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.

BACKGROUND: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. METHODS: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. RESULTS: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity. CONCLUSIONS: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.

Remote exposure to secondhand tobacco smoke is associated with lower exercise capacity through effects on oxygen pulse, a proxy of cardiac stroke volume.

BACKGROUND: Past exposure to secondhand tobacco smoke (SHS) is associated with exercise limitation. Pulmonary factors including air trapping contribute to this limitation but the contribution of cardiovascular factors is unclear. OBJECTIVE: To determine the contribution of cardiovascular mechanisms to SHS-associated exercise limitation. METHODS: We examined the cardiovascular responses to maximum-effort exercise in 245 never-smokers with remote, prolonged occupational exposure to SHS and no known history of cardiovascular disease. We estimated the contribution of oxygen-pulse (proxy for cardiac stroke volume) and changes in systolic blood pressures (SBP), diastolic blood pressures and heart rate (HR) towards exercise capacity, and examined whether the association of SHS with exercise capacity was mediated through these variables. RESULTS: At peak exercise (highest workload completed (WattsPeak)=156±46 watts (135±33 %predicted)), oxygen consumption and oxygen-pulse (O2-PulsePeak) were 1557±476 mL/min (100±24 %predicted) and 11.0±3.0 mL/beat (116±25 %predicted), respectively, with 29% and 3% participants not achieving their predicted normal range. Oxygen saturation at peak exercise was 98%±1% and remained >93% in all participants. Sixty-six per cent showed hypertensive response to exercise. In models adjusted for covariates, WattsPeak was associated directly with O2-PulsePeak, HRPeak and SBPPeak and inversely with SHS, air trapping (residual volume/total lung capacity) and rise of SBP over workload (all p<0.01). Moreover, SHS exposure association with WattsPeak was substantially (41%) mediated through its effect on O2-PulsePeak (p=0.038). Although not statistically significant, a considerable proportion (36%) of air trapping effect on WattsPeak seemed to be mediated through O2-PulsePeak (p=0.078). The likelihood of having baseline respiratory symptoms (modified Medical Research Council score ≥1) was associated with steeper rise in SBP over workload (p<0.01). CONCLUSION: In a never-smoker population with remote exposure to SHS, abnormal escalation of blood pressure and an SHS-associated reduction in cardiac output contributed to lower exercise capacity.

Actigraphy informs distinct patient-centered outcomes in Pre-COPD.

BACKGROUND: Actigraphy can provide useful patient-centered outcomes for quantification of physical activity in the "real-world" setting. METHODS: To characterize the relationship of actigraphy outputs with "in-laboratory" measures of cardiopulmonary function and respiratory symptoms in pre-COPD, we obtained actigraphy data for 8 h/day for 5 consecutive days a week before in-laboratory administration of respiratory questionnaires, PFT, and CPET to a subgroup of subjects participating in the larger study of the health effects of exposure to secondhand tobacco smoke who had air trapping but no spirometric obstruction (pre-COPD). Using machine learning approaches, we identified the most relevant actigraphy predictors and examined their associations with symptoms, lung function, and exercise outcomes. RESULTS: Sixty-one subjects (age = 66±7 years; BMI = 24±3 kg/m2; FEV1/FVC = 0.75 ± 0.05; FEV1 = 103 ± 17 %predicted) completed the nested study. In the hierarchical cluster analysis, the activity, distance, and energy domains of actigraphy, including moderate to vigorous physical activity, were closely correlated with each other, but were only loosely associated with spirometric and peak exercise measures of oxygen consumption, ventilation, oxygen-pulse, and anaerobic threshold (VO2AT), and were divergent from symptom measures. Conversely, the sedentary domain clustered with respiratory symptoms, air trapping, airflow indices, and ventilatory efficiency. In Regression modeling, sedentary domain was inversely associated with baseline lung volumes and tidal breathing at peak exercise, while the activity domains were associated with VO2AT. Respiratory symptoms and PFT data were not associated with actigraphy outcomes. DISCUSSION: Outpatient actigraphy can provide information for "real-world" patient-centered outcomes that are not captured by standardized respiratory questionnaires, lung function, or exercise testing. Actigraphy activity and sedentary domains inform of distinct outcomes.

Lung volumes identify an at-risk group in persons with prolonged secondhand tobacco smoke exposure but without overt airflow obstruction.

