Indomethacin prevents post-ERCP pancreatitis: the addition of topical epinephrine to indomethacin does not improve benefit

We read with interest this recent randomized control trial from Kamal et al. in the American Journal of Gastroenterology (1). They compared topical epinephrine spray applied to the papilla along with rectal indomethacin to rectal indomethacin alone in high-risk patients and found no significant difference in rates of post-endoscopic retrograde cholangiopancreatography (post-ERCP) pancreatitis (PEP) (6.7% vs. 6.4%). There were no differences in rates of moderate to severe PEP.

Several methods have been examined to reduce the risk of post-ERCP pancreatitis including improved patient selection, procedural techniques including different cannulation strategies and pancreatic duct (PD) stents, as well as topical and systemic pharmacological prophylaxis (2).

Different cannulation techniques have been studied and found to reduce the risk of PEP including wire-guided cannulation (3), physician controlled wire guided cannulation (4), and early-needle knife sphincterotomy (5). Insertion of PD stents has been shown to reduce the risk of PEP in high-risk patients and the risk of severe and necrotizing PEP (6). However, stent placement may have drawbacks, which include failed placement in up to 5–10% of patients in experienced centers, migration, and ductal perforation (7). Thus, the use of PD stents is limited to patients with an increased risk of moderate to severe pancreatitis and appears not additive to the use of rectal indomethacin in recent studies.

Multiple systemic pharmacologic agents including calcium channel blockers (8), nitrates (9), somatostatin analogs (10) and inflammatory agents have been studied to prevent the inflammatory cascade in post-ERCP pancreatitis, but known had shown promise until non-steroid inflammatory drugs (NSAIDs), in particular rectal indomethacin (11). In 2012 Elmunzer et al. published a landmark multicenter randomized trial comparing one dose of rectal indomethacin to placebo post-ERCP in high-risk individuals (12). It found that 9.2% of patients in the indomethacin group developed PEP compared to 16.9% in the placebo group, a statistically significant difference. Indomethacin also decreased the rate of moderate-to-severe pancreatitis, 4.4% to 8.8% in the placebo group. However, the majority of patients in this study had possible sphincter of Oddi dysfunction, a clinical entity where the benefit of ERCP is unclear and there is an elevated risk of PEP. Additionally, the majority (80%) of patients also had a pancreatic duct stent placed so it is unclear if it was the combined effect of indomethacin and the pancreatic duct stent that improved outcomes.

A recent randomized controlled trial involving 449 mainly average risk patients failed to find a benefit with rectal indomethacin administration when compared to placebo (13). However, 30% of patients in that study were considered high-risk and it was in a single center. However, a large multicenter randomized control trial in China showed significant reduction of PEP and moderate to severe PEP with routine pre-procedural administration of rectal indomethacin to all patients when compared to post-procedural administration of indomethacin to high-risk patients (14). This study only included patients with a native papilla. Additionally, a large retrospective cohort study involving 4,017 patients from our group included low-risk patients undergoing ERCP (15). We demonstrated that rectal-indomethacin reduced the odds of PEP by 65% and moderate to severe pancreatitis by 83%. Based on these studied the European Society for Gastrointestinal Endoscopy (ESGE) has recommended the usage of rectal indomethacin before or after ERCP in all patients undergoing ERCP, while the American Society for Gastrointestinal Endoscopy recommends usage in all high-risk patients and suggests usage in average-risk patients (16,17).

Aggressive hydration with lactated ringers has been studied as potential PEP prophylaxis. Buxbaum et al. conducted a pilot study in 62 patients comparing hydration to aggressive lactated ringers hydration post-procedure and found that 17% of patients in the standard hydration group developed PEP compared to no patients in the aggressive hydration group, a statistically significant difference (18). A larger follow-up randomized controlled trial (RCT) by Choi et al. compared aggressive hydration before, during and after the procedure to standard hydration following the procedure in 510 patients with a native papilla in three tertiary referral centers in Korea (19). They found that aggressive hydration significantly reduced the rates of PEP from 9.8% to 4.3% as well as the rate of moderate to severe pancreatitis. However given that the vast majority of ERCPs are performed in the ambulatory or outpatient setting, an 8 to 10 hours regimen is not felt to be feasible for the majority of patients undergoing ERCP and even for high-risk patients, which limits its applicability in clinical practice (20). Furthermore, rectal indomethacin was not administered in any of these studies, so it is unclear if LR offers additional benefit.

