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Effect of Albuterol on Maximal Exercise Capacity in Cystic Fibrosis^*

^* From the Department of Respiratory Medicine, Mater Adult Hospital, South Brisbane, QLD, Australia.

Correspondence to: David J. Serisier, DM, Department of Respiratory Medicine, Mater Adult Hospital, South Brisbane, QLD 4101, Australia; e-mail: david.serisier{at}mater.org.au

Abstract

Background: Inhaled, short-acting ß-adrenergic agonists (SAßAs) are widely prescribed in cystic fibrosis (CF) subjects, despite a lack of convincing data for efficacy and the potential for these agents to result in airway instability. We tested the hypothesis that inhaled albuterol would improve maximal exercise performance in CF subjects with airflow obstruction, as a result of acute bronchodilation.

Methods: Randomized, double-blind, placebo-controlled crossover study of the effect of inhaled albuterol on maximal exercise performance in 20 stable adult CF patients (mean ± SD age, 23.3 ± 6.1 years; FEV₁, 57.65 ± 17.13% of predicted).

Results: Ventilatory limitation to exercise was demonstrated in 16 subjects (80%). Significant bronchodilation occurred with exercise alone (end-exercise FEV₁, 2.24 ± 0.8 L; vs preexercise FEV₁, 2.09 ± 0.77 L; p < 0.0001), but albuterol resulted in significantly greater exercise-induced bronchodilation than placebo (change in FEV₁, 0.3 ± 0.15 L vs 0.15 ± 0.11 L; 95% confidence interval [CI], + 0.07 to + 0.23; p < 0.001). However, there was no difference in maximal workload achieved (albuterol, 158 ± 46 W; vs placebo, 158 ± 45 W; 95% CI, – 4.41 to + 4.71; p = 0.95), nor any other measure of exercise performance including maximal oxygen uptake.

Conclusions: Despite causing significant acute bronchodilation, inhaled albuterol did not improve maximal exercise performance in ventilatory-limited CF adults, adding to the body of literature that fails to show any clinical benefit of SAßAs in CF subjects. The current results provide further evidence to question the widespread use of these agents, although the potential for adrenergic ß-agonists to instead improve submaximal exercise performance merits further investigation.

Key Words: adrenergic ß-agonists • albuterol • cystic fibrosis • exercise • salbutamol

ß-adrenergic agonists are widely prescribed in subjects with cystic fibrosis (CF). In Europe, over half of all CF subjects and 80% of those with severe lung disease are prescribed regular bronchodilators.¹ The rationale for ß-adrenergic agonists is largely extrapolated from their use in asthma, as CF subjects also have a high incidence of acute bronchodilator responsiveness,² hyperreactivity to direct bronchial stimuli,² and atopy.³ However, acute bronchodilator reversibility is poorly reproducible in CF subjects,⁴⁵ and 10 to 20% of subjects actually demonstrate acute declines in spirometric values with bronchodilators.⁴ Furthermore, data suggest that bronchodilators may make large airways overly compliant in CF subjects, such that acute reversibility as assessed by standard lung function tests may actually represent increased early forced expiratory flow as a result of increased dead space, without any increase in mid- and end-expiratory flows.⁶ Such an effect may increase nonhomogeneous lung emptying⁷ and impair clearance of respiratory secretions, despite an apparent acute bronchodilator benefit. These considerations suggest that in CF subjects, spirometrically demonstrated acute bronchodilator reversibility is generally neither a useful measure of future potential clinical benefit nor a useful outcome measure in itself.

Unfortunately, there are no data that convincingly demonstrate alternative, clinically relevant benefits of short-acting bronchodilators in CF subjects. Although the prescription of ß-agonists has been advocated on the basis of improvements in ciliary beat frequency in vitro,⁸ radioaerosol clearance studies⁹ in CF subjects failed to demonstrate a positive effect of terbutaline on mucociliary clearance, and such benefits may be limited to healthy subjects.

