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, , 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 .4.5 Drugs used to prevent mucosal damage by increasing Gastrointestinal bleeding, a common mani- gastric pH may increase the risk of nosocomial . festation of mucosal injury, occurs in approx- imately 20% of intensive-care patients who 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.

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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: Hepatic or renal failure requiring and coagu- , lopathy. The overall risk of developing a Major trauma, stress hemorrhage without those risk factors was 0.1%. These findings call into question Major 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- 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 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 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 prophylaxis in ing.17 However, recent studies show a lack of the critically ill10; TABLE 1 lists the generally reduction in clinically important bleeding

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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. , 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

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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: Digoxin Warfarin Itraconazole Theophylline Phenytoin Phenytoin Propranolol Decreases levels of: Ketoconazole Itraconazole

Side effects Hypophosphatemia (rare) Diarrhea Diarrhea Universal Constipation Headache Headache Mental status changes Mental status changes prophylactic Hyperprolactinemia drug therapy Reduced androgen production Nosocomial Less More More is not cost- pneumonia risk effective Dosage 1 g by mouth Intravenous: 50 mg/hour 20 mg by mouth or nasogastric tube or 300 mg every 6 hours or intravenously every 6 hours Oral, enteral: 400 mg twice a day twice a day

Approximate $3.05 Intravenous: $29.64 Intravenous: $6.46 cost per day Oral: $3.21 Oral: $3.19 Disadvantages No intravenous form Drug interactions More expensive IV Drug interactions Nosocomial pneumonia risk Dosage must be lowered Dosage must be lowered in patients with renal in patients with renal insufficiency insufficiency Nosocomial pneumonia risk

"Lansoprazole has been studied less than omeprazole for this indication.

despite the use of prophylactic agents.11-12 The port) and earlier enteral nutrition.23>17 decline in bleeding from stress-related mucosal damage is theorized to be due to overall • SELECTING AN AGENT improvements in intensive care, with better (ie, more aggressive fluid replace- The medications commonly used for prevent- ment, cardiac support, and ventilatory sup- ing stress-related mucosal damage are sucral-

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antagonists Proton-pump inhibitors Nizatidine Omeprazole*

Orai Oral Oral Oral Nasogastric Nasogastric Nasogastric Duodenal Duodenal Intravenous Yes Yes Yes Yes Decreases levels of: May increase levels of: Decrease levels of: Increases levels of: Ketoconazole Warfarin Iron Phenytoin Itraconazole Oral quinolones Warfarin Decreases levels of: Ketoconazole Ketoconazole Itraconazole Decreases levels of: Itraconazole H? receptor antagonists Ketoconazole Digoxin Itraconazole Phenytoin Theophylline Headache Rash Hypermagnesemia Minimal No study has Diarrhea Nausea Gl distension Dizziness Vomiting Hypophosphatemia proved that Headache Diarrhea prophylactic Drowsiness Constipation More More More More? drugs reduce mortality 150 mg twice a day Intravenous: 50 mg 15 cc every 2-6 hours 20 mg daily by mouth or every 6-8 hours by mouth or by mouth enteral tube or 6.25-8.3 mg/hour nasogastric tube Oral, enteral: 150 mg 1-2 times a day

$3.00 Intravenous: $23.64 $0.82 $3.63 Oral: $3.19 Nosocomial pneumonia risk Nosocomial pneumonia risk Frequent dosing Expensive Dosage must be lowered Dosage must be lowered (every 2 hours) Less studied in patients with renal in patients with renal Side effects in stress-related insufficiency insufficiency Nosocomial pneumonia risk mucosal damage

SOURCE: DRUG PRICES FROM: DRUGS FOR TREATMENT OF PEPTIC ULCERS. MED LETT. JAN 3 1997: 39:1-3; AND DRUG TOPICS RED BOOK UPDATE. NOVEMBER 1996.

fate, histamine type-2 (H2) receptor antago- overt or occult bleeding with all these types of nists, and antacids (TABLE 2). Of these, only agents.16'18-22 Newer medications such as cimetidine, an H2 receptor antagonist, has omeprazole (a proton-pump inhibitor) and been approved by the Food and Drug misoprostol (a prostaglandin analog) are used Administration for this indication. However occasionally in clinical practice but have not some trials have demonstrated a reduction in been well studied.

