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Will Helicobacter pylori affect short-term rebleeding rate in peptic ulcer bleeding patients after successful endoscopic therapy?
THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 1999 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 94, No. 11, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00575-4
Will Helicobacter pylori Affect Short-Term Rebleeding Rate in Peptic Ulcer Bleeding Patients After Successful Endoscopic Therapy? Hwai-Jeng Lin, M.D., F.A.C.G., Guan-Ying Tseng, M.D., Yu-Hsi Hsieh, M.D., Chin-Lin Perng, M.D., Fa-Yauh Lee, M.D., F.A.C.G., Full-Young Chang, M.D., and Shou-Dong Lee, M.D., F.A.C.G. Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, and National Yang-Ming University, School of Medicine, Taipei, Taiwan, Republic of China
OBJECTIVE: Helicobacter pylori (H. pylori) can augment the pH-increasing effect of omeprazole in patients with peptic ulcer. A high intragastric pH may be helpful in preventing recurrent hemorrhage by stabilizing the blood clot at the ulcer base of bleeding peptic ulcer patients. Therefore, we hypothesized that omeprazole may reduce short-term rebleeding rate in these patients with H. pylori infection after initial hemostasis had been obtained. METHODS: Between July 1996 and December 1998, 65 bleeding peptic ulcer patients (24 gastric ulcer, 41 duodenal ulcer) who had obtained initial hemostasis with endoscopic therapy were enrolled in this trial. Thirty (46.2%) of them were found to have H. pylori infection by a rapid urease test and pathological examination. For all studied patients, omeprazole was given 40 mg intravenously every 6 h for 3 days. Thereafter, omeprazole was given 20 mg per os (p.o.) once daily for 2 months. A pH meter was inserted in the fundus of each patient under fluoroscopic guidance after intravenous omeprazole had been administered. The occurrence of rebleeding episode was observed for 14 days. RESULTS: In patients with H. pylori infection, intragastric pH (median, 95% confidence interval [CI]: 6.54, 5.90 – 6.68) was higher than in those without H. pylori infection (6.05, 5.59 – 6.50, p ⬍ 0.001). However, the patients with rebleeding (2 vs 3), volume of blood transfusion (median, range: 1000 ml, 0 –2250 vs 750, 0 –2000), number of operations (0 vs 1), mortality caused by bleeding (0 vs 0), and hospital stay (median, range: 6 days, 3–14 vs 7, 5–16) were not statistically different from those without H. pylori infection. CONCLUSIONS: Omeprazole does increase intragastric pH in bleeding peptic ulcer patients with H. pylori infection. However, the presence of H. pylori infection does not affect the short-term rebleeding rate in these patients. (Am J Gastroenterol 1999;94:3184 –3188. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Patients with major bleeding and endoscopic evidence of an ulcer with active bleeding or a nonbleeding visible vessel (NBVV) are at high risk for persistent or recurrent bleeding and should receive endoscopic therapy (1). Although a high initial hemostatic rate can be obtained with endoscopic therapy, rebleeding occurs in 10 –30% of these patients (2– 4). Rebleeding has been consistently described as the most important prognostic factor (1). If it can be prevented, mortality is reduced accordingly. Recent reports have shown that eradication of Helicobacter pylori (H. pylori) markedly reduces recurrence of peptic ulcer (5, 6) and long-term rebleeding in patients with peptic ulcer (7–10). However, the influence of H. pylori on shortterm rebleeding rate in patients with peptic ulcer bleeding is still unclear. Omeprazole (OME) markedly increases intragastric pH in the presence of H. pylori infection in patients with peptic ulcer or in healthy subjects (11–14). A high intragastric pH is helpful in stabilizing the blood clot of the peptic ulcer and may thus prevent rebleeding in these patients (15). Therefore, we hypothesized that by using OME, H. pylori might reduce short-term rebleeding rate in patients with peptic ulcer bleeding after successful endoscopic therapy. The objectives of this study were to observe the influence of intravenous OME on intragastric pH and short-term rebleeding rate in patients with peptic ulcer bleeding and H. pylori infection after initial hemostasis had been achieved.
