Stress Ulcer Prophylaxis in Hospitalized Patients

S t res s U l c e r Pro p h y l a x i s i n Hospitalized Patients Mary E. Anderson,

MD

KEYWORDS  Stress-related mucosal disease  Stress ulcer  Gastrointestinal bleeding  Prophylaxis  Histamine-2 receptor antagonist  Proton pump inhibitor

HOSPITAL MEDICINE CLINICS CHECKLIST

1. Start stress ulcer prophylaxis in critically ill patients who meet the following indications: a. Mechanical ventilation for >48 hours b. Coagulopathy (International Normalization Ratio [INR] >1.5, partial thromboplastin time [PTT] >2 times control value, platelet count <50,000) c. History of gastrointestinal ulcer or bleeding in year before admission d. At least 2 of the following: sepsis, intensive care unit stay longer than 1 week, occult bleeding for 6 days or longer, or corticosteroid therapy (>250 mg hydrocortisone or equivalent daily) e. See Box 1 for remainder of indications 2. Use histamine-2 receptor antagonists or proton pump inhibitors for prophylaxis. 3. Discontinue stress ulcer prophylaxis when patients’ risk factors resolve and before transfer out of the intensive care unit or discharge. 4. Monitor for complications of acid-suppressive therapy, including nosocomial pneumonia and Clostridium difficile colitis. 5. Recognize the overuse of stress ulcer prophylaxis in hospitalized patients and advocate for evidence-based prescribing practices.

DEFINITIONS

1. What is stress-related mucosal disease? Stress-related mucosal disease (SRMD) refers to the acute superficial inflammatory lesions of the gastric mucosa that can arise during serious illness.1 These lesions

No disclosures. Hospital Medicine Section, Department of Medicine, University of Colorado Hospital, University of Colorado School of Medicine, 12401 East 17th Avenue, Mailstop F-782, Aurora, CO 80045, USA E-mail address: [email protected] Hosp Med Clin 2 (2013) e32–e44 http://dx.doi.org/10.1016/j.ehmc.2012.07.004 2211-5943/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.

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Box 1 Indications for stress ulcer prophylaxis in intensive care unit (ICU) patients Mechanical ventilation for more than 48 hours Coagulopathy INR more than 1.5 PTT more than 2 times control value Platelet count less than 50,000 History of gastric ulceration or bleeding during the year before admission Presence of at least 2 of the following: Sepsis ICU stay longer than 1 week Occult bleeding for 6 days or longer Corticosteroid therapy (>250 mg of hydrocortisone or equivalent daily) Hepatic failure Hepatic or renal transplantation Partial hepatectomy Head injury with Glasgow Coma Score of less than or equal to 10 or inability to obey simple commands Thermal injury involving more than 35% of body surface area Multiple trauma with Injury Severity Score greater than or equal to 16 Spinal cord injury

typically begin as subepithelial petechiae but can progress to superficial erosions and even ulcerations.2 SRMD therefore encompasses such terms as hemorrhagic gastritis, erosive gastritis, stress gastritis, stress erosions, and stress ulcers or ulcerations. EPIDEMIOLOGY

1. What is the incidence of SRMD? As many as 74% to 100% of patients have endoscopically detectable mucosal damage within 24 hours of admission to the ICU.2 Similar endoscopic studies have not been performed in non–critically ill patients. 2. What is the clinical significance of SRMD? SRMD is generally asymptomatic. Symptomatic lesions can present anywhere on the spectrum from occult to overt to clinically significant gastrointestinal (GI) bleeding. Overt bleeding is defined as any visible blood loss, such as a bloody nasogastric tube aspirate, hematemesis, melena, or hematochezia.3 Clinically significant bleeding is defined as any overt bleeding causing hemodynamic instability or requiring blood transfusion. Up to 25% of ICU patients develop overt gastric bleeding and 0.6% to 5% develop clinically significant bleeding if not on stress ulcer prophylaxis (SUP).2 Overall, the incidence of stress-related mucosal bleeding seems to have declined

