Effect of twice daily inhaled albuterol on cardiopulmonary exercise outcomes, dynamic hyperinflation, and symptoms in secondhand tobacco-exposed persons with preserved spirometry and air trapping: a randomized controlled trial

Chronic exposure to secondhand tobacco smoke (SHS) is a risk factor for development of chronic obstructive pulmonary disease (COPD) [1‐3]. Lung function studies in people with history of long-term occupational exposure to SHS have shown the majority of those exposed to have preserved spirometry but also to have a remarkably wide distribution of lung volume indices that represent air trapping, specifically the ratio of residual volume or functional residual capacity to total lung capacity (RV/TLC or FRC/TLC) [4, 5]. Wide ranges of RV/TLC and FRC/TLC distributions have also been reported among people with history of direct smoking and preserved spirometry [6‐8]. The significance of these observations continues to be a topic of investigation, though several recent studies have shown that in these unobstructed tobacco smoke-exposed people, lung volumes that represent air trapping (elevated RV/TLC and FRC/TLC) can identify a subset with worse symptoms and lower exercise capacity who, at least in the case of those with history of active smoking, will progress to develop overt airflow obstruction and spirometric COPD [5‐7].

The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear, and a question remains on whether elevated RV/TLC or FRC/TLC is a consequence of an airway obstructive process that has not yet resulted in spirometric airflow obstruction by formal criteria, or the result of other yet unexplained lung parenchymal changes that cause an elevated RV/TLC and FRC/TLC without airway obstructive disease. A possible approach to investigate this question is to determine whether air trapping and its associated diminished exercise capacity and worse respiratory symptoms improve with the use of bronchodilators in this tobacco-exposed population with air trapping but preserved spirometry, based on the presumption that the main effect of bronchodilators is through its relief of airflow obstruction at the level of airways.

The main goal of this study was to understand the nature of air trapping in the setting of no spirometric obstruction in people at risk for COPD (pre-COPD) by investigating whether administration of bronchodilators in that setting could improve the adverse outcomes associated with air trapping including exercise tolerance. To investigate this, a clinical trial approach was taken, not to necessarily prove a recommendation for routine use of bronchodilators in pre-COPD, but rather to determine whether bronchodilation improves air trapping and its outcomes in that setting. We hypothesized that the exercise capacity and respiratory symptoms associated with air trapping in the absence of spirometric airflow obstruction (preserved spirometry) improve with administration of bronchodilators. To examine this hypothesis, we performed a clinical trial investigating the effectiveness of albuterol, a selective β2-adrenergic receptor agonist that relaxes airway smooth muscle and causes bronchodilation, in nonsmoking individuals at risk for COPD due to occupational exposure to SHS with preserved spirometry and air trapping, and assessed whether administration of albuterol improves their peak oxygen consumption (VO₂) and other performance indices on cardiopulmonary exercise testing (CPET) as well as their level of symptoms, quality of life, and daily physical activity.

In this clinical trial, we found that inhaled bronchodilator treatment with albuterol did not improve exercise capacity (VO₂, primary outcome) or other exercise performance indices, respiratory symptoms, quality of life, or daily physical activity (secondary outcomes) in nonsmoking SHS tobacco-exposed individuals with preserved spirometry but with air trapping (defined by RV/TLC > 0.35 or presence of EFL). The lack of efficacy was present regardless of how well the participants adhered to the inhalational treatment protocol (per-protocol analysis by ≥ 70%, ≥ 80%, or ≥ 90% adherence). However, in subgroup analysis of those with air trapping defined by an RV/TLC > 0.35 who had ≥ 90% adherence to treatment, inhaled albuterol did cause an improvement in exercise capacity (VO₂, primary outcome), some measures of dynamic hyperinflation, ventilation, and oxygen-pulse (a proxy of cardiac output); however, symptoms, quality of life, or daily physical activity level were not improved. Of note, inhaled albuterol also improved the diastolic blood pressure at peak exercise, an outcome that was not specified a priori in our study, but retrospectively was of interest given the consideration that air trapping may adversely contribute to cardiovascular diastolic dysfunction [9, 43, 44].

