Urgent Endoscopic Retrograde Cholangiopancreatography (ERCP) vs. Conventional Approach in Acute Biliary Pancreatitis Without Cholangitis: An Updated Systematic Review and Meta-Analysis

Gallstone disease is the common cause of acute pancreatitis. The role of early endoscopic retrograde cholangiopancreatography (ERCP) in biliary pancreatitis without cholangitis is not well-established. Thus, this study aims to compare the outcome of early ERCP with conservative management in patients with acute biliary pancreatitis without acute cholangitis. An online search of PubMed, PubMed Central, Embase, Scopus, and Clinicaltrials.gov databases was performed for relevant studies published till December 15, 2020. Statistical analysis was performed using RevMan v 5.4 (The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen). Odds Ratio (OR) with a 95% confidence interval was used for outcome estimation. Among 2700 studies from the database search, we included four studies in the final analysis. Pooling of data showed no significant reduction in mortality (OR 0.59, 95% CI 0.32 to 1.09; p=0.09); overall complications (OR 0.56, 95% CI 0.30 to 1.01; p=0.05); new-onset organ failure (OR 1.06, 95% CI 0.65 to 1.75; p=0.81); pancreatic necrosis (OR 0.80, 95% CI 0.49 to 1.32; p=0.38); pancreatic pseudo-cyst (OR 0.44, 95% CI 0.16 to 1.24; p=0.12); ICU admission (OR 1.64, 95% CI 0.97 to 2.77; p=0.06); and pneumonia development (OR 0.81, 95% CI 0.40 to 1.65; p=0.56) by urgent ERCP comparing with conventional approach for acute biliary pancreatitis without cholangitis. Henceforth, early ERCP in acute biliary pancreatitis without cholangitis did not reduce mortality, complications, and other adverse outcomes compared to the conservative treatment.


Introduction And Background
Acute pancreatitis (AP) is the most common pancreatic disease worldwide and one of the most common gastrointestinal causes of hospital admission [1,2]. The most common cause of AP is gallstones [3]. Impacted biliary stones and biliary sludge can cause reflux of pancreatic enzymes into the pancreas or cause transient obstruction of the ampulla, leading to inflammation of the pancreas [4]. Possible complications of AP include infection, pseudocyst, cholangitis, organ failure, etc. [5,6].
Conservative management for AP includes fluid replacement, pain control, input/output monitoring, nutritional support via the enteral or parenteral route, and antibiotics in selected cases. Endoscopic retrograde cholangiopancreatography (ERCP) is a therapeutic modality in several hepatobiliary diseases, including patients with biliary AP. Several observational studies and clinical trials have been performed comparing conservative management with ERCP in patients with biliary AP [7][8][9][10][11][12]. Relatively fewer studies have been conducted focusing only on patients with biliary AP without concomitant cholangitis. A metaanalysis conducted in 2008 found that early ERCP did not cause a significant reduction in the risk of overall complications and mortality in cases of AP without cholangitis [13]. More studies have been published since, with conflicting results [10,11]. The American Gastroenterological Association Institute Technical Review in 2018 recommended ERCP to be performed between 24-48 hours after the diagnosis of acute biliary pancreatitis but did not specify the timing of ERCP in patients with acute pancreatitis without concomitant cholangitis and recommends further studies on this topic [14].
While there is a universal agreement regarding an early ERCP within 24 hours in biliary AP complicated by cholangitis, the utility of an early ERCP in AP without cholangitis remains unclear. This study thus aims to compare the outcome of early ERCP with conservative management in patients with acute biliary pancreatitis without acute cholangitis.

Review Objectives
This study aims to determine the usefulness of early ERCP in the management of acute biliary pancreatitis without concomitant cholangitis by comparing the outcomes reported in previous studies such as mortality, local and systemic complications, and hospital stay between patients undergoing early ERCP (within 72 hours) to patients who were managed conservatively.

Methodology
This study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [15]. In addition, the study protocol was registered in the international prospective register of systematic reviews (PROSPERO ID: CRD42021226022) [16].

Types of Studies
In the initial review, we included all case studies (with five or more cases), cross-sectional studies, casecontrol studies, cohort studies, and clinical trials focusing on patients with acute biliary pancreatitis without concomitant cholangitis. We also included clinical trials in which the sequelae for cholangitis were given separately.

Types of Participants
Patients with acute biliary pancreatitis without cholangitis who were managed with either early ERCP (within 72 hours of presentation) or conservatively (e.g., no ERCP) were included in the study.

Types of Interventions
Patients diagnosed with acute biliary pancreatitis who underwent ERCP within 72 hours of presentation were included in the intervention group. Those who were managed conservatively were included in the control group.
Patient characteristics on admission were analyzed, including demographics, clinical status, the severity of pancreatitis, laboratory parameters, including serum bilirubin, serum aminotransferases, and alkaline phosphatase. Mortality, local and systemic complications were also compared.