Maximal aerobic exercise performance is an important functional outcome measure and an independent predictor of mortality in CF.¹⁰ While there may be multiple potential determinants of exercise limitation in CF subjects,^1112131415 CF subjects with significant lung disease demonstrate ventilatory constraint to maximal exercise performance¹⁶ that is associated with expiratory flow limitation and dynamic hyperinflation.¹⁷ Short-acting bronchodilators might be expected to result in improved exercise capacity in ventilatory-limited CF subjects by attenuating the development of dynamic hyperinflation as a result of bronchodilation, an effect that has been demonstrated in some studies¹⁸¹⁹ in subjects with COPD. Significant correlations between maximal exercise performance and daily physical activity²⁰ and between daily activity and quality of life²¹ have been shown in CF subjects. Therefore, identification of therapies that augment the exercise capabilities of exercise-limited CF adults might be expected to improve quality of life (and possibly even prognosis) and are of critical importance.

Dodd et al²² did not find any evidence of improved exercise capacity with inhaled albuterol in CF subjects despite significant increases in FEV₁; however, this was a small study (n = 8) and did not report whether subjects were ventilatory limited during exercise, a necessary prerequisite for expecting improvements in exercise performance with bronchodilation. Additionally, bronchial reactivity status of trial participants was not reported, in spite of data suggesting that CF subjects with bronchial responsiveness may be most likely to benefit from short-acting ß-agonists (SAßAs).²³ We sought to test the hypothesis that an SAßA would improve maximal exercise performance in a larger sample of CF subjects with significant airflow obstruction and ventilatory limitation to exercise, as a result of acute bronchodilation.

Materials and Methods

Subjects
Adults with CF previously diagnosed on standard clinical and laboratory criteria were recruited from the adult CF clinic at the Mater Adult Hospital, a regional specialist CF clinic in Australia. All subjects were 16 years of age and provided written informed consent. The protocol was approved by the Local Regional Ethics Committee.

Subjects with CF were included in the study if they had been clinically stable for at least 21 days and had received no supplemental antibiotic therapy over that period. Subjects were excluded if their usual maintenance therapies were altered in the preceding 21 days, if they were unable to exercise, had resting oxyhemoglobin saturations < 90%, or were intolerant of ß-adrenergic agonists. Subjects with moderate airways obstruction (FEV₁, 30 to 75% of predicted) were preferentially recruited.

Study Design and Procedures
This was a randomized, double-blind, placebo-controlled crossover study. Subjects performed two cycle ergometer tests on separate days within a 1-week period, after inhalation of six puffs of either albuterol (600 µg) or matching saline solution placebo in random order. No baseline exercise test was performed, as excellent reproducibility of maximal cycle ergometry testing in CF adults has previously been shown.²⁴

Randomization was performed using computer-generated block randomization in groups of four. The pharmacy department prepared and supplied trial drug as two indistinguishable metered-dose inhalers labeled "S" and "D," which were then administered according to the blinded randomization sequence. The unblinding code was held independently by a physician uninvolved in the trial conduct, and all measurements, data collection, and data entry were completed before treatment codes were broken. Trial subjects, trial supervisors, and all staff involved in direct patient care were unaware of treatment allocations at all times. To be eligible for full outcome analysis, a patient had to complete both arms of the trial.

Subjects were instructed to perform their usual daily chest physiotherapy prior to exercise tests. Prior to all tests, subjects withheld short-acting bronchodilators, nebulized therapies, and caffeine for at least 6 h, and long-acting bronchodilators for 24 h. Albuterol and placebo were delivered from identical, unmarked metered-dose inhalers through a large-volume spacer device. Participants inhaled maximally to total lung capacity from functional residual capacity after each puff and then breath-hold for 10 s. The warm-up period of exercise was commenced 10 min after completion of trial drug inhalation.

The same investigators performed all procedures. Spirometry was performed using a Vmax Mass Flow Sensor spirometer (SensorMedics, Viasys Healthcare; Yorba Linda, CA). Spirometry was performed prior to inhalation of trial drug, 60 s following completion of the exercise test (end-exercise FEV₁), and 10 min after exercise (to assess for exercise-induced bronchoconstriction). In order to ensure that complete blinding was maintained for the exercise tests, spirometry was not performed after trial drug inhalation and prior to exercise. On 2 further separate days, subjects also underwent baseline histamine bronchoprovocation testing according to the method of Yan et al²⁵ and acute bronchodilator reversibility testing to albuterol according to American Thoracic Society criteria.²⁶

