Stress Ulcers: Their Pathogenesis, Diagnosis, and Treatment

Symposium on Peptic Ulcer Disease

Stress Ulcers: Their Pathogenesis, Diagnosis, and Treatment Frank G. Moody, M.D.,* and Laurence Y. Cheung, M.D.t

Erosions of the gastroduodenal mucosa may occur acutely after major physical or thermal trauma, shock, sepsis, head injury, or the ingestion of a variety of chemical agents, such as aspirin and alcohol. It is customary to designate such lesions by the term "stress ulcers." Since acute ulcers have different morphologic characteristics, clinical manifestations, and underlying pathogenesis, it is helpful to consider their presence in the context of the clinical setting in which they occur. In this scheme, stress ulcers secondary to shock or physical trauma can be distinguished from those which follow head injury (Cushing's ulcer), burn (Curling ulcer), or drug ingestion (erosive gastritis). Superficial gastric erosions that occur after severe trauma, major operations with complications, or prolonged medical illness, usually occur in the fundus and body of the stomach. They are superficial and multiple with no evidence of chronicity. Cushing's ulcer, which occurs with intracranial tumor, head injury, or after cranial surgery, may involve esophagus, stomach, and duodenum. In contradistinction to other forms of erosive gastritis, acid secretion is usually high, possibly as a consequence of rise in intracranial pressure. Erosive gastritis induced by alcohol, aspirin, and other irritants, is exceedingly common as recognized by current frequent use of gastroscopy. In this review we will examine the evolving body of knowledge which provides insight into the etiology of stress erosions with the expectation of providing a better understanding of its pathogenesis and a more rational' basis for the early recognition, treatment, and prevention of this serious condition.

INCIDENCE Severely injured patients with multiple trauma are at high risk for developing erosive gastritis. Most clinical studies which do not employ routine endoscopy probably underestimate the incidence of this disease, >'Professor and Chairman, Department of Surgery, University of Utah College of Medicine, Salt Lake City, Utah tAssistant Professor of Surgery, University of Utah College of Medicine; Chief, Division of General Surgery, Veterans Administration Hospital, Salt Lake City, Utah

Surgical Clinics of North America- Vol. 56, No.6, December 1976

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since its recognition requires gastrointestinal bleeding or perforation. Lucas et aP4 have shown by gastroscopy that the incidence of stress ulcer in 40 severely injured patients was 100 per cent. In a similar study at the Brooke Army Surgical Research Institute9 of 29 patients with major burns, gastric erosions were found in 27 by sequential endoscopic examination. The majority of these patients had lesions within 72 hours after burn. Fortunately, only a small number of these patients demonstrated significant gastrointestinal hemorrhage. This low incidence of clinically detectable bleeding relates to the superficial nature of early lesions. As they penetrate deeper into the mucosa as a function of time, however, massive life-threatening hemorrhage becomes an all too frequent occurrence.

PATHOGENESIS While the precise mechanisms involved in the development of stress ulcers are unknown, current evidence supports a multifactorial etiology. The following discussion will focus on our current hypothesis based on recent experimental observations.

The Presence of Luminal Acid Hypersecretion of acid is an unlikely cause except in the pathogenesis of Cushing's ulcer. In fact, acid secretion has been normal or even low in most other forms of stress ulcer. On the other hand, it can be stated with certainty that some hydrogen ions are necessary for the development of stress ulcers, because all experimental models of this entity require a low gastric luminal pH.6. 22. 27 The "no acid-no ulcer" dictum implied by this important piece of knowledge has led to the concept that buffering of intragastric contents may prevent post-traumatic erosive gastritis. There is an accumulating body of knowledge to support this point of view. Ischemia Clinically, most patients who develop stress ulcers have experienced shock from hemorrhage, sepsis, or cardiac dysfunction. Diminished mucosal blood flow is a common denominator in animal experiments which employ restraint, hemorrhage, or endotoxemia for production of erosive gastritis. Therefore, a decrease in mucosal blood flow seems to be a common manifestation during the developmental phase of these types of erosions. The focal nature of such lesions has suggested that decrease in mucosal perfusion may be the result of opening of submucosal arteriovenous shunts. This concept has recently been challenged by both histologic studies and quantitative measurements of mucosal blood flow. 14 . 15.21 Guth and Smith21 failed to demonstrate submucosal arteriovenous shunts during normal, sympathetic nerve stimulation in rats. By using 42K, Delaney and Grim14 demonstrated that no more than 1 to 2 per cent of gastric blood flow passes through arteriovenous shunts in normal dogs. They have further shown that this

