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* From the Section of Pulmonary & Critical Care Medicine (Drs. Mahler and Baird), Dartmouth Medical School, Lebanon, NH; and Pulmonary Function and Cardiopulmonary Exercise Laboratories (Ms. Waterman and Mr. Ward), Dartmouth-Hitchcock Medical Center, Lebanon, NH.
Correspondence to: Donald A. Mahler, MD, FCCP, Section of Pulmonary & Critical Care Medicine, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756-0001; e-mail: Donald.a.mahler{at}hitchcock.org
Abstract
Background: The purpose of the study was to examine the responsiveness of a computerized system whereby the patient reports spontaneously any change in the intensity of breathlessness during exercise. The hypotheses were that hypercapnia would increase and hyperoxia would decrease the slope of power production-breathlessness ratings compared with a control condition during cycle ergometry.
Methods: Thirty adult subjects (15 women and 15 men) with persistent asthma (mean [± SD] FEV1/FVC ratio, 57 ± 10%) completed an initial familiarization visit and three study visits. All subjects inhaled two puffs of albuterol (180 µg) in order to standardize lung function prior to exercise. At visits 2 to 4, subjects breathed one of the three gas mixtures administered in a random order while performing a ramp exercise test. The experimental conditions were as follows: hypercapnia (5% carbon dioxide); hyperoxia (40% oxygen); and control (room air).
Results: Lung function was the same before and after exercise with the three experimental conditions. With hypercapnia, peak ventilation was increased, peak oxygen consumption, and power production were reduced, the slope of power-breathlessness was increased, and 25 patients (83%) reported breathlessness as the limiting symptom. With hyperoxia, peak ventilation was decreased, peak power production and the slope of power-breathlessness were unchanged, and 16 patients (53%) reported leg discomfort as the limiting symptom.
Conclusions: Breathing 5% carbon dioxide altered physiologic responses and the slope of power production-breathlessness during exercise. The responses to hyperoxia were inconsistent. The continuous method for patient-reported breathlessness was responsive to hypercapnia, but not to hyperoxia, during incremental exercise.
Key Words: adults with asthma • computer ratings of breathlessness • exercise testing • hypercapnia • hyperoxia
The symptom of breathlessness represents a unique sensation or experience that independently characterizes the condition of patients with various respiratory diseases.12 The patient can rate the intensity of breathlessness when a stimulus, such as physical exercise, is introduced under standard conditions. Using this approach, early studies34567 of patient-reported dyspnea had the subject provide a single rating at peak exertion; more recently, subjects have been asked to report breathlessness each minute (discrete method) during a cardiopulmonary exercise test.
There are limitations using the discrete method when the subject is asked to rate the intensity of breathlessness "on cue." First, the timing of reporting breathlessness is entirely arbitrary from the patient’s perspective. Second, if the patient is able to exercise for only 3 to 4 min, then a limited number of ratings of breathlessness may then be obtained.89 To enhance the patient’s ability to report the actual course of breathlessness during continuous exercise, we developed a system whereby the subject adjusts a computer mouse to indicate "whenever there is a change in the intensity of breathlessness."8
In previous investigations,8910 we established the validity and/or reliability of the continuous (CON) system in healthy children and those with asthma, in healthy adults, and in patients with COPD. We also showed the advantages of this approach compared with the discrete method. First, subjects report breathlessness spontaneously whenever there is a change in breathlessness with the CON method rather than an arbitrary time period each minute of exercise with the discrete approach. Second, we have found that subjects report twice the number of ratings of breathlessness with the CON system compared with the discrete method.89 A greater number of ratings enhance any calculation of slope and intercept as well as statistical analyses, especially in patients who can exercise for only a few minutes. Third, subjects actually report an increasing number of ratings as the exercise test progresses; this information is not captured with the discrete method.10
The purpose of the present study was to examine the responsiveness of the CON system in patients with persistent asthma during cycle ergometry. The ability to detect changes in breathlessness with an intervention is an important consideration for evaluating various treatments in patients with respiratory disease. We selected hypercapnic and hyperoxic gas mixtures as stimuli because of their opposing effects on ventilatory responses and their expected differential impact on patient-reported breathlessness. The following two hypotheses were tested compared with a control condition when the patients breathed room air: (1) hypercapnia increases ventilation and the slope of the relationship between power production and breathlessness ratings; and (2) hyperoxia decreases ventilation and the slope of the relationship between power production and breathlessness ratings.
