ACUTE GASTROINTESTINAL BLEEDING IN THE INTENSIVE CARE UNIT

HIGH RISK BLEEDING, PART I1

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ACUTE GASTROINTESTINAL BLEEDING IN THE INTENSIVE CARE UNIT The Gastroenterologist’s Perspective Umar Beejay, MD, and M. Michael Wolfe, MD

Significant advances have been made in understanding the pathophysiology and management of gastrointestinal bleeding occurring in the intensive care unit (ICU) setting, including improvements in endoscopic and radiographic techniques, advances in resuscitative measures, and development of more potent pharmacologic agents. Despite these advances, the mortality rate associated with gastrointestinal bleeding has remained unchanged at 8% to 10% over the last half-century, and hemorrhage still constitutes a major cause of morbidity and mortality in the ICU. The apparent failure of better clinical management to improve mortality rates associated with gastrointestinal bleeding may be partly due to selection bias. Patients who die of gastrointestinal hemorrhage generally have multiple chronic comorbidities and are elderly,lo1and these factors probabiy largely account for the unchanged mortality rate.141, 169, 174 Gastrointestinal bleeding may be divided into upper and lower sources, with the ligament of Treitz constituting the anatomic dividing line. Gastrointestinal bleeding in the ICU is usually detected as coffee grounds in the nasogastric aspirate; fecal occult blood; or as hematemesis, melena, or hematochezia in more acute circumstances. It may be accompanied by a decrease in hemoglobin and hematocrit or might present purely with symptoms from blood loss and hypovolemia. The clinical

From the Section of Gastroenterology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts

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approach to individuals with gastrointestinal hemorrhage depends not only on the severity, nature, and location of the bleed, but also on patient characteristics and comorbidities and the available medical skills and resources.1o1 This article focuses on stress-related erosive syndrome (SRES), the commonest cause of upper gastrointestinal bleeding in the ICU and lower gastrointestinal bleeding from intestinal vasculopathy. Many other causes of gastrointestinal bleeding that may be encountered in the ICU, most notably acid-peptic disorders and the sequelae of portal hypertension (esophageal varices), are discussed elsewhere in this issue. STRESS-RELATED EROSIVE SYNDROME Nomenclature

Lucas et a1114first described the condition now called SRES in 1971, and many terms are used to describe this condition, including stress

ulcer, hemorrhagic gastritis, stress gastritis, stress erosion, d i f l s e mucosal injury, erosive gastritis, and stress-related mucosal The main features of SRES are its relationship to physiologic stress, the diffuse nature of the mucosal injury, and the marked variability in its clinical course.20° SRESrelated overt hemorrhage manifests as hematemesis, bloody gastric aspirate, melena, or hematochezia. Clinically sigruficant SRES hemorrhage is defined as overt hemorrhage in combination with orthostatic changes in pulse and blood pressure, a 2 g/dl decline in hemoglobin and 2-unit packed erythrocyte transfusions within a 24-hour period, or 192 as gastric bleeding requiring surgery.42, Epidemiology

The incidence of overt SRES hemorrhage appears to be decreasing42 probably as a result of significant advances in the ICU monitoring and support of the critically ill patient, including optimization of hemodynamic status, tissue oxygenation, and treatment of sepsis.80The widespread use of prophylactic therapy is probably a less significant factor in producing this decrease.40The inadence of SRES depends, in part, on the diagnostic criteria. The definition may incorporate clinical or endoscopic criteria, or both. When microscopic blood loss is adopted as the sole clinical criterion, SRES occurs in virtually all ICU patients.=, 116, 149, 174 Use of a more clinically reasonable definition, as described in the previous nomenclature section, results in an inadence of clinically sigruficantSRES hemorrhage in 1%to 30% of ICU patients.'" 40, 46, 118, 174, 189 When esophagogastroduodenoscopy (EGD) is used for diagnosis, 75% to 100% of patients with endoscopically visible lesions have hemorrhage from SRES.so*'I4, 118*Il9, lm Even though the presence of endoscopically proven mucosal damage does not necessarily predict that 80, 95, lZ1, lZ8, 169* 202

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clinically sigruficant SRES hemorrhage will ensue, EGD remains the critical diagnostic test and diffuse shallow mucosal injury the diagnostic finding of SRES. Gastrointestinal bleeding from any cause in the ICU is associated with a fivefold increase in mortality.M,116,133*l69 Overt gastrointestinal bleeding from SRES is believed to contribute or cause death in 30% to 80% of critically ill 169 whereas ICU patients without gastrointestinal hemorrhage have a 10% to 25% mortality.M,lZ1,153 Risk Factors

