Preventive effect of ulinastatin and gabexate mesylate on post-endoscopic retrograde cholangiopancreatography pancreatitis

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ZHANG Zhi-feng(Department of Gastroenterology,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
YANG Ning(Department of Nephrology,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
ZHAO Gang(Department of Gastroenterology,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
ZHU Lei(Department of Gastroenterology,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
ZHU Ying(Department of Infectious diseases,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
WANG Li-xia(Department of Gastroenterology,First Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, Liaoning 116011, China)
Journal Title:
Volume 123, Issue 18, 2010
Key Word:
pancreatitis;cholangiopancreatography, endoscopic retrograde;meta-analysis

Abstract: Background Post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) is regarded as one of the worrisome complications of endoscopic retrograde cholangiopancreatography (ERCP). Results of randomized controlled trials evaluating the preventive effect of ulinastatin and gabexate mesylate (GM) on PEP are contradictory. The present study was designed to evaluate the prophylactic effect of ulinastatin and GM on PEP with meta-analyses of randomized controlled trials (RCTs).Methods Five electronic databases were searched for RCTs evaluating the preventive effect of ulinastatin and GM on PEP. Summary effects were assessed with the methods recommended by the Cochrane Collaboration.Results Twelve studies involving 5105 participants were included in our meta-analyses. Administration of ulinastatin decreased the incidence of PEP only at sufficient doses (OR, 0.39; 95% CI, 0.19 to 0.81; P=0.01). Number needed to treat (NNT) was 6. And administration of ulinastatin also reduced the incidence of post-ERCP hyperamylasemia (PEHA)(OR, 0.40; 95% CI, 0.28 to 0.58; P<0.000 01). Slow infusion of high-dose GM was effective for PEP prevention (OR, 0.44;95% CI, 0.25 to 0.79; P=0.006), and rapid infusion of low-dose GM also showed efficacy for PEP prophylaxis (OR, 0.37;95% CI, 0.20 to 0.69; P=0.002). NNT was 7 and 6 respectively. However, administration of GM at low doses and by slow infusions was ineffective (OR, 0.99; 95% CI, 0.64 to 1.55; P=0.98). Administration of GM had the tendency to reduce PEHA rate, but not to a statistical significance (OR, 0.86; 95% CI, 0.73 to 1.01; P=0.06). When low-quality studies were excluded, the meta-analysis with two high-quality studies indicated that ulinastatin did not reduce the rate of PEP (OR,0.63; 95% CI, 0.32 to 1.26; P=0.19) and PEHA incidence (OR, 0.80; 95% CI, 0.31 to 2.07; P=0.64). The meta-analysis with six high-quality studies showed that GM administration decreased PEP incidence (OR, 0.52; 95% CI, 0.29 to 0.91;P=0.02), while was not efficacious for PEHA prevention (OR, 0.88; 95% CI, 0.74 to 1.04; P=0.12).Conclusions Ulinastatin and GM may be of value for the prophylaxis of PEP. GM should be administered at high doses and by rapid infusions. And the doses of ulinastatin should be sufficient. However, the conclusions are not overwhelming.More large-sample size and high-quality RCTs are still needed to elucidate whether administrations of the two drugs really have prophylactic effect on PEP.

  • [1]Chen CC,Wang SS,Lu RH,Lu CC,Chang FY,Lee SD.The early changes of serum proinflammatory and anti-inflammatory cytokines after endoscopic retrograde cholangiopancreatography.Pancreas 2003; 26:375-380.
  • [2]Freeman ML,Guda NM.Prevention of post-ERCP pancreatitis:a comprehensive review.Gastrointest Endosc 2004; 59:845-864.
  • [3]Muddana V,Whitcomb DC,Papachristou GI.Current management and novel insights in acute pancreatitis.Expert Rev Gastroenterol Hepatol 2009; 3:435-444.
  • [4]Andriulli A,Loperfido S,Napolitano G,Niro G,Valvano MR,Spirito F,et al.Incidence rates of post-ERCP complications:a systematic survey of prospective studies.Am J Gastroenterol 2007; 102:1781-1788.