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Drug interactions. Sucralfate decreases RISK OF PNEUMONIA absorption of other oral drugs,23 particularly IN RANDOMIZED TRIALS quinolones, tetracycline, theophylline, digox- OF STRESS ULCER PROPHYLAXIS in, and phenytoin. It should therefore be avoided in patients who require oral Comparison No. of Common odds ratio quinolone ,23 and should be given trials (95% confidence interval) at least 2 hours after doses of digoxin, tetracy- cline, or phenytoin. Side effects. Because sucralfate is relative- H2 antagonists 3 vs antacids i ly nonabsorbable, it has minimal side effects; i the most common are hypophosphatemia and i i constipation due to the aluminum compo- i i nent. i Dosage. One gram by mouth or nasogas- Sucralfate vs 6 tric tube every 6 hours. Giving this agent via a antacids i in the duodenum bypasses the i i gastric mucosa and may reduce its efficacy. 1 i Cost. Sucralfate is relatively inexpensive i compared with other agents and does not i require pH monitoring or intravenous Sucralfate vs 11 |—| I access.10 H2 antagonists

H2 receptor antagonists

The availability of H2 receptor antagonists in 0.0 0.5 1.0 1.5 2.0 intravenous formulations makes them the (Risk less) (Risk greater) most frequently used drugs for stress ulcer pro- phylaxis. These agents competitively and FIGURE 2. According to a meta-analysis of randomized selectively inhibit the binding of histamine to trials of prophylactic therapy to prevent stress ulcers, H2 receptors in the parietal cells of the stom- the risk of nosocomial pneumonia is less in patients ach, decreasing the secretion of hydrogen ions treated with sucralfate than with antacids or hista- and raising the gastric pH.24 mine2 receptor antagonists, although the trend was Drug interactions. Cimetidine has mul- not statistically significant. The common odds ratio tiple drug interactions because it binds to indicates the extent of risk: if the odds ratio is 1.0, the the P450 enzyme system in the liver and chance of developing the outcome of interest is the inhibits the metabolism of drugs that are same, regardless of treatment group. An odds ratio of 2 0.5 means that the odds of a patient in the treatment metabolized by this system. 4 Ranitidine group developing the outcome of interest would be binds less to the P450 enzyme system than half that of the control group. does cimetidine, and famotidine and nizati- dine do not bind to it appreciably. All H2 SOURCE: MODIFIED FROM COOK ET AL, REFERENCE 21. receptor antagonists inhibit the absorption of ketoconazole and itraconazole, which have a pH-dependent absorption. Because Sucralfate antacids decrease the absorption of H2 Sucralfate degrades in the presence of acid and receptor antagonists when given orally, these binds to the gastric mucosal layer, releasing an two types of drugs should be given 2 hours aluminum base.23 It protects the mucosa by apart. Combination therapy with sucralfate acting as a barrier to hydrogen ions, rather has not been studied. than by increasing the gastric pH. Sucralfate Side effects are infrequent and include has not been well studied in critically ill neu- diarrhea, headache, and mental status rosurgical and burn patients10; therefore, H2 changes, primarily in the elderly. In case antagonists may be preferable as first-line reports, thrombocytopenia has been docu- agents in these populations. mented; however, the incidence is less than

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Comparison No. of Common odds ratio trials (95% confidence interval)

H2 antagonists vs antacids Overt bleeding 16

Clinically important 10 Gl bleeding Hj—I

Mortality rate 14 m

Sucralfate vs antacids Overt bleeding 10

Clinically important Gl bleeding 5

Mortality rate 11 Sucralfate vs The role H2 antagonists of H pylori in Overt bleeding 12 HH stress ulcers Clinically important 4 Gl bleeding is unclear

Mortality rate 11 I 1 1 1 [ 1 1 1 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 (Risk less) (Risk greater)

FIGURE 3. The results of randomized trials of stress ulcer prophylaxis have varied and depend on the outcome measured.

SOURCE: MODIFIED FROM COOK ET AL, REFERENCE 21.