Although the most important risk factor of SRES gastrointestinal bleeding is the type and severity of the underlying disease process,M,41, lo6, 83, 204 several other parameters are risk factors, as follows:9* 51, Respiratory failure requiring mechanical ventilation Coagulopathy Hypotension or shockao,98 Sepsisso, Multiple or severe trauma Extensive burns (>35%)% Severe central nervous system injury Hepatic failurezs,lO2, 190 Renal failure" Acute coronary syndromes14 Multiple system organ failurelZ, Aspiration pneumoniaa Post-organ transplant Major surgery and postsurgical states69,119 Long ICU stay169 A meta-analysis of 2252 patients by Cook et alMidentified mechanical ventilation (odds ratio, 15.6) and coagulopathy (odds ratio, 4.3)as the two most important risk factors. Without either of these, the risk of clinically sigruficant bleeding from SRES was about O.l%.M The probability of SRES hemorrhage increases proportionally with the number of risk factors present.8o, 147 Suggested risk factors for massive SRES hemorrhage include sepsis, hypotensive shock, acidosis, peritonitis, and multiple system organ failure.8o Natural History

The lesions of SRES differ from those of peptic ulcers in that they 114 The tend to be more shallow, more diffuse, and more initial lesions almost invariably occur in oxyntic gastric mucosa, the fundus, and the b o d p and occur within hours of the systemic insult.

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The lesions consist of multiple, shallow, punctate, subepithelial defects, usually associated with negligible surrounding inflammatory reaction,so and tend to ooze rather than bleed massively. If risk factors persist or worsen, the erosions and subepithelial petechial hemorrhages may become deeper and more extensive; diffuse ulceration may result in extensive areas of the upper gastrointestinal tract (distal esophagus, gastric antrum and duodenum) approximately 4 to 5 days after the initial injury.8oSome cases penetrate the muscularis mucosa, and perforation has occasionally been described. Profound hypoperfusion and sepsis result in deeper SRES lesions, and these are the lesions that tend to bleed profusely.81Although approximately 50% of early mucosal lesions have endoscopic evidence of recent or ongoing hemorrhage,8O the bleeding in these circumstances is -typically self-limited, and most of these patients do well with reversal of the underlying risk factors for SRES.&

Pathophysiology

The pathophysiology of bleeding from SRES is multifactorial,2l. lz8 with different factors assuming varying importance during the development of the lesions.106SRES lesions develop as a consequence of an imbalance between aggressive and defensive factors,8o the most important of which are respectively acid-pepsin production and mucosal p e r f u s i ~ n .lZ9, ~ ~179 , Luminal Acid- Pepsin

The old adage, "no acid-no still seems to hold true for SRES.11s,17s The importance of acid is confirmed by the observation that SRES lesions occur predominantly in oxyntic gastric mucosa and by many studies showing that maintenance of luminal pH above 3.5 to 4 prevents clinically significant bleeding from SRES.'" Further corroborative evidence includes experimental animal models that show a luminal acid concentration greater than 25 to 50 mmol/L is associated with ulcer formationg6and that systemically administered bicarbonate prevents ulcers induced by continuous acid instillation into dog stomachs.33 Increased stress16oand head injury1g,89 increase gastrin-mediated acid production. Despite the importance of acid in SRES, only a small amount of luminal acid may induce damage by upsetting the balance between aggressive and defensive factors, and SRES can occur even when gastric acid secretion is diminished. Although most studies regard acid as a prerequisite, some studies have suggested that acid alone is insufficient to cause SRES; in animal models, the combinations of acid and sepsis" 152 or acid and hemorrhage96were insufficient to incite gastric ulceration unless bile reflux was present. Because of the often varying levels of acid in SRES, some authors have differentiated Cushing's ulcers from SRES: They suggest that acid may be more important in Cushing's

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ulcerssoas manifested by the more frequent gastric acid hyper~ecretion'~~ and hyperga~trinemia'~ present in this condition. Mucosal Perfusion

Decreased mucosal perfusion is another major factor in the development of SRES?*, 82, 156 and gastric mucosal perfusion decreases early during any acute critical illness.18,44, 69, 77, lZ8Further evidence to support this hypothesis was presented by Moody et who showed an increase in gastric mucosal perfusion prevented ulceration. Decreased gastric mucosal perfusion promotes SRES through several mechanisms, including a decrease in the washout ejfiict,80 leading to local intramural acidosis, increased free radical formation,lso decreased acid-buffering capacity,s9,118 a decrease in the mucus and bicarbonate secretion,18oand possibly a defect in epithelial cell restituti0n.5~, 183 The end result of these effects is an increase in H + ion back-diffusion and disruption of the epithelial barrier.so,118, lZ7*177, 187 Fiddian-Green et aF3 emphasized the clinical importance of H + ion back-diffusion by showing a strong correlation between the degree of intramural pH and the development of massive bleeding from SRES (Fig. 1). Acid-Base Balance

Luminal acid comprises only part of a broad spectrum of acid-base balance that exists within the gastric epithelium. The importance of acidbase balance in SRES176was shown by Fiddian-Green,62who showed that the H + ion concentration in the mucosal interstitium was directly related not only to the local pH, but also to the degree of systemic acidosis. Bicarbonate plays a critical role in buffering and balancing this ions are produced at the basolateral local a ~ i d e m i a .97~ ~Bicarbonate , membrane of the gastric parietal ce11,1s6 are transferred by capillaries to the subepithelial area,71, and produce an alkaline tide that buffers the H+ ions that have diffused from the lumen.97Actively secreting gastric mucosa is more resistant to the effects of luminal acid than normal resting mucosa, indicating that a greater alkaline tide affords more protection to the gastric mucosa.186The contribution of bicarbonate is so powerful that it can neutralize the pH within the mucus gel on the epithelial cell surface despite a luminal pH of 1.5 to 2.0.67Regulation of gastric mucosal bicarbonate secretion is multifactorial, with paracrine, endocrine, and neural mechanisms being implicated.2 Gastric Epithelial Restitution

