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Because guidelines and strategies for pharmacologic treatment of COPD focus on specific classes of inhaled medications, there is an unmet need for information to guide health care professionals for selecting an inhaled medication delivery system that matches the unique characteristics of individual patients. This article provides guidance for selecting an inhaled medication delivery system based on three "key" patient factors: cognitive function, manual dexterity/strength, and peak inspiratory flow. In addition, information is provided about specific tests to assess these patient factors. Cognitive impairment with an estimated prevalence of 25% among patients with COPD adversely affects patients' ability to correctly use a handheld device. To our knowledge, the prevalence of impaired manual dexterity/strength has not been reported in those with COPD. However, 79% of patients with COPD have reported one or more physical impediments that could influence their ability to manipulate an inhaler device. The measurement of peak inspiratory flow against the simulated resistance (PIFr) of a dry powder inhaler establishes whether the patient has the inhalation ability for creating optimal turbulent energy within the device. A suboptimal PIFr for low to medium-high resistance dry powder inhalers has been reported in 19% to 84% of stable outpatients with COPD. Health care professionals should consider cognitive function, manual dexterity/strength, and PIFr in their patients with COPD when prescribing inhaled pharmacotherapy. Impairments in these patient factors are common among those with COPD and can affect the individual's competency and effectiveness of using inhaled medications delivered by handheld devices., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. M. G. H. has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Inogen, Pfizer, Novartis, Sanofi, and Menarini. D. A. M. reports the following: advisory boards, AstraZeneca, Boehringer Ingelheim, Theravance, Verona, and Viatris; royalties, author of COPD: Answers to Your Most Pressing Questions About Chronic Obstructive Pulmonary Disease (a book for those with COPD and their families); use of the baseline and transition dyspnea indexes by pharmaceutical companies; and an education website (https://www.donaldmahler.com) for those with COPD and their families., (Copyright © 2023 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Biomarkers in COPD may be clinical (prior exacerbation history), physiologic (FEV 1 ), or blood based (eosinophil count or fibrinogen level). Recent interest in using biomarkers to predict response to therapy in clinical practice has emerged. The benefits of inhaled therapy depend on the correct use of the inhaler, including an appropriate inspiratory flow. Of the available delivery systems, dry powder inhalers are unique because they have an internal resistance, are breath actuated, and are flow dependent. Ideally, the user inhales "forcefully" to generate turbulent energy (determined by an individual's inspiratory flow and the resistance of the device) within the device that disaggregates the powder so that the individual inhales the medication particles into the lower respiratory tract. Because of specific features of dry powder inhalers and the required optimal inspiratory flow, an unmet need exists to identify individuals who are likely or unlikely to benefit from dry powder medications. Peak inspiratory flow, defined as the maximum airflow generated during inhalation against the simulated resistance of a dry powder inhaler, is a physiologic measure that has biological plausibility, has good test characteristics (repeatability and reliability), and is generalizable. Current evidence supports peak inspiratory flow as a predictive therapeutic biomarker to optimize therapy in both outpatients with COPD as well as those hospitalized for an exacerbation before discharge. This approach is consistent with the precepts of precision medicine, which considers differences in a person's biological features, exposure, and lifestyle to prevent and treat disease., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Peak inspiratory flow (PIF) has been proposed as a measure to assess a patient's ability to use dry powder inhalers (DPIs). However, robust quality criteria to determine a repeatability limit for measuring PIF are lacking., Research Questions: What are the repeatability limits for measuring PIF? What is the relationship between PIF measured using the In-Check DIAL device at Diskus (GlaxoSmithKline; PIF D ) and HandiHaler (Boehringer Ingelheim; PIF HH ) resistances?, Study Design and Methods: Data from a randomized, controlled, phase 3 trial (study 0149; see Clinical Trial Registration data) were used to define repeatability limits for PIF. In addition, a model to characterize the relationship between PIF measured with the In-Check DIAL device at PIF D and PIF HH was defined using data from two randomized, controlled, phase 3 trials (studies 0128 and 0149)., Results: In study 0128, the mean values (SD) for PIF at zero resistance and PIF HH were 84.6 (33.4) and 57.3 (26.1) L/min, respectively. In study 0149, the mean values (SD) for PIF D and PIF HH were 42.4 (11.2) and 29.0 (8.3) L/min, respectively. At the mean level, the mean difference between measurement attempts for PIF D and PIF HH was small, < 5 and < 3 L/min, respectively. The repeatability limit was determined as 10 and 5 L/min for PIF D and PIF HH , respectively. Modeling the relationship between PIF D and PIF HH , after controlling for significant covariates, demonstrated that a PIF D value of 60 L/min was approximately equivalent to PIF HH of 40 L/min., Interpretations: This analysis demonstrated that the two highest values of PIF using the In-Check DIAL device among three inspiratory efforts, met the repeatability