Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD.

Exogenous opioid drugs, such as morphine, relieve breathlessness. The present study hypothesis was that endogenous opioids, released during the stress of exercise, modify dyspnoea in patients with chronic obstructive pulmonary disease. After familiarisation, patients performed an incremental treadmill exercise test followed by constant work on the treadmill for 10 min. At subsequent visits (2 to 3 days apart), patients received two puffs of albuterol, had a catheter placed in an arm vein for removal of blood to measure beta-endorphin immunoreactivity, received normal saline or 10 mg of naloxone intravenously in randomised order, and then performed high-intensity constant work rate exercise on the treadmill. The mean+/-sd age of the 17 patients (eight females and nine males) was 63+/-7 yrs, and post-bronchodilator forced expiratory volume in one second was 50+/-17% predicted. In both conditions, beta-endorphin levels increased three-fold from rest to end-exercise. The regression slope of breathlessness as a function of oxygen consumption (primary outcome), mean ratings of breathlessness throughout exercise and peak ratings of breathlessness were significantly higher with naloxone than normal saline. There were no differences in physiological responses throughout exercise between conditions. In conclusion, endogenous opioids modify dyspnoea during treadmill exercise in patients with chronic obstructive pulmonary disease by apparent alteration of central perception.

Effects of arformoterol twice daily, tiotropium once daily, and their combination in patients with COPD.

PURPOSE: Current guidelines support using in combination more than one class of long-acting bronchodilator for COPD patients whose symptoms are not controlled by mono-therapy. This 2-week, multi-center (34 sites), randomized, modified-blind, parallel group study evaluated the efficacy and safety of concomitant treatment with nebulized arformoterol (the formoterol(R,R)-isomer) BID and tiotropium DPI QD. METHODS: COPD patients (mean FEV(1) 1.37L, 45.4% predicted) were randomized to receive mono-therapy (either arformoterol 15microg BID [n=76] or tiotropium 18microg QD [n=80]), or combined therapy (sequential dosing of arformoterol 15microg BID and tiotropium 18microg QD [n=78]). Changes in pulmonary function, dyspnea, and rescue levalbuterol use were evaluated, as were safety outcomes. RESULTS: Mean FEV(1)AUC(0-24) (the primary endpoint) improved similarly from baseline for arformoterol (0.10L) and tiotropium (0.08L) treatment groups and greater for the combined therapy group (0.22L; all p-values <0.005). Peak FEV(1), peak FVC, 24-h trough FEV(1), and inspiratory capacity also improved similarly for the mono-therapies and greatest for the combined therapy. Dyspnea (mean transition dyspnea index) improved similarly for arformoterol (+2.3) and tiotropium (+1.8) and greatest with combined therapy (+3.1; p-values <0.05). Levalbuterol use decreased for all treatment groups (range -1.8 to -2.5 actuations/day). All treatments had similar frequency of adverse events. CONCLUSION: In this study, the combination of nebulized arformoterol 15microg BID plus tiotropium 18microg DPI QD was the most effective in improving pulmonary function and disease symptoms. Mono-therapy improvement with arformoterol or tiotropium was similar. All three treatments were well tolerated.

Outcomes for COPD pharmacological trials: from lung function to biomarkers.

The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Minimal important difference of the transition dyspnoea index in a multinational clinical trial.

