Dexamethasone as an adjuvant to peripheral nerve block

Carolyne Pehora; Annabel ME Pearson; Alka Kaushal; Mark W Crawford; Bradley Johnston

doi:10.1002/14651858.CD011770.pub2

. 2017 Nov 9;2017(11):CD011770. doi: 10.1002/14651858.CD011770.pub2

Dexamethasone as an adjuvant to peripheral nerve block

Carolyne Pehora ^1,^✉, Annabel ME Pearson ¹, Alka Kaushal ², Mark W Crawford ¹, Bradley Johnston ³

Editor: Cochrane Anaesthesia Group

PMCID: PMC6486015 PMID: 29121400

Abstract

Background

Peripheral nerve block (infiltration of local anaesthetic around a nerve) is used for anaesthesia or analgesia. A limitation to its use for postoperative analgesia is that the analgesic effect lasts only a few hours, after which moderate to severe pain at the surgical site may result in the need for alternative analgesic therapy. Several adjuvants have been used to prolong the analgesic duration of peripheral nerve block, including perineural or intravenous dexamethasone.

Objectives

To evaluate the comparative efficacy and safety of perineural dexamethasone versus placebo, intravenous dexamethasone versus placebo, and perineural dexamethasone versus intravenous dexamethasone when added to peripheral nerve block for postoperative pain control in people undergoing surgery.

Search methods

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, DARE, Web of Science and Scopus from inception to 25 April 2017. We also searched trial registry databases, Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia.

Selection criteria

We included all randomized controlled trials (RCTs) comparing perineural dexamethasone with placebo, intravenous dexamethasone with placebo, or perineural dexamethasone with intravenous dexamethasone in participants receiving peripheral nerve block for upper or lower limb surgery.

Data collection and analysis

We used standard methodological procedures expected by Cochrane.

Main results

We included 35 trials of 2702 participants aged 15 to 78 years; 33 studies enrolled participants undergoing upper limb surgery and two undergoing lower limb surgery. Risk of bias was low in 13 studies and high/unclear in 22.

Perineural dexamethasone versus placebo

Duration of sensory block was significantly longer in the perineural dexamethasone group compared with placebo (mean difference (MD) 6.70 hours, 95% confidence interval (CI) 5.54 to 7.85; participants1625; studies 27). Postoperative pain intensity at 12 and 24 hours was significantly lower in the perineural dexamethasone group compared with control (MD ‐2.08, 95% CI ‐2.63 to ‐1.53; participants 257; studies 5) and (MD ‐1.63, 95% CI ‐2.34 to ‐0.93; participants 469; studies 9), respectively. There was no significant difference at 48 hours (MD ‐0.61, 95% CI ‐1.24 to 0.03; participants 296; studies 4). The quality of evidence is very low for postoperative pain intensity at 12 hours and low for the remaining outcomes. Cumulative 24‐hour postoperative opioid consumption was significantly lower in the perineural dexamethasone group compared with placebo (MD 19.25 mg, 95% CI 5.99 to 32.51; participants 380; studies 6).

Intravenous dexamethasone versus placebo

Duration of sensory block was significantly longer in the intravenous dexamethasone group compared with placebo (MD 6.21, 95% CI 3.53 to 8.88; participants 499; studies 8). Postoperative pain intensity at 12 and 24 hours was significantly lower in the intravenous dexamethasone group compared with placebo (MD ‐1.24, 95% CI ‐2.44 to ‐0.04; participants 162; studies 3) and (MD ‐1.26, 95% CI ‐2.23 to ‐0.29; participants 257; studies 5), respectively. There was no significant difference at 48 hours (MD ‐0.21, 95% CI ‐0.83 to 0.41; participants 172; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. Cumulative 24‐hour postoperative opioid consumption was significantly lower in the intravenous dexamethasone group compared with placebo (MD ‐6.58 mg, 95% CI ‐10.56 to ‐2.60; participants 287; studies 5).

Perinerual versus intravenous dexamethasone

Duration of sensory block was significantly longer in the perineural dexamethasone group compared with intravenous by three hours (MD 3.14 hours, 95% CI 1.68 to 4.59; participants 720; studies 9). We found that postoperative pain intensity at 12 hours and 24 hours was significantly lower in the perineural dexamethasone group compared with intravenous, however, the MD did not surpass our pre‐determined minimally important difference of 1.2 on the Visual Analgue Scale/Numerical Rating Scale, therefore the results are not clinically significant (MD ‐1.01, 95% CI ‐1.51 to ‐0.50; participants 217; studies 3) and (MD ‐0.77, 95% CI ‐1.47 to ‐0.08; participants 309; studies 5), respectively. There was no significant difference in severity of postoperative pain at 48 hours (MD 0.13, 95% CI ‐0.35 to 0.61; participants 227; studies 3). The quality of evidence is moderate for duration of sensory block and postoperative pain intensity at 24 hours, and low for the remaining outcomes. There was no difference in cumulative postoperative 24‐hour opioid consumption (MD ‐3.87 mg, 95% CI ‐9.93 to 2.19; participants 242; studies 4).

Incidence of severe adverse events

Five serious adverse events were reported. One block‐related event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. Four non‐block‐related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia. The quality of evidence is very low due to the sparse number of events.

Authors' conclusions

Low‐ to moderate‐quality evidence suggests that when used as an adjuvant to peripheral nerve block in upper limb surgery, both perineural and intravenous dexamethasone may prolong duration of sensory block and are effective in reducing postoperative pain intensity and opioid consumption. There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not apply to participants at risk of dexamethasone‐related adverse events for whom clinical trials would probably be unsafe.

There is not enough evidence to determine the effectiveness of dexamethasone as an adjuvant to peripheral nerve block in lower limb surgeries and there is no evidence in children. The results of our review may not be apply to participants who at risk of dexamethasone‐related adverse events for whom clinical trials would probably be unsafe. The nine ongoing trials registered at ClinicalTrials.gov may change the results of this review.

Plain language summary

Dexamethasone and peripheral nerve block

What is a peripheral nerve block?

A nerve block prevents or relieves pain by interrupting pain signals that travel along a nerve to the brain. It involves an injection of local anaesthetic (a numbing agent) around a nerve either during or immediately after surgery. Pain relief from nerve block may last only a few hours after surgery, after which people may experience moderate to severe pain.

What is dexamethasone?

Dexamethasone is a steroid that may reduce pain and the inflammatory response to tissue damage after surgery (heat, pain, redness and swelling). In people receiving nerve block, dexamethasone may be given with the local anaesthetic around the nerve (perineural) or into a vein (intravenous) to prolong the pain relief from the peripheral nerve block.

What did the researchers investigate?

We looked for randomized controlled trials that investigated whether perineural or intravenous dexamethasone prolongs the length of time people experience pain relief from the peripheral nerve block when undergoing upper and lower limb surgery and reduces the intensity of pain after surgery. We also investigated whether perineural or intravenous dexamethasone cause any side effects or harms. We searched the medical literature for articles that included either adults or children undergoing upper or lower limb surgery with peripheral nerve block published up until 25 April 2017. We also assessed the quality of evidence for each outcome.

What did the researchers find?

We included 35 studies involving 2702 aged 15 to 78 years.

When compared with placebo, the duration of sensory block was prolonged in the perineural dexamethasone group by 6 and a half hours (27 studies, 1625 participants, low‐quality evidence) and in the intravenous dexamethasone group by six hours (8 studies, 499 participants, moderate‐quality evidence). When perineural and intravenous dexamethasone were compared, the duration of sensory block was longer in the perineural dexamethasone group by three hours (9 studies, 720 participants, moderate‐quality evidence).

Postoperative pain intensity at 12 hours after surgery was lower in the perineural dexamethasone group compared with placebo (5 studies, 257 participants, very low‐quality evidence) and at 24 hours after surgery (9 studies, 469 participants, low‐quality evidence). When we compared intravenous dexamethasone with placebo, postoperative pain intensity was also lower in the intravenous dexamethasone group than in the placebo group at 12 hours (3 studies, 162 participants, low‐quality evidence) and 24 hours (5 studies, 257 participants, low‐quality evidence). The amount of opioid pain medication required was also lower in participants receiving perineural and intravenous dexamethasone. There was no difference in postoperative pain intensity or the amount of opioid pain medication required when perineural and intravenous dexamethasone were compared. We concluded that one way of administering dexamethasone does not provide better pain relief over the other.

Five serious adverse events were reported in three studies. One block‐related adverse event (pneumothorax or collapsed lung) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however group allocation was not reported. The remaining events were non‐block‐related and occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the control group required hospitalization within one week of surgery; one for a fall and one for a bowel infection. One participant in the placebo group developed a chronic pain syndrome called Complex Regional Pain Sydrome, and one participant in the intravenous dexamethasone group developed pneumonia. The quality of evidence for safety issues was very low.

