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Emerging Therapies to Prevent Post-ERCP Pancreatitis

  • Endoscopy and Surgery (S Komanduri, Section Editor)
  • Published:
Current Gastroenterology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The aim of this review is to evaluate emerging, novel therapies for the prevention of post-ERCP pancreatitis.

Recent Findings

Rectal indomethacin reduces the risk of pancreatitis in low- and average-risk patients, who comprise the majority of patients undergoing ERCP. An 8-h protocol of aggressive lactated Ringer’s reduces the risk of pancreatitis in average-risk patients. Sublingual nitrate may provide additional benefit to rectal NSAIDs in preventing PEP. A tacrolimus trough > 2.5 ng/mL was recently shown to be associated with a lower risk of PEP in liver transplant patients undergoing ERCP.

Summary

Routine usage of rectal indomethacin in all patients undergoing ERCP reduces the risk of PEP. Pancreatic-duct stents reduce the risk of PEP in high-risk patients. There is emerging data that aggressive hydration with lactated Ringer’s and nitrates may further reduce PEP. Tacrolimus is a promising potential agent to prevent PEP but needs further clinical study.

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Abbreviations

CI:

Confidence interval

ERCP:

Endoscopic retrograde cholangiopancreatography

NSAIDs:

Non-steroidal anti-inflammatory drugs

OR:

Odds ratio

PD:

Pancreatic duct

PEP:

Post-ERCP pancreatitis

RCT:

Randomized control trial

SOD:

Sphincter of Oddi dysfunction

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, Dorsher PJ, et al. Complications of endoscopic biliary sphincterotomy. N Engl J Med. 1996;335(13):909–18. https://doi.org/10.1056/NEJM199609263351301.

    Article  CAS  PubMed  Google Scholar 

  2. Masci E, Toti G, Mariani A, Curioni S, Lomazzi A, Dinelli M, et al. Complications of diagnostic and therapeutic ERCP: a prospective multicenter study. Am J Gastroenterol. 2001;96(2):417–23. https://doi.org/10.1111/j.1572-0241.2001.03594.x.

    Article  CAS  PubMed  Google Scholar 

  3. Elmunzer BJ, Scheiman JM, Lehman GA, Chak A, Mosler P, Higgins PD, et al. A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012;366(15):1414–22. https://doi.org/10.1056/NEJMoa1111103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kochar B, Akshintala VS, Afghani E, Elmunzer BJ, Kim KJ, Lennon AM, et al. Incidence, severity, and mortality of post-ERCP pancreatitis: a systematic review by using randomized, controlled trials. Gastrointest Endosc. 2015;81(1):143–9 e9. https://doi.org/10.1016/j.gie.2014.06.045.

    Article  Google Scholar 

  5. Ito K, Fujita N, Noda Y, Kobayashi G, Horaguchi J, Takasawa O, et al. Relationship between post-ERCP pancreatitis and the change of serum amylase level after the procedure. World J Gastroenterol. 2007;13(28):3855–60.

    Article  CAS  Google Scholar 

  6. Thrower E, Husain S, Gorelick F. Molecular basis for pancreatitis. Curr Opin Gastroenterol. 2008;24(5):580–5. https://doi.org/10.1097/MOG.0b013e32830b10e6.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Williams JA. Regulation of acinar cell function in the pancreas. Curr Opin Gastroenterol. 2010;26(5):478–83. https://doi.org/10.1097/MOG.0b013e32833d11c6.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gorelick FS, Thrower E. The acinar cell and early pancreatitis responses. Clin Gastroenterol Hepatol. 2009;7(11 Suppl):S10–4. https://doi.org/10.1016/j.cgh.2009.07.036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Scheele G, Adler G, Kern H. Exocytosis occurs at the lateral plasma membrane of the pancreatic acinar cell during supramaximal secretagogue stimulation. Gastroenterology. 1987;92(2):345–53. https://doi.org/10.1016/0016-5085(87)90127-2.

    Article  CAS  PubMed  Google Scholar 

  10. Li H, Rao A, Hogan PG. Interaction of calcineurin with substrates and targeting proteins. Trends Cell Biol. 2011;21(2):91–103. https://doi.org/10.1016/j.tcb.2010.09.011.