Outcomes
In-hospital mortality was the primary outcome of the study. Rates of local and systemic complications, including new-onset organ failure, pneumonia, pancreatic necrosis and pseudocyst, and ICU admission, were secondary outcomes of interest.

Search methods for identification of studies
An online search of PubMed, PubMed Central, Embase, Scopus, and Clinicaltrials.gov databases was performed for studies published till December 15, 2020. Two reviewers independently performed searches which were then combined. MeSH headings included "Cholangiopancreatography, Endoscopic Retrograde", "Pancreatitis", "Pancreatitis, Acute Necrotizing", and "Cholangitis". Next, the title/abstract review followed by the full-text review was performed independently by two reviewers using the Covidence service. A third reviewer resolved conflicts in both steps. Finally, data extraction and review of bias were performed following a full-text review.

Electronic searches
The detailed search strategy has been attached in Appendix 1.

Data collection and analysis
RevMan 5.4 software (The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen) was used to analyze the data extracted from the selected studies. First, the heterogeneity among the studies was determined using the I 2 test. Then, a random/fixed-effect model was used based on heterogeneity to pool the various studies appropriately.

Selection of studies
The qualitative analysis included all studies where the patient either underwent early ERCP or was managed conservatively. Quantitative analysis included studies with intervention (early ERCP) and control groups. Case studies with less than five cases, editorials, opinions, letters to the editor, animal studies, studies published in other languages with no English translation were excluded.

Data extraction and management
The quality of the included studies was assessed vigorously.

Assessment of risk of bias in included studies
Cochrane risk of bias (ROB) was used for the assessment of bias in trials ( Figure 1) [17].

Assessment of heterogeneity
The I 2 test was used to assess heterogeneity using the Cochrane Handbook for Systematic Reviews of Interventions [18].

Assessment of reporting biases
Reporting bias was checked by prefixed reporting of the outcome.

Data synthesis
Statistical analysis was performed using RevMan v 5.4. Odds Ratio (OR) with a 95% confidence interval was used for outcome estimation. In addition, a random/fixed-effects model was used to pool data due as appropriate based on heterogeneity.

Sensitivity analysis
Sensitivity analysis was performed by analyzing the results of randomized controlled trials (RCTs) alone, excluding retrospective studies.

Results
We identified 2700 studies after thorough database searching and removed 98 duplicates. Title and abstracts of 2602 studies were screened. We excluded 2446 studies after the title and abstract review did not meet our inclusion criteria, and assessed the full text of 149 studies. A total of 145 studies were excluded for definite reasons ( Figure 2). We included four studies in the final qualitative analysis (

Qualitative summary
A qualitative summary of included papers is presented in Table 1.

Quantitative analysis
Total four studies meeting criteria were selected for quantitative synthesis.
Sensitivity analysis was carried out by excluding a non-randomized controlled trial (vanSantvoort HC et al.), a study carried before 2000, and using a random-effect model showed no significant changes in the result (Appendix 3-5).

Overall major complications
Three papers reported overall complications in their study. Pancreatic necrosis, new-onset persistent organ failure, bacteremia, cholangitis, pneumonia, or pancreatic insufficiency were considered as major complications. Pooling the data using fixed-effect model showed reduced major complications among urgent ERCP group comparing with conventional approach for acute biliary pancreatitis without cholangitis (OR 0.60, 95% CI 0.41 to 0.88; p=0.010; n= 493; I2 = 53%) (Figure 4). Considering moderate heterogeneity and rerunning the analysis using random-effect model could not reach level of significance (OR 0.56, 95% CI 0.30 to 1.01; p=0.05; I2 = 53%) (Appendix 6). Similarly, performing sensitivity analysis by excluding studies before 2000 and excluding non-randomized controlled trials also did not reach statistical significance across the two groups (Appendix 7, 8).

New-onset organ failure
Pooling the data using the fixed-effect model for new-onset organ failure among urgent ERCP group compared with a conventional approach for acute biliary pancreatitis without cholangitis showed no significant differences across two groups (OR 1.06, 95% CI 0.65 to 1.75; p=0.81; I2 = 0%) ( Figure 5). In addition, subgroup analysis taking specific organ failure and sensitivity analysis carried out by excluding vanSantvoort HC et al. showed no significant changes (Appendix 9, 10).

Pancreatic necrosis
Pooling the data using the fixed-effect model for pancreatic necrosis among urgent ERCP group compared with the conventional approach for acute biliary pancreatitis without cholangitis showed no significant differences across the two groups (OR 0.80, 95% CI 0.49 to 1.32; p=0.38; I2 = 0%) ( Figure 6). In addition, a sensitivity analysis excluding vanSantvoort HC et al. also showed no significant changes (Appendix 11). Three studies reported pancreatic necrosis [9][10][11].

Pancreatic pseudo-cyst
Pooling the data using the fixed-effect model for pancreatic pseudo-cyst among urgent ERCP group compared with the conventional approach for acute biliary pancreatitis without cholangitis showed no significant differences across two groups (OR 0.44, 95% CI 0.16 to 1.24; p=0.12; I2 = 0%) (Appendix 12).

