Martin 1992.

Methods	Double‐blind randomised, double‐dummy trial
Participants	Baseline characteristics Number randomised: 127 participants Number analysed: 127 participants Misoprostol Age (years; mean (SD)): 60.2 (15.2) Number of participants (n): 63 Gender (male/female; n): 39/24 Cimetidine Age (years; mean (SD)): 59.9 (17.5) Number of participants (n): 64 Gender (male/female; n): 40/24 Inclusion criteria Adults Undergone a surgical procedure requiring general anaesthesia within 14 days before meeting the other entry criteria Intubated requiring mechanical ventilation support Experience an episode of either hypotension or sepsis Exclusion criteria Pregnancy Psychiatric disorder requiring medication Upper GI malignancies Inflammatory bowel disease Active peptic ulcer disease and burns Recent central nervous system damage head injury requiring neurosurgical intervention or unstable spinal fractures Having had UCI surgery proximal to the ampoules of water within 30 days Receiving non‐steroidal anti‐inflammatory agents, antiulcer agents or antineoplastic agents Known allergies to either study medication Baseline imbalances: Quote: "The groups were clinically equivalent at entry with respect to age, gender race, risk factors such as hypotension, sepsis, coagulopathy, renal failure, hepatic failure, cardiac failure, adult respiratory distress syndrome (ARDS), gastric and duodenal lesions" Comment: no significant difference between the 2 groups with respect to demographic and baseline risk factors. Most participants were given a diagnosis of hypotension at baseline. Coagulopatyhy was present in 15 and 14 participants in both groups. Only 15 and 19 participants in both groups were free of any haemorrhagic gastric lesions at baseline
Interventions	Misoprostol Dose (total/d): 1200 mg Duration of treatment (days): see below Route: NG tube Intervention: 200 g mixed in 20 mL of water every 4 hours through their NG tube and IV placebo every 6 hours, or placebo tablet mixed in water through the NG tube Concomitant medications: Cimetidine Dose (total/d): 1200 mg Duration of treatment (days): see below Route: IV Intervention: cimetidine (IV) 300 mg every 6 hours and a placebo tablet mixed in water through the NG tube Concomitant medications: ‐ Adherence to regimen: Quote: "Patients meeting the above criteria for bleeding underwent an endoscopic evaluation within 12 hours and were removed from the study if a upper GI bleeding source was confirmed. All patients still in the study at 72 hours underwent a follow‐up endoscopy to determine whether the condition of the gastric or duodenal mucosa had changed. When possible, patients also underwent an endoscopy on exit from the study. If a patient underwent more than one follow‐up endoscopy, the score that represented the most severe damage was used" Duration of trial: July 1986 to January 1988. Duration of follow up: Quote: "All patients still in the study at 72 hours underwent a follow‐up endoscopy to determine whether the condition of the gastric or duodenal mucosa had changed" Notes duration of treatment: Patients were studied until 1 of 3 events occurred: 2 weeks of ICU management was completed Improvement allowed discharge from the ICU Significant upper gastrointestinal haemorrhage developed
Outcomes	Outcomes sought in review and reported in trial Incidence of upper GI bleeding considered a sign of organ failure and defined by any one of the following: Occurrence of haematemesis, melena, or haematochezia. Presence of bright red blood in the NG aspirate that did not immediately clear after lavage with 250 mL normal saline Drop in haemoglobin concentration over 2 consecutive measurements of at least 2 mg/dL with stools that had positive Hematest (Smith Kline Beckman, Sunnyvale, CA) results that were not attributable to other causes Note: GI bleeding developed 3 to 14 days after the first dose of study medication All‐cause mortality in ICU Outcomes sought but not reported in trial VAP All‐cause mortality in hospital Duration of ICU stay Duration of intubation Number of participants requiring blood transfusion Units of blood transfused Adverse events of interventions Outcomes reported in the trial but not used in review Participants with organ failure Gastric lesion scores
Notes	Setting: 25 medical centres in United States: Medical University of South Carolina, Charleston, South Carolina; Our Lady of Mercy Center, Bronx, New York; Cook County Hospital, Chicago, Illinois; Medical Center of Central George, Macon, Georgia; VA Medical Center, Dayton, Ohio, St. Francis Medical Center, Trenton, New Jersey; Maine Medical Center, Portland, Maine; VA Medical Center, Detroit, Michigan; Buffalo General Hospital, Buffalo, New York; University of South Alabama, Mobile, Alabama; Butterworth Hospital, Grand Rapids, Michigan; Indiana University Medical Center, Indianapolis, Indiana; Brackenridge Hospital, Austin,Texas; Meharry Medical Center, NashvilleTennessee; 6196 Eagle Crest Drive, Huntington Beach, California; Humana Hospital‐University, Louisville, Kentucky; Hershey Medical Center, Hershey, Pennsylvania; University Hospital, Columbia, Missouri; Denver General Hospital, Denver, Colorado; Truman Medical Center, Kansas City, Missouri; VA Medical Center, Long Beach, California; Chicago Medical School, North Chicago, Illinois; St. Louis University Medical Center, St. Louis, Missouri; Buffalo VA Medical Center, Buffalo, New York; University of Chicago, Chicago, Illinois Source of funding: ‐ Conflicts of interest: ‐ Ethics approval: Quote: "At each of the 25 institutions, the protocol was approved by the institutional review board" Informed consent: Quote: "Written informed consent was obtained from the patient or surrogate before study entry" Clinical trials registration: ‐ Sample size calculation: ‐ Additional notes: Mortality was significantly associated with adult respiratory distress syndrome (ARDS), at baseline or at subsequent development, upper GI haemorrhage and additional organ system failure. 87 participants were given diagnosis of haemorrhagic lesions, and 10 participants met the criteria of upper GI haemorrhage as per the study definition
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: not clearly mentioned in the study report
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Comment: This was a double‐blind 'double‐dummy study' in which placebo was administered to both groups. There personnel involved were blinded, and so the likelihood of performance bias is low
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: This was a double‐blind 'double‐dummy study' in which placebo was administered to both groups. GI bleeding was an objective outcome that was detected as per the definition in the study protocol
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: unclear whether outcome assessors were blinded. However, owing to the objective nature of the outcome of interest, the likelihood of detection bias is low
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: All randomised participants completed the trial and were included in the final analysis. There are no treatment withdrawals and no trial group changes. Therefore there is no attrition bias
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and reported
Other bias	Low risk	Comment: Source of funding is unclear. No other sources of bias are suspected