Antagonism of substance P and perception of breathlessness in patients with chronic obstructive pulmonary disease.

The objective of this study was to investigate whether substance P, an excitatory neuropeptide, modulates the perception of breathlessness by administering aprepitant, a selective antagonist that blocks neurokinin (NK)-1 receptor signaling. Individual targeted resistive load breathing (RLB) was used to provoke breathlessness. In Study 1, sixteen patients (age, 70±6 years) with chronic obstructive pulmonary disease (COPD) reported similar ratings of breathlessness during RLB between oral aprepitant (125mg) and placebo. After aprepitant, but not with placebo, there were significant increases in blood levels of substance P (+54±39%) and beta-endorphin (+27±17%). A similar design was used in Study 2 except that naloxone (10mg) was administered intravenously prior to RLB to block any effect of endogenous opioids. Nine patients with COPD reported comparable breathlessness ratings during RLB between aprepitant and placebo. Our results do not support a role for the substance P-NK-1 pathway in the perception of breathlessness in patients with COPD. With selective antagonism of NK-1 signaling, there was co-transmission of substance P and beta-endorphin neuropeptides.

Comparison of dry powder versus nebulized beta-agonist in patients with COPD who have suboptimal peak inspiratory flow rate.

BACKGROUND: A peak inspiratory flow rate (PIFR) of <60 L/min against the internal resistance (resist) of a dry powder inhaler (DPI) may limit the ability of a patient with chronic obstructive pulmonary disease (COPD) to achieve bronchodilation. The hypothesis was that lung function would be higher with a beta-agonist inhaled via nebulization compared with dry powder in patients with COPD who exhibit a PIFRresist of <60 L/min against the Diskus(®). METHODS: This study was randomized, single-blind, and crossover with spirometry and inspiratory capacity (IC) measured at 15, 30, and 120 min post treatment. The efficacy of arformoterol aerosol solution (15 µg/2 mL) via nebulizer was compared with salmeterol dry powder (50 µg) via Diskus. The primary outcome was the change in lung function from baseline at 2 hr as these two inhaled beta-agonists have the similar peak bronchodilator effect as measured by forced expiratory volume in 1 sec (FEV1). RESULTS: Twenty patients (15 females/5 males) with postalbuterol FEV1 of 0.83±0.31 L (38±12% predicted) and PIFRresist of 53±5 L/min completed the study. At 15 min, improvements in FEV1, forced vital capacity (FVC), and IC were significantly higher with arformoterol than with salmeterol. At 2 hr, changes in FVC and IC, but not FEV1, were significantly higher with arformoterol. At visit 3, patient preference was similar for salmeterol Diskus (n=8) and arformoterol solution (n=7), whereas five patients reported no preference. CONCLUSIONS: At peak effect (2 hr), volume responses were greater with arfomoterol via nebulizer compared with dry powder salmeterol in patients with COPD who had a PIFRresist of <60 L/min. Bronchodilator therapy via nebulization should be considered in patients with COPD who have a suboptimal PIFRresist against a particular DPI.

Effect of increased blood levels of ß-endorphin on perception of breathlessness.

BACKGROUND: Although opioid receptors are expressed broadly in the CNS and in peripheral sensory nerve endings including bronchioles and alveolar walls of the respiratory tract, it is unknown whether the modulatory effect of endogenous opioids on breathlessness occurs in the CNS or in the peripheral nervous system. The purpose of this investigation was to examine whether increased blood levels of ß-endorphin modify breathlessness by a putative effect of binding to peripheral opioid receptors in the respiratory tract. METHODS: Twenty patients with COPD (10 women and 10 men; age, 70 ± 8 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and unpleasantness of breathlessness ≥ 50 mm on a 100-mm visual analog scale. At two interventions, blood levels of ß-endorphin and adrenocorticotropic hormone (ACTH) were measured, ketoconazole (600 mg) or placebo was administered orally, and patients rated the two dimensions of breathlessness each minute during resistive load breathing (RLB). RESULTS: By inhibiting cortisol synthesis, ketoconazole led to significant increases in ß-endorphin (mean change, 20% ± 4%) and ACTH (mean change, 21% ± 4%) compared with placebo. The intensity and unpleasantness ratings of breathlessness and the endurance time during RLB were similar in the two interventions. CONCLUSIONS: The previously demonstrated modulatory effect of endogenous opioids on breathlessness appears to be mediated by binding to receptors within the CNS rather than to peripheral opioid receptors in the respiratory tract. An alternative explanation is that the magnitude of the ß-endorphin response is inadequate to affect peripheral opioid receptors. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01378520; URL: www.clinicaltrials.gov.