1%.24-26 Cimetidine also induces hyperpro- be higher in patients receiving antacids (FIGURE lactinemia and reduces androgen produc- 2).21 However, the link between H2 receptor tion.29 antagonists and pneumonia is somewhat con- H 7 receptor antagonists, by increasing the troversial, because the reported incidence has gastric pH, have also been implicated in bac- varied widely, from 0% to 50%.u.30 terial colonization of the gastric mucosa and Dosage. H2 receptor antagonists can be the development of nosocomial pneumonia.27 given by mouth, nasogastric or duodenal tube, Numerous studies have detected a higher inci- or intravenously in bolus doses or as continu- dence of pneumonia in patients receiving ous infusions. The advantage of a continuous these agents than in those receiving sucral- infusion is that it can keep the gastric pH at fate11'16-20.27-29; the incidence also appears to 3.5 or higher, whereas intermittent adminis-

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tration allows more fluctuation.31-34 The gas- Clinical trials are needed to compare the tric pH is often used as a marker of efficacy, efficacy and cost of proton-pump inhibitors, but the exact pH needed to prevent stress H2 receptor antagonists, and sucralfate. ulcers remains uncertain. One study found that the incidence of bleeding from stress- Prostaglandin analogues related mucosal damage was lower at a pH Prostaglandin analogues, such as misoprostol, greater than 3.5.35 However, even though they are used to prevent gastric ulcers in patients control pH better, continuous infusions of H2 taking nonsteroidal anti-inflammatory receptor antagonists have not been shown to drugs.39 Misoprostol has also been used to decrease the incidence of bleeding compared treat duodenal and gastric ulcers. A study that with bolus administration.34 compared cimetidine, antacids, and misopros- Dosages of H2 receptor antagonists should tol for preventing stress-related mucosal dam- be decreased in patients with renal insuffi- age in surgical patients found them all equally ciency. effective.14 However, the use of prostaglandin analogues has been limited by frequent Antacids adverse effects such as abdominal pain, diar- Antacids have been proved to prevent stress- rhea, and abortifacient activity.39 Until more related mucosal damaged6.20'35 However, their definitive trials are conducted, these agents frequent dosing, side effects, and possible link should not be used routinely in critically ill to nosocomial pneumonia in clinical trials19-29 patients. have led to a decline in their clinical use.10.12.36 9, WHAT AGENT IS MOST EFFECTIVE? Proton-pump inhibitors Consider Proton-pump inhibitors covalently bind to the Comparative studies have shown that switching to hydrogen-potassium pump in the parietal cells antacids, H2 receptor antagonists, and sucral- and decrease gastric acid production.37 Two fate are all effective for preventing stress-relat- an enteral proton-pump inhibitors are currently avail- ed mucosal damaged6"22 However, the data preparation able: omeprazole and lansoprazole. However, conflict as to what agent is best. For example, there is not enough information about lanso- a meta-analysis of studies conducted before when possible prazole available at this time to suggest its use 1995 found that the risk of overt bleeding was in preventing stress-related mucosal damage. significantly lower with H2 receptor antago- Side effects are minimal. nists than with antacids (FIGURES).21 The inci- Drug interactions. Like H2 receptor dence of overt bleeding was approximately antagonists, proton-pump inhibitors inhibit equal with sucralfate compared with H2 recep- the absorption of pH-dependent drugs, such as tor antagonists, and approximately equal with quinolone antibiotics. Omeprazole may also sucralfate compared with antacids. However, inhibit the metabolism of phenytoin and war- there was a trend toward more clinically farin. important bleeding with sucralfate than with Dosage and administration. The lack of H7 receptor antagonists or antacids. On the an intravenous form or stable oral liquid other hand, only sucralfate was associated preparation of omeprazole in the United with a decrease in mortality. Previous meta- States has limited its use for stress-related analyses showed different results.18.20 Because mucosal damage in intensive-care patients. of these conflicting data, comparative efficacy Recently, Phillips et al38 reported that no remains relatively equivocal. Criteria for clinically significant upper gastrointestinal selecting agents should include the adverse bleeding occurred in a series of mechanical- effect profile, drug interactions, route of ly ventilated surgical and burn patients who administration, and cost.22 received a specially made omeprazole sus- pension; however, the pneumonia rate was m ECONOMIC IMPLICATIONS 12%, again raising the question of acid inhi- bition leading to microbial colonization and Even though recent studies found that only a infection. small percentage of intensive-care patients are

