Low-pressure versus standard-pressure pneumoperitoneum in laparoscopic cholecystectomy: a systematic review and meta-analysis of randomized controlled trials

Introduction It has been previously demonstrated that the rise of intra-abdominal pressures and prolonged exposure to such pressures can produce changes in the cardiovascular and pulmonary dynamic which, though potentially well tolerated in the majority of healthy patients with adequate cardiopulmonary reserve, may be less well tolerated when cardiopulmonary reserve is poor. Nevertheless, theoretically lowering intra-abdominal pressure could reduce the impact of pneumoperitoneum on the blood circulation of intra-abdominal organs as well as cardiopulmonary function. However, the evidence remains weak, and as such, the debate remains unresolved. The aim of this systematic review and meta-analysis was to demonstrate the current knowledge around the effect of pneumoperitoneum at different pressures levels during laparoscopic cholecystectomy. Materials and methods This systematic review and meta-analysis were reported according to the recommendations of the 2020 updated Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines, and the Cochrane handbook for systematic reviews of interventions. Results This systematic review and meta-analysis included 44 randomized controlled trials that compared different pressures of pneumoperitoneum in the setting of elective laparoscopic cholecystectomy. Length of hospital, conversion rate, and complications rate were not significantly different, whereas statistically significant differences were observed in post-operative pain and analgesic consumption. According to the GRADE criteria, overall quality of evidence was high for intra-operative bile spillage (critical outcome), overall complications (critical outcome), shoulder pain (critical outcome), and overall post-operative pain (critical outcome). Overall quality of evidence was moderate for conversion to open surgery (critical outcome), post-operative pain at 1 day (critical outcome), post-operative pain at 3 days (important outcome), and bleeding (critical outcome). Overall quality of evidence was low for operative time (important outcome), length of hospital stay (important outcome), post-operative pain at 12 h (critical outcome), and was very low for post-operative pain at 1 h (critical outcome), post-operative pain at 4 h (critical outcome), post-operative pain at 8 h (critical outcome), and post-operative pain at 2 days (critical outcome). Conclusions This review allowed us to draw conclusive results from the use of low-pressure pneumoperitoneum with an adequate quality of evidence. Supplementary Information The online version contains supplementary material available at 10.1007/s00464-022-09201-1.

standard-pressure pneumoperitoneum for laparoscopic cholecystectomy is considered to be about 15 mmHg [3].
It has been previously demonstrated that the rise of intraabdominal pressures and prolonged exposure to such pressures can produce changes in the cardiovascular and pulmonary dynamic which, though potentially well tolerated in the majority of healthy patients with adequate cardiopulmonary reserve, may be less well tolerated when cardiopulmonary reserve is poor. In such cases, laparoscopic procedures may be avoided due to the potential adverse outcomes resulting from significant changes in the cardiovascular and pulmonary dynamic. There are several studies demonstrating changes in metabolic, humoral, and neurological systems following high-pressure pneumoperitoneum. [4][5][6][7][8] Nevertheless, theoretically lowering intra-abdominal pressure could reduce the impact of pneumoperitoneum on the blood circulation of intra-abdominal organs as well as cardiopulmonary function. Furthermore, some patients experience unpleasant post-surgical symptoms such as shoulder pain, seemingly specific to laparoscopic surgery [1,9]. Approximately one-third of the patients undergoing a laparoscopic procedure develop this complaint postoperatively [1,10]. The origin of shoulder pain is only partly understood, but it is commonly assumed that the cause is overstretching of the diaphragmatic muscle fibres owing to a high rate of insufflation [11]. Other causes, including peritoneal stretching and diaphragmatic irritation, have also been considered. [12] When considering such theories, potential solutions must also be postulated. Reducing insufflation pressure to improve post-operative outcomes seems a logical hypothesis.
Nevertheless, the evidence remains weak, and as such, the debate remains unresolved. In clinical practice, many surgeons continue to use high pneumoperitoneum pressures mainly due to personal preference and belief rather than due to scientific evidence.
The aim of this systematic review and meta-analysis was to demonstrate the current knowledge around the effect of pneumoperitoneum at different pressures levels during laparoscopic cholecystectomy.

Materials and methods
This systematic review and meta-analysis were conducted according to the recommendations of the 2020 updated Preferred Reporting Items for Systematic reviews and Metaanalyses (PRISMA) guidelines [13], and the Cochrane handbook for systematic reviews of interventions [14].

