Beyond Spirometry: Linking Wasted Ventilation to Exertional Dyspnea in the Initial Stages of COPD.

Exertional dyspnea, a key complaint of patients with chronic obstructive pulmonary disease (COPD), ultimately reflects an increased inspiratory neural drive to breathe. In non-hypoxemic patients with largely preserved lung mechanics - as those in the initial stages of the disease - the heightened inspiratory neural drive is strongly associated with an exaggerated ventilatory response to metabolic demand. Several lines of evidence indicate that the so-called excess ventilation (high ventilation-CO2 output relationship) primarily reflects poor gas exchange efficiency, namely increased physiological dead space. Pulmonary function tests estimating the extension of the wasted ventilation and selected cardiopulmonary exercise testing variables can, therefore, shed unique light on the genesis of patients' out-of-proportion dyspnea. After a succinct overview of the basis of gas exchange efficiency in health and inefficiency in COPD, we discuss how wasted ventilation translates into exertional dyspnea in individual patients. We then outline what is currently known about the structural basis of wasted ventilation in "minor/trivial" COPD vis-à-vis the contribution of emphysema versus a potential impairment in lung perfusion across non-emphysematous lung. After summarizing some unanswered questions on the field, we propose that functional imaging be amalgamated with pulmonary function tests beyond spirometry to improve our understanding of this deeply neglected cause of exertional dyspnea. Advances in the field will depend on our ability to develop robust platforms for deeply phenotyping (structurally and functionally), the dyspneic patients showing unordinary high wasted ventilation despite relatively preserved FEV1.

Lack of effect of an in-line filter on cardiopulmonary exercise testing variables in healthy subjects.

PURPOSE: Pathogen transmission during cardio-pulmonary exercise testing (CPET) is caused by carrier aerosols generated during respiration. METHODS: Ten healthy volunteers (age range: 34 ± 15; 4 females) were recruited to see if the physiological reactions to ramp-incremental CPET on a cycle ergometer were affected using an in-line filter placed between the mouthpiece and the flow sensor. The tests were in random order with or without an in-line bacterial/viral spirometer filter. The work rate aligned, time interpolated 10 s bin data were compared throughout the exercise period. RESULTS: From rest to peak exercise, filter use increased only minute ventilation ([Formula: see text]E) (Δ[Formula: see text]E = 1.56 ± 0.70 L/min, P < 0.001) and tidal volume (VT) (ΔVT = 0.10 ± 0.11 L, P = 0.014). Over the entire test, the slope of the residuals for [Formula: see text]CO2 was positive (0.035 ± 0.041 (ΔL/L), P = 0.027). During a ramp-incremental CPET in healthy subjects, an in-line filter increased [Formula: see text]E and VT but not metabolic rate. CONCLUSION: In conclusion, using an in-line filter is feasible, does not affect appreciably the physiological variables, and may mitigate risk of aerosol dispersion during CPET.

Validation of Constant Work Rate Cycling Endurance Time for Use in Chronic Obstructive Pulmonary Disease Clinical Trials.

RATIONALE: A COPD Foundation working group sought to identify measures of exercise endurance, a meaningful aspect of physical functioning in everyday life in COPD, but not fully accepted in regulatory decision making, hampering drug development. OBJECTIVE: To demonstrate, as we previously asserted [Casaburi COPD 2022;9:252], that constant work rate cycling endurance time is an appropriate exercise endurance measure in COPD patients. METHODS: To validate this assertion, we assembled an integrated database of endurance time responses, including 8 bronchodilator (2166 subjects) and 15 exercise training studies (3488 subjects) [Casaburi COPD 2022;9:520]. RESULTS: Construct validity was demonstrated: (i) similar peak physiologic and perceptual responses for constant work rate and incremental cycling, (ii) following bronchodilator therapy, greater endurance time increase in patients with more severe airflow limitation, (iii) following exercise training, similar endurance time increases across airflow limitation severities, (iv) correlations between changes in endurance time and changes in mechanistically-related physiologic and perceptual variables. Test-retest reliability was demonstrated, with consistency of changes in endurance time at two time points post-intervention. Responsiveness was confirmed, with significant increases in endurance time following active (but not placebo) bronchodilator therapy, with greater increases seen with more severe airflow limitation, and following exercise training. Based on regression analysis using multiple anchor variables, minimum important difference for endurance time increase is estimated to be approximately 1 minute. CONCLUSIONS: Constant work rate cycling endurance time is a valid exercise endurance measure in COPD, suitable for contributing to evaluation of treatment benefit supporting regulatory decision-making and evidence-based therapeutic recommendations.