INTRODUCTION: Exposure to secondhand smoke (SHS) is associated with occult obstructive lung disease as evident by abnormal airflow indices representing small airway disease despite having preserved spirometry (normal forced expiratory volume in 1 s-to-forced vital capacity ratio, FEV1/FVC). The significance of lung volumes that reflect air trapping in the presence of preserved spirometry is unclear. METHODS: To investigate whether lung volumes representing air trapping could determine susceptibility to respiratory morbidity in people with SHS exposure but without spirometric chronic obstructive pulmonary disease, we examined a cohort of 256 subjects with prolonged occupational SHS exposure and preserved spirometry. We elicited symptom prevalence by structured questionnaires, examined functional capacity (maximum oxygen uptake, VO2max) by exercise testing, and estimated associations of those outcomes with air trapping (plethysmography-measured residual volume-to-total lung capacity ratio, RV/TLC), and progressive air trapping with exertion (increase in fraction of tidal breathing that is flow limited on expiration during exercise (per cent of expiratory flow limitation, %EFL)). RESULTS: RV/TLC was within the predicted normal limits, but was highly variable spanning 22%±13% and 16%±8% across the increments of FEV1/FVC and FEV1, respectively. Respiratory complaints were prevalent (50.4%) with the most common symptom being ≥2 episodes of cough per year (44.5%). Higher RV/TLC was associated with higher OR of reporting respiratory symptoms (n=256; r2=0.03; p=0.011) and lower VO2max (n=179; r2=0.47; p=0.013), and %EFL was negatively associated with VO2max (n=32; r2=0.40; p=0.017). CONCLUSIONS: In those at risk for obstruction due to SHS exposure but with preserved spirometry, higher RV/TLC identifies a subgroup with increased respiratory symptoms and lower exercise capacity.

Reduced exercise tolerance and pulmonary capillary recruitment with remote secondhand smoke exposure.

RATIONALE: Flight attendants who worked on commercial aircraft before the smoking ban in flights (pre-ban FAs) were exposed to high levels of secondhand smoke (SHS). We previously showed never-smoking pre-ban FAs to have reduced diffusing capacity (Dco) at rest. METHODS: To determine whether pre-ban FAs increase their Dco and pulmonary blood flow (Qc) during exercise, we administered a symptom-limited supine-posture progressively increasing cycle exercise test to determine the maximum work (watts) and oxygen uptake (VO2) achieved by FAs. After 30 min rest, we then measured Dco and Qc at 20, 40, 60, and 80 percent of maximum observed work. RESULTS: The FAs with abnormal resting Dco achieved a lower level of maximum predicted work and VO2 compared to those with normal resting Dco (mean±SEM; 88.7±2.9 vs. 102.5±3.1%predicted VO2; p = 0.001). Exercise limitation was associated with the FAs' FEV(1) (r = 0.33; p = 0.003). The Dco increased less with exercise in those with abnormal resting Dco (mean±SEM: 1.36±0.16 vs. 1.90±0.16 ml/min/mmHg per 20% increase in predicted watts; p = 0.020), and amongst all FAs, the increase with exercise seemed to be incrementally lower in those with lower resting Dco. Exercise-induced increase in Qc was not different in the two groups. However, the FAs with abnormal resting Dco had less augmentation of their Dco with increase in Qc during exercise (mean±SEM: 0.93±0.06 vs. 1.47±0.09 ml/min/mmHg per L/min; p<0.0001). The Dco during exercise was inversely associated with years of exposure to SHS in those FAs with ≥10 years of pre-ban experience (r = -0.32; p = 0.032). CONCLUSIONS: This cohort of never-smoking FAs with SHS exposure showed exercise limitation based on their resting Dco. Those with lower resting Dco had reduced pulmonary capillary recruitment. Exposure to SHS in the aircraft cabin seemed to be a predictor for lower Dco during exercise.

Bronchial hyperresponsiveness, word descriptors, and ethnicity: women with mild asthma.