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Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. at risk of stress-related bleeding, most patients • THE AUTHORS' RECOMMENDATIONS still receive prophylactic therapy. Some researchers argue that the benefit of prophy- We recommend that only intensive-care laxis outweighs its risks and cost.4°,42 patients with risk factors that may predispose However, the overall cost to the institution them to stress-related mucosal damage should can be significant.3 A 1994 survey of pharma- receive prophylaxis; these risk factors include cy departments of academic health centers mechanical ventilation, coagulopathy, multi- revealed that each institution could save ple trauma, increased intracranial pressure, $60,000 to $200,000 per year by using H2 and multi-. receptor antagonists only in intensive-care Sucralfate seems to be the most cost-effec- patients at risk, and giving them orally or tive agent for preventing stress-related mucos- enterally instead of intravenously, when possi- al damage, since it has few adverse effects and ble.4M4 Once a patient's medical condition has been implicated less in the development improves (as indicated by extubation or ICU of nosocomial pneumonia. However, sucral- discharge), physicians should consider discon- fate can be given only by mouth or nasogastric tinuing prophylactic agents. tube and thus may not be suitable for all criti- It has been suggested that H2 receptor cally ill patients. There is still debate about antagonists should be reserved for intensive- the relative efficacy and advantages of the dif- care patients with respiratory failure requir- ferent agents for preventing this disorder. One ing more than 48 hours of mechanical ven- has to consider route of administration avail- tilation, coagulopathy (thrombocytopenia, able, drug interactions, side effects, and cost of disseminated intravascular coagulation, pro- these agents when choosing drug therapy. longed prothrombin time, or partial throm- More research is needed to calculate more boplastin time), or concomitant administra- accurately the risk of bleeding in various pop- Earlier enteral tion of steroids in high doses (> 250 mg of ulations and the risk of pneumonia with vari- feeding may hydrocortisone or an equivalent daily).43 ous agents, to provide cost-effective stress The least expensive but effective agent ulcer prophylaxis. • decrease ulcer should be used. Therefore, we recommend risk by itself switching to an oral preparation as soon as • REFERENCES possible. Evidence suggests that enteral feedings 1. Breugge WF, Peura DS. Stress-related mucosal damage: alone may be adequate to reduce stress- review of drug therapy. J Clin Gastroenterol 1980; 12:S35-S40. related mucosal damage and bleeding.45,46 2. Schuster DP. Stress ulcer prophylaxis: In whom? With The mechanism remains unknown, but one what? Crit Care Med 1993; 21:4-6. proposed mechanism is by alkalinization of 3. Wilcox CM, Spenney JG. Stress ulcer prophylaxis in med- ical patients: who, what and how much? Am J the stomach.45 Nutrition itself, whether Gastroenterol 1988; 83:1199-1211. parenteral or enteral, may maintain the 4. Lucas CE, Sugawa C, Riddle J, Rector F, Rosenberg B, Walt integrity and promote repair of the gastric A. Natural history and surgical dilemma of "stress" gas- tric bleeding. Arch Surg 1971; 102:266-273. mucosa.45,47 5. Brown TH, Davidson PF, Larson GM. Acute gastritis occur- According to a cost-effectiveness analy- ring within 24 hours of severe head injury. Gastrointest sis,30 prophylactic therapy with sucralfate cost Endocrinol 1989; 35:37-40. 6. Harris SK, Cone RC, Ruth WE. Gastrointestinal hemor- $103,715 per bleeding episode averted in a rhage in patients in a respiratory intensive care unit. low-risk population such as patients with a Chest 1977; 72:301-304. 0.1% risk of hemorrhage, but was much more 7. Kamada T, Fussamoto H, Kawano S, et al. Gastrointestinal bleeding following head injury: A clinical cost-effective in high-risk patients such as study of 433 cases. J Trauma 1977; 17:44-47. those with a 12% to 33% risk of bleeding. The 8. Cook DJ, Pearl RG, Cook RJ, Guyatt GH. Incidence of clini- same researchers calculated that therapy with cally important bleeding in mechanically ventilated patients. J Intensive Care Med 1991 ;167-174. cimetidine costs 6.5 times as much as with 9. Zuckerman GR, Shuman R. Therapeutic goals and treat- sucralfate, assuming that sucralfate and cime- ment options for prevention of stress ulcer syndrome. Am tidine are equally effective and taking into J Med 1987; 83(Suppl 6A):29-35. 10. Smyth M, Zarowltz BJ. Changing perspectives of stress account the risk of nosocomial pneumonia gastritis prophylaxis. Ann Pharmacother 1994; with cimetidine. 28:1073-1085.