A Hybrid Effectiveness/Implementation Clinical Trial of Adherence to Long-Term Oxygen Therapy for Chronic Obstructive Pulmonary Disease.

Rationale: Interventions to promote adherence to long-term oxygen therapy (LTOT) in chronic obstructive pulmonary disease (COPD) are needed. Objectives: To examine the real-world effectiveness of phone-based peer coaching on LTOT adherence and other outcomes in a pragmatic trial of patients with COPD. Methods: In a hybrid effectiveness/implementation pragmatic trial, patients were randomized to receive phone-based proactive coaching (educational materials, five phone-based peer coaching sessions over 60 d), reactive coaching (educational materials, peer coaching when requested), or usual care. Study staff members collected baseline and outcome data via phone at 30, 60, and 90 days after randomization. Adherence to LTOT over 60 days, the primary effectiveness outcome, was defined as mean LTOT use ⩾17.7 h/d. LTOT use was calculated using information about home oxygen equipment use in worksheets completed by study participants. Comparisons of adherence to LTOT between each coaching group and the usual care group using multivariable logistic regression models were prespecified as the primary analyses. Secondary effectiveness outcomes included Patient Reported Outcome Management Information System measures for physical, emotional, and social health. We assessed early implementation domains in the reach, adoption, and implementation framework. Results: In 444 participants, the proportions who were adherent to LTOT at 60 days were 74% in usual care, 84% in reactive coaching, and 70% in proactive coaching groups. Although reach, adoption by stakeholder partners, and intervention fidelity were acceptable, complete LTOT adherence data were available in only 73% of participants. Reactive coaching (adjusted odds ratio, 1.77; 97.5% confidence interval, 0.80-3.90) and proactive coaching (adjusted odds ratio, 0.70; 97.5% confidence interval, 0.34-1.46) did not improve adherence to LTOT compared with usual care. However, proactive coaching significantly reduced depressive symptoms and sleep disturbance compared with usual care and reduced depressive symptoms compared with reactive coaching. Unexpectedly, LTOT adherence was significantly lower in the proactive compared with the reactive coaching group. Conclusions: The results were inconclusive about whether a phone-based peer coaching strategy changed LTOT adherence compared with usual care. Further studies are needed to confirm the potential benefits of proactive peer coaching on secondary effectiveness outcomes and differences in LTOT adherence between proactive and reactive peer coaching. Clinical trial registered with ClinicalTrials.gov (NCT02098369).

Critical Power and Respiratory Compensation Point Are Not Equivalent in Patients with COPD.

INTRODUCTION: Several studies report that pulmonary oxygen uptake (V̇O 2 ) at the respiratory compensation point (RCP) is equivalent to the V̇O 2 at critical power (CP), suggesting that the variables can be used interchangeably to demarcate the threshold between heavy and severe intensity domains. However, if RCP is a valid surrogate for CP, their values should correspond even when assessed in patients with chronic obstructive pulmonary disease (COPD) in whom the "normal" mechanisms linking CP and RCP are impeded. The aim of this study was to compare V̇O 2 at CP with V̇O 2 at RCP in patients with COPD. METHODS: Twenty-two COPD patients (14 male/8 female; forced expiratory volume in 1 s, 46% ± 17% pred) performed ramp-incremental cycle ergometry to intolerance (5-10 W·min -1 ) for the determination of gas exchange threshold (GET) and RCP. CP was calculated from the asymptote of the hyperbolic power-duration relationship from 3-5 constant-power exercise tests to intolerance. CP was validated with a 20-min constant-power ride. RESULTS: GET was identified in 20 of 22 patients at a V̇O 2 of 0.93 ± 0.18 L·min -1 (75% ± 13% V̇O 2peak ), whereas RCP was identified in just 3 of 22 patients at a V̇O 2 of 1.40 ± 0.39 L·min -1 (85% ± 2% V̇O 2peak ). All patients completed constant-power trials with no difference in peak physiological responses relative to ramp-incremental exercise ( P > 0.05). CP was 46 ± 22 W, which elicited a V̇O 2 of 1.04 ± 0.29 L·min -1 (90% ± 9% V̇O 2peak ) during the validation ride. The difference in V̇O 2 at 15 and 20 min of the validation ride was 0.00 ± 0.04 L, which was not different from a hypothesized mean of 0 ( P = 0.856), thereby indicating a V̇O 2 steady state. CONCLUSIONS: In COPD patients, who present with cardiopulmonary and/or respiratory-mechanical dysfunction, CP can be determined in the absence of RCP. Accordingly, CP and RCP are not equivalent in this group.