limit. Altogether, these data provide guidance for measuring PIF against the simulated resistance of a specific DPI in clinical practice and research studies., Clinical Trial Registration: ClinicalTrials.gov; Nos.: NCT02518139 (study 0128) and NCT03095456 (study 0149); URL: www.clinicaltrials.gov., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Inhalation therapy is the mainstay of chronic obstructive pulmonary disease management, and inhaler selection can have a profound impact on drug delivery and medication adherence, as well as on treatment outcomes. Although multiple delivery systems, such as pressurized metered-dose inhalers, dry powder inhalers, slow-mist inhalers, and nebulizers, are available, clinical benefits achieved by patients rely on effective delivery of the inhaled medication to the airways. Among several factors influencing drug deposition, inspiratory flow is one of the most important. Inspiratory flow impacts drug delivery and subsequent clinical efficacy, making it necessary to adequately train patients to ensure correct inhaler use. Peak inspiratory flow is the maximal airflow generated during a forced inspiratory maneuver. Health care professionals need to select the appropriate delivery system after carefully considering patient characteristics, including lung function, optimal inspiratory flow, manual dexterity, and cognitive function. Herein, the role of inspiratory flow in the selection and use of inhaled therapy in patients with COPD is reviewed., Competing Interests: Declaration of competing interest Donald A. Mahler has participated in advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sunovion, and Theravance. He is on the speakers’ bureau for AstraZeneca, Boehringer Ingelheim, and Sunovion. He has received royalties from Hillcrest Media for COPD: Answers to Your Question, 2015; CRC Press for Dyspnea: Mechanisms, Measurement, and Management, 3rd edition, 2014; and pharmaceutical companies for use of the baseline and transition dyspnea indexes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the United States. Long-acting muscarinic antagonists (LAMAs) are a class of medications used as maintenance therapy for COPD. The GEM3 (Glycopyrrolate Effect on syMptoms and lung function) study assessed the long-term safety and efficacy of a LAMA, glycopyrrolate (GLY) 15.6 μg twice daily (b.i.d.), compared with an approved long-acting β2-agonist (LABA), indacaterol (IND) 75 μg once daily (q.d.) in patients with stable, symptomatic COPD with moderate-to-severe airflow limitation., Methods: This 52-week, multicenter, double-blind, parallel-group study randomized patients (1:1) of the United States to receive GLY 15.6 μg b.i.d. or IND 75 μg q.d. both delivered via the Neohaler(®) device. The primary objective was to assess the safety and tolerability in terms of adverse event (AE) reporting rates over 52 weeks. Safety was also determined by evaluating multiple secondary endpoints, including vital signs, electrocardiograms (ECGs), and time to first moderate or severe exacerbation. Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)., Results: Of the 511 randomized patients (GLY, n = 254; IND, n = 257), 81.6% completed the study. The overall incidences of AEs (GLY, 77.3%; IND, 77.0%) and serious AEs (GLY, 13.1%; IND, 13.3%) were comparable between the groups. The incidence of major adverse cardiovascular events was low and comparable between the groups. No clinically relevant differences for vital signs or ECG parameters were observed between the treatment groups. The three sudden deaths reported within 30 days of the treatment (GLY, n = 2; IND, n = 1) were adjudicated as unrelated to the study medication. In terms of efficacy, GLY 15.6 μg b.i.d. showed improvements in pre-dose FEV1 and FVC from baseline, which was comparable to those with IND 75 μg q.d., with no statistically significant differences. No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation., Conclusion: GLY 15.6 μg b.i.d. showed a long-term safety profile comparable to that of IND 75 μg q.d. and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation., Clinical Trial Registration Number: NCT01697696., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Although patients may find it difficult to describe their breathing discomfort, most are able to select statements among a list to describe their experience. The primary objective of this study was to examine sensitivity and specificity of descriptors of breathing discomfort prospectively in patients with common respiratory conditions as well as those patients who had refractory dyspnea., Methods: Outpatients answered "Yes" or "No" for each of 15 statements describing breathing discomfort, next selected the best three that most closely applied, and then completed the Hospital Anxiety Depression Scale-Anxiety subscale. Sensitivity, specificity, and predictive values were calculated for the descriptors by diagnosis., Results: "Work/effort" descriptors were selected as the best three by patients with COPD (n = 68), respiratory muscle weakness (n = 11), and refractory dyspnea (n = 17). Along with "work/effort" descriptors, "My chest feels tight" was among the best three in asthma (n = 22), with 38% sensitivity and 88% specificity. Along with "work/effort" descriptors, "My breathing is shallow" was among the best three in interstitial lung disease (n = 8), with 33% sensitivity and 84% specificity. Affective descriptors "frightening" (61% vs 31%, P = .002) and "awful" (66% vs 37%, P = .004) were reported more frequently in those with high anxiety scores compared with low anxiety scores., Conclusions: Although no descriptor achieved satisfactory sensitivity and specificity for identifying a particular condition, chest "tightness" was unique for asthma, whereas "shallow breathing" was unique for interstitial lung disease. Affective descriptors were associated with high anxiety scores.