Various topical agents have been studied for PEP prophylaxis. They involve topically spraying various pharmaceutical agents on the papilla prior to cannulation. A prior study by our group failed to show benefit for topical lidocaine, which has been shown to reduce cholecystokinin release and inhibit sphincter of Oddi spasm (21). Topical epinephrine was been studied as it causes arteriolar vasoconstriction and reduces papillary edema and transient pancreatic duct obstruction similar to pancreatic duct stents (22). Indeed, prior small single-center studies as well as a network meta-analysis had shown that topical epinephrine reduced the risk of PEP.

However, the multi-national multi-center randomized control trial by Kamal et al. failed to find any risk reduction with topical epinephrine when rectal indomethacin was used in high-risk patients. There are several potential reasons for these seemingly discordant results. First, rectal indomethacin has a systemic effect on multiple pathways both in pancreatic acinar tissue, vasculature and the immune system, which may reduce inflammation and could reduce the transient benefit of topical epinephrine (23). Indeed, mice studies have found that topical epinephrine’s effect only lasts for 1–5 minutes (24). Another potential reason for the lack of efficacy in this study is that multiple mechanisms contribute to PEP; transient pancreatic duct obstruction, papillary edema, chemical and thermal injury from radiocontrast in the pancreatic duct, and guidewire-associated trauma to the pancreatic duct (25). While topical epinephrine may address the role of papillary edema temporarily it does not address these other mechanisms. Thus, it is possible that a subgroup such as patients with only difficult cannulation may benefit while other subgroups are unlikely to have benefit. Finally, it is important to note that endoscopic techniques in practice and clinical trials vary substantially creating heterogeneity limiting the utility of meta-analysis, including the meta-analysis that demonstrated significant benefit with topical epinephrine.