  • [5]Sherman S,Ruffolo TA,Hawes RH,Lehman GA.Complications of endoscopic sphincterotomy.A prospective series with emphasis on the increased risk associated with sphincter of Oddi dysfunction and nondilated bile ducts.Gastroenterology 1991; 101:1068-1075.
  • [6]Cheung J,Tsoi KK,Quan WL,Lau JY,Sung JJ.Guidewire versus conventional contrast cannulation of the common bile duct for the prevention of post-ERCP pancreatitis:a systematic review and meta-analysis.Gastrointest Endosc 2009; 70:1211-1219.
  • [7]Madácsy L,Kurucsai G,Fejes R,Székely A,Székely I.Prophylactic pancreas stenting followed by needle-knife fistulotomy in patients with sphincter of Oddi dysfunction and difficult cannulation:new method to prevent post-ERCP pancreatitis.Dig Endosc 2009; 21:8-13.
  • [8]Bai Y,Xu C,Yang X,Gao J,Zou DW,Li ZS.Glyceryl trinitrate for prevention of pancreatitis after endoscopic retrograde cholangiopancreatography:a meta-analysis of randomized,double-blind,placebo-controlled trials.Endoscopy 2009; 41:690-695.
  • [9]Seta T,Noguchi Y,Shimada T,Shikata S,Fukui T.Treatment of acute pancreatitis with protease inhibitors:a meta-analysis.Eur J Gastroenterol Hepatol 2004; 16:1287-1293.
  • [10]Tsujino T,Komatsu Y,Isayama H,Hirano K,Sasahira N,Yamamoto N,et al.Ulinastatin for pancreatitis after endoscopic retrograde cholangiopancreatography:a randomized,controlled trial.Clin Gastroenterol Hepatol 2005;3:376-383.
  • [11]Yoo JW,Ryu JK,Lee SH,Woo SM,Park JK,Yoon WJ,et al.Preventive effects of ulinastatin on post-endoscopic retrograde cholangiopancreatography pancreatitis in high-risk patients:a prospective,randomized,placebo-controlled trial.Pancreas 2008; 37:366-370.
  • [12]Testoni PA,Mariani A,Masci E,Curioni S.Frequency of post-ERCP pancreatitis in a single tertiary referral centre without and with routine prophylaxis with gabexate:a 6-year survey and cost-effective analysis.Dig Liver Dis 2006; 38:588-595.
  • [13]Rudin D,Kiss A,Wetz RV,Sottile VM.Somatostatin and gabexate for post-endoscopic retrograde cholangiopancreatography pancreatitis prevention:meta-analysis of randomized placebo-controlled trials.J Gastroenterol Hepatol 2007; 22:977-983.
  • [14]Andriulli A,Leandro G,Federici T,Ippolito A,Forlano R,Iacobellis A,et al.Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP:an updated meta-analysis.Gastrointest Endosc 2007; 65:624-632.
  • [15]Higgins JPT,Green S,eds.Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 (updated February 2008).The Cochrane Collaboration,2008.(Accessed at
  • [16]Moher D,Cook DJ,Eastwood S,Olkin I,Rennie D,Stroup DF.Improving the quality of reports of meta-analyses of randomized controlled trials:the QUOROM statement.Quality of Reporting of Meta-analyses.Lancet 1999; 354:1896-1900.
  • [17]Glanville JM,Lefebvre C,Miles JN,Camosso-Stefinovic J.How to identify randomized controlled trials in MEDLINE:ten years on.J Med Libr Assoc 2006; 94:130-136.
  • [18]Cotton PB,Lehman G,Vennes J,Geenen JE,Russell RC,Meyers WC,et al.Endoscopic sphinc-terotomy complications and their management:an attempt at consensus.Gastrointest Endosc 1991; 37:383-393.
  • [19]Richter JE.Oesophageal motility disorders.Lancet 2001; 358:823-828.
  • [20]Jadad AR,Moore RA,Carroll D,Jenkinson C,Reynolds DJ,Gavaghan DJ,et al.Assessing the quality of reports of randomized clinical trials:is blinding necessary? Control Ciin Trials 1996; 17:1-12.
  • [21]Egger M,Davey Smith G,Schneider M,Minder C.Bias in meta-analysis detected by a simple,graphical test.BMJ 1997;315:629-634.