    Article  CAS  PubMed  Google Scholar 

  11. Zhang H, Neuhofer P, Song L, Rabe B, Lesina M, Kurkowski MU, et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J Clin Invest. 2013;123(3):1019–31. https://doi.org/10.1172/JCI64931.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Neuhofer P, Liang S, Einwachter H, Schwerdtfeger C, Wartmann T, Treiber M, et al. Deletion of IkappaBalpha activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A. Gastroenterology. 2013;144(1):192–201. https://doi.org/10.1053/j.gastro.2012.09.058.

    Article  CAS  PubMed  Google Scholar 

  13. Huang H, Liu Y, Daniluk J, Gaiser S, Chu J, Wang H, et al. Activation of nuclear factor-kappaB in acinar cells increases the severity of pancreatitis in mice. Gastroenterology. 2013;144(1):202–10. https://doi.org/10.1053/j.gastro.2012.09.059.

    Article  CAS  PubMed  Google Scholar 

  14. Newton R, Kuitert LM, Bergmann M, Adcock IM, Barnes PJ. Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-1beta. Biochem Biophys Res Commun. 1997;237(1):28–32. https://doi.org/10.1006/bbrc.1997.7064.

    Article  CAS  PubMed  Google Scholar 

  15. Ramudo L, Manso MA, Sevillano S, de Dios I. Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells during acute pancreatitis induced by bile-pancreatic duct obstruction. J Pathol. 2005;206(1):9–16. https://doi.org/10.1002/path.1747.

    Article  CAS  PubMed  Google Scholar 

  16. Lundberg AH, Eubanks JW 3rd, Henry J, Sabek O, Kotb M, Gaber L, et al. Trypsin stimulates production of cytokines from peritoneal macrophages in vitro and in vivo. Pancreas. 2000;21(1):41–51. https://doi.org/10.1097/00006676-200007000-00050.

    Article  CAS  PubMed  Google Scholar 

  17. Norman J. The role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg. 1998;175(1):76–83. https://doi.org/10.1016/s0002-9610(97)00240-7.

    Article  CAS  PubMed  Google Scholar 

  18. Norman JG, Franz MG, Fink GS, Messina J, Fabri PJ, Gower WR, et al. Decreased mortality of severe acute pancreatitis after proximal cytokine blockade. Ann Surg. 1995;221(6):625–31; discussion 31-4. https://doi.org/10.1097/00000658-199506000-00002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Norman J, Franz M, Messina J, Riker A, Fabri PJ, Rosemurgy AS, et al. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery. 1995;117(6):648–55. https://doi.org/10.1016/s0039-6060(95)80008-5.

    Article  CAS  PubMed  Google Scholar 

  20. Toyama MT, Patel AG, Nguyen T, Ashley SW, Reber HA. Effect of ethanol on pancreatic interstitial pH and blood flow in cats with chronic pancreatitis. Ann Surg. 1997;225(2):223–8. https://doi.org/10.1097/00000658-199702000-00011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Takeda K, Mikami Y, Fukuyama S, Egawa S, Sunamura M, Ishibashi T, et al. Pancreatic ischemia associated with vasospasm in the early phase of human acute necrotizing pancreatitis. Pancreas. 2005;30(1):40–9.

    PubMed  Google Scholar 

  22. Kukor Z, Mayerle J, Kruger B, Toth M, Steed PM, Halangk W, et al. Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. J Biol Chem. 2002;277(24):21389–96. https://doi.org/10.1074/jbc.M200878200.

    Article  CAS  PubMed  Google Scholar 

  23. Niederau C, Grendell JH. Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment. J Clin Invest. 1988;81(1):229–36. https://doi.org/10.1172/JCI113300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Guillaumes S, Blanco I, Villanueva A, Sans MD, Clave P, Chabas A, et al. Chloroquine stabilizes pancreatic lysosomes and improves survival of mice with diet-induced acute pancreatitis. Pancreas. 1997;14(3):262–6. https://doi.org/10.1097/00006676-199704000-00007.

    Article  CAS  PubMed  Google Scholar 

  25. Leach SD, Bilchik AJ, Karapetian O, Gorelick FS, Modlin IM. Influence of chloroquine on diet-induced pancreatitis. Pancreas. 1993;8(1):64–9. https://doi.org/10.1097/00006676-199301000-00013.

