Steroids and β-Agonists in Acute Respiratory Distress Syndrome: Timing Is Everything*

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Despite 5 decades of research, the acute respiratory distress syndrome (ARDS) remains a significant cause of morbidity and mortality. ARDS is even more common than previously appreciated and frequently under-recognized by clinicians (1). Although recent progress has been made in the management of ARDS (2–4), clinicians lack pharmacologic therapies that target the pathophysiology of lung injury and most of the advances in the treatment of ARDS aim to prevent iatrogenic injury (4–6).
Inflammation and noncardiogenic pulmonary edema are central to the pathogenesis of lung injury in ARDS. In order for lung injury to ultimately resolve, inflammatory infiltrates and edema fluid must be cleared from the alveolar space. Alveolar fluid clearance (AFC) is primarily driven by activity of the sodium-potassium adenosine triphosphatase (Na/K-ATPase) at the basolateral epithelial surface followed by the osmotic transport of water, a process that is impaired during ARDS (7). Corticosteroid treatment for ARDS is particularly appealing given their ability to both dampen inflammation and promote AFC (8). Systemic steroid treatment protocols for established ARDS or prevention of ARDS in at-risk patients have been studied extensively and were not shown to improve mortality in established ARDS (9). However, IV methylprednisolone did improve respiratory system compliance and oxygenation (PaO2/FIO2) when administered within 2 weeks of ARDS onset (9) leading some to speculate that steroids may be effective early in the course of ARDS.
Another strategy to increase AFC is the use of β-adrenergic agonists to increase activity of the Na/K-ATPase (7). The use of β-agonists for the treatment of established ARDS has been studied using both aerosolized and IV formulations. Following promising results from a phase II single-center study of IV salbutamol for ARDS (10), the National Institutes of Health ARDS network conducted the phase III AlbuteroL for the Treatment of ALI (acute lung injury) trial of aerosolized albuterol for established ARDS. Ultimately, that study was terminated for futility (ventilator-free days) after 282 subjects were enrolled (11). These disappointing results were replicated by the large multicenter trial of IV salbutamol (Beat-Agonist Lung injury Trial-2), stopped early due to increased mortality in the treatment group (12).
Despite extensive, supportive, preclinical data and sound physiologic rationale, clinical trials of corticosteroids and β-agonists apparently fail to improve outcomes in established ARDS; but why? There are many plausible explanations, including lack of fidelity in preclinical models, substantial heterogeneity in the etiology of ARDS in human trials, and changes in critical care practices (conservative fluid management and lower tidal volumes). However, the timing of the intervention may be most critical, as suggested by data from preclinical (13) and observational (14) studies. In this issue of Critical Care Medicine, Festic et al (15) take an important first step toward answering this question with the Lung Injury Prevention Study with Budesonide and Beta Agonist (LIPS-B) study, a phase IIa trial comparing blinded treatment with aerosolized budesonide (0.5 mg) and formoterol (20 μg) to placebo administered twice daily for 5 days. Based on a predicted 20% improvement in oxygen saturation to the FIO2 (S/F) ratio (80% power; p < 0.05) and allowing for dropout due to mortality or early discharge, the investigators met the target enrollment of at least 60 patients at risk for ARDS, as defined by a Lung Injury Prediction Score (LIPS) greater than or equal to 4 and a new requirement for greater than or equal to 2 L/min of supplemental oxygen. Patients were approached for consent in the emergency department (ED), and impressively, the median time from presentation to administration of study drug was less than 9 hours, demonstrating that early intervention for ARDS prevention is feasible.

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