Dyspnoea is a primary symptom of chronic obstructive pulmonary disease (COPD). The baseline (BDI) and transition (TDI) dyspnoea indices are commonly used instruments to assess breathlessness and the impact of intervention. Its validity and pattern of response in multinational clinical trials has not been established. In a retrospective analysis of a cohort of 997 COPD patients who received tiotropium, salmeterol or placebo, in addition to usual care, the validity and pattern of response of the BDI and TDI were examined. The BDI was significantly correlated with the dyspnoea diary (DD) score and the symptom and activity components of the St. George's respiratory questionnaire (SGRQ), establishing concurrent validity. Furthermore, the TDI was also correlated with the changes in DD, SGRQ symptom and activity scores. Construct validity was established by the association between baseline forced expiratory volume in one second (FEV1) and BDI and AFEVI with TDI. Physician's global evaluation (PGE) was significantly associated with BDI as well as APGE with TDI. Significant correlations have also been observed when the cohorts were classified according to native English and native non-English speaking countries. A change in PGE of 1 category (i.e. 2 units on an 8-point scale) was associated with a mean TDI of approximately 1 unit (0.9-1.3 mean focal score), lending further support to the clinical significance of this change inherent in the instrument's descriptors. TDI responders (i.e. focal score < or = 1 unit) used less supplemental salbutamol, had fewer exacerbations and had significantly improved health status as measured by impacts and total SGRQ scores compared with nonresponders. In conclusion, the transition dyspnoea index is a valid instrument when used in a multinational clinical trial and the patterns of response confirm a 1-unit change in the transition dyspnoea index focal score as being clinically important.

A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.

Effectiveness of salmeterol versus ipratropium bromide on exertional dyspnoea in COPD.

The hypothesis of the study was that salmeterol and ipratropium would have similar dyspnoea ratings during steady-state cycle ergometry at 1 h, but that salmeterol would reduce dyspnoea at 6 h after administration in patients with chronic obstructive pulmonary disease (COPD). The study design was a randomized, double-blind trial in 16 patients (aged 63 +/- 11 yrs) with symptomatic COPD. Two days after familiarization with testing procedures, patients were randomly assigned to receive either two puffs (42 microg) of salmeterol and two puffs of placebo inhaler, or two puffs (36 microg) of ipratropium from each of two inhalers (total, 72 microg). Two days later, patients received the alternative medication. During exercise at 60% of peak oxygen consumption patients rated dyspnoea and performed inspiratory capacity manoeuvres each minute. Forced expiratory volume in one second was 1.13+/-0.48 L (37+/-13% predicted). Dyspnoea ratings were similar for salmeterol and ipratropium at 1 and 6 h. Inspiratory capacity was similar for salmeterol and ipratropium at 1 h, but significantly higher for salmeterol at 6 h (delta = 120 mL; p = 0.03). It is concluded that with the doses used, salmeterol and ipratropium provided similar dyspnoea ratings during exercise at 1 and 6 h after administration.

Salmeterol plus theophylline combination therapy in the treatment of COPD.

BACKGROUND: Patients with COPD often require multiple therapies to improve lung function and decrease symptoms and exacerbations. Salmeterol and theophylline are indicated for the treatment of COPD, but the use of these agents in combination has not been extensively studied. OBJECTIVES: To compare the efficacy and safety of salmeterol plus theophylline vs either agent alone in COPD. METHODS: Randomized, double-blind, double-dummy, parallel-group trial in 943 patients with COPD. After an open-label theophylline titration period (serum levels, 10 to 20 microg/mL), patients were randomly assigned to receive salmeterol (42 microg bid) plus theophylline, salmeterol (42 microg bid), or theophylline for 12 weeks. Serial pulmonary function tests were completed on day 1 and treatment week 12. Patients kept diary cards and noted their peak flow rates, symptom scores, and albuterol use, and periodically completed quality-of-life and dyspnea questionnaires. RESULTS: All three groups significantly improved compared with baseline. Combination treatment with salmeterol plus theophylline provided significantly (p < or = 0.045) greater improvements in pulmonary function; significantly (p < or = 0.048) greater decreases in symptoms, dyspnea, and albuterol use; and significantly fewer COPD exacerbations (p = 0.023 vs theophylline). In general, treatment with salmeterol provided greater improvement in lung function and satisfaction with treatment compared with theophylline. Salmeterol treatment was also associated with significantly fewer drug-related adverse events (p < or = 0.042) than either treatment that included theophylline. The safety profile (adverse events, vital signs, and ECG findings) of the two treatments that included theophylline were similar. CONCLUSION: Patients with COPD may benefit from combination treatment with salmeterol plus theophylline, without a resulting increase in adverse events or other adverse sequelae.

