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Stress-related mucosal damage: An overview
Stress-Related Mucosal Damage: An Overview
Stress-related mucosal damage of the upper gastrointestinal tract occurs in the majority of critically ill patients. The more severe the underlying disease, the greater the chance that mucosal damage and subsequent bleeding will develop. Clinical outcome is determined by the type and severity of the underlying illness; however, cases with severe gastric damage, as diagnosed by endoscopic examination or by bleeding, have the poorest prognoses. Endoscopy is the most sensitive method for diagnosing stress-related mucosal damage. Other indicators of stress-related mucosal damage are macroscopic evidence of bleeding, blood transfusion requirement, or measures of occult bleeding; these tests cannot diagnose nonbleeding lesions. Low gastric pH values may also indicate physiologic response to stress, but such values are not uniformly correlated with the presence of injury. Vigorous acid suppression with prolonged periods of pH control may be necessary to treat stress-related mucosal damage and to prevent bleeding. Treatment modalities in current use include antacids, cimetidine, and other histamine (H&receptor antagonists, and, more recently, sucralfate. Current evidence indicates that antacids, given hourly and titrated to a preset pH goal, or primed continuous infusion of cimetidine are the most efficacious regimens in maintaining intragastric pH control.
DAVID A. PEURA, M.D. Washington,
D.C.
Stress-related mucosal damage of the upper gastrointestinal tract, once thought to be an uncommon complication of severe traumatic injury, is now known to occur in the majority of critically ill patients [l-4]. INCIDENCE AND DIAGNOSIS OF STRESS-RELATED MUCOSAL DAMAGE The reported incidence of stress-related mucosal damage varies from 6 percent to 100 percent [5-71, depending upon the patient population evaluated and the method used to monitor the patients. When endoscopy, the most reliable and sensitive diagnostic method, is employed, in 60 to 100 percent of patients, stress-related damage is found to develop shortly after admission to an intensive care unit [l-3,6] (Table I). Indeed, the widespread use of endoscopy has led to enhanced clinical awareness of stress-related mucosal damage and to an increase in reported incidence of the syndrome. However, the increase in incidence is also associated with advances in the care of critically ill patients so that those with previously lethal conditions now live to have mucosal injury develop [g]. Risk Factors Associated with Stress-Related Mucosal Damage. The risk factors associated with stress-related mucosal damage include such clinical conditions as severe burns (Curling’s ulcer) [lO,ll], central ner-
From the Division of Gastroenterology, Walter Reed Army Medical Center, Washington, D.C. Reauests for reorints should be addressed to Col. David A. Peura: Department of Gastroenterology, Walter Reed Army Medical Center, Washington, D.C. 20307-5001. The opinions and assertions contained herein are the private ones of the author and are not to be construed as official policy or refleeting the views of the Department of the Army or the Department of Defense.
December
18, 1987
The American
Journal
of Medicine
Volume
83
(suppl 8A)
3
SYMPOSIUM
TABLE
ON Hz-RECEPTOR
I
ANTAGONIST
Early Incidence Damage
= medical
Percent Abnormalities
Population
Lucas et al (1971) [l] Czaja et al (1974) [2] Peura and Johnson (1985) Poleski and Spanier (1986) intensive
Mucosal
of Stress-Related
Reference
MICU
THERAPY-PEURA
Trauma Burns MICU MICU
[3] [8]
100 74 74 60 (72 hours)
care unit.
I
p co.03
1
i Normal initial
_ ^
Minor endoscopic
Severe category
,...
L;orrelauon between initial encioscopic ance and mortality rate. Adapted with permission rgure
1.
appearfrom [3].
