CURRENT DRUG THERAPY DONALD G. VIDT, MD, EDITOR MARY BETH BOBEK, PharmD ALEJANDRO C. ARROLIGA, MD Critical care pharmacist, Cleveland Clinic. Acting director of the Medical Intensive Care m Unit and director of the fellowship program, CREDIT Department of Pulmonary and Critical Care, Cleveland Clinic. Stress ulcer prophylaxis: The case for a selective approach TRESS-RELATED MUCOSAL DAMAGE is a ABSTRACT syndrome of erosive gastritis that occurs in critically ill patients.1 The problem is so Although stress-related mucosal damage is common and potentially serious that most common (and potentially serious) in critically ill intensive-care patients now routinely receive drugs to prevent it,2^ and some physicians patients, the risk of clinically significant give these drugs to all their hospitalized gastrointestinal bleeding appears to be confined patients. However, we believe that this to patients with certain factors: mechanical approach is wrong. In this article, we review ventilation, coagulopathy, multiple trauma, the prophylactic drugs for stress-related mucosal damage and argue for using them increased intracranial pressure, and multiorgan selectively, in high-risk patients only. dysfunction. Because prophylactic therapy also poses risks, we advocate reserving it for patients • A COMMON AND SERIOUS PROBLEM in these high-risk groups. Approximately three fourths of all patients show some endoscopic evidence of gastroin- KEY POINTS testinal damage as early as 24 hours after admission into an intensive care unit.4.5 Drugs used to prevent mucosal damage by increasing Gastrointestinal bleeding, a common mani- gastric pH may increase the risk of nosocomial pneumonia. festation of mucosal injury, occurs in approx- imately 20% of intensive-care patients who Sucralfate seems to be the most cost-effective agent for do not receive prophylactic therapy.6'7 In preventing stress-related mucosal damage. However, it can only 2% to 6% of patients8 is the bleeding be given only by mouth or nasogastric tube and thus may clinically serious—ie, massive enough to not be suitable for all critically ill patients. cause a worrisome drop in blood pressure or hematocrit or requiring a blood transfusion. There is still debate about the relative efficacy and But in those patients the mortality rate is advantages of different agents for preventing stress-related more than 50%.9 mucosal damage. For any particular patient, the physician has to consider the route of administration available and §» WHY NOT GIVE the drug interactions, side effects, and cost of these agents PROPHYLACTIC DRUGS TO EVERYONE? when prescribing them. In the past 20 years, the incidence of overt bleeding has declined. Even though prophy- lactic therapy is being used commonly, there are several reasons why we believe that pro- phylactic drugs should not be given to all intensive-care patients. CLEVEI.AND CLINIC JOURNAL OF MEDICINE VOLU ME 64 • N UM BER 1 0 NOVEMBER / DECEMBER 1 997 533 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. STRESS ULCERS BOBEK AND ARROLIGA TABLE 1 accepted risk factors that were identified in recent studies.11-15 RISK FACTORS Cook et al11 conducted a multicenter FOR STRESS ULCERS trial involving 2,252 patients in medical and AND GASTROINTESTINAL surgical intensive care units. Only 1.5% of all BLEEDING IN CRITICALLY ILL PATIENTS patients had an episode of clinically impor- tant bleeding, and 69.7% of these patients Coagulopathy were already receiving prophylaxis. Only two Head injury independent risk factors for gastrointestinal bleeding were identified: respiratory failure Hepatic or renal failure requiring mechanical ventilation and coagu- Hypotension, shock lopathy. The overall risk of developing a Major trauma, polytrauma stress hemorrhage without those risk factors was 0.1%. These findings call into question Major surgery the need for prophylaxis in patients at low Mechanical ventilation risk. Multiple organ failure Further evidence comes from a random- ized, controlled study in medical intensive- Sepsis care patients, conducted by Ben-Menachem Severe burns et al,12 who found that the only identifiable risk factors for bleeding were high-dose steroid use and respiratory failure. Further, the inci- SOURCE: FISHER RL, PIPKIN GA, WOOD JR. STRESS-RELATED dence of clinically important bleeding was not MUCOSAL DISEASE: PATHOPHYSIOLOGY, PREVENTION AND TREATMENT. CRIT CARE CLINICS 1995:11:327-345. significantly lower in patients who received the prophylactic drugs sucralfate or cimetidine than in control patients. In surgical patients, other studies identi- Patients • Prophylactic drugs can cause side fied several other risk factors: multiple trau- effects; notably, drugs