Advances in the Evaluation of Respiratory Pathophysiology during Exercise in Chronic Lung Diseases

Abstract

Dyspnea and exercise limitation are among the most common symptoms experienced by patients with various chronic lung diseases and are linked to poor quality of life. Our understanding of the source and nature of perceived respiratory discomfort and exercise intolerance in chronic lung diseases has increased substantially in recent years. These new mechanistic insights are the primary focus of the current review. Cardiopulmonary exercise testing (CPET) provides a unique opportunity to objectively evaluate the ability of the respiratory system to respond to imposed incremental physiological stress. In addition to measuring aerobic capacity and quantifying an individual's cardiac and ventilatory reserves, we have expanded the role of CPET to include evaluation of symptom intensity, together with a simple "non-invasive" assessment of relevant ventilatory control parameters and dynamic respiratory mechanics during standardized incremental tests to tolerance. This review explores the application of the new advances in the clinical evaluation of the pathophysiology of exercise intolerance in chronic obstructive pulmonary disease (COPD), chronic asthma, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). We hope to demonstrate how this novel approach to CPET interpretation, which includes a quantification of activity-related dyspnea and evaluation of its underlying mechanisms, enhances our ability to meaningfully intervene to improve quality of life in these pathologically-distinct conditions.

Keywords: chronic obstructive pulmonary disease; dyspnea; exercise; interstitial lung disease; pulmonary mechanics; pulmonary vascular diseases.

Figure 1

Comparison of ventilation (A), ventilatory equivalent for carbon dioxide ($\dot{\text{V}}$_E/$\dot{\text{V}}$CO₂) (B), end-tidal CO₂ (C), and arterial oxygen saturation (D), all plotted against oxygen uptake, during incremental cycle exercise in healthy young and older adults. Values are mean ± SEM. ^*P < 0.05 healthy young versus older adults. P_ETCO₂, partial pressure of end-tidal carbon dioxide; SpO2, oxygen saturation by pulse oximetry. Reproduced with permission from the publisher (Faisal et al., 2015).

Figure 2

Proposed panel displays for interpretation of key perceptual (A), ventilatory, and dynamic respiratory mechanical responses (B–I) to incremental exercise test in patients with chronic respiratory diseases. Data showing these responses in patients with mild COPD and age-matched healthy controls. Values are mean ± SEM. ^*p < 0.05 mild COPD vs. healthy controls at rest, at standardized work rates or at peak exercise. V_E/VCO₂, ventilatory equivalent for carbon dioxide; IC, inspiratory capacity; IRV, inspiratory reserve volume; Fb, breathing frequency; PETCO₂, partial pressure of end-tidal carbon dioxide; SpO₂, oxygen saturation by pulse oximetry. Reproduced with permission from the publisher (Chin et al., 2013).

Figure 3

Dyspnea intensity (Borg units) (A), diaphragm electromyography (EMGdi) (B) and selected ventilatory and indirect gas exchange responses (C–I) to incremental cycle exercise test in patients with moderate COPD and age-matched healthy controls. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. ^*p < 0.05 for COPD vs. control subjects at rest, at standardized work rates, at peak exercise, or at the tidal volume-ventilation inflection points. EMGdi/EMGdi,max, an index of inspiratory neural drive to the crural diaphragm; $\dot{\text{V}}$E, minute ventilation; V_E/VCO₂, ventilatory equivalent for carbon dioxide; PETCO₂, partial pressure of end-tidal carbon dioxide; SpO₂, oxygen saturation by pulse oximetry; VT, tidal volume; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity. Reproduced with permission from the publisher (Faisal et al., 2016).

Figure 4

Tidal volume (VT) (A), breathing frequency (Fb) (B), dynamic inspiratory capacity (IC) (C), and inspiratory reserve volume (IRV) (D) are shown plotted against minute ventilation ($\dot{\text{V}}$E) in four disease severity quartiles based on FEV1 %predicted during constant work rate exercise in patients with COPD. Note the clear inflection (plateau) in the VT/$\dot{\text{V}}$E relationship which coincides with a simultaneous inflection in the IRV. After this point, further increases in VE are accomplished by accelerating Fb. Data plotted are mean values at steady-state rest, isotime (i.e., 2, 4 min), the VT/$\dot{\text{V}}$E inflection point, and peak exercise. VC, vital capacity; TLC, total lung capacity. Reproduced with permission from the publisher (O'Donnell et al., 2012).