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over the last several decades.4 This improvement has been attributed to advances in critical care, including better hemodynamic support and volume resuscitation in sepsis and greater use of SUP. However, when stress-related bleeding occurs, it is associated with significant morbidity and mortality. ICU length of stay may increase by as many as 11 days.3 Mortality approaches 50% in critically ill patients who develop stress-related mucosal bleeding, about 4-fold higher than in patients without this complication.5,6 3. What are the risk factors for SRMD? The 2 strongest independent risk factors for stress-related mucosal bleeding seem to be respiratory failure requiring mechanical ventilation for more than 48 hours (odds ratio 15.6) and coagulopathy (odds ratio 4.3).5 Other risk factors that have been identified include sepsis, shock, multiorgan failure, major trauma, major surgical procedures, severe head injury, spinal cord injuries, and high-dose corticosteroid use.7 Heparin and warfarin use per se do not seem to be independent risk factors after controlling for coagulopathy.5 It is unknown whether noninvasive mechanical ventilation is a risk factor for bleeding.8 PATHOPHYSIOLOGY

1. What is the pathophysiology of SRMD? The pathophysiology of SRMD is multifactorial and involves a breakdown in the protective gastric barrier in the face of abnormal physiologic stress. Critical illness is often associated with hypotension and catecholamine-induced vasoconstriction, which can lead to splanchnic hypoperfusion and mucosal ischemia.9 Release of various inflammatory mediators, such as cytokines and free oxygen radicals, can directly damage the gastric mucosa.10 Gastric acid hypersecretion has also been implicated but is not a consistent finding.11,12 A shift in arachidonic acid metabolism from prostaglandins to leukotrienes can impair epithelial cell turnover and reduce mucus and bicarbonate secretion, making it difficult for the gastric mucosa to heal.13 As the mucosal barrier becomes further compromised, luminal hydrogen ions and pepsin can diffuse back into the gastric mucosa and exacerbate the injury.9,12 The decreased GI motility that often accompanies severe illness can further prolong the exposure of the gastric mucosa to acid and other irritants.9 Acid therefore plays a permissive role in the formation of stress ulcers. 2. How do stress ulcers differ from traditional peptic ulcers? Stress ulcers are most commonly found in the gastric fundus, whereas peptic ulcers are usually located in the gastric body, antrum, and duodenum.10 The reasons for this difference are incompletely understood. Helicobacter pylori infection and nonsteroidal antiinflammatory drugs (NSAIDs) are well-established risk factors for peptic ulcers, but not stress ulcers. H pylori preferentially colonizes the antrum.14 NSAIDs also tend to cause distal ulcers; aside from their systemic inhibition of prostaglandin synthesis, the dissolving pills directly irritate the gastric mucosa as they settle in the dependent portion of the stomach.15 In addition, stress ulcers tend to be multiple and superficial, whereas peptic ulcers tend to be deeper with a greater risk for perforation. Cushing ulcers, which are single, deep ulcers in the stomach or duodenum associated with head trauma, are an exception to this pattern.

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DIAGNOSIS

1. How is SRMD diagnosed? Hospitalized patients with SRMD may have only occult GI bleeding with slowly developing anemia, or they may show signs of overt bleeding, ranging from coffee-ground material in their nasogastric tube aspirates to melena or even hematemesis or hematochezia. Tachycardia, hypotension, and hemorrhagic shock may occur in severe circumstances. It can be clinically difficult to distinguish stress-related mucosal bleeding from other causes of upper GI bleeding. Upper endoscopy can help confirm the source of the bleeding. PROPHYLAXIS