Summary of findings

Background

Description of the condition

Peripheral nerve block is a technique whereby local anaesthetic solution is infiltrated perineurally to provide anaesthesia, or analgesia, or both. Peripheral nerve block for intraoperative and postoperative pain management is associated with improved analgesia, fewer opioid‐related adverse events, earlier ambulation, and shorter hospital stay when compared with intravenous opioid analgesia alone (Barreveld 2013; Charlton 2010; Lin 2013). A limitation to the use of peripheral nerve blocks is that the analgesic effect of the block lasts only a few hours, resulting in early, moderate to severe pain, and thus the need for adjuvant therapies (Choi 2014; Cummings 2011). Peripheral nerve catheters that provide continuous infusion of local anaesthetic have been used to prolong the effects of local anaesthesia; however, continuous catheters require greater time and skill to insert than single‐shot peripheral block, may dislodge while in use, may be difficult to remove, and may add additional costs to health care (Adhikary 2012; Bowens 2011; Choi 2014). Several adjuvants have been used to attempt to prolong the analgesia provided by peripheral nerve block, including perineural and intravenous dexamethasone (Brummett 2012; Choi 2014; Popping 2009).

Description of the intervention

Dexamethasone is a corticosteroid drug that has been used as an adjuvant to reduce postoperative pain. Two systematic reviews have shown that study participants who received a single dose of intravenous dexamethasone perioperatively had lower pain scores and decreased opioid consumption after surgery compared with those given placebo (De Oliveira 2011; Waldron 2013). De Olivera 2013 studied three different intravenous doses: low‐dose (< 0.10 mg/kg), intermediate‐dose (0.11 to 0.20 mg/kg) and high‐dose (≥ 0.21 mg/kg). Low‐dose dexamethasone was not effective in reducing pain and opioid consumption; however, intermediate and high doses were effective (De Olivera 2013). Waldron 2013 performed a subgroup analysis of two doses of dexamethasone: 4 mg to 5 mg; and 8 mg to 10 mg, and did not find a dose‐response relationship.

Several randomized control trials (RCTs) have studied the use of perineural dexamethasone (i.e. dexamethasone added to the local anaesthesia solution) as an adjuvant to peripheral nerve block to improve analgesia provided by local anaesthetic alone (Bias 2014; Biradar 2013; Cummings 2011; Dar 2013; Golwala 2009; Movafegh 2006; Parrington 2010; Shaikh 2013; Tandoc 2011; Viera 2010; Yadov 2008). Perineural dexamethasone, as an adjuvant to peripheral nerve block, has been associated with faster onset of anaesthesia (Golwala 2009; Shrestha 2003; Talukdar 2013; Yadov 2008), longer duration of anaesthesia/analgesia (Biradar 2013; Cummings 2011; Dar 2013; Golwala 2009 Movafegh 2006; Parrington 2010; Shaikh 2013; Talukdar 2013; Tandoc 2011; Viera 2010; Vishnu 2014), decreased postoperative pain intensity (Cummings 2011; Dar 2013; Tandoc 2011; Yadov 2008), and decreased postoperative analgesia requirements compared with local anaesthetic alone (Shaikh 2013; Talukdar 2013; Tandoc 2011; Vishnu 2014; Yadov 2008).

Five systematic reviews have evaluated the efficacy of perineural dexamethasone versus placebo in participants undergoing surgery with peripheral nerve block. The number of trials and participants in each trial are as follows: Albrecht 2015 ‐ 29 trials, 1695 participants; Choi 2014 ‐ nine trials, 809 participants; De Oliveira 2014 ‐ nine trials, 760 participants; Huynh 2015 ‐ 12 trials, 512 participants; and Knezivic 2015 ‐ 14 trials, 1022 participants.

In all five reviews, the use of perineural dexamethasone was associated with longer duration of sensory block compared with placebo (Albrecht 2015; Choi 2014; De Oliveira 2014; Huynh 2015, Knezivic 2015). Neither the De Oliveira 2014 review nor the Huynh 2015 review found a difference in intensity of postoperative pain among participants who received perineural dexamethasone compared with placebo. The Knezivic 2015 review found intensity of pain at 24 and 48 hours after surgery was lower with dexamethasone compared with block alone. The remaining reviews did not evaluate intensity of postoperative pain (Albrecht 2015; Choi 2014). Opioid consumption was evaluated in three of five reviews. The De Oliveira 2014 and Knezivic 2015 reviews found a reduction in opioid consumption among participants who received perineural dexamethasone but the Choi 2014 review did not. Similarly, only two reviews evaluated postoperative nausea and vomiting, both reporting a reduction in the incidence of postoperative nausea and vomiting among participants who received perineural dexamethasone (Albrecht 2015; Huynh 2015). None of the reviews compared perineural dexamethasone with systemic dexamethasone, or systemic dexamethasone with placebo.

How the intervention might work

The exact mechanism by which dexamethasone reduces pain is not known. The decrease in pain intensity and the prolonged analgesia attained with the use of perineural dexamethasone may be the result of a local, or systemic action, or both (Fredrickson 2013). Dexamethasone may act locally on glucocorticosteroid receptors to induce vasoconstriction, thereby decreasing systemic absorption of local anaesthetics (Shishido 2002; Wang 2011). Other potential mechanisms of action include suppression of C‐fibre transmission of pain signals and direct action on the nerve cell to reduce neural discharge (Johansson 1990). Dexamethasone may act systemically by reducing the inflammatory response caused by surgical tissue injury (Christiansson 2009).

Why it is important to do this review

It is important to treat postoperative pain effectively. People who experience severe pain in the early postoperative period are at risk for development of chronic pain (Kehlet 2006; Vandenkerkoff 2012), which can dramatically affect their quality of life (Galvez 2007; Lame 2005; Smith 2007), and increase healthcare costs (Blyth 2003). In an attempt to augment postoperative pain management, people are often treated with opioids, which are associated with adverse events such as respiratory depression, nausea, vomiting, constipation and pruritus. Adequate treatment of people with pain through the use of peripheral nerve block may result in reduced opioid use and fewer opioid‐related harms (Avidan 2003; Hadzic 2005).

Use of perineural dexamethasone as an adjuvant to peripheral nerve block for postoperative pain is controversial. Animal studies have suggested that perineural dexamethasone is neurotoxic to peripheral nerves and has the potential to cause peripheral nerve damage; however, data in humans are limited (Ma 2010). Although no symptoms of peripheral nerve damage were reported in four RCTs examining perineural versus intravenous dexamethasone (Abdallah 2015; Desmet 2013; Kawanishi 2014; Rahangdale 2014), these studies may have been underpowered to detect differences in potential neurotoxic events (Williams 2014). Furthermore, in most studies, participants were followed for short periods (24 to 48 hours). Thus, adverse events such as persistent nerve palsy caused by peripheral nerve damage may not have been detected.

Intravenous dexamethasone may be used as an alternative to perineural dexamethasone and as an adjuvant to peripheral nerve block. In four RCTs, the effects of perineural and intravenous dexamethasone in participants receiving peripheral nerve block were studied (Abdallah 2015; Desmet 2013; Kawanishi 2014; Rahangdale 2014). In three of these studies, both perineural and intravenous dexamethasone were associated with prolonged sensory block when compared with placebo (Abdallah 2015; Desmet 2013; Rahangdale 2014). In one study, perineural but not intravenous dexamethasone was associated with prolonged sensory block when compared with placebo (Kawanishi 2014). In all four studies, no difference was observed in the duration of sensory block when perineural and intravenous dexamethasone were compared with each other.

Single‐dose intravenous dexamethasone is associated with complications such as hyperglycaemia, perineal irritation, postoperative infection, and delayed wound healing (Bartlett 2013; Crandell 2004; Pasternak 2004; Percival 2010; Perron 2003; Yared 2000). Rare adverse events include tumour lysis syndrome and psychosis after a single dose and avascular necrosis of bone after short‐term use (Fast 1984; Lerza 2002; Mc Donnell 2008; McKee 2001).

Although four systematic reviews have compared the efficacy of perineural dexamethasone versus placebo (Albrecht 2015; Choi 2014; De Oliveira 2014; Huynh 2015), to date, no comprehensive review has compared each method of dexamethasone delivery versus placebo, or perineural versus intravenous dexamethasone.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

We included all randomized controlled trials (RCTs) that evaluated the effectiveness of dexamethasone as an adjuvant to peripheral nerve block, irrespective of blinding and other design features (parallel or factorial). We did not exclude any study on the basis of language of publication or publication status. We excluded observational studies, quasi‐randomized trials and cluster‐randomized trials.

Types of participants

We included children (aged 1 month to 18 years) and adults (aged 19 years and older) undergoing upper and lower limb surgery who received a peripheral nerve block or a peripheral nerve block with the addition of dexamethasone. We excluded neonates.

Types of interventions

Our intervention groups included the following.

Participants who received peripheral nerve block and perineural dexamethasone (dexamethasone mixed with the local anaesthetic solution) versus those receiving peripheral nerve block and a perineural placebo or a non‐active comparator.
Participants who received peripheral nerve block and intravenous dexamethasone versus those receiving peripheral nerve block and intravenous placebo or a non‐active comparator.
Participants who received peripheral nerve block and perineural dexamethasone versus those receiving peripheral nerve block and intravenous dexamethasone.

We excluded participants who received local anaesthetic, or dexamethasone, or both, via more than one route (e.g. perineurally and subcutaneously).

Types of outcome measures

Primary outcomes

Duration of sensory block. We included all studies describing duration of sensory block regardless of how it was described.
Incidence of serious adverse events. We used the National Institutes of Health (NIH) definition of adverse events. A serious event includes death, a life‐threatening event that requires hospitalization or prolonged hospitalization, disability or congenital anomaly (NIH 2013).