MATERIALS AND METHODS Patients were accepted for endoscopic therapy if a peptic ulcer with active bleeding or an NBVV was observed within 12 h of hospital admission. The possibility of endoscopic therapy and use of intravenous OME were discussed with patients or their relatives, and a written informed consent was obtained before the trial. After initial hemostasis was achieved with endoscopic therapy (heater probe thermocoagulation [HPT], multipolar electrocoagulation [MPEC], or injection with 1:10,000 epinephrine), the patients were en-
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rolled in the study. Endoscopic therapy was performed as described in our previous studies (3). This study was approved by the Clinical Research Committee in Veterans General Hospital-Taipei, Republic of China. Patients were excluded from the study if they were pregnant; did not give a written informed consent; had bleeding tendency (platelet count ⬍50,000/mm3, serum prothrombin ⬍30% of normal, or taking anticoagulants); had uremia, hepatic failure or bleeding gastric cancer; had used anticholinergic agents, bismuth, antibiotics, H2-blockers, or proton pump inhibitors within 1 wk; or had an allergic history to proton pump inhibitors. After initial hemostasis had been obtained, we obtained two specimens from the greater curvature site of the gastric body, and two specimens from the greater curvature site of the gastric antrum. One specimen from each location was sent for pathological examination with modified Giemsa’s stain, and the other was tested with a rapid urease test. After initial hemostasis had been obtained, OME was given 40 mg intravenously every 6 h for 3 days. Thereafter, OME was given 20 mg per os (p.o.) once daily for 2 months. A nasogastric tube and a pH meter (Gastrograph Mark III, Solothur, Switzerland) were inserted in each patient’s fundus under fluoroscopic guidance after intravenous OME had been administered. The intragastric pH was recorded and stored at 6-s intervals for 24 h. Patients’ vital signs were checked every hour for the first 12 h, every 2 h for the second 12 h, and every 4 h for the next 24 h until they became stable, then four times daily. The Hb and Hct were checked at least once daily, and a blood transfusion was given if the Hb dropped to ⬍9 g/dL or if the patient’s vital signs deteriorated. The attending physicians or surgeons were made aware of the exact endoscopic findings and treatment given in each case. Endoscopy was undertaken 72 h later. If no blood clot or hemorrhage was observed at the ulcer base, the patient was discharged and followed up at the outpatient department. Active bleeding was defined as a continuous blood flow spurting or oozing from the ulcer base. An NBVV at endoscopy was defined as a discrete protuberance at the ulcer base that was resistant to washing and was often associated with the freshest clot in the ulcer base. Shock was defined as systolic pressure ⬍100 mm Hg and pulse rate ⬎100 beats/ min accompanied by cold sweats, pallor, and oliguria. Positive cigarette smoking was defined as ⱖ10 cigarettes per day for at least 1 yr. Positive alcohol drinking was defined as ⱖ40 g/day alcohol consumption for at least 6 months. Initial hemostasis was defined as no visible hemorrhage lasting for 5 min after endoscopic therapy. Ultimate hemostasis was defined as no rebleeding during the 14 days after endoscopic therapy. Rebleeding was suspected if unstable vital signs or continued tarry, bloody stools or a drop of Hb ⬎2 g/dl within 24 h were observed during hospitalization. For these patients, an emergency endoscopy was performed immediately. Rebleeding was concluded if either blood in the stom-
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ach 24 h after therapy or a fresh blood clot or bleeding in the ulcer base was found. All rebleeders were treated a second time by endoscopic hemostasis unless they refused. An emergency operation was performed if bleeding could not be controlled with HPT or MPEC or rebleeding occurred after two attempts with HPT or MPEC therapy. At entry to the study, the following data were recorded: age, gender, the location of the ulcer (esophagus/stomach/ duodenum/stoma), ulcer size, the appearance of gastric contents (clear/coffee grounds/blood), stigmata of bleeding (spurting/oozing/NBVV), vital signs, Hb, smoking, alcohol consumption, comorbid illness, and volume of blood transfusion. The outcome of measure was intragastric pH on the first day, rebleeding rate at 14 days after entry to the study. At day 14, volume of blood transfused, number of surgeries performed, and the mortality rates of the two groups were compared. We used the Mann-Whitney U test to compare the basic data of age, ulcer size, volume of blood transfused after entry, initial Hb, intragastric pH, and hospital stay between both groups. The 2 test, with or without Yates’ correction, and Fisher’s exact test were used when appropriate, to compare gender, location of the bleed, gastric contents, stigmata of bleeding, presence/absence of shock, number of rebleeding episodes, emergency operations, mortality, and the hemostatic effect between the two groups. A probability value of ⬍0.05 was considered significant.
RESULTS Between July 1996 and December 1998, 67 patients received endoscopic therapy for peptic ulcer bleeding. Two patients did not agree to enter the trial. The other 65 patients agreed to enter the trial. Thirteen patients were enrolled during admission (six in the HP⫹ group, seven in the HP⫺ group, p ⬎ 0.1). The other patients were enrolled on an outpatient basis. The modalities of endoscopic therapy in the HP⫹ group (heater probe or gold probe therapy, 16 patients; epinephrine injection followed by heater probe or gold probe therapy, eight; epinephrine injection, five; fibrin injection, one) were not statistically different from those of the HP⫺ group (heater probe or gold probe therapy, 23 patients; epinephrine injection followed by heater probe or gold probe therapy, six; epinephrine injection, 6) (p ⬎ 0.1). We found H. pylori infection in 30 (46.2%) of the enrolled patients. The age, gender, location of bleeds, gastric content, stigmata of bleeding, numbers in shock, Hb, numbers with smoking, alcohol consumption, and comorbid illness were comparable between the H. pylori-positive (Hp⫹) and H. pylori-negative (Hp⫺) groups (Table 1). Rebleeding episodes occurred in two of the Hp⫹ group (one on the 2nd day and the other on the 4th day of enrollment). One of them received HPT and the other received MPEC therapy. Both patients obtained ultimate hemostasis. Rebleeding episodes occurred in three patients of
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Table 1. Clinical Parameters of the Patients Studied*
Median age (range), yr Gender (M/F) Location of ulcers Stomach Duodenum Ulcer size, cm (median, range) Gastric content Clear/coffee ground/blood Stigmata of bleeding Spurting/oozing/NBVV No. in shock Median hemoglobin (g/L), (range) Smoking Alcohol drinking Comorbid illness
H. pyloriPositive (n ⫽ 30)
H. pyloriNegative (n ⫽ 35)
65 (23–91) 30/0
73 (29–89) 34/1
13 17 0.9, 0.2–2.5
11 24 1.0, 0.2–2.0
10/8/12
12/9/14
5/6/19 4 104 (64–154) 8 2 12
6/9/20 6 94 (70–151) 10 2 15
* There was no statistically significant difference between the groups studied. NBVV ⫽ nonbleeding visible vessel.
