The Impact of intra-abdominal Pressure on Perioperative Outcomes in Robotic-Assisted Radical Prostatectomy: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Objective The aim of the study is to analyze the impact of intra-abdominal pressure (IAP) on perioperative outcomes in robotic-assisted radical prostatectomy (RARP). Methods We searched the PubMed, Cochrane Library, Science, Embase, and CNKI databases systematically, and the retrieval date was from the inception of the databases to April 2022. Randomized controlled trials on high intraabdominal pressure (HIAP) and low intraabdominal pressure (LIAP) in RARP were included. The meta-analysis was performed using Review Manager software (version 5.3). Results Six studies involving 2,271 patients were included in the meta-analysis. Compared with patients who experienced HIAP, those who experienced LIAP had a lower incidence of postoperative ileus (POI) (risk ratio (RR): 0.42; 95% confidence interval (CI): 0.24 to 0.72; p = 0.002). However, there were no significant differences in hematoma (RR 2.22; 95% CI, 0.61 to 8.15; p = 0.23), positive margin rate (RR, 1.06; 95% CI, 0.84 to 1.32; p = 0.64), urinary retention (RR, 0.99; 95% CI, 0.51 to 1.94; p = 0.98), operative time (mean difference (MD), −0.36; 95% CI, −12.24 to 6.12; p = 0.51), or intraoperative blood loss (MD, −21.80; 95% CI, −55.28 to 11.68; p = 0.20) among patients undergoing LIAP and HIAP. Conclusion Our study of published trials indicates that using LIAP during RARP may reduce the incidence of POI, and there were no differences in terms of hematoma, positive margin rate, urinary retention, operative time, or intraoperative blood loss.


Introduction
Robot-assisted radical prostatectomy (RARP) has become the gold standard for localized prostate cancer treatment since its inception in the 20th century [1,2]. Te improved vision provided by the robotic system is combined with a better understanding of the surgical anatomy, allowing improved surgical techniques to optimize postoperative recovery [3]. RARP accounts for more than 85% of prostatectomies performed in the United States [2]. Te consistently reported benefts of RARP over open prostatectomy include a shorter duration of hospitalization and lower blood loss [4][5][6].
Over the past two decades, many studies on optimal intraabdominal pressure (IAP) for laparoscopy have emerged [7,8]. However, studies on the impact of pneumoperitoneum on RARP are limited. Te establishment of laparoscopic pneumoperitoneum can improve visualization, shorten operation time, and reduce blood loss [9]. However, abdominal insufation of carbon dioxide may cause many physiological changes, such as reduced cardiac output, increased peak airway pressure, oliguria, and systemic acidosis [10][11][12][13][14]. As study shows, laparoscopic cholecystectomy with lower pneumoperitoneum pressure can reduce hospital stay and postoperative pain [15]. However, using lower pneumoperitoneum pressures may limit visualization, prolong the operative time, increase blood loss, or cause unintended damage to organs [7].
Available evidence from currently published studies that can inform clinical practice includes a retrospective study in 2018 [16] and two randomized controlled trials (RCTs) published in 2020 [17] and 2021 [18]. Tese studies suggest that low IAP during RARP is associated with a signifcant reduction in the incidence of postoperative bowel obstruction compared with standard IAP [16][17][18]. However, the impact of low IAP on operative time, length of hospital stay, and other surgical outcomes is unknown. In addition, a meta-analysis published around the same time [19] concluded that the use of low IAP (LIAP) during laparoscopic cholecystectomy reduced postoperative pain, including shoulder pain and length of hospital stay, compared with standard IAP (defned as 12-14 mmHg). Critically, no published meta-analyses have compared the impact of high IAP (HIAP) and LIAP on perioperative outcomes in RARP. Given these data gaps and the availability of existing studies, we conducted a meta-analysis to discuss the impact of IAP on perioperative outcomes in RARP.

Search Strategy.
We systematically searched the PubMed, Cochrane Library, Science, Embase, and CNKI databases, and the retrieval date was from the database inception to April 2022. We searched the following terms: "prostate neoplasms," "prostate cancer," "prostatectomy," "prostatectomies," "suprapubic prostatectomy," "retropubic prostatectomy," "pneumoperitoneum," "insufation pressure," "abdominal pressure," and "pneumoperitoneum pressure." Search strategies were formulated for diferent databases. A manual search of the references of articles related to the topic was performed to broaden the scope of the search. All the included studies were independently evaluated by two reviewers (Y. D. and Y. Y.), and all differences were resolved through discussion.

