Objectives Pain is the foremost complication of chronic pancreatitis (CP), affecting about 70% of patients. However, the pathophysiological understanding and management of CP-related pain are complex, likely as patients have diverse “pain phenotypes” responding differently to treatment. This study aims to develop a bedside test panel to identify distinct pain phenotypes, investigate the temporal evolution, and determine whether they can be used to predict treatment response. Methods The INPAIN study is an international, multicenter, observational, longitudinal cohort study consisted of 4 substudies. The studies will prospectively enroll 400 CP patients (50 without pain and 350 with pain) and 50 control subjects, conducting biannual observations for 4 years. The test panel is consisted of comprehensive subjective and objective assessment parameters. Statistical analysis strategies differ across the substudies. A model to predict treatment efficacy will be developed using various machine learning techniques, including an artificial intelligence approach, with internal cross-validation. Trajectories in pain parameters will be characterized by graphical analysis and mixed effect models. Discussion The INPAIN study aims to comprehensively understand pain in CP through a test panel developed for routine clinical use. This tool has the potential to personalize treatments, improve clinical practice, enhance patient care, improve quality of life, and minimize treatment side effects.

INTRODUCTION: Post-ERCP pancreatitis (PEP) occurs in up to 15% of high risk patients. Symptoms after ERCP are common and usually determine admission. However, discharge of outpatients at risk for PEP is frequent after ERCP. In retrospective studies, discharged PEP patients are at increased risk for severity, possibly due to delays in IV fluid therapy. The aim of this study is to evaluate clinical predictors and outcomes in patients discharged and later admitted with delayed presentation of PEP. METHODS: We identified consecutive outpatients with PEP enrolled in a prospective study designed to evaluate the optimal rectal Indomethacin dose for prevention of PEP in high-risk patients. All patients received Indomethacin and were observed for at least 4 hours post-ERCP per protocol. All clinical data except IV fluids, recovery medications, and pain scores were collected prospectively. Diagnosis and severity of PEP was defined by Cotton criteria. RESULTS: 107/720 (14.9%) developed PEP. 135/720 (18.8%) were directly admitted after ERCP. While the direct admission rate in patients that developed PEP was higher ( P < 0.001), 58/107 (54.2%) were discharged and had a delayed presentation of PEP. Median time to presentation was 24 hours (IQR 15–31.75 h). Discharged patients were older (age 47.7 vs 41.1, P = 0.026), more often had a morning procedure (59.2% vs 39.7%, P = 0.044), less often had pancreatic stent placement (82.8% vs 95.9%, P = 0.032), spent less time in recovery (261 vs 312 minutes, P = 0.004), required less IV opioids (6.4 vs 17.3 MME, P < 0.001) and had lower pain scores (2.8 vs 6.5, P < 0.001) (Table 1). On multivariable analysis, an afternoon procedure (OR 4.00, P = 0.016) and pain score >3 (OR 1.37, P = 0.001) were associated with admission. While discharged patients were more likely to present with SIRS on admission (43.1% vs 10.2%, P < 0.001), a delayed presentation was not associated with severe PEP (Table 2). CONCLUSION: Delayed presentation of PEP after discharge of high-risk patients is frequent, but not associated with adverse outcomes or severe PEP. Systematic deployment of PEP prophylaxis with rectal Indomethacin, pancreatic stents, and IV fluids may attenuate the impact of delayed presentation on outcomes. Afternoon procedure time and increased pain appear to influence decisions to admit. However, given the frequency of delayed presentation of PEP, accurate and early diagnostic tests for PEP may be of clinical value.

