Recent advances in the supportive care of patients with acute respiratory distress syndrome (ARDS) have resulted in significant reductions in mortality (1–4). However, pharmacologic therapies specific for ARDS have remained elusive, and mortality remains unacceptably high (4, 5). The resolution of ARDS requires the removal of excess lung edema fluid and acute inflammatory cells accompanied by repair of the injured alveolar epithelium (5, 6). The absorption of excess alveolar fluid is an active, ATP-dependent process that involves the vectorial transport of sodium ions out of alveolar air spaces via the apical sodium and chloride channels and basolateral Na-K-ATPases in the alveolar epithelium (6–8). Confirming a wealth of preclinical data suggesting an important role for the removal of edema fluid, Ware and Matthay found that alveolar fluid clearance is impaired in the majority of patients with ARDS and that preservation of normal clearance is associated with better outcomes (9).

In animal models and human cells, the stimulation of b2-adrenergic receptors (b2ARs) increases the vectorial transport of sodium across the alveolar epithelium to improve edema clearance (6–8, 10–13). The efficacy of b2-agonist therapy in lung edema clearance in humans was confirmed in a clinical trial where the administration of the long-acting b2-agonist salmeterol reduced the incidence of high-altitude pulmonary edema in a high-risk group of travelers (14). These promising findings were the basis for clinical trials of b2-agonists for the treatment of ARDS. Encouraging results from a small phase II trial, the b-Agonist Lung Injury (BALTI)-1 trial (15), prompted two large-scale randomized control trials (16, 17). Unfortunately, both trials were terminated due to futility and safety concerns. In the Albuterol to Treat Acute Lung Injury (ALTA) study, patients with ARDS were randomized to receive either nebulized albuterol or placebo every 4 hours (16). There was no significant difference in the primary outcome of ventilator-free days or in the secondary outcomes of death before hospital discharge or toxicity. The concern that albuterol administered via inhalation may not have been delivered to the regions of the lung with the most severe edema was addressed in the second large, randomized control study, BALTI-2, in which patients with ARDS were randomized to receive a continuous intravenous infusion of salbutamol at the maximal dose that did not result in an increase in arrhythmias in critically ill patients (17). This study was terminated after an interim analysis showed an increase in 28-day mortality in the patients treated with salbutamol compared with placebo (34% vs. 23%).