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Efficacy and safety of gastrointestinal bleeding prophylaxis in critically ill patients: systematic review and network meta-analysis

BMJ 2020; 368 doi: (Published 06 January 2020) Cite this as: BMJ 2020;368:l6744

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Gastrointestinal bleeding prophylaxis for critically ill patients: a clinical practice guideline

  1. Ying Wang, pharmacist1,
  2. Zhikang Ye, PhD student1 2,
  3. Long Ge, methodologist3,
  4. Reed A C Siemieniuk, PhD candidate, general internist2 4,
  5. Xin Wang, pharmacist1,
  6. Yingkai Wang, MD candidate1,
  7. Liangying Hou, MD candidate3,
  8. Zhuo Ma, pharmacist1,
  9. Thomas Agoritsas, general internist2 5,
  10. Per Olav Vandvik, general internist6,
  11. Anders Perner, critical care clinician7,
  12. Morten H Møller, critical care clinician7,
  13. Gordon H Guyatt, methodologist2,
  14. Lihong Liu, pharmacist1
  1. 1Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
  2. 2Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Canada
  3. 3Evidence Based Social Science Research Center, School of Public Health, Lanzhou University, Lanzhou, China
  4. 4Department of Medicine, University of Toronto, Toronto, Canada
  5. 5Division of General Internal Medicine and Division of Clinical Epidemiology, University Hospitals of Geneva, Geneva, Switzerland
  6. 6Institute of Health and Society, University of Oslo, Norway
  7. 7Department of Intensive Care, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
  1. Correspondence to: L Liu, 8 Gongren Tiyuchang, Nanlu, Chaoyang District, Beijing, China liulihong{at}
  2. Accepted: 27 November 2019


Objective To determine, in critically ill patients, the relative impact of proton pump inhibitors (PPIs), histamine-2 receptor antagonists (H2RAs), sucralfate, or no gastrointestinal bleeding prophylaxis (or stress ulcer prophylaxis) on outcomes important to patients.

Design Systematic review and network meta-analysis.

Data sources Medline, PubMed, Embase, Cochrane Central Register of Controlled Trials, trial registers, and grey literature up to March 2019.

Eligibility criteria for selecting studies and methods We included randomised controlled trials that compared gastrointestinal bleeding prophylaxis with PPIs, H2RAs, or sucralfate versus one another or placebo or no prophylaxis in adult critically ill patients. Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. A parallel guideline committee (BMJ Rapid Recommendation) provided critical oversight of the systematic review, including identifying outcomes important to patients. We performed random-effects pairwise and network meta-analyses and used GRADE to assess certainty of evidence for each outcome. When results differed between low risk and high risk of bias studies, we used the former as best estimates.

Results Seventy two trials including 12 660 patients proved eligible. For patients at highest risk (>8%) or high risk (4-8%) of bleeding, both PPIs and H2RAs probably reduce clinically important gastrointestinal bleeding compared with placebo or no prophylaxis (odds ratio for PPIs 0.61 (95% confidence interval 0.42 to 0.89), 3.3% fewer for highest risk and 2.3% fewer for high risk patients, moderate certainty; odds ratio for H2RAs 0.46 (0.27 to 0.79), 4.6% fewer for highest risk and 3.1% fewer for high risk patients, moderate certainty). Both may increase the risk of pneumonia compared with no prophylaxis (odds ratio for PPIs 1.39 (0.98 to 2.10), 5.0% more, low certainty; odds ratio for H2RAs 1.26 (0.89 to 1.85), 3.4% more, low certainty). It is likely that neither affect mortality (PPIs 1.06 (0.90 to 1.28), 1.3% more, moderate certainty; H2RAs 0.96 (0.79 to 1.19), 0.9% fewer, moderate certainty). Otherwise, results provided no support for any affect on mortality, Clostridium difficile infection, length of intensive care stay, length of hospital stay, or duration of mechanical ventilation (varying certainty of evidence).

Conclusions For higher risk critically ill patients, PPIs and H2RAs likely result in important reductions in gastrointestinal bleeding compared with no prophylaxis; for patients at low risk, the reduction in bleeding may be unimportant. Both PPIs and H2RAs may result in important increases in pneumonia. Variable quality evidence suggested no important effects of interventions on mortality or other in-hospital morbidity outcomes.

Systematic review registration PROSPERO CRD42019126656.


  • Contributors: GHG, ZY, YW, and LL conceived the study. KD and ZY designed the search strategy, and KD performed the literature search. YW and XW screened studies for eligibility. XW, YW, Yingkai Wang, and ZM performed data extraction. YW, ZY, and GHG assessed the risk of bias. LG, LH, and YW performed data analysis. YW, RAS, LG, ZY, and GHG interpreted the data analysis and assessed the certainty of evidence. YW, LG, and ZY wrote the first draft of the manuscript, and all other authors revised the manuscript. GHG and LL are the guarantors. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This systematic review is linked to a BMJ Rapid Recommendation, which was funded by the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority. The funder did not play any role in the preparation and production of the systematic review.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; AP and MHM are the co-authors of the SUP-ICU trial (doi:10.1056/NEJMoa1714919); GHG is one of the investigators of the REVISE trial. There are no other relationships or activities that could appear to have influenced the submitted work.

  • Patient consent: Not required.

  • Ethical approval: Not required.

  • Data sharing: No additional data available.

  • Transparency: The manuscript’s guarantors (GHG and LL) affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • This manuscript not been deposited as a preprint.

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