and collectively the superiority of dexamethasone-containing local anaesthetic solutions over plain solutions in terms of durations of analgesia and motor blockade. As the quality of most of the studies was adequate, supported by an Oxford Modified Score value of more than 5, the results of this meta-analysis can be considered to have a low risk of bias. Three doses of dexamethasone were studied (4, 8 and 10 mg), making the results more heterogeneous. However, no dose effect
could be evaluated. Only one study by Tandocet et al.17 compared 4 and 8 mg of dexamethasone combined with bupivacaine. No difference was found between the two groups. The minimal effective dose of dexamethasone is also unknown. The definition of the duration of sensory blockade was the same in all the studies. It was considered as the delay between local anaesthetic administration and the first analgesic administration. This time accounts for the duration of analgesia, which is not, strictly speaking, the duration of the anaesthetic blockade. The aim of the administration of an adjuvant to a local anaesthetic solution is either to prolong anaesthesia or to prolong analgesia induced by local anaesthetic, or both. In the case of dexamethasone, the mean gain in the duration of analgesia is more than 6 h, which compares favourably with the prolongation achieved with other adjuvants such as neostigmine or clonidine.19,24 Unfortunately, the duration of motor blockade is also dramatically increased, which makes it less easy to manage in patients scheduled for ambulatory surgery or when a rapid recovery of motor function is required. In addition, in some patients, an extremely long duration of motor blockade could increase nerve block complications, necessitating prolonged monitoring until recovery of motor function, and increasing anxiety of patients. Finally, the benefit of adding dexamethasone to local analgesia with infiltration may be interesting to investigate for cases in which motor block may be problematic.9 The mechanism of action of dexamethasone is not documented. A drawback of the studies’ designs is that a third arm corresponding to intravenous administration of dexamethasone was included in only two trials.13,23 A comparable increase in the duration of analgesia was documented by the perineural and intravenous routes of administration in these two trials. In addition, intravenous dexamethasone increases the duration of analgesia after caudal block with ropivacaine in children.5 It is consequently difficult to consider that the local effect of dexamethasone is stronger than the systemic one, and this point needs to be clarified. No drug-related adverse effects, especially peripheral neuropathy, were reported in patients who received dexamethasone-containing local anaesthetic solution. However, the number of patients is not sufficient to permit definitive conclusions to be reached regarding the lack of neurotoxicity of dexamethasone. Epidemiological studies suggest that complications after regional anaesthesia affect about one in 8000 patients.25,26 These complications are drug-specific, and dose and timedependent.27 The safety of dexamethasone is controversial. In isolated nerve cells (dorsal root ganglia), Williams et al.28 found that ropivacaine-induced neurotoxicity was increased by large doses of dexamethasone (time and concentrationdependent). The mechanisms include an increase in the
Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Dexamethasone and peripheral nerve block 757
intracellular calcium flow (inducing cell apoptosis) and activation of induced apoptosis factors and caspase 3. Some studies have shown that dexamethasone activated apoptosis genes coding for the mRNA of tumour necrosis factor (TNF) a and b, and interleukin-1.29 Tissue injury depends on the injection site. After intrafascicular neural injection, direct injury to myelin and axons has been induced by hydrocortisone and triamcinolone. Similar injuries have been observed with dexamethasone, but to a lesser extent. Eventually, the neurotoxicity of dexamethasone may depend on the solvent associated with the active agent (propylene glycol).30 This meta-analysis has several limitations. First, peripheral nerve blocks were not ultrasound-guided in most cases. Second, the volume of injection was usually more than 20 ml. Utrasonography is now used commonly in regional anaesthesia and may increase the efficacy and the reliability of blocks. The benefit of dexamethasone needs further investigation when small volumes of local anaesthetic are used. Third, the current meta-analysis does not allow determination of whether perineural administration of dexamethasone is more effective than intravenous administration to prolong the duration of peripheral nerve blocks. Fourth, two trials included in the meta-analysis were not strictly controlled.19,21 Dexamethasone was compared with two other adjuvants (tramadol, epinephrine). However, the duration of postoperative analgesia was longer with dexamethasone. Fifth, only positive trials have been published. The possibility of publication bias cannot be ruled out completely. All trials included in this meta-analysis were positive with regard to the duration of postoperative analgesia with dexamethasone. Small doses of perineural dexamethasone, that is less than 4 mg, were not studied. The dose– response effect of adding dexamethasone to local anaesthetics remains unclear and needs further investigation. Others adjuvants such as a2-agonists prolong the duration of postoperative analgesia after peripheral nerve block but increase the risk of hypotension, fainting or sedation.24 Multimodal analgesia is frequently used for relieving postoperative pain. It combines several analgesics to provide equivalent or better analgesia with reduced analgesic side effects. This concept may be tested in the context of peripheral nerve block. High doses of dexamethasone increase the neurotoxicity induced by ropivacaine.28 Small doses of adjuvants (dexamethasone, clonidine) added to small volumes and/or low concentrations of local anaesthetics for nerve blocks need evaluation.
Conclusion This meta-analysis supports a significant prolongation of the peripheral nerve block by combining dexamethasone with local anaesthetic solution. Questions remain concerning the mechanism of action, the optimal dose, the
lack of toxicity and the comparison with intravenous administration.
Acknowledgements relating to this article Assistance with the study: none. Funding and sponsorship: this work was funded by departmental resources only. This work should be attributed to Department of Anaesthesiology and Intensive Care, Tenon Hospital, Assistance Publique Hpitaux de Paris, Pierre and Marie Curie University, Paris VI. Conflicts of interest: none. Presentation: this work was presented in part at the September 2012 annual meeting of the French Society of Anaesthesiology and Intensive Care (SFAR) in Paris, France.
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Eur J Anaesthesiol 2015; 32:751–758 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