Introduction: According to current GOLD strategy, patients with COPD classified as groups A and B may be treated with inhaled bronchodilators, either long-acting β2-agonist (LABA) or long-acting muscarinic antagonist (LAMA). However, there is little guidance on which class of agent is preferred and a lack of prospective data to differentiate the two., Methods: In this study, we performed post-hoc analyses of pooled data from two prospective, controlled clinical trials comparing the LABA indacaterol and LAMA tiotropium in 1422 patients with moderate airflow limitation and no history of exacerbations in the previous year. This population fits the definitions of GOLD A and B groups and could be further stratified by symptom severity using Baseline Dyspnea Index (i.e. modeling GOLD A or B) and inhaled corticosteroid (ICS) use at baseline. Outcomes measured after 12 weeks of treatment were lung function (forced expiratory volume in 1 s; FEV1), health status (St George's Respiratory Questionnaire; SGRQ), symptoms (Transition Dyspnea Index; TDI) and rescue medication use., Results: In 'GOLD A' patients not receiving ICS, differences favored indacaterol versus tiotropium (trough FEV1 0.05 L; rescue medication use -0.41 puffs/day; TDI total score 0.94 points; SGRQ total score -3.13 units, all p < 0.01). In 'GOLD B, no ICS' patients, compared with tiotropium, indacaterol treatment increased trough FEV1 (0.055 L, p < 0.05) and permitted a larger reduction in rescue medication use (-0.81 puffs/day, p = 0.004). In all patients, and in patients not using ICS, differences favored indacaterol for all variables., Conclusions: Our findings suggest that patients in GOLD groups A and B may experience greater benefits with indacaterol than with tiotropium., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dyspnea is the most prevalent symptom among patients with cardiac and respiratory diseases. It is an independent predictor of mortality in patients with heart disease, COPD, and the elderly. Studies using naloxone to block opioid-receptor signaling demonstrate that endogenous opioids modulate dyspnea in patients with COPD. Neuroimaging studies support a cortical-limbic network for dyspnea perception. A 2012 American Thoracic Society statement recommended that dyspnea be considered across three different constructs: sensory (intensity), affective (distress), and impact on daily activities. The 2013 GOLD (Global Initiative for Chronic Obstructive Lung Disease) executive summary recommended a treatment paradigm for patients with COPD based on the modified Medical Research Council dyspnea score. The intensity and quality of dyspnea during exercise in patients with COPD is influenced by the time to onset of critical mechanical volume constraints that are ultimately dictated by the magnitude of resting inspiratory capacity. Long-acting bronchodilators, either singly or in combination, provide sustained bronchodilation and lung deflation that contribute to relief of dyspnea in those with COPD. Opioid medications reduce breathing discomfort by decreasing respiratory drive (and associated corollary discharge), altering central perception, and/or decreasing anxiety. For individuals suffering from refractory dyspnea, a low dose of an opioid is recommended initially, and then titrated to achieve the lowest effective dose based on patient ratings. Acupuncture, bronchoscopic volume reduction, and noninvasive open ventilation are experimental approaches shown to ameliorate dyspnea in patients with COPD, but require confirmatory evidence before clinical use.

