The efficacy and safety of paravertebral block for postoperative analgesia in renal surgery: A systematic review and meta-analysis of randomized controlled trials

Background Paravertebral block (PVB) has been widely used in postoperative analgesia, especially in thoracic and breast surgery. However, the efficacy and safety of PVB for analgesia after renal surgery remains uncertain. Therefore, this study aimed to determine the postoperative analgesic efficacy and safety of PVB in renal surgery. Methods PubMed, Web of Science, Embase, and the Cochrane Library databases were systematically searched up to December 20, 2021. All randomized controlled trials (RCTs) evaluating the postoperative analgesic efficacy of PVB in renal surgery were collected. The meta-analysis was performed using RevMan 5.4 and Stata/MP 14.0 software. Results A total of 16 RCTs involving 907 patients were included in the meta-analysis. Ten studies investigated patients under percutaneous nephrolithotomy (PCNL), and six studies were done for patients under other renal surgery (nephrectomy or pyeloplasty). Compared with control groups (no block, sham block, or other nerve blocks), meta-analysis showed that PVB reduced 24-hour postoperative opioid consumption significantly (SMD = −0.99, 95%CI: −1.60–0.38, p = 0.001, I2 = 92%) and reduced pain scores at various time points within 24 h at rest and 1 h, 4 h, and 24 h at movement after renal surgery, furthermore, PVB prolonged the time to first postoperative analgesic requirement (SMD = 2.16, 95%CI: 0.94–3.39, p = 0.005, I2 = 96%) and reduced the incidence of postoperative additional analgesia (OR = 0.14, 95%CI: 0.06∼0.33, p < 0.00001, I2 = 50%). Subgroup analysis revealed that the postoperative analgesia effect of PVB was more significant in PCNL, and the use of bupivacaine for PVB seemed to have a better performance. Besides, there was no difference in the incidence of postoperative nausea, vomiting, and itching between PVB and control groups. Conclusion This study indicates that PVB may provide effective postoperative analgesia in patients under renal surgery, especially PCNL patients. Moreover, PVB is a safe analgesic method without significant analgesia-related complications.


Introduction
Postoperative pain is one of the most common and troublesome problems faced by patients undergoing various operations (1). Evidence showed that less than half of patients who undergo surgery reported adequate relief of postoperative pain, while about 75% reported moderate, severe, or extreme pain (2). Timely and effective postoperative pain management has always been a big concerned problem for surgeons and patients, as inadequate pain relief could lead to a prolonged hospital stay, affect recovery progress, and increase medical costs, even cause serious complications such as cardiovascular accidents and thrombosis (3). Renal surgery, especially in open nephrectomy and PCNL is accompanied by severe postoperative pain (4). At present, continuous epidural techniques, intravenous, or oral non-opioid analgesics, quadriceps lumborum block, and nerve block are widely used for postoperative pain management after renal surgery, of which epidural block is the most commonly used, and the analgesic effect of these methods are acceptable (5,6). However, some patients still develop chronic pain (7).
Paravertebral block (PVB) is a new analgesic method with an easy procedure, reliable curative effect, and few complications (8). Earlier studies indicated that PVB shows a significant analgesic effect for many surgical procedures; especially cardiothoracic surgery, breast surgery, and inguinal hernia repair (9-11). The application of PVB in renal surgery has been reported recently, and some studies have shown that PVB can effectively control the pain after renal surgery and reduce anesthetic-related complications (12). Therefore, the purpose of this study is to evaluate the effect of PVB on pain management after renal surgery and provide a reference for the selection of analgesic methods after renal surgery.

Search strategy
This study was performed by following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement (13). Two reviewers independently and comprehensively searched PubMed, Web of Science, Embase, and the Cochrane Library databases from inception to December 20, 2021. The following search terms were used: PVB and PCNL or nephrectomy or pyeloplasty or renal surgery. The search strategies for all databases are presented in the Supplementary Material. We also manually searched the references of all the included studies to identify other relevant articles. There was no language limitation in the literature search.

Inclusion and exclusion criteria
The inclusion criteria were defined by the population, intervention, comparison, outcome, and study design (PICOS) principle, see Table 1. The exclusion criteria of this study were: (1) duplicate articles; (2) studies were published as comments, reviews, case reports, letters, or conference abstracts; (3) studies with incomplete data; and (4) low-quality literature.

Data extraction and quality assessment
Two investigators independently completed data extraction and quality assessment, simultaneous cross-checking was conducted, and any disputes were solved by discussion or thirdparty intervention. The following relevant information was extracted from included articles: first author, publication year, country, number of patients, type of surgery, American Society of Anesthesiologists (ASA) score, age, gender, duration of operation, anesthesia time, interventions, follow-up time, and study outcomes. The primary outcomes were 24-hour postoperative opioid consumption, and pain scores at rest and movement at 1 h, 4 h, 6 h, 12 h, and 24 h after surgery. The secondary outcomes were the incidence of postoperative additional analgesia, time to first postoperative analgesic requirement, and the incidence of postoperative nausea, vomiting, and itching. The quality of the included studies was evaluated using the Cochrane Collaboration Risk of Bias Tool (14).

