Efficacy of Ultrasound-Guided Serratus Anterior Plane Block for Postoperative Analgesia in Patients Undergoing Breast Surgery: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

Objective Serratus anterior plane block (SAPB) provides effective thoracic analgesia. This systematic review and meta-analysis was conducted to assess the safety and efficacy of SAPB for postoperative analgesia after breast surgery. Methods A systematic literature search was performed using Embase, PubMed, Web of Science, and the Cochrane Library for eligible randomised controlled trials. The primary outcomes involved the administration of intraoperative and postoperative opioids. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was used for rating the quality of evidence for making recommendations. Results Overall, 13 studies comprising 826 patients met the inclusion criteria (412 in the SAPB group and 414 in the control group). Patients treated with SAPB exhibited a significantly lower postoperative opioid consumption (mean difference, −38.51 mg of oral morphine equivalent; 95% confidence interval (CI), −60.97 to −16.05; P < 0.01; I2 = 100%), whereas no difference was observed in the intraoperative opioid consumption (mean difference, −9.85 mg of oral morphine equivalent; 95% CI, −19.52 to −0.18; P=0.05; I2 = 94%). In addition, SAPB significantly decreased the occurrence of postoperative nausea and vomiting (risk ratio, 0.32; 95% CI, 0.19–0.55; P < 0.05;I2 = 38%) and reduced pain scores during the postoperative period (1 h: standardised mean difference (SMD), −1.23; 95% CI, −2.00 to −0.45; I2 = 92%; 2 h: SMD, −0.71; 95% CI, −1.00 to −0.41; I2 = 48%; 4 h: SMD, −1.52; 95% CI, −2.77 to −0.27; I2 = 95%; 6 h: SMD, −0.80; 95% CI, −1.51 to −0.08; I2 = 81%; 8 h: SMD, −1.12; 95% CI, −1.98 to −0.27; I2 = 92%; 12 h: SMD, −0.78; 95% CI, −1.21 to −0.35; I2 = 83%; and 24 h: SMD, −0.71; 95% CI, −1.20 to −0.23; I2 = 87%; P < 0.05 for all). Conclusion SAPB was safe and effective after breast surgery to relieve postsurgical pain. However, additional well-developed trials are required to validate these findings.


Introduction
According to global public health data, the most common type of cancer affecting women is breast cancer [1]. Surgical removal of the tumour is the primary treatment for breast cancer. However, postoperative pain continues to pose a problem in patients with breast cancer. Approximately 50% of patients who undergo breast surgery experience some degree of postoperative pain [2,3]. Severe pain hampers postoperative recovery [4] and prolongs the hospital stay [5]. In addition, the risk of progression of acute pain after breast surgery to chronic pain continues to remain [2]. erefore, various techniques for analgesia such as intercostal block [6], erector spinae plane block [7], and paravertebral block [8] are reported to ease severe postsurgical pain.
Serratus anterior plane block (SAPB) is a recently described interfascial plane block technique to relieve thoracic pain by injecting a local anaesthetic into the plane between the latissimus dorsi muscle and serratus anterior muscle [9]. SAPB provides effective postoperative analgesia by blocking the lateral cutaneous branches of the thoracic intercostal nerves. Previous studies have demonstrated that SAPB can be used as a locoregional analgesic technique to reduce pain after breast surgery [10,11]. However, the effectiveness of this method for inducing analgesia remains controversial. A recent randomised controlled trial (RCT) indicated that a deep SAPB did not have any beneficial effects on postoperative analgesic outcomes such as pain scores and opioid consumption [12]. However, no systematic and convincing proof related to this has been reported. erefore, we performed this systematic review and meta-analysis of RCTs to explore the safety and effectiveness of the SAPB technique in breast surgery.

