Prophylaxis of Gastrointestinal Tract Bleeding with Magaldrate in Patients Admitted to a General Hospital Ward
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R. ESTRUCH, E. PEDROL, A. CASTELLS, F. MASANES, R. M. MARRADES & A. URBANO-MARQUEZ Depts. of Internal Medicine and Gastroenterology, Hospital Clinic, University of Barcelona, Barcelona, Spain
Estruch R , Pedro1 E, Castells A, MasanCs F, Marrades RM, Urbano-Marquez A. Prophylaxis of gastrointestinal tract bleeding with magaldrate in patients admitted to a general hospital ward. Scand J Gastroenterol 1991, 26, 819-826 A randomized, placebo-controlled trial was performed to assess the effect of magaldrate (800 mg every 4 h) in reducing the rate of upper gastrointestinal tract bleeding among 100 consecutive patients with severe diseases admitted to a general hospital ward. Upper gastrointestinal tract bleeding occurred in 11 of 48 placebo-treated patients and in only 1 of 52 magaldrate-treated patients ( p < 0.01). Endoscopic examination of these patients showed gastric ulcer (two cases), multiple gastric mucosa ulcerations (nine), and no lesions (one). In three patients who received placebo the hemorrhage was clinically relevant and required transfusion of two or more blood units. Patients with two or more risk factors showed a higher rate of gastrointestinal hemorrhage ( p < 0.05). Respiratory failure and treatment with a high dose of corticosteroids were associated with the highest incidence of bleeding ( p < 0.05 for both). The only adverse reaction associated with magaldrate was a mild and self-limiting diarrhea in two cases. We conclude that patients seriously ill admitted to a general hospital ward should be treated with a prophylactic agent against stressinduced ulcer bleeding. Magaldrate is an effective and safe antacid to prevent gastrointestinal tract bleeding in such patients.
Key words: Antacids; gastrointestinal tract bleeding; magaldrate; prophylaxis; stress ulcer R . Estruch, M .D., Dept. of Internal Medicine, Hospital Clinic, Villarroell70, 08036 Barcelona, Spain
Seriously ill patients risk developing acute upper gastrointestinal tract bleeding from stress-induced gastritis and acute gastric ulcerations (1-5). Previous studies have found that antacids, sucralfate, and histamine H2-receptor antagonists are effective in protecting against acute upper gastrointestinal bleeding in critically ill patients treated in intensive care units (5-19). However, many patients with severe diseases treated in general hospital wards, who are not so critically ill that they need to be referred to an intensive care unit, probably have a similar incidence and severity of acute bleeding as those admitted to such units. We embarked, therefore, on a randomized placebo-
controlled trial to evaluate the incidence of acute gastrointestinal tract bleeding in seriously ill patients treated in a general hospital ward and the efficacy of a new antacid, magaldrate, in the prevention of gastrointestinal tract bleeding in such patients. MATERIALS AND METHODS Patient selection and treatment This study was conducted in the Hospital Clinic of Barcelona. This is a 1000-bed teaching hospital with a total of 40 beds in the surgical, medical, and coronary intensive care units. Patients requiring
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intubation and mechanical ventilation, those with acute gastrointestinal bleeding, acute myocardial infarction, shock, acute renal failure requiring hemodialysis, severe burns, and traumas, and those who had undergone cardiac, gastric, or esophageal surgical interventions are admitted to the different intensive care units. These Datients usually show a simplified acute physiologic score (SAPS) of seven points or more (20). The other patients are admitted to the general hospital wards. A series of 100 consecutive patients with severe diseases admitted to the Dept. of Internal Medicine of our hospital over a period of 8 months were selected for the study. The criteria for inclusion were respiratory failure (basal PO,, lower than 60 mmHg at admission), heart failure (requiring inotropic treatment), sepsis, thrombotic or hemorrhagic stroke, liver failure (encephalopathy or jaundice), renal insufficiency (serum creatinine above 350 pmol/l), or treatment with corticosteroids (more than 250 mg of prednisone a day), heparin (1 mg/kg body weight/ 4 h), or warfarin. Patients who had had any evidence of upper gastrointestinal tract bleeding before the study, those who had undergone cardiac, gastric, or esophageal operations, and those who had presented with regurgitation, heartburn, dysphagia, epigastric pain, or other gastrointestinal symptoms during the past year or were receiving treatment with antacids or H2receptor antagonist treatments were excluded from the study. Informed consent was obtained from each patient before inclusion in the trial, and the study was approved by our Institutional Committee on Clinical Investigation. This study was designed to be a randomized single-blind placebo-controlled study. Patients were randomized by a table of random numbers to receive either magaldrate or placebo in a dose of 800 mg at 8,12,16,20, and 24 h. These patients had usually had breakfast at 0900h, lunch at 1300h, and dinner at 1900h. Magaldrate is a new antacid whose structure is a mixed crystal of A1(OH)3 and Mg(OH)2in the form of a laminated lattice (21). Gastric pH was not assessed because the patients were able to feed themselves and did not need nasogastric intubation.