Types of participants
All the papers but one [51] included patients undergoing elective laparoscopic cholecystectomy, and one study also included patients undergoing emergency laparoscopic cholecystectomy [51]. Surgical indications were different: symptomatic gallstones, acalculous cholecystitis, gallbladder polyps, or any other condition. We applied no restriction based on the type of anaesthesia or patient positioning used, reporting that the same type of anaesthesia was used in both groups.

Types of outcome measures
According to the PICO criteria, we included general and clinical primary outcomes into the analysis: post-operative abdominal pain (assessed with the Visual Analogue Scale VAS) and shoulder pain, analgesic use, surgical morbidity, length of hospital stay (LOS), conversion rate (laparoscopic to open, or from low to standard/high pneumoperitoneum pressure), operative time, quality of life, and surgeon satisfaction. Secondary outcomes, defined as "functional", were respiratory function, cardiac function, liver function, and inflammatory response.

Search methods for the identification of studies to be included in the review
A computerized search was performed in MEDLINE (via PubMed), EMBASE, and the Cochrane Central Register of Controlled Trials databases for articles published from 1992 The studies identified by the primary search strategy were subsequently selected based on title, abstract, and full-text review by two independent reviewers (M.P. and G.M.) in Rayyan web app for systematic reviews (https:// www. rayyan. ai/). Articles published in languages other than English, nonrandomized studies, and animal and preclinical studies were excluded. Reference lists of relevant studies were searched manually, and the "related articles" function in PubMed was used.

Risk of bias assessment in the included studies
The risk of bias in the included randomized controlled trials was independently assessed by two authors (G.M and M.O.) using the Risk of bias assessment (RoB-2) tool without masking the trial names. The methodological quality of the RCTs was assessed based on sequence generation, allocation concealment, blinding of participants, personnel, and outcome assessors, incomplete outcome data, selective outcome reporting, and other sources of bias. Trials that were classified as low risk of bias in sequence generation, allocation concealment, blinding, incomplete data, and selective outcome reporting were judged at low bias risk.

Measures of treatment effect
We planned to use intention-to-treat analysis if such analysis was available from the included studies. All statistical analyses were performed using Reviewer Manager software (Reviewer Manager-RevMan-version 5.4.1, Sept. 2020, The Nordic Cochrane Centre, Cochrane Collaboration, www. train ing. cochr ane. org). The relative risk (RR) with 95% confidence interval (95% CI) was calculated for dichotomous variables, and the standardized mean difference (SMD), with 95% CI for continuous variables. Whenever continuous data were reported as medians and range, the method of Hozo et al. to estimate respective means and standard deviations was applied [57]. The point estimate of the RR value was considered statistically significant at P level < 0.05 if the 95% CI did not cross the value 1. The point estimate of the SMD value was considered statistically significant at P level < 0.05 if the 95% CI did not cross the value 0. Statistical heterogeneity of the results across studies was assessed using the Higgins' I 2 statistic and Chi-Square test. A P value of Chi-Square test < 0.10 with an I 2 value > 30% were considered as indicative of substantial heterogeneity. Moreover, both clinical (variability in the baseline characteristics of the participants, interventions, and outcomes studied) and methodological (variability in the study design and risk of bias) heterogeneities were considered to inform the decision to use the fixed-or random-effects model. Fixed-effects model (Mantel-Haenszel) was used if significant heterogeneity was absent, whereas a random-effects model was implemented for meta-analysis if significant heterogeneity was found, according to the method of DerSimonian and Laird [58]. We constructed a funnel plot to explore the risk of publication bias in the presence of at least 10 trials for the outcome. Asymmetry in the funnel plot of trial size against treatment effect was used to assess this bias.

Results of the meta-analysis
The results of the pooled analyses ae summarized in the summary of findings table prepared using GRADEPro (https:// grade pro. org/ cite/ grade pro. org.) [59] Fig. 2. Random-effects), however, this difference was not statistically significant (Fig. 3).

Conversion to open surgery
Conversion to open surgery was reported in seven studies (Dexter 1999   in the low-pressure group reported lower VAS compared with patients in the standard-pressure group (3 studies, 291 patients; SMD − 1.39, 95% CI − 2.51 to − 0.27; I 2 = 94%, Random effects), with a statistically significant difference (Online Fig. 7).

