The contribution of estimated dead space fraction to mortality prediction in patients with chronic obstructive pulmonary disease-a new proposal

Abstract

Background: Mortality due to chronic obstructive pulmonary disease (COPD) is increasing. However, dead space fractions at rest (V_D/V_Trest) and peak exercise (V_D/V_Tpeak) and variables affecting survival have not been evaluated. This study aimed to investigate these issues.

Methods: This retrospective observational cohort study was conducted from 2010-2020. Patients with COPD who smoked, met the Global Initiatives for Chronic Lung Diseases (GOLD) criteria, had available demographic, complete lung function test (CLFT), medication, acute exacerbation of COPD (AECOPD), Charlson Comorbidity Index, and survival data were enrolled. V_D/V_Trest and V_D/V_Tpeak were estimated (estV_D/V_Trest and estV_D/V_Tpeak). Univariate and multivariable Cox regression with stepwise variable selection were performed to estimate hazard ratios of all-cause mortality.

Results: Overall, 14,910 patients with COPD were obtained from the hospital database, and 456 were analyzed after excluding those without CLFT or meeting the lung function criteria during the follow-up period (median (IQR) 597 (331-934.5) days). Of the 456 subjects, 81% had GOLD stages 2 and 3, highly elevated dead space fractions, mild air-trapping and diffusion impairment. The hospitalized AECOPD rate was 0.60 ± 2.84/person/year. Forty-eight subjects (10.5%) died, including 30 with advanced cancer. The incidence density of death was 6.03 per 100 person-years. The crude risk factors for mortality were elevated estV_D/V_Trest, estV_D/V_Tpeak, ≥2 hospitalizations for AECOPD, advanced age, body mass index (BMI) <18.5 kg/m², and cancer (hazard ratios (95% C.I.) from 1.03 [1.00-1.06] to 5.45 [3.04-9.79]). The protective factors were high peak expiratory flow%, adjusted diffusing capacity%, alveolar volume%, and BMI 24-26.9 kg/m². In stepwise Cox regression analysis, after adjusting for all selected factors except cancer, estV_D/V_Trest and BMI <18.5 kg/m² were risk factors, whereas BMI 24-26.9 kg/m² was protective. Cancer was the main cause of all-cause mortality in this study; however, estV_D/V_Trest and BMI were independent prognostic factors for COPD after excluding cancer.

Conclusions: The predictive formula for dead space fraction enables the estimation of V_D/V_Trest, and the mortality probability formula facilitates the estimation of COPD mortality. However, the clinical implications should be approached with caution until these formulas have been validated.

Keywords: Acute exacerbation; Co-morbidity; Dead space and tidal volume ratio; Lung function; Mortality.

Figure 1. Flowchart.

Subjects with chronic obstructive pulmonary disease (COPD) were obtained between Jan 1, 2010 and Dec 31, 2020. ICD, international coding of diagnosis; PFT, pulmonary function test. An asterisk (*) indicates that these cases were excluded because single breath dilution method was used to determine lung volumes before 2013, which are significant different from those measured with body plethysmography after 2013.

Figure 2. Cox regression survival analysis was performed according to different values of V_D/V_Trest_esti (estimated V_D/V_Trest) and body mass index (BMI) for all 456 subjects with chronic obstructive pulmonary disease.

(A) estV_D/V_Trest < 61% is the reference value. (B) Normal BMI (18.5–23.9 kg/m²) is the reference value.