BACKGROUND: Few studies have examined the ethnic differences in symptom reporting and airway hyperresponsiveness (AHR) for women with mild asthma during a methacholine (McH) challenge. OBJECTIVE: The purpose of this sub-analysis was to determine: (1) whether AHR to McH varied by the ethnicity of women with mild asthma and (2) whether ethnic word descriptors (EWDs) varied by the ethnicity during induced bronchoconstriction. METHODS: Specific inclusion criteria included the following: FEV(1) (forced expiratory volume in 1 second) ≥ 70% predicted normal, PC(30) ≤ 8 mg/McH, ß(2) inhaler only, and self-reported ethnicity of African American (AFAM), Mexican American-Hispanic-Latino (MexAMLat), Asian-Pacific Islander (Asian PI), or white. Serial pulmonary function testing (PFT) and Borg, visual analogue scale (VAS), and EWDs were collected. RESULTS: A total of 44 women, mean age of 31.3 years old, with a mean baseline FEV(1) of 2.85 L comprised this sub-analysis. Ethnic-racial diversity included: 12 AFAMs, 5 MexAMLat, 13 Asian-PIs, and 14 whites. All had atopy ≥ 2 pinprick responses of 3 mm. At PC(30), Asian-PI women required a significantly (p < .05) smaller mean dose of McH 1.9 mg/mL. MexAMLat women required an McH dose of 1.6 mg/mL. At PC(30), McH dose was 2.9 mg/mL for AFAMs and 3.0 mg/mL for whites, respectively. Asian-PIs who used only upper airway EWDs at PC(30) vere itchy throat, itchy chin, and constricted throat (p < .001). AFAMs significant EWDs were itchy throat, itchy chin/face, and tight throat (p < .01). Lower airway EWD was used by both MexAMLat and whites. Significant EWD for Whites were tight chest (p < .01) and hard to inhale/lungs tight (p < .001). CONCLUSION: Asian-PI women required a significantly smaller dose (p < .05) of McH to induce a PC(30). AFAM and whites required a comparable dose of Mch at PC(30). Asian-PI and AFAM women used only upper airway EWD. Asian-PI women may be at a greater risk for acute asthma episodes that are not recognized or treated due to their upper airway symptom reporting.

Recruitment of asthmatic ethnic minorities into a methacholine research study: factors influencing participation.

BACKGROUND: How to recruit minority participants into research studies has been an issue since 1993, when NIH funding guidelines required minorities to be included as research participants. OBJECTIVE: The purpose of this analysis was to determine what factors affected recruitment of asthmatic minorities into a large bronchoconstrictor study involving African-Americans, Hispanics/Mexican Americans, Asian/Pacific Islanders, and whites with mild asthma (forced expiratory volume in the first second of expiration > or = 70%). METHODS: Ethnic minorities were recruited for 3 years. Recruitment strategies included physician and clinic referrals, newspaper ads, posters in health care settings, asthma databases, and electronic resources. FINDINGS: After 3 years, the total number of referrals was 650, with 50 from medical doctor clinic settings and 600 from all of the other resources. The inclusion/exclusion criteria were clearly listed, but only 64.5% (419/650) of respondents met inclusion criteria. Of these, only 31.9% (134/419) [corrected] met pulmonary function testing criteria. Only 5, or 1% of the 50 medical doctor clinic referrals met inclusion criteria--1 participated. A total of 106, or 82.8%, completed all of the study procedures; for 87.7% of participants this was their first research experience. Hispanics/Mexican Americans accounted for only 14.8% of the total recruitment responses. CONCLUSION: We believe our recruitment strategies did encourage ethnic minorities to participate, but the inclusion criteria of a positive methacholine response proved to be a study enrollment barrier.

Ethnic differences in methacholine responsiveness and word descriptors in African Americans, Hispanic-Mexican Americans, Asian-Pacific Islanders, and Whites with mild asthma.

OBJECTIVE: There is little asthma research that compares ethnic differences in airway responsiveness and word descriptors among African Americans, Hispanic-Mexican Americans, Asian-Pacific Islanders, and Whites. Thus, identifying ethnic differences in symptom descriptors and airway responsiveness may improve health outcomes by educating health professionals about treatment decisions that are culturally and ethnically sensitive. METHODS: Specific Inclusion criteria-forced expiratory volume in one second (FEV(1)) >or= 70% predicted normal; provocative concentration causing a 30% fall in FEV(1) (PC(30))

Pulmonary function abnormalities in never-smoking flight attendants exposed to secondhand tobacco smoke in the aircraft cabin.

OBJECTIVE: To determine whether the flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin have abnormal pulmonary function. METHODS: We administered questionnaires and performed pulmonary function testing in 61 never-smoking female flight attendants who worked in active air crews before the smoking ban on commercial aircraft (preban). RESULTS: Although the preban flight attendants had normal FVC, FEV1, and FEV1/FVC ratio, they had significantly decreased flow at mid- and low-lung volumes, curvilinear flow-volume curves, and evidence of air trapping. Furthermore, the flight attendants had significantly decreased diffusing capacity (77.5% +/- 11.2% predicted normal) with 51% having a diffusing capacity below their 95% normal prediction limit. CONCLUSIONS: This cohort of healthy never-smoking flight attendants who were exposed to secondhand tobacco smoke in the aircraft cabin showed pulmonary function abnormalities suggestive of airway obstruction and impaired diffusion.

