Update on Stress Ulcer Prophylaxis in Critically Ill Patients (2006)

Knowledge of risk factors and effectiveness of treatment are instrumental when implementing appropriate prophylaxis for stress ulcers. This article presents the epidemiology, pathophysiology, and medical management of stress-related mucosal disease.Optimal management of stress ulcer prophylaxis requires a concerted effort among all members of the healthcare team. This article presents an overview of the epidemiology and pathophysiology of stress-related mucosal disease (SRMD), medical management of SRMD, and the role of intensive care unit (ICU) nurses in improving the care of patients at risk for SRMD.SRMD encompasses 2 types of mucosal lesions: (1) stress-related injury, which is diffuse, superficial mucosal damage, and (2) discrete stress ulcers, which are deep focal lesions that penetrate the submucosa, most often in the body and fundal parts of the stomach.1 Stress-induced lesions that are preceded by mucosal congestion often lead to bleeding in focal areas and then eventually affect multiple areas of the upper gastrointestinal tract.1,2Gastroduodenal lesions are a common finding in the ICU. Within the first 24 hours after ICU admission, approximately 75% to 100% of critically ill patients have some endoscopic evidence of gastroduodenal or upper gastrointestinal lesions.3–6 Clinically significant bleeding, defined as gastroduodenal bleeding associated with clinically important complications (eg, hemodynamic compromise, need for blood transfusion, need for surgery),2,7 occurs in approximately 2% to 6% of ICU patients.8,9 Schuster et al10 found that 6% of patients in the ICU had overt bleeding (defined as any episode of coffee-ground emesis requiring lavage, hematemesis, or melena with or without a change in hemoglobin levels or hematocrit).Of note, the criteria used to define bleeding in clinical studies vary widely (eg, guaiac-positive stool or nasogastric aspirate, overt hematemesis, or the need for a blood transfusion).11 In one study,4 the mortality rate in patients with endoscopic evidence of ulcers, bleeding, or both within 18 hours of admission to a medical ICU was 57% compared with 24% in patients with either a normal mucosa, only nonhemorrhagic erosions, or petechial changes (P<.03). About 50% to 77% of critically ill patients with gastrointestinal bleeding will die, typically of the underlying medical condition or of multiple organ failure.4,10,12,13Both the etiology and pathophysiology of SRMD appear to be multifactorial and have not been fully elucidated. Ischemia and reperfusion are thought to cause the mucosal defenses to break down, resulting in mucosal injury and ulceration.14 The major factors of SRMD recognized to date include reduced blood flow, mucosal ischemia, hypoperfusion, and reperfusion injury. Under normal conditions, the integrity of the gastric mucosal is maintained by several factors, including the microcirculation and the mucus layer, which nourishes the mucosa and eliminates hydrogen ions, oxygen radicals, and other potentially toxic substances found in the gut lumen. The mucus layer protects the epithelial mucosal surface from hydrogen ions (including acid) and other potentially harmful substances. It also traps bicarbonate ions secreted by the mucosa to neutralize hydrogen ions. Thus, lesions develop when the mucosal barrier is unable to block the harmful effects of hydrogen ions and oxygen radicals.15Gastric hypoperfusion causes the release of nitric oxide, the production of oxygen radicals, and the reduction of prostaglandin synthesis. At normal levels, nitric oxide synthase enhances gastric mucosal integrity by maintaining blood flow and perfusion in the gastric mucosa. Elevated levels of nitric oxide synthase cause reperfusion hyperemia and cell death, an enhanced inflammatory response, and gastric and small-bowel dysmotility.15 Increased production of oxygen radicals and a reduced ability to clear them also causes inflammation, cell death, and further release of damaging cytokines.15 In addition, gastric epithelial turnover is accelerated while mucosal repair mechanisms are impaired.16Prostaglandin synthesis is decreased by gastric hypoperfusion, as well as by bicarbonate and mucus secretion, allowing back diffusion of hydrogen ions and pepsin that damage the mucosa epithelial layer.15 Normally, the buffering effect of bicarbonate and the mucus layer keep pH neutral even though the pH in the gastric lumen is often between 1.5 and 2.0.17 Additionally, upper gastrointestinal motility is slowed, a situation that reduces stomach emptying.18 This reduction in gastric emptying leads to prolonged exposure of the poorly defended mucosa to gastric acid, thus increasing the risk of ulceration.Peripheral oxygen saturation levels are not an indication of gastro-mucosal perfusion. In one study,19 critically ill patients with sepsis who required mechanical ventilation had approximately 50% less blood flow in the upper gastrointestinal tract than did patients who were undergoing elective endoscopy. Both critically ill and control patients, however, had normal peripheral oxygen saturation levels19 (Table 1).In a landmark, prospective, multicenter cohort investigation (N=2252), Cook et al8 studied the potential risk factors for stress ulceration in the ICU and the incidence of clinically important gastrointestinal bleeding. Clinically important gastrointestinal bleeding was defined as overt bleeding (in the absence of other causes) complicated by one of the following factors within 24 hours after the onset of bleeding8:Physicians were encouraged to withhold stress ulcer prophylaxis in all patients except those who had major burns, head injury, endoscopic or radiographic evidence of peptic ulcer or gastritis within the previous 6 weeks, organ transplants, or upper gastrointestinal bleeding 3 to 42 days before admission. Those patients received stress ulcer prophylaxis after admission to the ICU and were thus excluded from the study.8 The investigators found that respiratory failure requiring mechanical ventilation for longer than 48 hours (odds ratio 15.6) and coagulopathy (odds ratio 4.3) were strong independent risk factors for clinically important bleeding. Critically ill patients in the ICU who require mechanical ventilation for more than 48 hours or who have coagulopathy will benefit from stress ulcer prophylaxis.8 Findings from other studies20–22 suggest that older age, repair of abdominal aortic aneurysm, severe burns, multiple organ failure, neurological trauma, sepsis or septic shock, and high-dose corticosteroid therapy (intravenous or oral ≥40 mg/d) may also be risk factors for bleeding due to stress ulcers.In critically ill patients requiring mechanical ventilation and use of a nasogastric tube, acute gastrointestinal bleeding may become clinically evident, with a bloody gastric aspirate or the appearance of material that looks like coffee grounds in the gastric aspirate. In patients without a nasogastric tube, hematemesis or melena may be the first sign of gastric bleeding. Unexplained hypotension or a decrease greater than 2 g/dL in hemoglobin level should also prompt evaluation for bleeding in the upper gastrointestinal tract.23Because hypoperfusion appears to be an important factor in the development of SRMD, high-risk patients (eg, those receiving mechanical ventilation or who have coagulopathy) should be aggressively monitored and treated. In order to maintain hemodynamic optimization, frequent assessments should include determination of physiological, clinical (ie, blood pressure, skin color and appearance, skin warmth, and mental status), and laboratory (ie, hemoglobin and hematocrit levels and white blood cell counts) measures and serum electrolyte levels.Local irritants (eg, nonsteroidal anti-inflammatory drugs or aspirin) should be avoided.17 Measures to improve hemodynamic parameters should restrict the use of vasopressors when possible because use of these agents can worsen ischemia of the gastrointestinal tract. Vasopressors do increase blood pressure, but at the expense of mesenteric perfusion.24If possible, early enteral nutrition should be considered in certain patients. The gastroprotective effect of enteral feedings is an area of continued debate. Overall, studies in which the effects of enteral nutrition on gastric bleeding risk were evaluated have had numerous shortcomings, including inadequate statistical power, concurrent use of pharmacological prophylaxis, lack of a consistent enteral nutrition regimen, and variable definitions of bleeding.25 In a retrospective analysis, Raff et al26 found that enteral feedings initiated within 12 hours of trauma were as effective as histamine2 receptor antagonists (H2RAs) and/or antacids for reducing the risk of clinically significant hemorrhage in the upper gastrointestinal tract (ie, hemoglobin reduction >3 g/dL, shock, or the need for blood transfusion or surgical intervention). In a multicenter, randomized trial comparing sucralfate with ranitidine, Cook et al27 also found that the risk of clinically important gastric bleeding was reduced in patients receiving enteral feedings. However, patients in that study were not randomized to receive or not receive only enteral feedings. Thus, the results may actually be an indication that patients who tolerate enteral feedings are intrinsically less likely than patients who do not to have bleeding.27The American Society of Health-System Pharmacists Commission on Therapeutics has developed guidelines for stress ulcer prophylaxis based on studies in which (1) clinically important bleeding was used as a study end point and (2) prophylaxis was compared with no prophylaxis. Stress ulcer prophylaxis is recommended for adults admitted to the ICU who2These recommendations do not apply to patients with single-system injuries such as head trauma, spinal cord injury, or thermal injury; patients with these injuries were excluded from studies in which subjects were randomized to receive prophylaxis or no prophylaxis.2 In general, few studies with clinically important bleeding as an end point have indicated significant differences between the medications used for prophylaxis. However, the sample sizes needed to detect clinically important bleeding, a relatively rare event, were insufficient to preclude a type II statistical error. Comparative studies that have shown substantial differences in bleeding rates between treatment groups have had unexpectedly high bleeding rates in one of the groups.2Surveys28,29 indicate that approximately 86% of critically ill patients admitted to the ICU receive some form of stress ulcer prophylaxis. In 1995, when stress ulcer prophylaxis was first extensively evaluated, H2RAs were used 67% of the time.30 Sucralfate, a topically acting aluminum salt, was used in 24% of patients.30 In a more recent 2002 national survey of level I trauma centers, H2RAs and sucralfate were the preferred agents for stress ulcer prophylaxis in 71% and 25%, respectively, of institutions that had a preferred agent. In addition, omeprazole was the preferred agent at 3% of institutions.28 These data are changing with the introduction and increasing use of proton pump inhibitors (PPIs) in the ICU.H2RAs act by decreasing gastric acid secretion through reversible, competitive inhibition of histamine-stimulated acid secretion and are effective in reducing basal acid production. However, because gastrin and acetylcholine provide alternative pathways to the stimulation of acid secretion, acid suppression with H2RAs is incomplete, and H2RAs appear to be less effective than PPIs in preventing bleeding of stress ulcers.31In addition to the lack of potency of H2RAs, dosing can be difficult because of the nonlinear kinetics and short duration of action; patients often require 3 or 4 doses a day. Tolerance develops with H2RAs as early as 72 hours after administration, a characteristic that may make these agents less effective in situations in which intragastric pH levels must be sustained for a long period.32 However, the clinical significance of this finding has not been shown. Furthermore, evidence of the clinical benefit of H2RAs exists in the form of a landmark study involving critically ill patients who required mechanical ventilation. In that study,33 significantly lower rates of clinically important gastrointestinal bleeding were reported among patients who received ranitidine than among patients who received sucralfate.Drug interactions can occur with H2RAs, particularly with cimetidine. Cimetidine decreases clearance of warfarin, theophylline, phenytoin, lidocaine, and clarithromycin. Ranitidine interactions, though less frequent, can occur with nifedipine and cyclosporine. An additional significant disadvantage of H2RAs is the risk of neuropsychiatric effects.30 Nevertheless, H2RAs have been the agents of choice for stress ulcer prophylaxis, primarily because of their availability in an intravenous formulation.Sucralfate, although less widely used than H2RAs for stress ulcer prophylaxis, is another option.28,30 It coats the gastric mucosa and creates a thin, protective layer between the mucosa and the gastric acid in the lumen.17 H2RAs and sucralfate have comparable effectiveness for preventing stress ulcers, at 10% to 25% and at 15% to 40%, respectively.11 Some researchers34,35 found an association between increased gastric pH and growth of gram-negative organisms in samples obtained via bronchoalveolar lavage, as well as an increased risk of nosocomial pneumonia in patients with higher gastric pH. For this reason, sucralfate, which does not inhibit or neutralize gastric acid, was considered an attractive option. Cook et al,33 however, found no significant differences in the rates of ventilator-associated pneumonia, durations of ICU stay, or mortality rates between critically ill patients receiving ranitidine and those receiving sucralfate.In a more recent randomized controlled trial,35 intravenous omeprazole 40 mg daily was compared with intravenous famotidine 40 mg twice a day, sucralfate 1 g in suspension 4 times a day, and intravenous placebo. The incidence of nosocomial pneumonia did not differ significantly among the 4 groups; however, gastric colonization was significantly greater in the groups that received agents that increased pH (P<.05). Sucralfate is available in solution and suspension and can be administered through a nasogastric tube, although administration via a tube can be labor intensive.6 Sucralfate decreases the absorption of ciprofloxacin, norfloxacin, theophylline, tetracycline, phenytoin, cimetidine, ranitidine, l-thyroxine, ketoconazole, and digoxin.6 Use of sucralfate should be avoided in patients with compromised renal function to avoid aluminum accumulation and poisoning.36Findings from recent trials with high-risk patients (ie, those with coagulopathy or respiratory failure) suggest that administration of PPIs is also an effective method of preventing stress ulcers9,31,33,37–42 (Table 2). Because PPIs inhibit the final step in acid production (the generation of gastric hydrogen ions via hydrogen potassium adenosinetriphosphatase), they provide long-lasting suppression of acid secretion. In a clinical trial31 in which high-risk patients were given intravenous ranitidine 150 mg daily (n=35) or omeprazole 40 mg daily (n=32) by mouth or via a nasogastric tube, 31% of those given ranitidine experienced bleeding whereas only 6% of those given omeprazole had bleeding (P=.01). In recent open-label studies43,44 (n=60, n=75), no high-risk patients experienced bleeding while taking a PPI. These small-scale studies suggest that PPIs are effective for prophylaxis against stress ulcers. Additionally, their rapid onset of action, linear kinetics, longer duration of action, and lack of observed tolerance suggest that PPIs may have pharmacokinetic advantages relative to H2RAs.31,32,45 Furthermore, PPIs have been associated with relatively few drug interactions (Table 3). Additionally, PPIs are not renally eliminated, so complications associated with their use in patients with renal dysfunction are minimal.46–54PPIs can be given via a nasogastric tube in patients unable to take medications by mouth, although the process is both time and labor intensive. For example, 30 minutes must be allotted for dissolution when omeprazole is administered via nasogastric suspension. With simplified omeprazole, lansoprazole, and pantoprazole bicarbonate suspensions, effectiveness depends on several of the of of the tube, and to the form of omeprazole in the for use in preventing bleeding of stress may enteral However, gastric emptying may absorption and of drugs administered via nasogastric the availability of intravenous and more intravenous lansoprazole, have the of an intravenous PPI. studies have of oral PPIs H2RAs for of stress ulcers, few studies have intravenous is with intravenous pantoprazole in the and data indicate that the pH for preventing stress can be with this agent. oral medications are an intravenous should be to an oral of the because intravenous of both pantoprazole and are to the oral pantoprazole and can be at before with of intravenous pantoprazole can be administered as a rapid 2 minutes or can be for to 2 hours at can be by with of in or solution to a final of This solution can be for to hours at This pantoprazole can be administered and use of an is no longer with of for intravenous is at for 1 in of or solution a solution that is at for 24 whereas a solution by of in must be administered within 12 of intravenous requires the use of an and the should be 30 are also used for stress ulcer prophylaxis like sucralfate, are available in solution and suspension. must be administered to patients 1 to 2 however, and pH levels must be a situation that antacids and for nurses to particularly in have numerous including electrolyte and drug a antacids are used to stress such as are for stress ulcer prophylaxis patients an oral or are from the However, in a survey by et of institutions reported that approximately 50% of patients who received stress ulcer prophylaxis in the ICU were treatment after to such as of of prophylaxis in that most the risk of clinically important bleeding the ICU to be to continued should be for risk used to stress are associated with and that should be considered when the duration of that 30 patients at high risk for clinically important upper gastrointestinal bleeding (defined as those receiving prolonged mechanical ventilation or with significant coagulopathy) need to receive prophylaxis to 1 episode of bleeding. In more than patients who do not these criteria need to receive prophylaxis to 1 episode of bleeding. These suggest that stress ulcer prophylaxis is appropriate for patients at high risk but not for those at lower risk for clinically important bleeding in the upper of the gastrointestinal of several indicate that guidelines for stress ulcer prophylaxis can have a without increasing the risk for gastrointestinal bleeding. In the first of guidelines prophylaxis with or sucralfate to trauma patients at risk for clinically important gastrointestinal bleeding in an decrease in drug without an increase in bleeding. In another the of prophylaxis of days with the incidence of gastrointestinal bleeding and ventilator-associated pneumonia, drug of in the and duration of use were The of guidelines for stress ulcer prophylaxis increased from to and decreased daily from to In a recent guidelines that a treatment with famotidine and sucralfate reduced the of days of prophylaxis in a trauma ICU from 50% to 25% without care of PPIs vary among institutions as a of and in some may the of an the data on the use of PPIs for stress ulcer prophylaxis are et reported that PPIs can be relative to In their no patients in the experienced treatment whereas patients in the the underlying cause of SRMD is hypoperfusion of the mucosa in the upper of the gastrointestinal tract. Thus, early for both and in ICU patients are in a nasogastric tube that blood flow detect gut ICU nurses and with of ischemia must then be to the Thus, medications that improve gut hemodynamic parameters are and are thought to improve gastrointestinal this has been long-lasting agents that control pH without the development of tolerance are tolerance does not appear to develop in patients taking but more studies are care nurses with of the risk factors, and prophylaxis of stress-related bleeding can have a on a is either admitted or to the nurses must the for any risk factors for SRMD (ie, mechanical ventilation severe burns, multiple organ failure, neurological trauma, shock, and the administration of this has been stress ulcer prophylaxis should be considered and then with treatment include early and administration, of hemodynamic or treatment of and enteral should be early in appropriate patients because oral or enteral nutrition may improve Because they are of possible in the of medications to a nurses can the available and of administration with a is nurses can provide assessments of patients at risk for stress ulcers. and laboratory should be monitored so the ICU can be to any of renal function is in patients receiving sucralfate or For patients receiving agents that do not affect gastric such as sucralfate, is to of potential and of gastrointestinal bleeding. However, pH may be appropriate for patients receiving agents that neutralize gastric acid, gastric pH is not in the clinical and In one of institutions reported use of pH a pH or gastric for gastric pH. In addition, pH and do not appear to be the pH appear to be more than pH in critically ill patients with pH of or is considered the for of stress-related ulcers, although is of the need for in critically ill patients, nurses must also of potential drug interactions, both and effects should be well so that early of an can be recognized and medications can be must also be monitored for the early of gastrointestinal hematemesis, blood material that looks like coffee grounds in the nasogastric tube, or nurses should be that patients at risk for stress-related bleeding must be for pneumonia because of an gut particularly with the use of include decreased and changes on In patients, of include for with of risk factors and ICU care have decreased the incidence of stress-related bleeding. pantoprazole appears to be effective for stress ulcer prophylaxis. mechanical ventilation and coagulopathy are the 2 factors associated with the risk of stress-related bleeding. with this and effective should be to which patients are at high risk for stress-related bleeding and therapy is nurses a role in the care of patients at risk for stress ulcers. have the of and clinical should be to high-risk patients and to treatment with This should hemodynamic and as well as to the use of PPIs in these patients is and use is an important for and nurses to was by was by