Reply: Importance of the Kidney, Vessels, and Heart with Administration of β₂ Adrenergic Receptor Agonists in Patients Susceptible to Acute Respiratory Distress Syndrome

From the Authors:

We thank Drs. Snyder and Johnson for their insightful interest in our recent trial article (1). We agree with them that there are many potentially important nonbronchodilator effects of β-agonists, including stimulation of alveolar fluid clearance, effects upon inflammatory cells, and potentially promoting alveolar epithelial repair responses via MMP-9 (2–5). The wealth of supporting data from translational and animal/preclinical studies drove the hypothesis that β-agonists might work as a therapeutic or preventative agent in patients with or at risk of acute respiratory disease (ARDS). Unfortunately, as has been so often the case with developing new strategies for therapy in ARDS, translation of these findings into clinical benefits has been unsuccessful, with the BALTI-2 study finding an increased risk of death in patients with ARDS treated with intravenous β-agonists (6).

In their elegant discussion, Snyder and Johnson suggest that deleterious effects of β-agonists upon the kidney may have counteracted any beneficial effects of β-agonists upon alveolar fluid clearance in patients with ARDS. We agree that the effects of β₂-agonists upon renal sodium handling are important to consider. We reported no difference in daily fluid balance in the phase 2 BALTI-1 paper (7) but have no additional unpublished data from BALTI-2 (6) or BALTI-prevention (1) to help shed light on this action. However, we note that when intravenous β₂-adrenergic agonists were used for tocolysis during pregnancy, they have been associated with reduced sodium, potassium, and water excretion, leading to a reduced hematocrit and intravascular hypervolemia (8, 9) and development of maternal pulmonary edema (10).

Finally, we suggest that, although our BALTI-prevention trial did not reduce the incidence of ARDS, we did demonstrate some findings worthy of future study. We found that inhaled salmeterol resulted in a reduction in systemic inflammation, which resulted in reduced alveolar epithelial barrier dysfunction perioperatively. The magnitude of the effects was not sufficient to prevent postoperative ARDS but did significantly reduce the incidence of reported postoperative pneumonia

We suggest, therefore, that salmeterol protected the alveolar epithelium in patients undergoing esophagectomy by reducing inflammatory and epithelial damage during injurious one-lung ventilation. We agree with Snyder and Johnson that combination therapies, targeting different mechanisms implicated in the development of ARDS, are likely to be needed to successfully treat and prevent ARDS.