Secondary outcomes

Duration of motor block. We included all studies describing duration of motor block, regardless of how it was described.
Incidence of mild to moderate adverse events such as nausea/vomiting, pruritus, somnolence, oxygen desaturation, urinary retention, numbness/tingling.
Postoperative pain intensity (pain scores) at 12, 24 and 48 hours.
Postoperative opioid consumption at 12, 24 and 48 hours. We converted all opioids to oral morphine equivalents.
Participant satisfaction with pain control. Participant satisfaction is typically measured on a numerical rating scale (NRS).

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (inception to 25 April 2017), (Appendix 1) MEDLINE via Ovid (1966 to 25 April 2017) (Appendix 2), Embase via Ovid (1947 to 25 April 2017) (,Appendix 3) the Database of Abstracts of Reviews of Effectiveness (DARE) (inception to 25 April 2017), and Web of Science (Appendix 4) and Scopus (inception to 25 April 2017) . An experienced librarian assisted with the search strategy. The MEDLINE search strategy presented in Appendix 2 was adopted for searching the DARE and Scopus databases. We did not impose any language restrictions.

Searching other resources

We reviewed the reference lists of all included trials for additional studies that met our criteria, as well as trial registry databases (ClinicalTrials.gov (clinicaltrials.gov), EU Cinical Trials Register (clinicaltrialsregister.eu), and Current Controlled Trials (isrctn.com), Google Scholar and meeting abstracts from the American Society of Anesthesiologists, the Canadian Anesthesiologists' Society, the American Society of Regional Anesthesia, and the European Society of Regional Anaesthesia (2010 to April 2017).

Data collection and analysis

Selection of studies

Using the results of all searches, two review authors (AK and CP) independently screened titles and abstracts for eligibility according to the following criteria:.

The study described was an RCT.
Participants received a peripheral nerve block.
Dexamethasone was given perineurally (mixed with the local anaesthetic) or intravenously.

In cases of disagreement on eligibility, we consulted a third review author (BJ) to determine eligibility. If additional information was required, we contacted the first author of the trial.

Data extraction and management

Two review authors (AP and CP) independently extracted data and assessed the quality of each trial using a standardized, pre‐piloted form (Appendix 5). We resolved disagreements through discussion with a senior review author (BJ).

Assessment of risk of bias in included studies

Using the Cochrane 'Risk of bias' instrument, we assessed the risk of bias of each study using the following domains (Higgins 2011).

Random sequence generation.
Allocation concealment.
Blinding of participants and personnel.
Blinding of outcome assessment.
Selective reporting.
Missing participant data.

For each study, we classified risk of bias of each domain as low, high or unclear. If risk of bias was low for all domains or was low for five out of the six domains then we classified the risk of bias as low for that study. If two or more domains were classified as high or unclear risk of bias, we determined the study to be at high or unclear risk of bias, respectively.

Measures of treatment effect

We analysed continuous outcomes including pain scores, analgesic consumption, duration of sensory and motor block. and participant satisfaction by calculating the mean difference (MD) with corresponding 95% confidence interval (CI). We pooled dichotomous outcomes to calculate the risk ratio (RR) and the risk difference (RD) with corresponding 95% CI. We assumed a normal distribution of pain scores on the Visual Analogue Scale (VAS) or the numerical rating scale (NRS) among intervention and placebo groups, and we considered a 1.2 cm change/1.2 point change on the VAS/NRS as representative of a minimally important difference (MID) in acute pain (Johnston 2013; Kelly 2001).

Unit of analysis issues

We avoided unit of analysis errors as follows: if included studies had more than two study arms, we combined relevant groups to create a single pair‐wise comparison, or, if not possible, we selected one pair of interventions and excluded the others.

Dealing with missing data

We assessed the completeness of outcome data and determined whether missing outcome data may put continuous and dichotomous outcomes at risk of bias. If primary analyses for our critical outcome of interest suggested significant benefit (or harm), we conducted a sensitivity meta‐analysis to address missing participant data (Akl 2012; Ebrahim 2013).

To determine whether missing participant data represented risk of bias for continuous outcomes (pain at 12, 24 and 48 hours), we used the method described by Ebrahim 2013. For each outcome with missing data, we used four progressively stringent data input strategies based on observed outcomes for those individuals in the intervention and placebo arms for whom data were not missing.

If we found a significant difference in serious adverse events, to determine whether missing participant data represented risk of bias for dichotomous outcomes (serious adverse events), we conducted a sensitivity meta‐analysis using the worst‐case scenario assumption described by Akl 2013. If results were robust to the worst‐case scenario (all missing participants in the treatment experienced the outcome of interest, and none of the participants in the placebo group did), we concluded that the missing data did not represent a source of bias. If results of the sensitivity meta‐analysis were not robust to the worst‐case scenario, we tested more plausible assumptions. For participants missing from the intervention group, we assumed a range of ratios of event rates for those with missing data compared with those successfully followed of 2:1, 3:1 and 5:1 (Akl 2012).

Assessment of heterogeneity

We used the Cochran Q and I² tests to assess the potential for statistical heterogeneity between trials. For the Cochran Q, the null hypothesis is that the underlying effect is the same in each of the included studies. A P value less than 0.10 means that random error provides an unlikely explanation for observed differences in study results between trials. The I² statistic shows the percentage of variability due to differences between studies such that I² > 75% indicates considerable heterogeneity (Higgins 2011; Riley 2011).

Assessment of reporting biases

For outcomes reported in 10 or more trials, we assessed publication biases using a funnel plot (Higgins 2011).

Data synthesis

We entered data into Review Manager statistical software and analysed data using the DerSimonian‐Laird random‐effects model (Review Manager 2014).

If data for some outcomes were not amenable to meta‐analysis, we planned to use tables to describe the characteristics of each trial that contributed to our a priori outcomes. We planned to describe all trial populations, interventions, comparator(s), outcome(s) and follow‐up time points for outcomes not amenable to meta‐analysis.

Subgroup analysis and investigation of heterogeneity

We analysed the following subgroups.

Long‐acting local anaesthetics (e.g. ropivacaine, bupivacaine, levobupivacaine) versus medium‐acting local anaesthetics (e.g. lidocaine, mepivacaine).
Additives to local anaesthetics (e.g. clonidine, epinephrine) versus no additives to local anaesthetics.
Low‐dose dexamethasone (4 mg to 5 mg) versus high‐dose dexamethasone (8 mg to 10 mg).
Adult versus paediatric participants. (See Differences between protocol and review)
Studies at high/unclear risk of bias versus studies at low risk of bias.

Following are our a priori hypotheses for explaining heterogeneity between trials.

For the outcome, duration of sensory block, we anticipated that participants receiving dexamethasone along with long‐acting local anaesthetics (e.g. ropivacaine, bupivacaine, levobupivacaine) would show larger effects than those receiving dexamethasone with medium‐acting local anaesthetics (e.g. lidocaine, mepivacaine).
1. Choi et al in a systematic review and meta‐analysis compared the effects of short‐acting local anaesthetics and medium‐acting anaesthetics and found that the duration of analgesia in participants receiving long‐acting anaesthetics was longer than those receiving medium‐acting local anaesthetics (Choi 2014).
For the outcome, duration of sensory block, we anticipated that participants who receive additives to local anaesthesia (e.g. clonidine, epinephrine) would show a larger effect than those who do not.
1. In a systematic review of 20 RCTs of 573 participants, Popping and colleagues found that the duration of intermediate and long‐acting local anaesthetics was longer in participants who received clonidine (Popping 2009).
Although we conducted a subgroup analysis on dose of dexamethasone for the outcomes: pain intensity, duration of analgesia, and serious adverse events, we did not expect that participants who receive high‐dose dexamethasone would show any difference in effect when compared with those receiving low‐dose dexamethasone.
1. Albrecht and colleagues, in a systematic review of 29 RCTs of 1695 participants did not find a difference in duration of analgesia in participants who received 4 mg of dexamethasone compared with those who received 8 mg (Albrecht 2015). Differences in other outcomes, including intensity of pain and adverse events were not reported.
For the outcome of adult versus paediatric participants, we did not anticipate a difference in duration of analgesia or intensity of pain.
1. Currently, no evidence supports that the pharmacokinetics of dexamethasone is different in children when compared with adults.
For the outcomes of intensity of pain and duration of sensory block, we expected that trials with high risk of bias would show a larger effect than those with low risk of bias.
1. Our subgroup on risk of bias is based on previous literature suggesting that studies at high risk of bias are more likely to overestimate treatment effects (Nuesch 2009; Wood 2008).

Sensitivity analysis

We conducted a sensitivity analysis to assess the completeness of outcome data and to determine whether missing outcome data put continuous and dichotomous outcomes at risk of bias, using the methods described in Dealing with missing data.

'Summary of findings' table and GRADE

Two review authors (AP and CP) independently prepared a 'Summary of findings' table using GRADEprofiler software to assess the confidence of estimates of effect (GRADEpro GDT 2015), for the following outcomes of interest.

Duration of sensory block.
Incidence of serious adverse events
Postoperative pain intensity at 12 hours.
Postoperative pain intensity at 24 hours.
Postoperative pain intensity at 48 hours.

We used GRADE principles as described by Guyatt 2008, to independently assess the confidence in our pooled estimates of effect (i.e. overall quality of evidence) using the following criteria.