Gastric epithelial cell restitution (cell migration) is a defensive mech139 energy-de~endent~~? ls3 migration of epitheanism whereby a lial cells occurs toward areas of epithelial disruption, culminating in histologic and physiologic epithelial re~tituti0n.l~~ Epithelial restitution is believed to be an important component in maintaining the structural

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Intramural pH

Figure 1. Nomogram illustrating the relationship between intramural pH in the stomach and the probability (P) of massive bleeding from stress-related erosive syndrome (SRES). RF = risk factor. (From Fiddian-Green RG, McGough E, Pittenger G, et al: Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterology 85613-620,1983; with permission.)

and functional integrity of the gastric mucosal barrier.144176 Oxygen free radical formation6*and physiologic stress162 have been implicated in reducing the rate of cellular proliferation and possibly gastric epithelial restitution. Mucus-Bicarbonate Barrier

The gastric epithelium is covered by a 200-p deep unstirred layer of mucus gel, consisting of a glycoprotein matrix that acts as a physical barrier that prevents H+ ion back-diffusion and as a locus that traps the bicarbonate ions that have diffused from the gastric epithelium. The control of mucus secretion is multifactorial, with gastric mucosal perfusion'*O and paracrine, endocrine, and neural factors being implicated? Disruption of the mucus barrier by the bile reflux, uremic toxins, alcohol, aspirin, and other nonsteroidal anti-inflammatory drugs (NSAIDs) can result in increased mucosal permeability and H+ ion back-diffusion.126 Mucosal Prostaglandins Prostaglandins are 20-carbon chain end products of arachidonic metabolism and are produced endogenously by the gastric mucosa. They

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were first implicated as cytoprotective agents by Robert et allb1in 1979, who showed that mild luminal irritants induced prostaglandin formation that protected the gastric mucosa against further injurious topical agents. This process was termed adaptive cytoprotection.161More recently, the effects of exogenously administered prostaglandins on the gastric mucosa have been shown to be dose dependent."' At all doses, prostaglandins stimulate all mucosal defensive mechanisms to protect the gastric mucosa from injurious agents (e.g, NSAIDs and alcohol).70,Ib3 At higher doses, prostaglandins inhibit acid secretion by reducing parietal cell production of cyclic adenosine monophosphate (AMP),60,111, lZ6and this property is believed to be fundamental to their clinical effects. Free Oxygen Radicals

Toxic free oxygen radicals are involved in tissue injury in many systems. SRES-related gastric ulceration can be caused by oxidative damage of gastric mucosa,3 from hydroxyl (OH-) radical formation47 and disruption of the microvascular network by platelet-activating factor.=,170 The importance of oxygen free radicals is corroborated by evidence that free radical scavengers, such as allopurinol and dimethyl sulfoxide, decrease gastric mucosal injury in models of and aspirin-induced and ethanol-induced mucosal injury.lb7 Bile

Bile is a topical gastric mucosal irritant, and increased bile reflux has been shown to occur in critical illness.3oBile may produce gastric mucosal injury through a prostaglandin-mediated effect on gastric mucosal perfu~ion,'~~ reduction of gastric bicarbonate secretion,15sand an increase in gastric mucosal permeability. Although the exact role of bile salts in human SRES remains uncertain, bile salts lead to mucosal injury in animal shock m0de1s.l~~ Nutrition

Experimentally, enteral nutrition reduces stress ulceration,10o* 131 preserves gastric mucosal integrity by neutralizing reduces gastric motility, and stimulates gastric mucosal perf~sion.5~ These findings have led to small clinical trials that suggest a clinically meaningful benefit from the administration of enteral nutrition. Clinical Assessment History

SRES is usually asymptomatic and generally noted only when clinically significant bleeding occurs in the ICU. Bleeding usually manifests

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as coflee grounds in a nasogastric tube aspirate; as fecal occult blood; or as hematemesis, melena, or hematochezia when hemorrhage is brisk. Patients may also present with nausea, vomiting, and abdominal pain or with symptoms from volume depletion, shock, or anemia.IWDuring the initial assessment and resuscitation, a brief history and physical examination should be performed. Although clinical assessment has a 40% accuracy in predicting the source of gastrointestinal hemorrhage,’W a history of variceal bleed, prior acid-peptic disorders, gastroesophageal reflux disease, recent surgery, or NSAID use may decrease the pretest probability of SRES. The history should attempt to identify any risk factors that would increase the probability of SRES (see earlier). Physical Examination

