Hierarchical stratification of the factors related to exertional dyspnoea and exercise intolerance in male COPD patients

Abstract

Background: The order and extent of interactions across the factors affecting exertional dyspnoea (ED) and exercise intolerance (EI) in patients with chronic obstructive pulmonary disease (COPD) are not clear. We hypothesized that lung and non-lung variables were the primary variables, ED was the secondary variable and EI was the tertiary variable.

Methods: Data on demographics, blood tests, cardiac imaging, lung function tests and invasive dead space fractions (V_D/V_T) during incremental exercise test of 46 male COPD subjects were obtained. These variables were categorized by factor analysis and pair-wise correlation analysis was conducted. The best factor of each category was selected and then multivariate regression was conducted.

Results: Peak tidal inspiratory flow (V_T/T_Ipeak), V_D/V_Tpeak and tidal lung expansion capability, and resting diffusing capacity of the lungs (D_LCO)% predicted were the primary pulmonary factors most related to ED, whereas body mass index (BMI), haemoglobin and cholesterol levels were the primary non-pulmonary factors. In multivariate regression analysis, V_T/T_Ipeak, V_D/V_Tpeak and D_LCO% were the primary factors most related to ED (r² = 0.69); ED was most related to EI (r = -0.74 to -0.83).

Conclusion: Using hierarchical stratification and statistical methods may improve understanding of the pathophysiology of ED and EI in patients with COPD. KEY MESSAGESThe pathophysiology of exertional dyspnoea (ED) and exercise intolerance (EI) in chronic obstructive pulmonary disease (COPD) is complex. The order and extent of interactions across factors are not clear. In multivariate regression analysis, we found that tidal inspiratory flow, dead space fraction and resting diffusing capacity of the lungs % but not the non-pulmonary factors affected ED.Using correlation coefficients, we further found that ED was the secondary variable and EI was the tertiary variable.Hierarchical stratification of the important factors associated with ED and EI in patients with COPD clarifies their relationships and could be incorporated into management programmes and outcome studies for these patients.

Keywords: Exertional dyspnoea; air trapping; cholesterol; diffusing capacity; exercise capacity; incremental exercise test.

Figure 1.

A total of 116 variables of interest in nine categories used to correlate with exertional dyspnoea (slope of Borg score and oxygen uptake). % = % predicted, subscribed R, AT, pk, R-pk or pk-R = variables measured at rest, anaerobic threshold, peak exercise, gradient between at rest and at peak exercise or vice versa, post: measured after exercise; ADPA: the diameter of anterior descending pulmonary artery in mm; A4EDRV: apical four-chamber view end-diastolic right ventricle area in cm²; A4ESRV: apical four-chamber view end-systolic right ventricle area in cm²; BIL_D: direct bilirubin; BMI: body mass index; COHb: carboxyhaemoglobin; CTR: cardiac-thoracic ratio; Δ: delta = change; DBP: diastolic blood pressure; D_LCO: diffusing capacity for carbon monoxide; FEV₁: forced expired volume in one second; 20FEV₁ = 20 × FEV₁+20; FRC: functional residual capacity; FVC: forced vital capacity; GOT: aspartate aminotransferase; GPT: alanine aminotransferase; Hct/Hb: haematocrit/haemoglobin; HR: heart rate; HR_R/pk: heart rate at rest and at peak exercise ratio; HR_AT/pk: ratio of heart rate at and at peak exercise; HTR: Hila-thoracic ratio; IDC: inspiratory duty cycle; IVS: number of patients with paroxysmal intraventricular septum; MEP: maximum expiratory pressure; MetHb: methaemoglobin; Mid-arm: the mid-arm circumference in cm; MIP: maximum inspiratory pressure; MVV: maximum voluntary ventilation; OCD: oxygen-cost diagram; O₂P: oxygen pulse; PFR: peak flow rate; pk/AT: ratio of the given values at peak and anaerobic threshold; RER: respiratory exchange ratio: V’CO₂/V’O₂; RR: respiratory rate; RV: residual volume; RVW: right ventricle free wall thickness in mm; S4EDRV: subcostal four-chamber view end-diastolic right ventricle area in cm²; S4ESRV: subcostal four-chamber view end-systolic right ventricle area in cm²; S_aO₂: arterial oxyhaemoglobin saturation; SBP: systolic blood pressure; SVC: slow vital capacity; Smoke: cigarette consumption in pack-years; T_I: inspiratory time in second; TLC: total lung capacity; TR: number of patients with tricuspid valve regurgitation; Triceps: the thickness of triceps in mm; Vd/Vt: ratio of dead space and tidal volume: dead space fraction; V_E: minute ventilation; V_E/VCO₂: ventilatory equivalent for CO₂ output; VO₂: Oxygen uptake; ΔVO₂/ΔWR_{1st and 2nd}: the first and 2^nd slopes of change in VO₂ and work rate; V_T: tidal volume; V_T/T_I: ratio of tidal volume and inspiratory time: mean inspiratory flow rate; V_T/TLC: ratio of tidal volume and total lung capacity; WR: work rate.

Figure 2.

Flow chart illustrating the data processing steps.

Figure 3.

Hierarchical stratification of the pathophysiology of exertional dyspnoea and exercise intolerance (from primary (1°) to secondary (2°) to tertiary(3°)). Respiratory system (left Panel): the bottom (large circles indicating the lungs) indicates the relationships across the four primary pulmonary factors (PPFs); the large oval shape represents ventilatory muscle and the solid oval shape represents MIP%; the oval shape marked with ED i.e. exertional dyspnoea below the top oval shape is correlated with the PPFs; the top oval shape marked with EC i.e. exercise capacity is correlated with the PPFs and EC includes work rate at peak exercise % predicted (WR_peak%) and oxygen uptake per kg at peak exercise (V′O_2peak/kg). MIP%: maximum inspiratory pressure % predicted. Numbers indicate significant correlation coefficients; Numbers on the large oval shape indicate correlation coefficients between the PPFs and MIP%; NS indicates not significant. V_T/T_Ipeak: tidal inspiratory flow; D_LCO%: diffusing capacity of lung % predicted; V_Tpeak/TLC: peak tidal lung expansibility; V_D/V_Tpeak: peak dead space fraction. The correlation coefficients of ED with WR_peak% = -0.83; of ED with V′O₂/kg _peak = -0.74. Non-respiratory system (right panel): the bottom triangle indicates the relationships across the three primary non-pulmonary factors. The top circle indicates the cholesterol level; the right circle indicates haemoglobin (Hb) level; the left circle indicates body mass index (BMI).