PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of worldjgastrosurgLink to Publisher's site
 
World J Gastrointest Surg. 2010 January 27; 2(1): 9–13.
Published online 2010 January 27. doi:  10.4240/wjgs.v2.i1.9
PMCID: PMC2999192

How evidence-based are current guidelines for managing patients with peptic ulcer bleeding?

Abstract

Current guidelines for managing ulcer bleeding state that patients with major stigmata should be managed by dual endoscopic therapy (injection with epinephrine plus a thermal or mechanical modality) followed by a high dose intravenous infusion of proton pump inhibitors (PPIs). This paper aims to review and critically evaluate evidence supporting the purported superiority of a continuous infusion over less intensive regimens of PPIs administration and the need for adding a second hemostatic endoscopic procedure to epinephrine injection. Systematic searches of PubMed, EMBASE and the Cochrane library were performed. There is strong evidence for an incremental benefit of PPIs over H2-receptor antagonists or placebo for the outcome of patients with peptic ulcer bleeding following endoscopic hemostasis. However, the benefit of PPIs is unrelated to either the dosage (intensive vs standard regimen) or the route of administration (intravenous vs oral). There is significant heterogeneity among the 15 studies that compared epinephrine with epinephrine plus a second modality, which might preclude the validity of reported summary estimates. Studies without second look endoscopy plus re-treatment of re-bleeding lesions showed a significant benefit of adding a second endoscopic modality for hemostasis, while studies with second-look and re-treatment showed equal efficacy between endoscopic mono and dual therapy. Inconclusive experimental evidence supports the current recommendation of the use of dual endoscopic hemostatic means and infusion of high-dose PPIs as standard therapy for patients with bleeding peptic ulcers. Presently, the combination of epinephrine monotherapy with standard doses of PPIs constitutes an appropriate treatment for the majority of patients.

Keywords: Guidelines, Ulcer bleeding, Peptic ulcer, Endoscopic therapy, Pharmacotherapy, Proton pump inhibitors

INTRODUCTION

In patients with ulcer bleeding and endoscopic findings that predict an increased risk of further bleeding, current therapeutic guidelines have endorsed the adoption of combining endoscopic hemostatic techniques with post-hemostatic adjuvant pharmacotherapy as primary measures to reduce rate of re-bleeding and need for surgery[1-3]. In addition, they authoritatively suggest to deliver endoscopic hemostasis by combining dual procedures and to administer proton pump inhibitors (PPIs) under an intensive regimen of 80 mg stat followed by an infusion of 8 mg hourly for 72 h. The focus of a guideline is not prescriptive but aspires to recommend ideal therapy recognising that this has to be tempered by practical considerations that vary from patient to patient. However, in an era where medical litigation is increasing, adherence to guideline recommendations is widely adopted to reduce the likelihood of claims for malpractice.

Guideline recommendations are increasingly based on results of meta-analyses that summarize data from available studies in a quantitative fashion. Meta-analyses typically take a number of underpowered studies showing trends with similar point estimates and provide statistical power narrowing the surrounding uncertainty to achieve statistical and hopefully clinical significance. However, integrating the results of these studies is made difficult by variations in experimental design and composition of samples and may end up nullifying the clinical implementation of the summary statistics.

This paper will review available evidence on the appropriate management of patients with peptic ulcer bleeding, concentrating particularly on the purported superiority of a continuous infusion of PPIs administration over less intensive regimens and the need for adding a second hemostatic endoscopic procedure to epinephrine injection.

OPTIMAL REGIMEN OF PPIs ADMINISTRATION

In the past, pharmacologic agents such as splanchnic blood pressure modifiers (e.g. vasopressin, somatostatin, octreotide) and antifibrinolytic agents (e.g. tranexamic acid) were used to stop initial bleeding and to prevent re-bleeding. Unfortunately, these drugs proved to be of limited value because they do not affect gastric pH[4,5].