Table I. Principal diagnoses of the patients included in the study
Magaldrate
Placebo 24 3 1 2 1 5 1 4 3
Systemic vasculitis
28 4 1 2 2 3 3 2 2 2 2 1
Total
52
48
Chronic respiratory
Heart failure Chronicrenal failure Bronchial asthma
Neoplasms pneumonia
Liver cirrhosis Deep-vein thrombosis Thrombotic stroke Hemorrhagic stroke
1 1
2
Study protocol
Each patient’s demographic characteristics, diagnosis at admission, underlying diseases, medications, and evidence of upper gastrointestinal tract bleeding were recorded. The following laboratory analyses were also performed at admission: erythrocyte and leukocyte counts, hemoglobin, hematocrit, platelet count, prothrombin time, glucose, creatinine, electrolytes, uric acid, serum alanine and aspartate aminotransferases (ALAT, ASAT), gamma-glutamyl transpeptidase, lactic dehydrogenase, alkaline phosphatase, bilirubin, total protein, protein electrophoresis, cholesterol, and triglycerides. In addition, stools were examined for frank or occult blood with the Hemoccult@paper test (Smith, Kline and French Co.). Arterial blood gas measurements were also carried out in patients with respiratory failure. Patients were examined daily for evidence of hematemesis, melena, nausea, vomiting, abdominal pain, or diarrhea. Stools were also examined daily for the presence of occult blood. At the end of the study the laboratory variables previously analyzed were re-evaluated. The study ended when the patient was discharged from the general hospital unit. Prophylaxis was considered a failure when the patient developed frank hematemesis or melena or uniformly dark-blue reaction with the Hemoccult test on two consecutive stool readings. In these patients, laboratory assessment, nasogastric aspiration, and esophagogastroduodenal endos-
Prophylaxis of Gastrointestinal Bleeding
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copy were performed, and magaldrate or ranitidine was given if the patient was in the placebo or antacid group, respectively. Toxicity was assessed through symptomspecific questioning, and any drug-related side effects were recorded. The investigator was responsible for determining the relationship of any adverse effects to the therapeutic regimen. Statistical analysis The collected data were analyzed with the SPSS-XStatistical Package for the Social Sciences (22). Differences between groups were analyzed by means of the two-tailed t test for continuous variables and the Pearson chi-square test together with the Yates correction when necessary or Fisher exact test for quality variables. The data are presented as mean standard deviation
*
W). RESULTS Clinical data Fifty-seven men and 43 women with a mean age of 65 years (range, 20-92 years) were included in the study. No patients refused to participate in the trial. After randomization, 52 received magaldrate and 48 placebo. The principal diagnoses of these patients are shown in Table I. The mean SAPS of these patients was 3.5 1.6. Except for a slight difference in sex distribution, there were no statistically significant differences between antacid and placebo groups in the number of patients, age, underlying diseases, previous
*
treatments, or length of study per patient (Table 11). Fourteen patients in the antacid group and 15 in the placebo group had had a history of gastrointestinal diseases, mainly gastritis, peptic ulcer, and hiatal hernia; however, no differences were observed between the two groups. Furthermore, all these patients had remained asymptomatic during the year previous to the study. In addition, the Hemoccult paper test of stools was negative in all patients at the beginning of the study. Thirteen major risk factors for gastrointestinal tract bleeding were analyzed in each patient. These risk factors were respiratory failure, sepsis, heart failure, hepatic encephalopathy, jaundice, renal failure, stroke, hypotension, previous gastrointestinal disease, and treatment with corticosteroids, non-steroidal-anti-inflammatory drugs, heparin, or warfarin. There were 110 risk factors in 52 patients in the antacid group, with a mean of 2.11 risk factors per patient, and 97 in 48 patients in the placebo group, with a mean of 2.02 risk factors per patient. No significant differences in the percentage of patients with any of these risk factors were observed (Table 111). Furthermore, there were no statistically significant differences in the severity of these risk factors evaluated by clinical and laboratory assessment. Finally, there was one death in the placebo group (one patient with an hemorrhagic stroke) and two in the magaldrate group (one patient with an adenocarcinoma of the lung and the other with non-Hodgkin’s lymphoma). Gastrointestinal bleeding or complications related to ant-
Table 11. Clinical data of the patients included in the study Magaldrate ~~
~
Age (years) Sex W/F) (n> History of peptic ulcer ( n ) Gastritis Hernia hiatal Previous treatment with ( n ) NSAIDs Corticosteroids Warfarin Duration of the study (days) NSAIDs = non-steroidal anti-inflammatory drugs.
821
*
Placebo
*
64.5 16.8 24/28 I 4 3
67.4 16.1 33/15 6 3 6
5 18 0 6.78 2 2.8
5 19 1 7.34 4.2
*
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Table 111. Risk factors of acute gastrointestinal tract bleeding for the patients at the admission to the study
Respiratory failure Sepsis Heart failure Hepatic encephalopathy Jaundice Renal failure Stroke Hypotension Previous GI disease Corticosteroid NSAIDs Heparin Warfarin Total
Magaldrate
Placebo
31 5 9 2 3 2 4 2 14 30 4 4 0
27 3 3 4 4 3 2 2 15 28 1 4 1
110
97
NSAIDs = non-steroidal anti-inflammatory drugs; GI = gastrointestinal.
acid use were not thought to have contributed to death in any patient of the study. Gastrointestinal tract bleeding One of the 52 patients from the antacid group (1.9%) and 11 of the 48 patients who were not receiving prophylaxis (placebo group) (22.9%) had evidence of gastrointestinal tract bleeding during the period of the study ( p < 0.01). The clinical data of the patients who bled are shown
in Table IV. Three patients from the placebo group presented with a frank melena, and bleeding was detected by stool examination for occult blood in the remaining patients. Nasogastric aspirates demonstrated gastric hemorrhage in eight of these patients, and endoscopic examination showed a stress ulcer in two cases, erosive gastritis in eight, and no lesions in the last patient. In five patients the bleeding was mild (hematocrit decrease, less than 5%), in three it was moderate (hematocrit reduction, between 5% and lo%), and in the remaining three the gastrointestinal hemorrhage was severe, with a hematocrit decrease of more than l o % , and a blood transfusion of two or more units was required. The bleeding of the patient treated with magaldrate was mild (hematocrit decrease of 2%) and detected by stool examination. Endoscopy showed minimal erosive gastritis. Magaldrate was added to the therapy of the eight patients of the placebo group with mild or moderate gastrointestinal bleeding. The three patients with frank hemorrhage and the patient from the antacid group were treated with magaldrate and ranitidine. All patients stopped bleeding, and the Hemoccult test subsequently converted to trace and negative. Twelve patients in the magaldrate group and 11 in the placebo group had one risk factor.