1. What are the indications for SUP in ICU patients? The only existing guidelines for SUP were published by The American Society of Health-System Pharmacists (ASHP) in 1999.10 Updated guidelines are expected in late 2012.16 The indications for SUP are listed in Box 1. SUP is recommended only for a subset of ICU patients. SUP should be discontinued when the original risk factors have resolved. Although the Surviving Sepsis Campaign guidelines recommend SUP in all patients with severe sepsis, this is not a widely accepted practice.17,18 Evidence is also lacking regarding the use of SUP in patients admitted to the coronary care unit with acute coronary syndromes (ACS).19,20 These patients are often receiving aspirin, clopidogrel, unfractionated or low-molecular-weight heparin, and glycoprotein IIb/IIIa inhibitors, which might increase their risk of nosocomial GI bleeding. However, the American College of Cardiology and American Heart Association have stated that, until additional data are available, they are unable to make a recommendation regarding the use of SUP in patients with ACS.21 2. What is the role for SUP in the non-ICU setting? Few prospective trials have evaluated the role for SUP in non–critically ill patients.22–24 A recent retrospective case-control study by Qadeer and colleagues25 examined 17,707 patients admitted to the general internal medicine service at a tertiary care medical center. They found an incidence of hospital-acquired GI bleeding requiring upper endoscopy of only 0.4%. About 0.2% of the total cohort had culprit lesions, such as ulcers, on endoscopy that might have been prevented with acidsuppressive medications. However, statistical analysis did not show any protective effect of prophylaxis on the rates of bleeding. Overall, general medicine patients with GI bleeding fared similarly to controls. They were more likely to require blood transfusions during their hospitalization, but they were no more likely to require transfer to the ICU or to develop major complications. All-cause mortality was also similar between the 2 groups. Another retrospective case-control study by Faulk and colleagues26 of 11,645 patients on an inpatient rehabilitation service found an incidence of critical GI bleeding of just 0.3%. GI prophylaxis was not found to be protective. In summary, nosocomial GI bleeding is uncommon in non–critically ill patients. Based on current available evidence, SUP should not be used in this population. The use of acid-suppressive medications for the prevention of NSAID-induced ulcers is a separate topic.27–29

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3. What are the options for SUP? Various agents that protect the gastric mucosa from acid have been used for SUP. Antacids such as aluminum and magnesium hydroxide were historically used because of their ability to buffer stomach acid. Sucralfate does not neutralize acid but forms a protective barrier over the gastric mucosa. Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) both inhibit gastric acid secretion. The different options for SUP are listed in Table 1.10,30 Although many of these medications are routinely used for SUP in clinical practice, only certain drugs in each class have been approved by the US Food and Drug Administration (FDA) for this indication.31 Sucralfate is used off-label for SUP. Continuous infusion cimetidine is the only H2RA specifically FDA approved for SUP, and an oral omeprazole suspension now carries this indication. Most of the recommended doses have been derived from clinical trials. 4. What is the efficacy of SUP? The efficacy of SUP has primarily been studied in the ICU population. It has been estimated that only 30 patients at high risk for SRMD need to receive prophylaxis to prevent 1 GI bleed, compared with nearly 900 low-risk patients in the ICU.5 The relative efficacy of antacids, sucralfate, H2RAs, and PPIs in critically ill patients is also important. Meta-analyses have shown that H2RAs are better than placebo in Table 1 Dosing for agents used in SUP Medication

Normal Renal Function

Impaired Renal Function

Sucralfate

1 g by mouth every 6 h

No adjustment

Cimetidine

300 mg by mouth, NG, or IV every 6 h or 50 mg/h continuous infusion

If CrCl<30 mL/min: 300 mg by mouth, NG, or IV every 12 h or 25 mg/h continuous infusion

Famotidine

20 mg by mouth, NG, or IV every 12 h or 1.7 mg/h continuous infusion

If CrCl<30 mL/min: 20 mg by mouth, NG, or IV daily or 0.85 mg/h continuous infusion

Ranitidine

150 mg by mouth or NG every 12 h, 50 mg IV every 6–8 h, or 6.25 mg/h continuous infusion

If CrCl<50 mL/min: 150 mg by mouth or NG every 12–24 h, 50 mg IV every 12–24 h, or 2–4 mg/h continuous infusion

H2RAs

PPIs Esomeprazole 20–40 mg by mouth, NG, or IV every 24 h

No adjustment

Lansoprazole

30 mg by mouth, NG, or IV every 24 h No adjustment

Omeprazole

40 mg loading dose, then 20–40 mg by mouth, NG, or IV every 24 h

Pantoprazole

40 mg by mouth, NG, or IV every 24 h No adjustment

Rabeprazole

20 mg by mouth or NG every 24 h

No adjustment

No adjustment

Abbreviations: CrCl, creatinine clearance rate; IV, intravenously; NG, nasogastric tube. Data from American Society of Health-System Pharmacists. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health Syst Pharm 1999;56:347–79; and Zeitoun A, Zeineddine M, Dimassi H. Stress ulcer prophylaxis guidelines: are they being implemented in Lebanese health care centers? World J Gastrointest Pharmacol Ther 2011;2(4):27–35.

