Prevention of Complications in Hospitalized Patients Part III: Upper Gastrointestinal Stress Ulcers

CLINICAL REVIEW Prevention of Complications in Hospitalized Patients Part III: Upper Gastrointestinal Stress Ulcers Michael A. Pfeffer, M.D., and Michael S. Galindo, M.D. The Clinical Scenario A 70-year-old woman with a history of diabetes and hypertension is admitted to the hospital with fevers and back pain. At the time of admission, she is hypotensive, confused, and lethargic, with exquisite tenderness over the right costovertebral angle. Pyelonephritis is diagnosed, and the admitting physician orders aggressive fluid resuscitation, antibiotics, and intravenous morphine for pain control. Out of concern for gastrointestinal bleeding while she is in the hospital, he also prescribes famotidine. What are the risks and benefits of stress ulcer prophylaxis in this patient? Specific Aims In this review, we address the epidemiology, risk factors, and pathophysiology of stress ulcers in the hospital. The current evidence for preventive approaches is summarized, in particular drawing a distinction between patients in intensive care and those on general medical wards. We propose recommendations for the prevention of stress ulcers, highlighting current problems of overuse, misuse, and inappropriately long duration of treatment. Epidemiology Upper gastrointestinal stress ulcers occur frequently in hospitalized patients. Without prophylaxis, 2% to 6% of critically ill patients will develop clinically significant bleeding (i.e., resulting in hemodynamic instability, requiring blood transfusions, or needing surgical or endoscopic repair). 1-3 The need to undergo transfusions and emergent procedures further increases the risk and complexity of care in patients who are already gravely ill. In fact, clinically significant gastrointestinal bleeding due to stress ulcers is associated with a 40% to 77% increase in hospital mortality. 1,4-7 Subclinical disease is also common, and 75% to 100% of critically ill patients will develop some degree of gastric erosions or ulcerations within 24 hours of admission to the intensive care unit. These, however, are detectable only on endoscopy, often resolve with recovery from the acute illness, and may not be important clinically. 4,8-10 Risk factors for stress ulcers also correlate with increased overall mortality in intensive care, so these lesions may simply represent a marker for more severe disease status and worse prognosis. Most stress ulcers occur in patients in the intensive care unit (ICU) who are mechanically ventilated or who have significant coagulopathy (defined as an International Normalized Ratio (INR) > 1.5, an activated partial thromboplastin time (aptt) > 2 times the upper limit of normal, or platelets < 50,000). The adjusted hazard ratio of stress ulcers in mechanically ventilated and coagulopathic patients is 15.6 and 4.3, respectively. 1,2 Observational studies in the ICU have also shown an increased risk in patients with shock, sepsis, hepatic or renal failure, multiple traumas, extensive burns, organ transplantation, a history of peptic ulcer disease, and in those receiving high-dose steroids (> 250 mg of hydrocortisone daily). 1,2 In contrast, the incidence of clinically significant bleeding from stress ulcerations in non-critically ill patients is extremely low (<1%). 2 The large majority of studies on stress ulcers have examined patients in the ICU, with few rigorous studies in the general medical inpatient population and no randomized controlled trials. Therefore, the lessons learned from experience in the critically ill may not extend to the general inpatient population. The lower acuity of overall disease, lower severity of stress ulcers, and lower burden of medical comorbidity all suggest that the negative effect of stress ulcers on patients on general medical wards is extremely low. Pathophysiology Gastroduodenual stress ulcers develop in hospitalized patients as a result of multiple factors, all of which relate to a shift in the balance of ongoing damage and repair to the mucosa. Hypotension and sepsis cause splanchnic ischemia, and the stress of severe illness directly impairs the normal mucosal defense against 1

acid. 11 Malnutrition, advanced age, and a stressinduced catabolic state cause delayed healing. Mucosal damage from reperfusion, increased production of oxygen free radicals, acute central nervous system damage, and decreased gastric motility have also been implicated in the development of stress ulcers. 12,13 Coagulopathy and thrombocytopenia further exacerbate the problem by preventing hemostasis in those ulcers that develop bleeding. 2 Medications given to treat acute illnesses often contribute to stress ulcer development, most notably non-steroidal anti-inflammatories, corticosteroids, and anticoagulants such as heparin and warfarin. This long and varied list of insults to the mucosa has engendered great interest in therapies that either suppress gastric acidity or improve mucosal defense against acid. Stress Ulcer Prophylaxis Clinically significant gastrointestinal bleeding due to stress ulcerations can be reduced by up to 25% with prophylaxis in appropriate patients. 