Risk of bias.
Consistency.
Directness.
Precision.
Reporting bias.

For RCTs, we initially assigned high confidence ratings, but rated confidence as moderate, low or very low if we detected issues with risk of bias, consistency or other GRADE criteria. In particular, we categorized the quality of each pooled estimate as high (we are very confident that the true effect lies close to that of the estimate of the effect), moderate (we are moderately confident in the effect estimate ‐ the true effect is likely to be close to the estimate of the effect, but may be substantially different), low (our confidence in the effect estimate is limited ‐ the true effect may be substantially different from the estimate of the effect) or very low (we have very little confidence in the effect estimate ‐ the true effect is likely to be substantially different from the estimate of effect) (Guyatt 2008).

We referred discrepancies in assessment of the quality of evidence to a third review author (BJ) for a final decision.

Results

Description of studies

Results of the search

Please see the PRISMA flowchart for the selection process of the included studies (Figure 1):

We identified 3443 unique records in our literature search. Of these, 51 were potentially eligible. Nine were protocols found on ClinicalTrials.gov for which no results were available (NCT01277159; NCT01495624; NCT01586806; NCT01971645; NCT02178449; NCT02322242; NCT02436694; NCT02462148; NCT02506660). We excluded seven studies: two because there was no placebo group (Fredrickson 2013; Shethra 2007); one because participants received both perineural and intravenous dexamethasone (Lui 2015): one because the authors reported only a means without any variances, therefore we could not enter the data into a meta‐analysis (Percec 2014); and three were secondary publications of included studies (Arora 2010; Desmet 2012; Kim 2010), leaving 35 for inclusion in the review.

Included studies

Participants

The 35 included trials involved 2702 participants. All studies were in Americal Anesthesiology Society (ASA) I to III adolescent and adult participants aged 15 to 78 years. We did not find any studies in children aged less than 15 years. Length of follow‐up ranged from one day to six months after surgery. Surgical procedures included the forearm and hand (not including the elbow) (Abdallah 2015; Aliste 2017; Alarasan 2017; Lee 2016; Leurcharusmee 2016; Movafegh 2006; Parrington 2010; Saritas 2014; Shah 2015; Yadov 2008), forearm and hand (including the elbow) (Biradar 2013; Shah 2015; Shaikh 2013), arthroscopic shoulder (Chalifoux 2017; Chun 2016; Desmet 2013; Jadon 2015; Kawanishi 2014; Kim 2012; Sakae 2017; Tandoc 2011; Viera 2010; Woo 2015), both arthroscopic and open shoulder (Cummings 2011; Nallam 2014; Rosenfeld 2016), upper limb (Bias 2014; Dar 2013; Ganvit 2014; Golwala 2009; Kumar 2014; Talukdar 2013; Vishnu 2014), rotator cuff repair or subacromial decompression (Desmet 2015), and foot and ankle (Dawson 2016; Rahangdale 2014).

Type of block included interscalene brachial plexus (Chun 2016; Chalifoux 2017; Cummings 2011; Desmet 2013; Desmet 2015; Ganvit 2014; Jadon 2015; Kawanishi 2014; Kim 2012; Nallam 2014; Tandoc 2011; Viera 2010; Woo 2015), supraclavicular brachial plexus (Abdallah 2015; Alarasan 2017; Bias 2014; Biradar 2013; Dar 2013; Golwala 2009; Kumar 2014; Parrington 2010; Shaikh 2013; Talukdar 2013; Vishnu 2014; Yadov 2008), axillary brachial plexus (Aliste 2017; Movafegh 2006; Rosenfeld 2016; Saritas 2014), infraclavicular brachial plexus (Leurcharusmee 2016; Sakae 2017; Shah 2015), sciatic nerve (Rahangdale 2014), and ankle block (Dawson 2016).

Additives to local anaesthetic agent included epinephrine (Alarasan 2017; Biradar 2013; Ganvit 2014; Golwala 2009; Leurcharusmee 2016; Rahangdale 2014; Shaikh 2013; Tandoc 2011; Viera 2010; Yadov 2008), and clonidine (Viera 2010). No additives were used in the remaining studies.

Dexamethasone dose included 4 mg (Kawanishi 2014; Sakae 2017; Yadov 2008), 5 mg (Alarasan 2017; Chun 2016; Kim 2012), 7.5 mg (Woo 2015), 8 mg (Abdallah 2015; Aliste 2017; Bias 2014; Biradar 2013; Cummings 2011; Dar 2013; Dawson 2016; Ganvit 2014; Golwala 2009; Jadon 2015; Kumar 2014; Leurcharusmee 2016; Movafegh 2006; Nallam 2014; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Saritas 2014; Shah 2015; Shaikh 2013; Talukdar 2013; Tandoc 2011; Viera 2010; Vishnu 2014), and 10 mg (Chalifoux 2017; Desmet 2013; Desmet 2015; Lee 2016).

Comparators

In all included studies, participants received a peripheral nerve block with local anaesthesia. In studies comparing perineural dexamethasone and placebo, participants received either perineural dexamethasone or an equal volume of perineural saline. In studies comparing intravenous dexamethasone and placebo, participants received either intravenous dexamethasone or an equal volume of intravenous saline. In studies comparing perineural and intravenous dexamethasone, participants in the perineural dexamethasone group received dexamethasone perineurally and intravenous saline. Those in the intravenous dexamethasone group received dexamethasone intravenously and perineural saline.

Funding sources

Funding sources included: Merit Award form the Department of Anesthesia, Univerity of Toronto (Abdallah 2015), departmental sources (Alarasan 2017; Chalifoux 2017; Cummings 2011), Belgian Association for Regional Anesthesia (Desmet 2015), Department of Anesthesiology, Northwestern University (Rahangdale 2014), Buffalo Anesthesiology Associates (Tandoc 2011), and Department of Anesthesiology, Baystate Medical Center, Springfield, Massachutes (Viera 2010) (see Characteristics of included studies).

Contact with authors

We attempted to contact 15 authors for additional information (Abdallah 2015; Cummings 2011; Dar 2013; Desmet 2013; Desmet 2015; Jadon 2015; Kawanishi 2014; Kumar 2014; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Sakae 2017; Shah 2015; Viera 2010; Woo 2015), and were successful in obtaining data from seven (Abdallah 2015; Cummings 2011; Rahangdale 2014; Rosenfeld 2016; Sakae 2017; Shah 2015; Viera 2010).

Excluded studies

We excluded four studies from our review. Two lacked a placebo group (Fredrickson 2013; Shethra 2007), one reported data as median and range (minimum to maximum), therefore we could not enter the results in a meta‐analysis (Percec 2014), and in another, participants received both perineural and intravenous dexamethasone (Lui 2015) (see Characteristics of excluded studies).

Ongoing studies

We found nine ongoing trials at ClinicalTrials.gov (NCT01277159; NCT01495624; NCT01586806; NCT01971645; NCT02178449; NCT02322242; NCT02436694; NCT02462148; NCT02506660) (see Characteristics of ongoing studies).

Studies awaiting classification

There are no studies awaiting classification.

Risk of bias in included studies

The overall risk of bias was low in 13 studies (Abdallah 2015; Aliste 2017; Chalifoux 2017; Cummings 2011; Dawson 2016; Desmet 2013; Desmet 2015; Kumar 2014; Leurcharusmee 2016; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Woo 2015) and high/unclear in the remaining 22. Figure 2 shows authors' judgements about each risk of bias item presented as percentages across all included studies and Figure 3 shows review authors' judgements about each risk of bias item for each included study.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

In 24 studies the method of random sequence generation was adequately described, and we judged the risk of bias to be low (Abdallah 2015; Aliste 2017; Biradar 2013; Chalifoux 2017; Chun 2016; Cummings 2011; Dawson 2016; Desmet 2013; Desmet 2015; Jadon 2015; Lee 2016; Leurcharusmee 2016; Movafegh 2006; Nallam 2014; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Saritas 2014; Shah 2015; Talukdar 2013; Tandoc 2011; Viera 2010; Vishnu 2014; Woo 2015). In the 11 remaining, we judged the risk of bias to be unclear because the random sequence was not described.

In 15 studies the method of allocation concealment was adequately described, and we judged the risk of bias to be low (Abdallah 2015; Aliste 2017; Chalifoux 2017; Cummings 2011; Dar 2013; Dawson 2016; Desmet 2013; Desmet 2015; Jadon 2015; Kawanishi 2014; Kumar 2014; Leurcharusmee 2016; Parrington 2010; Rahangdale 2014; Rosenfeld 2016). In the remaining 20 we judged the risk of bias to be unclear because the method of allocation concealment was not described.

Blinding

Blinding of participants was adequately described in 16 studies (Abdallah 2015; Aliste 2017; Biradar 2013; Chalifoux 2017; Chun 2016; Cummings 2011; Kumar 2014; Leurcharusmee 2016; Movafegh 2006; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Sakae 2017; Saritas 2014; Shaikh 2013; Vishnu 2014).

Blinding of personnel was adequately described in 12 studies (Abdallah 2015; Aliste 2017; Chalifoux 2017; Cummings 2011; Dawson 2016; Desmet 2015; Kumar 2014; Leurcharusmee 2016; Rahangdale 2014; Rosenfeld 2016; Sakae 2017; Woo 2015).