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the prevention of stress-related bleeding, with an odds ratio of 0.47 (95% confidence interval [CI] 0.29–0.76).32,33 However, H2RAs do not seem to have a mortality benefit compared with placebo.30 H2RAs have not been shown to be more effective than antacids or sucralfate.34 The ASHP guidelines state that the choice of therapy should be made on an institution-specific basis, considering such factors as ease of administration, side effect profile, and cost.10 Antacids have fallen out of favor because of their labor-intensive dosing frequency. Sucralfate can be inconvenient because of its tendency to occlude nasogastric tubes, the lack of an intravenous formulation, and its interference with absorption of other medications. At the time the ASHP guidelines were released, there were insufficient data available to make recommendations about PPIs. PPIs might be expected to perform better than H2RAs as SUP because of more potent acid suppression. However, the data are still conflicting. A 2010 meta-analysis of 7 randomized controlled trials by Lin and colleagues35 did not find a substantial difference in stress-related mucosal bleeding between PPIs and H2RAs. A 2012 meta-analysis by Barkun and colleagues36 that included 6 other small studies found that PPIs significantly decreased the rates of bleeding compared with H2RAs, with an odds ratio of 0.30 (95% CI 0.17–0.54) and a number needed to treat of 39. PPIs had no mortality benefit compared with H2RAs. As of 2004, H2RAs were still the preferred choice for SUP for most intensivists.37,38 5. What are the adverse effects of SUP? Sucralfate, H2RAs, and PPIs are generally safe medications, particularly when used for a short period of time in the hospital.10,39 The main side effect of sucralfate is constipation. It can also cause aluminum toxicity in chronic renal insufficiency, although this does not seem to be a problem with short-term use. H2RAs are most commonly associated with headache, diarrhea, and dizziness, although they can occasionally cause cytopenias, hepatitis, and central nervous system toxicity. Cimetidine is also well known for causing drug-drug interactions through the cytochrome P450 system. The most common side effects of PPIs are headache, constipation, diarrhea, dizziness, and rash, with hypomagnesemia also recently reported.40 Several adverse effects of H2RAs and PPIs have attracted considerable attention in recent years and are described in more detail later. Although uncommon, these adverse effects become clinically relevant in light of the widespread overuse of SUP in the hospital and inappropriate continuation of SUP after discharge.41 Pneumonia

Acid-suppressive medications have been implicated in the development of community-acquired and hospital-acquired pneumonia.42,43 A large 2011 metaanalysis of 31 studies, including both outpatients and inpatients (ICU and non-ICU), found that H2RAs and PPIs conferred a 22% and 27% increased risk of pneumonia, respectively (95% CIs 1.11–1.46 and 1.09–1.36).44 This translated into a number needed to harm of about 200 for inpatients treated with acid suppressants. Acidsuppressive medications may predispose to aspiration pneumonia by promoting bacterial growth in the stomach and subsequent retrograde colonization of the pharynx. They may also lead to pneumonia by inhibiting white blood cell function.45–47 Clostridium difficile Colitis

Acid-suppressive medications have also been linked to community-acquired and nosocomial C difficile colitis.48–51 A prospective cohort study of 4143 hospitalized

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patients showed that the use of PPIs within 8 weeks before hospitalization or during hospitalization was associated with an increased risk of nosocomial C difficile infection (OR 2.64, 95% CI 2.71–4.09).49 It has been hypothesized that ingested C difficile bacteria and their toxins can better survive transit through the stomach when gastric acid contents are less acidic. The odds of nosocomial C difficile infection seem to increase with greater levels of pharmacologic acid suppression (OR 1 with no acid suppression, 1.53 with H2RAs, 1.74 with daily PPIs, and 2.36 with more than daily PPIs).52 This finding represents a number needed to harm of 533 for inpatients on daily PPIs. PPIs also increase the risk of recurrent C difficile infection.53,54 Fractures

Acid-suppressive medications may also be associated with an increased risk of fractures.55–63 A recent meta-analysis of 223,210 fracture cases found a modest association between chronic PPI use and the risk of hip fractures (OR 1.25, 95% CI 1.14–1.37) and vertebral fractures (OR 1.50, 95% CI 1.32–1.72).55 The number needed to harm with PPI therapy was 2672 for hip fracture and 337 for vertebral fracture per year. The mechanism behind this association is incompletely understood. PPIs do not necessarily inhibit calcium absorption or lower bone mineral density.58 Instead, they may interfere with osteoclast activity, which could negatively affect bone remodeling. Acute Interstitial Nephritis

