Known to some as “the single most important pediatric regional anesthesia technique,” caudal blockade is an effective and safe method of providing surgical anesthesia and postoperative analgesia for lower abdominal operations in children.1,2 Typically administered as a single injection, 1 limitation is the duration of analgesia from the block. Consequently, there has been high interest in so-called adjuvants or medications that prolong block duration. One such adjuvant is dexamethasone, which is known to extend the duration of peripheral nerve blocks when given by both the intravenous (IV) and perineural routes of administration.3 Speculated mechanisms of action of dexamethasone include a direct effect on nociceptive fibers and anti-inflammatory properties.4 Despite these analgesic benefits, the use of perineural dexamethasone remains off-label and controversial, with the US Food and Drug Administration recently issuing a warning regarding the epidural injection of corticosteroids due to the potential for “rare but serious adverse events.”5,6 Furthermore, there are theoretical concerns of delayed wound healing, surgical site infection, and hyperglycemia with the use of dexamethasone, albeit such sequelae have not consistently been reflected in clinical studies.7,8
Although randomized controlled trials (RCTs) have studied adjuvant dexamethasone for caudal blockade, no systematic review or meta-analysis exists to our knowledge.9,10 In addition, it is unknown if there is any benefit to targeted (eg, caudally administered) dexamethasone versus IV dosing or if the analgesic benefits of dexamethasone outweigh any steroid-related morbidity.7,9 For all these reasons, we performed a systematic review and meta-analysis of RCTs to investigate the role of dexamethasone as an adjuvant for caudal blockade. It was hypothesized that dexamethasone would prolong the duration of analgesia of caudal blockade in pediatric surgical patients compared to placebo, with caudal dexamethasone being superior to IV administration.
This systematic review and meta-analysis is reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement.11 Our institutional research ethics board does not require approval for systematic reviews and meta-analyses, as no data are being collected from patients. The study hypotheses and systematic review protocol were defined a priori.
Ovid Medline, Embase, and the Cochrane Library were searched without language restriction from inception to August 18, 2017, for RCTs meeting the listed inclusion criteria. Additionally, the first 20 pages of Google Scholar were searched on August 18, 2017, to capture gray literature (eg, nonindexed studies).
Study Selection Criteria
Studies had to recruit pediatric patients (age <18 years) receiving a caudal block in anticipation of providing surgical anesthesia or postoperative analgesia for surgery. Trials that involved healthy volunteers (eg, no planned surgery) were excluded.
Intervention and Control.
For inclusion, studies had to compare caudal or IV dexamethasone either directly to each other or to a control. The dosing of the local anesthetic for the caudal block had to be equivalent between arms. Studies were excluded if the comparator was active (eg, caudal dexamethasone versus caudal clonidine with no control arm).
The primary outcome was the duration of analgesia from the caudal block. Given the anticipation of heterogeneity in reporting of outcomes and challenges in assessing pain in pediatric patients, we accepted time to first rescue analgesia as an alternative if the study did not report the duration of analgesia. Secondary outcomes included resting pain scores, opioid and rescue analgesia consumption, parental or patient satisfaction, side effects (eg, postoperative nausea and vomiting [PONV]), postoperative glucose level, block failure, and block-related complications. Studies had to report at least 1 clinical outcome of interest for inclusion.
The full search strategy for each database is provided in Supplemental Digital Content 1, Appendix, http://links.lww.com/AA/C316. The search utilized a comprehensive combination of medical subject heading (MeSH) terms, free-text terms, and corresponding synonyms. Furthermore, the reference lists of included articles were manually reviewed for any additional studies meeting the inclusion criteria.