Table IV. Clinical data of the patients who presented evidence of upper gastrointestinal tract bleeding Treatment
Age
Sex
Previous GI disease
P
40 64 56 34 74 64 57 75 85 66 77 14
M
-
M M
G G -
M P P P P P P P
P P
P
F
M M F M M F F F
Medication
Stress
C C
RF RF TS RF H, S, RF, Rf HE RF HF RF RF, HF HS
Gastric lesions
Hematocrit decrease
Bleeding day
Ulcer EG EG EG EG EG EG EG EG
5% 2% 7% 8% 2% 2% 2% 4% 10% 4% 14% 16%
3
Ulcer EG
4 7 5 12 7 3
5 21 5 4 6
P = placebo; M = magaldrate; M = male; F = female; G = gastritis; H = heparin; C = corticosteroids; NSAID = non-steroidal anti-inflammatory drug; R F = respiratory failure; TS = thrombotic stroke; H = hypotension; S = sepsis; R = renal failure; HE = hepatic encephalophy; H F = heart failure; HS = hemorrhagic stroke; EG = erosive gastritis.
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Prophylaxis of Gastrointestinal Bleeding
Twenty-four patients in both groups showed 2 risk factors, and 16 in the former group and 12 in the latter group had 3 or more risk factors. In patients with 1 risk factor the frequency of bleeding was 0% (0 of 12 cases) for those receiving magaldrate and 9.1% (1 of 11) for those who received placebo ( p = NS). When two risk factors were present, the respective figures were 0% (0 of 24) and 20.8% (5 of 24) ( p = 0.02). Finally, when 3 or more risk factors were present, the percentage of bleeding was 6.2% (1 of 16) in the magaldrate group and 41.6% (5 of 12) in the placebo group ( p = 0.03) (Fig. 1). Furthermore, the incidence of gastrointestinal tract bleeding was significantly higher in patients with chronic respiratory failure and those who were treated with high doses of corticosteroids ( p < 0.05, both). Only 2 of the 15 patients from the placebo group and none from the antacid group with a history of previous gastric disease bled ( p = NS). Complications of treatment Seven patients in the antacid group and 10 in the placebo group developed epigastric pain,
r
26
24 22
1
nausea, or vomiting, but in all cases these complaints were related to other medications such as non-steroidal anti-inflammatory drugs or corticosteroids. None of these patients bled. The only symptom related to magaldrate treatment was diarrhea in two cases, but this complication was mild and self-limiting, so it was not necessary to discontinue the antacid therapy. No significant changes in laboratory variables were observed between the beginning and the end of the study.
DISCUSSION Bleeding in the upper gastrointestinal tract due to stress ulcers is a serious complication in critically ill patients and is associated with increased morbidity and mortality ( 1 4 ) . Previous studies have demonstrated a significantly higher rate of gastrointestinal hemorrhage in patients treated in intensive care units with respiratory failure, hypotension, extra-abdominal sepsis, peritonitis, burns, trauma, or hepatic failure and those who had undergone surgical procedures (4-19,23-25). Furthermore, the risk of bleeding seems to be
MAGALDRATE GROUP (n=52)
z -
0PATIENTS PATIENTS
CONTROL GROUP
3-b ~.
NUMBER
823
OF
RJSK
FACTORS
WITHOUT BLEEDING BLED
Fig. 1. Distribution of the patients by the number of risk factors and the number of patients who bled in each group.
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higher in the patients with combinations of these at these doses (3,4). Histamine H2-receptor serious complications (4-5). Controlled studies antagonists constitute a convenient alternative with critically ill patients have shown a rate of for this purpose (12,14,1618,34-36); however, upper gastrointestinal tract bleeding between it has been suggested that the currently approved 15% and 54% (4, 11-13, 18, 24). In our study, intravenous bolus regimen of cimetidine and which included seriously but not critically ill ranitidine may not consistently maintain the patients treated in a general hospital ward (Dept. intragastric pH above 4.0 in intensive-care-treated of Internal Medicine), the rate of gastrointestinal patients and that a constant intravenous infusion bleeding was 22.9%. Thus, the rate of hem- may be preferable (37-41). orrhagic complications in such patients is quite In the present study the intragastric pH could similar to that of those treated in intensive care not be assessed, since the patients included were units. Consequently, adequate prophylaxis able to feed themselves and did not need nasoshould also be administered to seriously ill gastric intubation. Thus, we decided to use a new patients admitted to a general hospital ward to antacid, magaldrate, which is able to restore pH prevent these events. As in other previous studies to above 4 even in the presence of large amounts (4,5), patients with various risk factors had a of acid (21). Furthermore, this drug acts against significantly higher rate of gastrointestinal bleed- other important factors in the pathogenesis of the ing than those with only one risk factor. In our stress-induced gastric lesions. Thus, magaldrate study the patients with respiratory failure and also inhibits pepsin, is able to bind bile acids and those treated with high doses of corticosteroids lysolecithin, and has a protective effect on gastric were the most prone to bleed. By contrast, mucosa (20,4243). On the other hand, the patients with inactive gastritis, peptic ulcer, or absorption of magnesium and aluminum from the reflux esophagitis did not have a higher risk of molecule is very low because it has the form of a bleeding. Only 2 of the 12 patients who bled had laminated lattice (21). Although antacid was not a history of gastritis, although they had been titrated in our study, significant benefit was noted asymptomatic for the previous 10 years. among those who received magaldrate as comBleeding in seriously ill patients has been pared with placebo in prevention of upper gasrelated to gastritis and acute gastritis ulceration, trointestinal tract bleeding. Furthermore, only as was the case in our patients, although esopha- two patients treated with magaldrate showed mild geal and duodenal lesions may also occur (26- and self-limiting diarrhea. 