Materials and Methods
Subjects
Inclusion criteria for all participants were as follows: age 
18 years; a clinical diagnosis of asthma; < 5 pack-years of cigarette smoking; previous or current FEV1/FVC ratio of < 70%; ability to exercise on the cycle ergometer; and no clinically important comorbid conditions. All subjects were recruited as patients in the outpatient pulmonary clinic at our institution and from advertisements in local newspapers. Institutional review board approval was obtained, as well as written informed consent from all participants.
A total of 31 subjects were recruited for the study. One subject withdrew after visit 1. The mean (± SD) anthropometric characteristics of the 30 subjects (15 women and 15 men) were as follows: age, 55 ± 16 years; height, 168 ± 9 cm; and weight, 82 ± 2 kg. All participants were using at least one controller medication and thus were considered to have persistent asthma. Asthma medications prescribed for the participants were albuterol metered-dose inhaler (n = 21), inhaled corticosteroids (n = 20), inhaled long-acting ß-agonist (n = 17), leukotriene receptor antagonist (n = 6), inhaled short-acting or long-acting anticholinergic medication (n = 6), and oral theophylline (n = 2).
Experimental Protocol
Each subject participated in four visits separated by intervals of 2 to 3 days. At visit 1, a medical history and spirometry (model CPL; Collins; Braintree, MA) were performed. Predicted values for spirometry were taken from Crapo et al.11 Next, the participant was familiarized with the equipment, pedaled on the cycle ergometer, and practiced using the computer system to provide ratings of breathlessness. The subject was then instructed not to take any short-acting or long-acting bronchodilator medication for 12 h prior to the subsequent three visits.
At visits 2 to 4, the subject performed spirometry and then inhaled two puffs of albuterol (180 µg) via metered-dose inhaler in order to standardize lung function at the visits prior to the exercise test. Spirometry was repeated 20 min after the inhalation of albuterol. Ten minutes later, the subject performed an incremental exercise test (ramp protocol 15 W/min) on an electronically braked cycle ergometer (Ergo-Metrics 800S; SensorMedics; Yorba Linda, CA) until symptom limitation. Expired gas was analyzed for minute ventilation (
E), oxygen consumption (O2), and carbon dioxide production for every breath using a metabolic measurement system (Cardiorespiratory Diagnostic Systems; MedGraphics; St. Paul, MN). The system was calibrated before each test.
The system used to rate breathlessness consisted of a computer, a monitor, and a mouse, as previously described.8 The subject was instructed to adjust the length of a green bar (0.7 cm wide) on the screen by changing the location of the mouse on a platform (in a direction toward or away from the body) to express the perceived level of breathlessness. No verbal cues were given as to when ratings were to be made. Each subject read the following written instructions at each visit: "This is a scale for rating breathlessness. The No. 0 represents no breathlessness. The No. 10 represents the strongest or greatest breathlessness that you have ever experienced. You should adjust the length of the green bar (up or down) by moving the position of the mouse at any time during the exercise when you experience a change in your breathlessness."
At visit 2, each subject was assigned randomly to receive one of the following three breathing conditions while exercising on the cycle ergometer:
The gas mixtures were added at the start of the cardiopulmonary exercise test and were delivered via reservoir bags and inspiratory tubing connected to the mouthpiece. The bags and connecting tubing were hidden from the sight of the patient. One investigator was aware of the breathing condition selected for each visit.
At the end of each exercise test at visits 2 to 4, the subject was asked whether breathlessness or leg discomfort was the major limiting symptom. Spirometry was repeated 15 min following completion of the exercise test because we considered that breathing the hypercapnic gas mixture might influence the ability of the patients to perform appropriate FVC maneuvers immediately after exercise.
Statistical Analysis
A change in breathlessness was indicated whenever the bar was moved down to correspond with a higher value on the intensity scale and was stationary for at least 1 s. The scale value after such change was treated as a single rating. Peak values for breathlessness were selected as the highest rating in the session, and peak values for the physiologic variables were selected as the maxima achieved within the last 2 min of exercise.
Both linear regression and power function models were applied to describe the relationships of breathlessness ratings as a function of the following three variables: power production (in watts); O2 (in milliliters per kilogram per minute); and E (in liters per minute) for each subject.8912 For the linear regression model, the mean Pearson product moment correlation coefficients were 0.94 for each of the three determinations. For the power function model, the mean correlations indicating goodness of fit were 0.94, 0.95, and 0.94 for power production, O2, and E, respectively. While different types of functions provide better fits for certain conditions and subjects, we used linear regression as a model of the relationships of interest here in keeping with our previous work.8912 Slopes and x-intercepts of the linear regression equation were calculated except for the O2-breathlessness relationship during the hyperoxic condition because O2 cannot be accurately measured when the subject is breathing a hyperoxic gas mixture.
