The clinical features of stress-related erosive syndrome have been well characterized since the initial endoscopic description by Lucas and colleagues in 1971. Stress-related lesions in the stomach and duodenum can be detected endoscopically within several hours of a critical illness, trauma, or surgery as multiple punctate subepithelial hemorrhages, erosions, or superficial ulcerations.
Mucosal injury maybe identified in 70 to 100% of critically ill patients admitted to an intensive care unit, and the risk of developing these lesions appears to be directly correlated with the severity of the underlying illness. The presence of endoscopic mucosal damage does not necessarily imply that clinically significant stress-related erosive syndrome hemorrhage will ensue, however, when documented, the presence of diffuse shallow mucosal injury is the landmark feature in the diagnosis stress-related erosive syndrome.
Many terms have been used to describe this entity, including stress ulcer syndrome, stress gastritis, stress-related mucosal disease, and stress related syndrome. The principal feature of stress-related erosive syndrome is its relationship to serious systemic disease, such as sepsis, massive burn injury, head injury associated with increased intracranial pressure, severe trauma, and multiple system organ failure.
The incidence of overt stress-related erosive syndrome hemorrhage appears to be declining. This decrease is likely due to significant advances in the intensive care unit monitoring and support of the critically ill patient, including optimization of hemodynamic status, tissue oxygenation, and treatment of sepsis. Estimates of the incidence of stress-related erosive syndrome are also affected by the criteria used to define the problem. The definition may incorporate clinical or endoscopic criteria or be a combination of both. When microscopic blood loss is adopted as the sole clinical criterion, stress-related erosive syndrome occurs in virtually 100% of intensive care unit patients.
Stress-related erosive syndrome-related overt hemorrhage is defined as hematemesis, bloody gastric aspirate, melena, or hematochezia. Clinically significant stress-related erosive syndrome hemorrhage is, in turn, defined as overt hemorrhage in combination with either orthostatic changes in pulse and blood pressure, a 2 g/dL drop in hemoglobin or 2 unit blood transfusion requirement within a 24-hour period. When this definition is adopted, stress-related erosive syndrome-related hemorrhage occurs in up to 30% of intensive care unit patients.
Once bleeding of any etiology occurs in the intensive care unit, mortality rates increase five fold. Overt gastrointestinal bleeding from stress-related erosive syndrome is felt to contribute to or cause death in up to 30 to 80% of critically ill patients, in contrast to the 10 to 25% mortality rate in intensive care unit patients without gastrointestinal hemorrhage. The vast majority of these deaths are not directly attributable to the upper gastrointestinal hemorrhage itself, but rather reflect the nature and severity of the underlying illness.
Although the pathophysiology of stress-related erosive syndrome is not fully understood, gastric acid and pepsin appear to play a dominant role in the development of the gastroduodenal lesions characteristic of this entity. Both increased stress and head injury are associated with increased gastrin-mediated acid production. As with other acid-related disorders, stress-related erosive syndrome appears to result from an imbalance between aggressive and defensive factors. Normal mechanisms of gastric mucosal integrity depend on an intact microcirculation, which ensures an adequate supply of nutrients to the mucosa and, in conjunction with the mucous layer, neutralizes hydrogen ions and other locally noxious agents.
Mucosal ischemia appears to be the critical factor in the pathogenesis of stress-related erosive syndrome. Critical illness is commonly associated with hypovolemia, the release of pro-inflammatory cytokines, and increased cathecolamines production, which in turn lead to splanchnic hypoperfusion. Reductions in mucosal blood flow promote intra-cellular acidosis, the release of nitric oxide, the production of oxygen-derived free radicals, increased cell permeability, a decrease in the synthesis of prostaglandins, and diminished acid buffering capacity In addition, mucosal ischemia leads to decreased mucus and bicarbonate secretion and defects in epithelial cell restitution after injury, all of which contribute to the back-diffusion of hydrogen ions into the gastroduodenal mucosa.
Back-diffusion of acid is thought to play a central role in the disruption of the surface epithelial barrier, which may later progress to erosive lesions resulting in clinically significant hemorrhage. Small amounts of luminal acid maybe sufficient to induce gastroduodenal damage, and stress-related erosive syndrome can occur even when gastric acid secretion is diminished.
Most patients in an intensive care unit are at risk for stress-related erosive syndrome, and those most susceptible to gastroduodenal mucosal injury are patients with severe systemic disease. Mechanical ventilation for at least 48 hours and coagulopathy (platelet count of < 50,000, a partial thromboplastin time of more than twice that of control subjects, or an International Normalized Ratio of prothrombin time of > 1.5) have been identified as the two single most important risk factors. Other risk factors include shock, sepsis, multiple or severe trauma, extensive burns (greater than 35% of body surface area), central nervous system lesions (ie, intracranial hypertension), renal failure, liver dysfunction, multiple system organ failure, aspiration pneumonia, postsurgical states, acute coronary syndromes, and length of ICUstay. The probability of stress-related erosive syndrome hemorrhage clearly increases proportionally to the number of risk factors present.
Although most individuals with stress-related mucosal injury remain asymptomatic, 10 to 20% of those who do not receive prophylactic therapy experience gastrointestinal bleeding of an occult or overt nature. The lesions of stress-related erosive syndrome differ from those of “classic” peptic ulcers in that they tend to be shallower and more diffuse in location. The initial lesions are almost invariably found in the acid secreting areas of the stomach, the fundus and the body, and occur within hours of systemic insult. The lesions consist of multiple, shallow, punctate, subepithelial defects, usually associated with little or no surrounding inflammatory reaction, which tend to ooze rather than bleed massively.
If risk factors persist or worsen, the erosions and subepithelial petechial hemorrhages may worsen both in depth and extent, so that extensive ulceration can occur in extended areas of the upper gastrointestinal tract (distal esophagus, gastric antrum, and duodenum) approximately 4 to 5 days after the initial injury. In a small proportion of cases, penetration into the muscularis mucosa and perforation has been described. Both profound hypo-perfusion and sepsis result in deeper stress-related erosive syndrome lesions, which tend to bleed profusely. Despite approximately 50% of early mucosal lesions having endoscopic evidence of recent or ongoing hemorrhage, the bleeding in these circumstances is typically self-limited, and the majority of patients do well once the underlying illness is resolved.
Mucosal Protective Agents
Experimentally, enteral nutrition reduces stress ulceration, preserves gastric mucosal integrity by neutralizing acid, and stimulates mucosal blood flow. Early administration of nutrition to patients with multiple traumas may also reduce the occurrence of septic complications and multiple organ dysfunction syndrome. These findings have led to some small, retrospective clinical trials that suggest a clinically meaningful effect from the administration of enteral nutrition . Enteral feeding was, however, found to be a significant risk factor for bleeding in a multicenter study.
This discrepancy may be due to differences in location of nutrient delivery. Tubes placed in the stomach may alkalinize stomach contents, whereas jejunal-feeding tubes may stimulate gastric acid secretion. Although it is widely believed that nutrition is of value in preventing stress-related erosive syndrome, no large scale, randomized clinical trials have compared enteral nutrition to pharmacologic therapy in stress-related erosive syndrome. Therefore, enteral nutrition cannot presently be recommended as an effective method in the prophylaxis of stress-related erosive syndrome.
Although cessation of active hemorrhage due to stress-related erosive syndrome with the use of antacids, H2RAS, proton pump inhibitors, and sucralfate has been reported, large, controlled trials evaluating their true efficacy have not been performed. Case reports suggest the efficacy of prostaglandins, somatostatin, and IV vasopressin, but none of these agents can be regarded as more than investigational at this point.
More aggressive forms of therapy are indicated when prophylactic therapy fails and clinically significant stress-related erosive syndrome hemorrhage persists.
Esophagogastroduodenoscopy accurately identifies the site of bleeding in over 95% cases of gastrointestinal hemorrhage, and not only provides prognostic information about the risk of rebleeding, but also offers a therapeutic potential. If single lesions with active bleeding or stigmata of recent hemorrhage are identified, control of hemorrhage by several means, including mucosal epinephrine injection, thermal coagulation, multipolar electrocoagulation, and clipping, is successful in over 90% of cases. Angiography with intraarterial embolization is useful when bleeding persists despite endoscopic treatment.
Stress-related erosive syndrome hemorrhage ceases spontaneously in up to 95% of patients treated conservatively, and only approximately 5% will experience massive stress-related erosive syndrome hemorrhage. Even among those patients with major hemorrhage, up to 90% will be controlled by a combination of pharmacotherapy, therapeutic Esophagogastroduodenoscopy, and interventional angiography. Surgery is reserved for cases of severe hemorrhage uncontrolled by other modalities.
The increase in gastric pH that follows the use of acid suppression therapy can permit gram-negative bacterial overgrowth, which is believed to be associated with an increased risk of nosocomial pneumonia. Unlike antacids and EfeRAs, sucralfate does not significantly elevate gastric pH and is accordingly associated with less gastric bacterial overgrowth. Moreover, an antibacterial mode of action for sucralfate has been suggested. A meta-analysis of trials by Cook and colleagues (1996) examined the drug class specific rates of nosocomial pneumonia and concluded that sucralfate causes significantly less nosocomial pneumonia. However, the results of various studies evaluating the risk of nosocomial pneumonia are widely inconsistent.
This is perhaps explained by differing definitions of pneumonia, small samples evaluated, and lack of blinding. As previously stated, a large study comparing sucralfate and ranitidine for the prevention of stress-related erosive syndrome-related bleeding in 1,200 patients requiring mechanical ventilation showed no significant differences in the rates of nosocomial pneumonia between the two groups. Taking all these issues into consideration, it appears that the positive attributes of H2RAS outweigh the possible risk of nosocomial pneumonia associated with their use. IV administration of H2RAS (or possibly proton pump inhibitors) may obviate the need for a nasogastric tube, which may also serve as a conduit for migration of bacteria from the stomach to the pharynx. Further outcome studies will be necessary before definite clinical conclusions can be drawn regarding any comparisons of sucralfate with antisecretory therapies.
Summary and Recommendations
SERSprophylaxis is recommended for the following groups: (1) patients with coagulopathy, (2) patients requiring mechanical ventilation for more than 48 hours, (3) patients with a history of gastrointestinal ulceration or bleeding within the last year, and (4) patients with any two of the other known risk factors (Table Risk Factors for Stress-Related Erosive Syndrome). Antacids, H2RAs, and sucralfate have all been shown to be effective in preventing clinically significant bleeding due to stress-related erosive syndrome, particularly if the intragastric pH is maintained > 4.
Although no studies evaluating IV proton pump inhibitors in the prophylaxis of stress-related erosive syndrome have been reported, available data suggest that intermittent or continuous IV administration of pantoprazole can maintain gastric pH > 4 in the fasting intensive care unit patient at high risk for bleeding, similar to cimetidine continuous infusion. Moreover, acid suppression with IV pantoprazole increases over time, whereas the inhibitory effects of EfeRAs are reduced by the second day of therapy. Oral administration of proton pump inhibitors cannot be recommended for SERS prophylaxis due to suboptimal bioavailability and uncertain efficacy of these agents when administered via nasogastric tube to fasting individuals.
Although the drug of choice depends to some extent on local preferences, until well-designed, randomized, controlled trials are performed, H2RAS by continuous IV infusion may represent the best option. Intermittent IV dosing or continuous infusion of a PPI might be expected not only to adequately inhibit acid secretion, but also to allow a smooth transition to oral PPI therapy, especially in patients who may require chronic maintenance therapy for other acid-related conditions, such as gastroesophageal reflux disease. None of the pharmacologic therapies reviewed is of proven value once hemorrhage begins; however, the interventional techniques at our disposal are very effective in controlling acute bleeding.
TABLE. Risk Factors for Stress-Related Erosive Syndrome
|Respiratory failure requiring mechanical ventilation|
|Hypotension and shock|
|Multiple or severe trauma|
|Severe central nervous system injury|
|Acute coronary syndromes|
|Multiple system organ failure|
|Major surgery and postsurgical states|
|Long intensive care unit stay|