the HP⫺ group (one on the first day, one on the second day, and one on the third day of enrollment). For these three patients, two obtained ultimate hemostasis after having received HPT; one received surgical intervention because of recurrent bleeding despite a second administration of HPT. There was no mortality from bleeding in either group. The volumes of blood transfusion and hospital stays were similar in both groups (Table 2). Overall, the intragastric pH was higher in the HP⫹ group (median, 95% confidence interval [CI]: 6.54, 5.90 – 6.68) than in the HP⫺ group (6.05, 5.59 – 6.50, p ⬍ 0.001). In the patients with gastric ulcer (GU), the intragastric pH was higher in the HP⫹ group (median, 95% CI: 6.4, 5.7– 6.7) than in the HP⫺ group (6.1, 4.9 – 6.5, p ⬍ 0.001). In the patients with duodenal ulcer (DU), the intragastric pH was higher in the HP⫹ group (median, 95% CI: 6.7, 5.9 – 6.9) than in the HP⫺ group (6.5, 5.7– 6.7, p ⬍ 0.001).
DISCUSSION A bleeding peptic ulcer remains a serious medical problem with significant morbidity and mortality. An ideal therapy includes a successful endoscopic therapy plus a low rebleeding rate. Table 2. Major Clinical Outcomes of Groups Studied* H. pyloriPositive (n ⫽ 30)
H. pyloriNegative (n ⫽ 35)
No. with rebleeding 2 3 Blood transfused after entry (ml), 1000 (0–2250) 750 (0–2000) median (range) No. of operations 0 1 Mortality due to bleeding 0 0 Days in hospital, median (range) 6 (3–14) 7 (5–16) * There was no statistically significant difference between the groups studied.
With conventional recommended doses of H2 blockers, intragastric pH cannot be maintained higher than 4.0 for a long time in patients with a bleeding peptic ulcer (16). The rebleeding rates of patients receiving H2 blockers and endoscopic therapy or oral omeprazole alone are around 10 – 30% (2, 15, 17). In this study, we used a high dose of intravenous omeprazole in every patient after successful endoscopic therapy. Pharmacologically, OME can quickly achieve an optimal intragastric pH condition for support of the physiological cascade of hemostasis (18). In our previous study, OME reduced rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy (19). Rebleeding episodes occur within 3 days in most instances after hemostasis has been obtained (2, 4, 20 –22). Therefore, we used OME intravenously for 3 days in this study. In this study, we obtained a similar rebleeding rate (5/65, 7.7%), which is much lower than those of other reports (2, 15, 17). The low rebleeding in this study may be explained by careful endoscopic therapy and usage of high dose of intravenous omeprazaole. Many clinical parameters (e.g., age, vital signs, color of gastric aspirate, initial Hb, and underlying comorbid illness) and endoscopic features (e.g., ulcer size and stigmata of bleeding) may influence the prognosis (23). All these parameters were similar between both studied groups. It has been reported that during treatment with OME, the intragastric pH is higher in patients with duodenal ulcer (12) and in healthy subjects (14) in the presence of H. pylori infection. In this study, we recorded 24-h intragastric pH in bleeding peptic ulcer patients receiving OME with or without H. pylori infection. We confirmed the previous studies showing that OME augmented the intragastric pH of bleeding peptic ulcer patients (either GU or DU) in the presence of H. pylori infection. In this study, we used OME intravenously and obtained similar results as the previous reports in which OME was administered orally. Therefore, the route of administration does not affect intragastric pH. The mechanisms by which H. pylori augments the pHincreasing effect of OME are still inconclusive, although several theories have been proposed. An increase in sensitivity of the parietal cell for proton-pump inhibitor, production of acid-neutralizing substances by H. pylori, or a combination of both have been proposed (11). Decreased secretory activity of the gastric parietal cells is proposed (24). H. pylori has been shown to increase alkaline substances, e.g., ammonia, carbamate, and leakage of bicarbonate from inflammatory mucosa (25, 26). H. pylori has been shown to block proton pump by producing fatty acid, most importantly 9,10-methyleneoctadecanoic acid and tetradecanoic acid (27). H. pylori can also produce a protein or protein-containing acid inhibitor (28). Gastritis caused by H. pylori leads to the synthesis of interleukin-1, a potent proton pump inhibitor (29). Chronic H. pylori infection may lead to mucosal atrophy with a subsequent decrease of acid output (30). H. pylori may lead
