We propose to utilize a newly developed chronic high cardiac output sepsis model in the rat to study the mechanisms and prevention of the sepsis-induced metabolic defects. The overall bacteriologic, hemodynamic, and metabolic status of the animals will be characterized by continuous monitoring of cardiac output and mean arterial blood pressure, body weight, food and water intake and blood cultures and chemistries. After 1, 2, 5, 7, 14 and 21 days of high output sepsis, skeletal muscle, heart, liver and kidney tissue metabolites and fuel utilization, mitochondrial substrate oxidation and energy metabolic functions and ensyme activities, skeletal muscle protein catabolism abscess fluid and plasma analyses of toxic substances will be performed. Morphologic characterization of muscle, heart, liver and kidney structural alterations will be made after 5 and 14 days of sepsis. The time course of the metabolic, protein catabolic, and tissue structural alterations will be correlated with the appearance of toxic substance(s) in the abscess fluid and plasma. A systematic separation, purification, and characterization of the toxic substance(s) from rat and human abscesses and plasma will be performed and biological activity of the crude and purified fractions of the toxic substance(s) determined by in vitro and in vivo assays in rats to determine whether they produce metabolic and hemodynamic responses similar to high output sepsis. Rabbits will be used to produce antibodies to the toxic substance(s) and these antibodies will be tested for their efficacy in preventing the induction of the sepsis-like state. The overall goal of these studies is to determine the primary factors responsible for the sepsis induced metabolic abnormalities, their early detection and possible prevention by specific antidotes.
