Ben‐Menachem 1994.

Methods	Single‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 304 participants Number analysed: 300 participants Sucralfate Age (years; mean (SD)): 60.1 (16.8) Number of participants (n): 100 Gender (male/female; n): 51/49 Cimetidine Age (years; mean (SD)): 59 (18.1) Number of participants (n): 100 Gender (male/female; n): 51/49 Control Age (years; mean (SD)): 59.6 (18) Number of participants (n): 100 Gender (male/female; n): 51/49 Inclusion criteria Age > 18 years Admitted to Medical ICU Informed consent from participant or legally authorised representative Exclusion criteria Expected stay at ICU of 24 hours or less Evidence of gastrointestinal bleeding (haematemesis, vomiting of' "coffee grounds", haematochezia, or melena) at time of admission to the ICU Treatment with antacids, H2 receptor antagonists, sucralfate, or omeprazole during the 24 hours before entering the ICU Use of non‐steroidal anti‐inflammatory agents, systemic anticoagulants, or thrombolytic agents during previous 7 days Surgery requiring general anaesthesia during previous 2 weeks Closed head injury or clinical evidence of increased intracranial pressure Grade 4 hepatic encephalopathy Oesophageal or gastric surgery in previous year History of gastrointestinal bleeding during previous year Pregnancy or lactation Baseline imbalances: Quote: "One hundred patients were randomly assigned to each of the treatments. The groups were similar with regard to age, gender, percentage of participants admitted from the emergency room, severity of illness, admission diagnoses, corticosteroid usage and coagulopathy. Patients often had more than one reason for ICU admission. The mean APACHE II scores for the control, sucralfate, and cimetidine groups were 16.5 ± 6.9, 16.8 ± 6.9, and 18.0 ± 8.0, respectively. Approximately one‐third of the patients in each group had APACHE II scores greater than 20.0 Comment: The 3 groups were similar with respect to demographic and other risk factors for stress haemorrhage at the beginning of the trial. The most common diagnosis on admission was pneumonia, which was reported in 89 participants. Bacterial pneumonia (control: 23; sucralfate: 26; cimetidine: 21). Non‐bacterial pneumonia was diagnosed (control: 9; sucralfate: 4; cimetidine: 6). Coagulopathy was present in 16, 14, and 21 participants in the 3 randomised groups
Interventions	Sucralfate Dose (total/d): 4 g Duration of treatment (days): ‐ Route: nasogastric tube Intervention: 1 g of medication orally or as a suspension through the nasogastric tube every 6 hours. Nasogastric tube was clamped for 1 hour after sucralfate administration Concomitant medications: 69% of participants received enteral nutrition through a 10‐Fr feeding tube. 1% received parenteral nutrition. Corticosteroids were used in all groups Cimetidine Dose (total/d): varies Duration of treatment (days): ‐ Route: IV Intervention: 300 mg intravenous loading dose followed by continuous intravenous infusion according to creatinine clearance: more than 50 mL/min, 900 mg/d; 20 to 50 mL/min, 600 mg/d; and less than 20 mL/min, 300 mg/d. Cimetidine dose was titrated to maintain gastric pH ≥ 4.0. With 2 consecutive gastric pH values < 4.0, dose was increased by the following amounts based on creatinine clearance: 300 mg/d, 200 mg/d, and 100 mg/d. Maximum allowable cimetidine doses for participants grouped by renal function were 2400 mg/d, 1600 mg/d, and 800 mg/d Concomitant medications: 57% of participants received enteral nutrition through a 10‐Fr feeding tube. 7% of cimetidine group received parenteral nutrition. Corticosteroids were used in all groups No prophylaxis Dose (total/d): ‐ Duration of treatment (days): ‐ Route: ‐ Intervention: ‐ Concomitant medications: 72% of participants received enteral nutrition through a 10‐Fr feeding tube. 1% received parenteral nutrition. Corticosteroids were used in all groups Adherence to regimen: Although 304 participants were randomised, only 300 (100 in each group) were part of the trial because 1 participant died 2 hours after admission, 3 participants were randomised on 2 different occasions, and second admissions were excluded. Results for only 291 participants were available when the trial was finally reviewed by the second committee. The 8 participants who did not agree to endoscopy might have been excluded from the trial denominator (unclear on the 1 remaining participant) Duration of trial: 1 February to 25 November 1992 Duration of follow up: until death or discharge from ICU
Outcomes	Outcomes sought in review and reported in trial Primary outcomes Clinically important GI bleeding defined as:   Persistent haematemesis (red blood or guaiac‐positive 'coffee grounds') that did not clear with 1.5 L saline lavage 3‐Point decrease in haematocrit during 24 hours accompanied by red blood or guaiac‐positive 'coffee grounds' material that cleared with lavage, or melena, or 3 guaiac‐positive stools without evidence of lower gastrointestinal bleed Any unexplained 6‐point decrease in haematocrit during a 48‐hour period (added as a safety measure because some participants would not receive prophylaxis) Note: Median time from ICU admission to onset of stress‐related haemorrhage was 5 days VAP defined as: Chest roentgenogram obtained 72 or more hours after ICU admission that showed a new and persistent infiltrate Fever, leucocytosis, or both Purulent tracheobronchial secretions Gram‐stained sputum showing more than 25 polymorphonuclear leucocytes and fewer than 10 squamous epithelial cells per low‐power field Recovery of an accepted nosocomial pathogen from sputum culture All‐cause mortality in ICU All‐cause mortality in hospital Duration of ICU stay Number of participants requiring blood transfusion Adverse events of interventions&& Note: Noscocomial pneumonia occurred after a mean of 6.9 ± 7.2 days in the ICU (median 9 days) Outcomes sought but not reported in trial Duration of intubation Units of blood transfused Outcomes reported in trial but not used in review Duration of hospital stay
