Effects of Adjunctive Therapy with Early Transfusion of Granulocytes in a Canine Model of S. aureus Pneumonia

Clinical Center

Investigators

Abstract

Nine days prior to each study, 1 or 2 donors were stimulated with G-CSF to increase endogenous neutrophil count. Donor granulocytes were collected via apheresis at the start of each study. The donor animals were recovered following collection and adopted out at the end of the study. Each cycle, two study animals were challenged intrabronchially with S. aureus, a potentially lethal dose of a gram positive bacteria. 4 h after bacterial inoculation during early sepsis, animals were randomized to receive either granulocytes (40-100 billion cells) or an equivalent volume of fresh frozen plasma over a 4-8 h period. The treatment randomization was applied to the 4 h WBC count (high vs low). All animals throughout the 96h study received standard intensive care support based on algorithms with clinical physiologic endpoints including: mechanical ventilation, fluid and vasopressor support, antibiotics, and continuous sedation. The data show survival time appears improved in animals receiving granulocyte therapy compared to plasma but does not result in improving the overall survival rate. Survival time is mostly improved in animals that had high WBC counts early during sepsis but this did not result in improving the overall survival rate. This may be due to the worsening lung injury observed as the study progresses though the increasing lung injury did not result in worsening survival. One possible factor to explain why granulocyte transfusion did not improve survival is the pattern of granulocyte trafficking within the body in response to infection. After being produced in the bone marrow, granulocytes first travel to the lung before translocating to sites of infection throughout the body. However, given that our model was of an infection local to the lung, any damaging effects of long term granulocyte activity would be concentrated within the lung. It is also possible that the number of granulocytes infused or the manner in which they were delivered either in duration or rate contributed to their lack of effectiveness.