MICROVASCULAR CONTROL BY TISSUE FACTORS IN SEPSIS

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Uncontrolled sepsis continues to generate a high morbidity and mortality in the surgical patient. Failure of several organ systems, even at remote sites, is often associated with death from sepsis, and a major defect in oxygen utilization has been consistently demonstrated in septic man. The primary premise of this proposal is that these two observations are directly related and that the basis for organ failure is a defect in oxygen utilization. This research will utilize three rat models of sepsis. An intra-abdominal abscess will be formed by the injection of an inoculum of 2 x 10-8 E. coli and 2 x 10-9 B. fragilis into the devitalized cecum of rats. In this model, an acute phase of peritonitis ensues with 40% of the animals dying within 48 hours, and with the remaining animals developing chronic indolent intra-abdominal abscesses. This model will be studied at 24 hours and at 4 days. A second model of sepsis will utilize slow intravenous infusion of E. coli endotoxin with mocrovascular observation being made during this infusion. The third model inolves sublethal intravenous infusion of live E. coli (6 x 10 8 organisms/100 gm body weight). Appropriate age and weight-matched nonseptic animals will serve as baseline controls. Direct in vivo observations of different sized arterioles in the cremaster muscle (a high metabolism tissue) will be made by television microscopy. Initially, changes in microvascular diameter will be quantitated to compare microvascular phenomena during the hyperdynamic and hpodynamic phases of sepsis in the three animal models. The longitudinal oxygen gradient (the decrease in blood oxygen tension) down the arteriolar tree will be measured in both phases of sepsis to determine the microvascular level where alterations in oxygen delivery might occur during sepsis. Then, the effects of local changes in tissue-environment oxygen tension (pO2), carbon dioxide (pCO2) and hydrogen ion (pH) on arteriolar responses to sepsis will be documented in the three animal models. Systemic sepsis and multiple systems organ-failure are frequently noted on surgical services. This study will address the basic mechanisms of altered oxygen utilization and subsequent organ failure, eventually to predict rationale for the development of more effective treatment modalities in septic man.