Article Screening and Data Extraction
All titles, abstracts, and full texts (where required to assess the study for inclusion) were reviewed in duplicate by 2 of the authors (M.A.C. and C.L.). Any disagreements were resolved by consensus with 1 of the authors (N.M.B.). Data from included studies were extracted independently in duplicate onto standardized forms by 3 of the authors (M.A.C., C.L., or D.J.S.). Extracted data included pertinent baseline demographic information of each study and the prespecified outcomes. To facilitate meta-analysis, medians, interquartile range, and range values were approximated into means and their corresponding standard deviation (SD) using methods suggested by the Cochrane Library.12 Where necessary (eg, data values not reported in text and only within bar graphs), numerical data were extracted from graphs by digital measurement. We attempted to contact principal investigators of included studies for additional information if required. Two studies did not report the SD value for their primary outcome and, after unsuccessful attempts to contact the original investigators, the SD values were estimated from the corresponding survival curve.13,14
Risk of Bias Evaluation
The Cochrane Risk of Bias Tool was utilized to appraise the risk of bias of included studies by 2 of the authors (M.A.C. and D.J.S.) and all discrepancies were resolved by consensus with another author (C.L.). We considered studies to be at low risk of bias if they scored 3 or higher on these criteria: (1) appropriately generated the randomization sequence, (2) appropriate allocation concealment, (3) blinded study personnel and participants, (4) blinded outcome assessors, and (5) reported data completely. Furthermore, the study had to demonstrate no significant selective reporting bias or other source of bias. Finally, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was utilized to provide an overall appraisal of the quality of evidence for each outcome.15
Statistical analysis was performed in Stata (Version 13.1 by StataCorp, College Station, TX). Standard summary measures were generated, with their corresponding 95% confidence intervals (CIs) and an α = .05. The weighted mean difference (WMD) describes the average difference between the intervention group and control group and it was utilized for continuous outcomes reported on the same scale (eg, the duration of analgesia). Similarly, the relative risk (RR) describes the probability of an outcome occurring in the intervention group versus control group and it was utilized to report binary data. The WMD was utilized to analyze the following outcomes: duration of analgesia (primary outcome), pain scores, patient satisfaction, blood glucose level, and rescue analgesia consumption. The RR was used to analyze rescue analgesia requirement, side effects (eg, PONV), and block failure. Where appropriate, the number needed to treat for benefit (NNTB) or harm was calculated using the 95% CIs of the corresponding RR.
The continuity correction was applied for zero event studies.16 All analyses were performed using a random-effects model using the methods of DerSimonian and Kacker.17 For multiple comparisons over time (eg, repeated pain scores), a Bonferroni correction was applied. Furthermore, to account for heterogeneity in reporting and assessment of pain scores between trials, pain scores were grouped in bands of time where necessary (eg, 6–8 hours). The I2 statistic was utilized to quantify heterogeneity. We interpreted an I2 value of 0%–25% as low heterogeneity, 25%–50% as moderate heterogeneity, and >50% as high heterogeneity. A funnel plot was constructed for the primary outcome and Egger’s regression performed to assess for statistical evidence of publication bias. A trim and fill procedure was performed to estimate an adjusted magnitude of effect in the setting of any publication bias.18
The prespecified subgroup analyses included block technique (ultrasound-assisted versus landmark), route of dexamethasone (IV versus caudal), dose of dexamethasone, type of local anesthetic (short-acting versus intermediate-acting versus long-acting), study quality (high versus low risk of bias), type of surgery (lower abdominal operations versus lower extremity surgery), and study location (developed countries versus developing countries).