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was not significantly changed during induced variation of blood flow by vasoactive drugs. 15 Recently Archibald et al. have confirmed this finding with radioactive microspheres in dogs under normal conditions and infusion of isoproterenol. Lastly we have demonstrated that there was no significant AV shunting during E. coli endotoxin infusion and hemorrhagic shock. 5 All of these data indicate that arteriovenous shunting is unlikely to play a significant physiologic role in the development of mucosal ischemia. The decrease in flow observed during hemorrhagic shock and en do toxemia is, therefore, a consequence of a restriction in blood flow to all layers of the gastric wall. Menguy and his colleagues26 provide evidence that shock-induced ischemia results in profound decrease in gastric mucosal energy metabolism. The extraordinary vulnerability of gastric mucosal energy metabolism results from the tissue's lack of glycogen and its relative inability to utilize anaerobic glycolysis as an alternate source of energy. They propose that the decrease in energy metabolism in the gastric mucosa is the cause of rapid cellular necrosis occurring in this tissue during hypovolemic shock.

Gastric Mucosal Permeability Exposure of gastric mucosa to alcohol, aSpIrIn, and a variety of other substances known as barrier breakers, results in increased backdiffusion of hydrogen ions and disruption of the mucosal surface. 11, 12 Ingestion of these substances is also associated with a high incidence of erosive gastritis. The mechanism of even this flagrant form of ulcerogenesis is unknown, but may relate to a rapid change in mucosal intracellular pH or osmolarity, or may be the consequence of loss of surface taxis, or biochemical events within the lamina propria beneath the surface epithelial cells. 33 It has been suggested that cause-effect relationships exist between ischemia and disruption of the mucosal barrier. However, disruption of the gastric permeability barrier by aspirin, bile salts, and alcohol does not cause mucosal ischemia. In fact, we have shown that mucosal blood flow measured by gamma-labeled microspheres actually increases under such circumstances. 4 On the other hand, ischemia following hemorrhagic shock in dogs27 and in subhuman primates,31 and administration of vasopressin in dogs does not render the mucosa more permeable to secreted acid. 10. IS We have also reported that intra-arterial infusion of E. coli endotoxin5 does not disrupt the mucosal barrier in spite of development of gastric erosions. These observations indicate that general disruption of the mucosal barrier (as evidenced by increased back-diffusion of hydrogen ions) is not an essential component of the pathologic process of stress ulcer but, if present, may in itself lead to the syndrome. The most likely explanation is that a synergistic relationship exists between ischemia and back-diffusion of intraluminal acid. This has been supported by the work of DenBesten and Hamza 17 and Ritchie and his colleagues 31 in dogs and monkeys respectively, in which they demonstrated that shock coupled with exposure of the mucosa to bile salts and acid will lead to severe ulcers, whereas shock or bile salts alone only cause mild mucosal damage. This has led to the hypothesis that mucosal blood flow may be essential in