28). The pathogenesis of these lesions is not comIn conclusion, seriously ill patients admitted to pletely understood. Although it is generally a general hospital ward should be treated prophyaccepted that acid is required for the formation lactically to prevent upper gastrointestinal of stress-induced gastric ulcerations, other factors hemorrhage, similarly to critically ill patients may play an important role in the pathogenesis admitted to an intensive care unit. In this study of these lesions-such as pepsin secretion, bile magaldrate has been shown to be a useful, effecsalt reflux, and the secretory state of the gastric tive, and safe antacid for prophylaxis against mucosa (29-31). stress-induced ulceration bleeding. Several studies had shown that maintenance of an intragastric pH above 4.0 is necessary to ACKNOWLEDGEMENT achieve effective prophylaxis treatment for upper gastrointestinal tract hemorrhage and stress Medication was supplied by Boehringer lesions in critically ill patients (4,18,31-32). Mannheim Laboratories. Antacid titration has been shown to be highly efREFERENCES fective in the prevention of upper gastrointestinal tract bleeding, but administration of large doses 1. Zinner MJ, Zuidema GD, Smith PL, Mignosa M. The prevention of upper gastrointestinaltract bleedof these drugs is necessary to increase intragastric ing in patients in an intensive care unit. Surg GynepH to above 4.0, and adverse effects are common col Obstet 1981, 153, 214-220
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Prophylaxis of Gastrointestinal Bleeding 2. Harris SK, Bone RC, Ruth WE. Gastrointestinal hemorrhage in patients in a respiratory intensive care unit. Chest 1977, 72, 301-304 3. Schuster DP, Rowley H, Feinstein S, McGue MK, Zuckerman GR. Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984, 76, 623-630 4. Hastings PR, Skillman JJ, Bushnell LS, Silen W. Antacid titration in the prevention of acute gastrointestinal bleeding. A controlled, randomized trial in 100critically ill patients. N Engl J Med 1978, 298, 1041-1045 5. Priebe HJ, Skillman JJ, Bushnell LS, Long PC, Silen W. Antacid versus cimetidine in preventing acute gastrointestinal bleeding. N Engl J Med 1980, 302, 426430 6. Borrero E, Mangolis IB, Bank S, Shulman N, Chardavoyne R. Antacid versus sucralfate in preventing acute gastrointestinal bleeding: a randomized trial in 100 critically ill patients. Am J Surg 1984, 148, 809-812 7. Tryba M, Zebounou F, Torok M, Zeuz M. Prevention of acute stress bleeding with sucralfate, antacids or cimetidine: a controlled study with pirenzepine as a basic medication. Am J Med 1985, 79(suppl 2C), 55-61 8. Borrero S, Bank S, Margolis I, Schulman ND, Chardavoyne R. Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who are critically ill. Am J Med 1985, ~ ~ ( S U P2C), P ~ 62-64 9. Sivestri N, Curzio M, Motta U, de Pietri P, Bonacina F, Minoja G. Cimetidine to prevent stress ulcers. Lancet 1980, 1, 885 10. Lawrie KJ, Cade JF. Ranitidine in prevention of acute upper gastrointestinal bleeding. Aust J Hosp Pharm 1983, 13, 130-133 11. MacDougall BRD, Bailey RJ, Williams R. H2receptor antagonists and antacids in the prevention of acute gastrointestinal hemorrhage in fulminant hepatic failure: two controlled trials. Lancet 1977, 1, 617-619 12. Poleski MH, Spanier AH. Endoscopic evaluation of cimetidine versus mylanta in prophylaxis of stress ulcerations. Gastroenterology 1982, 83, 111-115 13. Solem LD, Strate RG, Fisher RP. Antacid therapy and nutritional supplementation in the prevention of Curling’s ulcer. Surg Gynecol Obstet 1979, 148, 367-370 14. Stohtert JC, Simonowitz DA, Dellinger EP, et al. Randomized prospective evaluation of cimetidine and antacid control of gastric pH in the critically ill. Ann Surg 1980, 192, 169-174 15. Pescina I. Use of cimetidine in the prevention of stress ulcers in intensive care units. Clin Ther 1981, 3, 451-453 16. Cartier F, Gauthier-Lafave P, Larenc L, et al. Cimetidine in patients at risk of stress ulcers. Intensive Care Med 1980, 6, 54 17. Weigelt JA, Aurbakken CA, Gewerts BL, et al. Cimetidine versus antacids in prophylaxis for stress ulceration. Arch Surg 1981, 116, 597-601
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18. Zinner MJ, Zuidema GD, Smith PL, et al. The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981, 53, 214-220 19. Khan F, Parekh A , Pate1 S, et al. Results of gastric neutralization with hourly antacids and cimetidine in 320 intubated patients with respiratory failure. Chest 1981, 79, 409-412 20. Le Gall JR, Loirat P, Alperovitch A. Simplified acute physiological score for intensive care patients. Lancet 1983, 2, 741 21. Braun G. Riopan@-a new ulcer drug. Therapiewoche 1983, 47, 33-41 22. Nie NH, Hull CD, Jenkins JG, Steinbrenner K, Bent DH. Statistical package for the social sciences. McGraw-Hill, New York, 1975 23. Deweese MS. Gastrointestinal ulceration. J Trauma 1976, 7, 115-120 24. McAlhany JC, Czala AJ, Pruit BA. Antacid control of complications from acute gastroduodenal disease after burns. J Trauma 1976, 16, 645-648 25. McElwee HP, Sirinek KR, Levine BA. Cimetidine affords protection equal to antacids in prevention of stress ulceration following thermal injury. Surgery 1979, 86, 620-626 26. Anonymous. Prevention or cure for stress-induced gastrointestinal bleeding? Br Med J 1980,281, 631632 27. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ. Natural history and surgical dilemma of ‘stress’ gastric bleeding. Arch Surg 1971, 102, 266-273 28. Czaja AJ, McAlhany JC, Pruitt BA. Acute gastrointestinal disease after thermal injury. An endoscopy evaluation of incidence and natural history. N Engl J Med 1974, 291, 925-929 29. Ritchie WP. Acute gastric mucosa damage induced by bile salts, acid and ischemia. Gastroenterology 1975, 68, 699-707 30. Kivilaakso E, Fromm D, Silen W. Effect of the acid secretory state of intramural pH of rabbit gastric mucosa. Gastroenterology 1978, 75, 641-648 31. Kivilaakso E , Silen W. Pathogenesis of experimental gastric-mucosa injury. N Engl J Med 1979, 301, 364-369 32. Hillman K. Acute stress ulceration. Anaesth Intensive Care 1985, 3, 230-240 33. Gottlieb JE, Menashe PI, Cruz E. Gastrointestinal complications in critically ill patients: the intensivists’ overview. Am J Med 1986, 81, 227-238 34. Marchant J, Summers K, McIaac RL, Wood JR. A comparison of two ranitidine intravenous infusion regimens in critically ill patients. Aliment Pharmacol Ther 1988, 2, 55-63 35. More DG, Raper FR, Munro IA, Watson CJ, Boutagy JS, Shenfield GM. Randomized, prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985,97,215223 36. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987, 106, 562-567 37. Morris DL, Markharm S, Beachey A, Byme A.