To explore the definitiveness of the evidence base, trial sequential analysis (TSA) was performed for the primary outcome of duration of analgesia. TSA allows for the creation of trial sequential boundaries within a cumulative meta-analysis to determine when the sample size and P value are sufficient to definitively show an effect (suggesting more research is unlikely to significantly alter the current effect estimate) versus when the cumulative sample size is insufficient for the associated P value to be definitive (suggesting high risk of false-positive or false-negative results and indicating more research is required before definitive conclusions can be made).19,20 To perform the TSA, we assumed a 2-tailed α of .05, β of 80%, and clinically important treatment effect of 3 hours prolongation. The TSA was performed with version 0.9.5.5 Beta (Copenhagen Trial Unit, Copenhagen, Denmark) and the O’Brien-Fleming α and β spending functions were utilized in the calculations. Other authors have provided excellent descriptions of TSA and full discussion is beyond the scope of this systematic review.19
The initial search retrieved 87 citations and 6 additional studies were identified from the gray literature. Notable exclusions were 1 study that recruited adult patients, a trial where the control arm was another adjuvant (clonidine), and a conference presentation of an already included study.21–23 Ultimately, 14 RCTs recruiting 1315 pediatric surgical patients met the inclusion criteria (PRISMA flow diagram, Figure 1).9,10,13,14,24–33
Overview of Included Studies
The baseline demographics of included studies are listed in Supplemental Digital Content 2, Table, http://links.lww.com/AA/C317. All the studies involved lower abdominal operations (inguinal hernia repair, orchidopexy, or hypospadias repair), with the exception of 1 trial on lower limb orthopedic surgery.9 The majority of studies utilized a landmark technique to place the caudal block.9,14,24–28,31–33 In 3 studies, ultrasound assistance was used and 1 study did not clearly report the caudal placement technique.10,13,29,30 The caudal dose of dexamethasone was 0.1–0.2 mg/kg and, in studies that administered IV dexamethasone, the IV dose was 0.5–1.5 mg/kg generally up to 10 mg (Supplemental Digital Content 2, Table, http://links.lww.com/AA/C317). Furthermore, every study utilized long-acting local anesthetic (ropivacaine, bupivacaine, or levobupivacaine). Only 3 of the studies were conducted in developed countries, with 1 trial from the United States and 2 from South Korea.13,29,30 Paracetamol was the main nonnarcotic rescue analgesic used, particularly for pain management after discharge from the postanesthetic care unit (Supplemental Digital Content 2, Table, http://links.lww.com/AA/C317). A few trials also used rescue narcotic in the postanesthetic care unit: 4 studies utilized IV fentanyl, 1 trial administered morphine, and 1 study used intramuscular pethidine.13,14,29,30,33 A variety of pain scales were used to assess pain among the included RCTs, although overall the criteria for rescue analgesia administration were similar (Supplemental Digital Content 2, Table, http://links.lww.com/AA/C317). Only 2 studies explicitly stated that their dexamethasone formulation was preservative-free.10,13 One study reported administration of multimodal analgesia in the form of paracetamol.14 Eight of the 14 RCTs were deemed to be at low risk of bias (Cochrane Risk of Bias Assessment, Figure 2).9,10,13,28–32
Duration of Analgesia
Patients receiving caudal dexamethasone versus control experienced a longer duration of analgesia (WMD 5.43 hours, 95% CI, 3.52–7.35; P < .001; I2 = 99.3%; N = 9; Figure 3). The magnitude of prolongation was also similar for IV dexamethasone compared to control (WMD 5.51 hours; 95% CI, 3.56–7.46; P < .001; I2 = 98.9%; N = 5; Figure 3). The prespecified subgroup analyses are listed in the appendix (Supplemental Digital Content 3, Table, http://links.lww.com/AA/C318) and they were generally concordant with the overall pooled value. Notably, the magnitude of effect was larger (albeit less precise) among older children (7–17 years of age; WMD for duration of analgesia 6.21 hours; 95% CI, 2.42–10.00; P = .001) compared to younger children (1–6 years of age; WMD 3.93 hours; 95% CI, 3.58–4.27; P < .001). In addition, studies published in developed countries showed less benefit (WMD for duration of analgesia 3.98 hours; 95% CI, 2.35–5.62; P < .001) compared to trials conducted in developing countries (WMD 5.09 hours; 95% CI, 3.74–6.45; P < .001). Use of ultrasound assistance to perform the caudal block or low risk of bias of the study did not result in any meaningful differences compared to the overall pooled value (Supplemental Digital Content 3, Table, http://links.lww.com/AA/C318).
Pain scores (on a 10-point scale) are shown by time as Supplemental Digital Content 4, Figure, http://links.lww.com/AA/C319. As only 1 IV dexamethasone study reported pain scores, both the caudal and IV dexamethasone data are presented pooled together.29 Furthermore, 1 study reported an interquartile range of 0 for certain pain scores and, therefore, it was mathematically not possible to pool their data in meta-analysis.27 Patients receiving dexamethasone reported lower pain scores at 6 hours (WMD, −1.31; 95% CI, −2.07 to −0.54; P = .001; I2 = 88.1%; N = 6) and 24 hours (WMD, −0.80; 95% CI, −1.37 to −0.24; P = 006; I2 = 87.4%; N = 5) compared to control. In contrast, there were no differences in pain scores at 0 (earliest pain score taken in recovery room), 12, or 48 hours.
