The high (50-90%) mortality of acute intestinal ischemia is due largely to the appearance of irreversible tissue damage prior to therapeutic intervention. This project proposes to investigate those aspects of pathophysiology, diagnosis and treatment that are applicable to the management of patients with ischemic gastrointestinal disease. The major effort will study the basic mechanisms of hemodynamic control of the splanchnic circulation, with specific reference to the pathophysiology of nonocclusive mesenteric ischemia, stress erosions of the gastric mucosa, ischemic liver failure, acalculous cholecystitis, ischemic pancreatitis, and ischemic colitis under conditions of cardiogenic, hemorrhagic, and septic shock. In pig models of each form of shock, blood flow to each of these organs will be measured and hemodynamic parameters quantitated. Using specific agonists, and anatomic and pharmacologic blockade, the relative roles of the renin angiotensin axis, sympathetic nervous system and vasopressin will be evaluated as possible mediators of the profound, selective splanchnic vasospasm that causes these conditions. The role of the splanchnic resistance and capacitance vessels in the control of systemic hemodynamics, specifically total peripheral resistance, (""""""""afterload"""""""") and functional circulating blood volume (""""""""preload"""""""") will be similarly evaluated in these states. Using rat models of actual ischemic tissue damage simulating neonatal necrotizing enterocolitis, gastric mucosal stress erosions, and segmental intestinal vascular occlusion, this project will also investigate directly the contributions of the above vasoactive control mechanisms to the pathogenesis of these conditions. In these same models it will also use specific inhibitors of the generation and activity of oxygen free radicals to evaluate their role in the production of post-ischemic reperfusion injury in these diseases. Finally, this study will investigate new means for early recognition of intestinal ischemic disease in man. Serum levels of endotoxin, diamine oxidase and the BB isoenzyme of creatinine phosphokinase will be evaluated as indicators of early bowel ischemia in patients suspected to have intestinal vascular compromise. In addition, gamma camera images and activity washout curves obtained following the intraperitoneal administration of 133Xenon will be evaluated for their ability to detect early low flow states, prior to the development of ischemic tissue damage. These studies will be conducted in patients suspected to have mesenteric ischemia or strangulation obstruction.
Showing the most recent 10 out of 58 publications