No specific signs signify that SRES is more likely than other causes of upper gastrointestinal hemorrhage.lgl Some physical findings may suggest certain causes (e.g., signs of chronic liver disease suggest esophageal varices, and wasting, lymphadenopathy, and abdominal masses suggest malignancy). The physical examination is helpful in the assessment of the severity of hemorrhage, and the vital signs, skin turgor, jugular venous pressure, and orthostatic changes should be determined.IWThe abdomen should be examined to assess for tenderness, masses, hepatosplenomegaly, ascites, and bowel sounds; a rectal examination is critical to obtain valuable information on the color of the stool (melena or bright red blood).101 Diagnosis

SRES is definitively diagnosed by EGD in the appropriate clinical context.lo1Although the presence of multiple risk factors strongly suggests SRES, none are entirely specific.a*lg2 EGD can determine the precise bleeding source, provide prognostic information regarding the potential for rebleeding, and offer potential therapeutic intervention.lo9 Therapy

General Measures The treatment of established or presumed SRES involves the institution of general medical principles a plicable to the care of the critically ill patient at risk for gastrointestinal emorrhage. These measures include adequate and aggressive volume resuscitation,a, 173 control of sepsis (especially intra-abdominal),80and optimal tissue oxygenation.R Spe+c therapy is divided into noninvasive and interventional therapies. Norunvasive medical therapy emphasizes pharmacologic prophylaxis rather than treatment of active bleeding.= Interventional therapy encompasses

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endoscopic, angiographic, and surgical approaches to overt and clinically significant SRES-related hemorrhage. Prophylaxis

Although prophylaxis has dramatically reduced the incidence of bleeding in SRES:6 a reduction in mortality from this bleeding has not been shown.lsl Successful prophylaxis has been achieved by the application of specific pathophysiologic principles, as follows:16s Maintenance of gastric pH greater than 4 Optimization of gastric mucosal perfusion and oxygenation Maintenance and enhancement of mucosal defense systems Several modalities have been shown to be helpful, including the use of nonpharmacologic techniques such as enteral nutrition, as well as pharmacologic therapies that include acid-suppressive medications, mucosal protective agents, and prostaglandin analogues."', ,01 Medications that increase intragastric pH include antacids, H,-receptor antagonists, and proton-pump inhibitors (PPIS).'~~ Antacids. Antacids significantly reduce the frequency of overt and Ig2 They were clinically significant gastrointestinal bleeding from SRES.107, first evaluated in the prophylaxis of SRES in 1976,lZ4and since then several placebo-controlled trials have shown their efficacy against clinically significant SRES hemorrhage (Fig. 2).Ig2 The incidence of overt SRES bleeding was reduced from approximately 15% to 20% to 5% in the antacid arm of these trials. Antacids decrease intragastric acidity primarily by direct neutralization and by binding pepsin,192although other studies have postulated additional gastroprotective mechanisms.", 145 Aluminum-based antacids appear to increase mucus and bicarbonate production, increase gastric mucosal perfusion,52bind potentially injurious agents (e.g., bile acidsM), and stimulate epithelial cell r e n e ~ a 1 . The l ~ ~ goal of acid neutralization therapy is to raise the intragastric pH to 4 or greater to inhibit the conversion of pepsinogen to active pepsin and reduce proteolytic activity. Platelet aggregability increases at a pH greater than 5.9. Antacids are typically administered as 30- to 60-mL aliquots orally or via a nasogastric tube every 1 to 2 ,04 The regimen requires close monitoring of intragastric pH and individual titration to maintain the pH greater than 4. The side effects of magnesium-containing antacids include hypermagnesemia, and alkalemia, whereas aluminum-based antacids cause hypophosphatemia, constipation, and metabolic alkalosis as well as potentially toxic plasma aluminum levels in patients with renal in~ufficiency.'~~ All antacids may impair the systemic absorption of drugs, including antibiotics61,lo5 and H,-receptor antagonists. Histamine-2-Receptor Antagonists. H,-receptor antagonists have been shown unequivocally to reduce the incidence of overt and clinically significant SRES hemorrhage when compared with untreated controls

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Figure 2. Common odds ratios and 95% confidence intervals for the relative effectiveness of prophylactic drugs in the prevention of SRES-related hemorrhage and mortality. (Adapted from Cook DJ, Reeve BK, Guyatt GH, et al: Stress ulcer prophylaxis in critically ill patients: Resolving discordant meta-analyses. JAMA 275308314, 1996; with permission.)

