Dexmedetomidine as an Adjuvant to Local Anesthetics in Transversus Abdominis Plane Block: A Systematic Review and Meta-analysis.

OBJECTIVES: The objective of this meta-analysis was to evaluate the analgesic effects of dexmedetomidine (DEX) in transversus abdominis plane (TAP) blocks for abdominal surgery.
METHODS: Electronic databases, including PubMed, EMBASE, Chinese National Knowledge Infrastructure (CNKI), Wan Fang, and the Cochrane Library, were conducted to collect the randomized controlled trials (RCTs) from inception to March 2018. RCTs investigating the impact of adding DEX to local anesthetics for TAP blocks were included in this analysis. Pain scores (at rest and movement), opioid consumption, the duration of the TAP block and the common adverse effects were analyzed.
RESULTS: Twenty published trials including 1212 patients met the inclusion criteria. The addition of DEX significantly reduced pain scores 8 hours postoperatively at rest (WMD, -0.78; 95% CI, -1.27 to -0.30; P=0.001), 4 hours postoperatively on movement (WMD, -1.13; 95% CI, -1.65 to -0.60; P<0.001), and opioid consumption (WMD, -13.71; 95% CI, -17.83 to -9.60; P<0.001) when compared with control group. Furthermore, perineural DEX significantly prolonged the duration of the TAP block (WMD, 3.33; 95% CI, 2.85 to 3.82; P<0.001). It did not affect the incidence of postoperative nausea and vomiting, hypotension, bradycardia, somnolence, or pruritus.
CONCLUSIONS: DEX is a potential anesthetic adjuvant that can facilitate better postoperative analgesia, reduce postoperative analgesic requirements, and prolong the local anesthetic effect when administered in TAP blocks.

The transversus abdominis plane (TAP) block was first applied to abdominal surgery by Rafi1 in 2001. The local anesthetic (LA) was injected between the internal oblique muscle and the transversus abdominis from the side of the abdomen to block the T7-L1 spinal nerve ventral branches, which improved postoperative analgesia after abdominal surgery.

Systemic dexmedetomidine (DEX) produces sedative, analgesic, sympatholytic, and anesthetic-sparing effects.2 Recently, DEX as a local anesthetic adjuvant has been the subject of increasing interest as the potential to prolong blockade duration.3–5 The combined use of a local anesthetic agent and DEX, applied in a TAP block, which targets peripheral nociceptive receptors may be an ideal protocol for pain control after abdominal surgery.

Some meta-analyses indicated that perineural DEX can prolong the durations of sensory block and motor block as well as analgesia when administered in brachial plexus block.5–8 Unlike brachial plexus block, TAP block is a nondermatomal “field block,” which requires a large volume of anesthetics to cover several spinal nerves.9 To the authors’ knowledge, there are no published meta-analyses investigating the effect of DEX as an adjuvant in TAP blocks on postoperative pain. This study was designed to determine the effect of DEX as a local anesthetic adjuvant in TAP blocks.

MATERIALS AND METHODS

Studies were performed in accordance with the PRISMA protocol10 (Supplementary Table S1, Supplemental Digital Content 1, http://links.lww.com/CJP/A535).

Study Search Strategy

Two authors (QCS, SYL) independently searched the international databases (PubMed, EMBASE, and the Cochrane Library) and 2 Chinese databases (CNKI and Wan-Fang database) from inception to March 2018. Medical subject headings and text words of “dexmedetomidine” and “transversus abdominis plane block or TAP block” were used for databases searching. The details of the search strategies are summarized in Supplementary Table S2 (Supplemental Digital Content 2, http://links.lww.com/CJP/A536). No language restrictions were applied. In order to avoid omitting relevant clinical trials, we scanned conference summaries and reference lists of articles identified in the initial searches and contacted authors to obtain additional information for relevant trials.

Inclusion and Exclusion Criteria

Inclusion criteria were: (1) the study was a RCT; (2) adult patients undergoing abdominal surgery; (3) the test group was treated with TAP blocks using any LA agent combined with DEX, whereas the control group received LA agent alone; (4) outcomes: pain scores (at rest and movement), opioid consumption, the duration of analgesia, and incidence of postoperative nausea and vomiting (PONV), hypotension, bradycardia, somnolence, or pruritus.