Figure 5

Inter-relationships are shown between exertional dyspnea intensity, ventilation ($\dot{\text{V}}$E) (A) and the VT/IC ratio (B) in four disease severity quartiles based on FEV1 %predicted during constant work rate exercise in COPD. After the VT/IC ratio plateaus (i.e., the VT inflection point), dyspnea rises steeply to intolerable levels. There is a progressive separation of dyspnea/V$\dot{\text{V}}$E plots with worsening quartile. Data plotted are mean values at steady-state rest, isotime (i.e., 2, 4 min), the VT/$\dot{\text{V}}$E inflection point, and peak exercise. IC, inspiratory capacity, VT, tidal volume. Reproduced with permission from the publisher (O'Donnell et al., 2012).

Figure 6

Dyspnea intensity (Borg units) (A), diaphragm electromyography (EMGdi) (B), and selected ventilatory and indirect gas exchange responses (C–I) to incremental cycle exercise test in patients with interstitial lung disease (ILD) and age-matched healthy controls. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. ^*p < 0.05 for ILD vs. control subjects at rest, at standardized work rates, at peak exercise, or at the tidal volume-ventilation inflection points. EMGdi/EMGdi,max, an index of inspiratory neural drive to the crural diaphragm; $\dot{\text{V}}$E, minute ventilation; $\dot{\text{V}}$E/$\dot{\text{V}}$CO₂, ventilator equivalent for carbon dioxide; PETCO₂, partial pressure of end-tidal carbon dioxide; SpO₂, oxygen saturation by pulse oximetry; VT, tidal volume; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity. Reproduced with permission from the publisher (Faisal et al., 2016).

Figure 7

Relation between dyspnea intensity (Borg units) and diaphragm electromyography (EMGdi) (A) and V_T/IC (B) during incremental cycle exercise test in patients with moderate COPD, ILD and age-matched healthy controls. (C) Shows the relation between V_T/VC and EMGdi/EMGdi,max (an index of inspiratory neural drive to the crural diaphragm); note the similar blunted V_T/VC response to the increased neural drive in both ILD and COPD patients compared with healthy subjects. Values are mean ± SEM. Square symbols represent tidal volume-ventilation inflection points. Selection frequency of descriptors of exertional dyspnea at end-exercise in the three groups is shown in (D). ^*p < 0.05 for ILD vs. control subjects and ^†p < 0.05 for COPD vs. control subjects. COPD, chronic obstructive pulmonary disease; IC, inspiratory capacity; V_T, tidal volume; VC, vital capacity; ILD, interstitial lung disease. Reproduced from with permission from the publisher (Faisal et al., 2016).

Figure 8

Proposed panel displays for interpretation of key perceptual (A), ventilatory, and dynamic respiratory mechanical (B–I) responses to incremental exercise test in patients with chronic respiratory diseases. Data showing these responses in a patient with pulmonary arterial hypertension (PAH) and an age and gender matched healthy control. $\dot{\text{V}}$E/$\dot{\text{V}}$CO₂, ventilatory equivalent for carbon dioxide; PETCO₂, partial pressure of end-tidal carbon dioxide; SpO₂, oxygen saturation by pulse oximetry; Fb, breathing frequency; IRV, inspiratory reserve volume; TLC, total lung capacity.

Figure 9

Typical flow-volume curves in (A): a healthy subject and patients with (B) COPD, (C) ILD, and (D) PAH. In the patient with COPD, there is a leftward shift of the curve with noticeable expiratory flow limitation during exercise (i.e., tidal loops at peak exercise exceed maximal expiratory envelope). In the patient with ILD, there is a rightward shift of the curve with no expiratory flow limitation and adequate reserves of inspiratory and expiratory flow at end exercise. Note the markedly reduced inspiratory reserve volume (IRV) in both ILD and COPD patients compared with healthy subject (IRV, TLC-end-inspiratory lung volume). In PAH; the flow-volume curve is close to the healthy subject due to absence of respiratory mechanical problem in most classical cases. Solid lines, maximal and tidal loops at rest; dashed lines, tidal loops at peak exercise; dotted lines, predicted normal maximal expiratory loop. COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; TLC, total lung capacity; RV, residual volume; IC, inspiratory capacity; PAH, pulmonary arterial hypertension. Reproduced with permission from the publisher (O'Donnell et al., 1997, 1998).