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the disposal of back-diffused hydrogen ions. Under normal conditions, a small amount of hydrogen ions within the tissue may be rapidly cleared by blood flow, whereas erosions may develop when the ratio of mucosal blood flow to hydrogen ion back-diffusion is reduced in stressed subjects. Patients who are traumatized when acid, bile salts, aspirin, and alcohol bathe their gastric mucosa are probably at higher risk for developing acute ulcers than individuals who have a high intraluminal pH or are free from barrier breakers at the time of their accident. This postulation certainly does not answer all questions as regards etiology of stress ulcer. For example, the role of environmental stress may possibly be an important factor in the genesis of acute erosions. However, the precise mechanism remains obscure in spite of a large amount of recent work in the area,13· 29 What are humoral factors? It has been well established that physical stress, especially in association with shock, is accompanied by increased blood levels of catecholamines and cortisol. Although steroids potentiate the increased permeability of the gastric mucosa to hydrogen ions caused by bile salts, aspirin, and acetic acid, alone they do not cause disruption of the gastric mucosal barrier.7 In fact, pharmacologic doses of steroids attenuate erosion formation in restrained rats.23 The ulcerogenic potential of catecholamines has not been adequately studied. The focal nature of gastric erosion observed in clinical patients and in experimental animals9. 27 has not been explored. It is possible that ischemia occurs at a focal site and that, indeed, backdiffusion in these areas may be intense, leading to the discrete multiple lesions so characteristic of the stress ulcer syndrome. Laboratory and clinical investigation continue in the hope that future understanding of these questions may lead to more precise ways of prevention and treatment of this devastating disease.

CLINICAL MANIFESTATIONS Painless unexpected gastrointestinal bleeding from mouth or anus is the hallmark of stress ulcer. Although acute erosions may occur during or shortly after a traumatic incident, frank hemorrhage from these lesions is usually delayed for several days. Hematemesis and melena are of equal frequency. Clinical findings of associated illness or injury are often present. Peritonitis or other signs of severe sepsis may be in evidence and accompanied by varying degrees of respiratory, renal, cardiac, and hepatic failure. Clinical manifestations of massive bleeding from stress ulcers relate to amount and rate of blood loss and the patient's general condition at the onset of the bleed. Occasionally recognition of the source of cardiovascular collapse is delayed in an already critically ill patient. The sudden occurrence of hypovolemic shock with rapid pulse, hypotension, and cool moist skin, should bring this diagnosis to mind in a patient at risk. A drop in urine output is one of the more sensitive indicators of low tissue perfusion in the absence of renal disease.

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DIAGNOSTIC APPROACH Before specific diagnostic procedures are undertaken to identify the source of bleeding, blood volume must be restored. Blood should be drawn immediately for determination of hematocrit, coagulation factors, and cross match. Preferably two large bore catheters should be placed in antecubital veins, one inserted to the level of the superior vena cava in order to monitor central venous pressure. Certain features can be assessed quickly such as the general state of health, heart rate and rhythm, blood pressure, respiratory rate, and skin color and moisture. A nasogastric tube should be inserted in order to detect the presence of blood, or its rate of accumulation within the gastric lumen. Patients who develop gastrointestinal hemorrhage postinjury or after an episode of shock or sepsis should be considered to have stress ulcerations until proven otherwise. An aggressive diagnostic approach should be taken to confirm the diagnosis. Delays due to fear of "disturbing clots" are not justified. In fact, the initial approach should include vigorous lavage of the stomach in order to clear its lumen of clots and old blood. There is controversy as to whether the wash solution (usually saline) should be cold or warm. Cold saline will decrease mucosal blood flow but disturb coagulation; warm saline will increase mucosal perfusion but enhance coagulation. We are not aware of a randomized control trial which might serve to resolve the controversy. Hot or cold, lavage appears to be associated with cessation of bleeding in about 80 per cent of cases. Conventional radiologic examination of the stomach and duodenum by barium is of little help, since lesions are too superficial to be detected by this method. Many patients are also too ill for an adequate barium study. Endoscopy, therefore, is the diagnostic procedure of choice, since it can be done at the bedside. The new fiberoptic esophagogastroduodenoscope offers a simple, safe, and relatively atraumatic way to make a specific diagnosis. Lucas et al. 24 have described the characteristics of stress ulcers by sequential endoscopic examination in 42 patients with severe trauma. The earliest changes include interspersed foci of pallor and hyperemia mostly located in the proximal stomach. These foci are initially small, shallow, punctate erosions which progress to petechiae by 24 hours. The erosions become deeper with marginal swelling and may involve the entire stomach by 48 hours. The use of angiography in the diagnosis of stress ulcer is reserved only for those cases in which gastroscopy fails to demonstrate the bleeding site, or in which control of bleeding is to be gained by pharmacologic means.1 In patients with massive, persistent bleeding, we arrange angiography at the same time that endoscopy is performed. In an occasional case, angiography succeeds in identifying the bleeding site, when endoscopy fails. The inconvenience, and relative risk and expense, however, has placed angiography in a secondary role in the usual mild to intermediate bleed from post traumatic gastritis. In our experience, endoscopic findings in conjunction with the history, usually differentiates stress ulcer from other bleeding lesions, such

