Efficacy of Topical Epinephrine in Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Meta-analysis

Background/Aims: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP. As the clinical effectiveness of topical epinephrine in preventing PEP is elusive, this work attempts to assess its impact on PEP prevention. Materials and Methods: The databases Embase, Web of Science, PubMed, and Cochrane Library were searched for randomized controlled trials (RCTs) and retrospective cohort studies (RCSs) on topical epinephrine in PEP prevention (data cutoff, November 2022). Results: This study included a total of 10 research articles, involving 5683 patients, comprising 7 RCTs and 3 RCSs. The results of the meta-analysis indicated that epinephrine had no significant effect on preventing PEP or improving its severity. The meta-analysis results of RCTs subgroup revealed no significant difference in the incidence of PEP between patients receiving epinephrine treatment [alone/in combination with nonsteroidal anti-inflammatory drugs (NSAIDs)] vs. without epinephrine treatment (control group) (P = .23). However, patients treated with epinephrine alone experience a lower incidence of PEP compared to the control group (risk ratio [RR] = 0.28, 95% CI = 0.14-0.56, P = .0004). The treatment with epinephrine + NSAIDs vs. NSAIDs showed no significant difference (P = .95). The meta-analysis results of RCSs subgroup demonstrated a significant reduction in the incidence of PEP with the epinephrine + NSAIDs vs. NSAIDs (P < .05). Regarding the severity of PEP [mild, and moderate to severe (M-S)] in the RCT subgroup, the incidence of PEP was not reduced with epinephrine treatment (alone/in combination with NSAIDs) vs. control group. In the RCS subgroup, receiving epinephrine (alone/in combination with NSAIDs) reduced the incidence of mild PEP, while it had no effect on the incidence of M-S PEP. Conclusion: Epinephrine was not significantly effective in preventing PEP and improving its severity. The combined use of NSAIDs and epinephrine as a possible preventive measure requires further investigation into its efficacy.


INTRODUCTION
Endoscopic retrograde chola ngiop ancre atogr aphy (ERCP) is frequently used for the detection and treatment of biliary and pancreatic disorders.2][3] PEP has a high incidence and mortality rate due to factors related to both patients and procedures.Patient-related risk factors encompass youthfulness, dysfunction of the Oddi sphincter, and a history of prior PEP.Incubation difficulties or failures, sampling of pancreatic duct tissue, sphincterotomy of the Oddi sphincter, and papillectomy are all surgical risk factors. 4everal studies indicate that prophylactic pancreatic duct stenting can reduce the occurrence of PEP, particularly in terms of mitigating the risk of severe PEP.Despite the proven efficacy of pancreatic duct stenting, it requires an experienced endoscopist to minimize stent placement failure. 5,6Moreover, pancreatic duct stenting may give rise to significant adverse events, such as intraductal misplacement, inward migration, and pancreatic duct injury, making it an ineffective strategy for treating PEP. 7re than 35 drugs, including nonsteroidal anti-inflammatory drugs (NSAIDs), have been assessed for PEP prevention over the years. 8NSAIDs, in particular, have been shown in randomized controlled trials (RCTs) to be pivotal in the prevention of PEP. 9 In a network metaanalysis, Akbar et al 4 unveiled that rectal NSAIDs were more effective than pancreatic duct stents in controlling post-ERCP pancreatitis.According to a network metaanalysis, rectal NSID-based combination regimens were superior to single regimens in preventing PEP. 10 Despite using NSAIDs prior to ERCP, PEP occurs in 4%-9% of patients. 9,11art from NSAIDs, some protease inhibitors (gabexate mesilate, octreotide, ulinastatin, and nafamostat), nitroglycerin, and allopurinol are considered potential medications for the effective prevention of PEP. 8 However, some of these drugs are expensive, complex, or difficult to administer.3][14][15] Given these limitations, there is still a need to investigate drugs with minimal side effects, fewer contraindications, simple administration, and a pronounced preventive effect on PEP.
Xu et al 16 and Torun et al 12 found that epinephrine, alone or in combination with NSAIDs, can prevent PEP.But the study by Dar et al 17 revealed that PEP incidence cannot be reduced by the combination of epinephrine with diclofenac.Rectal NSAIDs and topical epinephrine are found to be the most effective drugs for preventing PEP in a network meta-analysis. 18But it included only 2 studies on epinephrine. 16,19The findings suggest that epinephrine alone, but not in combination with NSAIDs, may reduce PEP risk.Given the current debate over the efficacy of drugs in preventing PEP, we conducted this systematic review to better assess the role of epinephrine in PEP prevention.Additionally, we investigated its impact on patients with varying degrees of PEP severity.