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11. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gas- rhage: a cost effectiveness analysis. Crit Care Med 1996; trointestinal bleeding in critically ill patients. N Engl J 24:338-345. Med 1994; 330:377-381. 31. Ballestros MA, Hogan DL, Koss MA, Isenberg Jl. Bolus or 12. Ben-Menachem T, Fogel R, Patel RV, et al. Prophylaxis for intravenous infusion of ranitidine: effects of gastric pH stress-related gastric hemorrhage in the medical intensive and acid secretion. Ann Intern Med 1990; 112:334-339. care unit. A randomized, controlled, single-blind study. 32. Ostro MJ, Russell JA, Solidin SJ, Mahon WA, Jeejeebhoy Ann Intern Med 1994; 121:568-575. KN. Control of gastric pH with cimetidine: bolus versus 13. Halloran G, Zfass AM, Gayle WE,Wheeler CB, Miller JD. primed infusions. Gastroenterology 1985; 89:532-537. Prevention of acute gastrointestinal complications after 33. Frank W, Karlstadt R, Rockhold F, Palmer R, Malone M, severe head trauma: a controlled clinical trial of Cimeti- Young M. Comparison between continuous and intermit- dine prophylaxis. Am J Surg 1980; 139:44-48. tent infusion regimens of cimetidine in ulcer patients. 14. Pruitt BA, Goodwin CW. Stress ulcer disease in the burned Clin Pharmacol Ther 1989;46:234-239. patient. World J Surg 1981; 5:209-222. 34. Rovers JP, Sourney PF. A critical review of continuous

15. Martin LF, Booth FV, Reines HD, et al. Stress ulcers and infusion of H2-receptor therapy. Crit Care Med 1989; organ failure in intubated patients in surgical intensive 17:814-821. care units. Ann Surg 1992: 215:332-337. 35. Hastings PR, Skillman JJ, Bushnell LS, Silen W. 16. Shuman RB, Schuster DP, Zuckerman GR. Prophylactic titration in the prevention of acute gastrointestinal therapy for stress ulcer bleeding: a reappraisal. Ann bleeding: A controlled randomized trial in 100 critically ill Intern Med 1987; 106:562-567. patients. N Engl J Med 1978; 298:1041-1045. 17. Bresalier K. The clinical significance and pathophysiology 36. Fischer RL, Pipkin GA, Wood JR. Stress related mucosal of stress related gastric mucosal hemorrhage. J Clin disease: Pathophysiology, prevention and treatment. Crit Gastroenterol 1991; 13(suppl):S35-S43. Care Clin 1995; 11:323-345. 18. Tryba M. Prophylaxis of stress ulcer bleeding. J Clin 37. Maton PN. Omeprazole. N Engl J Med 1991; 324:965-975. Gastroenterol 1991; 13(Suppl 2):S44-S55. 38. Phillips JO, Metzler MH, Palmieri TL, Huckfelt RE, Dahl

