A hyperdynamic cardiovascular response (high cardiac output, low peripheral vascular resistance) is commonly seen in septic patients. This is usually associated with pulmonary edema secondary to changes in the lung microvascular permeability to protein. Although these symptoms of sepsis are commonly observed in the clinical setting, most laboratory studies concern themselves with the less common hypodynamic (low cardiac output high peripheral vascular resistance) form of the disease entity. Experimental hyperdynamic situations have only been produced thus far, by inducing infections in animal models and these are not easily reproducible. These latter may also involve pain. We propose to create hyperdynamic sepsis by injecting small dosages of endotoxin (LPS, 0.75ug/kg) into sheep which will be prepared for study with chronic lung lymph fistulas and cardiovascular catheterization. This dosage has previously been shown to induce pulmonary edema similar to that noted in the clinical setting. We will study the response to LPS over a 24 hr. period, comparing both cardiovascular and pulmonary changes. These changes will be correlated with changes in neutrophils in the blood and lung lymph, changes in lipoxygenase metabolites and changes in the components of the kallikrein-kinin system. All of these have previously been associated with vasodilation, alterations in lung microvascular permeability and increased cardiac outputs in both animals and septic patients. We will determine how these cardiopulmonary responses are changed by varying the dosage of LPS, its rate and frequency of administration and how these relate to hyper and hypodynamic situations. These will also be related to fluid administration after LPS. We will further evaluate the nature of these cardiopulmonary responses by administering agents which block or interfere with the lipoxygenase pathway, endogenous opiates, hydroxyl ions and products of Beta-lymphocytes. All of these systems have been reported to be related to the actions of LPS. We shall also determine whether the hyperdynamic situation is associated with an elevated O2 consumption, an index of a possible increased metabolism. Preliminary systemic and pulmonary data are presented which characterize the hyperdynamic state with LPS concomitant with increased lung lymph flow. There is also evidence of the simultaneous involvement of neutrophils and the kallikrein-kinin and lipoxygenase systems, in both of these responses.
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