Bliding of outcome assessors was adequately described in 21 studies(Abdallah 2015; Aliste 2017; Biradar 2013; Chalifoux 2017; Chun 2016; Cummings 2011; Desmet 2013; Desmet 2015; Jadon 2015; Kim 2012; Kumar 2014; Leurcharusmee 2016; Movafegh 2006; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Sakae 2017; Saritas 2014; Shaikh 2013; Vishnu 2014; Woo 2015).

Incomplete outcome data

We judged the risk for attrition bias to be low in 33 studies. There were no missing outcome data in 16 (Abdallah 2015; Alarasan 2017; Bias 2014; Cummings 2011; Dar 2013; Dawson 2016; Kim 2012; Kumar 2014; Lee 2016; Sakae 2017; Saritas 2014; Talukdar 2013; Viera 2010; Vishnu 2014; Woo 2015; Yadov 2008), and in 17, the number of participants with missing outcome data was balanced between groups (Aliste 2017; Biradar 2013; Chalifoux 2017; Chun 2016; Desmet 2013; Desmet 2015; Ganvit 2014; Golwala 2009; Jadon 2015; Kawanishi 2014; Leurcharusmee 2016; Nallam 2014; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Shaikh 2013; Tandoc 2011). We judged two studies to be at high risk of attrition bias. In one, over 30% of participants in each group were excluded from the study (Movafegh 2006), and in the other, only 41 of 53 participants enrolled were included in the analysis (Shah 2015).

Selective reporting

We judged 23 studies to be at low risk of reporting bias. Protocols were available for eight and all prespecified outcomes were reported (Abdallah 2015; Aliste 2017; Cummings 2011; Leurcharusmee 2016; Parrington 2010; Rahangdale 2014; Rosenfeld 2016; Woo 2015). In the remaining 15, protocols were not available, but all outcomes prespecified in the methods section were reported (Alarasan 2017; Biradar 2013; Chalifoux 2017; Dar 2013; Dawson 2016; Desmet 2013; Desmet 2015; Ganvit 2014; Kumar 2014; Lee 2016; Movafegh 2006; Nallam 2014; Shah 2015; Tandoc 2011; Viera 2010). Twelve studies were at high risk of selective outcome bias. In two, protocols were available but not all outcomes were reported as per protocol (Chun 2016; Sakae 2017), and in 10, not all outcomes were reported as described in the methods section (Bias 2014; Golwala 2009; Jadon 2015; Kawanishi 2014; Kim 2012; Saritas 2014; Shaikh 2013; Talukdar 2013; Vishnu 2014; Yadov 2008).

Other potential sources of bias

There were other potential sources of bias in two studies. Both were stopped early for benefit (Cummings 2011; Shah 2015), which may be a source of bias.

Effects of interventions

See: Table 1; Table 2; Table 3

Summary of findings for the main comparison. Perineural dexamethasone versus placebo.

Patient or population: participants undergoing surgery with peripheral nerve block  Setting: participants undergoing upper and lower limb surgery in hospitals in Australia, Bangledesh, Belgium, Brazil, India, Iran, Japan, Korea, Nepal, Turkey and USA Intervention: perineural dexamethasone Comparison: placebo
Outcomes	Anticipated absolute effects^* (95% CI)		№ of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk with placebo	Risk with perineural dexamethasone	№ of participants  (studies)	Quality of the evidence  (GRADE)
Duration of sensory block (we included all studies describing duration of sensory block, regardless of how it was described)	The mean duration of sensory block was 10.2 hours	The mean duration of sensory block in the perineural dexamethasone group was 6.70 hours longer (5.54 longer to 7.85 longer)	1625  (27 RCTs)	⨁⨁◯◯  LOW ^a
Incidence of serious adverse events (we used the NIH definition of adverse events. A serious event includes death, a life‐threatening event that requires hospitalization or prolonged hospitalization, disability or congenital anomaly)	In seven studies, authors reported that they assessed for serious adverse events. Five serious adverse events were reported in three studies: one block‐related adverse event (pneumothorax) occurred in one participant in a trial comparing perineural dexamethasone and placebo; however, group allocation was not reported. The remaining non‐block‐related events occurred in two trials comparing perineural dexamethasone, intravenous dexamethasone and placebo. Two participants in the placebo group required hospitalization within one week of surgery; one for a fall, and one for a bowel infection. One participant in the placebo group developed Complex Regional Pain Syndrome Type I and one in the intravenous dexamethasone group developed pneumonia.		620 (7 RCTs)	⨁◯◯◯  VERY LOW^b
Postoperative pain intensity at 12 hours (assessed by pain scores on an 11‐point VAS)	The mean postoperative pain intensity at 12 hours was 3.0	The mean postoperative pain score at 12 hours in the perineural dexamethasone group was 2.08 points lower (1.52 lower to 2.63 lower)	257  (5 RCTs)	⨁◯◯◯  VERY LOW^c
Postoperative pain intensity at 24 hours. (assessed by pain scores on an 11‐point VAS)	The mean postoperative pain intensity at 24 hours was 3.9	The mean postoperative pain score at 24 hours in the perineural dexamethasone group was 1.63 points lower (0.93 lower to 2.34 lower)	469  (9 RCTs)	⨁⨁◯◯  LOW ^d
Postoperative pain intensity at 48 hours (assessed by pain scores on an 11‐point VAS)	The mean postoperative pain intensity at 48 hours was 3.3	The mean postoperative pain score at 48 hours in the perineural dexamethasone group was 0.61 points lower (1.24 lower to 0.03 higher)	296  (3 RCTs)	⨁⨁◯◯  LOW ^e
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; MD: Mean difference; NIH: National Institute of Health; RCT: randomized controlled trial; VAS: Visual Analogue Scale.
GRADE Working Group grades of evidence   High‐quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.  Very low‐quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Patient or population: participants undergoing surgery with peripheral nerve block  Setting: participants undergoing upper and lower limb surgery in hospitals in Australia, Belgium, Brazil, Canada, Japan, Korea, Thailand and USA Intervention: intravenous dexamethasone Comparison: placebo
Outcomes	Anticipated absolute effects^* (95% CI)		№ of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk with placebo	Risk with intravenous dexamethasone	№ of participants  (studies)	Quality of the evidence  (GRADE)
Duration of sensory block (we included all studies describing duration of sensory block regardless of how it was described)	The mean duration of sensory block was 16.1 hours	The mean duration of sensory block in the intravenous dexamethasone group was 6.21 hours longer (3.53 longer to 8.88 longer)	499  (8 RCTs)	⨁⨁⨁◯  MODERATE ^a
Incidence of serious adverse events (we used the NIH definition of adverse events. A serious event includes death, a life‐threatening event that requires hospitalization or prolonged hospitalization, disability or congenital anomaly)	Please see incidence of serious adverse events in the perineural dexamethasone versus placebo 'Summary of findings' table.
Postoperative pain intensity at 12 hours (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 12 hours was 2.6	The mean postoperative pain score at 12 hours in the intravenous dexamethasone group was 1.24 points lower (2.44 lower to 0.04 lower)	162  (3 RCTs)	⨁⨁◯◯  LOW ^b
Postoperative pain intensity at 24 hours  (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 24 hours was 4.4	The mean postoperative pain score at 24 hours in the intravenous dexamethasone group was 1.26 points lower (2.23 lower to 0.29 lower)	257  (5 RCTs)	⨁⨁◯◯  LOW ^c
Postoperative pain intensity at 48 hours (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 48 hours was 3.7	The mean postoperative pain score at 48 hours in the intravenous dexamethasone group was 0.21 points lower (0.83 lower to 0.41 higher)	172  (3 RCTs)	⨁⨁◯◯  LOW ^d
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; MD: Mean difference; NIH: National Institute of Health; RCT: randomized controlled trial; VAS: Visual Analogue Scale.
GRADE Working Group grades of evidence   High‐quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.  Very low‐quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Patient or population: peripheral nerve block Setting: people undergoing upper or lower limb surgery with peripheral nerve block in hospitals in Australia, Belgium, Brazil, Canada and USA Intervention: perineural dexamethasone Comparison: intravenous dexamethasone
Outcomes	Anticipated absolute effects^* (95% CI)		№ of participants  (studies)	Quality of the evidence  (GRADE)
Outcomes	Risk with intravenous dexamethasone	Risk with perineural dexamethasone	№ of participants  (studies)	Quality of the evidence  (GRADE)
Duration of sensory block (we included all studies describing duration of sensory block regardless of how it was described)	The mean duration of sensory block was 20.6 hours	The mean duration of sensory block in the perineural dexamethasone group was 3.13 hours longer (1.68 longer to 4.58 longer)	720  (9 RCTs)	⨁⨁⨁◯  MODERATE ^a
Incidence of serious adverse events (we used the NIH definition of adverse events. A serious event includes death, a life‐threatening event that requires hospitalization or prolonged hospitalization, disability or congenital anomaly)	Please see incidence of serious adverse events in the perineural dexamethasone versus placebo 'Summary of findings' table.
Postoperative pain intensity at 12 hours (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 12 hours was 2.3	The mean postoperative pain score at 12 hours in the perineural dexamethasone group was 1.01 points lower (0.50 lower to 1.51 lower)	217  (3 RCTs)	⨁⨁◯◯  LOW ^b
Postoperative pain intensity at 24 hours (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 24 hours was 2.9	The mean postoperative pain score at 24 hours in the perineural dexamethasone group was 0.77 points lower (0.08 lower to 1.47 lower)	309  (5 RCTs)	⨁⨁⨁◯  MODERATE ^c
Postoperative pain intensity at 48 hours (measured using pain scores on an 11‐point VAS)	The mean postoperative pain score at 48 hours was 2.8	The mean postoperative pain score at 48 hours in the perineural dexamethasone group was 0.13 points higher (0.35 lower to 0.61 higher)	227  (3 RCTs)	⨁⨁◯◯  LOW ^d
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; MD: Mean difference; NIH: National Institute of Health; RCT: randomized controlled trial; VAS: Visual Analogue Scale.
GRADE Working Group grades of evidence   High‐quality: we are very confident that the true effect lies close to that of the estimate of the effect.  Moderate‐quality: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.  Low‐quality: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.  Very low‐quality: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