ICU admission
Pooling the data using the fixed-effect model for ICU admission rate among urgent ERCP group compared with the conventional approach for acute biliary pancreatitis without cholangitis showed a slightly higher chance of admission in the ERCP group but did not reach statistical significance (OR 1.64, 95% CI 0.97 to 2.77; p=0.06; I2 = 0%) (Appendix 13).

Pneumonia development
Pooling the data using the fixed-effect model for having pneumonia among the urgent ERCP group compared with the conventional approach for acute biliary pancreatitis without cholangitis showed no significant differences across the groups (OR 0.81, 95% CI 0.40 to 1.65; p=0.56; I2 = 0%) (Appendix 14).

Discussion
The study's significant findings were no differences in mortality, ICU admission, complications like pancreatic necrosis, pseudocyst, pneumonia development, and new-onset organ failure among patients with biliary pancreatitis without cholangitis with early ERCP compared to the control group. Although early ERCP was beneficial in reducing major complications while running the fixed-effect model, the same result was not replicated in the random effect model. The role of endoscopic retrograde cholangiopancreatography (ERCP) in the management of acute biliary pancreatitis with cholangitis is well established as per the European and American society of gastroenterology guidelines [19,20]. However, the current recommendation is to avoid ERCP in the absence of cholangitis and ongoing biliary obstruction as per both societies [19,20]. Although prior meta-analyses were conducted to evaluate the role of ERCP in acute biliary pancreatitis without cholangitis, most of the trials included in the analysis had a small sample size, a small number of patients with severe pancreatitis, delay in initiation of ERCP, non-gallstone etiologies, the inclusion of trials with cases of cholangitis and no proper data separating the outcome of those with and without cholangitis [7,8,13]. Thus, we conducted a meta-analysis including the results of Schepers et al.'s randomized controlled trial, the largest ERCP trial, including patients with severe gallstone pancreatitis. In Schepers et al.'s study, ERCP was done earlier than previous trials, and sphincterotomy was done universally in all patients [10].
We found no difference in mortality among the two groups receiving conservative management and endoscopic retrograde cholangiopancreatography for management of acute biliary pancreatitis without cholangitis. This finding was similar to Petrov et al.'s and Moretti et al.'s finding of no difference in mortality in patients with acute biliary pancreatitis without cholangitis [13,21]. Also, we found a reduction in major complications in patients with biliary pancreatitis without cholangitis undergoing ERCP compared to those receiving conservative management using the fixed-effect model. However, the result showed no significance with the random effect model considering the heterogeneity. Moretti et al. and Van Santvoot HR et al. found a decreased risk of pancreatitis-related complications for patients with predicted severe pancreatitis and severe acute biliary pancreatitis with cholestasis, respectively. However, Petrov et al. found no difference in complications among patients who underwent ERCP compared to conservative management [11,13,21]. Moretti et al. reported no difference in complications in mild acute biliary pancreatitis cases without cholangitis in the two groups [21]. Scheper et al. found no increased risk of respiratory complications with ERCP, as seen in previous trials [10].
Similarly, we found no difference in pneumonia among patients receiving conservative management and patients who underwent ERCP. One of the concerns with early ERCP for managing acute biliary pancreatitis without cholangitis is that ERCP has various complications and our findings of somehow decreased major complications are significant. However, we found no difference in local complications of pancreatitis like pancreatic pseudocyst and necrosis among patients receiving conservative treatment and early ERCP. Another interesting finding seen in Schepers's and Folsch's trials is the increased risk of cholangitis in patients undergoing conventional therapy than those undergoing early ERCP [8,10].
A comprehensive literature search was performed with a qualitative assessment of the included studies in our meta-analysis. Our meta-analysis explored the role of early ERCP in biliary pancreatitis without cholangitis, a condition in which an effective treatment modality is still evasive. The latest and largest randomized controlled trial results by Schepers et al. were included in our updated analysis [10]. The findings of our study have important implications for clinical practice because no beneficial role of early ERCP was properly established in acute biliary pancreatitis without cholangitis. However, our study has several limitations. Most of the trials included a low number of patients with severe pancreatitis. In addition, the timing to ERCP was variable among the various trials, variable definition of cholangitis in different included trials, and inclusion of various types of patients with varying severity of pancreatitis, and the presence or absence of cholestasis lead to significant biological heterogeneity. In addition, it is hard to ascertain concomitant cholangitis only based on the Charcot triad because gall stone pancreatitis can also cause fever, and cholangitis may sometimes develop in the absence of fever and jaundice [11]. So, some trials might have included patients with concomitant cholangitis.

Conclusions
Based on our meta-analysis taking patients with acute biliary pancreatitis without cholangitis, there is no benefit of early ERCP. Early ERCP in acute biliary pancreatitis without cholangitis did not reduce mortality, complications, and other adverse outcomes compared to the conservative treatment.     Three studies reported the pancreatic necrosis [9][10][11].