Diffusing Capacity and Mortality in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) mortality risk is often estimated using the BODE (body mass index, obstruction, dyspnea, exercise capacity) index, including body mass index, forced expiratory volume in 1 second, dyspnea score, and 6-minute walk distance. Diffusing capacity of the lung for carbon monoxide (DlCO) is a potential predictor of mortality that reflects physiology distinct from that in the BODE index. Objectives: This study evaluated DlCO as a predictor of mortality using participants from the COPDGene study. Methods: We performed time-to-event analyses of individuals with COPD (former or current smokers with forced expiratory volume in 1 second/forced vital capacity < 0.7) and DlCO measurements from the COPDGene phase 2 visit. Cox proportional hazard methods were used to model survival, adjusting for age, sex, pack-years, smoking status, BODE index, computed tomography (CT) percent emphysema (low attenuation areas below -950 Hounsfield units), CT airway wall thickness, and history of cardiovascular or kidney diseases. C statistics for models with DlCO and BODE scores were used to compare discriminative accuracy. Results: Of 2,329 participants, 393 (16.8%) died during the follow-up period (median = 4.9 yr). In adjusted analyses, for every 10% decrease in DlCO percent predicted, mortality increased by 28% (hazard ratio = 1.28; 95% confidence interval, 1.17-1.41, P < 0.001). When compared with other clinical predictors, DlCO percent predicted performed similarly to BODE (C statistic DlCO = 0.68; BODE = 0.70), and the addition of DlCO to BODE improved its discriminative accuracy (C statistic = 0.71). Conclusions: Diffusing capacity, a measure of gas transfer, strongly predicted all-cause mortality in individuals with COPD, independent of BODE index and CT evidence of emphysema and airway wall thickness. These findings support inclusion of DlCO in prognostic models for COPD.

Evaluation of Over-the-Counter Portable Oxygen Concentrators Utilizing a Metabolic Simulator.

BACKGROUND: Supplemental oxygen is designed to raise alveolar PO2 to facilitate diffusion into arterial blood. Oxygen is generally delivered by nasal cannula either by continuous or pulsatile flow. Battery-powered portable oxygen concentrators (POCs) facilitate ambulation in patients experiencing exertional hypoxemia. In the United States, the Food and Drug Administration (FDA) clears these devices to be sold by physician prescription. Recently, however, lower-cost devices described as POCs have been advertised by online retailers. These devices lack FDA clearance and are obtained over the counter (OTC) without prescription. This study determined whether a selected group of OTC POCs have oxygen delivery characteristics suitable for use by hypoxemic patients. METHODS: A metabolic simulator, capable of simulating a range of metabolic rates and minute ventilations, determined effects of oxygen supplementation delivered by a variety of devices on alveolar PO2 . Devices tested included 3 OTC POCs, an FDA-cleared POC, and continuous-flow oxygen from a compressed oxygen cylinder. End-tidal PETO2 , a surrogate of alveolar PO2 , was determined at each of each device's flow settings at 3 metabolic rates. RESULTS: Continuous-flow tank oxygen yielded a linear PETO2 increase as flow increased, with progressively lower slope of increase for higher metabolic rate. The prescription POC device yielded similar PETO2 elevations, though with somewhat smaller elevations in pulse-dose operation. One OTC POC was only technically portable (no on-board battery); it provided only modest PETO2 elevation that failed to increase as flow setting was incremented. A second OTC POC produced only minimal PETO2 elevation. A third OTC POC, a pulsed-dose device, produced meaningful PETO2 increases, though not as great as the prescription device. CONCLUSIONS: Only one of 3 OTC POCs tested was potentially of use by patients requiring ambulatory oxygen. Physicians and respiratory therapists should inform patients requiring portable oxygen that OTC devices may not meet their oxygenation requirements.