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Bolus or infusion ranitidine for the control of intragastric pH in critically ill patients. Am J Gastroenterol 1985, 80, 865 38. Dammann HG, Flasshoff D, Muller P, Kather H, Simon B. Ranitidine and intragastric pH-profiles in acutely ill patients. Ital J Gastroenterol 1981, 13, 199-200 39. Albin M, Friedlos J, Hillman K. Continuous intragastric pH measurement in the critically ill and treatment with parenteral ranitidine. Intensive Care Med 1985, 11, 291-291) 40. Reid SR, Bayliff CD. The comparative efficacy of cimetidine and ranitidine in controlling gastric pH Received 12 October 1990 Accepted 14 February 1991
in critically ill patients. Can Anaesth SOCJ 1986,33, 287-293 41. Rigaud D, Chastre J, Accary JP, Bonfils S, Gilbert C, Hance AJ. Intragastric pH profile during acute respiratory failure in patients with chronic obstructive pulmonary disease. Effects of ranitidine and enteral feeding. Chest 1986, 90, 58-63 42. Cousar GD, Gadacz TR. Comparison of antacids on the binding of bile salts. Arch Surg 1984, 119, 1018-1020 43. Borella LE, DiJoseph JF, Mir GN. Cytoprotective and antiulcer activities of the antacid magaldrate in the rat. Arzneimittelforsh 1989, 39, 786789
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R. ESTRUCH, E. PEDROL, A. CASTELLS, F. MASANES, R. M. MARRADES & A. URBANO-MARQUEZ Depts. of Internal Medicine and Gastroenterology, Hospital Clinic, University of Barcelona, Barcelona, Spain
Estruch R , Pedro1 E, Castells A, MasanCs F, Marrades RM, Urbano-Marquez A. Prophylaxis of gastrointestinal tract bleeding with magaldrate in patients admitted to a general hospital ward. Scand J Gastroenterol 1991, 26, 819-826 A randomized, placebo-controlled trial was performed to assess the effect of magaldrate (800 mg every 4 h) in reducing the rate of upper gastrointestinal tract bleeding among 100 consecutive patients with severe diseases admitted to a general hospital ward. Upper gastrointestinal tract bleeding occurred in 11 of 48 placebo-treated patients and in only 1 of 52 magaldrate-treated patients ( p < 0.01). Endoscopic examination of these patients showed gastric ulcer (two cases), multiple gastric mucosa ulcerations (nine), and no lesions (one). In three patients who received placebo the hemorrhage was clinically relevant and required transfusion of two or more blood units. Patients with two or more risk factors showed a higher rate of gastrointestinal hemorrhage ( p < 0.05). Respiratory failure and treatment with a high dose of corticosteroids were associated with the highest incidence of bleeding ( p < 0.05 for both). The only adverse reaction associated with magaldrate was a mild and self-limiting diarrhea in two cases. We conclude that patients seriously ill admitted to a general hospital ward should be treated with a prophylactic agent against stressinduced ulcer bleeding. Magaldrate is an effective and safe antacid to prevent gastrointestinal tract bleeding in such patients.
Key words: Antacids; gastrointestinal tract bleeding; magaldrate; prophylaxis; stress ulcer R . Estruch, M .D., Dept. of Internal Medicine, Hospital Clinic, Villarroell70, 08036 Barcelona, Spain
Seriously ill patients risk developing acute upper gastrointestinal tract bleeding from stress-induced gastritis and acute gastric ulcerations (1-5). Previous studies have found that antacids, sucralfate, and histamine H2-receptor antagonists are effective in protecting against acute upper gastrointestinal bleeding in critically ill patients treated in intensive care units (5-19). However, many patients with severe diseases treated in general hospital wards, who are not so critically ill that they need to be referred to an intensive care unit, probably have a similar incidence and severity of acute bleeding as those admitted to such units. We embarked, therefore, on a randomized placebo-
controlled trial to evaluate the incidence of acute gastrointestinal tract bleeding in seriously ill patients treated in a general hospital ward and the efficacy of a new antacid, magaldrate, in the prevention of gastrointestinal tract bleeding in such patients. MATERIALS AND METHODS Patient selection and treatment This study was conducted in the Hospital Clinic of Barcelona. This is a 1000-bed teaching hospital with a total of 40 beds in the surgical, medical, and coronary intensive care units. Patients requiring
820
R. Estruch et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by Kainan University on 04/16/15 For personal use only.