Remote second-hand tobacco exposure in flight attendants is associated with systemic but not pulmonary hypertension.

BACKGROUND: Second-hand tobacco smoke has been associated with cardiopulmonary dysfunction. We sought to examine the residual effects of remote second-hand smoke exposure on resting and exercise cardiopulmonary hemodynamics. We hypothesized that remote secondhand smoke exposure results in persistent cardiopulmonary hemodynamic abnormalities. METHODS: Participants were non-smoking flight attendants who worked in airline cabins prior to the in-flight tobacco ban. Participants underwent clinical evaluations and completed smoke exposure questionnaires. We used Doppler echocardiography to measure pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) at rest and during supine bicycle ergometer exercise, using the validated formula TRV/VTIRVOT x 10 + 0.16, where VTIRVOT is the velocity time integral at the right ventricular outflow tract and TRV is the tricuspid regurgitation velocity. The group was divided into quartiles according to the degree of smoke exposure. Analysis of variance was used to determine the differences in hemodynamic outcomes. RESULTS: Seventy-nine flight attendants were included in our analysis. Baseline characteristics among participants in each quartile of smoke exposure were similar except for history of systemic hypertension, which was more prevalent in the highest quartile. Peak exercise PASP rose to the same degree in all test groups (mean PASP 44 mm Hg, p = 0.25), and PVR increased by approximately 27% in all quartiles. There was no significant difference in pulmonary artery systolic pressure or pulmonary vascular resistance among quartiles of smoke exposure. CONCLUSIONS: We found that remote heavy second-hand smoke exposure from in-flight tobacco is associated with systemic hypertension but does not have demonstrable pulmonary hemodynamic consequences.

Adrenergic responsiveness: FEV1 and symptom differences in Whites and African Americans with mild asthma.

Decision-making about inhaler use is, in part, determined by the ability of asthmatic patients to compare their symptoms over time and to recall the previous response to the bronchodilator during an episode of asthma. The perception of airway symptoms across varied ethnic and cultural groups are poorly understood. Study purpose was (1) to determine if African Americans and Whites with mild asthma could accurately perceive bronchodilation and (2) to identify the word descriptors they used to describe their breathing. Sixteen African American and 16 White patients (34.5 +/- 9.7 years old, mean+/-SD) with mild atopic asthma (FEV1 > or =70% predicted normal) were given increasing doses of an inhaled bronchodilator (Albuterol) after a methacholine challenge. Albuterol (180 microg) was given, by spacer, at 15 min intervals until the FEV1 increased < 5%. Borg, VAS, and Word Descriptors were collected at baseline and after each dose of Albuterol. Baseline FEV1 after Methacholine provocation was 1.94 +/- .39 L for African Americans and 2.13 +/- .70 L for Whites. After 180 microg and again after 360 microg Albuterol, FEV1 increased to 2.88 +/- 0.48 L for African Americans and 3.37 +/- 0.91 L for Whites. But after 540 microg Albuterol, FEV1 decreased significantly (16%) to 2.42 +/- 1.19 L for African Americans while increasing only slightly to 3.47 +/- 0.95 L for Whites. After this dose, 10/16 African Americans felt "tight at the base of throat" (p < 0.01); 7/16 felt "speech-voice-tight" (p < 0.03) suggesting persistent airway discomfort despite marked improvement in FEV1, Borg and VAS scores compared with baseline values. Word descriptors by African Americans' are a more reliable measure of airway symptoms compared to FEV1, Borg or VAS.

Effects of treatment on two types of self-efficacy in people with chronic obstructive pulmonary disease.

Self-management is crucial in people with chronic diseases, and self-efficacy has been shown to impact patients' self-management. The purposes of this study were to 1) determine the effect of intervention on self-efficacy and 2) determine the relationship between domain-specific self-efficacy, walking performance, and symptom severity in patients with chronic obstructive pulmonary disease (COPD). Subjects (n=102, forced expiratory volume in 1 second % predicted 44.8+/-14) received one of three self-management interventions. Self-efficacy for walking and managing shortness of breath, walking performance, and shortness of breath severity were measured at baseline and after intervention. Self-efficacy increased after intervention (P<0.01). Self-efficacy for walking was positively related to walking performance (P<0.05). Self-efficacy for managing shortness of breath was positively related to symptom severity (P<0.05). This study examined two types of disease-specific self-efficacy in patients with COPD and demonstrated that improving self-efficacy is an important outcome of self-management interventions. Studies in other domains of self-efficacy are needed.

