Lactated Ringer's solution in combination with rectal indomethacin for prevention of post-ERCP pancreatitis and readmission: a prospective randomized, double-blinded, placebo-controlled trial

  • Shaffer R.S. Mok
    Correspondence
    Reprint requests: Shaffer R. S. Mok, MD, MBS, Cooper University Hospital, Department of Medicine, Division of Gastroenterology and Liver Diseases, 501 Fellowship Road, Suite 101, Mount Laurel, NJ 08054.
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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  • Henry C. Ho
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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  • Paurush Shah
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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  • Milan Patel
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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  • John P. Gaughan
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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  • Adam B. Elfant
    Affiliations
    Cooper Medical School of Rowan University, MD Anderson Cancer Center at Cooper, Department of Medicine, Division of Gastroenterology and Liver Diseases, Mount Laurel, New Jersey, USA
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Published:November 02, 2016DOI:https://doi.org/10.1016/j.gie.2016.10.033

      Background and Aims

      Prospective data have shown the benefit of rectal indomethacin (IND) for preventing post-ERCP pancreatitis (PEP). A recent pilot study demonstrated a lower incidence of PEP after an 8-hour lactated Ringer’s solution (LR) infusion. The aim of this study was to evaluate the efficacy of IND with or without bolus LR in patients at high-risk for PEP.

      Methods

      In this randomized, double-blinded, placebo-controlled trial we assigned patients to standard normal saline solution (NS) + placebo, NS + IND, LR + placebo, or LR + IND. Each liter of fluid infusion was completed within 30 minutes. Patients were determined high-risk based established criterion and excluded if they had pancreatitis, contraindications to IND, or signs of volume overload. Our primary outcome was PEP, defined by standardized criterion. Our secondary outcomes were severe acute pancreatitis, localized adverse events, death, length of stay, and readmission.

      Results

      Our sample consisted of 192 patients (48 per group) who completed follow-up at 24 hours and at 30 days post-ERCP. All patients had at least 1 high-risk criterion for PEP, and 56% had >1. PEP occurred in 3 patients (6%) in the LR + IND versus 10 (21%) in the NS + placebo group (P = .04). Readmission rates were lower in the LR + IND group (1 [2%]) versus the NS + placebo group (6 [13%]; P = .03). No differences were found between the other study groups. There was 1 case of severe pancreatitis (NS + IND) and 1 case of pseudocyst (LR + IND).

      Conclusions

      In patients at high risk for PEP, LR + IND reduced the incidence of PEP and readmission rates compared with NS + placebo. (Clinical trial registration number: NCT02641561.)

      Abbreviations:

      AE (adverse event), ARF (acute renal failure), IND (indomethacin), IVF (intravenous fluid), LR (lactated Ringer’s solution), NS (normal saline solution), NSAID (nonsteroidal anti-inflammatory drug), PD (pancreatic duct), PEP (post-ERCP pancreatitis)
      Acute pancreatitis is a feared adverse event (AE) of ERCP, resulting in significant medical cost and patient morbidity.
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      • Afghani E.
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      Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials.
      The incidence of post-ERCP pancreatitis (PEP) ranges widely in the literature, with rates from 1% to 10% for low-risk individuals to 25% to 30% without prophylaxis for individuals with high-risk factors such as pancreatic sphincterotomy, sphincter of Oddi dysfunction, and history of PEP.
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      One such agent is rectally administered indomethacin (IND), a nonsteroidal anti-inflammatory drug (NSAID) that acts by inhibiting cyclooxygenase and phospholipase A2, compounds believed to have pivotal roles in the pathogenesis of acute pancreatitis.
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      Based on findings of randomized trials and recommendations by the European Society of Gastrointestinal Endoscopy and the American Society for Gastrointestinal Endoscopy, IND is widely used as a preventive strategy for PEP.
      • Elmunzer B.J.
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      A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.
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      Effects of rectal indomethacin in the prevention of post-ERCP acute pancreatitis.
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      Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?.
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      Prevention of hyperamilasemia and pancreatitis after endoscopic retrograde cholangiopancreatography with rectal administration of indomethacin.
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      Effect of the administration of rectal indomethacin on amylase serum levels after endoscopic retrograde cholangiopancreatography, and its impact on the development of secondary pancreatitis episodes.
      • Sotoudehmanesh R.
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      Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP.
      • Yaghoobi M.
      • Rolland S.
      • Waschke K.A.
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      Meta-analysis: rectal indomethacin for the prevention of post-ERCP pancreatitis.
      • Elmunzer B.J.
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      • et al.
      A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis.
      • Dumonceau J.M.
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      Prophylaxis of post-ERCP pancreatitis: European Society for Gastrointestinal Endoscopy Guidelines–updated June 2014.
      • Anderson M.A.
      • Fisher L.
      • Jain R.
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      Complications of ERCP.
      • Kusterer K.
      • Enghofer M.
      • Zendler S.
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      Microcirculatory changes in sodium taurocholate-induced pancreatitis in rats.
      The use of an infusion of lactated Ringer’s solution (LR) has shown a benefit in the prevention of acute pancreatitis.
      • Kusterer K.
      • Enghofer M.
      • Zendler S.
      • et al.
      Microcirculatory changes in sodium taurocholate-induced pancreatitis in rats.
      • Strate T.
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      • Kleinhans H.
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      Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis.
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      Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation.
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      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
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      Association of greater intravenous volume infusion with shorter hospitalization for patients with post-ERCP pancreatitis.
      • DiMagno M.J.
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      • et al.
      Do larger periprocedural fluid volumes reduce the severity of post-endoscopic retrograde cholangiopancreatography pancreatitis?.
      • Buxbaum J.
      • Yan A.
      • Yeh K.
      • et al.
      Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography.
      The mechanism appears to be by attenuating tissue acidification, thus preventing zymogen activation, and maintaining a stable pancreatic microcirculation.
      • Kusterer K.
      • Enghofer M.
      • Zendler S.
      • et al.
      Microcirculatory changes in sodium taurocholate-induced pancreatitis in rats.
      • Strate T.
      • Mann O.
      • Kleinhans H.
      • et al.
      Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis.
      • Rinderknecht H.
      Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation.
      • Wu B.U.
      • Hwang J.Q.
      • Gardner T.H.
      • et al.
      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
      Two observational studies have used aggressive intravenous fluid (IVF) strategies in the periprocedural setting of ERCP, demonstrating lower rates of PEP and length of stay.
      • Sagi S.V.
      • Schmidt S.
      • Fogel E.
      • et al.
      Association of greater intravenous volume infusion with shorter hospitalization for patients with post-ERCP pancreatitis.
      • DiMagno M.J.
      • Wamsteker E.J.
      • Maratt J.
      • et al.
      Do larger periprocedural fluid volumes reduce the severity of post-endoscopic retrograde cholangiopancreatography pancreatitis?.
      A more recent pilot study evaluated the use of LR infusion and demonstrated lower rates of PEP (0%) when compared with 17% in the standard hydration group.
      • Buxbaum J.
      • Yan A.
      • Yeh K.
      • et al.
      Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography.
      This is a randomized, double-blinded, placebo-controlled trial that evaluated the use of IND with LR when compared with placebo to prevent PEP.

      Methods

       Study design

      Patients participating in this randomized, double-blinded, placebo-controlled trial were enrolled at a tertiary care center in the United States. This study was in compliance with the Declaration of Helsinki and approved by our institution's investigational review board (no. 14-091). This trial was registered online at clinicaltrials.gov (NCT02641561) before enrollment of any patients. A data and safety monitoring board provided oversight and performed an interim analysis midway through enrollment. This board included members of our investigational review board who were not directly involved in the study ERCPs.

       Patients

      Study-eligible patients were those undergoing ERCP and deemed high risk by standard criteria.
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.

      Rome Foundation. Rome III diagnostic criteria for functional gastrointestinal disorders. Rome Foundation. Available at: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed June 1, 2016. Retrieved June 2016.

