COMPARISON OF SUCRALFATE AND RANITIDINE TO PREVENT UPPER GASTROINTESTINAL BLEEDING A COMPARISON OF SUCRALFATE AND RANITIDINE FOR THE PREVENTION OF UPPER GASTROINTESTINAL BLEEDING IN PATIENTS REQUIRING MECHANICAL VENTILATION DEBORAH COOK, M.D., GORDON GUYATT, M.D., JOHN MARSHALL, M.D., DAVID LEASA, M.D., HUGH FULLER, M.B., RICHARD HALL, M.D., SHARON PETERS, M.D., FRANK RUTLEDGE, M.D., LAUREN GRIFFITH, M.SC., ALLAN MCLELLAN, M.D., GORDON WOOD, M.D., AND ANN KIRBY, M.D., FOR THE CANADIAN CRITICAL CARE TRIALS GROUP* ABSTRACT and coagulopathy are the strongest risk factors for Background Critically ill patients who require me- clinically important gastrointestinal bleeding.8-11 chanical ventilation are at increased risk for gastro- Randomized trials of prophylaxis against stress ul- intestinal bleeding from stress ulcers. There are con- cers, as compared with no prophylaxis, indicate that flicting data on the effect of histamine H2-receptor histamine H2-receptor antagonists and antacids pre- antagonists and the cytoprotective agent sucralfate vent clinically important gastrointestinal bleeding.12 on rates of gastrointestinal bleeding, ventilator-asso- Observational studies have suggested, however, that ciated pneumonia, and mortality. a higher gastric pH is associated with gastric micro- Methods In a multicenter, randomized, blinded, bial growth,13 tracheobronchial colonization,14 and placebo-controlled trial, we compared sucralfate with nosocomial pneumonia.15 In randomized trials, the the H2-receptor antagonist ranitidine for the preven- tion of upper gastrointestinal bleeding in 1200 pa- cytoprotective agent sucralfate, which does not alter tients who required mechanical ventilation. Patients the gastric pH, has been associated with a trend received either nasogastric sucralfate suspension (1 g toward a lower incidence of ventilator-associated every six hours) and an intravenous placebo or intra- pneumonia, both as compared with histamine H2- venous ranitidine (50 mg every eight hours) and a receptor antagonists and antacids16 and as compared nasogastric placebo. 17-30 with H2-receptor antagonists alone. Results The patients in the two groups had similar The need to evaluate patients at highest risk for base-line characteristics. Clinically important gastro- both bleeding and pneumonia31 and the need to intestinal bleeding developed in 10 of 596 (1.7 per- blind care givers and research personnel to the treat- cent) of the patients receiving ranitidine, as com- ment assignments, in order to minimize inflated treat- pared with 23 of 604 (3.8 percent) of those receiving 32 sucralfate (relative risk, 0.44; 95 percent confidence ment effects, prompted us to evaluate the rates of interval, 0.21 to 0.92; Pϭ0.02). In the ranitidine group, clinically important gastrointestinal bleeding, venti- 114 of 596 patients (19.1 percent) had ventilator-asso- lator-associated pneumonia, and mortality in a ran- ciated pneumonia, as compared with 98 of 604 (16.2 domized trial of 1200 patients who required me- percent) in the sucralfate group (relative risk, 1.18; 95 chanical ventilation and who were assigned to receive percent confidence interval, 0.92 to 1.51; Pϭ0.19). either ranitidine or sucralfate. There was no significant difference between the groups in mortality in the intensive care unit (ICU) METHODS (23.5 percent in the ranitidine group and 22.8 percent Enrollment in the sucralfate group) or the duration of the stay in the ICU (median, nine days in both groups). From October 1992 to May 1996, we screened consecutive pa- Conclusions Among critically ill patients requir- tients admitted to 16 participating intensive care units (ICUs) to identify adults who were projected to require mechanical ventila- ing mechanical ventilation, those receiving raniti- tion for at least 48 hours. Criteria for exclusion were a diagnosis dine had a significantly lower rate of clinically impor- of gastrointestinal bleeding or pneumonia on admission, gastrec- tant gastrointestinal bleeding than those treated tomy, a prognosis considered to be hopeless, previous randomiza- with sucralfate. There were no significant differences tion in this or another trial, or receipt of two or more previous in the rates of ventilator-associated pneumonia, the doses of open-label prophylactic therapy. The protocol was ap- duration of the stay in the ICU, or mortality. (N Engl J Med 1998;338:791-7.) ©1998, Massachusetts Medical Society. From McMaster University, Hamilton, Ont. (D.C., G.G., H.F., L.G., A.M.); the University of Toronto, Toronto (J.M.); the University of West- ROPHYLAXIS against stress ulcers has tra- ern Ontario, London (D.L., F.R., A.K.); Dalhousie University, Halifax, N.S. (R.H.); Memorial University, St. John’s, Newf. (S.P.); and Queen’s ditionally