Endurance Time During Constant Work Rate Cycle Ergometry in COPD: Development of an Integrated Database From Interventional Studies.

Introduction: The COPD Biomarkers Qualification Consortium (CBQC) was formed under COPD Foundation management, with the goal of qualifying biomarkers and clinical outcome assessments through established regulatory processes for chronic obstructive pulmonary disease (COPD). Within CBQC, a working group evaluated opportunities for qualification of an exercise endurance measure. In a recent publication (Chronic Obstr Pulm Dis. 2022; 9[2]:252-265), we described a conceptual framework establishing exercise endurance's direct relationship to an individual with COPD's experience of physical functioning in daily life, and that increase in exercise endurance is a patient-centered, meaningful treatment benefit. We further proposed endurance time during constant work rate cycle ergometery (CWRCE) as a useful efficacy endpoint in clinical therapeutic intervention trials. In this current publication, we describe the process of assembling an integrated database of endurance time responses to interventions in COPD. Methods: We sought participant-level data from published studies incorporating CWRCE as an outcome measure. A literature search screened 2993 publications and identified 553 studies for assessment. Two interventions had sufficient data across studies to warrant data extraction: bronchodilators and rehabilitative exercise training. Investigators were contacted and requested to provide participant-by-participant data from their published studies. Results: The final dataset included data from 8 bronchodilator studies (2166) participants and 15 exercise training studies (3488 participants). The database includes 71 variables per participant, comprising demographic, pulmonary function, and detailed physiologic response data. This paper provides a detailed description of the analysis population, while analysis supporting the validation/qualification process and addressing other scientific questions will be described in subsequent publications.

Resting Physiologic Dead Space as Predictor of Postoperative Pulmonary Complications After Robotic-Assisted Lung Resection: A Pilot Study.

Lung resection surgery carries significant risks of postoperative pulmonary complications (PPC). Cardiopulmonary exercise testing (CPET) is performed to predict risk of PPC in patients with severely reduced predicted postoperative forced expiratory volume in one second (FEV1) and diffusion of carbon monoxide (DLCO). Recently, resting end-tidal partial pressure of carbon dioxide (PETCO2) has been shown as a good predictor for increased risk of PPC. However, breath-breath breathing pattern significantly affects PETCO2. Resting physiologic dead space (VD), and physiologic dead space to tidal volume ratio (VD/VT), may be a better predictor of PPC than PETCO2. The objective of this study was to prospectively determine the utility of resting measurements of VD and VD/VT in predicting PPC in patients who underwent robotic-assisted lung resection for suspected or biopsy-proven lung malignancy. Thirty-five consecutive patients were included in the study. Patients underwent preoperative pulmonary function testing, symptom-limited CPET, and a 6-min walk test. In the first 2 min prior to the exercise portion of the CPET, we obtained resting VT, minute ventilation ( V ˙ E), VD (less instrument dead space), VD/VT, PETCO2, and arterial blood gases. PPC within 90 days were recorded. Fourteen (40%) patients had one or more PPC. Patients with PPC had significantly elevated resting VD compared to those without (0.318 ± 0.028 L vs. 0.230 ± 0.017 L (± SE), p < 0.006), and a trend toward increased VD/VT (0.35 ± 0.02 vs. 0.31 ± 0.02, p = 0.051). Area under the receiver operating characteristic (ROC) for VD was 0.81 (p < 0.002), VD/VT was 0.68 (p = 0.077), and PETCO2 was 0.52 (p = 0.840). Peak V ˙ O2, V ˙ E/ V ˙ CO2 slope, pulmonary function tests, 6-min walk distance and arterial blood gases were similar between the two groups. Intensive care unit and total hospital length of stay was significantly longer in those with PPC. In conclusion, preoperative resting VD was significantly elevated in patients with PPC. The observed increase in resting VD may be a potentially useful predictor of PPC in patients undergoing robotic-assisted lung resection surgery for suspected or biopsy-proven lung malignancy. A large prospective study is needed for confirmation.