vous system injury (Cushing’s ulcer) [12,13], sepsis [9,14161, respiratory failure [17,18], renal failure [19], hepatic failure [20], and multiple trauma [1,9]. There is evidence to suggest that the more severe an underlying illness or injury, the greater the chance of developing mucosal injury and subsequent bleeding [5,21]. Even though stress-related mucosal damage is common, patient mortality appears to be unrelated to the mucosal injury. Clinical outcome, rather, is determined by the severity and natural history of the underlying illness [19,22,23]. However, endoscopic evidence of severe gastric mucosal damage at the time of admission to an intensive care unit does portend a poor prognosis [3] (Figure 1). Furthermore, when progressive mucosal damage is associated with serious complications, such as massive bleeding and perforation, and if surgical intervention is required, mortality approaches 80 percent [1,19,24]. Endoscopic Diagnosis. Fiberoptic endoscopy has not only facilitated the early diagnosis of stress-related mucosal damage, but also has enabled its characterization and
4
December
18, 1987
The American
Journal
of Mdlcine
serial observations. Since the first endoscopic description of stress-related mucosai injury by Lucas and associates [l] in 1971, numerous investigators have observed the mucosal changes that occur in critically ill patients [2,3,8,25]. It is quite clear that macroscopic damage occurs early, often within hours of stress. If left untreated, this damage can rapidly progress over the next several days. Submucosal petechiae and hemorrhage are the first endoscopic abnormalities seen. These are later followed by erosions and superficial ulcers. Initially, damage is usually confined to the gastric fundus and body, but with progression it can involve the antrum, duodenum, and, on occasion, the distal esophagus. Because the lesions are superficial, they tend to ooze blood rather than bleed massively. in patients with central nervous system disease and sepsis, deeper lesions distributed throughout the entire upper gastrointestinal tract can develop. These deeper lesions can bleed massively and, on occasion, perforate. Although endoscopy is the most sensitive and specific method available for diagnosing stress-related mucosal damage, it is not practical to use in most clinical situations. However, endoscopic observation should remain the “gold standard” for monitoring the gastric mucosa of patients enrolled in clinical therapeutic trials. Evidence of Bleeding as a Diagnostic Indicator. Because clinical practicalities limit endoscopic surveillance, the bedside clinician must rely on other measures to diagnose stress-related mucosai damage. The presence of macroscopic upper gastrointestinal bleeding is a clinically reliable indicator of underlying mucosal damage. However, the presence of bleeding will most certainly underestimate the true prevalence of injury since nonbleeding mucosal lesions will not be diagnosed. Failure to identify nonbleeding lesions in high-risk patients can lead to a failure to institute appropriate prophylactic treatment. The reported incidence of bleeding also varies considerably, but most investigators place it at 10 to 20 percent of all cases of stress-related mucosal damage [6]. In a similar manner, blood transfusion requirement as an indication of stress-related mucosal damage will not identify nonbleeding mucosal lesions. Furthermore, critically ill patients often receive blood products for reasons other than gastrointestinal hemorrhage. Occult blood testing of the nasogastric aspirate has been used by many investigators to infer the presence or absence of stress-related mucosal damage [6,26,27]. This test is associated with false-positive [28,29] and false-negative [30] results and thus is too nonspecific to be reliable in a clinical setting [6,31,32]. pH Monitoring as a Diagnostic Indicator. Finally, the results of intermittent or continuous intragastric pH monitoring have been assumed to correlate with the presence or absence of underlying mucosal damage. pH measurements should be viewed as an indicator of physiologic response to stress and, in treatment trials, as a measure of response to an antisecretory agent. Although a persist-
Volume
83
(suppi 8A)
SYMPOSIUM
TABLE
II
Natural
History
of Stress-Related
Reference
ICU = intensive
[3]
ANTAGONIST
THERAPY-PEURA
Damage
Numberof Patients
Population
Lucas et al (1971) [l] Czaja et al (1974) [2] Le Gall et al (1976) [14] Kamada et al (1977) [12] Peura and Johnson (1985)
Mucosal
ON t&RECEPTOR
Trauma Burns ICU sepsis ICU no sepsis Head injury ICU
42 32 14 16 ? 18
Percentwith Lesions
Percentwith Bleeding
100 86 100 48 75
21 22 21 0 17
83
39
care unit.
