Peptic Ulcer Disease
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Cytoprotection and Stress Ulceration
Jeffrey Pilchrnan, MD,* Harvey B. Lefton, MD,t and Ceoffrey L. Braden, MDt.
CYTOPROTECTION The term "cytoprotection" has been used in recent years to denote the property of certain substances to protect the stomach from injury. vVhen discussing those agents that can cause injury to gastric mucosa and result in a pathologic state, cytoprotection has been referred to as stimulating natural defense mechanisms. An understanding of cytoprotection then really rcquires an understanding of the natural factors that promote well-being of the mucosa and those circumstances that alter the natural state. Cytoprotection is an ongoing physiologic process. It is a process in which the stomach actively repairs itself. This process does not involve the alteration of gastric acid secretion. Pathophysiology The key to the concept of cytoprotection is the maintenance and replenishment of gastric mucosal cells through the preservation and healing effect of the gastric microcirculation. Studies in laboratory animals using gastric irritants show the major role the microcirculation plays in preventing injury. It appears that prostaglandins help prevent hemorrhage by restoring the microcirculation. 21 These compounds also help prevent damage to mucosal cells and stimulate replenishment of mucosal and submucosal cells. There is not a change in gastric acid secretion; therefore, the process of protecting the mucosa appears to be independent of acid secretion. Studies have shown that there must be an intact adrenal gland producing glucocorticoids and catecholamines for this natural protective process to work. It also appears that sulfhydryls, carotenoids, colloidal bismuth, and sucralfate From the Division of Gastroenterology, Pennsylvania
~\'Iedical
College of Pennsylvania, Philadelphia,
*Clinical Assistant Professor of Medicine tClinical Professor of Medicine :j:Clinical Associate Professor of "'Iedicine
Medical Clinics of North America-\'ol. 75. :-.lo. 4, July 1991
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can play a pharmacologic role in protecting the mucosa. 23 These agents do not scem to inhibit gastric acid secretion. Studies indicate that vagal tone must be normal and acetylcholine production adequate for the natural and pharmacologic cytoprotective agents to work. Many irritative agents cause hemorrhage or ischemic infarcts of the mucosa and submucosal areas, while sparing the deeper layers of the stomach. Those agents that help in cytoprotection do so by preserving the microcirculation rather than directly preserving the injured mucosal cells. It is this microcirculation that provides the necessary oxygen and nutrients for the repair of superficial gastric damage. 23 Studies using either ethanol or aspirin to cause gastric injury have shown cytoprotective agents appear to protect the microcirculation rather than specifically the mucosa. Aspirin and other nonsteroidal anti-inflammatory agents injure mucosal cells and damage microcirculatory elements. Also, many of these drugs interfere with coagulation and platelet aggregation, enhancing the potential for serious bleeding. The benefit of cytoprotective agents is that they stimulate regeneration of injured areas rather than specifically protecting against the noxious substance. As can readily be seen, the integrity of the gastric mucosa then depends on an interplay of both defensive and aggressive factors. Gastric cells produce mucus, which has a protective effect by covering the mucosal cells. Mucus serves as a lubricant and also a bufier that traps microorganisms. The mucus mixes with secreted bicarbonate and may help to keep the pH of the surface of the stomach near neutral levels. Thus, the mucus layer has a direct protective effect by decreasing penetration of noxious agents and maintaining the neutral pH directly above the mucosal cells. Another protective efiect of the gastric mucosa is the way in which cell turnover occurs. The cells in the mucosa of the stomach are replaced every 2 to 4 days. These cells are extruded with the other neighboring cells filling in the space, so that there is minimal contact between the underlying basement membrane and the surface environment. This helps prevent injury to the submucosa. The major factor in mucosal defense is the microcirculation that supplies oxygen and nutrients to the epithelium. These capillaries also act by removing noxious agents that are absorbed. It appears, also, that the smooth muscle may play a role in the protection of the gastric microcirculation from injury. Hypercontractibility of the stomach can lead to localized arcas of ischemia. Some prostaglandins work by relaxing smooth muscle. This is one of the components of the cytoprotective effect. Experimental data are still needed to confirm this, but certainly there appears to be a muscular and vascular interplay to account for some aspects of mucosal integrity. In states of high muscular tone, there may be compromise of the microcirculation leading to localized ischemia and, therefore, to a greater chance for injury. When the mucosa is damaged, plasma proteins flow into the mucosa, and there is an increase in blood flow. This may aid in the removal of noxious substances. In experimental studies, when irritants are placed on the gastric mucosa, there does appear to be a reactive hyperemia in response to the toxic agent. This seems to help remove the substance. Experiments have shown that when there is even a temporary cessation of
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blood flow to the mucosa (30 to 60 seconds), hemorrhagic lesions result due to breakdown in the mucosal barrier. Neurons seem to play a role also by causing reflex vasodilatation when there is breakdown of the mucosal defcnse system. The sequence of injury seems to be that a noxious agent penetrates the mucus layer of the stomach. It then causes injury to the cell membrane. There may be increased permeability or destruction of the membrane, and this causes increased intravascular water, calcium, and sodium. This, in turn, causes either cell death or loss of the cell and results in direct vascular injury, with decreased blood flow and erosion. The microcirculation is then disrupted, and there is a release of mast cells with degranulation and leukotriene release. There may be frank bleeding or multiple small hemorrhages can occur in the submucosa. The direct effect on the capillaries can mean that within 1 minute of experimental injury to the mucosa, blood flow in the superficial subepithelial capillaries ceases. This can be reversed by using various cytoprotective agents. Cytoprotectivc Agents In trying to treat and prevent physiologic mucosal damage, it makes sense to use cytoprotective agents. These include sucralfate, carbenoxalone, colloidal bismuth, and prostaglandins. Prostaglandins have recently been available for use in preventing mucosal damage. They have been specifically recommended for older patients being treated with nonsteroidal anti-inflammatory agents. Endoscopic studies have shown that these patients often have asymptomatic erosions or ulcers. Therapy must be directed at preventing injury, since symptoms may not occur until late in the course of a lesion. The prostaglandins seem to enhance mucosal defenses by increasing both blood flow and mucus production. 4 Misoprostol, the only commercially available prostaglandin agent, is given in a dose of 200 f,Lg four times daily. This drug can cause increased muscular contraction of the gastrointestinal tract, resulting in abdominal pain and diarrhea. Watery diarrhea can occur in up to 20% of patients on this medication. The diarrhea seems to be related to the amount of drug and can be decreased by lowering the dose. It appears that a dose of at least 100 f,Lg four times daily is necessary to protect the gastric mucosa. Misoprostol is contraindicated in women who are pregnant or of childbearing age, as uterine contraction can occur with abortion. Carbenoxaloneis a derivative of licorice that has been used in Europe for its antiulcer effect. It can stimulate local mucus production. This agent is not available in the United States, mainly because of its side effects of hypertension, fluid retention, and hyperkalemia. Also, there appears to be a high rate of relapse of mucosal injury on cessation of the drug. The most widely promoted agent for mucosal defense is sucralfate. This is a compound consisting of a sulfated disaccharide with aluminum hydroxide. This agent does not appear to have a direct effect on either gastric acid or pepsin secretion. Endoscopic studies, however, have shown that sucralfate does bind to the base of ulcers and provides a coating against acid permcation. 26 The substance forms complexes with pepsin that result in the inactivation of pepsin. There also appears to be stimulation of local
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prostaglandin production by sucralfate with an increase in both bicarbonate and mucus production. Studies have shown that the drug is successful in promoting healing of gastric and duodenal inflammation. Sucralfate appears to have advantages over other agents in that it is safe and is minimally absorbed. These features would seem to make it most efficacious in pregnant patients. It has also recently been studied in smokers with ulcers. There seems to be a decrease in the efficacy of H2-blocking agents in smokers, whereas sucralfate is quite effective. Unlike the H 2-blockers, there does not appear to be any significant interaction with other drugs. Clinical data indicate that sucralfate produces changes in the gastric mucosa and increases the local release of luminal prostaglandins; specifically, there are an increased blood flow in the lamina propria, a renewal of surface epithelial cells, migration of mucous cells toward the surface, and an increase in the secretion of mucus. The major side effect of this agent is constipation. Some patients also note a metallic taste. A small amount of the aluminum component is absorbed, but the Significance of this is unknown. Colloidal bismuth is a combination of bismuth and citric acid that appears to have cytoprotective effects. It seems to play a role in suppressing H elicohacter pylori, a bacteria that may cause gastritis or ulcer disease. This agent is not available for use in the United States. European studies have shown that serum bismuth concentrations are elevated in patients taking the drug for 6 weeks, but, when used fllr this period, toxicity is not a factor.
