Natya Raghavan

Does the Respiratory System Limit Exercise in Mild Chronic Obstructive Pulmonary Disease

RATIONALE It is not known if abnormal dynamic respiratory mechanics actually limit exercise in patients with mild chronic obstructive pulmonary disease (COPD). We reasoned that failure to increase peak ventilation and Vt in response to dead space (DS) loading during exercise would indicate true ventilatory limitation to exercise in mild COPD. OBJECTIVES To compare the effects of DS loading during exercise on ventilation, breathing pattern, operating lung volumes, and dyspnea intensity in subjects with mild symptomatic COPD and age- and sex-matched healthy control subjects. METHODS Twenty subjects with Global Initiative for Chronic Obstructive Lung Disease stage I COPD and 20 healthy subjects completed two symptom-limited incremental cycle exercise tests, in randomized order: unloaded control and added DS of 0.6 L. MEASUREMENTS AND MAIN RESULTS Peak oxygen uptake and ventilation were significantly lower in COPD than in health by 36% and 41%, respectively. With added DS compared with control, both groups had small decreases in peak work rate and no significant increase in peak ventilation. In health, peak Vt and end-inspiratory lung volume increased significantly with DS. In contrast, the COPD group failed to increase peak end-inspiratory lung volume and had a significantly smaller increase in peak Vt during DS. At 60 W, a 50% smaller increase in Vt (P < 0.001) in response to added DS in COPD compared with health was associated with a greater increase in dyspnea intensity (P = 0.0005). CONCLUSIONS These results show that the respiratory system reached or approached its physiologic limit in mild COPD at a lower peak work rate and ventilation than in healthy participants. Clinical trial registered with www.clinicaltrials.gov (NCT 00975403).

Sex differences in exertional dyspnea in patients with mild COPD: Physiological mechanisms

The purpose of this study was to evaluate the physiological basis for sex-differences in exercise-induced dyspnea in patients with mild COPD. We compared operating lung volumes, breathing pattern and dyspnea during incremental cycling in 32 men (FEV(1)=86±10% predicted) and women (FEV(1)=86±12% predicted) with mild COPD and 32 age-matched controls. There were no sex differences in dyspnea in the control group at any work-rate or ventilation (V(E)). Women with COPD had significantly greater dyspnea than men at 60 and 80 W. At 80 W, dyspnea ratings were 5.7±2.3 and 3.3±2.5 Borg units (P<0.05) and the V(E) to maximal ventilatory capacity ratio was 72% and 55% in women and men, respectively (P<0.05). Comparable increases in dynamic hyperinflation were seen in both male and female COPD groups at symptom limitation but women reached tidal volume constraints at a lower work rate and V(E) than men. Superimposing mild COPD on the normal aging effects had greater sensory consequences in women because of their naturally reduced ventilatory reserve.

Mechanisms of exercise intolerance in Global Initiative for Chronic Obstructive Lung Disease grade 1 COPD

The purpose of this study was to determine if a dissociation existed between respiratory drive, as estimated by diaphragmatic electromyography (EMGdi), and its pressure-generating capacity during exercise in mild chronic obstructive pulmonary disease (COPD) and whether this, if present, had negative sensory consequences. Subjects meeting spirometric criteria for mild COPD (n=16) and age and sex-matched controls (n=16) underwent detailed pulmonary function testing and a symptom limited cycle test while detailed ventilatory, sensory and respiratory mechanical responses were measured. Compared with controls, subjects with mild COPD had greater ventilatory requirements throughout submaximal exercise. At the highest equivalent work rate of 60 W, they had a significantly higher: total work of breathing (32±17 versus 16±7 J·min−1; p<0.01); EMGdi (37.3±17.3 versus 17.9±11.7% of maximum; p<0.001); and EMGdi to transdiaphragmatic pressure ratio (0.87±0.38 versus 0.52±0.27; p<0.01). Dyspnoea–ventilation slopes were significantly higher in mild COPD than controls (0.17±0.12 versus 0.10±0.05; p<0.05). However, absolute dyspnoea ratings reached significant levels only at high levels of ventilation. Increased respiratory effort and work of breathing, and a wider dissociation between diaphragmatic activation and pressure-generating capacity were found at standardised work rates in subjects with mild COPD compared with controls. Despite these mechanical and neuromuscular abnormalities, significant dyspnoea was only experienced at higher work rates. Mild COPD patients experience respiratory mechanical abnormalities during exercise despite relatively preserved FEV1 http://ow.ly/yHukJ

Components of the COPD Assessment Test (CAT) associated with a diagnosis of COPD in a random population sample

Abstract The aim of this study was to determine if components of the COPD Assessment Test (CAT), a validated health status impairment instrument, had additional utility in identifying patients at risk for COPD in whom spirometry testing is appropriate. This study was part of the Canadian Obstructive Lung Disease prevalence study. Consenting participants ≥ 40 years of age were identified by random digit dialing. Smoking history, 8-item CAT scores, and post-bronchodilator spirometry were recorded for each. Stepwise logistic regression analysis was used to identify variables related to the presence of airway obstruction and a final logistic model was developed which best predicted COPD in this sample. Of the 801 individuals approached, 532 were included: 51 (9.6%) had COPD, the majority (92%) of whom fit GOLD I or II severity criteria. Items that correlated significantly with a COPD diagnosis included the CAT total score (p = 0.01) and its breathlessness (p < 0.0001) and phlegm (p = 0.001) components. The final logistic model included: age (<55 or ≥55 years), smoking status (current, former, never) and the CAT breathlessness score (ordinal scale 0–5). The area under the receiver-operating characteristic curve for this model was 0.77, sensitivity was 77.6%, specificity was 64.9% and the positive likelihood ratio was 2.21. In summary, the triad of smoking history, age at least 55 years and the presence of exertional breathlessness were key elements of a simple model which had reliable measurement properties when tested in a random population. This may help identify patients at risk for COPD for whom spirometry testing is recommended.