Statistical analysis
We used Review Manager Version 5.4 (Cochrane collaboration, the Nordic Cochrane Centre, Copenhagen, Denmark) and Stata/ MP version 14.0 to perform the meta-analysis. For dichotomous outcomes, such as the incidence of postoperative additional analgesia and nausea, vomiting, and itching were presented as odds ratios (OR) at 95% confidence interval (CI). For continuous outcomes, such as 24-hour postoperative opioid consumption, pain scores, and time to first postoperative analgesic requirement were expressed as the mean difference (MD) at 95% CI. If the measurement units were different, standardized mean difference (SMD) with 95%CI was used. The chi-squared test and I 2 statistics were used to evaluate heterogeneity across studies, and I 2 > 50% and/or p < 0.1 represented significant heterogeneity. The randomeffects model was applied to all analyzes to account for the clinical and methodological diversity among included studies. Sensitivity analysis was used to explore the stability of the results, and subgroup analysis was performed to investigate the effect of surgery type and anesthetic type on the results when high heterogeneity was detected. Funnel plots were used to evaluate publication bias where there were more than 10 studies. Begg and Eggers tests were further used to evaluate the asymmetry of funnel plots, and trim-and-fill analysis was performed to explore the impact of publication bias on the interpretation of the results. When p < 0.05, the difference was considered statistically significant.

Risk of bias assessment
The results of bias risk assessment for all RCTs are shown in Figure 2. All the included studies were rated as medium-or high-quality, and no low-quality literature was included. Flowchart of the study selection.   Risk of bias summary and risk of bias graph for the included studies.  (Table 3).  (Figures 4A-E). The results were stable on sensitivity analysis. Then subgroup analysis was carried out to explore whether pain scores at 1 h, 6 h, and 12 h at rest with high heterogeneity were affected by surgery type and anesthetic type. The results revealed that the postoperative pain scores of the PCNL and bupivacaine subgroups at 1 h, 6 h, and 12 h at rest were consistent with the overall outcomes. Similarly, the same results were observed at 12 h at rest in the other renal surgery subgroup and at 6 h, 12 h at rest in the ropivacaine subgroup, but no significant differences were found at 1 h, 6 h at rest in the other renal surgery subgroup and at 1 h at rest in ropivacaine subgroup ( Table 3).

Publication bias
A funnel plot was drawn based on the comparison of 24-hour postoperative opioid consumption, the distribution of the included studies was not symmetrical and there was a possibility of publication bias (Figure 9), which was also confirmed by Begg and Egger tests ( p = 0.007, p = 0.004). However, the trim-and-fill analysis indicated that the results of this study were not affected by publication bias.

Discussion
This study demonstrated that PVB may be an ideal analgesic method, which can improve the postoperative analgesia of patients undergoing renal surgery significantly. In particular, early postoperative opioid consumption and pain scores were reduced remarkably. Further, the first postoperative analgesia time was prolonged, and the postoperative additional analgesia rate was reduced. Meanwhile, the PVB did not increase the incidence of postoperative nausea, vomiting, and itching compared to other controls.
The basic principle of PVB is to inject local anesthetics into both sides of the vertebral body and near the spinal nerve roots out of the intervertebral foramen, in order to achieve the analgesic effect by blocking the paravertebral spinal nerve (31). In a comparative study as early as 1993, continuous PVB showed better postoperative pain relief than continuous epidural block after renal surgery (32). In recent years, clinical studies indicated that PVB can be used for postoperative FIGURE 8 Forest plot of the incidence of (A) nausea, (B) vomiting, and (C) itching. A previous meta-analysis of the analgesic effect of PVB in PCNL showed that PVB could reduce postoperative analgesic consumption and the use of additional analgesics, and prolong the time required for the first analgesia, but had no substantial effect on nausea, vomiting, and itching (36). This meta-analysis, which included all newly published RCTs of various types of renal surgery using PVB, showed that PVB significantly reduced 24-hour postoperative opioid consumption. Subgroup analysis showed that the results were statistically significant differences in PCNL and bupivacaine subgroups but not in other renal surgery and ropivacaine subgroups. Despite subgroup analysis, the sources of heterogeneity remain unclear. A recent study indicated that among patients undergoing PCNL, women need more postoperative analgesia than men (37), which might explain the heterogeneity among included studies. Moreover, the implementation methods of PVB of included RCTs were different, as well as the use of the concentration of anesthetics, which might contribute to the high heterogeneity. In addition, this meta-analysis also showed that PVB prolonged the time to first postoperative analgesia requirement and reduced the incidence of postoperative additional analgesia in renal surgery. Subgroup analysis revealed that the first postoperative analgesia time of PVB using bupivacaine was significantly prolonged, which was similar to the results of Saroa et al. (34), indicating that the use of bupivacaine for PVB was more beneficial for pain management of patients undergoing renal surgery. And the reduction in the Funnel plot of evaluating publication bias.
Zhao et al. 10.3389/fsurg.2022.865362 Frontiers in Surgery incidence of postoperative additional analgesia was more significant in PCNL. Based on the current pooled data analysis, we found that the use of PVB for other renal surgery may be less assuring compared to PCNL. None of the RCTs included in this study reported significant complications, and only a few cases of nausea, vomiting, and itching were reported. Furthermore, this study also showed that PVB performed well in the incidence of postoperative nausea, vomiting, and itching. Although the use of PVB for postoperative analgesia in renal surgery has obvious advantages, however, the lack of professional equipment, high technical difficulty, and potential risks might limit the promotion of this technology. Although this study was conducted in strict accordance with the Cochrane Manual standards, several limitations remain. First, the heterogeneity of primary outcome measures was high. The diversity of renal surgery types, the difference in blocking methods, the type and concentration of anesthetics, and the population composition of each study may be the sources of heterogeneity. Second, the asymmetry of the funnel plot indicated the possibility of publication bias, therefore, the results should be interpreted with caution. At last, the number of included studies and sample size were limited, which needs to be further confirmed by large-sample, multi-center, high-quality, and well-designed clinical studies.

Conclusion
In conclusion, this study indicates that PVB may provide effective postoperative analgesia in patients undergoing renal surgery, especially in PCNL. Moreover, PVB is a safe analgesic method without severe complications. Limited by the quality of included studies, the aforementioned results still need to be verified by more high-quality RCTs.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.