STRESS ULCERATION General Principles The decades of the 1950s through the 1970s saw increased recognition of, and an increased incidence of, stress-related gastric mucosal injury. Stress-related gastric injury initially was considered a surgical disease occurring in patients with trauma, shock, sepsis, severe burns, or central nervous system injury. It would often occur in the postoperative state. In 1842, Curling described acute duodenal ulceration in 10 extensively burned patients (Curling's ulcers). The incidence of bleeding is much greater with burns of 35% or more of the body. Harvey Cushing described acute gastric mucosal ulceration in patients with central nervous system injury due to either trauma or surgery (Cushing's ulcers). Advances in critical care, however, have extended this disease to the medical intensive care unit as well. Mechanical ventilation for respiratory failure, acute hemodialysis, sophisticated hemodynamic monitoring, and many other technologies have created an environment in which even the most critically ill patient has a chance of survival. The aging of the population continues as does the number of critically ill patients with multiorgan system failure. The net effect has been an increase in the number of patients susceptible to stress-related gastric mucosal injury, hereinafter referred to as stress ulceration. Whether the incidence of acute bleeding from stress ulceration has increased is unknown. Some studies suggest a
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decrease in the incidence of bleeding, presumably due to improved prophylactic therapy and better overall care in the modern ICU. Stress ulceration occurs predominantly as multiple asymptomatic lesions in the fundus and midbody of the stomach. These are the areas of functioning oxyntic gland mucosa. The antrum and duodenum are involved in approximately 15% of cases. Histologically, these lesions are superficial and do not extend through the mucosa. Superficial capillaries are the source of bleeding. This contrasts with peptic ulcer disease in which the lesions are few in number, are more commonly located in nonacid-producing areas, penetrate deeply beneath the mucosa, are associated with chronic inflammatory changes, and can cause massive bleeding from a single vessel. Lesions can occur within hours of stress. The background mucosal lesion is submucosal hemorrhage, which results in gastric petechiae or areas of hemorrhagic gastritis. Microscopic erosions then develop followed by superficial ulceration. Ulcers are located superficial to the submucosa. There is no fibrous base or intense inflammatory reaction as seen in chronic peptic ulcer disease. Pathogenesis The presence of acid and pepsin are prerequisites for the development of stress ulcerations. Decreases in gastric mucosal blood flow usually cause decreased acid secretion. Two conditions are exceptions, however. Sepsis and central nervous system injury are frequently associated with major and sometimes massive increases in gastric acid secretion. Gastric acid output in excess of 3 to 4 Llday is not uncommon. Trauma patients with central nervous system injury have higher gastrin levels than those without such injury. Patients with massive small bowel resection can also have gastrinmediated acid hypersecretion of this magnitude. Overall, it is the presence of acid, not the amount, that is the major factor. Complete suppression or neutralization of gastric acid prevents stress ulceration in all experimental models. The major inciting event for stress ulceration is loss of ability to preserve the integrity of the mucosa. Many factors are involved in normal gastric mucosal homeostasis. These include adequate mucosal blood flow, production of gastric mucus, maintenance of a pH gradient from the gastric lumen to intracellular space, acid-base balance, mucosal prostaglandins, and epithelial cell renewal. Bile acids and urea enhance the injury from back diffusion of H +. Bile acids enter the stomach by duodenal reflux and urea diffuses into the gastric lumen from blood. Bile salts and urea can also damage the mucosa directly. Mucosal Ischemia The stress state decreases gastric mucosal blood flow. This limits the ability of the mucosa to remove or neutralize luminal acids. Back diffusion of H+ ions causes intramucosal acidosis. Back diffusion of H+ occurs if the luminal acid concentration is high, if the mucosa is more permeable, and if mucosal blood flow is disturbed. II Bicarbonate production and delivery is impaired, which worsens the acidosis. Decreased oxygen delivery compromises aerobic metabolism, causing a high energy phosphate deficit.
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Ischemia also promotes the development of oxygen derived free radicals or superoxides, which can increase cellular damage. Gastric Mucus and Bicarbonate An intact laver of mucus functions as a mechanical barrier to the diffusion of H +.' Mucus also traps locally secreted bicarbonate, which functions as a buffer in the mucus laver of the stomach. Bicarbonate comes from two sources, plasma bicarbonate and as part of the alkaline tide from acid secretion by the parietal cell. Bicarbonate also helps to buffer intracellular acidosis. Prostaglandins Tissue injury causes the release of arachidonic acid, the precursor of all prostaglandins. Prostaglandins stimulate mucus secretion and bicarbonate, increase mucosal blood flow, and stimulate epithelial cell renewal. Administered in pharmacologic doses, they also exhibit an anti secretory effect. \Vhether severe stress reduces mucosal prostaglandin synthesis is unknown. Gastric Epithelial Cell Renewal Gastric injury results in epithelial migration from the sides of the gastric glands up to the surface to restore mucosal architecture. 11 An increase in synthesis of cells from the proliferative zone of the gastric glands also occurs. Agents such as gastrin, growth hormone, and epidermal growth factor experimentally stimulate cell division in the gastric mucosa. Epithelial migration does not occur in the healing of chronic peptic ulcer disease. Clinical Course Patients in the leD setting should be monitored for stress-related gastric bleeding. This can be accomplished with placement of a nasogastric tube. Gastric contents should be checked frequently for active bleeding as well as for occult blood. A gastrooccult test should be used because the conventional guaiac test is pH dependent and is only reliable in the pH range of 4 to 7. 24 Gastroscopy can be used to define the exact source if active bleeding develops. The ultimate prognosis depends on correcting the underlying disease that causes the stress state. Seventy-five to 100% of leD patients have endoscopic evidence of gastric injury within 24 to 48 hours. Approximately 20% of these patients will develop overt or occult bleeding. Approximately 2% to 5% will develop clinically significant bleeding. Therapy is directed at maintaining a constant gastric pH greater than 3.5. At that level, the incidence of bleeding diminishes significantly. At present, antacids, H 2 -blockers, and sucralfate are approximately equally effective as prophylaxis for stress ulceration. Therapy Gastric pH should be monitored hourly and a dose of antacids (usually 30 to 60 mL) should be given to maintain the pH above 3.5. This regimen has proved effective in many studies but is inconvenient to administer and can result in diarrhea and metabolic abnormalities. Magnesium intoxi-
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cation can occur in patients with renal bilure given magnesium-containing antacids. IS. :21 Drugs should be administered intravenously either by bolus or continuous infusion. A continuous infusion of cimetidine or ranitidine is more eflective at maintaining the pH above 3.0. These drugs have documented efficacy as prophylactic therapy. H:2-blockers may also act by cytoprotective mechanisms. They increase mucosal blood flow and stimulate mucus and prostaglandin synthesis.~· 12 Sucralf~lte is administered orally and is an effective prophylactic therapy. It functions as a weak antacid, has antipepsin activity, stimulates prostaglandin synthesis, and forms a protective coating over inflamed areas of mucosa.:2~ It also has the potential advantage of decreasing the incidence of nosocomial infections that havc been described in patients with highdose acid suppression.'"' 20 Its disadvantages are that it can only be administered orally and causes constipation in some patients. Prostaglandin E2 derivatives have been used as strcss ulcer prophylaxis in several studies and at present have not proved effective. Prostaglandin E I analogues are effective as prophylaxis against gastric injury induced by nonsteroidal anti-inflammatory drugs. Acute Hemorrhage Occasionally, life-threatening gastric bleeding occurs. If possible, patients should undergo emergency endoscopy to define the source. Therapeutic endoscopy using the heater probe, bipolar electrocoagulation, or laser photocoagulation is less helpful unless the bleeding points are limited. Antacids, H 2 -blockers, or sucralf~,te should be administered. In cases of massive bleeding, emergency arteriography can be performed with selective catheterization of the left gastric artery. An intra-arterial infusion of vasopressin for 48 to 72 hours can be given at a dosage of 0.2 to 0.4 units/ minute. Selective embolization of the left gastric artery can also be performed. The vasopressin should be gradually tapered before it is discontinued. Surgery plays a limited role because of the diffuse nature of the bleeding. There is no general consensus as to what operation to recommend in life-threatening situations. Vagotomy and pyloroplasty, subtotal and total gastrectomy, have a mortality approaching 80% and the rate of rebleeding is high unless a total gastrectomy is performed.