been recommended for the pre- University, Kingston, Ont. (G.W.) — all in Canada. Address reprint re- vention of upper gastrointestinal bleeding in quests to Dr. Cook at the Department of Medicine, St. Joseph’s Hospital, critically ill patients.1-3 Recent natural-histo- 50 Charlton Ave., Hamilton, ON L8N 4A6, Canada. Pry studies have documented a very low incidence of Other authors were Martin Tweeddale, M.D., University of British Co- lumbia, Vancouver; Joe Pagliarello, M.D., University of Ottawa, Ottawa, bleeding,4 however, suggesting that universal pro- Ont.; and Richard Johnston, M.D., University of Alberta, Edmonton. phylaxis may not be warranted.5-7 Respiratory failure *Other study investigators are listed in the Appendix. Volume 338 Number 12 ؒ 791 The New England Journal of Medicine proved by the institutional review boards of all the participating of units transfused minus 2 (i.e., if 4 units of packed cells were centers, and the patients or their proxies gave informed consent. transfused, the bleeding would be considered clinically important if the hemoglobin concentration did not rise by at least 2 g per Randomization deciliter). Patients were randomly assigned to study groups in blocks of Ventilator-Associated Pneumonia six, with stratification according to center, by means of a comput- er-generated random-number table prepared at the McMaster Attending intensivists at each center used a modified version of University Methods Center and managed by the ICU study phar- the criteria of the Centers for Disease Control and Prevention macist at each site who administered the coded drugs. All care (CDC)36 to identify patients in whom pneumonia was suspected givers and other research personnel were unaware of the random- on clinical grounds. These criteria were a new radiographic infil- ization schedule and the block size. trate that had persisted for at least 48 hours (as interpreted by designated study radiologists blinded to the patients’ treatment Blinding assignments) plus at least two of the following: a temperature above 38.5°C or below 35.0°C, a leukocyte count of more than The patients, research nurses, and all ICU care givers were un- 10,000 per cubic millimeter or less than 3000 per cubic millime- aware of the treatment assignments for the duration of the study. ter, purulent sputum, or isolation of pathogenic bacteria from an Therefore, clinicians did not monitor gastric pH. The radiolo- endotracheal aspirate. gists, outcome adjudicators, all investigators, and the study statis- Patients in whom ventilator-associated pneumonia was suspect- tician were also blinded until all events had been adjudicated and ed on clinical grounds underwent bronchoalveolar lavage or pro- the analyses completed. tected brush-catheter sampling by the study bronchoscopist.37,38 Two members of the pneumonia-adjudication committee exam- Drug Preparation, Dispensing, and Administration ined all relevant clinical and diagnostic documents related to pos- The bags of ranitidine (Zantac, Glaxo Wellcome; prepared by sible cases of pneumonia in duplicate and independently, classify- Baxter) and ranitidine placebo were identical in appearance. The ing patients according to several different methods. One method 36 sucralfate (Sulcrate, Hoechst Marion Roussel) and sucralfate pla- used was the modified CDC criteria described above ; another cebo slurries were identical in color, taste, and consistency. From was the Clinical Pulmonary Infection Score devised by Pugin et coded ranitidine bags and sucralfate bottles stored in each ICU al. (range, 0 to 12, with pneumonia defined by a score of 7 or 39 pharmacy, study pharmacists dispensed either active ranitidine higher). In addition, adjudicators used the criteria of the Mem- (50 mg every eight hours) and sucralfate placebo or active sucral- phis Ventilator-Associated Pneumonia Consensus Conference for fate (1 g every six hours) and ranitidine placebo. definite ventilator-associated pneumonia (if there was radiograph- Ranitidine was administered in intravenous bolus form, with ic evidence of abscess and a positive needle aspirate, or if there the dose adjusted for renal failure as follows: standard dose, 50 was histologic proof of pneumonia at biopsy or autopsy) and mg every 8 hours; dose for patients with an estimated creatinine probable ventilator-associated pneumonia (if bronchoalveolar la- clearance rate of 25 to 50 ml per minute, 50 mg every 12 hours; vage or protected brush-catheter sampling yielded positive quan- dose for patients with an estimated creatinine clearance rate below titative or semiquantitative cultures, if there was a positive blood 25 ml per minute, 50 mg every 24 hours; and dose for patients culture of an organism found within 48 hours of isolation in the dependent