Amany F. Elbehairy

Pulmonary Gas Exchange Abnormalities in Mild Chronic Obstructive Pulmonary Disease. Implications for Dyspnea and Exercise Intolerance.

RATIONALE Several studies in mild chronic obstructive pulmonary disease (COPD) have shown a higher than normal ventilatory equivalent for carbon dioxide ([Formula: see text]e/[Formula: see text]co2) during exercise. Our objective was to examine pulmonary gas exchange abnormalities and the mechanisms of high [Formula: see text]e/[Formula: see text]co2 in mild COPD and its impact on dyspnea and exercise intolerance. METHODS Twenty-two subjects (11 patients with GOLD [Global Initiative for Chronic Obstructive Lung Disease] grade 1B COPD, 11 age-matched healthy control subjects) undertook physiological testing and a symptom-limited incremental cycle exercise test with arterial blood gas collection. MEASUREMENTS AND MAIN RESULTS Patients (post-bronchodilator FEV1: 94 ± 10% predicted; mean ± SD) had evidence of peripheral airway dysfunction and reduced peak oxygen uptake compared with control subjects (80 ± 18 vs. 113 ± 24% predicted; P<0.05). Arterial blood gases were within the normal range and effective alveolar ventilation was not significantly different from control subjects throughout exercise. The alveolar-arterial O2 tension gradient was elevated at rest and throughout exercise in COPD (P<0.05). [Formula: see text]e/[Formula: see text]co2, dead space to tidal volume ratio (Vd/Vt), and arterial to end-tidal CO2 difference were all higher (P<0.05) in patients with COPD than in control subjects during exercise. In patients with COPD versus control subjects, there was significant dynamic hyperinflation and greater tidal volume constraints (P<0.05). Standardized dyspnea intensity ratings were also higher (P<0.05) in patients with COPD versus control subjects in association with higher ventilatory requirements. Within all subjects, Vd/Vt correlated with the [Formula: see text]e/[Formula: see text]co2 ratio during submaximal exercise (r=0.780, P<0.001). CONCLUSIONS High Vd/Vt was the most consistent gas exchange abnormality in smokers with only mild spirometric abnormalities. Compensatory increases in minute ventilation during exercise maintained alveolar ventilation and arterial blood gas homeostasis but at the expense of earlier dynamic mechanical constraints, greater dyspnea, and exercise intolerance in mild COPD.

Common Mechanisms of Dyspnea in Chronic Interstitial and Obstructive Lung Disorders

RATIONALE The mechanisms underlying dyspnea in interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD) are unknown. OBJECTIVES To examine whether the relationship between inspiratory neural drive to the diaphragm and exertional dyspnea intensity is different in ILD and COPD, given the marked differences in static respiratory mechanics between these conditions. METHODS We compared sensory-mechanical relationships in patients with ILD, patients with COPD, and healthy control subjects (n = 16 each) during incremental cycle exercise with diaphragmatic electromyography (EMGdi) and respiratory pressure measurements. MEASUREMENTS AND MAIN RESULTS In patients with mild to moderate ILD or COPD with similarly reduced inspiratory capacity, the peak oxygen uptake, work rate, and ventilation were lower (P < 0.05) than in healthy control subjects. EMGdi expressed as a percentage of the maximum (EMGdi/EMGdi,max), respiratory effort (esophageal pressure expressed as percentage of the maximum), and ventilation were higher (P < 0.05) at rest and during exercise in both patients with ILD and patients with COPD than in control subjects. Each of these measurements was similar in the ILD and COPD groups. A Vt inflection and critically reduced inspiratory reserve volume occurred at a lower (P < 0.05) ventilation in the ILD and COPD groups than in control subjects. Patients with ILD had greater diaphragmatic activity, whereas patients with COPD had greater expiratory muscle activity. The relationship between dyspnea intensity and EMGdi/EMGdi,max during exercise was similar in all three groups. In ILD and COPD, descriptors alluding to inspiratory difficulty were selected more frequently, with a greater disparity between EMGdi/EMGdi,max and Vt. CONCLUSIONS Disease-specific differences in mechanics and respiratory muscle activity did not influence the key association between dyspnea intensity and inspiratory neural drive to the diaphragm.