      • Prajapati D.N.
      • Hogan W.J.
      Sphincter of Oddi dysfunction and other functional biliary disorders: evaluation and treatment.
      Patients were included if they possessed historical criterion that placed them at high risk for PEP or were to undergo planned endoscopic intervention deemed at high risk (ie, ampullectomy) before the procedure. Major criteria included 1 of the following: suspicion for sphincter of Oddi dysfunction, personal history of PEP, more than 8 cannulation attempts, precut sphincterotomy, endoscopic papillary balloon dilation of an intact sphincter, endoscopic PD sphincterotomy, and ampullectomy. Patients were also included if they met 2 or more of the following minor criteria: female sex and age under 50 years, personal history of recurrent acute pancreatitis, PD injection leading to “acinarization” or over 3 PD injections, and PD cytology acquisition. Initial demographic data were obtained, including patient age, sex, race, medical history, prior ERCP data, and AEs if present. All patients underwent laboratory data including a basic metabolic panel, amylase levels, and lipase levels before their ERCP.
      Exclusion criteria were as follows: age under 18 years, pregnancy (because IND could lead to closure of a patent ductus arteriosus in the fetus), and active acute pancreatitis. NSAID-related exclusionary criteria included a true documented allergy to NSAIDs, use of NSAIDs the day of the procedure, acute renal failure (ARF; creatinine > 1.2 mg/dL), and active peptic ulcer disease. Contraindications to aggressive IVF hydration were also used as exclusionary criteria: evidence of clinical volume overload (peripheral or pulmonary edema), respiratory compromise (oxygen saturation < 90% on room air), chronic kidney disease (creatinine clearance < 40 mL/min), systolic congestive heart failure (ejection fraction < 45%), cirrhosis, and severe electrolyte disturbance with sodium < 130 mEq/L or >150 mEq/L. Patients were also excluded if they did not undergo a planned high-risk intervention and possessed no complete criterion that placed them at high risk for PEP.

       Intervention

      After informed consent was obtained, patients were randomized in a 1:1:1:1 ratio into 1 of 4 treatment groups: normal saline solution (NS) + rectal suppository placebo, NS + rectal IND, LR + placebo, or LR + IND. The randomization schedule was created by a computerized random number generator and was kept in our institution’s central pharmacy. To ensure blinding of both the endoscopist and the patient, this centralized pharmacy placed an opaque brown plastic bag over each liter of IVF administered. Additionally, this pharmacy provided one 100-mg rectal suppository or identical placebo. All suppositories were obtained from the same compounding pharmacy (Delran Pharmacy, Delran, NJ). All liter fluid infusions were completed within 30 minutes.
      ERCP-related interventions were performed by 1 of 2 fellowship-trained, experienced (>200 cases a year) therapeutic endoscopists. Patients who underwent PD interrogation received a prophylactic pancreatic stent. All cases were performed with a postgraduate year-6 gastroenterology fellow.
      Before undergoing ERCP, patients received a 1-L IVF infusion within a 30-minute time period. Each participant received the suppository after being sedated and before a cannulation attempt. Two nurses determined confirmation of suppository placement.

       Outcomes

      The primary study outcome was PEP defined by the presence of 2 of 3 of the following: (1) new or worsening abdominal pain that is clinically consistent with acute pancreatitis; and (2) associated pancreatic enzymes elevation ≥ 3 times the upper limit of normal 24 hours after the procedure; and (3) resultant or prolongation of existing hospitalization ≥ 2 nights.
      • Kochar B.
      • Akshintala V.S.
      • Afghani E.
      • et al.
      Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials.
      • Cotton P.B.
      • Lehman G.
      • Vennes J.
      • et al.
      Endoscopic sphincterotomy complications and their management: an attempt at consensus.
      • Tenner S.
      • Baillie J.
      • DeWitt J.
      • et al.
      American College of Gastroenterology Guideline: management of acute pancreatitis.
      Secondary outcomes included severe acute pancreatitis (persistent organ failure ≥ 48 hours), localized AEs (pseudocyst formation, abscess, walled of pancreatic necrosis), death, length of hospital stay in days, and readmission within 30 days.
      • Banks P.A.
      • Bollen T.L.
      • Dervenis C.
      • et al.
      Classification of acute pancreatitis 2012: revision of Atlanta classification and definitions by international consensus.
      AEs related to the study drugs were recorded including those related to NSAIDs: anaphylaxis, GI bleeding, and ARF. AEs related to IVF were also recorded: peripheral/pulmonary edema, hypoxia, congestive heart failure exacerbation, and ascites.
      To monitor all outcomes, subjects underwent a pain severity assessment using a 10-point Likert scale before ERCP and 2 hours, 24 hours, and 30 days after ERCP. All patients were kept in the recovery area for 2 hours after completion of their ERCP, and those experiencing worsening abdominal pain from baseline were admitted to or maintained in (if already hospitalized) the institution performing the ERCP. Clinical management included allowance for additional IVF and collection of a serum amylase and lipase at least once in a 24-hour period. Further clinical management was otherwise left to the discretion of the therapeutic endoscopist and GI consultation service who were unaware of study group assignment.
      In the case of delayed AEs, all patients were encouraged to return to the institution in which their procedure was performed. To ensure comprehensive data collection, participants received a telephone call or in-person encounter (when hospitalized) within 24 hours and also at 30 days from their procedure. All data were recorded by blinded study staff. To ensure triple blinding, each group was given a letter designation. The corresponding study group for each letter was unknown to the statistician at the time of data analysis.

