Zinner 1989.

Methods	Single‐blind randomised controlled trial
Participants	Baseline characteristics Number randomised: 371 Number analysed: 281 (for primary outcome) Misoprostol Age (years; mean (SD)): ‐ Number of participants (n): 187 Gender (male/female; n): 152/35 Antacid Age (years; mean (SD)): ‐ Number of participants (n): 181 Gender (male/female; n): 153/24 Inclusion criteria Participants scheduled to undergo major surgical procedures Expected to require at least 48 hours of postoperative monitoring in an ICU Participants with risk factors such as sepsis, trauma, electrolyte imbalance, diabetes, major burns, respiratory failure requiring ventilator assistance, congestive heart failure, arrhythmias requiring medication, or need for steroids Exclusion criteria Active peptic ulcer disease Oesophageal, gastric, or duodenal malignancies Oesophageal varices Gastric outlet obstruction Acute renal failure Concurrent therapy with salicylates, non‐steroidal anti‐inflammatory drugs, antiulcer therapy, or antineoplastic agents Baseline imbalances: Quote: "There were no statistical differences between the two treatment groups with respect to age, sex, or race. They were also comparable in mean height, weight, and vital signs on admission, and these did not differ with respect to study site. Initial gastric lesion scores were 0 or 1 in 88% of the patients, and initial duodenal lesion scores were 0 or 1 in 96% of the patients, with no significant differences between the two treatment groups (p = 0.141 and 0.848, respectively)" Comment: The 2 groups were similar with respect to demographic and baseline risk factors
Interventions	Misoprostol Dose (total/d): 1200 mcg Duration of treatment (days, mean (range)): max. 14 Route: NG tube or PO Intervention: misoprostol tablets containing 200 mcg of misoprostol (Searle Inc., Skokie, IL) every 4 hours plus placebo liquid antacid every 2 hours. Tablets were dissolved in 20 mL of water and were administered 6 times daily through a nasogastric tube, or were given orally if no tube was in place Concomitant medications: ‐ Antacid Dose (total/d): ‐ Duration of treatment (days, mean (range)): max 14 Route: NG tube or PO Intervention: antacid: placebo tablets every 4 hours plus magnesium‐aluminium hydroxide liquid antacid (Maalox TC, Rohrer Pharmaceuticals, Fort Washington, PA) every 2 hours. Tablets were dissolved in 20 mL of water and were administered 6 times daily through a nasogastric tube, or were given orally if no tube was in place. Antacid or placebo liquid was administered every 2 hours at a dose of 10, 20, 40, or 80 mL, increasing the dose upward as necessary during the first 72 hours to maintain gastric pH at 4.0 or higher. Samples were aspirated through the nasogastric tube every 2 hours and gastric pH was measured using litmus paper. After 72 hours, repeat endoscopic examinations were done and the liquid antacid or placebo was titrated downward to 20 mL every 4 hours Concomitant medications: ‐ Adherence to regimen: Quote: "Comparable numbers of patients completed the 14 days of treatment or were released earlier, having met the dietary requirement. By the eighth day, only 16% of the misoprostol group and 21% of the antacid group remained in the ICU (p = not significant). Total time of nasogastric medication administration was also somewhat shorter in the misoprostol group (655 patient days vs. 731 patient days in the antacid group), but again these differences were not statistically significant.", "141 in Misoprostol and 140 in Antacid were only analysed as they met the following four criteria for other evaluations 1. completed at least three days in the study, 2. took at least 80% of the assigned medication, 3. did not withdraw from the study except for side effects of the medication, 4. had sufficient follow up endoscopy information to permit outcome evaluation" Comment: 46 participants on misoprostol and 44 participants on antacid regimens were not unavailable for analysis of the primary outcome of GI bleeding Duration of trial: ‐ Duration of follow‐up: ‐
Outcomes	Outcomes sought in review and reported in trial Primary outcomes Clinically significant GI bleeding defined as persistent guaiac 4+ positive nasogastric aspirate, continuous for greater than 16 hours (2 consecutive nursing shifts) even after nasogastric lavage, bright red bleeding per nasogastric tube or by emesis, and guaiac‐positive stools and documented fall in haematocrit value (no participant had the event) Secondary outcomes Adverse events of interventions All‐cause mortality in ICU Outcomes sought but not reported in trial report Incidence of ventilator‐associated pneumonia All‐cause mortality in hospital Participants requiring blood transfusion Units of blood transfused Duration of ICU stay Duration of intubation Outcomes reported in report but not used in review Gastric pH Endoscopically confirmed upper GI lesions
