The most important finding from our study is that an increasing cumulative dose of SABD was significantly associated with reduced mortality. Patients in our study with ARDS were frequently treated with bronchodilators even though current guidelines do not propose their use [8, 18]. Other risk factors independently associated with mortality included higher MPM scores, lower PF, higher HRmax, and higher Kmin. We did not see a significant difference in the HRmax or the Kmin between patients receiving versus those not receiving bronchodilators. Most patients receiving bronchodilators received both albuterol and ipratropium via nebulization.
Multiple studies suggest mechanisms by which bronchodilators may lead to physiologic improvements in patients with ARDS. Beta-2 receptor stimulation has been found to increase alveolar fluid resorption and decrease capillary permeability, thereby reducing alveolar edema [19, 20]. Other studies have also shown that beta-agonists stimulate repair of the alveolar-capillary barrier and epithelial wound repair [21, 22]. Treating patients with IV albuterol appeared to decrease capillary membrane permeability, and in vitro studies showed that albuterol administration causes human lung epithelium to heal more quickly .
Less evidence is available to support a role for ipratropium in ARDS. In a rat model of acute pulmonary inflammation caused by cadmium inhalation, ipratropium diminished neutrophil numbers in bronchoalveolar lavage and reduced pulmonary edema as determined by lung weight . Rolla and colleagues administered inhaled ipratropium to a small cohort of patients with pulmonary edema due to congestive heart failure, demonstrating improved airflow attributed to amelioration of airway edema . The mechanism by which ipratropium might improve clinical outcomes in ARDS remains speculative. In addition to bronchodilation, physiologic studies suggest that muscarinic antagonists may affect mucus secretion, water and electrolyte secretion from epithelial cells, release of inflammatory mediators from airway epithelium, and fibroblast proliferation .
Despite preliminary data supporting a role for beta-agonists in the treatment of ARDS, the results of clinical trials have been disappointing. The BALTI-1  and BALTI-2  trials investigated the use of intravenous salbutamol in the treatment of patients with ARDS. In BALTI-1 results suggested a reduction of extravascular lung water in the treatment arm, but there was no difference in mortality between the treatment and placebo groups, and more patients in the treatment group had supraventricular dysrhythmias . The larger BALTI-2 trial was stopped early because of increased mortality in the treatment group . Treatment group patients in BALTI-2 also had longer ventilator times and increased risk of tachycardia and dysrhythmias . The ALTA trial  was a randomized, double-blind, placebo-controlled trial where nebulized albuterol was compared with placebo for the treatment of patients with acute lung injury using a primary outcome of ventilator-free days. The ALTA trial was stopped early because of futility. One important difference between ALTA and the current work is that our study examined patients with moderate to severe ARDS whereas ALTA targeted patients with mild disease. A metanalysis including these three trials demonstrated that beta-agonist treatment was not associated with improved mortality but was associated with decreased ventilator-free days and organ-failure free days .
Our finding of a strong association between cumulative SABD use and decreased mortality in ARDS patients has to our knowledge not been previously reported. Our study may have different results compared to previous work in this area because we studied patients with more severe disease. We chose to study cumulative SABD use in our multivariable analysis because most patients received both medications and the effects of each individually could not be distinguished. It is also conceivable that combination therapy of beta-agonists and muscarinic antagonists has salutary effects not seen with either agent alone. We considered that increased duration of treatment would affect cumulative SABD dose, and that the cohort receiving bronchodilators may be different than the cohort not receiving bronchodilators with respect to other factors. When we controlled our analysis for ICULOS that was different between the two cohorts, our findings remained robust.
We studied the difference in HRmax and Kmin between patients receiving and not receiving bronchodilators to assess whether there was evidence of adverse effects from albuterol in the cohort receiving this medication. There was no difference in these two parameters between the two cohorts of patients that we studied, although each risk factor was significantly associated with mortality. Among the risk factors that we found to be associated with mortality other than the cumulative use of SABD, the MPM is a validated severity of illness score , and derangements of oxygenation status, serum potassium, and heart rate are well known factors associated with mortality in the critically ill patient .
There are several limitations to our work. Our study is a retrospective, observational, single center study and our results may not be universally applicable. Bronchodilators were widely used among patients in our study, so that the cohort of patients not receiving bronchodilators was small compared to the group receiving bronchodilators and not equivalent in some respects. Most patients received both albuterol and ipratropium so that we could not distinguish whether the effects noted were due to one agent or the other, or both.
The finding of an association of the cumulative dose of SABD with decreased mortality in patients with severe ARDS is novel and provocative. These results should also be considered as preliminary and hypothesis generating, rather than definitive. Further prospective study of beta-agonist and muscarinic antagonists separately and in combination should be considered in patients with severe ARDS to learn if this intervention will change important patient outcomes to include mortality.