ently low intragastric pH value may permit stress-related mucosal injury to develop, one should not equate low pH values with the presence of injury or high pH values with the absence of injury. PROGRESSION OF STRESS-RELATED MUCOSAL DAMAGE AND COMPARISON WITH PEPTIC ULCERS
Stress-induced lesions tend to be clinically asymptomatic. The lesions are multiple and are located primarily in the gastric fundus and body, the acid-producing areas of the stomach. If left untreated, the lesions will progress and become generalized, but because they are usually superficial, perforation is uncommon. Serious gastrointestinal complications such as massive hemorrhage and perforation occur in 2 to 5 percent of untreated patients [7,24,33]. Furthermore, serial endoscopic surveillance of critically ill patients documents progression of untreated mucosal damage with bleeding occurring in about 20 percent of those patients with underlying lesions (Table II). Bleeding from stress-related mucosal damage tends to arise from superficial capillaries and is rarely massive. The presentation of stress-related mucosal damage contrasts quite clearly with the clinical picture seen with chronic peptic ulcer disease [34]. Peptic ulcers generally produce characteristic symptoms, are single, and are located primarily in the gastric antrum and duodenum, the non acid-producing areas of the upper gastrointestinal tract. Because peptic ulcers tend to be deep lesions, perforation and penetration occur more frequently. When bleeding occurs, it tends to arise from a single large vessel and can be massive. Although disruption of mucosal defense has been implicated in the pathogenesis of peptic disease, it is clear that secretion, and sometimes hypersecretion, of gastric acid is key in the development of peptic ulcers [34]. Recent evidence has pointed to an important role of nocturnal acid secretion in peptic disease. Therapy that suppresses acid secretion during this segment of the circadian cycle has proved effective in promoting rapid ulcer healing [35]. In stress-related mucosal damage, in contrast, the amount of acid and the time of its secretion are probably not as important in causing the condition as are the muco-
December 18,
1987
sal defensive factors that affect acid permeability [24,34,36-391. Mucosal defensive factors are discussed in detail in this publication by Dr. Thomas A. Miller [40]. In fact, hypersecretion of acid in critically ill patients is unusual except in those with central nervous system injury or sepsis, but in such patients risk of complications from stress-related mucosal damage is clearly increased. TREATMENT STRATEGIES MUCOSAL DAMAGE
FOR STRESS-RELATED
Because of the clinical differences between stress-related mucosal damage and peptic ulcer disease, treatment strategies differ. Although moderate acid suppression directed primarily at nocturnal acid appears to be sufficient to promote rapid peptic ulcer healing, more vigorous acid suppression with prolonged periods of pH control may be necessary to treat stress-related mucosal damage and prevent subsequent bleeding. Because lesions occur so early in the course of the disease, prevention may be impractical. Although therapy has not been shown to prevent the original lesions, which usually are seen on admission to the intensive care unit, it has been shown to prevent progression of lesions and to prevent bleeding [3,6]. Antacids and the histamine (H&receptor antagonists have been shown to be effective in preventing the progression of stress-related mucosal damage and subsequent bleeding [3,6]. Their beneficial effects have been attributed to their ability to raise intragastric pH levels [23,41]. In one recent, placebo-controlled study of 39 medical intensive care unit patients, 21 patients received intravenous cimetidine (300 mg every six hours). Cimetidine treatment was significantly better than placebo in stopping or preventing endoscopic evidence of bleeding, in reducing transfusion requirement, and in improving mucosal abnormalities [3]. Although the efficacy of cimetidine and other Hz-receptor antagonists has generally been attributed to their antisecretory effects, there is some evidence to suggest that they may also enhance mucosal defense [42-441. Under conditions of stress, for example, cimetidine has been shown to preserve gastric mucosal blood flow [43] and to simulate endogenous prostaglandin production [44]. Sucralfate, too, has been shown to pro-
The American Journal
of
Medicine
Volume 83 (suppl 6A)
5
SYMPOSIUM
ON HP-RECEPTOR
ANTAGONIST
THERAPY-PEURA
tect critically ill patients from bleeding associated with stress-related mucosal damage [45,46]. It presumably also works by enhancing mucosal defense because it has little effect on gastric acid secretion and intragastric pH. CURRENT ISSUES IN MANAGEMENT RELATED MUCOSAL DAMAGE
OF STRESS-
There are problems, unfortunately, with many of the clinical trials that have evaluated various pharmacologic agents used in the management of stress-related mucosal damage. Study designs are quite variable, and methods and patient populations are dissimilar. For example, some studies include patients in surgical intensive care units, others employ burn victims, and still others select patients with severe head trauma. It has been shown that the type of medical condition and its severity are both related to the incidence of stress-related mucosal damage, so studies employing different patient populations cannot be assumed to be directly comparable.