Exercise tests were performed at the same time of day for each subject. Cardiopulmonary exercise tests were performed using a Vmax 229D system (SensorMedics) configured in the breath-by-breath mode. Maximal, incremental exercise testing was performed on a calibrated, electromagnetically braked cycle ergometer (Ergo-Metrics 800S; SensorMedics) using a continuous ramp protocol²⁷ (5 W, 10 W, or 15 W ramped increase per minute, determined for each subject to achieve an exercise duration of 8 to 12 min, according to respiratory function and perceived aerobic fitness). Subjects maintained a pedal frequency of 55 to 65 rotations per minute, and the test was continued to exhaustion or until the subject was unable to sustain this pedal frequency. Borg scores for dyspnea and leg muscle fatigue were recorded during the test.

Subjects wore a nosepiece and breathed in an open circuit through a flanged rubber mouthpiece that was connected to a mass-flow sensor with a saliva trap. Ventilation was measured using the mass-flow sensor, and inspired and expired gas concentrations were continuously monitored with a rapid response multigas analyzer incorporating paramagnetic oxygen and infrared carbon dioxide sensors. The following were measured breath-by-breath: minute ventilation (E), oxygen consumption (O₂), carbon dioxide production, and respiratory quotient. Heart rate was monitored by ECG (Marquette Cardiosoft V3.0; Marquette; Hellige, Germany) and oxyhemoglobin saturation by pulse oximetry (Radical Masimo-SET; Masimo Corporation; Irvine, CA).

The highest workload, O₂, and E achieved during the last 30 s of exercise were recorded as the maximal workload (Wmax), maximal O₂ (O₂max), and maximal E (Emax). Maximal voluntary ventilation (MVV) was estimated as FEV₁ x 40, and ventilatory limitation to exercise was indicated by a Emax/MVV ratio > 0.8. The protocol-defined primary outcome measure was Wmax, comparing albuterol and placebo. Secondary outcome measures were O₂max and change in FEV₁.

Statistical Analysis
Using estimates of variability from published data in CF adults,²⁴ sample size calculation indicated that 20 subjects would provide 90% power to detect a 10-W increase in Wmax from 140 to 150 W at the 5% (two-sided) significance level. Analyses compared within-subject differences in outcomes between albuterol and placebo. There was no evidence of nonnormal distribution for any outcome variable using the one-sample Kolmogorov-Smirnov test. Therefore, outcome measures were assessed by complete crossover analysis of variance for repeated measures, including assessment for period effects and treatment/period interaction. Comparison of baseline measurements between the two treatment arms used paired t tests, while comparisons of nonpaired data used two-sample t tests. Pearson product moment correlation coefficients were computed to assess the degree of univariate association between numeric variables on appropriate measurement scales, and multivariate regression analysis was also performed; p < 0.05 was considered significant. Statistical software (StatsDirect version 2.2.5; StatsDirect Ltd; Cheshire, UK) was used for statistical analysis.

Results

Twenty-two adult CF subjects were enrolled and randomized, and 20 subjects completed the study. One subject declined to participate following enrollment, and a second subject did not complete the second exercise test for personal reasons. Data from both of these were excluded. Three subjects did not perform bronchoprovocation testing, and only seven subjects completed full Borg scores during the tests. Ten subjects received albuterol first, and 10 received placebo first. Baseline characteristics are shown in Table 1 .

There was a significant increase in FEV₁ in the placebo arm (end-exercise, 2.24 ± 0.8 L; vs before exercise, 2.09 ± 0.77 L; p < 0.0001), although the increase occurring with albuterol was significantly greater than this (Table 2 ; Fig 1 ). However, albuterol had no effect on Wmax or O₂max (Table 2). There were no differences in exercise duration (621 ± 145 s vs 627 ± 146 s; p = 0.38) or Borg scores for dyspnoea (end-exercise score, 6.86 ± 2.67 vs 6.14 ± 2.12; p = 0.38) or leg fatigue (end-exercise, 6.83 ± 2.93 vs 7.33 ± 2.94; p = 0.20), including Borg/time slopes. There was no evidence of period effect or treatment/period interaction for the primary outcome measure (p > 0.9 for both). While the difference in Emax between the two arms was not statistically significant (75 ± 34.29 L vs 73.42 ± 24.56 L; p = 0.30), the Emax/MVV ratio was significantly higher in the albuterol than placebo arms (0.94 ± 0.17 vs 0.90 ± 0.15; p = 0.05).