The role of gastric acid in bleeding peptic ulcers has been intensively investigated. In vitro, platelet aggregation, platelet disaggregation, coagulation, and fibrinolysis are strongly dependent on intragastric pH. Green et al[6] demonstrated that platelet aggregation and blood coagulation are optimal at pH 7.4. When the pH falls below 6.8, platelet aggregation and blood coagulation become abnormal and below 6.0, platelet aggregation is non-existent and disaggregation occurs. Finally, as pH falls below 4.0, fibrin clots are dissolved by gastric pepsin. In vivo studies have shown that a regimen including a high dose of a PPI can maintain intragastric pH at a nearly neutral level and inhibit acid production more effectively than an infusion of H2-receptor antagonists does[7,8]. In vivo, Laine et al[9] demonstrated that intragastric pH above 6.0 could be maintained for 67.8% of the 24 h study period in patients receiving intravenous PPI, and in 64.8% in those treated with frequent dosing schedule (3 h) of oral PPI. These in vitro and in vivo data generated the hypothesis that optimizing intragastric pH during acute bleeding from peptic ulcers by achieving profound acid suppression is needed to reduce the risk of morbidity and mortality during hospitalization. However, previous experimental evidence represents, at best, surrogate end points, whereas data from appropriate clinical investigations are the essential outcome measures on which clinical decisions should be based.

The British Society of Gastroenterology guidelines issued in 2002 were the first to recommend the use of high dose intravenous omeprazole therapy, consisting of a 80 mg stat dose followed by an infusion of 8 mg hourly for 72 h[1]. Four randomized trials were cited to support the recommendation[10-13], but much emphasis was reserved for the Lau et al[13] trial. In this study, patients randomized to receive the intensive dosage of PPIs had a reduction in the risk of recurrent bleeding from peptic ulcer which amounted to 7% for intravenous PPIs compared to 23% for patients in the placebo group. As the four surveyed trials were all placebo-controlled, a more appropriate conclusion would have indicated that the purported superiority of the intensive regimen of PPIs administration was apparent when compared with the placebo. The value of this schedule of PPIs administration as opposed to less intensive regimens remains unproven.

The benefit associated with the use of the high-dose intravenous PPI regimen was reiterated in recommendation 17 of the consensus conference, endorsed and organized in 2003 by the Canadian Association of Gastroenterology[2]. Recommendation 17 was issued after the appreciation of data from an ad-hoc meta-analysis, where the intensive regimen led to a statistically significant reduction in the absolute rate of re-bleeding compared with that registered after the administration of H2-receptor antagonists or placebo[14]. A recently updated Cochrane meta-analysis reinforced the recommendation[15]. Careful reading of component studies on which this proposition was based, lessens enthusiasm on the generalizability and applicability of the recommendation. Indeed, an inactive placebo or a less than optimal gastric inhibitory drug, the H2-receptor antagonists, were used as comparators in all investigations. Reasons for the lack of benefit of H2-receptor antagonists in bleeding peptic patients may be the failure to maintain optimal intragastric pH during the critical 72 h following the onset of the bleed, and the rapid onset of tolerance to H2-receptor antagonists’ antisecretory effect[16,17]. In addition, at the time previous guidelines were issued, there were studies proving that either high dose oral[18,19] or standard intravenous dose of PPIs[20,21] were also very effective in the prevention of re-bleeding in patients with high-risk peptic ulcers. However, the reported results received little consideration. A more judicious appreciation would have focused on those studies that made a direct comparison between the high intensive regimen of PPIs administration and the standard or oral regimens of PPIs use. Indeed, in a meta-analytical evaluation of the only two trials that compared the continuous high-dose infusion versus an intermittent bolus of intravenous PPIs administration, the pooled re-bleeding rates were 11.6% and 9.7% respectively, a non significant difference[22]. In line with these results, four subsequent reports failed to document an incremental benefit of intravenous over oral PPI regimens in the prevention of re-bleeding following endoscopic hemostasis[23-26].

After considering all previous information, the appropriate conclusion would be that there is strong evidence for an incremental benefit of PPIs over H2-receptor antagonists or placebo for the outcome of patients with peptic ulcer bleeding following endoscopic hemostasis. However, the benefit of therapy with PPIs is unrelated to either their dosage (the intensive or the standard regimen of intravenous drug administration) or the route of administration (iv vs po). As a practical consequence for the everyday clinical care for patients bleeding from peptic ulcers, we suggest standard doses of PPIs should be used as an adjuvant treatment after a successful endoscopic hemostasis. Preliminary recent investigation has also shown comparable efficacy between oral rabeprazole and intravenous regular doses of omeprazole in preventing re-bleeding in patients with high-risk bleeding peptic ulcer after successful endoscopic injection with epinephrine[27]. Future trials should further explore the benefit of the oral route vs the intermittent bolus of intravenous PPI administration.