Exclusion criteria were: (1) study designs other than a RCT; (2) reviews, letters, abstracts, editorials or studies that reported insufficient data; (3) DEX administered through nonperineural route. There were three disagreements about study selection were resolved by group discussion and consensus.

Data Extraction

Two reviewers independently extracted data from all included studies. The mean value and variance were for continuous variables, while proportions were for dichotomous outcomes. If data were presented as sample size, median, range or interquartile range, the author of the trial was contacted to inquire if they could provide raw data. Failing that, we used formulas to estimate the mean and standard deviation.11,12 Extracted data included first author, publication year, country, sample size, type of anesthesia, postoperative analgesia, and outcome measures. Pain scores (at rest and movement) were defined as primary outcome measures. Pain scores presented as a visual analog scale (VAS), where 0=no pain and 10=the most severe pain. Secondary outcomes were cumulative opioid consumption, the duration of analgesia and incidence of PONV, hypotension, bradycardia, somnolence, or pruritus. Using a published equivalence formula, cumulative opioid consumption, with opioid drugs other than morphine, was converted to morphine equivalent doses, where intravenous (i.v.) morphine 10 mg=i.v. sufentanil 10 μg=i.v. tramadol 100 mg=i.v. fentanyl 0.1 mg.13,14 There were two disagreements were resolved by discussion.

Assessment of Quality and Bias

To determine the quality of the included studies, risk of assessment was performed, according to the Cochrane Collaboration’s tool.15 Seven evidence-based domains were evaluated: (1) random sequence generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; (7) other bias. Each of these domains was judged as low risk, high risk or unclear risk.

For the assessment of publication bias, both Begg’s rank correlation and Egger’s linear regression tests were performed.10

Statistical Analysis

All statistical analyses were performed in Stata 14.0 (Stata Corp, College Station, TX) and Review Manager 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014). Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated for dichotomous data, and weighted mean differences (WMDs) with 95% CIs were calculated for continuous variables. Heterogeneity was measured by I2, with I2>50% indicating significant heterogeneity. If I2<50%, the fixed effects model was used; if I2>50%, a random effects model was used, and the heterogeneity was assessed. Subgroup analyses were performed for the outcome measures, according to surgery types (open surgery or laparoscopic surgery) and anesthesia (general anesthesia or spinal). Furthermore, meta-regression was used to explore the origin of heterogeneity, such as postoperative patient-controlled analgesia (PCA, yes or no), LA types (ropivacaine, bupivacaine or levobupivacaine), surgery types, DEX doses (<1 μg/kg or ≥11 μg/kg) and anesthesia. Sensitivity analyses were performed by excluding one study each time to evaluate the influence of a single study on the overall estimate.16

RESULTS

In total, 116 articles were initially identified from the electronic search. Of these, 40 were excluded due to duplication; 47 were further excluded after screening the titles and abstracts. By reading the full text of the remaining 29 articles, 9 studies were excluded because they failed to meet the inclusion criteria. Ultimately, 20 eligible studies involving 1212 participants were included in this meta-analysis.17–36 The search process is provided in Figure 1.

FIGURE 1

Flow chart of the review process.

The characteristics of the included studies are shown in Table 1. Eighteen trials performed general anesthesia, while spinal anesthesia was used in 2 trials; 16 trials underwent open surgery, whereas 4 trials received laparoscopic surgery. Ropivacaine was used in 14 trials as the local anesthetic, while 4 trials used bupivacaine, and 2 others used levobupivacaine. The DEX dosage was various, with 1 μg/kg in 6 studies, 0.5 μg/kg in 8 studies, 0.75 μg/kg in 3 studies, 100 μg in 1 study, 2 doses in one study, and 3 doses in one study. Eleven studies received postoperative PCA (7 studies with PCA sufentanil, 2 studies with PCA morphine, 1 study with PCA fentanyl, and 1 study with PCA dezocine and flurbiprofen). Pain scores were reported in all included trials. Eleven studies reported pain scores at rest, whereas the other 9 reported pain scores at rest and on movement. The risk assessment of the included studies is presented in Figure 2.