Literature Screening
Inclusion Criteria: (1) Subjects had to be ERCP patients over the age of 18; (2) the study had to compare epinephrine to a placebo or a combination of epinephrine and other drugs to the use of other drugs alone; (3) the PEP incidence had to be reported.

Exclusion Criteria:
(1) Studies that were published repeatedly or were guidelines, reviews, and case studies were excluded; (2) studies with data inconsistent or could not be extracted were excluded; (3) non-English language literature was excluded.

Data Extraction and Quality Assessment
Data extraction was done independently by 2 investigators, and disagreements were settled by a third investigator.The following information was excluded from the studies: literature authors, publication year, study design type, drug intervention type (grouping situation), sample size, and pancreatitis incidence rate.The Cochrane Risk of Bias Tool was utilized for quality assessment of included RCTs based on 6 domains: blinding of outcome assessment, blinding of investigators and participants, allocation concealment, random sequence generation, complete outcome data, reporting bias, and other apparent bias, with each domain being scored as high, low, or unclear risk of bias.The quality of cohort studies was assayed with the Newcastle-Ottawa Scale (NOS).The NOS assesses 3 quality parameters (selection, comparability, and outcome) that are divided into 8 specific items.Except for

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The incidence of post-endoscopic retrograde chola ngiop ancre atogr aphy (ERCP) pancreatitis (PEP) was lower in patients who received epinephrine treatment than those who did not.• Patients using epinephrine alone had a lower PEP incidence than those who did not.• No significant variations in PEP incidence between patients using nonsteroidal anti-inflammatory drugs (NSAIDs) combined with epinephrine and those using NSAIDs alone.

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This study showed that epinephrine had no appreciable impact on preventing PEP or improving PEP severity.
comparability, which can be adjusted based on specific topics of interest, with a maximum score of 2, each item on the scale starts with a score of one.As a result, the maximum score for each study is 9 points, and studies with scores less than 5 are considered to have a high risk of bias. 20

Outcome Measure
The primary outcome measure was the incidence of PEP.The severity of PEP was a secondary outcome measure.

Statistical Analysis
Meta-analysis was completed on Review Manager version 5.4.(The Cochrane Collaboration, 2020) using RR as an indicator of efficacy.The chi-square test was to measure heterogeneity among study results, and the heterogeneity was also tested using I 2 statistics.If I 2 ≤ 50% and P ≥ .1,no statistical heterogeneity was reflected, and a fixedeffects model was applied.Otherwise, statistical heterogeneity was suggested, and a random-effects model was applied.

Literature Search Results
Relevant studies on the preventive role of epinephrine in post-ERCP pancreatitis were identified through keyword searches in the database using the PRISMA flowchart (Figure 1).A total of 221 studies were initially collected.
Following the removal of duplicate studies (7 articles) and the exclusion of irrelevant literature based on title and abstract review, the remaining 31 articles were evaluated for eligibility.Twenty-one of them were excluded due to data unavailability.1,22 A total of 5683 patients were involved in the study.Some studies have compared the effectiveness of epinephrine vs. a placebo, while others have evaluated the effects of epinephrine + NSAIDs vs. NSAIDs. The maxium sample size was 941 and the minimum was 126.The characteristics of the literature are detailed in Table 1, which presents specific information on 7 RCTs and 3 RCSs.
The Cochrane Risk of Bias assessment reported that the risk of bias was low in all included RCTs, and results of the quality assessment were shown in Figure 2A and 2B.Three RCSs had NOS scores greater than 6.Overall, the studies included in this paper are characterized by a low risk of bias and high quality.