Acute interstitial nephritis related to PPI use is a rare, idiosyncratic event.64,65 Fewer than 100 cases have been reported in the literature, although the exact incidence is difficult to determine. Interaction Between PPIs and Clopidogrel

Clopidogrel is a prodrug that is converted to its active metabolite through the hepatic cytochrome P450 system, mainly CYP2C19.39,40 PPIs are also primarily metabolized through CYP2C19, raising the concern that they might decrease the antiplatelet effect of clopidogrel. In vitro studies have shown that PPIs, mainly omeprazole, interfere with clopidogrel’s antiplatelet activity. Such results led the FDA to issue warnings in 2009 to avoid the concomitant use of clopidogrel and omeprazole (or esomeprazole).66 However, there is limited evidence that these findings translate into clinically important outcomes. Most observational studies and the 1 randomized controlled trial to date have not shown an increased risk of cardiovascular events in patients concurrently on PPIs and clopidogrel.67–70 Keeping the FDA’s warning in mind, it is reasonable to conclude that most PPIs could be used for SUP in patients already on clopidogrel. PERFORMANCE IMPROVEMENT

1. Is SUP used appropriately in the inpatient setting? Numerous studies have been published in recent years about the overuse of acidsuppressive medications in hospitalized patients.41 Despite the ASHP guidelines, as many as 68% of critically ill patients with no risk factors for stress-induced bleeding receive SUP during their ICU stay.8 Most ICU patients have their SUP continued on transfer out of the ICU, even after their original risk factors have resolved.10,71 SUP is also frequently used in patients admitted directly to general medicine services

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and continued on hospital discharge, without evidence to support this practice, as detailed later. A 2000 study by Nardino and colleagues72 prospectively evaluated 226 patients admitted to a general medicine service at a community teaching hospital. They found that 122 patients (54%) received acid-suppressive therapy during their hospitalization. Acid-suppressive therapy was unnecessary in 65% of cases, with SUP being the most common justification for inappropriate prescribing. Overall use of acid-suppressive therapy increased as a result of hospitalization. Only 54 of the 122 patients (44%) had previously been on acid-suppressive therapy as an outpatient, but 88 (71%) were prescribed it on discharge. Even more concerning, 67% of patients started on acidsuppressive therapy in the hospital were discharged on it for inappropriate reasons. A 2006 study by Heidelbaugh and colleagues73 also found that SUP is overused in the non-ICU setting. Of 1769 patients admitted to a general medicine service at an academic medical center, 22% received SUP, and 54% of these were discharged home on acid-suppressive therapy. None of these patients received SUP appropriately, as defined by the ASHP guidelines. A 2006 study by Pham and colleagues74 had similar findings. In 2010, Reid and colleagues75 conducted a retrospective review of the use of PPIs in 9875 patients in a university-affiliated public safety net hospital and 6,520,100 patients in the University Health System Consortium. Of the nearly 1 million patients who received PPIs between 2008 and 2009, 73% did not have a valid indication for acidsuppressive therapy. SUP was cited as the reason for inappropriate prescribing in 56% of cases. Possible explanations for the persistent overuse of SUP include lack of knowledge of the indications for SUP, unfounded fear of the legal repercussions of not prescribing SUP, and unawareness of the side effects of acid-suppressive therapy.76 Hospitalists and other health care providers need to use SUP more appropriately in the inpatient setting. 2. What is the economic impact of the inappropriate use of SUP? The overuse of SUP can have a substantial economic impact on both patients and the health care system. The study by Heidelbaugh and colleagues,73 which included 1769 general medicine patients at a major university hospital, found that the inappropriate use of SUP increased annual inpatient costs by $44,096 and outpatient costs by $67,695, for a total of $111,791. In a large managed care organization, in which 68% of 29,348 patients were prescribed a PPI inappropriately at hospital discharge, inappropriate continuation for just 30 days after discharge was associated with a cost of more than $3 million over 4 years.77 Neither of these studies took into account the costs incurred from complications of SUP therapy. 3. What strategies can reduce the overuse of SUP? Although the overuse of SUP in hospitalized patients is well documented, few studies have explored potential solutions to the problem. Interventions that have been shown to improve prescribing patterns, at least temporarily, include the development of educational materials, pharmacist participation on rounds, and daily medication reconciliation by pharmacy staff.78–80 Additional strategies might include reevaluating the use of H2RAs and PPIs on standardized order sets or integrating decision-making prompts into the electronic medical record. Future quality improvement studies are needed to address this issue.

