Stress Ulcer Prophylaxis

Based on the work of Eamonn Sheerin, Oliver Flower and Jeremy Fernando

OVERVIEW

• Stress ulcers are gastric mucosal erosions that can develop in patients with a serious illness or severe injury.
• The primary goal of therapy related to stress ulcer is to prevent clinically important bleeding
• Multiple prophylaxis regimes have been proposed

STRESS ULCERS

Comparison with peptic ulcers

• stress-related mucosal injuries typically occur in the acid-producing areas of the stomach (i.e., corpus and fundus), unlike peptic ulcers, which tend to develop in the antrum or duodenum
• stress-related mucosal injury mainly involves small erosions that do not lead to bleeding but may develop into deeper ulcers, which cause bleeding
• Stress ulcers tend to cause gastrointestinal (GI) bleeding without associated abdominal pain,  unlike peptic ulcers

Epidemiology

• Endoscopy performed within 72 hours of a major burn or cranial trauma reveals acute mucosal abnormalities in greater than 75% of patients
•  clinically significant bleeding has
  — 1.5 to 8.5% incidence among all ICU patients
  — up to 15% among patients who do not receive stress ulcer prophylaxis

CHOICE OF PROPHYLAXIS

Options include:

• H2 blockers (tolerance after 72h)
• PPIs (potent, long-lasting, but maximal effect takes 2 days)
• sucralfate (less effective than H2 blockers in one MC RCT, but not in multiple other studies)
• antacids (not a viable option as labor-intensive dosing regimes and side-effects)

All reduce the frequency of overt GI bleeding in ICU patients compared to placebo or no prophylaxis

• Based on a recent meta-analysis, PPI is probably preferable to H2 blockers
• H2 blockers versus PPI (Barkun et al, 2012)
  – meta-analysis of 13 RCTs; n = 1587 patients
  — compared stress ulcer prophylaxis with a PPI to prophylaxis with an H2 blocker
  — found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54)
  — no difference in mortality or the incidence of nosocomial pneumonia

Enteral feeding is an alternative or addition to drugs

• improves splanchnic blood flow, improves macroscopic ulceration, stimulates GALT
• studies inconsistent in showing decreased GI bleeding (low quality)
• unclear if enteral feeding is sufficient protection in high risk patients

INDICATIONS FOR STRESS ULCER PROPHYLAXIS

Very high risk factors (Cook et al, 1994)

• Mechanical ventilation for more than 48 hours (OR 15.6)
• Coagulopathy (OR 4.3) – defined as INR over 1.5, platelets < 50 or a partial thromboplastin time (PTT) >2 times the control value

Other high risk factors:

• Past history of gastric ulcer or GI bleeding in past 12 months
• Trauma: TBI, spinal cord injury, or burns
• 2 0r more of: >1 week in ICU, occult GI bleeding, steroids (>250mg hydrocortisone per week)

Enteral nutrition protects against stress ulcers, but it is uncertain if withholding stress ulcer prophylaxis from patients who are at high risk for gastrointestinal bleeding is appropriate

COMPLICATIONS OF STRESS ULCER PROPHYLAXIS

General

• drug allergy, drug side-effects and drug interactions (esp cimetidine)
• pneumonia (HAP and CAP)

PPIs

• interstitial nephritis (rare — but PPIs are a major drug causes)
• Clostridium difficile enterocolitis (PPIs have dose-dependent relationship)
• GI upset and headaches
• long-term use associated with fractures, hypomagnesemia, hypocalcemia

H2 blockers

•  CNS side-effects (esp in the elderly)
• tolerance after 72h

EVIDENCE SUMMARY

Barkun AN, Bardou M, Pham CQ, Martel M. Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012 Apr;107(4):507-20; quiz 521. doi: 10.1038/ajg.2011.474. Epub 2012 Jan 31. PubMed PMID: 22290403.

• meta-analysis of 13 RCTs
• n = 1587 patients
• stress ulcer prophylaxis with a PPI vs prophylaxis with an H2 blocker
  -> found less GI bleeding among those who received a PPI (1.3 versus 6.6 percent, odds ratio 0.30, 95% CI 0.17-0.54) -> NNT 39
  -> no difference in mortality or the incidence of nosocomial pneumonia

Cook, D et al (1998) “A comparison of sucralfate and ranitidine for the prevention of upper gastrointestinal bleeding in patients requiring mechanical ventilation” Canadian Critical Care Trials Group, NEJM, 338:791-7

• MRCT
• placebo vs ranitidine vs sucralfate
  -> GIH: placebo ( ), ranitidine (1.7%), sucralfate (3.8%) – P < 0.05
  -> pneumonia incidence: ranitidine (19.2%), sucralfate (16.2%) – P > 0.05
  -> no change in LOS or mortality

Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010 Nov;38(11):2222-8. doi: 10.1097/CCM.0b013e3181f17adf. Review. PubMed PMID: 20711074.

