Despite encouraging results in preclinical studies, clinical experience with antiinflammatory in patients with sepsis have been disappointing to date. Tumor necrosis factor soluble receptor (TNFsr) is one such agent. In early preclinical work utilizing endotoxin or gram-negative bacteria infusion challenges, TNFsr was protective and improved survival. This protection appeared to be related in part to improvements in cardiovascular function with TNFsr. However, in clinical sepsis trials this agent was not beneficial and in some cases appeared to harmful effects. These finding suggest that factors not identified in preclinical studies may have altered the effects of TNFsr in clinical studies. One such factor may be the presence or absence of other supportive therapies. In clinical but not preclinical studies, subjects also have cardiovascular support with fluid administration. The presence of such support in clinical studies may have negated the beneficial effects of TNFsr on cardiovascular function and possibly accentuated adverse effects it may have had on host defense. In the present study, using a multifactorial design, we are testing the effects of fluid administration on TNFsr with both intravascular and extravascular infection in a rat model of sepsis.