Background Although rectal indometacin 100 mg is effective in reducing the frequency and severity of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients, the optimal dose is unknown, and pancreatitis incidence remains high. The aim of this study was to compare the efficacy of two dose regimens of rectal indometacin on the frequency and severity of pancreatitis after ERCP in high-risk patients. Methods In this randomised, double-blind, comparative effectiveness trial, we enrolled patients from six tertiary medical centres in the USA. Eligible patients were those at high risk for the development of pancreatitis after ERCP. We randomly assigned eligible patients (1:1) immediately after ERCP to receive either two 50 mg indometacin suppositories and a placebo suppository (standard-dose group) or three 50 mg indometacin suppositories (high-dose group). 4 h after the procedure, patients assigned to the high-dose group received an additional 50 mg indometacin suppository, whereas patients in the standard-dose group received an additional placebo suppository. The randomisation schedule, stratified according to study centre and with no other restrictions, was computer generated by an investigator who was uninvolved in the clinical care of any participants, distributed to the sites, and kept by personnel not directly involved with the study. These same personnel were responsible for packaging the drug and placebo in opaque envelopes. Patients, study personnel, and treating physicians were masked to study group assignment. The primary outcome of the study was the development of pancreatitis after ERCP. Analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01912716, and enrolment is complete. Findings Between July 9, 2013, and March 22, 2018, 1037 eligible patients were enrolled and randomly assigned to receive either standard-dose (n=515) or high-dose indometacin (n=522). Pancreatitis after ERCP occurred in 141 (14%) of 1037 patients-76 (15%) of 515 patients in the standard-dose indometacin group and 65 (12%) of 522 patients in the high-dose indometacin group (risk ratio [RR] 1.19, 95% CI 0.87-1.61; p=0.32). We observed 19 adverse events that were potentially attributable to study drug. Clinically significant bleeding occurred in 14 (1%) of 1037 patients-six (1%) of 515 patients in the standard-dose indometacin group and eight (2%) of 522 patients in the high-dose indometacin group (p=0.79). Three (1%) of 522 patients in the high-dose indometacin group developed acute kidney injury versus none in the standard-dose group (p=0.25). A non-ST elevation myocardial infarction occurred in the standard-dose indometacin group 2 days after ERCP. A transient ischaemic attack occurred in the high-dose indometacin group 5 days after ERCP. All 19 adverse events, in addition to the 141 patients who developed pancreatitis after ERCP, were considered serious as all required admission to hospital. We observed no allergic reactions or deaths at 30 day follow-up. Interpretation Dose escalation to rectal indometacin 200 mg did not confer any advantage compared with the standard 100 mg regimen, with pancreatitis incidence remaining high in high-risk patients. Current practice should continue unchanged. Further research should consider the pharmacokinetics of non-steroidal anti-inflammatory drugs to determine the optimal timing of their administration to prevent pancreatitis after ERCP. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Post-ERCP pancreatitis (PEP) occurs in 4% of patients and up to 30% in high-risk patients. Symptoms are common following ERCP and up to 10% of patients are admitted for management. In spite of this, rates of inadvertent discharge and readmission for PEP approaches 25% and is associated with severity in retrospective studies, likely due to delay in IV fluid (IVF) administration. However, recent studies have provided guidance for prophylactic interventions (NSAIDs, pancreatic stents, and post-procedure IVF) that may improve outcomes. In the setting of high-risk populations and prophylactic interventions, clinical predictors for inadvertent discharge and severity of PEP remains incompletely understood.

Background: It is believed, based on limited observational data, that an unsuccessful attempt to place a prophylactic pancreatic stent substantially increases the risk of post-ERCP pancreatitis (PEP).Objective: To better understand the risk of PEP in patients with failed pancreatic stent placement (FPS) and the impact of rectal indomethacin on this risk.Design: Secondary analysis of randomized, controlled trial data.Setting: University of Michigan and Indiana University.Patients: A total of 577 clinical trial participants at elevated risk for PEP.Interventions: Pancreatic stent placement.Main Outcome Measurements: Within the placebo group, we compared PEP rates in patients with FPS, patients who underwent successful stent placement, and in those without a stent attempt. We also performed a regression analysis evaluating the association between FPS and PEP. To define the protective effect of indomethacin, we repeated these analyses in the indomethacin group and in the full study cohort.Results: The incidence of PEP among patients in the placebo group who experienced FPS was 34.7%, significantly exceeding rates in patients who underwent successful stent placement (16.4%) and in those without a stent attempt (12.1%). After we adjusted for known PEP risk factors, FPS was found to be independently associated with PEP. Among the indomethacin group and in the full cohort, FPS was not associated with a higher risk of PEP.Limitations: Low event rate, FPS not prospectively captured.Conclusion: FPS appears to confer an increased risk of PEP, which is attenuated by rectal indomethacin administration. These findings highlight the importance of adequate training and proficiency before endoscopists attempt pancreatic stent placement and the routine use of rectal indomethacin in high-risk ERCP cases.