In addition, monitoring techniques for mucosal damage utilized in available clinical trials have often been insensitive and nonspecific. Some investigators have employed occult blood tests or clinical evidence of overt bleeding, both of which are nonspecific for mucosal damage, as their monitoring techniques; other investigators have utilized the more precise technique of fiberoptic endoscopy. Observation periods have often been too short to monitor adequately for the possibility of mucosal bleeding. Dosing regimens have not been standardized from study to study. In addition, fixed bolus doses of the HPreceptor antagonists have often been compared with doses of antacids titrated to achieve a target pH goal. These treatment regimens cannot be considered comparable. Comparisons of the results of such studies are of questionable validity. Future clinical trials should therefore address the problems encountered in previous trials. Such trials should be carefully designed to ensure their scientific validity as well as their clinical efficacy.
REFERENCES
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6.
9. 10.
11. 12.
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8
Lucas CE, Sugawa C, Riddle U, Rector F, Rosenberg B, Walt AJ: Natural history and surgical dilemma of “stress” gastric bleeding. Arch Surg 1971; 102: 266-272. Czaja AJ, McAlhany JC, Pruitt BA Jr: Acute gastroduodenal disease after thermal injury. An qndoscopic evaluation of incidence and natural history. N Et?@ J Med 1974; 291: 925-929. Peura DA, Johnson LF: Cimetidi@ for prevention and treatment of gastroduodenal mucosal IeQiQns in patients in an intensive care unit. Ann Intern Med l* 103: 173-l 77. Gottlieb JE, Menashe PI, Cruz EzGastrointestinal complications in critically ill patients: the intensivists’ overview. Am J Gastroenterol 1986; 81: 227-238. Zinner MJ, Zuidema GD, Smith PL, Mignosa M: The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 1981; 153: 214-220. Shuman RB, Schuster DP, Zuckerman GR: Prophylactic therapy for stress ulcer bleeding: a reappraisal. Ann Intern Med 1987; 106: 562-567. Schuster DP, Rowley H, Feinstein S, McGue MK, Zuckerman GR: Prospective evaluation of the risk of upper gastrointestinal bleeding after admission to a medical intensive care unit. Am J Med 1984; 76: 623-630. Poleski MH, Spanier AH: Endoscopic evaluation of cimetidine versus “Mylanta” in prophylaxis of stress ulceration. Am J Gastroenterol 1986; 81: 107-l 11. Lucas CE: Stress ulceration: the clinical problem. World J Surg 1981; 5: 139-151. McAlhany JC, Czaja AJ, Pruitt BA: Antacid control of complications from acute gastroduodenal disease after bums. J Trauma 1976; 16: 645-649. Pruitt BA Jr, Goodwin CW Jr: Stress ulcer disease in the burned patient. World J Surg 1981; 5: 209-222. Kamada T, Fusamoto H, Kawano S, et al: Gastrointestinal bleeding following head injury: a clinical study of 433 cases. J Trauma 1977; 17: 44-47. Halloran LG, Zfass AM, Gayle WE, Wheeler CB, Miller JD: Prevention of acute gastrointestinal complications after severe
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23. 24.
25.
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head trauma: a controlled clinical trial of cimetidine prophylaxis. Am J Surg 1980; 139: 44-48. Le Gall JR, Mignon FC, Rapin M, et al: Acute gastroduodenal lesions related to severe sepsis. Surg Gynecol Obstet 1976; 142: 377-380. Skillman JJ, Bushnell LS, Goldman H, Silen W: Respiratory failure, hypotension, sepsis, and jaundice. A clinical syndrome associated with lethal hemorrhage from acute stress ukxration of the stomach. Am J Surg 1969; 117: 523-529. Altemeier WA, Fullen WD, McDonough JJ: Sepsis and gastrointestinal bleeding. Ann Surg 1972; 175: 759-789. Khan F, Sertff NS: Stress ulcer bleeding as a major cause of death in patients undergoing treatment for acute respiratory failure (abstr). Chest 1976; 70: 430. Harris SK, Bone RC, Ruth WE: Gastrointestinal hemorrhage in patients in a respiratory intensive care unit. Chest 1977; 72: 301-304. Fischer RP, Stremple JF: Stress ulcers in post-traumatic renal insufficiency in patients from Vietnam. Surg Gynecol Obstet 1972; 134: 790-794. MacDougall BRD, Bailey RJ, Williams R: Hz-receptor antagonists and antacids in the prevention of acute gastrointestinal hemorrhage in fulminant hepatic failure. Two controlled trials. Lancet 1977; I: 617-619. Menguy R: The prophylaxis of stress ulceration (editorial). N Engl J Med 1980; 302: 461-462. Martin LF, Larson GM, Fry DE: Bleeding from stress gastritis: has prophylactic pH control made a difference? Am Surg 1985; 51: 189-193. Faist E, Baue AE, Dittmer H, Heberer G: Multiple organ failure in polytrauma patients. J Trauma 1983; 23: 775-787. Marrone CC, Silen W: Pathogenesis, diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterol 1984; 13: 635-650. McElwee HP, Sirinek KR, Levine BA: Cimetidine affords protection equal to antacids in prevention of stress ulceration following thermal injury. Surgery 1979; 86: 620-626.