Heart Rate Variability on 10-Second Electrocardiogram and Risk of Acute Exacerbation of COPD: A Secondary Analysis of the BLOCK COPD Trial.

Introduction: Autonomic dysfunction is common in chronic obstructive pulmonary disease (COPD), and worse autonomic function may be a marker of risk for acute exacerbations of COPD (AECOPD). Heart rate variability (HRV) is a measure of autonomic function. Our objective was to test whether lower (worse) HRV is a risk factor for AECOPD. Methods: We measured standard deviation of normal RR intervals (SDNN) and root mean square of successive RR interval differences (RMSSD) on 10-second electrocardiograms (ECGs) performed at screening and day 42 in participants in the Beta Blockers for the Prevention of Acute Exacerbations of COPD trial ( BLOCK-COPD), a placebo-controlled trial of metoprolol for prevention of AECOPD. We used Cox-proportional hazards models to test if these HRV measures were associated with risk of any AECOPD, and separately, hospitalized AECOPD. We tested associations using baseline HRV measures and incorporating HRV measures from day 42 as a time-varying covariate. We also tested for interactions with metoprolol assignment. Results: Of 532 trial participants, 529 (forced expiratory volume in 1 second [FEV1 ]41 ± 16.3 % predicted) were included in this analysis. We did not find a significant association between HRV measures and risk of AECOPD when all participants were analyzed together. There was a significant interaction between RMSSD and assignment to metoprolol on time to first hospitalized AECOPD; in the placebo group greater RMSSD was associated with a lower risk of hospitalized AECOPD (adjusted hazard ratio0.71, 95% confidence interval: 0.52 to 0.96, per 10 ms increase) but there was no association in the metoprolol group. Conclusions: Autonomic dysfunction as measured by HRV may be a risk factor for AECOPD. Future studies should analyze longer HRV recordings and their performance in broader samples of people with COPD, including those on beta-blockers.

A randomized, crossover, placebo controlled, double-blind trial of the effects of tiotropium-olodaterol on neuromuscular performance during exercise in COPD.

Exercise intolerance in chronic obstructive pulmonary disease (COPD) is associated with dyspnea, reduced inspiratory capacity (IC) and occurs with a neuromuscular "power reserve," i.e., an acute ability to increase isokinetic locomotor power. This power reserve is associated with resting forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) suggesting that treatments to target pulmonary function may protect neuromuscular performance and extend whole body exercise in COPD. We, therefore, tested whether combination long-acting ß-agonist and muscarinic antagonist bronchodilator therapy [long-acting muscarinic antagonist (LAMA) + long-acting ß-agonist (LABA); Stiolto Respimat] would ameliorate the decline in neuromuscular performance and increase endurance time during constant power cycling at 80% peak incremental power. Fourteen patients with COPD (4 female; 64 [58, 72] yr; FEV1 67% [56%, 75%] predicted; median [25th, 75th percentile]) participated in a randomized, placebo-controlled crossover trial (NCT02845752). Pulmonary function and cardiopulmonary exercise responses were assessed before and after 1 wk of treatment, with 2 wk washout between conditions. Performance fatigue was assessed using an ∼4-s maximal isokinetic cycling effort at preexercise, isotime, and intolerance. Isotime was the shorter exercise duration of the two treatment conditions. Significance was assessed using ANOVA with treatment as fixed factor and subject as random factor. FEV1 was greater with LAMA + LABA versus placebo (1.81 [1.58, 1.98] L vs. 1.72 [1.29, 1.99] L; P = 0.006), but IC at isotime, performance fatigue at isotime, and constant power endurance time were not different between conditions (each P > 0.05). A modest (∼95 mL) increase in FEV1 following 1 wk of combination LAMA + LABA treatment did not alleviate neuromuscular performance fatigue or enhance cycle exercise tolerance in patients with mild-to-severe COPD with largely preserved "static" lung volumes.NEW & NOTEWORTHY Bronchodilation is known to increase forced expiratory volume in 1 s (FEV1) and reduce hyperinflation in COPD. In a randomized controlled trial, we investigated whether combined inhaled long-acting ß-agonist and muscarinic antagonist would alleviate maximal voluntary neuromuscular performance fatigue or enhance maximal muscle activation during cycling in patients with COPD. Despite increased FEV1, combination bronchodilator therapy did not reduce neuromuscular performance fatigue or enhance muscle activity or exercise tolerance in patients with mild-to-severe COPD.