BACKGROUND:The accuracy of EUS in the locoregional assessment of ampullary lesions is unclear.OBJECTIVES:To compare EUS with ERCP and surgical pathology for the evaluation of intraductal extension and local staging of ampullary lesions.DESIGN:Retrospective cohort study.SETTING:Tertiary-care referral center.PATIENTS:All patients who underwent EUS primarily for the evaluation of an ampullary lesion between 1998 and 2012.INTERVENTION:EUS.MAIN OUTCOME MEASUREMENTS:Comparison of EUS sensitivity/specificity for intraductal and local extension with ERCP and surgical pathology by using the area under the receiver-operating characteristic (AUROC) curves and outcomes of the subgroup referred for endoscopic papillectomy.RESULTS:We identified 119 patients who underwent EUS for an ampullary lesion, of whom 99 (83%) had an adenoma or adenocarcinoma. Compared with ERCP (n = 90), the sensitivity/specificity of EUS for any intraductal extension was 56%/97% (AUROC = 0.77; 95% confidence interval [CI], 0.64-0.89). However, when using surgical pathology as the reference (n = 102), the sensitivity/specificity of EUS (80%/93%; AUROC = 0.87; 95% CI, 0.76-0.97) and ERCP (83%/93%; AUROC = 0.88; 95% CI, 0.77-0.99) were comparable. The overall accuracy of EUS for local staging was 90%. Of 58 patients referred for endoscopic papillectomy, complete resection was achieved in 53 (91%); in those having intraductal extension by EUS or ERCP, complete resection was achieved in 4 of 5 (80%) and 4 of 7 (57%), respectively.LIMITATION:Retrospective design.CONCLUSIONS:EUS and ERCP perform similarly in evaluating intraductal extension of ampullary adenomas. Additionally, EUS is accurate in T-staging ampullary adenocarcinomas. Future prospective studies should evaluate whether EUS can identify characteristics of ampullary lesions that appropriately direct patients to endoscopic or surgical resection.

BACKGROUND:Endoscopic papillectomy is increasingly used as an alternative to surgery for ampullary adenomas and other noninvasive ampullary lesions.OBJECTIVE:To measure short-term safety and efficacy of endoscopic papillectomy, define patient and lesion characteristics associated with incomplete endoscopic resection, and measure adenoma recurrence rates during long-term follow-up.DESIGN:Retrospective cohort study.SETTING:Tertiary-care academic medical center.PATIENTS:All patients who underwent endoscopic papillectomy for ampullary lesions between July 1995 and June 2012.INTERVENTION:Endoscopic papillectomy.MAIN OUTCOME MEASUREMENTS:Patient and lesion characteristics associated with incomplete endoscopic resection and ampullary adenoma-free survival analysis.RESULTS:We identified 182 patients who underwent endoscopic papillectomy, 134 (73.6%) having complete resection. Short-term adverse events occurred in 34 (18.7%). Risk factors for incomplete resection were jaundice at presentation (odds ratio [OR] 0.21; 95% confidence interval [CI] 0.07-0.69; P = .009), occult adenocarcinoma (OR 0.06; 95% CI, 0.01-0.36; P = .002), and intraductal involvement (OR 0.29; 95% CI, 0.11-0.75; P = .011). The en bloc resection technique was strongly associated with a higher rate of complete resection (OR 4.05; 95% CI, 1.71-9.59; P = .001). Among patients with ampullary adenoma who had complete resection (n = 107), 16 patients (15%) developed recurrence up to 65 months after resection.LIMITATIONS:Retrospective analysis.CONCLUSION:Jaundice at presentation, occult adenocarcinoma in the resected specimen, and intraductal involvement are associated with a lower rate of complete resection, whereas en bloc papillectomy increases the odds of complete endoscopic resection. Despite complete resection, recurrence was observed up to 5 years after papillectomy, confirming the need for long-term surveillance.

The utility of EUS in the locoregional staging of ampullary adenomas and adenocarcinomas is unclear, in terms of appropriately triaging patients for endoscopic, surgical, or medical therapy. We compared EUS and ERCP with surgical pathology for the assessment of intraductal extension and local staging of ampullary lesions.

Background: A fatty meal before ERCP relaxes the sphincter of Oddi and may facilitate biliary cannulation.Objective: To assess the effect of an oral fatty meal before ERCP on time to and success rate of biliary cannulation.Design: Human clinical study.Setting: Tertiary ERCP center.Patients: Adult patients with intact papilla undergoing ERCP for presumed biliary pathology.Interventions: Patients arriving more than 1 hour before the procedure were given oil by mouth. Patients not receiving oil served as controls. The need for a precut sphincterotomy was considered a failure of initial cannulation.Main Outcome Measurements: Appearance of the papillary orifice, bile flow, cannulation success rate, cannulation and fluoroscopy times.Results: A total of 86 patients received oil (mean age 52.8 years; 40% male), and 103 patients served as controls (mean age 53.3 years; 49% male). The papillary orifice was open in 52 of 86 (61%) and 38 of 103 (37%) patients in the oil and control groups, respectively (P = .002). Bile flow was seen in 59 of 86 (68%) and 50 of 103 (49%) patients, respectively (P = .009). The overall initial biliary cannulation success rate was 80 of 86 (93%) and 97 of 103 (94%), respectively (P = .77). There was no difference in cannulation success rates, cannulation, and fluoroscopy times for fellows or faculty endoscopists in each group. No pulmonary aspiration was seen in either group.Limitations: Unblinded study.Conclusions: The biliary orifice appeared more open and bile flow was seen in more patients receiving oil, but there was no difference in successful biliary cannulation rates and cannulation and fluoroscopy times in the 2 groups. (Gastrointest Endosc 2013;77:55-61.)