    Article  CAS  PubMed  Google Scholar 

  26. Bhoomagoud M, Jung T, Atladottir J, Kolodecik TR, Shugrue C, Chaudhuri A, et al. Reducing extracellular pH sensitizes the acinar cell to secretagogue-induced pancreatitis responses in rats. Gastroenterology. 2009;137(3):1083–92. https://doi.org/10.1053/j.gastro.2009.05.041.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lerch MM, Weidenbach H, Hernandez CA, Preclik G, Adler G. Pancreatic outflow obstruction as the critical event for human gall stone induced pancreatitis. Gut. 1994;35(10):1501–3. https://doi.org/10.1136/gut.35.10.1501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Thaker AM, Mosko JD, Berzin TM. Post-endoscopic retrograde cholangiopancreatography pancreatitis. Gastroenterol Rep (Oxf). 2015;3(1):32–40. https://doi.org/10.1093/gastro/gou083.

    Article  Google Scholar 

  29. Johnson GK, Geenen JE, Bedford RA, Johanson J, Cass O, Sherman S, et al. A comparison of nonionic versus ionic contrast media: results of a prospective, multicenter study. Midwest Pancreaticobiliary Study Group Gastrointest Endosc. 1995;42(4):312–6. https://doi.org/10.1016/s0016-5107(95)70128-1.

    Article  CAS  Google Scholar 

  30. King BF, Hartman GW, Williamson B Jr, LeRoy AJ, Hattery RR. Low-osmolality contrast media: a current perspective. Mayo Clin Proc. 1989;64(8):976–85. https://doi.org/10.1016/s0025-6196(12)61226-9.

    Article  CAS  PubMed  Google Scholar 

  31. Keynes WM. A nonpancreatic source of the proteolytic-enzyme amidase and bacteriology in experimental acute pancreatitis. Ann Surg. 1980;191(2):187–99. https://doi.org/10.1097/00000658-198002000-00010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Testoni PA, Bagnolo F, Caporuscio S, Lella F. Serum amylase measured four hours after endoscopic sphincterotomy is a reliable predictor of postprocedure pancreatitis. Am J Gastroenterol. 1999;94(5):1235–41. https://doi.org/10.1111/j.1572-0241.1999.01072.x.

    Article  CAS  PubMed  Google Scholar 

  33. Christoforidis E, Goulimaris I, Kanellos I, Tsalis K, Demetriades C, Betsis D. Post-ERCP pancreatitis and hyperamylasemia: patient-related and operative risk factors. Endoscopy. 2002;34(4):286–92. https://doi.org/10.1055/s-2002-23630.

    Article  CAS  PubMed  Google Scholar 

  34. Chen YK, Foliente RL, Santoro MJ, Walter MH, Collen MJ. Endoscopic sphincterotomy-induced pancreatitis: increased risk associated with nondilated bile ducts and sphincter of Oddi dysfunction. Am J Gastroenterol. 1994;89(3):327–33.

    CAS  PubMed  Google Scholar 

  35. Freeman ML, DiSario JA, Nelson DB, Fennerty MB, Lee JG, Bjorkman DJ, et al. Risk factors for post-ERCP pancreatitis: a prospective, multicenter study. Gastrointest Endosc. 2001;54(4):425–34. https://doi.org/10.1067/mge.2001.117550.

    Article  CAS  PubMed  Google Scholar 

  36. Vandervoort J, Soetikno RM, Tham TC, Wong RC, Ferrari AP Jr, Montes H, et al. Risk factors for complications after performance of ERCP. Gastrointest Endosc. 2002;56(5):652–6. https://doi.org/10.1067/mge.2002.129086.

    Article  PubMed  Google Scholar 

  37. Desilets DJ, Dy RM, Ku PM, Hanson BL, Elton E, Mattia A, et al. Endoscopic management of tumors of the major duodenal papilla: refined techniques to improve outcome and avoid complications. Gastrointest Endosc. 2001;54(2):202–8. https://doi.org/10.1067/mge.2001.116564.

    Article  CAS  PubMed  Google Scholar 

  38. Masci E, Mariani A, Curioni S, Testoni PA. Risk factors for pancreatitis following endoscopic retrograde cholangiopancreatography: a meta-analysis. Endoscopy. 2003;35(10):830–4. https://doi.org/10.1055/s-2003-42614.

    Article  CAS  PubMed  Google Scholar 

  39. Cennamo V, Fuccio L, Zagari RM, Eusebi LH, Ceroni L, Laterza L, 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(9):2343–50. https://doi.org/10.1038/ajg.2009.269.