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to enlarged gastric fold accompanied by hyposecretion of gastric acid (31). However, in our study, we recorded intragastric pH immediately after intravenous OME. Therefore, anatomical change due to H. pylori infection is not to be blamed for intragastric pH change. Overall, the prevalence of H. pylori in patients who present with a bleeding peptic ulcer is 15–20% lower than in patients with nonbleeding ulcer (32). In this study, we found that only 46.2% of bleeding peptic ulcer patients had H. pylori infection. This is somewhat lower than that of the previous report. This may be explained by the fact that the peptic ulcer was caused by ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) in the HP⫺ group. In the HP⫺ group, we found NSAID ingestion in eight of the 11 GU patients (72.7%) and in 15 of the 24 DU patients (62.5%). The rebleeding rate of the HP⫹ group (6.7%) was similar to that of the HP⫺ group (8.6%) in this study. To avoid a type II error, the sample size should be increased. However, the sample size should be increased to 3369 to be statistically significant (␣ ⫽ 0.9,  ⫽ 0.1). Therefore, we discontinued the study. Hospital stay, number of surgeries, and mortality of the two groups were similar. This may be due to the early detection of rebleeding episodes and aggressive endoscopic therapy given, thus minimizing the differences between the two groups. In conclusion, omeprazole does increase the intragastric pH in bleeding peptic ulcer patients with H. pylori infection. However, the presence of H. pylori infection does not affect the short-term rebleeding rate in these patients. Reprint requests and correspondence: Hwai-Jeng Lin, M.D., Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, Taiwan, ROC. Received Apr. 1, 1999; accepted Aug. 3, 1999.
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7. 8. 9.
10.
11. 12. 13. 14. 15. 16.
17.
18. 19.
REFERENCES 1. Consensus Development Panel. Consensus statement on therapeutic endoscopy and bleeding ulcers. Gastrointest Endosc 1990;36:S62–5. 2. Lin HJ, Lee FY, Kang WM, et al. Heat probe thermocoagulation and pure alcohol injection in massive peptic ulcer haemorrhage: A prospective, randomized controlled trial. Gut 1990;31:753–7. 3. Lin HJ, Wang K, Perng CL, et al. Heat probe thermocoagulation and multipolar electrocoagulation for arrest of peptic ulcer bleeding: A prospective, randomized comparative trial. J Clin Gastroenterol 1995;21:99 –102. 4. Laine L. Multipolar electrocoagulation versus injection therapy in the treatment of bleeding peptic ulcers: A prospective, randomized trial. Gastroenterology 1990;99:1303– 6. 5. Laine L, Hopkins RJ, Girardi LS. Has the impact of Helicobacter pylori therapy on ulcer recurrence in the United States been overstated? A meta-analysis of rigorously designed trials. Am J Gastroenterol 1998;93:1409 –15 6. Labenz J, Borsch G. Highly significant change of the clinical course of relapsing and complicated peptic ulcer disease after
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cure of Helicobacter pylori infection. Am J Gastroenterol 1994;89:1785– 8. Rokkas T, Karameris A, Mavrogeorgis A, et al. Eradication of Helicobacter pylori reduces the possibility of rebleeding in peptic ulcer disease. Gastrointest Endosc 1995;41:1– 4. Jaspersen D, Koerner T, Schorr W, et al. Helicobacter pylori eradication reduces the rate of rebleeding in ulcer hemorrhage. Gastrointest Endosc 1995;41:5–7. Riemann JF, Schilling D, Schauwecker P, et al. Cure with omeprazole plus amoxicillin versus long-term ranitidine therapy in Helicobacter pylori-associated peptic ulcer bleeding. Gastrointest Endosc 1997;46:299 –304. Macri G, Milani S, Surrenti E, et al. Eradication of Helicobacter pylori reduces the rate of duodenal ulcer rebleeding: A long-term follow-up study. Am J Gastroenterol 1998;93: 925–7. Smout AJPM. Is the sensitivity to gastric acid inhibition Helicobacter pylori status-dependent? Scand J Gastroenterol 1998;33(suppl 225):32–5. Labenz J, Tillenburg B, Peitz U, et al. Helicobacter pylori augments the pH-increasing effect of omeprazole in patients with duodenal ulcer. Gastroenterology 1996;110:725–32. Verdu´ EF, Armstrong D, Idstro¨m JP, et al. Effect of curing Helicobacter pylori infection on intragastric pH during treatment with omeprazole. Gut 1995;37:743– 8. Verdu´ EF, Armstrong D, Fraser R, et al. Effect of Helicobacter pylori status on intragastric pH during treatment with omeprazole. Gut 1995;36:539 – 43. Khuroo MS, Yattoo GN, Javid G, et al. A comparison of omeprazole and placebo for bleeding peptic ulcer. N Engl J Med 1997;336:1054 – 8. Reynolds JR, Walt PR, Clark AG, et al. Intragastric pH monitoring in acute upper gastrointestinal bleeding and the effect of intravenous cimetidine and ranitidine. Aliment Pharmacol Ther 1987;1:23–30. Gralnek IM, Jensen DM, Gornbein J, et al. Clinical and economic outcomes of individuals with severe peptic ulcer hemorrhage and nonbleeding visible vessel: An analysis of two prospective clinical trials. Am J Gastroenterol 1998;93:2047–56. Brunner G, Luna P, Thiesemann C. Drugs for pH control in upper gastrointestinal bleeding. Aliment Pharmacol Ther 1995;9:47–50. Lin HJ, Lo WC, Lee FY, et al. 