Background: Arformoterol tartrate (arformoterol, 15 μg bid) is a nebulized long-acting β2-agonist approved for maintenance treatment of COPD., Methods: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization., Results: Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05)., Conclusions: Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo., Trial Registry: ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov.

Background: The use of inhaled corticosteroids (ICSs) is associated with an increased risk of pneumonia in patients with COPD. However, the risks of other respiratory infections, such as TB and influenza, remain unclear.Methods: Through a comprehensive literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, and ClinicalTrials.gov from inception to July 2013, we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses by the Peto, Mantel-Haenszel, and Bayesian approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of TB and influenza.Results: Twenty-fi ve trials (22,898 subjects) for TB and 26 trials (23,616 subjects) for influenza were included. Compared with non-ICS treatment, ICS treatment was associated with a significantly higher risk of TB (Peto OR, 2.29; 95% CI, 1.04-5.03) but not influenza (Peto OR, 1.24;95% CI, 0.94-1.63). Results were similar with each meta-analytic approach. Furthermore, the number needed to harm to cause one additional TB event was lower for patients with COPD treated with ICSs in endemic areas than for those in nonendemic areas (909 vs 1,667, respectively).Conclusions: This study raises safety concerns about the risk of TB and influenza associated with ICS use in patients with COPD, which deserve further investigation.

Background: Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2) agonist is more protective than a once-daily longacting β(2) agonist alone against exacerbations of chronic obstructive pulmonary disease (COPD) is unknown. We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone., Methods: We did two replicate double-blind parallel-group 1 year trials. Both studies began on Sept 25, 2009. Study 1 ended on Oct 31, 2011, and study 2 on Oct 17, 2011. Eligible patients were aged 40 years or older, had a history of COPD, a smoking history of 10 or more pack-years, a ratio of forced expiratory volume in 1 s (FEV(1)) to forced vital capacity of 0·70 or less after bronchodilators (and an FEV(1) of 70% or less of predicted), and a documented history of one or more moderate or severe disease exacerbations in the year before screening. Patients were randomly assigned (1:1:1:1) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg, 100 μg, or 200 μg fluticasone furoate once daily. Our primary endpoint was the yearly rate of moderate and severe exacerbations. The trials were analysed separately and a pooled analysis was also done. These trials are registered with ClinicalTrials.gov (NCT01009463 and NCT01017952)., Findings: 1622 patients in study 1 and 1633 patients in study 2 were randomly assigned. In study 1, no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group (mean 0·90 events vs 1·05 events per year; ratio 0·9 [95% CI 0·7-1·0]). Because of the statistical hierarchy used, we could not infer significance for the 50 μg and 100 μg groups. In study 2, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (p=0·0398 for the 50 μg group, 0·0244 for the 100 μg group, and 0·0004 for the 200 μg group). In the pooled analysis, significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group (0·0141 for the 50 μg group, <0·0001 for the 100 μg group, and 0·0003 for the 200 μg group). Nasopharyngitis was the most frequently reported adverse event in both studies. Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone. Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group., Interpretation: Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD in patients with a history of exacerbation, but was also associated with an increased pneumonia risk., Funding: GlaxoSmithKline., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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 β-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 β-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 β-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 β-endorphin response is inadequate to affect peripheral opioid receptors., Trial Registry: ClinicalTrials.gov; No.: NCT01378520; URL: www.clinicaltrials.gov.

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.

