A Randomized Trial of GM-CSF in Patients with ALI

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Despite significant progress in intensive care unit care and ventilator management, respiratory failure due to acute lung injury (ALl) and the acute respiratory distress syndrome (ARDS) remains a major health problem, with approximately >30% mortality despite enormous expenditure of health care resources. Survivors face long term consequences for quality of life. New therapies are needed both to improve early survival and to decrease long term sequelae of this syndrome. Granulocyte-macrophage colony stimulating factor (GMCSF) is a rnultifunctional cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF has a distinctive combination of activities making it an ideal candidate for a therapeutic intervention in ALI/ARDS. It is essential for normal maturation of alveolar macrophages and has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Preliminary studies for this application demonstrate that GM-CSF can protect mice against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients; this biological is approved by the FDA has been well-tolerated in trials involving critically ill patients. This proposal is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS. A randomized, placebo-controlled trial of GM-CSF (250 mcg/M2/day x 14 days) will be performed with 5 Specific Aims. These Aims will determine the effect of treatment with GM-CSF on: 1) days free of mechanical ventilation (days 1-28) (the primary endpoint of this study), mortality, ICU stay, and incidence of ventilator-associated pneumonia; 2) physiologic variables associated with respiratory failure; 3) parameters of alveolar epithelial dysfunction; 4) alveolar rnacrophage function for host defense in the context of ARDS; 5) quality of life and progression to fibrosis in survivors of ARDS. For each patient enrolled, clinical parameters (both acute and late) and serial bronchoalveolar lavage specimens will be collected. When completed, these Specific Aims will determine whether treatment with recombinant GM-CSF will improve outcome in these critically ill patients, and will determine through which of four potential mechanisms GM-CSF is acting.