β2-Agonists and Acute Respiratory Distress Syndrome

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 β2-adrenergic receptors (β2ARs) increases the vectorial transport of sodium across the alveolar epithelium to improve edema clearance (6–8, 10–13). The efficacy of β2-agonist therapy in lung edema clearance in humans was confirmed in a clinical trial where the administration of the long-acting β2-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 β2-agonists for the treatment of ARDS. Encouraging results from a small phase II trial, the β-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%). The combined results of the ALTA and BALTI-2 trials do not support the use of β2-agonists for the treatment of ARDS and suggest that intravenous administration of β2-agonists may be harmful. However, it remains possible that β2-agonists might be useful to prevent the development of ARDS in high-risk patients. In this issue of the Journal, Perkins and colleagues (pp. 674–683) tested this hypothesis in patients undergoing elective esophagectomy, a procedure that carries a high risk for the development of postoperative ARDS (18). They examined the rates of postoperative ARDS in patients randomized to receive either inhaled salmeterol or placebo in the first 72 hours after surgery. Unfortunately, the results were negative; the rates of ARDS as well as the secondary outcomes, which included organ failure, survival, or health-related quality of life, were similar irrespective of β2-agonist therapy. Although study-specific concerns might have masked a small effect—the intraoperative tidal volume in the patients receiving β2-agonists was higher and the drug was given only 2 hours prior to the operation—the overall findings of the study do not support a role for β2-agonist therapy to prevent ARDS. These results leave us asking why β2-agonist therapy has been ineffective in improving or preventing ARDS. Measures of extravascular lung water were reduced in patients receiving β2-agonists in the BALTI-1 trial and in a subgroup of patients included in the most recent BALTI prevention trial, making it less likely that the drugs failed to improve vectorial sodium transport. One potential explanation is that pulmonary edema, although an important consequence of ARDS, is not a major driver of mortality. Only a minority of patients with ARDS die as a result of acute hypoxemia (the majority of deaths are attributable to the development of multiple organ dysfunction later in the course of the critical illness), and only patients with severe lung injury and hypoxemia have benefited from therapies for ARDS that improve oxygenation (2, 19). Another explanation is that although the systemic cardiovascular effects of β2-agonists are small, they might offset their potential benefits on lung edema clearance. This would explain why increased mortality was observed in the BALTI-2 but not the ALTA trial. Finally, β2-agonists may have detrimental off-target effects on other cells present in the injured lung. Indeed, β2-adrenergic receptors are expressed not only on the alveolar epithelial cells but also on other cells within the lung, including resident and recruited inflammatory cells (20). Although several short-term studies suggest that stimulation of β2ARs down-regulates inflammation, there are hints from the sepsis literature that the opposite may be the case. The β-blockers may be useful in the treatment of sepsis due to their beneficial effects on metabolism, glucose homeostasis, cytokine expression, and cardiac function, and in contrast, the use of drugs that stimulate βARs may be associated with detrimental effects and worsened outcomes (21–24). Interestingly, much of the preclinical data supporting the use of β2-agonists was performed in sterile models of ARDS (hyperoxia, ischemia reperfusion, or LPS), and β2-agonists were effective in patients at risk for high-altitude pulmonary edema, which results in edema with minimal inflammation. What can we learn from the failure of β2-agonists in these trials? First, the available data suggest that even in the injured lung, agents that drive vectorial sodium transport can reduce extravascular lung water, potentially improving edema clearance. Moving forward, we need to look for mechanisms to selectively stimulate these pathways without the potential off-target effects of β2-agonists. Second, we need to understand more about the potential harmful effects of β2-agonists in patients with ARDS. Are these effects limited to those on the cardiovascular system, or do β2ARs on cells present in the injured lung play a role in the pathophysiology of ARDS, and might these pathways be targeted for therapy? Third, we need to improve our preclinical models of ARDS. Studies in sterile lung injury models need to be complemented by more clinically relevant models (e.g., viral or bacterial pneumonia). Finally, we need to develop biomarkers that identify specific populations of patients with ARDS who might benefit from selected therapies and understand why our surrogate markers for outcomes in phase II trials failed to predict the outcome of these large clinical trials. Improved selection of patients for targeted therapies and better markers to predict the response to novel therapies in phase II trials will speed the flow of new agents for ARDS from the bench to bedside.