View larger version (7K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Change in FEV1 with placebo and albuterol. (boxes and whiskers representing mean, 95% CI, and range).

Using baseline placebo arm data, potential correlations between lung function and nutritional status to maximal exercise performance were explored. Wmax was closely and significantly correlated to FEV₁ (r = 0.80, p < 0.001) and less strongly correlated with body mass index (BMI) [r = 0.59, p = 0.006]. The relationship between Wmax and FEV₁ was confirmed on multiple linear regression analysis (r = 0.72, p < 0.001), while BMI was not significantly related (r = 0.38, p = 0.12). However, there was no relationship seen between the differences in bronchodilation between albuterol and placebo arms and corresponding differences in Wmax achieved (r = 0.006, p = 0.98).

Discussion

The current study demonstrates that inhaled albuterol does not improve indexes of maximal exercise performance in CF subjects with moderate severity airways obstruction, despite causing significant acute bronchodilation. This lack of benefit persisted when only subgroups with positive bronchoprovocation test results, significant acute bronchodilator reversibility, or ventilatory limitation to exercise were considered. Furthermore, these findings are consistent with those reported by Dodd et al²² in a smaller sample.

Although some previous investigations have demonstrated improvements in exertional dyspnoea and exercise performance with ß-agonists²⁸ and anticholinergic agents¹⁹ in subjects with severe COPD, this effect appears to be inconsistent.¹⁸ It has been suggested that the explanation for this may relate to the particular breathing pattern adopted by COPD subjects during exercise, such that bronchodilation is beneficial in only a subgroup.²⁹ Such an effect is unlikely to explain our findings, as there was no discrete group of "improvers" to suggest variability in response, with only three subjects showing 5% higher Wmax on the albuterol arm (and three subjects showing 5% higher Wmax with placebo).

Erroneously concluding that bronchodilators do not improve exercise capacity in subjects with airways obstruction may result from failing to study subjects who are ventilatory limited, only including subjects who do not bronchodilate, using an inadequate dose of bronchodilator, confounding due to learning effect, or inadequate patient numbers.¹⁸ In the current study, ventilatory limitation was demonstrated in the majority of subjects, significant bronchodilation was seen (also implying adequate dosing), and there was no evidence of period effect or treatment-period interaction for Wmax. Furthermore, excellent reproducibility of maximal cycle ergometry testing in CF adults has previously been shown.²⁴ Finally, the current study provided 90% power to detect a difference in means of only 7.25 W (an increase of 4.6% from 158 to 165.25 W) at the 5% significance level.

The magnitude of exercise-induced bronchodilation with albuterol (150 mL or 7% greater than placebo) is sufficient to expect that an improvement in parameters of exercise performance would have been demonstrable in this group of ventilatory-limited subjects. Why then did these CF subjects fail to increase maximal exercise performance?

If subjects in the current study were not truly ventilatory limited or if the primary determinant of ventilatory limitation was not dynamic hyperinflation, then bronchodilators could not be expected to improve exercise performance. Stein et al³⁰ showed that the calculated MVV significantly underestimated sprint MVV in CF children with FEV₁ <79% of predicted (although there are no similar data in adult CF subjects as far as we are aware). However, at the time that our trial was undertaken, those data were not available and the calculated MVV was generally endorsed as an acceptable alternative.³¹ Additionally, the use of encroachment on breathing reserve (as a function of MVV) to define ventilatory constraint is subject to limitations, foremost being the lack of information provided on the specific breathing strategy adopted by individuals and hence the inability to determine specific constraints to ventilation.³² Exercise tidal flow-volume loops provide a useful visual index of ventilatory limitation that also inform about the determinants of ventilatory constraint; however, at the present time there remains a lack of validated quantitative measures using these. Using definitions of expiratory flow limitation proposed by Johnson et al,³² all but two subjects in the current study showed expiratory flow limitation, with the majority demonstrating severe expiratory flow limitation (> 50% of tidal volume exceeding the expiratory boundary of the maximal flow volume loop). Finally, while the recent data of McKone and colleagues³³ confirm the importance of ventilatory constraint in the determination of exercise limitation in CF subjects, their results suggest that arterial hypoxemia (rather than pulmonary mechanics) may be the primary limiting factor. However, their study was conducted in subjects with severe lung disease (mean FEV₁, 39% of predicted) who acquired significant hypoxemia (mean end-exercise oxyhemoglobin saturation, 89%), in contrast to our group of subjects with moderate lung disease. Significant arterial hypoxemia did not develop in our test subjects, and therefore arterial hypoxemia is unlikely to have been a primary limiting factor, although it may have played some role.

