SIC: Stress Ulcer Prophylaxis in the ICU (1999)

“In this large, randomized trial in a mixed population of critically ill patients, sucralfate was as effective as histamine-2-receptor antagonists for the prevention of clinically important gastrointestinal bleeding.”

— The Canadian Critical Care Trials Group

1. Publication Details

  • Trial Title: A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation.
  • Citation: Cook D, Guyatt G, Marshall J, et al; for the Canadian Critical Care Trials Group. A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation. N Engl J Med. 1998;338(12):791-797. doi:10.1056/NEJM199803193381203.
  • Published: March 19, 1998, in The New England Journal of Medicine.
  • Author: Deborah Cook, M.D., M.Sc.
  • Funding: Medical Research Council of Canada.

2. Keywords

Stress Ulcer Prophylaxis, Gastrointestinal Bleeding, Mechanical Ventilation, Sucralfate, Ranitidine, H2-Receptor Antagonist, Ventilator-Associated Pneumonia (VAP).

3. The Clinical Question

In adult patients requiring mechanical ventilation (Population), is sucralfate (Intervention) as effective as the H2-receptor antagonist ranitidine (Comparison) in preventing clinically important upper gastrointestinal bleeding (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Critically ill, mechanically ventilated patients are at risk for stress-related mucosal damage and gastrointestinal (GI) bleeding. Prophylaxis with agents that either neutralize gastric acid (antacids), block its production (H2-receptor antagonists), or provide a mucosal barrier (sucralfate) was common practice.
  • Knowledge Gap: While H2-receptor antagonists were effective at preventing bleeding, there was a concern that by raising gastric pH, they could promote bacterial overgrowth and increase the risk of ventilator-associated pneumonia (VAP). Sucralfate, which does not alter gastric pH, was a potential alternative that might be safer. A large, rigorous trial was needed to compare the two strategies.
  • Proposed Hypothesis: The authors hypothesized that sucralfate would be as effective as ranitidine in preventing clinically important GI bleeding but would be associated with a lower rate of VAP.

5. Study Design and Methods

  • Design: A prospective, multicenter, randomized, blinded, controlled trial.
  • Setting: 29 intensive care units (ICUs) in Canada.
  • Trial Period: Enrollment from October 1990 to March 1996.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were expected to require mechanical ventilation for at least 48 hours.
    • Exclusion Criteria: Active GI bleeding on admission, contraindications to either study drug, or receiving therapeutic anticoagulation.
  • Intervention: Sucralfate slurry, 1 g administered via nasogastric tube every 6 hours.
  • Control: Ranitidine, 50 mg intravenously every 8 hours.
  • Management Common to Both Groups: Blinding was maintained by preparing both the active drug and a placebo in identical syringes for both nasogastric and intravenous administration. All other aspects of ICU care were at the discretion of the treating team.
  • Power and Sample Size: The trial was powered to detect a 2.5 percentage point difference in the rate of clinically important bleeding, requiring approximately 1200 patients.
  • Outcomes:
    • Primary Outcome: Clinically important GI bleeding (defined as overt bleeding with hemodynamic instability, a drop in hemoglobin, or the need for transfusion).
    • Secondary Outcomes: Ventilator-associated pneumonia, ICU length of stay, and ICU mortality.