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36.
Hastings PR, Skillman JJ, Bushnell LS, Silen W: Antacid titration in the prevention of acute gastrointestinal bleeding: a controlled randomized trial in 100 critically ill patients. N Engl J Med 1978; 298: 1041-1045. Priebe JH, Skillman JJ, Bushnell LS, Long PC, Silen W: Antacid versus cimetidine in preventing acute gastrointestinal bleeding. A randomized trial in 75 critically ill patients. N Engl J Med 1980; 302: 426-430. Norfleet RG, Rhodes RA, Saviage K: False-positive “hemoccult” reaction with cimetidine (letter). N Engl J Med 1980; 302: 467. Hauser A, Quigley ML, Driever CW, Montalvo AA, Robbins T: More on false-positive “hemoccult” reaction with cimetidine (letter). N Engl J Med 1981; 304: 847-848. 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. Fiddian-Green RG, McGough E, Pittenger G, Rothman E: Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterology 1983; 85: 613-620. Pinilla JC, Oleniuk FH, Reed D, Malik B, Laverty WH: Does antacid prophylaxis prevent upper gastrointestinal bleeding in critically ill patients? Crit Care Med 1985; 13: 646-650. Bank S: Stress ulcers-prevention of gastrointestinal bleeding in critical care units. Med J Aust 1985; 142 (suppl): S17-S20. Brooks FP: The pathophysiology of peptic ulcer disease. Dig Dis Sci 1985; 30 (suppl): 15S-29s. Howden CW, Hunt RH: Single nocturnal doses of Hz-receptor antagonists in duodenal ulcer. Postgrad Med 1985; November (suppl): 17-22. Peura DA: Stress-related mucosal damage. Clin Ther 1986; 8
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18,1987
37. 38.
39.
40. 41.
42. 43.
44.
45.
46.
ON H,-RECEPTOR
ANTAGONIST
THERAPY-PEURA
(suppl A): 14-23. Flemstrom G, Turhberg LA: Gastroduodenal defensive mechanisms. Clin Gastroenterol 1984; 13: 327-354. Kivilaakso E: Pathogenetic mechanisms in experimental gastric stress ulceration. Stand J Gastroenterol 1985; 20 (suppl 110): 57-62. Kauffman GL Jr: Mucosal damage to the stomach: how, when, and why? Stand J Gastroenterol 1984; 19 (suppl 105): 1926. Miller TA: Mechanisms of stress-related mucosal damage. Am J Med 1987; 83 (suppl 6A): 8-14. Peura DA: Treatment and prevention of stress-related mucosal damage with cimetidine. Postgrad Med 1985; November (suppl): 93-99. Kimmey MB, Silverstein FE: Mucosal protective effects of cimetidine. Postgrad Med 1985; November (suppl): 85-91. Kitojima M, Sohma S: Defensive factors in the mechanism of developmental gastric ulcer with regard to mucosal blood flow. In: Tagamet new dimensions. And more. Philadelphia: Widermere Communications, 1984; 81-91. Okada M, Nagoa S, lmai S: Effect of cimetidine on prostaglandin level and blood flow. In: Tagamet new dimensions. And more. Philadelphia: Widermere Communications, 1984; 105113. Borrero E, Bank S, Margolis I, et al: Comparison of antacid and sucralfate in the prevention of gastrointestinal bleeding in patients who are critically ill. Am J Med 1985; 79 (suppl2G): 6264. Tryba M, Zevounou F, Torok M. et al: Prevention of acute stress bleeding with sucralfate, antacids, or cimetidine: a controlled study with pirenzepine as a basic medication. Am J Med 1985; 79 (suppl 2G): 55-61.
