“Patients with mild COPD frequently present with chronic dyspnea and poor exercise capacity, often to a greater extent than would be expected based on their resting lung function values,” explains Michael K. Stickland, PhD. “Although effective in more severe cases of COPD, therapies that improve dynamic mechanical abnormalities and exertional dyspnea show minimal positive effects in patients with mild COPD. A growing body of research provides evidence that reduced breathing efficiency is linked to poor exercise capacity in mild COPD, and that reduced breathing efficiency may be due to pulmonary vascular dysfunction, which ultimately leads to gas-exchange abnormalities and increased exertional dyspnea.”

For a study published in The Journal of Physiology, Dr. Stickland and colleagues aimed to determine if acute modulation of the pulmonary vasculature helps improve breathing efficiency. Additionally, they sought to determine if improved breathing efficiency would lead to clinically meaningful improvements in dyspnea and exercise capacity.

Experimental iNO Increased Peak Oxygen Uptake

The study team completed a multigroup, randomized, double-blind, placebo-controlled, crossover trial to test the effect of inhaled nitric oxide (iNO) on physiological and perceptual responses. They conducted a standardized cardiopulmonary exercise test on a cycle ergometer in patients with mild COPD and age-matched healthy controls. Participants completed the activity while breathing either medical-grade gas or 40 parts per million of nitric oxide while researchers measured physiological and perceptual variables, along with peak exercise intensity.

Experimental iNO increased peak oxygen uptake in patients with mild COPD, secondary to reduced exercise ventilation and perceived dyspnea. “It is likely that iNO improved blood flow distribution throughout the lung, which decreased the total amount of dead space,” Dr. Stickland says. “The observed reduction in dyspnea and increased exercise capacity occurred without any significant changes in dynamic breathing mechanics or oxygen saturation. To our knowledge, this is the first study to demonstrate that experimental manipulation of pulmonary circulation alone can positively impact dyspnea and exercise capacity in mild COPD.”

Targeting Pulmonary Vasculature With More Practical Vasodilator Therapies

The researchers observed improvement in peak VO2 and work rate in patients with mild COPD. “The data indicate that the improvement in exercise capacity was largely due to a reduction in ventilatory demand and dyspnea at standardized submaximal exercise intensities,” Dr. Stickland says. “At the exercise intensity of 60 watts, 87% of patients with mild COPD reported an iNO-mediated decrease in dyspnea that equaled or exceeded the minimal clinically important difference of 1 Borg unit (Table).”

These findings may help explain why patients with mild COPD demonstrate significant exertional dyspnea, despite having relatively preserved airway function, and identify a potential pulmonary vascular target to improve dyspnea and exercise capacity in mild COPD, according to Dr. Stickland. “Targeting the pulmonary vasculature with more practical vasodilator therapies may improve dyspnea and exercise capacity in mild COPD,” he adds.

Dr. Stickland and colleagues hope for more invasive physiological trials that would provide definitive evidence that iNO improves pulmonary gas-exchange and reduces dead space during exercise in patients with mild COPD. “In addition, there may be a threshold of disease severity past which interventions that target the pulmonary vasculature may not be effective in COPD, and we need to better understand this,” explains Dr. Stickland. “Larger-scale clinical trials are recommended to determine if more practical vasodilator therapies lead to improved dyspnea and exercise capacity.”