Post-operative pain at 1 day (VAS)
Post-operative pain at 1 day was reported in eight studies (Barczynski 2003

Overall complications
Overall complications were reported in 12 studies (Dexter 1999 . The difference in the incidence of post-operative complications between the two groups was not statistically significant (12 studies, 877 patients; RR 1.10, 95% CI 0.83 to 1.45; I 2 = 0%, Fixed effects) (Online Fig. 18).

Bleeding
The occurrence of bleeding was reported in two studies (Perrakis 2003; Singla 2014). The difference in the incidence of bleeding was equivalent in the two groups (2 studies, 140 patients; RR 0.71, 95% CI 0.24 to 2.14; I 2 = 0%, Fixed effects) (Online Fig. 19).

Intra-operative bile spillage
Intra-operative bile spillage was reported in eight studies (Sarli 2000

Quality of Evidence assessment (GRADE)
According to the GRADE criteria, overall quality of evidence was high for intra-operative bile spillage (critical outcome), overall complications (critical outcome), shoulder pain (critical outcome), and overall post-operative pain (critical outcome). (Fig. 2) Overall quality of evidence was moderate for conversion to open surgery (critical outcome), post-operative pain at 1 day (critical outcome), post-operative pain at 3 days (important outcome), and bleeding (critical outcome). Overall quality of evidence was low for operative time (important outcome), length of hospital stay (important outcome), post-operative pain at 12 h (critical outcome), and was very low for post-operative pain at 1 h (critical outcome), post-operative pain at 4 h (critical outcome), post-operative pain at 8 h (critical outcome), and post-operative pain at 2 days (critical outcome) (Figs. 3, 4).
Most of the articles included came from Turkey (10) and India (10), followed by Iran (3) Tables 3, 4, 5, and 6 show the results relating to postoperative pain. In all included articles pain was evaluated by a Visual Analogue Scale (VAS). The time of pain evaluation ranges between one hour after surgery and three days after surgery. Table 7 shows the complications occurred. Overall 96 and 74 intra-and post-operative complications were observed among patients who underwent cholecystectomy with low pressure and with high pressure, respectively.

Discussion
Laparoscopic surgery has increased in popularity in recent years due to a reduced operative stress response and improved clinical outcomes including reduced operation time, bleeding, opioid requirement, and reduced LOS when compared to open surgery [60].
The creation of pneumoperitoneum may be overlooked or not considered a significant operative factor, however, it constitutes the first step of every laparoscopic procedure and should be given due consideration.
In this systematic review of the available literature on the topic, we found out that lowering the pneumoperitoneum pressure has a positive impact on post-operative pain, while may be linked to longer operative time when considering elective laparoscopic cholecystectomy.
Traditionally, the standard intra-abdominal pressure used was around 15 mmHg [3]; although laparoscopic surgery is labelled a minimally invasive procedure, such pressures may lead to a disruption in mechanical and biochemical balance.
The cardiovascular and pulmonary systems are the most affected by increased intra-abdominal pressure as demonstrated in several published studies [61][62][63][64]. Although these cardiorespiratory changes may be tolerated by healthy adults with adequate cardiopulmonary reserve, when these reserves are compromised, the use of laparoscopy is limited [12]. As laparoscopic procedures become standardized, the question arises as to the optimum maintenance pressure for pneumoperitoneum.
International guidelines recommend the use of 'the lowest intra-abdominal pressure allowing adequate exposure of the operative field rather than a routine pressure" [64]. In a previous meta-analysis, overall quality of evidence for advantages of low-pressure PP compared to high-pressure PP was evaluated [65]. The meta-analysis took into consideration all published papers where a low-pressure (LP) peritoneum was used. The authors concluded that the main impact of the use of low-pressure pneumoperitoneum is on post-operative pain and analgesic consumption, but the safety profile of LP must be better defined, as the analysis of the existing literature could only produce a low-to-moderate level of evidence.
In this study, we chose to consider elective laparoscopic cholecystectomy only, as the index procedure for the metaanalysis for two main reasons: firstly, to reduce bias linked to outcomes related to the complexity of laparoscopic procedures and secondly, because the elective laparoscopic cholecystectomy is considered a cornerstone procedure for the minimally invasive surgeon.
A Cochrane review already exists on this topic, and the primary conclusion was that although laparoscopic cholecystectomy can be completed successfully using low pressure in approximately 90% of people undergoing laparoscopic cholecystectomy, no conclusive evidence exists to support its utilization of LP in healthy low anaesthetic risk patients and that the safety must be better defined. As a result of this, the authors did not recommend LP pneumoperitoneum unless future trials demonstrate a clinical benefit. Although, a significative reduction in post-operative shoulder pain was  Male in total sample size demonstrated, its influence on other considered parameters was either inconclusive or not significant. In conclusion, though lowering intra-abdominal pressure may decrease the associated detrimental effects of standard/high-pressure pneumoperitoneum, the safety of low-pressure pneumoperitoneum has not been fully defined. In our analysis, the pressures reported as low in the considered studied ranged from 6 to 10 mmHG. While in the standard/high-pressure groups, 12 to 15 mmHg pressures were applied.
Regarding post-operative pain, the time-frame considered in the included studies was highly variable. However, generally, patients in the low-pressure group reported lower VAS if compared with patients in the standard-pressure group. This difference was less significant in the first and second post-operative days and was not reported 3 days from the operation. Nevertheless, the evaluation of shoulder pain was reported in 12 studies and patients in the low-pressure group reported significantly lower rates of post-operative shoulder pain compared with patients in the standard-pressure group.