intubation and mechanical ventilation, those with acute gastrointestinal bleeding, acute myocardial infarction, shock, acute renal failure requiring hemodialysis, severe burns, and traumas, and those who had undergone cardiac, gastric, or esophageal surgical interventions are admitted to the different intensive care units. These Datients usually show a simplified acute physiologic score (SAPS) of seven points or more (20). The other patients are admitted to the general hospital wards. A series of 100 consecutive patients with severe diseases admitted to the Dept. of Internal Medicine of our hospital over a period of 8 months were selected for the study. The criteria for inclusion were respiratory failure (basal PO,, lower than 60 mmHg at admission), heart failure (requiring inotropic treatment), sepsis, thrombotic or hemorrhagic stroke, liver failure (encephalopathy or jaundice), renal insufficiency (serum creatinine above 350 pmol/l), or treatment with corticosteroids (more than 250 mg of prednisone a day), heparin (1 mg/kg body weight/ 4 h), or warfarin. Patients who had had any evidence of upper gastrointestinal tract bleeding before the study, those who had undergone cardiac, gastric, or esophageal operations, and those who had presented with regurgitation, heartburn, dysphagia, epigastric pain, or other gastrointestinal symptoms during the past year or were receiving treatment with antacids or H2receptor antagonist treatments were excluded from the study. Informed consent was obtained from each patient before inclusion in the trial, and the study was approved by our Institutional Committee on Clinical Investigation. This study was designed to be a randomized single-blind placebo-controlled study. Patients were randomized by a table of random numbers to receive either magaldrate or placebo in a dose of 800 mg at 8,12,16,20, and 24 h. These patients had usually had breakfast at 0900h, lunch at 1300h, and dinner at 1900h. Magaldrate is a new antacid whose structure is a mixed crystal of A1(OH)3 and Mg(OH)2in the form of a laminated lattice (21). Gastric pH was not assessed because the patients were able to feed themselves and did not need nasogastric intubation.
Table I. Principal diagnoses of the patients included in the study
Magaldrate
Placebo 24 3 1 2 1 5 1 4 3
Systemic vasculitis
28 4 1 2 2 3 3 2 2 2 2 1
Total
52
48
Chronic respiratory
Heart failure Chronicrenal failure Bronchial asthma
Neoplasms pneumonia
Liver cirrhosis Deep-vein thrombosis Thrombotic stroke Hemorrhagic stroke
1 1
2
Study protocol
Each patient’s demographic characteristics, diagnosis at admission, underlying diseases, medications, and evidence of upper gastrointestinal tract bleeding were recorded. The following laboratory analyses were also performed at admission: erythrocyte and leukocyte counts, hemoglobin, hematocrit, platelet count, prothrombin time, glucose, creatinine, electrolytes, uric acid, serum alanine and aspartate aminotransferases (ALAT, ASAT), gamma-glutamyl transpeptidase, lactic dehydrogenase, alkaline phosphatase, bilirubin, total protein, protein electrophoresis, cholesterol, and triglycerides. In addition, stools were examined for frank or occult blood with the Hemoccult@paper test (Smith, Kline and French Co.). Arterial blood gas measurements were also carried out in patients with respiratory failure. Patients were examined daily for evidence of hematemesis, melena, nausea, vomiting, abdominal pain, or diarrhea. Stools were also examined daily for the presence of occult blood. At the end of the study the laboratory variables previously analyzed were re-evaluated. The study ended when the patient was discharged from the general hospital unit. Prophylaxis was considered a failure when the patient developed frank hematemesis or melena or uniformly dark-blue reaction with the Hemoccult test on two consecutive stool readings. In these patients, laboratory assessment, nasogastric aspiration, and esophagogastroduodenal endos-
Prophylaxis of Gastrointestinal Bleeding
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copy were performed, and magaldrate or ranitidine was given if the patient was in the placebo or antacid group, respectively. Toxicity was assessed through symptomspecific questioning, and any drug-related side effects were recorded. The investigator was responsible for determining the relationship of any adverse effects to the therapeutic regimen. Statistical analysis The collected data were analyzed with the SPSS-XStatistical Package for the Social Sciences (22). Differences between groups were analyzed by means of the two-tailed t test for continuous variables and the Pearson chi-square test together with the Yates correction when necessary or Fisher exact test for quality variables. The data are presented as mean standard deviation
*
W). RESULTS Clinical data Fifty-seven men and 43 women with a mean age of 65 years (range, 20-92 years) were included in the study. No patients refused to participate in the trial. After randomization, 52 received magaldrate and 48 placebo. The principal diagnoses of these patients are shown in Table I. The mean SAPS of these patients was 3.5 1.6. Except for a slight difference in sex distribution, there were no statistically significant differences between antacid and placebo groups in the number of patients, age, underlying diseases, previous
*
treatments, or length of study per patient (Table 11). Fourteen patients in the antacid group and 15 in the placebo group had had a history of gastrointestinal diseases, mainly gastritis, peptic ulcer, and hiatal hernia; however, no differences were observed between the two groups. Furthermore, all these patients had remained asymptomatic during the year previous to the study. In addition, the Hemoccult paper test of stools was negative in all patients at the beginning of the study. Thirteen major risk factors for gastrointestinal tract bleeding were analyzed in each patient. These risk factors were respiratory failure, sepsis, heart failure, hepatic encephalopathy, jaundice, renal failure, stroke, hypotension, previous gastrointestinal disease, and treatment with corticosteroids, non-steroidal-anti-inflammatory drugs, heparin, or warfarin. There were 110 risk factors in 52 patients in the antacid group, with a mean of 2.11 risk factors per patient, and 97 in 48 patients in the placebo group, with a mean of 2.02 risk factors per patient. No significant differences in the percentage of patients with any of these risk factors were observed (Table 111). Furthermore, there were no statistically significant differences in the severity of these risk factors evaluated by clinical and laboratory assessment. Finally, there was one death in the placebo group (one patient with an hemorrhagic stroke) and two in the magaldrate group (one patient with an adenocarcinoma of the lung and the other with non-Hodgkin’s lymphoma). Gastrointestinal bleeding or complications related to ant-
Table 11. Clinical data of the patients included in the study Magaldrate ~~
~
Age (years) Sex W/F) (n> History of peptic ulcer ( n ) Gastritis Hernia hiatal Previous treatment with ( n ) NSAIDs Corticosteroids Warfarin Duration of the study (days) NSAIDs = non-steroidal anti-inflammatory drugs.
821
*
Placebo
*
64.5 16.8 24/28 I 4 3
67.4 16.1 33/15 6 3 6
5 18 0 6.78 2 2.8
5 19 1 7.34 4.2
*
R . Estruch et al.
