Prod'hom 1994.

Methods	Single‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 375 participants Number analysed: 244 participants Antacids Age (years; mean (SD)): 46 (17.9) Number of participants (n): 81 Gender (male/female; n): 55/26 Ranitidine Age (years; mean (SD)): 52.2 (18.1) Number of participants (n): 80 Gender (male/female; n): 54/26 Sucralfate Age (years; mean (SD)): 46.4 (17.5) Number of participants (n): 83 Gender (male/female; n): 56/27 Inclusion criteria Admitted to the adult medical and surgical intensive care units Receiving mechanical ventilation Nasogastric tube in place Exclusion criteria Active upper gastrointestinal bleeding Treatment with antacids H2 blockers or sucralfate during the preceding 48 hours Creatinine levels greater than 200 mL/L Esogastric surgery, cardiac surgery or organ transplantations Likely to be extubated within 24 hours Baseline imbalances: Quote: "At randomisation, no statistically significant difference was found among the three groups in terms of age (P = 0.058), sex (P > 0.2), APACHE II scores (P > 0.2), Glasgow coma scores (P > 0.2), and other underlying characteristics such as pneumonia on admission, participants receiving antibiotic therapy or enteral nutrition" Comment: The 3 groups were similar. Among the participants from surgical ICU, 30, 28, and 33 participants in the antacid, ranitidine, and sucralfate groups were requiring emergency surgery. Most participants from surgical ICU were diagnosed with trauma requiring some form of intervention. Among participants from the medical ICU, most had some pulmonary disease; 9, 7, and 6 participants were diagnosed with pneumonia on admission to each of the respective groups
Interventions	Antacid Dose (total/d): 240 mL Duration of treatment (days): until extubation unless interrupted earlier for any of the following predetermined reasons: an increase in blood creatinine level to more than 200 mol/L, removal of the nasogastric tube, moribund state, discharge from intensive care units, or side effects likely to be related to the stress ulcer regimen Route: NG tube Intervention: hospital‐made suspension containing 5.4% aluminium hydroxide and 1.5% magnesium hydroxide with a buffer capacity of 1.2 mEq/mL, administered every 2 hours. The standard dose of 20 mL was doubled if the gastric pH (tested with pH‐indicator strips [Merck and Co., Darmstadt, Germany] before each administration) was less than 4.0. After administrating, the NG tube was flushed with 10 mL of sterile water and clamped for 30 minutes Concomitant medications: 22 received enteral nutrition, 22 received antibiotics Ranitidine Dose (total/d): 150 mg Duration of treatment (days): until extubation unless interrupted earlier for any of the following predetermined reasons: an increase in blood creatinine level to more than 200/xmol/L, removal of the nasogastric tube, moribund state, discharge from intensive care units, or side effects likely to be related to the stress ulcer regimen Route: IV Intervention: administered as a continuous intravenous infusion of 150 mg/d (100 mg/d if blood creatinine level was between 150 and 200 mol/L) Concomitant medications: 20 received enteral nutrition, and 18 received antibiotics Sucralfate Dose (total/d): 6 g Duration of treatment (days): until extubation unless interrupted earlier for any of the following predetermined reasons: an increase in blood creatinine level to more than 200/xmol/L, removal of the nasogastric tube, moribund state, discharge from intensive care units, or side effects likely to be related to the stress ulcer regimen Route: NG tube Intervention: administered every 4 hours as 1 g of suspension diluted in 20 mL of sterile water. After administered, the NG tube was flushed with 10 mL of sterile water and clamped for 30 minutes. Concomitant medications: 23 received enteral nutrition, and 15 received antibiotics Adherence to regimen: Quote: "375 were randomly assigned to a treatment group and 258 were eventually intubated for more than 24 hours. Fourteen were un assessable because of missing data (4, 3, and 7 patients in the antacid, ranitidine, and sucralfate groups, respectively). Thus, 244 patients could be analysed. Of these 244 patients, 81 received antacid, 80 received ranitidine, and 83 received sucralfate.The protocol had to be interrupted before extubation in 23 (28%) of the patients in the antacid group, 19 (24%) of the patients in the ranitidine group, and 17 (20%) in the sucralfate group. Renal insufficiency developed in 5, 8, and 6 patients in the antacid, ranitidine, and sucralfate groups, respectively. In the antacid group, 6 patients developed diarrhoea or ileus, which was attributed to the treatment. In the ranitidine group, one patient developed leukopaenia and another patient developed a rash. Removal of the nasogastric tube, withdrawal of supportive care, or discharge from the hospital was the other reason for premature protocol interruption. Five patients in the antacid group, 5 patients in the ranitidine group, and 8 patients in the sucralfate group had these characteristics. In addition, protocol violation prompted interruption of treatment in 7 patients in the antacid group, 4 patients in the ranitidine group, and 3 patients in the sucralfate group. For patients in whom the protocol was interrupted, the total number of assessable days before interruption was not statistically different among the three groups (P > 0.2)" Comment: It is also mentioned that physicians had to modify the anti‐stress ulcer prophylaxis regimen in 1, 2, and 3 participants in the antacid, ranitidine, and sucralfate groups, respectively, due to GI bleed Duration of trial: January 1989 to January 1991 Duration of follow up: not clearly mentioned in the study report. Probably until death or discharge
