The Effect of Inhaled Nitric Oxide on Pulmonary Gas-exchange in COPD

BACKGROUND

Chronic Obstructive Pulmonary Disease (COPD) is a respiratory disorder typically caused by smoking and is characterized by airway obstruction. Exertional dyspnea (perceived breathlessness) is a hallmark of COPD regardless of severity and is the primary reason for exercise intolerance even in patients with mild COPD. Dyspnea in COPD has been shown to profoundly reduce patient quality of life, physical activity, and impair patients' ability to complete day-to-day tasks. Previous work in mild COPD has demonstrated that exertional dyspnea is the result of increased work of breathing during exercise, and that this increased work of breathing comes from: 1) an exaggerated ventilatory response to exercise (i.e. increased minute ventilation relative to carbon dioxide production, V̇E/V̇CO2), and 2) airflow limitation (i.e. expiratory flow limitation and resulting dynamic hyperinflation). A great deal of work has focused on improving airflow limitation in COPD; however, very little has been done to understand and treat the exaggerated ventilatory response to exercise in COPD.

Several previous studies in mild COPD have consistently shown an elevated ventilatory response (i.e. greater V̇E/V̇CO2) during exercise. The elevated V̇E/V̇CO2 response to exercise appears to be clinically important, as it independently predicts mortality in COPD. This increased V̇E/V̇CO2 in mild COPD appears to be secondary to increased deadspace ventilation (i.e. sections of the lung with ventilation, but no perfusion), and this increased deadspace ventilation results in a compensatory increase in total minute ventilation (i.e. increased V̇E/V̇CO2) to maintain effective alveolar ventilation and arterial blood gas homeostasis.

The underlying mechanism(s) for the increased deadspace ventilation and V̇E/V̇CO2 during exercise in mild COPD is currently unclear; however, pulmonary microvascular abnormalities and hypoperfusion of pulmonary capillaries are potential pathophysiologic mechanisms. Downregulation of NO bioavailability, secondary to persistently reduced endothelial NO synthase (eNOS), contributes to pulmonary vascular endothelial dysfunction and the development of both emphysema and pulmonary arterial hypertension (PAH) in COPD. Inhaled nitric oxide (iNO) is used to treat disorders of the pulmonary vasculature such as forms of PAH. By increasing NO bioavailability, pulmonary vascular function is improved. Previous work in PAH patients has shown that typical clinical doses (20-40 parts per million (ppm)) of iNO can reduce pulmonary vascular resistance and increase exercise capacity (V̇O2peak). Despite emerging evidence that COPD is associated with pulmonary vascular dysfunction, there is limited research investigating iNO as a therapeutic intervention in COPD. The investigators recently completed a randomized double-blinded controlled trial examining the effectiveness of 40 ppm iNO on V̇O2peak in mild COPD. As compared to placebo (inhaled room air), iNO improved V̇O2peak and dyspnea in COPD secondary to a reduction in ventilatory inefficiency (V̇E/V̇CO2), suggesting that vascular dysfunction is an important contributor to ventilation, dyspnea and exercise intolerance in mild COPD.

The reduction in V̇E/V̇CO2 during exercise with iNO would suggest that iNO increases pulmonary microvascular perfusion, leading to improved V̇A/Q̇ matching, reduced deadspace ventilation and therefore reduced ventilation for a given metabolic demand. However, this needs to be demonstrated experimentally. The gold standard for evaluation of V̇A/Q̇ matching is the multiple inert gas elimination technique (MIGET), as this technique is able to quantify V̇A/Q̇ matching by the relative distribution of ventilation (log SDV) and perfusion (log SDQ)27. Further, MIGET allows for quantification of pure deadspace (sections of ventilation with no perfusion) as compared to high V̇A/Q̇ regions of the lung (i.e. ventilation with low relative perfusion). Should iNO reduce deadspace and improve V̇A/Q̇, this would clearly establish that vascular dysfunction (and not vascular destruction) contributes to V̇A/Q̇ mismatch in mild COPD, and that the reduction in V̇E/V̇CO2 and improvement in exercise capacity with iNO is explained by improved V̇A/Q̇ matching. Further, this finding would help identify a vascular target to improve dyspnea, exercise tolerance, and by extension quality of life in COPD.