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

Abstract

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 (ClinicalTrials.gov: 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.

Figure 1. CONSORT diagram of enrollment

One patient in treatment arm was excluded for having ARDS on noninvasive ventilation prior to enrollment. This patient received a single dose of study drug but shortly afterwards was changed to comfort care and died without being intubated or having a post-treatment S/F measured to allow assessment of primary outcome. One patient randomized to placebo arm had ventricular fibrillation prior to enrollment and was excluded prior to receiving study drug.

Figure 2. S/F ratio by treatment day

Plot of least square (LS) means of saturation divided by FiO2 (S/F) ratio to day 5 from mixed effects modeling of S/F by study day, treatment, and interaction between treatment and study day. *Denotes individual days as well as entire model with significant (< 0.05) unadjusted P values for day*treatment interaction. N=number of hospitalized patients remaining in the study without adjustment for last S/F for early discharges.

Figure 3. Unadjusted and adjusted treatment by study day effects on S/F (interactions) with the 95% CI of LS means

Forest plots of confidence intervals of treatment effect in unadjusted and adjusted models by treatment interactions with shock, age and LIPS (Lung Injury Prediction Score). Full model with simultaneous adjustment for all covariates appeared over-fitted and not presented.