    Article  PubMed  Google Scholar 

  40. Xinopoulos D, Bassioukas SP, Kypreos D, Korkolis D, Scorilas A, Mavridis K, et al. Pancreatic duct guidewire placement for biliary cannulation in a single-session therapeutic ERCP. World J Gastroenterol. 2011;17(15):1989–95. https://doi.org/10.3748/wjg.v17.i15.1989.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Tse F, Yuan Y, Moayyedi P, Leontiadis GI, Barkun AN. Double-guidewire technique in difficult biliary cannulation for the prevention of post-ERCP pancreatitis: a systematic review and meta-analysis. Endoscopy. 2017;49(1):15–26. https://doi.org/10.1055/s-0042-119035.

    Article  PubMed  Google Scholar 

  42. Sundaralingam P, Masson P, Bourke MJ. Early precut sphincterotomy does not increase risk during endoscopic retrograde cholangiopancreatography in patients with difficult biliary access: a meta-analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2015;13(10):1722–9 e2. https://doi.org/10.1016/j.cgh.2015.06.035.

    Article  Google Scholar 

  43. Cotton PB, Lehman G, Vennes J, Geenen JE, Russell RC, Meyers WC, et al. Endoscopic sphincterotomy complications and their management: an attempt at consensus. Gastrointest Endosc. 1991;37(3):383–93.

    Article  CAS  Google Scholar 

  44. Singh P, Das A, Isenberg G, Wong RC, Sivak MV Jr, Agrawal D, 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(4):544–50.

    Article  Google Scholar 

  45. Tarnasky PR, Palesch YY, Cunningham JT, Mauldin PD, Cotton PB, Hawes RH. Pancreatic stenting prevents pancreatitis after biliary sphincterotomy in patients with sphincter of Oddi dysfunction. Gastroenterology. 1998;115(6):1518–24.

    Article  CAS  Google Scholar 

  46. 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(2):209–13.

    Article  CAS  Google Scholar 

  47. Cha SW, Leung WD, Lehman GA, Watkins JL, McHenry L, Fogel EL, et al. Does leaving a main pancreatic duct stent in place reduce the incidence of precut biliary sphincterotomy-associated pancreatitis? A randomized, prospective study. Gastrointest Endosc. 2013;77(2):209–16. https://doi.org/10.1016/j.gie.2012.08.022.

    Article  PubMed  Google Scholar 

  48. 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;57(3):291–4. https://doi.org/10.1067/mge.2003.124.

    Article  PubMed  Google Scholar 

  49. Dumonceau JM, Rigaux J, Kahaleh M, Gomez CM, Vandermeeren A, Deviere J. Prophylaxis of post-ERCP pancreatitis: a practice survey. Gastrointest Endosc. 2010;71(6):934–9, 9 e1–2. https://doi.org/10.1016/j.gie.2009.10.055.

    Article  Google Scholar 

  50. Sotoudehmanesh R, Khatibian M, Kolahdoozan S, Ainechi S, Malboosbaf R, Nouraie M. Indomethacin may reduce the incidence and severity of acute pancreatitis after ERCP. Am J Gastroenterol. 2007;102(5):978–83. https://doi.org/10.1111/j.1572-0241.2007.01165.x.

    Article  CAS  PubMed  Google Scholar 

  51. Ethridge RT, Chung DH, Slogoff M, Ehlers RA, Hellmich MR, Rajaraman S, et al. Cyclooxygenase-2 gene disruption attenuates the severity of acute pancreatitis and pancreatitis-associated lung injury. Gastroenterology. 2002;123(4):1311–22. https://doi.org/10.1053/gast.2002.35951.

    Article  CAS  PubMed  Google Scholar 

  52. Ding X, Chen M, Huang S, Zhang S, Zou X. Nonsteroidal anti-inflammatory drugs for prevention of post-ERCP pancreatitis: a meta-analysis. Gastrointest Endosc. 2012;76(6):1152–9. https://doi.org/10.1016/j.gie.2012.08.021.

    Article  PubMed  Google Scholar 

  53. • Levenick JM, Gordon SR, Fadden LL, Levy LC, Rockacy MJ, Hyder SM, et al. Rectal indomethacin does not prevent post-ERCP pancreatitis in consecutive patients. Gastroenterology. 2016;150:911–7. https://doi.org/10.1053/j.gastro.2015.12.040. A randomized controlled trial of 449 average risk patients did not find that rectal indomethacin reduced PEP.

  54. •• Luo H, Zhao L, Leung J, Zhang R, Liu Z, Wang X, 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(10035):2293–301. https://doi.org/10.1016/S0140-6736(16)30310-5. A randomized controlled trial of 2600 average risk patients demonstrated significant benefit with routine usage of rectal indomethacin.

