Relieving exertional dyspnea during the 3-min constant speed shuttle test in patients with COPD with indacaterol/glycopyrronium versus tiotropium: the RED trial.

BACKGROUND: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. METHODS: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. RESULTS: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean -1.00, 95% confidence interval (CI) -1.49 to -0.52] but not with tiotropium alone (mean -0.36, 95% CI -0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of -0.64, 95% CI -1.11 to -0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI -0.44 to 0.61). CONCLUSION: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation.The reviews of this paper are available via the supplemental material section.

Metabolic profiles among COPD and controls in the CanCOLD population-based cohort.

A high prevalence of intermediate cardiometabolic risk factors and obesity in chronic obstructive pulmonary disease (COPD) has suggested the existence of pathophysiological links between hypertriglyceridemia, insulin resistance, visceral adiposity, and hypoxia or impaired pulmonary function. However, whether COPD contributes independently to the development of these cardiometabolic risk factors remains unclear. Our objective was to compare ectopic fat and metabolic profiles among representative individuals with COPD and control subjects and to evaluate whether the presence of COPD alters the metabolic risk profile. Study participants were randomly selected from the general population and prospectively classified as non-COPD controls and COPD, according to the Global Initiative for Chronic Obstructive Lung Disease classification. The metabolic phenotype, which consisted of visceral adipose tissue area, metabolic markers including homeostasis model assessment of insulin resistance (HOMA-IR), and blood lipid profile, was obtained in 144 subjects with COPD and 119 non-COPD controls. The metabolic phenotype was similar in COPD and controls. The odds ratios for having pathologic values for HOMA-IR, lipids and visceral adipose tissue area were similar in individuals with COPD and control subjects in multivariate analyses that took into account age, sex, body mass index, tobacco status and current medications. In a population-based cohort, no difference was found in the metabolic phenotype, including visceral adipose tissue accumulation, between COPD and controls. Discrepancies between the present and previous studies as to whether or not COPD is a risk factor for metabolic abnormalities could be related to differences in COPD phenotype or disease severity of the study populations.

Automatic Oxygen Titration During Walking in Subjects With COPD: A Randomized Crossover Controlled Study.

BACKGROUND: Arterial oxygen desaturation frequently occurs in patients with COPD during daily activities at home. Oxygen flow is usually set at fixed and low rates for ambulatory patients. We evaluated an innovative closed-loop system (FreeO2) that automatically adjusts the oxygen flow to the patient's needs in subjects with COPD during walking followed by recovery time, such as during ambulatory conditions. METHODS: Patients with COPD who exhibited oxygen desaturation on exertion were included in the study. Subjects performed endurance shuttle walk tests followed by 10 min of recovery. The tests were conducted in a random order and in crossover with the 3 following conditions: subjects breathing (1) air at 2 L/min, (2) oxygen at 2 L/min, or (3) FreeO2 (variable oxygen flow). SpO2, pulse rate, PETCO2 , breathing frequency, and oxygen flow were continuously recorded during the 3 conditions. The primary outcome was the percentage of time within the SpO2 target of 92-96%. Secondary outcomes included the endurance shuttle walk test time and distance. RESULTS: Sixteen subjects with COPD were recruited. The percentage of time with SpO2 in the target range (92-96%) was higher while using the FreeO2, and time with severe oxygen desaturation (SpO2 <88%) was lower with FreeO2 in comparison with constant-flow oxygen and air testing conditions (0.6% vs 23.9% vs 52.2%, P < .001). In comparison with air, walking distance was increased by 35% with oxygen (P = .045) and by 63% with FreeO2 (P < .001). The walking distance was increased by 17% with FreeO2 in comparison with constant oxygen, but the difference was not statistically significant (P = .22). CONCLUSIONS: Automatic titration of oxygen flow during walking to maintain oxygen saturation in a specified range improves oxygenation and may improve exercise tolerance during daily activity, such as walking, in patients with COPD in comparison with room air and fixed oxygen administration. (ClinicalTrials.gov registration: NCT02150434.).

Distal leg muscle function in patients with COPD.

Quadriceps muscle weakness and increased fatigability are well described in patients with chronic obstructive pulmonary disease (COPD). Whether these functional alterations also exist in distal leg muscles in patients with COPD is uncertain. Fifteen patients with COPD and 15 aged-matched healthy controls performed a 12-minute standardized treadmill exercise during which a fixed total expense of 40 Kcal was reached. The strength of i) dorsiflexors, ii) plantar flexors and iii) quadriceps was assessed at rest and after exercise using maximal voluntary contraction (MVC) and potentiated twitch force (Twpot). Resting MVC and Twpot were significantly lower in patients with COPD when compared with controls respectively for i) dorsiflexors (24.9 ± 8.4 vs. 31.2 ± 8.5 Nm, p < 0.05 and 4.3 ± 1.3 vs. 5.7 ± 1.8 Nm, p < 0.05), ii) plantar flexors (49.5 ± 11.8 vs. 62.1 ± 19.6 Nm, p < 0.05 and 10.8 ± 3.5 vs. 13.4 ± 2.7 Nm, p < 0.05), and iii) quadriceps muscles. There was a greater force loss in the distal leg muscles 15 minutes post-exercise in patients with COPD, while the strength of the quadriceps muscle remained stable in both groups. Patients with COPD had weaker dorsiflexor and plantar flexor muscles when compared to age-matched healthy controls. In addition, when exposed to the same absolute walking task, the fatigability of the distal leg muscles was higher in patients with COPD.

Detecting improvements in dyspnea in COPD using a three-minute constant rate shuttle walking protocol.