Occupational exposure to SHS, a risk factor for development of COPD [1‐3], is associated with both reduced diffusing capacity [4, 45] and wide distributions of lung volume indices, such as RV/TLC or FRC/TLC, that represent air trapping despite preserved spirmtery [4, 5]. Studies have shown that even in the absence of spirometric airflow obstruction, elevated RV/TLC or FRC/TLC can identify a subset of individuals with worse exercise capacity and symptoms who may progress to develop overt airflow obstruction and spirometric COPD [5‐8]. Thus, air trapping in the setting of preserved spirometry may represent an early small airway disease, which contributes to exercise limitation and symptoms, probably through dynamic hyperinflation, even in the absence of spirometric airflow obstruction [5, 45]. In such a case, bronchodilator treatment may be useful in relieving air trapping and dynamic hyperinflation and thus improving exercise capacity.

Although our findings in this study are not supportive of such hypothesis, in the subgroup with RV/TLC > 0.35 and high adherence to treatment, bronchodilator use with albuterol did improve exercise capacity and dynamic hyperinflation, suggesting that at least in those with significant air trapping, as measured by elevated RV/TLC, bronchodilator could be advantageous. However, further research, perhaps in people with preserved spirometry but more significant air trapping, is needed to confirm this possibility. Compared to people with history of occupational SHS exposure and no direct smoking, people with history of direct smoking have a much wider distribution of lung volumes representing air trapping with approximately a third showing abnormal RV/TLC greater than the upper limit of predicted normal values [5‐7]. Thus, it is plausible that inhaled bronchodilator treatment could have a larger effect in those with history of direct smoking and preserved spirometry who have significant air trapping. A recent a randomized controlled trial on the utility of bronchodilators in direct tobacco-exposed persons with preserved spirometry who had respiratory symptoms found that bronchodilator treatment did not alleviate respiratory symptoms [46]. However, lung volumes were not assessed in that study, and thus stratification of the participants by their lung volumes or air trapping could not be done, making it impossible to distinguish smokers with preserved spirometry with abnormal/high RV/TLC or FRC/TLC who may have been more likely to benefit from bronchodilators.

During the course of this study, we recruited and enrolled nonsmoking participants with preserved spirometry and air trapping. To improve recruitment, we enrolled participants with air trapping defined as (1) those with RV/TLC > 0.35, a limit that we had previously determined as a reasonable cutoff for presence of exercise limitation and symptoms [5], but also (2) those with EFL as determined by presence of graphic overlap of tidal breathing on maximum expiratory flow-volume loop at rest or during exercise. EFL has been shown to be associated with air trapping and dynamic hyperinflation, both of which contribute to exercise limitation and worse respiratory symptoms [5, 47‐49]. Two interesting observations from our study in this regard are that in this non-obese population at risk for COPD due to occupational SHS exposure but with preserved spirometry, about 20% of those with RV/TLC > 0.35 did not have any EFL at rest or during exercise, while some with RV/TLC ≤ 0.35 had EFL even at rest. Given the subgroup analysis finding of albuterol effectiveness in those with RV/TLC > 0.35 and high adherence to therapy, these observations suggest resting lung volumes that represent air trapping such as RV/TLC may be better predictors of performance response to bronchodilator treatment than the presence of EFL at rest or during exercise. These findings are consistent with our previous studies in implicating lung volumes as better prognostic indicators for lung disease presence in pre-COPD when flows are within normal limits.