DIEULAFOY'S LESION The overwhelming majority of massive acute upper gastrointestinal bleeding can be explained by obvious anatomic pathology. However, it is estimated that 5% to 10% of bleeding from the upper gastrointestinal tract remains unexplained despite standard evaluation. Dieulafoy's lesion consists of an abnormally large submucosal artery that usually ruptures into the stomach and causes massive bleeding. Although the lesion was first described by Callard in 1884, it bears the name of Dieulafoy, who characterized three cases in 1898. Dieulafoy's lesion should be distinguished from other gastric vascular abnormalities such as arteriovenous malformations, vascular neoplasms, or true vascular aneurysms.
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Clinical Presentation and Diagnosis
A review of confirmed patients with this disorder shows the typical presentation of upper gastrointestinal bleeding, which is often quite impressive in volume and recurrent in nature. There mayor may not be associated dyspeptic symptoms or a previous history of peptic ulcer disease. The youngest patient was 20 months old, the oldest 93 years, and the median age was ,54 years. Alcohol use has been implicated in a large percentage of patients in some series; in other series, it does not appear to play a role. The diagnosis is usually made by gastroscopy or laparotomy, which shows the classic findings of a visible vessel most often located high in the fundus of the stomach and within 5 to 6 cm of the esophagogastric junction. There may be a small mucosal erosion, usually less than ,5 mm in diameter, surrounded by normal mucosa. yI ultiple endoscopies may be necessary to define the bleeding point because of the minute nature of the lesion or the volume of blood in the stomach at the time of the endoscopy. Despite the overwhelming majority being found in the proximal stomach, a small percentage have been located in the distal stomach beyond 10 cm from the esophagogastric junction. Lesions havc also been describcd in the duodenum and jejunum, as well as the colon, The incidence of this lesion is not known, and it most likely occurs more frequently than reported in the literature, In general, barium studies are not helpful in diagnosis, nor is angiography particularly diagnostic, except to rule out another diagnosis. The diagnosis should always be entertained in a patient with repetitive bleeding without definitive diagnosis on repeated endoscopies, Sometimes a lesion can be missed even at laparotomy, and occasionally the bleeding can be precipitated by having the surgeon swab the suspicious area with a gauze and watching for arterial bleeding. Pathogenesis
The pathogenesis of this lesion remains unclear. Dieulafoy initially believed the lesion to be the initial stage of a gastric ulcer, which he called "exulceratio simplex," It was also thought that arteriosclerosis and aneurysmal dilatation played a role. However, several studies have not borne this out, It is agreed that the bleeding is caused by a dysplastic, unusually large-sized artery coursing through the submucosa and ranging in diameter between 1 and 3 mm, There are no signs of deep ulceration with penetration of the muscularis propria or aneurysmal dilation; inflammation and arteriosclerosis arc prominently absent. ~1 ultiple histopathologic characteristics of the lesion as described by Juler show (1) a gastric mucosal defect with fibrinoid necrosis at the base; (2) large thick-walled arteries at the base; (:3) a dysplastic artery below the muscularis mucosa; and (4) large thick-walled veins adjacent to the artery. to The theory of so-called "caliber persistent arteries" have been proposed by Voth and later expanded upon hy Molnar to explain large volume bleeding from a small mucosal injury. 19 In this theory, the normal reduction of vascular size seen as the vessels penetrate the muscular wall of the stomach does not occur with this lesion, leaving a dysplastic vessel susceptible to rupture by its proximity to a small mucosal injury. They further explained the propensity of bleeding from the upper stomach by noting
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that in the rcgion of the lesscr curvc, the submucosal arteries do not arise from the large extensive plexus in the suhmucosa but rathcr arise directlv b'om the arterial chain along the lesser curvature of the stomach. Juler argucs that the thrombosis precedes the gastric mucosal breakdown and hypothesizes that chronic gastritis predisposes to vascular dysplasia, leading to thrombosis, necrosis of the vascular wall, and eventual rupture. . Management Surgical treatment has been considered the treatment of choice for this lesion. However, with the advent of therapeutic endoscopy, this trend may be changing. During surgery, the surgeon must focus on the cardia and the fundus of the stomach. Operative procedures include ligation of the vessel, proximal gastric resection, wedge resection, and even ~tandard peptic surgery. Several authors give excellent results with simple ligation; others, however, state that rebleeding rates are substantial and thus resection is necessary, especially to confirm the histologic diagnosis. "Blind" Billroth 11 resections or a total gastrectomy should be avoided at all costs. Standard "ulcer surgery" such as vagotomy and pyloroplasty appear to be unnecessary for this disease. Angiography is helpful to identify extravasation of dye into the gastric lumen but otherwise is not specific except to rule out aneurysmal formations or arteriovenous shunting. Case reports exist regarding the use of arterial vasopressin or gastric artery embolization with bleeding from this disordcr. The results appear to be mixed, and thus the role of therapeutic angiography in this disorder remains to be defined. The role of therapeutic endoscopy has changed over the past several years and now has a role in this disorder. YIultiple endoscopic modalities have been used, most using thermal devices such as the heater probe, laser, or bicap, again, with variable rcsults. Pointner et al endoscopically treated 33 patients with Dieulafoy's disease, 18 of them successfully using a combination of thermal devices as well as sclerotherapy. Lin et al successfully treated eight patients with this disorder using various modalities including injection techniques. 15 Long-term follow-up results are lacking in most of these studies and the numhers are quitc small. Certainly, high-risk surgical patients should be offered the alternative of endoscopic treatment if at all feasible. General medical measures such as volume replacement are, of course, important, but gastric lavage, antiulcer therapy, and intravenous pitressin appear to have no effect on controlling bleeding. Before the endoscopic era, the prognosis of Dieulafoy's lesion was poor, probably because of poor recognition, with mortality approaching 80%. Subsequently, more recent series showed a marked improvement in survival with mortality approximating 25%. This is a testament to earlier diagnosis, endoscopic treatment, and earlier surgical therapy with avoidance of "blind" peptic operations. SUMMARY The stomach possesses many mechanisms for protection against stress ulceration. The gastric microcirculation, prostaglandins, mucus secretion,
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epithelial cell renewal, and muscle tone arc f~lCtors involved in gastric cytoprotection. Therapy is partially directed at augmenting these natural physiologie dcfense mechanisms to prevent and promote healing of stress ulceration. Drugs such as sucralfate, carbenoxalone, colloidal bismuth, and prostaglandins are used. Stress ulceration is an important cause of upper gastrointestinal tract hemorrhage in postoperative and critically ill patients in the intensive care unit setting. Preventive therapy includes neutralization of gastric acid by antacids, suppression of gastric acid secretion by II 2 -receptor blockers, administration of cytoprotective agents, and correction of the underlying stress state. Active bleeding requires accurate diagnosis by gastroscopy. Additional therapy may be necessary, including intra-arterial administration of vasopressin and occasionally surgery. ,. Dieulafoy's lesion is an unusual stress-related cause for upper gastrointestinal bleeding. The area of mucosal injury is minute but underneath lies a large submucosal gastric artery. It can cause massive bleeding and is often missed at initial gastroscopy. The pathogenesis of Dieulafoy's lesion is complex and the mainstay of therapy has been surgical. Ligation of the vessel, wedge resection, or proximal gastric resection is performed. Therapeutic endoscopy with endoscopic cauterization or injection has changed the approach to this lesion.
