High Volume Lactated Ringer's Solution and Pancreatitis

Perioperative Intravenous Administration of High Volume Lactated Ringer's Solution and the Risk of Post-Endoscopic Retrograde Cholangiopancreatography (ERCP) Pancreatitis

The purpose of this study is to examine whether giving large amounts of intravenous (IV) fluids will reduce the risk of developing a complication known as post-ERCP pancreatitis (PEP). Pancreatitis is inflammation of the pancreas, and it is the most frequent serious complication of ERCP. Typically, a small amount of IV fluids are given during this procedure (~ 1 liter). We are testing whether using a larger amount of fluids (2 - 3 liters) will reduce the risk of PEP.

This trial is designed as a phase II/III study. The phase II portion of the trial will be completed to establish safety and efficacy data prior to proceeding with a phase III study. The phase II trial will enroll 110 patients that are undergoing elective ERCP as outpatients. Following the phase II portion, if the data suggests that the intervention arm (high volume group) is safe, the investigators will begin enrolling patients who are undergoing ERCP in a more urgent setting as inpatients. We plan on enrolling 1,400 consecutive high risk patients undergoing ERCP. We are assuming a baseline PEP risk of 9.2%. Fluid administration will be based on Ideal Body Weight (IBW) in order to standardize the aggressive fluid administration across all body weights and reduce the potential for adverse cardiopulmonary outcomes. All participants will be monitored for 90 minutes following their procedure to assess the development of any adverse symptoms. Analysis by a data safety monitoring board (DSMB) will take place throughout the study. The DSMB is comprised of a panel of experts independent of NorthShore University HealthSystem.

Pancreatitis, Endoscopic retrograde cholangiopancreatography, Cholangiopancreatography, Endoscopic Retrograde, ERCP, High Volume, Lactated Ringer, Intravenous Administration, Sphincterotomy, Endoscopic, Pancreas

Patients will be randomized to receive intravenous Lactated Ringer's solution. In the high volume group (intervention arm), patients will receive fluids prior to, during, and after the completion of the procedure. Patients in the high volume group will receive fluids via infusion by the following weight based regimen: initial bolus of LR prior to ERCP of 7.5 cc/kg over 1 hour LR fluid infusion during the procedure at 5 cc/kg/hr Post-procedure bolus of 20 cc/kg over 90 minutes

Patients will be randomized to receive intravenous Lactated Ringer's solution. In the low volume group (control arm), patients will receive fluids at the start of the ERCP. The fluids will be administered via infusion at a rate of 1.5 cc/kg/hr. Fluids may be continued through the 90 minute post-procedure observation period.

Patients will be randomized to low volume or high volume group. Patient in the low volume group will receive fluids via infusion at a rate of 1.5 cc/kg/hr. Fluid administration may be continued through the 90 minute post-procedure observation period. Patients in the high volume group will receive fluids via infusion by the following weight based regimen: initial bolus of LR prior to ERCP of 7.5 cc/kg over 1 hour LR fluid infusion during the procedure at 5 cc/kg/hr Post-procedure bolus of 20 cc/kg over 90 minutes

Patients will be monitored after procedure to see if they develop abdominal pain. If so, serum amylase and lipase blood draws will be completed at least once every 24 hours following procedure to monitor the development of post-ERCP pancreatitis. If patients do not develop abdominal pain following the procedure, research staff will follow up with the patients 5 days and 29 days after the procedure to evaluate for the development of post-ERCP pancreatitis and other related or unrelated complications.

A portion of the study will assess whether there is a significant risk of adverse events related to fluid overload states in the high volume (HV) intervention arm. We anticipate the rate of adverse events in patients randomized to the HV arm to be small. By using more modest, weight based regimens, we aim to optimize benefit while eliminating overly aggressive fluid administration and causing undue harm.

