First do no harm: surrogate endpoints and the lesson of β-agonists in acute lung injury

β2-adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies of acute lung injury (ALI).

Objective: To determine whether an aerosolized β2-agonist would improve clinical outcomes in patients with ALI. Design: Multi-center, phase III randomized, placebo-controlled clinical trial. Setting: 33 hospitals participating National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Subjects: Patients who were intubated and receiving mechanical ventilation, had bilateral infiltrates consistent with edema on frontal chest radiograph, had a ratio of PaO2 to FIO2 (fraction of inspired oxygen) of 300 or less, and not had clinical evidence of left atrial hypertension. A maximum enrolment of 1,000 patients was planned. Intervention: Patients were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. Outcomes: The primary outcome variable was ventilator-free days (VFD). Secondary outcome measures included mortality before hospital discharge on day 60 and day 90, the number of intensive care unit (ICU)-free days and the number of organ failure-free days.

There were 282 patients enrolled before the trial was stopped for futility after the second interim analysis. The VFDs difference with albuterol treatment was unfavourable by -2.2 days, well past the futility boundary of -0.4 VFDs. VFDs were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 days, respectively; 95% confidence interval for the difference, -4.7 to 0.3 days; P = 0.087). Rates of death before hospital discharge and the number of organ failure-free days were also not significantly different between the two groups. The number of ICU-free days was lower in the albuterol group in comparison with the placebo group (means of 13.5 and 16.2 days respectively; 95% confidence intervals for the mean difference, -4.9 to -0.4 days; P = 0.023). Overall, heart rates were significantly higher in the albuterol group by approximately 5 beats/minute in the first 2 days after randomization (P < 0.05), but rates of new onset atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different.

These results suggest that aerosolized albuterol does not improve clinical outcomes in ALI patients. Routine use of β2 agonist therapy in mechanically ventilated ALI patients cannot be recommended.