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 – 8. Lin HJ, Perng CL, Lee FY, et al. Clinical courses and predictors for rebleeding in patients with peptic ulcers and nonbleeding visible vessels: A prospective study. Gut 1994;35: 1389 –93. Lin HJ, Perng CL, Wang K, et al. Long-term results of heater probe thermocoagulation for patients with massive peptic ulcer bleeding: A prospective observation. Am J Gastroenterol 1995;90:44 –7. Lin HJ, Wang K, Perng CL, et al. Natural history of bleeding peptic ulcers with a tightly adherent blood clot: A prospective observation. Gastrointest Endosc 1996;43:470 –3. Laine L, Peterson WL. Bleeding peptic ulcer. N Engl J Med 1994;331:717–27. Taguchi Y, Kaito M, Gabazza EC, et al. Helicobacter pylori inhibits the secretory activity of gastric parietal cells in patients with chronic gastritis. Scan J Gastroenterol 1997;32: 656 – 63. Triebling AT, Korsten MA, Dulgosz JW, et al. Severity of Helicobacter-induced gastric injury correlates with gastric juice ammonia. Dig Dis Sci 1991;36:1089 –96.
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26. Mobley HLT, Hausinger RP. Microbial ureases: Significance, regulation and molecular characterization. Microbiol Rev 1989;53:85–108. 27. Beil W, Birkholz C, Wagner S, et al. Interaction of H. pylori and its fatty acids with parietal cells and gastric H⫹/K⫹ ATPase. Gut 1994;35:1176 – 80. 28. Cave DR, Vargas M. Effect of a Campylobacter pylori protein on acid secretion by parietal cells. Lancet 1989;ii:187–91. 29. Tache´ Y, Sapera E. Potent inhibition of gastric acid secretion and ulcer formation by centrally and peripherally administered interleukin-1a. Ann NY Acad Sci 1992;664:353– 68.
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30. Borody, TJ, Andrews P, Jankiewicz E, et al. Apparent reversal of early gastric mucosal atrophy after triple therapy for Helicobacter pylori. Am J Gastroenterol 1993;88:1266 – 8. 31. Yasunaga Y, Shinimura Y, Kanayama S, et al. Improved fold width and increased acid secretion after eradication of the organism in Helicobacter pylori-associated enlarged fold gastritis. Gut 1994;35:1571– 4. 32. Jensen DM, You S, Pelayo E, et al. The prevalence of Helicobacter pylori and NSAID use in patients with severe UGI haemorrhage and their portential role in recurrence of ulcer bleeding. Gastroenterology 1992;102:A85.
Vol. 94, No. 11, 1999 ISSN 0002-9270/99/$20.00 PII S0002-9270(99)00575-4
Will Helicobacter pylori Affect Short-Term Rebleeding Rate in Peptic Ulcer Bleeding Patients After Successful Endoscopic Therapy? Hwai-Jeng Lin, M.D., F.A.C.G., Guan-Ying Tseng, M.D., Yu-Hsi Hsieh, M.D., Chin-Lin Perng, M.D., Fa-Yauh Lee, M.D., F.A.C.G., Full-Young Chang, M.D., and Shou-Dong Lee, M.D., F.A.C.G. Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, and National Yang-Ming University, School of Medicine, Taipei, Taiwan, Republic of China
OBJECTIVE: Helicobacter pylori (H. pylori) can augment the pH-increasing effect of omeprazole in patients with peptic ulcer. A high intragastric pH may be helpful in preventing recurrent hemorrhage by stabilizing the blood clot at the ulcer base of bleeding peptic ulcer patients. Therefore, we hypothesized that omeprazole may reduce short-term rebleeding rate in these patients with H. pylori infection after initial hemostasis had been obtained. METHODS: Between July 1996 and December 1998, 65 bleeding peptic ulcer patients (24 gastric ulcer, 41 duodenal ulcer) who had obtained initial hemostasis with endoscopic therapy were enrolled in this trial. Thirty (46.2%) of them were found to have H. pylori infection by a rapid urease test and pathological examination. For all studied patients, omeprazole was given 40 mg intravenously every 6 h for 3 days. Thereafter, omeprazole was given 20 mg per os (p.o.) once daily for 2 months. A pH meter was inserted in the fundus of each patient under fluoroscopic guidance after intravenous omeprazole had been administered. The occurrence of rebleeding episode was observed for 14 days. RESULTS: In patients with H. pylori infection, intragastric pH (median, 95% confidence interval [CI]: 6.54, 5.90 – 6.68) was higher than in those without H. pylori infection (6.05, 5.59 – 6.50, p ⬍ 0.001). However, the patients with rebleeding (2 vs 3), volume of blood transfusion (median, range: 1000 ml, 0 –2250 vs 750, 0 –2000), number of operations (0 vs 1), mortality caused by bleeding (0 vs 0), and hospital stay (median, range: 6 days, 3–14 vs 7, 5–16) were not statistically different from those without H. pylori infection. CONCLUSIONS: Omeprazole does increase intragastric pH in bleeding peptic ulcer patients with H. pylori infection. However, the presence of H. pylori infection does not affect the short-term rebleeding rate in these patients. (Am J Gastroenterol 1999;94:3184 –3188. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION Patients with major bleeding and endoscopic evidence of an ulcer with active bleeding or a nonbleeding visible vessel (NBVV) are at high risk for persistent or recurrent bleeding and should receive endoscopic therapy (1). Although a high initial hemostatic rate can be obtained with endoscopic therapy, rebleeding occurs in 10 –30% of these patients (2– 4). Rebleeding has been consistently described as the most important prognostic factor (1). If it can be prevented, mortality is reduced accordingly. Recent reports have shown that eradication of Helicobacter pylori (H. pylori) markedly reduces recurrence of peptic ulcer (5, 6) and long-term rebleeding in patients with peptic ulcer (7–10). However, the influence of H. pylori on shortterm rebleeding rate in patients with peptic ulcer bleeding is still unclear. Omeprazole (OME) markedly increases intragastric pH in the presence of H. pylori infection in patients with peptic ulcer or in healthy subjects (11–14). A high intragastric pH is helpful in stabilizing the blood clot of the peptic ulcer and may thus prevent rebleeding in these patients (15). Therefore, we hypothesized that by using OME, H. pylori might reduce short-term rebleeding rate in patients with peptic ulcer bleeding after successful endoscopic therapy. The objectives of this study were to observe the influence of intravenous OME on intragastric pH and short-term rebleeding rate in patients with peptic ulcer bleeding and H. pylori infection after initial hemostasis had been achieved.
MATERIALS AND METHODS Patients were accepted for endoscopic therapy if a peptic ulcer with active bleeding or an NBVV was observed within 12 h of hospital admission. The possibility of endoscopic therapy and use of intravenous OME were discussed with patients or their relatives, and a written informed consent was obtained before the trial. After initial hemostasis was achieved with endoscopic therapy (heater probe thermocoagulation [HPT], multipolar electrocoagulation [MPEC], or injection with 1:10,000 epinephrine), the patients were en-
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rolled in the study. Endoscopic therapy was performed as described in our previous studies (3). This study was approved by the Clinical Research Committee in Veterans General Hospital-Taipei, Republic of China. Patients were excluded from the study if they were pregnant; did not give a written informed consent; had bleeding tendency (platelet count ⬍50,000/mm3, serum prothrombin ⬍30% of normal, or taking anticoagulants); had uremia, hepatic failure or bleeding gastric cancer; had used anticholinergic agents, bismuth, antibiotics, H2-blockers, or proton pump inhibitors within 1 wk; or had an allergic history to proton pump inhibitors. After initial hemostasis had been obtained, we obtained two specimens from the greater curvature site of the gastric body, and two specimens from the greater curvature site of the gastric antrum. One specimen from each location was sent for pathological examination with modified Giemsa’s stain, and the other was tested with a rapid urease test. After initial hemostasis had been obtained, OME was given 40 mg intravenously every 6 h for 3 days. Thereafter, OME was given 20 mg per os (p.o.) once daily for 2 months. A nasogastric tube and a pH meter (Gastrograph Mark III, Solothur, Switzerland) were inserted in each patient’s fundus under fluoroscopic guidance after intravenous OME had been administered. The intragastric pH was recorded and stored at 6-s intervals for 24 h. Patients’ vital signs were checked every hour for the first 12 h, every 2 h for the second 12 h, and every 4 h for the next 24 h until they became stable, then four times daily. The Hb and Hct were checked at least once daily, and a blood transfusion was given if the Hb dropped to ⬍9 g/dL or if the patient’s vital signs deteriorated. The attending physicians or surgeons were made aware of the exact endoscopic findings and treatment given in each case. Endoscopy was undertaken 72 h later. If no blood clot or hemorrhage was observed at the ulcer base, the patient was discharged and followed up at the outpatient department. Active bleeding was defined as a continuous blood flow spurting or oozing from the ulcer base. An NBVV at endoscopy was defined as a discrete protuberance at the ulcer base that was resistant to washing and was often associated with the freshest clot in the ulcer base. Shock was defined as systolic pressure ⬍100 mm Hg and pulse rate ⬎100 beats/ min accompanied by cold sweats, pallor, and oliguria. Positive cigarette smoking was defined as ⱖ10 cigarettes per day for at least 1 yr. Positive alcohol drinking was defined as ⱖ40 g/day alcohol consumption for at least 6 months. Initial hemostasis was defined as no visible hemorrhage lasting for 5 min after endoscopic therapy. Ultimate hemostasis was defined as no rebleeding during the 14 days after endoscopic therapy. Rebleeding was suspected if unstable vital signs or continued tarry, bloody stools or a drop of Hb ⬎2 g/dl within 24 h were observed during hospitalization. For these patients, an emergency endoscopy was performed immediately. Rebleeding was concluded if either blood in the stom-