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CLINICAL GUIDELINES

American Society of Health-System Pharmacists. ASHP therapeutic guidelines on stress ulcer prophylaxis. Am J Health Syst Pharm 1999;56:347–79. REFERENCES

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20. Wu H, Jing Q, Want J, et al. Pantoprazole for the prevention of gastrointestinal bleeding in high-risk patients with acute coronary syndromes. J Crit Care 2011; 26:434.e1–6. 21. Kushner FG, Smith SC, Anderson JL, et al. 2009 Focused Updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guidelines and 2007 focused update) and ACC/ AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update). J Am Coll Cardiol 2009;54(23): 2205–41. 22. Estruch R, Pedrol E, Castells A, et al. Prophylaxis of gastrointestinal tract bleeding with magaldrate in patients admitted to a general hospital ward. Scand J Gastroenterol 1991;26:819–26. 23. Grau JM, Casademont J, Fernandez-Sola J, et al. Prophylaxis of gastrointestinal tract bleeding in patients admitted to a general hospital ward. Scand J Gastroenterol 1993;28:244–8. 24. Janicki T, Stewart S. Stress-ulcer prophylaxis for general medical patients: a review of the evidence. J Hosp Med 2007;2(2):86–92. 25. Qadeer MA, Richter JE, Brotman DJ. Hospital-acquired gastrointestinal bleeding outside the critical care unit: risk factors, role of acid suppression, and endoscopy findings. J Hosp Med 2006;1(1):13–20. 26. Faulk CE, Sandoval A, Draughon M, et al. Critical gastrointestinal bleeding at an inpatient rehabilitation center: incidence, risk factors, and the role of gastrointestinal prophylaxis. PM R 2010;2(12):1104–12. 27. Lanza FL, Chan FK, Quigley EM, et al. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009;104:728–38. 28. Lazzaroni M, Porro GB. Management of NSAID-induced gastrointestinal toxicity: focus on proton pump inhibitors. Drugs 2009;69(1):51–69. 29. Wilcox CM, Allison J, Benzuly K. Consensus development conference on the use of nonsteroidal anti-inflammatory agents, including cyclo-oxygenase-2 enzyme inhibitors and aspirin. Clin Gastroenterol Hepatol 2006;4:1082–9. 30. Zeitoun A, Zeineddine M, Dimassi H. Stress ulcer prophylaxis guidelines: are they being implemented in Lebanese health care centers? World J Gastrointest Pharmacol Ther 2011;2(4):27–35. 31. Food and Drug Administration. Drugs@FDA. Available at: http://www.accessdata. fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed April 14, 2012. 32. Cook DJ, Reeve BK, Guyatt GH, et al. Stress ulcer prophylaxis in critically ill patients. Resolving discordant meta-analyses. JAMA 1996;275(4):308–14. 33. Marik PE, Vasu T, Hirani A. Stress ulcer prophylaxis in the new millennium: a systematic review and meta-analysis. Crit Care Med 2010;38(11):2222–8. 34. Huang J, Cao Y, Liao C, et al. Effect of histamine-2-receptor antagonists versus sucralfate on stress ulcer prophylaxis in mechanically ventilated patients: a meta-analysis of 10 randomized controlled trials. Crit Care 2010;14:R194. 35. Lin PC, Chang CH, Hsu PI, et al. The efficacy and safety of proton pump inhibitors vs histamine-2 receptor antagonists for stress ulcer bleeding prophylaxis among critical care patients: a meta-analysis. Crit Care Med 2010;38(4):1197–205. 36. Barkun AN, Bardou M, Pham CQ, et al. 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;107:507–20. 37. Devlin JW, Welage LS, Olsen KM. Proton pump inhibitor formulary considerations in the acutely ill part 2: clinical efficacy, safety, and economics. Ann Pharmacother 2005;39(11):1844–51.

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