Background: Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD. The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status, using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators., Methods: Individual patient data were pooled from three randomized, placebo-controlled studies (NCT00393458; NCT00567996; NCT00463567), conducted in patients with moderate-to-severe COPD. Treatments were double-blind indacaterol 150 μg (n = 746) or 300 μg (n = 853) once-daily, formoterol 12 μg twice-daily (n = 556), salmeterol 50 μg twice-daily (n = 333) and placebo (n = 1185); and open-label tiotropium 18 μg once-daily (n = 415). Evaluation after 6 months' treatment was by transition dyspnoea index (TDI; minimum clinically important difference [MCID] ≥1 point), and St George's Respiratory Questionnaire (SGRQ; MCID ≥4 units)., Results: Differences from placebo in TDI total score were 1.01 (indacaterol 150 μg) 1.28 (indacaterol 300 μg), 0.74 (formoterol), 0.92 (salmeterol) and 0.88 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91, 2.69, 2.02, 1.79 and 1.49 (all p < 0.05). Differences versus placebo in SGRQ total score were -4.4 (indacaterol 150 μg), -3.4 (indacaterol 300 μg), -2.8 (formoterol), -4.0 (salmeterol) and -1.7 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID of 1.95, 1.63, 1.54, 1.82 and 1.29 (all p < 0.05 apart from tiotropium)., Conclusions: Indacaterol provided clinically important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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.

Background: This consensus statement was developed based on the understanding that patients with advanced lung or heart disease are not being treated consistently and effectively for relief of dyspnea., Methods: A panel of experts was convened. After a literature review, the panel developed 23 statements covering five domains that were considered relevant to the topic condition. Endorsement of these statements was assessed by levels of agreement or disagreement on a five-point Likert scale using two rounds of the Delphi method., Results: The panel defined the topic condition as "dyspnea that persists at rest or with minimal activity and is distressful despite optimal therapy of advanced lung or heart disease." The five domains were: measurement of patient-reported dyspnea, oxygen therapy, other therapies, opioid medications, and ethical issues. In the second round of the Delphi method, 34 of 56 individuals (61%) responded, and agreement of at least 70% was achieved for 20 of the 23 statements., Conclusions: For patients with advanced lung or heart disease, we suggest that: health-care professionals are ethically obligated to treat dyspnea, patients should be asked to rate the intensity of their breathlessness as part of a comprehensive care plan, opioids should be dosed and titrated for relief of dyspnea in the individual patient, both the patient and clinician should reassess whether specific treatments are serving the goal of palliating dyspnea without causing adverse effects, and it is important for clinicians to communicate about palliative and end-of-life care with their patients.

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.

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.

The course of COPD has traditionally been equated with an accelerated decline in the forced expiratory volume in one second (FEVi) over time in patients with COPD, compared to healthy individuals. However, other important clinical outcomes associated with COPD also worsen over time and should also be considered in conceptualizing the course of COPD. These include health status, breathlessness related to activities of daily living, exercise capacity, the frequency of exacerbations, and peripheral muscle weakness. These outcomes are often quite responsive to therapy of COPD. Presently there is no evidence that any treatment other than smoking cessation can normalise the rate of decline of FEVi, and therefore be considered as modifying the physiologic course of the disease. Thus, smoking cessation reigns as the primary disease modifying strategy in COPD. Even though there are a number of smoking cessation products on the market and smoking prevalence continues to decrease marginally each year, more needs to be done to provide comprehensive programmes to help people quit smoking. In the US in 2004, 37.5% of preventable deaths were found to be tobacco-related. The FEVi does not reflect the clinical manifestations or the total burden of this multidimensional illness. As novel therapeutic agents become available that may alter the underlying pathology of COPD, additional markers and outcomes of disease progression will be needed to provide a more comprehensive assessment. There has been increasing interest in predicting and assessing mortality as it is the final outcome of disease progression. In this review we have considered three approaches toward modifying the course of COPD: smoking cessation, reduction in lung hyperinflation through medical and surgical approaches, and long-term pharmacotherapy.

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.

