Abstract: We identified 2292 unique records.We included 129 records reporting on 121 studies, including 12 ongoing studies and two studies awaiting classification. We judged the overall risk of bias of two studies as low. Selection bias was the most relevant risk of bias domain across the included studies, with 78 studies not clearly reporting the method used for random sequence generation. Reporting bias was the domain with least risk of bias, with 12 studies not reporting all outcomes that researchers intended to investigate. Any intervention versus placebo or no prophylaxis In comparison with placebo, any intervention seems to have a beneficial effect on the occurrence of upper GI bleeding (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.57; moderate certainty of evidence). The use of any intervention reduced the risk of upper GI bleeding by 10% (95% CI -12.0% to -7%). The effect estimate of any intervention versus placebo or no prophylaxis with respect to the occurrence of nosocomial pneumonia, all-cause mortality in the ICU, duration of ICU stay, duration of intubation (all with low certainty of evidence), the number of participants requiring blood transfusions (moderate certainty of evidence), and the units of blood transfused was consistent with benefits and harms. None of the included studies explicitly reported on serious adverse events. Individual interventions versus placebo or no prophylaxis In comparison with placebo or no prophylaxis, antacids, H2 receptor antagonists, and sucralfate were effective in preventing upper GI bleeding in ICU patients. Researchers found that with H2 receptor antagonists compared with placebo or no prophylaxis, 11% less developed upper GI bleeding (95% CI -0.16 to -0.06; RR 0.50, 95% CI 0.36 to 0.70; 24 studies; 2149 participants; moderate certainty of evidence). Of ICU patients taking antacids versus placebo or no prophylaxis, 9% less developed upper GI bleeding (95% CI -0.17 to -0.00; RR 0.49, 95% CI 0.25 to 0.99; eight studies; 774 participants; low certainty of evidence). Among ICU patients taking sucralfate versus placebo or no prophylaxis, 5% less had upper GI bleeding (95% CI -0.10 to -0.01; RR 0.53, 95% CI 0.32 to 0.88; seven studies; 598 participants; moderate certainty of evidence). The remaining interventions including proton pump inhibitors did not show a significant effect in preventing upper GI bleeding in ICU patients when compared with placebo or no prophylaxis. Regarding the occurrence of nosocomial pneumonia, the effects of H2 receptor antagonists (RR 1.12, 95% CI 0.85 to 1.48; eight studies; 945 participants; low certainty of evidence) and of sucralfate (RR 1.33, 95% CI 0.86 to 2.04; four studies; 450 participants; low certainty of evidence) were consistent with benefits and harms when compared with placebo or no prophylaxis. None of the studies comparing antacids versus placebo or no prophylaxis provided data regarding nosocomial pneumonia. H2 receptor antagonists versus proton pump inhibitors H2 receptor antagonists and proton pump inhibitors are most commonly used in practice to prevent upper GI bleeding in ICU patients. Proton pump inhibitors significantly more often prevented upper GI bleeding in ICU patients compared with H2 receptor antagonists (RR 2.90, 95% CI 1.83 to 4.58; 18 studies; 1636 participants; low certainty of evidence). When taking H2 receptor antagonists, 4.8% more patients might experience upper GI bleeding (95% CI 2.1% to 9%). Nosocomial pneumonia occurred in similar proportions of participants taking H2 receptor antagonists and participants taking proton pump inhibitors (RR 1.02, 95% CI 0.77 to 1.35; 10 studies; 1256 participants; low certainty of evidence). This review shows that antacids, sucralfate, and H2 receptor antagonists might be more effective in preventing upper GI bleeding in ICU patients compared with placebo or no prophylaxis. The effect estimates of any treatment versus no prophylaxis on nosocomial pneumonia were consistent with benefits and harms. Evidence of low certainty suggests that proton pump inhibitors might be more effective than H2 receptor antagonists. Therefore, patient-relevant benefits and especially harms of H2 receptor antagonists compared with proton pump inhibitors need to be assessed by larger, high-quality RCTs to confirm the results of previously conducted, smaller, and older studies.

Plain-language summary: The evidence is current to August 2017. We included 106 studies with a total of 15,027 critically ill participants of any age and any gender. Relevant effects were found for the following drugs: H2 receptor antagonists, antacids, sucralfate, and proton pump inhibitors. H2 receptor antagonists inhibit gastric acid secretion by blocking histamine receptors but can cause a small number of blood platelets (thrombocytopaenia), inflammation of the kidney (interstitial nephritis), and confusion. Antacids neutralise stomach acid but may cause diarrhoea or constipation. Proton pump inhibitors inhibit the final stage of gastric acid production, and it has been found that they may be associated with increased risk of Clostridium difficile diarrhoea. Ulcer protective agents, such as sucralfate, create a barrier between the gastric acid and the gastric mucosa by coating it. They may, however, cause constipation and interfere with the absorption of certain antibacterial agents. In comparison with placebo or no preventive treatment, H2 receptor antagonists, antacids, and sucralfate might be effective in preventing clinically important upper GI bleeding in ICU patients. Hospital-acquired pneumonia was most likely to occur in ICU patients taking either H2 receptor antagonists or sucralfate when compared with patients given placebo or no preventive treatment. Evidence of low certainty suggests that proton pump inhibitors were more effective than H2 receptor antagonists in preventing upper GI bleeding in ICU patients. With proton pump inhibitors, 25 of 1000 people were likely to develop upper GI bleeding, and with H2 receptor antagonists, 73 of 1000 people (95% confidence interval 46 to 115 people) were likely to develop upper GI bleeding. The effect of H2 receptor antagonists versus proton pump inhibitors with respect to the risk for developing hospital-acquired pneumonia was consistent with benefits and harms. Our certainty in the evidence ranged from low to moderate. For effects of different interventions compared with placebo or no prophylaxis, the certainty of evidence was moderate (H2 receptor antagonists) or low (antacids and sucralfate). For effects of H2 receptor antagonists compared with placebo or no preventive treatment on risk of hospital-acquired pneumonia, the certainty of evidence was low. For effects of H2 receptor antagonists compared with proton pump inhibitors on hospital-acquired pneumonia, the certainty of evidence was also low.