    Article  CAS  PubMed  Google Scholar 

  55. •• Thiruvengadam NR, Forde KA, Ma GK, Ahmad N, Chandrasekhara V, Ginsberg GG, et al. Rectal indomethacin reduces pancreatitis in high- and low-risk patients undergoing endoscopic retrograde cholangiopancreatography. Gastroenterology. 2016;151(2):288–97 e4. https://doi.org/10.1053/j.gastro.2016.04.048. A large retrospective cohort study looked at 4017 consecutive patients who underwent ERCP and demonstrated that patients who received indomethacin had significantly lower rates of PEP and moderate to severe PEP.

    Article  CAS  Google Scholar 

  56. Dumonceau JM, Andriulli A, Elmunzer BJ, Mariani A, Meister T, Deviere J, et al. Prophylaxis of post-ERCP pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) Guideline - updated June 2014. Endoscopy. 2014;46(9):799–815. https://doi.org/10.1055/s-0034-1377875.

    Article  PubMed  Google Scholar 

  57. • Committee ASoP, Chandrasekhara V, Khashab MA, Muthusamy VR, Acosta RD, Agrawal D, et al. Adverse events associated with ERCP. Gastrointest Endosc. 2017;85(1):32–47. https://doi.org/10.1016/j.gie.2016.06.051. The updated ASGE guidelines recommend rectal indomethacin usage in high-risk patients and consideration in low-risk patients.

    Article  Google Scholar 

  58. Kellum JA, Song M, Li J. Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells. Am J Physiol Regul Integr Comp Physiol. 2004;286(4):R686–92. https://doi.org/10.1152/ajpregu.00564.2003.

    Article  CAS  PubMed  Google Scholar 

  59. Davenport A, Will EJ, Davison AM. The effect of lactate-buffered solutions on the acid-base status of patients with renal failure. Nephrol Dial Transplant. 1989;4(9):800–4.

    CAS  PubMed  Google Scholar 

  60. Ashley SW, Schwarz M, Alvarez C, Nguyen TN, Vdovenko A, Reber HA. Pancreatic interstitial pH regulation: effects of secretory stimulation. Surgery. 1994;115(4):503–9.

    CAS  PubMed  Google Scholar 

  61. Noble MD, Romac J, Vigna SR, Liddle RA. A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis. Gut. 2008;57(11):1566–71. https://doi.org/10.1136/gut.2008.148551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Takacs T, Rosztoczy A, Maleth J, Rakonczay Z Jr, Hegyi P. Intraductal acidosis in acute biliary pancreatitis. Pancreatology. 2013;13(4):333–5. https://doi.org/10.1016/j.pan.2013.05.011.

    Article  PubMed  Google Scholar 

  63. • de Madaria E, Herrera-Marante I, Gonzalez-Camacho V, Bonjoch L, Quesada-Vazquez N, Almenta-Saavedra I, et al. Fluid resuscitation with lactated Ringer's solution vs normal saline in acute pancreatitis: a triple-blind, randomized, controlled trial. United European Gastroenterol J. 2018;6(1):63–72. https://doi.org/10.1177/2050640617707864. In a randomized controlled trial, LR significantly reduced inflammation clinically when compared to NS for treatment of AP and reduced macrophages and NF-κB activation.

    Article  Google Scholar 

  64. Foitzik T, Hotz HG, Schmidt J, Klar E, Warshaw AL, Buhr HJ. Effect of microcirculatory perfusion on distribution of trypsinogen activation peptides in acute experimental pancreatitis. Dig Dis Sci. 1995;40(10):2184–8.

    Article  CAS  Google Scholar 

  65. Cote GA, Sagi SV, Schmidt SE, Lehman GA, McHenry L, Fogel E, et al. Early measures of hemoconcentration and inflammation are predictive of prolonged hospitalization from post- endoscopic retrograde cholangiopancreatography pancreatitis. Pancreas. 2013;42(5):850–4. https://doi.org/10.1097/MPA.0b013e318287c9d4.

    Article  CAS  PubMed  Google Scholar 

  66. Kushner T, Majd N, Sigel K, Liverant ML, Wong S-Y, Patel KK, et al. 449 blood urea nitrogen as a predictor of development of post-endoscopic retrograde cholangiopancreatography pancreatitis: a case- control study. Gastrointest Endosc. 2012;75(4):AB141–AB2. https://doi.org/10.1016/j.gie.2012.04.066.