OPTIMAL ENDOSCOPIC HEMOSTASIS

Controversy has also surrounded the best modality to deliver and achieve endoscopic hemostasis in bleeding peptic ulcers. All endoscopic treatments appear superior to pharmacotherapy alone[14,22,28], while epinephrine monotherapy has been rated less effective in preventing further bleeding than epinephrine injection followed by a second endoscopic modality[29-32]. Dual endoscopic therapy is theoretically attractive to increase efficacy, and the combination of epinephrine injection followed by thermal therapy has gained wide acceptance. However, data supporting the superiority of dual endoscopic treatment over epinephrine monotherapy are extremely limited. By referring to the only trial available on the comparison of dual vs monotherapy[28] at the time guidelines were issued, the British Society of Gastroenterology acknowledged that the combination of adrenaline injection plus heater probe was no better than injection alone for the overall population of peptic ulcer bleeders. They also pointed out the results of a post hoc analysis of the same study showing better outcomes in the subset of patients with active arterial bleeding who received combination therapy[1]. This relevant observation would imply that no single endoscopic treatment fits all kinds of bleeding peptic ulcers and that individual patients would benefit from a slightly different approach in endoscopic hemostasis. Unfortunately, this indication has not been pursued further.

Conversely, both the Canadian consensus statements and guidelines issued by the American Society of Gastrointestinal Endoscopy rated epinephrine monotherapy inferior to dual endoscopic therapy in re-bleeding, need for surgery, and mortality[2,3]. This statement found support in several successive meta-analyses[14,30-33]. Fifteen clinical trials have compared epinephrine with epinephrine plus a second modality[28,34-47]. By inspecting the Forrest plots of these analyses, there was significant heterogeneity among the studies, which might preclude the validity of reported summary estimates. Indeed, an advantage for the combined endoscopic approach was apparent from only 6 of the 15 clinical trials[34,35,41-44], while in the remaining 9 trials, epinephrine monotherapy proved as effective as epinephrine injection plus a second modality. Laine and McQuaid noted that in these trials, assessment of the therapeutic outcome was confounded by second look plus re-treatment. Meta-analyses of studies without second look plus re-treatment showed a significant benefit of adding the second modality for further bleeding and surgery, while studies with second-look and re-treatment showed no suggestion of a difference[32]. Consequently, in line with these findings, two strategies seem to be equally effective: the first one would suggest to treat all patients with dual endoscopic modalities and the second one would argue to deliver epinephrine monotherapy to all patients and re-treat only the small proportion of rebleeders with a second endoscopic modality.

In addition, the majority of reviewed studies administered pharmacotherapy as adjuvant treatment to endoscopic therapy. Therefore, it is highly plausible that the outcome of interest, i.e. the rebleeding rate, might be the combined result of either the modality of endotherapy (single or dual) and the type of the pharmacotherapy (placebo, H2-receptor antagonists, or PPIs) being administered. Summary statistics provided by meta-analyses were driven by results of adjuvant medical therapies that are not generally used at present. Marmo et al[31] handled this heterogeneity among the studies with subgroup analysis and meta-regression and found that the type of dual therapy applied and the post-hemostasis adjuvant therapy with PPIs could explain the heterogeneity. Since only two studies applied omeprazole as adjuvant treatment[34,45], a strategy presently considered standard practice, the applicability of current guidelines could be limited. In light of this factor, a more appropriate interpretation of the meta-analytical data would have been that dual therapy was superior to epinephrine monotherapy when medical therapy other than PPIs was given.

CONCLUSION

This paper has highlighted the real difficulties in interpreting the wide array of heterogeneous studies, each examining one aspect of the management of peptic ulcer bleeding. Consequently, insufficient experimental evidence supports current guideline recommendations to treat patients with major stigmata of haemorrhage by dual endoscopic therapy, comprising of injection with epinephrine plus a thermal or mechanical modality, followed by high-dose intravenous infusion of PPI drugs. The significant heterogeneity across the studies invalidates the generalizability of the results of meta-analyses on which these guidelines were based. Whether the indiscriminate use of combined endoscopic therapy and high-dose infusion of PPIs is uniformly necessary in all patients with peptic ulcer hemorrhage remains questionable. Determination of patient subgroups most likely to benefit from the aggressive therapeutic program, as suggested by available guidelines, is necessary to ensure that the highest risk patients are optimally treated. Algorithms for optimal management of bleeding peptic ulcers will continue to be a subject of research interest. At this time, a two-pronged approach that combines injection monotherapy with adjuvant standard intravenous dose of PPIs can offer protection against early re-bleeding in the great majority of patients with peptic ulcer bleeding.