REFERENCES 1. AI-Kawas FH, O'Keek J: Nd:Yag laser treatment of a bleeding Dieulafoy"s lesiou. Gastrointest Endosc 33:38, 1987 2. Baker DE: I\lisoprostol: '\iew drug evaluation. Prac GastroenteroI13:8, 1989 3. Bruggeman TM, Wood JG, Davenport HW: Local control of blood flow in the dog's stomach: Vasodilatation caused hy acid hack-diffusion following topical application of salicylic acid. C;astroenterology 77:7:36, 1979 4. Chadhnry TK, Jacobsen ED: Prostaglandin cvtoprotection of gastric mucosa. Gastroenterology 74:59, 1978 5. Driks ~IR, Craven DE, Celli BR, et al: l\'osoeomial pneumonia in intubated patients given sucral£ate as compared with antacids or histamine type 2 blockers. The role of gastric colonization. N Engl J Med 317:1:376. 1987 6. Durham JD. KUlllpe DA. Rothbarth LJ. et al: Dieulafoy disease: Arteriographic findings and treatment. Radiologv 174:937, 1990 7. Friedman CJ. Oillinger NIJ, Suratt PM, et al: Prophylaxis of upper gastrointestinal helllorrhage in patients requiring mechanical ventilation. Crit Care Med 10:316, 1982 8. Goldenherg SP: Endoscopic treatment of Dieulafoy's lesion of the duodenum. Am J Gastroenterol 87:4.52, 1990 9. Hoffman.r. Beck H, Jemen JE: Dieulafoy's lesion. Surg Gynecol Obstet 1.59:,537, 1984 10. Juler GL, Labitzke HG, Lamb H, et al: The pathogenesis of Dieulaf()y's gastric erosion. Am J Gastroenterol 79:195, 1984 11. Kivilaasko E, Frolllll1 D, Silen \V: Relationship between ulceration and intramural pH of gastric mucosa during hemorrhagic shock. Surgery 84: 70, 1978 12. Konturek SI. Brzozowshi T. Piastucki J, et al: Gastric mucosal protection by agents altering gastric mucosal sulfhydryls. Digestion :37:65, 1987 13. Lacey EH, Ito S: Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Lab Invest 51:57:3, 1984 14. Lewis JH, \Veingold AB: The lIse of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol 80:912, 1985 15. Lin HJ, Lee FY, Tsai YT, et al: Therapeutic endoscopy f()r Dieulaf()y's disease. J Clin Gastroenterol 1l:.507, 1989
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Hi. LoperfiC\o S: Endoscopic hemostatis of gastrie bleeding Irom Dieulal()y's ulcer with histoacrv!. Endoscopy 21 :199, 191>9 17. Lllcas CE: Stress ulceration: The dinic,,1 problem. \Vorld J Surg 5:1:39, 1981 1H. 'v!arrollP CC, Silcn \V: Pathogenesis. diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterol 1:3:6:3,5 19H4 19. ~lolnar P, i\liko T: ~lultiple arterial caliber persistence resulting in hematomas and [atal rupturc of the gastric wall. Am J Surg Pathol 6:8:3, 1982 20. ~lovlin GC, Patenson DG, Headley-Whyte J, et al: Aspiration of gastric bacteria in antacid-treated paticnts: A frequent cause of postoperative colonization of the airway. Lancet 1:242, 1982 2l. Schiessel H, Feil \V, \Venzl E: Mechanisms of stress ulceration and implications for treatment. Gastroenterol Clin North Am 19(1): 101, 1990 29 Shuman HB, Schuster DP. Zuckerman CR: Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern 'vIed 104:562, 19H7 2:3. Silen \V, Ito S: ~lechanisms for rapid re-epithelization of the gastric mucosal surface. Am Rev Physiol 47:217, 1985 24. Starlinger ~l, Sporn P, Schemper M, et al: The use of the hemoccult test for detection of blood in gastric aspirates. Scand J Gastroenterol 18:72:3, 198:3 25. Szabo S, Gallagher GT, Homer HC. et al: Role of the adrenal cortex and gastric mucosal protection bv prostaglandins, sullhydryls, and cill1etidine in the rat. Gastroenterology 8,5: 1:384, 198:3 26. Tarnawski A, Hollander D, Krause \V], et al: Effect of sucralfate on normal gastric mucosa. Histologic, ultrastrnctural and hmctional assessment. Gastroenterology 84:1:3:30, 198:3 27. Try],a ~l, Zervounov F. Torok lvI, et a1: Prevention of acute stress bleeding with s\lcralf~\te, antacids, or cimetidine. Am J "ied (suppl 26):55, 1986 28. Van Zanten SJ. Bartelsman JF, Schipper "lE, et al: Recurrent massive hematemesis from Dielllafov's vascular malformations. Gut 27:21:3, 1986 29. vVallace JL: Mucosal defense: New avenucs for treatment of ulcer disease? Gastroenterol Clin North Am 19:87, 1990 30. Zinner MJ, Zuiclcma GD, Smith PL, et al: The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 15:3:214, 1981
Address reprint requcsts to Geoffrey L. Braden, I\ID Suite IL 22 2 Bala Plaza Bala CyI\wyd, PA 19004
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Cytoprotection and Stress Ulceration
Jeffrey Pilchrnan, MD,* Harvey B. Lefton, MD,t and Ceoffrey L. Braden, MDt.