    Article  Google Scholar 

  67. Buxbaum J, Yan A, Yeh K, Lane C, Nguyen N, Laine L. Aggressive hydration with lactated Ringer’s solution reduces pancreatitis after endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol. 2014;12(2):303–7 e1. https://doi.org/10.1016/j.cgh.2013.07.026.

    Article  CAS  PubMed  Google Scholar 

  68. •• Choi JH, Kim HJ, Lee BU, Kim TH, Song IH. Vigorous periprocedural hydration with lactated ringer’s solution reduces the risk of pancreatitis after retrograde cholangiopancreatography in hospitalized patients. Clin Gastroenterol Hepatol. 2017;15(1):86–92 e1. https://doi.org/10.1016/j.cgh.2016.06.007. A randomized controlled trial involving 510 patients demonstrated that aggressive hydration with LR was superior to standard hydration with LR in preventing PEP.

    Article  CAS  PubMed  Google Scholar 

  69. Zhang ZF, Duan ZJ, Wang LX, Zhao G, Deng WG. Aggressive hydration with lactated ringer solution in prevention of postendoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. J Clin Gastroenterol. 2017;51(3):e17–26. https://doi.org/10.1097/MCG.0000000000000781.

    Article  CAS  PubMed  Google Scholar 

  70. Elmunzer BJ. Combination pharmacoprophylaxis for post-ERCP pancreatitis: working toward an evidence base. Gastrointest Endosc. 2017;85(5):1014–6. https://doi.org/10.1016/j.gie.2016.12.015.

    Article  PubMed  Google Scholar 

  71. Staritz M, Poralla T, Ewe K. Meyer zum Buschenfelde KH. Effect of glyceryl trinitrate on the sphincter of Oddi motility and baseline pressure. Gut. 1985;26(2):194–7. https://doi.org/10.1136/gut.26.2.194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sudhindran S, Bromwich E, Edwards PR. Prospective randomized double-blind placebo-controlled trial of glyceryl trinitrate in endoscopic retrograde cholangiopancreatography-induced pancreatitis. Br J Surg. 2001;88(9):1178–82. https://doi.org/10.1046/j.0007-1323.2001.01842.x.

    Article  CAS  PubMed  Google Scholar 

  73. Hao JY, Wu DF, Wang YZ, Gao YX, Lang HP, Zhou WZ. Prophylactic effect of glyceryl trinitrate on post-endoscopic retrograde cholangiopancreatography pancreatitis: a randomized placebo-controlled trial. World J Gastroenterol. 2009;15(3):366–8. https://doi.org/10.3748/wjg.15.366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lyu Y, Wang B, Cheng Y, Xu Y, Du W. Comparative efficacy of 9 major drugs for postendoscopic retrograde cholangiopancreatography pancreatitis: a network meta-analysis. Surg Laparosc Endosc Percutan Tech. 2019;29(6):426–32. https://doi.org/10.1097/SLE.0000000000000707.

    Article  PubMed  Google Scholar 

  75. • Tomoda T, Kato H, Ueki T, Akimoto Y, Hata H, Fujii M, et al. Combination of diclofenac and sublingual nitrates is superior to diclofenac alone in preventing pancreatitis after endoscopic retrograde cholangiopancreatography. Gastroenterology. 2019;156(6):1753–60 e1. https://doi.org/10.1053/j.gastro.2019.01.267. A randomized controlled trial involving 886 patients demonstrated that a sublingual nitrate plus 50 mg of diclofenac was superior to diclofenac alone in preventing PEP.

    Article  CAS  Google Scholar 

  76. Jin S, Orabi AI, Le T, Javed TA, Sah S, Eisses JF, et al. Exposure to radiocontrast agents induces pancreatic inflammation by activation of nuclear factor-kappaB, calcium signaling, and calcineurin. Gastroenterology. 2015;149(3):753–64 e11. https://doi.org/10.1053/j.gastro.2015.05.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. •• Wen L, Javed TA, Yimlamai D, Mukherjee A, Xiao X, Husain SZ. Transient high pressure in pancreatic ducts promotes inflammation and alters tight junctions via calcineurin signaling in mice. Gastroenterology. 2018;155(4):1250–63 e5. https://doi.org/10.1053/j.gastro.2018.06.036. This study created a model of pancreatic duct hypertension using intraducal infusion of saline and demonstrated that this lead to pancreatitis through dysregulated calcium signaling and the calcineurin dependent inflammatory cascade. Tacrolimus prevented pancreatitis in this mice model.