Footnotes

Peer reviewer: Simone Ferrero, MD, San Martino Hospital and University of Genoa, Largo Rosanna Benzi1, Genova 16132, Italy

S- Editor Li LF L- Editor Roemmele A E- Editor Yang C

References

1. British Society of Gastroenterology Endoscopy Committee. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut. 2002;51 Suppl 4:iv1–iv6. [PMC free article] [PubMed]
2. Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2003;139:843–857. [PubMed]
3. Adler DG, Leighton JA, Davila RE, Hirota WK, Jacobson BC, Qureshi WA, Rajan E, Zuckerman MJ, Fanelli RD, Hambrick RD, et al. ASGE guideline: The role of endoscopy in acute non-variceal upper-GI hemorrhage. Gastrointest Endosc. 2004;60:497–504. [PubMed]
4. Morgan DG, Hunt RH. Medical management of gastrointestinal bleeding. Eur J GastroHepato. 1990;2:73–78.
5. Barkun AN, Cockeram AW, Plourde V, Fedorak RN. Review article: acid suppression in non-variceal acute upper gastrointestinal bleeding. Aliment Pharmacol Ther. 1999;13:1565–1584. [PubMed]
6. Green FW Jr, Kaplan MM, Curtis LE, Levine PH. Effect of acid and pepsin on blood coagulation and platelet aggregation. A possible contributor prolonged gastroduodenal mucosal hemorrhage. Gastroenterology. 1978;74:38–43. [PubMed]
7. Netzer P, Gaia C, Sandoz M, Huluk T, Gut A, Halter F, Hüsler J, Inauen W. Effect of repeated injection and continuous infusion of omeprazole and ranitidine on intragastric pH over 72 hours. Am J Gastroenterol. 1999;94:351–357. [PubMed]
8. Labenz J, Peitz U, Leusing C, Tillenburg B, Blum AL, Börsch G. Efficacy of primed infusions with high dose ranitidine and omeprazole to maintain high intragastric pH in patients with peptic ulcer bleeding: a prospective randomised controlled study. Gut. 1997;40:36–41. [PMC free article] [PubMed]
9. Laine L, Shah A, Bemanian S. Intragastric pH with oral vs intravenous bolus plus infusion proton-pump inhibitor therapy in patients with bleeding ulcers. Gastroenterology. 2008;134:1836–1841. [PubMed]
10. Schaffalitzky de Muckadell OB, Havelund T, Harling H, Boesby S, Snel P, Vreeburg EM, Eriksson S, Fernström P, Hasselgren G. Effect of omeprazole on the outcome of endoscopically treated bleeding peptic ulcers. Randomized double-blind placebo-controlled multicentre study. Scand J Gastroenterol. 1997;32:320–327. [PubMed]
11. Hasselgren G, Lind T, Lundell L, Aadland E, Efskind P, Falk A, Hyltander A, Söderlund C, Eriksson S, Fernström P. Continuous intravenous infusion of omeprazole in elderly patients with peptic ulcer bleeding. Results of a placebo-controlled multicenter study. Scand J Gastroenterol. 1997;32:328–333. [PubMed]
12. Lin HJ, Lo WC, Lee FY, Perng CL, Tseng GY. A prospective randomized comparative trial showing that omeprazole prevents rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy. Arch Intern Med. 1998;158:54–58. [PubMed]
13. Lau JY, Sung JJ, Lee KK, Yung MY, Wong SK, Wu JC, Chan FK, Ng EK, You JH, Lee CW, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med. 2000;343:310–316. [PubMed]
14. Bardou M, Toubouti Y, Benhaberou-Brun D, Rahme E, Barkun AN. Meta-analysis: proton-pump inhibition in high-risk patients with acute peptic ulcer bleeding. Aliment Pharmacol Ther. 2005;21:677–686. [PubMed]
15. Leontiadis GI, Sharma VK, Howden CW. Proton pump inhibitor treatment for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2006:CD002094. [PubMed]
16. Merki HS, Wilder-Smith CH. Do continuous infusions of omeprazole and ranitidine retain their effect with prolonged dosing? Gastroenterology. 1994;106:60–64. [PubMed]
17. Walt RP, Cottrell J, Mann SG, Freemantle NP, Langman MJ. Continuous intravenous famotidine for haemorrhage from peptic ulcer. Lancet. 1992;340:1058–1062. [PubMed]