       Statistical analysis

      A total of 96 subjects (or 48 per group, n = 192) were needed to detect a difference in PEP rates of .24 in the NS + placebo group versus .05 (ie, 1/21) in the LR + IND group assuming a medium effect size with 80% power using the Fisher exact test. A difference in the rate of PEP between groups of .19 was selected based on differences found in prior studies. Elmunzer et al
      • Elmunzer B.J.
      • Scheiman J.M.
      • Lehman G.A.
      • et al.
      A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.
      found a decrease of .08 with use of rectal IND, and Buxbaum et al
      • Buxbaum J.
      • Yan A.
      • Yeh K.
      • et al.
      Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography.
      found a decrease of .17 with the use of LR infusion. We hypothesized that the combination of these 2 therapies would lead to a greater decrease in PEP than these prior studies, and therefore .19 was selected and deemed clinically meaningful. Differences between these groups and LR + placebo and, IND + NS groups were not accounted for in our power calculation and are considered exploratory analyses. However, to evaluate these exploratory analyses (NS + IND and LR + placebo), an additional 96 patients were added to the study.
      Descriptive statistics were used to summarize demographic variables such as age, gender, race, length of stay, and diagnosis and disease characteristics such as reasons for ERCP, disease intervention, pain, and outcome variables. Data tables were generated for those variables with means, standard deviations, medians, interquartile ranges, and confidence intervals. The Fisher exact test was used to evaluate the primary outcome. A nonparametric χ2 test was used to analyze categorical data. Data analysis was performed using Systat version 13 (Synstat Software, San Jose, Calif) and SPSS version 22 (IBM Corp, Armonk, NY). A P < .05 was considered statistically significant.

