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A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis with Respiratory Dysfunction

Intensive Care Unit, The Royal Melbourne Hospital; Department of Pharmacology, University of Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia

Correspondence and requests for reprints should be addressed to Dr. Jeffrey J. Presneill, Intensive Care Unit, The Royal Melbourne Hospital, Victoria 3050, Australia. E-mail: intensive{at}ozemail.com.au

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis. We investigated whether GM-CSF therapy improved clinically diagnosed severe sepsis and respiratory dysfunction in critically ill patients. This randomized, double-blind, placebo-controlled phase II study added low-dose (3 mcg/kg) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients, with a further eight patients receiving placebo. GM-CSF–treated patients showed improvement in Pa_O2/FI_O2 over 5 days (p = 0.02) and increased peripheral blood neutrophils (p = 0.08), whereas alveolar neutrophils decreased (p = 0.02). GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction. GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function. We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration, despite functional activation of both circulating neutrophils and pulmonary phagocytes. In addition, GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome, suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction.

Key Words: granulocyte-macrophage colony-stimulating factor • acute respiratory distress syndrome • human • sepsis • phagocytosis • neutrophils

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