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as reactivation of a chronic duodenal or gastric ulcer, or esophageal varices. An upper barium gastrointestinal study, however, is sometimes helpful in identifying other potential sources of bleeding.

TREATMENT Once stress ulcers are associated with significant hemorrhage, mortality exceeds 50 per cent, indicating the lethal nature of this complication. Therefore, early recognition and prevention of deeper penetration of erosions is important. All patients should be given adequate supportive care for shock and sepsis with careful monitoring of the extent of hemorrhage. Patients with blee'ding should be checked for coagulation defects, and specific clotting abnormalities should be corrected. Fresh whole blood is used as part of volume replacement for every sixth unit of blood transfusion. If fresh blood is not available, fresh frozen plasma and platelet packs may be helpful. Gastric aspiration is indicated to remove duodenal content which may have refluxed into the stomach as a result of adynamic ileus, since bile salts and pancreatic juice are injurious to the gastric mucosal membrane. 31 The use of antacids in the treatment of stress ulcers has been reported as being effective in a clinical study of a small number of patients. s However, these observations were not made in a properly controlled, randomized study; hence, they must be regarded as inconclusive. Silen32 suggested the instillation of 15 ml of any commonly employed liquid antacid via the gastric tube, with subsequent clamping of the tube for 15 to 20 minutes. Continuous gastric aspiration is then begun. After 1 hour of suction, the pH of the gastric aspirate is tested with pH paper. If the pH is above 4.5, suction can be repeated for another hour. If the pH is below 4.5, another dose of antacid is instilled. Since it is safe and simple, we have been using antacid on patients with stress ulcers, in the absence of massive hemorrhage. Since the neutralizing capacities of commonly used antacids vary significantly, we prefer to use the potent ones such as Ducon or Mylanta II. There has been recent enthusiasm for pharmacologic control of stress ulcer bleeding by continuous intra-arterial infusion of vasoconstrictors into the gastric blood supply.1 While different vasoconstrictors have been used by several authors, vasopressin has been the most commonly used. Since vasopressin should be infused selectively into the left gastric artery, subs elective catheterization of these vessels is required. The value of this technique has been encouraging;! however, it has not been established by a prospective well controlled study. We use this therapy when conservative management fails to control bleeding. The experience gained to date suggests that the intra-arterial infusion of vasoconstrictors can control stress ulcer bleeding in most cases. Transendoscopic control of upper gastrointestinal bleeding is currently in the development stage. Gaisford reported on the transendoscopic control of bleeding in 33 patients from a variety of mucosal lesions including stress ulcers. Bleeding was immediately controlled in all but

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Table 1.