CYTOPROTECTION The term "cytoprotection" has been used in recent years to denote the property of certain substances to protect the stomach from injury. vVhen discussing those agents that can cause injury to gastric mucosa and result in a pathologic state, cytoprotection has been referred to as stimulating natural defense mechanisms. An understanding of cytoprotection then really rcquires an understanding of the natural factors that promote well-being of the mucosa and those circumstances that alter the natural state. Cytoprotection is an ongoing physiologic process. It is a process in which the stomach actively repairs itself. This process does not involve the alteration of gastric acid secretion. Pathophysiology The key to the concept of cytoprotection is the maintenance and replenishment of gastric mucosal cells through the preservation and healing effect of the gastric microcirculation. Studies in laboratory animals using gastric irritants show the major role the microcirculation plays in preventing injury. It appears that prostaglandins help prevent hemorrhage by restoring the microcirculation. 21 These compounds also help prevent damage to mucosal cells and stimulate replenishment of mucosal and submucosal cells. There is not a change in gastric acid secretion; therefore, the process of protecting the mucosa appears to be independent of acid secretion. Studies have shown that there must be an intact adrenal gland producing glucocorticoids and catecholamines for this natural protective process to work. It also appears that sulfhydryls, carotenoids, colloidal bismuth, and sucralfate From the Division of Gastroenterology, Pennsylvania
~\'Iedical
College of Pennsylvania, Philadelphia,
*Clinical Assistant Professor of Medicine tClinical Professor of Medicine :j:Clinical Associate Professor of "'Iedicine
Medical Clinics of North America-\'ol. 75. :-.lo. 4, July 1991
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can play a pharmacologic role in protecting the mucosa. 23 These agents do not scem to inhibit gastric acid secretion. Studies indicate that vagal tone must be normal and acetylcholine production adequate for the natural and pharmacologic cytoprotective agents to work. Many irritative agents cause hemorrhage or ischemic infarcts of the mucosa and submucosal areas, while sparing the deeper layers of the stomach. Those agents that help in cytoprotection do so by preserving the microcirculation rather than directly preserving the injured mucosal cells. It is this microcirculation that provides the necessary oxygen and nutrients for the repair of superficial gastric damage. 23 Studies using either ethanol or aspirin to cause gastric injury have shown cytoprotective agents appear to protect the microcirculation rather than specifically the mucosa. Aspirin and other nonsteroidal anti-inflammatory agents injure mucosal cells and damage microcirculatory elements. Also, many of these drugs interfere with coagulation and platelet aggregation, enhancing the potential for serious bleeding. The benefit of cytoprotective agents is that they stimulate regeneration of injured areas rather than specifically protecting against the noxious substance. As can readily be seen, the integrity of the gastric mucosa then depends on an interplay of both defensive and aggressive factors. Gastric cells produce mucus, which has a protective effect by covering the mucosal cells. Mucus serves as a lubricant and also a bufier that traps microorganisms. The mucus mixes with secreted bicarbonate and may help to keep the pH of the surface of the stomach near neutral levels. Thus, the mucus layer has a direct protective effect by decreasing penetration of noxious agents and maintaining the neutral pH directly above the mucosal cells. Another protective efiect of the gastric mucosa is the way in which cell turnover occurs. The cells in the mucosa of the stomach are replaced every 2 to 4 days. These cells are extruded with the other neighboring cells filling in the space, so that there is minimal contact between the underlying basement membrane and the surface environment. This helps prevent injury to the submucosa. The major factor in mucosal defense is the microcirculation that supplies oxygen and nutrients to the epithelium. These capillaries also act by removing noxious agents that are absorbed. It appears, also, that the smooth muscle may play a role in the protection of the gastric microcirculation from injury. Hypercontractibility of the stomach can lead to localized arcas of ischemia. Some prostaglandins work by relaxing smooth muscle. This is one of the components of the cytoprotective effect. Experimental data are still needed to confirm this, but certainly there appears to be a muscular and vascular interplay to account for some aspects of mucosal integrity. In states of high muscular tone, there may be compromise of the microcirculation leading to localized ischemia and, therefore, to a greater chance for injury. When the mucosa is damaged, plasma proteins flow into the mucosa, and there is an increase in blood flow. This may aid in the removal of noxious substances. In experimental studies, when irritants are placed on the gastric mucosa, there does appear to be a reactive hyperemia in response to the toxic agent. This seems to help remove the substance. Experiments have shown that when there is even a temporary cessation of
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blood flow to the mucosa (30 to 60 seconds), hemorrhagic lesions result due to breakdown in the mucosal barrier. Neurons seem to play a role also by causing reflex vasodilatation when there is breakdown of the mucosal defcnse system. The sequence of injury seems to be that a noxious agent penetrates the mucus layer of the stomach. It then causes injury to the cell membrane. There may be increased permeability or destruction of the membrane, and this causes increased intravascular water, calcium, and sodium. This, in turn, causes either cell death or loss of the cell and results in direct vascular injury, with decreased blood flow and erosion. The microcirculation is then disrupted, and there is a release of mast cells with degranulation and leukotriene release. There may be frank bleeding or multiple small hemorrhages can occur in the submucosa. The direct effect on the capillaries can mean that within 1 minute of experimental injury to the mucosa, blood flow in the superficial subepithelial capillaries ceases. This can be reversed by using various cytoprotective agents. Cytoprotectivc Agents In trying to treat and prevent physiologic mucosal damage, it makes sense to use cytoprotective agents. These include sucralfate, carbenoxalone, colloidal bismuth, and prostaglandins. Prostaglandins have recently been available for use in preventing mucosal damage. They have been specifically recommended for older patients being treated with nonsteroidal anti-inflammatory agents. Endoscopic studies have shown that these patients often have asymptomatic erosions or ulcers. Therapy must be directed at preventing injury, since symptoms may not occur until late in the course of a lesion. The prostaglandins seem to enhance mucosal defenses by increasing both blood flow and mucus production. 4 Misoprostol, the only commercially available prostaglandin agent, is given in a dose of 200 f,Lg four times daily. This drug can cause increased muscular contraction of the gastrointestinal tract, resulting in abdominal pain and diarrhea. Watery diarrhea can occur in up to 20% of patients on this medication. The diarrhea seems to be related to the amount of drug and can be decreased by lowering the dose. It appears that a dose of at least 100 f,Lg four times daily is necessary to protect the gastric mucosa. Misoprostol is contraindicated in women who are pregnant or of childbearing age, as uterine contraction can occur with abortion. Carbenoxaloneis a derivative of licorice that has been used in Europe for its antiulcer effect. It can stimulate local mucus production. This agent is not available in the United States, mainly because of its side effects of hypertension, fluid retention, and hyperkalemia. Also, there appears to be a high rate of relapse of mucosal injury on cessation of the drug. The most widely promoted agent for mucosal defense is sucralfate. This is a compound consisting of a sulfated disaccharide with aluminum hydroxide. This agent does not appear to have a direct effect on either gastric acid or pepsin secretion. Endoscopic studies, however, have shown that sucralfate does bind to the base of ulcers and provides a coating against acid permcation. 26 The substance forms complexes with pepsin that result in the inactivation of pepsin. There also appears to be stimulation of local
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prostaglandin production by sucralfate with an increase in both bicarbonate and mucus production. Studies have shown that the drug is successful in promoting healing of gastric and duodenal inflammation. Sucralfate appears to have advantages over other agents in that it is safe and is minimally absorbed. These features would seem to make it most efficacious in pregnant patients. It has also recently been studied in smokers with ulcers. There seems to be a decrease in the efficacy of H2-blocking agents in smokers, whereas sucralfate is quite effective. Unlike the H 2-blockers, there does not appear to be any significant interaction with other drugs. Clinical data indicate that sucralfate produces changes in the gastric mucosa and increases the local release of luminal prostaglandins; specifically, there are an increased blood flow in the lamina propria, a renewal of surface epithelial cells, migration of mucous cells toward the surface, and an increase in the secretion of mucus. The major side effect of this agent is constipation. Some patients also note a metallic taste. A small amount of the aluminum component is absorbed, but the Significance of this is unknown. Colloidal bismuth is a combination of bismuth and citric acid that appears to have cytoprotective effects. It seems to play a role in suppressing H elicohacter pylori, a bacteria that may cause gastritis or ulcer disease. This agent is not available for use in the United States. European studies have shown that serum bismuth concentrations are elevated in patients taking the drug for 6 weeks, but, when used fllr this period, toxicity is not a factor.
