Karlstadt 1990.

Methods	Multi‐centre double‐blind randomised placebo‐controlled trial
Participants	Baseline characteristics Number randomised: 87 participants Number analysed: 87 participants Cimetidine Age (years; mean (SD)): 56.5 (22.8) Number of participants (n): 54 Gender (male/female; n): 31/23 Placebo Age (years; mean (SD)): 61.9 (18.8) Number of participants (n): 33 Gender (male/female; n): 16/17 Inclusion criteria Participants admitted to ICUs were eligible for entry into the trial if they had at least 1 of the following conditions generally regarded as risk factors for bleeding: Major thoracic or abdominal surgery Major multiple trauma Hypotension, defined as a decrease in blood pressure greater than 30/20 mmHg (systolic/diastolic) Hypovolemic shock, defined as a syndrome of inadequate tissue perfusion characterised by systolic blood pressure < 90 mmHg (or a decrease of 30 mmHg in previously hypertensive patients) Sepsis, defined by the presence of peritonitis, confirmed bacteraemia, or the complex of fever, elevated white blood cell count, and hypotension with a bacteriologically determined source of infection Acute respiratory failure, defined as the need for assisted ventilation for longer than 24 hours Exclusion criteria Active upper GI bleeding, history of peptic ulcer or upper gastrointestinal surgery Severe chronic hepatic failure, defined by the presence of portal systemic encephalopathy or ascites secondary to chronic liver disease Renal failure, defined by elevated serum creatinine, indicating creatinine clearance < 30 mg/min Treatment with other drugs such as antacids, other H2‐receptor antagonists, and sucralfate that would interfere with evaluation of investigative treatment effects Pregnancy or lactation Age < 16 years Known hypersecretory disorders (e.g. peptic ulcer, burns) or patients considered likely to bleed from non‐stress‐related conditions (e.g. varices, uraemic gastritis) Baseline imbalances: Quote: "Patient demographics and risk factors for bleeding on entry into the study show that the treatment groups were comparable" Comment: Participants from 14 centres were comparable with respect to demographic characteristics and baseline risk factors. Almost 40% of study participants had acute respiratory failure at baseline, of whom 14% had pneumonia
Interventions	Cimetidine Dose (total/d): 1500 mg Duration of treatment (days): probably 7 days Route: IV Intervention: continuous intravenous 50 mg/h infusion. Patients received an initial 300 mg dose of cimetidine Concomitant medications: Average number of medications administered concomitantly during the trial was 8 (range, 1 to 20) in the cimetidine group and 7 (range, 2 to 23) in the placebo group. All participants had a nasogastric tube in place Placebo Dose (total/d): ‐ Duration of treatment (days): probably 7 days Route: IV Intervention: placebo; 0.9% saline infused over 15 to 20 minutes, followed by continuous infusion by IVAC or IMED Concomitant medications: Average number of medications administered concomitantly during the trial was 8 (range, 1 to 20) in the cimetidine group and 7 (range, 2 to 23) in the placebo group. All participants had a nasogastric tube in place Adherence to regimen: Quote: "The average time in the study was longer for patients treated with cimetidine (mean, 83 hours ± 53) than for patients treated with placebo (mean, 53 hours ± 41). This difference was because more patients treated with placebo bled and left the study early" "Two patients being treated with cimetidine experienced adverse events for which they were withdrawn from the study: one developed moderate nausea and vomiting and one developed a change in mental status. In both cases, the adverse experiences were reversible. No patients treated with placebo were withdrawn from treatment, but adverse experiences attributed to placebo treatment included one case of mental confusion" Duration of trial: ‐ 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 Upper GI haemorrhage in critically ill patients defined by 1 of the following: Haematemesis or the presence of more than 10 mL of bright red blood in a single aspirate Melena or haematochezia (unless upper GI endoscopy clearly indicated that the melena did not arise from an upper GI site) Presence of 'coffee grounds' positive for haemoglobin by Gastroccult (Smith Kline Diagnostics, Sunnyvale, CA) in the nasogastric aspirate on each of 3 consecutive 6‐ hourly observations (over 12 hours) and a 1‐gram decrease in haemoglobin over 24 hours Gastroccult‐positive 'coffee grounds' aspirate that did not clear with lavage Secondary outcomes Incindence of pneumonia All‐cause mortality in ICU Adverse reactions of interventions Outcomes sought but not reported in trial All‐cause mortality in hospital Duration of ICU stay Duration of intubation Number of participants requiring transfusion of more than 2 units of blood Number of units of blood transfused Outcomes reported in trial but not used in review Time until occurrence of bleeding Stress‐related upper gastrointestinal mucosal damage
Notes	Setting: The study was a multi‐centric study involving 14 centres; University of Kentucky, Lexington, KY; Boston City Hospital, Boston, King Drew Medical Center, Los Angeles, CA; Winthrop University Hospital, Mineola, NY; Ellis Hospital, Schenectady, NY; Detroit Rec. Hospital, Detroit, MI; Mt. Sinai Medical Center, New York, Hartford Hospital, Hartford, CT; St. Thomas Hospital, Akron, OH; Cleveland Metro General Hospital, Cleveland, OH; University of Oklahoma Health Science Center, Oklahoma City, OK; Ravenswood Hospital, Chicago, IL; Brookdale Hospital, Brooklyn, NY; University of Texas Health Science Center, San Antonio, TX Source of funding: Study appears to have been funded by Smith Kline & French Laboratories, Philadelphia, PA, although this is not clearly mentioned in the study report Conflicts of interest: Ethics approval: Quote: "The study was approved by all institutional review boards" Comment: This study was approved by the ethics committees at all 14 centres Informed consent: Quote: " ...and all patients (or their legal guardians) provided written, informed consent" Comment: For participating in the trial, informed consent was obtained from participants or their legal guardians Clinical trials registration: not provided in the study report Sample size calculation: not clearly mentioned in the study report Additional Notes:Staphylococcus aureus was the organism found to have caused pneumonia. One participant treated with cimetidine had melena, but the upper GI source could not be detected, so this participant was not categorised as having an upper GI bleed
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: not enough information about sequence generation reported
Allocation concealment (selection bias)	Unclear risk	Comment: not enough information about allocation concealment reported
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: This was a placebo‐controlled trial; unclear about whether participants and study personnel were blinded
Blinding (detection bias) Clinically important upper GI bleeding	Low risk	Comment: unclear whether outcome assessors were blinded. GI bleeding was an objective outcome detected as per the definition in the study protocol
Blinding (detection bias) Nosocomial pneumonia	High risk	Comment: Outcome assessors were not blinded. Study had no clear mention of the definition to detect pneumonia. Moreover 14% of participants had pneumonia on entry into the study. Lack of blinding could have influenced detection of this condition, as it is mentioned that the physician did not attribute pneumonia to the study medication
Blinding of outcome assessment (detection bias) Adverse reactions of interventions	Unclear risk	Comment: Outcomes of interest were in part objective in nature; for other outcomes, the definition is not described and no blinding is in place
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "All patients who received study drugs were included in the denominator for analysis" Comment: All randomised participants were part of the final analysis
Selective reporting (reporting bias)	Low risk	Comment: All intended outcomes were analysed and reported
Other bias	Low risk	Comment: Lead author is affiliated with Smith Kline & French Laboratories, Philadelphia, PA. Clear conflict of interest. No other sources of bias suspected