Mechanisms of exertional dyspnoea in symptomatic smokers without COPD.

Dyspnoea and activity limitation can occur in smokers who do not meet spirometric criteria for chronic obstructive pulmonary disease (COPD) but the underlying mechanisms are unknown. Detailed pulmonary function tests and sensory–mechanical relationships during incremental exercise with respiratory pressure measurements and diaphragmatic electromyography (EMGdi) were compared in 20 smokers without spirometric COPD and 20 age-matched healthy controls. Smokers (mean±sd post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity 75±4%, mean±sd FEV1 104±14% predicted) had greater activity-related dyspnoea, poorer health status and lower physical activity than controls. Smokers had peripheral airway dysfunction: higher phase-III nitrogen slopes (3.8±1.8 versus 2.6±1.1%·L−1) and airway resistance (difference between airway resistance measured at 5 Hz and 20 Hz 19±11 versus 12±7% at 5 Hz) than controls (p<0.05). Smokers had significantly (p<0.05) lower peak oxygen uptake (78±40 versus 107±45% predicted) and ventilation (61±26 versus 97±29 L·min−1). Exercise ventilatory requirements, operating lung volumes and cardio-circulatory responses were similar. However, submaximal dyspnoea ratings, resistive and total work of breathing were increased in smokers compared with controls (p<0.05); diaphragmatic effort (transdiaphragmatic pressure/maximumal transdiaphragmatic pressure) and fractional inspiratory neural drive to the diaphragm (EMGdi/maximal EMGdi) were also increased (p<0.05) mainly reflecting the reduced denominator. Symptomatic smokers at risk for COPD had greater exertional dyspnoea and lower exercise tolerance compared with healthy controls in association with greater airways resistance, contractile diaphragmatic effort and fractional inspiratory neural drive to the diaphragm. Exertional dyspnoea in smokers without COPD is linked to higher inspiratory neural drive to the crural diaphragm http://ow.ly/e9Z7302uFM6

Physiologic Characterization of the Chronic Bronchitis Phenotype in GOLD Grade IB COPD

BACKGROUND Smokers with persistent cough and sputum production (chronic bronchitis [CB]) represent a distinct clinical phenotype, consistently linked to negative clinical outcomes. However, the mechanistic link between physiologic impairment, dyspnea, and exercise intolerance in CB has not been studied, particularly in those with mild airway obstruction. We, therefore, compared physiologic abnormalities during rest and exercise in CB to those in patients without symptoms of mucus hypersecretion (non-CB) but with similar mild airway obstruction. METHODS Twenty patients with CB (≥ 3 months cough/sputum in 2 successive years), 20 patients without CB but with GOLD (Global Initiative for Chronic Obstructive Lung Disease) grade IB COPD, and 20 age- and sex-matched healthy control subjects underwent detailed physiologic testing, including tests of small airway function and a symptom-limited incremental cycle exercise test. RESULTS Patients with CB (mean ± SD postbronchodilator FEV1, 93% ± 12% predicted) had greater chronic activity-related dyspnea, poorer health-related quality of life, and reduced habitual physical activity compared with patients without CB and control subjects (all P < .05). The degree of peripheral airway dysfunction and pulmonary gas trapping was comparable in both patient groups. Peak oxygen uptake was similarly reduced in patients with CB and those without compared with control subjects (% predicted ± SD, 70 ± 26, 71 ± 29 and 106 ± 43, respectively), but those with CB had higher exertional dyspnea ratings and greater respiratory mechanical constraints at a standardized work rate than patients without CB (P < .05). CONCLUSIONS Patients with CB reported greater chronic dyspnea and activity restriction than patients without CB and with similar mild airway obstruction. The CB group had greater dynamic respiratory mechanical impairment and dyspnea during exercise than patients without CB, which may help explain some differences in important patient-centered outcomes between the groups.