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Table 111. Risk factors of acute gastrointestinal tract bleeding for the patients at the admission to the study
Respiratory failure Sepsis Heart failure Hepatic encephalopathy Jaundice Renal failure Stroke Hypotension Previous GI disease Corticosteroid NSAIDs Heparin Warfarin Total
Magaldrate
Placebo
31 5 9 2 3 2 4 2 14 30 4 4 0
27 3 3 4 4 3 2 2 15 28 1 4 1
110
97
NSAIDs = non-steroidal anti-inflammatory drugs; GI = gastrointestinal.
acid use were not thought to have contributed to death in any patient of the study. Gastrointestinal tract bleeding One of the 52 patients from the antacid group (1.9%) and 11 of the 48 patients who were not receiving prophylaxis (placebo group) (22.9%) had evidence of gastrointestinal tract bleeding during the period of the study ( p < 0.01). The clinical data of the patients who bled are shown
in Table IV. Three patients from the placebo group presented with a frank melena, and bleeding was detected by stool examination for occult blood in the remaining patients. Nasogastric aspirates demonstrated gastric hemorrhage in eight of these patients, and endoscopic examination showed a stress ulcer in two cases, erosive gastritis in eight, and no lesions in the last patient. In five patients the bleeding was mild (hematocrit decrease, less than 5%), in three it was moderate (hematocrit reduction, between 5% and lo%), and in the remaining three the gastrointestinal hemorrhage was severe, with a hematocrit decrease of more than l o % , and a blood transfusion of two or more units was required. The bleeding of the patient treated with magaldrate was mild (hematocrit decrease of 2%) and detected by stool examination. Endoscopy showed minimal erosive gastritis. Magaldrate was added to the therapy of the eight patients of the placebo group with mild or moderate gastrointestinal bleeding. The three patients with frank hemorrhage and the patient from the antacid group were treated with magaldrate and ranitidine. All patients stopped bleeding, and the Hemoccult test subsequently converted to trace and negative. Twelve patients in the magaldrate group and 11 in the placebo group had one risk factor.
Table IV. Clinical data of the patients who presented evidence of upper gastrointestinal tract bleeding Treatment
Age
Sex
Previous GI disease
P
40 64 56 34 74 64 57 75 85 66 77 14
M
-
M M
G G -
M P P P P P P P
P P
P
F
M M F M M F F F
Medication
Stress
C C
RF RF TS RF H, S, RF, Rf HE RF HF RF RF, HF HS
Gastric lesions
Hematocrit decrease
Bleeding day
Ulcer EG EG EG EG EG EG EG EG
5% 2% 7% 8% 2% 2% 2% 4% 10% 4% 14% 16%
3
Ulcer EG
4 7 5 12 7 3
5 21 5 4 6
P = placebo; M = magaldrate; M = male; F = female; G = gastritis; H = heparin; C = corticosteroids; NSAID = non-steroidal anti-inflammatory drug; R F = respiratory failure; TS = thrombotic stroke; H = hypotension; S = sepsis; R = renal failure; HE = hepatic encephalophy; H F = heart failure; HS = hemorrhagic stroke; EG = erosive gastritis.
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Prophylaxis of Gastrointestinal Bleeding
Twenty-four patients in both groups showed 2 risk factors, and 16 in the former group and 12 in the latter group had 3 or more risk factors. In patients with 1 risk factor the frequency of bleeding was 0% (0 of 12 cases) for those receiving magaldrate and 9.1% (1 of 11) for those who received placebo ( p = NS). When two risk factors were present, the respective figures were 0% (0 of 24) and 20.8% (5 of 24) ( p = 0.02). Finally, when 3 or more risk factors were present, the percentage of bleeding was 6.2% (1 of 16) in the magaldrate group and 41.6% (5 of 12) in the placebo group ( p = 0.03) (Fig. 1). Furthermore, the incidence of gastrointestinal tract bleeding was significantly higher in patients with chronic respiratory failure and those who were treated with high doses of corticosteroids ( p < 0.05, both). Only 2 of the 15 patients from the placebo group and none from the antacid group with a history of previous gastric disease bled ( p = NS). Complications of treatment Seven patients in the antacid group and 10 in the placebo group developed epigastric pain,
r
26
24 22
1
nausea, or vomiting, but in all cases these complaints were related to other medications such as non-steroidal anti-inflammatory drugs or corticosteroids. None of these patients bled. The only symptom related to magaldrate treatment was diarrhea in two cases, but this complication was mild and self-limiting, so it was not necessary to discontinue the antacid therapy. No significant changes in laboratory variables were observed between the beginning and the end of the study.
DISCUSSION Bleeding in the upper gastrointestinal tract due to stress ulcers is a serious complication in critically ill patients and is associated with increased morbidity and mortality ( 1 4 ) . Previous studies have demonstrated a significantly higher rate of gastrointestinal hemorrhage in patients treated in intensive care units with respiratory failure, hypotension, extra-abdominal sepsis, peritonitis, burns, trauma, or hepatic failure and those who had undergone surgical procedures (4-19,23-25). Furthermore, the risk of bleeding seems to be
MAGALDRATE GROUP (n=52)
z -
0PATIENTS PATIENTS
CONTROL GROUP
3-b ~.
NUMBER
823
OF
RJSK
FACTORS
WITHOUT BLEEDING BLED
Fig. 1. Distribution of the patients by the number of risk factors and the number of patients who bled in each group.
