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Randomized Clinical Trial of a Combination of an Inhaled Corticosteroid and Beta Agonist in Patients at Risk of Developing the Acute Respiratory Distress Syndrome*

Festic, Emir MD1; Carr, Gordon E. MD2; Cartin-Ceba, Rodrigo MD3; Hinds, Richard F. MS4; Banner-Goodspeed, Valerie MPH5; Bansal, Vikas MBBS1; Asuni, Adijat T. MPH6; Talmor, Daniel MD5; Rajagopalan, Govindarajan PhD7; Frank, Ryan D. MS8; Gajic, Ognjen MD4; Matthay, Michael A. MD9; Levitt, Joseph E. MD6

doi: 10.1097/CCM.0000000000002284
Clinical Investigations

Objectives: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance.

Design: Double-blind, randomized clinical trial ( NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the Fio2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome.

Setting: Five academic centers in the United States.

Patients: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome.

Interventions: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days.

Measurements and Main Results: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group (p = 0.02) and independent of shock (p = 0.04). Categorical change in S/F improved (p = 0.01) but not after adjustment for shock (p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%).

Conclusions: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

1Department of Critical Care, Mayo Clinic, Jacksonville, FL.

2Division of Pulmonary and Critical Care, Department of Medicine, University of Arizona, Tucson, AZ.

3Department of Critical Care, Mayo Clinic, Scottsdale, AZ.

4Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic, Rochester, MN.

5Department of Anesthesia, Beth Israel Deaconess Medical Center, Boston, MA.

6Division of Pulmonary and Critical Care, Department of Medicine, Stanford University, Stanford, CA.

7Department of Immunology, Mayo Clinic, Rochester, MN.

8Department of Health-Science Research/Biostatistics, Mayo Clinic, Jacksonville, FL.

9Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, CA.

*See also p. 914.

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Supported, in part, by National Institutes of Health grants 5KL2 TR000136, UL1TR000135 (E.F.), and K23HL091334 (J.E.L.); and National Heart Lung and Blood Institute grant R37HL51856 (M.A.M.).

Drs. Festic, Cartin-Ceba, Banner-Goodspeed, Talmor, and Levitt received support for article research from the National Institutes of Health (NIH). Drs. Festic, Carr, Hinds, Banner-Goodspeed, and Levitt disclosed off-label product use where budesonide and formoterol inhaled use is not approved for prevention of acute respiratory distress syndrome, but are U.S. Food and Drug Administration-approved for other pulmonary indications and the same standard doses were used. Dr. Talmor’s institution received funding from National Heart, Lung, and Blood Institute (NHLBI). Dr. Matthay’s institution received funding from GlaxoSmithKline (sepsis grant), Amgen (acute lung injury grant), GlaxoSmithKline (consulting); he received funding from Roche-Genentec (chair of data safety monitoring board [DSMB] for trials). He reports reports DSMB service for GlaxoSmithKline; and he received funding for consulting from the following: Quark Pharmaceuticals, BayerHealth Care, Boerhringer-Ingelheim, Cerus Therapeutics, Incardia Therapeutics, Biomark Pharmaceuticals, Thesan Pharmaceuticals, and Biogen. He received an Amgen grant to study lung injury in mice and a GlaxoSmithKline grant to study biomarkers of sepsis. Dr. Levitt’s institution received funding from NIH/NHLBI K23 Career Development Award. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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