      Results

       Patients

      From March 2015 until June 2016, a total of 352 patients met initial screening, from which 52 patients were excluded. After initial exclusion, 108 patients declined to consent for the study, leading to a total of 192 patients enrolled in the study. See Figure 1 for details of screening and enrollment. An interim analysis was performed by the data and safety monitoring board December 2015 after 96 patients were enrolled and allowed continued patient accrual.
      Figure thumbnail gr1
      Figure 1Flow diagram with enrollment and outcomes. NSAID, nonsteroidal anti-inflammatory drug; CKD, chronic kidney disease; CHF, congestive heart failure; PUD, peptic ulcer disease; ARF, acute renal failure; NS, normal saline solution; IND, indomethacin; LR, lactated Ringer's solution.
      Forty-eight patients were randomized to each of the 4 study groups. Demographics and risk factors for PEP did not differ between the study groups (Table 1). Fifty-six percent of patients had more than 1 major risk factor for PEP. There was no difference between groups in the number of patients who underwent PD injection and insertion of a prophylactic stent. All patients completed 24-hour and 30-day post-ERCP follow-up.
      Table 1Baseline patient characteristics
      Adapted from Freeman et al.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      NS + placebo (n = 48)NS + IND (n = 48)LR + placebo (n = 48)LR + IND (n = 48)P value
      Mean age, y58625863.44
      Sex
       Female29 (60%)33 (69%)35 (73%)23 (48%).06
       Male19 (40%)15 (31%)13 (27%)25 (52%)
      Race
       White32 (67%)35 (73%)40 (83%)40 (83%).56
       African American3 (6%)3 (6%)3 (6%)4 (8%)
       Hispanic10 (21%)8 (17%)4 (8%)3 (6%)
       Asian2 (4%)2 (4%)1 (2%)1 (2%)
       Other1 (2%)000
      Clinical suspicion of SOD
       Any8 (17%)8 (17%)11 (23%)6 (13%).31
       Type 12 (4%)4 (8%)2 (4%)1 (2%).63
       Type 26 (13%)4 (8%)8 (17%)5 (9%).69
       Type 3
      Subjects enrolled before removal of SOD type 3 diagnosis.
      001 (2%)01.00
       SOD manometry3 (6%)02 (4%)0.17
      Mean risk score (number)
      Fifty-six percent of patients had >1 risk factor.
      21.92.21.5.83
      Female and age < 5011 (23%)10 (21%)16 (33%)5 (11%).06
      Normal total bilirubin (<1 mg/dL)27 (56%)33 (69%)25 (52%)23 (48%).30
      History of PEP3 (6%)1 (2%)3 (6%)0.32
      History of recurrent pancreatitis10 (21%)7 (15%)11 (23%)10 (21%).78
      Difficult cannulation (>8 attempts)6 (13%)8 (17%)5 (10%)6 (13%).87
      Biliary sphincterotomy38 (79%)40 (83%)41 (85%)36 (75%).62
      Balloon dilation of an intact sphincter10 (21%)9 (19%)11 (23%)10 (21%).74
      Precut sphincterotomy1 (2%)01 (2%)01.00
      Plastic biliary stent8 (17%)5 (10%)10 (21%)11 (23%).38
      SEMS7 (15%)6 (13%)3 (6%)3 (6%).62
      Pancreatography15 (31%)12 (25%)15 (31%)10 (21%).59
      Pancreatic sphincterotomy5 (10%)4 (8%)6 (13%)2 (4%).59
      Minor duct papillotomy3 (6%)3 (6%)4 (8%)1 (2%).69
      >3 Injections of the PD + 1 to the tail9 (19%)5 (10%)9 (19%)6 (13%).58
      Pancreatic acinarization6 (13%)5 (10%)7 (15%)7 (15%).96
      PD cytology1 (2%)2 (4%)1 (2%)01.00
      PD stent placement15 (31%)12 (25%)15 (31%)10 (21%).59
      Ampullectomy2 (4%)1 (2%)01 (2%).90
      Trainee involvement48 (100%)48 (100%)48 (100%)48 (100%)1.00
      Values are n (%), unless otherwise noted. P values were calculated using χ2 testing.
      NS, Normal saline solution; IND, indomethacin; LR, lactated Ringer's solution; PEP, post-ERCP pancreatitis; SOD, sphincter of Oddi dysfunction; SEMS, self-expanding metal stent; PD, pancreatic duct.
      Subjects enrolled before removal of SOD type 3 diagnosis.
      Fifty-six percent of patients had >1 risk factor.

       Primary outcome

      PEP occurred in 28 of 192 patients (15%). The NS + placebo group had 10 patients (21%) and the LR + IND group 3 (6%) (Table 2, Fig. 2). Our other experimental therapies had 6 episodes (13%) of PEP in the NS + IND group and 9 (19%) in the LR + placebo group. A significant difference was detected between the NS + placebo and LR + IND groups in rate of PEP (P = .04). This result corresponded to an absolute risk reduction of 14.6% and a relative risk reduction of 70.0%. The number needed to treat was 6.9 for LR + IND. No differences were detected between any of the other experimental group comparisons that were calculated, exploratory, as hypothesis generating (Fig. 2).
      Table 2Primary and secondary study outcomes
      NS + placebo (n = 48)NS + IND (n = 48)LR + placebo (n = 48)LR + IND (n = 48)P value
      PEP10 (21%)6 (13%)9 (19%)3 (6%)
      Comparative data available in Figures 2 and 3.
      Severe PEP01 (2%)001.00
      Pseudocyst0001 (2%)1.00
      Pulmonary edema1 (2%)0001.00
      Renal failure1 (2%)1 (2%)1 (2%)1 (2%)1.00
      GI bleeding00001.00
      Anaphylaxis00001.00
      Death1 (2%)2 (4%)2 (4%)1 (2%)1.00
      Readmission6 (13%)2 (4%)2 (4%)1 (2%)
      Comparative data available in Figures 2 and 3.
      Mean length of stay, days2.32.21.94.3.50
      Values are n (%), unless otherwise noted. P value for primary PEP calculated by the Fisher exact test.
      NS, Normal saline solution; IND, indomethicin; LR, lactated Ringer's solution; PEP, post-ERCP pancreatitis.
      Comparative data available in Figures 2 and 3.
      Figure thumbnail gr2
      Figure 2The incidence of the primary outcome of post-ERCP pancreatitis. Bars from left to right indicate NS + placebo (Pl), NS + IND, LR + Pl, and LR + IND groups. The difference between the NS + Pl versus LR + IND group was significant (P = .04). ns, Not significant; NS, normal saline solution; IND, indomethicin; LR, lactated Ringer's solution; Pl, placebo; PEP, post-ERCP pancreatitis.