Pediatric patients receiving dexamethasone had less chance of requiring narcotic rescue analgesia in the postanesthetic care unit (RR, 0.30; 95% CI, 0.18–0.51; P < .001; I2 = 0.0%; N = 5; NNTB = 5; 95% CI for NNTB 4–7).14,29–31,33 The results were similar when subgrouped by caudal route of administration (RR, 0.33; 95% CI, 0.18–0.60; P < .001; I2 = 0.0%; N = 4; NNTB = 6; 95% CI for NNTB 5–9) or IV dosing (RR, 0.21; 95% CI, 0.07–0.65; P = .007; N = 1; NNTB = 4; 95% CI for NNTB 3–8).
This analgesic benefit also extended postoperatively where the data for rescue analgesia use after discharge from the postanesthetic care unit similarly favored the dexamethasone group (RR, 0.46; 95% CI, 0.23–0.92; P = .03; I2 = 96.0%; N = 9; NNTB = 3; 95% CI for NNTB 2–20).9,13,14,24,27,29–31,33 These data were not significant in subgroup analysis by route of administration: caudal dexamethasone versus placebo (RR, 0.46; 95% CI, 0.20–1.09; P = .08; I2 = 96.5%; N = 7) and IV dexamethasone versus placebo (RR, 0.58; 95% CI, 0.16–2.11; P = .41; I2 = 97.6%; N = 3).
Finally, for studies that reported the doses of rescue analgesia administered, patients receiving dexamethasone required less doses compared to control (−0.92 doses; 95% CI, −1.26 to −0.59; P < .001; I2 = 80.8%; N = 5).9,14,28,30,32 The data were also similar whether the dexamethasone was given caudally (−0.95 doses; 95% CI, −1.32 to −0.57; P < .001; I2 = 85.1%; N = 4) or intravenously (−1.12 doses; 95% CI, −1.17 to −0.80; P < .001; I2 = 78.9%; N = 3) versus control.
Only 2 studies reported patient satisfaction and heterogeneity in reporting methodology precluded meta-analysis.24,29 More parents rated satisfaction with their child’s analgesia as excellent in the caudal dexamethasone group compared to control in 1 study24; similarly in the other trial, a higher proportion of parents were satisfied in the IV dexamethasone group.29
PONV was reduced in patients receiving dexamethasone compared to control (RR, 0.47; 95% CI, 0.30–0.73; P = .001; I2 = 0.0%; NNTB = 11; 95% CI for NNTB 8–21; N = 9).9,10,27–33 When subgrouped by route of administration, the results were similar for caudal dexamethasone versus control (RR, 0.44; 95% CI, 0.28–0.71; P = .001; I2 = 0.0%; N = 8; NNTB = 10; 95% CI for NNTB 8–18) compared to IV dexamethasone versus control (RR, 0.28; 95% CI, 0.08–0.96; P = .04; I2 = 50.4%; N = 3; NNTB = 5; 95% CI for NNTB 4–83).
The rest of the secondary outcomes are summarized in Table 1. Rates of pruritus,27,28,33 urinary retention,10,28,32,33 bradycardia,27,28,32 residual motor block,28,30 and respiratory depression27,28,33 were not different between groups and the number of events per trial for these outcomes ranged from 0 to 1 (Table 1).
With regard to dexamethasone-specific complications, only 1 study reported blood glucose levels, which were similar between groups.9 Furthermore, there were no other adverse effects that could plausibly be attributed to dexamethasone reported, apart from 2 cases of wound dehiscence in 1 trial involving 1 patient in each of the dexamethasone group and control group.30
Caudal blockade had a high success rate among studies that reported failure rates, with 7 studies reporting no failed blocks.10,24,28,30,32,33 In the only study to report a block failure, 3 blocks failed in the caudal dexamethasone group compared to 1 in the control arm.27
The funnel plot for the primary outcome data was asymmetrical (Supplemental Digital Content 5, Figure, http://links.lww.com/AA/C320) and Egger’s regression was not significant (P = .25). Taken together with the fact that all studies favored the intervention (dexamethasone), there is likely publication bias present. To further characterize the effect of any publication bias on the overall magnitude of effect, a trim and fill procedure was performed and it demonstrated a more modest magnitude of effect when adjusting for the presence of studies theoretically missing due to publication bias (WMD, 3.26 hours favoring dexamethasone versus placebo; 95% CI, 1.98–4.54 hours; P < .001).