18. Khuroo MS, Yattoo GN, Javid G, Khan BA, Shah AA, Gulzar GM, Sodi JS. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med. 1997;336:1054–1058. [PubMed]
19. Javid G, Masoodi I, Zargar SA, Khan BA, Yatoo GN, Shah AH, Gulzar GM, Sodhi JS. Omeprazole as adjuvant therapy to endoscopic combination injection sclerotherapy for treating bleeding peptic ulcer. Am J Med. 2001;111:280–284. [PubMed]
20. Schonekas H, Ahrens H, Pannewick U, Ell C, Koop H, Petrisch W, Klein M, Fischer R. Comparison of two doses of intravenous pantoprazole in peptic ulcer bleeding. Gastroenterology. 1999;116:A305.
21. Udd M, Miettinen P, Palmu A, Heikkinen M, Janatuinen E, Pasanen P, Tarvainen R, Kairaluoma MV, Lohman M, Mustonen H, et al. Regular-dose versus high-dose omeprazole in peptic ulcer bleeding: a prospective randomized double-blind study. Scand J Gastroenterol. 2001;36:1332–1338. [PubMed]
22. Andriulli A, Annese V, Caruso N, Pilotto A, Accadia L, Niro AG, Quitadamo M, Merla A, Fiorella S, Leandro G. Proton-pump inhibitors and outcome of endoscopic hemostasis in bleeding peptic ulcers: a series of meta-analyses. Am J Gastroenterol. 2005;100:207–219. [PubMed]
23. Hung WK, Li VK, Chung CK, Ying MW, Loo CK, Liu CK, Lam BY, Chan MC. Randomized trial comparing pantoprazole infusion, bolus and no treatment on gastric pH and recurrent bleeding in peptic ulcers. ANZ J Surg. 2007;77:677–681. [PubMed]
24. Yüksel I, Ataseven H, Köklü S, Ertuğrul I, Başar O, Odemiş B, Ibiş M, Saşmaz N, Sahin B. Intermittent versus continuous pantoprazole infusion in peptic ulcer bleeding: a prospective randomized study. Digestion. 2008;78:39–43. [PubMed]
25. Andriulli A, Loperfido S, Focareta R, Leo P, Fornari F, Garripoli A, Tonti P, Peyre S, Spadaccini A, Marmo R, et al. High- versus low-dose proton pump inhibitors after endoscopic hemostasis in patients with peptic ulcer bleeding: a multicentre, randomized study. Am J Gastroenterol. 2008;103:3011–3018. [PubMed]
26. Bajaj JS, Dua KS, Hanson K, Presberg K. Prospective, randomized trial comparing effect of oral versus intravenous pantoprazole on rebleeding after nonvariceal upper gastrointestinal bleeding: a pilot study. Dig Dis Sci. 2007;52:2190–2194. [PubMed]
27. Tsai JJ, Hsu YC, Perng CL, Lin HJ. Oral or intravenous proton pump inhibitor in patients with peptic ulcer bleeding after successful endoscopic epinephrine injection. Br J Clin Pharmacol. 2009;67:326–332. [PMC free article] [PubMed]
28. Chung SS, Lau JY, Sung JJ, Chan AC, Lai CW, Ng EK, Chan FK, Yung MY, Li AK. Randomised comparison between adrenaline injection alone and adrenaline injection plus heat probe treatment for actively bleeding ulcers. BMJ. 1997;314:1307–1311. [PMC free article] [PubMed]
29. Calvet X, Vergara M, Brullet E, Gisbert JP, Campo R. Addition of a second endoscopic treatment following epinephrine injection improves outcome in high-risk bleeding ulcers. Gastroenterology. 2004;126:441–450. [PubMed]
30. Kahi CJ, Jensen DM, Sung JJ, Bleau BL, Jung HK, Eckert G, Imperiale TF. Endoscopic therapy versus medical therapy for bleeding peptic ulcer with adherent clot: a meta-analysis. Gastroenterology. 2005;129:855–862. [PubMed]
31. Marmo R, Rotondano G, Piscopo R, Bianco MA, D'Angella R, Cipolletta L. Dual therapy versus monotherapy in the endoscopic treatment of high-risk bleeding ulcers: a meta-analysis of controlled trials. Am J Gastroenterol. 2007;102:279–289; quiz 469. [PubMed]
32. Laine L, McQuaid KR. Endoscopic therapy for bleeding ulcers: an evidence-based approach based on meta-analyses of randomized controlled trials. Clin Gastroenterol Hepatol. 2009;7:33–47; quiz 1-2. [PubMed]