Continuous measurement of breathlessness during exercise: validity, reliability, and responsiveness.

A continuous method for recording changes in breathlessness (dyspnea) during exercise is introduced and compared with the traditional discrete method. In study 1, a category-rating scale was presented on a computer screen, and 14 healthy, young female subjects exercised on a cycle ergometer until exhaustion. Two approaches were used to obtain ratings of breathlessness: a discrete method, in which subjects gave single judgments every minute, and a continuous method, in which subjects throughout exercise moved the mouse so that a bar on the screen extended to the desired location along the scale. Psychophysical results relating measures of breathlessness and the variables of work, oxygen consumption, and minute ventilation were statistically indistinguishable with the two methods, and both methods were highly reliable across test sessions. In study 2, both measurement methods were employed, and the subjects were 14 healthy, young males. In each of two sessions (discrete or continuous method), subjects first rated their breathlessness during an incremental test in which the workload was increased over time and levels of work, and minute ventilation were recorded. Subjects then exercised for 10 min at 60% of the maximal oxygen consumption achieved during the incremental test. At two points during steady-state exercise, a respiratory load was introduced that lasted for 1 min. It was possible to determine the responsiveness of subjects to onset and offset of the respiratory load for the continuous method but not for the discrete method. In study 3, patients with chronic obstructive pulmonary disease employed both methods, and it was found that the continuous method was better at determining whether subjects showed a significant positive slope of the regression line between breathlessness ratings and physiological variables.

Pathophysiology of dyspnea.

Dyspnea may be defined as an uncomfortable sensation of breathing. The sense of respiratory effort, chemoreceptor stimulation, mechanical stimuli arising in lung and chest wall receptors, and neuroventilatory dissociation may all contribute to the sensation of dyspnea. Different mechanisms likely give rise to qualitatively different sensations of dyspnea. In most patients, dyspnea is probably due to a combination of mechanisms. For example, in asthma, a heightened sense of effort, neuroventilatory dissociation, and vagal stimuli arising from bronchoconstriction and airway inflammation may all play a role. Patients with different disorders and different mechanisms of dyspnea use different phrases to describe their breathing discomfort. Hence, the language patients use to describe their dyspnea may provide clues to the etiology of their symptoms.

Descriptors of breathlessness in healthy individuals: distinct and separable constructs.

STUDY OBJECTIVES: We tested the hypothesis that descriptors of breathlessness represent distinct and separable cognitive constructs, and predicted that the use of descriptors of breathlessness by healthy individuals is the same as their use by patients with cardiopulmonary disease. DESIGN: Cluster analyses obtained in healthy individuals were compared with those obtained previously in patients who complained of breathing discomfort. In addition, we used multidimensional scaling (MDS) techniques to analyze relationships among descriptors in healthy individuals. SETTING: Public university. PARTICIPANTS: The participants were 100 healthy individuals (48 men and 52 women) ranging in age between 18 and 65 years (mean, 27.9+/-11.7 years). MEASUREMENTS AND RESULTS: Participants judged the dissimilarity among pairs of 15 descriptors of breathlessness that were used previously to examine the experience of dyspnea in patients who complained of breathing discomfort. Cluster analysis solutions obtained in the healthy individuals were virtually identical to those obtained previously in patients. Three dimensions (attributes) of breathing discomfort were uncovered with MDS: "Depth and frequency of breathing," "Perceived need, or urge, to breathe," and "Difficulty breathing and phase of respiration." The results did not depend on age, sex, levels of education, or the presence of uncomfortable awareness of breathing with activities. CONCLUSIONS: The relations among descriptors of breathlessness obtained in healthy individuals support the contention that the association of different clusters with different disease states reflects distinct and separable cognitive constructs that are not simply dependent on the presence of an underlying pathophysiology or on a specific disease condition. Our results in healthy individuals also suggest that distinct qualities of breathlessness relate to different physiologic mechanisms underlying respiratory discomfort.

How should health-related quality of life be assessed in patients with COPD?

The traditional approach of caring for patients with chronic respiratory disease has been to rely on pulmonary function tests to quantify the severity and to assess response to therapy. However, patients with respiratory conditions seek medical attention because of symptoms, particularly dyspnea, and impaired ability to function, which clearly impact on an individual's health-related quality of life (HRQOL). Accordingly, instruments have been developed to provide a standardized method to measure health status and levels of impairment. One of the major reasons for measuring HRQOL is to detect how much HRQOL has changed in response to therapy (an evaluative instrument). A minimum clinically significant change has been established for some HRQOL instruments in order to indicate the relative value of any measured change and to guide the interpretation as to whether the change is "clinically meaningful." Selected studies using disease-specific instruments have demonstrated that beta(2)-agonist, anticholinergic, and theophylline medications can improve HRQOL, as compared with placebo therapy.

Target dyspnea ratings predict expected oxygen consumption as well as target heart rate values.

A target heart rate (THR) is the traditional method to prescribe and monitor exercise training intensity in healthy individuals. However, patients with chronic obstructive pulmonary disease (COPD) are limited by ventilatory impairment and dyspnea rather than cardiovascular factors. An alternative approach is to use dyspnea ratings as a target for exercise training in patients with respiratory disease just as ratings of perceived exertion have been used in healthy individuals. The study was a randomized, parallel group trial comparing the ability of patients with COPD to accurately and reliably produce an exercise intensity using a target dyspnea rating (TDR) versus a THR. At Visit 1 patients performed an incremental exercise test on the cycle ergometer, and target values were calculated at approximately 75% of maximal oxygen consumption (V O2). At Visits 2 (3 to 5 d later) and 3 (2 wk later) each patient was instructed to produce a TDR or a THR for 10 min of submaximal exertion. Anthropometric characteristics, lung function, and exercise performance were similar for the 22 patients in each group at Visit 1. For the TDR group the dyspnea target was 2.5 +/- 1.5 at an expected V O2 of 0.88 +/- 0.28 L/min; for the THR group the heart rate (HR) target was 114 +/- 15 beats/min at an expected V O2 of 0.76 +/- 0.29 L/min (p = 0.18 for V O2 between groups). Compared with the expected V O2 from Visit 1, the individual percent differences in V O2 at Visit 2 were -3.9 +/- 18.1% (TDR) and -0.5 +/- 23.2% (THR) (p = 0.58); at Visit 3 the individual percent differences in V O2 were -2.3 +/- 17.0% (TDR) and 2.6 +/- 30.6% (THR) (p = 0.52). The number of patients < 10% and >/= 10% of the expected V O2 were similar for the two groups at Visits 2 (p = 0.38) and 3 (p = 0.27). There were no significant differences for V O2 values (absolute or individual percent) at Visits 2 and 3 for each group and between the groups (p = 0.79). In conclusion, patients with symptomatic COPD demonstrated a comparable ability to use dyspnea ratings and HR as a target to accurately and reliably produce an expected exercise intensity (approximately 75% of V O2max) for 10 min of submaximal exertion.

Efficacy of salmeterol xinafoate in the treatment of COPD.

STUDY OBJECTIVES: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. DESIGN: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. SETTING: Multiple sites at clinics and university medical centers throughout the United States. PATIENTS: Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. INTERVENTIONS: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. RESULTS: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. CONCLUSIONS: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.

Comparison of dyspnea ratings during submaximal constant work exercise with incremental testing.

PURPOSE: The purpose of this study was to determine whether dyspnea ratings would be similar during submaximal (as used for training) and incremental (as used in testing) exercise at specific intensities in patients with chronic obstructive pulmonary disease (COPD). METHODS: We studied 20 patients with COPD. Age was 66 +/- 9 yr (mean +/- SD); FEV1 was 43 +/- 14% pred. At Visit 1 patients provided dyspnea ratings (0 to 10 scale) each minute during incremental exercise on the cycle ergometer. At Visit 2 patients rated dyspnea during production of submaximal exercise for 10 min at two intensities. RESULTS: Peak oxygen consumption (VO2) was 13.9 +/- 3.2 mL.kg-1.min-1. At visit 2 VO2 was stable, but dyspnea ratings increased slightly. Dyspnea ratings (2.0 +/- 1.2) during submaximal exercise were higher than during incremental exercise (1.1 +/- 0.7) at 55 +/- 8% of peak VO2 (P = 0.02) but were similar (4.3 +/- 1.5 vs 3.9 +/- 1.5) at 77 +/- 8% of peak VO2 (P = 0.40). CONCLUSIONS: In patients with COPD, dyspnea ratings were similar during steady state compared with equivalent levels of incremental exercise at a "high" intensity, but were slightly higher at the "low" exercise intensity. These data support the potential use of dyspnea ratings obtained during incremental exercise as a target for exercise training in patients with respiratory disease.

Pulmonary rehabilitation.

There has been a resurgence of interest in pulmonary rehabilitation mainly because the prevalence of COPD has increased, scientific studies document consistent benefits (increased exercise endurance and reduced dyspnea), and thoracic surgeons recognize that preoperative and postoperative conditioning enhances the results of lung volume reduction surgery and lung transplantation. Although education and psychosocial/behavioral interventions are important components of a multidimensional program, exercise training of the upper and lower extremities is essential to achieve the described improvements. Current programs vary considerably in the frequency, intensity, and duration of exercise reconditioning. Two "key" questions relating to pulmonary rehabilitation are as follows. What is an appropriate training intensity? How should patients monitor the training intensity? Maintenance exercise programs and the development of home- or community-based programs will be important future developments.

Dyspnea ratings for prescription of cross-modal exercise in patients with COPD.

STUDY OBJECTIVE: To investigate the ability of patients with COPD to reproduce an exercise intensity accurately on the treadmill using dyspnea ratings obtained during incremental exercise on the cycle ergometer (cross-modal exercise prescription). DESIGN: Five visits over an 8-week period. PATIENTS: Thirteen symptomatic patients with stable COPD. Age was 67+/-6 years (mean+/-SD). FEV1 was 1.15+/-0.22 L (45+/-7% predicted). INTERVENTIONS: At each visit, patients performed spirometry and exercise. Visit 1 was a practice incremental exercise test on the cycle ergometer. At visit 2 (1 week later), patients estimated the intensity of dyspnea using the 0 to 10 category-ratio scale during an incremental exercise test on the cycle ergometer (cycle estimation trial). Visit 3, 5 weeks later, was a practice session on the treadmill. At visit 4, 1 week later, patients were instructed to produce specific intensities of dyspnea (ie, dyspnea targets) at 50% and at anaerobic threshold (AT) or 80% of peak oxygen consumption (VO2) as calculated from results at visit 2 (treadmill production trial). Visit 5, 1 week later, was the treadmill estimation trial. MEASUREMENTS AND RESULTS: Lung function was stable at all visits. Dyspnea ratings were 1.9+/-0.9 at 50% of VO2 and 5.6+/-1.5 at AT/80% of peak VO2 (17.5+/-3.3 mL/kg/min). The VO2 at the treadmill production trial (761+/-185 mL/min) was significantly higher than at the cycle estimation trial (612+/-159 mL/min) at the low dyspnea target (p < 0.0002; upward bias, 26+/-16%). In contrast, there was no significant difference in VO2 values (929+/-176 mL/min vs 948+/-259 mL/min) at the high dyspnea target (p > 0.5; 0+/-11% bias). CONCLUSIONS: Patients with COPD can use dyspnea ratings from an incremental cycle ergometry test to regulate exercise on the treadmill without systematic bias at an intensity of 80% of peak VO2, but exceed the desired VO2 when using the dyspnea rating at an intensity of 50% of peak VO2.