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Year : 2017  |  Volume : 1  |  Issue : 6  |  Page : 31-33

Stress ulcer prophylaxis: Back to square one

1 Department of Emergency and Critical Care, College of Medicine, Imam Abdulrahman Ben Faisal University, Dammam, Saudi Arabia
2 Department of Medicine, Division of Critical Care and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada

Date of Web Publication23-Nov-2017

Correspondence Address:
Waleed Alhazzani
Department of Medicine, Division of Critical Care, McMaster University, St Joseph's Healthcare Hamilton, 50 Charlton Avenue, Postal Code L8N 4A6, Hamilton, Ontario
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2543-1854.219136

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Pharmacologic prophylaxis against stress ulcer-related gastrointestinal (GI) bleeding with acid suppression has been the standard of care for decades. Worldwide, proton pump inhibitors (PPIs) are more commonly used than histamine-2-receptor antagonists. However, recent observational studies suggest that PPIs increase the risk of ventilator-associated pneumonia (VAP) and Clostridium difficile infection (CDI). Further, the incidence of GI bleeding appears to be lower than in the past, perhaps related to immediate resuscitation and enteral nutrition. a large randomized trial is needed to test the efficacy and safety of withholding PPIs in the ICU.

Keywords: Critical illness, gastrointestinal bleeding, pneumonia, stress ulcers

How to cite this article:
Alshahrani M, Alhazzani W. Stress ulcer prophylaxis: Back to square one. Saudi Crit Care J 2017;1, Suppl S2:31-3

How to cite this URL:
Alshahrani M, Alhazzani W. Stress ulcer prophylaxis: Back to square one. Saudi Crit Care J [serial online] 2017 [cited 2023 Jan 29];1, Suppl S2:31-3. Available from: https://www.sccj-sa.org/text.asp?2017/1/6/31/219136

  Introduction Top

Pharmacologic stress ulcer prophylaxis in mechanically ventilated patients is considered the standard of care in most intensive care units (ICUs) worldwide. Stress ulceration in the gastrointestinal (GI) tract of critically ill patients is a consequence of reduced gastric blood flow, increased acid secretion, and impaired gastric protective mechanisms.

  Who is at Risk? Top

A large prospective observational study (n = 2252) found that mechanical ventilation for >48 h and coagulopathy were the strongest predictors of clinically important GI bleeding in the ICU.[1] A recent international observational study of 1034 patients showed that comorbidities, liver disease, need for renal replacement therapy, and coagulopathy were associated with higher risk of clinically important GI bleeding. Interestingly, mechanical ventilation was not associated with increased risk of bleeding.[2] This could be explained by the change in ventilation strategies over the years, using less tidal volumes and pressures, which may have attenuated the effect on gastric blood flow. However, it remains uncertain whether mechanical ventilation is associated with higher risk of GI bleeding nowadays.

  How Common are Stress Ulcers? Top

Endoscopic studies from decades ago confirmed the presence of gastric mucosal changes in most critically ill patients. However, only few patients develop clinically important GI bleeding. Cook et al. reported a clinically important bleeding rate of 1.5% (95% confidence interval [CI] 1.0%–2.1%).[1] Despite the perceived decline in rates of clinically important GI bleeding over the years, the results of a recent international observational study challenged this perception and reported a bleeding rate of 2.6% (95% CI 1.6%–3.6%).[2]

  Can Enteral Nutrition Prevent Gastrointestinal Bleeding? Top

Despite the general belief that enteral nutrition could prevent stress ulceration in the upper GI tract; there is insufficient evidence to support this. There are no randomized trials examining the effect of enteral feeds versus not on GI bleeding in critically ill patients; furthermore, as early enteral nutrition becoming a common practice, there will likely be no such studies in the future. A randomized trial in burn patients showed that administration of enteral nutrition was associated with increased gastric blood flow, but no clinical outcomes were reported.[3] Recently, two randomized controlled trials (RCTs) compared the use of proton-pump inhibitors (PPIs) to placebo for stress ulcer prophylaxis, majority of patients in the two trials received early enteral nutrition, and there was no significant difference in the risk of GI bleeding in both studies,[4],[5] indirectly suggesting that enteral nutrition may have a protective effect.