1 In patients with significant risk factors for stress ulcers, prophylaxis should be initiated as soon as possible, as the risk is greatest during the resuscitation period. 1 Current guidelines from the American Society of Health System Pharmacists (ASHP) and the American College of Chest Physicians (ACCP) recommend that stress ulcer prophylaxis be used in critically ill patients at high risk for clinically sufficient gastrointestinal bleeding from stress ulcerations (i.e., mechanical ventilation > 48 hrs and/or coagulopathic, as above). Prophylaxis should also be considered for patients in intensive care with 2 or more of the following risk factors 12,14 : Sepsis or hypotension Prolonged ICU stay (> 7 days) Hepatic or renal failure History of peptic ulcer disease Use of high-dose steroids (> 250 mg/day of hydrocortisone or equivalent) Burns over > 35% of total body surface area Immediately after organ transplantation Head trauma with Glasgow Coma Scale < 10 Multiple traumas The indications for prophylaxis in patients on general medical wards are less clear, given the lack of evidence from controlled trials and low rate of bleeding in this population. There are currently no evidence-based guidelines regarding stress ulcer prophylaxis in patients on general medical wards. 15 Patients who have an ongoing indication for histamine-2 receptor antagonist (H2RA) or proton-pump inhibitor (PPI) use, such as reflux esophagitis or peptic ulcer disease, should continue their usual regimen while in the hospital. In the absence of these chronic conditions, we recommend that stress ulcer prophylaxis be used only in general ward patients with significant coagulopathy plus one of the above risk factors. Patients without coagulopathy but with 3 or more of the above risk factors should also receive prophylaxis. It should be noted that although stress ulcers have been shown to be associated with poor outcomes, attempts at prevention have not translated into improved outcomes. Randomized controlled trials of prophylaxis have not been shown to provide benefits on patient-oriented end points such as overall survival, survival to hospital discharge, length of stay, or prevention of functional decline. 3,16,17 The choice of prophylactic strategy is not well established. To our knowledge, no literature exists regarding non-pharmacologic preventive measures. Histamine-2 receptor antagonists have historically been the agent of choice, as they have been the most widely studied. More recent studies directly comparing oral PPIs to intravenous or oral H2RAs have demonstrated either a benefit or non-inferiority with PPIs. While PPIs are not approved by the United States Food and Drug Administration (FDA) for use in stress ulcer prophylaxis, they are probably at least as effective as H2Ras. 15,18-20 Sucralfate, an oral drug that may improve gastric mucosal defense, has been investigated as a prophylactic against stress ulcers. Although superior to placebo, it was shown to be inferior to H2RAs in a large randomized controlled trial. 16 Use of sucralfate is also limited by its need for frequent dosing, lack of a parenteral route, and concerns about malabsorption of other orally administered drugs. For these reasons, sucralfate is not recommended for prophylaxis against stress ulcers. Clinicians should also be alert to medications that promote stress ulcers, and avoid the use of nonsteroidal anti-inflammatory drugs, steroids, and anticoagulants in those at high risk. When patients require these medications, concomitant use of acid suppression therapy should be considered, according to the guidelines above. Clinicians currently use a variety of drugs and routes 2

of administration for stress ulcer prophylaxis, 21 but intravenous cimetidine is the only medication approved by the FDA for this purpose. It is given as an infusion of 50 mg per hour (maximum use of 7 days), and the dose should be reduced by 50% in patients with moderate to severe renal impairment. Alternatively, patients may be given 300 mg intravenously every 6 hours. Cimetidine is a known cytochrome P450 inhibitor and frequently affects the blood levels of other medications. Clinicians should pay careful attention to the dosing of concomitant antifungals, immunosuppressants, and antiarrhythmics. Newer H2RAs such as famotidine and ranitidine have fewer drug-drug interactions and are simpler to use than cimetidine but still require a 50% dose reduction in those with renal impairment. Common regimens are famotidine 20 mg intravenously or orally twice a day, and ranitidine 150 mg orally twice a day or 50 mg intravenously every 8 hours. If a PPI is used, we recommend omeprazole or pantoprazole, 40 mg orally once a day. It is worth noting that no studies have evaluated the use of intravenous PPIs as prophylaxis. Thus, for patients unable to tolerate oral medications, intravenous H2RAs are the accepted option. 