Notes	Setting: 16 university‐associated medical centres: King/Drew Medical Center, Los Angeles, University of Minnesota Hospitals, Minneapolis, MN, Georgetown University Hospital, Washington, DC, Denver General Hospital, Denver, Health Science Center, Brooklyn, NY: Cook County Hospital, Chicago, IL, Minneapolis VA Medical Center, Minneapolis, Hines VA Hospital, Milton S. Hershey Medical Center, VA Medical Center, Fresno, CA, W.P, Temple University Hospital, Philadelphia, PA, University of California, Irvine, CA, VA Medical Center, San Francisco, CA, University Texas Health Science Center, Dallas, TX, Johns Hopkins Medical Institutions, Baltimore Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: Quote: "The Institutional Review Board at each of the study sites approved the protocol" Informed consent: Quote: "Each patient gave written informed consent" Clinical trials registration: ‐ Sample size calculation: Quote: "The protocol was designed to require a minimum of 270 fully evaluable patients to complete the study (135 in each group). This sample size is sufficient to detect differences of 20% or more between two treatment groups (p = 0.05; power = 0.90) with two‐sided tests of significance. That is, this study size should detect a clinically significant difference between misoprostol and antacid that is greater than 20%"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not clearly mentioned in the study report
Allocation concealment (selection bias)	Unclear risk	Comment: nNot clearly mentioned in the study report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Acceptable candidates were randomly assigned to each group and they received either tablets containing 200 mcg of misoprostol every four hours plus placebo liquid antacid every two hours, or placebo tablets every four hours plus magnesium‐aluminum hydroxide liquid antacid every two hours. Tablets were dissolved in 20 mL of water and administered six times daily through a nasogastric tube, or were given orally if no tube was in place" Comment: This was a 'double‐dummy' placebo‐controlled trial, and participants and study personnel appear to be blinded. Therefore, the likelihood of performance bias is low
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: This was a 'double‐dummy' placebo‐controlled trial. Moreover, GI bleeding was an objective outcome that was detected as per the definition in the study protocol. Therefore, there is no likelihood of performance bias in this study
Blinding (detection bias) Nosocomial pneumonia	Unclear risk	Comment: Study did not address this outcome
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Low risk	Comment: This was a 'double‐dummy' placebo‐controlled trial. However, 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: Not all 371 randomised participants were part of the final analysis. The study was designed in such a way that only those participants who met certain criteria for evaluation of the primary outcome (as described under 'adherence to the regimen') were included in the study report (141 participants in misoprostol and 140 participants in antacid groups). A per‐protocol analysis was done. However, the participants for whom outcomes were reported were well balanced between groups. Therefore, the likelihood of bias due to attrition is low
Selective reporting (reporting bias)	High risk	Comment: Study says that all randomised participants were analysed for safety of the drug, but this was true only for the adverse event of diarrhoea and not for other adverse events. The reasons for excluding some of the participants is not clearly mentioned in the study report
Other bias	Low risk	Comment: unclear on the source of funding. No other form of bias detected

ADH: antidiuretic hormone.

APACHE: Acute Physiologic Assessment and Chronic Health Evaluation.

APS: acute physiology score.

BAL: bronchoalveolar lavage.

BMI: body mass index.

bw: body weight.

CABG: coronary artery bypass graft.

CNS: central nervous system.

CXR: chest X‐ray.

GCS: Glasgow Coma Scale.

GD: gastroduodenal.

GI: gastrointestinal.

ICU: intensive care unit.

IMED: infusion pump.

IQR: interquartile ratio.

ITT: intention‐to‐treat.

IV: intravenous.

IVAC: infusion pump.

NG: nasogastric.

NPO: nothing by mouth.

NSAID: non‐steroidal anti‐inflammatory drug.

OR: odds ratio.

PaO2: partial pressure of oxygen in arterial blood.

PCT: procalcitonin

PICU: paediatric intensive care unit.

PSB: protected specimen brush.

SD: standard deviation.

SE: standard error.

SICU: surgical intensive care unit.

SOFA: sepsis‐related organ failure assessment score.

SRMD: stress‐related mucosal disease.

SUP: stress‐ ulcer prophylaxis

TISS: therapeutic intervention scoring system.

VAP: ventilator‐associated pneumonia.

WBC: white blood cell.