In conclusion, routine usage of rectal indomethacin is warranted in all patients, as is consideration of concomitant pancreatic duct stents in high-risk patients. Usage of aggressive hydration can be considered but it is unclear if offers incremental benefit when rectal indomethacin is used. Topical therapies such as topical epinephrine have not shown benefit in reducing PEP and this study by Kamal et al. demonstrates that it does not offer additional benefit when used with rectal indomethacin in high-risk patients, but may offer benefit in certain subgroups, which have yet to be defined.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Dr. Jia Zhu (Shenyang Pharmaceutical University, Shenyang, China).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/amj.2019.04.04). The authors have no conflicts of interest declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Kamal A, Akshintala VS, Talukdar R, et al. A Randomized Trial of Topical Epinephrine and Rectal Indomethacin for Preventing Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis in High-Risk Patients. Am J Gastroenterol 2019;114:339-47. [Crossref] [PubMed]
2. Badalov N, Tenner S, Baillie J. The Prevention, recognition and treatment of post-ERCP pancreatitis. JOP 2009;10:88-97. [PubMed]
3. Cennamo V, Fuccio L, Zagari RM, et al. Can a wire-guided cannulation technique increase bile duct cannulation rate and prevent post-ERCP pancreatitis?: A meta-analysis of randomized controlled trials. Am J Gastroenterol 2009;104:2343-50. [Crossref] [PubMed]
4. Buxbaum J, Leonor P, Tung J, et al. Randomized Trial of Endoscopist-Controlled vs. Assistant-Controlled Wire-Guided Cannulation of the Bile Duct. Am J Gastroenterol 2016;111:1841-7. [Crossref] [PubMed]
5. Cennamo V, Fuccio L, Zagari RM, et al. Can early precut implementation reduce endoscopic retrograde cholangiopancreatography-related complication risk? Meta-analysis of randomized controlled trials. Endoscopy 2010;42:381-8. [Crossref] [PubMed]
6. Singh P, Das A, Isenberg G, et al. Does prophylactic pancreatic stent placement reduce the risk of post-ERCP acute pancreatitis? A meta-analysis of controlled trials. Gastrointest Endosc 2004;60:544-50. [Crossref] [PubMed]
7. Aizawa T, Ueno N. Stent placement in the pancreatic duct prevents pancreatitis after endoscopic sphincter dilation for removal of bile duct stones. Gastrointest Endosc 2001;54:209-13. [Crossref] [PubMed]
8. Prat F, Amaris J, Ducot B, et al. Nifedipine for prevention of post-ERCP pancreatitis: a prospective, double-blind randomized study. Gastrointest Endosc 2002;56:202-8. [Crossref] [PubMed]
9. Nøjgaard C, Hornum M, Elkjaer M, et al. Does glyceryl nitrate prevent post-ERCP pancreatitis? A prospective, randomized, double-blind, placebo-controlled multicenter trial. Gastrointest Endosc 2009;69:e31-7. [Crossref] [PubMed]
10. Andriulli A, Leandro G, Federici T, et al. Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc 2007;65:624-32. [Crossref] [PubMed]
11. Sotoudehmanesh R, Khatibian M, Kolahdoozan S, et al. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol 2007;102:978-83. [Crossref] [PubMed]
12. Elmunzer BJ, Scheiman JM, Lehman GA, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med 2012;366:1414-22. [Crossref] [PubMed]
13. Levenick JM, Gordon SR, Fadden LL, et al. Rectal Indomethacin Does Not Prevent Post-ERCP Pancreatitis in Consecutive Patients. Gastroenterology 2016;150:911-7; quiz e19.
14. Luo H, Zhao L, Leung J, et al. Routine pre-procedural rectal indometacin versus selective post-procedural rectal indometacin to prevent pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography: a multicentre, single-blinded, randomised controlled trial. Lancet 2016;387:2293-301. [Crossref] [PubMed]
15. Thiruvengadam NR, Forde KA, Ma GK, et al. Rectal Indomethacin Reduces Pancreatitis in High- and Low-Risk Patients Undergoing Endoscopic Retrograde Cholangiopancreatography. Gastroenterology 2016;151:288-97.e4. [Crossref] [PubMed]
16. Dumonceau JM, Andriulli A, Elmunzer BJ, et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated June 2014. Endoscopy 2014;46:799-815. [Crossref] [PubMed]
17. ASGE Standards of Practice Committee. Adverse events associated with ERCP. Gastrointest Endosc 2017;85:32-47. [Crossref] [PubMed]
18. Buxbaum J, Yan A, Yeh K, et al. Aggressive hydration with lactated Ringer's solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol 2014;12:303-7.e1. [Crossref] [PubMed]
19. Choi JH, Kim HJ, Lee BU, et al. Vigorous Periprocedural Hydration With Lactated Ringer's Solution Reduces the Risk of Pancreatitis After Retrograde Cholangiopancreatography in Hospitalized Patients. Clin Gastroenterol Hepatol 2017;15:86-92.e1. [Crossref] [PubMed]
20. Elmunzer BJ. Combination pharmacoprophylaxis for post-ERCP pancreatitis: working toward an evidence base. Gastrointest Endosc 2017;85:1014-6. [Crossref] [PubMed]
21. Schwartz JJ, Lew RJ, Ahmad NA, et al. The effect of lidocaine sprayed on the major duodenal papilla on the frequency of post-ERCP pancreatitis. Gastrointest Endosc 2004;59:179-84. [Crossref] [PubMed]
22. Wen L, Javed TA, Yimlamai D, et al. Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice. Gastroenterology 2018;155:1250-63.e5. [Crossref] [PubMed]
23. Ethridge RT, Chung DH, Slogoff M, et al. Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury. Gastroenterology 2002;123:1311-22. [Crossref] [PubMed]
24. Chung SC, Leung JW, Leung FW. Effect of submucosal epinephrine injection on local gastric blood flow. A study using laser Doppler flowmetry and reflectance spectrophotometry. Dig Dis Sci 1990;35:1008-11. [Crossref] [PubMed]
25. Rinderknecht H. Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci 1986;31:314-21. [Crossref] [PubMed]