One interesting finding in our study was the decline in diastolic blood pressure that was observed in response to albuterol administration. While change in diastolic blood pressure was not a priori hypothesized as an outcome of albuterol therapy, there are potential mechanistic rationales that could explain the observed effect. In patients with diastolic heart failure (heart failure with preserved ejection fraction or HFpEF), both intravenous administration of dobutamine (a β-agonist) and inhalational administration of albuterol (2.5 mg via nebulization, which is roughly equivalent to four 90 mcg inhalation via metered dose inhaler) have been shown to elicit pulmonary and systemic vasodilatory effects along with a decline in systolic and diastolic blood pressure [50‐52]. These studies however did not include any characterization of pulmonary status of the participating subjects. On the other hand, HFpEF has been described in patients with COPD whether severe [53] or mild [54] and even in those with preserved spirometry (normal FEV₁/FVC) with declining vital capacity, as it happens with higher RV and RV/TLC and air trapping [55]. Given the above, another potential explanation for these observations could be the presence of air trapping. Lungs occupy the same finite space (thoracic cavity) as heart and great vessels, and increased lung volumes as it happens with air trapping and dynamic hyperinflation could introduce space limitation and changes to intrathoracic pressure, which in turn could contribute to cardiovascular dysfunction [9, 56]. Studies have described arterial stiffness as well as abnormalities in myocardial wall motion and relaxation in presence of abnormal lung volumes and air trapping [55, 57], all of which could contribute to increased ventricular end-diastolic pressure and hence increased diastolic blood pressure. Therefore, the changes in diastolic blood pressure seen with albuterol treatment in our study may have their origin in the effects of albuterol on lung volumes in addition to any direct effects on vasculature.

Our study has limitations that should be kept in view. First, the study sample size was small and further suffered from the research holds applied during the COVID-19 pandemic. Given that the final number of participants was significantly fewer than what was proposed in the original sample size and power calculation, the study was underpowered to detect the changes in the primary outcome. However, while the main study findings were negative, the subgroup analyses did provide interesting evidence suggesting the usefulness of bronchodilator therapy in the context of preserved spirometry with air trapping in individuals at risk for COPD. The findings also suggest that the nature of lung volume indices representing air trapping in the setting of preserved spirometry may in fact be an airway process not captured by airflow measures but observed on lung volume measurements. Second, studying the nature of air trapping in the setting of preserved spirometry may have been better performed in a population with more severe air trapping but preserved spirometry. Such population may be studied by enrolling individuals with history of direct smoking who have preserved spirometry but significant air trapping. However, the purpose of the current study was to examine the nonsmoking population with history of occupational SHS exposure. Epidemiologic data suggest that nearly 21% of the US population continue to be exposed to tobacco smoke [58], and thus understanding the health effects associated with exposure to SHS, which is a COPD risk factor, is of significant public health importance. Understanding whether inhaled bronchodilators could have beneficial effects on performance of respiratory system and exercise capacity could provide rationale for such therapy for when the respiratory demands are similarly increased during diseases such as respiratory infections. Third, we used albuterol, a short-acting β-agonist bronchodilator (SABA), instead of a long-acting or an ultra-long-acting β-agonist bronchodilator (LABA or ULABA) to test our hypothesis. Routine use of albuterol at high doses (800 mcg per day on four times a day dosing) in people with asthma has been reported to be associated with increased airway hyperresponsiveness as well as tachyphylaxis [59‐62], although other studies have also documented opposing results showing that the airway bronchodilator responses are maintained even with high doses of albuterol [63‐65]. However, the overall evidence in the literature suggests that in those without history of asthma or COPD, the lower doses and frequencies utilized in our study should not dampen the bronchodilator response. Moreover, such dampening of response would have resulted in a bias towards null hypothesis. Furthermore, while using LABA or ULABA may have been a more superior choice for the purpose of this study, we settled on using a short-acting agent in this study population with no overt obstruction because of concerns about adherence to therapy as those with milder symptoms or lung function abnormalities might be more likely to discontinue the use of study medication with occurrence of any mild adverse effects.

In conclusion, we did not find a significant improvement from albuterol on exercise performance, respiratory symptoms, quality of life, or daily physical activity level in this population at risk for COPD due to occupational exposure to SHS who had preserved spirometry but also air trapping and/or expiratory airflow limitation. However, in the subset of those participants in whom air trapping was strictly defined by RV/TLC > 0.35, albuterol did improve exercise performance and some measures of dynamic hyperinflation although no other outcomes. This study suggests that air trapping in the setting of pre-COPD (tobacco-exposed persons with preserved spirometry) may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction. In addition, it suggests that stratification of the tobacco-exposed persons with preserved spirometry by lung volumes and air trapping may help in identifying a subset who do benefit from the use of bronchodilators. Further study of this approach in persons with history of direct smoking and preserved spirometry who may have more severe air trapping should be able to provide a clinically useful indication in that population.