Background and AimThere are no data specifically correlating early intravenous volume infusion (IVI) with the length of hospitalization for postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP).MethodsWe conducted a retrospective cohort study of patients admitted within 24h after ERCP to our institute with PEP. IVI during the first 24h after ERCP was assessed. Primary outcome was severity of PEP, defined by length of hospitalization according to consensus guidelines: mild3, moderate 4-10, and severe>10 days.ResultsOf 72 eligible patients, 41 (56.9%) had mild and 31 (43.1%) moderate/severe PEP. Both groups had comparable demographics, indications, and procedural factors except patients with moderate/severe PEP were older (median age 49 vs 36 years, P=0.05) and more likely to be discharged and readmitted within the first 24h (41.9% vs 14.6%, P<0.01). Patients with mild PEP received significantly greater IVI during the first 24h (2834mL [2046, 3570] vs 2044mL [1227, 2875], P<0.02) and 50% more fluid post-ERCP (2270mL [1435, 2961] vs 1515 [950-2350], P<0.02) compared with those with at least moderate PEP.ConclusionIn patients with PEP, greater IVI during the first 24h after ERCP is associated with reduced length of hospitalization. Lower IVI was more commonly observed in individuals who were discharged and then readmitted during the first 24h.

OBJECTIVES:Hemoconcentration markers are predictors of severe acute pancreatitis but have not been specifically evaluated in post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP).METHODS:Case-control study of patients undergoing ERCP for suspected sphincter of Oddi dysfunction. We identified patients with PEP (PEP positive) and controls (PEP negative) in a 1:2 ratio. blood urea nitrogen (BUN) and hematocrit (Hct) were measured before procedure, upon admission, and 24 hours later. Preprocedure levels of BUN and Hct were analyzed to control for confounders. Among the PEP-positive patients, BUN level, Hct level, and systemic inflammatory response syndrome are compared between severe and mild/moderate cases.RESULTS:There were 149 PEP-positive patients, including 18 patients (12.1%) with severe PEP and 301 PEP-negative controls. After adjusting, higher preprocedure BUN level (odds ratio [OR], 1.05 [1.01, 1.10]; P < 0.02) and pancreatic sphincterotomy (OR, 1.60 [1.01, 2.55]; P < 0.05) were associated with PEP, whereas older age (OR, 0.98 [0.96, 0.99]; P < 0.02) and a greater body mass index (OR, 0.97 [0.94, 0.99]; P < 0.03) with a lower rate.Difference in BUN level of 0.0 or greater (failure to decline) had a sensitivity of 71% and a specificity of 79% for differentiating severe from mild/moderate PEP. Patients with severe PEP were more likely to have systemic inflammatory response syndrome upon admission (44.4% [21.5, 67.4]) and after 24 hours (61.1% [38.6, 83.6] versus mild/moderate (9.2% [4.2, 14.1], 10.6% [5.4,16.0]; P < 0.0001 for each).CONCLUSIONS:Preprocedure BUN level is associated with the development of PEP. The preprocedure BUN level and failure of the BUN level to decline during the first 24 hours are associated with prolonged hospitalization.