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(see Fig. 2).'81,192 A meta-analysis of 16 studies by Shuman et which involved 2133 patients, showed no significant difference in efficacy between antacids and H,-receptor antagonists in the prevention of clinically significant SRES hemorrhage. Both regimens were superior to placebo and were tolerated equally well. A more recent meta-analysis by Tryba and has suggested that H,-receptor antagonists may be more effective than antacids in SRES prophylaxis. H,-receptor antagonists inhibit acid secretion by binding to the histamine-2 receptor located on the basolateral membrane of the parietal cell."' Cimetidine is typically administered intravenously by continuous infusion at doses of 37.5 to 100 mg/h, whereas ranitidine is dosed at 6.25 to 12.5 mg/h and famotidine at 1.7 to 2.1 mg/h; all can be administered with or without a loading dose."' Continuous H,-receptor antagonist infusion appears to provide more stable acid suppression than bolus therapy.6,8, 73, 135 Although H,-receptor antagonists are considered to be safe, they have class-specific and individual side-effect profiles."' The most prominent class-specific effect is central nervous system toxicity?6 which appears to be idiosyncratic rather than dose related and occurs more frequently in elderly patients, usually within the first 2 weeks of therapy.26Cimetidine and ranitidine, in contrast to famotidine and nizatidine, inhibit the clearance of drugs by the cytochrome P450 system and interfere with the clearance of a wide variety of drugs." Although hematologic toxicity, liver dysfunction, and minor increases in creatinine occur with cimetidine, ranitidine, and famotidine, antiandrogenic effects seem to be specific to cimetidine.'" Proton-Pump Inhibitors. PPIs are not generally recommended for SRES prophylaxis because of a lack of evidence of significant benefit.'92 136 have shown promise, but no large randomized Several small studieslo8, clinical trials have been performed. Two studies in mechanically ventilated ICU patients suggested that a simplified omeprazole suspension may prevent clinically significant SRES hemorrhage and is safe and costeffective. The study design was limited in scope, however, with few study '4~ PPIs are substituted benzimidazoles that irreversibly block the H +/ K+-ATPase,the enzyme mediating the final common step in acid secretion. PPIs are prodrugs, which are metabolized to an active sulfenamide moiety in the highly acidic milieu of the secretory canaliculus of acti155 The sulfenamide moivated parietal cells after systemic absorption.122, ety forms a disulfide bond with the H+/K+-ATPase and irreversibly inactivates the enzyme. PPIs are significantly less active when administered to fasting individuals because prodrug activation occurs only in activated parietal cells.'" Four PPIs are currently available: omeprazole, lansoprazole, pantoprazole,66and rabepraz~le.'~~ All PPIs are available as oral agents, and pantoprazole is available as an intravenous preparation as well.'03 The typical oral dose for omeprazole is 20 mg orally daily, lansoprazole is 30 mg orally daily, rabeprazole is 20 mg orally daily, and pantoprazole is 40 mg orally daily. Difficulties in the oral

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administration of omeprazole to mechanically ventilated ICU patients have not been resolved despite the development of an omeprazole suspension that is somewhat effective in keeping gastric pH greater than 4.'" PPI side effects are minimal but include headache, diarrhea, and nausea.'" Significant drug interactions seem to occur only with rabeprazole, which interacts with digoxin and ketoconazo1e.lm,155 Mucosal Protective Agents Sucrazfate. The role of sucralfate in the prophylaxis of clinically sigruficant SRES hemorrhage is controversiaLZmA review by Tryba"O suggests that sucralfate is an effective prophylactic agent. It has been touted as the ideal agent because of its low side-effect profile, which possibly includes a lower incidence of nosocomial pneumonia (Fig. 3).17, *,19z In many studies, however, sucralfate was not statistically superior Nevertheless, to the reference group in preventing SRES hem~rrhage.'~ it has been suggested that sucralfate is of comparable efficacy to H,receptor antagonists and antacids in SRES prophylaxis.18,zz, Sucralfate is a basic nonabsorbable aluminum salt of sucrose octasulfate.201 It is relatively insoluble in aqueous solution and is poorly absorbed from the gastrointestinal tract. Despite its weak antacid properties,192its protective effect is not mediated by acid suppression or neutralization but by a cytoprotedive effect on the.gastric mucosa. The mucosal protection afforded by sucralfate is. mediated by numerous different mechanisms,2°1including formation of a protective barriers" lE; stimulation of gastric mucosal perfusion,201mucus, and bicarbonatezo1 and stimulasecretion by an effect on endogenous prostaglandin^^^, lE5; tion of various growth factors that have been implicated in ulcer healing.%1% 193 Sucralfate is available as tablets or as a liquid slurry that is administered 1 g orally or by nasogastric tube every 4 to 6 hours. Despite the apparent advantages of sucralfate, including its ease of administration, lack of need for monitoring, lack of need for supplemental antacid therapy and its cost-effectiveness,lZ it cannot be recommended as the Although drug of choice in SRES because of discordant study res~1ts.l~ sucralfate is well tolerated, constipation occurs in 2% to 4% of patients,zo1 and aluminum toxicity has occurred in patients with chronic renal fai1~re.l~~~ Prostaglandin Analogues. Synthetic prostaglandin derivatives (e.g., misoprostol) have not been shown to be effective in the prophylaxis of SRES, despite the promise shown in early trials.', 196, 203 Synthetic prostaglandin analogues exert a protective effect at low doses and have been demonstrated to protect the gastric mucosa from a variety of agents.*O1Given the relatively high cost and major side effects associated with prostaglandin analogues, it is unlikely that any large-scale randomized clinical trial will be performed to investigate the role of prostaglandin analogues in SRES hemorrhage. Their use is not recommended. Entmal Nutrition. Early implementation of enteral nutrition has been demonstrated to protect against the bacterial translocation that occurs across atrophic intestinal mucosa,144and animal studies115and

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Figure 3. Common odds ratio and 95% confidence intervals for the risk of pneumonia in randomized trials of SRES prophylaxis. (Adapted from Cook DJ, Reeve BK, Guyatt GH, et al: Stress ulcer prophylaxis in critically ill patients: Resolving discordant rneta-analyses. JAMA 275308314, 1996; with permission.)