STRESS ULCERATION General Principles The decades of the 1950s through the 1970s saw increased recognition of, and an increased incidence of, stress-related gastric mucosal injury. Stress-related gastric injury initially was considered a surgical disease occurring in patients with trauma, shock, sepsis, severe burns, or central nervous system injury. It would often occur in the postoperative state. In 1842, Curling described acute duodenal ulceration in 10 extensively burned patients (Curling's ulcers). The incidence of bleeding is much greater with burns of 35% or more of the body. Harvey Cushing described acute gastric mucosal ulceration in patients with central nervous system injury due to either trauma or surgery (Cushing's ulcers). Advances in critical care, however, have extended this disease to the medical intensive care unit as well. Mechanical ventilation for respiratory failure, acute hemodialysis, sophisticated hemodynamic monitoring, and many other technologies have created an environment in which even the most critically ill patient has a chance of survival. The aging of the population continues as does the number of critically ill patients with multiorgan system failure. The net effect has been an increase in the number of patients susceptible to stress-related gastric mucosal injury, hereinafter referred to as stress ulceration. Whether the incidence of acute bleeding from stress ulceration has increased is unknown. Some studies suggest a
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decrease in the incidence of bleeding, presumably due to improved prophylactic therapy and better overall care in the modern ICU. Stress ulceration occurs predominantly as multiple asymptomatic lesions in the fundus and midbody of the stomach. These are the areas of functioning oxyntic gland mucosa. The antrum and duodenum are involved in approximately 15% of cases. Histologically, these lesions are superficial and do not extend through the mucosa. Superficial capillaries are the source of bleeding. This contrasts with peptic ulcer disease in which the lesions are few in number, are more commonly located in nonacid-producing areas, penetrate deeply beneath the mucosa, are associated with chronic inflammatory changes, and can cause massive bleeding from a single vessel. Lesions can occur within hours of stress. The background mucosal lesion is submucosal hemorrhage, which results in gastric petechiae or areas of hemorrhagic gastritis. Microscopic erosions then develop followed by superficial ulceration. Ulcers are located superficial to the submucosa. There is no fibrous base or intense inflammatory reaction as seen in chronic peptic ulcer disease. Pathogenesis The presence of acid and pepsin are prerequisites for the development of stress ulcerations. Decreases in gastric mucosal blood flow usually cause decreased acid secretion. Two conditions are exceptions, however. Sepsis and central nervous system injury are frequently associated with major and sometimes massive increases in gastric acid secretion. Gastric acid output in excess of 3 to 4 Llday is not uncommon. Trauma patients with central nervous system injury have higher gastrin levels than those without such injury. Patients with massive small bowel resection can also have gastrinmediated acid hypersecretion of this magnitude. Overall, it is the presence of acid, not the amount, that is the major factor. Complete suppression or neutralization of gastric acid prevents stress ulceration in all experimental models. The major inciting event for stress ulceration is loss of ability to preserve the integrity of the mucosa. Many factors are involved in normal gastric mucosal homeostasis. These include adequate mucosal blood flow, production of gastric mucus, maintenance of a pH gradient from the gastric lumen to intracellular space, acid-base balance, mucosal prostaglandins, and epithelial cell renewal. Bile acids and urea enhance the injury from back diffusion of H +. Bile acids enter the stomach by duodenal reflux and urea diffuses into the gastric lumen from blood. Bile salts and urea can also damage the mucosa directly. Mucosal Ischemia The stress state decreases gastric mucosal blood flow. This limits the ability of the mucosa to remove or neutralize luminal acids. Back diffusion of H+ ions causes intramucosal acidosis. Back diffusion of H+ occurs if the luminal acid concentration is high, if the mucosa is more permeable, and if mucosal blood flow is disturbed. II Bicarbonate production and delivery is impaired, which worsens the acidosis. Decreased oxygen delivery compromises aerobic metabolism, causing a high energy phosphate deficit.
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Ischemia also promotes the development of oxygen derived free radicals or superoxides, which can increase cellular damage. Gastric Mucus and Bicarbonate An intact laver of mucus functions as a mechanical barrier to the diffusion of H +.' Mucus also traps locally secreted bicarbonate, which functions as a buffer in the mucus laver of the stomach. Bicarbonate comes from two sources, plasma bicarbonate and as part of the alkaline tide from acid secretion by the parietal cell. Bicarbonate also helps to buffer intracellular acidosis. Prostaglandins Tissue injury causes the release of arachidonic acid, the precursor of all prostaglandins. Prostaglandins stimulate mucus secretion and bicarbonate, increase mucosal blood flow, and stimulate epithelial cell renewal. Administered in pharmacologic doses, they also exhibit an anti secretory effect. \Vhether severe stress reduces mucosal prostaglandin synthesis is unknown. Gastric Epithelial Cell Renewal Gastric injury results in epithelial migration from the sides of the gastric glands up to the surface to restore mucosal architecture. 11 An increase in synthesis of cells from the proliferative zone of the gastric glands also occurs. Agents such as gastrin, growth hormone, and epidermal growth factor experimentally stimulate cell division in the gastric mucosa. Epithelial migration does not occur in the healing of chronic peptic ulcer disease. Clinical Course Patients in the leD setting should be monitored for stress-related gastric bleeding. This can be accomplished with placement of a nasogastric tube. Gastric contents should be checked frequently for active bleeding as well as for occult blood. A gastrooccult test should be used because the conventional guaiac test is pH dependent and is only reliable in the pH range of 4 to 7. 24 Gastroscopy can be used to define the exact source if active bleeding develops. The ultimate prognosis depends on correcting the underlying disease that causes the stress state. Seventy-five to 100% of leD patients have endoscopic evidence of gastric injury within 24 to 48 hours. Approximately 20% of these patients will develop overt or occult bleeding. Approximately 2% to 5% will develop clinically significant bleeding. Therapy is directed at maintaining a constant gastric pH greater than 3.5. At that level, the incidence of bleeding diminishes significantly. At present, antacids, H 2 -blockers, and sucralfate are approximately equally effective as prophylaxis for stress ulceration. Therapy Gastric pH should be monitored hourly and a dose of antacids (usually 30 to 60 mL) should be given to maintain the pH above 3.5. This regimen has proved effective in many studies but is inconvenient to administer and can result in diarrhea and metabolic abnormalities. Magnesium intoxi-
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cation can occur in patients with renal bilure given magnesium-containing antacids. IS. :21 Drugs should be administered intravenously either by bolus or continuous infusion. A continuous infusion of cimetidine or ranitidine is more eflective at maintaining the pH above 3.0. These drugs have documented efficacy as prophylactic therapy. H:2-blockers may also act by cytoprotective mechanisms. They increase mucosal blood flow and stimulate mucus and prostaglandin synthesis.~· 12 Sucralf~lte is administered orally and is an effective prophylactic therapy. It functions as a weak antacid, has antipepsin activity, stimulates prostaglandin synthesis, and forms a protective coating over inflamed areas of mucosa.:2~ It also has the potential advantage of decreasing the incidence of nosocomial infections that havc been described in patients with highdose acid suppression.'"' 20 Its disadvantages are that it can only be administered orally and causes constipation in some patients. Prostaglandin E2 derivatives have been used as strcss ulcer prophylaxis in several studies and at present have not proved effective. Prostaglandin E I analogues are effective as prophylaxis against gastric injury induced by nonsteroidal anti-inflammatory drugs. Acute Hemorrhage Occasionally, life-threatening gastric bleeding occurs. If possible, patients should undergo emergency endoscopy to define the source. Therapeutic endoscopy using the heater probe, bipolar electrocoagulation, or laser photocoagulation is less helpful unless the bleeding points are limited. Antacids, H 2 -blockers, or sucralf~,te should be administered. In cases of massive bleeding, emergency arteriography can be performed with selective catheterization of the left gastric artery. An intra-arterial infusion of vasopressin for 48 to 72 hours can be given at a dosage of 0.2 to 0.4 units/ minute. Selective embolization of the left gastric artery can also be performed. The vasopressin should be gradually tapered before it is discontinued. Surgery plays a limited role because of the diffuse nature of the bleeding. There is no general consensus as to what operation to recommend in life-threatening situations. Vagotomy and pyloroplasty, subtotal and total gastrectomy, have a mortality approaching 80% and the rate of rebleeding is high unless a total gastrectomy is performed.