The American
Journal
of MedWne
Volume
83 (suppl8A)
7
Stress-related mucosal damage of the upper gastrointestinal tract occurs in the majority of critically ill patients. The more severe the underlying disease, the greater the chance that mucosal damage and subsequent bleeding will develop. Clinical outcome is determined by the type and severity of the underlying illness; however, cases with severe gastric damage, as diagnosed by endoscopic examination or by bleeding, have the poorest prognoses. Endoscopy is the most sensitive method for diagnosing stress-related mucosal damage. Other indicators of stress-related mucosal damage are macroscopic evidence of bleeding, blood transfusion requirement, or measures of occult bleeding; these tests cannot diagnose nonbleeding lesions. Low gastric pH values may also indicate physiologic response to stress, but such values are not uniformly correlated with the presence of injury. Vigorous acid suppression with prolonged periods of pH control may be necessary to treat stress-related mucosal damage and to prevent bleeding. Treatment modalities in current use include antacids, cimetidine, and other histamine (H&receptor antagonists, and, more recently, sucralfate. Current evidence indicates that antacids, given hourly and titrated to a preset pH goal, or primed continuous infusion of cimetidine are the most efficacious regimens in maintaining intragastric pH control.
DAVID A. PEURA, M.D. Washington,
D.C.
Stress-related mucosal damage of the upper gastrointestinal tract, once thought to be an uncommon complication of severe traumatic injury, is now known to occur in the majority of critically ill patients [l-4]. INCIDENCE AND DIAGNOSIS OF STRESS-RELATED MUCOSAL DAMAGE The reported incidence of stress-related mucosal damage varies from 6 percent to 100 percent [5-71, depending upon the patient population evaluated and the method used to monitor the patients. When endoscopy, the most reliable and sensitive diagnostic method, is employed, in 60 to 100 percent of patients, stress-related damage is found to develop shortly after admission to an intensive care unit [l-3,6] (Table I). Indeed, the widespread use of endoscopy has led to enhanced clinical awareness of stress-related mucosal damage and to an increase in reported incidence of the syndrome. However, the increase in incidence is also associated with advances in the care of critically ill patients so that those with previously lethal conditions now live to have mucosal injury develop [g]. Risk Factors Associated with Stress-Related Mucosal Damage. The risk factors associated with stress-related mucosal damage include such clinical conditions as severe burns (Curling’s ulcer) [lO,ll], central ner-
From the Division of Gastroenterology, Walter Reed Army Medical Center, Washington, D.C. Reauests for reorints should be addressed to Col. David A. Peura: Department of Gastroenterology, Walter Reed Army Medical Center, Washington, D.C. 20307-5001. The opinions and assertions contained herein are the private ones of the author and are not to be construed as official policy or refleeting the views of the Department of the Army or the Department of Defense.
December
18, 1987
The American
Journal
of Medicine
Volume
83
(suppl 8A)
3
SYMPOSIUM
TABLE
ON Hz-RECEPTOR
I
ANTAGONIST
Early Incidence Damage
= medical
Percent Abnormalities
Population
Lucas et al (1971) [l] Czaja et al (1974) [2] Peura and Johnson (1985) Poleski and Spanier (1986) intensive
Mucosal
of Stress-Related
Reference
MICU
THERAPY-PEURA
Trauma Burns MICU MICU
[3] [8]
100 74 74 60 (72 hours)
care unit.
I
p co.03
1
i Normal initial
_ ^
Minor endoscopic
Severe category
,...
L;orrelauon between initial encioscopic ance and mortality rate. Adapted with permission rgure
1.
appearfrom [3].
