Clinical analgesic efficacy of pectoral nerve block in patients undergoing breast cancer surgery

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Introduction
Breast cancer is the most commonly diagnosed cancer in women. [1] In 2018, it is estimated that there were 266,120 new cases of invasive breast cancer diagnosed in women in the United States, and more than 40,920 people will die from breast cancer. [1,2] Most of the time, surgery is considered the primary treatment for breast cancer, while radiation therapy, chemotherapy, and hormone therapy are given as adjuvant therapies. [3,4] More than half of breast surgery patients experience severe acute postoperative pain, and acute postoperative pain is followed by persistent pain in approximately 25% to 50% of patients. [5,6] Severe acute pain is a risk factor for chronic pain following breast cancer surgery, which is associated with impaired quality of life. [7,8] Regional anesthesia techniques can provide better acute pain control and improve patient satisfaction. [9][10][11] The pectoral nerve (Pecs) block, a novel technique described by Blanco in 2011, can provide analgesia for breast surgery. [12] In this new technique, local anesthetic is injected into the interfascial plane between the pectoralis major and minor muscles (Pecs I block) to anesthetize the medial and lateral pectoral nerves. Blanco and colleagues proposed a second version of the Pecs block in 2012, called "modified Pecs block" or Pecs block type II (Pecs II block). [13] For Pecs II block, local anesthetic is deposited deeper to the Pecs I injection site and above the serratus anterior muscle at the third rib, which aims to block the pectoral nerves, the intercostobrachial, lateral branches of intercostal nerves III, IV, V, VI, and the long thoracic nerve. [13] To date, a number of studies have confirmed that Pecs block is a simple and easy-to-learn technique that produces good analgesia for radical breast surgery [14][15][16][17] . However, some well-designed randomized controlled trials (RCTs) have failed to show that Pecs block can offer superior analgesia after breast surgery. [18,19] The Pecs block is widely used for postoperative analgesia after breast surgery. [13] Compared to thoracic paravertebral and thoracic epidural blocks, the Pecs block has less technical complexity and fewer complications. [13,15] Is there enough evidence to support the use of Pecs block for radical mastectomy? In this study, we conducted a meta-analysis to evaluate clinical analgesic efficacy of Pecs block in patients undergoing breast cancer surgery.

Study search strategy
We systematically searched the PubMed, EMBASE, Cochrane Library, and Web of Science databases from inception to November 2018. Medical subject headings and text words "pectoral nerve block, Pecs block, Pecs I and Pecs II blocks or PECS" and "breast cancer or radical mastectomy" were used to search for trials of interest. Details of the search strategies are summarized in Supplementary Table S2, http://links.lww.com/ MD/D975. The search was restricted to articles in the English language. In order to avoid omitting relevant clinical trials, we also searched conference summaries and references for potential eligible reports.

Selection criteria
Inclusion criteria were as follows: (1) studies designed as RCTs; (2) female patients undergoing breast cancer surgery; (3) experimental groups treated with general anesthesia (GA) plus Pecs block, and the control group with GA alone; (4) outcomes such as pain scores, postoperative opioid consumption (in the postanesthesia care unit [PACU] and at 24 hours after surgery), intraoperative fentanyl consumption, time to first request for analgesia, and incidence of postoperative nausea and vomiting (PONV).

Data extraction
Two reviewers (QCS, SYL) independently extracted data from the selected studies. Disagreements were resolved by group consensus. The following information was extracted from studies that met the inclusion criteria: first author, year of publication, country, number of patients, study design, and outcome measures. If data were presented as median and interquartile range, we contacted the author for necessary data. Failing that, the mean was considered to be equivalent to the median, and the standard deviation = interquartile range/1.35. [21]

Quality assessment
We used the Cochrane Risk of Bias Tool to assess the quality of the included studies. [27] The evaluation should include the following domains: (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. Any disagreements were resolved by discussion.
For the assessment of publication bias of the studies included in the final analysis, both Begg rank correlation and Egger linear regression tests were performed. [28,29] 2.6. 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 with 95% confidence intervals (CIs) were calculated for dichotomous data, and weighted mean differences with 95% CIs were calculated for continuous variables. Heterogeneity was measured by I 2 , with I 2 > 50% indicating significant heterogeneity. If I 2 50%, the fixed effects model was used; if I 2 > 50%, a random effects model was used, and the heterogeneity was assessed. Subgroup analyses were performed for the outcome measures, according to time of block (before GA, after GA, or after surgery) and local anesthetic types (ropivacaine, bupivacaine, or levobupivacaine). Sensitivity analyses were performed by excluding 1 study each time to evaluate the influence of a single study on the overall estimate. [30] This is a meta-analysis. Thus, ethical approval was not necessary and the informed consent was not given.  Figure 1 presents a summary of the study search process. A total of 358 relevant studies were initially identified. Of these, 127 were excluded due to duplication. After screening of the titles and abstracts, 208 were further excluded. By reading the full text of the remaining 23 articles, 10 of them were additionally excluded because they failed to meet the inclusion criteria. Thus, 13 RCTs with 940 patients were finally assessed in this meta-analysis. [14][15][16][17][18][19][31][32][33][34][35][36][37]

Study characteristics
The characteristics of the included studies are summarized in Table 1. Thirteen trials compared Pecs block in combination with GA to GA alone in mastectomy surgery. Of these 13 trials, 8 performed Pecs block after the induction of anesthesia, 2 performed before the induction of anesthesia, and 2 applied at the completion of the surgery. Eleven studies underwent ultrasound guided Pecs block and the other 2 applied Pecs block under direct visualization. Among these 13 trials, 5 used ropivacaine, 6 used bupivacaine, and 2 others used levobupivacaine. Pain scores were reported in all included trials. The risk assessment of the included studies is presented in Figure 2. Eleven trials did not have a high risk of bias for any of the evaluated criteria. One study had a high risk of detection bias, while 1 study had a high risk of attrition bias.