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higher in the patients with combinations of these at these doses (3,4). Histamine H2-receptor serious complications (4-5). Controlled studies antagonists constitute a convenient alternative with critically ill patients have shown a rate of for this purpose (12,14,1618,34-36); however, upper gastrointestinal tract bleeding between it has been suggested that the currently approved 15% and 54% (4, 11-13, 18, 24). In our study, intravenous bolus regimen of cimetidine and which included seriously but not critically ill ranitidine may not consistently maintain the patients treated in a general hospital ward (Dept. intragastric pH above 4.0 in intensive-care-treated of Internal Medicine), the rate of gastrointestinal patients and that a constant intravenous infusion bleeding was 22.9%. Thus, the rate of hem- may be preferable (37-41). orrhagic complications in such patients is quite In the present study the intragastric pH could similar to that of those treated in intensive care not be assessed, since the patients included were units. Consequently, adequate prophylaxis able to feed themselves and did not need nasoshould also be administered to seriously ill gastric intubation. Thus, we decided to use a new patients admitted to a general hospital ward to antacid, magaldrate, which is able to restore pH prevent these events. As in other previous studies to above 4 even in the presence of large amounts (4,5), patients with various risk factors had a of acid (21). Furthermore, this drug acts against significantly higher rate of gastrointestinal bleed- other important factors in the pathogenesis of the ing than those with only one risk factor. In our stress-induced gastric lesions. Thus, magaldrate study the patients with respiratory failure and also inhibits pepsin, is able to bind bile acids and those treated with high doses of corticosteroids lysolecithin, and has a protective effect on gastric were the most prone to bleed. By contrast, mucosa (20,4243). On the other hand, the patients with inactive gastritis, peptic ulcer, or absorption of magnesium and aluminum from the reflux esophagitis did not have a higher risk of molecule is very low because it has the form of a bleeding. Only 2 of the 12 patients who bled had laminated lattice (21). Although antacid was not a history of gastritis, although they had been titrated in our study, significant benefit was noted asymptomatic for the previous 10 years. among those who received magaldrate as comBleeding in seriously ill patients has been pared with placebo in prevention of upper gasrelated to gastritis and acute gastritis ulceration, trointestinal tract bleeding. Furthermore, only as was the case in our patients, although esopha- two patients treated with magaldrate showed mild geal and duodenal lesions may also occur (26- and self-limiting diarrhea. 28). The pathogenesis of these lesions is not comIn conclusion, seriously ill patients admitted to pletely understood. Although it is generally a general hospital ward should be treated prophyaccepted that acid is required for the formation lactically to prevent upper gastrointestinal of stress-induced gastric ulcerations, other factors hemorrhage, similarly to critically ill patients may play an important role in the pathogenesis admitted to an intensive care unit. In this study of these lesions-such as pepsin secretion, bile magaldrate has been shown to be a useful, effecsalt reflux, and the secretory state of the gastric tive, and safe antacid for prophylaxis against mucosa (29-31). stress-induced ulceration bleeding. Several studies had shown that maintenance of an intragastric pH above 4.0 is necessary to ACKNOWLEDGEMENT achieve effective prophylaxis treatment for upper gastrointestinal tract hemorrhage and stress Medication was supplied by Boehringer lesions in critically ill patients (4,18,31-32). Mannheim Laboratories. Antacid titration has been shown to be highly efREFERENCES fective in the prevention of upper gastrointestinal tract bleeding, but administration of large doses 1. Zinner MJ, Zuidema GD, Smith PL, Mignosa M. The prevention of upper gastrointestinaltract bleedof these drugs is necessary to increase intragastric ing in patients in an intensive care unit. Surg GynepH to above 4.0, and adverse effects are common col Obstet 1981, 153, 214-220
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18. Zinner MJ, Zuidema GD, Smith PL, et al. The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981, 53, 214-220 19. Khan F, Parekh A , Pate1 S, et al. Results of gastric neutralization with hourly antacids and cimetidine in 320 intubated patients with respiratory failure. Chest 1981, 79, 409-412 20. Le Gall JR, Loirat P, Alperovitch A. Simplified acute physiological score for intensive care patients. Lancet 1983, 2, 741 21. Braun G. Riopan@-a new ulcer drug. Therapiewoche 1983, 47, 33-41 22. Nie NH, Hull CD, Jenkins JG, Steinbrenner K, Bent DH. Statistical package for the social sciences. McGraw-Hill, New York, 1975 23. Deweese MS. Gastrointestinal ulceration. J Trauma 1976, 7, 115-120 24. McAlhany JC, Czala AJ, Pruit BA. Antacid control of complications from acute gastroduodenal disease after burns. J Trauma 1976, 16, 645-648 25. McElwee HP, Sirinek KR, Levine BA. Cimetidine affords protection equal to antacids in prevention of stress ulceration following thermal injury. Surgery 1979, 86, 620-626 26. Anonymous. Prevention or cure for stress-induced gastrointestinal bleeding? Br Med J 1980,281, 631632 27. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt AJ. Natural history and surgical dilemma of ‘stress’ gastric bleeding. Arch Surg 1971, 102, 266-273 28. Czaja AJ, McAlhany JC, Pruitt BA. Acute gastrointestinal disease after thermal injury. An endoscopy evaluation of incidence and natural history. N Engl J Med 1974, 291, 925-929 29. Ritchie WP. Acute gastric mucosa damage induced by bile salts, acid and ischemia. Gastroenterology 1975, 68, 699-707 30. Kivilaakso E, Fromm D, Silen W. Effect of the acid secretory state of intramural pH of rabbit gastric mucosa. Gastroenterology 1978, 75, 641-648 31. Kivilaakso E , Silen W. Pathogenesis of experimental gastric-mucosa injury. N Engl J Med 1979, 301, 364-369 32. Hillman K. Acute stress ulceration. Anaesth Intensive Care 1985, 3, 230-240 33. Gottlieb JE, Menashe PI, Cruz E. Gastrointestinal complications in critically ill patients: the intensivists’ overview. Am J Med 1986, 81, 227-238 34. Marchant J, Summers K, McIaac RL, Wood JR. A comparison of two ranitidine intravenous infusion regimens in critically ill patients. Aliment Pharmacol Ther 1988, 2, 55-63 35. More DG, Raper FR, Munro IA, Watson CJ, Boutagy JS, Shenfield GM. Randomized, prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985,97,215223 36. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987, 106, 562-567 37. Morris DL, Markharm S, Beachey A, Byme A.
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