Effects of individual self-management education on clinical, biological, and adherence outcomes in asthma.

BACKGROUND: Asthma guidelines urge teaching patients the knowledge and skills required for self-management, based on the assumption that education will lead to improved skills and better asthma control. METHODS: In a prospective, randomized controlled trial of 65 adults with mild-to-moderate asthma, we examined whether an educational self-management intervention would improve adherence to inhaled corticosteroid therapy, decrease markers of airway inflammation, and improve clinical control. Peak flow, symptoms, and adherence were monitored for 7 weeks. After a 1-week run-in, subjects were assigned randomly to either the educational intervention or control group. The 30-minute intervention was delivered and reinforced at biweekly intervals. RESULTS: Compared with the control group, the intervention group had improvements in adherence to inhaled corticosteroid therapy (by 30% vs. -5%, P = 0.01), self-reported control of asthma (by 14% vs. 5%, P = 0.04), and perhaps quality of life (by 37% vs. 21%, P = 0.06). The direction of change for all other clinical outcomes was more favorable in the intervention group, but not significantly so. Markers of inflammation in sputum decreased more in the intervention group, with sputum eosinophils declining significantly (P = 0.02). CONCLUSION: In asthmatic patients treated with inhaled corticosteroids, education and training in self-management improves adherence with inhaled therapy, perceived control of asthma, and sputum eosinophilia.

Understanding how asthmatics perceive symptom distress during a methacholine challenge.

The way, or ways, in which asthmatics recognize specific symptom(s) with varying degrees of their airway obstruction, or asthma severity, is poorly understood. Our purpose was to gain a better understanding of how asthma patients during acute episodes, based on their symptom perception, decide when to seek symptom relief. A cross-sectional design was used to study 32, 16 per group, African Americans and Caucasians with a mean age of 34.5 years. All had mild, stable asthma (FEV1 > or = 70%), were non-smokers, atopic, and had not used inhaled or oral steroids for 3 months. Their mean baseline FEV1 was 97.5% predicted; all were controlled with intermittent use of a beta agonist inhaler. All had a bronchoconstrictor challenge using a provocative concentration of methacholine to achieve a 30% fall (PC30) in their FEV1. After achieving a PC30 and before their first dose of a bronchodilator was given, all subjects were asked: "If you felt this way at home would you take your inhaler?" Subjects were blinded to the fact that the yes/no question was asked when their FEV1 was reduced by 30%. In both groups, 44% responded "no" that they would not use their inhaler at that point in time. This finding suggests that those subjects, the 44% who failed to associate a change in their symptoms with increased airflow obstruction, may be at risk for life-threatening episodes.

Exercise training improves outcomes of a dyspnea self-management program.

PURPOSE: The purpose of this study was twofold: (1) to determine whether exercise training adds to the benefit of a dyspnea self-management (DM) program; and (2) to determine if there is a "dose response" to supervised exercise training (0, 4, or 24 sessions) in dyspnea, exercise performance, and health-related quality of life. METHODS: Subjects with chronic obstructive pulmonary disease (n = 103, 46 men, 57 women; age 66 +/- 8 years; forced expiratory volume in 1 second 44.8 +/- 14% predicted) were randomized to DM, DM-exposure, or DM-training. Dyspnea self-management included individualized education about dyspnea management strategies, a home-walking prescription, and daily logs. Outcomes were measured at baseline and 2 months as part of a 1-year longitudinal randomized clinical trial. Outcomes included dyspnea during laboratory exercise and with activities of daily living (Chronic Respiratory Questionnaire [CRQ]), Shortness of Breath Questionnaire, Baseline/Transitional Dyspnea Index), exercise performance (incremental treadmill tests (ITTs) and endurance treadmill tests (ETTs), 6-minute walk (6MW), and health-related quality of life (SF-36). RESULTS: The DM-training group had significantly greater improvements than the DM-exposure and the DM groups in dyspnea at isotime during ITT (P =.006); exercise performance during ITT (P =.005), ETT (P =.003), and 6MW (P =.01); SF-36 Vitality (P =.031); and CRQ mastery (P =.007). There was a dose-dependent improvement in CRQ dyspnea scores (P <.05) with significant improvements only in the DM-training and DM-exposure groups. CONCLUSION: Exercise training substantially improved the impact of a dyspnea self-management program with a home walking prescription (DM). This impact tended to be dependent on the "dose" of exercise.