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ach 24 h after therapy or a fresh blood clot or bleeding in the ulcer base was found. All rebleeders were treated a second time by endoscopic hemostasis unless they refused. An emergency operation was performed if bleeding could not be controlled with HPT or MPEC or rebleeding occurred after two attempts with HPT or MPEC therapy. At entry to the study, the following data were recorded: age, gender, the location of the ulcer (esophagus/stomach/ duodenum/stoma), ulcer size, the appearance of gastric contents (clear/coffee grounds/blood), stigmata of bleeding (spurting/oozing/NBVV), vital signs, Hb, smoking, alcohol consumption, comorbid illness, and volume of blood transfusion. The outcome of measure was intragastric pH on the first day, rebleeding rate at 14 days after entry to the study. At day 14, volume of blood transfused, number of surgeries performed, and the mortality rates of the two groups were compared. We used the Mann-Whitney U test to compare the basic data of age, ulcer size, volume of blood transfused after entry, initial Hb, intragastric pH, and hospital stay between both groups. The 2 test, with or without Yates’ correction, and Fisher’s exact test were used when appropriate, to compare gender, location of the bleed, gastric contents, stigmata of bleeding, presence/absence of shock, number of rebleeding episodes, emergency operations, mortality, and the hemostatic effect between the two groups. A probability value of ⬍0.05 was considered significant.
RESULTS Between July 1996 and December 1998, 67 patients received endoscopic therapy for peptic ulcer bleeding. Two patients did not agree to enter the trial. The other 65 patients agreed to enter the trial. Thirteen patients were enrolled during admission (six in the HP⫹ group, seven in the HP⫺ group, p ⬎ 0.1). The other patients were enrolled on an outpatient basis. The modalities of endoscopic therapy in the HP⫹ group (heater probe or gold probe therapy, 16 patients; epinephrine injection followed by heater probe or gold probe therapy, eight; epinephrine injection, five; fibrin injection, one) were not statistically different from those of the HP⫺ group (heater probe or gold probe therapy, 23 patients; epinephrine injection followed by heater probe or gold probe therapy, six; epinephrine injection, 6) (p ⬎ 0.1). We found H. pylori infection in 30 (46.2%) of the enrolled patients. The age, gender, location of bleeds, gastric content, stigmata of bleeding, numbers in shock, Hb, numbers with smoking, alcohol consumption, and comorbid illness were comparable between the H. pylori-positive (Hp⫹) and H. pylori-negative (Hp⫺) groups (Table 1). Rebleeding episodes occurred in two of the Hp⫹ group (one on the 2nd day and the other on the 4th day of enrollment). One of them received HPT and the other received MPEC therapy. Both patients obtained ultimate hemostasis. Rebleeding episodes occurred in three patients of
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Table 1. Clinical Parameters of the Patients Studied*
Median age (range), yr Gender (M/F) Location of ulcers Stomach Duodenum Ulcer size, cm (median, range) Gastric content Clear/coffee ground/blood Stigmata of bleeding Spurting/oozing/NBVV No. in shock Median hemoglobin (g/L), (range) Smoking Alcohol drinking Comorbid illness
H. pyloriPositive (n ⫽ 30)
H. pyloriNegative (n ⫽ 35)
65 (23–91) 30/0
73 (29–89) 34/1
13 17 0.9, 0.2–2.5
11 24 1.0, 0.2–2.0
10/8/12
12/9/14
5/6/19 4 104 (64–154) 8 2 12
6/9/20 6 94 (70–151) 10 2 15
* There was no statistically significant difference between the groups studied. NBVV ⫽ nonbleeding visible vessel.
the HP⫺ group (one on the first day, one on the second day, and one on the third day of enrollment). For these three patients, two obtained ultimate hemostasis after having received HPT; one received surgical intervention because of recurrent bleeding despite a second administration of HPT. There was no mortality from bleeding in either group. The volumes of blood transfusion and hospital stays were similar in both groups (Table 2). Overall, the intragastric pH was higher in the HP⫹ group (median, 95% confidence interval [CI]: 6.54, 5.90 – 6.68) than in the HP⫺ group (6.05, 5.59 – 6.50, p ⬍ 0.001). In the patients with gastric ulcer (GU), the intragastric pH was higher in the HP⫹ group (median, 95% CI: 6.4, 5.7– 6.7) than in the HP⫺ group (6.1, 4.9 – 6.5, p ⬍ 0.001). In the patients with duodenal ulcer (DU), the intragastric pH was higher in the HP⫹ group (median, 95% CI: 6.7, 5.9 – 6.9) than in the HP⫺ group (6.5, 5.7– 6.7, p ⬍ 0.001).
