Hypercapnia in advanced chronic obstructive pulmonary disease: A secondary analysis of the national emphysema treatment trial

Rationale: Hypercapnia develops in one third of patients with advanced chronic obstructive pulmonary disease (COPD) and is associated with increased morbidity and mortality. Multiple factors in COPD are thought to contribute to the development of hypercapnia including increased carbon dioxide (CO2) production, increased dead space ventilation, and the complex interactions of deranged respiratory system mechanics, inspiratory muscle overload and the ventilatory control center in the brainstem. However, these factors have not previously been systematically analyzed in a large, well-characterized population of severe COPD patients. Methods: This is a secondary analysis of the clinical, physiologic and imaging data from the National Emphysema Treatment Trial (NETT). All patients with complete baseline data for the key predictor variables were included. An inclusive list of 32 potential predictor variables were selected a priori based on consensus of the investigators and literature review. Stepwise variable selection yielded 10 statistically significant associations in multivariate regression. Results: A total of 1419 patients with severe COPD were included in the analysis; mean age 66.4 years (standard deviation 6.3), 38% females, and 422 (29.7%) had baseline hypercapnia. Key variables associated with hypercapnia were low resting partial pressure of oxygen in blood, low minute ventilation (Ve), high volume of exhaled carbon dioxide, low forced expiratory volume in 1 second, high residual volume, lower % emphysema on chest computed tomography, use of oxygen, low ventilatory reserve (high Ve/maximal voluntary ventilation), and not being at high altitude. Low diffusing capacity for carbon monoxide showed a positive association with hypercapnia in univariate analysis but a negative correlation in multivariate analysis. Measures of dyspnea and quality of life did not associate with degree of hypercapnia in multivariable analysis. Conclusions: Hypercapnia in a well-characterized cohort with severe COPD and emphysema is chiefly related to poor lung mechanics, high CO2 production, and a reduced ventilatory capability. Hypercapnia is less impacted by gas exchange abnormalities or the presence of emphysema.