    Article  CAS  Google Scholar 

  78. •• Thiruvengadam NR, Forde KA, Chandrasekhara V, Ahmad NA, Ginsberg GG, Khungar V, et al. Tacrolimus and indomethacin are safe and effective at reducing pancreatitis after endoscopic retrograde cholangiopancreatography in patients who have undergone liver transplantation. Clin Gastroenterol Hepatol. 2020;18(5):1224–32 e1. https://doi.org/10.1016/j.cgh.2019.10.014. This retrospective cohort study of 337 liver transplant patients undergoing ERCP demonstrated that a tacrolimus trough level > 2.5 ng/mL was significantly associated with lower rates of PEP and indomethacin usage provided additional benefit.

    Article  CAS  Google Scholar 

  79. McKay CJ, Imrie CW, Baxter JN. Somatostatin and somatostatin analogues--are they indicated in the management of acute pancreatitis? Gut. 1993;34(11):1622–6. https://doi.org/10.1136/gut.34.11.1622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bordas JM, Toledo-Pimentel V, Llach J, Elena M, Mondelo F, Gines A, et al. Effects of bolus somatostatin in preventing pancreatitis after endoscopic pancreatography: results of a randomized study. Gastrointest Endosc. 1998;47(3):230–4. https://doi.org/10.1016/s0016-5107(98)70318-9.

    Article  CAS  PubMed  Google Scholar 

  81. Andriulli A, Clemente R, Solmi L, Terruzzi V, Suriani R, Sigillito A, et al. Gabexate or somatostatin administration before ERCP in patients at high risk for post-ERCP pancreatitis: a multicenter, placebo-controlled, randomized clinical trial. Gastrointest Endosc. 2002;56(4):488–95. https://doi.org/10.1067/mge.2002.128130.

    Article  PubMed  Google Scholar 

  82. Poon RT, Yeung C, Liu CL, Lam CM, Yuen WK, Lo CM, et al. Intravenous bolus somatostatin after diagnostic cholangiopancreatography reduces the incidence of pancreatitis associated with therapeutic endoscopic retrograde cholangiopancreatography procedures: a randomised controlled trial. Gut. 2003;52(12):1768–73. https://doi.org/10.1136/gut.52.12.1768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Andriulli A, Solmi L, Loperfido S, Leo P, Festa V, Belmonte A, et al. Prophylaxis of ERCP-related pancreatitis: a randomized, controlled trial of somatostatin and gabexate mesylate. Clin Gastroenterol Hepatol. 2004;2(8):713–8. https://doi.org/10.1016/s1542-3565(04)00295-2.

    Article  CAS  PubMed  Google Scholar 

  84. Wang G, Xiao G, Xu L, Qiu P, Li T, Wang X, et al. Effect of somatostatin on prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis and hyperamylasemia: a systematic review and meta-analysis. Pancreatology. 2018;18(4):370–8. https://doi.org/10.1016/j.pan.2018.03.002.

    Article  CAS  PubMed  Google Scholar 

  85. Xu LH, Qian JB, Gu LG, Qiu JW, Ge ZM, Lu F, et al. Prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis by epinephrine sprayed on the papilla. J Gastroenterol Hepatol. 2011;26(7):1139–44. https://doi.org/10.1111/j.1440-1746.2011.06718.x.

    Article  PubMed  Google Scholar 

  86. Matsushita M, Takakuwa H, Shimeno N, Uchida K, Nishio A, Okazaki K. Epinephrine sprayed on the papilla for prevention of post-ERCP pancreatitis. J Gastroenterol. 2009;44(1):71–5. https://doi.org/10.1007/s00535-008-2272-8.

    Article  PubMed  Google Scholar 

  87. • Luo H, Wang X, Zhang R, Liang S, Kang X, Zhang X, et al. Rectal indomethacin and spraying of duodenal papilla with epinephrine increases risk of pancreatitis following endoscopic retrograde cholangiopancreatography. Clin Gastroenterol Hepatol. 2019;17(8):1597-606 e5. https://doi.org/10.1016/j.cgh.2018.10.043. This randomized controlled trial found that the combination of rectal indomethacin and topical epinephrine increased the risk of PEP when compared to rectal indomethacin alone.

