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β2 Agonists
β2 agonists have numerous potentially beneficial effects in ALI, ranging across several cell types. Alveolar ventilation can be improved via bronchial smooth muscle relaxation, increased mucociliary clearance, and enhanced surfactant secretion; alveolar epithelial cell repair and survival are enhanced, as is improved alveolar ion transport necessary for alveolar fluid clearance; alveolar perfusion is similarly improved, with decreased endothelial permeability and increased local fibrinolysis. Also, β2 agonists reduce inflammatory cytokine production. Numerous small clinical studies have investigated these physiological effects.
Improvement in ventilatory parameters was demonstrated in four studies, where the use of β2 agonists was associated with reductions in airflow resistance, peak and plateau airway pressure, and increased lung compliance.
The effects of β2 agonists on alveolar fluid clearance have been studied directly and indirectly. An early study of intravenous terbutaline, at a dose of 7 μg/kg over 30 minutes, in 10 ARDS patients with increased lung vascular permeability, showed that 5 of 6 subjects who responded to the infusion by decreasing vascular permeability survived, whereas the remaining 4 subjects, who did not improve their permeability, died. A small crossover study in 21 patients after lung resection compared inhaled salbutamol with ipratropium bromide, and reported improvements in extravascular lung water, pulmonary permeability, and PaO2:FiO2 ratio with salbutamol use, despite increased cardiac output. A retrospective study of salbutamol in ALI associated increasing inhaled doses of this therapy with improved outcomes. Similarly, a single-center, randomized, placebo-controlled, double-blind trial (the β-agonist lung injury trial [BALTI]) in 40 patients with ALI demonstrated intravenous salbutamol use decreased extravascular lung water (9.2 ± 6 vs 13.2 ± 3 mL/kg; 95% CI for difference, 0.2 to 8.3 mL/kg; p = 0.038).
Based on these promising results both UK and US researchers undertook large phase 3 multicenter studies investigating β2 agonists in ALI. Both studies have proved disappointing and were terminated early for futility and safety concerns. The Albuterol Treatment for Acute Lung Injury (ALTA) study used inhaled albuterol (5 mg every 4 hours), but was terminated after enrollment of 282 patients, out of a planned maximum of 1,000 patients, because no benefit was seen in either the primary end point of duration of ventilation (albuterol treated 14.4 days vs 16.6; 95% CI for difference −4.7 to 0.3 days, p = 0.087), or 60-day mortality (albuterol treated 23.0% vs 17.7%; 95% CI for difference −4.0 to 14.7%, p = 0.30). The UK BALTI-2 study tested intravenous salbutamol at a dose of 15 μg/kg/h in 326 patients within 72 hours of the development of ALI. The trial was stopped after the second interim analysis for safety concerns because more deaths had occurred in the salbutamol-treated group (34% vs 23%; risk ratio 1.47, 95% CI, 1.03 to 2.08). Several reasons have been proposed for these poor results, including unwanted cardiac stimulation, increasing myocardial oxygen demand, especially in the setting of induced tachyarrhythmias, increased ventilation-perfusion mismatch caused by salbutamol-induced vasodilation, and metabolic abnormalities including hypokalemia, hypomagnesemia, and lactic acidosis.
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