Trial Sequential Analysis
The TSA revealed that the cumulative z curve has crossed the trial sequential monitoring boundary for benefit (Supplemental Digital Content 6, Figure, http://links.lww.com/AA/C321). This suggests that sufficient evidence has accrued to definitively conclude that dexamethasone is superior to placebo for prolongation of caudal blockade.
Caudal blockade is 1 of the most common regional anesthesia techniques performed to provide postoperative analgesia after pediatric surgery. This systematic review and meta-analysis included 14 RCTs of pediatric patients receiving caudal blockade with or without adjuvant dexamethasone after primarily lower abdominal surgeries. The main findings of the analysis are highlighted in the summary of findings table (Table 2). Current evidence demonstrates significant prolongation of the duration of analgesia from caudal blockade with adjuvant dexamethasone, which ranged from approximately double to triple that of the control arm. Interestingly, both caudal and IV administration each had a similar estimated mean difference in magnitude of effect when compared to placebo (Figure 3). Important limitations include the high statistical heterogeneity in the primary analysis—despite the clinical homogeneity among the trials.
Secondary benefits of adjuvant dexamethasone were many. Per 1000 patients treated, usage of adjuvant dexamethasone results in 338 (95% CI, 51–482) less patients requiring rescue analgesia, 217 (95% CI, 153–255) less patients requiring rescue narcotic in the postanesthetic care unit, and 98 (95% CI, 50–130) less cases of PONV compared to control. Pain scores were also reduced at 6 hours (WMD, −1.31; 95% CI, −2.07 to −0.54; P = .001; I2 = 88.1%; N = 6) and 24 hours (WMD, −0.80; 95% CI, −1.37 to −0.24; P = 006; I2 = 87.4%; N = 5), but the reduction was less than the 2-point reduction (on a 10-point numeric rating scale) that would be considered clinically meaningful.34 Moreover, studies used different pediatric pain scales (eg, the pediatric objective pain score and FLACC [face, legs, activity, cry, consolability] scale), which limits the external validity of the pooled pain score results. Otherwise, serious adverse events among the included studies were rare and could not definitively be linked to dexamethasone administration.30
Our findings highlight the important benefits of adjuvant dexamethasone in caudal blockade. Given that caudal dexamethasone remains off-label, one wonders if the most cautious and simpler route of administration is IV.6 Indeed, the subgroup analyses presented by route of administration attest to the similar effect sizes and magnitudes of effect between caudal and IV dexamethasone with regard to the most important patient outcomes (eg, duration of analgesia and PONV). In addition, the usage of IV dexamethasone is already recommended by certain guidelines for the prophylaxis of PONV in pediatric surgical patients.35 However, the IV doses of dexamethasone utilized among the included studies were typically 0.5 mg/kg (to a maximum of 10 mg).29 This dose is higher than the 0.1–0.15 mg/kg recommended for PONV prophylaxis, but lower than some of the higher doses utilized in pediatric otolaryngology surgery.35,36 Therefore, clinicians must keep in mind that higher doses of IV dexamethasone (0.5 mg/kg up to 10 mg) may be required to achieve the adjuvant effect demonstrated herein, given that there are no published data on the effectiveness of lower doses of IV dexamethasone (eg, 0.1 mg/kg) for prolonging caudal blockade.
