Clinical experience with immunomodulators in patients with sepsis has 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 by Immunex, this agent appeared harmful. These findings suggest that factors not yet identified may alter the effects of immunomodulation with such agents. 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, we are testing the effects of fluid administration on TNFsr in a rat model of sepsis.