Background: Pulmonary rehabilitation has become a standard of care for patients with chronic lung diseases. This document provides a systematic, evidence-based review of the pulmonary rehabilitation literature that updates the 1997 guidelines published by the American College of Chest Physicians (ACCP) and the American Association of Cardiovascular and Pulmonary Rehabilitation., Methods: The guideline panel reviewed evidence tables, which were prepared by the ACCP Clinical Research Analyst, that were based on a systematic review of published literature from 1996 to 2004. This guideline updates the previous recommendations and also examines new areas of research relevant to pulmonary rehabilitation. Recommendations were developed by consensus and rated according to the ACCP guideline grading system., Results: The new evidence strengthens the previous recommendations supporting the benefits of lower and upper extremity exercise training and improvements in dyspnea and health-related quality-of-life outcomes of pulmonary rehabilitation. Additional evidence supports improvements in health-care utilization and psychosocial outcomes. There are few additional data about survival. Some new evidence indicates that longer term rehabilitation, maintenance strategies following rehabilitation, and the incorporation of education and strength training in pulmonary rehabilitation are beneficial. Current evidence does not support the routine use of inspiratory muscle training, anabolic drugs, or nutritional supplementation in pulmonary rehabilitation. Evidence does support the use of supplemental oxygen therapy for patients with severe hypoxemia at rest or with exercise. Noninvasive ventilation may be helpful for selected patients with advanced COPD. Finally, pulmonary rehabilitation appears to benefit patients with chronic lung diseases other than COPD., Conclusions: There is substantial new evidence that pulmonary rehabilitation is beneficial for patients with COPD and other chronic lung diseases. Several areas of research provide opportunities for future research that can advance the field and make rehabilitative treatment available to many more eligible patients in need.

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.

Study Objective: To examine the effect of fluticasone propionate, 250 microg/salmeterol, 50 microg combination (FSC 250/50) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD., Design: This was a randomized, double-blind, parallel-group study., Patients: Eligible patients were > or = 40 years old with a diagnosis of COPD, prealbuterol FEV(1) < 70% of predicted, FEV1/FVC ratio > or = 0.70, and functional residual capacity (FRC) > or = 120% of predicted normal., Interventions: Patients were randomized to FSC 250/50; salmeterol, 50 microg; or placebo twice daily for 8 weeks. Predose and postdose spirometry, plethysmography, and constant-load cycle cardiopulmonary exercise test evaluations were compared. The primary comparison was FSC 250/50 with placebo. The salmeterol group was included for exploratory comparisons with FSC 250/50., Results: A total of 185 patients (mean baseline FEV1 of 41% predicted) were enrolled. At rest, FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity (IC) compared with placebo (differences of - 0.35 +/- 0.12 L and 0.33 +/- 0.06 L [mean +/- SE], respectively, at week 8; p > or = 0.003) and increased exercise endurance time (difference, 132 +/- 45 s; p = 0.004). At a standardized time during exercise (isotime), FSC 250/50 increased postdose IC by 0.20 +/- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation (p < 0.05 vs placebo at week 8). Improvement in exercise time was significantly correlated with the increase in IC (r = 0.45, p < 0.001) but not FEV1 (r = 0.23, p = 0.08). Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50., Conclusion: We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo.

Evaluation of the effectiveness of treatment for chronic obstructive pulmonary disease (COPD) requires the assessment of both clinical and physiological measures. Parameters such as the forced expiratory volume in 1 s are well established in providing an indication of the degree of airflow limitation. However, additional measurements, such as dyspnoea, functional status and health status, are required to provide a complete picture of COPD. Indeed, dyspnoea is the predominant symptom of COPD experienced by the patient, which treatment is designed to reduce. Methods of assessing dyspnoea have developed over the previous five decades. The most widely used instruments for assessing the impact of dyspnoea are the baseline dyspnoea index, the transition dyspnoea index and the Medical Research Council Questionnaire. A more comprehensive approach to the assessment of disability caused by dyspnoea and fatigue is provided by assessments of functional status, such as the pulmonary functional status and dyspnoea questionnaire. Respiratory-specific health status questionnaires, such as the St. George's Respiratory Questionnaire, attempt to capture the wide range of effects of COPD into a single score that reflects the overall impact of the disease. Developing the means to measure the effects of COPD is important, both in terms of understanding disease pathophysiology for research purposes, and in terms of accurately assessing the effects of treatment on the patient. Future developments will include computerising these methodologies to permit faster and more individual patient-centred measurements.