Prevalence and COPD phenotype for a suboptimal peak inspiratory flow rate against the simulated resistance of the Diskus® dry powder inhaler.

BACKGROUND: Patients who exhibit a suboptimal peak inspiratory flow rate (PIFR) against the resistance (resist) of a dry powder inhaler (DPI) may not be able to effectively inhale the medication into their lower respiratory tract. PIFRresist was measured using the In-Check DIAL(®) to simulate the resistance of the Diskus(®) DPI in patients with chronic obstructive pulmonary disease (COPD) who were ≥ 60 years of age and had forced expiratory volume in 1 sec (FEV1) of ≤ 50% predicted. Our objectives were to: establish the prevalence of a suboptimal PIFRresist (< 60 L/min) in this population; identify a phenotype of patients with COPD who exhibit a suboptimal PIFRresist; and assess test-retest reliability of PIFRresist. METHODS: PIFRresist and inspiratory capacity (IC) were measured after spirometry was performed in patients with advanced COPD. Repeat measurement of PIFRresist was performed in a subset of patients who returned for scheduled follow-up appointments. RESULTS: The prevalence of a PIFRresist of <60 L/min was 19% among 213 patients. The clinical phenotype of these 41 patients included predominantly female gender (80%), shorter height, and lower values for forced vital capacity (FVC) and IC as percentage predicted compared with the 172 patients with PIFRresist of > 60 L/min. Multivariate regression analysis performed on all patients demonstrated that age, gender, height, FVC % predicted, and IC % predicted were independent predictors of PIFRresist (R(2)=36%). Repeat testing showed no difference between the PIFRresist values. CONCLUSIONS: Approximately one out of five patients with advanced COPD and ≥ 60 years of age exhibited a suboptimal PIFRresist against the Diskus. For the first time, a clinical phenotype of such patients with a suboptimal PIFRresist was identified. It is reasonable to measure a patient's PIFR against the simulated resistance of a specific DPI if there is concern about clinical benefit using the dry powder medication.

Longitudinal changes in patient-reported dyspnea in patients with COPD.

BACKGROUND: Although guidelines recommend monitoring symptoms in patients with chronic obstructive pulmonary disease (COPD), there is limited information on the longitudinal changes in patient-reported dyspnea (PRD) related to activities of daily living. The hypothesis was that PRD scores on the modified Medical Research Council (mMRC) scale, the self-administered computerized (SAC) transition dyspnea index (TDI), and the University of California San Diego Shortness of Breath questionnaire (UCSD SOBQ) would demonstrate progression over two years. METHODS: Observational cohort study of symptomatic patients with stable COPD evaluated every 6 months for 2 years. Patients rated the impact of activities of daily living on dyspnea using three patient-reported instruments presented in random order, and then performed post-bronchodilator (pBD) spirometry. RESULTS: Seventy patients (37 female/33 male; age: 66 ± 9 years; and pBD forced expiratory volume in one second [(FEV1): 51 ± 16% predicted] participated. Using fixed effects regression modeling, there was significant worsening in the PRD scores with the SAC TDI (-0.9 ± 2.7; p = 0.03) and UCSD SOBQ (+5.7 ± 18.3; p = 0.001), but not with the mMRC scale (p = 0.52). Both pBD FEV1 (p = 0.19) and pBD forced vital capacity (p = 0.65) were unchanged. CONCLUSIONS: Multidimensional instruments (SAC TDI and UCSD SOBQ) demonstrated the frequently observed decline in PRD experienced by patients with COPD. The progression in PRD occurred despite stable lung function. Monitoring PRD provides unique clinical information and should be considered along with measuring lung function to assess patient status over time.

Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD.