Literature Review of Operative Results (1949-1971 )':' NUMBER

NUMBER

OF

WITH

PROCEDURE

PATIENTS

REBLEEDING

Exploration only Subtotal gastrectomy Vagotomy and gastrectomy Vagotomy and drainage Vagotomy and drainage wi suture ligation (present series) Total gastrectomy

27 95 54 177 21

16 50 9 52 2

12

0

NUMBER OF PER CENT

DEATHS

PER CENT

59 51 17 29 9.5

13 32 13 41 5

48 38 24 23 24

0

2

17

'Updated from Drapanas et al. (modified from Wilson, W. S., Gadacz, T., Olcott, C., III, and Blaisdell, F. W.: Superficial gastric erosions: Response to surgical treatment. Am. J. Surg.,

126:136, 1973.).

two who subsequently required an operation for recurring hemorrhage. The value of such an approach is obvious and no doubt will receive extensive study during the ensuing years. However, as the complications from this procedure are not yet known, it is too early to recommend it for general use in the management of bleeding stress ulcers. In most patients, bleeding stops with the aid of saline lavage, or selective arterial infusion with vasoconstrictors, but a small percentage of patients will continue to bleed and will require surgery. As a review of reported results of surgical therapy reveals little solid evidence to support the use of one type of operative procedure or another, the choice of procedure is open to question. Several recent surgical series 19 • 34 seem to favor vagotomy and pyloroplasty as an initial operation, but there are too many variables in this large collection of data to allow a definite conclusion to be made (Table 1). On the other hand, Menguy and his associates25 have reported unsatisfactory results for vagotomy and pyloroplasty because bleeding continued or recurred in a large number of patients. Therefore, they advocate that the best results in terms of control of bleeding were obtained with total and near total gastrectomy. In our own experience, we have had fairly satisfactory results with vagotomy and pyloroplasty and oversewing the bleeding ulcers as an initial operation for bleeding stress ulcers. Subtotal gastric resection is reserved for those in whom bleeding continues after the initial operation. The San Francisco experience reported by Wilson and his colleagues34 would appear to support this point of view.

PREVENTION Since results of all forms of therapy are poor, prevention of development and progression of stress erosions would appear to offer the most rational approach to the management of this disease. Many drugs and chemicals have been shown to protect animals from the development of

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stress ulcers, but none have been tested in patients. The following methods of prevention have been advocated in patients. Buffering of the Luminal Content Since stress ulcer will not occur if the luminal content is buffered, neutralizing intraluminal acid with antacid would be expected to prevent its development. 32 However, the effectiveness of this treatment has not been tested in a large group of patients with proper control. This is probably due to the difficulties of maintaining luminal pH neutral by conventional methods. Inhibitors of Acid Secretion The use of inhibitors of acid secretion, such as prostaglandins and the H2 receptor antagonists, metiamide or cimetidine, has been reported to reduce the incidence of stress ulcer in animal experiments. 20 So far, these observations have not been extended to clinical studies, and it is an area that undoubtedly will receive more attention in the ensuing year for the prevention of stress ulcer. Others Methods to augment gastric mucosal regeneration, such as administration of vitamin A, growth hormone, and hyperalimentation, have been suggested to protect mucosal injury from stress. Several recent studies have demonstrated the importance of vitamin A in preserving the function and promoting the normal proliferation of mucous cells in the gastrointestinal tract in animals,3, 16,30 a result which has not been reproducible by other investigators. 28 Clinical studies have also reported a reduction in stress ulcers developing in patients receiving large doses of vitamin A.3 However, the presence of stress ulcers in these studies was not confirmed by endoscopic examination, and the accuracy of diagnosis is therefore questioned. Growth hormone, which stimulates RNA and protein synthesis, has been shown in animals to partially protect the gastric mucosa from stress-induced injury. A small clinical study has shown that in six of eight patients with stress ulcers, the bleeding was controlled by human growth hormone. 35 The protective effect of intravenous hyperalimentation on gastric mucosal regeneration has been studied in a small number of patients undergoing abdominal aortic surgery? Although it has shown that positive nitrogen balance was achieved in hyperalimented patients, its effect on mucosal regeneration and gastric secretion remains inconclusive. These observations certainly need to be extended to a large number of patients in a prospective study, At the present time we are reluctant to recommend the use of these methods for the prevention of stress ulcers.