DIEULAFOY'S LESION The overwhelming majority of massive acute upper gastrointestinal bleeding can be explained by obvious anatomic pathology. However, it is estimated that 5% to 10% of bleeding from the upper gastrointestinal tract remains unexplained despite standard evaluation. Dieulafoy's lesion consists of an abnormally large submucosal artery that usually ruptures into the stomach and causes massive bleeding. Although the lesion was first described by Callard in 1884, it bears the name of Dieulafoy, who characterized three cases in 1898. Dieulafoy's lesion should be distinguished from other gastric vascular abnormalities such as arteriovenous malformations, vascular neoplasms, or true vascular aneurysms.
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Clinical Presentation and Diagnosis
A review of confirmed patients with this disorder shows the typical presentation of upper gastrointestinal bleeding, which is often quite impressive in volume and recurrent in nature. There mayor may not be associated dyspeptic symptoms or a previous history of peptic ulcer disease. The youngest patient was 20 months old, the oldest 93 years, and the median age was ,54 years. Alcohol use has been implicated in a large percentage of patients in some series; in other series, it does not appear to play a role. The diagnosis is usually made by gastroscopy or laparotomy, which shows the classic findings of a visible vessel most often located high in the fundus of the stomach and within 5 to 6 cm of the esophagogastric junction. There may be a small mucosal erosion, usually less than ,5 mm in diameter, surrounded by normal mucosa. yI ultiple endoscopies may be necessary to define the bleeding point because of the minute nature of the lesion or the volume of blood in the stomach at the time of the endoscopy. Despite the overwhelming majority being found in the proximal stomach, a small percentage have been located in the distal stomach beyond 10 cm from the esophagogastric junction. Lesions havc also been describcd in the duodenum and jejunum, as well as the colon, The incidence of this lesion is not known, and it most likely occurs more frequently than reported in the literature, In general, barium studies are not helpful in diagnosis, nor is angiography particularly diagnostic, except to rule out another diagnosis. The diagnosis should always be entertained in a patient with repetitive bleeding without definitive diagnosis on repeated endoscopies, Sometimes a lesion can be missed even at laparotomy, and occasionally the bleeding can be precipitated by having the surgeon swab the suspicious area with a gauze and watching for arterial bleeding. Pathogenesis
The pathogenesis of this lesion remains unclear. Dieulafoy initially believed the lesion to be the initial stage of a gastric ulcer, which he called "exulceratio simplex," It was also thought that arteriosclerosis and aneurysmal dilatation played a role. However, several studies have not borne this out, It is agreed that the bleeding is caused by a dysplastic, unusually large-sized artery coursing through the submucosa and ranging in diameter between 1 and 3 mm, There are no signs of deep ulceration with penetration of the muscularis propria or aneurysmal dilation; inflammation and arteriosclerosis arc prominently absent. ~1 ultiple histopathologic characteristics of the lesion as described by Juler show (1) a gastric mucosal defect with fibrinoid necrosis at the base; (2) large thick-walled arteries at the base; (:3) a dysplastic artery below the muscularis mucosa; and (4) large thick-walled veins adjacent to the artery. to The theory of so-called "caliber persistent arteries" have been proposed by Voth and later expanded upon hy Molnar to explain large volume bleeding from a small mucosal injury. 19 In this theory, the normal reduction of vascular size seen as the vessels penetrate the muscular wall of the stomach does not occur with this lesion, leaving a dysplastic vessel susceptible to rupture by its proximity to a small mucosal injury. They further explained the propensity of bleeding from the upper stomach by noting
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that in the rcgion of the lesscr curvc, the submucosal arteries do not arise from the large extensive plexus in the suhmucosa but rathcr arise directlv b'om the arterial chain along the lesser curvature of the stomach. Juler argucs that the thrombosis precedes the gastric mucosal breakdown and hypothesizes that chronic gastritis predisposes to vascular dysplasia, leading to thrombosis, necrosis of the vascular wall, and eventual rupture. . Management Surgical treatment has been considered the treatment of choice for this lesion. However, with the advent of therapeutic endoscopy, this trend may be changing. During surgery, the surgeon must focus on the cardia and the fundus of the stomach. Operative procedures include ligation of the vessel, proximal gastric resection, wedge resection, and even ~tandard peptic surgery. Several authors give excellent results with simple ligation; others, however, state that rebleeding rates are substantial and thus resection is necessary, especially to confirm the histologic diagnosis. "Blind" Billroth 11 resections or a total gastrectomy should be avoided at all costs. Standard "ulcer surgery" such as vagotomy and pyloroplasty appear to be unnecessary for this disease. Angiography is helpful to identify extravasation of dye into the gastric lumen but otherwise is not specific except to rule out aneurysmal formations or arteriovenous shunting. Case reports exist regarding the use of arterial vasopressin or gastric artery embolization with bleeding from this disordcr. The results appear to be mixed, and thus the role of therapeutic angiography in this disorder remains to be defined. The role of therapeutic endoscopy has changed over the past several years and now has a role in this disorder. YIultiple endoscopic modalities have been used, most using thermal devices such as the heater probe, laser, or bicap, again, with variable rcsults. Pointner et al endoscopically treated 33 patients with Dieulafoy's disease, 18 of them successfully using a combination of thermal devices as well as sclerotherapy. Lin et al successfully treated eight patients with this disorder using various modalities including injection techniques. 15 Long-term follow-up results are lacking in most of these studies and the numhers are quitc small. Certainly, high-risk surgical patients should be offered the alternative of endoscopic treatment if at all feasible. General medical measures such as volume replacement are, of course, important, but gastric lavage, antiulcer therapy, and intravenous pitressin appear to have no effect on controlling bleeding. Before the endoscopic era, the prognosis of Dieulafoy's lesion was poor, probably because of poor recognition, with mortality approaching 80%. Subsequently, more recent series showed a marked improvement in survival with mortality approximating 25%. This is a testament to earlier diagnosis, endoscopic treatment, and earlier surgical therapy with avoidance of "blind" peptic operations. SUMMARY The stomach possesses many mechanisms for protection against stress ulceration. The gastric microcirculation, prostaglandins, mucus secretion,
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epithelial cell renewal, and muscle tone arc f~lCtors involved in gastric cytoprotection. Therapy is partially directed at augmenting these natural physiologie dcfense mechanisms to prevent and promote healing of stress ulceration. Drugs such as sucralfate, carbenoxalone, colloidal bismuth, and prostaglandins are used. Stress ulceration is an important cause of upper gastrointestinal tract hemorrhage in postoperative and critically ill patients in the intensive care unit setting. Preventive therapy includes neutralization of gastric acid by antacids, suppression of gastric acid secretion by II 2 -receptor blockers, administration of cytoprotective agents, and correction of the underlying stress state. Active bleeding requires accurate diagnosis by gastroscopy. Additional therapy may be necessary, including intra-arterial administration of vasopressin and occasionally surgery. ,. Dieulafoy's lesion is an unusual stress-related cause for upper gastrointestinal bleeding. The area of mucosal injury is minute but underneath lies a large submucosal gastric artery. It can cause massive bleeding and is often missed at initial gastroscopy. The pathogenesis of Dieulafoy's lesion is complex and the mainstay of therapy has been surgical. Ligation of the vessel, wedge resection, or proximal gastric resection is performed. Therapeutic endoscopy with endoscopic cauterization or injection has changed the approach to this lesion.