    Article  CAS  Google Scholar 

  88. • Kamal A, Akshintala VS, Talukdar R, Goenka MK, Kochhar R, Lakhtakia S, 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(2):339–47. https://doi.org/10.14309/ajg.0000000000000049. This randomized controlled trial demonstrated that there was no additional benefit in reducing PEP with topical epinphephrine when added to rectal indomethacin when compared to rectal indomethacin alone in high-risk patients undergoing ERCP.

    Article  PubMed  Google Scholar 

  89. Leonhardt U, Seidensticker F, Stockmann F, Creutzfeldt W. Effect of camostate administration for two weeks on experimental pancreatitis in mice and rats. Pancreas. 1993;8(1):98–102. https://doi.org/10.1097/00006676-199301000-00017.

    Article  CAS  PubMed  Google Scholar 

  90. Ohshio G, Saluja AK, Leli U, Sengupta A, Steer ML. Esterase inhibitors prevent lysosomal enzyme redistribution in two noninvasive models of experimental pancreatitis. Gastroenterology. 1989;96(3):853–9.

    Article  CAS  Google Scholar 

  91. Yu G, Li S, Wan R, Wang X, Hu G. Nafamostat mesilate for prevention of post-ERCP pancreatitis: a meta-analysis of prospective, randomized, controlled trials. Pancreas. 2015;44(4):561–9. https://doi.org/10.1097/MPA.0000000000000310.

    Article  PubMed  Google Scholar 

  92. Zheng M, Bai J, Yuan B, Lin F, You J, Lu M, et al. Meta-analysis of prophylactic corticosteroid use in post-ERCP pancreatitis. BMC Gastroenterol. 2008;8:6. https://doi.org/10.1186/1471-230X-8-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Barkay O, Niv E, Santo E, Bruck R, Hallak A, Konikoff FM. Low-dose heparin for the prevention of post-ERCP pancreatitis: a randomized placebo-controlled trial. Surg Endosc. 2008;22(9):1971–6. https://doi.org/10.1007/s00464-007-9738-2.

    Article  CAS  PubMed  Google Scholar 

  94. Bai Y, Gao J, Zhang W, Zou D, Li Z. Meta-analysis: allopurinol in the prevention of postendoscopic retrograde cholangiopancreatography pancreatitis. Aliment Pharmacol Ther. 2008;28(5):557–64. https://doi.org/10.1111/j.1365-2036.2008.03756.x.

    Article  CAS  PubMed  Google Scholar 

  95. Silvis SE, Vennes JA. The role of glucagon in endoscopic cholangiopancreatography. Gastrointest Endosc. 1975;21(4):162–3. https://doi.org/10.1016/s0016-5107(75)73837-3.

    Article  CAS  PubMed  Google Scholar 

  96. Prat F, Amaris J, Ducot B, Bocquentin M, Fritsch J, Choury AD, et al. Nifedipine for prevention of post-ERCP pancreatitis: a prospective, double-blind randomized study. Gastrointest Endosc. 2002;56(2):202–8. https://doi.org/10.1016/s0016-5107(02)70178-8.

    Article  PubMed  Google Scholar 

  97. Sofuni A, Maguchi H, Itoi T, Katanuma A, Hisai H, Niido T, et al. Prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis by an endoscopic pancreatic spontaneous dislodgement stent. Clin Gastroenterol Hepatol. 2007;5(11):1339–46. https://doi.org/10.1016/j.cgh.2007.07.008.

    Article  PubMed  Google Scholar 

  98. Choudhary A, Bechtold ML, Arif M, Szary NM, Puli SR, Othman MO, et al. Pancreatic stents for prophylaxis against post-ERCP pancreatitis: a meta-analysis and systematic review. Gastrointest Endosc. 2011;73(2):275–82. https://doi.org/10.1016/j.gie.2010.10.039.

    Article  PubMed  Google Scholar 

  99. He X, Zheng W, Ding Y, Tang X, Si J, Sun LM. Rectal indomethacin is protective against pancreatitis after endoscopic retrograde cholangiopancreatography: systematic review and meta-analysis. Gastroenterol Res Pract. 2018;2018:9784841–7. https://doi.org/10.1155/2018/9784841.

    Article  PubMed  PubMed Central  Google Scholar 

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Thiruvengadam, N.R., Kochman, M.L. Emerging Therapies to Prevent Post-ERCP Pancreatitis. Curr Gastroenterol Rep 22, 59 (2020). https://doi.org/10.1007/s11894-020-00796-w

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