Improving gas exchange and exercise tolerance in mild COPD patients

Abstract

In their recent study, Phillips et al. (2021) focused on patients with mild chronic obstructive pulmonary disease (COPD) who have an exaggerated ventilatory response to exercise contributing to exertional dyspnoea, resulting in exercise intolerance. This is an important area of research with huge translational potential because 3.6–11.7% of the adult population worldwide have been diagnosed with COPD with ∼30% of diagnosed cases considered mild (Anecchino et al. 2007; Adeloye et al. 2015). The progression of COPD from mild to severe in this population is probably affected by the patient’s aversion to exercise as a result of exertional dyspnoea. In addition, with reduced exercise capacity and less overall activity, these COPD patients are at greater risk of comorbidities related to obesity, diabetes, cardiovascular dysfunction and stroke, leading to higher mortality. Therapeutic strategies that target early intervention to avoid the vicious cycle of ineffective gas exchange and reduced exercise capacity in mild COPD patients are probably very beneficial. Previous research on mild COPD patients has uncovered an elevated ventilatory equivalent to CO2 production (V̇E/V̇CO2 ) during exercise, secondary to increased dead space ventilation. Currently, the cause of the increased dead space ventilation is unknown, although this is considered to be a result of microvascular dysfunction and corresponding pulmonary capillary hypoperfusion. Importantly, mild COPD patients have been found to have minor airflow obstruction but diminished gas exchange capacity and reduced pulmonary capillary blood volume, which appear to contribute to dyspnoea (Tedjasaputra et al. 2018). Phillips et al. (2021) took a novel approach to solving dyspnoea-related exercise intolerance in mild COPD patients by administering inhaled nitric oxide (NO) to selectively vasodilate the pulmonary circulation and thereby improve perfusion. This simple but novel approach targets pulmonary perfusion, whereas most COPD therapies have targeted improving ventilation with bronchodilation (Phillips et al. 2021). Mild COPD patients increased O2 uptake during exercise, with improved V̇E/V̇CO2 , reduced dyspnoea and improved exercise tolerance after they received inhaled NO. These positive results indicate that microvascular perfusion limits gas exchange and exercise capacity in mild COPD patients. Just as Phillips et al. (2021) took a simple but novel approach to exertional dyspnoea in mild COPD patients, a novel approach to understanding and treating COPD needs to be implemented clinically. Mild COPD is diagnosed by spirometry (forced expiratory volume in 1 s and forced vital capacity) thresholds but does not address the actual physiological basis underlying dyspnoea with exertion, which is impaired gas exchange. Inhaled NO was able to improve exertional dyspnoea inmildCOPD patients, although, however effective, this treatment is not practical as an intervention that can be continuously applied to large numbers of mild COPD patients to improve pulmonary rehabilitation and exercise training because of the cost and complications associated with drug delivery and themedical staff required. Additionally, a comparison between delivery methods of pulmonary vasodilators is warranted because it is possible the inhaled NO will primarily affect well-ventilated areas of the lung, which should already be normally participating in gas exchange. Phillips et al. (2021) demonstrated that these well-ventilated areas could participate in additional gas exchange once perfusion was improved; however, if perfusion of the pulmonary circulation was increased uniformly throughout the lung, it is a possible that under-ventilated areas of the lung could contribute to gas exchange and exercise capacity could be improved even more in this COPD cohort. Previous research on mild COPD has demonstrated that exertional dyspnoea is the result of increased respiratory neural drive that comes from an exaggerated ventilatory response to exercise and airflow limitation (Guenette et al. 2014). The study by Phillips et al. (2021) beautifully isolated one aspect of this problem and demonstrated that increased pulmonary perfusion has a benefit without altering the airflow limitation. In a clinical setting, focus on both ventilation and perfusion should be employed to enable the greatest positive effect on patients. One could imagine that, if bronchodilators were concurrently used to reduce airflow obstruction before the use of inhaled NO, pulmonary perfusion could be increased even more, with a greater improvement in ventilation–perfusion matching and gas exchange efficiency. As the study by Phillips et al. (2021) clearly shows, dead space is the enemy of gas exchange, and this may underlie impaired exercise in a number of respiratory diseases. Although the study by Phillips et al. (2021) focuses on mild COPD, the results could be extended to other obstructive lung diseases or even recovering COVID patients with lingering gas exchange impairment. Phillips et al. (2021) used a combination of spirometry, plethysmography and the diffusing capacity for carbon monoxide (DLCO) to assess pulmonary function. Although spirometry and plethysmography are useful tools for diagnosing COPD, as well as measuring lung volumes and respiratory system compliance, they do not add much value to understanding the primary function of the lung, which is gas exchange. DLCO was used to gain insight into the transfer capacity of oxygen in the lung and showed marked reductions in COPD patients compared to controls. As a result of the competitive binding of carbon monoxide and NO to haemoglobin in DLCO measurements, Phillips et al. (2021) were unable to assess oxygen transfer responses to inducible NO (iNO). Future studies would benefit from the use of new end-tidal gas sampling methods to measure impaired pulmonary gas exchange in disease cohorts such as mild COPD patients and their gas exchange response to iNO (West et al. 2018). This new less invasive method for assessing gas exchange combines measures of end-tidal PO2 with calculated arterial PO2 to estimate