Stress-related mucosal disease in critically ill patients

Best Practice & Research Clinical Gastroenterology Vol. 17, No. 3, pp. 327 –344, 2003 doi:10.1053/ybega.2003.386, www.elsevier.com/locate/jnlabr/ybega

1 Stress-related mucosal disease in critically ill patients Donald R. Duerksen*

MD, FRCPC

Associate Professor of Medicine Division of Gastroenterology, Department of Medicine, St Bonfaice Hospital, C5 120 409 Tache Avenue, Winnipeg, Man., Canada R2H 2A6

Stress-related mucosal disease is common in critically ill patients and can result in significant morbidity. The pathophysiology of this condition is multifactorial but mucosal ischaemia and gastric acid have pivotal roles. The major risk factors for developing stress-related mucosal bleeding are prolonged mechanical ventilation and coagulopathy. The mainstay of clinical management is prevention with acid-suppressing medications and cytoprotective agents. This chapter discusses medications used to prevent this condition and suggests an approach for management. Recent developments in gastroenterology include the development and use of proton pump inhibitors and the discovery of the association Helicobacter pylori with gastritis. The role of each of these in stressrelated mucosal disease is discussed. Finally, an approach to the bleeding critically ill patient is presented. Key words: stress diagnosis; stress therapy; stress complications; critical care; intensive care units; gastrointestinal haemorrhage aetiology; gastrointestinal haemorrhage diagnosis; gastrointestinal haemorrhage therapy; peptic ulcer prevention and control; gastrointestinal haemorrhage prevention and control.

Critically ill patients admitted to an intensive care unit are susceptible to a number of diverse complications, some related to their underlying disease, some to medications and others to haemodynamic instability or tissue hypoxia. Specific to the upper gastrointestinal (GI) tract, critically ill patients appear susceptible to diffuse mucosal injury of the stomach which can result in significant upper gastrointestinal bleeding associated with an increased morbidity and mortality. This manifestation is different from that in the general population in which peptic ulcer disease and gastrooesophageal reflux disease are common upper gastrointestinal abnormalities. This chapter examines the incidence, risk factors, pathophysiology, prevention and treatment of stress-related mucosal disease. DEFINITIONS The syndrome of stress-related mucosal damage of the GI tract was first described in 1971 by Lucas et al1 who termed this ‘stress-related erosive syndrome’. Since then, *Tel.: þ 1-204-237-2796; Fax: þ 1-204-233-7154. E-mail address: [email protected] 1521-6918/03/$ - see front matter Q 2003 Elsevier Science Ltd. All rights reserved.

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numerous terms have been used to describe stress-related gastric damage in critically ill patients, including haemorrhagic gastritis, stress ulceration, stress erosions, stress gastritis, diffuse mucosal injury, stress-related mucosal disease, stress-related mucosal damage, stress-related mucosal bleeding and erosive gastritis. All of these terms imply a physiological stress that causes a mucosal morphologic abnormality to the gastric mucosa. There does not appear to be a significant inflammatory component to the mucosa in this entity and therefore the use of the term ‘gastritis’ is not histologically accurate.2 In this chapter I refer to this condition as stress-related mucosal disease, damage or bleeding. Gastric ulcerations in the setting of burns and head injury, states of extreme physiological stress, have been referred to as Curling and Cushing ulcers, respectively. Harvey Cushing first described the association between CNS injury and gastroduodenal disease in 1932.3 In the 1970s Czaja et al4 performed endoscopic studies that demonstrated diffuse gastroduodenal injury in patients with severe cutaneous burns. Since these initial descriptions it has become apparent that the physiological stress of critical illness is associated with stress-related mucosal injury and bleeding. Stress-related mucosal bleeding may be subcategorized according to the severity of bleeding as follows5: 1. Occult bleeding. This is defined as guaiac-positive stools or nasogastric aspirates. 2. Overt bleeding. This is defined as clinical evidence of bleeding in the form of haematemesis or nasogastric returns of coffee grounds or gross blood. 3. Clinically significant bleeding. This has been defined in clinical studies6 as overt bleeding accompanied by at least one of the following four features: * a spontaneous drop in systolic or diastolic blood pressure of . 20 mm Hg or * an increase in pulse rate of 20 beats per minute (BPM) and decrease in systolic BP of 10 mm Hg or * a decrease in haemoglobin of 2 g/dl or * failure to increase haemoglobin after transfusion by at least the number of units transfused minus 2. In summary, clinically important bleeding is overt bleeding complicated by haemodynamic changes or by the need for transfusion, indicated by the presence of hypotension, tachycardia or orthostasis or as a drop in haemoglobin of . 20 g/l.6 This distinction is important in reviewing studies on the topic as occult bleeding, and even overt bleeding, are relatively common, but they infrequently result in clinically significant bleeding. Practice point † clinically significant bleeding is the most important endpoint to consider when examining clinical studies on stress-related mucosal disease PATHOPHYSIOLOGY The cause of stress-related mucosal disease in critically ill patients is felt to be multifactorial. Gastric mucosal damage results from an imbalance between factors

