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-Adrenergic Agonist Therapy as a Potential Treatment for Acute Lung Injury

Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California

Edward Abraham, M.D.

Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Acute lung injury develops in approximately 200,000 patients per year in the United States and has an overall mortality of approximately 40% (1). Although lung-protective ventilation with lower tidal volumes (6 ml/kg/ideal body weight) and plateau airway pressure limits (< 30 cm H₂O) have substantially reduced mortality (2), there is still a need for new therapies that can further decrease mortality in patients with acute lung injury (3).

On the basis of randomized, placebo-controlled clinical trials, a number of different therapeutic strategies, including surfactant, inhaled nitric oxide, prone position, and several antiinflammatory approaches, have failed to improve clinical outcomes in patients with acute lung injury (4). New therapies currently being tested in small phase II trials include activated protein C, because of its anticoagulant and antiinflammatory properties (5), and granulocyte-macrophage colony–stimulating factor, because of its potential to reduce alveolar epithelial cell death (6).

The use of -adrenergic agonists as a potential therapy for acute lung injury has generated considerable interest. Studies in several species, including the ex vivo human lung, have demonstrated that -agonists can increase the rate of vectorial salt and water transport across the normal alveolar and distal airway epithelia by 50 to 100% over baseline levels. Treatment with a -agonist enhances the rate of alveolar fluid clearance by increasing intracellular cAMP. The effects of -agonists on cAMP lead to increased sodium, chloride, and net fluid transport across distal lung epithelium (7, 8). The rate of alveolar fluid clearance can also be increased by -agonist therapy in experimental acute lung injury resulting from ischemia–reperfusion or acid instillation (9, 10). In the same studies, -agonist treatment decreased lung vascular injury and edema formation, perhaps in part by inhibition of endothelial cell contraction and through reducing intercellular gaps.

-Agonists also have well-recognized antiinflammatory properties. For example, stimulation of -adrenergic receptors on mononuclear cells and macrophages reduces their capacity to release proinflammatory cyokines during human endotoxemia (11). These observations have now been extended to studies in human subjects who were challenged with inhaled endotoxin. In a recent article in the AJRCCM, pretreatment with an inhaled ₂-agonist markedly reduced neutrophil influx, neutrophil degranulation, and accumulation of tumor necrosis factor in the airspaces of human volunteers exposed to inhaled endotoxin (12). Thus, several mechanisms of action support the potential value of -agonist therapy as a treatment for acute lung injury.

Until recently, there were no data to assess the effect of -agonist therapy on lung fluid balance in patients. However, in this issue of the Journal (pp. 281–287), Perkins and colleagues (13) report the results of a clinical trial of 40 patients with acute lung injury in which the effects of -agonists were examined. Salbutamol (albuterol) was administered intravenously at a dose of 15 µg/kg/hour in a double-blind, randomized manner. Extravascular lung water on Day 7, the primary outcome variable, was lower in the salbutamol-treated patients compared with the placebo control subjects (9.2 vs. 13.2 ml/kg, p = 0.04). Post hoc analysis indicated that extravascular lung water was significantly lower in the treated group at earlier time points as well. Plateau airway pressure was also 6 cm H₂O lower at Day 7 in the salbutamol-treated group (p = 0.049), and there was a trend toward lower acute lung injury scores in the salbutamol-treated patients.

Despite the positive results, there are important limitations to this clinical trial. The study was small, the method used for measuring lung water in the patients has not been sufficiently validated, and the decrease in lung water was not matched by a significant improvement in all the physiologic indices of lung function. For example, oxygenation did not improve in the salbutamol-treated patients. There was no difference in mortality or ventilator-free days, but the study was too small to evaluate these endpoints. Nevertheless, the results indicate that a multicenter clinical trial may be warranted to test the possible therapeutic benefit of -agonist therapy for acute lung injury.

One major issue in considering the design of a larger clinical trial is selection of the optimal route for administration of a -agonist in patients with acute lung injury. In the Perkins and colleagues' trial (13), -agonist therapy was delivered by the intravenous route. However, intravenous administration was associated with a higher incidence of supraventricular arrhythmias in the patients who were randomized to salbutamol as compared with placebo (26 vs. 10%, p = 0.2). Is there an alternative to the intravenous route? In a double-blind, randomized trial, pretreatment with inhaled salmeterol reduced the incidence of high-altitude pulmonary edema in subjects at risk for this clinical problem (14). Therapeutic levels of albuterol can be achieved in the pulmonary edema fluid of ventilated patients with acute lung injury using standard aerosolization procedures (15). In view of the favorable findings with inhaled -agonists, as shown in the latter two studies, coupled with the cardiac side effects in the Perkins and colleagues' trial (13), it may be preferable to use aerosolized delivery in the design of a larger clinical trial.

Although there are reasons to believe that -adrenergic agonist therapy may be beneficial in patients with acute lung injury, are there mechanisms that may limit the efficacy of this promising therapy? Alveolar fluid clearance is impaired in most patients with acute lung injury, a finding that correlates with increased mortality (16). It is possible that the alveolar epithelium may be too injured in some patients to respond to -adrenergic agonist therapy with an up-regulation of alveolar fluid clearance. In addition, the potential beneficial effects of -adrenergic agonists on lung inflammation and lung vascular permeability may not be sufficiently potent to favorably affect lung fluid balance in clinical acute lung injury. Finally, down-regulation of pulmonary ₂ receptors might impair the efficacy of -agonist therapy (7). However, this problem seems less likely because Perkins and colleagues (13) reported a significant reduction in lung water after 7 days of treatment.

On balance, aerosolized -agonist therapy should be safe and may prove to be effective in improving clinical outcomes in patients with acute lung injury. -agonist treatment has the potential to reduce the severity of pulmonary edema by attenuating inflammatory injury to the pulmonary circulation and by accelerating the resolution of alveolar edema. A randomized, double-blind, multicenter clinical trial is warranted to test the potential efficacy of -adrenergic agonist therapy for patients with acute lung injury.

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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