PEP Incidence
The experimental groups, comprising individuals treated with either epinephrine alone or epinephrine + NSAIDs, were compared to the control groups, consisting of patients administered a placebo or NSAIDs.The summarized results are presented in Figure 3A.It was observed that the incidence of PEP was lower in patients with epinephrine treatment (alone/in combination with NSAIDs) vs. without epinephrine treatment (control group).However, the observed difference lacked statistical significance (RR = 0.56, 95% CI = 0.32-0.99,P = .05).Subgroup analyses were conducted based on the study type.In the RCTs subgroup analysis, the incidence of PEP showed no difference (RR = 0.73, 95% CI = 0.43-1.22,P = .23).However, the RCSs subgroup analysis results were significant (RR = 0.10, 95% CI = 0.02-0.43,P = .002).
Incidence of Moderate-to-Severe PEP Eight studies 12,16,17,19,21,23,24,26 presented the incidence of M-S PEP.The summarized results are presented in Supplementary Figure 1C.It was observed that patients with epinephrine treatment (alone/in combination with NSAIDs) had a lower incidence of M-S PEP compared to those without epinephrine treatment (control group) (RR = 0.61, 95% CI = 0.39-0.97,P = .04).However, subgroup analyses for RCTs and RCSs both showed no significant difference in the incidence of M-S PEP between the 2 groups (> .05).