Outcomes	Outcomes sought in review and reported in trial Primary outcomes Incidence of nosocomial pneumonia defined as: "Criteria for the diagnosis of ventilator‐associated pneumonia were predetermined and derived from those of 'Salata and colleagues' as presence of a new or progressive infiltrate on the chest radiograph consistent with pneumonia, without other obvious cause, and associated with conditions A or B or both, defined as follows. Condition A refers to any of the following findings: pleural fluid or blood culture positive for an organism also isolated in the tracheal aspirate, radiographic cavitation, or histopathologic evidence of pneumonia. Condition B includes at least two of the following: tracheal aspirates with more than 25 leukocytes per low‐power field (x100) on a Gram stain, new leukocytosis defined as a leukocyte count greater than 10 x 109/L with an increase of at least 25% over baseline, or body temperature greater than 38.5°C with an increase of at least 1°C above baseline. The latter two criteria were considered only when other causes for these findings were excluded. Pneumonia was considered to be caused by a pathogen when it was cultured in high counts as the sole or predominant microorganism in the tracheal aspirate culture" "Using the criteria of Langer and colleagues, early‐onset and late‐onset pneumonia were diagnosed if they occurred during the first 4 days of or 4 days after the initiation of mechanical ventilation, respectively. Consequently, only patients observed for more than 4 days could be evaluated for the development of late‐onset pneumonia. A second episode of pneumonia was diagnosed when it was clearly temporally distinct from the first episode and when it involved other areas of the lungs. Pneumonia was attributed to a given anti‐stress ulcer prophylactic regimen if it developed during treatment or within 2 days after extubation or treatment interruption" Incidence of macroscopic GI bleeding: "Gastric aspirates were examined for the macroscopic presence of blood ('coffee ground' material or fresh blood). The severity of gastric haemorrhage was assessed by clinical criteria (physical signs, blood transfusion requirements, and outcome) All‐cause mortality in the hospital Participants requiring blood transfusion All‐cause mortality during hospitalisation Adverse events of interventions Note: Early‐onset pneumonia developed in 9, 8, and 7 participants in antacid, ranitidine, and sucralfate groups, respectively. Late‐onset pneumonia developed in 11, 14, and 4 participants in the antacid, ranitidine, and sucralfate groups, respectively.Three of the 4 cases of late‐onset pneumonia in the sucralfate group were observed on day 5 Note: In the antacid group, GI bleeding developed on third day for 2 and on day 18 for 1 participant. In the ranitidine group; it was diagnosed on the second day for 2 participants and on days 3, 4, and 6 for the remaining 3 participants. In the sucralfate group, it was detected on the second day for three and on days 3, 5,8,12, and 23 for the remaining participants. Outcomes sought but not reported in trial All‐cause mortality in ICU Duration of ICU stay Duration of intubation Outcomes reported but not used in review Intragastric pH status Gastric colonisation All‐cause mortality during mechanical ventilation (mortality in ICU after extubation is not clear)
Notes	Setting: Division Autonome de Medecine Preventive Hospitaliere, Centre Hospitalier Universitaire Vaudois, CH‐1011 Lausanne, Switzerland Source of funding: by Merck and Co. Conflicts of interest: ‐ Ethics approval: ‐ Informed consent: ‐ Clinical trials registration: ‐ Sample size calculation: ‐ Additional notes: Mortality was attributed to pneumonia in 4 participants (1 in the antacid and 3 in ranitidine groups, respectively, whereas it was attributed to GI haemorrhage in 1 participant from the sucralfate group. Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, alone or in combination, accounted for more than half of early‐onset pneumonia cases (54%), whereas gram‐negative bacilli were most commonly isolated in late‐onset pneumonia
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was done using a random permutable table to generate a random treatment list" Comment: Method adopted to obtain random sequence generation is clearly mentioned in the study report
Allocation concealment (selection bias)	Low risk	Quote: "Treatment regimens were included in opaque, sealed envelopes" Comment: Method adopted to obtain allocation concealment is clearly mentioned in the study report
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: This was not a placebo‐controlled trial, and the different modes of administering study interventions would not have made it possible to blind study personnel and participants
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: There is no clear mention of blinding outcome assessors. However, GI bleeding was an objective outcome detected as per the definition in the study protocol
Blinding (detection bias) Nosocomial pneumonia	Low risk	Quote: "They were interpreted by a pneumologist who had knowledge of all relevant data except for the patient's stress ulcer prophylactic regimen, gastric pH, or colonization data" Comment: VAP was detected as per the definition in the study protocol by an outcome assessor who was blinded to the above mentioned participant data
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Comment: There is no clear mention of blinding outcome assessors. However, all other outcomes of interest were objective in nature
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Of the initial 375 randomised participants, only 258 were part of the analysis, as only these participants were in the trial for longer than 24 hours, as this was criterion was necessary to measure the outcomes of interest. Data on 14 participants were missing, and they seem to be well balanced across the 3 groups
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and reported in the study
Other bias	Low risk	Comment: The study was funded by Merck and Co. However, the role of the sponsor in the conduct and reporting of the trial is unclear. No other form of bias was detected