SUMMARY Stress ulcers are multiple, superficial erosions which occur mainly in the fundus and body of the stomach. They develop after shock, sepsis, and trauma and are often found in patients with peritonitis and other

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chronic medical illness. Stress ulcers should be differentiated from reactivation of chronic duodenal or gastric ulcers, Cushing's ulcer following head injury, or drug-induced gastritis. Digestive symptoms are usually absent, hemorrhage is the most common manifestation, and perforation and obstruction are rare. The presence of luminal acid and ischemia are necessary for the production of stress ulcer, while disruption of the gastric mucosal barrier by refiuxed duodenal content may contribute to the pathogenesis. Endoscopy is the mainstay of the diagnostic procedure, and angiography should be used if endoscopy fails to identify the bleeding lesions. Medical management should include volume replacement, nasogastric aspiration, and the use of antacid. Selective intraarterial infusion of pitressin has shown encouraging preliminary results. Surgical treatment is reserved only for those patients who continue to bleed despite all medical management. The operation of choice is open to question. We prefer vagotomy, pyloroplasty, and oversewing the ulcers as an initial operation. Since the result of all forms of therapy has been poor, it seems reasonable to try to prevent ulcer development. The use of vitamin A, hyperalimentation, and growth hormones is still in an experimental stage. Large clinical studies with case control are necessary before recommendations can be made. The use of potent and frequent antacid to buffer the gastric content has shown promising results; however, these observations need to be confirmed in a properly controlled and randomized study.

REFERENCES 1. Athanasoulis, C. A., Brown, B., and Shapiro, J. H.: Angiography in the diagnosis and management of bleeding stress ulcers and gastritis. Am. J. Surg., 125:468, 1973. 2. Byrd, H. S., Lazarus, H. M., and Torma, M. J.: Effects of parenteral alimentation on postoperative gastric function. Am. J. Surg., 130:688,1975. 3. Chernov, M. S., Cook, F. B., Wood, M., et al.: Stress ulcers: A preventable disease. J. Trauma, 12:831, 1972. 4. Cheung, L. Y., Moody, F. G., and Reese, R. S.: Effect of aspirin, bile salts, and ethanol on canine gastric mucosal blood flow. Surgery, 77:786, 1975. 5. Cheung, L. Y., Reese, R. S., and Moody, F. G.: Direct effect of endotoxin on the gastric mucosal microcirculation and electrical gradient. Accepted for publication in Surgery. 6. Cheung, L. Y., Stephenson, L. W., Moody, F. G., et al.: Direct effect of endotoxin on canine gastric mucosal permeability and morphology. J. Surg. Res., 10:417, 1975. 7. Chung, R. S. K., Field, M., and Silen, W.: Gastric mucosal permeability to H+: Effects of prednisolone and acetylsalicylic acid on the co-efficient of H+ diffusion. Gastroenterology, 58:1038,1970. 8. Curtis, L. E.; Simonian, S., Buerk, C. A., et al.: Evaluation of the effectiveness of controlled pH in management of massive upper gastrointestinal bleeding. Am. J. Surg., 125:474,1972. 9. Czaja, A. J., McAlhany, J. C., and Pruitt, B. A., Jr.: Acute gastroduodenal disease after thermal injury. N. Eng. J. Med., 291 :925, 1974. 10. Davenport, H. W., and Barr, L. L.: Failure of ischemia to break the dog's gastric musosal barrier. Gastroenterology, 65:619,1973. 11. Davenport, H.W.: Ethanol damage to canine oxyntic glandular mucosa. Proc. Soc. Exp. BioI. Med., 126:657, 1967. 12. Davenport, H. W.: Gastric mucosal injury by fatty and acetylsalicylic acids, Gastroenterology, 46:245, 1964. 13. Davis, R. A., and Brooks, F. P.: Experimental peptic ulcer associated with lesions or stimulation of the central nervous system. Surg. Gynec. Obstet., 116:307, 1963. 14. Delaney, J. P., and Grim, E.: Canine gastric blood flow and its distribution. Am. J. Physiol., 297:1195,1964.