Date form completed(dd/mm/yyyy)
Name/ID of person extracting data
Report title (title of paper/abstract/report from which data are extracted)
Report ID (ID for this paper/abstract/report)
Reference details
Report author contact details
Publication type (e.g. full report, abstract, letter)
Study funding sources (including role of funders)
Possible conflicts of interest (for study authors)
Notes:

Study characteristics	Eligibility criteria (insert eligibility criteria for each characteristic as defined in the Protocol)		Yes	No	Unclear	Location in text (pg & ¶/fig/table)
Type of study	Randomized control trial
Participants
Types of interventions
Types of outcome measures
INCLUDE		EXCLUDE
Reason for exclusion
Notes:

	Description (include comparative information for each group (i.e. intervention and placebos) if available)	Location in text (pg & ¶/fig/table)
Population description (from which study participants are drawn)
Inclusion criteria
Exclusion criteria
Method/s of recruitment of participants
Informed consent obtained	Yes/No/Unclear
Notes:

	Descriptions as stated in report/paper	Location in text (pg & ¶/fig/table)
Aim of study
Design(e.g. parallel, cross‐over, cluster)
Unit of allocation (by individuals, clusters/groups or body parts)
Start date
End date
Total study duration
Ethical approval needed/obtained for study	Yes/No/Unclear
Notes:

Domain	Risk of bias			Support for judgement	Location in text (pg & ¶/fig/table)
Domain	Low risk	High risk	Unclear risk	Support for judgement	Location in text (pg & ¶/fig/table)
Random sequence generation (selection bias)
Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)				Outcome group: All/
(if required)				Outcome group:
Blinding of outcome assessment (detection bias)				Outcome group: All/
(if required)				Outcome group:
Incomplete outcome data (attrition bias)
Selective outcome reporting? (reporting bias)
Other bias
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Total no. randomly assigned (or total population at start of study for NRCTs)
Withdrawals and exclusions (if not provided below by outcome)
Age
Sex
American Society of Anesthesiologists (ASA) classification
Subgroups measured
Subgroups reported
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Group name
No. randomly assigned to group (specify whether no. people or clusters)
Description(include sufficient detail for replication, e.g. content, dose, components)
Duration of treatment period
Timing(e.g. frequency, duration of each episode)
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Outcome name
Time points measured
Time points reported
Outcome definition(with diagnostic criteria if relevant)
Person measuring/reporting
Unit of measurement (if relevant)
Scales: upper and lower limits(indicate whether high or low score is good)
Is outcome/tool validated?	Yes/No/Unclear
Imputation of missing data   (e.g. assumptions made for ITT analysis)
Assumed risk estimate (e.g. baseline or population risk noted in Background)
Power
Notes:

		Description as stated in report/paper						Location in text (pg & ¶/fig/table)
Comparison
Outcome
Subgroup
Time point   (specify whether from start or end of intervention)
Post‐intervention or change from baseline?
Results	Intervention				Comparison
	Mean		SD (or other variance)	No. participants	Mean	SD (or other variance)	No. participants

No. missing participants and reasons
No. participants moved from other group and reasons
Other results reported
Unit of analysis (individuals, clusters/groups or body parts)
Statistical methods used and appropriateness of these methods(e.g. adjustment for correlation)
Reanalysis required?(specify)		Yes/No/Unclear
Reanalysis possible?		Yes/No/Unclear
Reanalysed results
Notes:

Does the study directly address the review question? (issues of partial or indirect applicability)	Yes/No/Unclear
Notes:

	Description as stated in report/paper	Location in text (pg & ¶/fig/table)
Key conclusions of study authors
References to other relevant studies
Correspondence required for further study information(from whom, what and when)
Notes:

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of sensory block	27	1625	Mean Difference (IV, Random, 95% CI)	6.70 [5.54, 7.85]
2 Duration of sensory block: long‐ versus medium‐acting local anaesthetic subgroups	26	1572	Mean Difference (IV, Random, 95% CI)	6.78 [5.62, 7.94]
2.1 Long‐acting local anaesthetic	20	1315	Mean Difference (IV, Random, 95% CI)	7.81 [6.40, 9.21]
2.2 Medium‐acting local anaesthetic	6	257	Mean Difference (IV, Random, 95% CI)	3.98 [1.76, 6.20]
3 Duration of sensory block: additive versus no additive subgroups	27	1625	Mean Difference (IV, Random, 95% CI)	6.70 [5.54, 7.85]
3.1 Additives	6	336	Mean Difference (IV, Random, 95% CI)	7.29 [3.77, 10.81]
3.2 No additives	21	1289	Mean Difference (IV, Random, 95% CI)	6.60 [5.30, 7.89]
4 Duration of sensory block: high‐ versus low‐dose dexamethasone subgroups	27	1627	Mean Difference (IV, Random, 95% CI)	6.70 [5.53, 7.86]
4.1 High‐dose dexamethasone	23	1447	Mean Difference (IV, Random, 95% CI)	7.09 [5.81, 8.38]
4.2 Low‐dose dexamethasone	4	180	Mean Difference (IV, Random, 95% CI)	4.32 [1.80, 6.85]
5 Duration of sensory block: high/unclear versus low risk of bias subgroups	26	1625	Mean Difference (IV, Random, 95% CI)	6.70 [5.54, 7.85]
5.1 High or unclear risk of bias	19	1037	Mean Difference (IV, Random, 95% CI)	6.28 [5.01, 7.56]
5.2 Low risk of bias	8	588	Mean Difference (IV, Random, 95% CI)	8.21 [4.56, 11.85]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of motor block	16	912	Mean Difference (IV, Random, 95% CI)	5.87 [4.44, 7.30]
2 Duration of motor block: long‐ versus medium‐acting local anaesthetic subgroups	16	912	Mean Difference (IV, Random, 95% CI)	5.87 [4.44, 7.30]
2.1 Long‐acting local anaesthetic	13	764	Mean Difference (IV, Random, 95% CI)	6.61 [4.58, 8.65]
2.2 Medium‐acting local anaesthetic	3	148	Mean Difference (IV, Random, 95% CI)	2.59 [2.42, 2.76]
3 Duration of motor block: additives verus no additives subgroups	16	912	Mean Difference (IV, Random, 95% CI)	5.87 [4.44, 7.30]
3.1 Additives	5	280	Mean Difference (IV, Random, 95% CI)	7.47 [3.58, 11.36]
3.2 No additives	11	632	Mean Difference (IV, Random, 95% CI)	5.26 [3.17, 7.35]
4 Duration of motor block: high‐ versus low‐dose dexamethasone subgroups	16	912	Mean Difference (IV, Random, 95% CI)	5.87 [4.44, 7.30]
4.1 High‐dose dexamethasone	15	872	Mean Difference (IV, Random, 95% CI)	5.75 [4.29, 7.22]
4.2 Low‐dose dexamethasone	1	40	Mean Difference (IV, Random, 95% CI)	8.1 [4.69, 11.51]
5 Duration of motor block: high/unclear versus low risk of bias subgroups	16	912	Mean Difference (IV, Random, 95% CI)	5.87 [4.44, 7.30]
5.1 High/unclear risk of bias	14	809	Mean Difference (IV, Random, 95% CI)	5.67 [4.18, 7.16]
5.2 Low risk of bias	2	103	Mean Difference (IV, Random, 95% CI)	7.93 [2.74, 13.13]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall incidence of block‐related adverse events	10	677	Risk Ratio (M‐H, Random, 95% CI)	1.17 [0.99, 1.39]
2 Numbness/tingling 14 days after surgery	5	323	Risk Ratio (M‐H, Random, 95% CI)	1.76 [0.80, 3.89]
3 Residual motor block/weakness 24 hours after surgery	3	259	Risk Ratio (M‐H, Random, 95% CI)	4.69 [0.57, 38.68]
4 Horner Syndrome	4	321	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.73, 1.36]
5 Hoarseness	4	353	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.65, 2.34]
6 Diaphragmatic paresis	2	172	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.66, 3.23]
7 Dyspnoea	4	274	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.01, 8.14]
8 Vascular injury	1	100	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.19, 21.36]
9 Cranial nerve 12 palsy	1	83	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.77]
10 Bruising	1	37	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.07, 15.64]
11 Overall non‐block‐related adverse events	10	625	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.35, 1.68]
12 Postoperative nausea and vomiting	10	585	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.26, 1.14]
13 Deep sedation	1	60	Risk Ratio (M‐H, Random, 95% CI)	7.0 [0.38, 129.93]
14 Dermatological symptoms (pruritus/rash)	1	83	Risk Ratio (M‐H, Random, 95% CI)	2.93 [0.32, 27.02]
15 Syncope/fainting	1	83	Risk Ratio (M‐H, Random, 95% CI)	1.95 [0.18, 20.71]
16 Bradycardia	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.12, 3.71]
17 Hypotension	2	140	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.21, 2.13]
18 Headache/10‐pound fluid gain/diarrhoea/frequent urination/muscle soreness	1	83	Risk Ratio (M‐H, Random, 95% CI)	2.93 [0.12, 69.92]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at12 hours	5	257	Mean Difference (IV, Random, 95% CI)	‐2.08 [‐2.63, ‐1.52]
2 Postoperative pain intensity at 12 hours: medium‐ versus long‐acting local anaesthetic subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐2.08 [‐2.63, ‐1.53]
2.1 Long‐acting local anaesthesia	4	234	Mean Difference (IV, Random, 95% CI)	‐2.21 [‐2.77, ‐1.66]
2.2 Medium‐acting local anaesthesia	1	23	Mean Difference (IV, Random, 95% CI)	‐1.22 [‐2.38, ‐0.06]
3 Postoperative pain intensity at 12 hours: additive versus no additive subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐2.08 [‐2.63, ‐1.52]
3.1 Additives	1	23	Mean Difference (IV, Random, 95% CI)	‐1.20 [‐2.36, ‐0.04]
3.2 No additives	4	234	Mean Difference (IV, Random, 95% CI)	‐2.21 [‐2.77, ‐1.66]
4 Postoperative pain intensity at 12 hours: high‐ versus low‐dose dexamethasone subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐2.08 [‐2.63, ‐1.52]
4.1 High‐dose dexamethasone	3	177	Mean Difference (IV, Random, 95% CI)	‐2.17 [‐3.29, ‐1.06]
4.2 Low‐dose dexamethasone	2	80	Mean Difference (IV, Random, 95% CI)	‐1.99 [‐2.75, ‐1.22]
5 Postoperative pain intensity at 12 hours: high/unclear versus low risk of bias subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐2.08 [‐2.63, ‐1.52]
5.1 High/unclear versus low risk of bias	3	103	Mean Difference (IV, Random, 95% CI)	‐1.81 [‐2.53, ‐1.09]
5.2 Low risk of bias	2	154	Mean Difference (IV, Random, 95% CI)	‐2.61 [‐3.88, ‐1.34]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at 24 hours	9	469	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.34, ‐0.93]
2 Postoperative pain intensity at 24 hours: long‐ versus medium‐acting local anaesthetic subgroups	9	469	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.34, ‐0.93]
2.1 Long‐acting local anaesthesia	7	409	Mean Difference (IV, Random, 95% CI)	‐1.75 [‐2.60, ‐0.90]
2.2 Medium‐acting local anaesthesia	2	60	Mean Difference (IV, Random, 95% CI)	‐1.08 [‐2.07, ‐0.09]
3 Postoperative pain intensity at 24 hours: additive versus no additive subgroups	9	469	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.34, ‐0.93]
3.1 Additives	3	158	Mean Difference (IV, Random, 95% CI)	‐2.13 [‐3.43, ‐0.82]
3.2 No additives	6	311	Mean Difference (IV, Random, 95% CI)	‐1.41 [‐2.31, ‐0.51]
4 Postoperative pain intensity at 24 hours: high‐ versus low‐dose dexamethasone subgroups	9	469	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.34, ‐0.93]
4.1 High‐dose dexamethasone	7	389	Mean Difference (IV, Random, 95% CI)	‐1.59 [‐2.71, ‐0.47]
4.2 Low‐dose dexamethasone	2	80	Mean Difference (IV, Random, 95% CI)	‐1.87 [‐3.21, ‐0.52]
5 Postoperative pain intensity at 24 hours: high/unclear versus low risk of bias subgroups	9	469	Mean Difference (IV, Random, 95% CI)	‐1.63 [‐2.34, ‐0.93]
5.1 High/unclear risk of bias	4	185	Mean Difference (IV, Random, 95% CI)	‐1.90 [‐2.79, ‐1.00]
5.2 Low risk of bias	5	284	Mean Difference (IV, Random, 95% CI)	‐1.43 [‐2.91, 0.04]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at 48 hours	4	296	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.24, 0.03]
2 Postoperative pain intensity at 48 hours: additives versus no additives subgroups	4	296	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.24, 0.03]
2.1 No additives	2	155	Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.36, ‐0.36]
2.2 Additives	2	141	Mean Difference (IV, Random, 95% CI)	‐0.23 [‐1.80, 1.34]
3 Postoperative pain intensity at 48 hours: high/unclear versus low risk of bias subgroups	4	296	Mean Difference (IV, Random, 95% CI)	‐0.61 [‐1.24, 0.03]
3.1 High/unclear risk of bias	1	88	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐2.24, 0.24]
3.2 Low risk of bias	3	208	Mean Difference (IV, Random, 95% CI)	‐0.45 [‐1.30, 0.40]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative opioid consumption at 24 hours	6	380	Mean Difference (IV, Random, 95% CI)	‐19.25 [‐32.51, ‐5.99]
2 Opioid consumption at 24 hours medium‐ versus long‐acting local anaesthetic subgroups	6	380	Mean Difference (IV, Random, 95% CI)	‐19.25 [‐32.51, ‐5.99]
2.1 Long‐acting local anaesthetic	5	335	Mean Difference (IV, Random, 95% CI)	‐21.22 [‐35.20, ‐7.25]
2.2 Medium‐acting local anaesthetic	1	45	Mean Difference (IV, Random, 95% CI)	4.0 [‐33.91, 41.91]
3 Opioid consumption at 24 hours: additive versus no additive subgroups	6	380	Mean Difference (IV, Random, 95% CI)	‐19.25 [‐32.51, ‐5.99]
3.1 Additives	2	142	Mean Difference (IV, Random, 95% CI)	‐30.17 [‐58.58, ‐1.76]
3.2 No additives	4	238	Mean Difference (IV, Random, 95% CI)	‐12.98 [‐26.28, 0.32]
4 Opioid consumption at 24 hours: high/unclear versus low risk of bias subgroups	6	380	Mean Difference (IV, Random, 95% CI)	‐19.25 [‐32.51, ‐5.99]
4.1 High/unclear risk of bias	1	88	Mean Difference (IV, Random, 95% CI)	‐45.0 [‐57.58, ‐32.42]
4.2 Low risk of bias	5	292	Mean Difference (IV, Random, 95% CI)	‐13.55 [‐23.36, ‐3.75]

PERMALINK

Dexamethasone as an adjuvant to peripheral nerve block

Carolyne Pehora

Annabel ME Pearson

Alka Kaushal

Mark W Crawford

Bradley Johnston

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' table and GRADE

Results

Description of studies

Results of the search

1.

Included studies

Participants

Exclusion criteria

Settings

Interventions

Comparators

Funding sources

Contact with authors

Excluded studies

Ongoing studies

Studies awaiting classification

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Perineural dexamethasone versus placebo.

Summary of findings 2. Intravenous dexamethasone versus placebo.

Summary of findings 3. Perineural versus intravenous dexamethasone.

Perineural dexamethasone verus placebo

Primary outcomes

1. Duration of sensory block

4.