Methods
e present systematic review and meta-analysis was performed according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Systematic Literature Search.
A systematic literature search was conducted using online databases, including Embase, PubMed, the Cochrane Library, and Web of Science, from the date of the establishment of the database to 31 March 2021 without any language restriction, and relevant RCTs were identified. e PubMed search criteria were as follows: (1) "serratus anterior block" (All Fields), "serratus anterior plane block" (All Fields), or "SAP block" (All Fields), (2) "sap block" (All Fields), "SAPB" (All Fields), and (3) "breast surgery" (All Fields), "breast cancer" (All Fields), "breast" (All Fields), or "breasts" (All Fields). Search strategies for other databases are shown in Supplementary Materials. Furthermore, we manually searched for the references in the relevant literature.

Selection Criteria and Data Extraction.
Studies meeting the following inclusion criteria were included in this analysis: (1) participants: studies involving patients undergoing breast surgery; (2) intervention: studies clearly describing SAPB as an auxiliary technique for analgesia regardless of the timing of placement of the regional block before or after general anesthesia; (3) comparison: studies with no intervention, sham block, or incision infiltration; (4) outcome: studies reporting opioid consumption or postoperative pain score; and (5) study design: RCTs. e following articles were excluded from this study: (1) review or case reports; (2) trials on animals or research involving cadaver dissection; (3) conference abstracts; and (4) duplicate publications.
EndNote X9 was used to pick out authentic trials from duplicate ones. Two different authors checked the authenticity of the article titles and abstracts and carefully assessed the full texts to ensure that the articles met the eligibility criteria for this study. e data were collected from authentic publications and were independently cross-checked by the two authors. e data collected included the first author's name, sample size, age, surgery type, SAPB, general anesthesia techniques, comparison, postoperative opioids analgesia, and pain measurements. For trials with incomplete data, corresponding authors were contacted via e-mail to obtain the complete information.

Quality and Risk Assessment.
e risk of bias in the publications included in this study was assessed using Cochrane Review Manager (Version 5.3; the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark, 2014). We used the following methods to assess bias: random sequence generation, allocation concealment, incomplete outcome data, double blinding, blinding of outcome assessment, and selective reporting. Each study was individually analysed by two reviewers and was classified into three groups: low risk, unclear risk, and high risk. e quality of evidence was examined using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to obtain results as per the following criteria: study design, inconsistency rating in results, risk of bias, and rating of indirectness of evidence. e quality of evidence was classified into 4 groups as high, moderate, low, and very low.

Primary and Secondary
Outcomes. Intraoperative and postoperative 24 h opioid consumptions were the primary outcomes. e dose of different types of opioids consumed was converted to an equivalent dose of oral morphine according to GlobalRPh (http://www.globalrph.com/ narcotic). Secondary outcomes included the occurrence of adverse events and scores of postsurgical pain at different time points. Results from a previous study showed a correlation between the scores obtained on the visual analogue scale (VAS) and the numeric rating score (NRS) [13]; therefore, we analysed the pain scores obtained using these two scales. For studies that measured pain scores at different states, active pain scores were included in this meta-analysis.

Statistical Analysis.
e meta-analysis was performed using Review Manager (version 5.3; the Nordic Cochrane Centre, the Cochrane Collaboration, Copenhagen, Denmark, 2014) and Stata V.12.0 (StataCorp LP, USA). A pooled risk ratio (RR) and 95% confidence intervals (CIs) were calculated for dichotomous outcomes. P < 0.05 was considered significant. Mean difference (MD) and 95% confidence interval (CI) were measured using the same units for continuous data, whereas standardised mean difference (SMD) was used for different units. e data reported as medians (ranges) were converted to mean and standard deviation similar to those performed in previous studies [14,15]. We assessed heterogeneity among trials using the statistic. High heterogeneity may be observed because of methodological and clinical factors; therefore, despite the low value, the random effects model was implemented in this meta-analysis. Sensitivity analysis was performed to assess the stability of the primary outcome.

Publication Bias.
We did not evaluate the publication bias because only a few studies were included in this analysis [38].

Sensitivity
Analysis. Sensitivity analysis was performed for postoperative opioid consumption. e estimate of effect did not change, indicating the robustness of the formulated result (Figure 7).