33. Barkun AN, Martel M, Toubouti Y, Rahme E, Bardou M. Endoscopic hemostasis in peptic ulcer bleeding for patients with high-risk lesions: a series of meta-analyses. Gastrointest Endosc. 2009;69:786–799. [PubMed]
34. Lo CC, Hsu PI, Lo GH, Lin CK, Chan HH, Tsai WL, Chen WC, Wu CJ, Yu HC, Cheng JS, et al. Comparison of hemostatic efficacy for epinephrine injection alone and injection combined with hemoclip therapy in treating high-risk bleeding ulcers. Gastrointest Endosc. 2006;63:767–773. [PubMed]
35. Rutgeerts P, Vantrappen G, Broeckaert L, Coremans G, Janssens J, Hiele M. Comparison of endoscopic polidocanol injection and YAG laser therapy for bleeding peptic ulcers. Lancet. 1989;1:1164–1167. [PubMed]
36. Balanzó J, Villanueva C, Sainz S, Espinós JC, Mendez C, Guarner C, Vilardell F. Injection therapy of bleeding peptic ulcer. A prospective, randomized trial using epinephrine and thrombin. Endoscopy. 1990;22:157–159. [PubMed]
37. Choudari CP, Palmer KR. Endoscopic injection therapy for bleeding peptic ulcer; a comparison of adrenaline alone with adrenaline plus ethanolamine oleate. Gut. 1994;35:608–610. [PMC free article] [PubMed]
38. Chung IK, Ham JS, Kim HS, Park SH, Lee MH, Kim SJ. Comparison of the hemostatic efficacy of the endoscopic hemoclip method with hypertonic saline-epinephrine injection and a combination of the two for the management of bleeding peptic ulcers. Gastrointest Endosc. 1999;49:13–18. [PubMed]
39. Chung SC, Leong HT, Chan AC, Lau JY, Yung MY, Leung JW, Li AK. Epinephrine or epinephrine plus alcohol for injection of bleeding ulcers: a prospective randomized trial. Gastrointest Endosc. 1996;43:591–595. [PubMed]
40. Chung SC, Leung JW, Leong HT, Lo KK, Li AK. Adding a sclerosant to endoscopic epinephrine injection in actively bleeding ulcers: a randomized trial. Gastrointest Endosc. 1993;39:611–615. [PubMed]
41. Garrido Serrano A, Guerrero Igea FJ, Perianes Hernández C, Arenas Posadas FJ, Palomo Gil S. Local therapeutic injection in bleeding peptic ulcer: a comparison of adrenaline to adrenaline plus a sclerosing agent. Rev Esp Enferm Dig. 2002;94:395–405. [PubMed]
42. Kubba AK, Murphy W, Palmer KR. Endoscopic injection for bleeding peptic ulcer: a comparison of adrenaline alone with adrenaline plus human thrombin. Gastroenterology. 1996;111:623–628. [PubMed]
43. Lin HJ, Tseng GY, Perng CL, Lee FY, Chang FY, Lee SD. Comparison of adrenaline injection and bipolar electrocoagulation for the arrest of peptic ulcer bleeding. Gut. 1999;44:715–719. [PMC free article] [PubMed]
44. Lin HJ, Perng CL, Lee SD. Is sclerosant injection mandatory after an epinephrine injection for arrest of peptic ulcer haemorrhage? A prospective, randomised, comparative study. Gut. 1993;34:1182–1185. [PMC free article] [PubMed]
45. Pescatore P, Jornod P, Borovicka J, Pantoflickova D, Suter W, Meyenberger C, Blum AL, Dorta G. Epinephrine versus epinephrine plus fibrin glue injection in peptic ulcer bleeding: a prospective randomized trial. Gastrointest Endosc. 2002;55:348–353. [PubMed]
46. Sollano JD, Ang VN, Moreno JA. Endoscopic hemostasis of bleeding peptic ulcers: 1:10000 adrenalin injection vs. 1:10000 adrenalin +1% aethoxysclerol injection vs. heater probe. Gastroenterol Jpn. 1991;26 Suppl 3:83–85. [PubMed]
47. Villanueva C, Balanzó J, Espinós JC, Fábrega E, Sáinz S, González D, Vilardell F. Endoscopic injection therapy of bleeding ulcer: a prospective and randomized comparison of adrenaline alone or with polidocanol. J Clin Gastroenterol. 1993;17:195–200. [PubMed]

Articles from World Journal of Gastrointestinal Surgery are provided here courtesy of Baishideng Publishing Group Inc