REFERENCES 1. AI-Kawas FH, O'Keek J: Nd:Yag laser treatment of a bleeding Dieulafoy"s lesiou. Gastrointest Endosc 33:38, 1987 2. Baker DE: I\lisoprostol: '\iew drug evaluation. Prac GastroenteroI13:8, 1989 3. Bruggeman TM, Wood JG, Davenport HW: Local control of blood flow in the dog's stomach: Vasodilatation caused hy acid hack-diffusion following topical application of salicylic acid. C;astroenterology 77:7:36, 1979 4. Chadhnry TK, Jacobsen ED: Prostaglandin cvtoprotection of gastric mucosa. Gastroenterology 74:59, 1978 5. Driks ~IR, Craven DE, Celli BR, et al: l\'osoeomial pneumonia in intubated patients given sucral£ate as compared with antacids or histamine type 2 blockers. The role of gastric colonization. N Engl J Med 317:1:376. 1987 6. Durham JD. KUlllpe DA. Rothbarth LJ. et al: Dieulafoy disease: Arteriographic findings and treatment. Radiologv 174:937, 1990 7. Friedman CJ. Oillinger NIJ, Suratt PM, et al: Prophylaxis of upper gastrointestinal helllorrhage in patients requiring mechanical ventilation. Crit Care Med 10:316, 1982 8. Goldenherg SP: Endoscopic treatment of Dieulafoy's lesion of the duodenum. Am J Gastroenterol 87:4.52, 1990 9. Hoffman.r. Beck H, Jemen JE: Dieulafoy's lesion. Surg Gynecol Obstet 1.59:,537, 1984 10. Juler GL, Labitzke HG, Lamb H, et al: The pathogenesis of Dieulaf()y's gastric erosion. Am J Gastroenterol 79:195, 1984 11. Kivilaasko E, Frolllll1 D, Silen \V: Relationship between ulceration and intramural pH of gastric mucosa during hemorrhagic shock. Surgery 84: 70, 1978 12. Konturek SI. Brzozowshi T. Piastucki J, et al: Gastric mucosal protection by agents altering gastric mucosal sulfhydryls. Digestion :37:65, 1987 13. Lacey EH, Ito S: Rapid epithelial restitution of the rat gastric mucosa after ethanol injury. Lab Invest 51:57:3, 1984 14. Lewis JH, \Veingold AB: The lIse of gastrointestinal drugs during pregnancy and lactation. Am J Gastroenterol 80:912, 1985 15. Lin HJ, Lee FY, Tsai YT, et al: Therapeutic endoscopy f()r Dieulaf()y's disease. J Clin Gastroenterol 1l:.507, 1989
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Hi. LoperfiC\o S: Endoscopic hemostatis of gastrie bleeding Irom Dieulal()y's ulcer with histoacrv!. Endoscopy 21 :199, 191>9 17. Lllcas CE: Stress ulceration: The dinic,,1 problem. \Vorld J Surg 5:1:39, 1981 1H. 'v!arrollP CC, Silcn \V: Pathogenesis. diagnosis and treatment of acute gastric mucosal lesions. Clin Gastroenterol 1:3:6:3,5 19H4 19. ~lolnar P, i\liko T: ~lultiple arterial caliber persistence resulting in hematomas and [atal rupturc of the gastric wall. Am J Surg Pathol 6:8:3, 1982 20. ~lovlin GC, Patenson DG, Headley-Whyte J, et al: Aspiration of gastric bacteria in antacid-treated paticnts: A frequent cause of postoperative colonization of the airway. Lancet 1:242, 1982 2l. Schiessel H, Feil \V, \Venzl E: Mechanisms of stress ulceration and implications for treatment. Gastroenterol Clin North Am 19(1): 101, 1990 29 Shuman HB, Schuster DP. Zuckerman CR: Prophylactic therapy for stress ulcer bleeding: A reappraisal. Ann Intern 'vIed 104:562, 19H7 2:3. Silen \V, Ito S: ~lechanisms for rapid re-epithelization of the gastric mucosal surface. Am Rev Physiol 47:217, 1985 24. Starlinger ~l, Sporn P, Schemper M, et al: The use of the hemoccult test for detection of blood in gastric aspirates. Scand J Gastroenterol 18:72:3, 198:3 25. Szabo S, Gallagher GT, Homer HC. et al: Role of the adrenal cortex and gastric mucosal protection bv prostaglandins, sullhydryls, and cill1etidine in the rat. Gastroenterology 8,5: 1:384, 198:3 26. Tarnawski A, Hollander D, Krause \V], et al: Effect of sucralfate on normal gastric mucosa. Histologic, ultrastrnctural and hmctional assessment. Gastroenterology 84:1:3:30, 198:3 27. Try],a ~l, Zervounov F. Torok lvI, et a1: Prevention of acute stress bleeding with s\lcralf~\te, antacids, or cimetidine. Am J "ied (suppl 26):55, 1986 28. Van Zanten SJ. Bartelsman JF, Schipper "lE, et al: Recurrent massive hematemesis from Dielllafov's vascular malformations. Gut 27:21:3, 1986 29. vVallace JL: Mucosal defense: New avenucs for treatment of ulcer disease? Gastroenterol Clin North Am 19:87, 1990 30. Zinner MJ, Zuiclcma GD, Smith PL, et al: The prevention of upper gastrointestinal tract bleeding in patients in an intensive care unit. Surg Gynecol Obstet 15:3:214, 1981
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