Identifying a Heart Rate Recovery Criterion After a 6-Minute Walk Test in COPD.

BACKGROUND: Slow heart rate recovery (HRR) after exercise is associated with autonomic dysfunction and increased mortality. What HRR criterion at 1-minute after a 6-minute walk test (6MWT) best defines pulmonary impairment?. STUDY DESIGN AND METHODS: A total of 5008 phase 2 COPDGene (NCT00608764) participants with smoking history were included. A total of 2127 had COPD and, of these, 385 were followed-up 5-years later. Lung surgery, transplant, bronchiectasis, atrial fibrillation, heart failure and pacemakers were exclusionary. HR was measured from pulse oximetry at end-walk and after 1-min seated recovery. A receiver operator characteristic (ROC) identified optimal HRR cut-off. Generalized linear regression determined HRR association with spirometry, chest CT, symptoms and exacerbations. RESULTS: HRR after 6MWT (bt/min) was categorized in quintiles: ≤5 (23.0% of participants), 6-10 (20.7%), 11-15 (18.9%), 16-22 (18.5%) and ≥23 (18.9%). Compared to HRR≤5, HRR≥11 was associated with (p<0.001): lower pre-walk HR and 1-min post HR; greater end-walk HR; greater 6MWD; greater FEV1%pred; lower airway wall area and wall thickness. HRR was positively associated with FEV1%pred and negatively associated with airway wall thickness. An optimal HRR ≤10 bt/min yielded an area under the ROC curve of 0.62 (95% CI 0.58-0.66) for identifying FEV1<30%pred. HRR≥11 bt/min was the lowest HRR associated with consistently less impairment in 6MWT, spirometry and CT variables. In COPD, HRR≤10 bt/min was associated with (p<0.001): ≥2 exacerbations in the previous year (OR=1.76[1.33-2.34]); CAT≥10 (OR=1.42[1.18-1.71]); mMRC≥2 (OR=1.42[1.19-1.69]); GOLD 4 (OR=1.98[1.44-2.73]) and GOLD D (OR=1.51[1.18-1.95]). HRR≤10 bt/min was predicted COPD exacerbations at 5-year follow-up (RR=1.83[1.07-3.12], P=0.027). CONCLUSION: HRR≤10 bt/min after 6MWT in COPD is associated with more severe expiratory flow limitation, airway wall thickening, worse dyspnoea and quality of life, and future exacerbations, suggesting that an abnormal HRR≤10 bt/min after a 6MWT may be used in a comprehensive assessment in COPD for risk of severity, symptoms and future exacerbations.

Haemoglobin as a biomarker for clinical outcomes in chronic obstructive pulmonary disease.

In COPD, anaemia is associated with increased morbidity, but the relationship between haemoglobin over its entire observed range and morbidity is poorly understood. Such an understanding could guide future therapeutic targeting of haemoglobin in COPD management. Leveraging the COPDGene study, we conducted a cross-sectional analysis of haemoglobin from COPD participants, examining symptoms, quality of life, functional performance, and acute exacerbations of COPD (AECOPD). Haemoglobin was analysed both as a continuous variable and categorised into anaemia, normal haemoglobin, and polycythaemia groups. Fractional polynomial modelling was used for continuous analyses; categorical models were multivariable linear or negative binomial regressions. Covariates included demographics, comorbidities, emphysema, diffusing capacity, and airflow obstruction. From 2539 participants, 366 (14%) were identified as anaemic and 125 (5%) as polycythaemic. Compared with normal haemoglobin, anaemia was significantly associated with increased symptoms (COPD Assessment Test score: p=0.006, modified Medical Research Council (mMRC) Dyspnoea Score: p=0.001); worse quality of life (St. George's Respiratory Questionnaire (SGRQ) score: p<0.001; Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) General Health: p=0.002; SF-36 Physical Health: p<0.001), decreased functional performance (6-min walk distance (6MWD): p<0.001), and severe AECOPD (p=0.01), while polycythaemia was not. Continuous models, however, demonstrated increased morbidity at both ends of the haemoglobin distribution (p<0.01 for mMRC, SGRQ, SF-36 Physical Health, 6MWD, and severe AECOPD). Evaluating interactions, both diffusing capacity and haemoglobin were independently associated with morbidity. We present novel findings that haemoglobin derangements towards either extreme of the observed range are associated with increased morbidity in COPD. Further investigation is necessary to determine whether haemoglobin derangement drives morbidity or merely reflects systemic inflammation, and whether correcting haemoglobin towards the normal range improves morbidity.