Although alternative adjuvants for caudal blockade exist, they are either thought to be associated with increased side effects (eg, opioids) or are more costly (eg, dexmedetomidine) compared to dexamethasone, with similar magnitudes of effect as demonstrated by other investigations.37,38 Furthermore, these alternative adjuvants do not have the antiemetic properties possessed by dexamethasone, which is important as PONV is the leading cause of admission after elective surgery and very distressing to patients.39
Despite the homogeneity of study populations and strict inclusion criteria, there was still very high statistical heterogeneity for the duration of analgesia analysis. Interestingly, all the RCTs were concordant in favoring the dexamethasone over control for prolongation of analgesic duration. We speculate that the very narrow CIs reported by certain studies inflated the calculated I2 value (Figure 3). Furthermore, subgroup analysis by a priori suspected sources of heterogeneity (Supplemental Digital Content 3, Table, http://links.lww.com/AA/C318) revealed lower statistical heterogeneity among trials conducted in developed countries (N = 2; I2 = 15.7%), in studies where the caudal blockade was facilitated by ultrasound (N = 2; I2 = 0.0%), and in trials that used relatively higher doses of caudal dexamethasone (0.2 mg/kg; N = 2; I2 = 0.0%). Nonetheless, given the high statistical heterogeneity, the results should be interpreted with caution. Taken together with the minor deficiencies in reporting of allocation concealment, most of the outcomes were assigned a GRADE rating of moderate to high (Table 2).15
Regarding the safety of dexamethasone, only 2 serious adverse events (wound dehiscence) were reported in 1 study, with 1 event in the dexamethasone arm and control arm, respectively.30 Interestingly, this trial was the only 1 to report formal follow-up of patients 1 week postoperatively.30 Furthermore, only a minority of studies explicitly reported dexamethasone-related complications.9,24,26,29,30 Taken together with the lack of long-term follow-up, it is possible that additional dexamethasone-related complications were underreported among the rest of the included RCTs, which overall only comprised a relatively small number of patients. Even so, for IV administration at least, other data investigating the usage of perioperative dexamethasone have demonstrated a reasonable safety profile.8
In pediatric surgical patients presenting for mainly lower abdominal surgery, this systematic review and meta-analysis revealed clinically meaningful prolongation of the duration of analgesia from caudal blockade by adjuvant dexamethasone versus placebo. In addition to doubling to tripling the duration of analgesia, adjuvant dexamethasone has a rescue analgesia sparing effect and reduces PONV. The major limitation of the analysis was the high statistical heterogeneity for the primary outcome, despite the clinical similarity of the included RCTs.
In light of the results and given the off-label status of caudal dexamethasone, we suggest that the IV route be utilized. The caveat with this recommendation is that the IV doses of dexamethasone were much higher than that used in standard practice (eg, 0.5 vs 0.1 mg/kg).1 It remains unknown if smaller doses of dexamethasone (eg, 0.1–0.15 mg/kg) prolong caudal blockade to the same extent as the higher doses studied in existing trials. Nonetheless, given the importance of optimal pain control for pediatric patients, dexamethasone has an important role for prolonging the duration of caudal blockade—particularly when the alternatives are other adjuvants that are thought to be associated with more side effects (eg, opioids), increased cost (eg, dexmedetomidine), or lack the antiemetic effects of dexamethasone.37,38
Dr Chong is grateful to Dr Janet Martin and Davy Cheng of the Medical Evidence, Decision Integrity, Clinical Impact (MEDICI) Centre at Western University (London, Ontario, Canada) for providing access to the statistical analysis software. Furthermore, we thank fellow department members Dr Mohamad Ahmad, Jonathan Brookes, and Enda Connolly for their expert review of the final manuscript (listed in alphabetical order by last name; Department of Anesthesia and Perioperative Medicine, Western University, London, Ontario, Canada).
Name: Matthew A. Chong, MD.
Contribution: This author helped conceive the idea for the meta-analysis, design the search strategy, select study articles, extract the data, perform the data analysis, create the figures/tables, and prepare the manuscript.
Name: Daniel J. Szoke, MD.
Contribution: This author helped with the data extraction, risk of bias assessment, and contributed to the final manuscript.
Name: Nicolas M. Berbenetz, MD.
Contribution: This author assisted with the data analysis, screening study articles, figure creation, and contributed to the final manuscript.
Name: Cheng Lin, MD.
Contribution: This author helped screen study articles, assist with the data extraction, and revise the final manuscript.
This manuscript was handled by: Richard Brull, MD, FRCPC.
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