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Antacids vs Placebo/control: 3 trials

4 Receptor Antagonists vs Antacids: 3 trials

Sucralfate vs Placebolconhol: 2 trials

Sudfate vs Ankids: 6 trials

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small human trials have suggested efficacy.150, Nevertheless, no largescale, controlled clinical trials have compared enteral nutrition with pharmacologic therapy in SRES prophylaxis. Enteral nutrition cannot be recommended as an effective prophylactic method in the treatment of SRES. Medical Therapy of Actively Bleeding Stress-Related Erosive Syndrome

Although cessation of active hemorrhage resulting from SRES with administration of antacids,&,,05 H,-receptor antagonists,3E, 49, ,05 PPIS,'~, ~ 3 37 , and su~xalfate'~~ has been reported, this finding has not been tested in large randomized, controlled trials. Case reports suggest the efficacy of prostaglandin^,^^, lg7 ~omatostatin,~~~ pirenzepine?O and intravenous vasopres~in,~~~ but all these agents are currently regarded as investigational. lnterventional Therapy

More aggressive therapies are indicated when prophylactic therapy fails, and clinically sigruficant SRES hemorrhage persists. Isolated bleeding sites may be treated by endoscopic or angiographic techniques, although little has been published regarding the efficacy of these modalities in the treatment of SRES.29Surgery is reserved for cases of severe hemorrhage uncontrolled by other modalities.123 Endoscopy. EGD is the principal diagnostic procedure for SRESassociated hem~rrhage.~~ Not only does EGD accurately identify the site of bleeding in more than 95% cases of upper gastrointestinal hemorrhage, but also it provides prognostic information about the risk of rebleeding and offers a therapeutic potential.101,109 The precise role of endoscopic therapy in the management of clinically significant SRES hemorrhage is difficult to defineF9 primarily because of the diffuse nature of lesions in SRES, which do not lend themselves readily to endoscopic hemostasis.m If single lesions with active bleeding or stigmata of recent hemorrhage are identified, however, control of hemorrhage is successful in more than 90% of cases.=*lo9Diagnostic EGD is a safe and simple procedure with a morbidity of 1%and mortality of less than 0.1%.lloEGD should be performed within 24 hours in stable patients or as soon as volume status is optimized and any coagulopathy that might be present is corrected. Angiography. hgiography offers a useful diagnostic and therapeutic tool in managing SRESrelated hemorrhage, with vasopressin infusion and intra-arterial embolization being equally successful at controlling hemorrhage. SRES hemorrhage tends to occur from small vessels and multiple sites, and a sigzuficant portion of the stomach may be involved in the bleeding?O Of SRES hemorrhage, 95% emanates from the proximal stomach, with at least 85% of lesions supplied by the left gastric artery.94 Vasopressin, an intra-arterial vasoconstrictor, acts at the level of the

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small arterial branches and capillaries and was the modality of choice in the 1980~.~, 35, 56, 91 More recently, intra-arterial embolization has become more popular because of comparable success and lower complication 75, 132 Embolization is accomplished with small fragments of Gelfoam sponge or Gelfoam powder and may be effective in treating SRES hemorrhage in 67% of patients.ll*, Surgery. SRES hemorrhage ceases spontaneously in 95% of patients treated conservatively, and only approximately 5% experience massive SRES hemorrhage. Even among patients with major hemorrhage, 90% are controlled by a combination of pharmacotherapy, therapeutic EGD, and interventional angiography.lZ9,175 This efficacy, coupled with the lower incidence of SRES in the 1990s, renders surgical intervention rare in SRES management. Nevertheless, surgery continues to constitute an important component of the diagnostic and therapeutic armamentarium in treating refractory SRES bleeding. Indications for surgery in SRES hemorrhage include transfusion needs greater than 6 to 8 units of packed erythrocytes during 24 hours or persistent bleeding despite optimal endoscopic or angiographic therapy116The decision to opt for surgery must be individualized because the results of surgery are uniformly and mortality rates in most series approach 100%.128 Once surgery is elected, the approach of choice is a vagotomy with drainage, in combination with oversewing of individual bleeding sites." lZ9,lg9 Vagotomy is thought to reduce gastric mucosal perfusion and acid ~ecreti0n.l'~ Recurrent hemorrhage after this surgery occurs in 20% to 50% of patients,8s and a second operation is often contemplated. More extensive surgery of subtotal gastric resection with or without a vagotomy was not superior to the combination of vagotomy, drainage, and oversewing in a small case series.l16 Other approaches to this difficult problem include total gastrectomyS8and gastric devascularization, the latter involving ligation of the left and right gastric and gastroepiploic arteries, which can be attempted in cases in which SRES hemorrhage is diffuse.l16Gastric devascularization achieved complete initial control of bleeding in a small series (21 patients), with a mortality rate as low as 38%.'" After devascularization, a second-look procedure should be considered after 24 to 48 hours because of the great risk of gastric necrosis.116 Complications of Stress-Related Erosive Syndrome Nosocomial Pneumonia