vous system injury (Cushing’s ulcer) [12,13], sepsis [9,14161, respiratory failure [17,18], renal failure [19], hepatic failure [20], and multiple trauma [1,9]. There is evidence to suggest that the more severe an underlying illness or injury, the greater the chance of developing mucosal injury and subsequent bleeding [5,21]. Even though stress-related mucosal damage is common, patient mortality appears to be unrelated to the mucosal injury. Clinical outcome, rather, is determined by the severity and natural history of the underlying illness [19,22,23]. However, endoscopic evidence of severe gastric mucosal damage at the time of admission to an intensive care unit does portend a poor prognosis [3] (Figure 1). Furthermore, when progressive mucosal damage is associated with serious complications, such as massive bleeding and perforation, and if surgical intervention is required, mortality approaches 80 percent [1,19,24]. Endoscopic Diagnosis. Fiberoptic endoscopy has not only facilitated the early diagnosis of stress-related mucosal damage, but also has enabled its characterization and
4
December
18, 1987
The American
Journal
of Mdlcine
serial observations. Since the first endoscopic description of stress-related mucosai injury by Lucas and associates [l] in 1971, numerous investigators have observed the mucosal changes that occur in critically ill patients [2,3,8,25]. It is quite clear that macroscopic damage occurs early, often within hours of stress. If left untreated, this damage can rapidly progress over the next several days. Submucosal petechiae and hemorrhage are the first endoscopic abnormalities seen. These are later followed by erosions and superficial ulcers. Initially, damage is usually confined to the gastric fundus and body, but with progression it can involve the antrum, duodenum, and, on occasion, the distal esophagus. Because the lesions are superficial, they tend to ooze blood rather than bleed massively. in patients with central nervous system disease and sepsis, deeper lesions distributed throughout the entire upper gastrointestinal tract can develop. These deeper lesions can bleed massively and, on occasion, perforate. Although endoscopy is the most sensitive and specific method available for diagnosing stress-related mucosal damage, it is not practical to use in most clinical situations. However, endoscopic observation should remain the “gold standard” for monitoring the gastric mucosa of patients enrolled in clinical therapeutic trials. Evidence of Bleeding as a Diagnostic Indicator. Because clinical practicalities limit endoscopic surveillance, the bedside clinician must rely on other measures to diagnose stress-related mucosai damage. The presence of macroscopic upper gastrointestinal bleeding is a clinically reliable indicator of underlying mucosal damage. However, the presence of bleeding will most certainly underestimate the true prevalence of injury since nonbleeding mucosal lesions will not be diagnosed. Failure to identify nonbleeding lesions in high-risk patients can lead to a failure to institute appropriate prophylactic treatment. The reported incidence of bleeding also varies considerably, but most investigators place it at 10 to 20 percent of all cases of stress-related mucosal damage [6]. In a similar manner, blood transfusion requirement as an indication of stress-related mucosal damage will not identify nonbleeding mucosal lesions. Furthermore, critically ill patients often receive blood products for reasons other than gastrointestinal hemorrhage. Occult blood testing of the nasogastric aspirate has been used by many investigators to infer the presence or absence of stress-related mucosal damage [6,26,27]. This test is associated with false-positive [28,29] and false-negative [30] results and thus is too nonspecific to be reliable in a clinical setting [6,31,32]. pH Monitoring as a Diagnostic Indicator. Finally, the results of intermittent or continuous intragastric pH monitoring have been assumed to correlate with the presence or absence of underlying mucosal damage. pH measurements should be viewed as an indicator of physiologic response to stress and, in treatment trials, as a measure of response to an antisecretory agent. Although a persist-
Volume
83
(suppi 8A)
SYMPOSIUM
TABLE
II
Natural
History
of Stress-Related
Reference
ICU = intensive
[3]
ANTAGONIST
THERAPY-PEURA
Damage
Numberof Patients
Population
Lucas et al (1971) [l] Czaja et al (1974) [2] Le Gall et al (1976) [14] Kamada et al (1977) [12] Peura and Johnson (1985)
Mucosal
ON t&RECEPTOR
Trauma Burns ICU sepsis ICU no sepsis Head injury ICU
42 32 14 16 ? 18
Percentwith Lesions
Percentwith Bleeding
100 86 100 48 75
21 22 21 0 17
83
39
care unit.