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promoting mucosal injury and host defences. The factors important in the development of stress-related mucosal disease are detailed below. Host defence Mucosal prostaglandins Prostaglandins have a variety of beneficial effects with respect to mucosal protection, including stimulation of mucosal blood flow, stimulation of mucous and bicarbonate production and enhancement of epithelial cell growth and repair.7 There does not seem to be a selective impairment of prostaglandin production in patients with stress-related mucosal disease. Mucous bicarbonate barrier This layer of glycoprotein matrix and bicarbonate, adherent to the mucosal surface, forms a physical barrier to the influx of acid and pepsin and helps to prevent injury to the surface epithelium.8 This layer is also important in trapping bicarbonate anions that have diffused from the gastric epithelial cells. Epithelial restitution and regeneration This refers to a rapid energy-dependent migration of epithelium toward areas of epithelial disruption and results in the restoration of epithelial integrity.8 This process may be impaired by physiological stresses as well as oxidative injury. Mucosal blood flow Mucosal blood flow enhances mucosal defence by removing acid from the mucosa, supplying the mucosa with bicarbonate, and supplying oxygen to the mucosal epithelial cells.9 Cell membrane and tight junctions The tight junctions between gastric epithelial cells prevent the back-diffusion of hydrogen ions. Substances such as bile salts may damage this barrier, resulting in diffusion of gastric contents and increased injury.10 Aggressive factors promoting mucosal injury Acid Acid-related mucosal injury is central to the pathogenesis of stress-related mucosal damage. However, with the exception of sepsis and head-injury patients10 there does not appear to be acid hypersecretion and in some patients there may actually be gastric acid hyposecretion.1,11 However, small amounts of acids may cause injury, particularly in the susceptible host. The importance of acid in the pathogenesis of stress-related mucosal bleeding has been demonstrated in trials looking at the prevention of injury. Numerous studies have shown that maintaining intragastric pH above 3.5 – 5 can prevent mucosal injury.12 Physiologically, there are several potential mechanisms through which inhibiting acid may prevent stress-related mucosal bleeding. As well as inducing mucosal injury, secretion of acid may prevent formation of surface clots and aggregation of platelets.12