Dynamic airway function during exercise in COPD assessed via impulse oscillometry before and after inhaled bronchodilators.

Assessing airway function during exercise provides useful information regarding mechanical properties of the airways and the extent of ventilatory limitation in COPD. The primary aim of this study was to use impulse oscillometry (IOS) to assess dynamic changes in airway impedance across a range of exercise intensities in patients with GOLD 1-4, before and after albuterol administration. A secondary aim was to assess the reproducibility of IOS measures during exercise. Fifteen patients with COPD (8 males/7 females; age = 66 ± 8 yr; prebronchodilator FEV1 = 54.3 ± 23.6%Pred) performed incremental cycle ergometry before and 90 min after inhaled albuterol. Pulmonary ventilation and gas exchange were measured continuously, and IOS-derived indices of airway impedance were measured every 2 min immediately preceding inspiratory capacity maneuvers. Test-retest reproducibility of exercise IOS was assessed as mean difference between replicate tests in five healthy subjects (3 males/2 females). At rest and during incremental exercise, albuterol significantly increased airway reactance (X5) and decreased airway resistance (R5, R5-R20), impedance (Z5), and end-expiratory lung volume (60% ± 12% vs. 58% ± 12% TLC, main effect P = 0.003). At peak exercise, there were moderate-to-strong associations between IOS variables and IC, and between IOS variables and concavity in the expiratory limb of the spontaneous flow-volume curve. Exercise IOS exhibited moderate reproducibility in healthy subjects which was strongest with R5 (mean diff. = -0.01 ± 0.05 kPa/L/s; ICC = 0.68), R5-R20 (mean diff. = -0.004 ± 0.028 kPa/L/s; ICC = 0.65), and Z5 (mean diff. = -0.006 ± 0.021 kPa/L/s; ICC = 0.69). In patients with COPD, exercise evoked increases in airway resistance and decreases in reactance that were ameliorated by inhaled bronchodilators. The technique of exercise IOS may aid in the clinical assessment of dynamic airway function during exercise.NEW & NOTEWORTHY This study provides a novel, mechanistic insight into dynamic airway function during exercise in COPD, before and after inhaled bronchodilators. The use of impulse oscillometry (IOS) to evaluate airway function is unique among exercise studies. We show strong correlations among IOS variables, dynamic hyperinflation, and shape-changes in the spontaneous expiratory flow-volume curve. This approach may aid in the clinical assessment of airway function during exercise.

The effect of long-acting dual bronchodilator therapy on exercise tolerance, dynamic hyperinflation, and dead space during constant work rate exercise in COPD.