1.1. Analysis.

Subgroup analysis

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of sensory block	8	499	Mean Difference (IV, Random, 95% CI)	6.21 [3.53, 8.88]
2 Duration sensory block: additive versus no additive subgroups	8	499	Mean Difference (IV, Random, 95% CI)	6.21 [3.53, 8.88]
2.1 Additives	1	49	Mean Difference (IV, Random, 95% CI)	6.20 [0.68, 11.72]
2.2 No additives	7	450	Mean Difference (IV, Random, 95% CI)	6.21 [3.33, 9.08]
3 Duration of sensory block: high‐ versus low‐dose dexamethasone subgroups	8	499	Mean Difference (IV, Random, 95% CI)	6.21 [3.53, 8.88]
3.1 High‐dose	6	437	Mean Difference (IV, Random, 95% CI)	7.45 [5.55, 9.35]
3.2 Low‐dose	2	62	Mean Difference (IV, Random, 95% CI)	2.25 [1.21, 3.30]
4 Duration of sensory block: high/unclear versus low risk of bias subgroups	8	499	Mean Difference (IV, Random, 95% CI)	6.21 [3.53, 8.88]
4.1 High/unclear risk of bias	2	62	Mean Difference (IV, Random, 95% CI)	2.25 [1.21, 3.30]
4.2 Low risk of bias	6	437	Mean Difference (IV, Random, 95% CI)	7.45 [5.55, 9.35]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of motor block	3	139	Mean Difference (IV, Random, 95% CI)	5.04 [3.07, 7.00]
2 Duration of motor block: additive versus no additive subgroups	3	139	Mean Difference (IV, Random, 95% CI)	5.54 [3.11, 7.97]
2.1 Additives	1	49	Mean Difference (IV, Random, 95% CI)	6.60 [2.32, 10.88]
2.2 No additives	2	90	Mean Difference (IV, Random, 95% CI)	3.67 [‐2.77, 10.11]
3 Duration of motor block high‐ versus low‐dose dexamethasone subgroups	3	139	Mean Difference (IV, Random, 95% CI)	5.04 [3.07, 7.00]
3.1 High‐dose dexamethasone	2	99	Mean Difference (IV, Random, 95% CI)	5.96 [4.03, 7.90]
3.2 Low‐dose dexamethasone	1	40	Mean Difference (IV, Random, 95% CI)	3.10 [0.23, 5.97]
4 Duration of motor block: high/unclear versus low risk of bias subgroups	3	139	Mean Difference (IV, Random, 95% CI)	5.04 [3.07, 7.00]
4.1 High/unclear risk of bias	2	99	Mean Difference (IV, Random, 95% CI)	5.96 [4.03, 7.90]
4.2 Low risk of bias	1	40	Mean Difference (IV, Random, 95% CI)	3.10 [0.23, 5.97]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall incidence of block‐related adverse events	5	393	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.69, 1.70]
2 Numbness/tingling 14 days after surgery	2	101	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.31, 9.26]
3 Residual motor block/muscle weakness 24 hours after surgery	3	265	Risk Ratio (M‐H, Random, 95% CI)	2.68 [0.80, 8.90]
4 Horner syndrome	2	214	Risk Ratio (M‐H, Random, 95% CI)	0.89 [0.63, 1.26]
5 Hoarsenss	2	215	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.45, 1.71]
6 Dyspnoea	3	219	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.11, 3.74]
7 Cranial nerve 12 palsy	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.77]
8 Overall non‐block‐related adverse events	5	258	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.38, 3.97]
9 Postoperative nausea and vomiting	3	134	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.12, 3.78]
10 Dermatological symptoms	2	124	Risk Ratio (M‐H, Random, 95% CI)	1.88 [0.09, 40.62]
11 Dizziness/wrist, hand or finger pain, constipation	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.37 [0.02, 8.77]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at 12 hours	3	162	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐2.44, ‐0.04]
2 Postoperative pain intensity at 12 hours: high‐ versus low‐dose dexamethasone subgroups	3	162	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐2.44, ‐0.04]
2.1 High‐dose dexamethasone	2	122	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐3.16, ‐0.44]
2.2 Low‐dose dexamethasone	1	40	Mean Difference (IV, Random, 95% CI)	‐0.5 [‐1.41, 0.41]
3 Postoperative pain intensity at 12 hours: high/unclear versus low risk of bias subgroups	3	162	Mean Difference (IV, Random, 95% CI)	‐1.24 [‐2.44, ‐0.04]
3.1 High/unclear risk of bias	1	40	Mean Difference (IV, Random, 95% CI)	‐0.5 [‐1.41, 0.41]
3.2 Low risk of bias	2	122	Mean Difference (IV, Random, 95% CI)	‐1.80 [‐3.16, ‐0.44]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at 24 hours	5	257	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐2.23, ‐0.29]
2 Postoperative pain intensity at 24 hours: additive versus no additive subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐2.23, ‐0.29]
2.1 Additive	1	49	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐2.75, 0.95]
2.2 No additive	4	208	Mean Difference (IV, Random, 95% CI)	‐1.33 [‐2.48, ‐0.18]
3 Postoperative pain intensity at 24 hours: high‐ versus low‐dose dexamethasone subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐2.23, ‐0.29]
3.1 High‐dose dexamethasone	4	217	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐2.54, ‐0.07]
3.2 Low‐dose dexamethasone	1	40	Mean Difference (IV, Random, 95% CI)	‐1.1 [‐2.49, 0.29]
4 Postoperative pain intensity at 24 hours: high/unclear versus low risk of bias subgroups	5	257	Mean Difference (IV, Random, 95% CI)	‐1.26 [‐2.23, ‐0.29]
4.1 High/unclear risk of bias	1	40	Mean Difference (IV, Random, 95% CI)	‐1.1 [‐2.49, 0.29]
4.2 Low risk of bias	4	217	Mean Difference (IV, Random, 95% CI)	‐1.31 [‐2.54, ‐0.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Postoperative pain intensity at 48 hours	3	172	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.80, 0.44]
2 Postoperative pain intensity at 48 hours: additive versus no additive subgroups	3	172	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.80, 0.44]
2.1 Additive	1	49	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.60, 1.20]
2.2 No additive	2	123	Mean Difference (IV, Random, 95% CI)	‐0.17 [‐0.87, 0.52]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 24‐hour opioid consumption	5	287	Mean Difference (IV, Random, 95% CI)	‐6.58 [‐10.56, ‐2.60]
2 24‐hour opioid consumption: additive verus no additive subgroups	5	287	Mean Difference (IV, Random, 95% CI)	‐6.58 [‐10.56, ‐2.60]
2.1 Additive	1	53	Mean Difference (IV, Random, 95% CI)	‐4.0 [‐13.33, 5.33]
2.2 No additive	4	234	Mean Difference (IV, Random, 95% CI)	‐6.93 [‐11.41, ‐2.46]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of sensory block	9	720	Mean Difference (IV, Random, 95% CI)	3.13 [1.68, 4.58]
2 Duration of sensory block additive versus no additive subgroups	9	720	Mean Difference (IV, Random, 95% CI)	3.13 [1.68, 4.58]
2.1 Additive	3	331	Mean Difference (IV, Random, 95% CI)	3.94 [2.66, 5.21]
2.2 No additive	6	389	Mean Difference (IV, Random, 95% CI)	2.67 [0.00, 5.34]
3 Duration sensory block high‐dose versus low‐dose dexamethasone subgroups	9	720	Mean Difference (IV, Random, 95% CI)	3.13 [1.68, 4.58]
3.1 High‐dose dexamethasone	6	508	Mean Difference (IV, Random, 95% CI)	2.35 [0.04, 4.66]
3.2 Low‐dose dexamethasone	3	212	Mean Difference (IV, Random, 95% CI)	4.14 [2.48, 5.81]
4 Duration sensory block high/unclear versus low risk of bias subgroups	9	720	Mean Difference (IV, Random, 95% CI)	3.13 [1.68, 4.58]
4.1 High/unclear risk of bias	3	162	Mean Difference (IV, Random, 95% CI)	4.67 [2.29, 7.04]
4.2 Low risk of bias	6	558	Mean Difference (IV, Random, 95% CI)	2.30 [0.23, 4.37]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of motor block	5	421	Mean Difference (IV, Random, 95% CI)	3.13 [0.99, 5.27]
2 Duration of motor block: additive versus no additive subgroups	5	340	Mean Difference (IV, Random, 95% CI)	2.75 [0.32, 5.19]
2.1 Additive	1	50	Mean Difference (IV, Random, 95% CI)	4.0 [‐0.03, 8.03]
2.2 No additive	4	290	Mean Difference (IV, Random, 95% CI)	2.39 [‐0.58, 5.37]
3 Duration of motor block: high‐ versus low‐dose dexamethasone subgroups	5	421	Mean Difference (IV, Random, 95% CI)	3.13 [0.99, 5.27]
3.1 High‐dose dexamethasone	4	381	Mean Difference (IV, Random, 95% CI)	2.47 [‐0.25, 5.19]
3.2 Low‐dose dexamethasone	1	40	Mean Difference (IV, Random, 95% CI)	5.0 [2.53, 7.47]
4 Duration of motor block: high/unclear versus low risk of bias subgroups	5	421	Mean Difference (IV, Random, 95% CI)	3.13 [0.99, 5.27]
4.1 HIgh/unclear risk of bias	1	40	Mean Difference (IV, Random, 95% CI)	5.0 [2.53, 7.47]
4.2 Low risk of bias	4	381	Mean Difference (IV, Random, 95% CI)	2.47 [‐0.25, 5.19]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Overall incidence of block‐related adverse events	5	406	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.93, 1.55]
2 Numbness/tingling 14 days after surgery	3	232	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.27, 3.49]
3 Residual motor block/weakness at 24 hours	3	248	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.62, 2.37]
4 Horner syndrome	2	197	Risk Ratio (M‐H, Random, 95% CI)	1.2 [0.77, 1.87]
5 Hoarsness	2	197	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.48, 2.09]
6 Cranial nerve 12 motor palsy	1	81	Risk Ratio (M‐H, Random, 95% CI)	0.31 [0.01, 7.39]
7 Overall incidence of non block‐related adverse events	5	316	Risk Ratio (M‐H, Random, 95% CI)	1.34 [0.37, 4.78]
8 Postoperative nausea and vomiting	5	312	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.22, 1.80]
9 Dermatologicial symptoms (pruritus/rash)	1	79	Risk Ratio (M‐H, Random, 95% CI)	4.42 [0.22, 89.18]
10 Syncope/fainting	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	4.42 [0.22, 89.18]
11 Dizziness	2	178	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.06, 2.72]
12 Wrist, hand or finger pain	1	79	Risk Ratio (M‐H, Random, 95% CI)	0.29 [0.01, 7.02]
13 Headache, 10‐pound fluid gain/diarrhoea/frequent urination/ muscle soreness	1	79	Risk Ratio (M‐H, Random, 95% CI)	2.65 [0.11, 63.16]