6. Key Results

  • Enrollment and Baseline: 1200 patients were randomized (596 to sucralfate, 604 to ranitidine). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the rate of clinically important GI bleeding between the sucralfate and ranitidine groups (1.7% vs 1.8%; P=0.92).
  • Secondary Outcomes: There was no significant difference in the incidence of ventilator-associated pneumonia (19.1% in the sucralfate group vs 16.2% in the ranitidine group; P=0.19). There were also no significant differences in ICU mortality or length of stay.
  • Adverse Events: Adverse event rates were low and similar between the two groups.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The proportion of patients with clinically important GI bleeding was compared between the two groups.
  • Key Statistic(s) Reported:
    • GI Bleeding: Relative Risk (RR) 0.92 (95% CI, 0.42 to 2.03).
    • VAP: RR 1.18 (95% CI, 0.92 to 1.51).
  • Interpretation of Key Statistic(s):
    • Confidence Interval (CI): For both the primary outcome (bleeding) and the key secondary outcome (VAP), the 95% confidence interval widely crosses 1.0, indicating no statistically significant difference between sucralfate and ranitidine.
  • Clinical Impact Measures: Not applicable as no significant difference was shown between the two active treatments.
  • Subgroup Analyses: No significant interactions were found in pre-specified subgroup analyses.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, and blinded design provided high-quality evidence. The use of a clinically important, objective primary endpoint was a major strength.
  • Generalizability: The inclusion of a large number of diverse ICUs increases the external validity of the findings.
  • Methodological Rigor: The elaborate blinding procedure, involving both IV and NG placebos for each group, was a key strength that minimized bias.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial was conducted before the widespread use of proton-pump inhibitors (PPIs), which are now the most common agents for stress ulcer prophylaxis. Therefore, the results do not directly inform the choice between sucralfate and PPIs.
  • Other: The overall rate of bleeding was lower than anticipated, which can make it harder to detect a true difference between treatments.

10. Conclusion of the Authors

“In critically ill patients who require mechanical ventilation, sucralfate and ranitidine are equally effective in preventing clinically important upper gastrointestinal bleeding. There is no evidence that sucralfate is associated with a lower incidence of ventilator-associated pneumonia.”

11. To Summarize

  • Impact on Current Practice: This was a landmark trial in critical care. It demonstrated that sucralfate was a viable alternative to H2-blockers for stress ulcer prophylaxis and, importantly, it refuted the prevailing hypothesis that acid suppression increased the risk of VAP. This finding gave clinicians reassurance about the safety of acid-suppressive therapy, which paved the way for the later adoption of the more potent PPIs.
  • Specific Recommendations:
    • Patient Selection: For mechanically ventilated ICU patients at risk for stress ulcer bleeding.
    • Actionable Intervention: Both sucralfate and H2-receptor antagonists are effective options for preventing clinically important GI bleeding.
    • Expected Benefit: Both agents effectively reduce the risk of bleeding.
  • What This Trial Does NOT Mean: This trial does not mean that all ICU patients require stress ulcer prophylaxis. It studied a high-risk population (mechanically ventilated patients), and prophylaxis is generally reserved for such patients.
  • Implementation Caveats: Sucralfate administration via nasogastric tube can be cumbersome and may lead to tube occlusion.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was designed to resolve the clinical uncertainty created by previous, smaller studies and meta-analyses that had suggested a link between acid suppression and VAP.
  • Influence on Subsequent Research: By demonstrating the safety of acid suppression with regard to VAP, this trial set the stage for subsequent studies comparing H2-blockers to the more potent PPIs. The PULP-V trial (2020) later compared PPIs to placebo and questioned the need for routine prophylaxis in a modern ICU setting.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The main unresolved question following this trial was whether the more potent acid suppression of PPIs offered a benefit over H2-blockers.
  • Future Directions: Research in this area has evolved to question which patients benefit from prophylaxis at all, given the low baseline rates of bleeding in modern ICU care, and to compare PPIs against H2-blockers or placebo.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, addressing a choice between two standard-of-care prophylactic strategies and testing a major safety hypothesis (the VAP link).
  • Methods: The study’s design was exceptionally rigorous for its time, with a large sample size, multicenter recruitment, and robust blinding. The primary endpoint was clinically meaningful and well-defined.
  • Results: The trial showed a clear equivalence between sucralfate and ranitidine for preventing GI bleeding and, importantly, a null result for the VAP outcome, effectively refuting the hypothesis that acid suppression was harmful.
  • Conclusions and Applicability: The authors’ conclusions are strongly supported by the data. The results were highly applicable at the time and fundamentally shifted the debate around stress ulcer prophylaxis, reassuring clinicians about the safety of acid suppression and influencing practice for decades.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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