       Secondary outcomes

      There was 1 case of severe acute pancreatitis in the NS + IND group (.5% total, 2% in each group) and 1 case of pancreatitis leading to pseudocyst (localized AE) in the LR + IND group. All deaths (6 total) that occurred in the study were in patients with malignancy who were placed on hospice care. One death occurred in the NS + placebo group, 2 each in the NS + IND and LR + placebo groups, and 1 in the LR + IND group. The mean length of stay was not different between groups. There was a significant difference in readmission rates between the NS + placebo group (13%) when compared with the LR + IND group (2%) (P = .03). There were no statistical differences in readmission rates found between the other experimental study group comparisons (Fig. 3).
      Figure thumbnail gr3
      Figure 3The incidence of secondary outcome readmission rates. Bars from left to right indicate NS + placebo (Pl), NS + IND, LR + Pl, and LR + IND groups. The difference between the NS + Pl versus LR+IND group was significant (P = .03). ns, Not significant; NS, normal saline solution; IND, indomethicin; LR, lactated Ringer's solution; Pl, placebo.

       Adverse events

      A total of 5 AEs (3%) occurred. Each study group contained 1 patient who developed ARF. One patient each in the NS + placebo and LR + placebo groups developed this AE despite no NSAID exposure. One patient in the NS + IND group experienced severe acute pancreatitis with ARF 1 week after ERCP. One patient in the LR + IND group developed a splenic laceration with hemodynamic shock and ARF requiring splenectomy after ERCP. There was 1 case of pulmonary edema in a patient (NS + placebo) with stage IV breast cancer with hepatobiliary metastasis. This patient was later found to have a pulmonary embolism, which may have contributed to her hypoxia, and was placed on hospice. There were no cases of GI bleeding or anaphylaxis related to NSAIDs (Table 2).