OBJECTIVES:A recent large-scale randomized controlled trial (RCT) demonstrated that rectal indomethacin administration is effective in addition to pancreatic stent placement (PSP) for preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk cases. We performed a post hoc analysis of this RCT to explore whether rectal indomethacin can replace PSP in the prevention of PEP and to estimate the potential cost savings of such an approach.METHODS:We retrospectively classified RCT subjects into four prevention groups: (1) no prophylaxis, (2) PSP alone, (3) rectal indomethacin alone, and (4) the combination of PSP and indomethacin. Multivariable logistic regression was used to adjust for imbalances in the prevalence of risk factors for PEP between the groups. Based on these adjusted PEP rates, we conducted an economic analysis comparing the costs associated with PEP prevention strategies employing rectal indomethacin alone, PSP alone, or the combination of both.RESULTS:After adjusting for risk using two different logistic regression models, rectal indomethacin alone appeared to be more effective for preventing PEP than no prophylaxis, PSP alone, and the combination of indomethacin and PSP. Economic analysis revealed that indomethacin alone was a cost-saving strategy in 96% of Monte Carlo trials. A prevention strategy employing rectal indomethacin alone could save approximately $150 million annually in the United States compared with a strategy of PSP alone, and $85 million compared with a strategy of indomethacin and PSP.CONCLUSIONS:This hypothesis-generating study suggests that prophylactic rectal indomethacin could replace PSP in patients undergoing high-risk ERCP, potentially improving clinical outcomes and reducing healthcare costs. A RCT comparing rectal indomethacin alone vs. indomethacin plus PSP is needed.

Intravenous volume resuscitation (IVR) represents the most important early clinical intervention in pancreatitis to minimize the severity of its course. There are no data correlating volume resuscitation with the severity of post-ERCP pancreatitis (PEP), a unique etiology of pancreatitis in that many patients present earlier in the disease course versus non-iatrogenic etiologies. The aim of this study was to compare early IVR in patients with mild versus moderate to severe PEP.

The performance of ERCP in bariatric Roux-en-Y gastric bypass (RYGB) is challenging due to long roux limb. We herein describe indications and outcomes of gastrostomy-assisted ERCP (GERCP) and double balloon enteroscopy-assisted ERCP (DBERCP) for the patients with prior bariatric RYGB anatomy.

BACKGROUND Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). METHODS In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights. RESULTS A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P=0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P=0.03). CONCLUSIONS Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.).

Techniques to facilitate biliary cannulation during ERCP are desirable. A prior report has shown that a liquid fatty meal prior to ERCP may facilitate biliary cannulation by relaxing the sphincter of Oddi. Aim: To assess the effect of oral administration of oil prior to ERCP on deep biliary cannulation at a tertiary ERCP center involving trainees and faculty endoscopists.

BACKGROUND & AIMS: The role of sphincter of Oddi manometry (SOM) in the management of patients with idiopathic recurrent acute pancreatitis requires clarification. We evaluated the therapeutic effects of endoscopic sphincterotomy in patients with recurrent acute pancreatitis and the prognostic significance of pancreatic sphincter dysfunction (SOD). METHODS: We performed a randomized trial of endoscopic retrograde cholangiopancreatography with SOM for patients with idiopathic recurrent acute pancreatitis. Patients with pancreatic SOD (n = 69) were assigned randomly to groups that received only biliary sphincterotomy (BES) or a combination of biliary and pancreatic sphincterotomy (DES); patients who underwent normal SOM (n = 20) were assigned randomly to groups that received BES or a sham surgery. The primary outcome was incidence of recurrent acute pancreatitis during the follow-up period (minimum, 1 year; maximum, 10 years). We also determined the incidence of chronic pancreatitis and analyzed factors associated with recurrence of acute pancreatitis. RESULTS: Among the 69 patients with SOD, 48.5% who received BES and 47.2% who received DES had recurrent acute pancreatitis (95% confidence interval, -22.3 to 24.9; P = 1.0). In patients with normal SOM (n = 20), 27.3% of those who received BES and 11.1% of those who received the sham surgery had recurrent acute pancreatitis (95% confidence interval, -49.5 to 17.2; P = .59). Overall, 16.9% of subjects developed chronic pancreatitis during a median follow-up period of 78 months (interquartile range, 35-108 mo). The odds of recurrent acute pancreatitis during follow-up evaluation were significantly greater among patients with SOD than those with normal SOM (unadjusted hazard ratio, 3.5; 95% confidence interval, 1.07-11.4; P < .04), and remained so after adjusting for potential confounders (hazard ratio, 4.3; 95% confidence interval, 1.3-14.5; P < .02). CONCLUSIONS: Among patients with pancreatic SOD, DES and BES have similar effects in preventing recurrence of acute pancreatitis. Pancreatic SOD is an independent prognostic factor, identifying patients at higher risk for recurrent acute pancreatitis. Clinical Trials Registration: Clinicaltrials. gov (NCT01583517).

The therapeutic impact of ERCP with sphincterotomy in the management of patients with idiopathic recurrent acute pancreatitis (RAP) needs further study. We conducted a single center, feasibility, randomized trial to determine 1) the role of pancreatic manometry in predicting future episodes of RAP and 2) differences in the efficacy of no, biliary (BES) or pancreatobiliary (dual) endoscopic sphincterotomy (DES).