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

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 individuals 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.

Physiological impairment in mild COPD

Chronic obstructive pulmonary disease (COPD) is a common and often progressive inflammatory disease of the airways, alveoli and microvasculature that is both preventable and treatable. It is well established that smokers with mild airway obstruction, as spirometrically defined, represent the vast majority of patients with COPD, yet this population has not been extensively studied. An insidious preclinical course means that mild COPD is both underdiagnosed and undertreated. In this context, recent studies have confirmed that even patients with mild COPD can have extensive physiological impairment, which contributes to poor perceived health status compared with non‐smoking healthy controls. This review describes the heterogeneous pathophysiology that can exist in COPD patients with only mild airway obstruction on spirometry. It exposes the compensatory adaptations that develop in such patients to ensure that the respiratory system fulfils its primary task of maintaining adequate pulmonary gas exchange for the prevailing metabolic demand. It demonstrates that adaptations such as increased inspiratory neural drive to the diaphragm due to combined effects of increased mechanical loading and chemostimulation underscore the increased dyspnoea and exercise intolerance in this population. Finally, based on available evidence, we present what we believe is a sound physiological rationale for earlier diagnosis in this population.

Exertional dyspnoea in COPD: the clinical utility of cardiopulmonary exercise testing.

Activity-related dyspnoea is often the most distressing symptom experienced by patients with chronic obstructive pulmonary disease (COPD) and can persist despite comprehensive medical management. It is now clear that dyspnoea during physical activity occurs across the spectrum of disease severity, even in those with mild airway obstruction. Our understanding of the nature and source of dyspnoea is incomplete, but current aetiological concepts emphasise the importance of increased central neural drive to breathe in the setting of a reduced ability of the respiratory system to appropriately respond. Since dyspnoea is provoked or aggravated by physical activity, its concurrent measurement during standardised laboratory exercise testing is clearly important. Combining measurement of perceptual and physiological responses during exercise can provide valuable insights into symptom severity and its pathophysiological underpinnings. This review summarises the abnormal physiological responses to exercise in COPD, as these form the basis for modern constructs of the neurobiology of exertional dyspnoea. The main objectives are: 1) to examine the role of cardiopulmonary exercise testing (CPET) in uncovering the physiological mechanisms of exertional dyspnoea in patients with mild-to-moderate COPD; 2) to examine the escalating negative sensory consequences of progressive respiratory impairment with disease advancement; and 3) to build a physiological rationale for individualised treatment optimisation based on CPET. Measurement of symptom intensity, ventilatory control and mechanics during exercise exposes mechanisms of dyspnoea http://ow.ly/6OXQ3020tEA

Resting Physiological Correlates of Reduced Exercise Capacity in Smokers with Mild Airway Obstruction