15 Oral PPIs and intravenous H2RAs also have a significant cost advantage over intravenous PPIs. Risks of Stress Ulcer Prophylaxis Several concerns have been raised about the widespread practice of prescribing prophylactic PPIs and H2RAs to general medical patients. First, multiple studies have demonstrated an increase in the rate of community-acquired pneumonia 22,23 and Clostridium difficile colitis 24 in patients on chronic acid-suppression therapy. Second, there is a trend toward an increased frequency of hip fractures in patients on PPIs. 25 Third, there are significant drug-drug interactions with the use of PPIs and H2RAs, such as reduction of antimicrobial drug levels, increased INR in those on warfarin, and reduction of calcium carbonate absorption (which may partially explain increased rates of hip fracture). Finally, H2RAs have some central antihistamine activity, and may cause mental status changes in elderly patients at high risk for delirium. 26 Together with the low potential for benefit in most patients on general medicine wards, these concerns should limit physicians' enthusiasm for prescribing stress ulcer prophylaxis. Inappropriate Use of Prophylaxis In recent years, the use of stress ulcer prophylaxis outside the ICU has expanded greatly as clinicians have applied ICU guidelines to patients on the general medical ward. 15,27,28 However, no trial to date compares either H2RAs or PPIs to placebo in the prevention of clinically significant gastrointestinal bleeding in this patient population. Given the very low rates of significant stress ulcers in general medical patients (0.1%), it is highly unlikely that such a trial would show any significant benefit with prophylaxis. To prevent one episode of clinically important bleeding in high-risk patients, the number needed to treat is about 30, but that number rises to 900 or more in low-risk patients. 2 Inappropriate prophylaxis on general medicine wards has been documented extensively. In a retrospective chart review of non-icu patients at a university hospital, 22% of patients were started on stress ulcer prophylaxis with either a PPI or a H2RA. Of those patients prescribed prophylaxis, 54% were discharged home on acid suppression therapy. The annual cost of stress ulcer prophylaxis in the study was estimated at $44,000, not taking into account the costs of ongoing therapy after discharge. 27 It is important to recognize which patients benefit from stress ulcer prophylaxis in order to provide appropriate care to at-risk patients while avoiding unnecessary use of PPIs and H2RAs. Conclusions Gastrointestinal stress ulcers are associated with severe illness. Attempts at preventing them may have an impact in appropriate high-risk patients, particularly in the intensive care setting, and effective regimens have been developed. Clinicians in the hospital should strive to use established regimens in selected patients, starting at the time of admission and applied on a consistent basis. The costs and adverse effects of stress ulcer prophylaxis are significant, so clinicians should make efforts to limit inappropriate use and ensure that prophylaxis is discontinued when risk factors resolve. Further research is sorely needed to define the most appropriate method of stress ulcer prophylaxis in general medicine inpatients. Resolution of Clinical Scenario Following appropriate antibiotics and resuscitation, the patient slowly improved, but her hemoglobin on the third hospital day had dropped from 13 mg/dl to 10 mg/dl. Stool studies for occult blood were 3

negative. Blood tests showed normal iron stores but a decreased reticulocyte count consistent with anemia related to sepsis and aggressive fluid repletion. She was discharged home in good condition after 6 days. This case illustrates a familiar example of a patient who could reasonably have foregone stress ulcer prophylaxis, given the presence of only one risk factor at the time of admission. Summary of Recommendations 1. Routine prophylaxis against stress ulcers is not recommended for the large majority of patients admitted to the general medical ward. 2. Stress ulcer prophylaxis is recommended in patients in intensive care who require mechanical ventilation or have a significant coagulopathy: INR > 1.5 (may be from the disease process or from anticoagulant therapy) aptt > 2 times upper limit of normal Platelets < 50,000 3. Stress ulcer prophylaxis may be beneficial in patients in the ICU with 2 or more of the risk factors below, and in medicine ward patients with 3 or more risk factors: Sepsis or shock Prolonged ICU stay (> 7 days) Hepatic or renal failure Head trauma with Glasgow Coma Scale < 10 Multiple traumas Extensive burns Immediately after organ transplantation History of peptic ulcer disease High-dose steroid use (> 250 mg of hydrocortisone daily) 4. Patients on general medical wards with a significant coagulopathy may benefit from stress ulcer prophylaxis if there are one or more additional risk factors as above. 5. For appropriate patients, we recommend famotidine 20 mg orally or intravenously twice a day, or pantoprazole 40 mg orally daily if a PPI is preferred. 6. Patients with a chronic indication for a PPI or H2RA should continue these medications while in the hospital. 7. Drugs for stress ulcer prophylaxis should be discontinued when risk factors have resolved. 8. 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