DISCUSSION
We analyzed epinephrine for PEP prevention in 5,683 ERCP patients using data from 10 studies.When compared to patients not treated with epinephrine, our findings suggested that patients treated with epinephrine alone had a lower PEP incidence and could effectively reduce the incidence of mild PEP.However, combination of epinephrine and NSAIDs did not have significant effect in preventing incidence of PEP or improving M-S PEP.
PEP is a well-known ERCP complication that can adversely affect patients' quality of life and increase their mortality rate.The ASGE and ESGE have issued guidelines to reduce the incidence and severity of PEP, which include prophylactic medications and pancreatic stenting. 27,28Adrenaline, NSAIDs, hydration, protease inhibitors, and pancreatic enzyme secretion inhibitors are examples of preventive medications.Choi et al 29 investigated the impact of perioperative aggressive intravenous fluid resuscitation (IVFR) on the prevention of PEP.The results indicated that IVFR combined with LRS had a preventive effect on both high-risk and moderate-risk cases, reducing the severity of PEP. Park et al 30 compared the effects of ulinastatin and nafamostat in preventing PEP.The results showed that the incidence of PEP was 1.9% and 3.8%, respectively, indicating that both drugs reduced the incidence of PEP.Furthermore, the placement of a prophylactic pancreatic stent (PSP) can reduce the risk of PEP by alleviating the pancreatic duct hypertension caused by surgery-induced edema and pancreatic duct stricture. 31,32PSP can significantly reduce the incidence of mild, moderate, and severe pancreatitis in high-risk patients, according to a meta-analysis of RCTs. 33,34The efficacy of PSP in preventing PEP was investigated by comparing it to a control group that received non-stent procedures, and the results showed a lower incidence of PEP with PSP. 35Additionally, the length of pancreatic stents affects their effectiveness in preventing PEP.A prospective randomized trial compared the efficacy of 3 cm and 5 cm pancreatic stents in preventing PEP, revealing that the 3 cm stent outperforms the 5 cm stent. 36shintala et al 18 conducted a comparative and ranking analysis of drugs for the direct and indirect prevention of PEP using Bayesian network meta-analysis.The results revealed that topical adrenaline is the most effective drug for preventing PEP (OR: 0.25, 95% CI 0.06-0.66)and has been recommended by the American Society for Gastrointestinal Endoscopy (ASGE) guidelines.The proposed mechanism of action involves vasoconstriction mediated by adrenaline, leading to the constriction of small arterial vessels in the papillary mucosa.This, in turn, results in the direct relaxation of the Oddi sphincter and a reduction in capillary permeability, thereby decreasing papillary edema and subsequent pancreatic duct outflow obstruction to prevent PEP. 16,19,25,37Matsushita et al 19 conducted the first RCT on epinephrine for PEP prevention.They observed a reduced PEP incidence in the epinephrine group (0/185) compared to control group (4/185) (P = .12).But the sample size was called into question.Another RCT by Xu et al 16 observed a reduction in PEP incidence in the epinephrine group (9/461) as compared with the control group (31/480) (P = .008).Our meta-analysis revealed that patients who used epinephrine alone had a lower incidence of PEP than those who did not.However, due to high heterogeneity among included studies, we performed a subgroup analysis.Results showed that in RCTs, topical use of epinephrine significantly decreased PEP incidence, while in RCSs, epinephrine use had no significant preventive impact on PEP.Variations in metaanalysis results may be attributed to differences in study design types.For instance, there is a potential bias in subject selection in the RCSs subgroup.Despite the lower heterogeneity, the number of patients included in this study is relatively small.In addition, the results of RCTs subgroup analysis were not significant, which could be related to the high heterogeneity caused by the large differences in drug groups and sample size.To further investigate the preventive effect of epinephrine on PEP severity, we conducted a categorical analysis of the included studies.Firstly, local epinephrine treatment had no significant impact on overall incidence of mild PEP.In mild PEP, the pooled results of the meta-analysis show that epinephrine treatment has no significant impact on the overall incidence rate of PEP (P = .08).However, in the subgroup analysis with a study design of RCSs, a significant decrease in the incidence rate of mild PEP is observed (P = .003).In M-S PEP, the use of epinephrine significantly reduces the incidence rate of PEP (P = .04).
NSAIDs are recommended for the prevention of PEP, primarily by rectal administration of diclofenac or indomethacin prior to or after ERCP, and RCTs have confirmed this conclusion. 9,380][41][42] In a recent double-blind clinical trial involving 164 patients, it has been found that combination therapy is more effective than the sole use of indomethacin, with incidence rates of 2.4% and 4.9%, respectively. 43Conversely, in a multicenter double-blind randomized controlled study, Kamal et al 25 have discovered that the combined use of epinephrine and NSAIDs (indomethacin) does not reduce the incidence of PEP compared to the use of NSAIDs alone (6.4% vs. 6.7%).In a large-scale (1158 cases) double-blind trial conducted in China (ClincialTrials.gov number: NCT03057769), the combination therapy of epinephrine and NSAIDs (indomethacin) has been found to increase the risk of PEP. 17 Therefore, our study included literature from both RCTs and RCSs to analyze the preventive effects of epinephrine and NSAIDs, either alone or in combination, on PEP.Our results indicated that, compared to the sole use of NSAIDs, the combination of epinephrine and NSAIDs was ineffective in preventing the incidence of PEP.Three possible reasons can explain our findings.Firstly, the mechanism by which epinephrine prevents PEP is by inducing vasoconstriction at the level of the duodenal papilla by binding to α-1 receptors, 25,44 thereby reducing tissue edema around the pancreatic duct (PD) opening to prevent PEP. 18,22However, the spray of epinephrine may lead to reduced blood supply, diminishing the local concentration of NSAIDs (indo metha cin/d iclof enac) in pancreatic tissue, counteracting the beneficial effects of NSAIDs. 18Secondly, there may be an interaction between topical epinephrine and NSAIDs.8][49] Thirdly, NSAIDs have a wide impact on various tissues, which could interfere with the action of topical epinephrine, rendering them ineffective. 50Further research is needed to comprehensively evaluate the biological distribution of NSAIDs with or without epinephrine in human or animal subjects, shedding light on their mechanisms of action.
The study has some limitations.First, 3 studies are RCSs, and the results of their subgroup analysis are more significant than those of the RCTs subgroup analysis, which may introduce bias.Second, because of the small number of included studies, some results for RCTs and RCSs subgroups could not be analyzed, potentially leading to bias in meta-analysis results.Third, the clinical characteristics of patients included in the study, particularly the combination of drugs, dose and concentration of drugs used, the definition of PEP, and the definition of severity, were different, resulting in study heterogeneity.Fourth, some studies lacked data on high-risk PEP patients, and more studies are needed for further analysis of subgroup analysis of severity.Fifth, patients with preventive placement of pancreatic stents were excluded from the study, which could be one of the factors influencing heterogeneity.

Figure 1 .
Figure 1.PRISMA flowchart for the included studies.

Figure 2 .
Figure 2. (A) Overall risk of bias; (B) risk of bias for each RCT.

Figure 3 .
Figure 3.Comparison of the incidence of PEP.(A) Comparison between patients receiving epinephrine treatment and those not receiving epinephrine treatment; (B) Comparison between epinephrine monotherapy and placebo/no-treatment patients; (C) Comparison between the combination of epinephrine and NSAIDs and the use of NSAIDs alone.