The possibility of an increased risk of nosocomial pneumonia has hindered the use of acid-suppressive therapy in SRES. This notion stemmed from the gastric bacterial overgrowth that can occur within a few days in an alkaline intragastric milieu (pH >4). Higher gastric pH directly correlates with logarithmic increases in the concentration of gram-negative organisms in the gastric aspirate.= In contrast to antacids

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and H,-receptor antagonists, sucralfate does not significantly elevate gastric pH and is accordingly associated with less gastric bacterial overgrowth than the former drugs. Moreover, Tryba and othersB,lg3,lg8 have suggested sucralfate has antibacterial effects. A meta-analysis of trials by concluded that sucralfate causes significantly less nosocomial pneumonia than the other classes of drugs. Driks et alS showed a pneumonia rate of 12% with sucralfate, compared with a 23% incidence in patients receiving both H,-receptor antagonists and antacids. On stratification, however, antacids were associated with a 23% incidence of pneumonia, whereas the H,-receptor antagonists group had an incidence of only 5.9% (less than those receiving sucralfate). Further outcome studies are necessary before making definite conclusions regarding comparisons of sucralfate with antisecretory therapies.

MESENTERIC VASCULOPATHY

Acute mesenteric vasculopathy, formerly referred to as acute mesenteric ischemia, is associated with a high mortality despite sigruficant advances in understanding its pathophysiologic mechanisms, natural history, and therapy.l6tZ7 The common delay in diagnosis has devastating consequences on its morbidity and mortality rates.16 Nonocclusive mesenteric vasculopathy (NOMV) is a subset of mesenteric vasculopathy (Fig. 4) and accounts for a small proportion of gastrointestinal hemorrhage in the ICU. NOMV refers to mesenteric vasospasm occurring in the absence of arterial or venous occlusion that overcomes the normal autoregulatory mechanisms of intestinal perfusi0n.2~

NONOCCLUSIVE MESENTERIC VASCULOPATHY

Gastrointestinal hemorrhage is not the predominant symptom in NOMV and generally occurs as a small volume bleed. N O W should be considered whenever unexplained abdominal pain or gastrointestinal hemorrhage occurs in the presence of congestive heart failure, myocardial infarction, pulmonary edema, or hypovolemic shock ~tates.2~

Epidemiology Mesenteric vasculopathy accounts for 0.1% of hospital admissions,lS2 and NOMV accounts for 20% to 30% of episodes of acute mesenteric vasculopathy.92The incidence of NOMV seems to be declining, probably because of better hemodynamic monitoring, the greater use of vasodilator agents, and the diminished use of digitalis preparations.

c:

W

Retroperitoneal fibrosis

Neurofibromatosis

Median arcuate ligament syndrome

Embolus Thrombus Nonocclusive

/eriTbstructir

Acute

~

I

Acute

~

Fulminant

Partly reversible

Multivessel

chronic

Chmruc mesenmic ischemia

, Ischemic colitis

Colonic

Transiendreversible

Chronic

Venous obstruction

Superior mesenteric

/

(Inmnsic Cardiovascular Disease: thrombus. embolus. atherosclerosis, and vasosuasm)

PRIMARY ( INTESTINALVASCULOP.4THY)

Figure 4. Classification of mesenteric ischemia. (From Cappell MS: Intestinal (mesenteric) vasculopathy: I: Acute superior mesenteric arteriopathy and venopathy. Gastroenterol Clin North Am 27:783825, 1998; with permission.)

Volvulus

Surgical injury

Intestinal hernia

Cancer infiltrating mesentery

Carcinoid

Blunt injury

Adhesions

Vascular Trauma

Amy loidosis

I \

Bowel Strangulation

Extraintestinal vascular compression

/

(Extrinsic Vascular Compression)

SECONDARY

MESENTERIC ISCHEMIA

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Pathophysiology

NOMV is due primarily to mesenteric vasospasm, which in the absence of a thromboembolic cause, disrupts and overwhelms the homeostatic mechanisms involved in the autoregulation of intestinal perfusi0n.2~The vasospasm occurs predominantly as a reaction to mesenteric vasculature low-flow states resulting from systemic hypotension of any cause. Clinical Presentation History

Symptoms depend on the site, severity, and cause of N O W as well as the extent and degree of the collateral circulation. Comorbidities also play a role, with symptoms being masked in elderly confused, and critically ill individuals. The initial clinical presentation is usually subtle and nonspecific.&4Pain o c m s in only 75% to 85% of cases and is typically out of proportion to the physical findings.57,93 A history of postprandial pain is he1 ful, particularly when an acute event occurs in the setting of probable k o n i c mesenteric ischemia. Lower gastrointestinal bleeding can occur but is not the commonest presentation. Other symptoms include nausea, vomiting, abdominal distention, and diarrhea.27Hematochezia may occur when bowel infarction is imminent.137 Physical Findings

Physical findings are usually absent initially but become more prominent with increasing i~chemia.2~ They include fever, tachycardia, hypotension, hyperventilation, confusion, abdominal distention, tenderness, rigidity, rebound, and high-pitched or absent bowel s0unds.2~ Of individuals, 75% may have occult blood in the stool, but overt gastrointestinal 93 hemorrhage is less Diagnosis