  What is the Most Effective Prophylactic Agent? Top

PPIs are the most commonly used agents, followed by histamine-2 receptor antagonists (H2RAs). This pattern of practice is consistent with the results of recent systematic reviews, the most recent of which included 19 RCTs (n = 2117 patients), and showed that PPIs significantly reduced clinically important bleeding compared to H2RAs.[6] Sucralfate is rarely used nowadays; it has been found to be less effective than H2RAs in preventing GI bleeding;[7] however, a recent meta-analysis of 21 RCTs (n = 3121 patients) showed no significant difference in risk of bleeding between H2RAs and sucralfate in the ICU.[8]

  Does Stress Ulcer Prophylaxis Increase the Risk of Infections? Top

It is plausible to assume that the use of acid suppressive therapy could result in altered bacterial flora in the GI tract, subsequently leading to the development of pneumonia, Clostridium difficile, and other infections. Meta-analyses comparing PPIs and H2RAs on pneumonia outcome suffered from imprecision and hence were inconclusive.[6],[9] A propensity-matched analysis found that PPIs, compared to H2RA use, was associated with a small increase in the risk of Clostridium difficile infection and pneumonia. Although this association was based on observational studies, these results generated enough concern in the field. Interestingly, sucralfate may result in lower risk of pneumonia compared to H2RAs, as shown in a recent meta-analysis of randomized trials.[8] It remains unclear if any of the observed infectious complications with PPIs and H2RAs are true.

  Should we Continue to Prescribe Stress Ulcer Prophylaxis? Top

The low incidence of GI bleeding and the concern about increased nosocomial infections created an equipoise about the use of stress ulcer prophylaxis in the ICU. In addition, patients' values and preferences with regard to these outcomes have not been studied before. Finally, the impact on cost and resource utilization is unknown.

The universal use of stress ulcer prophylaxis, particularly PPIs, is now under question. Five RCTs (n = 604) compared placebo (withholding of prophylaxis) to PPIs, the pooled analysis showed no significant difference in GI bleeding, ventilator-associated pneumonia, or Clostridium difficile infection.[5] The results were too imprecise to provide any solid conclusions; however, it generated enough confidence to conduct large RCTs.

Currently, two large international RCTs are ongoing; the first is SUP-ICU trial (NCT02467621) which is comparing pantoprazole to placebo in critically ill patients; the target sample size is 3350 patients.[10] The second is the REVISE (Re-Evaluating the Inhibition of Stress Erosions) trial. This is an international, multicenter, pragmatic, noninferiority trial that compares withholding prophylaxis (placebo) to intravenous pantoprazole in mechanically ventilated patients. The REVISE trial will be conducted in North America, Australia, and Saudi Arabia, with a target sample size of 4800 patients. The results of these two RCTs will inform practice and help clinicians to make decisions regarding the everyday use of stress ulcer prophylaxis in the ICU.

  Conclusion Top

Despite extensive research in this area, there are several important unanswered questions. The universal use of stress ulcer prophylaxis should be re-evaluated, and higher quality evidence is needed to justify the widespread use of acid-suppressive agents.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med 1994;330:377-81.  Back to cited text no. 1
Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, et al. Prevalence and outcome of gastrointestinal bleeding and use of acid suppressants in acutely ill adult intensive care patients. Intensive Care Med 2015;41:833-45.  Back to cited text no. 2
Yan H, Peng X, Huang Y, Zhao M, Li F, Wang P, et al. Effects of early enteral arginine supplementation on resuscitation of severe burn patients. Burns 2007;33:179-84.  Back to cited text no. 3
Selvanderan SP, Summers MJ, Finnis ME, Plummer MP, Ali Abdelhamid Y, Anderson MB, et al. Pantoprazole or placebo for stress ulcer prophylaxis (POP-UP): Randomized double-blind exploratory study. Crit Care Med 2016;44:1842-50.  Back to cited text no. 4
Alhazzani W, Guyatt G, Alshahrani M, Deane AM, Marshall JC, Hall R, et al. Withholding pantoprazole for stress ulcer prophylaxis in critically ill patients: A Pilot randomized clinical trial and meta-analysis. Crit Care Med 2017;45:1121-9.  Back to cited text no. 5
Alshamsi F, Belley-Cote E, Cook D, Almenawer SA, Alqahtani Z, Perri D, et al. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: A systematic review and meta-analysis of randomized trials. Crit Care 2016;20:120.  Back to cited text no. 6
Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, et al. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. Canadian Critical Care Trials Group. N Engl J Med 1998;338:791-7.  Back to cited text no. 7
Alquraini M, Alshamsi F, Møller MH, Belley-Cote E, Almenawer S, Jaeschke R, et al. Sucralfate versus histamine 2 receptor antagonists for stress ulcer prophylaxis in adult critically ill patients: A meta-analysis and trial sequential analysis of randomized trials. J Crit Care 2017;40:21-30.  Back to cited text no. 8
Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: A systematic review and meta-analysis. Crit Care Med 2013;41:693-705.  Back to cited text no. 9
Krag M, Perner A, Wetterslev J, Wise MP, Borthwick M, Bendel S, et al. Stress ulcer prophylaxis with a proton pump inhibitor versus placebo in critically ill patients (SUP-ICU trial): Study protocol for a randomised controlled trial. Trials 2016;17:205.  Back to cited text no. 10


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