Comparison of data for the three conditions was performed with repeated-measures multivariate analysis of variance. When the repeated-measures multivariate analysis of variance indicated a significant difference among the three conditions, paired t tests were used to compare the results. All data are reported as the mean ± SD. The Cochran Q test was used to analyze differences in the reported symptoms that limited exercise under the three conditions. A p value of < 0.05 (two-tailed test) was considered statistically significant.
Results
Lung function after the inhalation of albuterol was similar at visits 2 to 4 (Table 1
). For the group, there were no significant changes in lung function following exercise with the three experimental conditions. Only one patient demonstrated evidence of a 10% decrease in FEV1 after exercise while breathing room air compared to the postbronchodilator FEV1 value. Results from incremental cardiopulmonary exercise testing are reported in Table 2
.
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O2 (change, –4.6 mL/kg/min; p < 0.001) were reduced, and peak E was higher (change, +5.4 L/min; p = 0.003). With hyperoxia, exercise duration and peak power production were similar, and peak E was reduced (change, –3.3 L/min; p = 0.001).
Measures of Breathlessness
None of the subjects reported any difficulty in rating their breathlessness with the computer system. With hypercapnia, the slopes were higher and the x-intercepts were lower for both the power-breathlessness relationship (p < 0.05) [Fig 1
] and the O2-breathlessness relationship (p < 0.05). With hyperoxia, there were no significant differences for parameters of the linear functions between power and breathlessness or between E and breathlessness.
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Discussion
The major findings were as follows: (1) there were no differences in lung function following exercise with hypercapnic or hyperoxic gas mixtures compared to the control condition; (2) in general, hypercapnia impaired exercise performance (ie, decreased values for exercise time, peak O2, and peak power production), whereas hyperoxia had no effect on exercise time or peak power production; (3) hypercapnia increased the slopes of power-breathlessness and O2-breathlessness based on measures obtained continuously throughout exercise, while hyperoxia did not alter the power-breathlessness parameters. Thus, the CON method for patient-reported breathlessness was responsive to the hypercapnia stimulus, but not to the hyperoxia gas mixture.
For this investigation, we selected individuals with persistent asthma to examine the responsiveness of the CON system in order to expand the patient population beyond those of our previous studies in patients with COPD.912 Hypercapnia and hyperoxia were chosen as experimental stimuli for the following two reasons: (1) these gas mixtures have opposing effects on ventilation and would therefore be expected to have different impacts on the intensity of breathlessness; and (2) previous studies on physiologic and symptomatic exercise responses in patients with COPD have primarily focused on the effect of bronchodilator medications. Thus, we wanted to evaluate the responsiveness of the CON system in a patient population with a chronic respiratory disease other than COPD and used two distinct stimuli that were expected to increase breathlessness (hypercapnia) as well as to decrease breathlessness (hyperoxia) rather than examine a bronchodilator medication with its expected effect on decreasing the intensity of breathlessness.
Each subject inhaled two puffs of albuterol at visits 2 to 4 in order to standardize bronchodilator therapy prior to exercise. As a group, the subjects demonstrated significant bronchodilator responses to albuterol as expected with the diagnosis of asthma. It was likely that the use of albuterol before exercise prevented the development of exercise-induced bronchoconstriction (EIB) [Table 1]. Neither breathing a hypercapnic nor a hyperoxic gas mixture altered postexercise lung function. In two previous studies,1314 investigators showed that breathing 100% oxygen attenuated EIB in asthmatic subjects. However, subjects in these studies were required to have reproducible EIB and to withhold all bronchodilator medications for 4 to12 h prior to testing.1314
Hypercapnia has been used routinely to investigate ventilatory responsiveness at rest. It is well known that breathing carbon dioxide leads to an increase in arterial PCO2 that is sensed rapidly in the medulla and mid-brain to produce changes in pH and ventilation. To the best of our knowledge, the present study is the first to examine physiologic and breathlessness responses to a hypercapnic challenge during exercise. As anticipated, our subjects increased E during exercise while breathing the 5% carbon dioxide gas mixture. Exercise duration, peak power production, and peak O2 were lower with hypercapnia compared with the control condition. Our data suggest that the asthmatic group stopped exercise at a high intensity of breathlessness (mean rating, 8.4 ± 2.7 U), which occurred at a lower power production due to the hypercapnic stimulus.
Hyperoxia has been used widely to investigate the perception of exertional breathlessness, primarily in patients with COPD. The results of our study in asthmatic subjects support previous observations15161718 that oxygen therapy reduces exercise E in patients with COPD. The modest (approximately 3 L/min) but significant reduction in peak exercise E with breathing the 40% oxygen gas mixture in our patients with asthma was similar to the findings of Dean et al19 (–3 L/min at exercise isotime with 40% oxygen) and O’Donnell et al17 (approximately 4 L/min at exercise isotime with 60% oxygen) in patients with COPD. The reduction in E observed in these various studies was presumably due to the attenuation of peripheral chemoreceptor activity.
Our patients with asthma did not increase exercise performance while breathing a hyperoxic gas mixture. This finding contrasts with reports171920 of improvements in exercise endurance during oxygen breathing during constant work exercise tests in patients with COPD. These differences may be due to the type of exercise test (ie, incremental vs constant work) as well as the baseline characteristics of the subjects. For example, our asthmatic subjects had a mean FEV1 of 76% predicted and, as a group, were not ventilatory limited (breathing reserve, 48%). Patients with COPD who have been studied171920 breathing a hyperoxic gas mixture have exhibited severe airway obstruction (FEV1, < 40% predicted) and demonstrated ventilatory limitation during exercise.
The primary objective of this study was to examine the responsiveness of the computerized system whereby subjects provide ratings of breathlessness continuously throughout exercise. Hypercapnia was a potent stimulus and increased the slopes of power-breathlessness and O2-breathlessness relationships. These results are consistent with our subjects reporting breathlessness as the major complaint (83%) at end exercise with hypercapnia. In contrast, breathing the 40% O2 did not alter the slopes of the relationship of the two physiologic variables (ie, power production and E) and breathlessness. It is likely, although unproven, that the reduction in exercise ventilation (approximately 3 L/min at peak exercise) with hyperoxia was not sufficient in magnitude to affect breathlessness ratings in our subjects with asthma, whereas the same decrease in exercise E with hyperoxia reduced ratings of breathlessness in patients with severe COPD.1719 An alternative explanation is that some of the patients with asthma may have been "poor perceivers" to breathing a hyperoxic gas mixture.
A study by Kosmas and colleagues21 has shown that dynamic hyperinflation due to expiratory flow limitation during exercise developed in 13 of 20 stable patients with asthma. Of note, these subjects did not use inhaled short-acting or long-acting bronchodilators for 8 and 24 h, respectively, prior to testing. We did not include the assessment of dynamic hyperinflation in our study because we were concerned that having our patients perform inspiratory capacity maneuvers at specific time periods (eg, every 2 min) during exercise might distract them from providing continuous ratings of breathlessness. Prospective testing will be required to determine whether performing inspiratory capacity maneuvers, particularly at high intensities of exercise, affects the experience and reporting of breathlessness by subjects using the CON reporting system.
Various studies have reported slopes relating a physiologic variable to ratings of dyspnea during exercise testing. For example, Teramoto et al22 and Tsukino et al23 found significant decreases in the slope of O2-dyspnea with single doses of bronchodilators in patients with COPD. In contrast, in two separate studies Oga and colleagues2425 found no difference when comparing the ratios (ie, change in dyspnea/change in O2) with bronchodilator therapy. These ratios, however, were based on only two data points (at rest and at the end of exercise). In a recent study12 of patients with COPD, we found that the slope of the O2-breathlessness relationship during exercise was reduced after a single dose of a albuterol/ipratropium bromide solution compared with placebo. Investigators reported1617 that the relationship between E and breathlessness was the same whether subjects breathed room air or supplemental oxygen. Based on the available data, the slopes of the power production-breathlessness and O2-breathlessness relationships generally demonstrate more consistent responsiveness to stimulus intervention than the slope of the relationship describing E and breathlessness.3151617
In this study, we focused on the measurement criterion of the responsiveness of the CON system because researchers and pharmaceutical companies are interested in evaluating whether a particular treatment reduces the severity of breathlessness. Our data from subjects with persistent asthma expand our previous experience with the CON system in healthy individuals and in patients with COPD.912 The present findings along with our results of acute bronchodilator therapy in patients with COPD clearly demonstrate the responsiveness of the CON method to different stimuli during exercise testing in patients with chronic respiratory disease.
Footnotes
Abbreviations: CON = continuous; EIB = exercise-induced bronchoconstriction; E = minute ventilation; O2 = oxygen consumption
This study was supported by National Institutes of Health, Small Business Innovation grant 2 R44 HL068493–02 (principal investigator, Dr. Baird).
Dr. Mahler, Ms. Waterman, and Mr. Ward have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Dr. Baird is Scientific Director of Psychological Applications, which owns the copyright of the continuous measurement of breathlessness program.
Received for publication May 30, 2006. Accepted for publication September 20, 2006.
References
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