A thorough history should be obtained, which must include careful questioning regarding vascular disease (coronary, cerebral, renal, or peripheral), use of vasoconstrictive drugs, previous thromboembolic disease, and vasculitis. The physical examination should include a careful abdominal inspection and a search for evidence of vascular disease in other organ systems. Although most initial diagnostic tests are nonspecific, the abdominal radiograph is helpful in excluding other abdominal disorders (obstruction, volvulus, perforation), and specific findings are ~ , ~most ~ useful tests are computed found in only about 25% of c a ~ e s .The tomography (CT) of the abdomen and mesenteric angiography. Abdomi-

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Table 1. COMPARISON OF THE ANGIOGRAPHIC FINDINGS ASSOCIATED WITH NONOCCLUSIVE INTESTINAL VASCULOPATHY AND THROMBOEMBOLIC DISEASE Type of Obstruction

Embolus

Thrombus

Nonocclusive

Location

Appearance

Other Findings

50% middle colic artery, 25% ileocolic artery, 15% SMA origin, 10% distal to ileocolic artery or distal SMA branches Characteristically at SMA orifice

Sharp, rounded filling defects (meniscus sign)

Poor contrast flow beyond obstruction, collaterals uncommon, minimal atherosclerosis, multiple lesions Collaterals common, extramesenteric atherosclerosis

Diffuse involvement at multiple sites of SMA and SMA branches

Extensive, irregular mesenteric obstruction, planar vascular defect from thrombus Alternating spasm and dilation (string-ofsausages sign), pruned arterial tree, spasm of mesenteric arcades, no embolus or thrombus

Slowed mesenteric flow, aortic reflux of contrast during injection, impaired intramural filling

SMA = Superior mesenteric artety. From Cappell M S Intestinal (mesenteric) vasculopathy: I. Acute superior mesenteric artheriopathy and venopathy. Gastroenterol Clin North Am 2778?4325,1998; with permission.)

nal CT is more helpful in diagnosing mesenteric venopathy and excluding other abdominal conditions. The CT findings in mesenteric arteriopathy are usually less specific, but CT can sometimes show mucosal thumbprinting or contrast enhancement of a thickened bowel wall segment.140 Mesenteric angiography represents the gold standard for diagnosing mesenteric arteriopathy and should be performed early if the diagnosis is suspected. Angiography can define the site of occlusion and help distinguish between NOMV and arterial or venous thromboembolic phenomena (Table 1). Arterial vasospasm is associated with specific arteriographic findings, including pruning of the arterial tree and impaired intramural vascular filling.36,92 Less useful tests in the diagnosis of NOMV include EGD and colonoscopy, which may be useful in localizing a bleeding site once hemorrhage occurs. Therapy General Measures

Once NOMV is diagnosed as the cause of gastrointestinal hemorrhage, therapy is predominantly supportive. Intravascular volume replacement should be aggressive, and potentially exacerbating factors, such as congestive heart failure and arrhythmia, should be treated.

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Vasoconstrictive medications should be discontinued and broad-spectrum antibiotics started if bacterial sepsis or translocation is suspected. Fluid balance should be monitored carefully, oxygen supplementation instituted, and anemia c0rrected.2~ Specific Measures

Treatment of the underlying cause is the most effective therapy in NOMV. Systemic vasodilator therapy via the angiographic catheter is effective in reversing mesenteric vasodpasm and helping to minimize or prevent further bowel ischemia and infarction. Success may also be judged clinically with diminution of abdominal pain or other symptoms, reduced abdominal signs, and improvement in laboratory parameter^.^^ If no improvement is seen clinically or angiographically or if the clinical findings become worse, urgent exploratory laparotomy is indicated with resection of compromised or infarcted bowel. Vasodilator therapy may be used postoperatively to prevent further vasospasm and improve bowel perfusion. SUMMARY

Although SRES-associatedhemorrhage previously constituted a significant cause of bleeding in the ICU, improvements in ICU management and the institution of prophylactic measures in high-risk patients have sigdicantly reduced SRESassociated hemorrhage since the 1980s. Antacids, Hz-receptor antagonists, and sucralfate have been shown to be effective in preventing clinically sigruficant bleeding resulting from SRES, particularly when the intragastric pH is maintained at greater than 4. A selective approach should be adopted in SRES prophylaxis: Patients on mechanical ventilation, with coagulopathy, or with two of the other known risk factors should receive pro phyla xi^.'^ Although the drug of choice depends to some extent on local preferences, an Hzreceptor antagonist by continuous intravenous infusion may represent the best option. No pharmacologic therapy is of proven value3 once hemorrhage begins, but the current interventional techniques are eff ective in controlling hemorrhage. Gastrointestinal bleeding from NOMV has become less common with improvements in the hemodynamic monitorin of critically ill patients, but this disease must always be considered w en lower gastrointestinal bleeding occurs in the context of relative hypoperfusion. For SRES and NOMV, treatment of the underlying disease or diseases is the optimal route to prevention.

a

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