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Pepsin Activation of pepsin is pH dependent and is impaired if the pH is . 4.5.5 Pepsin may cause direct injury to the gastric mucosa, particularly if there already has been some injury.13,14 In addition, pepsin facilitates the lysis of clots, which could enhance bleeding from stress-related mucosal disease.5 Mucosal hypoperfusion Mucosal hypoperfusion is an important factor in the pathogenesis of stress-induced mucosal disease. Gastric mucosal perfusion decreases early during critical illness.15 There are several mechanisms through which mucosal hypoperfusion contributes to stress-related mucosal damage.10 Diminished blood flow causes an energy deficit by impairing oxygen and nutrient blood flow to the mucosa. This makes the mucosal epithelial cells more susceptible to injury. Decreased blood flow also impairs acid – base status as there is an inability to remove back-diffused Hþ ions from the mucosa and to supply additional bicarbonate. Finally, mucosal ischaemia results in the formation of free radicals (see below), which further injure the mucosa. Reperfusion injury Mucosal hypoperfusion also leads to increased release of nitric oxide, which results in microcirculatory vasodilatation and mucosal hyperaemia. This results in an enhanced immune response with an increase in inflammatory cells and cell-damaging cytokines. In animal models, reperfusion injury is a major cause of stress-related mucosal damage.16 Intramucosal acid –base balance Intramucosal acid – base balance is important in the maintenance of mucosal integrity. Normally, a mucous layer protects the surface of the epithelium and traps bicarbonate ions that are secreted by the mucosal cells. The bicarbonate neutralizes any acid that diffuses through this layer.17 Decreased bicarbonate secretion leads to acid trapping and intramucosal acidosis, which increases local injury.8 Systemic acidosis Intramucosal acidosis is critically important in the development of stress-related mucosal injury. A systemic acidosis will result in increased acid delivery to the mucosa as well which could potentiate intramucosal hyperacidity, particularly in the setting of impaired bicarbonate delivery to the mucosa.9 Free oxygen radicals Toxic free oxygen radicals are generated in states of tissue hypoxia. They induce oxidative injury to the mucosa probably by affecting cell membranes.18 In animal models free radical scavengers such as allopurinol may decrease gastric mucosal injury.19 There are no clinical trials of using free radical scavengers in the prevention of stress-related mucosal damage. Bile salts Bile salts reflux from the duodenum into the stomach and in animal models they appear to have a role in stress-related damage.20,21 There are several mechanisms through

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which bile acids may cause injury, including reducing mucosal blood flow through a prostaglandin-mediated mechanism, reducing bicarbonate secretion, and increasing gastric permeability.21,22 The exact role in humans is uncertain at present and there appears to be no major role for bile-acid-binding medications in the prevention of stress-related mucosal disease.

Helicobacter pylori Since its association with gastritis was first described, Helicobacter pylori is considered to be the major cause of gastric and duodenal ulceration. There have been several studies examining the role of H. pylori in patients with stress-related mucosal disease. Two studies looking at the presence of H. pylori antibodies in critically ill patients with stressrelated bleeding have reported an increased incidence of bleeding in patients who were antibody-positive as compared with those who were antibody negative.23,24 Supporting the possible pathogenic role of H. pylori in stress gastritis is the finding of an increased prevalence of H. pylori seropositivity in ICU patients as compared with community controls.25 In this study, intensive care unit nurses also had an increased prevalence of H. pylori infection compared with controls, and nosocomial transmission was postulated as a possible explanation for the high prevalence of H. pylori in ICU patients. There are, however, studies that contradict the findings of these studies and which suggest that there is no correlation between H. pylori and stress-related mucosal disease. In a study comparing the prevalence of H. pylori in patients with clinically significant stress-related bleeding and matched critically ill controls, there was no increased prevalence of H. pylori in the bleeding patients.26 In a study which looked at the prevalence of H. pylori as measured by breath testing, there was a low incidence of H. pylori positivity, possibly due to suppression used by routine use of antibiotics for gut decontamination.27

Practice point † at present there are no prospective data which demonstrate a causal role for H. pylori in stress-related mucosal disease and therefore no indication for routine eradication of H. pylori in these patients

Drugs Acetyl salicyclic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs). By inhibiting prostaglandins, these medications impair host defence and render the mucosa susceptible to injury. They are associated with an increased incidence of gastric and duodenal ulceration.28 Corticosteroids. Many critically ill patients receive systemic corticosteroids for a variety of reasons. Studies have demonstrated that corticosteroids do not appear to be independently associated with an increased risk of gastroduodenal ulceration but, in combination with NSAIDs, increase the risk of NSAIDs in a synergistic fashion.29 There is no evidence that NSAIDs increase the susceptibility of critically ill patients to stressrelated gastrointestinal damage.