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15. Delaney, J. P., and Grim, E.: Experimentally induced variations in canine gastric blood flow and its distribution. Am. J. Physiol., 208:353, 1965. 16. DeLuca, L., and Wolf, G.: Vitamin A and protein synthesis in mucous membranes. Am. J. Clin. Nutr., 22:1050, 1969. 17. DenBesten, L., and Hamza, K. N.: Effect of bile salts on ionic permeability of canine gastric mucosa during experimental shock. Gastroenterology, 62:417, 1972. 18. Dorricott, N. J., Isenberg, H., and Silen, W.: Effect of intraarterial vasopressin on canine gastric mucosal permeability. Gastroenterology, 65:625, 1973. 19. Drapanas, T., Woolverton, W. C., Reeder, J. W., et al.: Experiences with surgical management of acute gastric mucosal hemorrhage: A unified concept in the pathophysiology. Ann. Surg., 173:628, 1971. 20. Foster, L. D., and Shirazi, S. S.: Effect of metiamide in prevention of experimental stress ulcers. Surg. Forum, 26:360, 1975. 21. Guth, P. H., and Smith, E.: Neural control of gastric mucosal blood flow in the rat. Gastroenterology, 69:935, 1975. 22. Harjola, R. T., and Sivula, A.: Gastric ulceration following experimentally induced hypoxia and hemorrhagic shock: In vivo study of pathogenesis in rabbits. Ann. Surg., 163:21, 1966. 23. Kawaruda, Y., Weiss, R., and Matsumoto, T.: Pathophysiology of stress ulcers: Pharmacologic doses of steroid. Am. J. Surg., 129:249, 1975. 24. Lucas, C. E., Sugawa, C., and Riddle, J.: Natural history and surgical dilemma of "stress" gastric bleeding. Arch. Surg., 102:266, 1971. 25. Menguy, R., Gadacz, T., and Zajtchuk, R.: The surgical management of acute gastric mucosal bleeding. Arch. Surg., 99:198, 1969. 26. Menguy, R., Desbaillets, L., and Masters, Y. F.: Mechanism of stress ulcer: Influence of hypovolemic shock on energy metabolism in the gastric mucosa. Gastroenterology, 66:46, 1974. 27. Moody, F. G., and Aldrete, J. S.: Hydrogen permeability of canine gastric secretory epithelium during formation of acute superficial erosions. Surgery, 70:154, 1971. 28. Rasche, R., and Butterfield, W. C.: Vitamin A pretreatment of stress ulcers in rats. Arch. Surg., 106:320, 1973. 29. Reed, J. D., Sanders, D. J., et al.: Nerve stimulation on gastric acid secretion and mucosal blood flow in the anesthetized cat. J. Physiol., 214:1, 1971. 30. Requena, R., Forte, R., Knopf, M., et al.: Intracellular potassium and vitamin A in the prevention of stress ulcers. Surg. Forum, 23:388, 1972. 31. Ritchie, W., Jr.: Ischemia and the gastric mucosal barrier: A note of caution. Surgery, 76:366, 1974. 32. Silen, W., and Skillman, J. J.: Stress ulcer, acute erosive gastritis and the gastric mucosal barrier. Adv. Int. Med., 19:195, 1974. 33. Torma, M. J., Moody, F. G., Cheung, L. Y., et al.: Surface and microcirculatory effects of carbenoxolone on aspirin-induced erosive gastritis in dogs. In Avery Jones, F., and Parke, D. V. (eds.): Fourth Symposium on Carbenoxoline, 1975, p. 41. 34. Wilson, W. S., Gadacz, T., Olcott, C., et al.: Superficial gastric erosions: Response to surgical treatment. Am. J. Surg., 126:133, 1973. 35. Winawer, S. J., Sherlock, P., Sonenberg, M., et al.: Beneficial effect of human growth hormone on stress ulcers. Arch. Intern. Med., 135:569, 1975. Department of Surgery University of Utah Medical Center Salt Lake City, Utah 84132