Abstract and Introduction
Abstract
Rationale: Despite recent advances in critical care and ventilator management, acute lung injury and acute respiratory distress syndrome continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor may be beneficial for patients with acute respiratory distress syndrome.
Objectives: To determine whether intravenous infusion of granulocyte-macrophage colony stimulating factor would improve clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome.
Design: A randomized, double-blind, placebo-controlled clinical trial of human recombinant granulocyte-macrophage colony stimulating factor vs. placebo. The primary outcome was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization. Secondary outcomes included mortality and organ failure-free days.
Setting: Medical and surgical intensive care units at three academic medical centers.
Patients: One hundred thirty individuals with acute lung injury of at least 3 days duration were enrolled, out of a planned cohort of 200 subjects.
Interventions: Patients were randomized to receive human recombinant granulocyte-macrophage colony stimulating factor (64 subjects, 250 μg/M) or placebo (66 subjects) by intravenous infusion daily for 14 days. Patients received mechanical ventilation using a lung-protective protocol.
Measurements and Main Results: There was no difference in ventilator-free days between groups (10.7 ± 10.3 days placebo vs. 10.8 ± 10.5 days granulocyte-macrophage colony stimulating factor, p = .82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving granulocyte-macrophage colony stimulating factor (p = .31) and organ failure-free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days granulocyte-macrophage colony stimulating factor, p = .16) were not statistically significant. There were similar numbers of serious adverse events in each group.
Conclusions: In a randomized phase II trial, granulocyte-macrophage colony stimulating factor treatment did not increase the number of ventilator-free days in patients with acute lung injury/acute respiratory distress syndrome. A larger trial would be required to determine whether treatment with granulocyte-macrophage colony stimulating factor might alter important clinical outcomes, such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov]). (Crit Care Med 2012; 40:90 –97)
Introduction
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of acute pulmonary disease that causes significant morbidity and mortality throughout the United States. ALI/ARDS is a common response to multiple systemic or lung-specific insults, although sepsis syndrome is the most common predisposing factor. The annual incidence of ALI/ARDS in the United States may be as high as 75 per 100,000 population. Since ARDS was first described in 1967 there have been significant improvements in ancillary management strategies for care for these patients. In particular, a lungprotective ventilatory strategy and conservative approach to fluid management have been shown to improve patient outcomes in large multicenter trials. Nonetheless, ALI/ARDS causes a significant burden of disease, with prolonged mechanical ventilation in the majority of patients and 30% mortality in recent series of selected patients. ARDS leads to long-term limitations in health-related quality of life in survivors. To date, the search for pharmacologic interventions targeted to the pathophysiology of ARDS has been disappointing. New therapeutic approaches that address the underlying pathophysiology and complications of this condition and improve outcomes are clearly needed.
Granulocyte-macrophage colony stimulating factor (GM-CSF) is critically important for normal pulmonary homeostasis. Local expression of GM-CSF in the lung is required for maturation of alveolar macrophages, and thus for normal surfactant clearance and pulmonary innate immunity. GM-CSF is also a growth and survival factor for alveolar epithelial cells, which are a primary site of injury in individuals with ARDS. In human patients with ALI/ARDS, increased expression of GM-CSF in bronchoalveolar lavage (BAL) fluid is correlated with increased survival, supporting the hypothesis that GM-CSF plays an important protective role in the injured lung. Preclinical data from animal models suggest that GM-CSF might be of benefit in ALI/ARDS both by limiting early epithelial cell injury and by maintaining alveolar macrophage function. Based on these considerations, we hypothesized that GM-CSF would act at multiple points to improve the outcome of patients with ALI/ARDS. Therefore, we carried out a prospective, randomized, placebo-controlled multicenter trial of recombinant human GM-CSF for patients with ALI/ARDS. The primary outcome was days free from mechanical ventilation in the first 28 days, while secondary outcomes included 28-day mortality and duration of organ failure.