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Practice point † stress-related mucosal disease results from a complex interaction of mucosal injury and cytoprotection (see Table 1). Mucosal ischaemia and reperfusion injury have a central role in the pathogenesis of mucosal injury, allowing acid and pepsin to injure the mucosa diffusely. Acid and pepsin enhance clot lysis and inhibit platelet formation, predisposing the injured mucosa to haemorrhage

Research agenda † the role of Helicobacter pylori in stress-related mucosal disease is unknown and requires further investigation PATHOLOGY The initial lesions are shallow, diffuse erosions that occur in the body and fundus of the stomach, areas of oxyntic gastric mucosa. In more advanced states, the antrum and duodenum may be involved. The lesions tend to be multiple and shallow, not penetrating the muscularis mucosa.10

EPIDEMIOLOGY The prevalence of stress-related mucosal disease in critically ill patients depends to a large extent on the definitions used and on the use of prophylactic medications. When endoscopic studies have looked at the prevalence of mucosal injury there is an incidence of 75 – 100%, with the development of mucosal damage occurring within hours of the ‘injury’.1,4,30 When occult bleeding is used as an endpoint, the prevalence ranges from 15 to 50%. Clinically overt bleeding, as previously defined, occurs in approximately 5% of critically ill patients.5 Clinically significant bleeding is much less common. In a multicentre Canadian study, in which the majority of patients received prophylaxis31, the prevalence of clinically significant bleeding was 3.5%. Other studies have demonstrated an even lower incidence of clinically significant bleeding, ranging from 0.17 to 1.5%.32,33 Table 1. Pathophysiology of stress-related bleeding. Mucosal defence factors

Aggressive factors

Major importance

Impaired mucosal blood flow

Acid Pepsin Intramucosal acidosis Reperfusion injury Free radical formation

Unknown significance

Disruption in tight junctions Impaired epithelial cell restitution and regeneration

Helicobacter pylori Bile acids

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In general, the prevalence of stress-related mucosal bleeding appears to be decreasing.14,34 This is probably related, in part, to better overall ICU care with attention to optimizing haemodynamics and tissue oxygenation, identification of the high-risk patient, and use of appropriate prophylactic therapy.35 Two other treatments that are widely used in intensive care units – enteral feeding36 and use of vasodilator medications37,38 – may have beneficial effects on stress-related mucosal disease.

Practice point † clinically significant stress-related mucosal bleeding is uncommon in centres using prophylactic therapy and seems to be decreasing

CLINICAL SIGNIFICANCE OF STRESS-RELATED MUCOSAL DISEASE Despite advances in the management of critically ill patients and in prophylaxis therapy for stress-related mucosal bleeding, clinically important gastrointestinal bleeding still occurs. In a recent analysis of patients enrolled in a multicentre study there was an increased mortality rate (RR of 1.8 – 4.1) and an ICU stay that was increased 4 – 8 days in patients with clinically significant stress-related bleeding as compared with non-bleeding patients.31 Therefore, despite the relatively low prevalence of this problem in critically ill patients, optimizing prophylaxis and management is important to the overall care of these patients. Practice point † stress-related bleeding is associated with an increased morbidity and mortality; therefore, optimizing prevention is important RISK FACTORS A heterogeneous group of patients with different underlying medical conditions and morbidities are admitted to critical care units. Prophylaxis against bleeding may be associated with side-effects and complications, and administration to all patients may not be cost effective. For this reason many investigators have examined populations of critically ill patients to determine risk factors for stress-related gastrointestinal mucosal damage and bleeding. Cook et al33 conducted a prospective multicentre study evaluating possible risk factors for clinically important stress-related bleeding in patients admitted to intensive care units. The two strong independent risk factors associated with bleeding were respiratory failure (OR 15.6) and coagulopathy (OR 4.3) as defined by a platelet count , 50 000 per cubic millimetre, an International Normalized Ratio of . 1.5 or a partial thromboplastin time . 2.0 times the control value. In patients without these two risk factors, the incidence of clinically significant bleeding was 0.1% whereas the incidence was 3.7% in those patients with one or both of the risk factors. A number of other factors have been associated with an increased risk of stressrelated mucosal disease. Risk factors for stress-related mucosal bleeding8,10,35,61,68 are

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listed below: † † † † † † † † † † †

Prolonged mechanical ventilation (. 48 hours) Coagulopathy Shock Severe sepsis CNS injury/surgery Severe burns (. 30%) Multiple organ failure Renal failure Hepatic failure Multiple trauma Post organ transplant