Table 5
Post-operative pain outcomes and analgesic consumption from RCTs included in Metanalysis.
Author (  Patients converted and excluded from the studies   These findings were associated with a significantly lower analgesic consumption reported at any time by patients in the low-pressure group. Pain after laparoscopic procedures can be divided into three components: referred shoulder pain, superficial or incisional wound pain, and deep intra-abdominal pain [66]. The different types of pain may correspond to different etiologies. Referred pain is most often attributed to CO2-induced diaphragm and/or phrenic nerve irritation causing referred pain to the C4 dermatome, stretching of the diaphragm, and/ or residual pockets of gas in the abdominal cavity [67,68]. Deep intra-abdominal pain is mainly caused by bowel traction, stretch of the abdominal wall, and compression of intraabdominal organs. However, according to the results of our review, such symptoms could be attributable to the pressure of the pneumoperitoneum.
Unlike the pre-existing review, we found that a lower pressure may significantly increase the operative time. Only 8 studies reported shorter operative times in the LPLC group and this difference was never significant, compared with the remaining 36 studies, where the operative time in the LPLC groups was always, and in many cases, significantly [51], higher.
A prolonged operative time was reported to be a consequence of the surgeon's reduced visibility [40]. The reported reduced visibility was not, however, associated with an increased rate of intra-operative complications or conversion rate.
The effect of a prolonged operative time with a low-pressure peritoneum on clinical outcomes was not deducible from the included studies.
When considered, cardiac and pulmonary function did not appear to differ between the included groups. Ekici et al. [16] report on the effect of high-pressure laparoscopic cholecystectomy (HPLC) on QT length. They report a significant increase in the QT dispersion (QTd) and was associated with QT dispersion (QTcd) in the HPLC group. Additionally, there was a temporary increase in HR, which was significantly higher in the HPLC group. Such increases in QTd and QTc are associated with increased risk of arrhythmias and cardiac events. Similarly, the Umar et al. paper reports a significant increase in mean HR, SP, and MAP during insufflation, at exsufflation and at 10, 20, and 30 min after exsufflation in the HPLC group. It was concluded that high-pressure pneumoperitoneum resulted in greater changes in haemodynamic parameters as well as peritoneal CO2 absorption.
The majority of the participants in the trials reviewed were low anaesthetic risk patients undergoing elective laparoscopic cholecystectomy. Therefore, the findings of this review are applicable only to a similar group of patients.
Interestingly, we observed that, unlike previous reviews, most of the included trials were assessed as having a low risk of bias.
As compared with many other surgical trials, the pneumoperitoneum pressure offers an easily measurable factor, meaning it is possible to perform large scale randomized trials, which has allowed us to draw conclusive results from the use of LPLC.
Potential biases are mainly linked to the difficulties associated with blinding the operators. The quality of the evidence is moderate to high for conversion and post-operative pain, respectively.
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