that decrease the acidi- ma, head trauma, increased intracranial pres- without risk ty erf the stomach may contribute to nosoco- sure, and burns.10-13'14 A multicenter study factors have a mial pneumonia by making the environment found that mechanically ventilated postoper- of the stomach more hospitable to bacterial ative patients with hypotension or sepsis very low risk growth. were at significant risk of stress-related of bleeding • Prophylactic drugs increase the com- mucosal damage even if prophylaxis was pro- plexity of care by interfering with the actions vided; other risk factors identified were coag- of other drugs and, with some of them, by ulopathy and renal, hepatic, and respiratory necessitating gastric pH monitoring to cali- failure.15 brate their dosage. • Universal prophylactic drug therapy is "TIC THERAPY not cost-effective, as the risk of serious gas- REDUCE MORTALITY? trointestinal bleeding appears to be confined to certain well-defined groups. Prophylactic therapy remains controversial • Prophylactic drug therapy has not because no study has clearly demonstrated that been proved unequivocally to reduce the it reduces mortality.12'16 One reason why it is mortality rate, as studies have yielded con- difficult to derive firm conclusions is that the flicting results. studies conducted to date have varied consid- erably in their design, patient populations, def- • WHO IS AT RISK FOR STRESS ULCERS? initions of stress-related mucosal damage, and medication regimens.10'16 The overall inci- There is controversy about what pre-existing dence of overt bleeding appears to be decreas- conditions warrant stress ulcer prophylaxis in ing.17 However, recent studies show a lack of the critically ill10; TABLE 1 lists the generally reduction in clinically important bleeding 534 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 1 0 NOVEMBER / DECEMBER 1997 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. What causes stress ulcers? The pathogenesis of stress-related Stress mucosal damage is not fully under- stood but most likely is multifactori- ActivatioI n of: al. 17,36,48-50 Basically, physiologic stress Sympathetic nervous system Neuroendocrine system Hypotension may lead to breakdown of the stom- ach wall through several interrelated processes (shown schematically at Decreased Increasei d gastric Vasoconstriction gastrointestinal acid secretion right and in a cross-section of the motility (some conditions) DecreaseI d gastric blood gastric epithelium below). Decreased gastric Of note, Helicobacter pylori, an bicarbonate secretion flow Bile 1reflu x (?) organism known to contribute to the pathogenesis of peptic ulcers, has recently been implicated in the Reperfusion damage Free radical formation development of stress-related mucos- al damage as well.50 More studies are Prostaglandins • • Decreased epithelial proliferation needed to confirm this finding. Increased permeability Decreased intramucosal pH Decreased bicarbonate secretion I allows gastric acid to damage the epithelium, as hydrogen UlceratioI n -< ions diffuse into an epithelium made more permeable by ischemia, resulting in intramural acidosis, cell death, and ulceration. H+ H+ H+ HCO3 Decreased gastric motility Ulcer H+ -Epitheliun may, in theory, facilitate bile H+ reflux and breakdown of the life» mucosal barrier. Sympathetic nerve fiber Activation of the sympathetic nervous Decreased gastric blood flow system and the neurohormonal system, is due to vasoconstriction (mediated by the alpha triggered by the stress, in turn causes adrenergic nervous system and the neuroendocrine decreased gastric motility, decreased system) or to hypotension. The resulting ischemia causes gastric blood flow, and decreased decreased secretion of bicarbonate in the stomach and bicarbonate secretion. duodenum, decreased mucosal proliferation, and increased permeability of the gastric epithelium. Reperfusion damage leads to formation of free radicals. SOURCE: ALGORITHM ADAPTED FROM BRESALIER, REFERENCE 15 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 64 • NUMBER 10 NOVEMBER / DECEMBER 1997 535 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. m FACTORS TO CONSIDER IN SELECTING DRUGS Factor Sucralfate H2 receptor Cimetidine Famotidine Route Oral Oral Oral Nasogastric Nasogastric Nasogastric Duodenal Duodenal Intravenous Intravenous pH Monitoring No Yes Yes Drug interactions Decreases levels of: Increases levels Decreases levels of: Oral quinolones of many drugs, especially: Warfarin Digoxin Warfarin Itraconazole Theophylline Phenytoin Phenytoin Propranolol Decreases levels of: Ketoconazole Itraconazole Side effects Hypophosphatemia (rare) Diarrhea Diarrhea Universal