Randomized, Placebo-controlled Clinical Trial of an Aerosolized β₂-Agonist for Treatment of Acute Lung Injury

Abstract

Rationale: b 2 -Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies. Objectives: This clinical trial was designed to test the hypothesis that an aerosolized b 2 -agonist, albuterol, would improve clinical outcomes in patients with acute lung injury (ALI). Methods: We conducted a multicenter, randomized, placebocontrolled clinical trial in which 282 patients with ALI receiving mechanical ventilation were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days. The primary outcome variable for the trial was ventilator-free days. Measurements and Main Results: Ventilator-free days were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 d, respectively; 95% confidence interval for the difference, -4.7 to 0.3 d; P ¼ 0.087). Rates of death before hospital discharge were not significantly different between the albuterol and placebo groups (23.0 and 17.7%, respectively; 95% confidence interval for the difference, -4.0 to 14.7%; P ¼ 0.30). In the subset of patients with shock before randomization, the number of ventilator-free days was lower with albuterol, although mortality was not different. Overall, heart rates were significantly higher in the albuterol group by approximately 4 beats/minute in the first 2 days after randomization, but rates of new atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different. Conclusions: These results suggest that aerosolized albuterol does not improve clinical outcomes in patients with ALI. Routine use of b 2 -agonist therapy in mechanically ventilated patients with ALI cannot be recommended. Clinical trial registered with www.clinicaltrials.gov (NCT 00434993).Keywords: pulmonary edema; acute respiratory distress syndrome; alveolar epitheliumIn patients with acute lung injury and the acute respiratory distress syndrome (ALI/ARDS), inflammation of the pulmonary circulation increases vascular permeability. Fluid leaks from blood vessels into the pulmonary interstitium and alveoli. Recovery from this form of acute respiratory failure requires that the pulmonary edema resolve. The resolution of alveolar edema is driven by active transport of sodium and chloride ions from the luminal space across both type I and type II alveolar epithelial cells, creating an osmotic gradient for the reabsorption of water (1-4). The rate of alveolar fluid transport is increased by endogenous or exogenous cyclic AMP stimulation, which increases ion transport through epithelial sodium channels and chloride channels such as the cystic fibrosis transmembrane regulator (5, 6). In the ex vivo human lung, the rate of alveolar fluid clearance can be doubled by treatment with a cyclic AMP b 2 -adrenergic receptor agonist (7,8).Alveolar epithelial fluid clearance is impaired during ALI/ ARDS, and decreased resolution of alveolar edema is associated with increased mortality (9, 10). There are several potential mechanisms of decreased...

Electroporation-Mediated Gene Delivery of Na+,K+-ATPase, and ENaC Subunits to the Lung Attenuates Acute Respiratory Distress Syndrome in a Two-Hit Porcine Model

“…Studies have shown if the initial pulmonary edema can be reduced by increasing alveolar fluid clearance or alveolar barrier function, inflammation and subsequent injury can also be lessened (8, 9). While a number of pharmacological approaches to modulate alveolar fluid clearance have been proposed in animal and human studies, including the use of β 2 -adrenergic receptor agonists, the results from several multi-center clinical trials have not shown significant benefit (10, 11). In light of this, we and others have tested whether gene therapy approaches may be alternatives.…”

Airway surface liquid volume expansion induces rapid changes in amiloride-sensitive Na+transport across upper airway epithelium-Implications concerning the resolution of pulmonary edema

“…It was ineffective as a treatment of pulmonary edema in two relatively recent multicenter clinical trials in critically ill patients either with acute lung injury (Matthay et al. 2011) or ARDS (Gao Smith et al. 2012) despite evidence of beneficial effect observed in cell culture as well as animal studies (Fronius 2013).…”

Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps

“…The overall survival rates of ALI/ARDS are around 20-40% 4-7 . The prognosis of survival is better for mild ARDS as compared to severe ARDS with an intermediate risk for moderate ARDS (according to the ‘ Berlin definition ’) 1 .…”

“…Protein-based strategies have tested the administration of recombinant human proteins such as activated protein C (drotrecogin α), granulocyte macrophage colony stimulating factor (GM-CSF) and surfactant protein C based agents to ALI/ARDS patients 24-26 . Additional trials have used methylprednisolone, nitric oxide, β2-adrenergic receptor agonists (albuterol, salbutamol), and antioxidants (N-acetylcysteine) 7, 27-30 . All of these pharmacologic interventions were unable to demonstrate significant clinical efficacy (Table 1).…”