TABLE 1

Characteristics of the Included Studies

FIGURE 2

Risk of bias assessment. A, Risk of bias graph; B, Risk of bias summary.

The primary outcomes of pain scores at rest and on movement at 7 different time points are summarized in Table 2. Pooled analysis demonstrated significantly lower pain scores (WMD, −0.78; 95% CI, −1.27 to −0.30; P=0.001) 8 hours postoperatively at rest and 4 hours postoperatively on movement (WMD, −1.13; 95% CI, −1.65 to −0.60; P<0.001) in patients treated with combination of DEX and local anesthetic compared with local anesthetic alone (Figs. 3, 4). This statistically significant effect was also seen at 1, 6, 12, and 24 hours postoperatively at rest and at 2, 6, 12, and 24 hours postoperatively on movement. Meta-regression revealed that anesthesia (P=0.027) was associated with the significant heterogeneity 8 hours postoperatively at rest, while postoperative PCA (P=0.29), LA types (P=0.45), DEX doses (P=0.077) and surgery types (P=0.393) did not contribute to the heterogeneity. Sensitivity analysis was typically performed to check the robustness of these results, with pooled WMDs ranging from −0.50 (95% CI, −0.71 to −0.30) to −0.63 (95% CI, −0.85 to −0.40) (Fig. 5). Begg’s funnel plot (P = 0.152, Fig. 6) showed no evidence of publication bias, however, Egger’s test (P=0.025) indicated publication bias. The reasons of different statistical significance between these 2 test methods might derive from the small size of this study or the amount of included studies.

TABLE 2

Pain Scores at Rest and on Movement at 7 Different Time Points for the Comparison of DEX Group and Control Group

FIGURE 3

DEX versus control group: a forest plot of pain scores 8 hours postoperatively at rest. CI indicates confidence interval; DEX, dexmedetomidine; WMD, weighted mean difference.

FIGURE 4

DEX versus control group: a forest plot of pain scores 4 hours postoperatively on movement. CI indicates confidence interval; DEX, dexmedetomidine; WMD, weighted mean difference.

FIGURE 5

DEX versus control group: the sensitivity analysis of pain scores 8 hours postoperatively at rest. CI indicates confidence interval; DEX, dexmedetomidine.

FIGURE 6

DEX versus control group: the Begg’s funnel plot of pain scores 8 hours postoperatively at rest. DEX indicates dexmedetomidine; WMD, weighted mean difference.

Twelve trials provided opioid consumption data at 24 hours. Pooled data found a statistically significant lower opioid consumption (WMD, −13.71; 95% CI, −17.83 to −9.60; P<0.001) in patients treated with combination of DEX and local anesthetic compared with local anesthetic alone (Fig. 7). Meta-regression showed that surgery types (P<0.001) were associated with the significant heterogeneity, whereas postoperative PCA (P=0.27), LA types (P=0.51), DEX doses (P=0.60) and anesthesia (P=0.28) did not contribute to the heterogeneity. Sensitivity analysis was typically performed to check the robustness of these results, with pooled WMDs ranging from −10.73 (95% CI, −14.90 to −71.68) to −15.14 (95% CI, −19.62 to −10.67). Begg’s funnel plot (P=0.41) and Egger’s test (P=0.076) showed no evidence of publication bias.

FIGURE 7

DEX versus control group: a forest plot of morphine equivalents 24 hours postoperatively. CI indicates confidence interval; DEX, dexmedetomidine; WMD, weighted mean difference.

The duration of the TAP block was provided in 8 of the 20 included trials. Pooled results showed that DEX prolonged the block duration (WMD, 3.33; 95% CI, 2.85 to 3.82; P<0.001) (Fig. 8). Meta-regression showed that anesthesia (P=0.013) was associated with the significant heterogeneity, while surgery types (P=0.68), postoperative PCA (P=0.34), LA types (P=0.25) and DEX doses (P=0.48) did not contribute to the heterogeneity. Sensitivity analysis was typically performed to check the robustness of these results, with pooled WMDs ranging from 3.13 (95% CI, 2.74 to 3.53) to 3.49 (95% CI, 3.01 to 3.96). Begg’s funnel plot (P=0.9) and Egger’s test (P=0.52) showed no evidence of publication bias.