Inclusion/Exclusion
Criteria. Following the PICOS principle, inclusion criteria were as follows: (1) studies were performed in adults diagnosed with prostate cancer; (2) included patients who received RARP; (3) compared different pneumoperitoneum pressures; (4) full papers containing at least one outcome parameter, such as the occurrence of postoperative ileus (POI), operative time, blood loss, positive margin, and so on; and (5) had an RCTor cohort study design. Exclusion criteria were as follows: non-RCTs, studies with incomplete or unavailable data, animal studies, systematic reviews, and reviews or republished studies.

Data Extraction.
We extracted the following data from the studies in the meta-analysis: author, publication year, study design, basic information, pneumoperitoneum pressure, operative time, blood loss, positive margin, and occurrence of POI, hematoma, and urinary retention. When there was a continuous variable, the average value and standard deviation were calculated.

Quality Assessment.
According to the recommendations of evidence-based medicine research guidelines, the risk of bias in Cochrane systematic reviews was used to evaluate the literature quality [20,21]. Te quality of the included studies was assessed using six indicators: randomization method, concealment of allocation scheme, blinding, completeness of outcome data, selective reporting of study results, and other sources of bias. Regarding the classifcation of quality assessments: studies with ≥5 items were considered to have a low risk of bias; 3-4 items, a moderate risk of bias; and <3 items, a high risk of bias. One article had a low risk of bias, and the other fve articles all had a moderate risk of bias, all articles were of high quality. In Figure1(a), the standard is "+," and the non-compliance is "−." Figure 1(b) shows the proportion of each item in the methodological assessment.

Statistical Analysis.
A meta-analysis of the included studies was performed using Review Manager version 5.3. For dichotomous variables, the risk ratio (RR) and 95% confdence interval (CI) were used as efcacy indicators for statistical analysis. Heterogeneity between studies was assessed using the Q-test and I 2 -test. If p < 0.05 or I 2 >50%, heterogeneity was considered to exist, and the randomefects model was used to combine the data; however, if (p ≥ 0.05 or I 2 ＜ 50%), no heterogeneity was considered to exist, and data were combined using a fxed-efects model. p < 0.05 indicated that diferences were statistically signifcant. A funnel plot was drawn to analyze potential publication bias.

Registration.
Te study was registered on PROSPERO (CRD42022351780).

Study Characteristics.
A total of 919 articles were initially retrieved. However, 843 articles were excluded because there were duplicates or irrelevant to our study. After reading the full text, another 70 articles were excluded. Finally, six studies with 2271 patients were included in our metaanalysis [16,17,[22][23][24][25] (Figure 2). Te characteristics of the included studies are shown in Table 1. Te risk of bias in the Cochrane systematic reviews was used to evaluate the quality of the studies. All studies had a risk of bias, but most were moderate, and the average quality of each study was good. Te results are shown in Figure 1.

Demographic
Variables. Demographic variables were analyzed according to the included studies for each outcome parameter. Tere were no statistically signifcant diferences between the demographic variables of the included studies ( Table 2).