      Discussion

      In this group of high-risk patients undergoing ERCP, this study demonstrated a lower incidence of PEP in patients who received combination therapy with LR + IND compared with NS + placebo. Readmission rates were lower between patients receiving LR + IND compared with those receiving NS + placebo. The strategy of LR + IND demonstrated a number needed to treat of 6.9 to prevent 1 episode of PEP.
      In a climate of raising healthcare costs, quality measures, and swift patient care, the ability to admit every ERCP patient for an 8-hour infusion of LR is somewhat cumbersome. Essentially, this is why we sought to evaluate the ability for a rapid IVF infusion in combination with IND to prevent PEP. The combination therapy also demonstrated lower 30-day readmission rates, also of use to the U.S. endoscopist. We believe that using a more practical combination of preventative strategies in patients at high-risk for PEP was more beneficial than a single-modality approach.
      Because Freeman et al’s study
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      evaluated risk factors that increase the pretest probability of PEP, early patient identification and initiation of prophylactic strategies have become vital to preventing this AE. In the current study, all individuals were high risk. Prior studies evaluating this population with certain high-risk features have reported rates of PEP from 13% to 30%.
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      • Freeman M.L.
      • DiSario J.A.
      • Nelson D.B.
      • et al.
      Risk factors for post-ERCP pancreatitis: a prospective, multicenter study.
      • Vandervoort J.
      • Soetikno R.M.
      • Tham T.C.
      • et al.
      Risk factors for complications after performance of ERCP.
      • Rabenstein T.
      • Hahn E.G.
      Post-ERCP pancreatitis: new momentum.
      The inclusion of only this group of patients may be an explanation of the high incidence of PEP (15%) in the study groups and was similar to prior trials used prophylactic PD stent placement.
      • Freeman M.L.
      Pancreatic stents for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.
      • Choudhary A.
      • Bechtold M.L.
      • Arif M.
      • et al.
      Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review.
      • Mazaki T.
      • Mado K.
      • Masuda H.
      • et al.
      Prophylactic pancreatic stent placement and post-ERCP pancreatitis: an updated meta-analysis.
      When evaluating preventative strategies aimed at ductal pressure equilibration, our population also had equivalent rates of PD interrogation and subsequent stent placement across all study groups. Having similar rates of prophylactic PD stent placement likely led to further homogeneity across all study groups, allowing for a more accurate comparison of our therapeutic interventions.
      • Freeman M.L.
      Pancreatic stents for prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis.
      • Choudhary A.
      • Bechtold M.L.
      • Arif M.
      • et al.
      Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review.
      • Mazaki T.
      • Mado K.
      • Masuda H.
      • et al.
      Prophylactic pancreatic stent placement and post-ERCP pancreatitis: an updated meta-analysis.
      Other than ductal pressure change with PD stent placement, unique to our study is that it involved the evaluation of 2 strategies that may counteract the pathogenesis of PEP in different ways. Numerous prospective trials have evaluated downstream inactivation of the inflammatory cascade with rectal IND showing significantly lower rates of PEP when compared with placebo.
      • Elmunzer B.J.
      • Scheiman J.M.
      • Lehman G.A.
      • et al.
      A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.
      • Döbrönte Z.
      • Toldy E.
      • Márk L.
      • et al.
      Effects of rectal indomethacin in the prevention of post-ERCP acute pancreatitis.
      • Döbrönte Z.
      • Szepes Z.
      • Izbéki F.
      • et al.
      Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?.
      • Montaño Loza A.
      • García Correa J.
      • González Ojeda A.
      • et al.
      Prevention of hyperamilasemia and pancreatitis after endoscopic retrograde cholangiopancreatography with rectal administration of indomethacin.
      • Montaño Loza A.
      • Rodríguez Lomelí X.
      • García Correa J.E.
      • et al.
      Effect of the administration of rectal indomethacin on amylase serum levels after endoscopic retrograde cholangiopancreatography, and its impact on the development of secondary pancreatitis episodes.
      • Sotoudehmanesh R.
      • Khatibian M.
      • Kolahdoozan S.
      • et al.
      Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP.
      In this study we observed a trend toward reduced PEP in the IND alone arm (13%) compared with placebo (21%), although this difference was not statistically significant, presumably because of the small sample size of this exploratory comparative analysis. Although there was a trend toward a difference between these groups, we realize this finding is somewhat contradictory to prior data regarding the use of IND alone for high-risk patients.
      • Elmunzer B.J.
      • Scheiman J.M.
      • Lehman G.A.
      • et al.
      A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis.
      • Döbrönte Z.
      • Toldy E.
      • Márk L.
      • et al.
      Effects of rectal indomethacin in the prevention of post-ERCP acute pancreatitis.
      • Döbrönte Z.
      • Szepes Z.
      • Izbéki F.
      • et al.
      Is rectal indomethacin effective in preventing of post-endoscopic retrograde cholangiopancreatography pancreatitis?.
      • Montaño Loza A.
      • García Correa J.
      • González Ojeda A.
      • et al.
      Prevention of hyperamilasemia and pancreatitis after endoscopic retrograde cholangiopancreatography with rectal administration of indomethacin.
      • Montaño Loza A.
      • Rodríguez Lomelí X.
      • García Correa J.E.
      • et al.
      Effect of the administration of rectal indomethacin on amylase serum levels after endoscopic retrograde cholangiopancreatography, and its impact on the development of secondary pancreatitis episodes.
      • Sotoudehmanesh R.
      • Khatibian M.
      • Kolahdoozan S.
      • et al.
      Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP.
      It is important to note that this comparative analysis was performed as exploratory, and our statistical power was not generated for this particular comparison. Therefore, it is difficult to generate conclusions from this finding. However, demonstrating a difference of IND in combination with LR may suggest a synergistic interaction of these 2 agents that is beneficial for preventing PEP.
      When evaluating fluid strategies in acute pancreatitis, our study examined LR + placebo and LR + IND compared with NS. Prior studies have suggested the benefit of aggressive IVF resuscitation to improve pancreatic microvasculature viability, prevent pancreatic acidification, zymogen activation, and initiation of the inflammatory cascade, thus reducing the incidence of systemic inflammatory response syndrome.
      • Kusterer K.
      • Enghofer M.
      • Zendler S.
      • et al.
      Microcirculatory changes in sodium taurocholate-induced pancreatitis in rats.
      • Strate T.
      • Mann O.
      • Kleinhans H.
      • et al.
      Microcirculatory function and tissue damage is improved after therapeutic injection of bovine hemoglobin in severe acute rodent pancreatitis.
      • Rinderknecht H.
      Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation.
      • Wu B.U.
      • Hwang J.Q.
      • Gardner T.H.
      • et al.
      Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis.
      An aggressive IVF strategy with LR was evaluated in a prospective manner, which demonstrated lower rate of PEP.
      • Buxbaum J.
      • Yan A.
      • Yeh K.
      • et al.
      Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography.
      This aggressive LR strategy involved in Buxbaum et al’s study required admission and IVF infusion over 8 hours. Although we realize this study had great merit for preventing PEP, we chose to evaluate a more practical, 1-L LR infusion, completed typically within 30 minutes. When comparing our LR + placebo group (LR alone), we found no difference in the rates of PEP as compared with NS + placebo (19% vs 20%). Although contradictory to prior study of LR for preventing PEP, again it was difficult to demonstrate a true conclusion from this comparison, because our trial was not specifically powered for this comparison. This may indicate a possible interaction between IND and LR that may prove beneficial to prevent PEP. Additionally, this exploratory analysis should serve as a means for generating further study.
      Overall, the treatments used in this study were well tolerated by patients with similar rates of AEs between the study groups. Also, based on the clinical circumstances of each AE, they are unlikely related to the study participation. There were no cases of anaphylaxis or GI bleeding. Patients who would be at high risk for volume overload were excluded, and therefore our data cannot be extrapolated to these populations. There was 1 case of ARF in each of our study groups. Two of these patients did not receive IND, so this was not the cause of their ARF. One patient in the NS + IND group developed ARF from PEP and the patient in the LR + IND group after hemorrhage from a splenic laceration, again unlikely unrelated to NSAID exposure because these events occurred well after the initial 24 hours of NSAID exposure.
      A strength of this study included rigorous inclusion criteria for high-risk patients and 100% capture of follow-up data. Recent studies evaluating no reduction in the incidence of in PEP with IND have included those at average risk for PEP.
      • Levenick J.M.
      • Gordon S.R.
      • Fadden L.L.
      • et al.
      Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients.
      Other than inclusion criterion, our randomization and triple-blinding strategy likely significantly reduced possible bias involved in this study. Potential limitations of this study include our sample size. This study was powered based on detecting a statistically significant difference between NS + placebo and LR + IND among high-risk patients. Given our small number of patients, we realize that our findings, although significant, are possibly potentially underpowered. We also did not power this study to detect a difference between our other comparative groups (NS + IND and LR + placebo) but rather performed exploratory analyses and used these components of our study as hypothesis generating. Therefore, we realize that these results may have been prone to Type II statistical errors. An additional possible limitation is that this is a single-center experience. In conclusion, this randomized, double-blinded, placebo-controlled trial suggests that LR infusion plus rectal IND can reduce the incidence of PEP and postprocedure readmission compared with NS + placebo in high-risk patients.

      Acknowledgments

      The authors thank David L. Diehl, MD, FACP, FASGE, for his thorough review of the manuscript and Abhi Chandel, MD, and Brittany Scarpato, MD, for assisting with data extraction. Special thanks to Jeffrey Costanzo, MD, and Tara Lautenslager, MD, for enrolling subjects. The authors also thank Carla Vogel, RPh, for performing blinding and allocation sequence generation and dispensing study medications. Finally, the authors thank the Certified Registered Nurse Anesthetists, nurses at our institution for administering study medications, and technician James Irwin for assisting with obtaining all needed supplies to complete this study.

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      Linked Article

      • Indomethacin and lactated Ringer’s hydration to prevent post-ERCP pancreatitis: right combination but wrong volume
        Gastrointestinal EndoscopyVol. 86Issue 5
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          We read with interest the recent study by Mok et al1 describing the role of rectal indomethacin combined with lactated Ringer’s solution (LR) infusion to prevent post-ERCP pancreatitis (PEP). The investigators’ strategy to combat PEP by using 2 potentially synergistic agents with different mechanisms of action draws parallels to the very successful strategy of using multidrug cocktails to treat the human immunodeficiency virus and more recently hepatitis C.2,3 Rectal indomethacin has been proved to prevent pancreatitis in high-risk cases and may have a role for average-risk procedures.
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