ently low intragastric pH value may permit stress-related mucosal injury to develop, one should not equate low pH values with the presence of injury or high pH values with the absence of injury. PROGRESSION OF STRESS-RELATED MUCOSAL DAMAGE AND COMPARISON WITH PEPTIC ULCERS
Stress-induced lesions tend to be clinically asymptomatic. The lesions are multiple and are located primarily in the gastric fundus and body, the acid-producing areas of the stomach. If left untreated, the lesions will progress and become generalized, but because they are usually superficial, perforation is uncommon. Serious gastrointestinal complications such as massive hemorrhage and perforation occur in 2 to 5 percent of untreated patients [7,24,33]. Furthermore, serial endoscopic surveillance of critically ill patients documents progression of untreated mucosal damage with bleeding occurring in about 20 percent of those patients with underlying lesions (Table II). Bleeding from stress-related mucosal damage tends to arise from superficial capillaries and is rarely massive. The presentation of stress-related mucosal damage contrasts quite clearly with the clinical picture seen with chronic peptic ulcer disease [34]. Peptic ulcers generally produce characteristic symptoms, are single, and are located primarily in the gastric antrum and duodenum, the non acid-producing areas of the upper gastrointestinal tract. Because peptic ulcers tend to be deep lesions, perforation and penetration occur more frequently. When bleeding occurs, it tends to arise from a single large vessel and can be massive. Although disruption of mucosal defense has been implicated in the pathogenesis of peptic disease, it is clear that secretion, and sometimes hypersecretion, of gastric acid is key in the development of peptic ulcers [34]. Recent evidence has pointed to an important role of nocturnal acid secretion in peptic disease. Therapy that suppresses acid secretion during this segment of the circadian cycle has proved effective in promoting rapid ulcer healing [35]. In stress-related mucosal damage, in contrast, the amount of acid and the time of its secretion are probably not as important in causing the condition as are the muco-
December 18,
1987
sal defensive factors that affect acid permeability [24,34,36-391. Mucosal defensive factors are discussed in detail in this publication by Dr. Thomas A. Miller [40]. In fact, hypersecretion of acid in critically ill patients is unusual except in those with central nervous system injury or sepsis, but in such patients risk of complications from stress-related mucosal damage is clearly increased. TREATMENT STRATEGIES MUCOSAL DAMAGE
FOR STRESS-RELATED
Because of the clinical differences between stress-related mucosal damage and peptic ulcer disease, treatment strategies differ. Although moderate acid suppression directed primarily at nocturnal acid appears to be sufficient to promote rapid peptic ulcer healing, more vigorous acid suppression with prolonged periods of pH control may be necessary to treat stress-related mucosal damage and prevent subsequent bleeding. Because lesions occur so early in the course of the disease, prevention may be impractical. Although therapy has not been shown to prevent the original lesions, which usually are seen on admission to the intensive care unit, it has been shown to prevent progression of lesions and to prevent bleeding [3,6]. Antacids and the histamine (H&receptor antagonists have been shown to be effective in preventing the progression of stress-related mucosal damage and subsequent bleeding [3,6]. Their beneficial effects have been attributed to their ability to raise intragastric pH levels [23,41]. In one recent, placebo-controlled study of 39 medical intensive care unit patients, 21 patients received intravenous cimetidine (300 mg every six hours). Cimetidine treatment was significantly better than placebo in stopping or preventing endoscopic evidence of bleeding, in reducing transfusion requirement, and in improving mucosal abnormalities [3]. Although the efficacy of cimetidine and other Hz-receptor antagonists has generally been attributed to their antisecretory effects, there is some evidence to suggest that they may also enhance mucosal defense [42-441. Under conditions of stress, for example, cimetidine has been shown to preserve gastric mucosal blood flow [43] and to simulate endogenous prostaglandin production [44]. Sucralfate, too, has been shown to pro-
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tect critically ill patients from bleeding associated with stress-related mucosal damage [45,46]. It presumably also works by enhancing mucosal defense because it has little effect on gastric acid secretion and intragastric pH. CURRENT ISSUES IN MANAGEMENT RELATED MUCOSAL DAMAGE
OF STRESS-
There are problems, unfortunately, with many of the clinical trials that have evaluated various pharmacologic agents used in the management of stress-related mucosal damage. Study designs are quite variable, and methods and patient populations are dissimilar. For example, some studies include patients in surgical intensive care units, others employ burn victims, and still others select patients with severe head trauma. It has been shown that the type of medical condition and its severity are both related to the incidence of stress-related mucosal damage, so studies employing different patient populations cannot be assumed to be directly comparable.
In addition, monitoring techniques for mucosal damage utilized in available clinical trials have often been insensitive and nonspecific. Some investigators have employed occult blood tests or clinical evidence of overt bleeding, both of which are nonspecific for mucosal damage, as their monitoring techniques; other investigators have utilized the more precise technique of fiberoptic endoscopy. Observation periods have often been too short to monitor adequately for the possibility of mucosal bleeding. Dosing regimens have not been standardized from study to study. In addition, fixed bolus doses of the HPreceptor antagonists have often been compared with doses of antacids titrated to achieve a target pH goal. These treatment regimens cannot be considered comparable. Comparisons of the results of such studies are of questionable validity. Future clinical trials should therefore address the problems encountered in previous trials. Such trials should be carefully designed to ensure their scientific validity as well as their clinical efficacy.
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