Despite advances in antibiotic therapy and cardiopulmonary support, septic shock remains a highly lethal disease. Sepsis is the leading cause of death in trauma and immunosuppressed patients hospitalized in intensive care units. Cellular mediators such as the neutrophil may play paradoxical roles in this process. While it is clear that the neutrophil is important in host defense, in vitro and in vivo studies suggest that the neutrophil, under the influence of other activated endogenous mediators, has the potential to contribute to tissue injury during sepsis. Recombinant colony stimulating factors such as granulocyte (rG-CSF) and granulocyte-macrophage colony stimulating factor (rGM-CSF) are capable of both increasing bone marrow leukocyte production as well as increasing the activity level of circulating and resident tissue cells. Administration of these factors improves survival in irradiated neutropenic animal models and decreases the frequency of infection in neutropenic patients, possibly via both direct bone marrow and peripheral effects. The use of such factors in non-neutropenic patients with sepsis has the potential to be either harmful or beneficial. We have now shown that rG-CSF pretreatment in a nonneutropenic canine model of lethal bacterial peritonitis improves cardiovascular function and survival. These improvements are associated with decreases in circulating endotoxin levels. Although rG-CSF accelerates alveolar neutrophil recruitment in this model, pulmonary injury is not worsened. In addition to reductions in circulating endotoxin levels, we have now shown that rG- CSF pretreatment reduces circulating tumor necrosis factor (TNF) levels as well. It is not clear whether this is a direct effect related to rG-CSF, or whether rG-CSF modulated increases in host defense improve bacterial or bacterial toxin clearance. In order to determine whether rG-CSF pretreatment improves the clearance of microbial toxins themselves, we have started a study in which we are evaluating the effects of rG-CSF pretreatment in animals challenged with endotoxin alone. Endotoxin levels and clearance, as well as serum cytokine levels and cardiopulmonary measures will be assessed over a 6 h period during this study. In order to study the efficacy of the acute administration of rG-CSF during bacterial peritonitis , we plan to start a study this November assessing the effects of therapy with rG-CSF at the onset of sepsis. Pilot studies will be done initially to determine an optimal dosing regimen of rG-CSF which will maximize increases in circulating neutrophil numbers.