The accumulation of multiple risk factors increases the risk of stress-related bleeding. Practice point † the most important risk factors for stress-related bleeding are prolonged mechanical ventilation and coagulopathy

PROPHYLAXIS Based on the discussion on pathophysiology of stress-related mucosal disease, it is clear that ischaemia is central to the pathogenesis of the mucosal abnormalities and that acid is an important factor in inducing and perpetuating injury. There is an inverse relationship between the intramural pH in the stomach and the probability of massive stress-related bleeding.39 The goal of acid-neutralizing therapy is to maintain a pH . 4. Most of the studies examining the prevention of stress-related bleeding have assessed the effectiveness of acid-reducing therapies. Other agents may be effective in enhancing mucosal protection. The agents utilized in preventing stress-related mucosal bleeding are summarized below.

Antacids These were first evaluated in 197640 and randomized controlled trials have demonstrated efficacy in preventing clinically significant stress-related bleeding.8 Antacids directly neutralize luminal gastric acid but also bind pepsin and bile acids35 and may stimulate prostaglandin release from the mucosa.41 Antacids are usually administered every 1 –2 hours in 30– 60 ml aliquots. This frequency of administration is one of the disadvantages of this therapy. In addition, aluminium-containing antacids may be associated with hypophosphataemia and toxic aluminium levels in renal failure patients, while magnesium-containing antacids may be associated with diarrhoea and hypermagnesaemia. Antacids may also impair the absorption of other medications, including antibiotics.

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Histamine-2-receptor antagonists Histamine-2-receptor antagonists (H2RAs) inhibit acid production by binding to the histamine-2 receptor on the basement membrane of the parietal cell. These medications can be administered parenterally, and available H2RAs include cimetidine, ranitidine, nizatidine and famotidine. The most frequent method of administration is bolus intravenous administration, although continuous infusions may be more effective in suppressing gastric acid.42 In general, these medications are well tolerated. Side-effects include CNS toxicity manifest by confusion and hallucinations, particularly in the elderly and in patients with renal and liver failure. Bronchoconstriction may occur in patients with obstructive lung disease. One of the properties of H2RAs which limits their effectiveness is the development of tolerance which occurs within 72 hours after administration.43 H2RAs have also been associated with adverse chronotropic and inotropic effects and, experimentally, may induce a dosedependent coronary vasoconstriction.35 The clinical significance of these effects is unclear. Cimetidine and ranitidine inhibit the clearance of drugs by affecting the cytochrome P450 system, an effect that is not seen with the other two clinically available H2RAs. Several meta-analyses have shown that H2RAs are effective in decreasing stressrelated mucosal damage and bleeding.12,35,44 If the endpoint is clinically important bleeding, the RR with H2RAs is 0.44 (95% CI 0.21 – 0.88).35 There has been concern that, by inhibiting acid, there is bacterial overgrowth in the stomach leading to microaspiration and an increased incidence of nosocomial pneumonia.45 – 47 In a study which randomized 130 patients to receive sucralfate or intravenous H2RAs there was a trend ðP ¼ 0:11Þ toward an increased rate of pneumonia in the acid-suppressed group.48 Numerous other small studies have examined this issue but a meta-analysis did not demonstrate any significant difference in pneumonia rates between sucralfate and H2RAs. In an attempt to answer this question definitively, a large multicentre randomized study compared sucralfate and ranitidine in patients with patients requiring mechanical ventilation.6 In this study of 1200 patients, there was a decreased incidence of bleeding in the ranitidine group (RR 0.44 95% CI 0.21 – 0.93) as compared to the sucralfate group, and no difference in the incidence of nosocomial pneumonia (RR 1.18 95% CI 0.92 –1.51). There is no evidence that prophylactic use of H2RAs is associated with a decrease in mortality.12 When H2RAs and antacids are compared with sucralfate, there is a significant decrease in mortality in the sucralfate group.35 This was most pronounced in long-term mechanically ventilated patients. Tryba and Cook35 suggested that this may be due to a beneficial effect of sucralfate on intestinal permeability and thus prevent bacterial translocation and multiple organ failure. This hypothesis has not been proven.

Practice points † H2RAs are effective in preventing clinically significant stress-related bleeding and do not appear to increase the risk of nosocomial pneumonia † there is no evidence that prophylactic use of H2RAs decreases mortality in critically ill patients

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Proton pump inhibitors Proton pump inhibitors (PPIs) are substituted benzimidazoles which irreversibly bind the hydrogen potassium (Hþ/Kþ) ATPase, the enzyme responsible for secreting acid into the gastric lumen.49 PPIs are prodrugs that are initially absorbed and then diffuse into the canaliculi of the gastric parietal cells through the basolateral membrane where they are converted into their active form. In this form, they covalently bind the Hþ/Kþ ATPase which is continually synthesized in the cytosol of the cell and is activated when it inserts into the canalicular membrane. Proton pumps are re-synthesized every 36 –48 hours and therefore inhibitors are usually administered once daily. Because PPIs affect the final common pathway of acid secretion, they are more potent suppressors of acid than the H2 receptor antagonists. Currently available PPIs include omeprazole, lanzoprazole, pantoprazole, rabeprazole and esomeprazole. Omeprazole inhibits the cytochrome P450 system and therefore may affect the elimination of certain drugs. Recently, an intravenous formulation of PPI, pantoprazole, has become available in North America.50 In the management of high-risk duodenal and gastric ulcers, PPIs have been effective in reducing bleeding rates.49 This has never been demonstrated with H2 receptor antagonists. Therefore there is reason to believe that these medications may be more efficacious in preventing stress-related mucosal bleeding as well. There are several small studies examining the role of PPIs in preventing stressrelated mucosal disease in critically ill patients.51 – 53 These studies have utilized nasogastric administration of omeprazole, in two of the studies supplied as a simplified suspension of omeprazole dissolved in sodium bicarbonate. In two of the studies there was no clinically significant bleeding in the omeprazole group51,52, while in the third study the bleeding rate was 6%.53 These studies also demonstrate the ability of this PPI to maintain a pH . 5.5 for several days. Extrapolation from the first two studies is limited, given that they lack a comparison group, have a small sample size and are on open-label design. The third study has limitations in that it, too, has a small sample and the bleeding rate of the H2RA group is significantly higher than historical controls. All of the current studies of PPI therapy in stress-related disease have been with oral medications. The administration of PPIs by nasogastric tube is associated with certain difficulties. The drug must be dissolved in sodium bicarbonate to protect the drug from gastric acid. Critically ill patients may have delayed gastric emptying and therefore bioavailability may be limited. Preparation is time consuming and administration may clog small-bore feeding tubes.54 In studies using intravenous omeprazole, a continuous infusion was able to maintain pH . 6 for 24 hours whereas bolus infusion maintained this for 12 hours.55 Thus far there are no published clinical trials of intravenous PPIs in stress prophylaxis.

Research agenda † currently there are no large randomized studies that demonstrate superiority of PPIs over other therapies in preventing stress-related mucosal bleeding. Clinical studies are needed to determine potential benefits, optimal administration route and cost effectiveness

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Sucralfate Sucralfate is a basic non-absorbable aluminium salt of sucrose octasulphate.35 Its mechanism of protection against stress-related mucosal damage is multifactorial: sucralfate forms a protective barrier on the surface gastric epithelium, stimulates mucous and bicarbonate secretion, stimulates epidermal growth factor and epithelial renewal, improves mucosal blood flow, and enhances prostaglandin release.8 It also improves the quality of mucous but does not decrease the pH of the gastric lumen. Sucralfate is administered as a nasogastric slurry and must be given every 4 –6 hours. In some institutions, it is given at a dosage of 3 grams three times daily although studies have used 1 gram four times daily.6,56 Sucralfate is generally well tolerated but may cause constipation, and aluminium toxicity may occur in patients with renal failure. Sucralfate is effective in decreasing stress-related bleeding compared with placebo and also, in meta-analyses, is associated with a decreased mortality35 (see section on H2RAs). However, sucralfate appears to be less effective than H2RAs in decreasing clinically significant bleeding.6

Practice point † sucralfate is effective in decreasing stress related mucosal bleeding and is also associated with a decreased mortality

Prostaglandin analogues Prostaglandins are important cytoprotective agents that could have a role for the prevention of stress-related mucosal disease. The synthetic prostaglandin E1 analogue, misoprostol, is available as an oral agent and has demonstrated effectiveness in preventing NSAID-related gastric injury and complications.29 In addition to its cytoprotective effects, at high doses misoprostol may induce acid suppression. In a prospective study comparing antacids with misoprostol 200 mg every 4 hours there was no clinically evident gastrointestinal bleeding in either group; there was a 25% incidence of diarrhoea in the misoprostol group.57 There have been limited studies on the use of prostaglandin analogues in stress-related bleeding, due probably to cost and diarrhoeal side-effects.

Practice point † currently there is no role for the prophylactic use of prostaglandin analogues in the prevention of stress-related mucosal disease

Enteral nutrition Enteral feeding may have beneficial effects in decreasing stress-related mucosal disease. As acid injury may potentiate mucosal ischaemic changes, enteral nutrition could potentially decrease stress ulceration by raising intragastric pH.

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There have been no randomized controlled studies examining the effectiveness of enteral feeding in preventing stress related mucosal bleeding. There are several studies that have associated enteral feeding with a lower incidence of stress-related bleeding. In studies of mechanically ventilated patients58 and burn patients59,60, enteral feeding has been associated with less bleeding. In a regression analysis, Cook et al61 demonstrated that enteral feeding was associated with a significantly lower bleeding rate in 1077 critically ill patients. Other studies in critically ill patients, however, have demonstrated that enteral feeding does not have a significant effect on increasing gastric pH and therefore may be ineffective in affording gastroprotection.62,63 Research agenda † randomized trials are needed to determine the effectiveness of enteral feeding in patients in preventing stress-related mucosal bleeding

Summary of prevention of stress-related mucosal bleeding (see Table 2) The two agents most commonly used in primary prevention of stress-related mucosal bleeding are intravenous H2RAs and sucralfate. Based on the above discussion, H2RAs appear to be more effective in preventing stress-related mucosal bleeding and are not associated with a significantly increased risk of pneumonia, but sucralfate is associated with a decreased mortality. Because of associated sideeffects and costs, prophylaxis should be used judiciously in high-risk individuals. A proposed algorithm for approaching prophylaxis in critically ill patients is outlined in Figure 1.

CLINICAL PRACTICE GUIDELINES FOR STRESS PROPHYLAXIS Since the late 1970s there has been considerable interest in stress-related mucosal damage and ways of preventing the significant bleeding associated with it. Many studies have been small or have demonstrated conflicting results, and thus there is a significant spectrum of clinical practice related to primary prevention. The two major issues to

Table 2. Summary of prevention of stress-related mucosal bleeding in studies comparing active agent with placebo. Agent

Decreased overt clinical bleeding

Decreased clinically important bleeding

Antacids H2 receptor antagonists Sucralfate Prostaglandin analogues Proton pump inhibitors

2a þ 2a Insufficient data Insufficient data

2a þ Insufficient datab Insufficient data Insufficient data

a b

Trends towards decreased bleeding but 95% CI . 1. Only one study comparing sucralfate with placebo. In comparison with H2RAs, similar efficacy.

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Identify the high-risk patient Mechanical ventilation > 48 hours Platelet < 50000 mm3 INR > 1.5 PTT> 2x normal Shock severe sepsis CNS injury / surgery Severe burns (>30%) Renal failure Hepatic failure Multiple trauma Post organ transplant Yes No

No prophylaxis

Access to stomach

Yes

No

Sucralfate

Ranitidine

1 gram NG q6h

50 mg IV q8h

If indication for prophylaxis resolved, stop prophylaxis If gastric feeding initiated and tolerated, consider stopping prophylaxis Figure 1. Prevention of stress-related mucosal disease in high-risk patients.

consider are the appropriate patient population for administering prophylaxis and the optimal prevention regime. Recently, several authors have developed clinical practice guidelines based on reviews of the literature.64,65 In each of these studies the investigators compared the practice of stress-related prophylaxis before and after

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the implementation of the clinical practice guideline. In a Canadian study, there was an increase in appropriate use of prophylaxis from 75.8 to 91.1% and an almost 50% reduction in medication-related costs after implementation of the clinical practice guideline.65 In an American study, the use of prophylaxis decreased by 17%, and no patient developed significant gastrointestinal bleeding.64 There was significant economic saving with the introduction of the clinical practice guideline.

Practice point † clinical practice guidelines may result in more cost effective and appropriate use of stress-related prophylactic therapy TREATMENT OF STRESS-RELATED MUCOSAL BLEEDING The mainstay of the clinical management of stress-related mucosal bleeding is prevention. Studies have demonstrated that the incidence of clinically significant bleeding is very low in the setting of prophylaxis.32,34 In situations where stress-related mucosal bleeding occurs despite prophylaxis the following approach is recommended: † General supportive measures, including aggressive volume resuscitation and optimizing tissue oxygenation. † Urgent endoscopy. This is required to establish the diagnosis and exclude other potential causes of bleeding such as erosive oesophagitis, Mallory – Weiss tear, oesophageal or gastric varices, peptic ulcer disease, or arteriovenous malformations. These causes of GI bleeding may be amenable to therapeutic endoscopy, which has been associated with a decrease in bleeding, need for surgery and mortality. † If the endoscopic findings are consistent with stress-related mucosal disease, further therapy is largely empiric. There are no randomized clinical trials comparing the optimal treatment method of active stress-related mucosal bleeding. In the absence of any randomized controlled studies, the following approach is recommended. † Empiric therapy with a PPI. This benefits high-risk patients with peptic ulcer disease and is associated with minimal morbidity.50 In patients who have already been treated with an H2RA or sucralfate, it would appear reasonable to attempt to control bleeding with a PPI. If available, an intravenous PPI would be recommended. † Empiric therapy with somatostatin. Somatostatin has benefit in treating individuals with portal hypertension but has no demonstrated benefit in individuals with nonvariceal bleeding. There are case reports of its use in treating gastric erosions66 and, given its good safety profile, it could be considered if bleeding persists despite intravenous PPI therapy. † Angiography. In patients with persistent bleeding, despite empiric medical therapy with a PPI and/or somatostatin, angiography should be attempted. Significant bleeding may be controlled with intra-arterial embolization.67 The morbidities with angiography are fewer than those with surgery. † Surgery. The vast majority of bleeding related to stress-induced mucosal disease will resolve with supportive therapy and acid inhibition. In patients who are refractory to this therapy and in whom angiography does not control the bleeding, surgery is required. The optimal surgical procedure needs to be individualized and options

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include a vagotomy and pyloroplasty, subtotal gastrectomy or total gastrectomy. Indications for surgical management include a transfusion requirement of . 8 units in 24 hours or persistent bleeding despite medical therapy and angiography.8

Practice point † there are no clinical studies to dictate management in situations where stressrelated mucosal bleeding occurs despite prophylaxis. Given the low morbidity and benefits in peptic-ulcer-related bleeding with PPI therapy, this should be considered as initial therapy

SUMMARY Stress-related mucosal damage is frequent in critically ill patients. Clinically significant stress-related gastrointestinal bleeding is uncommon in patients receiving adequate prophylactic therapy. The pathophysiology of stress-related mucosal damage is multifactorial, with mucosal ischaemia and gastric acid important pathogenic factors. Currently, there is no direct evidence to support a significant role for Helicobacter pylori in the pathogenesis of stress-related mucosal disease. Prolonged mechanical ventilation and coagulopathy are the two major risk factors for stress-related mucosal bleeding. Additional risk factors include shock, severe sepsis, CNS injury/surgery, severe burns (. 30%), multiple organ failure, renal failure, hepatic failure, multiple trauma, and post organ transplant. Patients at high risk should be given prophylaxis with intravenous infusions of histamine-2-receptor antagonists or intragastric sucralfate. There does not appear to be an increased risk of pneumonia in patients receiving acid-suppression therapy with H2 receptor antagonists. Clinical studies are required before recommending the use of proton pump inhibitors for prophylaxis. The role of enteral feeding in preventing stress-related mucosal bleeding requires further clinical investigation. Prevention of stress-related mucosal bleeding is important as it has been associated with an increased morbidity and mortality.

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