First request for analgesia
First requests for analgesia were available in 6 studies. On average, Pecs block delayed the time to first request for analgesia by 296.69 minutes (95% CI: 139.91-453.48, P < .001, I 2 = 99.9%) (Fig. 8). No evidence of publication bias was observed on Begg test (P = .133) or Egger test (P = .109). Sensitivity analysis did not significantly alter the summarized results.

PONV and block-related complications
Five studies investigated the incidence of PONV. There was no statistically significant difference in PONV (S.2, http://links.lww. com/MD/D973). One study reported block-related complications such as bleeding and hematoma in 3 patients. However, no blockrelated complications were reported in the other 12 studies.

Subgroup analyses
Subgroup analyses are shown in Table 3. Use of time of block (before/after induction of GA or after completion of the surgery) and local anesthetic types (ropivacaine, bupivacaine, or levobupivacaine) may account for heterogeneity in some of the findings.

Discussion
This is one of the first meta-analyses to examine the clinical analgesic efficacy of Pecs block in patients undergoing breast cancer surgery. Our meta-analysis showed that the use of Pecs block significantly reduced VAS pain scores up to 24 hours postoperatively. In addition, breast cancer patients receiving Pecs block had significantly less intraoperative and postoperative opioid consumption than the control group. The analgesic effect of Pecs block was also demonstrated by a longer time to the first request for analgesia. There was no statistically significant difference in PONV and complications related to Pecs block. Surgery is the first choice of treatment for breast cancer, and regional anesthesia may potentially reduce the post-mastectomy pain syndrome. [38] It has been implicated that regional anesthesia could reduce tumor recurrence and metastases after mastectomy. [3] Kairaluoma and Ibarra suggested that paravertebral block significantly reduces the acute and chronic pain compared to the sham block. [39,40] As the thoracic paravertebral space is in close relation to the pleural space, thoracic paravertebral block has potential risks of pneumothorax and total spinal anesthesia. [41] In recent years, a less invasive and more effective Pecs block has become popular for perioperative pain control in patients undergoing breast cancer surgery. [12][13][14][15] In this meta-analysis, the use of Pecs block significantly decreased VAS pain scores by 1.90 points in the PACU and 2.17 points at postoperative 1 hour. Although the reduction of VAS pain scores reduced to 1.01 points at 24 postoperatively, the difference remained significant. Moreover, Pecs block prolonged the time to first analgesic   [36] Although conventional opioid analgesics remain the mainstay of postoperative pain management, their use may be limited by potentially harmful effects. [42,43] Steyaert and colleagues demonstrated that patients who needed opioids in the immediate postoperative period were associated with the presence of chronic pain after mastectomy with axillary lymph node dissection. [44] Therefore, a multimodal approach to improve postoperative analgesia must be utilized, including local infiltration, regional anesthesia, and nonopioid analgesics. [42,43] In the current meta-analysis, the use of Pecs block decreased intraoperative (fentanyl equivalent) opioid consumption by À85.52 mg. However, we found levobupivacaine failed to decrease intraoperative opioid consumption after performing subgroup analysis. Only 2 studies involving 130 participants investigated the efficacy of levobupivacaine. Because of relative smaller sample size, the result should be interpreted with caution as the statistical power of this analysis is low. Furthermore, postoperative (morphine equivalent) opioid consumption was 1.93 mg lower in the PACU and 11.88 mg lower at 24 hours. The opioid sparing effect led to increased patient satisfaction and decreased length of hospital stay. [17,36]      This meta-analysis has several limitations that should be considered. First, high heterogeneity was found in some outcome measures. Although subgroup analyses (time of block and local anesthetic types) and sensitivity analyses were performed to identify the potential heterogeneity, we failed to change the heterogeneity. Second, despite a comprehensive search strategy and lack of language restriction, we found publication bias in the analysis of intraoperative and postoperative opioid consumption Table 3 Subgroup analyses.

Subgroups
No. of studies WMD (95% CI) P-value for heterogeneity I 2 test (%)  when we performed Egger test. However, this was not confirmed with Begg test, which is less susceptible to false positive results. [45] Third, 10 included studies performed Pecs block after induction when patients were unconscious. The quality of the block was not assessed before surgery, which might contribute to the heterogeneity of the analysis. Fourth, although opioid doses were converted to fentanyl and morphine equivalent doses, the calculations might result in some degree of variation. Lastly, due to insufficient information from original trials, we could not evaluate the efficacy of Pecs block on important outcomes such as sensory block duration, length of hospital stay, postoperative chronic breast pain, and tumor recurrence and metastases.
In conclusion, our meta-analysis indicated that adding Pecs block to GA procedures led to lower VAS pain scores, more significant opioid sparing, and longer time to first analgesic request in patients undergoing breast cancer surgery compared with GA procedures alone. Further studies are needed to investigate the long-term outcomes such as postoperative chronic pain, tumor recurrence and metastases, and recovery of shoulder function in these patients.