19. Tryba M. Sucralfate verses antacids or H2-antagonists for NG. A prospective study of simplified omeprazole suspen- stress ulcer prophylaxis: a meta- analysis on efficacy and sion for the prophylaxis of stress-related mucosal dam- pneumonia rate. Crit Care Med 1991; 19:942-949. age. Crit Care Med 1996; 24:1793-1800. 20. Cook DJ, Witt LG, Cook RJ, Guyatt GH. Stress ulcer pro- 39. Jones JB, Bailey RT. Misoprostol: a prostaglandin E, ana- phylaxis in the critically ill: a meta-analysis. Am J Med log with antisecretory and cytoprotective properties. DICP 1991; 91:519-527. 1989; 23:276-278. 21. Cook DJ, Reeve BK, Guyat GH, et al. Stress ulcer prophy- 40. Peura DA, Koretz RL. Prophylactic therapy of stress-relat- laxis in critically ill patients. JAMA 1996; 275:308-314. ed mucosal damage: why, which, who and so what? Am J 22. Fabian TC, Boucher BA, Croce MA, et al. Pneumonia and Gastroenterol 1990; 85:935-937. stress ulceration in severely injured patients. Arch Surg 41 Tryba M, Kulka PJ. Critical care pharmacotherapy, a 1993; 128:185-192. review. Drugs 1993; 45:338-352. 23. McCarthy DM. Sucralfate. N Eng J Med 1991; 325:1017-1024. 42. Yim JM, Matuszewski KA, Vlasses PH. Issues related to

24. Feldman M, Burton ME. Histamine2-receptor antagonists. the routine use of H2-receptor antagonists for prophylaxis N Engl J Med 1990; 323:1672-1680. of stress ulcers in critical care patients. P & T 25. Mc Daniel JL, Stein JJ. Thrombocytopenia with Cimetidine 1996:128-134. Therapy (letter). N Engl J Med 1979; 300:864. 43. Compendium of cost savings projects: pharmacy. Oak 26. Humpheries JE. Thrombocytopenia associated with famo- Brook, III: University Hospital Consortium; 1994. tidine In a hemophiliac. Ann Pharmacother 1992; 26:262. 44. Pemberton LB, Schaefer N, Goehring L, Gaddis M, Arrighi 27. Tyrba M. The gastropulmonary route of infection—fact or DA. Oral ranitidine as prophylaxis for gastric stress ulcers fiction? Am J Med 1991; 91(suppl. 2A):135S-146S. in intensive care unit patients: serum concentrations and 28. Driks MR, Craver DE, Celli BR, et al. Nosocomial pneumo- cost comparisons. Crit Care Med 1993; 21:339-342. nia in intubated patients given sucralfate as compared 45. Pingleton SK, Hadzima SK. Enteral alimentation and gas- with antacids or histamine type 2 blockers. N Eng J Med trointestinal bleeding in mechanically ventilated patients. 1987; 317:1376-1382. Crit Care Med 1983; 11:13-16. 29. Prodhom G, Leuenberger P, Koerfer J, et al. Nosocomial 46. Choctaw WT, Fujita C, Zawack BE. Prevention of upper pneumonia in mechanically ventilated patients receiving gastrointestinal bleeding in burn patients: a role for 'ele- antacids, ranitidine, or sucralfate as prophylaxis for stress mental' diet. Arch Surg 1980; 115:1073-1076. ulcer. Ann Intern Med 1994; 120:653-662. 47. Ruiz-Satana S, Ortiz E, Gonzalez B, Bolanos J, Ruiz- 30. Ben-Menachem T, McCarthy BD, Fogel R, et al. Santana AJ, Manzano JL. Stress-induced gastroduodenal Prophylaxis for stress-related gastrointestinal hemor- lesions and total parental nutrition in critically ill patients: frequency, complication, and value of prophylactic treat- ment. A prospective, randomized study, Crit Care Med 1991; 19:887-891. 48. Miller TA. Mechanism of stress- related mucosal damage. One Hour Category I CME Credit Am J Med 1987; 83(Suppl 6A):8-14. 49. Stremple JF, Mori H, Lev R, Glass GB. The stress ulcer syn- is now available OMLINE|at the drome. Curr Prob Surg. April 1973:1-64. B 50. Ellison RT, Perez-Perez G, Welsh CH, et al. Risk factors for upper gastrointestinal bleeding in intensive care unit Cleveland Clinic Journal of Medicine patients: Role of Helicobacter pylori. Crit Care Med 1996; 24:1974-1981. Web site: www.ccf.org/pc/gim/cme/opencme.htm

ADDRESS: Mary Beth Bobek, PharmD, Department of Pharmacy, SI01, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195.

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