DISCUSSION A bleeding peptic ulcer remains a serious medical problem with significant morbidity and mortality. An ideal therapy includes a successful endoscopic therapy plus a low rebleeding rate. Table 2. Major Clinical Outcomes of Groups Studied* H. pyloriPositive (n ⫽ 30)
H. pyloriNegative (n ⫽ 35)
No. with rebleeding 2 3 Blood transfused after entry (ml), 1000 (0–2250) 750 (0–2000) median (range) No. of operations 0 1 Mortality due to bleeding 0 0 Days in hospital, median (range) 6 (3–14) 7 (5–16) * There was no statistically significant difference between the groups studied.
With conventional recommended doses of H2 blockers, intragastric pH cannot be maintained higher than 4.0 for a long time in patients with a bleeding peptic ulcer (16). The rebleeding rates of patients receiving H2 blockers and endoscopic therapy or oral omeprazole alone are around 10 – 30% (2, 15, 17). In this study, we used a high dose of intravenous omeprazole in every patient after successful endoscopic therapy. Pharmacologically, OME can quickly achieve an optimal intragastric pH condition for support of the physiological cascade of hemostasis (18). In our previous study, OME reduced rebleeding in patients with bleeding peptic ulcer after successful endoscopic therapy (19). Rebleeding episodes occur within 3 days in most instances after hemostasis has been obtained (2, 4, 20 –22). Therefore, we used OME intravenously for 3 days in this study. In this study, we obtained a similar rebleeding rate (5/65, 7.7%), which is much lower than those of other reports (2, 15, 17). The low rebleeding in this study may be explained by careful endoscopic therapy and usage of high dose of intravenous omeprazaole. Many clinical parameters (e.g., age, vital signs, color of gastric aspirate, initial Hb, and underlying comorbid illness) and endoscopic features (e.g., ulcer size and stigmata of bleeding) may influence the prognosis (23). All these parameters were similar between both studied groups. It has been reported that during treatment with OME, the intragastric pH is higher in patients with duodenal ulcer (12) and in healthy subjects (14) in the presence of H. pylori infection. In this study, we recorded 24-h intragastric pH in bleeding peptic ulcer patients receiving OME with or without H. pylori infection. We confirmed the previous studies showing that OME augmented the intragastric pH of bleeding peptic ulcer patients (either GU or DU) in the presence of H. pylori infection. In this study, we used OME intravenously and obtained similar results as the previous reports in which OME was administered orally. Therefore, the route of administration does not affect intragastric pH. The mechanisms by which H. pylori augments the pHincreasing effect of OME are still inconclusive, although several theories have been proposed. An increase in sensitivity of the parietal cell for proton-pump inhibitor, production of acid-neutralizing substances by H. pylori, or a combination of both have been proposed (11). Decreased secretory activity of the gastric parietal cells is proposed (24). H. pylori has been shown to increase alkaline substances, e.g., ammonia, carbamate, and leakage of bicarbonate from inflammatory mucosa (25, 26). H. pylori has been shown to block proton pump by producing fatty acid, most importantly 9,10-methyleneoctadecanoic acid and tetradecanoic acid (27). H. pylori can also produce a protein or protein-containing acid inhibitor (28). Gastritis caused by H. pylori leads to the synthesis of interleukin-1, a potent proton pump inhibitor (29). Chronic H. pylori infection may lead to mucosal atrophy with a subsequent decrease of acid output (30). H. pylori may lead
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to enlarged gastric fold accompanied by hyposecretion of gastric acid (31). However, in our study, we recorded intragastric pH immediately after intravenous OME. Therefore, anatomical change due to H. pylori infection is not to be blamed for intragastric pH change. Overall, the prevalence of H. pylori in patients who present with a bleeding peptic ulcer is 15–20% lower than in patients with nonbleeding ulcer (32). In this study, we found that only 46.2% of bleeding peptic ulcer patients had H. pylori infection. This is somewhat lower than that of the previous report. This may be explained by the fact that the peptic ulcer was caused by ingestion of nonsteroidal antiinflammatory drugs (NSAIDs) in the HP⫺ group. In the HP⫺ group, we found NSAID ingestion in eight of the 11 GU patients (72.7%) and in 15 of the 24 DU patients (62.5%). The rebleeding rate of the HP⫹ group (6.7%) was similar to that of the HP⫺ group (8.6%) in this study. To avoid a type II error, the sample size should be increased. However, the sample size should be increased to 3369 to be statistically significant (␣ ⫽ 0.9,  ⫽ 0.1). Therefore, we discontinued the study. Hospital stay, number of surgeries, and mortality of the two groups were similar. This may be due to the early detection of rebleeding episodes and aggressive endoscopic therapy given, thus minimizing the differences between the two groups. In conclusion, omeprazole does increase the intragastric pH in bleeding peptic ulcer patients with H. pylori infection. However, the presence of H. pylori infection does not affect the short-term rebleeding rate in these patients. Reprint requests and correspondence: Hwai-Jeng Lin, M.D., Division of Gastroenterology, Department of Medicine, Veterans General Hospital-Taipei, Taiwan, ROC. Received Apr. 1, 1999; accepted Aug. 3, 1999.
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7. 8. 9.
10.
11. 12. 13. 14. 15. 16.
17.
18. 19.
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