Preventing Post-ERCP Pancreatitis Michael Chang, MD

Overview Risk of Post-ERCP pancreatitis (PEP) Basics – Patient, Procedural Pancreatic duct stenting Rectal Indomethacin Hydration

Overall Risk of PEP Systematic review in GIE 2015. -108 RCTs -13,296 patients in the placebo or no-stent arms. Incidence of PEP: -Overall 9.7% (CI, 8.6%-10.7%) -13% in North America, 8.4% in Europe, 9.9% in Asia RCTs. ERCPs conducted before and after 2000 had a PEP incidence of 7.7% and 10%, respectively. Overall Mortality rate was 0.7%. Severity of Pancreatitis: 8857 patients where severity was recorded -65% (5.7%) mild, 30% (2.6%) moderate, and 5% (0.5%) severe “High-risk”: 2345 patients -Overall 14.7% -8.6% mild, 3.9% moderate, and 0.8% severe -0.2% mortality rate. Kochar B. at al. GIE 2015

High risk: 1 or more of the following Risk of PEP High risk: 1 or more of the following Suspicion of SOD Pancreatic sphincterotomy History of PEP Precut sphincterotomy Age <50 Pneumatic dilation Female sex Ampullectomy >2 episodes of pancreatitis Multiple contrast injections to PD Multiple cannulation attempts Excessive injection into PD Kochar B. at al. GIE 2015

Basics of Prevention Patient selection and proper indication! Avoid ERCP if an alternative, less invasive modality is available (EUS or MRCP) Endoscopic proficiency / Good endoscopic technique: -Selective biliary cannulation -Avoid excessive contrast injection -Less attempts at cannulation -Wire guided cannulation(?) -Experienced team/technician

Wire Guided Cannulation Multiple RTC analyzing risk of PEP using wire guided cannulation (GWC) vs. dye injection First and large RTC published in GIE, 2004 -400 patients randomized to GWC vs contrast dye injection with sphincterotome -Similar baseline characteristics -PEP occurred in 0/200 cases in GWC arm vs 8/200 cases in contrast arm. P<0.01 *Single center, single endoscopist Lella F. et al. GIE 2004

Wire Guided Cannulation Prospective, RTC comparing GWC vs dye injection. -Cross over if cannulation was unsuccessful in 10 minutes (Fellow 5 minutes, Attending 5 minutes) Cannulation was successful without crossover in 323/413 patients (78.2 %): 167/202 (81.4 %) in the guide-wire arm and 156/211 (73.9 %) in the contrast arm (P = 0.03). 413 patients PEP occurred in 29/413 (7.0 %) 16/202 (7.9%) in GWC arm 13/211 (6.2%) in contrast arm P = 0.48 Bailey A. et al. Endoscopy 2008

Wire Guided Cannulation Meta-analysis from Endoscopy, 2013 12 RCTs, 3450 patients GWC significantly reduced PEP vs contrast-assisted cannulation. Risk ratio [RR] 0.51, CI 0.32 – 0.82 Guide Wire Cannulation: -Greater primary cannulation success. RR 1.07 -Fewer precut sphincterotomies. RR 0.75 -Risk reduction in PEP with GWC existed only in “non-crossover” trials (RR 0.22, 95 %CI 0.12 – 0.42) Tse F. et al. Endoscopy 2013

Pancreatic Duct Stenting Prospective, RTC, 80 patients All patients with suspected pancreatic sphincter hypertension (SOD) 41 patients randomized to pancreatic duct stent 39 patients to no stent Tarnasky PR et al. Gastroenterol 1998

Pancreatic Duct Stenting Post ERCP Pancreatitis: 10/39 (26%) in the no stent group 3/41 (7.3%) in the PD stent group P = 0.03 Relative risk, 10.5 (95% CI, 1.4-78.3) *Only 1 patient in the stent group developed pancreatitis after sphincterotomy, and 2 others developed pancreatitis at the time of stent extraction. Tarnasky PR et al. Gastroenterol 1998

Pancreatic Duct Stenting Prospective, RTC, 74 patients included in analysis High-risk patients; Young, women, SOD ~ 70% 36 patients to standard of care 38 patients to stenting; -5F nasopancreatic catheter -5F, 2-cm long pancreatic stent Fazel A, et al. Gastrointest Endosc. 2003