Discussion
RARP is the gold standard treatment for localized prostate cancer treatment [1,2]. As study shows, laparoscopic cholecystectomy with lower pneumoperitoneum pressure can reduce hospital stay and postoperative pain [15]. However, the use of lower pneumoperitoneum pressures has many limitations. Terefore, we conducted a meta-analysis to discuss the impact of IAP on the perioperative outcomes of RARP. Postoperative parameters are important in assessing the safety of surgery, and the postoperative parameters assessed in our study included POI, hematoma, positive margin rate, and urinary retention. Our meta-analysis focused on assessing whether low-pressure pneumoperitoneum could reduce the incidence of POI. Regarding the incidence of POI, our study showed that there was a signifcant diference between the HIAP and LIAP groups, which is consistent with the results of most studies; the incidence of POI in the LIAP group was signifcantly lower than that in the HIAP group. Te incidence of POI ranges from 3% to 10% in urological procedures, with approximately $1.5 billion annually in U.S. health care costs [26,27]. Schilling et al. found that increasing the pneumoperitoneum pressure from 10 mmHg to 15 mmHg reduced the blood fow to the jejunum and colon by 32% and 44%, respectively [28]. During laparoscopic surgery, the compression of intestinal gas may lead to decreased mesenteric blood fow and decreased intestinal motility, which may lead to prolonged recovery time of intestinal function, possibly contributing to the development of POI [29]. However, interestingly, Rohlof et al. found that two other independent variables that contributed to the increased risk of POI, smoking, and maintenance IV fuids were independently associated with a higher incidence of POI [17]. Although these variables are unlikely to be the direct cause of POI, it is important to consider these factors.
Other postoperative parameters, included hematoma formation, positive margin rate, and urinary retention. Our study showed that there was no statistically signifcant diference between the HIAP group and the LIAP group. Tese secondary results demonstrated noninferiority in the LIAP group, indicating that the use of lower pneumoperitoneum pressures is safe when performing RARP. However, because of the limited data available in the study, and the low event rates for some outcomes, the ability to detect a signifcant diference may be difcult even if different IAP levels had a signifcant efect on these outcomes.
Another major problem of low-pressure pneumoperitoneum is the assessment of the intraoperative parameters. In terms of operative time and intraoperative blood loss, our study showed that there was no statistically signifcant diference between the HIAP group and the LIAP group. Surgeons are concerned that the use of lower pneumoperitoneum pressures may limit visualization and lead to blood loss, increased operative time, and unintended damage to organs and structures. Christensen et al. found that there was a statistically signifcant increase of 10.5 minutes in the mean operating time among patients in the 6 mmHg group (145.7 vs. 155.2 min; p < 0.001) and a 20 mL increase in estimated blood loss (119.3 vs. 139.9 mL; p < 0.001) [22]. However, Johnstone et al. found that the operative time was 136.5 minutes (120-195) in the HIAP group and 120 minutes (106-145) in the LIAP group. Despite the use of lower pneumoperitoneum pressures, the LIAP group had a shorter operative time, although the diference was not statistically signifcant (p � 0.0525). At the same time, intraoperative blood loss in the LIAP group Journal of Oncology 5 was signifcantly reduced, with an average blood loss of 35 mL less than that in the HIAP group (145 vs. 181 mL; p � 0.0029) [25]. Te reason for this may be the diferent experiences of doctors in diferent institutions, and the difference in the operation may lead to deviations in the experimental results. Typically, 15 mmHg is the standard pneumoperitoneum pressure used during surgery. In our meta-analysis, four of the included studies used the standard pneumoperitoneum pressure as the HIAP group. However, the disadvantage is that in the study by Modi et al., 15 mmHg was used as the low pneumoperitoneum pressure group [23]. Te research results of Modi et al. showed that 17 cases (8.46%) of complications were found in the control group and 47 cases (8.55%) in the experimental group; the diference in the incidence of complications between the groups was not  statistically signifcant. Tis suggests that the use of 20 mmHg pressure in RARP is safe and that increased infation pressure is not associated with higher complication rates. However, the incidence of POI in the HIAP group was still signifcantly higher than that in the LIAP group (6 vs. 0), which is consistent with the results of our meta-analysis. At the same time, combined with the results of this study, it is also proven that lower pneumoperitoneum pressure is not inferior to higher pneumoperitoneum pressure. In the study by Rohlof et al., 12 mmHg was used as the high pneumoperitoneum pressure group, and the primary endpoint of the study was the occurrence of POI. Te study showed that seven patients experienced POI, including fve (4.8%) in the HIAP group and two (2%) in the LIAP group [17]. Unfortunately, the fndings were not statistically signifcant but could demonstrate that lowering pneumoperitoneum pressure may reduce the incidence of POI. Terefore, the lack of standardized IAP may lead to some inconsistency between the results of RCT in the literature. Terefore, to reduce the resulting analytical error, our analysis was based only on evidence from RCTs. Ten, we only included studies with RARP-specifc data to improve homogeneity and comparability.
We rigorously completed this meta-analysis under the guidance of PRISMA [16], but our analysis still has some certain limitations. First, most of the included studies adopted a retrospective study design, only six articles were included, and some studies had small sample sizes and low levels of evidence. Second, the number of clinical studies included in the evaluation of various indicators was limited, and it was difcult to obtain valid evidence. Also, the number of clinical studies included in the evaluation of various indicators is limited and it is difcult to obtain valid evidence. Tird, the lack of standardized IAPs may have contributed to some inconsistencies between the results of RCT studies in the literature. Fourth, diferences in surgeon skills, hospital protocols, and hospital resources may have contributed to the observed heterogeneity in some measures. Nonetheless, our meta-analysis included high-level evidence, some of the included studies were prospective studies, most of the included studies were published in the past fve years, and outcome indicators are well documented, which greatly increase the credibility of our results.

Conclusion
Our study of published trials indicates that using LIAP during RARP may reduce the incidence of POI, and there were no diferences in terms of hematoma, positive margin rate, urinary retention, operative time, or intraoperative blood loss.