RATIONALE: We examined the responsiveness of a 3-minute constant rate shuttle walking protocol to detect improvements in exertional dyspnea following acute bronchodilation in COPD. Our hypothesis was that the 3-minute constant rate shuttle walking protocol would be able to adequately put forth improvements in exertional dyspnea following acute bronchodilation in this population. METHODS: Using a placebo controlled, double-blind cross-over design, 39 patients with moderate to severe COPD performed a 3-min constant rate shuttle walking test during which they were asked to walk on a flat corridor at a speed that was externally imposed by an audio signal. During the test, dyspnea was graded using the 10-point modified Borg scale. The test was performed twice, following the administration of saline placebo or of 500 µg nebulized ipratropium bromide. RESULTS: Improvements of respiratory pattern (respiratory rate and tidal volume) and statistically and clinically significant reductions in Borg dyspnea scores (∆ dyspnea score = 1.0 ± 0.2, p < 0.01) were seen during the 3-min shuttle walking protocol with ipratropium bromide compared to placebo. CONCLUSION: This 3-minute shuttle walking protocol adequately detected dyspnea and breathing pattern improvements following acute bronchodilation in COPD.

Physiological correlates of endurance time variability during constant-workrate cycling exercise in patients with COPD.

RATIONALE: The endurance time (T(end)) during constant-workrate cycling exercise (CET) is highly variable in COPD. We investigated pulmonary and physiological variables that may contribute to these variations in T(end). METHODS: Ninety-two patients with COPD completed a CET performed at 80% of peak workrate capacity (W(peak)). Patients were divided into tertiles of T(end) [Group 1: <4 min; Group 2: 4-6 min; Group 3: >6 min]. Disease severity (FEV(1)), aerobic fitness (W(peak), peak oxygen consumption [VO2(peak)], ventilatory threshold [VO2(VT)]), quadriceps strength (MVC), symptom scores at the end of CET and exercise intensity during CET (heart rate at the end of CET to heart rate at peak incremental exercise ratio [HR(CET)/HR(peak)]) were analyzed as potential variables influencing T(end). RESULTS: W(peak), VO2(peak), VO2(VT), MVC, leg fatigue at end of CET, and HR(CET)/HR(peak) were lower in group 1 than in group 2 or 3 (p≤0.05). VO2(VT) and leg fatigue at end of CET independently predicted T(end) in multiple regression analysis (r = 0.50, p = 0.001). CONCLUSION: T(end) was independently related to the aerobic fitness and to tolerance to leg fatigue at the end of exercise. A large fraction of the variability in T(end) was not explained by the physiological parameters assessed in the present study. Individualization of exercise intensity during CET should help in reducing variations in T(end) among patients with COPD.

Significance of changes in endurance shuttle walking performance.

BACKGROUND: The endurance shuttle walking test (ESWT) has shown good responsiveness to interventions in patients with chronic obstructive pulmonary disease (COPD). However, the minimal important difference (MID) for this test remains unknown, therefore limiting its interpretability. METHODS: Patients with COPD who completed two or more ESWTs following pulmonary rehabilitation (n=132; forced expiratory volume in 1 s (FEV1) 48 ± 22%) or bronchodilation (n=69; FEV1 50 ± 12%) rated their performance of the day in comparison with their previous performance on a 7-point scale ranging from -3 (large deterioration) to +3 (large improvement). The relationship between subjective perception of changes and objective changes in performance during the shuttle walk was evaluated. RESULTS: Following pulmonary rehabilitation, the anchor-based approach did not allow a valid estimation of the MID in the ESWT performance to be obtained. After bronchodilation, patient ratings of change correlated significantly with the difference in walking distance (r=0.53, p<0.001) and endurance time (r=0.55, p<0.001). For the pharmacotherapy data, regression analysis indicated that a 65 s (95% CI 45 to 85) change in endurance time and a 95 m (95% CI 60 to 115) change in walking distance were associated with a 1-point change in the rating of change scale. These changes represented 13-15% of the baseline values. CONCLUSIONS: A change in endurance shuttle walking performance of 45-85 s (or 60-115 m) after bronchodilation is likely to be perceived by patients. This MID value may be specific to the intervention from which it was derived.

Physiology of walking in patients with moderate to severe chronic obstructive pulmonary disease.

PURPOSE: Little is known about the physiology of walking in chronic obstructive pulmonary disease (COPD). Our objective was to evaluate the cardiac and respiratory responses as well as the electrical activity of lower limb muscles during walking in patients with COPD compared with healthy controls. METHODS: Cardiorespiratory parameters were monitored during a 6-min walking test (6 MWT) in 10 patients with COPD and 11 healthy controls. Surface EMG (sEMG) data were recorded in five muscle groups (soleus, medial gastrocnemius, tibialis anterior, vastus lateralis, and rectus femoris) of the right leg during walking. The integrated signal (iEMG) and the median frequency were obtained from the sEMG signal of each muscle group. RESULTS: Although the walking distance and speed were significantly reduced in patients with COPD compared with those in controls, patients walked at a higher percentage of peak VO2. The overall sEMG patterns were similar between patients with COPD and controls. A fall in the sEMG median frequency during the 6 MWT was observed for the vastus lateralis and the rectus femoris in patients with COPD and in controls suggesting a muscle fatiguing contracting profile. CONCLUSION: The 6 MWT was performed at a relatively higher intensity in patients with COPD compared with healthy controls. The progressive fall in the sEMG median frequency of the vastus lateralis and rectus femoris in both groups suggested the occurrence of a muscle fatiguing profile during walking. The performance of a daily activity such as walking imposes a high physiological demand in patients with COPD.