GRADE Assessment.
All studies included were RCTs. Most studies showed a relatively high . e "inconsistency" was classified as serious. Some trials reported median pain scores and opioid consumption. e "indirectness" was graded as serious. e GRADE levels were low and moderate for the outcomes. e total outcomes of the GRADE assessment are concisely shown in Table 2.

Discussion
is systematic review and meta-analysis revealed that ultrasound-guided SAPB decreased opioid consumption (low quality) to a significant level and relieved pain after breast surgery (low quality). In addition, SAPB decreased the occurrence of PONV (moderate quality). Procedure-related complications were not seen in the studies included in the analysis.
Patients undergoing breast cancer surgery experience varying degrees of acute and chronic pain with an incidence of up to 60% [39]. Various analgesic techniques have been used in breast surgeries, including paravertebral block [8], intercostal block [6], and pectoral nerve block [40]. Paravertebral block and intercostal nerve block are associated with a risk of development of pneumothorax (0.3%-11.4%); therefore, these methods are not the preferred choice of anaesthesiologists [41,42]. Effective control of pain after breast surgery is very important not only to more effectively manage acute pain but also to improve postoperative recovery [43]. e development of ultrasound-guided regional block and the introduction of new regional analgesia techniques have increased the safety and effectiveness of perioperative analgesia for thoracic surgery. Ultrasound-guided SAPB is a recently described regional block technique. It involves the injection of a local anaesthetic into the region between the serratus anterior and intercostal muscles [9]. e thoracic  [44] reported that SAPB might provide effective analgesia after breast surgery; however, the control group in that meta-analysis included patients who received a paravertebral block. e results of our meta-analysis revealed that SAPB remarkably decreased the levels of postoperative opioid consumption and decreased pain compared with that in the control group, which indicated that SAPB could provide effective analgesia after breast surgery. However, a recent RCT [12] showed that SAPB did not improve analgesic outcomes in patients who underwent ambulatory breast cancer surgery. is could be because "breast surgery," as the type of surgery being performed, is too generic a term and involves all degrees of trespass; therefore, comparison of the results obtained in this study with our results may be difficult. Moreover, deep SAPB alone was performed in a previous study, and Mayes et al. [45] reported that injecting methylene blue deep into the serratus anterior muscle did not produce a consistent spread area. e results of our meta-analysis revealed no difference in intraoperative opioid consumption between the two groups. is finding may be because the extent of SAPB was not sufficient to control intraoperative pain. Results similar to those of our study were reported by Alessandro et al. in patients undergoing thoracoscopic surgery [46].

Random sequence generation (selection bias)
Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias) Other bias

Pain Research and Management
In addition, we observed that patients treated with SAPB had a significantly lower incidence of PONV. is may be a result of less opioid usage during the postoperative period. e results of a recent RCT with a large sample indicated that the incidence of PONV was 44.3% after general anesthesia [47]. Effective prevention of PONV is important in the implementation of enhanced recovery after surgery. Reduction of PONV is useful in expediting discharge for outpatients [48].
Procedure-related complications were not seen in the studies included in this analysis. SAPB is a relatively safe technique of regional block, and potential block-related complications such as bleeding and infection at the puncture site have not been reported. To date, only a case report by Desai described the development of pneumothorax following SABP in a patient undergoing wire-guided wide local excision of a lump in the right breast [49]. However, as a novel regional block technique, high-quality trials are required to ensure the safety of SAPB.
Our meta-analysis had some limitations. e analysis was performed with a limited number of participants. erefore, studies with a larger sample size should be performed in the future. Furthermore, a high level of clinical heterogeneity may be present because of the various general and local anesthetics administered to the patients. We were unable to compare the advantages and disadvantages of SAPB with other techniques of regional anesthesia because of an insufficient number of RCTs pertaining to this topic.

Conclusion
SAPB is safe and effective in inducing postoperative analgesia after breast surgery. However, well-designed trials are required to validate these findings.

Data Availability
All data generated or analysed during this study are included within this published article and its supplementary information files.