  • [22]Chen XT,Fei ZY,Shen YF,Peng WH,Wang RW.The clinical observation of ulinastatin on prevention of post ERCP acute pancreatitis.Shandong Med J (Chin) 2005; 45:44-45.
  • [23]Song AL,Yi LN,Kou ZM.The preventive effect of ulinastatin on post ERCP hyperamylasemia and acute pancreatitis.J Lanzhou Univ (Med Sci) (Chin) 2005; 31:24-40.
  • [24]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; 56:488-495.
  • [25]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; 2:713-718.
  • [26]Benvenuti S,Zancanella L,Piazzi L,Comberlato M,Chilovi F,Germana B,et al.Prevention of Post-ERCP pancreatitis with somatostatin versus gabexate mesilate:a randomized placebo-controlled multicenter study.Dig Liver Dis 2006; 38Suppl 1:S15.
  • [27]Xiong GS,Wu SM,Zhang XW,Ge ZZ.Clinical trial of gabexate in the prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis.Braz J Med Biol Res 2006; 39:85-90.
  • [28]Manes G,Ardizzone S,Lombardi G,Uomo G,Pieramico O,Porro GB.Efficacy of postprocedure administration of gabexate mesylate in the prevention of post-ERCP pancreatitis:a randomized,controlled,multicenter study.Gastrointest Endosc 2007; 65:982-987.
  • [29]Cavallini G,Tittobello A,Frulloni L,Masci E,Mariana A,Di Francesco V.Gabexate for the prevention of pancreatic damage related to endoscopic retrograde cholangiopancreatography.Gabexate in digestive endoscopy-Italian Group.N Engl J Med 1996; 335:919-923.
  • [30]Meng FD,Wu YD,Ji M,Zhang ST,Li WY,Wang QG,et al.Prophylactic effect of Gabexate on post-ERCP pancreatitis:a clinical observation.Chin J Dig Endosc (Chin) 2007; 24:100-102.
  • [31]Lee BK,Zhou DW,Wang XJ.Clinical assessment of gabexate,octreotide in prevention of post ERCP hyperamylasemia and pancreatitis.China Prac Med (Chin) 2007; 2:105-107.
  • [32]Cheng CL,Sherman S,Watkins JL,Barnett J,Freeman M,Geenen J,et al.Risk factors for post-ERCP pancreatitis:a prospective multicenter study.Am J Gastroenterol 2006; 101:139-147.
  • [33]Zhang Y,Chen QB,Gao ZY,Xie WF.Meta-analysis:octreotide prevents post-ERCP pancreatitis,but only at sufficient doses.Aliment Pharmacol Ther 2009; 29:1155-1164.
  • [34]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; 60:544-550.
  • [35]Andriulli A,Leandro G,Niro G.Mangia A,Festa V,Gambassi G,et al.Pharmacologic treatment can prevent pancreatic injury after ERCP:a meta-analysis.Gstrointest Endosc 2000;51:1-7.
  • [36]Gaisano HY,Gorelick FS.New insights into the mechanisms of pancreatitis.Gastroenterol 2009; 136:2040-2044.
  • [37]Mayer J,Rau B,Gansauge F,Gansauge F,Beger HG.Inflammatory mediators in human acute pancreatitis:clinical and pathophysiological implications.Gut 2000; 47:546-552.
  • [38]Cook JW,Karaakozis S,Kim D,Provido H,Gongora E,Kirkpatrick JR.Interleukin-10 attenuates proinflammatory cytokine production and improves survival in lethal pancreatitis.Am Surg 2001; 67:237-241.
  • [39]Di Francesco V,Mariani A,Angelini,Masci E,Frulloni L,Talamini G,et al.Effects of gabexate mesilate,a protease inhibitor,on human sphincter of Oddi motility.Dig Dis Sci 2002; 47:741-774.
  • [40]Kong J,Wu SD,Zhang XB,Li ZS,Shi G,Wang W,et al.Choledochoscope manometry about different drugs on the Sphincter of Oddi.World J Gastroenterol 2008; 14:5907-5912.
  • [41]Jüni P,Witschi A,Bloch R,Egger M.The hazards of scoring the quality of clinical trials for meta-analysis.JAMA 1999;282:1054-1060.
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