ABSTRACT Smokers with minor spirometric abnormalities can experience persistent activity-related dyspnea and exercise intolerance. Additional resting tests can expose heterogeneous physiological abnormalities, but their relevance and association with clinical outcomes remain uncertain. Subjects included sixty-two smokers (≥20 pack-years), with cough and/or dyspnea and minor airway obstruction [forced expiratory volume in one-second (FEV1) ≥80% predicted and >5th percentile lower limit of normal (LLN) (i.e., z-score >−1.64) using the 2012-Global Lung Function Initiative equations]. They underwent spirometry, plethysmography, oscillometry, single-breath nitrogen washout, and symptom-limited incremental cycle exercise tests. Thirty-two age-matched nonsmoking controls were also studied. Thirty-three (53%) of smokers had chronic obstructive pulmonary disease by LLN criteria. In smokers [n = 62; age 65 ± 11 years; smoking history 43 ± 19 pack-years; post-bronchodilator FEV1 z-score −0.60 ± 0.72 and FEV1/FVC z-score −1.56 ± 0.87 (mean ± SD)] versus controls, peak oxygen uptake (̇VO2) was 21 ± 7 vs. 32 ± 9 ml/kg/min, and dyspnea/̇VO2 slopes were elevated (both p < 0.0001). Smokers had evidence of peripheral airway dysfunction and maldistribution of ventilation when compared to controls. In smokers versus controls: lung diffusing capacity for carbon monoxide (DLCO) was 85 ± 22 vs. 105 ± 17% predicted, and residual volume (RV)/total lung capacity (TLC) was 36 ± 8 vs. 31 ± 6% (both p < 0.01). The strongest correlates of peak ̇VO2 were DLCO% predicted (r = 0.487, p < 0.0005) and RV/TLC% (r = −0.389, p = 0.002). DLCO% predicted was also the strongest correlate of dyspnea/̇VO2 slope (r = −0.352, p = 0.005). In smokers with mild airway obstruction, associations between resting tests of mechanics and pulmonary gas exchange and exercise performance parameters were weak, albeit consistent. Among these, DLCO showed the strongest association with important outcomes such as dyspnea and exercise intolerance measured during standardized incremental exercise tests.

Mild chronic obstructive pulmonary disease: why spirometry is not sufficient!

ABSTRACT Introduction: Chronic obstructive pulmonary disease (COPD) – an inflammatory disease of the airways, alveoli and lung microvasculature – is a leading cause of death worldwide. Smokers with milder airway obstruction constitute the majority of patients with this disease. Many studies have shown increased morbidity, activity-related dyspnea, exercise intolerance and mortality in such patients, compared with age-matched healthy populations. Clinical evaluation of symptomatic smokers with ostensibly mild airway obstruction poses a challenge in clinical practice as spirometry can obscure extensive heterogeneous pathophysiological impairment. Areas covered: A detailed review of the evidence for complex biological, physiological and radiological abnormalities in smokers who barely fit arbitrary spirometric criteria for COPD diagnosis. A brief discussion of the debate about current diagnostic spirometric criteria for COPD that can lead to diagnostic confusion and, in-some-instances, to inappropriate management. Finally, we provide a review of the clinical implications of these structural and functional abnormalities and try to build a solid rationale for earlier detection and effective, timely management. Expert commentary: The prevalence of mild COPD among smokers is high, yet under-diagnosis remains a major problem and there is lack of evidence-based management recommendations for this sub-population. Further tests beyond spirometry are useful in uncovering patho-physiological derangements that are clinically relevant.

Ventilatory Inefficiency and Exertional Dyspnea in Early Chronic Obstructive Pulmonary Disease

&NA; Exertional dyspnea is present across the spectrum of chronic obstructive pulmonary disease (COPD) severity. However, without realizing it themselves, patients may decrease daily physical activity to avoid distressing respiratory sensations. Dyspnea also may be associated with deconditioning. Cardiopulmonary exercise testing can uncover exertional dyspnea and its physiological determinants in patients with preserved or only mildly reduced FEV1. Dyspnea in mild COPD can largely be explained by increased “wasted” ventilation in the physiological dead space, which heightens the drive to breathe and worsens the inspiratory mechanical constraints. During incremental exercise testing, this is readily identified as an excessive ventilation‐to‐metabolic demand, that is, a high ventilation (Symbole) to carbon dioxide output (Symbolco2) relationship. Linking increases in Symbole/Symbolco2 to exertional dyspnea may provide objective evidence that a patients poor exercise tolerance is not just a consequence of deconditioning. This information should prompt a proactive therapeutic approach to increase the available ventilatory reserve by, for example, giving inhaled bronchodilators. Considering that the structural determinants of ventilatory inefficiency (early emphysema, ventilation‐perfusion mismatching, and microvascular disease) may progress despite only modest changes in FEV1, serial Symbole/Symbolco2 measurements might also prove valuable to track disease progression in these symptomatic patients. Symbol. No caption available.