Although unlikely, it is possible that the inability to demonstrate exercise benefits is the result of ß-adrenergic effects unrelated to bronchial smooth muscle. Albuterol may result in deterioration in ventilation/perfusion matching, as has been shown for fenoterol when administered to stable COPD subjects with hypoxia at rest.³⁴ Additionally, ß-agonists may impair peripheral skeletal muscle oxygen uptake,³⁵ and it is possible that such an effect may have accentuated the impairments of peripheral muscle metabolism¹⁴ and oxygen uptake¹⁵ that others have shown in CF subjects.

Airway instability with bronchodilation has been demonstrated in CF subjects at rest⁶ and during submaximal exercise³⁶ due to loss of bronchomotor tone. Thus, it may be that an increase in physiologic dead space during maximal exercise is the reason for the failure to improve maximal exercise performance despite bronchodilation. In the current study, the demonstration of a significantly higher Emax/MVV ratio in the albuterol arm, without associated improvements in any measure of exercise performance, suggests that the increases in ventilation seen with albuterol were ineffective, perhaps due to increases in ventilation of dead space. Furthermore, while placebo Wmax correlated most strongly with baseline FEV₁ (FEV₁ explaining almost two thirds of the variance), there was no correlation between changes in FEV₁ and Wmax with albuterol, suggesting dissociation of this relationship when lung function was related to bronchodilation. Unfortunately, we did not have reliable isotime dead space or inspiratory capacity data from the current studies to allow any further assessment of the possible contribution of these mechanisms.

Despite the inability to demonstrate any improvement in maximal exercise performance, SAßAs may improve submaximal endurance exercise. Submaximal exercise tests may better demonstrate differences in exercise performance due to reduced hyperinflation, as well as being more representative of daily activities. In COPD subjects, Oga and colleagues³⁷ found that a submaximal test was more sensitive than a maximal exercise test for detecting improvements in exercise performance in response to oxitropium. Furthermore, data suggest that walking is more sensitive than cycling for demonstrating improved exercise endurance as a result of bronchodilation in COPD subjects, perhaps due to less leg muscle fatigue.³⁸

The current results provide further evidence to question the widespread use of SAßAs by CF adults. While bronchodilation is generally considered a clinically important outcome in airways diseases such as asthma and COPD, there remains a lack of similar evidence in CF. Although we found no specific evidence of deleterious effects of albuterol, our results add to the literature arguing against the routine use of these agents.

In summary, there was no beneficial effect of inhaled albuterol on maximal exercise performance in ventilatory-limited CF subjects, despite causing significant bronchodilation. These findings may represent increases in dead space ventilation due to bronchodilation or indicate inadequate sensitivity of maximal incremental cycle ergometry. Our data add to the body of literature that fails to demonstrate any significant benefit of SAßAs in CF subjects, and cautions against their continued widespread use in this patient group. However, the potential for adrenergic ß-agonists to instead improve submaximal exercise performance in ventilatory-limited CF adults merits further investigation.

Acknowledgements

We are sincerely grateful to the CF patients who so willingly donated their time and effort to be involved in this study.

Footnotes

Abbreviations: BMI = body mass index; CF = cystic fibrosis; CI = confidence interval; MVV = maximal voluntary ventilation; SAßA = short-acting ß-adrenergic agonist; E = minute ventilation; Emax = maximal minute ventilation; O₂ = oxygen consumption; O₂max = maximal oxygen consumption; Wmax = maximal workload

This work was performed at Mater Adult Hospital, South Brisbane, Australia.

The authors have no conflicts of interest to disclose.

Received for publication July 6, 2006. Accepted for publication December 6, 2006.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Serisier, D. J. Articles by Bowler, S. D. Search for Related Content PubMed PubMed Citation Articles by Serisier, D. J. Articles by Bowler, S. D.