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Stress Ulcer Prophylaxis: A Review of the Evidence

OVERVIEW. HISTORY OF STRESS ULCER PROPHYLAXISPATHOPHYSIOLOGYPROPHYLACTIC AGENTSEVIDENCE FOR AND AGAINST TREATMENT. History of the Stress Ulcer. 1842: Curling described series in burn patients1932: Dr. Cushing reported ulcers with surgery and trauma1970s: Development of H2 receptor antagonists.

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Stress Ulcer Prophylaxis: A Review of the Evidence

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    1. Stress Ulcer Prophylaxis: A Review of the Evidence Jeff Thurlby, MD Anesthesia / Critical Care Fellow

    2. OVERVIEW HISTORY OF STRESS ULCER PROPHYLAXIS PATHOPHYSIOLOGY PROPHYLACTIC AGENTS EVIDENCE FOR AND AGAINST TREATMENT

    3. History of the Stress Ulcer 1842: Curling described series in burn patients 1932: Dr. Cushing reported ulcers with surgery and trauma 1970s: Development of H2 receptor antagonists

    4. History of the Stress Ulcer 1990’s: Dr. Cook and the Canadian Critical Care Trials Group perform landmark trials on ICU usage of H2 receptor antagonists.

    5. History of the Stress Ulcer 1990s to 2000: Proton Pump inhibitors make more efficient gastric alkalinization possible.

    6. The Present: How Much is Enough?

    7. Pathophysiology Mucosal erosions in up to 75-100% of patients within 72 hours of major trauma or burns by endoscopy. Depriest, J. Postgrad Med 1995.

    8. Pathophysiology Loss of mucosal integrity Hypersecretion of acid? Hypoperfusion of microcirculation? Decreased mucous layer?

    9. Pathophysiology The mucous layer is primarily secreted by pyloric glands. The layer traps bicarbonate ions to help neutralize hydrogen ions.

    10. Pathophysiology Hypoperfusion: Release of Nitric Oxide Decrease in Prostaglandin Synthesis Cycle of cell damage / death and release of cytokines / inflammation / more hypoperfusion / reperfusion injury Fennerty, M. Brian. Crit Care Med. 2002; S351-5.

    11. Pathophysiology ABSENT MUCOSAL BARRIER + GASTRIC ACID =

    12. Prophylactic Options ANTACIDS H2 BLOCKERS SUCRALFATE PROSTAGLANDIN ANALOGS PROTON PUMP INHIBITORS

    13. Prophylactic Options Antacids: May work as well as H2 blockers for neutralizing acid. Antacids must be given to frequently and in larger volumes to be effective.

    14. Prophylactic Options H2 Blockers: Decrease stimulation of histamine on parietal cell acid secretion. Most trials show lower risk of significant GI hemorrhage. Shuman, RB. Prophylactic therapy for stress ulcer bleeding. Ann Int Med 1987; 106: 562-8.

    15. Prophylactic Options H2 antagonists: Inhibit acid secretion in a dose-dependent competitive manner. Reduce volume of gastric acid and [H+] Well absorbed with half life of 2 to 3 hours. Goodman & Gilman’s Pharmacological Basis of Therapeutics. 9th ed.

    16. Prophylactic Options H2 Antagonist Adverse Effects: Cimetidine no longer available in U.S. Rantidine: Rare and often <> placebo Somnolence / confusion > elderly Bradycardia with rapid infusion Goodman & Gilman’s Pharmacological Basis of Therapeutics. 9th ed.

    17. Prophylactic Options SUCRALFATE: Adheres to epithelial cells and “restores” a cytoprotective barrier. Binds bile salts Stimulates prostaglandin synthesis Stimulates local epidermal growth factor Goodman & Gilman’s Pharmacological Basis of Therapeutics. 9th ed.

    18. Prophylactic Options SUCRALFATE ADVERSE EFFECTS: Constipation 2% Dry mouth 1% Rare complaints of abdominal distension. Decreased bioavailability of tetracycline, phenytoin, digoxin, fluoroquinolones, ketoconazole.

    19. Prophylactic Options Prostaglandin Analogs PGE 2 and PGI 2 inhibit acid secretion and increase mucus and bicarbonate. May have a more useful role in patients who are dependent on NSAIDS.

    20. Prophylactic Options PROTON PUMP INHIBITORS The final mediator of acid secretion is the H+, K+ -- ATPase pump unique to the parietal cell. PPIs are prodrugs that are activated by protonation and covalently bind to a cysteine residue and inactivate the ATPase enzyme.

    21. Prophylactic Options PPI ADVERSE EFFECTS: 1.5 to 3% with GI side effects. Rare CNS effects (headache, somnolence) Rare rash and elevation of liver transaminases. INCREASED NOSOCOMIAL PNEUMONIA?

    22. Prophylactic Options NUTRITION In one burn study, enteral nutrition alone had significantly lower gi hemorrhage when compared to cimetidine in 526 patients. Raff, T. Burns 1997; 23:313

    23. The Patient at Risk Cook, D. et al. NEJM 1994; 330:377-81. Prospective Multicenter Cohort Study to evaluate risk factors in stress ulceration. Documented “Clinically Important” (overt bleeding with hemodynamic compromise or transfusion).

    24. The Patient at Risk 2252 patients. 33 with clinically significant bleeding. Two strong risk factors: Respiratory Failure Coagulopathy Increased Risk to 3.7% of bleed.

    25. The Patient at Risk 1405 patients without these risk factors 0.1 % (.02 to 0.5 95% confidence interval)

    26. Conclusion Few critically ill patients have significant gi bleeding and prophylaxis can be withheld unless they have coagulopathy or require mechanical ventilation.

    27. Exclusion Criteria? Hematochezia, “Coffee grounds,” melana, epistaxis, facial trauma, previous gastrectomy. Did not withhold prophylaxis in case of head injury, 30% burns, transplants, diagnosis of peptic ulcer or gastritis in 6 weeks or recent UGI bleed. Mostly cardiac and pulmonary ICU patients.

    28. Risk Factors Respiratory Failure p<.001 Coagulopathy p<.001 Hypotension p=.08 Sepsis p=.17 Hepatic Failure p=.27 Renal Failure p=.26 Glucocorticoids p=.26

    29. JAMA META-ANALYSIS PURPOSE: To elucidate the effects of stress ulcer prophylaxis on gi bleeding, pneumonia and mortality in critically ill patients. STUDY SELECTION: 63 randomized trials included

    30. JAMA META-ANALYSIS Result: Determined that stress ulcer prophylaxis decreases incidence of overt and clinically important GI bleeding with an odds ratio of .44 and 95% confidence interval of .22 to .88.

    31. JAMA GUIDE (a/b)/(c/d)

    32. Conclusions Strong evidence of reduced clinically important gi bleeding with H2 receptor antagonists. Sucralfate may be as effective and have less risk of ventilator associated pneumonia.

    33. Dr. Cook does not sleep.

    34. Sucralfate vs. Ranitidine vs. Placebo? METHODS: Multicenter, randomized, blinded, placebo-controlled trial. Compared 1200 patients who required mechanical ventilation. RESULTS: Clinically important bleeding in 1.7% ranitidine and 3.8% sucralfate. P=.02

    35. Ventilator Associated Pneumonia 19.1% ranitidine vs. 16.2% sucralfate with P=0.19. No significant difference in mortality.

    36. FUTURE STUDIES

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