BACKGROUND: Endogenous opioids are naturally occurring peptides released by the brain in response to noxious stimuli. Although these naturally occurring peptides modulate pain, it is unknown whether endogenous opioids affect the perception of breathlessness associated with a specific respiratory challenge. The hypothesis is that intravenous administration of naloxone, used to block opioid signaling and inhibit neural pathways, will increase ratings of breathlessness during resistive load breathing (RLB) in patients with chronic obstructive pulmonary disease (COPD). METHODS: Fourteen patients with COPD (age, 64 ± 9 years) inspired through resistances during practice sessions to identify an individualized target load that caused ratings of intensity and/or unpleasantness of breathlessness ≥ 50 mm on a 100 mm visual analog scale. At two intervention visits, serum beta-endorphins were measured, naloxone (10 mg/25 ml) or normal saline (25 ml) was administered intravenously, and patients rated the two dimensions of breathlessness each minute during RLB. RESULTS: Patient ratings of intensity (p = 0.0004) and unpleasantness (p = 0.024) of breathlessness were higher with naloxone compared with normal saline. Eleven patients (79%) reported that it was easier to breathe during RLB with normal saline (p = 0.025). RLB led to significant increases in serum beta-endorphin immunoreactivity and decreases in inspiratory capacity. There were no significant differences in physiological responses between interventions. CONCLUSIONS: Endogenous opioids modulate the intensity and the unpleasantness of breathlessness in patients with COPD. Differences in breathlessness ratings between interventions were clinically relevant based on the patients' global assessment.

Mechanism of greater oxygen desaturation during walking compared with cycling in patients with COPD.

BACKGROUND: Patients with COPD exhibit greater oxyhemoglobin desaturation during walking than with cycling. The purpose of this investigation was to investigate differences in ventilatory responses and gas exchange as proposed mechanisms for this observation. METHODS: Arterial blood gas and lactate levels were measured in 12 patients with COPD (aged 68 ± 6 years) during incremental treadmill and cycle exercise. The primary outcome to assess the ventilatory response to exercise was Pao2. The primary outcome to assess impairment in exercise gas exchange was the difference between partial pressures of alveolar and arterial oxygen (Pao2 - Pao2). RESULTS: Pao2 in patients was significantly lower at peak exercise for treadmill walking (51.4 ± 6.8 mm Hg) compared with cycling (60.4 ± 10.7 mm Hg) (P = .002). The initial increase in Pao2 with cycling occurred prior to the onset of the anaerobic threshold. At peak exercise, Pao2 was significantly higher with cycling compared with walking (P = .004). The anaerobic threshold occurred at a lower oxygen consumption during cycling than walking (P = .001), and peak lactate levels were higher with cycling (P = .019). With progressive exercise, Pao2 - Pao2 increased similarly during treadmill and cycle exercise. CONCLUSIONS: The higher Pao2 during cycling minimized the magnitude of oxyhemoglobin desaturation compared with walking. The enhanced respiratory stimulation during cycling appears due to an initial neurogenic process, possibly originating in receptors of exercising muscles, and a subsequent earlier onset of anaerobic metabolism with higher lactate levels during cycling.

Advantages of endurance treadmill walking compared with cycling to assess bronchodilator therapy.

BACKGROUND: Walking is a familiar daily activity that is generally limited by breathlessness, whereas cycling is an uncommon physical effort typically limited by leg discomfort. The hypothesis was that patients with COPD would exhibit greater improvements in exercise endurance and relief of breathlessness with bronchodilator therapy during treadmill walking compared with cycling. METHODS: In this randomized, 2 x 2, double-blind, placebo-controlled, crossover trial, 20 patients with COPD (age, 64 +/- 7 years; FEV(1), 56 +/- 14% predicted) performed constant-load endurance exercise on the treadmill and cycle ergometer at 85% of capacity after inhaling normal saline (NS) or arformoterol (ARF) (15 microg). RESULTS: Increases in endurance times and consistency of responses were greater with treadmill walking (Delta: 157 +/- 286 s; P = .024; 80% improved) than with cycle exercise (Delta: 110 +/- 219 s; P = .038; 65% improved) with ARF compared with NS. However, these changes were not significantly different. The slope of breathlessness-time (mean Delta = -29%; P = .007) and the magnitude of oxygen desaturation were significantly lower with ARF compared with NS during treadmill, but not cycle, exercise. Inspiratory capacity values were similar between modes of exercise when comparing the same study medication. CONCLUSIONS: Improved endurance times support both constant-load treadmill and cycle exercise to assess the efficacy of bronchodilator therapy in patients with COPD. Unique differences in physiologic and perceptual responses with bronchodilation demonstrate advantages of treadmill walking as an exercise stimulus. TRIAL REGISTRATION: clinicaltrials.gov; Identifier: NCT00754546.

Patient-reported dyspnea in COPD reliability and association with stage of disease.

BACKGROUND: Although questionnaires are used frequently with patients to self-report the severity of dyspnea as related to activities of daily living, the reliability of these instruments has not been established. The two purposes of this study were to examine the test-retest reliability of three widely used dyspnea instruments and to compare dyspnea scores at different stages of disease. METHODS: At paired baseline visits, 101 stable patients with COPD were tested; at paired follow-up visits at 3 months, 89 of these patients were tested. At each visit, patients rated dyspnea with three instruments presented in random order and then performed post-bronchodilator therapy lung function tests. RESULTS: Patient-reported dyspnea scores and lung function were similar at baseline (interval, 6 +/- 5 days) and follow-up visits (interval, 4 +/- 2 days). Intraclass correlation coefficients at baseline and at follow-up were 0.82 and 0.82, respectively, for the modified Medical Research Council scale; 0.90 and 0.84, respectively, for the self-administered computerized versions of the baseline dyspnea index and transition dyspnea indexes; and 0.95 and 0.89 for the University of San Diego Shortness of Breath Questionnaire results. Dyspnea ratings were significantly related to the stage of disease severity based on percent predicted FEV(1) (p < 0.001). CONCLUSIONS: Test-retest reliability was acceptable for patient-reported dyspnea scores using three clinical instruments at baseline and at the 3-month follow-up. Our results demonstrate for the first time that patient-reported dyspnea ratings are related to the stage of disease severity.

Perceptual and physiologic responses during treadmill and cycle exercise in patients with COPD.

BACKGROUND: Although the cycle ergometer is the traditional mode for exercise testing in patients with respiratory disease, this preference over the treadmill does not consider perceptual responses. Our hypotheses were as follows: (1) the regression slope between breathlessness and oxygen consumption (Vo(2)) is greater on the treadmill than on the cycle ergometer; and (2) the regression slope between leg discomfort and Vo(2) is greater on the cycle ergometer than on the treadmill. METHODS: Twenty patients (10 men/10 women) with COPD (mean +/- SD postbronchodilator FEV(1), 50 +/- 15% of predicted) used a continuous method to report changes in breathlessness and in leg discomfort during cycle and treadmill exercise. RESULTS: Patients reported an earlier onset of breathlessness and leg discomfort during cycling. Peak ratings of breathlessness were higher on the treadmill, whereas peak ratings of leg discomfort were higher on the cycle ergometer. The regression slopes for breathlessness as a function of Vo(2) and of minute ventilation (Ve) were higher on the treadmill. The regression slopes between leg discomfort and Vo(2) were similar for treadmill and cycle exercise. Peak Vo(2) was significantly higher with treadmill exercise (mean Delta = 8%; p = 0.002). CONCLUSIONS: Patients with COPD exhibit different perceptual and physiologic responses during treadmill walking and cycling. Although ratings of breathlessness are initially higher with cycling at equivalent levels of Vo(2), the changes in breathlessness as a function of physiologic stimuli (Vo(2) and Ve) are greater during treadmill exercise. Leg discomfort is the predominant symptom throughout cycling.

Validity and responsiveness of the self-administered computerized versions of the baseline and transition dyspnea indexes.

BACKGROUND: Numerous instruments have been developed to examine the impact of activities on breathlessness. The primary purpose of this study was to examine the validity and responsiveness of the self-administered computerized (SAC) versions of the multidimensional baseline dyspnea index (BDI) and the transition dyspnea index (TDI). METHODS: Sixty-five patients with COPD who complained of exertional breathlessness were evaluated at an initial visit and after receiving standard therapy at two academic medical centers. Dyspnea scores from the SAC versions were compared with those obtained with the Medical Research Council (MRC) scale and with the original interview versions of the BDI and TDI. RESULTS: At the initial visit, all three dyspnea instruments showed similar correlations among themselves and with lung function. At the follow-up visit (mean [+/- SD] time after initial visit, 48 +/- 16 days), breathlessness scores were improved on all three instruments. Correlations were consistently higher for both versions of the TDI, and changes in lung function compared with corresponding values for DeltaMRC scale. Although 55% of patients reported no change in breathlessness on the MRC scale following treatment, the mean SAC and interview TDI scores were increased by 1.0 +/- 2.4 and 1.4 +/- 2.5, respectively, in these same patients. CONCLUSIONS: Both versions of the BDI and the MRC scale showed concurrent validity at the initial visit. The SAC TDI demonstrated responsiveness to standard therapy that was comparable with the findings of the interview TDI, but was better than that recorded with the MRC scale. The advantages of the SAC TDI include a patient-reported score on a continuous scale using computer technology.

Responsiveness of patient-reported breathlessness during exercise in persistent asthma.

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] FEV(1)/FVC ratio, 57 +/- 10%) completed an initial familiarization visit and three study visits. All subjects inhaled two puffs of albuterol (180 microg) 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.

Continuous ratings of breathlessness during exercise by children and young adults with asthma and healthy controls.

Although it is recommended and common practise for adults with respiratory disease to rate symptoms (e.g., dyspnea and/or leg discomfort) during exercise testing, there are no reports on whether children can rate their perception of breathlessness during exercise. Our aims were to evaluate the ability of children and young adults with asthma to continuously rate breathlessness on the 0-10 category-ratio (CR-10) scale with a computerized system during cycle ergometry, and to compare their results with those of healthy subjects. At an initial visit, subjects were familiarized with equipment and exercise protocol, and practised rating breathlessness while cycling. At a follow-up visit (2-4 days later), subjects performed incremental exercise and rated breathlessness using a computer system, mouse, and monitor. Changing the position of the mouse caused movement of a vertical bar located adjacent to the CR-10 scale to indicate the severity of breathlessness. Baseline characteristics of the 14 subjects with asthma (age, 15 +/- 3 years) and 33 healthy subjects (age, 16 +/- 2 years) were similar. The two groups had comparable levels of fitness as measured by peak oxygen consumption (VO(2)). Correlations between exercise physiologic variables (power production, VO(2), and minute ventilation) and breathlessness ratings were >0.90. Subjects reported progressively more ratings of breathlessness with increasing exercise intensities. There were no differences between groups for slopes, x-intercepts, and absolute thresholds relating physiologic variables and breathlessness. In conclusion, children and young adults with asthma as well as healthy individuals of comparable age successfully used the computerized system to rate breathlessness continuously during cycle ergometry. Both groups reported more ratings of breathlessness with this technique as exercise progressed.

Development of self-administered versions of modified baseline and transition dyspnea indexes in COPD.

In this study we developed self-administered versions of modified baseline and transition dyspnea indexes and compared the scores obtained by this method with the mean value obtained by two trained interviewers. Twenty-five patients (14 males/11 females) with chronic obstructive disease who had a chief complaint of "breathlessness" were tested. Age was 66+/-11 years; forced expiratory volume in one second was 48+/-23% predicted. The baseline total scores were 5.0+/-1.8 for the interviewers and 5.4+/-2.0 for the self-administered method. For the baseline dyspnea scores the correlations were 0.83 (p<0.0001) between self-administration and the mean value of two interviewers and 0.75 (p<0.0001) between the two interviewers. The transition total scores, obtained an average of 102 days (range, 7-377 days) later, were - 0.1+/-3.0 for the interviewers and - 0.4+/-3.0 for the self-administered method. For the transition dyspnea scores the correlations were 0.94 (p<0.0001) between self-administration and the mean value of two interviewers and 0.83 (p<0.0001) between the two interviewers. The self-administered dyspnea scores had similar correlations with measures of lung function as did the interview dyspnea scores. We conclude that self-administered versions of the modified baseline and transition dyspnea indexes provide comparable scores as those obtained by trained and experienced interviewers. The advantages of the self-administered versions include standardized methodology and computerized scoring.