Study Objective: To investigate the efficacy and safety of a fully human monoclonal antibody recognizing the chemokine interleukin (IL)-8 in patients with COPD., Design: Randomized, double-blind, parallel-group, placebo-controlled trial., Setting: Eighteen clinics/hospitals in the United States., Patients: One hundred nine patients with stable COPD., Interventions: Three IV infusions of either monoclonal antibody recognizing IL-8 (800-mg loading dose; 400-mg subsequent doses) or active buffer solution administered monthly over a 3-month period., Measurements and Results: The differences in the transition dyspnea index (TDI) total score, the primary outcome measure, between fully human monoclonal IgG(2) antibody directed against IL-8 and placebo were 0.8, 1.0, 0.8, and 0.3 at week 2 (p = 0.046) and months 1 to 3, respectively. At all time points, the proportion of patients achieving >/= 1 point improvement in the TDI was greater for the monoclonal antibody group compared with the placebo group: 28% vs 11% at week 2 (p = 0.028). There were no significant differences observed for lung function, health status, 6-min walking distance, and adverse events between groups., Conclusions: The results of this phase 2 study suggest that neutralization of IL-8 with monoclonal antibody therapy may improve dyspnea in patients with COPD. These results support the further investigation of monoclonal antibody therapy targeting IL-8 for the treatment of this disease.

Study Objectives: The objectives of this study were as follows: (1) to compare results of the discrete and the continuous methods for measuring breathlessness; (2) to examine test-retest reliability; (3) and to test the hypothesis that patients with COPD have higher slopes and lower x-intercepts and absolute thresholds for power production, oxygen consumption (O(2)), and minute ventilation as independent variables and breathlessness ratings as the dependent variable, as compared with healthy subjects., Design: Visit 1 (familiarization) and visit 2 and visit 3 (2 days apart) with randomized assignment of the discrete and continuous methods for subjects rating breathlessness during cycle ergometry., Setting: Cardiopulmonary exercise laboratory in a university medical center., Participants: Twenty-four patients with COPD (mean age, 66 +/- 8 years [+/- SD]) and 24 healthy subjects (mean age, 66 +/- 10 years)., Interventions: None., Measurements and Results: Ratings of breathlessness on the Borg scale on cue with subjects moving and pressing the computer mouse button to indicate a rating (discrete method) or by moving the position of the mouse to adjust a vertical bar to indicate a change in breathlessness (continuous method). There were no significant differences in results between visit 2 and visit 3. Although peak exercise variables were similar with the discrete and continuous methods, both groups provided significantly more ratings of breathlessness with the continuous method. Patients with COPD exhibited higher slopes, lower x-intercepts, and lower absolute thresholds (breathlessness rating >/==" BORDER="0"> 0.5 ["just noticeable"] on the Borg scale) for power production and O(2)-breathlessness compared with healthy subjects (p < 0.05)., Conclusions: Elderly patients with COPD and healthy subjects are able to use the continuous method successfully. Reliability is excellent for both methods. The continuous method provides a greater number of breathlessness ratings over the course of exercise, and allows the clinician to calculate an absolute threshold and just-noticeable differences. Regression parameters and absolute thresholds discriminate between patients with COPD and healthy subjects.

Ths object of this study was to examine validity, meaningful effect sizes, and patterns of response of the Transition Dyspnea Index (TDI) in a clinical trial cohort of chronic obstructive pulmonary disease (COPD) patients. The design was a retrospective analysis of data from a randomized, double-blind placebo-controlled clinical trial. We analyzed fifty clinical investigation sites in United States. There were 921 patients with stable COPD. Tiotropium 18 microg dry powder or matching placebo was used. Patients were allowed to remain on usual care less ipratropium bromide. Construct validity was demonstrated by significant correlations (P <.05) between Baseline Dyspnea Index (BDI) and other baseline measures, as well as between TDI and changes in other measures at the end of 1 year. Concurrent validity was observed by the significant correlation between TDI and dyspnea diary responses. Changes in TDI focal score were in the range of one unit when the group was stratified by a minimal change in the physician's global evaluation. Significantly less (P <.05) supplemental albuterol was observed in the group of responders defined by a one-unit improvement in TDI. Responders also had few exacerbations and better health status. The validity of the TDI is supported in a large clinical trial setting. A one-unit change in the TDI focal score represented the minimal important difference.