We investigated whether dual bronchodilator therapy (glycopyrrolate/formoterol fumarate; GFF; Bevespi Aerosphere) would increase exercise tolerance during a high-intensity constant work rate exercise test (CWRET) and the relative contributions of dead space ventilation (VD/VT) and dynamic hyperinflation (change in inspiratory capacity) to exercise limitation in chronic obstructive pulmonary disease (COPD). In all, 48 patients with COPD (62.9 ± 7.6 yrs; 33 male; GOLD spirometry stage 1/2/3/4, n = 2/35/11/0) performed a randomized, double blind, placebo (PL) controlled, two-period crossover, single-center trial. Gas exchange and inspiratory capacity (IC) were assessed during cycle ergometry at 80% incremental exercise peak work rate. Transcutaneous [Formula: see text] (Tc[Formula: see text]) measurement was used for VD/VT estimation. Baseline postalbuterol forced expiratory volume in 1 s (FEV1) was 1.86 ± 0.58 L (63.6% ± 13.9 predicted). GFF increased FEV1 by 0.18 ± 0.21 L relative to placebo (PL; P < 0.001). CWRET endurance time was greater after GFF vs. PL (383 ± 184 s vs. 328 ± 115 s; difference 55 ± 125 s; P = 0.013; confidence interval: 20-90 s), a 17% increase. IC on GFF was above placebo IC at all time points and fell less with GFF vs. PL (P ≤ 0.0001). Isotime tidal volume (1.54 ± 0.50 vs. 1.47 ± 0.45 L; P = 0.022) and ventilation (52.9 ± 19.9 vs. 51.0 ± 18.9 L/min; P = 0.011) were greater, and respiratory rate was unchanged (34.9 ± 9.2 vs. 35.1 ± 8.0 br/min, P = 0.865). Isotime VD/VT did not differ between groups (GFF 0.28 ± 0.08 vs. PL 0.27 ± 0.09; P = 0.926). GFF increased exercise tolerance in patients with COPD, and the increase was accompanied by attenuated dynamic hyperinflation without altering VD/VT.NEW & NOTEWORTHY This study was a randomized clinical trial (NCT03081156) that collected detailed physiology data to investigate the effect of dual bronchodilator therapy on exercise tolerance in COPD, and additionally to determine the relative contributions of changes in dead space ventilation (VD/VT) and dynamic hyperinflation to alterations in exercise limitation. We utilized a unique noninvasive method to assess VD/VT (transcutaneous carbon dioxide, Tc[Formula: see text]) and found that dual bronchodilators yielded a moderate improvement in exercise tolerance. Importantly, attenuation of dynamic hyperinflation rather than change in dead space ventilation was the most important contributor to exercise tolerance improvement.

Transcutaneous PCO2 for Exercise Gas Exchange Efficiency in Chronic Obstructive Pulmonary Disease.

Gas exchange inefficiency and dynamic hyperinflation contributes to exercise limitation in chronic obstructive pulmonary disease (COPD). It is also characterized by an elevated fraction of physiological dead space (VD/VT). Noninvasive methods for accurate VD/VT assessment during exercise in patients are lacking. The current study sought to compare transcutaneous PCO2 (TcPCO2) with the gold standard-arterial PCO2 (PaCO2)-and other available methods (end tidal CO2 and the Jones equation) for estimating VD/VT during incremental exercise in COPD. Ten COPD patients completed a symptom limited incremental cycle exercise. TcPCO2 was measured by a heated electrode on the ear-lobe. Radial artery blood was collected at rest, during unloaded cycling (UL) and every minute during exercise and recovery. Ventilation and gas exchange were measured breath-by-breath. Bland-Altman analysis examined agreement of PCO2 and VD/VT calculated using PaCO2, TcPCO2, end-tidal PCO2 (PETCO2) and estimated PaCO2 by the Jones equation (PaCO2-Jones). Lin's Concordance Correlation Coefficient (CCC) was assessed. 114 measurements were obtained from the 10 COPD subjects. The bias between TcPCO2 and PaCO2 was 0.86 mmHg with upper and lower limit of agreement ranging -2.28 mmHg to 3.99 mmHg. Correlation between TcPCO2 and PaCO2 during rest and exercise was r2=0.907 (p < 0.001; CCC = 0.941) and VD/VT using TcPCO2 vs. PaCO2 was r2=0.958 (p < 0.0001; CCC = 0.967). Correlation between PaCO2-Jones and PETCO2 vs. PaCO2 were r2=0.755, 0.755, (p < 0.001; CCC = 0.832, 0.718) and for VD/VT calculation (r2=0.793, 0.610; p < 0.0001; CCC = 0.760, 0.448), respectively. The results support the accuracy of TcPCO2 to reflect PaCO2 and calculate VD/VT during rest and exercise, but not in recovery, in COPD patients, enabling improved accuracy of noninvasive assessment of gas exchange inefficiency during incremental exercise testing.