Re-evaluating the Utility of Stress Ulcer Prophylaxis in the Critically Ill Patient: A Clinical Scenario-Based Meta-Analysis

Pharmacotherapy. 2019 Mar;39(3):408-420. doi: 10.1002/phar.2172. Epub 2018 Sep 6.


Study objective: Because recent studies have challenged the efficacy of stress ulcer prophylaxis (SUP) in the critically ill patient, our objective was to evaluate the efficacy of SUP with proton pump inhibitors (PPIs) or histamine2 -receptor antagonists (H2 RAs) against placebo, control, no therapy, or enteral nutrition alone in critically ill adults.

Design: Meta-analysis with trial sequential analysis (TSA) of 34 randomized controlled trials.

Patients: A total of 3220 critically ill adults who received PPIs or H2 RAs versus placebo, control, no therapy, or enteral nutrition.

Measurements and main results: A systematic review was performed using a random effects meta-analysis with TSA according to a predefined protocol. Randomized controlled trials comparing PPIs or H2 RAs with either placebo, control, no therapy, or enteral nutrition alone were identified through a comprehensive search of the literature. Two blinded reviewers independently assessed studies for inclusion, risk of bias, and extracted data using Cochrane Collaborative methodology. The predefined primary outcomes were clinically important, overt, and any (clinically important plus overt) gastrointestinal bleeding. Secondary outcomes included pneumonia, Clostridium difficile-associated diarrhea (CDAD), and mortality. Subgroup analyses were conducted for the primary outcome by PPI or H2 RA use, intensive care unit (ICU) subtype, studies published after early goal-directed therapy (EGDT), the presence of risk factors for stress ulceration, and enteral nutrition use. Of the 34 trials included, 33 were judged as high risk of bias and 1 was judged as low risk. Use of SUP significantly reduced clinically important bleeding (risk ratio [RR] 0.53, 95% confidence interval [CI] 0.37-0.76, p<0.001; I2 = 0%), overt bleeding (RR 0.55, 95% CI 0.39-0.76, p=0.0003; I2 = 53%), and any bleeding (RR 0.54, 95% CI 0.41-0.71, p<0.00001; I2 = 58%). TSA confirmed these findings. No significant differences in pneumonia, CDAD, or mortality were noted. Subgroup analyses revealed significant reductions in clinically important bleeding with SUP in neurosurgical patients (RR 0.37, p<0.05) but not in surgery/trauma or medical ICU patients with risk factors. SUP provided no benefit in studies published after EGDT. SUP significantly reduced clinically important bleeding regardless of the use of enteral nutrition (p<0.05).

Conclusion: This meta-analysis demonstrated that SUP use was associated with significant reductions in bleeding but not mortality. SUP should not be abandoned until large randomized trials demonstrate the futility of this intervention.

Keywords: critical illness; histamine H2 antagonists; meta-analysis; peptic ulcer prevention and control; proton pump inhibitors; stress.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adult
  • Critical Illness*
  • Enteral Nutrition / methods
  • Gastrointestinal Hemorrhage / prevention & control
  • Histamine H2 Antagonists / administration & dosage
  • Humans
  • Intensive Care Units*
  • Peptic Ulcer / prevention & control*
  • Proton Pump Inhibitors / administration & dosage
  • Randomized Controlled Trials as Topic
  • Risk Factors


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors