Prevention of Stress Ulcer Bleeding: A Review W. P. GEUS & C. B. H. W. LAMERS Dept. of Intensive Care, Leyenburg Hospital, The Hague, and Dept. of Gastroenterology, University Hospital, Leiden, The Netherlands
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Geus WP, Lamers CBHW. Prevention of stress ulcer bleeding: a review. Scand J Gastroenterol 1990, 25(suppl 178). 32-41 The pathophysiology of stress ulcers is complex. There is either too much acid and pepsin or inadequate mucosal defenses. The incidence of upper GI bleeding due to stress ulcers in the ICU is 5-25% depending upon the minimum criterion of bleeding. For the individual patient the risk of bleeding is determined by his underlying condition and the number of risk factors. SAPS and APACHE I1 may assist in identifying those patients. Attainment of an increase in intragastricpH is effective and frequently necessary to prevent stress ulcer bleeding and reduces the incidence of overt bleeding. Based on presently available information the most suitable regime for prevention of stress ulcer bleeding is a continuous infusion or fixed bolus dosing of cimetidine or ranitidine. With respect to the side effects, ranitidine appears to be the more favorable of these two H? blockers. The position of sucralfate in the prophylaxis has not yet been established. Key words: Antacids; bacterial overgrowth; bleeding criterion; cimetidine; critically ill; ranitidine; risk factors; septicemia; stress ulcers; sucralfate
W. P. Geus, M . D . , Depi. of Intensive Care, Leyenburg Hospital, Leyweg 275, P.O. Box 40551. 2504 LN The Hague, The Netherlands
In association with stress critically ill patients admitted to an intensive care unit (ICU) may develop erosive lesions of the upper gut (1). Stress can be a result of a traumatic injury, a lifethreatening illness. a prolonged surgical procedure, shock, septicemia, or a postoperative complication such as pulmonary, hepatic, or renal failure. The lesions differ from peptic ulcers of non-stressed individuals. The lesions are multiple and located primarily in the gastric fundus and body, the acid-producing areas of the stomach. The most reliable and sensitive method to diagnose stress lesions is endoscopy. When endoscopy is employed, stress lesions are found to develop in 60% to 100% of the patients shortly after admission to an intensive care unit ( 2 4 ) . The first endoscopic abnormalities are submucosal petechiae and hemorrhage, followed by erosions and superficial ulcers. Initially, the damage is usually confined to the gastric fundus and body, but with progression it can involve the antrum, duodenum, and the distal esophagus. The lesions are often superficial and tend to ooze
blood rather than bleed massively. However, deeper lesions can develop, for instance, in patients with septicemia or with central nervous system disorders. These deeper lesions can bleed massively and, on occasion, perforate. Massive gastrointestinal bleeding, although relatively rare, can result in a mortality rate of up to 80% ( 5 ) . Much confusion exists as to the nomenclature of these stress-related lesions. Several names have been used interchangeably, such as, stress ulcer, hemorrhagic gastritis, stress gastritis, stress erosion, diffuse mucosal injury, and erosive gastritis. Recently, Peura (5) introduced terms as stress-related mucosal damage, and Thompson & Cloud (6) stress-associated gut (gastric) erosions. In sum, these terms describe the multifocal self-digestion of the gastric mucosa that occurs concomittantly with many life-threatening conditions (7). The literature dealing with the prophylaxis of stress ulcerations is scattered. Several misconceptions obscure the risk of stress ulcer bleeding
Prevention of Stress Ulcer Bleeding
and the effect of acid-reducing prophylaxis. This review describes the pathophysiology of stressrelated mucosal lesions, defines the risk of stress ulcer bleeding and the criteria of stress ulcer bleeding, and compares the efficacy of drugs generally used in the prevention of stress ulcer bleeding.
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PATHOPHYSIOLOGY The pathophysiology of stress-related lesions is not well understood. It is appropriate to think of an imbalance between aggressive and defensive mucosal factors. Aggressive factors comprise gastric acid and reflux of bile into the stomach, while defensive factors comprise mucosal permeability, mucosal blood flow, gastric mucus, prostaglandins, and epithelial cell renewal. Gastric acid Gastric acid in the stomach has been shown to be a prerequisite for the development of mucosal damage (8, 9). Schwartz’s adagium ‘no acid, no ulcer’ remains a central theme in the various theories of pathogenesis. In 36 stressed patients Robbins et al. (10) demonstrated significantly higher acid values than in a control group of 19 normal individuals. Pepsin concentrations in the stressed group were higher than in the control group. Increased acidity of gastric juice has also been observed in some patients with head injuries (11) or sepsis. Histamine release during sepsis may increase gastric acid secretion. Martin et al. (12) have clearly demonstrated that antacids and cimetidine fail to control the gastric pH during sepsis. Bile reflux Bile reflux into the stomach has been shown to be more common among critically ill patients, especially in the postoperative condition, than in the healthy population (13). Also experimentally, bile reflux has been proved to play a role in the formation of mucosal injury in shock models. A study in dog stomachs demonstrated that neither ischemia nor bile were ulcerogenic in the presence of acid, but the combination of these factors produced severe mucosal lesions (14).
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Mucosal permeability The gastric mucosal barrier is the ability of the gastric epithelium to maintain a hydrogen ion gradient between the lumen and tissue. Disruption of this barrier may result from various compounds, such as bile salts, urea, aspirin, or alcohol, when these agents are applied topically to the gastric epithelium. The result of disruption of the gastric mucosal barrier is a change in mucosal permeability. In this condition hydrogen ions diffuse back into the mucosa. A reduction in the transmucosal potential difference occurs, indicating that normal electrochemical gradients between the mucosa and gastric lumen have been deranged. Unrestricted back-diffusion of hydrogen ions leads to direct damage of the gastric mucosa (15). Mucosal blood flow Animal studies have demonstrated that stress causes a rapid reduction in gastric mucosal blood flow with resulting mucosal ischemia (9). Ischemia brings about a defect in mucosal A T P concentrations, while it also increases back-diffusion of hydrogen ions into the mucosa and impairs the mucosal defensive mechanism (16). Lactic acid accumulates during localized hypoxia due to decreased gastric blood flow. The development of massive bleeding from stress-related mucosal damage is highly correlated with intramural acidosis (17). Gastric mucus The gastric epithelium is normally covered by a thin layer of mucus gel. This gel, consisting of a matrix of glycoprotein acts as an unstirred layer that resists proton diffusion. The role of this mucus barrier in stress-related mucosal damage remains ill-defined. Robert & Kauffman (18) found a reduction in the hexosamine content (a major component of gastric mucus) of the gastric juice and the gastric mucosa of fasting animals prior to development of experimental ulcers. They also showed that corticosteroids decrease the hexosamine contents of the gastric mucosa. These findings suggest that the fasted state and a physiologic response to stress (increased levels of circulating corticosteroids) in most critically
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W.P. Geus & C. B. H . W . Lamers
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ill or traumatized patients could play a contributory role in the development of mucosal damage.
They demonstrated also a close relation between the risk of bleeding and the severity of illness. In a prospective study Schuster et al. (24) found in 14% of 174 medical ICU patients (179 admisProstaglandins sions), without prophylactic therapy, evidence for The role of prostaglandins is unclear. High either occult or overt gastrointestinal bleeding. In concentrations of the prostaglandins PGEz and 6Yo of the patients they found overt bleeding. PGIz are present in the gastric mucosa. These However, the mortality rate was 90% among the prostaglandins increase gastric mucosal blood patients with overt bleeding, and 30% of the flow, and stimulate secretion of mucus and bi- deaths were directly related to bleeding. In none carbonate (16). Prostaglandins also induce a de- of these two studies was the cause of occult crease of gastric acid secretion (15). These effects bleeding endoscopically verified. are dose dependent. Prostaglandins protect the Hastings et al. (25) observed gastrointestinal mucosa of the stomach against the damaging bleeding in 4% of 51 critically ill patients given effects of agents like indomethacin, aspirin, and antacids hourly (titration) to maintain the pH of alcohol (19, 20). Van Essen et al. (21) demon- the gastric contents above 3.5. In the control strated that PGEz did not exert a beneficial effect group of 49 critically ill patients 24% bled. in the prevention of stress ulcerations. Analysisof all the patients showed that an increasing prevalence of respiratory failure, septicemia, Epithelial cell renewal peritonitis, jaundice, renal failure, and hypotenExperimentally, it has been shown that during sion was correlated with a greater frequency of stress the gastric mucosa has a decreased rate of bleeding. cellular proliferation and deoxyribonucleic acid In 17'/0 of 433 cases of head injury Kamada et synthesis (22). Agents such as pentagastrin, al. (26) found gastrointestinal bleeding. A close growth hormone, and epidermal growth factor. relationship was seen between the frequency of which stimulate protein and deoxyribonucleic bleeding and the severity of injury. Bleeding was acid synthesis and cell division, may prevent diagnosed by the presence of blood in aspirated mucosal damage in animals. Fasting decreases gastric juice, by hematemesis or melena, or by deoxyribonucleic acid, ribonucleic acid, and pro- direct observation of blood loss from the stomach tein synthesis in the gastric epithelium (18, 22). by endoscopy. Inhibition of cell division and proliferation imShuman et al. (27) reviewed all trials of propairing the ability to replace extruded cells may phylactic therapy with cimetidine published from contribute to the development of stress injury. 1976 to 1985, in which there was a control arm consisting of placebo or no therapy. Variation in study design, in particular the definition of bleedINCIDENCE OF BLEEDING AND RISK ing and its measurement, makes comparison of FACT0 R S the various trials difficult. In these studies the The incidence of endoscopically verified stress- incidence of occult bleeding in the control patients related lesions in patients admitted to an intensive ( N = 187) was 27%, while the incidence of overt care unit is 6(LlOO% ( 2 4 ) . However, clinically it bleeding in these control patients ( n = 720) was is of utmost importance to know how many of 15%. these patients do actually bleed as a result of The detection of occult bleeding with guaiac stress-related mucosal damage. reagent (Hemoccult) may give both false-positive Zinner et al. (23) reported an incidence of and false-negative reactions. Layne et al. (28) bleeding of 20% in a group of 100 ICU patients found that gastric juice that was neutralized with who received no prophylactic therapy. Occult commercial antacids was less sensitive to blood blood detection (positive guaiac test) was used as detection by guaiac reagent than gastric juice minimum criterion for gastrointestinal bleeding. obtained from patients given intraveneus cimeti-
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Prevention of Stress Ulcer Bleeding
dine. The authors concluded that the finding of more occult bleeding in cimetidine-treated versus antacid-treated critically ill patients may be directly related to the method of blood detection rather than occurrence of bleeding per se. Long et al. (20) showed false-negative results with the Hemoccult slide test when the pH of the gastric juice was below 2 and false-positive results when the pH of the gastric juice was between 2 to 4. Derrida et al. (30) studied the risk of occult gastrointestinal bleeding in patients at high risk of stress ulcerations. Criteria for inclusion in the study were: a ) sepsis associated with one or more organ failures; b) presence of two or more organ failures; and c) major operative procedure and/or multiple trauma. The simplified acute physiology score (SAPS (31, 32)) within the first 24h after admission to the ICU in this group was 14.7 f 5.2 (SD). indicating that these patients were indeed severely ill. In this study Derrida et al. found occult bleeding in 1 1 of 41 patients (27%,).The cause of bleeding was endoscopically verified, and in 8 patients of the 11 (72%) acute stress lesions were found. In the other three patients the cause of bleeding was trauma induced by the nasogastric tube, benign gastric tumor, and esophageal varices. Occult bleeding was followed by overt gastrointestinal bleeding in 4 of the 1 1 patients. Occult bleeding was tested with Gastroccult. This reagent can detect occult blood in gastric juice independent of the pH (33). The authors also established a clear relationship between the incidence of bleeding and the number of 'risk factors'. Risk factors Hastings et al. (25) and Priebe et al. (34) identified a number of risk factors that increase the likelihood of bleeding from stress ulceration. Risk factors comprise sepsis, peritonitis, respiratory failure, head injury, multiple trauma, severe burn injuries, severe hepatic dysfunction or failure, hypotension, renal failure, and major operative procedures (7,25,35). It is now generally agreed that these factors are the most important determinants of bleeding (1,7, 17,23,30, 35). The differences in the reported prevalence of bleeding from stress lesions in various reports are most likely due to the number of risk factors for
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bleeding of the patients including in the various studies or scatter in the criterion of bleeding. The extent to which a single risk factor determines the pathogenesis of stress-related mucosal damage is unknown. The probability of stress ulcer bleeding clearly rises as the number of risk factors increases (25, 34). The presence or absence of sepsis appears to be an all-important determinant of clinically significant stress ulceration (35). Conclusions The incidence of upper gastrointestinal bleeding a s a result of stress-related mucosal damage in patients admitted to an ICU is 5-25%, depending on the minimum criterion of gastrointestinal bleeding (minimum criterion overt bleeding, 5 % ; minimum criterion occult bleeding, 25%). Scores of disease severity, such as SAPS and APACHE 11. may assist in identifying those patients who are at high risk for bleeding from stress ulcers. For the individual patient the risk of bleeding is determined by his underlying condition and the number of risk factors.
PREVENTION OF STRESS ULCER BLEEDING The first step in the prevention of stress erosions is active general support and therapeutic measures aimed to control the primary disease process in each critically ill patient. Rapid restoration of physiological homeostasis should limit the injury to the gastric mucosa (36). Shoemaker et al. (37) demonstrated in a clinical study that aggressive shock treatment considerably reduced the incidence of stress bleeding. According to Zuckerman & Shuman (38) the concept of prophylactic therapy for prevention of stress ulcer bleeding is based on three premisses: 1 ) the morbidity and mortality related to stress ulcer syndrome are significant; 2 ) the population at risk for stress ulcer syndrome can be identified prior to bleeding or perforation; and 3) prophylactic treatment that decreases gastric acidity or improves gastric mucosal defense mechanisms will prevent ulcer formation or progression of ulceration to bleeding or perforation.
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The rationale for prophylaxis with antacids or H2-receptor antagonist is based on a considerable number of published reports that have clearly demonstrated the efficacy of gastric acid neutralization with topical antacids and H2-receptor antagonists in the prevention of stress ulcer bleeding (39). Furthermore, pepsinogen is not converted in pepsin in gastric juice of a pH above 4. Besides antacids or H2-receptor antagonists, sucralfate acting as a mucosal protective agent can be used. Although the exact mechanismsof action of sucralfate are unknown, it has been established that sucralfate does not neutralize gastric acid or inhibit its secretion. It is difficult to compare the efficacy of prophylactic regimes for stress ulcer bleeding, since various definitions of bleeding, various gastric pH goals, and different dosage regimes have been used. Additionally, heterogeneous groups of critically ill patients (difference in SAPS) have been studied. Overt bleeding, as measured by hematemesis, melena, or bleeding requiring transfusion, is the best clinical indication of treatment failure because overt bleeding is associated with an increase in the ICU mortality rate (24). Cimetidine and antacids Prophylactic therapy with cimetidine or antacids did not show any drop in the incidence of mucosal lesions found soon after admission to the intensive care unit (3, 4042). Only one study indicated that cimetidine might diminish the number of gastric mucosal lesions found at a later time during the patient's ICU stay (3). It is therefore possible that cimetidine prevents the progression of early mucosal lesions to more severe forms and inhibits the onset or progression to clinically significant bleeding (3). In the above-mentioned review Shumann et al. (27) showed that when overt bleeding was used as the minimum criterion, there was no significant difference between antacids and cimetidine in the prevention of overt bleeding (3.3% of 458 as compared with 2.7% of 402 patients, respectively). Both agents were more effective than placebo (15% of 720 patients) in the prevention of overt bleeding. Lacroix et al. (43) performed a meta-analysis of 15 randomized studies on the
prophylaxis with cimetidine and/or antacids of upper gastrointestinal bleeding acquired in the ICU. In this meta-analysis the authors demonstrated that there is no firm justification to choose antacids over cimetidine to prevent upper gastrointestinal bleeding. The results of this metaanalysis also suggest that both cimetidine and antacids are effective in preventing upper gastrointestinal bleeding, although many studies were not well designed, and a file drawer problem was possible. Antacids In many studies antacids were given hourly (25) or every 2h (23). Doses of standard-strength antacids varied from 20 to 160ml/h (6). Gastric pH was usually monitored for a minimal of 2 h in aspirated gastric juice (36). The degree of acid suppression varied with the dosage regimen employed. Hourly antacid therapy with pH titration was usually compared with acid suppression by H2-receptor antagonists (44). Hourly antacid therapy and cimetidine were equally effective in the prevention of upper gastrointestinal bleeding (27, 43). The difficulties of hourly administration of antacids via a nasogastric tube in ICU patients and the increased nursing time requirements have made the intravenously administration of HZreceptor antagonists an attractive alternative. Ranitidine and antacids In a randomized trial of gastric pH control for stress ulcer prophylaxis Noseworthy et al. (45) compared ranitidine and antacids in 86 patients admitted to an ICU. Gastrointestinal bleeding was reported if melena occurred, if there was an aspirate of bright red blood from the nasogastric tube on two occasions over a 4 h time span, or if there was an unexplained fall in hemoglobin. They concluded that ranitidine given intravenously in a dose of 200mg/day was as effective as antacids in reducing acidity and preventing stress ulcer bleeding in the critically ill. Cimetidine and ranitidine The H2-receptor antagonist ranitidine has been studied to a lesser extent than cimetidine as an agent for prophylaxis of stress ulcer bleeding.
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Prevention of Stress Ulcer Bleeding
Comparing these two agents, Barth et al. (46) found no difference in the efficacy of cimetidine and ranitidine for stress ulcer bleeding prophylaxis in a non-placebo-controlled randomized study of 193 critically ill patients comparing these two agents. Laurie & Code (47) compared the ability of cimetidine and ranitidine to elevate gastric pH values and monitored aspirated gastric juice for occult bleeding. Results from this study comprising 20 patients showed no difference between the prophylactic agents. Siepler et al. (48) found that a constant infusion of cimetidine (1200 mg/day) or of ranitidine (230 mg/day) provided excellent prophylaxis for stress ulcer bleeding in 227 ICU patients on TPN. The two regimens provided similar p H profiles. More et al. (40) compared the effects of intravenous doses of ranitidine and cimetidine in 48 critically ill patients and found a more effective control of the gastricpH with ranitidine than with cimetidine. In agreement with these results Ketterl et al. (50) also found a clear advantage of ranitidine in patients with peritonitis or sepsis. These reports suggest that the efficacy of ranitidine to control gastric pH and to prevent stress ulcer bleeding is similar or superior to that of cimetidine.
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administrations of H2-blockers are needed, ranitidine appears to be the more favorable of the two drugs. Associated with the use of large doses of antacids in the critically ill, a relatively high incidence of side effects, such as diarrhea or constipation and electrolyte disturbances, has been reported (1). Rausch et al. (53) found a significant rise of the serum aluminum concentration following administration of the antacids magaldrate (Riopan@) or aluminium hydroxide (TrigastriIB), in a dose of 10 ml six times a day, in patients with a normal or slightly impaired renal function. Sucralfate
Sucralfate is a non-absorbable aluminum salt of sucrose octasulfate with cytoprotective effects that may be mediated in part by enhanced gastric prostaglandin synthesis (54). The compound produces an ulcer-adhering complex with a proteinaceous exudate at the ulcer site. Sucralfate also absorbs bile salts and inhibits pepsin. It is suggested that a sucralfate albumin film acts as a barrier to the diffusion of hydrogen ions. This barrier effect may possibly be beneficial for stress ulcer prophylaxis. The number of studies and patients reported in the literature dealing with the prevention of stress ulcer bleeding by sucralfate is Side effects The use of H2 blockers and antacids may be small in comparison with studies published on complicated by a number of side effects. Cime- prevention of stress ulcer bleeding with antacids tidine is known t o bind to cytochrome P-450 or H2-receptor antagonists. Borrero et al. (55) randomized 155 patients microsomal enzymes and thus reduces the clearance of drugs metabolized by these enzymes, such admitted to a medical or surgical ICU to receive as metronidazole, diazepam, propanolol, theo- either antacids or sucralfate. The criteria for phylline, phenytoin, labetalol, lidocaine, verap- admission to the study included the presence of amil, and warfarin. In addition, cimetidine has one or more risk factors for gastrointestinal been reported to cause dose-dependent confusion bleeding. Eighty patients received 1gof sucralfate and mental depression, especially in the elderly every 6 h, while 75 patients were given antacids (51). A lower incidence of adverse drug reactions hourly (30 or 60ml) to titrate p H to greater than and mental confusion has been reported with the 3.5. Clinical bleeding (defined as frank blood or use of ranitidine. The binding of ranitidine to the coffee-ground aspirate from the nasogastric tube, cytochrome P-450 system occurs to a much lesser melena, or positive Gastroccult) occurred in three sucralfate and two antacid patients. In all cases the extent than the binding of cimetidine. Coursin et al. (52) reported that a bolus in- bleeding was limited to occult blood in the gastric jection of intraveneus cimetidine in critically ill aspirate. In a study involving 74 ICU patients, 38 patients was followed by moderate hypotension, of whom received sucralfate (1 g every 4 h) and 36 whereas bolus injections of ranitidine did not. patients receiving antacids to maintain the gastric They concluded that if relatively rapid bolus p H above 4, Bresalier e t al. (56) found no
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W.P. Geus & C.B. H.W.Lamers
significant differnce in the incidence of significant upper gastrointestinal bleeding between the two treatment groups. Studying the effect of sucralfate as compared to that of antacids, Tryba (57) found in each treatment group one case of macroscopically visible bleeding in 100 ventilated surgical ICU patients. These three studies suggest that bleeding rates under sucralfate are comparable with antacids. In a study of the antibacterial activity of sucralfate, Tryba & Mantey-Stiers (58) found in vitro inhibition of bacterial growth in human aspirated gastric juice by sucralfate. The question as to whether sucralfate possesses any antibacterial property in gastric juice in vivo is not answered by this laboratory experiment. In fact, Winter & Willatts (59) showed colonization of aspirated gastric juice in 36 of 84 patients despite treatment with sucralfate. In the above-mentioned study of Tryba (57), 100 ventilated surgical ICU patients were randomized to receive either sucralfate or an antacid. Fifty patients received every 4 h 1 g sucralfate, and 50 other patients received every 2 h 10 ml antacid. The gastric pH was determined every 8 h. When patients with primary thoracic trauma or pneumonia were excluded, nosocomial pneumonia developed in significantly fewer patients in the sucralfate group (3 of 29) than in the antacid group (11 of 32). It is remarkable that 90% of the pH determinations in the antacid group were above 4, compared with 54% of the pH samples in the sucralfate group. In studies by Du Moulin et al. (60) high levels of gastric pH were correlated with logarithmic increases in the concentrations of gram-negative bacilli in aspirated gastric juice. Gastric colonization also is affected by age, malnutrition, antibiotics. and disease of the gastrointestinal tract (61). Driks et al. (62) studied the incidence of nosocomial pneumonia in 130 mechanically ventilated patients receiving prophylactic sucralfate, antacids combined with H2 blockers (cimetidine or ranitidine), or H2 blockers alone. They concluded that the incidence of pneumonia in patients on sucralfate was 7 of 61, compared with 16 of 69 patients receiving antacids, H2 blockers, or a combination of antacids and H2 blockers (NS). A
further analysis of the data revealed that I of 17 patients who received H2 blockers alone developed pneumonia, 9 of the 39 who received antacids, and 6 of 13 who received the combination. However, this study does not allow to conclude that sucralfate should be preferred to antacids or H2 blockers, because the treatments of antacids and H2 blockers were not standardized and the differences in pneumonia rates were not statistically significant (63). COMMENTS Although the pathophysiology of stress ulcers is not entirely clear, gastric acid and pepsin seem to play a key role in stress ulcer bleeding. In this review we have demonstrated that attainment of an increase in intragastric pH is effective and frequently necessary to prevent overt stress ulcer bleeding. In this respect H2 blockers and antacid therapy with pH titration are equally effective. However, doses of antacids given in accordance with this treatment are high and associated with a number of side effects. Moreover, the frequent administration causes an intensive workload of the nursing staff. Hence H2 blockers, intravenously administrated, are an attractive alternative. Dealing with the prevention of stress ulcer bleeding, some questions remain unanswered: What is the optimal gastric pH value that will prevent bleeding, and how long should this optimal pH value be maintained? How important is an elevated gastric pH in relation to bacterial overgrowth and nosocomial pneumonia? How accurate is the gastric aspiration technique in measuring pH levels? Recent studies (50, 64-66) in which continuous infusion of cimetidine or ranitidine was shown to be significantly better in maintaining elevated gastric pH values than fixed-bolus dosing have raised the issue of optimal dosing. The prevention of stress ulcer bleeding with H2receptor antagonists or antacids is a balancing act between undermedication and overmedication, or between bleeding from stress ulcers and bacterial overgrowth. Intragastric pH monitoring can be a valuable tool in research in ICU patients to answer the above-mentioned questions and to prevent patients for under- o r over-medication
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Prevention of Stress Ulcer Bleeding
(67, 68). The position of sucralfate in the prophylaxis has not yet been established. The number of patients studied and reported in the literature is small compared with thc published data on antacids and H2 blockers. Active bleeding from stress ulcers is still an important clinical problem that is much better prevented than treated (63). The efficacy of acidmodulating agents, vasopressin. o r somatostatin in the medical management of stress ulcer bleeding has not yet been demonstrated. The available data suggest that somatostatin and H2 blockers may have a moderate effect (69, 70). Surgical treatment of actively bleeding stress ulcers has also been unsatisfactory regardless of the procedure chosen (71). O n the basis of presently available information, it would appear that the most suitable regimen for prevention of stress ulcer bleeding would be a repeated bolus injection regime or a primed continuous infusion of cimetidine or ranitidine. With respect to the side effects, ranitidine appears to be the more favourable of these t w o H2 blockers.
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phylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern Med 1987, 106, 562-567 28. Layne EA, Mellow MH, Lipman TO. Insensitivity of guaiac slide tests for detection of blood in gastric juice. Ann Intern Med 1981, 94, 774-776 29. Long PC, Wilentz KV, Sudlow G , et al. Modification of the Hemoccult slide test for occult blood in gastric juice. Crit Care Med 1982, 10. 692-693 30. Dcrrida S. Nury B, Slama R, et al. Occult gastrointestinal bleeding in high-risk intensive care unit patients receiving antacid prophylaxis: Frequency and significance. Crit Care Med 1989. 17, 122-125 31. Le Gall JR, Loirat P. Alperovitch A, et al. A simplified acute physiology score for ICU patients. Crit Care Med 1984, 12, 975-977 32. Knaus WA. Draper EA, Wagner DP, Zimmerman JE. APACHE 11: A severity of disease classification system. Crit Care Med 1985, 13. 81X-829 33. Rosenthal P, Thompson J , Singh M. Detection of occult blood in gastric juice. J Clin Gastroenterol 1984, 119-121 34. Priebe HJ, Skillman JJ. Bushnell LS, et al: Antacid versus cimetidine in preventing acute gastrointestinal bleeding: A randomized trial in 75 critically ill patients. N Engl J Med 1980, 302, 42W30 35. Knight A. Bihari D. Tinker J. Stress ulceration in the critically ill patient. Br J Hosp Med 1985. 33, 216-219 36. Weigelt JA. Current status of stress ulceration prophylaxis. In: Vincent JL, ed. Update in intensive care and emergency medicine. Springer-Verlag, Bcrlin. 1989. 361-367 37. Shoemaker WC. Bland RD. Appel PL. Therapy of critically ill postoperative patients based on outcome prediction and prospective clinical trials. Surg Clin N Am 1985, 65, 81 1-833 38. Zuckerman GR. Shuman R. Therapeutic goals and treatment options for prevention of stress ulcer syndrome. Am J Med 1987. 83(suppl 6A), 29-35 39. Miller TA. Stress erosive gastritis In: Moody FG, ed. Surgical treatment of digestive disease. Yearbook Medical Publishers, Chicago, 1986, 20F215 40. Halloran LG, Ziass AM, Gayle WE, et al. Prevention of acute gastrointestinal complications after severe head injury: A controlled trial of cimetidine prophylaxis. Am J Surg 1980. 139, 44-48 41. Cartier F, Gauthier-Lafaye P. Lareng L, et al. Cimetidine in patients at risk of stress ulcers: A multicenter controlled trial [Abstract]. Intensive Care Med 1980, 6, 54. 42. McElwee HP, Sinnek KR. Levine BA. Cimetidine affords protection equal to antacids in prevention of stress ulceration after thermal injury. Surgery 1979, 86, 620-626. 43. Lacroix J, Invante-Rivard C, Jenicek M, et al. Prophylaxis of upper gastrointestinal bleeding in intensive care units: A meta-analysis. Crit Care Med 1989, 17, 862-869 44. Critchlow JF. Comparative efficacy of parenteral histamine (H,)-antagonists in acid suppression for the prevention of stress ulceration. Am J Med 1987, 83(suppl 6A) 23-28 45. Noseworthy TW, Shustack A, Johnston RG, et al. A randomized clinical trial comparing ranitidine
and antacids in critically ill patients. Crit Care Med 1987, 15, 817-819 46. Barth HO, Brunner G , Berg F, et al. Ranitidine vs cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 193 critically ill patients. Intensivmedicin 1984, 21, 15-18 47. Laurie K, Code J. Ranitidine in prevention of acute upper gastrointestinal bleeding. Aust J Hosp Pharm, 1983, 13, 130-133 48. Siepler J , Prindiville T, Nishikawa R, Trudeau W. Prophylaxis of stress ulceration in the ICU: A comparison of cimetidine and ranitidine constant infusion. Gastroenterology 1987, 92, 1639 49. More DG, Raper RF, Munro IA, Watson CJ, Boutagy JS, Shenfield GM. Randomised prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985,97, 2 15-223 50. Ketterl R, Holscher AH, Weiser HF. Siewert JR. Kontrolle des intragastralen pH-Wertes bei sepsis bzw. peritonitis durch ranitidin versus cimetidin. Eine doppelblindstudie. Z Gastroenterol 1984. 22, 602-608 51. Powel RJ, Donn KH. Histamine H?-antagonist drug interactions in perspective: Mechanistic concepts and clinical implications. Am J Med 1984, 77 (SUPPI SB). 57-84 52. Coursin DB, Farin-Rusk C, Springman MD, Goelzer SL. The hemodynamic effects of intravenous cimetidine versus ranitidine in intensive care unit patients: A double-blind, prospective, cross-over study. Anesthesiology, 1988, 69, 975978 53. Rauch H. Fleischer F, Bohrer H. Jurs G , Wilhelm M, Krier C. Serum aluminium levels of intensive care patients treated with two different antacids for prevention of stress ulceration. Intensive Care Med 1989. 15. 84-86 54. Tarnawski A, Hollander D. Gergely H. The mechanism of protective, therapeutic and prophylactic actions of sucralfate. Scand J Gastroenterol 1987. 22. 7-13 55. Borrero E, Bank S, Margolis I, et al. Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who arc critically ill. Am J Med 1985. 79(suppl 2C), 62-64 56. Bresalier RS, Grendell JH. Cello JP, Meyer AA. Sucralfate suspension versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients. Am J Med 1987, 83(suppl 3B). 11&116 57. Tryba M. Risk of acute stress bleeding and nosocomial pneumonia in ventilated ICU patients: sucralfate versus antacids. Am J Med 1987,83(suppl 3B) 117-124 58. Tryba M, Mantey-Stiers F. Antibacterial activity of sucralfate in human gastric juice. Am J Med 1987, 83 (suppl 38) 125-127 59. Winter RJ, Willatts SM. Gastric pH and colonisation using sucralfate. Proceedings of the 10th international symposium on intensive care and emergency medicine, Brussels, March 1990 60. Du Moulin GC, Paterson DG, Hedley-White J , Lisbon A. Aspiration of gastric bacteria in antacid-
Prevention of Srress Ulcer Bleeding treated patients: A frequent cause of postoperative colonisation of thc airway. Lancet 1982, 1,242-245 61. Graven DE. Daschner FD. Nosocomial pneumonia in the intuhated patient: Role of gastriccolonisation. Eur J Clin Microbiol Infect Dis, 1989, 40-50 62. Driks MR. Craven DE. Celli BR. et al. Nosocomial pneumonia in intubated patients given sucralfate as compared with antacids or histaminc type 2 blockers. N Engl J Mcd, 1987, 317, 1 3 7 6
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1382 63. Kleiman RL, Adair CG, Ephgrave KS. Stress
ulcers: current understanding of pathogenesis and prophylaxis. Drug Intell Clin Pharm 1988. 22, 452-460 64. Ostro MJ. Russel JA, Solden SJ. Mahon WA. Jecjeeboy KN. Control of gastric pH with cimctidine: holusses versus primed infusions. Gastroenterology IYXS, 89. 532-537 65. Morris DL. Markham S. Bcachey A. Byrnc A. Bolus or infusion ranitidine for the control of intragastric pH in critically ill patients. Am J Gastroenterol 1985. 80. 865-866
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66. Ballesteros MA, Hogan DL, Koss MA, Isenberg JI. Bolus or intravenous infusion of ranitidine: Effects on gastric pH and acid secretion. Ann Intern Med 1990, 112, 334339 67. Geus WP, Westra P, Smith SJ. de Haas JAM, Lamers CBHW. Preliminary results concerning the effectiveness of continuous intragastric p H monitoring in the critically ill. Proceedings of the 10th international symposium on intensive care and emergency medicine, Brussels. March, 1990 68. Durham R, Weigelt J. Monitoring gastric pH levels. Surg Gynecol Ohstet 1989, 169, 14-16 69. Knodcll R G , Garjian PL, Schreiher JB. Newer agents available for treatment of stress-related upper gastrointestinal tract mucosal damage. Am J Med 1987, 83(suppl6A), 36-40 70. Collins R , Langman M. Treatment with histamine H? antagonists in acute upper gastrointestinal hemorrhage. N Engl J Med 1985, 313, 660-666 71. Hubert JP. Kiernan PD. Welch JS. Remine WH. Bcahrs O H . The surgical management of bleeding stress ulcers. Ann Surg 1981). 191. 672-679
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Geus WP, Lamers CBHW. Prevention of stress ulcer bleeding: a review. Scand J Gastroenterol 1990, 25(suppl 178). 32-41 The pathophysiology of stress ulcers is complex. There is either too much acid and pepsin or inadequate mucosal defenses. The incidence of upper GI bleeding due to stress ulcers in the ICU is 5-25% depending upon the minimum criterion of bleeding. For the individual patient the risk of bleeding is determined by his underlying condition and the number of risk factors. SAPS and APACHE I1 may assist in identifying those patients. Attainment of an increase in intragastricpH is effective and frequently necessary to prevent stress ulcer bleeding and reduces the incidence of overt bleeding. Based on presently available information the most suitable regime for prevention of stress ulcer bleeding is a continuous infusion or fixed bolus dosing of cimetidine or ranitidine. With respect to the side effects, ranitidine appears to be the more favorable of these two H? blockers. The position of sucralfate in the prophylaxis has not yet been established. Key words: Antacids; bacterial overgrowth; bleeding criterion; cimetidine; critically ill; ranitidine; risk factors; septicemia; stress ulcers; sucralfate
W. P. Geus, M . D . , Depi. of Intensive Care, Leyenburg Hospital, Leyweg 275, P.O. Box 40551. 2504 LN The Hague, The Netherlands
In association with stress critically ill patients admitted to an intensive care unit (ICU) may develop erosive lesions of the upper gut (1). Stress can be a result of a traumatic injury, a lifethreatening illness. a prolonged surgical procedure, shock, septicemia, or a postoperative complication such as pulmonary, hepatic, or renal failure. The lesions differ from peptic ulcers of non-stressed individuals. The lesions are multiple and located primarily in the gastric fundus and body, the acid-producing areas of the stomach. The most reliable and sensitive method to diagnose stress lesions is endoscopy. When endoscopy is employed, stress lesions are found to develop in 60% to 100% of the patients shortly after admission to an intensive care unit ( 2 4 ) . The first endoscopic abnormalities are submucosal petechiae and hemorrhage, followed by erosions and superficial ulcers. Initially, the damage is usually confined to the gastric fundus and body, but with progression it can involve the antrum, duodenum, and the distal esophagus. The lesions are often superficial and tend to ooze
blood rather than bleed massively. However, deeper lesions can develop, for instance, in patients with septicemia or with central nervous system disorders. These deeper lesions can bleed massively and, on occasion, perforate. Massive gastrointestinal bleeding, although relatively rare, can result in a mortality rate of up to 80% ( 5 ) . Much confusion exists as to the nomenclature of these stress-related lesions. Several names have been used interchangeably, such as, stress ulcer, hemorrhagic gastritis, stress gastritis, stress erosion, diffuse mucosal injury, and erosive gastritis. Recently, Peura (5) introduced terms as stress-related mucosal damage, and Thompson & Cloud (6) stress-associated gut (gastric) erosions. In sum, these terms describe the multifocal self-digestion of the gastric mucosa that occurs concomittantly with many life-threatening conditions (7). The literature dealing with the prophylaxis of stress ulcerations is scattered. Several misconceptions obscure the risk of stress ulcer bleeding
Prevention of Stress Ulcer Bleeding
and the effect of acid-reducing prophylaxis. This review describes the pathophysiology of stressrelated mucosal lesions, defines the risk of stress ulcer bleeding and the criteria of stress ulcer bleeding, and compares the efficacy of drugs generally used in the prevention of stress ulcer bleeding.
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PATHOPHYSIOLOGY The pathophysiology of stress-related lesions is not well understood. It is appropriate to think of an imbalance between aggressive and defensive mucosal factors. Aggressive factors comprise gastric acid and reflux of bile into the stomach, while defensive factors comprise mucosal permeability, mucosal blood flow, gastric mucus, prostaglandins, and epithelial cell renewal. Gastric acid Gastric acid in the stomach has been shown to be a prerequisite for the development of mucosal damage (8, 9). Schwartz’s adagium ‘no acid, no ulcer’ remains a central theme in the various theories of pathogenesis. In 36 stressed patients Robbins et al. (10) demonstrated significantly higher acid values than in a control group of 19 normal individuals. Pepsin concentrations in the stressed group were higher than in the control group. Increased acidity of gastric juice has also been observed in some patients with head injuries (11) or sepsis. Histamine release during sepsis may increase gastric acid secretion. Martin et al. (12) have clearly demonstrated that antacids and cimetidine fail to control the gastric pH during sepsis. Bile reflux Bile reflux into the stomach has been shown to be more common among critically ill patients, especially in the postoperative condition, than in the healthy population (13). Also experimentally, bile reflux has been proved to play a role in the formation of mucosal injury in shock models. A study in dog stomachs demonstrated that neither ischemia nor bile were ulcerogenic in the presence of acid, but the combination of these factors produced severe mucosal lesions (14).
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Mucosal permeability The gastric mucosal barrier is the ability of the gastric epithelium to maintain a hydrogen ion gradient between the lumen and tissue. Disruption of this barrier may result from various compounds, such as bile salts, urea, aspirin, or alcohol, when these agents are applied topically to the gastric epithelium. The result of disruption of the gastric mucosal barrier is a change in mucosal permeability. In this condition hydrogen ions diffuse back into the mucosa. A reduction in the transmucosal potential difference occurs, indicating that normal electrochemical gradients between the mucosa and gastric lumen have been deranged. Unrestricted back-diffusion of hydrogen ions leads to direct damage of the gastric mucosa (15). Mucosal blood flow Animal studies have demonstrated that stress causes a rapid reduction in gastric mucosal blood flow with resulting mucosal ischemia (9). Ischemia brings about a defect in mucosal A T P concentrations, while it also increases back-diffusion of hydrogen ions into the mucosa and impairs the mucosal defensive mechanism (16). Lactic acid accumulates during localized hypoxia due to decreased gastric blood flow. The development of massive bleeding from stress-related mucosal damage is highly correlated with intramural acidosis (17). Gastric mucus The gastric epithelium is normally covered by a thin layer of mucus gel. This gel, consisting of a matrix of glycoprotein acts as an unstirred layer that resists proton diffusion. The role of this mucus barrier in stress-related mucosal damage remains ill-defined. Robert & Kauffman (18) found a reduction in the hexosamine content (a major component of gastric mucus) of the gastric juice and the gastric mucosa of fasting animals prior to development of experimental ulcers. They also showed that corticosteroids decrease the hexosamine contents of the gastric mucosa. These findings suggest that the fasted state and a physiologic response to stress (increased levels of circulating corticosteroids) in most critically
34
W.P. Geus & C. B. H . W . Lamers
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ill or traumatized patients could play a contributory role in the development of mucosal damage.
They demonstrated also a close relation between the risk of bleeding and the severity of illness. In a prospective study Schuster et al. (24) found in 14% of 174 medical ICU patients (179 admisProstaglandins sions), without prophylactic therapy, evidence for The role of prostaglandins is unclear. High either occult or overt gastrointestinal bleeding. In concentrations of the prostaglandins PGEz and 6Yo of the patients they found overt bleeding. PGIz are present in the gastric mucosa. These However, the mortality rate was 90% among the prostaglandins increase gastric mucosal blood patients with overt bleeding, and 30% of the flow, and stimulate secretion of mucus and bi- deaths were directly related to bleeding. In none carbonate (16). Prostaglandins also induce a de- of these two studies was the cause of occult crease of gastric acid secretion (15). These effects bleeding endoscopically verified. are dose dependent. Prostaglandins protect the Hastings et al. (25) observed gastrointestinal mucosa of the stomach against the damaging bleeding in 4% of 51 critically ill patients given effects of agents like indomethacin, aspirin, and antacids hourly (titration) to maintain the pH of alcohol (19, 20). Van Essen et al. (21) demon- the gastric contents above 3.5. In the control strated that PGEz did not exert a beneficial effect group of 49 critically ill patients 24% bled. in the prevention of stress ulcerations. Analysisof all the patients showed that an increasing prevalence of respiratory failure, septicemia, Epithelial cell renewal peritonitis, jaundice, renal failure, and hypotenExperimentally, it has been shown that during sion was correlated with a greater frequency of stress the gastric mucosa has a decreased rate of bleeding. cellular proliferation and deoxyribonucleic acid In 17'/0 of 433 cases of head injury Kamada et synthesis (22). Agents such as pentagastrin, al. (26) found gastrointestinal bleeding. A close growth hormone, and epidermal growth factor. relationship was seen between the frequency of which stimulate protein and deoxyribonucleic bleeding and the severity of injury. Bleeding was acid synthesis and cell division, may prevent diagnosed by the presence of blood in aspirated mucosal damage in animals. Fasting decreases gastric juice, by hematemesis or melena, or by deoxyribonucleic acid, ribonucleic acid, and pro- direct observation of blood loss from the stomach tein synthesis in the gastric epithelium (18, 22). by endoscopy. Inhibition of cell division and proliferation imShuman et al. (27) reviewed all trials of propairing the ability to replace extruded cells may phylactic therapy with cimetidine published from contribute to the development of stress injury. 1976 to 1985, in which there was a control arm consisting of placebo or no therapy. Variation in study design, in particular the definition of bleedINCIDENCE OF BLEEDING AND RISK ing and its measurement, makes comparison of FACT0 R S the various trials difficult. In these studies the The incidence of endoscopically verified stress- incidence of occult bleeding in the control patients related lesions in patients admitted to an intensive ( N = 187) was 27%, while the incidence of overt care unit is 6(LlOO% ( 2 4 ) . However, clinically it bleeding in these control patients ( n = 720) was is of utmost importance to know how many of 15%. these patients do actually bleed as a result of The detection of occult bleeding with guaiac stress-related mucosal damage. reagent (Hemoccult) may give both false-positive Zinner et al. (23) reported an incidence of and false-negative reactions. Layne et al. (28) bleeding of 20% in a group of 100 ICU patients found that gastric juice that was neutralized with who received no prophylactic therapy. Occult commercial antacids was less sensitive to blood blood detection (positive guaiac test) was used as detection by guaiac reagent than gastric juice minimum criterion for gastrointestinal bleeding. obtained from patients given intraveneus cimeti-
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Prevention of Stress Ulcer Bleeding
dine. The authors concluded that the finding of more occult bleeding in cimetidine-treated versus antacid-treated critically ill patients may be directly related to the method of blood detection rather than occurrence of bleeding per se. Long et al. (20) showed false-negative results with the Hemoccult slide test when the pH of the gastric juice was below 2 and false-positive results when the pH of the gastric juice was between 2 to 4. Derrida et al. (30) studied the risk of occult gastrointestinal bleeding in patients at high risk of stress ulcerations. Criteria for inclusion in the study were: a ) sepsis associated with one or more organ failures; b) presence of two or more organ failures; and c) major operative procedure and/or multiple trauma. The simplified acute physiology score (SAPS (31, 32)) within the first 24h after admission to the ICU in this group was 14.7 f 5.2 (SD). indicating that these patients were indeed severely ill. In this study Derrida et al. found occult bleeding in 1 1 of 41 patients (27%,).The cause of bleeding was endoscopically verified, and in 8 patients of the 11 (72%) acute stress lesions were found. In the other three patients the cause of bleeding was trauma induced by the nasogastric tube, benign gastric tumor, and esophageal varices. Occult bleeding was followed by overt gastrointestinal bleeding in 4 of the 1 1 patients. Occult bleeding was tested with Gastroccult. This reagent can detect occult blood in gastric juice independent of the pH (33). The authors also established a clear relationship between the incidence of bleeding and the number of 'risk factors'. Risk factors Hastings et al. (25) and Priebe et al. (34) identified a number of risk factors that increase the likelihood of bleeding from stress ulceration. Risk factors comprise sepsis, peritonitis, respiratory failure, head injury, multiple trauma, severe burn injuries, severe hepatic dysfunction or failure, hypotension, renal failure, and major operative procedures (7,25,35). It is now generally agreed that these factors are the most important determinants of bleeding (1,7, 17,23,30, 35). The differences in the reported prevalence of bleeding from stress lesions in various reports are most likely due to the number of risk factors for
35
bleeding of the patients including in the various studies or scatter in the criterion of bleeding. The extent to which a single risk factor determines the pathogenesis of stress-related mucosal damage is unknown. The probability of stress ulcer bleeding clearly rises as the number of risk factors increases (25, 34). The presence or absence of sepsis appears to be an all-important determinant of clinically significant stress ulceration (35). Conclusions The incidence of upper gastrointestinal bleeding a s a result of stress-related mucosal damage in patients admitted to an ICU is 5-25%, depending on the minimum criterion of gastrointestinal bleeding (minimum criterion overt bleeding, 5 % ; minimum criterion occult bleeding, 25%). Scores of disease severity, such as SAPS and APACHE 11. may assist in identifying those patients who are at high risk for bleeding from stress ulcers. For the individual patient the risk of bleeding is determined by his underlying condition and the number of risk factors.
PREVENTION OF STRESS ULCER BLEEDING The first step in the prevention of stress erosions is active general support and therapeutic measures aimed to control the primary disease process in each critically ill patient. Rapid restoration of physiological homeostasis should limit the injury to the gastric mucosa (36). Shoemaker et al. (37) demonstrated in a clinical study that aggressive shock treatment considerably reduced the incidence of stress bleeding. According to Zuckerman & Shuman (38) the concept of prophylactic therapy for prevention of stress ulcer bleeding is based on three premisses: 1 ) the morbidity and mortality related to stress ulcer syndrome are significant; 2 ) the population at risk for stress ulcer syndrome can be identified prior to bleeding or perforation; and 3) prophylactic treatment that decreases gastric acidity or improves gastric mucosal defense mechanisms will prevent ulcer formation or progression of ulceration to bleeding or perforation.
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W .P . Gem & C. B. H.W.Lamers
The rationale for prophylaxis with antacids or H2-receptor antagonist is based on a considerable number of published reports that have clearly demonstrated the efficacy of gastric acid neutralization with topical antacids and H2-receptor antagonists in the prevention of stress ulcer bleeding (39). Furthermore, pepsinogen is not converted in pepsin in gastric juice of a pH above 4. Besides antacids or H2-receptor antagonists, sucralfate acting as a mucosal protective agent can be used. Although the exact mechanismsof action of sucralfate are unknown, it has been established that sucralfate does not neutralize gastric acid or inhibit its secretion. It is difficult to compare the efficacy of prophylactic regimes for stress ulcer bleeding, since various definitions of bleeding, various gastric pH goals, and different dosage regimes have been used. Additionally, heterogeneous groups of critically ill patients (difference in SAPS) have been studied. Overt bleeding, as measured by hematemesis, melena, or bleeding requiring transfusion, is the best clinical indication of treatment failure because overt bleeding is associated with an increase in the ICU mortality rate (24). Cimetidine and antacids Prophylactic therapy with cimetidine or antacids did not show any drop in the incidence of mucosal lesions found soon after admission to the intensive care unit (3, 4042). Only one study indicated that cimetidine might diminish the number of gastric mucosal lesions found at a later time during the patient's ICU stay (3). It is therefore possible that cimetidine prevents the progression of early mucosal lesions to more severe forms and inhibits the onset or progression to clinically significant bleeding (3). In the above-mentioned review Shumann et al. (27) showed that when overt bleeding was used as the minimum criterion, there was no significant difference between antacids and cimetidine in the prevention of overt bleeding (3.3% of 458 as compared with 2.7% of 402 patients, respectively). Both agents were more effective than placebo (15% of 720 patients) in the prevention of overt bleeding. Lacroix et al. (43) performed a meta-analysis of 15 randomized studies on the
prophylaxis with cimetidine and/or antacids of upper gastrointestinal bleeding acquired in the ICU. In this meta-analysis the authors demonstrated that there is no firm justification to choose antacids over cimetidine to prevent upper gastrointestinal bleeding. The results of this metaanalysis also suggest that both cimetidine and antacids are effective in preventing upper gastrointestinal bleeding, although many studies were not well designed, and a file drawer problem was possible. Antacids In many studies antacids were given hourly (25) or every 2h (23). Doses of standard-strength antacids varied from 20 to 160ml/h (6). Gastric pH was usually monitored for a minimal of 2 h in aspirated gastric juice (36). The degree of acid suppression varied with the dosage regimen employed. Hourly antacid therapy with pH titration was usually compared with acid suppression by H2-receptor antagonists (44). Hourly antacid therapy and cimetidine were equally effective in the prevention of upper gastrointestinal bleeding (27, 43). The difficulties of hourly administration of antacids via a nasogastric tube in ICU patients and the increased nursing time requirements have made the intravenously administration of HZreceptor antagonists an attractive alternative. Ranitidine and antacids In a randomized trial of gastric pH control for stress ulcer prophylaxis Noseworthy et al. (45) compared ranitidine and antacids in 86 patients admitted to an ICU. Gastrointestinal bleeding was reported if melena occurred, if there was an aspirate of bright red blood from the nasogastric tube on two occasions over a 4 h time span, or if there was an unexplained fall in hemoglobin. They concluded that ranitidine given intravenously in a dose of 200mg/day was as effective as antacids in reducing acidity and preventing stress ulcer bleeding in the critically ill. Cimetidine and ranitidine The H2-receptor antagonist ranitidine has been studied to a lesser extent than cimetidine as an agent for prophylaxis of stress ulcer bleeding.
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Prevention of Stress Ulcer Bleeding
Comparing these two agents, Barth et al. (46) found no difference in the efficacy of cimetidine and ranitidine for stress ulcer bleeding prophylaxis in a non-placebo-controlled randomized study of 193 critically ill patients comparing these two agents. Laurie & Code (47) compared the ability of cimetidine and ranitidine to elevate gastric pH values and monitored aspirated gastric juice for occult bleeding. Results from this study comprising 20 patients showed no difference between the prophylactic agents. Siepler et al. (48) found that a constant infusion of cimetidine (1200 mg/day) or of ranitidine (230 mg/day) provided excellent prophylaxis for stress ulcer bleeding in 227 ICU patients on TPN. The two regimens provided similar p H profiles. More et al. (40) compared the effects of intravenous doses of ranitidine and cimetidine in 48 critically ill patients and found a more effective control of the gastricpH with ranitidine than with cimetidine. In agreement with these results Ketterl et al. (50) also found a clear advantage of ranitidine in patients with peritonitis or sepsis. These reports suggest that the efficacy of ranitidine to control gastric pH and to prevent stress ulcer bleeding is similar or superior to that of cimetidine.
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administrations of H2-blockers are needed, ranitidine appears to be the more favorable of the two drugs. Associated with the use of large doses of antacids in the critically ill, a relatively high incidence of side effects, such as diarrhea or constipation and electrolyte disturbances, has been reported (1). Rausch et al. (53) found a significant rise of the serum aluminum concentration following administration of the antacids magaldrate (Riopan@) or aluminium hydroxide (TrigastriIB), in a dose of 10 ml six times a day, in patients with a normal or slightly impaired renal function. Sucralfate
Sucralfate is a non-absorbable aluminum salt of sucrose octasulfate with cytoprotective effects that may be mediated in part by enhanced gastric prostaglandin synthesis (54). The compound produces an ulcer-adhering complex with a proteinaceous exudate at the ulcer site. Sucralfate also absorbs bile salts and inhibits pepsin. It is suggested that a sucralfate albumin film acts as a barrier to the diffusion of hydrogen ions. This barrier effect may possibly be beneficial for stress ulcer prophylaxis. The number of studies and patients reported in the literature dealing with the prevention of stress ulcer bleeding by sucralfate is Side effects The use of H2 blockers and antacids may be small in comparison with studies published on complicated by a number of side effects. Cime- prevention of stress ulcer bleeding with antacids tidine is known t o bind to cytochrome P-450 or H2-receptor antagonists. Borrero et al. (55) randomized 155 patients microsomal enzymes and thus reduces the clearance of drugs metabolized by these enzymes, such admitted to a medical or surgical ICU to receive as metronidazole, diazepam, propanolol, theo- either antacids or sucralfate. The criteria for phylline, phenytoin, labetalol, lidocaine, verap- admission to the study included the presence of amil, and warfarin. In addition, cimetidine has one or more risk factors for gastrointestinal been reported to cause dose-dependent confusion bleeding. Eighty patients received 1gof sucralfate and mental depression, especially in the elderly every 6 h, while 75 patients were given antacids (51). A lower incidence of adverse drug reactions hourly (30 or 60ml) to titrate p H to greater than and mental confusion has been reported with the 3.5. Clinical bleeding (defined as frank blood or use of ranitidine. The binding of ranitidine to the coffee-ground aspirate from the nasogastric tube, cytochrome P-450 system occurs to a much lesser melena, or positive Gastroccult) occurred in three sucralfate and two antacid patients. In all cases the extent than the binding of cimetidine. Coursin et al. (52) reported that a bolus in- bleeding was limited to occult blood in the gastric jection of intraveneus cimetidine in critically ill aspirate. In a study involving 74 ICU patients, 38 patients was followed by moderate hypotension, of whom received sucralfate (1 g every 4 h) and 36 whereas bolus injections of ranitidine did not. patients receiving antacids to maintain the gastric They concluded that if relatively rapid bolus p H above 4, Bresalier e t al. (56) found no
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W.P. Geus & C.B. H.W.Lamers
significant differnce in the incidence of significant upper gastrointestinal bleeding between the two treatment groups. Studying the effect of sucralfate as compared to that of antacids, Tryba (57) found in each treatment group one case of macroscopically visible bleeding in 100 ventilated surgical ICU patients. These three studies suggest that bleeding rates under sucralfate are comparable with antacids. In a study of the antibacterial activity of sucralfate, Tryba & Mantey-Stiers (58) found in vitro inhibition of bacterial growth in human aspirated gastric juice by sucralfate. The question as to whether sucralfate possesses any antibacterial property in gastric juice in vivo is not answered by this laboratory experiment. In fact, Winter & Willatts (59) showed colonization of aspirated gastric juice in 36 of 84 patients despite treatment with sucralfate. In the above-mentioned study of Tryba (57), 100 ventilated surgical ICU patients were randomized to receive either sucralfate or an antacid. Fifty patients received every 4 h 1 g sucralfate, and 50 other patients received every 2 h 10 ml antacid. The gastric pH was determined every 8 h. When patients with primary thoracic trauma or pneumonia were excluded, nosocomial pneumonia developed in significantly fewer patients in the sucralfate group (3 of 29) than in the antacid group (11 of 32). It is remarkable that 90% of the pH determinations in the antacid group were above 4, compared with 54% of the pH samples in the sucralfate group. In studies by Du Moulin et al. (60) high levels of gastric pH were correlated with logarithmic increases in the concentrations of gram-negative bacilli in aspirated gastric juice. Gastric colonization also is affected by age, malnutrition, antibiotics. and disease of the gastrointestinal tract (61). Driks et al. (62) studied the incidence of nosocomial pneumonia in 130 mechanically ventilated patients receiving prophylactic sucralfate, antacids combined with H2 blockers (cimetidine or ranitidine), or H2 blockers alone. They concluded that the incidence of pneumonia in patients on sucralfate was 7 of 61, compared with 16 of 69 patients receiving antacids, H2 blockers, or a combination of antacids and H2 blockers (NS). A
further analysis of the data revealed that I of 17 patients who received H2 blockers alone developed pneumonia, 9 of the 39 who received antacids, and 6 of 13 who received the combination. However, this study does not allow to conclude that sucralfate should be preferred to antacids or H2 blockers, because the treatments of antacids and H2 blockers were not standardized and the differences in pneumonia rates were not statistically significant (63). COMMENTS Although the pathophysiology of stress ulcers is not entirely clear, gastric acid and pepsin seem to play a key role in stress ulcer bleeding. In this review we have demonstrated that attainment of an increase in intragastric pH is effective and frequently necessary to prevent overt stress ulcer bleeding. In this respect H2 blockers and antacid therapy with pH titration are equally effective. However, doses of antacids given in accordance with this treatment are high and associated with a number of side effects. Moreover, the frequent administration causes an intensive workload of the nursing staff. Hence H2 blockers, intravenously administrated, are an attractive alternative. Dealing with the prevention of stress ulcer bleeding, some questions remain unanswered: What is the optimal gastric pH value that will prevent bleeding, and how long should this optimal pH value be maintained? How important is an elevated gastric pH in relation to bacterial overgrowth and nosocomial pneumonia? How accurate is the gastric aspiration technique in measuring pH levels? Recent studies (50, 64-66) in which continuous infusion of cimetidine or ranitidine was shown to be significantly better in maintaining elevated gastric pH values than fixed-bolus dosing have raised the issue of optimal dosing. The prevention of stress ulcer bleeding with H2receptor antagonists or antacids is a balancing act between undermedication and overmedication, or between bleeding from stress ulcers and bacterial overgrowth. Intragastric pH monitoring can be a valuable tool in research in ICU patients to answer the above-mentioned questions and to prevent patients for under- o r over-medication
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Prevention of Stress Ulcer Bleeding
(67, 68). The position of sucralfate in the prophylaxis has not yet been established. The number of patients studied and reported in the literature is small compared with thc published data on antacids and H2 blockers. Active bleeding from stress ulcers is still an important clinical problem that is much better prevented than treated (63). The efficacy of acidmodulating agents, vasopressin. o r somatostatin in the medical management of stress ulcer bleeding has not yet been demonstrated. The available data suggest that somatostatin and H2 blockers may have a moderate effect (69, 70). Surgical treatment of actively bleeding stress ulcers has also been unsatisfactory regardless of the procedure chosen (71). O n the basis of presently available information, it would appear that the most suitable regimen for prevention of stress ulcer bleeding would be a repeated bolus injection regime or a primed continuous infusion of cimetidine or ranitidine. With respect to the side effects, ranitidine appears to be the more favourable of these t w o H2 blockers.
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and antacids in critically ill patients. Crit Care Med 1987, 15, 817-819 46. Barth HO, Brunner G , Berg F, et al. Ranitidine vs cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 193 critically ill patients. Intensivmedicin 1984, 21, 15-18 47. Laurie K, Code J. Ranitidine in prevention of acute upper gastrointestinal bleeding. Aust J Hosp Pharm, 1983, 13, 130-133 48. Siepler J , Prindiville T, Nishikawa R, Trudeau W. Prophylaxis of stress ulceration in the ICU: A comparison of cimetidine and ranitidine constant infusion. Gastroenterology 1987, 92, 1639 49. More DG, Raper RF, Munro IA, Watson CJ, Boutagy JS, Shenfield GM. Randomised prospective trial of cimetidine and ranitidine for control of intragastric pH in the critically ill. Surgery 1985,97, 2 15-223 50. Ketterl R, Holscher AH, Weiser HF. Siewert JR. Kontrolle des intragastralen pH-Wertes bei sepsis bzw. peritonitis durch ranitidin versus cimetidin. Eine doppelblindstudie. Z Gastroenterol 1984. 22, 602-608 51. Powel RJ, Donn KH. Histamine H?-antagonist drug interactions in perspective: Mechanistic concepts and clinical implications. Am J Med 1984, 77 (SUPPI SB). 57-84 52. Coursin DB, Farin-Rusk C, Springman MD, Goelzer SL. The hemodynamic effects of intravenous cimetidine versus ranitidine in intensive care unit patients: A double-blind, prospective, cross-over study. Anesthesiology, 1988, 69, 975978 53. Rauch H. Fleischer F, Bohrer H. Jurs G , Wilhelm M, Krier C. Serum aluminium levels of intensive care patients treated with two different antacids for prevention of stress ulceration. Intensive Care Med 1989. 15. 84-86 54. Tarnawski A, Hollander D. Gergely H. The mechanism of protective, therapeutic and prophylactic actions of sucralfate. Scand J Gastroenterol 1987. 22. 7-13 55. Borrero E, Bank S, Margolis I, et al. Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who arc critically ill. Am J Med 1985. 79(suppl 2C), 62-64 56. Bresalier RS, Grendell JH. Cello JP, Meyer AA. Sucralfate suspension versus titrated antacid for the prevention of acute stress-related gastrointestinal hemorrhage in critically ill patients. Am J Med 1987, 83(suppl 3B). 11&116 57. Tryba M. Risk of acute stress bleeding and nosocomial pneumonia in ventilated ICU patients: sucralfate versus antacids. Am J Med 1987,83(suppl 3B) 117-124 58. Tryba M, Mantey-Stiers F. Antibacterial activity of sucralfate in human gastric juice. Am J Med 1987, 83 (suppl 38) 125-127 59. Winter RJ, Willatts SM. Gastric pH and colonisation using sucralfate. Proceedings of the 10th international symposium on intensive care and emergency medicine, Brussels, March 1990 60. Du Moulin GC, Paterson DG, Hedley-White J , Lisbon A. Aspiration of gastric bacteria in antacid-
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