Inclusion Criteria: Patients to be included in the study are those undergoing ERCP with the following: Clinical suspicion of sphincter of Oddi dysfunction History of post-ERCP pancreatitis (at least one episode) Pancreatic sphincterotomy Pre-cut (access) sphincterotomy Ampullectomy Exclusion Criteria: Age < 18 years old Intrauterine pregnancy or breastfeeding mother Congestive heart failure Advanced/symptomatic coronary artery disease Known ascites Renal failure Active or recent gastrointestinal hemorrhage Acute pancreatitis within 72 hours prior to ERCP

Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, Moore JP, Fennerty MB, Ryan ME, Shaw MJ, Lande JD, Pheley AM. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996 Sep 26;335(13):909-18. doi: 10.1056/NEJM199609263351301.

Elmunzer BJ, Scheiman JM, Lehman GA, Chak A, Mosler P, Higgins PD, Hayward RA, Romagnuolo J, Elta GH, Sherman S, Waljee AK, Repaka A, Atkinson MR, Cote GA, Kwon RS, McHenry L, Piraka CR, Wamsteker EJ, Watkins JL, Korsnes SJ, Schmidt SE, Turner SM, Nicholson S, Fogel EL; U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012 Apr 12;366(15):1414-22. doi: 10.1056/NEJMoa1111103.

Feurer ME, Adler DG. Post-ERCP pancreatitis: review of current preventive strategies. Curr Opin Gastroenterol. 2012 May;28(3):280-6. doi: 10.1097/MOG.0b013e3283528e68.

Choudhary A, Bechtold ML, Arif M, Szary NM, Puli SR, Othman MO, Pais WP, Antillon MR, Roy PK. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc. 2011 Feb;73(2):275-82. doi: 10.1016/j.gie.2010.10.039.

Fazel A, Quadri A, Catalano MF, Meyerson SM, Geenen JE. Does a pancreatic duct stent prevent post-ERCP pancreatitis? A prospective randomized study. Gastrointest Endosc. 2003 Mar;57(3):291-4. doi: 10.1067/mge.2003.124.

Wu BU, Hwang JQ, Gardner TH, Repas K, Delee R, Yu S, Smith B, Banks PA, Conwell DL. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011 Aug;9(8):710-717.e1. doi: 10.1016/j.cgh.2011.04.026. Epub 2011 May 12.

Gardner TB, Vege SS, Pearson RK, Chari ST. Fluid resuscitation in acute pancreatitis. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1070-6. doi: 10.1016/j.cgh.2008.05.005. Epub 2008 Jul 10.

Warndorf MG, Kurtzman JT, Bartel MJ, Cox M, Mackenzie T, Robinson S, Burchard PR, Gordon SR, Gardner TB. Early fluid resuscitation reduces morbidity among patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011 Aug;9(8):705-9. doi: 10.1016/j.cgh.2011.03.032. Epub 2011 Apr 8.

Freeman ML, DiSario JA, Nelson DB, Fennerty MB, Lee JG, Bjorkman DJ, Overby CS, Aas J, Ryan ME, Bochna GS, Shaw MJ, Snady HW, Erickson RV, Moore JP, Roel JP. Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc. 2001 Oct;54(4):425-34. doi: 10.1067/mge.2001.117550.

de-Madaria E, Soler-Sala G, Sanchez-Paya J, Lopez-Font I, Martinez J, Gomez-Escolar L, Sempere L, Sanchez-Fortun C, Perez-Mateo M. Influence of fluid therapy on the prognosis of acute pancreatitis: a prospective cohort study. Am J Gastroenterol. 2011 Oct;106(10):1843-50. doi: 10.1038/ajg.2011.236. Epub 2011 Aug 30.

Nasr JY, Papachristou GI. Early fluid resuscitation in acute pancreatitis: a lot more than just fluids. Clin Gastroenterol Hepatol. 2011 Aug;9(8):633-4. doi: 10.1016/j.cgh.2011.03.010. Epub 2011 Mar 21. No abstract available.

Wu M, Jiang S, Lu X, Zhong Y, Song Y, Fan Z, Kang X. Aggressive hydration with lactated ringer solution in prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review and meta-analysis. Medicine (Baltimore). 2021 Apr 23;100(16):e25598. doi: 10.1097/MD.0000000000025598.