Notes	Setting: Henry Ford Hospital and Health Sciences Center, Detroit, Michigan Source of funding: Quote: "Grant support: in part from the Henry Ford Hospital Research and Education Funds to Dr. Ben‐Menachem and to Dr. Fogel" Conflicts of interest: ‐ Ethics approval: Quote: "This protocol was reviewed and approved by the Henry Ford Hospital Institutional Review Board" Informed consent: Quote: "Informed consent was obtained from the patient or from legally authorized representatives when the patient could not provide consent" Clinical trials registration: ‐ Sample size calculation: Quote: "We estimated sample size to provide 80% power to detect a 75% reduction in bleeding rate, that is, a 12% bleeding rate for the control group compared with a 3% rate in either of the two treatment groups. We used an alpha value of 0.05 (two‐tailed) adjusted for the comparison of the control group with each of the prophylaxis groups. As a result of these assumptions, 160 patients were needed in each of the three groups” Additional notes: Mechanical ventilation was used in 65, 72, and 76 participants in the 3 respective groups. Respiratory failure and high dose of corticosteroid were independently associated with increased risk of stress‐related haemorrhage. According to the trial report, 43 participants satisfied the criteria for significant GI bleeding (as per the definition), and 19 of these participants did not have stress‐related bleeding (as determined by oesophagogastroduodenoscopy). Among them, 12 participants (4 controls, 3 receiving sucralfate, and 5 receiving cimetidine) had a normal result of endoscopy, suggesting that the change in haematocrit was due to fluid shifts. Seven participants bled from causes not due to stress ulceration, and 8 participants did not have endoscopy (5 did not give consent, 1 participant with lymphoma and thrombocytopaenia died of multiple‐organ system failure 10 days after the bleeding episode. Three of the 8 participants met criterion 3 of diagnosis Quote: "Two of 20 patients in the control group with coagulopathy had stress‐related haemorrhage. In the cimetidine and sucralfate groups, the incidences were 1 of 22 and 2 of 17, respectively (P > 0.05)"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was by sealed envelope using the permuted block design" Comment: Method to generate a random sequence is clearly mentioned in the trial report
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was by sealed envelope using the permuted block design" Comment: Method for allocation concealment is clearly mentioned in the trial report
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: This was a single‐blind trial, and the mode of drug administration could not have allowed blinding. Therefore, risk of performance bias is high
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Quote: "The primary study end point was substantial haemorrhage from stress gastritis. Information regarding hematocrit, haemoccult status of stool and nasogastric aspirate, and volume status [were] presented daily to two investigators who were blinded to therapy" Comment: Trial report mentions blinding of outcome assessors for the primary outcome of GI bleed, which was an objective outcome detected as per the definition used in the trial
Blinding (detection bias) Nosocomial pneumonia	Low risk	Comment: Outcome assessors were not blinded. However, this was an objective outcome that was diagnosed as per the definition used in the trial protocol. Therefore, the likelihood of performance or detection bias is low
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Comment: All other outcomes of interest were objective in nature, so the likelihood of detection bias is low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: Although 304 participants were randomised, only 300 were analysed, as 1 participant died 2 hours after admission, 3 were randomised on 2 different occasions, and second admissions were excluded. Results for only 291 participants were available when the trial was finally reviewed by the second committee. The 8 participants who did not agree to endoscopy might have been excluded from the trial denominator (unclear for the 1 remaining participant). However, intention‐to‐treat analysis was done with 100 participants in each of the 3 groups. Therefore, there was no attrition bias
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes are reported. A subgroup analysis was desirable for participants who received enteral feeds
Other bias	Low risk	Comment: This trial was supported in part by Henry Ford Hospital Research and Education Funds. The role of the sponsor in the conduct and reporting of this trial is unclear. No other form of bias is suspected