Effect of adjunct fluticasone propionate on airway physiology during rest and exercise in COPD.

RATIONALE Combination therapy with corticosteroid and long-acting β(2)-agonists (LABA) in a single inhaler is associated with superior effects on airway function and exercise performance in COPD compared with LABA monotherapy. The physiological effects of adding inhaled corticosteroid monotherapy to maintenance bronchodilator therapy (long-acting anticholinergics and LABA singly or in combination) in COPD are unknown. METHODS This was a randomized, double-blind, placebo-controlled, crossover study (NCT00387036) to compare the effects of inhaled fluticasone propionate 500 μg (FP500) twice-daily and placebo (PLA) on airway function during rest and exercise, measured during constant work rate cycle exercise at 75% of maximum incremental cycle work rate, in 17 patients with COPD (FEV(1) ≤ 70% predicted). RESULTS After treatment with FP500 compared to PLA, there were significant increases in post-dose measurements of FEV(1) (+115 mL, P = 0.006) and the FEV(1)/FVC ratio (+2.5%, P = 0.017), along with decreases in plethysmographic residual volume (-0.32L; P = 0.031), functional residual capacity (-0.30L, P = 0.033), and total lung capacity (-0.30L, P = 0.027) but no changes in vital capacity or inspiratory capacity (IC). Post-treatment comparisons demonstrated a significant improvement in endurance time by 188 ± 362 s with FP500 (P = 0.047) with no concomitant increase in dyspnea intensity. End-inspiratory and end-expiratory lung volumes were reduced at rest and throughout exercise with FP500 compared with PLA (P < 0.05). CONCLUSION Inhaled FP500 monotherapy was associated with consistent and clinically important improvements in FEV(1), static lung volumes, dynamic operating lung volumes, and exercise endurance when added to established maintenance long-acting bronchodilator therapy in patients with moderate to severe COPD.

Recent advances in pharmacotherapy for dyspnea in COPD.

Dyspnea is the most distressing symptom experienced by those suffering from advanced stages of chronic obstructive pulmonary disease (COPD). Activity-related dyspnea in COPD is multifactorial but is associated with increased central neural drive, impaired dynamic respiratory mechanics and abnormal respiratory muscle function. Each of these components can potentially be targeted for pharmacotherapy. Recent advances in the pharmacotherapy of COPD include the development of new long-acting bronchodilators which, when combined, provide sustained improvements in dyspnea. Additionally, novel applications of older therapies such as opiates, furosemide, helium-oxygen, and statins show early promise as dyspnea-relieving interventions in COPD. Effective pharmacological manipulation of the affective dimension of dyspnea remains an important challenge. In this review of the recent literature in this field, we highlight the main advances that have been achieved.

Severe Bronchorrhea in a Patient with Bronchioloalveolar Carcinoma

Mucinous bronchioloalveolar carcinoma (BAC) can be associated with significant bronchorrhea. A 46-year-old man presented with BAC with 2,000 mL of sputum production on a daily basis, which prevented him from being extubated. As this condition is rare, there are only case reports outlining the therapy for the associated bronchorrhea. We used azithromycin, scopolamine, and inhaled fluticasone with moderate success. The initiation of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, resulted in dramatic improvement in the volume of pulmonary secretions produced. The patients EGFR mutation status was subsequently found to be negative, which supports the hypothesis that the mechanism of reduction of bronchorrhea is independent of the antiproliferative effect of the drug.

The role of pharmacotherapy in mild to moderate chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide and most of those afflicted have mild to moderate disease as measured by spirometry. There is mounting evidence that even mild airway obstruction is associated with activity-related dyspnea, exercise limitation, impaired quality of life, increased hospitalization and mortality. As our understanding of the complex, heterogeneous pathophysiology and clinical consequences of milder COPD continues to grow, there is increasing interest in the potential impact of therapeutic interventions beyond smoking cessation. Unfortunately, few clinical trials have included patients with mild to moderate disease and the evidence base for pharmacological treatment in this subpopulation is currently lacking. Recent short-term mechanistic studies confirm that reversal of airway smooth muscle cholinergic tone consistently improves respiratory mechanics during rest and exercise in mild COPD but long-term clinical benefits remain to be evaluated. Secondary analysis of large, prospective studies designed to evaluate the efficacy of long-acting bronchodilators, inhaled corticosteroids and combination therapy indicate that patients with moderate COPD achieve comparable benefits to those with advanced disease. In the absence of evidence-based guidelines for the management of milder COPD, treatment choices are driven mainly by clinical presentation: for those with persistent and troublesome activity-related dyspnea a trial of inhaled bronchodilator therapy is justified; for those with a propensity for recurrent infective exacerbations, consideration of additional anti-inflammatory treatment seems reasonable. In this paper, we review the current knowledge base and emerging paradigm for the pharmacological treatment of mild to moderate COPD.