Pancreatic Duct Stenting Post ERCP Pancreatitis: 10/36 in no stent group 2/38 in stent group *both cases mild P = 0.05 Fazel A, et al. Gastrointest Endosc. 2003

Pancreatic Duct Stenting Meta-analysis; 4 RTCs and 1 prospective trial included 481 patients Singh, P. et al. Gastrointest Endosc 2004

Pancreatic Duct Stenting Singh, P. et al. Gastrointest Endosc 2004

Pancreatic Duct Stenting Updated meta-analysis; 14 RTCs 1541 patients -760 Stent placement 781 Control group 201/1541 had PEP -53 (7 %) Stent group -148 (19 %) Control group Overall RR = 0.39, CI 0.29–0.53 RR = 0.45, mild to moderate PEP RR = 0.26, severe PEP P < 0.001 Mazaki T. et al. J Gastroenterol. 2014

Rectal Indomethacin RTC, multicenter All high-risk patients 602 patients enrolled -295 pts 100mg indomethacin -307 pts in placebo group Elmunzer BJ et al. NEJM. 2012

Post-ERCP pancreatitis: Indomethacin group - 27/295 patients (9.2%) Placebo group – 52/307 patients (16.9%) P=0.005 NNT 13, Relative risk reduction of 46% Indomethacin appeared to be protective regardless of whether patients had undergone pancreatic stenting Elmunzer BJ et al. NEJM. 2012

Rectal Indomethacin Single blinded, RTC, multicenter 2600 patients; 1297 Pre-procedure indomethacin 1303 “risk-stratified”, post-procedural indomethacin Luo, H. et al. Lancet. 2016

Rectal Indomethacin Luo, H. et al. Lancet. 2016

Aggressive Hydration Pilot study from 2014 62 patients, assigned to groups (2:1) to receive aggressive hydration with Lactated Ringer's solution or standard hydration with the same solution Aggressive group: n=39 - 3 mL/kg/h during the procedure (~200mL/hr for 70kg male) -20mL/kg bolus after (~1.5L for 70k male) - 3 mL/kg/h for 8 hours after the procedure (~1.5L for 70kg male) Standard of care group: n=23 1.5 mL/kg/h (~100mL/hr for 70kg male) during and for 8 hours after procedure Buxbaum J et al. Clin Gastroenterol Hepatol. 2014

Aggressive Hydration Buxbaum J et al. Clin Gastroenterol Hepatol. 2014

Aggressive Hydration Pancreatic duct stents only used in “high risk cases”; pre-cut, only 5% of pts No rectal indomethacin used Buxbaum J et al. Clin Gastroenterol Hepatol. 2014

Aggressive Hydration RTC - 510 patients Vigorous IVF with LR: 10 mL/kg bolus prior and after 3 mL/kg/h during and for 8 hours after Standard IVF: LR 1.5 mL/kg/h during and 8 hours after Choi. et al. CGH 2017

Aggressive Hydration Post ERCP Pancreatitis: 11/255 patients w/vigorous IVFR 25/255 patients w/standard IVFR RR 0.41 (P = .016) Moderate or severe PEP: 0.4% in the vigorous IVFR group 2% in the standard IVFR (P = .040) Choi. et al. CGH 2017

Rectal Indomethacin +IV Hydration Randomized, Double Blind, Clinical Trial Total of 192 patients All patients had at least 1 high-risk criterion for PEP and 56% had >1 IVF was 1L bolus prior to procedure in all groups 100mg Indomethacin PR Patients randomized 1:1:1:1 NS + Placebo NS + Retcal Indomethacin LR + Placebo LR + Rectal Indomethacin Mok. et al. GIE 2016

Rectal Indomethacin +IV Hydration PEP 3 patients (6%) in the LR + IND 10 (21%) in the NS + placebo group (P = .04) Readmission rates: 1 patient (2%) LR + IND 6 patients (13%) NS + placebo group (P = .03) Mok. et al. GIE 2016

Conclusion Overall Risk of Post-ERCP pancreatitis (PEP) ~ 10% Most efficient method to reduce Post-ERCP pancreatitis is not to perform ERCP if not indicated Pancreatic duct stenting Rectal Indomethacin Hydration

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