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Human recombinant granulocyte macrophage colony stimulating factor (GM-CSF or Leukine) did not reduce ventilator-days in patients with acute lung injury / ARDS in a randomized trial published in the January 2012 Critical Care Medicine.
Why would it have? Interestingly, patients with ARDS with higher levels of GM-CSF in their BAL fluid are more likely to survive. GM-CSF maintains homeostasis in the lung and is required for proper maturation of alveolar macrophages, which are themselves responsible for surfactant clearance/balance and pulmonary innate immunity. GM-CSF also promotes survival and growth of alveolar epithelial cells -- the very cells injured in ARDS. (Actually, I'll stop saying "acute lung injury" -- remember, the expertocracy has informed us there's no such thing as ALI any more -- only "mild ARDS").
Faced with all these tantalizing clues, Robert Paine III, Theodore Standiford, Marc Moss, Greg Martin et al endeavored to find out if giving GM-CSF to ARDS patients would improve their outcomes. (Spoiler alert! It didn't.)
What They Did
Authors enrolled 130 patients with ARDS of at least 3 days duration and randomized them to receive either GM-CSF or placebo for 14 days. (The original enrollment target was 200, but enrollment was slower than expected.) Most patients had sepsis (67 vs 73% in the placebo vs GM-CSF groups respectively). All patients received lung protective ventilation. Primary outcome was ventilator free days; secondary outcomes were mortality and organ failure free days. The trial was largely funded by the National Institutes of Health (NIH); Berlex, Bayer, and Genzyme provided study drug free of charge.
What They Found
GM-CSF did not reduce ventilator days: patients in both groups had ~10.5 ventilator free days in the 28 days following enrollment. There were no statistically significant differences in 28 day mortality or organ failure free days, either. GM-CSF also did not noticeably affect oxygenation or inflammatory biomarkers. There was a high rate of adverse events in both groups, unsurprising for patients this ill; no adverse events were deemed to be due to study drug.
What It Means
Although authors say “one cannot extrapolate to the outcome had the additional 70 subjects been enrolled,” the numerical near-identicality in observed ventilator free days between groups would seem to make a true difference unlikely (although I admit I haven't run the numbers through SAS). Authors hypothesize that giving GM-CSF earlier (they started giving it on day 3) might have a greater effect, and would be worth trying in future trials. Some have suggested giving GM-CSF through the endotracheal tube; authors here sagely point out that the most injured portions of the lung in ARDS may not be ventilated, limiting the expected efficacy of study drug by this route.
GM-CSF was safe here and in earlier trials. Previously in non-neutropenic septic patients, GM-CSF showed some benefit on soft/surrogate endpoints (e.g., faster resolution of sepsis; improved gas exchange) -- although a meta-analysis of 12 trials testing GM-CSF in 2,380 patients with sepsis without neutropenia did not show any benefit.
Clinical Takeaway: For those keeping score at home, it's now ARDS 12 (or so), Feeble Humans 1 (for low tidal volume ventilation). But hey, at least these authors are trying to find something that works ... I'm just sitting here blogging about it.
Paine R 3d et al. A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury. Crit Care Med 2012;40:90-97.