FIGURE 8

DEX versus control group: a forest plot of the duration of analgesia. CI indicates confidence interval; DEX, dexmedetomidine; WMD, weighted mean difference.

For adverse events, pooled analysis showed no difference in the incidence of PONV, hypotension, bradycardia, somnolence, hypotension, and pruritus between DEX and the control group (Table 3).

TABLE 3

The Incidences of Adverse Events

Subgroup analyses are shown in Table 4. Use of surgery and anesthesia types was performed to identify the origin of heterogeneity.

TABLE 4

Subgroup Analyses

DISCUSSION

This meta-analysis demonstrated that DEX as a local anesthetic adjuvant on TAP block not only significantly reduced postoperative pain and opioid consumption but also prolonged the sensory block in patients undergoing abdominal surgery. There was no difference in the incidence of PONV, hypotension, bradycardia, somnolence, or pruritus between the DEX and control groups.

Postoperative pain remains a challenge worldwide. Inadequate treatment of pain can lead to patient anxiety, stress, extended hospital stays and dissatisfaction.37–39 Much attention has been paid to management of acute postoperative pain in recent years. The TAP block is a regional anesthetic technique that provides postoperative analgesia for abdominal surgery.40 The pooled results from our meta-analysis showed that DEX treatment reduced VAS pain scores by 0.78 points 8 hours postoperatively at rest and 1.13 points 4 hours postoperatively on movement. The lower pain scores can allow earlier ambulation after surgery and promote the satisfaction of analgesia of the patient. Meanwhile, opioid consumption was 13.71 mg lower in the DEX treatment group. Moreover, perineural DEX extended the duration of the TAP block by 3.33 hours compared with the control group.

Several recent studies demonstrated that DEX as potential LA adjuvant facilitates better and longer analgesia.41–43 The spinal and peripheral analgesic mechanisms of DEX could be contributed to its highly selective affinity to alpha-2 adrenergic receptor (α2AR).44 Similar to clonidine, DEX has an effect on presynaptic neuronal receptors and reduces norepinephrine release at peripheral afferent nociceptors.45 Furthermore, some evidence indicated that DEX played an inhibitory role in delayed rectifier K+ current and Na+ current, which resulted in a reduction in neuronal activity.46 Another study showed that adding DEX to ropivacaine increased the duration of analgesia by blocking the hyperpolarization-activated cation current.4 Our results were consistent with some recent meta-analyses that DEX as an adjuvant could prolong the duration of brachial plexus block.3–5 Currently, the safety of the perineural administration of DEX has received increased attention. In our study, DEX did not increase the incidence of hypotension or bradycardia. The low incidence of adverse events may be due to small dose of DEX administered.

Our study is the first to use meta-analysis to invest the effect of DEX as an adjuvant in TAP blocks on postoperative pain. However, there were several limitations of this meta-analysis. First, high heterogeneity was found in some outcome measures. Although subgroup and sensitivity analyses failed to change the heterogeneity, meta-regression indicated that anesthesia and surgery types were associated with the significant heterogeneity. Second, our study might be influenced by publication bias (Begg’s funnel plot and Egger’s test). Since DEX is only approved intravenous administration by the US Food and Drug Administration and Health Canada, most of included studies were performed in developing countries.47 Meanwhile, because of the language barrier, our search strategy is likely to include studies in English and Chinese database. Third, because of the limited number of included trials, a detailed meta-regression including all possible predictors could not be examined. Finally, the calculations of morphine equivalents may have introduced bias. These factors could affect our results. Therefore, the current results should be interpreted with caution.

In summary, this meta-analysis provided evidence that DEX is a favorable LA adjuvant with lower postoperative pain intensity and a significant reduction in opioid consumption as well as enhanced duration of the TAP block. More trials with strict design are required to confirm these findings.

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