Study design

• meta-analysis of RCTs
• histamine-2 receptor blockers vs placebo
• 17 studies (1836 patients)
• primary end point: clinically significant GIH
• secondary end points: incidence of HAP and hospital mortality.
• sub group analysis performed by grouping studies by enteral nutrition or no enteral nutrition

Results

• overall: significant decrease in risk of gastrointestinal bleeding (OR 0.47, p < 0.02)
  -> BUT only noted in a subgroup of patients who did not receive enteral nutrition (OR 1.26, CI 0.43-3.7)
  -> if patients enterally fed, prophylaxis did not alter the risk of GI bleeding
• overall: no increase in risk of HAP
  -> BUT, those who were enterally fed had an increased risk of HAP (p 0.02, or 2.81) — ? both increasing gastric pH and thus allowing gastric multiplication of bacteria and subsequent aspiration
• overall: stress ulcer prophylaxis did not change mortality
  -> BUT, was higher in patients were fed enterally and received a histamine-2 receptor blocker (OR 1.89; 95% CI 1.04-3.44)

Internal Validity

• clinically significant GIH was defined by each individual study
• if there wasn’t a definition of clinically significant bleeding then endoscopic bleeding was used
• used H2 antagonists: cimetidine, ranitidine, famotidine
• varying doses
• some studies ran infusions
• only 3 studies looked at enteral nutrition

External Applicability

• many centers use PPIs not H2-antagonists
• those who were fed may have been sicker than those that weren’t which may explain increase in HAP and death (confounding)
• it included both patients who are at high risk and low risk for stress ulceration –  the harmful effects of prophylaxis seen among patients receiving enteral nutrition may have been due to unnecessary prophylaxis in low risk patients

Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, Winton TL, Rutledge F, Todd TJ, Roy P, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994 Feb 10;330(6):377-81. PubMed PMID: 8284001. [Free Fulltext]

• A multicenter prospective cohort study of 2252 ICU patients identified two major risk factors for clinically important GI bleeding (defined as overt GI bleeding leading to hemodynamic deterioration or requiring blood transfusion) due to stress ulceration
  (1) Mechanical ventilation for more than 48 hours (OR 15.6)
  (2) Coagulopathy (OR 4.3) – defined as INR over 1.5, platelets < 50 or a partial thromboplastin time (PTT) >2 times the control value
• The incidence of clinically important GI bleeding among patients with one or both of these risk factors was 3.7 percent.
• In patients with neither RF the incidence was 0.1 percent, and the study authors concluded that prophylaxis was not indicated in these patients.

AN APPROACH TO STRESS ULCER PROPHYLAXIS

• feed early unless contraindicated
• don’t use prophylaxis if feeding established
• if unable to establish enteral feed, risk assess for GIH: if high risk -> use prophylaxis (some would use prohylaxis in this group regardless of whether they are enterally fed)
• PPIs are generally preferred, but ranitidine is an acceptable alternative
• if stress ulcers develop treat appropriately
• be vigilant for  hospital acquired pneumonia and C. difficile enterocolitis if stress ulcer prophylaxis given
• reassess daily and de-escalate stress ulcer prophylaxis when no longer needed

References and Links

Journal articles and textbooks

• 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:(3)693-705. [pubmed]
• Barkun AN, Bardou M, Pham CQ, Martel M. Proton pump inhibitors vs. histamine 2 receptor antagonists for stress-related mucosal bleeding prophylaxis in critically ill patients: a meta-analysis. Am J Gastroenterol. 2012 Apr;107(4):507-20; quiz 521. PMID: 22290403.
• Cook DJ, Griffith LE, Walter SD, Guyatt GH, Meade MO, Heyland DK, Kirby A, Tryba M; Canadian Critical Care Trials Group. The attributable mortality and length of intensive care unit stay of clinically important gastrointestinal bleeding in critically ill patients. Crit Care. 2001 Dec;5(6):368-75. PMC83859.
• Cook DJ, Fuller HD, Guyatt GH, Marshall JC, Leasa D, Hall R, Winton TL, Rutledge F, Todd TJ, Roy P, et al. Risk factors for gastrointestinal bleeding in critically ill patients. Canadian Critical Care Trials Group. N Engl J Med. 1994 Feb 10;330(6):377-81. PMID: 8284001.
• Cook D, Guyatt G, Marshall J, Leasa D, Fuller H, Hall R, Peters S, Rutledge F, Griffith L, McLellan A, Wood G, Kirby A. 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 Mar 19;338(12):791-7. PMID: 9504939.
• Marik PE, Vasu T, Hirani A, Pachinburavan M. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med. 2010 Nov;38(11):2222-8. PMID: 20711074.
• Quenot JP, Thiery N, Barbar S. When should stress ulcer prophylaxis be used in the ICU? Curr Opin Crit Care. 2009 Apr;15(2):139-43. PMID: 19578324.

FOAM and web resources

• ICN — 50. Good Housekeeping